ZixuanKe/management_rule_phi3.5_unsup · Datasets at Hugging Face

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Hum Mol Genet, 6: 813–820Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Fujita H, Asano N, Kishimoto M, TanidaY, Kakinuma T, Mitsui H, Tada Y, Wakugawa M, Torii H, Komine M, Asahina A, andTamaki K (2002) Interleukin-12 p40 gene (IL12B) 3’-untranslated region polymorphism isassociated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci,30: 161–166Valdimarsson H, Baker BS, Jonsdottir I, and Fry L (1986) Psoriasis: a disease of abnormalkeratinocyte proliferation induced by T lymphocytes. Immunol Today, 7: 256–259Valdimarsson H, Sigmundsdottir H, and Jonsdottir I (1997) Is psoriasis induced by streptococcal superantigens and maintained by M-protein-specific T cells that cross-react with keratin? Clin Exp Immunol, 107 Suppl 1: 21–24Vollmer S, Menssen A, Trommler P, Schendel D, and Prinz JC (1994) T lymphocytes derivedfrom skin lesions of patients with psoriasis vulgaris express a novel cytokine pattern that isdistinct from that of T helper type 1 and T helper type 2 cells. Eur J Immunol, 24:2377–2382Weinshenker BG, Bass BH, Ebers GC, and Rice GP (1989) Remission of psoriatic lesions withmuromonab-CD3 (orthoclone OKT3) treatment. J Am Acad Dermatol, 20: 1132–1133Weisenseel P, Laumbacher B, Besgen P, Ludolph-Hauser D, Herzinger T, Roecken M, WankR, and Prinz JC (2002) Streptococcal infection distinguishes different types of psoriasis. JMed Genet, 39: 767–768Zhou X, Krueger J, Kao M, Lee E, Du F, Menter A, Wong W, and Bowcock A (2003) Novelmechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the63,100-element oligonucleotide array. Physiol Genomics, 13: 69–78 10 Chronic Urticaria as anAutoimmune DiseaseMichihiro Hide, Malcolm W. Greaves IntroductionUrticaria is conventionally classified as acute, intermittent and chronic (Greaves 2000a). Acute urticaria which frequently involves an IgE-mediated immunological mechanism, is common, its causes often recognised by thepatient, and will not be considered further. Intermittent urticaria – frequentbouts of unexplained urticaria at intervals of weeks or months – will be discussed here on the same basis as ‘ordinary’ chronic urticaria. The latter isconventionally defined as the occurrence of daily or almost daily whealingfor at least six weeks. The etiology of chronic urticaria is usually obscure. Thedifferent clinical varieties of chronic urticaria will be briefly considered here,and attention will be devoted to a newly emerged entity – autoimmune chronicurticaria, since establishing this diagnosis has conceptual, prognostic and therapeutic implications. Contact urticaria and angioedema without urticaria willnot be dealt with in this account. Classification of Chronic UrticariaThe clinical subtypes of chronic urticaria are illustrated in the pie-chart ofFig. 1. The frequency of these subtypes is based upon the authors’ experienceat the St John’s Institute of Dermatology in UK. Whilst there may well be minor differences, it is likely that the frequency distribution of these subtypeswill be essentially similar in most centres in Europe and North America (Greaves 1995, 2000b). However, our experience suggests that the incidence ofangioedema, especially that complicated by ordinary chronic urticaria is substantially lower in Japan and south Asian countries (unpublished observation). 310 Michihiro Hide and Malcolm W. Greaves Fig. 1. Chronic urticaria. Frequency of different subtypes in the authors’ practices.The proportions are probably not very different elsewhere Physical UrticariasThese comprise about one third to one fourth of all urticaria patients seen inthe authors’ services. The diagnosis is mainly made from careful history taking, appropriate clinical examination, and physical challenge testing is performed when necessary. It is important to identify patients in whom a physicalurticaria is the main, if not the only, cause of the patient’s symptoms. In thiscase, further investigation is not indicated, with rare exceptions (see below).Almost invariably, patients with this diagnosis are over-investigated by thetime they are referred to the urticaria clinic. Skin prick testing, RAST (radioallergo sorbent tests), food exclusion diets, etc, are not normally indicated inpatients with a physical urticaria with the exception of food-dependent exercise-induced urticaria, a rare variety of urticaria, which develops followingexercise after food ingestion.It is also important to appreciate that different physical urticarias can occur concurrently in the same patient; cold and cholinergic urticarias represent a well recognised example. Furthermore, chronic ‘idiopathic’ urticaria isoften associated with dermographism or delayed pressure urticaria. The investigation and management of chronic urticaria should be influenced by establishing the relative contributions of coexisting forms of chronic urticariato the patient’s overall disability. Symptomatic DermographismThis common physical urticaria presents mainly in teenagers or adults of either sex. Like most physical urticarias, individual itchy wheals, produced bygentle stroking or rubbing of the skin, last less than 30 minutes before fading(Fig. 2). Angioedema and mucosal whealing do not occur and there are no Chronic Urticaria as an Autoimmune Disease 311 Fig. 2. Symptomatic Dermographism. Upper left hand panel: use of a graduated dermograhpometer to test for sensitivity to a dermographic stimulus. Upper right hand panel:graded wheal and flare response to a range of pressures. Lower panel: gentle stroking byround end of a pen rod with a certain pressure may readily disclose abnormal reaction ofpatients. systemic symptoms but pruritus is troublesome. The etiology is unknown although skin reactivity can be passively transferred to non-human primates byintracutaneous injection of donor serum from a dermographic patient (Murphyet al. 1987). As with the majority of physical urticarias, investigations are pointless and any role for food items has not been substantiated. The prognosis isfor eventual improvement in two to three years in most patients. Low sedationantihistamines such as loratidine 10 mg, cetirizine 10 mg or fexofenadine120–180 mg are usually effective in relieving the itch, although additional treatment by a sedative antihistamine such as hydroxyzine 25 mg at night mayalso be useful. Combinations of H1- and H2- antihistamines may be useful. Cholinergic UrticariaCholinergic urticaria is common in children and young adults, although rarein the elderly. Historically, this type of urticaria has been classified as a physical urticaria. However, a recent consensus report for “definition, classification, 312 Michihiro Hide and Malcolm W. Greaves Fig. 3. Cholinergic Urticaria. Typical monomorphic symmetrical maculopapular eruptionevoked by heat or exertion or stress and routine diagnosis of urticaria” (Zuberbier et al. 2001) for urticaria andangioedema classified this urticaria as a special type of urticaria, apart fromphysical urticarias. Symptoms of cholinergic urticaria, typically widespreadpruritic monomorphic maculopapular lesions, develop in conditions causingsweating, such as exercise, hot bath taking, or emotional stimuli (Hirschmannet al. 1987) (Fig. 3). If the patient rests, cools off or relaxes, the eruption subsides in 15–45 minutes. Typical areas of predilection include the face, neck,fronts of elbows, wrists and popliteal fossae, although almost any area of thebody can be involved. It may be accompanied by angioedema and systemicsymptoms include wheezing or, rarely, anaphylactoid symptoms. Cholinergicurticaria can be disabling, especially when provoked by occupational or emotional triggers. The diagnosis is established by appropriate challenge testing(Commens et al. 1978) (exercise, a hot bath or mental arithmetic) and/or skintest with acetylcholine. No further investigations are indicated.The prognosis is for gradual improvement over the course of months oryears in most patients, although the authors have several patients in whomcholinergic urticaria remains unremitting. The condition normally respondsreasonably well to avoidance of provoking factors, together with regular dailytreatment by an H1-antihistamine, especially in children.Clinical variants include persistent cholinergic urticaria (Murphy et al. 1983),in which the rash is evident even at rest, and exercise-induced angioedema(Lawrence et al. 1981). Rarely patients may give a clear history of food provocation – either association of onset non-specifically with food intake, or specifically with certain food items (Zuberbier et al. 1993).The pathomechanisms are incompletely understood. The local wheals canbe blocked by atropinisation of the skin indicating involvement of acetylcholine, and histamine release has also been confirmed – presumably derivedfrom mast cells (Herxheimer 1956). Wheal and flare reaction to autologoussweat and sweat-provoked histamine release from their basophils have been Chronic Urticaria as an Autoimmune Disease 313 Fig. 4. Cold Urticaria. Local whealing response to application of an ice cube for 10 min demonstrated in some populations of patients with cholinergic urticaria(Adachi et al. 1994). These reactions have been suggested to be mediated byspecific IgE, but the antigen in human sweat has not been identified yet. Cold UrticariaThis less common physical urticaria occurs in children and adults. Whealingis rapidly provoked by exposure to cold fluids or cold surfaces (Fig. 4). Angioedema of the oropharynx is common, e.g. after sucking an iced lolly. Systemic symptoms are common and may be severe – especially when provokedby extensive body immersion, as in sea-bathing. Cold urticaria is due to histamine release (Keahey et al. 1980), and cold-reactivity can be passivelytransferred to non-human primates by donor serum from affected individuals (Misch et al. 1983). The transferable factor has been variously attributedto IgE or IgM. Rarely cryoglobulins and cold agglutinin can be identified insufferers’ serum. These are usually sought routinely but positive results areexceptional. No other investigations are worth while.In adults cold urticaria may be highly disabling especially in outdoor workers. It responds rather poorly to antihistamine treatment in all but the mildestcases and in children. Cold tolerance treatment (repeated cold exposure toinduce a temporary refractory state) is effective but requires a highly motivated patient (Bentley-Phillips et al. 1976). Some remain crippled by coldsensitivity despite all these measures. 314 Michihiro Hide and Malcolm W. Greaves Delayed Pressure UrticariaThis common and disabling physical urticaria is arguably not a true urticariasince the wheals characteristically are of more than 24 hours’ duration (Lawloret al. 1989a). As its name suggests, whealing occurs following a latent periodof 2–4 hours after application of pressure perpendicular to the skin. Commonexamples of triggering factors include a tight waistband, tight footwear andgolf club, tennis racquet, or steering wheel grips. Pain is more characteristicthan itch although both may occur, and there is no angioedema and no mucosalinvolvement. A skin biopsy reveals an inflammatory infiltrate in which eosinophils are prominent but there is no vasculitis. Mild systemic symptoms arecommon including arthralgia and fatigue. The pathomechanisms in delayedpressure urticaria are unknown. In Caucasian populations about 40 per centof patients with chronic ‘idiopathic’ urticaria have accompanying delayedpressure urticaria (Sabroe et al. 1999a), and it is doubtful if it ever occurs asan isolated clinical entity.Treatment is very difficult. Early claims of the value of the antihistaminecetirizine have not been substantiated and antihistamines are usually poorlyeffective. Non-steroid anti-inflammatory agents are also usually disappointing and in severely disabled patients substantial dosage with oral steroids(e.g. prednisone 30–40 mg daily) may be necessary to control symptoms. Other Physical UrticariasThese are rare, and include solar urticaria (Ramsay 1977), aquagenic urticaria (Sibbald et al. 1981), vibratory angioedema (Lawlor et al. 1989b) andheat urticaria (Koro et al. 1986). Although it may be useful to determine theaction spectrum needed to evoke solar urticaria, generally no further investigations are needed beyond establishing the diagnosis by appropriate challenge tests. Antihistamine therapy is helpful to varying degrees in membersof this group, which will not be discussed further. The reader is referred tomore detailed accounts of these physical urticarias published recently elsewhere (Black 2004). Food Additive-Evoked Chronic UrticariaAt some stage in the course of their disease, many patients with chronic urticaria believe they have an ‘allergy’ to food items, and this belief is often reinforced by gratuitous advice from relatives and friends, and even by healthcare professionals including dermatologists and allergists. In fact, a relationship between food and chronic urticaria can be substantiated infrequently.The gold standard should be placebo-controlled challenge testing (May 1985;Pastorello 1995). In our urticaria clinics chronic urticaria can be demonstrably attributable to a food additive in no more than five per cent of patients. Chronic Urticaria as an Autoimmune Disease 315 We ask patients to keep a diary and report fluctuations in severity of whealingand itching but daily measurements of plasma tryptase or urinary excretionof histamine and its metabolites can be used to provide a quantitative measure of exacerbations. Urticarial VasculitisA full description of the etiology, pathomechanisms, clinical presentation, investigation and treatment is outside the scope of this article. However, thesubject has recently been comprehensively reviewed (O’Donnell and Black1995). Only a very brief outline will be included here. EtiologyIn the majority of patients, no cause is evident but recognised etiological factors include virus infections (hepatitis B and C and HIV) and paraproteinaemia.Urticarial vasculitis may also be the first, or very early, clinical manifestationof autoimmune disease (lupus, Sjogren’s syndrome) or ulcerative colitis orCrohn’s disease. Drug hypersensitivity may also be an occasional cause. Clinical Presentation and InvestigationIn contrast with ‘ordinary’ urticaria, individual wheals are of duration greaterthan 24 hours. Itching is variable and may be less prominent than painful tenderness. Some staining of the skin may be evident due to purpura and whealsmay show a predilection for pressure-bearing areas, such as the waistband.There may be associated systemic symptoms of which arthralgia is especiallycommon. Urticarial vasculitis tends to pursue a chronic unremitting course. TreatmentUrticarial vasculitis responds poorly to H1-antihistamines. Other drugs whichhave been proposed include dapsone, antimalarials and colchicine. Systemicsteroids may be effective but, given the frequently prolonged duration of thedisease, systemic complications are almost inevitable. Other measures worthconsidering in selected patients include intravenous immunoglobulin, parenteral gold injections and plasmapheresis. Chronic ‘Idiopathic’ UrticariaThis is conventionally defined as the daily, or almost daily, occurrence ofwheals and itching for 6 weeks or more (Greaves 1995) (Fig. 5). The differencebetween acute urticaria that appears daily for a few days and chronic idiopathic 316 Michihiro Hide and Malcolm W. Greaves Fig. 5. Chronic “Idiopathic” Urticaria. This 11 year-old child was treated elsewhere with aprolonged course of systemic steroids. The child is clearly Cushingoid, and still has widespreadurticaria urticaria with disease duration for months is not clear, in terms of pathomechanism. The average duration of chronic idiopathic urticaria is two–three years,but most patients eventually move into remission. EtiologyIf the small subgroup of patients substantiated to be reactive to a food additive is eliminated, then, at least until recently, the cause in the remainder wasunknown. There have been several reports attempting to implicate local and/or systemic infections of viruses, bacteria, and fungi, such as hepatitic C virus (Kanazawa et al. 1996), Helicobacter pylori (H.pylori) (Wedi et al. 1998;Schnyder et al. 1999), and candida (Henz BM et al. 1998). However, they are Chronic Urticaria as an Autoimmune Disease 317 either anecdotal or may be exacerbatory rather than causative for some populations of patients. Aspirin is a recognized cause of flare-up of urticaria(Grattan 2003). In a study reported by one of us (MWG), although upwards40 per cent of chronic urticaria patients had evidence of H.pylori infection,treatment of this produced no higher remission rate than when the same treatment was given to chronic urticaria patients who did not have evidence ofH.pylori (Burova et al. 1998). Nevertheless it is feasible that H.pylori may havean indirect role in autoimmune chronic urticaria (Greaves 2001) (see below).Parasite infestation is not a cause in industrialized countries, but may be important in some developing countries (Wolfrom et al. 1995). Recently a subgroup of chronic idiopathic urticaria patients has proved to have a specificautoimmune basis (Hide et al. 1993) and this subset will be discussed in greaterdetail below. PathomechanismsHistamine is clearly implicated in the pathogenesis of the wheals and itch.Although histamine, derived from dermal mast cells, is a major contributor tothe itch, its role in the wheals, which last several hours and are relatively poorlyresponsive to H-antihistamines, is less clear. Probably mast cell-derived cytokines, proteases and eicosanoids are also involved. Blood basophils and eosinophils are also prominent in skin biopsy material from wheals of all ages andmay also be a source of vasoactive mediators (Sabroe et al. 1999b; Ying et al.2002; Caproni et al. 2003).The observation that histamine releasing activity could be demonstratedin the serum or plasma of some patients with chronic idiopathic urticaria (Grattan et al. 1986) eventually led to the recognition of autoimmune urticaria asthe cause in an important subset of patients with this condition (Hide et al. 1993)(see below). Clinical Features and InvestigationCharacteristically the wheals are intensely itchy, of less than 24 hours’ duration individually and clear without marking the skin. Angioedema occurs inup to 50 per cent and affects skin and/or mucous membranes. Systemic symptoms are minimal. Delayed pressure urticaria occurs concurrently in up to 40per cent of patients (Sabroe et al. 1999a). When delayed pressure urticaria isan accompanying feature, it is important to establish whether this physicalurticaria or the accompanying spontaneous wheals and angioedema are theprincipal causes of the patient’s disability, since if it is the former, as alreadyindicated, no further investigations are worth while. The incidence of chronicidiopathic urticaria complicated with angioedema and delayed pressureurticaria, appears not so high in Japan and Asian countries according to theauthors’ experiences, although precise figures have not been reported. 318 Michihiro Hide and Malcolm W. Greaves Chronic idiopathic urticaria, with or without angioedema and delayedpressure urticaria, is a seriously disabling condition, causing occupational, social and personal disability of the same order as that consequent upon severecoronary artery disease (O’Donnell et al. 1997).Patients with chronic urticaria are almost invariably over-investigated. Nolaboratory investigations are normally indicated in the first instance. Effortsshould be directed at excluding urticarial vasculitis (by skin biopsy), foodadditive factors (by placebo-controlled challenge testing) and possibly a differential white blood cell count (for eosinophilia) in areas where parasiteinfestation is endemic. In severely affected patients, poorly responsive toH-antihistamines, referral to a specialised unit for investigation for autoimmune chronic urticaria should be considered (see below). TreatmentGeneral measures are important including a cool work and domestic environment, and avoidance of alcohol indulgence, aspirin, food additives suchas preservatives and azo dyes, and wearing of tight clothes. Although almostinevitably associated with modern living, stress, fatigue and intercurrent virus infections should at least be recognised by patients as probable causes ofoccasional flare-ups of chronic urticaria.H1-antihistamines are the mainstay of drug treatment. It is important toestablish the diurnal periodicity of symptoms (itch occurs predominantly inthe evening and at night) in timing the dosage. Most patients require an earlymorning dose of a low sedation antihistamine and supplementation in the eveningwith a further dose either of the same or, alternatively, a sedative antihistamine. If the latter is prescribed, it is important to draw the patient’s attentionto the possibility of significant impairment of cognitive function the next morning (Pirisi 2000). Topical application of 1% menthol in aqueous cream maybe appreciated by patients as a rapid temporary relief from pruritus.Oral steroids in short tapering courses can be useful in emergencies whenrapid control is necessary. However, they are not recommended as a routinetreatment of chronic urticaria, owing to the imbalance of efficacy and side effects (Fig. 5).It has been proposed that H1-antihistamines may exert an ‘anti-allergic’action independently of H1 receptors (Hayashi and Hashimoto 1999). This consists of down-regulation of adhesion molecule expression leading to reducedeosinophil and neutrophil migration and possibly a mast cell ‘stabilising’ effect. However, such actions of H1-antihistamines, if substantiated, probablyoccur only with regimens involving well above the licensed dosages.H2-antihistamines (e.g. cimetidine) do have a small statistically significantadditive effect when combined with H1-antihistamines but it is probably notsubstantial enough to be clinically useful. Recently developed cysteinyl leukotriene receptor antagonists may be very effective in a certain population of Chronic Urticaria as an Autoimmune Disease 319 patients. The efficacy of montelukast by itself or in combination with H1-antihistamine has been shown by controlled trials (Pacor et al. 2001; Erbagci Z2002.). On the other hand, others have proved negative (Reimers 2002). Aggravation of urticaria by aspirin in combination with other leukotriene antagonists has been reported (Ohnishi-Inoue et al. 1998). Autoimmune Chronic UrticariaBetween 30 and 50 per cent of patient with chronic ‘idiopathic’ urticaria havebiologically functional autoantibodies against the high affinity IgE receptoror less commonly against IgE itself (Niimi et al. 1996). In these cases the antibody is deemed to be the cause of the disease. These patients are describedas having autoimmune chronic urticaria (Hide et al. 1993; Hide et al. 1994). EtiologyThe reason why these autoantibodies are present and causative in some patients with chronic urticaria and not others is unclear. Genetic factors areprobably important. We have recently reported results of HLA class II associations in 100 patients with chronic urticaria (O’Donnell et al. 1999). Thosewhose sera were positive for anti-FceRI or anti-IgE autoantibodies showed ahighly significantly increased frequency of HLA DRB104 (DR4) alleles. Thereis also a positive association with other autoimmune diseases, notably autoimmune thyroid disease in patients with autoimmune urticaria (Leznoff et al.1983; Leznoff and Sussman 1989).As mentioned above, a high incidence of H.pylori infection in patients withchronic idiopathic urticaria has already been remarked. One of us (MWG) haspreviously suggested that H.pylori infection could lead to development ofanti-FcRI autoantibodies by molecular mimicry (Greaves 2001). PathomechanismsMost patients with autoimmune chronic urticaria have IgG autoantibodiesdirected against the alpha-chain of the high affinity IgE receptors (FcRIa) expressed on dermal mast cells or blood basophils (Niimi et al. 1996). Histamine release evoked by these antibodies from basophil leucocytes of healthydonors can be inhibited by prior incubation with human recombinant alphachain. Some of them bind to FcRIa, regardless of the binding of IgE. However, the binding of most of these types of autoantibodies is interfered withcompetitively by IgE to various degrees (Hide et al. 1995). Removal of Ig	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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E(by lactic acid stripping) enables the autoantibody to release histamine butreconstituting the IgE on the surface of the basophils inhibits release (Niimiet al. 1996). Precise epitope mapping on FcRIa has not yet been carried out. 320 Michihiro Hide and Malcolm W. Greaves Fig. 6. Autoimmune Chronic Urticaria: Pathomechanisms. Schematic representation of adermal mast cell. The high affinity IgE receptor (FcRI) is represented by g1 and g2, b and achains. The a chain possesses two domains (a1 and a2). In this instance IgG anti-FceRI bindsto, and cross-links via a2 domain. ITAM = Immunoreceptor Tyrosine Kinase Activation Motif.Lyn, Syk = protein kinases. PKC = protein kinase C In about five per cent of patients with chronic idiopathic urticaria, the IgGautoantibody reacts with the Fc portion of IgE itself. These anti-IgE autoantibodies bind to the 4th domain of the IgE heavy chain (Grattan and Francis1999). For histamine release to occur, either anti- FcRIa or anti-IgE autoantibodies normally cross-link adjacent high affinity IgE receptors throughthe a chain or IgE respectively (Fig. 6).The role of complement activation is controversial. Our own data, whichindicated that the histamine-releasing activity of anti-FcRIa autoantibodies washeat-stable, argues against complement involvement. The heat-resistance ofhistamine releasing activity in sera of patients with chronic urticaria has alsobeen observed by other authors (Zweiman et al. 1996; Tong et al. 1997). However, other authors, using specific inhibitors of complement components,decomplemented sera and/or the reconstitution with C5, have reported evidence that in some circumstances the reaction between anti- FcRIa autoantibodies and dermal mast cells may be complement-dependent (Fiebiger et al.1998; Fagiolo et al. 2000; Kikuchi and Kaplan 2002). Kikuchi and Kaplan (2001)showed the histamine release activity of serum IgG from 2 out of 6 patientswas substantially enhanced by serum with complement, whereas that from Chronic Urticaria as an Autoimmune Disease 321 Table 1. Functional Properties of Anti-FceRIa and Anti-IgE Autoantibodies1. Cause whealing in human skin following intradermal injection(see autologous serum skin test) (Sabroe et al. 1999c)2. Release histamine from dermal mast cells and blood basophils (Niimi et al. 1996)3. Reduce numbers of circulating blood basophils4. Serum levels are proportional to disease activity (Grattan et al. 1992, 2000; Zweiman Bet al. 1996; O’Donnell BF et al. 1998)5. Removal by plasmapheresis results in remission of chronic urticaria in autoantibodypositive patients (Grattan et al. 1992)6. Effectiveness of other immunomodulative therapies, such as cyclosporine-A andintravenous immunoglobulin (Grattan et al. 2000, O’Donnell BF et al. 1998) the other 4 patients was not, suggesting a heterogeneity of anti-FceRI autoantibodies in terms of the complement dependency for histamine release. Thepopulation density of FceRI on the surface of dermal mast cells and basophils,and/or the binding avidity of autoantibodies may be crucial – a low population density and a moderate binding avidity may allow monovalent bindingof the autoantibodies with complement activation. The subclasses of IgG inautoimmune urticaria are predominantly IgG1 and IgG3 which may readily activate complements (Fiebiger et al. 1998).Subsequent intracellular events involve the activation of protein tyrosinekinases lyn and syk via immunoreceptor tyrosine kinase activation motifs located on the intracellular portions of the b and g chains of FceRI. (Rivera J 2002)That these anti-FceRI and anti-IgE autoantibodies are functional is indicatedby evidence listed in Table 1.Can autoimmune chronic urticaria be regarded as an autoimmune disease?Evidence includes the inverse relationship between blood basophil numbersand histamine content on the one hand and levels of serum anti-FceRIa autoantibody on the other. Removal of the antibodies by plasmapheresis leads toremission of the urticaria (Grattan et al. 1992). The antibody also reproducesthe urticarial wheal when introduced as an autologous serum injection intohuman skin, and causes histamine release from dermal mast cells and bloodbasophils (Niimi et al. 1996). Reproduction of urticaria in an animal model bysensitisation to the alpha-chain of FceRI has not yet been carried out even witha transgenic mouse expressing FceRIa (Fung-Leung 1996). However, it shouldbe noted that urticarial eruptions are not apparently observed even in thesystemic anaphylactic reactions induced by antigen in animals, such as rodents and guinea-pigs.Increased histamine releasability from dermal mast cells and basophils isan important additional factor in the pathogenesis (Sabroe et al. 1998). Numerous previously published reports have shown that although mast cell numbers and histamine content of skin are essentially normal in chronic urticaria,various chemical histamine-releasing agents (codeine, compound 48/80) causeexaggerated whealing when injected into uninvolved skin of patients with 322 Michihiro Hide and Malcolm W. Greaves chronic urticaria (Juhlin and Michaelsson 1969, Smith CH et al 1992). Thisenhanced histamine releasability is probably due to the action of cytokines orneurokines released locally. These cytokines also cause up-regulation of adhesion molecule expression, leading to the substantial leucocyte infiltratecharacteristic of the histological appearances of autoimmune urticaria.The organ selectivity of anti-FceRIa autoantibodies is puzzling. Human lungmast cells express FceRIa but patients with anti- FceRI autoantibodies get urticaria without pulmonary symptoms. If complement is involved in evoked histamine release by anti- FceRIa autoantibodies, then this anomaly is explicablesince dermal but not lung mast cells express complement receptors. Alternatively, local cytokine and micro-circulatory differences between lung andskin may restrict access of the autoantibodies to tissue mast cells in the lungs.There is also functional heterogeneity between dermal and lung mast cells(Lowman et al. 1988). However, the reasons for fact that lung mast cells are evidently ‘ring fenced’ against FceRI and anti-IgE autoantibodies remain obscure. Clinical and Histological FeaturesDetailed comparative reviews of the symptoms, clinical presentation and natural history of autoimmune and non-autoimmune chronic urticaria have failedto reveal differences sufficiently distinctive to be of diagnostic value (Sabroeet al. 1999a). However, the disease does tend to run a more aggressive andprotracted course in patients who possess anti-FcRI autoantibodies than thosewithout an autoimmune etiology. Patients with autoimmune urticaria also tendto be less responsive to routine antihistamine treatment than non-autoimmunepatients. Again, the difference is not so conspicuous as to be useful as a discriminating marker for an autoimmune etiology.Sabroe et al. have also recently reported that the peripheral blood basophilleucocyte count is greatly reduced in patients with anti-FceRIa autoantibodiescompared with patients who did not have these antibodies (Sabroe et al. 1998).This is not an original observation; Rorsman (1961) noted almost 45 years’ agothat chronic urticaria was associated with basopenia in some patients withchronic ‘idiopathic’ (but not physical) urticaria. The fate of the cells is of interest; degranulation or destruction in the peripheral blood is an obvious possibility. Indeed, Kaplan’s group found the increase of basophils in skin ofchronic idiopathic urticaria with or without autoantibodies as well as T cells,eosinophils and neutrophils (Ying et al. 2002). The alternative of redistribution into the lesional skin of chronic urticaria may account for the basopenia.Sabroe (1999b) recently carried out a detailed histological study of skinbiopsy material from patients with autoimmune and non-autoimmune urticaria. No significant differences were found apart from reduced numbers ofactivated eosinophils (EG2+) in lesional skin of autoimmune patients in whichthe wheal biopsied was more than 12 hours old. There is no vasculitis in autoimmune urticaria. More recently Kaplan’s group also found no difference Chronic Urticaria as an Autoimmune Disease 323 in either the numbers of inflammatory cells or the pattern of cytokine expressions between patients with and without autoantibody (Ying et al. 2002). DiagnosisAs pointed out above, there are no clinical or histological features which canbe used as a paradigm in diagnosis (Sabroe et al. 1999a). The cornerstone ofdiagnosis is clearly detection of anti-FceRIa or anti-IgE autoantibodies in serum of patients with chronic urticaria. However, we have found the autologousserum skin test to be a useful screening procedure. As recently describedand characterised (Sabroe et al. 1999c), this test is based upon the originalfinding by Grattan (1986) that the serum of some patients with chronic ‘idiopathic’ urticaria would cause a red wheal upon autologous injection into thepatient’s uninvolved skin. This test has now been optimised for sensitivity andspecificity (Sabroe et al. 1999c).Autologous serum, collected during exacerbation of the chronic urticaria,is injected into uninvolved skin of the forearm in volume 0.05 ml. An equalvolume of phosphate-buffered saline acts as a vehicle control. The local response is measured at 30 minutes and is deemed positive if the wheal is redin colour and at least 1.5 mm diameter greater than the saline control (Fig. 7).This autologous serum skin test (ASST) is positive in about 40 per cent of patients with chronic idiopathic urticaria (Table 2). In this test, false negativereactions are rare, but false positives may occasionally occur and some of thesera probably contain other wheal-producing mediators including the ‘mastcell specific’ factor. This non-immunoglobulin mediator retained by 3 KDultrafiltration membranes was reported by us (Kermani et al. 1995) and appears to be present in about eight per cent of patients with chronic urticaria.It requires further characterisation.There is one study that showed no correlation between ASST and clinical features in chronic idiopathic urticaria, except for the frequency of complication with angioedema (Nettis et al. 2002).However, ASST shows a reasonable concordance with in vitro measurementsof serum anti-FceRI or anti-IgE autoantibodies, which also significantly correlated with clinical severities (Zweiman et al. 1996; Sabroe et al. 1999a).A positive autologous serum skin screening test requires confirmation byin vitro analysis for anti-FceRIa and anti-IgE autoantibodies. The current goldstandard consists of demonstration by bioassay that either blood basophils ordermal mast cells release histamine or other mediators upon incubation withthe patient’s serum. Low IgE basophils predominantly detect anti-FceRI autoantibodies, whereas high IgE basophils detect anti-IgE autoantibodies and antiFceRI autoantibodies that are non-competitive with IgE. Low IgE basophilsmay be directly obtained from low IgE (1 IU/ml) donors or prepared by lacticacid treatment of ordinary donors’ leukocytes. To distinguish between the twotypes of autoantibody, it is desirable to carry out inhibition experiments utilising human recombinant a-chain and monoclonal IgE. However, for practical 324 Michihiro Hide and Malcolm W. Greaves Fig. 7. Autologous Serum Skin Test. PBS = Phosphate-buffered saline; serum: undiluted0.05 ml. Both serum and plasma show positive results at 30 min purposes, this is usually unnecessary. In our hands, 25 per cent of chronic idiopathic urticaria sera can be confirmed to contain anti-FceRIa autoantibodies, whereas about five percent have anti-IgE autoantibodies (Niimi et al.1996, Sabroe et al. 1999a).As high as 76 per cent of chronic idiopathic urticaria patients were foundto have anti-FceRIa autoantibodies by Kaplan’s group using a rat basophilicleukaemia cell line expressing a-chain of human FcRI, which integrates chimeric FceRI with endogenous rat b and g chains of the receptor and using release of b-hexosaminidase as an indicator of cell degranulation (RBL-48) (Tonget al. 1997). This figure is even higher than that they observed by humanbasophils (52%). In our hands, however, the sensitivities of RBL-48 cell andother cell lines expressing human FceRIa for anti-FceRIa antibodies are notas high as human basophils obtained from healthy donors (unpublished Chronic Urticaria as an Autoimmune Disease 325 observation). Further studies with standardized conditions may be necessaryto establish the usability of RBL cells expressing human FceRIa.Some investigators have used immunoassays (immunoblotting, ELISA,immunoprecipitation) (Fiebiger et al. 1995, 1998; Sabroe et al. 1998; Kikuchiand Kaplan 2001). These assays measure immunoreactive FceRIa autoantibodies and show false positives when compared with bioassays. False positivesare particularly prone to occur in autoimmune diseases including Sjögren’ssyndrome, dermatomyositis, pemphigus and pemphigoid (Fiebiger et al. 1998).However, unlike the anti-FceRIa autoantibodies in urticaria which are of subtype IgG1 and IgG3, these antibodies are predominantly of the IgG2 and IgG4subtypes. More important, they are non-functional, being inactive (non-histamine-releasing) against basophil leucocytes. Kikuchi and Kaplan (2001)showed no correlation between positive histamine release activity and immunoblotting in sera of patients with chronic urticaria. The ELISA, though initially promising, has not yet confirmed expectations in terms of specificity anddemonstration of linearity between level of antibody and immunoreactivity.Horn et al (1999) detected substantial amount of anti-FceRIa antibodies in serafrom healthy donors and demonstrated that these antibodies are cross-reactive with tetanus toxoid by ELISA. He used recombinant protein consistingof two moieties of the extracellular part of human FceRIa flanking one moiety of human serum albumin. Although the affinities of such autoantibodiesagainst the recombinant FceRIa were low (3.4x10–6 and 7.1x10–7 M), healthydonor sera containing these autoantibodies showed histamine release activity as well as sera of patients with chronic idiopathic urticaria, using basophilstreated with IL-3. They recently cloned anti-FceRIa autoantibodies from healthydonors and patients with chronic idiopathic urticaria. Both autoantibodieshad the same amino acid sequence and showed the activity of histamine release from basophils that were not occupied by IgE (Pachlopnik et al. 2004).On the other hand, immunoreactivity against FceRIa in ELISA studied byFiebiger et al (1998) and that in immunoblotting by the authors (Sabroe et al.2002) were significantly correlated with basophil histamine release activities(p<0.0001, x2; data were re-calculated by the authors). Moreover, recent studies of IgE and FceRIa revealed that cross linkage between FceRI and FcgRIImay inhibit histamine release from human mast cells and basophils (Tam etal. 2004) and binding of certain types of monomeric IgE could activate FceRIby itself (Pandey et al. 2004). It is feasible that autoantibodies against FceRIcould mimic either of such functions. Taken together, the overall assessmentof functional autoantibodies with histamine releasing assay using humanbasophils, or possibly mast cells, should be the gold standard for the detection of pathological autoantibodies.Recently published values for anti-FceRIa autoantibodies incidences and positive reactions in autologous serum skin test in chronic urticaria are listed inTable 2.A better screening test than ASST is badly needed. Rapid flow cytophotometric methods for enumeration of circulating blood basophils offer prospects Asero et al(2001) Horn et al(1999) Sabroe et al(1999) ASST4) 3) ASST 205/306(67%) 55/155(35%)ELISA(sFceRIa) 21/21(100%)9)5/21(9.5%) 34/53 (64%) 20/121 (17%)19/87 (22%)of ASST+ 1/21(4.7%)9) HBHR (IL-3+) 6HBHR6 54/155 (35%) 31/68 (48%)28/65 (46%)HBHR6 HBHR8foreskin-MC HR 6 Western blot(sFceRIa) 39/86 (45%)33/50 (66%)of autoAb+6/36 (17%)of autoAb- Ferrer et al(1998) 6) HBHR (IL-3+) ELISA(sFceRIa) Fiebiger et al(1998) 106/281 (38%) 26/50 (52%)38/50 (76%) HBHR6RBL cells Tong et al(1997) Niimi et al(1996) 21/70 (30%)anti-FceRIa12/13 anti-IgE 1/13 12/32 (37%) 14/25 (56%) HBHR6 Western blot(sFceRIa) HBHR6 Zweiman et al(1996) 98/163(60%) 20/25(80%) Bioassay 47/163 (29%)anti-FceRIa 38 (23%)anti-IgE 9 (6%) 2) ASST ASST1) Immunoassay HBHR6) Fiebiger et al(1995) Grattan et al(1991) Skin test Table 2. Prevalence of Anti-FceRI Autoantibodies in Chronic Idiopathic Urticaria 326Michihiro Hide and Malcolm W. Greaves 27/78(35%) 81/180(45%) 4) 5) Sabroe et al(2002) Hide et al(unpublishedresults) 3 32/78(41%)HR+ 20HR- 12 Determined as positive if flare diameter is ³ 5 mm than saline control OR serum-induced flare is larger than the flare induced by intradermalinjection of 20ml of 10mg/ml histamine at 30 min Human basophil histamine release in the presence (if noted) or absence of IL-3 b-hexosaminidase release from rat basophilic leukemia cell line transfected with human FceRIa Histamine release from isolated foreskin mast cells When criteria for “positive” was set so as to exclude all data of all healthy controls 5 6 7 8 9 Histamine release from skin slices Determined as positive if wheal-and-flare area is ³ 50% of the reaction induced by a prick test with 10 mg/ml histamine at 15 and 40 min 4 10 Determined as positive if diameter of wheal with flare is ³ 2 mm than saline control at 30 min Determined as positive if diameter of wheal plus redness is ³ 1.5 mm than saline control at 30 min. The condition was determined to obtain theoptimal sensitivity and specificity for the identification of patients with histamine-releasing activity 15/25 (60%)of ASST+anti-FceRIa11/25 anti-IgE4/25 27/78 (35%)31/78 (40%) 3 HBHR6 HBHR6skin sliceMC HR10 111/260 (43%) 2 Determined as positive if wheal volume ³ 10 mm than saline control at 60 min Western blot(sFceRIa) HBHR6 Western blot(sFceRIa) 122/260(47%) Bioassay Immunoassay 1 ASST ASST 42/102(41.2%) 3) ASST Nettis et al(2002) Kikuchi andKaplan(2001) Skin test Table 2. Prevalence of Anti-FceRIa Autoantibodies in Chronic Idiopathic Urticaria Chronic Urticaria as an Autoimmune Disease327 328 Michihiro Hide and Malcolm W. Greaves of an effective test, since basophil numbers are usually greatly reduced inantibody-positive patients (Sabroe et al. 1998). Treatment of Autoimmune UrticariaThe routine treatment of autoimmune chronic urticaria is essentially the sameas that for non-autoimmune urticaria. All patients with chronic urticaria shouldreceive antihistamines commencing with a low-sedation antihistamine suchas loratidine 10 mg, cetirizine 10 mg, evastine 10 mg or fexofenadine 60 to180 mg, (in Japan, fexofenadine is licensed for 120 mg; 60 mg each in morning and evening) usually administered in the morning. Since pruritus is mainlya problem in the evening and at night, it is useful to give a second dose of thesame antihistamine in the evening or before retiring for the night. This represents a total daily dosage in excess of the licensed recommended dosage.In patients troubled by severe nocturnal pruritus, a sedative antihistaminesuch as hydroxyzine 25 mg may be indicated. However, patients should bewarned that impairment of cognitive function may be a problem the following morning (Pirisi 2000).Patients with autoimmune chronic urticaria may respond poorly to theabove antihistamine regime. Systemic steroids are unsuitable as long termtreatment for chronic urticaria although short tapering courses may be usefulto meet specific contingencies. In patients with recalcitrant autoimmunechronic urticaria which is causing significant disability, cyclosporin may beeffective (Grattan et al. 2000). The dosage for an average adult is 3–4 mg/kg/day and one of us (MWG) usually prescribe this dosage for two–three months.There is rarely a rebound withdrawal. About one-third of patients remain inremission after cyclosporin has been withdrawn; one-third relapse but onlymildly and one-third relapse to their former pretreatment level of disease activity and may have to be recontinued on cyclosporin. Chronic autoimmuneurticaria is not a licensed indication for cyclosporine and the usual precautions regarding renal function, blood pressure monitoring and unwanted interactions with other concurrently administered drugs metabolised via thecytochrome P450 enzyme pathway have to be considered.We have previously reported positive results using more aggressive formsof immunotherapy including intravenous immunoglobulin (O’Donnell et al.1998) and plasmapheresis (Grattan et al. 1992) in selected patients with autoimmune urticaria. We ought to emphasise that these treatment modalitiesare temporary symptom relieving rather than curative. Nevertheless, it is noteworthy that histamine releasing activities of the patients had decreased ordiminished in accordance with urticarial symptoms after the treatments, endorsing the pathological role of autoantibodies and rationale for immunotherapies for chronic autoimmune urticaria.More selective immunotherapeutic strategies are on the horizon. These include administration of humanised structure-based peptides representing the Chronic Urticaria as an Autoimmune Disease 329 antibody-binding sites on the a-chain. This development will be dependenton epitope mapping, and should enable induction of desensitisation in antiFceRI-positive individuals. Alternatively down regulation of the FceRI population density on mast cells could be achieved by administration of anti-IgEantibodies reactive with the C3 domain of the IgE heavy chain (MacGlashanet al. 1987). Development of tolerance to the alpha chain of FceRI might alsobe possible by oral administration (Weiner 1997). ReferencesAdachi J, Aoki T, Yamatodani A (1994) Demonstration of sweat allergy in cholinergic urticaria. J Dermatol Sci 7: 142–149Adams DD (1988) Long-acting thyroid stimulator: how receptor autoimmunity was discovered. J Autoimmunity 1: 3–9Asero R, Tedeschi A, Lorini M, Salimbeni R, Zanoletti T, Miadonna A (2001) Chronic urticaria: novel clinical and serological aspects. Clin Exp Allergy 31: 1105–1110Bentley-Phillips CB, Black AK, Greaves MW (1976) Induced tolerance in cold urticariacaused by cold-evoked histamine release. Lancet ii: 63–66Black AK, Lawlor F, Greaves MW (1996) Consensus meeting on the definition of physicalurticarias and urticarial vasculitis. Clin Exp Dermatol 21: 424–426Black, AK, Physical and Cholinergic Urticarias. In: Urticaria and Angioedema. Eds MalcolmW Greaves, Allen P Kaplan. Marcel Dekker, New York, (2004) chapter 8, pp171 – 214Burova GP, Mallet AI, Greaves MW (1998) Is Helicobacter pylori a cause of chronic urticaria?Br J Dermatol 139 (Suppl): 42Caproni M, Volpi W, Macchia D, Giomi B, Manfredi M, Campi P, Cardinali C, D’Agata A,Fabbri P. (2003) Infiltrating cells and related cytokines in lesional skin of patients withchronic idiopathic urticaria and positive autologous serum skin test. Exp Dermatol 2:621–628Commens CA, Greaves MW (1978) Tests to establish the diagnosis in cholinergic urticaria.Brit J Dermatol 98: 47–51Erbagci Z (2002) The leukotriene receptor antagonist montelukast in the treatment of chronicidiopathic urticaria: a single-blind, placebo-controlled, crossover clinical study. J AllergyClin Immunol 110: 484–848Fagiolo U, Kricek F, Ruf C, Peserico A, Amadori A, Cancian M.(2000) Effects of complementinactivation and IgG depletion on skin reactivity to autologous serum in chronic idiopathicurticaria. J Allergy Clin Immunol 106: 567–572Ferrer M, Kinet JP, Kaplan AP (1998) Comparative studies of functional and binding assaysfor IgG anti-FceRIah (a-subunit) in chronic urticaria. J Allergy Clin Immunol 101: 672–676Fiebiger E, Maurer D, Holubar H, Reininger B, Hartmann G, Woisetschlager M, Stingl G(1995) Serum IgG autoantibodies directed against the alpha chain of FceRI: a selectivemarker and pathogenetic factor for a distinct subset of chronic urticaria patients. J Clin Invest 96: 2606–2612Fiebiger E, Hammerschmid F, Stingl G, Maurer D (1998) Anti-FceRIa autoantibodies in autoimmune-mediated disorders. J Clin Invest 101: 243–261Fung-Leung W-P, Sousa-Hitzien JD, Ishaque A (1996) Transgenic mice expressing the human high affinity immunoglobulin (Ig)E receptor a chain, respond to human IgE in mastcell degranulation and allergic reactions. J Exp Med 183: 49–56Grattan CEH, Wallington TB, Warin RP (1986) A serological mediator in chronic idiopathicurticaria: a clinical immunological and histological evaluation. Br J Dermatol 114: 583–590Grattan CEH, Francis DM, Hide M, Greaves MW (1991) Detection of circulating histamine releasing autoantibodies with functional properties of anti-Ig	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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J InvestigDermatol Symp Proc. 6: 123–127 11 Lichen Planus, Lichenoid Eruptions andCutaneous Graft-Versus-Host-ReactionMiklós Simon Jr. IntroductionLichen planus (LP) is a noncontagious, inflammatory, pruritic, papular mucocutaneous disease of unknown etiology that most commonly affects middleaged adults. In 1869 Erasmus Wilson described the cutaneous “leichen planus”in 50 case histories and recorded oral lesions in 3 of his patients (Wilson, 1869).Weyl and Wickham noted the surface markings on the papules and pointedout the importance of these marks in establishing the clinical diagnosis of LP(Weyl, 1885; Wickham, 1895). After Neumann, Weyl, Caspary, and Poór, Darierdescribed the histopathology of LP (Darier, 1909), the only important addition has been the demonstration of “colloid bodies” at the dermoepidermaljunction by Thyresson and Moberger (1957). The direct immunofluorescencefindings in LP have been extensively studied for the first time by Barthelmesand Haustein (1970) and Baart de la Faille Kuyper and Baart de la Faille (1974),respectively.LP has a worldwide distribution. The prevalence of LP in the general population is of the order of 0.9 to 1.2% (Scully & El-Kom, 1985). It appears initially during the fifth or sixth decade and affect women preferentially. LP ofchildhood is unusual, but familial cases have been observed (Copeman, 1978).A weak association with HLA-A3, B8, B16, B35 and a significantly increasedHLA-DR1 (DRB1* 0101) antigen frequency has been reported in patients withidiopathic LP (Simon jr et al, 1984; Powell et al, 1986; La Nasa et al, 1995). Inaddition, TNF-a and IFNg polymorphisms contributing to susceptibility to LPwere described, very recently (Carrozzo et al, 2004).The cause of LP is unknown. Evidence points to the possibility that analteration of epidermal cell antigens (bacterial/viral infections, contact sensitizers, trauma etc.) induces a cell-mediated immune response similar to thatseen in cutaneous graft-versus-host-reaction (cGVHR). Drugs may induce lichenoid eruptions (LDE). LDE (probably an allergic type IV reaction) produces 334 Miklós Simon Jr. mucocutaneous lesions that are clinically and histologically indistinguishablefrom (idiopathic) LP. LDE usually appear as a symmetric eruption on the trunkand extremities and sometimes fail to exhibit classic Wickham striae. Medications commonly associated with the development of LDE are antimalarials,gold, penicillamine, methyldopa, b-blockers, angiotensin-converting enzymeinhibitors, spironolactone, lithium, cinnarizine, nonsteroidal anti-inflammatory drugs, thiazide, phenothiazine derivatives, allopurinol, tetracycline, andsulfonylurea agents (Ellgehausen et al, 1998).There have been several reports of patients with LP in association with autoimmune disorders, notably with systemic lupus erythematosus, thymoma,myasthenia gravis, dermatomyositis, ulcerative colitis, primary biliary cirrhosis, chronic active hepatitis, pemphigus vulgaris, dermatitis herpetiformis, bullouspemphigoid, alopecia areata, vitiligo, Sjögren’s syndrome, morphea, andsystemic sclerosis suggesting there may also be an immunological basis forclassical LP (Simon jr, 1985). Immune PathogenesisDirect immunofluorescence studies of lesional and uninvolved skin in patientswith LP demonstrated an irregular deposition of fibrin and complement alongthe dermoepidermal junction, especially in the dermal papillary region andaround hair follicles, in the active papular lesions. The colloid bodies fluoresced brightly with IgM and with other immunoglobulins and complementcomponents (Barthelmes & Haustein, 1970; Baart de la Faille-Kuyper & Baartde la Faille, 1974; Simon jr et al, 1983). In 1984, Olsen et al described an LPspecific antigen (LPSA) found by indirect immunofluorescence in the granular or spinous layer of the epidermis of lesional tissue (Olsen et al, 1984). Thecirculating anti-LPSA antibodies are more likely to be markers of the diseasethan to be causative.In 1975 Touraine et al (1975) and Saurat et al (1975) reported a lichenoideruption that occurred in two men who had received allogenic bone marrowtransplants from their sisters. It now seems likely that this lichenoid tissue reaction is a later and more chronic manifestation of a GVHR in which the target appears to be the basal cell layer of the epidermis. The clinical pictureand the histologic and direct immunofluorescence findings were essentiallythe same as those in idiopathic LP. Immunopathological investigations oflesional skin in these patients revealed intraepidermal a predominance ofCD3+CD8+CD11a+CD16+CDw137+T-lymphocytes and a net-like specific positive staining when exposed to HLA-DR, CD54, CD36, CD21, CD16, and CD1monoclonal antibodies, recently (Simon jr & Hunyadi, 1992; Anasetti, 2004). Cutaneous GVHR occurs most commonly in patients undergoing bone marrowtransplantation, after solid organ transplant, but is also seen in fetuses ob- Lichen Planus, Lichenoid Eruptions and cGVHR 335 taining maternal leukocytes via maternal-fetal transfusion and in bloodtransfusions transplanting immunocompetent cells into immunodeficient recipients. The precise pathophysiology of GVHR is not known. However, several studies demonstrate that acute GVHR occurring in humans is inducedby donor T-lymphocytes reactive against recipient cells expressing differenttissue antigens. On the other hand, T-cells recognizing host-specific antigensare present in the blood and the skin of patients with chronic GVHR (Aractingi& Chosidow, 1998). A significant association between polymorphism of TNF-a,IFN-g, IL-10, and IL-6 and the development of severe GVHR has been demonstrated, recently (Takahashi et al, 2000; Cavet et al, 2001).The pathologic process in LP is a cell-mediated response localized to thedermoepidermal junction and characterized by degeneration of keratinocytesin the basal layer and disruption of the basement membrane. The basementmembrane zone is an interface composed of epidermal basal cell surfaceglycoproteins, laminin, fibronectin, type IV collagen, and supporting mesenchymal extracellular proteoglycans. These proteins and oligosaccharides maybe identified immunohistochemically by monospecific antibodies and highaffinity lectins, respectively.The earliest features of LP are changes in, and close to the epidermal basalcell layer, which may occur in the absence of demonstrable changes in thedermis. Studies concerning the evolution of lesions of LP demonstrated, thatone of the first observable changes is the appearance of Langerhans cells (Ragaz& Ackerman, 1981). Shortly after appearance of Langerhans cells basalkeratinocytes undergo flattening and hydropic changes, their nuclei are injured at an early phase of the mitotic cycle. These basal cell changes in LPare accompanied by a dense mononuclear inflammatory T-lymphocyte infiltrate subepidermal and at the dermoepidermal interface, the location of whichmakes a relationship to the basal epithelial changes highly likely.In the course of examining keratinocyte-lymphocyte interactions in vitroNickoloff et al (1988) reported prominent adherence by both allogeneic andautologous T-lymphocytes and monocytes to cultured keratinocytes after pretreatment of keratinocytes with IFNg. The binding of these mononuclear cellsto IFNg-treated keratinocytes involves the lymphocyte function-associatedantigen-1 (LFA-1) molecule on T-cells and the intercellular adhesion molecule-1 (ICAM-1) induced by IFNg or TNF-a on keratinocytes (Griffiths et al,1989). Biopsy specimens from lesional skin of LP patients exhibited intraepidermal specific positive staining when exposed to ICAM-1 (CD54), HLA-DR,NF-kappaB, CXCL9, 10, 11, CD1, and CD120a antibodies (Malmnäs Tjernlund,1980; Simon jr, 1988; Griffiths et al, 1989; Simon jr & Gruschwitz, 1997; Iijimaet al, 2003; Santoro et al, 2003). CD54 expression in lesional keratinocytes inLP, similar to that in various cutaneous inflammatory conditions (LangeWantzin et al, 1988; Griffiths et al, 1989), may be an important initiator ofkeratinocyte-lymphocyte interaction, whereas HLA-DR expression in keratinocytes seems to be more important in postadherence antigenic recognitionand/or presentation to activated T-lymphocytes (Messadi et al, 1988). 336 Miklós Simon Jr. In LP, the cellular infiltrate is predominantly composed of T-lymphocytesand monocytes as detected by hetero- and monoclonal antibodies, nonspecific esterase, lysosyme, and, selectively by peanut agglutinin lectin (Walker,1976). The role of these T-lymphocytes, probably antigen activated T-cells,is not quite clear, however, autoradiographic investigations revealed a threeto four times higher lymphoblast proliferation rate in LP lesions than in psoriasis or contact dermatitis (Lachapelle & De la Brassine, 1973). Langerhanscells in the epidermis and subepidermal may also be identified with the useof light microscopy by formalin resistent sulfhydril dependent nucleosidetriphosphatase, ultrastructurally by the presence of Birbeck’s granules, immunohistochemically by monoclonal antibodies or S-100 calf brain protein. Theirparticipation in LP, and close vicinity to the T-lymphocytes, combined withlocal and systemic release of various cytokines (e.g. TNF-a, IL-6, IFNg) both inthe skin and in the serum, would seem to provide antigen processing activityand the induction of a hypersensitivity reaction (Giannotti et al, 1983; Soehnchen et al, 1992). In addition, soluble mediators of cell damage produced byT-cells may induce keratinocyte apoptosis and formation of colloid bodies.Examinations of different lymphocyte subpopulations in cutaneous inflammatory infiltrate of active LP revealed the existence of T-lymphocytes ofboth the CD4+ and the CD8+ phenotype. In early phases of LP lesions thelymphocytes observed in close contact with large, non-lymphoid cells wereidentified as CD4+T-cells (Bhan et al, 1982). In the late phases of LP lesionsintraepidermal lymphocytes almost constantly exhibited CD8-positivity (Simon jr & Keller, 1984). The dermoepidermal interface, from the pathogeneticpoint of view probably the most important zone, showed a predominance ofHLA-DR+CD25+LFA-1+TNF–R+CCR5+CXCR3+CCL5+CXCL10+CD3+CD8+TCRgd+- Fig. 1. Typical purple polygonal papules of LP Lichen Planus, Lichenoid Eruptions and cGV	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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HR 337 T-lymphocytes (Malmnäs Tjernlund, 1980; Simon jr & von den Driesch, 1994;Gadenne et al, 1994; Simon jr & Gruschwitz, 1997; Iijima et al, 2003).Immunological characterization of different T-lymphocyte subpopulationsin peripheral blood of LP patients, by means of the indirect immunofluorescence technique using monoclonal antibodies, clearly documented a reducedpercentage of the CD8+T-cell subset, normal pan T-, CD4+T-, and B-lymphocyte values as compared with the controls (Simon jr & Keller, 1984). The phytohemagglutinin response of lymphocytes from LP patients was in the samerange as that of healthy controls (Cerni et al, 1976).A markedly diminished, to the severity of the disease related natural killercell activity against K562 target cells was revealed in patients with extensiveerosive LP of oral mucosa, generalized acute eruptive and moderate cutaneous LP as compared with that of patients with non-erosive LP of oral mucosaand healthy controls. Interleukin-2 failed to restore completely reduced natural killer cell activities in all groups of patients investigated (Simon jr et al, 1989).The in vitro effect of peripheral blood lymphocytes on syngeneic oral epithelial cells using a modified 51Cr release macro-assay in patients with LPresulted as a substantial lymphocytotoxicity in comparison to the controls.This positive lymphocytotoxicity is probably generated by sensitized effectorlymphocytes via specific recognition of foreign antigenic structures on syngeneic oral target cells (Simon jr et al., 1983). Similar results were found usingCD8+ T-cell lines and clones cultured from LP lesions against autologous lesional keratinocytes, recently (Sugerman et al, 2000). These findings may be regarded as a functional evidence for the pathogenetic role of CD8+ cytotoxicT-cells in the course of LP. Clinical FeaturesLichen Planus, Lichenoid EruptionsThe cutaneous lesions of LP consist of pruritic faintly erythematous to violaceous, flat-topped, polygonal papules, occasionally showing central umbilication. A thin, transparent scale may be discerned atop the lesions. A networkof fine white lines or puncta referred to as Wickham striae is present in manywell-developed papules (Fig. 1).LP lesions are usually distributed symmetrically, the disease tends to involve the flexural areas (wrists, arms, legs) preferentially. The thighs, lumbararea, trunk, neck, and the dorsal surfaces of the hands with the nails may alsobe affected. The face and scalp are usually spared in classic LP. Inverse LPaffects the axillae, groin, and inframammary regions. Nail changes includelongitudinal ridging and splitting of the nail plate, onycholysis, pterygiumformation, or complete loss of the nail plate. Mucous membranes are in morethan half of the patients additional sites of involvement. Erosive mucosal LP 338 Miklós Simon Jr. is extremely painful often pursues a chronic course with little tendency tospontaneous resolution. It may predispose to squamous cell carcinoma, butthe risk is fairly low. In generalized LP, the eruption often spreads within 1–3month from onset of the disease. Koebner’s isomorphic response (LP develops at the site of exogenous irritation) is common (Fox & Odom, 1985; Boyd &Neldner, 1991). Clinical VariantsSeveral distinctive variants of LP need to be recognized, since lack of characteristic skin changes in these cases makes the clinical diagnosis difficult. Theprototypic papule of LP can be altered/modified in morphology, configuration or anatomic distribution.Linear LP. Linear group of typical LP papules, usually on the extremities. Thelinear pattern may develop secondary to trauma, in zosteriform or segmentalarrangement or even in the site of healed herpes zoster.Annular LP. Annular lesions develop from a ring of typical LP papules thatprogress peripherally and produce central clearing. Annular lesions are common on the penis and scrotum but may occur on the trunk or extremities.Bullous LP. Rare variant of LP characterized by the development of bullae onpreexisting LP papules. The bullae, which appear mostly on the extremitieswith mild constitutional symptoms, usually resolve in a few month. Bullae arising from normal skin in LP patients are more characteristic of lichen planuspemphigoides, which is a unique condition with circulating IgG autoantibodies reacting to 180- and/or 200-kDa antigen within the basement membrane zone.Erosive/ulcerative LP. This is a very rare variant of LP presenting with chronic,painful bullae and ulcerations of the soles of the feet, and sometimes of themucous membranes, associated with cicatricial alopecia of the scalp and permanent loss of the toenails. The lesions on the feet tend not to heal and havea definite risk of development of a squamous cell carcinoma in the chroniculcerations.Hypertrophic LP. The extensor sides of the shins and interphalangeal jointsare preferentially affected with highly pruritic, lichenified, violaceous, or hyperpigmented plaques (LP verrucous). The lesions are often symmetric, sometimesshow accentuated, elevated follicle swellings and chalky hyperkeratoses. Scarring occurs after healing of the lesions. Malignant degeneration is not uncommon.Atrophic LP. In some cases, atrophy of LP papules may produce sharply demarcated, whitish, atrophic maculae. These lesions can coalesce and form largerplaques most common on the trunk or lower extremities. This LP variant is Lichen Planus, Lichenoid Eruptions and cGVHR 339 Fig. 2. Reticular LP in buccal mucosa rare and needs to be distinguished from lichen sclerosus et atrophicus andguttate morphea.Follicular LP. This form of LP may occur alone or simultaneously with othermucocutaneous changes of LP. It forms isolated or aggregated, pinheadsized, red papules, which carry a conical acuminated hyperkeratosis (LP acuminatus). Sites of predilection include the trunk, neck, sacral region, and theproximal extremities. Follicular LP of the scalp also occurs in an isolated formand leads to scarred alopecia (LP follicularis decalvans). This condition affects women more than men. Perifollicular erythema and acuminate keratotic plugs are characteristic features. The symptom combination of follicularLP on the trunk and on the scalp with nail dystrophy has been described asLassueur-Graham-Little syndrome.Actinic LP. This variant is more common in the tropics, especially in childrenand young adults, on sun-exposed parts of the body such as the face, theback of the hands, the lower forearms, and the chest. The extremely pruriticpapular lesions are hyperpigmented with violaceous-brown color, which frequently show annular configuration. The course is subacute, and the condition tends to heal spontaneously.Mucosal LP. LP can affect the mucosal sites of mouth, glans penis, vulva, vagina, collum uteri, anus, conjunctiva, nose, larynx, trachea, esophagus, stomach, urethra, bladder, and tympanic membrane.Oral LP is present in some 60–70% of dermatological patients with LP. As thesole manifestation of the disease, it makes up 15% to 35% of the patient populace. The buccal mucosa (bilateral) and the tongue are most often affected 340 Miklós Simon Jr. Fig. 3. Disseminated lichenoid GVHR but the gums, floor of the mouth, palate, and lips have also been documented.The mucosal lesions consist of lacy, reticulated white streaks (Fig. 2), whitepapules and plaques, and erythematous, atrophic or ulcerated patches withpainful, burning sensations.Particular clinical forms are characteristic for certain regions of the oralmucosa. Reticular LP is the most common type. It affects the buccal mucosapredominantly. The margins of the tongue show generally lace-like and/orerosive LP, the dorsal surface exhibits usually round, white plaques or smoothatrophic areas. Most cases of carcinoma appear to arise in patients with longstanding erosive LP of the tongue or buccal mucosa. Gingival involvement ofLP may potentially lead to the picture of desquamative gingivitis (Scully &El-Kom, 1985).Lesions of the male genitalia are observed in about 25% of cases. Theglans penis is most commonly affected, exhibiting annular lesions frequently.Similar changes can occur on the scrotal skin as well. Occasionally, the glanspenis has erosive lesions and is the only site of LP involvement (Alinovi et al,1983). The female genitalia demonstrate generally patches of leukoplakia orerythroplakia, with variable atrophy. Desquamative vaginitis is most commonly due to LP. The labia minora agglutinate and vaginal adhesions, in association with burning pain, may prevent sexual intercourse (Edwards &Friedrich jr, 1988; Soper et al, 1988). Lichen Planus, Lichenoid Eruptions and cGVHR 341 Fig. 4. Erosive buccal lesions in a patient with lichenoid GVHR Cutaneous Graft-Versus-Host-Reaction (cGVHR)Mucocutaneous lesions of GVHR occur in 20 to 80% of posttransplant casesafter marrow infusion. There are two forms: in the acute form the cutaneouseruption begins between the fifth and fiftieth day, in the chronic form two tosix months after grafting. Some patients experience both forms of cGVHR,sequentially (Harper, 1987).In acute cGVHR the eruption generally begins with tender erythematousmacules on the upper trunk, neck, hands, and feet. As a cGVHR evolves, thedistribution of erythematous macules increases, becoming confluent overbroad body surfaces. At later stages, erythroderma may ensue. Generalizederythroderma with bullae formation and desquamation portend a poor prognosis. The clinical picture of subepidermal bullae with a necrotic roof in thesepatients greatly resembles toxic epidermal necrolysis. Oral and/or ocular involvement in acute cGVHR may occur but are less common then in chroniccGVHR (Volc-Platzer, 1992; Aractingi & Chosidow, 1998).The incidence of a chronic cGVHR, divided artificial into lichenoid andsclerodermoid forms, is roughly 25%. This two forms of chronic cGVHR clearlyoverlap in many patients.In the lichenoid form, which may also occur soon after transplantation, erythematous to violaceous polygonal papules appear acrally and may be seenon the palms and soles. In addition, lichenoid cGVHR favors the ears, periorbitalregion, trunk, buttocks, hips, and thighs as well. In some cases lichenoidpapules can occur around hair follicles. LP-like cGVHR can also affect thenails, with onychatrophia and pterygium. The disseminated lichenoid eruptionin chronic cGVHR is clinically indistinguishable from LP (Fig. 3). Pruritus and 342 Miklós Simon Jr. postinflammatory hyperpigmentation are also present. Oral involvement istypical, with white lacy patches and/or painful erosions on the tongue andbuccal mucosa (Fig. 4).The sclerodermoid form of a chronic cGVHR greatly resembles sclerodermawith variably distributed, hyper- and/or hypopigmented, somewhat atrophicplaques. Some patients develop only few sclerodermoid plaques, other onesdevelop widespread disease associated with alopecia, chronic cutaneousischemia with ulceration, joint contractures and debilitating fasciitis. Of note,acrosclerosis and Raynaud phenomenon are uncommon in chronic sclerodermatous GVHR, in contrast to systemic sclerosis. The mucosa of the gums,palate, and lips can become atrophic and occasionally ulcerate. Sicca symptoms often accompany the sclerodermoid form due to diminished salivary andlacrimal output (Volc-Platzer, 1992; Aractingi & Chosidow, 1998).Despite the apparent simplicity of the traditional classification of GVHRinto acute and chronic phases, defined as number of days after transplantation, this separation is not that precise. The lichenoid chronic GVHR may beobserved as early as day 30 after transplantation and acute GVHR may appear/persist after day 100 in some cases. Moreover, atypical variants of cGVHR havebeen described that do not fit into this diagnostic classification either. DiagnosisThe diagnosis of LP, LDE, cGVHR rests on the combination of anamnesticdata, clinical, histopathologic, and immunofluorescence/immunohistochemical findings. Special immunophenotypic and T-cell receptor genotypic analyses are sometimes required to define the underlying pathology manifestingas lichenoid dermatitis more precisely.The clinical differential diagnosis of lichenoid dermatoses, depending onthe manifestation of the disease, involves generalized granuloma annulare,psoriasis guttata, papular sarcoid, lichen amyloidosus, scabies, pityriasis rosea,pityriasis rubra pilaris, and papular secondary syphilis. Mucous membranelesions may be confused with leukoplakia, mucous patches of syphilis, candidiasis, oral hairy leukoplakia, lupus erythematosus, chronic ulcerative stomatitis, paraneoplastic pemphigus, and cicatricial pemphigoid. TherapyLichen Planus, Lichenoid EruptionsApart from the very rare instances of possible malignant transformation (ulcerative LP, LP verrucosus, erosive/atrophic mucosal LP), LP is a benign diseasewith spontaneous remissions and exacerbations. Consequently, any treatment Lichen Planus, Lichenoid Eruptions and cGVHR 343 strategy must be safe and unlikely to aggravate the disease. Avoidance of potentially provocative medications (Ellgehausen et al, 1998), unless absolutelyrequired, and minimizing trauma to skin and mucosal tissues are recommended. Patients with actinic LP must be protected by sunscreens. Oral erosive/atrophic LP lesions are painful and are frequently associated with poororal hygiene. For these patients, good oral hygiene (the use of an antibacterial mouthwash e.g. chlorhexidine) and regular professional dental care needto be encouraged.Evaluating the efficacy of different forms of treatment in cutaneous LP isdifficult since LP tends to regress spontaneously after varying amounts of time.A large variety of topical and systemic therapies are available, and this rangeof options may be attributed to the chronicity, symptomatology, and variableresponsiveness of the disease. In mild cases, treatment should be symptomatic: antihistamines for pruritus and topical glucocorticoids for their antipruritic and anti-inflammatory effects. Severe, acute cases may benefit from atapered course of systemic glucocorticoids or retinoids for two to eight weeks.Relapses may occur, however, chronic systemic glucocorticoid use should beavoided. Narrowband UVB, ultraviolet A1, PUVA photochemotherapy (or bathPUVA) solely or combined with systemic retinoids may have beneficial effectin such cases. Systemic cyclosporine administration has many side effects, therefore it should be considered as a drug of last resort. Hypertrophic LP may alsobenefit from intralesional glucocorticoids, or topical glucocorticoids underocclusion, or tar preparations. Ulcerative and hypertrophic LP of the palmsand soles is frequently disabling and uncomfortable. Use of split-thicknessskin grafts to cover these lesions has been proved an effective way to manage such patients (Lendrum, 1974; Simon jr, 1990; Simon jr & Hunyadi, 1990;Simon jr & von den Driesch, 1994; Boyd, 2000; Saricaoglu et al, 2003; Polderman et al, 2004).Non-erosive LP of mucous membranes generally does not need any treatment and may resolve spontaneously. Erosive oral and/or genital LP can beexceptionally difficult to control, but may respond to high potency topical glucocorticoids (in Orabase or intralesional), topical retinoic acid (tretinoin orisotretinoin gel), cyclosporine or tetracycline rinses, and topical tacrolimus(FK-506) (Hodgson et al, 2003). 308-nm UVB excimer laser showed encouraging results in these patients, recently (Kollner et al, 2003). Topical anaesthetics also provide symptomatic benefit for patients who have difficulty witheating and chewing. Newer antifungal agents may be useful in mucosalLP with evidence of Candida colonization.Systemic treatment with oral glucocorticoids and retinoids may be considered for particularly severe erosive mucosal LP lesions, but remissions areshort-lived and the risk of serious side-effects is high. Nevertheless, oral glucocorticoids may be of value in the management of acute episodes, when topicalor intralesional glucocorticoids alone failed to achieve adequate control. Inrecalcitrant cases, steroid sparing agents such as azathioprine, mycophenolate mofetil, methotrexate or cyclosporine are generally added. Anecdotal 344 Miklós Simon Jr. reports have suggested improvement in mucosal erosive LP with a numberof systemic agents including griseofulvin, dapsone, hydroxychloroquine,low-molecular-weight heparin, and thalidomide. The administration of lowdose cyclophosphamide for the treatment of severe oral LP, unresponsive tothe aforementioned therapies, appears to induce remissions that are sustained. Extracorporeal photochemotherapy has recently been examined forthe treatment of erosive LP, mainly involving oral and vulvar tissues. All patients experienced complete remission, and some have showed a durable response. Surgical excision, CO2 laser, Nd: YAG laser, and cryotherapy haveall been used for treatment of recalcitrant mucosal LP. In general, surgery isreserved for removal of dysplastic areas in patients at high risk. Patients under a great deal of stress frequently show improvement when their emotionalenvironment is altered (Boyd, 2000; Setterfield et al, 2000). Cutaneous Graft-Versus-Host-Reaction(cGVHR)The best way of treating (c)GVHR is to prevent it from occurring by irradiatingblood products before transfusion. Patients receiving allogeneic transplantsare placed on methotrexate, cyclosporine, or both before marrow infusion.Recent data indicate that FK-506 is more effective than cyclosporine in theprevention of GVHR when each drug is used in combination with methotrexate(Hiraoka et al, 2001).If acute GVHR has already occurred, initial therapy usually includes systemic glucocorticoids. Anti-thymocyte globulin, azathioprine, mycophenolatemofetil, pentostatin, cyclosporine, FK-506, and monoclonal antibodies, directedagainst effector cell populations (CDw52, CD25) or cytokines (TNF-a), mayalso be used separately or in combination. Narrowband UVB, PUVA or extracorporeal photochemotherapy may be useful in the treatment of patients withacute cGVHR. Keratinocytes treated with UV-A and UV-B are known to produce immunosuppressive cytokines. Depletion and morphologic alterationsof dendritic cells also occur (Queen et al, 1989; Aubin et al, 1995; Hale et al,1996; Richter et al, 1997; Dall’Amico & Zacchello, 1998; GrundmannKollmann et al, 2002).Chronic GVHR is treated similar to acute GVHR. Glucocorticoids, cyclosporine, azathioprine, mycophenolate mofetil, and methotrexate are administered in various combinations, depending on the severity of the disease.Tacrolimus ointment, pimecrolimus cream or PUVA treatment generally control widespread lichenoid GVHR effectively (Volc-Platzer et al, 1990; Choi &Nghiem, 2001). Mucous membrane manifestations may improve with thesetherapies as well. It is unclear whether PUVA (or bath PUVA) is able to reverse the cutaneous changes in sclerodermatous GVHR (Aubin et al, 1995).Ultraviolet A1 phototherapy may be considered as an appropriate approach Lichen Planus, Lichenoid Eruptions and cGVHR 345 for these patients (Calzavara Pinton et al, 2003). Extracorporeal photochemotherapy has also been reported as beneficial (Greinix et al, 2000). SummaryLichenoid dermatoses encompass, based on the microscopic pattern of inflammation and skin response, a significant group of dermatologic conditions whosepathophysiologic mechanisms are unclear. Lichen planus (LP), the prototype,is an inflammatory disorder with characteristic purple, polygonal, pruriticpapules of the skin and may be accompanied by mucosal lesions. There aremany similar clinical variants described, ranging from lichenoid drug eruptions (LDE) to association with other diseases such as the cutaneous graftversus-host-reaction (cGVHR). This chapter delineates some of the recentaspects of the etiopathogenesis, clinical manifestations and treatment modalities of LP, LDE, and cGVHR. ReferencesAlinovi A, Barella PA, Benoldi D (1983) Erosive lichen planus involving the glans penis alone.Int J Dermatol. 22: 37–38Anasetti C (2004) Advances in the prevention of graft-versus-host disease after hematopoieticcell transplantation. Transplantation 77: S79-S83Aractingi S, Chosidow O (1998) Cutaneous graft-versus-host disease. Arch Dermatol 134:602–612Aubin F, Brion A, Deconinck E, Plouvier E, Herve P, Humbert P, Cahn JY (1995) Phototherapyin the treatment of cutaneous graft-versus-host disease. Our preliminary experience in resistant patients. Transplantation 59: 151–155Baart de la Faille-Kuyper EH, Baart de la Faille H (1974) An immunofluorescence study of lichen planus. Br J Dermatol. 90: 365–371Barthelmes H, Haustein UF (1970) Nachweis von Fibrinablagerungen beim Lichen ruberplanus mit Hilfe der Immunfluoreszenzhistologie. Derm Mschr 156: 85–96Bhan AK, Harrist TJ, Murphy GF, Mihm jr MC (1982) T cell subsets and Langerhans cells inlichen planus: In situ characterization using monoclonal antibodies. Br J Dermatol 105:617–622Boyd AS, Neldner KH (1991) Lichen planus. J Am Acad Dermatol 25: 593–619Boyd AS (2000) New and emerging therapies for lichenoid dermatoses. Dermatol Clin 18:21–29Calzavara Pinton P, Porta F, Izzi T, Venturini M, Capezzera R, Zane C, Notarangelo LD (2003)Prospects for ultraviolet A1 phototherapy as a treatment for chronic cutaneous graft-versus-host disease. Haematologica 88: 1169–1175Carrozzo M, Uboldi de Capei M, Dametto E, Fasano ME, Arduino P, Broccoletti R, Vezza D,Rendine S, Curtoni ES, Gandolfo S (2004) Tumor necrosis factor-alpha and interferon-gamma polymorphisms contribute to susceptibility to oral lichen planus. 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Br Med J 295: 401–402Hiraoka A, Ohashi Y, Okamoto S, Moriyama Y, Nagao T, Kodera Y, Kanamaru A, Dohy H,Masaoka T; Japanese FK506 BMT (Bone Marrow Transplantation) Study Group (2001)Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogenic bone marrow transplantation. Bone Marrow Transplant28: 181–185Hodgson TA, Sahni N, Kaliakatsou F, Buchanan JA, Porter SR (2003) Long-term efficacy andsafety of topical tacrolimus in the management of ulcerative/erosive oral lichen planus.Eur J Dermatol 13: 466–470Iijima W, Ohtani H, Nakayama T, Sugawara Y, Sato E, Nagura H, Yoshie O, Sasano T (2003)Infiltrating CD8+ T cells in oral lichen planus predominant express CCR5 and CXCR3 andcarry respective chemokine ligands RANTES/CCL5 and IP-10/CXCL10 in their cytolyticgranules: a potential self-recruiting mechanism. Am J Pathol 163: 261–268Kollner K, Wimmershoff M, Landthaler M, Hohenleutner U (2003) Treatment of oral lichenplanus with the 308-nm UVB excimer laser. Early preliminary results in eight patients. Lasers Surg Med 33: 158–160La Nasa G, Cottoni F, Mulargia M, Carcassi C, Vacca A, Pizzati A, Ledda A, Montes	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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Hautarzt 43: 669–677Volc-Platzer B, Hönigsmann H, Hinterberger W, Wolff K (1990) Photochemotherapy improves chronic cutaneous graft-versus-host disease. J Am Acad Dermatol 23: 220–228Walker DM (1976) Identification of subpopulations of lymphocytes and macrophages in theinfiltrate of lichen planus lesions of skin and oral mucosa. Br J Dermatol 94: 529–534Weyl A (1885) Bemerkungen zum Lichen planus. Dtsch Med Wschr 11: 624–626Wickham LF (1895) Sur un signe pathognomonique du lichen de Wilson (lichen plan). Strieset ponctuations grisâtres. Annls Derm Syph Paris 6: 517–520Wilson E (1869) On leichen planus. J Cut Med 3: 117–132 12 Small Vessel VasculitidesPeter Lamprecht and Wolfgang L. Gross IntroductionVasculitis of small blood vessels of the skin, i.e. arterioles, capillaries and venules, is found in cutaneous leukocytoclastic vasculitis (CLA) as well as in systemic vasculitides. CLA is restricted to the skin, whereas ANCA-associatedand several immune complex-mediated systemic vasculitides are characterized by an involvement of – predominantly – small vessels affecting variousorgans including the skin.Primary systemic vasculitides, where no underlying disease or agent isknown, are to be distinguished from secondary vasculitides, i.e. secondary toother diseases of either autoimmune or other origin. ANCA-associated andimmune complex-mediated vasculitides are the major immunopathogeneticcategories which involve small vessels (Table. 1) (for review: Gross 2003). PathophysiologyANCA-Associated VasculitidesSubstantial evidence from in vitro experiments and animal models supportsthe view, that anti-neutrophil cytoplasmic antibodies (ANCA) have a role inthe immunopathogenesis of Wegener’s granulomatosis (WG) and microscopicpolyangiitis (MPA), giving rise to the “ANCA-cytokine sequence theory”(Figure 1) (Gross et al. 1991). The target autoantigens proteinase 3 (PR3) andmyeloperoxidase (MPO) are expressed on the cell surface of neutrophil granulocytes and monocytes after priming with TNF-a or IL-1 (Falk et al. 1988,Jenne et al. 1990, Falk et al. 1990, Csernok et al. 1990). ANCA directed againstthese enzymes of neutrophil azurophilic granula (PR3-ANCA and MPO-ANCA)induce activation of primed neutrophil granulocytes, which degranulate andrelease reactive oxygen radicals and lytic enzymes subsequently. PR3- and 350 Peter Lamprecht and Wolfgang L. Gross Table 1. Small vessel vasculitides affecting the skinPrimary systemic vasculitis ANCA-associated vasculitis1. Wegener’s granulomatosis (WG)2. Microscopic vasculitis (MPA)3. Churg-Strauss syndromeImmune complex-mediated primary systemicvasculitis1. Cutaneous leukocytoklastic angiitis (CLA)2. Henoch-Schönlein purpura (HSP)3. Essential cryoglobulinemic vasculitis (ECV) Secondary systemic vasculitis Immune complex-mediated secondary systemicvasculitis1. Rheumatoid vasculitis (RV)2. HCV-associated CV3. Secondary vasculitis or CV in SLE, Sjögren’ssyndrome and other connective tissue diseases4. Secondary vasculitis or CV in infectiousdiseases, e.g. bacterial endocarditis5. Paraneoplastic vasculitis Abbreviations: ANCA = anti-neutrophil cytoplasmic antibody; HCV = hepatitis C virus;SLE = systemic lupus erythematosus Fig. 1. ANCA-cytokine sequence theory: Cytokine primed polymorphonuclear leukocytes(PMN) translocate and express intracytoplasmic proteinase 3 (PR3) or myeloperoxidase(MPO) on their cell surface. PR3 or MPO become accessible to anti-neutrophil cytoplasmicantibodies (ANCA). ANCA bind via Fc and Fab proportions to PMN. Activated PMN adhereto endothelial cells via adhesion molecule interaction and release oxygen radicals (ROS) andother substances. As a consequence endothelial damage is found (update and review byCsernok and Gross 2000) Small Vessel Vasculitides 351 MPO-ANCA bind to surface-expressed PR3 or MPO via F(ab’)2 and Fcg receptor (FcgRIIa or FcgIIIb). Binding of ANCA to PR3 or MPO as well as to theFcg receptor is necessary for full activation (Csernok et al. 1990, Porges et al.1994, Kocher et al. 1998). ANCA-activated neutrophil granulocytes up-regulate gene expression of inflammatory mediators and release cytokines such asIL-8 and leukotrienes (Grimminger et al. 1996, Yang et al. 2002). Productionof IL-8 by ANCA stimulated neutrophils and monocytes within the intravascular department and/or endothelial cells may frustrate transendothelialleukocyte migration and favor premature degranulation with subsequentendothelial damage (Cockwell et al. 1999). Moreover, ANCA also favor firmadhesion of rolling neutrophil granulocytes and promote their migration invitro (Radford et al. 20001). Pauci-immune, necrotizing vasculitis is seen as aresult of the complex interaction of ANCA, neutrophil granulocytes and endothelial cells. An in vivo animal model has provided further support of thepivotal role of ANCA and neutrophil granulocytes for the induction of vasculitis(Xiao et al. 2002).The inciting agent(s) triggering the aforementioned pathophysiologicalcascade in ANCA-associated vasculitides are still unknown. Staphylococcusaureus nasal carriage is associated with the activity of WG in the upper respiratory tract. A prophylaxis with trimethoprim/sulfmethooxazole results ina significant reduction in the relapse rate (Stegeman et al. 1996). B-cell superantigens such as staphylococcal protein A might play a role in the expansionof autoreactive PR3 producing B-cells residing within granulomatous lesionsof the respiratory tract (Voswinkel et al. 2002). One hypothesis suggests thata polypeptide translated from the antisense DNA strand of PR3 or to a mimicof this peptide may induce anti-idiotypic PR3-ANCA production (Pendergraftet al. 2004). Granulomatous Lesions in WG and CSSWegener’s granulomatosis (WG) and Churg Strauss syndrome (CSS) arecharacterized by small vessel vasculitis and necrotizing granulomatous lesions in the respiratory tract and other locations, e.g. the orbita and the skin(Lamprecht and Gross 2004). Granulomatous lesions in WG are made up ofCD4+ (-positive) and CD8+ T-cells, monocyte derived tissue macrophages, giant cells, B-cells, and neutrophil granulocytes surrounding a necrotic center.Peripheral blood T-cells and monocytes produce Th1-type cytokines in WG,but they secrete higher amounts of IFNg during the initial disease stage (localized WG) as compared to generalized WG. A subset of circulating T-cellslacking the co-stimulatory molecule CD28 is expanded in WG. The expansion of CD28– T-cells is already evident in early disease, i.e. localized WG restricted to the respiratory tract (Lamprecht et al. 2003). The expansion of CD28–T-cells correlates with organ involvement. Circulating peripheral blood aswell as CD4+CD28– T-cells within granulomatous lesions are a major source 352 Peter Lamprecht and Wolfgang L. Gross of Th1-type cytokine secretion and may favor recruitment of T-cells andmonocytes into granulomatous lesions (Komosci et al. 2002, Lamprecht et al.2003). Th1-type CD28– T-cells subset display features of effector memoryT-cells (Lamprecht et al. 2003, Lamprecht et al. 2004). Moreover, a subset ofautoreactive PR3-specific T-cells producing TNF-a can be detected in WG(Winek et al. 2004). These studies suggest that an aberrant Th1-type dominated immune response might play a role during initiation of WG, whereasadditive Th2-type cytokine production may play a role during late diseasestages (Komocsi et al. 2002, Sneller 2002, Lamprecht et al. 2003, Lamprechtand Gross 2004). Granulomatous lesions in CSS consist of lymphocytes, macrophages and eosinophils. A predominance of the Th2 cytokine profile is seenin Churg Strauss syndrome (Fujioka et al. 1998, Tsukadaira et al. 1999, Kieneet al. 2001). Immune Complex-Mediated VasculitidesDeposition or in situ formation of immune complexes in the vessel wall mayresult in the subsequent evolution of vasculitis. Additional factors such as thesize of the complexes, composition, charge, complement activation, hydrostatic pressure on the wall and efficiency or ineffectivity of reparative mechanisms determine, whether the initial lesion will eventually progress to anecrotizing vasculitis (for review: Gross 2003). Immune complexes formed inantigen excess circulate until the aforementioned factors contribute to theirdeposition in blood vessel walls. Activation of neutrophils, up-regulation ofendothelial adhesion molecules and cytokine release facilitate further leukocyte recruitment. The membrane attack complex of complement plays a significant role in altering the endothelial cell membrane integrity. Activatedneutrophils release proteolytic enzymes, especially collagenases and elastases, along with free oxygen radicals that further damage the vessel wall(Claudy 1998).Cryoglobulinemic vasculitis (CV) is an immune complex-mediated vasculitis predominately affecting small vessels. Cryoglobulins are cold-precipitablemonoclonal or polyclonal immunoglobulins. Cryoglobulins can induce colddependent activation of complement and hypocomplementemia, followedby leukocyte attraction and vessel damage (Wei et al. 1997). The skin is frequently involved. CV is usually found in the presence of type II cryoglobulinemia, i.e. mixed monoclonal IgMk and polyclonal IgG cryoglobulinemia.The monoclonal IgM component often (>75%) has rheumatoid factor activity(for review: Lamprecht et al. 1999). The non-enveloped HCV core protein isa constitutive component of type II cryoglobulins and might contribute tocryoprecipitation in hepatitis C virus (HCV)-associated CV. Binding of HCVcore protein to the globular domain of the C1q receptor on the surface of bothleukocytes and endothelial cells may favor the interaction of HCV core proteincontaining type II cryoglobulin and endothelial cells (Sansonno et al. 2003). Small Vessel Vasculitides 353 Fig. 2. Immune complex vasculitis. A. Clinical presentation with petechial purpura of thelower legs. B. Histopathology with diapedesis of erythrocytes and fragmentation of neutrophilgranulocytes. C. Depositis of immune complexes around dermal blood vessels detected bydirect immunofluorescence microscopy Clinical Classification and AppearanceClassificationANCA-associated, pauci-immune vasculitides (WG, MPA, CSS) and immunecomplex-mediated vasculitides (CLA, HSP, ECV) comprise the group of primary systemic vasculitides affecting predominantly small vessels accordingto the definition of the Chapel Hill Consensus (CHC) conference (Jennette etal. 1994). Whereas the CHC nomenclature gives names and definitions ofprimary systemic vasculitides, the American College of Rheumatology (ACR) 354 Peter Lamprecht and Wolfgang L. Gross classification criteria distinguish selected vasculitides from each other on thebasis of criteria with high level sensitivity and specificity (Hunder et al. 1990).Neither the CHC nomenclature nor the ACR classification criteria can betaken as diagnostic criteria. Some authors consider the ACR classification oflimited value for the diagnosis of vasculitis (Rao et al. 1998). Clinical Appearance: SkinThe typical aspect of CLA and skin involvement in systemic small vessel vasculitides is the palpable purpura (for review: Csernok and Gross 2000). Purpurais a manifestation mainly of postvenule capillary vasculitis. The lower limbsare most frequently affected by the palpable purpura due to the higher hydrostatic pressure in these vessels (Hautmann et al. 1999). Hydrostatic pressure may also account for the accentuation of the purpura during the day seenin some patients. Petechiae may occur secondary to widespread capillarydamage. Urticaria vasculitis results from a progression of the small vessel vasculitis to fibrinoid necrosis of postcapillary venules, i.e. necrotizing vasculitis.Urticaria typically persists for more than 24 hours in these cases (Schur 1993).Small hemorrhages with slightly nodular character at the tips of the fingers (Osler’s nodes) and on the palms, especially on the thenar eminences(Janeway lesions) are seen in secondary immune complex-mediated smallvessel vasculitides in infectious endocarditis. These lesions indicate an important differential diagnosis with regard to the etiology of vasculitis (Schuret al. 1993). Pyoderma gangrenosum or dermatitis ulcerosa may be encountered in several systemic diseases, e.g. inflammatory bowel diseases, and insmall vessel vasculitides (Powell et al. 1985).Nailfold splinter hemorrhages and infarcts are vasculitic manifestationsmainly of arterioles and small arteries. The vasculitis may progress and include small arteries causing cutaneous ulcers and acral necrosis. Pathologicexamination often reveals fibrinoid necrosis and thrombosis with little inflammatory infiltration. Vasospasm of dermal ascending arterioles with hyperperfusion of unaffected vessels gives rise to livedo reticularis. Progression to livedovasculitis may result in purpura, cutaneous nodules and ulceration predominantly of the lower extremities (Schur 1993). Clinical Appearance: Systemic VasculitisConstitutional signs such as malaise, weight loss, fever, arthralgia and myalgia may proceed other symptoms of systemic vasculitis. Multi-organ involvement may be found in every systemic small vessel vasculitis. However,mono- or oligosymptomatic courses may be encountered at times. Vasculitidesdiffer with respect to the preferential involvement of distinct vascular areas(Table. 2): Pulmonary-renal syndrome is more likely in WG and MPA, whereas Small Vessel Vasculitides 355 Table 2. Typical aspects of ANCA-associated vasculitides (WG, MPA, CSS) and immunecomplex-mediated vasculitides (CLA, CV, sec. SVV in SLE, RV)Vasculitis Clinical findings Laboratory findings Histology WG Starts in the upperrespiratory tract,pulm.-renal syndr. Compl. « or ,C-ANCA,PR3-ANCA Granulomatous lesions,pauci-imm. vasc. MPA Pulm-renal syndr. Compl. « or ,P-ANCA,MPO-ANCA Pauci-imm. vasc. CSS Asthma, pulmonaryinfiltration, PNP,cardiac involvement Eosinophilia,compl. « or ,less often: ANCA Pauci-imm. vasc.,eosinophilinfiltration CLA Purpura Compl. « or ¯ Leukocyt. vasculitis ECV, HCV-ass.CV Purpura, arthralgia,weakness, PNP, GN Compl. ¯, RF,Imm. compl. vasc.cryoglobulin,HCV-ab., HCV-RNA Sec. vasculitis inSLE Purpura, PNP, GN,cerebral vasculitis Compl. ¯, ANA, dsImm. compl. vasc.DNA ab., anti-Sm ab. RV Purpura, ulcers, PNP HSP Purpura, arthralgia,GN, abdominal pain Compl. ¯, RFCompl. ¯, IgA − Imm. compl. vasc.Imm. compl. vasc.with IgA ANCA = anti-neutrophil cytoplasmic antibody (Immunofluorescence patterns: C-ANCA =cytoplasmic pattern ANCA, P-ANCA = perinuclear pattern ANCA; ELISA: PR3-ANCA =proteinase 3 ANCA, MPO = myeloperoxidase ANCA), WG = Wegener’s granulomatosis,MPA = microscopic polyangiitis, CSS = Churg Strauss syndrome, CLA = cutaneousleukocytoclastic angiitis, CV = cryoglobulinemic vasculitis (ECV = essential CV, HCV-ass.CV = hepatitis C virus associated CV), sec. = secondary, GN = glomerulonephritis, PNP =polyneuropathy, RA = rheumatoid arthritis, SVV = small vessel vasculitis, SLE = sytemiclupus erythematosus, RV = rheumatoid vasculitis, ab. = antibody, Imm. compl. vasc. =immune complex-mediated vasculitis, Compl. = complement, ANA = antinuclear ab.,ds-DNA ab. =double strand DNA ab, Leukocyt. vasc. = leukocytoclastic vasculitis, Immunecompl.–med. vasc. = immune complex-mediated vascultis other diseases such as systemic lupus erythemtosus (SLE) less often cause thissyndrome. Purpura and renal involvement are common in CV, polyneuropathyand gastrointestinal vasculitis in CV and CSS, and cardiac involvement inCSS. Proceeding nasal obstruction, crusting, epistaxis and/or otitis mediaand mastoiditis is usually found in WG. Episcleritis is often seen in WG andMPA. Asthma bronchiale, eosinophilia and pulmonary infiltrations togetherwith cardiac involvement and/or polyneuropathy are frequently seen in CSS.Severe renal disease is less frequent in CSS compared to WG and MPA.Neuropathy and cardiac disease are frequently encountered in severe CSS. 356 Peter Lamprecht and Wolfgang L. Gross Coronary arteritis and myocarditis are the principle causes of morbidity andmortality in CSS (Jennette and Falk 1997; Savage et al. 1997). CSS may evolveover a period of time starting with allergic rhinitis, asthma bronchiale. Thereafter, a hypereosinophilic syndrome with infiltrative eosinophilic disease,e.g. eosinophilc pneumonia and gastroenteritis will ensue, and finally smallvessel vasculitis with granulomatous lesions is seen in CSS (Lanham et al.1984). The triad of arthralgia, purpura and weakness (so-called Meltzer’s triad)is frequently seen in essential CV (ECV) and in HCV-associated CV. CV frequently involves the kidneys and peripheral nerves (Ferri et al. 1991). Purpura,cutaneous ulcers and polyneuropathy in a patient with long-standing rheumatoid arthritis (RA) is suggestive of rheumatoid vasculitis (RV). Purpura, arthritis, and abdominal pain in a child with a nephritic sediment is found inHenoch-Schönlein purpura (HSP). HSP has a peak incidence at the age offive years. The disease often begins after an upper respiratory tract infection(Jennette and Falk 1997; Savage et al. 1997).Small vessel vasculitides may affect different structures within the sameorgan or body region giving rise to a variety of symptoms: Affection of theear in WG may include sensoneurinal deafness due to vasculitis of the innerear and/or cochlear nerve, otitis media, and mastoiditis. CSS and CV maycause abdominal pain due to gastro-intestinal vasculitis or vasculitis of thegall bladder. Renal involvement in immune complex-mediated vasculitismay result in mesangioproliferative and other forms of glomerulonephritis,whereas focal and segment necrotizing glomerulonephritis is more commonin ANCA-associated vasculitis (Jennette and Falk 1997). Renal vas	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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culitis ofsmall and medium sized renal arteries is seen at least in one third of the patients with cryoglobulinemic glomerulonephritis (D’Amico 1998). Pulmonarysmall vessel vasculitis may result in dyspnoea, cough, hemoptysis due to either bronchial ulcerations or frank hemorrhagic alveolitis. Full-blown pulmonary-renal syndrome will cause renal and respiratory failure. Centralnervous involvement may cause cranial nerve palsies, seizures, stroke andother symptoms. Cardiac involvement may be indicated by arrhythmias dueto coronariitis or myocarditis, pericardial effusion, and angina pectoris (Savage et al. 1997).Secondary vasculitides in SLE and other connective tissue diseases orrheumatoid arthritis are usually proceeded by typical symptoms of their underlying autoimmune disease. Thus, rheumatoid vasculitis is usually encountered after previous long-lasting rheumatoid arthritis. In case of unusual symptomconstellations paraneoplastic vasculitis, secondary vasculitis in infectious diseases such as bacterial endocarditis, and drug-induced vasculitides shouldbe excluded. It has to be kept in mind, that small vessel vasculitides are alsoseen in primary immunodeficiencies, e.g. bare lymphocyte syndrome (TAPdeficiency and others), CVID, hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), and tumor necrosis factor receptor-associated periodicsyndrome (TRAPS) (Sais et al. 1996, Moins-Teisserenc et al. 1999, Lamprechtet al. 2004). Small Vessel Vasculitides 357 DiagnosisClinical ParametersA detailed patient history, physical examination and focused laboratory investigation are vital in diagnosing vasculitic disorders. The goals of the workup include identification of a cause of the disease and/or the underlyingimmunopathogenetic mechanism, classification of the disease, and determination of the disease activity and extent. The latter is all the more importantas stage-adapted therapy and assessment of the treatment’s efficacy are onlypossible if there are uniform and reproducible measures of the extent and activity of organ involvement in the vasculitic disease. A prerequisite for this isa standardized evaluation of the clinical, radiological and laboratory findingsby an interdisciplinary team of expert physicians (internal medicine, neurology, ophthalmology, dermatology, radiology etc.) (Gross et al. 2000).A detailed patient history and physical examination should give rise to apreliminary diagnosis. CLA requires a detailed drug history as drugs causeca. 10% of vasculitic skin lesions. Drugs that have been implicated are penicillins, aminopenicillins, sulfonamides, allopurinol, thiazides, hydantoins andpropylthiouracil (Jennette and Falk 1997). Laboratory TestsLaboratory tests are used to ascertain the type of vasculitis. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) indicate inflammation.Low complement levels are seen in immune complex-mediated vasculitidesincluding CV, whereas normal or elevated complement levels are found inANCA-associated vasculitides (Gross et al. 2000). Furthermore, low complement levels may indicate hereditary complement deficiencies, which maycause SLE-like diseases with secondary vasculitides. C-ANCA are stronglyassociated with “classic” WG. The principle target antigen for C-ANCA inWG is PR3 (Csernok et al. 1990, Jenne et al. 1990). Only few WG patients(<5%) have a P-ANCA with MPO specificity. In PR3-ANCA positive WG ahigher disease extent is seen as compared to MPO-ANCA positive WG (Schönermarck et al. 2000). ANCA-negative WG is rarely encountered (Lamprechtet al. 2000). Combing the detection of C-ANCA resp. P-ANCA in IFT andPR3-ANCA resp. MPO-ANCA in ELISA yields a high sensitivity and specificity for WG and MPA (Hagen et al. 1998). Despite their high sensitivity andspecificity, C-ANCA and PR3-ANCA may be found in other diseases thanWG, e.g. subacute bacterial endocarditis or severe CV (Choi et al. 2000). RFmay be found in various conditions such as RV, CV and endocarditis. Autoantibodies, e.g. ANA, ds-DNA antibodies, anti Sm, anti SSA, anti-SSB etc.,will be seen in secondary vasculitides in SLE, Sjögren’s syndrome and other 358 Peter Lamprecht and Wolfgang L. Gross connective tissue diseases. Low level autoantibodies such as ANA may alsobe found in CV. ANA may be seen in RV and a variety of other diseases. Serum levels of IgA are elevated in half of the patients with HSP. As infectionsmay cause secondary vasculitis, HBV, HCV, HIV, and bacterial infectionsshould be excluded. Serial blood cultures may be necessary (Gross et al. 2000).ALT and AST may not necessarily be elevated in HCV-associated CV (Lamprecht et al. 1999). Procalcitonin may help to differentiate between autoimmune diseases and bacterial infections and sepsis (Moosig et al. 1998). Additional DiagnosticsEchocardiography should rule out vegetations on the leaves. Primary immunodeficiencies also have to be considered. Quantitative assessment of immunoglobulin classes including IgD, lymphocyte subpopulations, standardizedcutaneous tests for various T-cell specific antigens, complement levels, MHCclass I and II expression, tests for the assessment of the functional status ofvarious neutrophils, lymphocytes etc., and moleculargenetic analysis of mutations of the MEFV-gene (Familial Mediterranean fever), MVK-gene (HIDS),or TNFRSF1A-gene (TRAPS) may be necessary in selected patients (Baumertet al. 1992, Moins-Teisserenc et al. 1999, Lamprecht et al. 2004).Arteriogramms are helpful in identifying vasculitis of medium-sized arteries, e.g. renal, coronar or intestinal vessels, or even larger arteries. These vascular areas may sometimes be involved in addition to the small vessel vasculitis.The definite diagnosis of vasculitis is dependent on the demonstration ofvascular involvement by biopsy. Biopsy specimen should be obtained fromclinically involved tissue. Applying immunohistochemistry is helpful in distinguishing immune complex mediated from pauci-immune (ANCA-associated)vasculitides (Gross et al. 2000). TherapyCutaneous Leukocytoclastic Vasculitis(CLA)CLA is usually limited to a single episode that resolves spontaneously withinweeks or a few months. Approximately 10% will have recurrent disease atintervals of months to years. Drugs that could cause the disease should bestopped. Oral corticosteroid therapy is indicated in severe cutaneous disease.Progressive, steroid resistant CLA is rarely encountered and may necessitateadditional immunosuppressive therapy such as azathioprine. Critical reevaluation of the diagnosis should also take place in such cases (Jennette andFalk 1997). Small Vessel Vasculitides 359 ANCA-Associated VasculitisInduction of remission is achieved with combined oral corticosteroids andoral cyclophosphamide in life threatening conditions and severe, progressive vasculitis in WG, MPA and CSS. Oral cyclophosphamide at 2mg/kg/dayis preferentially used in severe conditions (”Fauci’s scheme” or”NIH standard”), whereas cyclophosphamide i.v. (15mg/kg every 3 weeks) may onlybe expected as a successful alternative in less severe disease (ReinholdKeller et al. 1994). Reduction of the corticosteroid dose should be startedcarefully as cyclophosphamide therapy becomes effective after 7–10 days.Tapering of corticosteroids is aimed at reaching the lowest effective dose after having achieved a stable remission for more than three months. Dosesshould at least range below the so-called “Cushing” level at this time in order to prevent adverse effects (Savage et al. 1997).About 5% of patients remain resistant to “Fauci’s scheme”. A transientincrease of the cyclophosphamide dose to 4mg/kg for approximately two weeksand subsequent reduction on the basis of the patients leukocyte count mayovercome the initial therapy resistance in some patients (Schmitt and Gross1998). In cases resistant to conventional therapy high dose intravenous immunoglobulin may be effective (Jayne et al 2000). T-cell directed biologicals,such as anti-thymocyte globulin (ATG) and humanized monoclonal antibodies to CD4 and CD52 have been reported to induce remission in small caseseries, but adverse effects may be substantial (Schmitt et al. 2004). 15-deoxyspergualin proved to be efficient in the treatment of refractory WG in anothersmall case series (Birck et al. 2003). Both the chimeric monoclonal antiTNF-a antibody infliximab and the human soluble p75 TNF-a receptor fusionprotein etanercept have been successfully applied in patients with refractoryWG (Stone et al. 2000; Lamprecht et al. 2002).Corticosteroids and cyclophosphamide predispose patients to serious adverse effects. Cyclophosphamide causes premalignant hemorrhagic cystitis,ovarian and testicular failure and myelodysplastic syndrome (Hoffman et al.1992; Reinhold-Keller et al. 2000). Mesna is beneficial in avoiding hemorrhagiccystitis (Reinhold-Keller et al. 2000). Less toxic treatment is highly desirable.However, only patients with non-life threatening WG or MPA may be treatedsafely with methotrexate (0,3 mg/kg/week i.v.) and corticosteroids for the induction of remission (Langford et al 2000). Azathioprine can be used for themaintenance of remission after induction of remission with cyclophosphamide(Jayne et al. 2003). Methotrexate and leflunomide may be alternatives for themaintenance of remission in WG and MPA (deGroot et al. 1996, Metzler etal. 2004). Nasal S. aureus carriage is associated with activity of WG in the upper respiratory tract. A prophylaxis with trimethoprim/sulfmethooxazole results in a significant reduction in the relapse rate (Stegeman et al. 1996).Mupirocin ointment is also used for the reduction of nasal S. aureus carriage.CSS is often controlled with high-dose corticosteroid treatment. Refractory and relapsing disease may require addition of a cytotxic drug similar to 360 Peter Lamprecht and Wolfgang L. Gross the treatment of WG and MPA (Jennette and Falk 1997). Interferon-a (IFN-a)therapy has been reported to induce remission in CSS and substantial reduction of the prednisolone requirement in patients who had attained incompleteremission with cyclophosphamide or methotrexate. The mechanism of actionof IFN-a in CSS has not been clearly established, but switch in the cytokineprofile as well as down-regulation of IgE receptors on eosinophils and lymphocytes may be relevant (Tatsis et al. 1998; Metzler et al. 2000). Cryoglobulinemic VasculitisEssential CV, i.e. non-infection or other disease related CV, is treated similarto the treatment protocol for WG and MPA. Plasma pheresis has been recommended in life-threatening conditions, progressive glomerulonephritis andpolyneuropathy (Lamprecht et al. 1999). Severe, progressive vasculitis andlife-threatening conditions of HCV-associated CV may also be treated withoral cyclophosphamide and corticosteroids (“Fauci’s scheme”) for the induction of remission. Plasmapheresis may be added (D’Amico 1998). The monoclonal anti-CD20 antibody rituximab targeting B-cells has been shown to beefficacious in severe HCV-associated CV (Zaja et al. 2003). IFN-a and ribavirinare applied in less severe disease in order to attempt HCV elimination(Donada et al. 1998). However, caution is recommended for the treatment ofpolyneuropathy with IFN-a (Ferri et al. 1993). Addition of corticosteroids maybe beneficial in controlling cutaneous vasculitis despite the risk of delayedvirus elimination and easier evolution of escape-mutants from immune surveillance (Dammacco et al 1994). Secondary CV in infectious endocarditisshould be controlled by antibiotic treatment and valve replacement if indicated. Transient addition of corticosteroids may be necessary in order to control vasculitic manifestations, e.g. glomerulonephritis (Choi et al. 2000). Henoch-Schönlein PurpuraHSP has a good prognosis in general. Pulmonary disease, rapidly progressive renal failure and peripheral polyneuropathy are uncommon (Jennette andFalk 1997). Adult onset HSP is rare. Corticosteroids and azathioprine may bebeneficial in patients with progressive renal insufficiency (Bergstein et al. 1998). Miscellaneous Secondary VasculitidesRV shows histopathological similarities to polyarteritis nodosa and requiresequally aggressive therapy. Intermittent intravenous bolus cyclophosphamideplus methylprednisolone for the induction of remission has been demonstratedto improve healing of vasculitic lesions including leg ulcers and neuropathy. Small Vessel Vasculitides 361 Bolus therapy result in a lower incidence of relapse and a lower mortalitycompared with other treatments. Comparatively high doses of cyclophosphamide (15–20mg/kg per bolus) and short treatment intervals (14 and 21 days)are necessary to control the often aggressive course of the disease (Scott andBacon 1984). Although there are no controlled studies for the maintenance ofremission in RV, practical considerations suggest to treat the patient withDMARDS used in RA, preferably methotrexate.Secondary vasculitis in SLE is treated with intermittent intravenous boluscyclophosphamide and corticosteroids according to the Austin’s scheme. Theoriginal Austin’s scheme included monthly intermittent intravenous boluscyclophosphamide (0,5–1,0g/m2 body surface area) plus low-dose oral prednisolone (starting with up to 0,5mg/kg per day) (Austin et al. 1986; Boumpaset al. 1991). Secondary vasculitides in other connective tissue diseases aretreated analogous to the Austin’s scheme in SLE.Secondary vasculitis in bacterial endocarditis is treated similar to secondary CV due to endocarditis (see 12.4.3). Paraneoplastic vasculitis may require treatment similar to the treatment protocol for WG and MPA for thevasculitic manifestations, e.g. cutaneous ulcers, acral necrosis, or polyneuropathy. Therapy of the underlying neoplasm is essential for the control of thevasculitis. Rheumatic symptoms and vasculitis secondary to primary immunodeficiencies may improve upon intravenous immunoglobulin administration in some disease conditions, e.g. CVID (Sais et al. 1996; Gause et al. 2000)and in TAP deficiency (Gadola et al. 2000). SummarySmall vessel vasculitides affecting the skin are seen in primary systemicvasculitides, i.e. the ANCA-associated vasculitides (WG, MPA, CSS) and theimmune complex-mediated vasculitides (ECV, HSP, CLA). Secondary immunecomplex-mediated vasculitides, e.g. in SLE and other connective tissue diseases, paraneoplastic conditions, and in infectious diseases, also frequentlyinvolve small vessels of the skin. Diagnosis is made upon a detailed patienthistory, physical examination, focused laboratory investigation, and demonstration of vasculitis by biopsy. Stage-adopted therapy aims at inducing andmaintaining remission of the respective vasculitis. 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In: Kelley WN, Harris ED Jr, Ruddy S, Sledge CB(eds) Textbook of Rheumatology, Volume 2. WB Saunders Company, Philadelphia London Toronto Montreal Sydney Tokyo, pp 1017–1042Scott DG, Bacon PA (1984) Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med 76: 377–384Sneller MC (2002) Granuloma formation, implications for the pathogensis of vasculitis.Cleveland Clin J Med 69(Suppl. 2): SII-40-SII43Stegeman CA, Cohen Tervaert JW, de Jong PE, Kallenberg CGM (1996) Trimethoprimsulfmethoxazole (Co-trimoxazole) for the prevention of relapses in Wegener’s granulomatosis. N Engl J Med 335: 16–20Stone JH for the WGET investigators (2000) Etanercept in Wegner’s granulomatosis (WG):Design of a randomized, multi-center trial. Clin Exp Immunol 120 (Suppl 1): 72Tatsis E, Schnabel A, Gross WL (1998) Interferon-alpha treatment of four patients with theChurg-Strauss syndrome. Ann Intern Med 129: 370–374Tsukadaira A, Okubo Y, Kitano K, Horie S, Momose T, Takashi S, Suzuki J, Isobe M,Sekiguchi M (1999) Eosinophil active cytokines and surface analysis of eosinophils inChurg-Strauss syndrome. Allergy Asthma Proc 20: 39–44Voswinkel J, Müller A, Lamprecht P, Gause A, Gross WL (2002) Does ANCA formation resultfrom an antigen-triggered immune response in Wegener’s endonasal inflamed tissue?(Abstract) Cleveland Clin. J. Med. 69-Supl.2: SII-159.Wei G, Yano S, Kuroiwa T, Hiromura K, Maezawa A (1997) Hepatitis C virus (HCV)-inducedIgG-IgM rheumatoid factor (RF) complex may be the main causal factor for cold-dependent activation of complement in patients with rheumatic disease. Clin Exp Immunol107:83–88.Winek J, Müller A, Csernok E, Gross WL, Lamprecht P (2004) Frequency of proteinase 3(PR3)-specific autoreactive T-cells determined by cytokine flow cytometry in Wegener’sgranulomatosis. J Autoimmun 22: 79–85Xiao H, Heeringa P, Hu P, Liu Z, Zhao M, Aratani Y, Maeda N, Falk RJ, Jennette JC (2002)Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 110: 955–963Yang JJ, Preston GA, Alcorta DA, Waga I, Munger WE, Hogan SL, Sekura SB, Phillips BD,Thomas RP, Jennette JC, Falk RJ (2002) Expression profile of leukocyte genes activatedby anti-neutrophil cytoplasmic autoantibodies (ANCA). Kidney Int 62: 1638–1649.Zaja F, De Vita S, Mazzaro C, Sacco S, Damiani D, De Marchi G, Michelutti A, Baccarani MFanin R, Ferraccioli G (2003). Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 101: 3827–3834 13 VitiligoKarin U. Schallreuter IntroductionVitiligo (from vitula (latin) = calf, vitium (latin) = mistake) is an acquired idiopathic epidermal pigment loss which can occur anywhere on the body. Thecause of this ancient disease is still unknown.The incidence of vitiligo worldwide has not been accurately determined,but studies in Europe indicate that 0.5% of the population may be affected,meanwhile in India reports of 4–8% have been suggested (Ortonne and Bose1993). Even if the lower value is correct, vitiligo must be regarded as one skindisease confronting Dermatologists worldwide (Ortonne and Bose 1993). Thisdisabling depigmentation disorder was recognised thousands of years ago.Several hypotheses have been put forward for the depigmentation processbut none of them can conclusively explain the plethora of clinical and basicscientific data (Ortonne and Bose 1993, LePoole et al. 1993a). The clinical signature of the disease is the loss of constitutive pigment from the skin, and mostpublications account for this by either showing a decreased number of functioning melanocytes or the complete absence of these cells in the depigmented epidermis (Ortonne and Bose 1993, LePoole et al. 1993a, LePoole et al.1993b, Xie et al. 1999). A recent study by Tobin et al proved that melanocytesare still present, even in long standing vitiligo (Tobin et al. 2000). There hasbeen much debate over, how melanocytes lose their functionality and viability, and certainly the most popular hypothesis is still selective autoimmunityto melanocytes. Clinical Picture and ClassificationThe typical lesion of vitiligo has a chalk white colour without any other epidermal changes and varies in size and location. 368 Karin U. Schallreuter Vitiligo can be diagnosed by demonstrating a distinct fluorescence in thedepigmented epidermis when it is exposed to Wood’s light (UVA 351 nm),whereas leucodermas of other origin do not fluoresce (Schallreuter et al. 1994a).A comparison of vitiligo and a laser induced leucoderma is shown in Figure 1.The disease has several characteristic patterns but can involve the entireskin surface.–– ––– Focal vitiligo is characterised by the appearance of one or more isolatedmacules anywhere on the body.Segmental vitiligo is characterised by unilateral appearance in dermatomal or almost dermatomal distribution. Rarely this form can be mixedwith generalised vitiligo (Figure 2).Generalised vitiligo (vitiligo vulgaris) is characterised by symmetricaldistribution of white areas anywhere on the integument.Acrofacial vitiligo involves distal digits and acrofacial as well as genitoanal areas.Universal vitiligo describes depigmentation in > 80% of the entire integument. The disease can involve mucosal surfaces as well as palms and soles. Activevitiligo is often associated with pruritus in the freshly depigmenting skin(Schallreuter, unpublished results). Koebnerisation has been observed in morethan 40% of patients (Ortonne and Bose 1993). Fig. 1. Differential diagnosis of clinical leucoderma upon WOOD’s light (351 nm)examination A. Vitiligo vulgaris: i. Clinical picture; ii. N.B. Presence of bluish fluorescence ischaracteristic for vitiligo. B. Laser induced leucoderma: i. Clinical picture; ii. N.B. Absence of anyfluorescence under WOOD’s light Vitiligo 369 Fig. 2. Segmental vitiligo mixed with generalised vitiligo (vulgaris). A. Before treatment. B.After treatment with low dose narrowband UVB activated pseudocatalase (PC-KUS). NB:The repigmentation of segmental vitiligo is considerably slower! Pathomechanisms – a Critical AnalysisI. Autoimmunity in VitiligoOver the past, a variety of techniques have been used in the detection of antibodies to melanocytes in patients with vitiligo. These include indirect immunofluorescence, immunoprecipitation, immunoblotting and complementdependent cytolysis of melanocytes (Naughton et al. 1983a, Naughton et al.1983b, Naughton et al. 1986a, Naughton et al. 1986b, Galbraith et al. 1988,Norris et al. 1988, Harning et al. 1991, Cui et al. 1992, Cui et al. 1993). Theseantibodies are believed to be important in the progress of the disease, becausethey have been found to be cytotoxic to melanocytes under in vitro conditions (Norris et al. 1988, Cui et al. 1993). The presence of anti-melanocyte antibodies has been correlated with the activity of skin depigmentation (Naughtonet al. 1986a, Harning et al. 1991). Recent work has focused on attempts toidentify specific antibodies against melanocytes in vitiligo (Cui et al. 1992).Since several of the antigens are not specific and can cross-react, most attention has been given to antibodies reacting with proteins specific for melanocytes. In this context, research has focused on the detection of antibodies againsttyrosinase and tyrosinase related proteins 1 and 2 (TRP-1 and TRP-2) (Songet al. 1994, Baharav et al. 1996, Kemp et al. 1997a, Kemp et al. 1997b, Kempet al. 1998 and Okamato et al. 1998). Since tyrosinase is a glycoprotein whichis extremely stable to proteolytic digestion, it appeared to be a good candidate for the elicitation of an immune response (Wood and Schallreuter 1991,Laskin and Piccinini 1996). In addition, tyrosinase, TRP-1 and TRP-2 areregarded as melanosome specific as well as being key proteins in the controlof pigmentation. TRP-1 is a melanosomal membrane associated protein whichhas 43% sequence homology to tyrosinase and it controls both the activity andstability of this key enzyme in melanogenesis (Halaban and Moellmann 1990,Orlow et al. 1993). Halaban and Moellmann were the first to demonstrate 370 Karin U. Schallreuter that TRP-1 has catalase/peroxidase activities and these authors suggested thatit functions by protecting tyrosinase from oxidative degradation (Halabanand Moellmann 1990). In this context, it has been established that H2O2 is apotent competitive inhibitor of human tyrosinase and that superoxide anionradical is a preferred substrate for this enzyme compared to molecular oxygen (Wood and Schallreuter 1991). Thus, melanogenesis has been consideredas anti-oxidant defence mechanism protecting the melanocyte against oxidative stress (Wood et al. 1999). Jimbow et al reported that melanocytes established from the perilesional skin of patients with vitiligo expressed a TRP-1containing 11 additional amino acids at the C-terminal end of its sequenceand this sequence was identical to murine TRP-1 (Jimbow et al. 2001). Theinitial transcript for human and murine TRP-1 shows 93% sequence homology(Boissy et al. 1998). However, post-translational processing via an unidentified protease occurs in the human system producing a protein lacking 11 residues from the C-terminal. It has been proposed that this protease appears tobe either lost, inhibited or inactivated in vitiligo (Jimbow et al. 2001). Interestingly, in vitiliginous melanocytes the murine form of TRP-1 is expressedand this protein loses its function for protecting melanosome integrity due todefective interactions with both tyrosinase as well as the melanosome chaperonecalnexin (Manga et al. 2000, Jimbow et al. 2001). Animal models lacking active TRP-1 develop an adaptive autoimmune response to melanocytes, thusproviding an example to support a potential role for H2O2 in fostering an immune response (Austin and Boissy 1995, Rutault et al. 1999).To date the results obtained on tyrosinase antibodies in vitiligo are controversial. Xie et al could not confirm the presence of antibodies to tyrosinasein 54 patients’ sera (Xie et al. 1999). These authors reported a non-specificprotein comigrating with tyrosinase at 62 kD (Xie et al. 1999). Therefore, itwas concluded that this protein most likely gave false positive results as reported by Song et al (Song et al. 1994, Xie et al. 1999). Very recently Kemp etal have re-examined the antibodies and this group delineated epitope regionson tyrosinase reacting with these antibodies (Kemp et al. 1999). Accordingly,three epitope regions were found in the centre of the tyrosinase molecule(i.e. amino acids 240–255, 289–294 and 295–300) and two others towards theC-terminal end (i.e. amino acids 435–447 and 461–479). The centrally locatedepitopes had sequence homology with regions of TRP-1 and TRP-2, whichconsequently could explain the cross reactivity observed for these closely related proteins (Kwon 1993, Yokoyama et al. 1994). Two of the five patientsexamined cross-reacted with both TRP-1 and TRP-2 and one patient reactedonly with the 289–294 and 295–300 regions of tyrosinase (Kemp et al. 1999).Two patients reacted only with tyrosinase 435–447 and 461–479 and did notrecognise TRP-1 or TRP-2 (Kemp et al. 1999). Based on these results, it canbe concluded that multiple autoantibodies to tyrosinase occur in vitiligo. However, the frequency of tyrosinase antibody expression in this disease remainsextremely low (i.e. = 5%). Whether these anti-tyrosinase antibodies can account for the progress of vitiligo in these few patients remains currently Vitiligo 371 unanswered. Similar low frequencies for TRP-1 and TRP-2 were found in vitiligopatients (i.e. 3 out of 53) (Kemp et al. 1997, Kemp et al. 1998). Based on thislow expression, it is very likely that tyrosinase, TRP-1 and TRP-2 antibodiesdo not play a major role in vitiligo and that other melanocyte autoantigensmust be more significant targets. It should be recognised that during the period from 1994 to 1999 autoantibodies to tyrosinase in vitiligo have lost theirscientific significance from 61% down to 0–5% (Song et al. 1994, Kemp et al.1999, Xie et al. 1999). In conclusion, it seems unconvincing that autoantibodiesto tyrosinase, TRP-1 and TRP-2 account for the loss of functioning melanocytes in this disease. Moreover, recently three membrane associated antigenshave been detected at the cell surface of melanocytes with molecular weightsof 90, 75 and 40 kD, in addition to the non-specific 62 kD protein that comigrates with tyrosinase (Xie et al. 1999). However, the structure/function ofthese proteins and their specificity to the melanocyte requires more rigorousexamination before they can be unambiguously proved to be part of the postulated autoimmune response in vitiligo. A critical analysis of all data published and a reevaluation of 320 patients with vitiligo failed to support theinvolvement of classical autoimmunity in vitiligo. However, there are indeedincreased thyroid peroxidase (TPO) antibody levels compared to controls. Avery recent study failed to link these results to the clinical outcome of vitiligoand to autoimmune thyroiditis (M Hashimoto) (J Diehle, Medical Thesis, U ofHamburg, 2004).Hence, the question remains “Are there specific autoantigens in the depigmentation disorder vitiligo?” II. The Neural HypothesisIt is believed that neurochemical mediators released from nerve endings cancause destruction of MC’s. Its has been proposed that some intermediates orend products of catecholamines destroy the pigment (reviewed in Nordlundet al. 1988). Neural factors were thought to be involved in 30% of patientswith vitiligo. III. The Self Destruction HypothesisBased on both laboratory and clinical experiments melanin precursor toxicity was implicated for the loss of pigment cells. The melanocyte synthses melanin by the oxidation of L-tyrosine via L-dopa to L-dopaquinone.Subsequently, L-dopaquinone oxidises through several steps into a variety of indoles and free radicals. These phenolic compounds can damage MC’sin vitro and in vivo (Boissy and Manga 2004). 372 Karin U. Schallreuter IV. Virus and VitiligoRecently Grimes et al have proposed a viral aetiology for this disease (Grimeset al. 1996, Grimes et al. 1999). Using PCR techniques, cytomegalovirus (CMV)and Epstein Barr virus (EBV) have been detected in the epidermis of patientswith this disorder. Based on these findings, the authors suggested a viral induced patho-mechanism. Since this study was undertaken in California thedirect association of CMV with vitiligo is difficult to assess, since 85% of thepopulation in California test positive for CMV but the incidence of vitiligo isonly approximately 0.5%. A recent study re-examined the hypothesis of viralinduced disease on 72 patients with vitiligo compared to healthy controls (n= 70). The outcome showed no direct evidence for CMV, Herpes virus I/IIand varicella virus using PCR techniques in skin biopsies as well as in the serum from these patients (Würfel et al. 2000). However, even these findingscannot exclude a viral involved ‘hit/run’ mechanism, despite there is no direct evidence for virus detection in loco or in serum. In fact, it has beenshown in animal models that virus infection can trigger an autoimmune response due to molecular mimicry of viral peptide sequences activating subsets of T-cells. This hypothesis could support viral induced T-cells as a targetagainst melanocytes. In these models the virus causing autoimmunity escapes detection after the onset of the disease (Herrath and Oldstone 1996,Morse et al. 1999). In this context, it is noteworthy that viruses can attract aninfiltrate of leukocytes and macrophages leading to the ‘oxygen burst’ concomitant with the production of reactive oxygen species (ROS), such as superoxide anion radical (O2-) and hydrogen peroxide (H2O2). V. Oxidative Stress in VitiligoNowadays there is accumulating evidence that vitiligo is a disease affectingthe entire epidermis, although most of the studies have concentrated on themelanocyte (Schallreuter et al. 1999a, Schallreuter 1999b). In addition to theloss of functioning melanocytes, the keratinocytes and Langerhans cells aredisturbed in this disease (Nordlund and Ortonne 1992, Tobin et al. 2000). Ithas been demonstrated by various investigators that the entire epidermis ofpatients shows signs for oxidative stress yielding various degrees of vacuolation in all epidermal cells including dilation of the rough endoplasmic reticulum in melanocytes (Moellmann et al. 1982, Bhawan and Bhutani 1983, Boissyet al 1991, Nordlund and Ortonne 1992, Schallreuter et al, 1999a, Schallreuter 1999b, Tobin et al 2000). This oxidative stress can continue even in melanocytes and keratinocytes cultured under in vitro conditions unless thesecultures are protected by anti-oxidant enzymes for instance catalase (Medranoand Nordlund 1990, Schallreuter et al. 1999a). The proof of oxidative stress invitiligo has been accomplished ‘in vivo’ by measuring hydrogen peroxide (H2O2)directly in the depigmented epidermis by non-invasive Fourier Transform Vitiligo 373 (FT) Raman spectroscopy, where H2O2 yields a distinctive peak due to the O– O stretch at 875 cm–1 (Schallreuter et al. 1999a). This epidermal H2O2 can beremoved by a synthetic catalyst that oxidises H2O2 to O2 and H2O, thus mimicking the reaction catalysed by natural catalase. The active catalyst is a nar23- 2row band UVB-activated bis MnIII (EDTA) (HCO ) complex and has beennamed ‘pseudocatalase’ (Schallreuter et al. 1995a). Pseudocatalase can arrest the progress of the disease in 95% of all patients and initiates repigmentation in approximately 60% of those treated topically with this modality(Schallreuter et al. 1995a, Schallreuter 1999a). The biochemical basis for theaccumulation of H2O2 in patients with vitiligo has been the target of much research. Initially it was shown that these patients have low levels of catalasein their entire epidermis (Schallreuter et al. 1991). However, although catalaselevels are decreased, the expression of catalase mRNA remains unaltered inthese patients (Schallreuter et al. 2004). These early data were confirmed,showing that melanocytes established from the non-lesional skin of thesepatients contained lower than normal catalase activities (Maresca et al. 1997).These in	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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vitro results were in agreement with increased epidermal H2O2 levels (mM range) in vivo. Under these conditions this reactive oxygen speciescan inactivate catalase by degradation of the porphyrin active site after concentrations exceeding Vmax levels (Aronoff 1965). In the presence of low catalaselevels, glutathione peroxidase functions as a back up enzyme for the efficient removal of H2O2. In this context, it has been shown that these enzymeactivities are also compromised in this patient group (Beazley et al. 1999).Several investigators have reported the presence of a cellular infiltrate inthe perilesional skin of patients with vitiligo (Ortonne and Bose 1993). Thepresence of this infiltrate indicates the likelihood of the biological ‘oxygenburst’ leading to the generation of superoxide anion radical (O2-) from O2 viaNADPH-oxidase (Darr and Fridovich 1994, Marks et al. 1996, Stark 1998). In anormal inflammatory reaction O2- concentrations increase up to 20 fold. Afterdisproportionation this concentration would produce a 10 fold increase inH2O2 (Darr and Fridovich 1994). The perilesional border in vitiligo frequentlycontains an infiltrate but the numbers of infiltrating neutrophils and macrophages as well as T-cells are usually very low or even absent in long lastingdisease. Therefore, it is very difficult to assess the H2O2 contribution derivingfrom this perilesional infiltrate. Indeed, cells in the perilesional epidermis invitiligo show the same degree of vacuolation (i.e. lipid peroxidation) as cellsin both lesional and non-lesional skin (Schallreuter et al. 1999a, Tobin et al.2000). However, recently it has been shown that H2O2 can activate peripheral blood dendritic cells by upregulating surface markers known to be involved in T-cell interactions (Rutault et al. 1999). This H2O2 driven processpromotes interaction with MHC class II molecules (DQ and DR) as well ascostimulatory molecules CD 40 and CD 86 (Rutault et al. 1999). After exposing dendritic cells in culture to H2O2 these cells promote T-cell proliferationcompared to untreated controls lacking H2O2 exposure (Rutault et al. 1999).The effect of H 2O 2 can be blocked in vitro upon the addition of the anti- 374 Karin U. Schallreuter oxidant N-acetyl cysteine (Rutault et al. 1999). In the same context, it has beenshown that solar simulated irradiation upregulates epidermal Langerhanscell B7.1 and B7.2 costimulatory molecules (Laihia and Jansen 1997). It hasbeen shown in vivo and in vitro that H2O2 is generated by UVB (311 nm) andUVA using FT-Raman spectroscopy (Schallreuter et al. 1999a). Therefore itcan be concluded that H2O2 could modulate the response of epidermal Langerhans cells and other dendritic cells in vitiligo (Laihia and Jansen 1997, Schallreuter et al. 1999a, Tobin et al. 2000). These data could directly link oxidativestress from H2O2 to the onset of an adaptive immune response (Laihia andJansen 1997). Moreover, these results may also be a rationale that the immune response in vitiligo is most likely a secondary event linked to oxidativestress with an overproduction of H2O2 in the skin.To date a plethora of studies have recognised several sources and consequences of H2O2 in vitiligo:1. Defective de novo synthesis/recycling and regulation of the essentialcofactor (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (Schallreuter et al.1994a, Schallreuter et al. 1994b).– Induction of GTP-CH1 (rate limiting step for de novo 6BH4 synthesis(Shimizu et al. 2003).– Deactivation of pterin-4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR). (Both enzymes are involved in 6BH4recycling). (Schallreuter et al. 2001, Hasse et al. 2004).2. Increased epidermal monoamine oxidase A activities (Schallreuter et al.1996a).3. Increased NADPH-oxidase activities from the activation of neutrophilsand macrophages that can sometimes be observed in the perilesionalinfiltrate in vitiligo (Darr and Fridovich 1994).4. Increased TNFa production (Moretti et al. 2002).5. Photo-oxidation of epidermal 6-biopterin and sepiapterin (Rokos et al.2002).6. Increased inducible nitric oxide synthase (Schallreuter et al. 1999b).7. Deactivation of acetylcholinesterase (Schallreuter et al. 2004).8. Oxidation of epidermal albumin (Rokos et al. 2004). VI. Pteridines in VitiligoIn 1994 it was finally discovered that the fluorescent compounds present invitiliginous epidermis were oxidised pterins (Schallreuter et al. 1994a, Schallreuter et al. 1994b) (Figure 1). This accumulation of oxidised pterins arosefrom the recognition that these patients have a defective de novo synthesis/recycling/regulation of the essential cofactor (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4) (Schallreuter et al. 1994a, Schallreuter et al. 1994b) (Figure 3). Defective recycling of 6BH4 causes accumulation of its abiogenic isomer Vitiligo 375 Fig. 3. Defective 6BH4 synthesis leading to 7BH4 production in vitiligo. Both epidermalmelanocytes and keratinocytes have the full capacity for de novo synthesis/recycling of 6BH4(Schallreuter et al. 1994a, Schallreuter et al. 1994b). The rate limiting step for the de novosynthesis of 6BH4 is GTP-cyclohydrolase I (GTP-CH-I) which is regulated by H2O2 (Shimizu etal. 2003). This enzyme is also controlled by L-phenylalanine (positive feedback) via theGTP-CH-I feedback regulatory protein (GFRP), as well as several cytokines (TNFa, IL-2,IFNg, MGF). 6BH4 down regulates GTP-CH-I via GFRP. Furthermore, 6BH4 is the essentialcofactor (a) for phenylalanine hydroxylase to metabolise L-phenylalanine to L-tyrosine inmelanocytes and keratinocytes, and (b) for tyrosine hydroxylase to convert L-tyrosine toL-dopa in catecholamine biosynthesis in epidermal keratinocytes and melanocytes. It isalso a regulator of tyrosinase activity in melanocytes, inhibiting the enzyme by an allostericmechanism. The recycling of 6BH4 is catalysed by the rate-limiting pterin-4a-carbinolaminedehydratase (PCD) via quinonoid dihydropterin (qBH2) and its reduction by dihydropteridinereductase (DHPR) in the presence of NADH. If 6BH4 is overproduced, as in vitiligo, then4a-hydroxy-BH4 is non-enzymatically converted to high levels of 7BH4, which in turn inhibitphenylalanine hydroxylase, yielding a compromised L-tyrosine supply 7BH4 and it was shown that molar concentrations of 7BH4 inhibit phenylalanine hydroxylase (PAH) thus preventing the turnover of L-phenylalanineto L-tyrosine resulting in a build up of L-phenylalanine in the epidermis (Davis et al. 1992). This build up has been indeed demonstrated in vivo by FTRaman Spectroscopy (Schallreuter et al. 1998). Only recently it has been discovered that H2O2 deactivates the rate limiting recycling enzyme pterin-4acarbinolamine dehydratase (PCD) because H2O2 alters directly the structureof this bifunctional protein (Schallreuter et al. 2001). The deactivation ofPCD by H2O2 as observed in vivo and in vitro could contribute to the immuneresponse considering that lymphocytes and dendritic cells do express PCDand produce H2O2 themselves via NADPH oxidase (Darr and Fridovich 1994, 376 Karin U. Schallreuter Marks et al. 1996 and Stark 1998). Consequently, the build up of H2O2 wouldbe autocatalytic. Furthermore, it should be noted that H2O2 rapidly oxidises6BH4 to 6-biopterin and this oxidation product has been shown to be cytotoxic to melanocytes with an LC50 = 10–7 M (Schallreuter et al. 1994c). Furtherinvestigation demonstrated the presence of pterin 6-carboxylic acid as the final oxidation product of 6-biopterin and other pterins. This photo-oxidationcoincides with the generation of H2O2 (Rokos et al. 2002). Hence, defectivepterin synthesis coupled to oxidative stress can directly influence melanocyte populations and integrity in vitiligo primarily due to the cytotoxicity of6-biopterin and other oxidised pterins. Only very recently it was demonstratedthat epidermal H2O2 travels to the vascular system and there it can influencethe cholinergic pathway via acetylcholine esterase (Schallreuter et al. 2004).It also has been shown that dihydropteridine reductase, the last step in 6BH4recycling, can be deactivated in peripheral blood cells by H2O2 in the mmolarrange (Hasse et al. 2004). VII. Catecholamines in VitiligoThe presence of increased levels of 6BH4 and low levels of L-tyrosine invitiligo provides ideal conditions for increased activity of tyrosine hydroxylase (TH), the key enzyme for catecholamine biosynthesis (Schallreuter et al.1995b). Both keratinocytes and melanocytes express TH isoform I, the mostactive of the four different isoforms of this enzyme (Schallreuter et al. 1995b,Marles et al. 2003). In this context it has been reported that patients with active vitiligo have elevated levels of noradrenaline in skin and plasma, as wellas high levels of catecholamine metabolites in their urine (Schallreuter et al.1994b, Morrone et al. 1992). Increased noradrenaline synthesis in the epidermis of these patients causes the induction of the catecholamine degradingenzymes monoamine oxidase A (MAO-A) and catecholamine-O-methyltransferase (COMT) (LePoole et al. 1994, Schallreuter et al. 1996a). MAO-Aproduces H2O2 as a reaction product from the oxidation of noradrenaline, andtherefore the increased expression of epidermal MAO-A yields severe oxidative stress (Schallreuter et al. 1996a). VIII. Calcium Homeostasis and Oxidative Stress in VitiligoThe influence of oxidative stress on calcium uptake/efflux has been knownfor a long time (Marks et al 1996). Earlier studies on the transport of isotopically labelled calcium with keratinocytes and melanocytes established fromthe depigmented epidermis of patients with vitiligo revealed a significantdecrease in the rates for calcium uptake in these cells (Schallreuter et al. 1988,Schallreuter et al. 1996b). Several investigators have shown that the extracellular concentration of calcium, which controls the kinetics for its uptake Vitiligo 377 and efflux, strongly influences melanogenesis in melanosomes. Recently ithas been confirmed that L-phenylalanine transport and its intracellular turnover to L-tyrosine is a calcium dependent process in normal human melanocytes (Schallreuter et al. 1999c). This essential amino acid is actively transportedin these cells via the well established L-phenylalanine/sodium/calcium ATP-aseantiporter system described previously for the active transport of neutral aminoacids (Schallreuter et al. 1999c). Since the majority of eumelanin is synthesised in melanocytes from the autocrine conversion of L-phenylalanine toL-tyrosine via PAH, then the perturbation of calcium homeostasis in thesecells from these patients could also play a crucial role in the loss of pigmentin vitiliginous melanocytes (Schallreuter et al. 1996b, Schallreuter et al. 1999c).In this context it is noteworthy that epidermal calcium homeostasis also relies on both the adrenergic and cholinergic signal transduction. Only recentlyit was shown that acetylcholinesterase, the degrading step for acetylcholineis also deactivated by H2O2 (Schallreuter et al. 2004). IX. Genetic and/or Environmental Factors in VitiligoThe application of FT-Raman spectroscopy for in vivo analysis of the depigmented epidermis indicates that all untreated patients contain higher thannormal levels of H2O2 by following the peak at 875 cm-1 (Schallreuter et al. 1999a).In addition, all patients have more total phenylalanine in their depigmentedskin at 1004 cm–1, measured also in vivo by the same method, compared totheir pigmented skin (Schallreuter et al. 1998). This defect in phenylalaninemetabolism has been recognised also in the systemic turnover of L-phenylalanine in this patient group (n>1000) after receiving an oral loading with thisessential amino acid (Schallreuter et al. 1998). Interestingly all patientsshowed a normal rate for the phenylalanine turnover compared to controls,but 40% of the patients tested, revealed pathological L-phe/L-tyr ratios similar to phenylketonurea heterozygotes (Schallreuter et al. 1998). In this context, it is interesting that approximately 35–40% of the patients have a positivefamily history for vitiligo, strongly suggesting a genetic predisposition forthis disease (Ortonne and Bose 1993). However, to date there is no evidencefor any mutation on the PAH gene in vitiligo. The defective recycling of 6BH4via pterin 4a-carbinolamine dehydratase (PCD) suggested the possibility ofa polymorphism in this gene (Schallreuter et al. 1994a, Schallreuter et al. 1994b),but recent studies have shown that PCD is directly deactivated by H2O2(Schallreuter et al. 2001). Examination of the sequence of the PCD gene revealed only wild type enzyme (Schallreuter et al. 2001). Another report onvitiligo suggested that this disease is caused by a mutation in GTP-cyclohydrolase I (GTP-CH-I), the rate limiting enzyme for 6BH4 synthesis (De la FuenteFernandez 1997), but this result could not be substantiated (Blau et al. 1996,Schallreuter and Blau 1997). An attempt to search for a possible mutation inthe regulatory protein GFRP revealed wild type sequence for the 6BH4 binding 378 Karin U. Schallreuter domain (KUS, unpublished results). Whether the polymorphism in the catalasegene of affected individuals can account for vitiligo needs to be substantiated (Casp et al. 2002). Only recently the involvement of chromosome 17 hasbeen invoked where special autoimmunity alleles are implicated (Spritz et al.2004). However, so far this finding was only shown in one family.Therefore a genetic analysis may be more feasible for those patients whohave both autoimmune disorders and vitiligo indicating a true subset of thedisease. In our hands the majority of the patients (> 4000) only have vitiligo. No Increased Risk for Skin Cancer in VitiligoIt is generally accepted that the cutaneous pigment protects against the development of skin cancers despite the sun protection factor (SPF) for this melanin is only ranging between 2–5. Since patients with vitiligo lack this protectivemechanism, it would be anticipated that affected individuals run a higherrisk for skin cancer. Surprisingly, these patients even with long standingvitiligo (>47 years duration) have no evidence for increased photodamage suchas actinic keratosis and solar elastosis as well as increased numbers of basalcell and squamous cell carcinoma (Calanchini–Postizzi and Frenk 1987, Schallreuter et al. 2002).The reason for this paradox response in vitiligo is still unknown. Recentlyan increased epidermal functioning p53 has been detected, but this increasedp53 is not associated with apoptosis in these patients (Schallreuter et al. 2003).In this context it should be noted that p53 can be induced by mmolar levels ofH2O2 (Vile GF 1997). Hence, this scenario could be valid in vitiligo. The question remains, whether p53 is induced as a direct protective mechanism inprevention of skin cancer in this disease which could be an interesting newconcept to explain the observed paucity of solar induced damage and skincancer. Further work is needed to gain more insight into these interestingobservations. Newer Treatment ConceptsBased on the evidence provided there is no doubt that epidermal generation/accumulation of H2O2 plays a central role in vitiligo.This concept is in agreement with the clinical observation where patientswith this disorder, regardless of the time of onset and duration of the disease,age, gender and skin phototype respond to a topically applied pseudocatalase (PC-KUS) with a loss of epidermal and systemic H2O2 accumulation concomitant with repigmentation (Schallreuter et al. 1999a; Schallreuter et al. 2001,Hasse et al. 2004; Schallreuter et al. 2004) (Figure 5). Vitiligo 379 Fig. 4. Epidermal oxidative stress in acute vitiligo. Toluidine blue staining. NB: The extensivevacuolation (V) is based on lipid peroxidative damage due to H2O2 (Tobin et al. 2000) Fig. 5. Extensive facial vitiligo in skin phototype VI (Fitzpatrick Classification). A. Beforetreatment. B. After treatment with low dose narrowband UVB activated pseudocatalase(PC-KUS) 380 Karin U. Schallreuter If vitiligo would fit the criteria of an autoimmune disease, one would expect that the treatment is more successful after the introduction of topical orsystemic immunosuppressive drugs. However, the published clinical resultsare rather disappointing. Even the use of systemic as well as local corticosteroids failed to control the disease in the majority of patients. Topical application of tacrolimus and pimecrolimus as recent local treatment modalities areeffective in the repigmentation of facial vitiligo but fail the management ofother body areas. Apart from pseudocatalase (PC-KUS) the most promisingtreatment at the present time seems to be the use of narrowband UVB (311nm)with increasing doses twice or 3 times per week at least over 1 year. The precise mechanism of action remains to be established (Westerhof et al. 1999,Hamzavi et al. 2004). SummaryWhat did we learn? Despite autoimmunity is still the favoured hypothesis forvitiligo, the evidence to date does not support that vitiligo belongs into thegroup of primary autoimmune diseases. The low frequency of vitiligo antibodies specific for melanocytes could most likely be caused by the influenceof H2O2 on the immune system as a secondary response. To date there is accumulating evidence that other autoimmune phenomena in association withvitiligo are a rather random event.In the light of epidermal and systemic H2O2 accumulation, it is tempting tospeculate that environmental (exogenous) or systemic (endogenous) triggerfactors could be the mechanisms for the ‘hit’ that increases H2O2 productionvia NADPH-oxidase in the microenvironment. This could tip the balance andcause the initial loss of constitutive pigmentation due to the generation ofhydroxyl radicals (OH•) from H2O2 via the UV-catalysed Haber-Weiss reaction(Darr and Fridovich 1994). However, in the subsequent process of the disease,the origin of H2O2 derives from various sources, which could well foster the‘run’ mechanism, where H2O2 activates T-cell proliferation with consequentactivation of T-cell clones (Rutault et al. 1999, LePoole et al. 2004). A cellularinfiltrate in the perilesional skin in active vitiligo can contribute to a temporaryoxygen burst yielding H2O2. However, vacuolation/lipid peroxidation, expected to be exacerbated by the oxygen burst, is not different in the perilesionalskin compared to lesional skin and the normally pigmented epidermis. Allcompartments can have the same extent of vacuolation (Tobin et al. 2000) (Figure 4). Moreover, many of the described mechanisms are perturbed and areobserved in both the lesional and non lesional skin of patients with vitiligoindicating that the entire skin participates in the depigmentation process.Despite that our knowledge on vitiligo has improved, there is still no complete concept in understanding of those factors underlying the initiation ofthis disease. Future work is needed to get a better picture which allows the Vitiligo 381 development of a more effective treatment or even cure of this ancient disfiguring disease. ReferencesAronoff S (1965) Catalase: kinetics of photo-oxidation. 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J Invest Dermatol 97: 395–404Boissy RE, Sakai C, Zhao H, Kobayashi T, Hearing VJ (1998) Human tyrosinase related protein-1 (TRP-1). Exp Dermatol 7: 198–204Boissy RE, Manga P (2004) On the etiology of contact/occupational vitiligo. Pigment Cell Res17: 208–14Calanchini-Postizzi E, Frenk E (1987) Long-term actinic damage in sun-exposed vitiligo andnormally pigmented skin. Dermatologica 174: 266–71Casp CB, She JX, McCormack WT (2002) Genetic association of the catalase gene (CAT) withvitiligo susceptibility. Pigment Cell Res 15: 62–6Cui J, R Harning, M Henn, J-C Bystryn (1992) Identification of pigment cells antigens definedby vitiligo antibodies. J Invest Dermatol 98: 162–165Cui J, Arita Y, Bystryn J-C (1993) Cytolytic antibodies to melanocytes in vitiligo. J InvestDermatol 100: 812–815Cui J, Chen D, Misfeldt ML, Swinfard RW, Bystryn J-C (1995) Antimelanoma antibodies inswine with spontaneously regressing melanoma. Pigment Cell Res 8: 60–63Darr D, Fridovich I (1994) Free radicals in cutaneous biology. J Invest Dermatol 102: 671–675Davis MD, Ribeiro P, Tipper J, Kaufman S (1992) 7-Tetrahydrobiopterin, a naturally occurring analogue of tetrahydrobiopterin, is a cofactor for and a potential inhibitor of the aromatic amino acid hydrolases. Proc Natl Acad Sci USA 89: 10108–10113De la Fuente-Fernandez R (1997) Mutations in GTP-cyclohydrolase I gene and vitiligo. Lancet 350: 640Diehle J (2004) Med Thesis, University of Hamburg, GermanyGalbraith GM, Miller D, Emerson DL (1988) Western blot analysis of serum antibody reactivity with human melanoma cell antigens in alopecia areata and vitiligo. Clin ImmunolImmunopathol 48: 317–324Grimes PE, Sevall JS, Vojdani A (1996) Cytomegalovirus DNA identified in skin biopsy specimens of patients with vitiligo. J Am Acad Dermatol 1996; 35:21–26Grimes PE, Elkadi T, Sanders, J (1999) Epstein-Barr virus infection in patients with vitiligo(abstr). J Invest Dermatol 112: 604Halaban R, Moellmann GE (1990) Murine and human b-locus pigmentation genes encode aglycoprotein (gp75) with catalase activity. Proc Nat Acad Sci USA 1990 87:4809–4813Hamzavi I, Jain H, Mclean D, Shapiro J, Zeng H, Lui H (2004) Parametric modelling ofnarrowband UVB phototherapy for vitiligo using a novel quantitative tool: the VitiligoArea Scoring Index. Arch Dermatol 140: 677–83Harning R, Cui J, Bystryn J-C (1991) Relation between the incidence and level of pigment cellantibodies and disease activity in vitiligo. J Invest Dermatol 97: 1078–1080 382 Karin U. Schallreuter Hasse S, Gibbons NC, Rokos H, Marles LK, Schallreuter KU (2004) Perturbed 6-tetrahydrobiopterin recycling via decreased dihydropteridine reductase in vitiligo: more evidence forH2O2 stress. J Invest Dermatol 122: 307–313Herrath MG, Oldstone MB (1996) Virus induced autoimmune disease. Curr Opin Immunol 8:878–885Jimbow K, Chen H, Park JS, Thomas P (2001) Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase related protein in vitiligo. Br J Dermatol144: 55–65Kemp EH, Gawkrodger DJ, MacNeil S, Watson PF, Weetman AP (1997a) Detection oftyrosinase autoantibodies in vitiligo patients using 35S-labelled recombinant humantyrosinase in a radioimmunoassay. J Invest Dermatol 109: 69–73Kemp EH, Gawkrodger DJ, Watson PF, Weetman AP (1997b) Immunoprecipitation of melanogenic enzyme autoantigens with vitiligo sera: evidence for cross-reactive autoantibodies to tyrosinase and tyrosinase-related protein-2 (TRP-2). Clin Exp Immunol 109:495–500Kemp EH, Waterman, Gawkrodger DJ, Watson PF, Weetman AP (1998) Autoantibodies totyrosinase-related protein-1 (TRP-1) detected in the sera of vitiligo patients using a quantitative radiobinding assay. Br J Dermatol 139: 798–805Kemp EH, Waterman EA, Gawkrodger DJ, Watson PF, Weetman AP (1999) Identification ofepitopes on tyrosinase which are recognised by autoantibodies from patients with vitiligo.J Invest Dermatol 1	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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13: 267–271Kwon BS (1993) Pigmentation genes: the tyrosinase gene family and the pmel17 gene family.J Invest Dermatol 100: 134S-140SLaihia JK, Jansen CT (1997) Upregulation of human epidermal Langerhans cell B7–1 andB7–2 costimulatory molecules in vivo by solar stimulating irradiation. Eur J Immunol 27:984–989Laskin JD, Piccinini LA (1986) Tyrosinase isozyme heterogeneity in differentiating B16/C3melanoma. J Biol Chem 261: 16626–16635LePoole IC, Das PK, van den Wijngaard RM, Bos JD, Westerhof W (1993a) Review of theetiopathomechanism of vitiligo: A convergence theory. Exp Dermatol 2: 146–153LePoole IC, van dan Wijngaard RM, Westerhof W, Dutrieux RP, Das PK (1993b) Presence orabsence of melanocytes in vitiligo lesions: an immunohistochemical investigation. J Invest Dermatol 100: 816–822LePoole C, Wijngaard Van den, Smit NPM, Oosting J, Westerhof W, Pavel S (1994) Catechol-O-methyl transferase in vitiligo. Arch Dermatol Res 286: 81–86Le Poole IC, Wankowicz-Kalinska A, van der Wijngaard RMJGJ, Nickoloff BJ, Das PK (2004)Autoimmune aspects of depigmentation in vitiligo. J Invest Dermatol Symp Proc 9: 68–72Manga P, Sato K, Ye L, Beerman F, Lamoreux ML, Orlow SJ (2000). Mutational analysis of themodulation of tyrosinase by tyrosinase related proteins 1 and 2 in vitro. J Pigment Cell Res13: 364–374Maresca V, Roccella M, Roccella F, Camera E, Del Porto G, Passi S, Grammatico P, Picardo M(1997) Increased sensitivity to peroxidative agents as a possible pathogenic factor ofmelanocyte damage in vitiligo. J Invest Dermatol 109: 310–313Marks DB, Marks AD, Smith CM (1996) Oxygen metabolism and oxygen toxicity. In: BasicMedical Biochemistry: A Clinical Approach. Baltimore: Williams and Wilkins 327–340Marles LK, Peters EM, Tobin DJ, Hibberts NA, Schallreuter KU (2003) Tyrosine hydroxylaseisoenzyme I is present in human melanosomes: a possible novel function in pigmentation.Exp Dermatol 12: 61–70Medrano EE and Nordlund JJ (1990) Successful culture of adult human melanocytes obtained from normal and vitiligo donors. J Invest Dermatol 95: 441–445Moellmann G, Klein-Angerer S, Scollay DA, Nordlund JJ, Lerner AB (1982) Extracellulargranular material and degeneration of keratinocytes in the normally pigmented epidermis of patients with vitiligo. J Invest Dermatol 79: 321–330Moretti S, Spallanzani A, Amato L et al. (2002) New insights into the pathogenesis of vitiligo:imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 15: 87–92Morrone A, Picardo M, De Luca C, Terminali O, Passi S, Ippolito F (1992) Catecholamines andvitiligo. 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Physiology and Pathophysiology. Oxford University Press, OxfordNorris DA, Kissinger RM, Naughton GK, Bystryn J-C (1998) Evidence for immunologic mechanisms in human vitiligo: patients’ sera induce damage to human melanocytes in vitro bycomplement-mediated damage and antibody-dependent cellular toxicity. J Invest Dermatol 90: 783–789Okamoto T, Irie RF, Fujii S, Huang SKS, Nizze AJ, Morton DL, Hoon DSB (1998) Anti-tyrosinase related protein-2 immune response in vitiligo patients and melanoma patients receiving active-specific immunotherapy. J Invest Dermatol 111: 1034–1039Orlow SJ, Boissy RE, Moran D, Pifka-Hinst S (1993) Subcellular distribution of tyrosinase andtyrosinase related protein 1: Implications for melanosomal biogenesis. J Invest Dermatol100:55–64Ortonne JP, Bose SK (1993) Vitiligo: Where do we stand? Pigment Cell Res 8: 61–72Rokos H, Beazley WD, Schallreuter KU (2002) Oxidative stress in vitiligo: photo-oxidation ofpterins produces H2O2 and pterin-6-carboxylic acid. Biochem Biophys Res Commun 292:805–11Rokos H, Moore J, Hasse S, Gillbro JM, Wood JM, Schallreuter KU (2004) In vivo Fluorescence Excitation Spectroscopy and in vivo FT-Raman Spectroscopy in human skin: Evidence of H2O2 oxidation of epidermal albumin in patients with vitiligo. J Raman Spectrosc35: 125–130Rutault K, Alderman C, Chain BM, Katz DR (1999) Reactive oxygen species activate humanperipheral blood dendritic cells. Free Radic Biol Med 26: 232–238Schallreuter KU, Pittelkow MR (1988) Defective calcium uptake in keratinocyte cell culturesfrom vitiliginous skin. Arch Dermatol Res 280: 137–139Schallreuter KU, Wood JM, Berger J (1991) Low catalase levels in the epidermis of patientswith vitiligo. J Invest Dermatol 97: 1081–1085Schallreuter KU, Wood JM, Pittelkow MR, Gütlich M, Lemke KR, Rödl W, Swanson NN,Hitzemann K, Ziegler I (1994a) Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science 263: 1444–1446Schallreuter KU, Wood JM, Ziegler I, Lemke KR, Pittelkow MR, Lindsey NJ, Gütlich M(1994b) Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochim Biophys Acta 1226: 181–192Schallreuter KU, Büttner G, Pittelkow MR, Wood JM, Swanson NN, Körner C (1994c)Cytotoxicity of 6-biopterin to human melanocytes. Biochem Biophys Res Communs 204:43–48Schallreuter KU, Wood JM, Lemke KR, Levenig C (1995a) Treatment of vitiligo with a topicalapplication of pseudocatalase and calcium in combination with short-term UVB exposure:a case study on 33 patients. Dermatol 190: 223–229Schallreuter KU, Lemke KR, Pittelkow MR, Wood JM, Körner C, Malik R (1995b) Catecholamines and keratinocyte differentiation. J Invest Dermatol 104: 953–957Schallreuter KU, Wood JM, Pittelkow MR, Büttner G, Swanson NN, Körner C, Ehrke C(1996a) Increased monoamine oxidase A activity in the epidermis of patients with vitiligo.Arch Dermatol Res 288: 14–18Schallreuter KU, Pittelkow MR, Swanson NN (1996b) Defective calcium transport in vitiliginous melanocytes. Arch Dermatol Res 288: 11–13 384 Karin U. Schallreuter Schallreuter KU, Blau N (1997) GTP-cyclohydrolase and vitiligo. Lancet 350: 1254Schallreuter KU, Zschiesche M, Moore J, Panske A, Hibberts NA, Herrmann FH, MetelmannHR, Sawatzki J (1998) In vivo evidence for compromised phenylalanine metabolism invitiligo. Biochem Biophys Res Commun 243: 395–399Schallreuter KU, Moore J, Wood JM, Beazley WD, Gaze DC, Tobin DJ, Marshall HS, PanskeA, Panzig E, Hibberts NA (1999a) In vivo and in vitro evidence for hydrogen peroxide(H2O2) accumulation in the epidermis of patients with vitiligo and its successful removalby a UVB-activated pseudocatalase. J Invest Dermatol Symp Proc 4: 91–96Schallreuter KU (1999b). Successful treatment of oxidative stress in vitiligo. Skin PharmacolAppl Skin Physiol 12: 132–138Schallreuter KU, Wood JM (1999c) The importance of L-phenylalanine transport and itsautocrine turnover to L-tyrosine for melanogenesis in human epidermal melanocytes.Biochem Biophys Res Commun 262: 423–428Schallreuter KU, Moore J, Wood JM, Beazley WD, Peters EMJ, Marles LK, Behrens-WilliamsSC, Dummer R, Blau N, Thöny B (2001) Epidermal H2O2 accumulation alters tetrahydrobiopterin (6BH4) recycling in vitiligo: Identification of a general mechanism in regulation ofall 6BH4 dependent processes? J Invest Dermatol 116: 167–74Schallreuter KU, Tobin DJ, Panske A (2002) Decreased photodamage and low incidence ofnon-melanoma skin cancer in 136 sun-exposed caucasian patients with vitiligo. Dermatology 204: 194–201Schallreuter KU, Behrens-Williams S, Khaliq TP et al. (2003) Increased epidermal functioningwild-type p53 expression in vitiligo. Exp Dermatol 12: 268–277Schallreuter KU, Elwary SM, Gibbons NC, Rokos H, Wood JM (2004) Activation/deactivationof acetylcholinesterase by H2O2: more evidence for oxidative stress in vitiligo. BiochemBiophys Res Commun 315: 502–508Shimizu S, Shiota K, Yamamoto S et al. (2003) Hydrogen peroxide stimulates tetrahydrobiopterin synthesis through the induction of GTP-cyclohydrolase I and increases nitric oxidesynthase activity in vascular endothelial cells. Free Radic Biol Med 34: 1343–52Song Y, Connor E, Li Y, Zorovich B, Balducci P, Maclaren N (1994) The role of tyrosinase inautoimmune vitiligo. Lancet 344: 1049–1052Spritz RA, Gowan K, Bennett DC, Fain PR (2004) Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles inan autoimmune diathesis. Am J Hum Genet 74: 188–91Stark JM(1998) Immunological adjuvance of metabolic origin: oxidative stress, postulatedimpaired function of thiol proteases and immunogenicity. Scand J Immunol 48: 475–479Tobin DJ, Swanson NN, Pittelkow MR, Peters EMJ, Schallreuter KU (2000) Melanocytes arenot absent in lesional skin of long duration vitiligo. J Pathol 2000 191: 407–416Vile GF (1997) Active oxygen species mediate the solar ultraviolet radiation-dependent increasein the tumour suppressor protein p53 in human skin fibroblasts. FEBS Lett 412: 70–74Westerhof W, Nieuweboer-Krobotova L, Mulder PG, Glazenburg EJ (1999) Left-right comparison study of the combination of fluticasone propionate and UVA vs either fluticasonepropionate or UVA alone for the long term treatment of vitiligo. Arch Dermatol 135:1061–6Wood JM, Schallreuter KU (1991) Studies on the reactions between human tyrosinase,superoxide anion, hydrogen peroxide and thiols. 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Biochim Biophys Acta 1217: 317–321 14 Alopecia areataPia Freyschmidt-Paul, Kevin McElwee and Rolf Hoffmann Classification and Clinical AppearanceAlopecia areata (AA) is the symptomless loss of hair in either small circumscribed patches (Fig. 1), which may remain discrete or may expand into totalloss of all scalp (Fig. 2) and even body hairs. AA is a common human diseasewith a lifetime risk of 1.7% in the general population. It is characterized by areversible patchy hair loss most commonly involving the scalp although otherregions of the head, including eyelashes and beard, may also be affected.The typical patient with AA notes the sudden appearance of circular patch ofhair loss. Areas of activity in the lesion may be indicated by the presence of“exclamation mark” hairs (Fig. 3) which are usually 2–4mm long and mayhave a dark expanded tip and a depigmented root. The disease may sometimes lead to complete scalp baldness (Alopecia areata totalis) or even totalbody hair loss (Alopecia areata universalis). AA of the neck is called the ophiasis Fig. 1. Patchy alopecia areata: two small round bald patches in a child 386 Pia Freyschmidt-Paul et al. Fig. 2. Alopecia areata totalis. In this example the whole scalp is affected type. AA may be observed at any age with no sex predominance. AA is morelikely to occur in adolescents. AA is not life-threatening but rather psychologically and socially disturbing.The course of AA is unpredictable and typically characterized by phasesof acute hair loss followed by spontaneous hair regrowth and waxing and waning of the lesions. However, in severe forms hair loss can persist for manyyears. Very often AA shows a mild clinical course with only few small baldpatches, and hair regrowth after some weeks or months. However, the severe forms are usually chronic. The prognosis for AA is defined by the age atdisease onset, duration, nails signs, the extent of hair loss and the presence Alopecia areata: Classification and Appearance 387 Fig. 3. Exclamation mark hairs at advancing edge of patch of alopecia areata of atopic dermatitis. This means that a patient with AA universalis for manyyears, with a first episode of AA during childhood, associated nail changesand atopic dermatitis has only a small chance to experience hair regrowth.Except the nails, which may show typical signs of AA such as small pits,red spotted lunulae or verticular ridging (Fig.4), no other organs are affectedby this disease. Sometimes small nail pits are the first signs of a developingAA and hair loss may occur later. Only exeptionally nails may fall off (Onychomadesis) due to a severe nail AA. Sometimes all nails are affected. Nailinvolvement is usually associated with wide spread AA. There are some publications which describe the association of AA with other autoimmune diseasessuch as Vitiligo or Type 1 diabetes mellitus. However, there is considerabledebate about the practical value of those observations. In our view only Hashimotos thyroiditis tends to be more common in AA.As hair loss is sudden, hair regrowth occurs without any indicators. Theinitial hair regrowth after an episode of AA is often white due to a delay inrepigmentation of hairs. Interestingly, the last hairs to be affected by AA arewhite hairs, explaining how scalp hair can appear to become white overnight. DiagnosisThe clinical history of abrupt onset of patchy hair loss, the lack of infection,black dots, exclamation mark hairs, are all suggestive of the diagnosis of AAand in most cases the diagnosis of AA can be made clinically. There is noblood test to confirm or to rule out the diagnosis. In rare cases differential diagnosis such as chronic discoid lupus erythematosus, Lichen planopilaris, syphilis, traction alopecia, metastasis to the scalp, mycosis fungoides or alopecia 388 Pia Freyschmidt-Paul et al. Fig. 4. Mild nail dystrophy in alopecia areata with pitting and ridging mucinosa must be taken into consideration. Especially in AA of the diffuse typeit might be difficult to make the diagnosis. Then a scalp biopsy is indicated. HistopathologyHistopathological features of AA include peri- and intrafollicular lymphocytic infiltrates involving only anagen hair follicles with subsequent miniaturization of these follicles. The lymphocytic infiltrate is located around the hairbulb with some lymphocytes invading the hair follicle (Fig. 5). Destructionof hair follicles or scarring usually does not occur in AA and therefore hairregrowth is possible at any timepoint of the disease, either spontaneously or Alopecia areata: Classification and Appearance 389 Fig. 5. Histology of alopecia areata. Lymphocytes are clustered around the hair bulb andextend into the dermal papilla (LM x 100) due to a successful treatment. The process usually involves terminal hairs butcan affect vellus hairs as well. Molecular Genetics –the Present KnowledgeAA has been proposed to be an autoimmune disease based on several indirect observations in humans and animal models of the disease (McElwee et al. 390 Pia Freyschmidt-Paul et al. 1999c). Genetic influence has been clearly demonstrated in most other autoimmune diseases and one would expect that AA is no exception. AA is clearlya complex disease, it does not segregate according to the rules of Mendelianinheritance (Van der Steen et al. 1992a; Shellow et al. 1992; Colombe et al. 1995;Sharma et al. 1996a). As with other autoimmune diseases, AA is most likely apolygenic disorder where susceptibility is dictated by several major genes andthe phenotype may be modified by numerous minor genes. Rodent ModelsIsolated examples of AA have been identified in several species. However,the limited characterization or availability of these examples restricts theirusefulness in any genetic research for AA (McElwee et al. 1998b). Two rodent models have been developed and characterized for use in AA research,the Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse (Michieet al. 1991; Sundberg et al. 1994). Both models are inbred strains. Despitetheir inbred nature, rodents may have a wide variety of hair loss presentations from isolated patches, or diffuse AA, to near universal hair loss. AA inboth rodent models has been shown to be an autosomal polygenic trait withpartial phenotype penetrance by analysis of breeding programs.The DEBR, originally a hybrid between BDIX and Wistar rats, has beenintercrossed for over 35 generations. Two separate inbred DEBR sub-strainsexist, one black hooded and the other brown, but with similar AA phenotypeproperties. Hair loss is associated with a primarily CD4+ and CD8+ lymphocyte cell infiltrate of anagen stage hair follicles and production of hair folliclespecific antibodies (Zhang and Oliver 1994, McElwee et al. 1996). Spontaneous expression of AA develops in 42% of individuals with onset from 7 monthsof age in both males and females. Hair loss typically first develops in symmetrical bald patches on the flanks. Multiple patches may develop to affectthe head, dorsal and ventral skin with approximately 15% of affected individuals reaching a near universal hair loss state. DEBR have been cross bredwith PVG/OlaHsd rats yielding 21% affected F1 offspring (Oliver, personalcommunication) suggesting PVG/OlaHsd rats contain few AA susceptibilitygenes. PVG/OlaHsd rats may be one of several strains suitable for use in anintercross or backcross breeding strategy to identify AA susceptibility andseverity modifying genes by linkage disequilibrium.C3H/HeJ mice have existed as a unique inbred strain at the Jackson Laboratory since 1947, but onset of the AA phenotype was first observed in several individuals of a C3H/HeJ mouse colony in 1993. The mouse breedingpattern permitted tracing the genetic history of the affected mice to a singlebreeding pair at generation F198 (Sundberg et al. 1994), suggesting a geneticmodification of the strain in one parent. The frequency of spontaneous AAexpression in aged mice, up to 18 months old, increased to approximately 20% Alopecia areata: Classification and Appearance 391 in 3–4 generations for over 300 mice evaluated (Sundberg et al. 1994). Bothmales and females are affected with initially ventral hair loss typically developing in females from 6 months and in males from 10 months of age. Hairloss may progress to the dorsal surface and reach near universal loss in 10%of affected individuals. Histopathology shows all affected anagen stage hairfollicles to be affected by non-scaring focal inflammation of primarily CD4++and CD8 lymphocytes and hair follicle specific autoantibodies are present ata high titer (Tobin et al. 1997; Freyschmidt-Paul et al. 1999).Recent studies have demonstrated that all adult C3H/HeJ mice are susceptible to AA. Grafting skin from spontaneous AA affected mice to normalhaired C3H/HeJ mice consistently promotes onset of AA 8–10 weeks aftergrafting (McElwee et al. 1998a). Skin grafts from AA affected mice to the histocompatible C3H/OuJ and C3HeB/FeJ inbred strains promotes AA onset witha similar phenotype and pathology, but in only 40% of graft recipients (McElweeet al. 1998a). Crosses between C3H/HeJ mice with AA and mice from theclosely related strain with no history of age associated alopecia, yielded F1and subsequent generation mice with an AA expression frequency of 10–12%(Sundberg et al. 1994). The AA induction technique suggests that while inbred C3H/HeJ mice may all be genetically susceptible, the AA phenotypemust be activated. It is possible that the environment provides a trigger forinitial disease onset. The apparent reduced susceptibility of the C3H/OuJand C3HeB/FeJ strains to AA suggest that these strains carry fewer AA susceptibility genes as compared to the C3H/HeJ strain. The segregation pattern of phenotypes suggests that AA in laboratory mice is under the controlof one or more dominant gene alleles.A preliminary backcross study between C3H/HeJ mice and C57BL6/J micesuggested a tentative locus for susceptibility on mouse Chromosome 6 (37cM,1 recombinant/24 alleles with D6MIT230 is 4.2 cM, p = 3×10–6, 95% confidenceinterval of the distance is 0.1–21.1 cM) (McElwee et al. 1999a). Within thisregion are numerous immunoglobulin genes, a gene for cytokine TGFa, aswell as genes for the lymphocyte surface markers CD8 and Ly36. The mouselocus corresponds to human chromosome region 2p13. Thus, this region maybe worthy of close attention within a genome wide screen. C3H/HeJ micecross bred with C57/BL6J mice yield 7% of affected F1 generation mice (10%affected females, 2% affected males) and intercross studies with C57BL6/Jmice are in progress with up to 13 candidate gene loci under investigationsupporting the hypothesis that AA is a polygenic disease (Sundberg et al. 2003). Human EpidemiologyThere is a higher incidence of AA in genetically related individuals. This suggests that at least some people are genetically predisposed to develop AA.The triggers for the onset of AA may be environmental, but the resistance of 392 Pia Freyschmidt-Paul et al. the AA lesion to treatment, its persistence and regression, and its extent overthe body may be influenced by the presence and interaction of multiple genes.Several studies suggest that AA has a genetic basis (Van der Steen et al. 1992a;Colombe et al. 1995). AA with similar times of onset or similar hair loss patterns has been reported in monozygotic twins (Hendren 1949; Weidman etal. 1956; Bonjean et al. 1968; Stankler 1979; Cole and Herzlinger 1984; Scerriand Pace 1992; Alsaleh et al. 1995). Families with several generations of AAaffected individuals also suggest AA may be a genetically determined disease (Shelton and Hollander 1942; Goldshtein and Chipizhenko 1978; Hordinskyet al. 1984; Valsecchi et al. 1985; Van der Steen et al. 1992a; Sharma et al.1996a; Sharma et al. 1996b).Epidemiological studies provide basic evidence for AA susceptibilitygenes. Numerous studies suggest AA may be more frequently expressed ingenetically related individuals. Typically, 10 to 20% of patients with AA Table 1. Incidence of alopecia areata in reported epidemiological studiesPercentage withfamily history Geographic location Source 3% UK Barber 1921 20% UK Brown 1929 20% France Sabouraud 1929 19% UK Anderson 1950 10% USA Muller and Winkelmann 1963 3.4% Italy Olivetti and Bubola 1965 6.3% Portugal Bastos Araujo	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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and Poiares Baptista 1967 25% UK Cunliffe et al. 1969 17% Sweden Gip et al. 1969 27% USA Sauder et al. 1980 24% UK Friedmann 1981 11% Belgium De Weert et al. 1984 6.6% Germany Lutz and Bauer 1988 18% Netherlands De Waard 1989 11.4% Germany Gollick and Orfanos 1990 16% Germany Van der Steen et al. 1992 42% USA Shellow et al. 1992 11.5% Korea Ro Bi 1995 9% India Sharma et al. 1996a 12.4%* India Sharma et al. 1996b Children aged 16 or younger Alopecia areata: Classification and Appearance 393 indicate at least one other affected family member (Table 1). In contrast, thelifetime risk of AA expression in the general population has been suggestedto be 1.7% (Safavi et al. 1995). Familial incidence may be significantly higherthan reported in epidemiological studies as the marked psycho-social consequences of hair loss inhibit some individuals from seeking diagnosis. In addition, some may not be aware of their hair loss if it is limited or develops in anarea not immediately visible to the individual.A strong association has been observed between AA and trisomy 21(Down’s syndrome). In 1000 patients and 1000 control subjects, Du Vivier andMunro observed 60 cases of trisomy 21 individuals with AA versus 1 control(Du Vivier and Munro 1975). Carter and Jegasothy identified 19 cases of AAin 214 trisomy 21 affected patients and the statistical relationship is furthersupported in other studies (Wunderlich and Braun-Falco 1965; Carter andJegasothy 1976). The genetic mutation for autoimmune polyendocrinopathysyndrome type 1 (AIRE, autoimmune regulator gene) (Finnish-GermanAPECED Consortium 1997) is also associated with a 29 to 37% prevalence ofAA (Betterle et al. 1998). These studies suggest that candidate gene loci forAA susceptibility may be present on human chromosome 21.Associations of AA with other autoimmune diseases have also been reported. Between 7% and 27% of AA affected patients may also have a thyroiddisease, including goiter presence, myxedema and Hashimoto’s thyroiditis(Cunliffe et al. 1969; Milgraum et al. 1987; Shellow et al. 1992; Puavilai et al.1994). Co-expression of vitiligo and AA has also been reported at between4% and 9% (Muller and Winkelmann 1963; Main et al. 1975). However, thestatistical significance of these disease associations when compared to appropriate control populations has been disputed elsewhere (Salamon et al. 1971;Gollick and Orfanos 1990; Schallreuter et al. 1994). Numerous case reportsdetail concordant presence of AA with other autoimmune diseases, such asdiabetes and myasthenia gravis, although the statistical significance is unknown (McElwee et al. 1998b). HLA GenesHuman leukocyte antigen (HLA) genes on human chromosome 6 code forthe major histocompatibility complex (MHC) proteins that are important inpresentation of antigens and self recognition by immune cells. MHC class Iantigens comprise the HLA-B, HLA-C and HLA-A loci in this order. MHCclass II is coded by genes in the HLA-D region that is subdivided into geneclusters HLA-DP, HLA-DQ, and HLA-DR (Vogel and Motulsky 1997). MHC+class I antigens are expressed on almost all nucleated cells. CD8 lymphocyteshave the capacity to recognize cellular antigens presented in association withMHC class I via their T cell receptors. In contrast, MHC class II antigens arenormally expressed on antigen presenting cells (APCs), such as macrophages 394 Pia Freyschmidt-Paul et al. and Langerhans’ cells, and expression may be induced on other nucleatedcells during inflammatory processes such as AA (Messenger and Bleehen1985; Bröcker et al. 1987). CD4+ lymphocytes may recognize antigen plus MHCclass II complexes on APCs. Different MHC proteins may have superior presenting properties for particular antigens compared to other MHC complexesand consequently some antigen plus MHC complexes will be more effective intheir activation of lymphocytes than others. In part, this may determine theability of lymphocytes to respond to the hair follicle antigen(s) targeted in AA andmay define how potent an immune response against a particular antigen will be.Genetic research into other autoimmune diseases has shown HLA encoding alleles to segregate with specific disease phenotypes. However, inconsistent results have been found with analysis of HLA class I haplotypes of theA and B series and AA. Some studies report statistically significant associations, but other studies found no HLA class I association (Kuntz et al. 1977;Zlotogorski et al. 1990). HLA-A2, B40 and Aw32, B18 have each been reportedas associated with AA (Hordinsky et al. 1984; Valsecchi et al. 1985). Associations between HLA-B12 in Finnish patients, HLA-B18 in Israelis, B13 and B27in Russians have also been suggested (Kianto et al. 1977; Hacham-Zadeh etal. 1981; Averbakh and Pospelov 1986).Genetic analysis studies in AA have primarily focused on the HLA-Dgenes (MHC class II encoding) as the most likely region for genes that regulate susceptibility, severity of, or resistance to disease (Duvic et al. 1991). Consistent associations have been observed between class II haplotypes and AAincluding DR4 (Friedman 1985; Frentz et al. 1986; Orecchia et al. 1987; Duvicet al. 1991; de Andrade et al. 1999), DR5 (Friedman 1985; Frentz et al. 1986;Orecchia et al. 1987), DR6 (de Andrade et al. 1999), DR7 (Averbakh andPospelov 1986) and broad antigen DQ3 (Welsh et al. 1994; Colombe et al. 1995;Colombe et al. 1999). More recent research has shown allele DRB11104(DR11) to be present with significant increased expression in patients withAA (Colombe et al. 1995; Colombe et al. 1999) and this was confirmed in otherstudies (Morling et al. 1991; Welsh et al. 1994; Duvic et al. 1995). AlleleDRB10401 (DR4) was strongly associated with AA totalis and universalis subgroups (Colombe et al. 1999). DQB10301 (DQ7 by serology) was also significantly expressed only in association with AA totalis and universalis (Colombeet al. 1995; Duvic et al. 1995; Colombe et al. 1999). Other studies implicate otherDQB1 alleles, DQB1302, DQB1601, and DQB1*603, in AA (de Andrade et al.1999). The current consensus is that AA in humans has a genetic basis, but is notalways in a familial aggregation (Van der Steen et al 1992; Colombe et al. 1995).It has been suggested that the HLA gene products, the MHC antigens,could be important for the presentation of an unknown AA antigen. Aberrant expression of MHC proteins within AA affected hair follicles is frequentlyfound, but the question of its true significance remains (Messenger and Bleehen1985; Bröcker et al. 1987). There are many more alleles that code for otherfactors within, and outside of, the immune system that may be vital in the development of AA. Alopecia areata: Classification and Appearance 395 Non HLA GenesThe HLA gene region is likely to be only one of several gene loci involved inAA, but limited research has been conducted in other areas of the genome.One investigation has shown an association between AA and allele 2 polymorphism for the IL-1rn gene on human chromosome 2 that codes for the IL-1receptor antagonist (Tarlow et al. 1994). Results indicated allele 2 was present in 41% of controls versus 44% in individuals with patchy AA, 66% of thosewith alopecia totalis and 77% of alopecia universalis affected individuals(Tarlow et al. 1994). Allele 2 is known to influence IL-1b production. Galbraithet al. identified the IL-1b-1,2 genotype as significantly increased in frequencyfor individuals with extensive, but not patchy, AA further suggesting that thesevere form of disease may be associated with increased IL-1b production(Galbraith et al. 1999).Genes for immunoglobulin heavy (Gm) and light (Km) chain genotypeson human chromosome 14 have also been implicated in AA susceptibility(Galbraith et al. 1984; Galbraith and Pandey 1989) with the suggestion thatIL-1b (IL-1b -1,2) and light chain (KM-1,3) genotypes may interact to increaseAA susceptibility (Galbraith et al. 1999). TNFa gene polymorphisms, or adjacent genes in the HLA region may also influence AA susceptibility (Galbraithand Pandey 1995; Cork et al. 1996). Involvement of all these gene loci, assusceptibility or severity modifying genes, is consistent with an autoimmunepathogenesis of AA. ConclusionsRodent model research has shown that AA is an immune mediated diseaseand strongly suggests that the mechanism is autoimmune in nature (McElweeet al. 1999c). It is probable that AA susceptibility and severity modifyinggenes will primarily be involved in the immune system, but other susceptibility genes may control hair follicle function. From observation in humansand animal models, AA can be described as an polygenic disease with a variablespectrum of severity. While previous research studies have understandablyfocused on the HLA region and identification of marker genes segregatingwith the AA phenotype, there is a clear need for genome wide analysis to define further candidate susceptibility, severity modifying, and possibly resistance gene loci. Human population analysis suggests potential gene loci maybe located on chromosomes 2, 6, 14, and 21 (Du Vivier and Mundo 1975;Colombe et al. 1995; Duvic et al. 1995; Galbraith et al. 1999). Careful categorization of DNA samples based on phenotypic presentation of hair loss in theindividual will be important for defining sub-categories of AA. It might be possible to define specific alleles with association to particular AA phenotypessuch as patchy AA, AA totalis, or AA universalis. 396 Pia Freyschmidt-Paul et al. TherapyVarious methods to treat AA have been described, but for many of them onlyanecdotal reports exist and the alleged treatment success might be attributedto spontaneous remission. Because of the high rate of spontaneous hairregrowth in AA, the only treatments that can be regarded as evidence-basedare those proven to be effective either after exclusion of spontaneous remission by treating every patient on one half of the scalp only or in a doubleblind, placebo controlled study including a very large number of patients.Furthermore, studies evaluating treatments for AA should preferably includepatients with AA totalis, AA universalis and extensive patchy AA (> 25%scalp hair loss) persisting longer than 3 months, because these patients havea worse prognosis than patients with limited patchy AA. These patients arealso the ones who are most in need of an effective treatment. Any treatmenthas to be suitable for long-term therapy, because AA is a disease that canpersist for many years or even life. Hence, all therapeutic approaches showing severe side-effects are inappropriate for AA in the long run. Immunosuppressive TreatmentsCorticosteroidsTopical, intralesional, and systemic corticosteroids have been used for thetreatment of AA with different rates of success and side effects. Topical CorticosteroidsTopical treatment of AA with corticosteroid creams, ointments or lotions isfrequently used. However, only two placebo-controlled studies reported atreatment response (Pascher et al. 1970; Leyden and Kligman 1972), but bothstudies do not fulfill the criteria for evidence based treatment of AA (40% ofdrop outs in the first study, patients with only limited AA in the second study).Furthermore, both studies were performed in the 1970s and they have notbeen confirmed by others over the last 30 years (Weitgasser 1968; Verbov1973; Lehnert 1974; Montes 1977). Only one placebo-controlled study withan appropriate number of patients has been performed to date, but the rateof treatment success was not statistically significant (Charuwichitatrana et al.2000).The failure of topical corticosteroids is most likely due to the insufficientpenetration of topically applied drugs dissolved in ointments, creams or lotions to the hair bulb. Improved penetration by occlusive treatment has beentried without success (Lehnert 1974) or with a response rate of only 17,8% Alopecia areata: Therapy 397 (Tosti et al. 2003). Considering the lack of treatment response and the sideeffects of topically applied corticosteroids, we conclude that topical corticosteroids are not an effective method of treating AA. Intralesional CorticosteroidsIntralesional injections of corticosteroid crystal suspensions, primarily triamcinolone acetonide, have been used for the treatment of AA for more than 40years (Kalkoff and Macher 1958). Several studies reported hair regrowth atthe site of injection in the majority of cases (Kalkoff and Macher 1958; Orentreich et al. 1960; Porter and Burton 1971; Fülöp and Vajda 1971; Abell andMunro 1973; Frentz 1977). Most of these studies tried to exclude spontaneoushair regrowth by comparing the injected sites of the scalp with non-injectedareas, especially in alopecia totalis. However, in practice it is impossible totreat the whole scalp by intralesional injections of corticosteroids and so thistreatment is only indicated in patchy AA with longstanding bald areas. Apartfrom the sometimes painful procedure of injection, permanent skin atrophycan occur after injection. Taken together, intralesional injection of corticosteroids is a reasonable treatment in exceptional, selected cases of longstanding small patches of AA, but has potentially significant side effects. Systemic CorticosteroidsAA has been treated with systemic corticosteroids since 1952 (Dillaha andRothman 1952). Whereas initially corticosteroids were applied orally daily orevery other day for several months, this approach is obsolete today. The dosesthat are required to maintain hair regrowth in AA are between 30 and 150mg prednisolone daily, giving rise to unacceptable side effects such as hypertension, diabetes, immunosuppression, osteoporosis and susceptibility tothrombosis.Since 1975 several authors have performed pulsed administration of corticosteroids in single doses, given once monthly in order to reduce the sideeffects of corticosteroids to an acceptable level, but all studies which notedhair regrowth, were uncontrolled and the majority of patients had patchy AA(Perriard-Wolfensberger et al. 1993; Sharma 1996; Friedli et al. 1998; Sharmaand Muralidhar 1998; Seiter et al. 2001). Moreover, other studies reported atreatment failure after corticosteroid pulse therapy (Burton and Shuster 1975;Schulz et al. 1996). Controlled studies should be conducted to prove the efficacy and long-term value of this treatment. In particular, the efficacy in interrupting acute phases of rapid hair loss by pulsed administration of oralcorticosteroids should be investigated. According to the data currently available, pulsed administration of corticosteroids for AA cannot be recommended. 398 Pia Freyschmidt-Paul et al. PUVASeveral studies have been performed on the treatment of AA with PUVA using either oral application of 8-methoxypsoralen (8-MOP) with ultraviolet Aradiation (UVA) of the scalp or the whole body, or topical application of 8-MOPand UVA radiation on the scalp, including one study with topical applicationof psoralen via the PUVA-turban (Larkö and Swanbeck 1983; Claudy andGagnaire 1983; Lassus et al. 1984; Mitchell and Douglass 1985; Healy andRogers 1993; Taylor and Hawk 1995; Behrens-Williams et al. 2001). Some investigations seemed to show good results (Claudy and Gagnaire 1983; Lassuset al. 1984; Healy and Rogers 1993; Taylor and Hawk 1995; Behrens-Williamset al. 2001, Whitmont and Cooper 2003), but there were no controls in any ofthe studies. Moreover, there were a high number of AA recurrences in mostof the studies (between 30% and 50% of successfully treated patients) afterinitial hair regrowth that strongly decreases the efficacy of PUVA treatmentfor AA (Claudy and Gagnaire 1983; Lassus et al. 1984; Healy and Rogers 1993;Taylor and Hawk 1995). This high number of relapses is most likely due tothe fact that regrown hair inhibits the UVA light from reaching the skin.Technical improvement such as a comb emitting UVA light have been tried,but so far no results have been reported. Unfortunately, a continuous hairregrowth after the initial response has to be actively maintained for severalyears in most cases of AA. With regard to the increased risk of skin malignancies after long-term PUVA therapy, PUVA therapy cannot be recommendedfor AA even if technical improvement like a UVA-comb should ultimatelyprove to be effective. Immunomodulatory TreatmentsDiphenylcyclopropenone and Squaric Acid DibutylesterAA has been treated with contact sensitizers for more than 25 years. Dinitrochlorobenzene (DNCB) was the first sensitizer that was used for the treatment of AA (Happle and Echternacht 1977), but because it has been shownto be mutagenic in the Ames test, it can no longer be used (Happle 1979, 1985).Today diphenylcyclopropenone (DCP) or squaric acid dibutylester (SADBE),that are not mutagenic in the Ames test, are widely used in European statesand in Canada. TreatmentTreatment with contact sensitizers is preceded by sensitization of the patientwith 2% DCP solution on a small area of the scalp. Two weeks later, treatment is initiated by application of a 0.001% DCP solution, followed by weekly Alopecia areata: Therapy 399 application of increasing concentrations of DCP until a mild eczematous reaction is obtained. In this way, an appropriate eliciting concentration of DCPfor each patient is identified. This concentration has to be applied once aweek to induce a mild eczematous reaction that is characterized by itchingand erythema, without blistering or oozing. SADBE is used in those patientswho become tolerant to DCP. It is applied in the same way and shows a similar rate of response.Initial hair regrowth is usually visible after 8–12 weeks. Treatment has tobe continued once weekly until complete hair regrowth is obtained. Treatment intervals are then decreased and eventually treatment may be discontinued. However, if a relapse occurs after discontinuation of therapy, treatmentcan be restarted immediately to stop further progression of AA and inducerenewed hair growth. Treatment should initially always be applied on onehalf of the scalp and the other side left untreated to exclude a spontaneoushair regrowth coincidental to treatment initiation. Treatment is continued onboth sides only after the treated side has shown a response in the form of betterhair growth on the treated side (Fig. 1). Side EffectsA mild eczematous reaction and enlargement of retroauricular lymph nodesare desired reactions and inherent to treatment. They are usually well tolerated if the patients are informed that these reactions are desirable for the therapeutic effect. Undesired side effects are noted in 2–5% of patients (Hoffmannand Happle 1996). Vesicular or bullous reactions sometimes occur at the Fig. 6. Treatment of AA with a contact sensitizer: Unilateral contact dermatitis after applicationof a contact sensitizer on the left side of the scalp (a); unilateral hair growth on the treated side(b); complete hair growth after treatment of both sides (c) 400 Pia Freyschmidt-Paul et al. beginning of treatment before the individual appropriate concentration hasbeen determined. Dissemination of allergic contact dermatitis, urticarial orerythema multiforme-like reactions may occur (Perret et al. 1990) but canbe successfully treated with topical corticosteroids. Pigmentary disturbancessuch as postinflammatory hyperpigmentation with spotty hypopigmentation(“dyschromia in confetti”) have been observed, especially in patients withdark skin, but resolved within 1 year after discontinuation of treatment inmost cases (van der Steen and Happle 1992; Hoffmann and Happle 1996).Apart from these acute and subacute side effects, no long-term side effectshave been reported after 20 years of DCP (23 years of SADBE) treatment worldwide of about 10,000 patients, including children. However, it should be bornein mind that DCP and SADBE are not approved therapeutic substances. StudiesMore than 25 studies have been performed to test the efficacy of AA treatment with a contact sensitizer. The most significant controlled studies arelisted in Table 2. In contrast to corticosteroid and PUVA treatment studies,the majority of contact sensitizer treatment studies were controlled, most ofthem using an untreated side of the scalp as a control. When comparing therates of response obtained in various therapeutic modalities, one should bearin mind that spontaneous regrowth is excluded in these controlled, withinpatient studies, but not in the uncontrolled ones. The response rate of treatment with a contact sensitizer varies between 29% and 78% (see Table 1).The differences may be explained in part by the different extent and duration of AA prior to treatment in the patients of each study, and in part by differences in the method of treatment. However, the median response rate ofall studies is 49%, rendering contact sensitizers an effective therapeutic toolfor AA. Mode of ActionThe mode of action of the treatment with contact sensitizers is so far poorlyunderstood. It has been shown that treatment with a contact sensitizer changesthe composition and localization of the perifollicular infiltrate in humans andin the C3H/HeJ mouse-model for AA (Happle et al. 1986; Freyschmidt-Paulet al. 1999). In both, mice and men, the localization of the inflammatory infiltrate shows a shift from peribulbar before treatment to the upper dermis aftertherapy. However, in human AA the CD4:CD8 ratio changes from 4:1 beforeto 1:1 after therapy, while in mice successful treatment with a contact sensitizeris associated with an increase in the number of CD4+ cells and a decrease inthe number of CD8+ cells. Hoffmann et al. demonstrated that after treatmentwith a contact sensitizer the mRNA-expression of IFNg is reduced while theexpression of IL-10 is increased (Hoffmann et al. 1994). Whether this is due DCPDCPDCPDCPDCPDCPDCPDCPSADBESADBESADBESADBE Steen van der, et al., 1991 Macdonald Hull et al., 1991 Macdonald Hull et al., 1991 Hoting et Boehm, 1992 Gordon et al., 1996 Schuttelaar et al., 1996 Weise et al., 1996 Cotellessa et al., 2001 Wiseman et al., 2001 Happle et al., 1980 Case et al., 1984 Caserio 1987 Micali et al., 1996 129 2 11 26 113 14 43 10 12 11 33 4 78 0 8 18 8 5 Patchy AA 8 5 10 27 35 42 22 16 36 20 45 8 32 20 8 37 22 AA totalis 0 7 0 0 0 40 0 0 14 0 0 29 14 0 1 0 0 AA universalis Clinical form of AA (number ofpatients) ULT, unilateral treatment, untreated side serves as control DCPDCP Monk, 1989 DCPDCP DCP Happle et al., 1984 Macdonald Hull and Norris, 1988 DCP Happle et al., 1983 Ochsendorf et al., 1988 ContactSensitizer Reference Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Controlledstudy 137 14 21 53 148 56 105 26 children 48 45 78 12 children 139 14 28 27 45 27 Number ofpatients Table 2. Treatment of AA with Contact Sensitizers, Controlled Studies Including Patients with Severe, Longstanding AA 64% 29% 52% 70% 77,9% 48% 48% 32% 38% 51% 55% 33% 50.4% 43% 29% 37% 58% 68% Cosmeticallyacceptable hairregrowth Alopecia areata: Therapy401 402 Pia Freyschmidt-Paul et al. to a Th1-Th2 shift or whether it is caused by the introduction of regulatoryT-cells with a type 2 cytokine profile is the object of current investigations.Immunohistochemical studies furthermore have shown in humans and in theC3H/HeJ mouse-model of AA, that treatment with a contact sensitizer reduces the aberrant expression of MHC-I and MHC-II molecules on the lowerhair follicle epithelium (Bröcker et al. 1987; Freyschmidt-Paul et al. 1999).From these data it can be concluded that treatment with a contact sensitizerrestores the immune privilege of the lower hair follicle epithelium. Other TreatmentsIrritant Contact Dermatitis – AnthralinWhile treatment of AA with an allergic contact dermatitis has been proven tobe effective, treatment of AA with an irritant contact dermatitis has neverbeen shown to be successful in a controlled study. In a half-side controlledstudy, using 0.1% anthralin that resulted in a mild irritant contact dermatitis,no difference between treated and untreated side was observed (Nelson andSpielvogel 1985). Therefore, anthralin cannot be recommended for the treatment of AA. MinoxidilBecause the antihypertensive agent minoxidil causes hypertrichosis as a sideeffect, Weiss et al. attempted to use it as a treatment for various forms of hairloss, including alopecia areata (Weiss et al. 1984). But all studies that claimsuccessful treatment of AA with minoxidil did not fulfill the criteria of evidence based treatment of AA (Weiss et al. 1984, Fiedler-Weiss et al. 1986,Price 1987a, b; Ranchoff et al. 1989)Six other placebo-controlled studies performed by various groups did notshow a statistically significant difference between the hair growth of patientstreated with the placebo or with minoxidil (Frentz 1984; Maitland et al. 1984;Vanderveen et al. 1984; White and Friedmann 1985; Vestey and Savin 1986;Fransway and Muller 1988). In three of these studies cosmetically acceptablehair regrowth was not even observed in any patient (Vanderveen et al. 1984;White and Friedmann 1985; Fransway and Muller 1988). In summary, minoxidilis not useful in the treatment of AA. SummaryAlopecia areata is regarded as a T-cell mediated autoimmune disease that isdirected against a so far unknown autoantigen of the hair follicle. There is a Alopecia areata: Therapy 403 genetic predisposition to develop alopecia areata, whereas environmental triggers have not yet been identified. The diagnosis can be established by characteristic clinical features including severe forms such as alopecia areata totalisand universalis. Nail changes may help confirm the diagnosis. In some caseshistopathological examination may be necessary, whereas other laboratoryinvestigations are unnecessary. Because of the high rate of spontaneous remission, the efficacy of a rational treatment for AA has to be proven in controlled studies. An ideal treatment should be highly effective but associatedwith only minor side effects. According to the rules of evidence-based medicine, treatment with	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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a contact sensitizer is at present the most effectivetreatment of alopecia areata showing only mild side effects. However, it is atime-consuming and in some cases ineffective therapeutic approach, whichis why it is necessary to develop new, more specific forms of treatment. 404 Pia Freyschmidt-Paul et al. PathogenesisThe complete pathogenesis picture for AA has yet to be determined. However, recent research has made much progress in our understanding of thedisease mechanism. There is numerous circumstantial evidence in support ofthe notion that AA is fundamentally an inflammation driven disease and maybe autoimmune in nature. Observation of a peri- and intra-follicular inflammation of the target anagen hair follicle primarily by T lymphocytes in bothhumans and animal models is the most compelling morphological evidence(Perret et al. 1984; Ranki et al. 1984; Zhang et al. 1994; Sundberg et al. 1994).In addition to a lymphocytic infiltrate there is increased presence of antigenpresenting cells such as macrophages and particularly Langerhans cellsaround, and sometimes within, dystrophic hair follicles (Wiesner-Menzel andHapple, 1984; Zhang et al. 1994). Furthermore, inflammatory markers include up regulation of ICAM and ELAM expression on the endothelium ofblood vessels closely associated with affected hair follicles (Nickloff andGriffiths 1991; McDonagh et al. 1993; Zhang et al. 1994). Changes in cytokinelevels, particularly activating cytokines such as IL-2 and IFNg, have beennoted during AA inflammation with corresponding alteration of cytokineconcentrations after successful topical counter irritant therapy (Hoffmann etal. 1994). MHC class I and II expression on hair follicle epithelial structuresnormally devoid of MHC expression is associated with hair follicle inflammation and AA (Bröcker et al. 1987; McDonagh et al. 1993). Certain MHCclass II haplotypes seem to be associated with predisposal of the individualtowards AA, a common observation in autoimmune diseases (Duvic et al. 1991;Colombe et al. 1999). Hair follicle specific IgG autoantibodies have been foundin increased concentrations in the peripheral blood of AA affected individuals compared to normal, non-affected humans (Tobin et al. 1994a, Tobin etal. 1994b). AA may respond to a range of immunomodulatory treatments(Hoffmann and Happle, 1999). All these and other circumstantial evidence(McElwee et al. 1999c; McElwee et al. 2002b) are of some assistance in understanding the pathogenesis of AA. However, detailed characterization andfunctional studies are required to demonstrate the significance of these circumstantial observations and to elucidate disease mechanisms. Primarily dueto ethical limitations, functional studies cannot readily be conducted in humans. Consequently, animal models of human AA are required. Immune System TargetsAA is generally believed to have an autoimmune pathogenesis (Paus et al.1993; McDonagh and Messenger, 1996). While the evidence in support ofthis idea is compelling, the primary requirement to prove the autoimmune Alopecia areata: Pathogenesis 405 nature of AA, to identify a self antigen as the primary target that can initiatethe disease mechanism and lead to development of the phenotype, has yet tobe proven. Without this evidence, AA can only be described as a putative autoimmune disease. Using a SCID-human model of AA, Gilhar et al claimedmelanogenesis related antigens to be inciting agents for the activation ofpathogenic cells involved in AA (Gilhar et al. 2001). Circumstantially, thereare several claimed cases of selective pigmented hair loss and white hair survival in AA affected individuals (Plinck et al. 1993; Messenger and Simpson,1997; Camacho, 1997). Much has been made of this observed phenomenonin defining potential targets of inflammation in AA. However, there are manymore unreported examples of AA affected individuals losing both pigmentedand non-pigmented hair and in a mouse model of AA white hair can be successfully targeted by inflammatory cells (McElwee et al. 2001a).While it is quite possible for melanocyte derived antigens to be involvedin AA, they need not be the primary agents in precipiting disease onset.Downstream of the disease activation event it is likely that the phenomena ofepitope spreading (Chan et al. 1998) results in the targeting of numerous antigenic epitopes from diverse sources within the hair follicles. Logically, onewould expect the primary target for follicular inflammation to be a key component in hair fiber production, the targeting of which would lead to growthcessation. While follicular dermal papilla cells may be a candidate source ofthe primary antigenic target for inflammatory cells (Nutbrown et al. 1996),the most likely source of the primary inciting agent are follicular keratinocytes. Circumstantial evidence in support of this view includes the identification of hair follicle specific autoantibodies which target keratinocyte derivedepitopes and that intra-follicular penetrating inflammatory cells in humansand animal models primarily take up residence in keratinocyte comprisedroot sheath and matrix locations (McElwee et al. 2003b). However, beyondthese speculations, little is known about the nature of the antigenic targetson which inflammatory cells focus in AA. It is quite possible that differentclinical AA presentations may be associated with different antigenic epitopetargeting patterns. The Humoral Immune System in AAAutoantibodies against hair follicle antigens have been identified in both humans and animal models of AA with significantly increased frequency compared to the general population. Tobin et al, demonstrated production ofantibodies with heterogeneous targeting of hair follicle structures and similar heterogeneity of morphological targeting has been found in mouse andrat models of AA (McElwee et al. 1996a; Tobin et al. 1997). Trichohyalin andspecific keratins, have been defined as targets for some of the antibodies(Tobin et al. 2003). The diversity of autoantibody production with no consistent 406 Pia Freyschmidt-Paul et al. structure targeting observed in serum samples from different patients,suggests autoantibodies are not the dominant factor in AA development.Other evidence also supports this view with time line evaluation studies on amouse model for AA indicating cellular targeting for the follicle occurs priorto an upregulation in genes associated with antibody production (Carroll etal. 2002). Transfer of serum from AA patients to skin in a SCID-human modelalso failed to regenerate the disease phenotype (Gilhar et al. 1992). However, this does not invalidate antibody investigation. Autoantibodies in serum from AA patients may hold important clues to the targets for cellularinflammation in AA. Autoantibodies may yet be shown to play a secondaryrole in the disease pathogenesis. One small study involving the transfer ofequine AA-derived antibodies to normal haired mice promoted an increasein telogen state hair follicles, although no apparent development of cellularinflammation was induced and systemic AA did not develop (Tobin et al. 1998).Autoantibodies then may play a secondary role accentuating the chronic disease state but it seems unlikely they are the primary mediators of AA. The Cellular Immune System in AAIn many autoimmune diseases and animal models of autoimmune diseaselymphocytes are identified as the primary disease mediator. Most commonly,CD4+ lymphocytes have been identified as the primary pathogenic cell subset retaining the ability to transfer many autoimmune diseases, but other subsets including CD8+ cells have also been identified as important in diseasepathogenesis (eg. Ablamunits et al. 1999; Huseby et al. 2001). The predominantly CD4+ and CD8+ lymphocyte inflammation of hair follicles suggests thesecells to be the primary instigators of the disease phenotype in AA. Depletingthe inflammatory cell number with immunosuppressive therapies reinforcesthe general view that these cells hold the key to hair growth inhibition in AA(Freyschmidt-Paul et al. 2001). In rodent models this has been taken a stepfurther with the selective removal of CD4+ or CD8+ cells by injections monoclonalantibodies. Depletion of one or other lymphocyte population permits hairregrowth, but with replacement of the depleted cell population the AA phenotype redevelops (McElwee et al. 1996b; McElwee et al. 1999b; Carroll etal. 2002).Recent cell subset transfer studies have further characterized the importance of CD4+ and CD8+ lymphocytes in AA. Human AA-affected, skin-derived cells have been shown to reinduce inflammatory hair loss in xenograftsof previously AA affected skin grafted to scid/scid mice (Gilhar et al. 1998).Separation of CD4+ and CD8+ cell subsets and their transfer to this model suggested each cell type alone was not capable of reinducing hair loss, but incombination hair loss redeveloped (Gilhar et al. 2002). In C3H/HeJ mice subcutaneous injection of CD8+ cells led to the rapid development of localized Alopecia areata: Pathogenesis 407 hair loss at the site of injection but no further development of hair loss. Incontrast, injection of CD4+/CD25- cells resulted in little localized hair loss butsuccessful transfer of the disease systemically with the development of multiple alopecia patches (McElwee et al. in press). Thus, it is the CD4+/CD25cell population in the C3H/HeJ mouse model that retains the capacity totransfer the systemic AA phenotype to naive hosts and most likely promotesAA via promotion of APC activity and subsequent stimulation of hair follicleautoreactive CD8+ cells. This pathogenic activity defines the CD4+/CD25- cellpopulation as a key component of AA and a prime target for the develop+ment of therapeutic strategies. CD8 cells, although apparently the primaryeffectors of the actual hair loss phenotype, are largely under the control ofCD4+/CD25- cells. Mechanisms of Cellular Action on the Hair FollicleIt seems then that the cellular immune system is the principal promoter ofAA. The question remains how might leukocytes act on hair follicles to promote hair loss. Studies so far implicate a combination of mechanisms. Cytotoxicity may be mediated through Fas – Fas ligand (FasL) interaction. Thebinding of Fas expressed on target cells by FasL on activated lymphocytesleads to apoptosis of the Fas expressing cell. This mechanism of tissue destruction is not MHC restricted and has the potential to damage innocent bystander cells not directly targeted by the pathogenic lymphocyte clones. Fas –FasL signaling is also believed to promote antigen presentation (Siegel et al.2000). In the C3H/HeJ mouse model for AA, Fas and FasL are significantlydifferentially expressed in skin infiltrating lymphocytes and Fas is highly expressed on human and mouse dystrophic hair follicle keratinocytes (Bodemeret al. 2000; McElwee et al. 2002a; Freyschmidt-Paul et al. 2003). Histocompatible mice deficient in Fas or FasL are comparatively resistant to the induction of AA. This resistance was in part localized to the skin as Fas and FasLdeficient skin transplanted to AA affected mice resisted immune activity andcontinued to grow hair (Freyschmidt-Paul et al. 2003). The possibility of anautocrine and paracrine action of Fas and FasL within and between hair follicle keratinocytes may add to the action of the inflammatory infiltrate and mayexplain why FasL deficient hair follicles were also relatively resistant to AA.Perforin, produced by cytotoxic cells, is a potent mediator of cell lysis(Russell and Ley, 2002). For perforin induced lysis of target cells to occur, theT cell receptor of an autoreactive cell must ligand with the relevant antigenicpeptide presented in conjunction with MHC on the target cell. Whether perforinmediated cell destruction occurs in AA is unknown, but the presence of highlyactivated CD8+ cells within dystrophic hair follicles and the high expressionof MHC molecules on hair follicle keratinocytes circumstantially suggestsMHC restricted, perforin mediated, tissue damage could occur. Granzymes, 408 Pia Freyschmidt-Paul et al. that may gain access to target cells via perforin or induce apoptosis independent of perforin through binding cell surface receptors (Motyka et al. 2000),have been identified as highly expressed in human AA (Bodemer et al. 2000;Carroll et al. 2002). Inducible nitric oxide synthase expression is apparentduring mouse AA development which may suggest a role for nitric oxide indisease pathogenesis (McElwee, personal observations).Lymphocytes need not have close contact with hair follicle keratinocytesto exert an effect. Cytokines such as TNFa may have a negative impact onthe survival of hair follicle keratinocytes in AA (Janssen et al. 2003). IFNg mayinhibit cell proliferation and promote keratinocyte expression of MHC molecules that will aid other inflammatory mechanisms (Schroder et al. 2004).Other cytokines may negatively regulate keratinocyte cell proliferation andencourage hair follicles to truncate their growth cycle and enter a telogenresting state (Randall, 2001). Overall, cytokines may be significant modulators of hair follicle disruption. Disease Modulating FactorsWhile the fundamental mechanism of AA is essentially self contained it islikely there are exterior factors that influence the disease course. Thus farvarious, candidate genetic influences have been identified in human and rodent model AA (described elsewhere). In addition, epigenetic factors arealso probably involved in determining an individual’s susceptibility to AA.Epigenetic factors may be both susceptibility and severity modifiers of AAand act in two ways: They may modify an individual’s general susceptibilityto a disease activation event. Alternatively, they may be involved in determining the future prognoses for hair loss in terms of extent, hair loss pattern,duration or chronicity of disease, and/or resistance to treatment, once onsetof overt hair loss has been initiated.Recently, using the C3H/HeJ mouse model, interferon gamma (IFNg) hasbeen identified as a key player in precipitating onset of hair loss (FreyschmidtPaul et al. 2004). Injecting IFNg into mice known to be genetically susceptibleto AA brings forward the time at which AA onset develops and increases thefrequency of mice expressing the AA while transgenic knockout mice genetically deficient in IFNg are incapable of developing AA. In the real world,IFNg expression is increased in response to a variety of insults, particularlyinfectious agents (Schroder et al. 2004). It is generally accepted that an infectious agent might promote autoimmune disease onset through mimicry ofantigenic epitopes (Wucherpfennig, 2001). If an infectious agent expressesantigens that are similar to self antigens found naturally in hair follicles thenexposure to the pathogen may elicit a cross reactivity to the to the hair folliclelocated antigens. However, the knowledge that IFNg is involved in diseasedevelopment suggests that there need not be a specific relationship between Alopecia areata: Pathogenesis 409 pathogen-expressed antigens and hair follicle antigens. Rather, responses tothe general “viral load” might play a key role in AA for some (Stewart andSmoller, 1993; Kissler et al. 2001). It is conceivable then that an individualgenetically susceptible to AA might experience onset of hair loss subsequentto infectious agent exposure or exposure to any other factor that promotes inan increase in IFNg. Chronic exposure or cumulative exposure to multiplepathogens may increase the level of susceptibility to disease onset.Increased levels of IFNg alone are unlikely to induce AA onset in any oneindividual. If this were true, AA would be expressed with a much higher frequency within the population than is the case. It is likely that multiple genetic and epigenetic factors must interact correctly for actual disease onset tooccur. Rodent model research has shown that hormones can influence thedegree of susceptibility to AA induction. Ovariectomized mice had a relatively reduced rate of AA development compared to estradiol supplementedmice. In contrast mice supplemented with testosterone were fully resistant toAA development compared to gonadectomized mice (McElwee et al. 2001b).Hormonal influence in humans is suggested by old case reports assertingtemporary hair growth in AA affected women during the late stages of pregnancy or improvement with onset of menopause (Sabouraud 1913, LévyFranckel 1925, Walker 1950). Model research has also shown that increaseddietary soy oil content can reduce AA susceptibility (McElwee et al. 2003a).While this is of little practical value in understanding human AA, it demonstrates the potential influence of environmental factors on AA susceptibility.To protect against inappropriate immune system activation, and to calmdown activated immune cells after a pathogenic challenge has been cleared,immune regulatory mechanisms are exploited. CD4+/CD25+ cells have beenidentified as one of probably several lymphocyte regulatory cell subsets thatcan restrain pathogenic cell activity. CD4+/CD25+ cells are essential for maintaining homeostasis, are able to suppress the induction of autoimmune disease,suppress CD4+/CD25– cells, and can inhibit the effector function of autoreac+tive CD8 cells (Suri-Payer et al. 1998; Gao et al. 1999; Annacker et al, 2001).Little is currently known about immune regulatory mechanisms in human AA.Recent studies in the skin graft induced AA mouse model revealed thatCD4+/CD25+ cell levels drop significantly on activation of AA and prior to theonset of overt hair loss (Zöller et al. 2002). In contrast, sham grafted mice areable to maintain CD4+/CD25+ cell numbers and quickly recover normal inflammatory cell numbers after injury. This apparent active depression of regulatory cells in AA challenged mice may be a key factor in AA susceptibility.++CD4 /CD25 cells or CD8 cells from AA affected mice transferred to unaffected mice can induce some form of AA, but if CD4+/CD25+ cells are addedto the mixture the disease onset is partially inhibited (McElwee et al. in press).This indicates the potential importance of regulatory cell failure in AA development. Why regulatory cells fail to appropriately restrain onset of AA is notknown but further examination of CD4+/CD25+ cells and other regulatorycells may reveal significant insights into AA susceptibility and development. 410 Pia Freyschmidt-Paul et al. There are likely other epigenetic factors that modulate AA. Stress hasbeen suggested as a potential instigator of autoimmune diseases possiblythrough glucocorticoid modulation of inflammatory cytokine expression(Elenkov and Chrousos, 2002). Stress has also been postulated as a potentialinfluence on AA development although the evidence is only circumstantial(Mehlman and Griesemer, 1968; Colon et al. 1991; Liakopoulou et al, 1997;Kavak et al, 2002). AA frequency and severity is apparently associated witha greater frequency of allergies as compared to the general population (Muller and Winkelmann, 1963; Ikeda, 1965; Penders, 1968; De Waard-van derSpek et al. 1989; Weise et al. 1996). Whether there is a direct relationshipwhereby an allergic response is capable of increasing immune system sensitivity and instability such that AA susceptibility increases, or whether theincreased frequency of allergies in AA patients is merely a reflection of genetically determined immune system sensitivity remains to be determined. Otherpromoters of the immune system in autoimmune diseases may include drugsand toxins (Bigazzi, 1994; Elkayam et al. 1999; Holsapple, 2002). In principle,one or more of these factors may modulate the immune system in AA, but inpractice little is known about the effects of environmental stimuli on AA inrodent models or humans.With time and changes in epigenetic factors that may influence AA, sothe degree of susceptibility to AA will fluctuate. While an individual may havea genetic susceptibility to AA that may be regarded as an unmovable baseline, additional epigenetic factors may increase or depress overall AA susceptibility. Only if an individual receives multiple signals that cumulativelyincrease the susceptibility to disease above a threshold level for expressionwill an episode of AA actually develop. This may also help explain why thepresentation of the AA phenotype is so varied. Individuals with chronic extensive AA, versus those with an isolated AA patch, may have a dominantgenetic susceptibility to disease and relatively minor epigenetic modificationof this genetic susceptibility. In others who whose AA waxes and wanes, orwho present with multiple episodes of AA expression and remission may bemore greatly impacted by epigenetic factors and their changing influencewith time. Disease InitiationWe still do not know the disease phenotype precipitating event, but one hypothesis is that AA develops in susceptible individuals due to a failure in hairfollicle immunoprotection. Anagen stage hair follicles are regarded as immuneprivileged sites (Westgate et al. 1991; Paus et al. 1999), but follicle immunoprotection is likely only transient due to the nature of the hair follicle cycle.Research suggests the onset of catagen is associated with an infiltration ofimmune cells, candidate antigen presenting cells (Parakkal, 1969; Westgate Alopecia areata: Pathogenesis 411 et al. 1991; Paus, 1996; Eichmüller et al. 1998). Regression of the hair folliclein catagen involves high levels of apoptosis and significant remodeling of thelower transient portion of the hair follicle (Weedon and Strutton, 1981; Lindneret al. 1997). It is possible then that the immune system is constantly exposedto low levels of hair follicle derived antigens as hair follicles cycle throughcatagen and given the ability of dendritic cells to present apoptosis derivedantigens. Autoimmune disease is not regarded as an all or nothing event.Rather, there are degrees of autoreactivity and a threshold level above whichovert autoimmune disease is induced (Ludewig et al. 2001; McElwee et al.2001b). A reflection of this may be the low level of hair follicle specific antibodies found in some humans and rodents in the absence of overt AA (Tobinet al. 1994a; Tobin et al. 1994b; Tobin et al. 1997). If however, catagen regression became disordered and the immune cell infiltrate associated withcatagen inappropriately presented antigenic peptides in association with expression of costimulatory molecules, antigen presentation to the immunesystem might breach the threshold for stimulation of autoreactive cells. In agenetically susceptible individual, resident in a permissible environment,AA might follow. SummaryOverall, we still cannot claim AA is an autoimmune disease with completeconfidence, but all the evidence produced so far points in that direction andprovides compelling supporting evidence. Circumstantial evidence from observing the state of humans with AA has been supplemented with indirect,functional evidence from a variety of animal models. In the near future, animal model and human genome screening will likely define loci involved inAA susceptibility and resistance. 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J Am Acad Dermatol 49: 96–98Valsecchi R, Vicari O, Frigeni A, Foiadelli L, Naldi L, Cainelli T (1985) Familial alopeciaareata – genetic susceptibility or coincidence? Acta Derm Venereol 65: 175–7Van der Steen PH, Baar van JMJ, Perret C, Happle R (1991) Treatment of alopecia areata withdiphenylcyclopropenone. J Am Acad Dermatol 24: 253–7Van der Steen P, Traupe H, Happle R, Boezeman J, Strater R, Hamm H (1992a) The geneticrisk for alopecia areata in first degree relatives of severely affected patients. Acta DermVenereol (Stockh) 72: 373–5Van der Steen PH, Happle R (1992b) Dyschromia in confetti as a side effect of topicalimmunotherapy with diphenylcyclopropenone. Arch Dermatol 128: 518–20Van der Veen EE, Ellis CN, Kang S, Case P, Headington JT, Voorhees JJ, Swanson NA (1984)Topical minoxidil for hair regrowth. J Am Acad Dermatol 11: 416–421Verbov J (1973) Steroid solution treatment of alopecia areata. Arch Derm 108:135Vestey JP, Savin JA (1986) A trial of 1% minoxidil used topically for severe alopecia areata.Acta Derm Venereol (Stockh) 66: 179–80Vogel F, Motulsky AG (1997) Human Genetics: Problems and Approaches. 3rd ed. Berlin:Springer-Verlag, 223–6Walker SA, Rothman S (1950) Alopecia areata. A statistical study and consideration of endocrine influences. J Invest Dermatol 14: 403–413Weedon D, Strutton G (1981) Apoptosis as the mechanism of the involution of hair follicles incatagen transformation. Acta Derm Venereol 61: 335–9Weidman AI, Zion LS, Mamelok AE (1956) Alopecia areata occurring simultaneously in identical twins. Arch Dermatol 74: 424–6Weise K, Kretzschmar L, John SM, Hamm H (1996) Topical immunotherapy in alopeciaareata: anamnestic and clinical criteria of prognostic significance. Dermatology 192:129–133Weiss VC, West DP, Fu TS, Robinson LA, Cook B, Cohen RL, Chambers DA (1984) Alopeciaareata treated with topical minoxidil. Arch Dermatol 120: 457–63Weitgasser H (1968) Erfahrungen mit einer Triamcinolon-Tinktur bei entzündlichen Dermatosen. Z Hautkr 43: 505–8Welsh EA, Clark HH, Epstein SZ, Reveille JD, Duvic M (1994) Human leukocyte antigen-DQB1*03 alleles are associated with alopecia areata. J Invest Dermatol 103: 758–63Westgate GE, Craggs RI, Gibson WT (1991) Immune privilege in hair growth. J InvestDermatol 97: 417–420White SI, Friedmann PS (1985) Topical minoxidil lacks efficacy in alopecia areata. ArchDermatol 121: 591Whitmont K, Cooper A (2003) PUVA treatment of alopecia areata totalis and universalis: aretrospective study. Australas J Dermatol 44: 106–109Wiseman MC, Shapiro J, MacDonald N, Lui H (2001) Predictive model for immunotherapy ofalopecia areata with diphencyprone. Arch Dermatol 137: 1063–1068Wucherpfennig KW (2001) Mechanisms for the induction of autoimmunity by infectiousagents. J Clin Invest 108: 1097–104Wunderlich C, Braun-Falco O (1965) Mongolismus und Alopecia areata. Med Welt 10: 477–81Zandman-Goddard G, Shoenfeld Y (2002) HIV and autoimmunity. Autoimmun Rev 1: 329–37Zhang JG, Oliver RF (1994) Immunohistological study of the development of the cellular infiltrate in the pelage follicles of the DEBR model for alopecia areata. Br J Dermatol 130:405–14 420 Pia Freyschmidt-Paul et al. Zlotogorski A, Weinrauch L, Brautbar C (1990) Familial alopecia areata: No linkage withHLA. Tissue Antigens 36: 40–1Zöller M, McElwee KJ, Engel P, Hoffmann R (2002) Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopeciaareata. J Invest Dermatol 118: 983–92 15 Novel Therapeutic Approaches inAutoimmune Skin DisordersSybille Thoma-Uszynski and Rüdiger Eming IntroductionThe medical management of autoimmune skin disorders is complex. At present,the mainstay of therapy of most of the previously characterized autoimmuneskin diseases is based on mid- to long-term administration of immunosuppressive drugs. Although therapeutic immunosuppression took away the fatality of many autoimmune skin disorders, there are several pitfalls associatedwith longterm immunosuppression. Under this light, there is an urgent needto incorporate novel efficient therapeutic applications which harbor fewer sideeffects in the medical management of autoimmune skin diseases.Immunological tolerance and breakdown of or escape from self-toleranceare incompletely understood. Deeper insight into immune mechanisms of selftolerance should extend the possibilities for specific therapeutic interventions in autoimmune diseases. Principally, therapeutic strategies are targetedto distinct steps in the sequence of events which lead to a misbalance in immune function and/or break of tolerance and eventually to overt autoimmunedisease. These include bone marrow ablation, general immunosuppression,modulating autoantigen recognition, cytokine function, autoantibody production and degradation, gene transcription or inhibiting cellular immune responses. During the past several years the development of biologic agents(biologics) interfering with key steps in the immunopathogenesis of autoimmune diseases have profoundly changed the way of treating autoimmunedisorders. This chapter reviews the most recent developments and the corresponding clinical applications. Immunomodulatory Drug DevelopmentRecent drug development extended the spectrum of anti-inflammatory and/orimmunosuppressive pharmaceuticals. 422 Sybille Thoma-Uszynski and Rüdiger Eming Mycophenolic AcidMycophenolic acid (MPA), an immunosuppressive agent that blocks lymphocyte purine synthesis (Lipsky 1996), had been introduced into the managmentof psoriasis, but now becomes increasingly popular for other clinical applications, including autoimmune bullous skin disorders, such as pemphigus vulgaris(PV) and bullous pemphigoid (BP) (Bohm et al. 1997; Enk and Knop 1999;Grundmann-Kollmann et al. 1999). One recent study applied it as monotherapyin PV and BP and disease activity was successfully suppressed (GrundmannKollmann et al. 1999). Mimouni et al. conducted a historical prospective studyincluding 31 patients with PV and 11 pemphigus foliaceus (PF)-patients,evaluating the role of MPA as a corticosteroid-sparing agent (Mimouni et al.2003). Complete remission was achieved in 71% and 45% of the patients withPV and PF, respectively. The authors considered MPA as an effective andwell tolerated adjuvant in the treatment of patients with pemphigus (Mimouniet al. 2003). Powell et al. confirmed these conclusions by evaluating the efficacy and safety of mycophenolate mofetil (MMF) combined with glucocorticosteroids in a group of 17 pemphigus patients (Powell et al. 2003). In thisstudy, treatment with MMF was an effective steroid-sparing immunosuppressant to 12 of the 17 patients (Powell et al. 2003). Recent studies demonstrate good responses to treatment with MMF in various nephrological autoimmune disorders. Filler et al. reported effective treatment of pediatric patientswith vasculitis and connective tissue disease involving the kidney, i.e. SLE,antiphospholipid antibody syndrome or Wegener granulomatosis (Filler etal. 2003). Contreras et al. showed that for patients with proliferative lupus nephritis maintenance therapy with MMF or azathioprine (AZA) seems to be moreefficacious and safer than i.v.-cyclophosphamide treatment (Contreras et al.2004). A recent study by Budde et al. with renal transplant patients demonstrated that MMF can safely be converted to enteric-coated mycophenolate sodium without compromising the safety and efficacy of the drug(Budde et al. 2004). This enteric-coated formulation reduces the adverse effects in the upper gastrointestinal tract compared to MPA. The current status ofMPA as a promising compound in the dermatological field is reviewed byFrieling and Luger (Frieling and Luger 2002). Immunosuppressive MacrolidesImmunosuppressive macrolides represent a new class of substances whichmodulate inflammatory processes. They can be topically applied and are potential alternatives to corticosteroid therapy. Tacrolimus (FK506)The macrolide lactone tacrolimus (FK506), introduced into transplantationmedicine for prevention of allograft rejection, is now also applied for treat- Novel Therapeutic Approaches in Autoimmune Skin Disorders 423 ment of inflammatory skin disorders such as atopic eczema, psoriasis, pyodermagangrenosum, Behcet’s disease, alopecia areata and lichen planus (Assmannet al. 2000). Functionally similar, but structurally different to cyclosporin A,FK506 binds to immunophilins and this complex specifically inhibits calcineurinephosphatase and early gene expression after T cell stimulation, but with a 10to 100 fold stronger immunosuppressive potency than cyclosporin A (Sawadaet al. 1987).It has been shown that topical application of FK506 has a wide spectrumof effects including reduced expression of costimulatory molecules on immunocompetent cells and cytokine production in the skin (Homey et al. 1998). Ithas been used to treat patients with systemic sclerosis with moderate success(Morton and Powell 2000). A cohort of recent case reports demonstrated thesuccessful topical treatment of different autoimmune blistering disorderswith tacrolimus, including vesicular pemphigoid (Chuh et al. 2004), cases oflocalized pemphigoid (Chu et al. 2004; Ko et al. 2004) and labial pemphigusas reported by Hodgson et al. (2003). Vecchietti et al. reported the case of apatient with CD20+ follicular non Hodgkin’s lymphoma developing paraneoplastic pemphigus with severe stomatitis and painful ulceration on the dorsumof the tongue (Vecchietti et al. 2003). In addition to treatment with monoclonalanti-CD20 antibody (Rituximab®), the patient was given an oral suspensionof tacrolimus 0,03%, three 5-min rinses per day. The mucosal lesion clearedwithin six weeks and relapses of mucosal ulcerations responded well to reintroduction of a two week course of topical tacrolimus. (Vecchietti et al. 2003).Furthermore, effective topical treatment of Hailey-Hailey´s disease (Rabeniet al. 2003; Sand et al. 2003) and recalcitrant chronic discoid lupus erythematosus (CDLE) (Walker et al. 2003) with tacrolimus have recently been described.Thus the current results may prove tacrolimus a useful adjunct in the topicaltreatment of a variety of cutaneous autoimmune disorders. Sirolimus (Rapamycin)Sirolimus (Rapamycin) is another macrolide which also binds to immunophilins.In contrast to cyclosporin A and tacrolimus, the sirolimus FKBP12 complex inhibits the mammalian target of rapamycin and interferes with cell cycling events. Ascomycin (ASM 981)Another related macrolactam derivative, ASM 981 or ascomycin has beenspecifically developed for the treatment of inflammatory skin diseases. It inhibits via complex formation with FKBP12 calcineurin phosphatase and genetranscription. Thereby, it suppresses Th1 and Th2 cytokine production,downmodulates release of proinflammatory mast cell mediators and of note,also decreases the release of the proinflammatory cytokine, TNF-a (Grassberger et al. 1999). 424 Sybille Thoma-Uszynski and Rüdiger Eming This new generation of macrolid derivatives represents a class of T celldependent immunosuppressive agents. Their application in dermatologyholds great potential to more specifically influence immune dysregulation indistinct autoimmune disorders and warrants controlled clinical trials. LeflunomideLeflunomide is a new immunomodulatory drug which had been approvedfor treatment of rheumatoid arthritis (RA) (Prakash and Jarvis 1999). Thespecific mode of action is not clear; it presumably inhibits the mitochondrialenzyme dihydro-orotate dehydrogenase and subsequently, pyrimidine biosynthesis with suppressive effects on cytotoxic T cells and antibody production. In addition, leflunomide exerts an antiinflammatory action throughinhibition of leucotriene B4 (LTB4) formation and chemotaxis (Chong et al.1999). Furhermore, it is an antiproliferative agent (Kurtz et al. 1995). One recent study suggests that it also blocks TNF-a receptor signaling (Manna etal. 2000). Leflunomide has been successfully applied and shown to be of particular value in critical situations where steroids are contraindicated andother steroid-sparing agents are not tolerated (Nousari and Anhalt 2000). Itsefficacy and safety profile make it a potential agent for hyperproliferativeand inflammatory dermatoses (Herrmann et al. 2000). Lately, however, reports on substantial liver toxicity contributed to concerns regarding its handling, particular if applied as part of a combination therapy with potentialadditive or synergistic toxic effects (Weinblatt et al. 2000; Emery et al. 2000).Lately, also cystic macular edema has been reported as a severe adverseevent after administration of leflunomide (Barak et al. 2004). Antigen Specific Approaches for Therapy ofAutoimmune DiseasesThe ideal treatment for autoimmune diseases would be to induce long lasting autoantigen specific tolerance. A precondition for such treatment is thatthe disease-associated autoantigens are well characterized. This holds truefor only few, mostly organ-specific autoimmune diseases such as myasteniagravis (MG), Hashimoto’s disease, autoimmune diabetes mellitus or the autoimmune skin diseases BP and PV (Stanley 1989; Patrick 1990). Therapy by Autoantigen AdministrationSeveral experimental animal models of autoimmune disease are established.In these models, autoantigens are used to induce the autoimmune disease Novel Therapeutic Approaches in Autoimmune Skin Disorders 425 such as MBP for experimental autoimmune encephalitis (EAE), insulin forautoimmune diabetes mellitus, acetylcholine receptor (AchR) for experimental autoimmune myasthenia gravis (EAMG), and thyroglobulin for experimental autoimmune thyroiditis, and others. Depending on the dose androute of administration, exogenous administration of proteins that usuallyrepresent self-antigens can lead to tolerance induction and prevention of autoimmune disease. This paradoxical use of self-antigens to treat autoimmune disease has been verified in the aforementioned experimental animalmodels as well.The antigen is delivered either via a tolerizing route, e.g. via oral/intestinal or nasal mucosa, or in a tolerogenic form, e.g. as soluble peptide MHCcomplex. Systemic administration (intraperitoneal, intravenous or subcutanousinjection) of high dose peptide or monomeric protein can induce clonal deletion,clonal anergy or immune deviation (Liblau et al. 1997). Examples of systemicantigen immunotherapy in experimental autoimmune disease are reviewedby Libleau and colleagues (Liblau et al. 1997).Experimental proof of that principle had been brought about by Chen etal. who tolerized mice via oral administration of myelin basic protein (MBP).Isolated T cell clones from the mesenteric lymph nodes showed a Th2-typecytokine pattern and induced suppression of EAE. Thus mucosa-associatedregulatory T cells are generated upon an oral vaccination approach (Chen etal. 1994).Distinct mechanisms are involved during antigen-induced tolerance. Highdose antigen administration leads to antigen-induced T cell apoptosis via FasLor TNF-a-dependent pathways. Continuous presence of antigen can lead to Tcell hyporesponsiveness or clonal anergy. Low dose antigen administrationcan induce regulatory T cells which secrete anti-inflammatory cytokines,such as IL-4, IL-10 or TGF-b and suppress APC and/or effector T cell function and possibly compete with effector T cells for antigen presentation.The administration of the random peptide copolymer glatiramer acetate(Copaxone) is another related approach. Previously shown to be partially effective in multiple sclerosis (MS) it was thought to suppress autoreactiveT cells specifically (Johnson et al. 2000). A recent study, however, revealedthat the T cell receptor (TCR) is engaged in a degenerate, antigen-non specific way and immune function is altered by induction of cross-reactive regulatory Th2 responses with bystander suppressor effects on APC and/or effectorT cells in MS patients (Duda et al. 2000). Although shown in MS, it could be apotent agent also for other autoimmune diseases which are alleviated upon aTh2 shift.Antigen-specific immune therapy has not made it yet to broad clinical application. Although neither significant toxicity nor exacerbation of autoimmunedisease had overshadowed recent and ongoing clinical trials, a clear clinicalefficacy could not yet been demonstrated (Faria and Weiner 1999). 426 Sybille Thoma-Uszynski and Rüdiger Eming Modified Antigens to Induce ToleranceAltered Peptide LigandsThe TCR interacts with the peptide MHC-complex with high specificity. Theon/off time of such interaction determines which co-stimulatory moleculesparticipate in the immunologic synapse with functional consequences onsubsequent T cell activation. According to this “strength of signal theory”there is either full T cell activation, partial activation or T cell anergy. Full vs.partial T cell activation may lead to an opposite cytokine profile, e.g. Th1 vs.Th2, a phenomenon called immune deviation. An altered peptide ligand (APL)has slightly changed residues of an immunodominant self-epitope which impair the T cell strength of signal (Fig. 1). Thus a single TCR can productivelyrecognize a large continuum of related ligands (Kersh and Allen 1996a). Thisflexibility is crucial for T cell development and harbors the possibility for bothbeneficial and harmful effects on peripheral T cells (Kersh and Allen 1996b). Fig. 1. Natural peptide ligands and altered peptide ligands (APL). The T cell receptor of anautoreactive T cell is fully stimulated by its natural ligand. Slight modification of the naturalpeptide ligand results in an APL. Interaction of an APL with the autoreactive T cell can lead topartial activation with a possible shift of the cytokine profile or to T cell anergy, both desiredeffects regarding therapeutic intervention in states of autoimmunity Novel Therapeutic Approaches in Autoimmune Skin Disorders 427 The APL strategy has been applied in several animal models of autoimmune diseases, and EAE being a well established animal model of MS inparticular: A single TCR antagonistic peptide has been shown to inhibit EAE(Kuchroo et al. 1994). A single amino acid shift of a myelin basic protein peptide produced an APL which mediated immune deviation by changing thecytokine profile towards a protective Th2 or Th0 pattern while retaining crossreactivity to the native peptide (Nicholson et al. 1995).Recently, first phase II clinical trials in humans applied the APL approach.One	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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study compared the APL of MBP to placebo. The APL-treated groupwas clinically stable and fine analysis revealed that lesions were reduced involume and number. The APL induced a regulatory type 2 T helper cell response that cross-reacted with the native peptide (Kappos et al. 2000). Thesecond phase II clinical trial to treat MS with an MBP peptide (aa 83–99)derived APL induced an exacerbation of the disease in three individuals, andthe trial had therefore to be halted (Bielekova et al. 2000). In two of the threepatients, clinical worsening could be attributed to the APL as immunologicalstudies demonstrated the encephalitogenic potential of the APL peptide (aa83–99).Although principally appealing to modulate the fine tuning of the immunologic synapse by APL, severe considerations arise from these first clinicalexperiences. In light of an individual T cell repertoire in the outbred humanpopulation, the functional effects of APLs seem unpredictable and problematic. Complementary PeptidesAccording to the molecular recognition theory, peptides encoded by theantisense RNA are designated as complementary or antisense peptides, caninteract with the natural peptide due to their hydropathic complementarity(Blalock 1990). Antibodies raised against complementary peptides of a ligandcan recognize its receptor, thus antibodies against complementary peptidesposses the ability to bind antibodies against sense or natural peptides (Aragaet al. 1996). Proof of principle had been given by animal models of AMG andEAE (Araga and Blalock 1994; Araga et al. 1996, 1999, 2000). These studiesshowed that a complementary peptide vaccine approach resulted in T cellanergy and blocking of T cell help in particular (Araga et al. 1999, 2000). Thecomplementary peptide approach has also been shown to alter B cell-mediated autoimmune diseases by induction of anti-idiotypic antibodies to pathogenic autoantibodies (Smith et al. 1987; Araga and Blalock 1994). One recentstudy based on the molecular recognition theory aimed to develop a complementary peptide vaccine to BP (Nie et al. 1999). Choosing the extracellular noncollagenous immunodominant NC16A domain of BP180, the putative majorBP autoantigen, to derive complementary peptides from, failed however todemonstrate binding to the natural peptides. Thus the targeted epitope was 428 Sybille Thoma-Uszynski and Rüdiger Eming not eligible for complementary peptide vaccine development for BP (Nie etal. 1999). This result does not preclude that other yet undefined BP180 epitopescan be targeted using the complementary peptide approach. Tolerogenic Dendritic CellsDendritic cells (DC) are the most powerful antigen presenting cells and initiate immune responses after uptake, processing and presentation of foreignantigen. In addition to their eminent role in host defense, DC are also heldresponsible in triggering autoimmune diseases by presenting autoantigensto autoreactive T cells (Ludewig et al. 1998, 1999; Link et al. 1999; Drakesmith et al. 2000). Several immuntherapeutic strategies utilize the antigenpresenting capacity of DC, such as DC vaccine for treatment of cancer or infection. Recent attempts included also to modify DC function such that subsequent T cell activation would be inhibited or downregulated. For instance,monocyte-derived human DC cultured in the absence of IL-4 and in thepresence of low concentrations of GM-CSF were maturation-resistant and induced hyporesponsiveness of T cells and prolonged cardiac allograft survival(Lutz et al. 2000).Appropriate cytokine treatment can convert immunogenic into tolerogenicDC (Drakesmith et al. 2000). IL-10-treated DC had a reduced allostimulatorycapacity and induced a state of T cell anergy (Steinbrink et al. 1997, 1999). Incontrast to cytokine treatment which halts DC maturation, it has been shownrecently that also fully mature DC are able to induce anergy in T cell clonesreactive with thyroid peroxidase antigen and are able to process and presentan immunodominant epitope with antagonistic altered peptide features(Quaratino et al. 2000). Recently, DC that take up apoptotic cells were described to induce peripheral tolerance to self antigens (Huang et al. 2000;Sauter et al. 2000).More and more functional properties are ascribed to cytokines, chemokines and other factors within the network of immune regulation. One suchfactor is the neuropeptide alpha-melanocyte stimulating hormone (a-MSH)which has been shown to exert anti-inflammatory effects by antagonizingIL-1, IL-6 and TNF-a (Becher et al. 1999). a-MSH signals via the melanocortinreceptor 1 (MC-1R) which is present on both monocytes and DC. Indicativefor the potentially anti-inflammatory and/or immunosuppressive role of a-MSHis the observation that it downregulates the expression of the co-stimulatorymolecules CD86 and CD40 on monocyte-derived DC (Becher et al. 1999).Although the term DC defines a heterogeneous population with differentfunctional properties ranging from powerful to poor T cell activators, thereare therapeutic possibilities emerging to functionally modulate DC into mediators of tolerance in T cell-dependent autoimmune diseases (Fig. 2). Novel Therapeutic Approaches in Autoimmune Skin Disorders 429 Fig. 2. Immunogenic and tolerogenic dendritic cells (DC). Immunogenic DC can be derivedfrom monocytes by in vitro culture in the presence of a cytokine cocktail, usually containingGM-CSF and IL-4. Addition of TNF-a or LPS induces complete maturation. Variations of thecytokine cocktail in terms of content and concentration of the cytokines can modify theresulting DC regarding maturation state and immunogenicity. Depicted are cytokinecombinations in the presence of which tolerogenic DC have been generated Modulating the Effector Phase of Autoimmune DiseasesSince many autoimmune diseases share common effector pathways of inflammation it is a rational strategy to target this effector phase. Attempts to neutralize proinflammatory cytokines in conditions where these cytokines representpathogenic key elements, are promising and most clinical experience hasbeen collected regarding TNF-a. Inhibition of TNF-a SynthesisTNF-a mediates inflammatory effects by acting on multiple target cells andby inducing cascades of other cytokines such as IL-1, IL-6 and IL-8 facilitating leukocyte chemotaxis and angiogenesis. Elevated serum levels are detectable in many autoimmune diseases including RA, Crohn’s disease andMS. Ways to neutralize a cytokine include alteration of cytokine transcription/translation, administration of monoclonal antibodies against the cytokine orcytokine receptor, soluble cytokine receptors or nonactivating cytokineantagonists. In humans, TNF-a neutralization has been accomplished by in- 430 Sybille Thoma-Uszynski and Rüdiger Eming Table 1. Immunomodulatory and Anti-Inflammatory Mode of Action of ThalidomideInhibition of TNF-a production by monocytes/macrophagesReduced TNF-a mRNA half-lifeInhibition of IL-12 productionInhibition of leukocyte chemotaxisReduced phagocytosis by polymorphonuclear granulocytesIncreased IL-4 and IL-5 synthesis by mononuclear cellsInhibition of IFN-g production by mononuclear cells Table 2. Dermatological Disorders that are Responsive to Treatment with ThalidomideDisorder Initial therapeuticdaily dose Reference Erythema nodosum leprosum 400 mg Iyer et al. 1971 Stomatitis aphthosa 200–400 mg Brodthagen 1985,Grinspan 1985 Behcet‘s disease 100–400 mg Ghate and Jorizzo 1999 Cutaneous lupus erythematosus 100–400 mg Ordi-Ros et al. 2000,Kyriakis et al. 2000 Systemic lupus erythematosus 100–400 mg Khamashta et al. 2000 Prurigo nodularis 400 mg Warren et al. 1998,Daly and Shuster 2000 Pyoderma gangrenosum 200–400 mg Federman and Federman 2000 HIV-associated symptoms 200–400 mg Berger et al. 1995,Herranz et al. 1998 hibitors of cytokine production, monoclonal antibodies and genetically engineered soluble TNF-receptors.Thalidomide, a sedative drug originally introduced for sleep disordershas been among the first drugs known to exert anti-inflammatory action byinhibition of TNF-a synthesis (Calabrese and Fleischer 2000). There are additional effects exerted by thalidomide on immune function that are still incompletely understood (Table 1). Thalidomide reduces neutrophil phagocytosisand inhibits monocyte phagocytosis. A major immunomodulatory effect ofthalidomide is the selective, but incomplete inhibition of TNF-a productionby human monocytes. This effect is presumably the consequence of a significantly reduced half-life of TNF-a mRNA (Moraes et al. 2000).Since TNF-a is a major proinflammatory cytokine, the inhibition of thiscytokine by thalidomide may explain its effectiveness in a variety of inflammatory disorders. Conditions such as lepromatous leprosy which are highlyresponsive to thalidomide (FDA approval for this indication) are character- Novel Therapeutic Approaches in Autoimmune Skin Disorders 431 ized by elevated serum TNF-a levels. Relief of the symptoms is accompaniedby a decrease of serum TNF-a levels. There are, however, disastrous examples that demonstrate that thalidomide does not always reduce overall TNF-asynthesis. A double-blinded randomized study in drug-induced toxic epidermal necrolysis, a condition characterized by most severe epidermolysis ofskin and mucosa and elevated TNF-a concentrations in skin lesions and serum showed that treatment with thalidomide significantly increased the riskof a fatal outcome of this disorder. Patients with toxic epidermal necrolysishad even elevated TNF-a serum levels upon treatment with thalidomide (Wolkenstein et al. 1998).Apart from leprosy, thalidomide has been successfully applied in Behcet’sdisease and HIV-associated aphthosis, cutaneous and systemic lupus erythematosus and prurigo syndromes (Table 2). Removal or Inhibition of Pathogenic AutoantibodiesA key feature and pathogenetic hallmark of many autoimmune skin disorders is the formation of autoantibodies that interfere with the function of thetarget antigen. Autoimmune bullous skin disorders, such as pemphigus vulgaris(PV) and bullous pemphigoid (BP), are well characterized by the presence ofdistinct disease-precipitating antibodies. Removal of pathogenic autoantibodies contributes to reduced disease activity. PV as a paradigmatic disorder ofantibody-mediated autoimmunity correlates in intensity with the concentration of circulating autoantibodies. Moreover, transfer of the patients’ autoantibodies into mice reproduces the characteristic pathology of this disorder(Amagai et al. 1994, 1995). For more than 25 years, attempts have been madeto reduce levels of circulating autoantibodies as a therapeutic strategy (Fig. 3). PlasmapheresisPlasmapheresis has been one of the mainstays in the treatment of pemphigusfor several years but has not yet developed into a first-line therapy of autoimmune disases. This is greatly due to limited patient numbers which do not allowthe appropriate conduction of controlled clinical trials to confirm a statistically proven benefit (Schneider 1996). Plasmapheresis has been applied totreat a series of autoimmune diseases: In PV, BP, and severe epidermolysisbullosa acquisita (EBA), plasmapheresis led to a substantial steroid sparingeffect of immunosuppressive therapy (Sondergaard et al. 1995, 1997; Yamadaet al. 1997; Egan et al. 2000; Turner et al. 2000). Plasmapheresis has provenbeneficial in systemic lupus erythematosus, particularly in lupus nephritis(Wallace 1999; Braun et al. 2000), and also in systemic sclerosis (Dau andCallahan 1994) and dermatomyositis (Bennington and Dau 1981; Dau 1994).Unfortunately, plasmapheresis does not only remove pathogenic antibodiesbut also causes a significant loss of additional plasma components. 432 Sybille Thoma-Uszynski and Rüdiger Eming Fig. 3. Mechanism of action of intravenous immunoglobulin (IVIG) therapy. The intracellularFcRn receptor in endothelial cells binds pinocytosed IgG at acid pH in the endosome andredirects it to the neutral pH at the cell surface. Unbound IgG is degraded in the lysosome. Instates of hypergammaglobulinemia, FcRn becomes saturated, and lysosomal degradation isincreased. This IgG depleting mechanisms contributes to degradation of pathogenic IgG(autoantibodies) during high dose IVIG therapy. Therapeutic approaches targeting the FcRnwith either synthetic ligands or neutralizing mAb would predict the same IgG depletingcatablism without the risks and costs associated with IVIG therapy. Figure adapted from Yuand Lennon 1999 ImmunoadsorptionSeveral models demonstrated that selective adsorption of pathogenic autoantibodies may prevent the experimental induction of autoimmune bullousskin disorders of the pemphigus group. Amagai et al. demonstrated thatpemphigus sera can be depleted from IgG reactive with the autoantigens ofPV, desmoglein 3 and pemphigus foliaceus, desmoglein 1, by preadsorptionof the sera over immobilized protein A (Amagai et al. 1994, 1995). The IgGautoantibody-depleted sera no longer induced pemphigus-like blisters uponpassive transfer into newborn mice.Immunoadsorption is a novel therapeutic strategy aimed at removing distinct protein components from the patient’s plasma. Similarly to leukapheresis,peripheral blood from the patient is collected and separated by centrifugation into plasma and cellular components. The plasma fraction is then subjected to passage over an affinity column coated with protein A sepharose,peptides with IgG binding capacity, tryptophane-PVA or phenylalaninePVA. The most important advantages of adsorption apheresis over unselectiveplasma exchange (i.e. plasmapheresis) are: Novel Therapeutic Approaches in Autoimmune Skin Disorders ––– 433 Selective removal of pathogenic plasma proteins (i.e. antibodies, cytokines)No loss of essential plasma proteinsNo requirement for adequate protein replacement The tremendous costs of immunoadsorption, however, exceed those of unselective plasma exchange by a factor greater than 2. The different adsorbents currently available for therapeutic trials have distinct adsorption profilesand may be selectively utilized to remove distinct antibody subtypes (Ikonomovet al. 1992). Immunoadsorption has been successfully employed for the removalof circulating autoantibodies in systemic lupus erythematosus (Kutsuki et al.1998; Gaubitz et al. 1998). Recently, immunoadsorption has been successfullyemployed in the treatment of recalcitrant pemphigus vulgaris and pemphigusfoliaceus (Luftl et al. 2003; Eming et al. [submitted]). Single yet unpublishedcase reports suggest a beneficial effect of immunoadsorption in severe pemphigoid gestationis and EBA. High Dose Intravenous ImmunoglobulinsModifying the immune system by repeated intravenous administration of highdose intravenous immunoglobulins has become an attractive therapeutic option to treat cases of autoimmune disorders that are resistant to conventionalimmunosuppressive drug regimens. The underlying mechanism of such treatment, however, remained obscure until recently. Immunoglobulins may exert immunomodulatory effects by several ways. These include Fc receptorblockade, regulatory capacity of anti-idiotypic antibodies or cytokine modulation via effectors on cytokine synthesis (Yu and Lennon 1999). An accelerated rate of IgG catabolism has been proposed to be the most likely mechanismin mediating the beneficial action of intravenous immunoglobulins in antibody-dependent autoimmune disorders (Ghetie and Ward 1997; Yu andLennon 1999). A specialized intracellular Fc receptor, FcRn, is abundantlyexpressed in endothelial cells and binds pinocytosed IgG in an pH-dependent manner, namely only in the acidic endosome. IgG is released whenendosomic transport vesicles reach the neutral pH of the cell surface. Unbound IgG is transfered to lysosomes for rapid degradation. FcRn becomessaturated in states of hypergammaglobulinemia, resulting in an increased rateof IgG catabolism. IgG depletion via FcRn receptor saturation convincinglyexplains the temporary benefit of intravenous immunoglobulin therapy inantibody-mediated autoimmune diseases. Based on this mechanism, a therapeutic strategy would be to target FcRn, e.g. by neutralizing antibodies orsynthetic ligands to decrease levels of circulating pathogenic autoantibodies(Yu and Lennon 1999). These fundamental insights into IgG catabolism harbor great potential for therapeutic intervention at the effector level (Fig. 4).Intravenous immunoglobulins have been highly beneficial in restoring therapeutic responsiveness to standard immunosuppressive treatment in disorders that were otherwise refractory (Table 3). Intravenous immunoglobulins 434 Sybille Thoma-Uszynski and Rüdiger Eming Fig. 4. Therapeutical effect of infliximab (anti-TNF-a) in an inflammatory skin disorder. Apatient with recalcitrant subcorneal pustular dermatosis (Sneddon-Wilkinson) respondedpromptly to infliximab therapy. Shown are pre-(left) and posttreatment (right) fotographs ofthe patient’s neck. Disseminated pustules completely resolved after a single course oftreatment and the patient remained in stable remission for several months (provided by Dr. C.Voigtländer, Erlangen, Germany) may be highly effective in therapy-refractory PV, linear IgA bullous dermatosis (incl. chronic bullous disease of childhood), EBA and mucous membranepemphigoid. In drug-induced toxic epidermal necrolysis, a condition characterized by extensive and uncontrolled epidermal necrolysis of large skin areas, immediate treatment with intravenous immunoglobulins resulted in adramatic beneficial response in some patients (Viard et al. 1998). This effectseems to be mediated by the anti-apoptotic action of anti-Fas IgG in the immunoglobulin preparations preventing apoptotic keratinocyte death. Targeting Immune Cells in Autoimmune DiseasesBiologicsBiologic agents or “biologics” represent a new group of substances includingmonoclonal antibodies, fusion and recombinant proteins possessing biological activity. These proteins can either be isolated from animal tissues or nowa- Novel Therapeutic Approaches in Autoimmune Skin Disorders 435 Table 3. Dermatological Disorders Treated with Intravenous ImmunoglobulinsDisorder Therapeutic Trial Reference Dermatomyositis Double-blind,placebo-controlled Dalakas 1998 Pemphigus vulgaris Open Harman and Black 1999;Sibaud et al. 2000 Epidermolysis bullosa Open Kofler et al. 1997 Bullous Pemphigoid Open Harman and Black 1999 Linear IgA bullous dermatosis Open Letko et al. 2000 Mucous Membrane Pemphigoid Open Foster and Ahmed 1999 Toxic epidermal necrolysis Open Viard et al. 1998 Chronic (autoimmune) urticaria Open O’Donnell et al. 1998 Lupus erythematosus Open Hundt et al. 2000;Viertel et al. 2000;Enk and Knop 2000 Morphea Open Wollina et al. 1998 Systemic sclerosis Open Levy et al. 2000 Pyoderma gangrenosum Single case Dirschka et al. 1998 Vasculitides Open Jayne et al. 2000;Ong and Benson 2000 days commonly be synthesized by biotechnological methods, i.e. recombinantDNA techniques. The use of biologics in other specialties, i.e. hematooncology(erythropoietin, GM-CSF) or organ transplantation (anti-CD25-antibodies) hasbeen known for years. The more defined understanding of the pathophysiology of autoimmune diseases has led to the therapeutical use of biologics inchronic inflammatory disorders like RA or Crohn’s disease (Feldman et al.1998). More recently, in the dermatological field psoriasis serves as a modelfor a chronic, T cell mediated (auto-) immune disease which has been an important subject for new therapeutic strategies using biologics (Gottlieb andBos 2002). With regard to the immunpathophysiology of psoriasis the immunologic strategies of biologics aim at inhibition of T cell activation, depletionof activated T cells, inhibition of T cell adhesion and inhibition of proinflammatory cytokines. Regarding therapy of inflammatory autoimmune diseasesantibodies which target B cells and autoantibody-producing plasma cells areof particular interest.Most of the listed biologics are being investigated in clinical trials (phaseI-III) for the treatment of moderate to severe plaque psoriasis. Alefacept andefalizumab are approved for the treatment of moderate to severe plaque psoriasis, whereas infliximab is approved for psoriatic arthritis, Crohn’s disease 436 Sybille Thoma-Uszynski and Rüdiger Eming Table 4. Biologic therapies and their sites of actionSubstances Target Type Company Inhibition of T cell activationAlefacept (LFA3TIP)CD2-LFA-3-interactionCTLA4-Ig (BMS 188667) CD80/CD86 costimulationIDEC 114CD80 costimulation fusion proteinchimeric fusion proteinprimatized mAb Biogen IDECBristol Myers SquibbBiogen IDEC humanized IgG1 mAb Genentech/XOMA Inhibition of T cell migrationEfalizumab (hu1124) CD11a(LFA-1-ICAM-interaction)CDP 850E-selectinBimosiamose (TBC-1269) anti-pan-selectinEfomycine MP- and E-selectin humanized mAbsmall moleculesamll molecule CelltechEncysive IL-2R fusion protein Ligand CD2CD3CD3CD4CD4CD25CD25 humanized mAbmurine IgG2a mAbhumanized mAbhuman mAbhumanized IgG4 mAbchimeric IgG1 mAbhumanized IgG1mAb CD20 chimeric IgG1 mAb Roche humanized IgG1 mAb ILEX Reduction of activated T cellsDAB398IL-2(denileukin diftitox)Siplizumab/MEDI-507OKT3VisilizumabHuMax-CD4OKTcdr4aBasiliximabDaclizumab MedimmuneCilag Lab.PDLGenmab A/SIMUCLONENovartisRoche Depletion of B cellsRituximab Depletion of lymphocytesCampath-1H/Alemtuzumab CD52 Blocking the activity of inflammatory cytokinesInfliximabAtlizumabEtanerceptABX-IL8HuZAF/Fontolizumab TNFaIL-6RTNFaIL-8IFNg chimeric IgG1 mAbhumanized mAbfusion proteinhuman mAbhumanized mAb Centocor/EssexRoche/ChugaiWyethAbgenixPDL and rheumatoid arthritis and etanercept is approved for the treatment ofpsoriatic and rheumatoid arthritis. Basiliximab and daclizumab are indicatedfor the prophylaxis of acute organ rejection in patients receiving renal transplants. Rituximab is being used for the treatment of low-grade B cell nonHodgkin’s lymphoma. For simplification, each substance is listed in one categoryonly. Note that some biologics have multiple effects, i.e. efalizumab also inhibits T cell activation. Novel Therapeutic Approaches in Autoimmune Skin Disorders 437 Inhibition of T cell activationAlefacept Alefacept is a fully human, recombinant fusion protein consisting of the extracellular domain of the leucocyte function-associated antigen type 3 (LFA-3)fused to the Fc-portion of human IgG1. It is produced by recombinant DNAtechnology in a Chinese Hamster Ovary (CHO) mammilian expression system (Biogen IDEC 2003). By effectively blocking the interaction between CD2which is highly expressed on memory effector T cells and LFA-3 expressedon APC, alefacept inhibits the activation of effector T cells. Treatment withalefacept also reduces the number of CD4/CD45 RO-positive memory T cellsthrough binding of its Fc-portion to FcgIII-receptors on natural killer cells(NK cells) or macrophages. This leads to the induction of a granzyme B-mediated apoptosis preferentially in CD4/CD45 RO-positive memory T cells(Ellis et al., 2001). Recent studies by Gordon et al. revealed a relationship between the decrease in circulating CD4+ memory T lymphocytes and the improvement of the psoriatic skin lesions (Gordon et al. 2003). Since January2003, alefacept is approved by the FDA for the treatment of moderate to severe plaque psoriasis. The treatment regimen is a course of 12 weekly injections (15 mg i.m./week) followed by a 12 week treatment free observationperiod (Biogen Idec 2003). The results of two phase III trials show that aftertwo i.v.- or i.m.-alefacept courses, respectively about 40% of the patientsshowed a ³ 75% reduction in their PASI-scores (Krueger et al. 2002; Lebwohlet al. 2003). The response to alefacept was durable, since the median duration of a > 50% reduction in PASI was 216 days for patients who initiallyachieved a 75% reduction in PASI (Krueger and Callis 2003). Alefacept is reported to be well tolerated both by i.v. and i.m. administration with a consistent safety profile in the clinical trials (Gordon et al. 2003). Commonlyreported infections in patients treated with alefacept were similar to those inpatients receiving placebo. In both phase III studies there did not appear to be acorrelation between infections and CD4+ cell counts below 250 cells/ml(Ortonne 2003 and Krueger et al. 2003). Kraan et al reported that alefacepttreatment in psoriatic arthritis shows promising results (Kraan et al. 2002). Efalizumab Efalizumab (hu 1124, anti-CD11a) is a humanized IgG1 version of the murineanti-human CD11a monoclonal antibody MHM24 (Werther et al. 1996). CD11aand CD18 are subunits of the lymphocyte b2-integrin LFA-1 that primarilybinds to the intercellular adhesion molecules ICAM-1 ICAM-2 and ICAM-3expressed on leukocytes, epithelial cells including keratinocytes and endothelial cells (Janeway et al. 2001). The main function of integrins on the cellsurface of T lymphocytes is to mediate cell adhesion with APC, endothelial 438 Sybille Thoma-Uszynski and Rüdiger Eming cells and extracellular matrix. In vitro studies by Werther et al. showed thatby blocking the LFA-1–ICAM-1 interaction, efalizumab inhibits key pathogenic steps in psoriasis like T cell activation, T cell extravasation and T celladhesion to keratinocytes (Werther et al. 1996). In two	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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recent phase III trialswith s.c. administered efalizumab nearly 1100 psoriatic patients had been randomized to treatment with an initial conditioning dose of 0,7 mg/kg in weekone followed by weekly doses of efalizumab 1 mg/kg or 2 mg/kg or placebo.Compared to the placebo group, in which 3,4% achieved PASI 75, 29% ofthe patients in the 1 mg/kg group and 28% in the 2 mg/kg group achieved a³ 75% reduction in their PASI-score (Gordon et al. 2002). The clinical improvement correlated with sustained efalizumab levels in the serum, T cell CD11asaturation and down modulation, decreased epidermal and dermal T cellcounts, histologic improvement and increased counts of circulating lymphocytes (Menter et al. 2001). FDA approved efalizumab for the treatment ofmoderate to severe psoriasis in October 2003. At present, safety data for 2762patients treated during 13 clinical trials are available, showing a good safetyprofile for efalizumab (Leonardi et al. 2004). Long term results based on treatment for up to 24 months revealed no new common (> 5% of the patients) adverse events. The incidence of serious infection or malignancy in efalizumabtreated patients was low and similar to the placebo group (Leonardi et al. 2004). CTLA-4Ig/IDEC-114 In addition to antigen-induced signals, the proliferation and differentiationof T cells requires a second signal provided by costimulatory molecules onAPC. A well characterized costimulatory pathway includes CD28 on T cellsbinding to the costimulatory molecules B7–1 (CD80)/B7–2 (CD86) on activatedAPC. Another T cell surface receptor for CD80/CD86, CTLA-4 (CD152) inhibits T cell activation (Abbas et al. 2000). CTLA-4Ig and IDEC-114 are biologicals targeting these costimulatory signals by binding to CD80 and CD86on APC, thus inhibiting T cell activation. IDEC-114 is a primatized anti-humanCD80 monoclonal antibody blocking the CD28-CD80 ligation without affecting the CD80-CTLA-4-interaction (Schopf 2001). Gottlieb et al. presenteddata on a single-dose phase I/II trial with 24 psoriatic patients who were administered IDEC-114 in i.v.-doses ranging from 0,05–15 mg/kg. IDEC-114demonstrated mild clinical and histologic improvements in patients of thehigher-dose groups (Gottlieb et al. 2000). A follow-up study (multiple dose,phase I/II) showed a PASI 50% reduction in 40% of the observed patients.The maximal clinical effect was observed 12 weeks after the last infusion(IDEC 2001). CTLA-4 Ig is a fusion protein composed of the extracellular domain of CTLA-4 (CD152) and the Fc domain of human IgG1. In an open phaseI/II dose escalation trial CTLA-4Ig showed a dose dependent improvementin psoriatic patients. In the high dose group (50 mg/kg) about 90% of thestudy patients experienced a 50% PASI reduction (Abrams et al. 2000). An Novel Therapeutic Approaches in Autoimmune Skin Disorders 439 earlier study by Abrams et al. indicated a decreased ability of the treated patients to mount T cell dependent antibody responses (Abrams et al. 1999).Currently, CTLA-4Ig is being investigated in other inflammatory disorderssuch as rheumatoid arthritis or organ transplantation (Gottlieb and Bos 2002). Depletion of Activated T LymphocytesInterleukin-2 Interleukin-2 (IL-2) is the principal cytokine which is secreted by antigenactivated T lymphocytes in the early phase of antigen recognition. IL-2 functionsas an autocrine growth and differentiation factor for the T cells. Its high affinityreceptor consists of the three non-covalently associated subunits IL-2Ra (CD25),IL-2Rb (CD122) and IL-2Rg (CD132). The TCR-dependent activation of naiveT cells leads to the upregulation of the a chain (CD25) which then enables Tcells to respond to low concentration of IL-2 through their high affinity receptor. Therefore, CD25 is also considered an early activation marker for T cells.This is the rationale for using anti-CD25 monoclonal antibodies or denileukindiftitox (DAB389IL-2) which is composed of recombinant IL-2 and part of diphteriatoxin. All three substances aim at eliminating pathogenic T cells. Basiliximab Basiliximab is a chimeric monoclonal antibody consisting of the heavy andlight chain of the variable region of the murine anti-human CD25 antibodyRFT5 and the heavy chain and k-light chain of the Fc region of human IgG1.Basiliximab specifically binds to the IL-2 receptor (IL-2R) with high affinity(Amlot et al. 1995). Binding of basiliximab to the IL-2R prevents further binding of IL-2 to the receptor. This way basiliximab inhibits IL-2-dependent proliferation of antigen-activated T cells (Onrust et al. 1999). Since May 1998basiliximab is approved for the prevention of acute organ rejection afterallogeneic renal transplantation. It is combined with other immunosuppressive drugs as cyclosporin or corticosteroids. So far, in different case reportsbasiliximab has been reported to treat severe recalcitrant psoriasis in combination with cyclosporin (Owen et al. 2000; Bell et al. 2002). Kaegi and Heyerdemonstrated the successful treatment of a 29-year old patient with severeatopic dermatitis with two i.v.-infusions of basiliximab (20 mg/infusion) together with low-dose cyclosporin (150 mg/d) (Kaegi and Heyer 2001). Daclizumab Daclizumab is the humanized variant of the murine anti-human CD25 monoclonal antibody MAT (murine anti TAC). In vitro studies demonstrated a high 440 Sybille Thoma-Uszynski and Rüdiger Eming affinity of daclizumab for the alpha chain (CD25) of the human IL-2R (Queenet al. 1989; Junghans et al. 1990). Daclizumab shows a dose dependent inhibition of the IL-2-dependent proliferation of human T cells. An open phase IIclinical trial by Krueger et al. included 19 psoriatic patients who underwenttreatment with four cycles of daclizumab, initially 2 mg/kg and 1 mg/kg, respectively at weeks 2, 4, 8 and 12 (Krueger et al. 2000). Daclizumab showeda moderate clinical improvement with a mean PASI reduction of 30%. In astudy by Willenbacher et al. daclizumab was used to treat 16 patients withgrade III-IV graft-vs.-host disease (GvHD) (Willenbacher et al. 2001). Asonly nine patients showed a clinical response and three patients died of serious infections, daclizumab demonstrated a limited effectiveness when usedas a monotherapy. Denileukin diftitox (DAB389-IL-2) This recombinant fusion protein contains human IL-2 linked to a portion ofthe diphteria toxin molecule. Activated T lymphocytes expressing the highaffinity IL-2R internalize denileukin diftitox by receptor mediated endocytosis. The intracellular release of the diphteria toxin blocks the protein-synthesisof the T cells and finally leads to cell death (Martin et al. 2001). Currentlydenileukin diftitox is approved for the treatment of cutaneous T cell lymphoma.Martin et al. demonstrated results of a dose-escalation trial with 35 psoriaticpatients who were given 12 infusions of denileukin diftitox over a peroid ofeight weeks. Seven out of 15 patients in the high dose group (5 ìg/kg) showeda minimal PASI reduction of 50% (Martin et al. 2001). The dose dependentadverse effects included fever/chills, asthenia, myalgia and rush. Siplizumab (Medi-507) CD2 is a 50 kD glycoprotein containing two extracellular Ig domians and it isexpressed on more than 90% of mature T cells, NK cells and up to 70% ofthymocytes (Abbas et al. 2000). Binding of CD2 to its principal ligand LFA-3(CD58) on APC increases the strength of adhesion between T lymphocytesand APC. There is further evidence that the CD2-LFA-3 interaction enhancesTCR-mediated activation of T cells (Abbas et al. 2000). Siplizumab (Medi-507)is a humanized anti-CD2 monoclonal IgG1 antibody which is currently investigated for its efficacy in the treatment of moderate to severe psoriasis. In threephase I/II trials, siplizumab was administered as a single i.v.-dose, eight weeklyi.v.-infusions or as 12 weekly s.c.-doses (Langley et al. 2001). In the high dosegroups (5–7 mg in the s.c.-group or 40 mg/kg in the i.v.-study) more than 55%of the patients showed at least a 50% reduction in PASI, while 33% of the patients experienced a 75% PASI reduction (Langley et al. 2001). With a maximum 12h post-dose, the number of circulating T lymphocytes in the peripheral Novel Therapeutic Approaches in Autoimmune Skin Disorders 441 blood decreased by 50%. Siplizumab was considered generally safe andwell tolerated. The side effects included fever/chills and flu-like symptoms(MedImmune, R&D pipeline, available at http://www.medimmune.com). Depletion of B LymphocytesRituximab Arising from haematopoietic stem cells, B lymphocytes pass through different maturation steps. Finally, mature B cells give rise to plasma cells producing immunoglobulins. The surface markers CD19 and CD20 appear early inthe B cell development and remain present until the stage of mature B cells.Rituximab (anti-CD20) is a chimeric IgG1k monoclonal antibody with murinevariable region and human constant regions, recognizing human CD20. In1997 rituximab was the first mAb to be approved for the treatment of relapsedor refractory, low-grade B cell follicular non-Hodgkin’s lymphoma (NHL) bythe FDA. In lymphoma patients receiving the standard regimen with fourweekly treatments of 375 mg/m2, profound B cell depletion is observed andsustained for 6–9 months (Gorman et al. 2003). Thus rituximab seems to bepromising for the treatment of antibody-mediated autoimmune diseases. Inpatients with systemic lupus erythematosus (SLE) significant B cell depletioncorrelated with clinical improvement (Anolik et al. 2003). In an open studyincluding five patients with refractory dermatomyositis, all patients reportedmarked improvement in both muscle strength and dermatitis within 1–3 months.The clinical improvement sustained for at least six months (Levine 2003). Thereare several recent reports indicating successful treatment of autoimmunebullous disorders with rituximab. Cooper et al. (2003) and Herrmann et al.(2003) reported good clinical responses in patients with severe PV upontreatment with rituximab (Coopet et al. 2003; Herrmann et al. 2003). Borradoriet al reported the rapid improvement of paraneoplastic pemphigus in a 61year-old woman with CD20+ follicular non Hodgkin’s lymphoma grade I, aftera regimen with rituximab 375 mg/m2 once a week for four weeks (Borradoriet al. 2001). Another case report showed rapid clinical response to rituximabin a patient with treatment-resistant pemphigus foliaceus (Goebeler et al. 2003). Inhibition of Lymphocyte Migration and ExtravasationTo eliminate (auto-) antigens in the effector phase of an (auto-) immune response, memory and effector T cells home to the sites of inflamed peripheraltissues, i.e. to inflamed dermis. Among the adhesion molecules which areimportant for leukocyte recruitment, selectins (E- and P-selectin) are expressedon activated endothelium and initiate leukocyte recruitment by binding tooligosaccharides (sialyl LewisX) on the cells surface of circulating leukocytes.Therefore selectins are considered as crucial targets for interrupting the 442 Sybille Thoma-Uszynski and Rüdiger Eming initiation and perpetuation of a T cell mediated, inflammatory (auto-) immune response. CDP850 CDP 850 is a humanized anti-E-selectin monoclonal antibody. Bhushan et al.performed a randomized clinical trial including nine psoriatic patients withmoderate to severe chronic plaque psoriasis. While nine patients received 20mg/kg CDP850 as a single i.v. infusion, four control patients received placebo infusions (Bhushan et al. 2002). Eight weeks post infusion, there was nosignificant reduction in PASI from baseline for the CDP850 treated groupcompared to the placebo group. These results demonstrate that blockade ofE-selectin alone does not have sufficient impact on the treatment of psoriasis, probably due to alternative pathways for leukocyte adherence to endothelium (Bhushan et al. 2002). Bimosiamose (TBC1269)/Efomycine M Both compounds are so called small molecules and as anti-pan-selectins theymay overcome the ineffectiveness of monoclonal antibodies directed againstsingle adhesion molecules. Preliminary data from recent clinical pilot studieson psoriatic patients treated with bimosiamose strongly suggest an effectiverole in the treatment of psoriasis (Friedrich et al. 2003). Schon et al. presenteddata in the psoriasis-SCID-mouse model showing that efomycine M effectively inhibits leukocyte recruitment and thus alleviates cutaneous inflammatory responses (Schon et al. 2002). This substance is currently in furtherclinical development. Neutralization of TNF-a by Monoclonal AntibodiesRecently, several recombinant antibodies and receptor agonists have beenintroduced to block bioactive TNF-a in rheumatological disorders and inflammatory bowel disease. In fact, these antibodies have contributed to the recentrenaissance of antibody therapy in general. Infliximab, a chimeric mousehuman IgG1 monoclonal antibody (mAb) against TNF-a has been provenhighly effective in several clinical trials in RA (Elliott et al. 1994a; Elliott et al.1994b). The Crohn’s disease study group demonstrated that anti-TNF-a wasa potent therapy in gastrointestinal and cutaneous Crohn’s disease (Targanet al. 1997; Geyer et al. 2000). Recent studies evaluated infliximab for treatment of ankylosing spondylitis and found significant improvement of clinicaland laboratory parameters (Van den Bosch et al. 2000a, 2000b; Brandt et al.2000). Novel Therapeutic Approaches in Autoimmune Skin Disorders 443 Etanercept is a dimeric molecule consisting of two human p75 sTNFRextracellular domains attached to the Fc portion of human IgG1. By now,extensive experience has been collected with etanercept in the treatmentof adult RA (Weinblatt et al. 1999). It has been demonstrated that particularlyearly phase treatment is clinically very effective in preventing irreversiblebone destruction (Bathon et al. 2000). In addition, the pediatric rheumatologycollaborative study group recently reported that anti-TNF-a therapy withetanercept in children with polyarticular juvenile RA is a save and efficienttherapy with a high clinical response rate (Lovell et al. 2000).Potential dermatological indications for treatment with anti-TNF-a antibodies include recalcitrant psoriasis arthritis (Maini et al. 1999) and plaquepsoriasis where first clinical trials are initiated, pyoderma gangraenosum andother conditions with elevated TNF-a levels. A recent study demonstratedthat infliximab was highly efficient in the treatment of psoriatic plaques thatwere otherwise unresponsive to concomitant treatment with methotrexate(Oh et al. 2000; Ogilvie et al. 2001). Infliximab was also highly effective in recalcitrant subcorneal pustular dermatosis (Sneddon-Wilkinson) (Fig. 5), a skindisorder characterized by disseminated pustules which is associated with RAand inflammatory bowel disease (Voigtländer et al. 2001). Pyoderma gangrenosum is yet another disorder that may be highly responsive to treatmentwith anti-TNF-a antibodies as observed in a single case with a chronic re- Fig. 5. Immune intervention in autoantibody-mediated skin disorders. Circulating pathogenicautoantibodies cause loss of integrity of the skin by interfering with adhesion moleculefunction in autoimmune blistering diseases of the pemphigus and pemphigoid group. Removalof these antibodies by several techniques allows reconstitution of epidermal or dermal/epidermal adhesion. These therapeutical approaches may be also useful to removeautoantibodies or proinflammatory cytokines in other skin autoimmune diseases such assystemic scleroderma, lupus erythematosus and dermatomyositis 444 Sybille Thoma-Uszynski and Rüdiger Eming fractory course (Jenne et al. 2004). Recently, the administration of infliximabwas highly effective in chronic disseminated granuloma annulare (Hertl etal. 2005) and a case of therapy-refractory pemphigus vulgaris. Jacobi et al.reviewed the current therapeutic applications for the two TNFa inhibitorsinfliximab and etanercept in inflammatory skin disorders (Jacobi et al. 2003). Inhibition of Other Pro-Inflammatory CytokinesAttempts to neutralize other proinflammatory cytokines included IL-1 (Campion et al. 1996; Bresnihan et al. 1998; Jiang et al. 2000) and IL-6 (Yoshizakiet al. 1998) with encouraging results for RA.Since TNF-a blockade also affects circulating levels of TNF-dependentcytokines such as IL-1 and IL-6 it seems currently superior to inhibit this keycytokine to stop autoaggressive inflammatory responses.To modulate inflammatory responses, other anti-inflammatory cytokineshave been administered with therapeutic intention: IL-10 has been used successfully in psoriasis (Asadullah et al. 1998, 1999). Although IL-10 leads to asignificant clinical response rate, its use may be restricted to severe forms ofpsoriasis due to potential immunosuppressive side effects of systemic IL-10administration. The immunomodulatory cytokine IL-11 had been administered to patients in Crohn’s disease (Sands et al. 1999). The clinical responserate was moderate in this short term trial, the therapeutic potential of IL-11appears limited due to its thrombocytopoietic properties. In an open-labelphase I dose-escalation clinical trial, Trepicchio et al. reported significantimprovement in seven out of twelve psoriasis patients treated with oprelevkin(recombinant humanized IL-11). There was a correlation between the clinical response and a decrease in proinflammatory cytokines (Trepicchio et al.1999). Peptide T is an octapeptide from the V2 region of gp120 of HIV.Raychaudhuri et al. demonstrated its immunmodulatory effects leading to anupregulation of IL-10 and a decrease of IFNg and IL-2 production (Raychaudhuri et al. 1999). Due to this anti-inflammatory effect, peptide T showed clinical improvement in psoriatic patients in several clinical trials (Gulliver et al.1999). Moreover, Talme et al. demonstrated by immunohistology that peptide T treated psoriasis patients showed decreased dermal lymphocytic infiltrates (Talme et al. 1995). Keratinocyte-derived IL-8 is involved in leukocyterecruitment to inflammed dermis (Barker et al. 1991; Biasi et al. 1998) andangiogenesis which is also a prominent characteristic of chronically inflammedskin (Nickoloff et al. 1994). ABX-IL8 is a fully humanized anti-IL-8 IgG 2monoclonal antibody that has been used for treating psoriasis patients (Lohneret al. 1999). In dose-escalating clinical trials ABX-IL8 was well tolerated andgenerally safe. So far its clinical efficacy in improving psoriasis is moderateso that its further clinical development in the field of psoriasis had been discontinued. IL-4 is considered the principal cytokine promoting the develop- Novel Therapeutic Approaches in Autoimmune Skin Disorders 445 ment of Th2-type effector T cells. Its capacity to counterbalance Th1-dominated,proinflammatory immune responses led to the use of IL-4 in clinical trials.Recently, twenty psoriasis patients devided into five groups received increasing doses of IL-4 over six weeks. 18 patients receiving higher doses ofIL-4 showed a statistically significant PASI reduction of 60 to 80% in thisstudy (Ghoreschi et al. 2003). Extracorporeal PhotopheresisPhotopheresis is a leukapheresis-based therapy with ultraviolett A (UVA) irradiation of ex-vivo isolated peripheral blood mononuclear cells (PBMC) plussystemically administered 8-methoxypsoralen (8-MOP). After UVA-irradiation, the PBMC are re-infused into the patients. The ECP procedure consistsof several steps: first, a portion of PBMC is collected and secondly, incubatedwith 8-MOP; alternatively, 8-MOP is administered systemically and third,followed by UVA irradiation. Fourth, the UVA-irradiated PBMC are reinfusedintravenously (Andreu et al. 1994). ECP is usually well tolerated with onlyminor side effects (Perotti et al. 1999; Salvaneschi et al. 2000). The molecularmode of action of 8-MOP/UVA is the formation of DNA and RNA photo adducts(i.e. thymidine dimers) leading to an alteration of DNA and protein synthesis.The immunological basis for the responses of patients to photopheresis ispresumably due to the induction of anti-clonotypic immunity directed againstpathogenic clonal T cell populations. Treatment-induced apoptosis of pathogenic T cells and activation of antigen presenting cells may be critical in thistherapeutic process (Rook et al. 1999).In addition to cutaneous T cell lymphoma (CTCL) (Bisaccia et al. 2000),the treatment modality of ECP has been applied to several autoimmune diseases (Table 5), including RA, systemic sclerosis (Schwartz et al. 1997), SLE(Knobler 1994) and PV (Wollina et al. 1999). Several case reports and caseseries suggest efficacy of ECP, but few controlled studies have been conducted to test this hypothesis (Owsianowski et al. 1996). Immunoablation and Stem Cell TransplantationImmunoablation and subsequent autologous or allogenic hematopoietic stemcell transplantation (HSCT) has emerged as a recent treatment modality forsevere autoimmune diseases (Marmont 2000). Insight into a response of autoimmune disorders to immunoablation and subsequent stem cell transplantioncomes from animal models and patient cases with concomitant malignancies(Passweg et al. 1999). 446 Sybille Thoma-Uszynski and Rüdiger Eming Table 5. Extracorporeal Photopheresis in Dermatological DisordersDisorder Trial Reference Chronic graft versus host disease Open Dall’Amico et al.1997 PV, BP Open Wollina et al. 1999 Epidermolysis bullosa acquisita Open Gordon et al. 1997 SLE Open Richter et al. 1998 Systemic sclerosis Open Krasagakis et al. 1998 MS Double-blind,placebo-controlled Rostami et al. 1999 First clinical trials or cases have been reported for progressive MS (Fassaset al. 2000; Burt et al. 1998), systemic lupus erythematosus (SLE) (Burt et al.1999a, 2000), RA (Burt et al. 1999b; Snowden et al. 1999) and chronic autoimmune thrombocytopenia (Pavletic 1997; Skoda et al. 1997). The mechanismof remission of autoimmune disease is not entirely clear. There is ongoingdebate whether dose-intense immunosuppression, as performed with nonmyeloablative conditioning is sufficient to induce remission. Under currentview, although autologous stem cell transplants are associated with a lowercomplication rate, allogeneic stem cell grafts seem preferable for treatmentof autoimmune diseases in order not to reintroduce the autoimmunity intothe recipient (Burt and Traynor 1999b). An allograft provides a new stem cellsource, and a controlled graft versus host effect could further contribute tomodulation and eradication of autoreactive lymphocytes.Overall, immunoablation followed by HSCT is an aggressive treatmentand should be reserved for a carefully selected patient collective. Precise preand posttransplant assessment of the immune system should unravel furtherdetails on tolerance and immunity. It remains to be determined whether thistherapy can induce true long-term peripheral tolerance and whether the curative efficacy weighs out the treatment-associated risks. Summary and ConclusionsTremendous progress has been made in understanding autoimmune processesand autoimmune diseases. Novel therapies begin to emerge and techniquesin use for some time have been refined and enrich the spectrum of treatmentmodalities. New immunomodulatory drugs currently help to reduce corticosteroid induced morbidity, but are also applied as monotherapy. These includemycophenolic acid, immunosuppressive macrolides and leflunomide. Novel Therapeutic Approaches in Autoimmune Skin Disorders 447 Antigen specific immunotherapy includes oral, mucosal or systemic autoantigen delivery and tolerance induction. Modified antigens are administeredin form of altered peptide ligands or complementary peptides. As antigenspecific therapy in perfection appears the use of tolerogenic dendritic cellsas mediators of specific tolerance induction.The effector phase of an autoimmune disease involves production of autoantibodies and release of proinflammatory cytokines. Therapeutic approachesare aimed at removing these compounds from the circulation and includeplasmapheresis, immunoadsorption, high dose intravenous immunoglobulintherapy, and most potently, TNF-a blockade.Dysregulated cellular immune responses in autoimmune diseases are targeted by antibody therapy to eliminate distinct cell populations, by extracorporeal photopheresis and, most aggressively, by immunoablation followedby hematopoietic stem cell transplantation. In this scenario, the use of biologicswill help to more specifically modulate crucial events in the effector phase ofan inflammatory autoimmune response. This can be achieved by the inhibition of proinflammatory cytokines such as TNF-a and costimulatory moleculesrequired for T cell activation.Based on increasing knowledge about tolerance and immunity, new horizons for therapeutic intervention are visible. 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N Engl J Med 340: 227–228 Subject IndexAcantholysis 47Acanthosis 293ACE inhibitors 177, 207Acetylcholine esterase 376Acid Blockers 207Acitretin 218, 302Acral annular plaques 209Acrodermatitis chronica atrophicans 173Acrodermatitis continua suppurativahallopeau 303Acrosclerosis 249Acute cutaneous lupus erythematosus 183,188Acute guttate psoriasis 298Acute urticaria 309Adenocarcinomas 78Alefacept 220, 436, 437Allergic contact dermatitis 400, 402Allergic rhinitis 356Alopecia areata 145, 385, 420– totalis 385–386, 395– universalis 385, 395Alopecia mucinosa 387Altered peptide ligand (APL) 426American College of Rheumatology 174,184, 209, 353Amyloidosis 172Anagen hair follicle 404ANCA-associated vasculitides 351, 355,357, 361ANCA-associated vasculitis 359ANCA-cytokine sequence theory 350Anchoring fibrils 109, 117, 119Anemia 196Anetoderma 274Angioedema 310, 313, 317, 329Angiokeratomas 232Annular erythema 208, 274Anthralin 300, 402Anti-FceRIa autoantibodies 321–323Antibiotics 74Antibodies 193, 246, 369, 380Antibody-antigen complexes 80 Antibody-dependent cellular cytotoxicity187, 204Anticardiolipin antibodies 201, 213, 248,274Anticentromere antibodies 145Anticoagulants 256Anti-Cytokines 178Anti-DNA-antibodies 194Anti-double-stranded DNA antibodies 213,219Anti-endomysium autoantibodies 97Anti-FceRI autoantibodies 321, 324–325Anti-fibrillin-1 antibody 248Antigen specific immunotherapy 425, 447Antigen spreading 49Antihistamines 311, 328Anti-IgE autoantibodies 320, 321, 322Anti-La/SSB 204, 213Antimalarials 144, 152, 196, 206, 217, 240Anti-melanocyte antibodies 369Anti-neutrophil cytoplasmic antibodies(ANCA) 274, 350, 355Antinuclear antibodies 1, 172, 193, 198,212, 238, 267, 275, 277–278Antinuclear matrix antibody 248Antiphospholipid antibodies 145, 218,248Antiphospholipid antibody syndrome 422Antiplatelets 256Anti-Ro/SS-A antibodies 194, 204, 213,265, 278Anti-Scl 70, 145Anti-Sm 213Anti-TNF-a antibodies 17, 303, 443Anti-U1 RNP antibody 213, 246Aplastic anemia 144, 217Apoptosis 186, 263Arteriogramms 358Arthralgias 145,	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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209, 356Arthritis 170, 209–210Arthropod reaction 77Ascomycin (ASM 981) 423Asthma bronchiale 356 458 Subject Index Atopic childhood eczema 291Atopic dermatitis 387, 423Atrophoderma 140Atrophy 165, 168Atypical pneumonia 192Auspitz sign 298Autoantibodies 1, 6, 13, 16, 46, 71, 80, 110,123, 127, 138, 146, 165, 212, 246, 325,328, 431–433Autoantigens 10, 424Autoimmune bullous diseases 95, 122Autoimmune bullous skin disorders 95,122, 119, 422, 431–432Autoimmune diabetes 425Autoimmune pathogenesis 404Autoimmune polyendocrinopathysyndrome type 1 210, 393Autoimmune thrombocytopenia 74, 446Autoimmune thyroiditis 100, 210, 371Autoimmune urticaria 309, 320, 322, 328Autologous serum skin test 321Autoreactive B cells 1, 9Autoreactive lymphocytes 8, 13Autoreactive T cells 9, 74, 81, 425–426, 428Azathioprine 79, 197, 219, 239, 358 B cell dysregulation 138B cell receptor 2B cell tolerance 10B Lymphocytes 441b4 integrin 78Basement membrane zone 71, 102, 119,124Basiliximab 436, 439Bath-PUVA 176Behcet's disease 431, 450Beta Blockers 207b-haemolytic streptococci 294, 297Biologics 421, 434Biopsy 358Biostatistics 25Blaschko's lines 142Bone marrow 2, 166Bone marrow transplant 178BP188 1, 57, 76, 78, 81, 84BP238 76, 78, 81, 84Breast Implants 34–35Brunsting-Perry pemphigoid 109Bullous morphea 141Bullous pemphigoid 39, 71, 102, 109, 122,422, 431, 435, 446Bullous SLE 116C3H/HeJ mouse-model 400Calcinosis 235, 240–241Calcitriol 150Calcium channel blockers 175, 207 Calcium Homeostasis 376Captopril 57, 74Cardiac involvement 355Catalase 373Catecholamines 376CD11a 437CD4+/CD25+ cells 409Celiac disease 105Cell-mediated cytotoxicity 204Cell-substrate adhesion 85Cellular infiltrate 373CENP antibodies 169, 172Central Tolerance 3Chapel Hill Consensus 353Chemokine receptors 295Chemotaxis 424Chilblain lupus 190, 198Chlorambucil 79, 239Chloroquine 196, 216, 240Cholinergic Urticaria 312Chronic active hepatitis 11Chronic bullous disease of childhood 115,434Chronic cutaneous lupus erythematosus183–187, 188, 190–191, 196–197Chronic cutaneous lupus erythematosus– ACR criteria 191– American College of Rheumatology 183– ANA 194– Annular erythema 192– Anti-SS-A antibodies 187, 193– Antinuclear antibodies 194– Antiphospholipid syndrome 194– Anti-Ro/SS-A 186– Arthralgia 191–192– Autoantibodies 186– CDLE 186, 188– Chilblain 190– Chilblain lupus 194– Classification 183– Clinical Appearance 187– Cytokines 186– Diagnosis 186, 192– Direct Immunofluorescence 193– ELISA 194– Generalized DLE 188, 194– Hypertrophic DLE 188– Kaposi-Irgang disease 189– Keratinocyte apoptosis 186– Lipathrophy 190– Localized form of DLE 188– Lupus band test 193– Lupus panniculitis 189, 194– Lupus pernio 190–191– Lupus profundus 189–190– Lupus tumidus 191–192– Mucous membrane involvement 191 Subject Index– Nephritis 189– Papular mucinosis 192– Pathogenesis 185– Photosensitivity 186–187, 191–192– Polymorphous light eruption 191– Raynaud's phenomenon 192– SCLE 183–184, 186–187, 195– Serological Tests 194– T helper 2 response 187– Therapeutic options 195– Ultraviolet radiation 186Chronic discoid lupus erythematosus 189,387, 423Chronic graft versus host disease 344, 446Chronic idiopathic urticaria 316–317, 318,320, 325–326, 329Chronic plaque psoriasis 294, 298, 303Chronic ulcerative stomatitis 342Chronic urticaria 310, 319, 323Chronic urticaria– Anti-FceRIa autoantibodies 320–324– Aquagenic urticaria 314– Arthralgia 314– Autoantibodies 319– Autoimmune chronic urticaria 319– Autologous Serum Skin Test 324– Cholinergic urticaria 312–313– Classification 309– Cold agglutinin 313– Cold urticaria 313– Cryoglobulins 313– Delayed pressure urticaria 314– Dermographism 310– Eosinophils 314– Food additive-evoked 314– Food provocation 312– H1-antihistamines 318– Helicobacter pylori 317, 319– High affinity IgE receptors 319– Histamine 317– Oral steroids 318– Physical urticaria 310, 314– Solar urticaria 314– Systemic steroids 328– Treatment 328– Urticaria vasculitis 310, 315– Vibratory angioedema 314Chronic urticaria 309Churg Strauss syndrome 351–352Cicatricial pemphigoid 74, 78, 102, 109Ciclosporine 79Clofazimine 197Clonal anergy 425Coal tars 301Cochrane review 27Colchicine 104, 126Collagen 149, 178 459 – bundles 135, 167– degradation 167– metabolism 138– synthesis 153, 167– vascular diseases 165– collagenase I 149– collagenous domain 112Colloid bodies 334, 336Complement 137, 206, 320Complementary peptides 427Congenital heart block 265, 276Connective tissue growth factor 167Contact dermatitis 77Contact sensitizers 398, 400–401Contact urticaria 309Contraceptives 73Corticosteroid pulse therapy 397Corticosteroids 16, 144, 176, 219, 235, 241,256, 359C-reactive protein 357CREST syndrome 248Crohn's disease 117, 211, 442Cryoglobulin 278, 352Cryoglobulinemic vasculitis 274, 352, 360Cryptic epitopes 265Cutaneous calcinosis 173Cutaneous Graft-Versus-Host-Reaction333, 343, 344Cutaneous leukocytoclastic vasculitis 349,358Cutaneous lupus erythematosus 183, 187,204, 217, 430Cutaneous sclerosis 209Cutaneous T cell lymphoma (CTCL) 445Cutaneous vasculitis 274Cyclophosphamide 79, 177, 197, 239, 256,268, 359–360Cyclosporin A 104, 127, 153, 175, 219, 239,256, 279–280, 302Cytolysis of melanocytes 369Cytomegalovirus infection 166, 372Cytotoxic T cells 204 Daclizumab 436, 439Dapsone 102, 104, 196Deep morphea 143Delayed pressure urticaria 310Dendritic cells 428Denileukin diftitox 440Depigmentation process 367Dermal capillaries 293Dermal-epidermal junction 95, 102, 212Dermatitis herpetiformis Duhring 77, 96–95– Autoantibodies 102– Autoimmune disorders 100– Celiac disease 95, 97 460 Subject Index – Clinical presentation 95, 100– Diagnosis 100– Direct immunofluorescence microscopy100– Endomysium 97, 99– Gluten 97, 100, 105– Histopathology 101– IgA 99–100, 102, 105– Immunofluorescence microscopy 100,102– Neutrophils 102– Therapy 102– Tissue transglutaminase 97Dermatomyositis 34, 45, 74, 170, 174, 230,234, 236, 239, 242, 261, 325, 432, 435,441– Amyopathic dermatomyositis 230, 232,236– Anti-Ro (SS-A) 238– Arthralgias 234– Calcinosis 235– Cardiopulmonary involvement 235, 238,240– Classification 229– Corticosteroids 239– Cutaneous Manifestations 230– Cytokines 229– Diagnosis 237– Drug-Induced DM 237– Dysphagia 234– Electromyography 237– Facial erythema 230– Gottron's papules 230–231– Heliotrope rash 230– Immunofluorescence microscopy 233– Immunosuppressive agents 239–240– Intravenous immune globulin 239– Malignancy 236, 238, 240– Muscle involvement 234, 237– Myopathy 229, 233– Myositis 229, 239– Myositis-specific antibodies (MSAs) 238– Photosensitivity 231, 233– Polymyositis 229, 233, 235– Pulmonary involvement 235– Systemic corticosteroids 239– Systemic Features 234– Therapy 239Dermoepidermal basement membrane 57,60Dermographism 310Desmogleins 1, 3, 14, 46, 49–50, 57, 432Desquamation 297Diabetes 393Digital ulceration 179Dihydrofolate reductase 302Dinitrochlorobenzene 398 Diphenylcyclopropenone 398Direct immunofluorescence microscopy 75,334Discoid lupus erythematosus 198Disease Modulating Factors 408Distal dysphagia 235Distal interphalangeal arthritis 299Dithranol 300Diuretics 207DNA-topoisomerase I 172Down's syndrome 393D-penicillamine 57, 74, 152, 237Drug-induced lupus erythematosus 145,208Drug-induced pemphigus 45–46Drug-induced toxic epidermal necrolysis434Dyshidrosiform pemphigoid 72 Echocardiography 358Efalizumab 220, 303, 436–437Efomycine 442Electromyogram 229Endothelial adhesion molecules 352Endothelin-1 175, 249Endothelium 137, 166, 351Enteropathy 97Environmental factors 170, 206, 294, 377Envoplakin 50Enzyme linked immunosorbent assays 76,123Eosinophilc pneumonia 356Eosinophilia 144–146, 355Eosinophilic fasciitis 144, 172Eosinophils 82Eotaxin 82Epidemiology 25–27, 39, 133, 203, 391– Analytic 25–26– Autoimmune skin disorders 25– BP 39– Bullous pemphigoid 38– Case series 25– Case-control studies 36, 38, 40, 50– Case-control study 26, 31– Chronic discoid lupus erythematosus28–29– Cohort studies 26– Control group 26– Controlled trials 27– Cross-sectional studies 26– Dermatomyositis 36– Descriptive 25–26, 28– Etiology 25– Evidence Based Medicine 27– Incidence 26, 28, 32, 38– Morbidity 26 Subject Index––––––––––– Morphea 32Mortality 26Odds-ratio 26Ordinary review 27Population 26Prevalence 26, 28, 32–33, 38Risk Factors 25–26, 29, 32, 38Smoking 31SSc 33–34, 36–37Systematic review 27Systemic lupus erythematosus 28–29,32, 34, 36– Systemic sclerosis 32–33Epidermal atrophy 212Epidermal cell antigens 333Epidermal keratinocytes 46, 48, 63Epidermal transglutaminase 101Epidermal-dermal junction 100Epidermolysis bullosa acquisita 77, 102,109, 131, 435, 446– Anchoring fibrils 109–110, 112–113,117–118, 120– Autoantibodies 112, 115, 117–119,122–123– Basement membrane zone 109– BP-like presentation 114– Brunsting-perry pemphigoid 115– Bullous SLE 111, 116–117, 122–123, 128– Classical EBA 114– Clinical manifestations 113– Clinical presentation 113, 119– Colchicine 126– Collagen 109– CP 115– Crohn's disease 117– Diagnosis 118– Direct immunofluorescence 118– Direct salt split skin immunofluorescence121– EBA 109–110, 112–113, 115–116,118–120, 122, 125–126, 434– Electron microscopy 119– ELISA 119, 123– Etiology 110– Hemidesmosomes 110– Histology 119– IgA 115–116– Immune adsorption 127– Immunoblot analysis 123– Immunoelectron microscopy 120– Immunoglobulins 127– Immunosuppressive agents 126– Incidence 110– Indirect immunofluorescence 119– LABD-like presentation 115– Lamina densa 110, 125– Lamina lucida 118 461 ––––––– Pathogenesis 110–111, 118Photopheresis 127Salt-split skin 121Suction split immunofluorescence 125Systemic glucocorticoids 126Therapy 125Type VII collagen 110–113, 115–117,122–125, 127– Western blot analysis 122Epithelial hyperplasia 297Epitope 81, 405Epstein Barr virus 266, 372Erythema 188Erythema annulare centrifugum 211, 278Erythema gyratum repens 209, 211Erythema multiforme 56, 208, 400Erythemato-squamous plaques 298Erythematous papules 95Erythroderma 72, 209Erythrodermic psoriasis 299Esophageal dysfunction 249Esophageal involvement 145Etanercept 219, 436, 443Exclamation mark hairs 385, 387Experimental autoimmune encephalitis425Experimental autoimmune myastheniagravis 425Experimental autoimmune thyroiditis 425Extracellular matrix synthesis 139,166Extracorporeal photochemotherapy 127,153, 175, 344Extracorporeal photopheresis 445–446Extraglandular symptoms 275 Facial erythema 249Fas ligand 407Fauci's scheme 359–360Fc receptor 433FceRI 321, 324, 329FcRn 433–434Fibrillar collagens 167Fibrillarin 172Fibrillin 1 146, 248Fibroblasts 138Fibronectin 112Fibrotic process 168, 178Finger tip ulcerations 175Fingernails 298Fixed urticaria 77Flexual psoriasis 298Fluorescent overlay antigen mapping 125Focal vitiligo 368Fodrin 265Follicular inflammation 404Follicular plugging 209 462 Subject Index Foxp3 6Free oxygen radicals 352Fumaric acid esters 302–303 Gastrointestinal vasculitis 355Gene loci 291Generalised vitiligo 368–369Generalized disease 196Generalized morphea 134, 137, 141Generalized pustular psoriasis vonZumbusch 299Genetics 291Gestational pemphigoid 73Gingival involvement 340Gingival telangiectasia 232Glandular cells 262Glatiramer acetate 425Glomerulonephritis 360Glucocorticosteroids 195Glucose-6-phosphate deficiency 196Glucose-6-phosphate dehydrogenase 217Gluten 105Gluten sensitive enteropathy 211Gluten-free diet 105–106Gold 197Graft-versus-Host-Reaction 344Granular IgA deposits 100Granuloma annulare 211, 444Granulomatous lesions 351, 356Granzyme 262Gutatte psoriasis 292Guttate morphea 139 H2-blockers 178Haemopoetic stem cell 178Hair follicle 404, 407Hair follicle antigens 405, 409Hair regrowth 396–397H-antihistamines 317Hashimoto's thyroiditis 74, 145, 393Helicobacter pylori 316Hemidesmosomes 84, 120Hemifacial atrophy 143Hemolytic anemia 196Hemorrhagic cystitis 359Henoch-Schönlein purpura 360Hereditary angioedema 210Herpes gestationis 73High affinity IgE receptor 320High dose intravenous immunoglobulins62, 433HIV-associated aphthosis 431HLA class II alleles 45–46, 74, 205, 319, 394Human leukocyte antigen 393Hydroxychloroquine 153, 196, 216, 239 Hypereosinophilic syndrome 356Hypergammaglobulinemia 146, 433Hyperglobulinemic purpura 273, 275, 278Hyperpigmentation 188Hypertension 177Hypertrophic DLE 198Hypothyroidism 276 Idiopathic inflammatory myopathies 229IgA antibodies 105IgA gammopathies 58IgE-mediated diseases 17IgE receptor 320IgG catabolism 433Ignorance 5, 7Immune complex-mediated vasculitides349, 352–353, 361Immune deviation 425–426Immune pathogenesis 334Immune phenomena 248Immunoablation 445Immunoadsorption 62, 432–433Immunodominant 81, 426Immunoglobulin 1–2, 7, 9–10, 14–15, 120Immunohistochemistry 358Immunological tolerance 421Immunomodulatory treatments 86, 398,404, 421Immunopathogenesis 213, 421Immunophilins 423Immunosuppression 147, 254, 301, 421Immunosuppressive macrolides 422Immunosuppressive therapy 62, 150, 241,396Immunotherapy 425Incidence 26, 28, 134Inclusion body myositis 230, 240Indirect immunofluorescence 75Infectious agents 10Inflammatory alveolitis 177Inflammatory bowel disease 117, 126, 442Inflammatory infiltrate 166, 295Infliximab 436, 442–444Inhibition of pathogenic autoantibodies431Insulin-resistance 233a6b4 integrin 85Intercellular adhesion molecule-1 335Interferon-a 175Interferon-g 7, 153Interferons 197Interleukin-1 52Interleukin-2 439Interleukin-8 102Intermittent urticaria 309Interstitial pneumonitis 235 Subject IndexIntimal hyperplasia 166Intra-epidermal microabscesses 298Intrafollicular lymphocytic infiltrates 388Intralesional corticosteroids 397Intrathymic selection 4Intravenous immunoglobulin 127, 219, 328,359, 433–434Irritant contact dermatitis 402Ischemic injury 136Isotretinoin 218 Jo-1 antibodies 172, 235Joint contractures 144Junctional adhesion complexes 84Juvenile DM 237–238 Keratinocyte 186, 204, 294–295, 297, 336Keratoacanthoma 188Keratoconjunctivitis sicca 267Kidney failure 179Koebner's isomorphic response 186, 188,191, 338, 368 LABD antigen 78, 116Laboratory tests 357Lamina densa 125Lamina lucida 102, 120–122Laminin 265Laminin-5 78, 81, 85, 122Laminin-6 78Langerhans cells 335, 372, 374, 404Leflunomide 359, 424Leucocyte function-associated antigentype 3 437Leucoderma 368Leukaemia 144Leukocyte attraction 352Leukocytoclastic vasculitis 274–275, 278Leukopenia 212Lichen planopilaris 387Lichen planus 11, 145, 188, 231, 333, 337,342, 423Lichen sclerosus 139, 145Lichenoid dermatoses 244, 334, 342, 345Light microscopy 75Lilac ring 139, 142Linear IgA bullous dermatosis 77, 95, 97,110, 434Linear morphea 142, 145Lipatrophy 190Lipodystrophy 233Lipopolysacharides 12Livedo vasculitis 354Local inflammation 82 463 Localized morphea 148Localized scleroderma 133, 135, 151, 172,176Low complement levels 357L-phenylalanine 375Lupus 315Lupus band test 193, 214Lupus erythematosus 74, 100, 145, 183,203, 230, 245, 435– Lupus nephritis 422, 431– Lupus panniculitis 190, 193, 196, 198,209– Lupus profundus 190– Lupus-like syndrome 219Lyme borreliosis 136Lymph drainage 175Lymphocytic infiltrate 191, 267–	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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268, 404Lymphocytic perivascular infiltrates 165Lymphoma 105Lysyl pyridinoline 167Lytic enzymes 349 Macrolides 422Malar erythema 231Malar rash 183, 278Mast cells 15, 322Matrix metalloproteinase 82MCTD 245, 249, 252Mechanic hands 173Mechanobullous disease 114, 126Melanocyte autoantigens 371Melanogenesis 370Melanosome 370, 377Meltzer's triad 356Membrane thickening 166Memory T cells 1Metalloproteinases 176, 262Methemoglobulinemia 196Methotrexate 79, 150, 152, 197, 206, 219,239–240, 302, 359–361, 4438-Methoxypsoralen 302, 398Methylprednisolone 219MHC class II 110, 404Microchimerism 166Microscopic polyangiitis 349Microvascular injury 166Milia formation 114Mimicry 408Minoxidil 402Mixed connective tissue disease 245, 247,250, 255Mixed connective tissue disease (MCTD)– Alarcon-Segovia's criteria 252– Anticardiolipin antibody 248– Anti-casein kinase II (CKII) antibody246 464–––– Subject Index Anti-DNA antibody 246Anti-EC antibody 247Anti-HSP 70kDa antibody 246Anti-human endogenous retrovirus(HERV) p30gag ant 248– Anti-U1snRNP autoantibodies 245– Arthritis 250– Autoantibodies 246–301– Classification 252–254– Clinical appearance 249–250– CREST syndrome 248– Criteria 252–255– Diagnostic criteria 250, 252– Endothelin-1 247– Esophageal dysfunction 249– Etiopathogenesis 245– HLA class II 247, 249– Immunological aberrations 247– Leukocytopenia 249– Myositis 250– Nonsteroidal anti-inflammatory drugs 254– Pericarditis 249– Pleuritis 249– Prognosis 256– Pulmonary hypertension 248, 250, 256– Raynaud's phenomenon 250– Sausage-like fingers 249– Sharp's criteria 252– Survival rate 252– Systemic corticosteroids 254– T cell characteristics 247– The Research Committee of theJapanese Ministry 252– Therapy 254– Thrombocytopenia 249Mixed cryoglobulinemia 274Molecular mimicry 11, 246 296, 372Monoamine oxidase A 374Monocytes 349Monozygotic twins 392Morbilliform exanthem 209Morning stiffness 192Morphea 133, 136, 150, 152, 154, 435Morphea en plaque 134Mucocutaneous lesions 48, 341Mucosal inflammation 262Mucous membrane pemphigoid 434–435Multiple sclerosis 425Munro microabscesses 293Muscle biopsy 229Muscle disease 234Muscle weakness 176Mutilating psoriatic arthritis 299Myalgia 170Myasthenia gravis 393Mycophenolate mofetil 79, 127, 219, 239,302 Mycophenolic acid 422Myelin basic protein (MBP) 425Myelodysplastic syndrome 359Myeloperoxidase 349Myenteric nerve plexus 177Myocardial fibrosis 178Myopathy 230, 240Myositis 236, 240Myxedema 393 Nail involvement 387–388Nail pits 387Nailfold capillary dilatation 169Nailfold splinter hemorrhages 354Nasolabial folds 209Necrotizing vasculitis 351Neonatal lupus 274, 276Nephropathy 152, 175, 210Neurological disorders 192Neutrophil elastase 82Neutrophilic granulocytes 293, 298, 349,351Non HLA genes 395Non steroidal anti-inflammatory agents176, 207Nuclear antigens 264 Oedema 168Oesophagus 177Onychomadesis 387Ophiasis 385Oral cavity 72Ortho-hyperkeratosis 293Overlap syndrome 172, 174, 176Oxidative stress 370, 372, 376, 379 Palmoplantar pustular psoriasis 299Palpable purpura 274, 354Panniculitis 233Pansclerotic morphea 144Papillary dermis 102, 295Papular mucinosis-like lesions 234Parakeratosis 293Paraneoplastic dermatosis 210Paraneoplastic pemphigus 45, 77, 342, 441Paraneoplastic vasculitis 356Parry–Romberg syndrome 143Passive transfer 52Patchy hair loss 385Pathogenesis 187, 294Pathogen associated molecular pattern 7Pathogenic autoantibodies 431Pauci-immune vasculitides 353, 358PBL-SCID mouse model 53 Subject IndexPemphaxin 49Pemphigoid 325Pemphigoid gestationis 73, 110Pemphigoid nodularis 72Pemphigus 45, 325, 431–432Pemphigus– a9 acetylcholine receptor 50– Acantholysis 46, 48, 52, 57, 63– Animal models 52–53– Antinuclear Ab 58– Auto-Ab 56– Autoantigens 61– Autoreactive B cells 51, 53– Autoreactive T cells 51–52– Azathioprin 62– B cell lymphoma 56– BP238 50, 57– Castleman's tumor 56– CD4+ T lymphocytes 51– Cholinergic receptor 50– Clinical phenotype 53, 54– Cyclophosphamide 62– Cyclosporin A 62– Desmocollins 47, 50, 58– Desmoglein 3-deficient mouse 52– Desmoplakins I 50, 57– Direct Immunofluorescence microscopy57, 60– Drug-induced pemphigus 57– Dsg1 53, 55, 57, 61, 63– Dsg3 47–48, 51, 53, 55, 57, 61– ELISA 58, 61– Envoplakin 57– Epidemiology 45– Epitopes 48– Etiopathogenesis 46– Fogo selvagem 55– Gastrointestinal disease 58– Glucocorticoids 61– Hallopeau type 60– HD1/plektin 50, 57– Histopathology 60– HLA-DQb10503 51– HLA-DRb10410 46, 51– HLA-DRb1*1409 46– IgA pemphigus 58– Immunological diagnosis 59– Immunosuppression 62– Immunosuppressive agents 62– Immunosuppressive therapy 62– Incidence 45– Indirect immunofluorescence microscopy60– Interferon-g 57– Intraepidermal neutrophilic dermatosis58– Intravenous immunoglobins 62 ––––––––––––– 465 Lung epithelium 56Lymphoma 45Methotrexate 62Monoclonal IgA gammopathies 58Mucosal involvement 54, 58Mycophenolate mofetil 62Nuclear antigens 50Oral lesions 54, 57Paraneoplastic pemphigus 56Pathogenic auto-Ab 51PBL-SCID Mouse 53Pemphaxin 50Pemphigus erythematosus (SenearUsher) 58– Pemphigus foliaceus 54, 56– Pemphigus herpetiformis 58– Pemphigus sebor rhoicus 56– Pemphigus vegetans 58– Pemphigus vulgaris 54, 56– Penicillamine 45– Periplakin 50, 57– Plasmapheresis 62– Rare pemphigus variants 58– Subcorneal pustular dermatosis 58– Therapy 61– Thymoma 56– Type Neumann 58Pemphigus erythematosus 50Pemphigus foliaceus 45, 432, 441Pemphigus variants 61Pemphigus vulgaris 14, 16, 45, 52, 422, 435Penicillin 153Peptide MHC complex 425–426Perforin 262, 407Pericarditis 250Perifollicular infiltrate 400Peripheral tolerance 3, 5, 428Periplakin 50Perniotic lupus 190Phenylalanine metabolism 375, 377Phenytoin 153Phosphodiesterase-inhibitors 175Phospholipase C 48Photochemotherapy 301–302Photodynamic therapy 153Photopheresis 175Photo-protective clothing 215Photoprovocation 194Photosensitivity 192, 206, 214Phototherapy 301Physiotherapy 175Pimecrolimus 196, 380Pityriasiform lesions 209Plaque morphea 134, 137, 139, 147Plaque psoriasis 435, 443Plaque-like mucinosis 233Plasmapheresis 127, 152, 321, 431 466 Subject Index Plasminogen activator 48, 82–83Plectin 81, 85Pleuritis 249PM-Scl complex 170, 172PM-Scl overlap syndrome 173Poikiloderma 231–232Polymorphic light eruption 211Polymyositis 170–171, 174, 236–237, 240,245Polyneuropathy 355, 360Porphyria cutanea tarda 114, 172, 211Postinflammatory hyperpigmentation400PR3-specific T-cells 352Precursor T cells 2Prednisolone 254Pregnancy 73Pretibial pemphigoid 72Prevalence 26, 34, 133Prognostic markers 80Progressive systemic scleroderma– Alveolitis 177– ANA 172– Anti centromer (CENP-B) antibodies169– Anti-DNA-topoisomerase I antibodies169– Anti-ds DNA antibodies 172– Antifibrotic agents 175– Arthralgia 176– Autoantibodies 165, 171–172– Autoantibody profile 171– Calcinosis 175– Cardiac involvement 178– Clinical presentation 168, 172– Collagen synthesis 167, 175, 178– Collagens 167, 175, 180– Dermatohistopathology 174– Diagnosis 171– Diffuse cutaneous SSc (dSSc) 168–169– D-penicillamine 175– Extracellular matrix 166–167– Gastrointestinal Involvement 177– HLA gene 165– Immune dysregulation 165– Immunosuppressive agents 175– Incidence 168– Interferon-g 175– Limited cutaneous SSc (lSSc) 168–169– Methotrexate 175– Mixed connective tissues disease(MCTD) 170– Musculosceletal involvement 176– Overlap syndromes 170– Physical therapy 174– Pulmonary involvement 170, 175, 177– Quality of life 168 – Raynaud's syndrome 166, 169–170, 172,175, 178– Renal involvement 176– Sclerodactily 172– Scleroderma-like syndromes 170, 173– Scleromyositis (PM-Scl-associated) 170– Skin involvement 175– Synthetase syndrome 170– Systemic lupus erythematosus 172, 178– Systemic sclerosis sine scleroderma169– TGF-beta 167, 178– Therapy 174, 178– UV radiation 176– Vascular pathology 166Propanolol 57Prostacycline 175, 177, 254Prostaglandin 254Proteases 48, 104Proteinase 3 349Proton pump inhibitors 177Prurigo 77Pruritic eruption 95Pseudocatalase 373Pseudolymphoma 276Psoralens 149, 302Psoriasis 17, 231, 298, 423, 435, 444– Psoriasis arthritis 443– Psoriasis cum pustulatione 299– Psoriasis vulgaris 291– Psoriasis-subtypes 292– Psoriatic arthritis 299– Psoriatic autoantigens 296– Psoriatic skin lesions 295–296– Psoriatic spondylarthritis 299– PSORS1 292– PSORS2 292– Psychosocial situation 168Pteridines 374Pulmonary embolism 248Pulmonary fibrosis 179Pulmonary hypertension 250Pulmonary involvement 56, 177Pulse methylprednisolone therapy 239Purpura 278, 355–356Pustular arthroosteitis 299Pustular psoriasis 299, 303PUVA 149, 176Pyoderma gangrenosum 354, 423, 430,435, 443 Quinacrine hydrochloride 216 Radiation 136Rashes 278 Subject IndexRaynaud's phenomenon 133, 166, 171,342Raynaud's syndrome 169Receptor type 1 antagonists 175Regulatory T cell 6, 17, 296Relaxin 175Renal involvement 176, 355Repigmentation 378Respiratory failure 56Retinoids 197Retrovirus 248Rheumatoid arthritis 74, 145, 171, 178, 210,219, 246, 267, 424, 447Rheumatoid factor 213, 275, 352Rheumatoid vasculitis 356Risk factor 29, 31Rituximab 220, 360, 436, 441RNA Polymerase I, III 172Ro autoantigen 204Ro/SS-A 211, 214Rodnan skin score 146, 168, 175 Salicylic acid 301Salivary glands 261–262, 264Salt split skin immunofluorescence 121Scabies 77Scl-70 172SCLE 192–193, 204, 208–209, 211,213–216, 233Scleroderma 133, 138, 170, 176, 230, 250,261, 342– Scleroderma adultorum Buschke 172– Scleroderma overlap syndromes 170– Sclerodermiform genodermatoses 173– Scleromyositis 170– Scleromyxoedema 172– Sclerosis 136, 142, 144– Sclerotic lesions 142– Secondary immune complex-mediatedvasculitides 356, 361Secondary epitopes 81Segmental vitiligo 368–369Self antigens 428Self MHC molecules 265Self-tolerance 421Self-antigens 4, 11Self-reactive T and B Cells 9Shulman Syndrome 144Sicca symptoms 192, 268, 270Silica dust 170Siplizumab 440Sirolimus (Rapamycin) 423Sjogren's syndrome 100, 192, 210–211,248, 261, 265, 271–273, 278-280, 281,283, 285, 287, 289– Antibodies 265 467 – Anti-cardiolipin antibodies 276– Apoptosis of glandular epithelial cells264– Arthralgia 275, 280– Arthralgias– Arthritis 275– Autoantibodies 264, 267, 276– Autoantigens 264– Central nervous system involvement274– Complete heart block 265– Cutaneous manifestations 271– Differential diagnosis 277– Dyspareunia 276– Environmental agents 266– Epidemiology 267– European (EEC) criteria 261, 267– Extraglandular manifestations 273, 275– Extra-glandular symptoms 280– Fatigue 276– Genetic factors 277– Hepatitis C infection 274– HLA associations 277– Hypergammaglobulemic purpura 273– Lacrimal glands 266– Leukopenia 275– Lymphoma 278– Mucosal surface abnormalities 268– Myalgias 275– Myositis 275– Nephritis 277–278– Pathogenesis 261– Peripheral neuropathy 273– Pulmonary involvement 274– Salivary gland 264, 271– San Diego criteria 261– Sialadenitis 264– Sicca symptoms 267, 278– SS-A 264, 276– SS-B 264– Therapeutic principles 279– T-lymphocytes 262– Vasculitis 277– Xerostomia 267Sjogren's syndrome 34, 174, 315Skin cancer 378Skin fragility 112, 114, 117Skin involvement 137Skin prick testing 310Skin sclerosis 146Skin thickness 149Skin-infiltrating T cells 149SLE 110, 177, 183, 191, 197, 209, 220, 248,252, 277–279, 446Small vessel vasculitides 209, 361Soluble CD4 receptor 137Spinous cell carcinoma 188 468 Subject Index Spliceosome 247Squaric acid dibutylester 398SS-A 265, 267, 274SS-A antigens 265SS-B 267, 267, 274SSc 165–166, 168, 171–172, 175–178, 248,252Staphylococcus aureus 351Stem Cell transplantation 445Steroids 206Stomach 177Stratified epithelia 71Streptococcal antigens 294, 297Streptococcal infections 11Subacute cutaneous lupus erythematosus188, 196, 233– ACLE 203, 209– ACR 209– Acute cutaneous LE 203– Alopecia 209– ANA 212, 221– Antimalarials 216– Autoantibodies 204, 212– CCLE 203– Chronic cutaneous LE 203– Clofazimine 219– Cutaneous manifestations 208– Dapsone 218– Definition 203– Differential diagnosis 211– Direct immunofluorescence 213– DLE 208–209– Environmental factors 206– Epidemiology 203– Etiology 204– Exfoliative erythroderma 209– Histopathology 212– HLA-DR3 205– Immunoglobulin 219– Immunoglobulins 213– La/SS-B autoantibodies 212– Laboratory findings 211– Livedo reticularis 209– Local corticosteroids 215– Local therapy 214– Nephritis 209– Nonlesional lupus band test 214– Photosensitivity 206– Prognosis 220– Progressive generalized poikiloderma209– Raynaud's phenomenon 209– Retinoids 218– Ro/SS-A autoantibody 211, 213, 221– Serological findings 213– SLE 220– Smoking 217 – Systemic corticosteroids 219– Systemic disease 209– Systemic therapy 216– Thalidomide 217– Ultraviolet A-1 phototherapy 220– UV light 204– UVA protection 215Subcorneal pustular dermatosis(Sneddon-Wilkinson) 443Subcutaneous amyloid 274Subcutaneous morphea 143Subepidermal bullous diseases 102, 118,122, 341Sublamina densa zone 118–121Sulfmethooxazole 351, 359Sulphapyridine 104Sulphasalazine 153Sun protection factor 215Sunlight induced papulonodular mucinosis209Superantigens 3Superficial morphea 141Susceptibility haplotypes 46Sweet's syndrome 211Symmetric psoriatic polyarthritis 299Systemic disease 194Systemic glucocorticoids 63, 152, 343,397Systemic lupus erythematosus 13, 171,183, 203, 261, 334, 355, 446, 430–431,433, 441Systemic sclerosis 33, 133–134, 146, 165,172, 245, 423, 431, 435, 445–446Systemic therapy 302Systemic vasculitides 349, 353–354, 361 T cell anergy 426, 428T cell epitopes 11T cell receptor (TCR) 1, 4, 425–426T cells 404, 425T helper (Th) cells 8Tacrolimus (FK506) 153, 196, 380, 422Tazarotene 301T-B cell Interactions 2, 16TCR 265, 296Telangiectasia 231Th1 cytokines 82Th2 cytokines 82Thalidomide 196, 430–431Therapy 79, 279Throat infection 294, 300Thrombocytopenia 144, 212Thromboembolisms 248Thrombosis 192, 218Thymic maturation 2Thymus 2, 265 Subject IndexTissue hypoxia 166Tissue injury 296TNF-a 353, 429, 442TNF-a gene polymorphisms 395TNF-a receptor 424, 430TNF-a-antagonists 303Tobacco use 214Toenails 298Tolerance 3, 10, 16, 264, 421, 424–426Tolerogenic dendritic cells (DC) 428–429Toll-like receptors 7Tonsillectomy 300Topical calcipotriol 150Topical corticosteroids 79, 147, 396Topical tacrolimus 215Topical therapy 300Topoisomerase 265Toxic pustuloderma 218Traction alopecia 387Transforming growth factor-b 167Transglutaminase 97, 105Trauma-induced blisters 112Trichohyalin 405Trimethoprim 351, 359Tumor necrosis factor-a 52Tumor necrosis factor-b, 356Type I collagen 167Type I diabetes mellitus 100, 270Type VII collagen 78, 109–112, 115,117–118, 122–123Type XVII collagen 76Tyrosinase 369Tyrosinase antibodies 370 469 U1-RNA-70 kDa protein complex 172, 246Ultraviolet A radiation 147, 398Universal vitiligo 368Urticaria 309Urticarial plaques 97Urticarial vasculitis 274, 315, 318, 354UV exposure 214UV light 204UVA1 176UV-B spectrum 301 Vascular inflammation 229Vascular system 165Vasculitis 77, 275, 277, 349, 357–358, 435Vasodilatators 254, 256Verrucous DLE 188Vessel damage 352Virus infections 186Vitamin D analogues 150, 301Vitiligo 100, 145, 367, 383– acrofacial 368Vulvar pemphigoid 72 Weakness 356Wegener's granulomatosis 349, 351, 422Wickham striae 337 Xeropthalmia 261Xerostomia 261,	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. 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267X-linked chronic granulomatous disease 211 Springer and the EnvironmentW E AT S PRINGER FIRMLY BELIEVE THAT AN INTERnational science publisher has a special obligation tothe environment, and our corporate policies consistently reflect this conviction.W E ALSO EXPECT OUR BUSINESS PARTNERS – PRINTERS ,paper mills, packaging manufacturers, etc. – to committhemselves to using environmentally friendly materials and production processes.T HE PAPER IN THIS BOOK IS MADE FROM NO - CHLORINEpulp and is acid free, in conformance with international standards for paper permanency. <\|end\|>	management	Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt	[ 29871, 29906, 29953, 29955, 29990, 29899, 2324, 287, 17168, 293, 3803, 352, 290, 271, 681, 17135, 29871, 29906, 29896, 29896, 13, 19634, 261, 322, 278, 16738, 29956, 382, 15531, 317, 12089, 4214, 1001, 383, 8193, 1988, 29979, 20700, 5265, 29923, 12064, 3446, 1299, 13764, 2672, 4945, 29876, 1288, 10466, 9805, 261, 756, 263, 4266, 10788, 362, 304, 1552, 5177, 29892, 322, 1749, 17266, 403, 24833, 5718, 2705, 9432, 445, 7602, 2463, 29889, 29956, 382, 14445, 6156, 8528, 4162, 1783, 438, 4574, 350, 3308, 8895, 1799, 349, 8322, 13865, 29903, 785, 12089, 23845, 29903, 1919, 19773, 3533, 29879, 29892, 4870, 6751, 12012, 332, 414, 29892, 2992, 29889, 785, 304, 9063, 386, 1567, 295, 1960, 304, 773, 5177, 635, 19780, 17279, 322, 5802, 10174, 29889, 29911, 17714, 349, 3301, 1001, 2672, 3446, 3235, 16437, 8949, 8519, 14861, 2287, 3895, 11698, 448, 5868, 29931, 1955, 8895, 29886, 15323, 322, 338, 22193, 3889, 29892, 297, 378, 13390, 411, 6121, 20801, 363, 5650, 9410, 3819, 29889, 13, 32007 ]	[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1 ]	55

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Greaves IntroductionUrticaria is conventionally classified as acute, intermittent and chronic (Greaves 2000a). Acute urticaria which frequently involves an IgE-mediated immunological mechanism, is common, its causes often recognised by thepatient, and will not be considered further. Intermittent urticaria – frequentbouts of unexplained urticaria at intervals of weeks or months – will be discussed here on the same basis as ‘ordinary’ chronic urticaria. The latter isconventionally defined as the occurrence of daily or almost daily whealingfor at least six weeks. The etiology of chronic urticaria is usually obscure. Thedifferent clinical varieties of chronic urticaria will be briefly considered here,and attention will be devoted to a newly emerged entity – autoimmune chronicurticaria, since establishing this diagnosis has conceptual, prognostic and therapeutic implications. Contact urticaria and angioedema without urticaria willnot be dealt with in this account. Classification of Chronic UrticariaThe clinical subtypes of chronic urticaria are illustrated in the pie-chart ofFig. 1. The frequency of these subtypes is based upon the authors’ experienceat the St John’s Institute of Dermatology in UK. Whilst there may well be minor differences, it is likely that the frequency distribution of these subtypeswill be essentially similar in most centres in Europe and North America (Greaves 1995, 2000b). However, our experience suggests that the incidence ofangioedema, especially that complicated by ordinary chronic urticaria is substantially lower in Japan and south Asian countries (unpublished observation). 310 Michihiro Hide and Malcolm W. Greaves Fig. 1. Chronic urticaria. Frequency of different subtypes in the authors’ practices.The proportions are probably not very different elsewhere Physical UrticariasThese comprise about one third to one fourth of all urticaria patients seen inthe authors’ services. The diagnosis is mainly made from careful history taking, appropriate clinical examination, and physical challenge testing is performed when necessary. It is important to identify patients in whom a physicalurticaria is the main, if not the only, cause of the patient’s symptoms. In thiscase, further investigation is not indicated, with rare exceptions (see below).Almost invariably, patients with this diagnosis are over-investigated by thetime they are referred to the urticaria clinic. Skin prick testing, RAST (radioallergo sorbent tests), food exclusion diets, etc, are not normally indicated inpatients with a physical urticaria with the exception of food-dependent exercise-induced urticaria, a rare variety of urticaria, which develops followingexercise after food ingestion.It is also important to appreciate that different physical urticarias can occur concurrently in the same patient; cold and cholinergic urticarias represent a well recognised example. Furthermore, chronic ‘idiopathic’ urticaria isoften associated with dermographism or delayed pressure urticaria. The investigation and management of chronic urticaria should be influenced by establishing the relative contributions of coexisting forms of chronic urticariato the patient’s overall disability. Symptomatic DermographismThis common physical urticaria presents mainly in teenagers or adults of either sex. Like most physical urticarias, individual itchy wheals, produced bygentle stroking or rubbing of the skin, last less than 30 minutes before fading(Fig. 2). Angioedema and mucosal whealing do not occur and there are no Chronic Urticaria as an Autoimmune Disease 311 Fig. 2. Symptomatic Dermographism. Upper left hand panel: use of a graduated dermograhpometer to test for sensitivity to a dermographic stimulus. Upper right hand panel:graded wheal and flare response to a range of pressures. Lower panel: gentle stroking byround end of a pen rod with a certain pressure may readily disclose abnormal reaction ofpatients. systemic symptoms but pruritus is troublesome. The etiology is unknown although skin reactivity can be passively transferred to non-human primates byintracutaneous injection of donor serum from a dermographic patient (Murphyet al. 1987). As with the majority of physical urticarias, investigations are pointless and any role for food items has not been substantiated. The prognosis isfor eventual improvement in two to three years in most patients. Low sedationantihistamines such as loratidine 10 mg, cetirizine 10 mg or fexofenadine120–180 mg are usually effective in relieving the itch, although additional treatment by a sedative antihistamine such as hydroxyzine 25 mg at night mayalso be useful. Combinations of H1- and H2- antihistamines may be useful. Cholinergic UrticariaCholinergic urticaria is common in children and young adults, although rarein the elderly. Historically, this type of urticaria has been classified as a physical urticaria. However, a recent consensus report for “definition, classification, 312 Michihiro Hide and Malcolm W. Greaves Fig. 3. Cholinergic Urticaria. Typical monomorphic symmetrical maculopapular eruptionevoked by heat or exertion or stress and routine diagnosis of urticaria” (Zuberbier et al. 2001) for urticaria andangioedema classified this urticaria as a special type of urticaria, apart fromphysical urticarias. Symptoms of cholinergic urticaria, typically widespreadpruritic monomorphic maculopapular lesions, develop in conditions causingsweating, such as exercise, hot bath taking, or emotional stimuli (Hirschmannet al. 1987) (Fig. 3). If the patient rests, cools off or relaxes, the eruption subsides in 15–45 minutes. Typical areas of predilection include the face, neck,fronts of elbows, wrists and popliteal fossae, although almost any area of thebody can be involved. It may be accompanied by angioedema and systemicsymptoms include wheezing or, rarely, anaphylactoid symptoms. Cholinergicurticaria can be disabling, especially when provoked by occupational or emotional triggers. The diagnosis is established by appropriate challenge testing(Commens et al. 1978) (exercise, a hot bath or mental arithmetic) and/or skintest with acetylcholine. No further investigations are indicated.The prognosis is for gradual improvement over the course of months oryears in most patients, although the authors have several patients in whomcholinergic urticaria remains unremitting. The condition normally respondsreasonably well to avoidance of provoking factors, together with regular dailytreatment by an H1-antihistamine, especially in children.Clinical variants include persistent cholinergic urticaria (Murphy et al. 1983),in which the rash is evident even at rest, and exercise-induced angioedema(Lawrence et al. 1981). Rarely patients may give a clear history of food provocation – either association of onset non-specifically with food intake, or specifically with certain food items (Zuberbier et al. 1993).The pathomechanisms are incompletely understood. The local wheals canbe blocked by atropinisation of the skin indicating involvement of acetylcholine, and histamine release has also been confirmed – presumably derivedfrom mast cells (Herxheimer 1956). Wheal and flare reaction to autologoussweat and sweat-provoked histamine release from their basophils have been Chronic Urticaria as an Autoimmune Disease 313 Fig. 4. Cold Urticaria. Local whealing response to application of an ice cube for 10 min demonstrated in some populations of patients with cholinergic urticaria(Adachi et al. 1994). These reactions have been suggested to be mediated byspecific IgE, but the antigen in human sweat has not been identified yet. Cold UrticariaThis less common physical urticaria occurs in children and adults. Whealingis rapidly provoked by exposure to cold fluids or cold surfaces (Fig. 4). Angioedema of the oropharynx is common, e.g. after sucking an iced lolly. Systemic symptoms are common and may be severe – especially when provokedby extensive body immersion, as in sea-bathing. Cold urticaria is due to histamine release (Keahey et al. 1980), and cold-reactivity can be passivelytransferred to non-human primates by donor serum from affected individuals (Misch et al. 1983). The transferable factor has been variously attributedto IgE or IgM. Rarely cryoglobulins and cold agglutinin can be identified insufferers’ serum. These are usually sought routinely but positive results areexceptional. No other investigations are worth while.In adults cold urticaria may be highly disabling especially in outdoor workers. It responds rather poorly to antihistamine treatment in all but the mildestcases and in children. Cold tolerance treatment (repeated cold exposure toinduce a temporary refractory state) is effective but requires a highly motivated patient (Bentley-Phillips et al. 1976). Some remain crippled by coldsensitivity despite all these measures. 314 Michihiro Hide and Malcolm W. Greaves Delayed Pressure UrticariaThis common and disabling physical urticaria is arguably not a true urticariasince the wheals characteristically are of more than 24 hours’ duration (Lawloret al. 1989a). As its name suggests, whealing occurs following a latent periodof 2–4 hours after application of pressure perpendicular to the skin. Commonexamples of triggering factors include a tight waistband, tight footwear andgolf club, tennis racquet, or steering wheel grips. Pain is more characteristicthan itch although both may occur, and there is no angioedema and no mucosalinvolvement. A skin biopsy reveals an inflammatory infiltrate in which eosinophils are prominent but there is no vasculitis. Mild systemic symptoms arecommon including arthralgia and fatigue. The pathomechanisms in delayedpressure urticaria are unknown. In Caucasian populations about 40 per centof patients with chronic ‘idiopathic’ urticaria have accompanying delayedpressure urticaria (Sabroe et al. 1999a), and it is doubtful if it ever occurs asan isolated clinical entity.Treatment is very difficult. Early claims of the value of the antihistaminecetirizine have not been substantiated and antihistamines are usually poorlyeffective. Non-steroid anti-inflammatory agents are also usually disappointing and in severely disabled patients substantial dosage with oral steroids(e.g. prednisone 30–40 mg daily) may be necessary to control symptoms. Other Physical UrticariasThese are rare, and include solar urticaria (Ramsay 1977), aquagenic urticaria (Sibbald et al. 1981), vibratory angioedema (Lawlor et al. 1989b) andheat urticaria (Koro et al. 1986). Although it may be useful to determine theaction spectrum needed to evoke solar urticaria, generally no further investigations are needed beyond establishing the diagnosis by appropriate challenge tests. Antihistamine therapy is helpful to varying degrees in membersof this group, which will not be discussed further. The reader is referred tomore detailed accounts of these physical urticarias published recently elsewhere (Black 2004). Food Additive-Evoked Chronic UrticariaAt some stage in the course of their disease, many patients with chronic urticaria believe they have an ‘allergy’ to food items, and this belief is often reinforced by gratuitous advice from relatives and friends, and even by healthcare professionals including dermatologists and allergists. In fact, a relationship between food and chronic urticaria can be substantiated infrequently.The gold standard should be placebo-controlled challenge testing (May 1985;Pastorello 1995). In our urticaria clinics chronic urticaria can be demonstrably attributable to a food additive in no more than five per cent of patients. Chronic Urticaria as an Autoimmune Disease 315 We ask patients to keep a diary and report fluctuations in severity of whealingand itching but daily measurements of plasma tryptase or urinary excretionof histamine and its metabolites can be used to provide a quantitative measure of exacerbations. Urticarial VasculitisA full description of the etiology, pathomechanisms, clinical presentation, investigation and treatment is outside the scope of this article. However, thesubject has recently been comprehensively reviewed (O’Donnell and Black1995). Only a very brief outline will be included here. EtiologyIn the majority of patients, no cause is evident but recognised etiological factors include virus infections (hepatitis B and C and HIV) and paraproteinaemia.Urticarial vasculitis may also be the first, or very early, clinical manifestationof autoimmune disease (lupus, Sjogren’s syndrome) or ulcerative colitis orCrohn’s disease. Drug hypersensitivity may also be an occasional cause. Clinical Presentation and InvestigationIn contrast with ‘ordinary’ urticaria, individual wheals are of duration greaterthan 24 hours. Itching is variable and may be less prominent than painful tenderness. Some staining of the skin may be evident due to purpura and whealsmay show a predilection for pressure-bearing areas, such as the waistband.There may be associated systemic symptoms of which arthralgia is especiallycommon. Urticarial vasculitis tends to pursue a chronic unremitting course. TreatmentUrticarial vasculitis responds poorly to H1-antihistamines. Other drugs whichhave been proposed include dapsone, antimalarials and colchicine. Systemicsteroids may be effective but, given the frequently prolonged duration of thedisease, systemic complications are almost inevitable. Other measures worthconsidering in selected patients include intravenous immunoglobulin, parenteral gold injections and plasmapheresis. Chronic ‘Idiopathic’ UrticariaThis is conventionally defined as the daily, or almost daily, occurrence ofwheals and itching for 6 weeks or more (Greaves 1995) (Fig. 5). The differencebetween acute urticaria that appears daily for a few days and chronic idiopathic 316 Michihiro Hide and Malcolm W. Greaves Fig. 5. Chronic “Idiopathic” Urticaria. This 11 year-old child was treated elsewhere with aprolonged course of systemic steroids. The child is clearly Cushingoid, and still has widespreadurticaria urticaria with disease duration for months is not clear, in terms of pathomechanism. The average duration of chronic idiopathic urticaria is two–three years,but most patients eventually move into remission. EtiologyIf the small subgroup of patients substantiated to be reactive to a food additive is eliminated, then, at least until recently, the cause in the remainder wasunknown. There have been several reports attempting to implicate local and/or systemic infections of viruses, bacteria, and fungi, such as hepatitic C virus (Kanazawa et al. 1996), Helicobacter pylori (H.pylori) (Wedi et al. 1998;Schnyder et al. 1999), and candida (Henz BM et al. 1998). However, they are Chronic Urticaria as an Autoimmune Disease 317 either anecdotal or may be exacerbatory rather than causative for some populations of patients. Aspirin is a recognized cause of flare-up of urticaria(Grattan 2003). In a study reported by one of us (MWG), although upwards40 per cent of chronic urticaria patients had evidence of H.pylori infection,treatment of this produced no higher remission rate than when the same treatment was given to chronic urticaria patients who did not have evidence ofH.pylori (Burova et al. 1998). Nevertheless it is feasible that H.pylori may havean indirect role in autoimmune chronic urticaria (Greaves 2001) (see below).Parasite infestation is not a cause in industrialized countries, but may be important in some developing countries (Wolfrom et al. 1995). Recently a subgroup of chronic idiopathic urticaria patients has proved to have a specificautoimmune basis (Hide et al. 1993) and this subset will be discussed in greaterdetail below. PathomechanismsHistamine is clearly implicated in the pathogenesis of the wheals and itch.Although histamine, derived from dermal mast cells, is a major contributor tothe itch, its role in the wheals, which last several hours and are relatively poorlyresponsive to H-antihistamines, is less clear. Probably mast cell-derived cytokines, proteases and eicosanoids are also involved. Blood basophils and eosinophils are also prominent in skin biopsy material from wheals of all ages andmay also be a source of vasoactive mediators (Sabroe et al. 1999b; Ying et al.2002; Caproni et al. 2003).The observation that histamine releasing activity could be demonstratedin the serum or plasma of some patients with chronic idiopathic urticaria (Grattan et al. 1986) eventually led to the recognition of autoimmune urticaria asthe cause in an important subset of patients with this condition (Hide et al. 1993)(see below). Clinical Features and InvestigationCharacteristically the wheals are intensely itchy, of less than 24 hours’ duration individually and clear without marking the skin. Angioedema occurs inup to 50 per cent and affects skin and/or mucous membranes. Systemic symptoms are minimal. Delayed pressure urticaria occurs concurrently in up to 40per cent of patients (Sabroe et al. 1999a). When delayed pressure urticaria isan accompanying feature, it is important to establish whether this physicalurticaria or the accompanying spontaneous wheals and angioedema are theprincipal causes of the patient’s disability, since if it is the former, as alreadyindicated, no further investigations are worth while. The incidence of chronicidiopathic urticaria complicated with angioedema and delayed pressureurticaria, appears not so high in Japan and Asian countries according to theauthors’ experiences, although precise figures have not been reported. 318 Michihiro Hide and Malcolm W. Greaves Chronic idiopathic urticaria, with or without angioedema and delayedpressure urticaria, is a seriously disabling condition, causing occupational, social and personal disability of the same order as that consequent upon severecoronary artery disease (O’Donnell et al. 1997).Patients with chronic urticaria are almost invariably over-investigated. Nolaboratory investigations are normally indicated in the first instance. Effortsshould be directed at excluding urticarial vasculitis (by skin biopsy), foodadditive factors (by placebo-controlled challenge testing) and possibly a differential white blood cell count (for eosinophilia) in areas where parasiteinfestation is endemic. In severely affected patients, poorly responsive toH-antihistamines, referral to a specialised unit for investigation for autoimmune chronic urticaria should be considered (see below). TreatmentGeneral measures are important including a cool work and domestic environment, and avoidance of alcohol indulgence, aspirin, food additives suchas preservatives and azo dyes, and wearing of tight clothes. Although almostinevitably associated with modern living, stress, fatigue and intercurrent virus infections should at least be recognised by patients as probable causes ofoccasional flare-ups of chronic urticaria.H1-antihistamines are the mainstay of drug treatment. It is important toestablish the diurnal periodicity of symptoms (itch occurs predominantly inthe evening and at night) in timing the dosage. Most patients require an earlymorning dose of a low sedation antihistamine and supplementation in the eveningwith a further dose either of the same or, alternatively, a sedative antihistamine. If the latter is prescribed, it is important to draw the patient’s attentionto the possibility of significant impairment of cognitive function the next morning (Pirisi 2000). Topical application of 1% menthol in aqueous cream maybe appreciated by patients as a rapid temporary relief from pruritus.Oral steroids in short tapering courses can be useful in emergencies whenrapid control is necessary. However, they are not recommended as a routinetreatment of chronic urticaria, owing to the imbalance of efficacy and side effects (Fig. 5).It has been proposed that H1-antihistamines may exert an ‘anti-allergic’action independently of H1 receptors (Hayashi and Hashimoto 1999). This consists of down-regulation of adhesion molecule expression leading to reducedeosinophil and neutrophil migration and possibly a mast cell ‘stabilising’ effect. However, such actions of H1-antihistamines, if substantiated, probablyoccur only with regimens involving well above the licensed dosages.H2-antihistamines (e.g. cimetidine) do have a small statistically significantadditive effect when combined with H1-antihistamines but it is probably notsubstantial enough to be clinically useful. Recently developed cysteinyl leukotriene receptor antagonists may be very effective in a certain population of Chronic Urticaria as an Autoimmune Disease 319 patients. The efficacy of montelukast by itself or in combination with H1-antihistamine has been shown by controlled trials (Pacor et al. 2001; Erbagci Z2002.). On the other hand, others have proved negative (Reimers 2002). Aggravation of urticaria by aspirin in combination with other leukotriene antagonists has been reported (Ohnishi-Inoue et al. 1998). Autoimmune Chronic UrticariaBetween 30 and 50 per cent of patient with chronic ‘idiopathic’ urticaria havebiologically functional autoantibodies against the high affinity IgE receptoror less commonly against IgE itself (Niimi et al. 1996). In these cases the antibody is deemed to be the cause of the disease. These patients are describedas having autoimmune chronic urticaria (Hide et al. 1993; Hide et al. 1994). EtiologyThe reason why these autoantibodies are present and causative in some patients with chronic urticaria and not others is unclear. Genetic factors areprobably important. We have recently reported results of HLA class II associations in 100 patients with chronic urticaria (O’Donnell et al. 1999). Thosewhose sera were positive for anti-FceRI or anti-IgE autoantibodies showed ahighly significantly increased frequency of HLA DRB1*04 (DR4) alleles. Thereis also a positive association with other autoimmune diseases, notably autoimmune thyroid disease in patients with autoimmune urticaria (Leznoff et al.1983; Leznoff and Sussman 1989).As mentioned above, a high incidence of H.pylori infection in patients withchronic idiopathic urticaria has already been remarked. One of us (MWG) haspreviously suggested that H.pylori infection could lead to development ofanti-FcRI autoantibodies by molecular mimicry (Greaves 2001). PathomechanismsMost patients with autoimmune chronic urticaria have IgG autoantibodiesdirected against the alpha-chain of the high affinity IgE receptors (FcRIa) expressed on dermal mast cells or blood basophils (Niimi et al. 1996). Histamine release evoked by these antibodies from basophil leucocytes of healthydonors can be inhibited by prior incubation with human recombinant alphachain. Some of them bind to FcRIa, regardless of the binding of IgE. However, the binding of most of these types of autoantibodies is interfered withcompetitively by IgE to various degrees (Hide et al. 1995). Removal of Ig

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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36

E(by lactic acid stripping) enables the autoantibody to release histamine butreconstituting the IgE on the surface of the basophils inhibits release (Niimiet al. 1996). Precise epitope mapping on FcRIa has not yet been carried out. 320 Michihiro Hide and Malcolm W. Greaves Fig. 6. Autoimmune Chronic Urticaria: Pathomechanisms. Schematic representation of adermal mast cell. The high affinity IgE receptor (FcRI) is represented by g1 and g2, b and achains. The a chain possesses two domains (a1 and a2). In this instance IgG anti-FceRI bindsto, and cross-links via a2 domain. ITAM = Immunoreceptor Tyrosine Kinase Activation Motif.Lyn, Syk = protein kinases. PKC = protein kinase C In about five per cent of patients with chronic idiopathic urticaria, the IgGautoantibody reacts with the Fc portion of IgE itself. These anti-IgE autoantibodies bind to the 4th domain of the IgE heavy chain (Grattan and Francis1999). For histamine release to occur, either anti- FcRIa or anti-IgE autoantibodies normally cross-link adjacent high affinity IgE receptors throughthe a chain or IgE respectively (Fig. 6).The role of complement activation is controversial. Our own data, whichindicated that the histamine-releasing activity of anti-FcRIa autoantibodies washeat-stable, argues against complement involvement. The heat-resistance ofhistamine releasing activity in sera of patients with chronic urticaria has alsobeen observed by other authors (Zweiman et al. 1996; Tong et al. 1997). However, other authors, using specific inhibitors of complement components,decomplemented sera and/or the reconstitution with C5, have reported evidence that in some circumstances the reaction between anti- FcRIa autoantibodies and dermal mast cells may be complement-dependent (Fiebiger et al.1998; Fagiolo et al. 2000; Kikuchi and Kaplan 2002). Kikuchi and Kaplan (2001)showed the histamine release activity of serum IgG from 2 out of 6 patientswas substantially enhanced by serum with complement, whereas that from Chronic Urticaria as an Autoimmune Disease 321 Table 1. Functional Properties of Anti-FceRIa and Anti-IgE Autoantibodies1. Cause whealing in human skin following intradermal injection(see autologous serum skin test) (Sabroe et al. 1999c)2. Release histamine from dermal mast cells and blood basophils (Niimi et al. 1996)3. Reduce numbers of circulating blood basophils4. Serum levels are proportional to disease activity (Grattan et al. 1992, 2000; Zweiman Bet al. 1996; O’Donnell BF et al. 1998)5. Removal by plasmapheresis results in remission of chronic urticaria in autoantibodypositive patients (Grattan et al. 1992)6. Effectiveness of other immunomodulative therapies, such as cyclosporine-A andintravenous immunoglobulin (Grattan et al. 2000, O’Donnell BF et al. 1998) the other 4 patients was not, suggesting a heterogeneity of anti-FceRI autoantibodies in terms of the complement dependency for histamine release. Thepopulation density of FceRI on the surface of dermal mast cells and basophils,and/or the binding avidity of autoantibodies may be crucial – a low population density and a moderate binding avidity may allow monovalent bindingof the autoantibodies with complement activation. The subclasses of IgG inautoimmune urticaria are predominantly IgG1 and IgG3 which may readily activate complements (Fiebiger et al. 1998).Subsequent intracellular events involve the activation of protein tyrosinekinases lyn and syk via immunoreceptor tyrosine kinase activation motifs located on the intracellular portions of the b and g chains of FceRI. (Rivera J 2002)That these anti-FceRI and anti-IgE autoantibodies are functional is indicatedby evidence listed in Table 1.Can autoimmune chronic urticaria be regarded as an autoimmune disease?Evidence includes the inverse relationship between blood basophil numbersand histamine content on the one hand and levels of serum anti-FceRIa autoantibody on the other. Removal of the antibodies by plasmapheresis leads toremission of the urticaria (Grattan et al. 1992). The antibody also reproducesthe urticarial wheal when introduced as an autologous serum injection intohuman skin, and causes histamine release from dermal mast cells and bloodbasophils (Niimi et al. 1996). Reproduction of urticaria in an animal model bysensitisation to the alpha-chain of FceRI has not yet been carried out even witha transgenic mouse expressing FceRIa (Fung-Leung 1996). However, it shouldbe noted that urticarial eruptions are not apparently observed even in thesystemic anaphylactic reactions induced by antigen in animals, such as rodents and guinea-pigs.Increased histamine releasability from dermal mast cells and basophils isan important additional factor in the pathogenesis (Sabroe et al. 1998). Numerous previously published reports have shown that although mast cell numbers and histamine content of skin are essentially normal in chronic urticaria,various chemical histamine-releasing agents (codeine, compound 48/80) causeexaggerated whealing when injected into uninvolved skin of patients with 322 Michihiro Hide and Malcolm W. Greaves chronic urticaria (Juhlin and Michaelsson 1969, Smith CH et al 1992). Thisenhanced histamine releasability is probably due to the action of cytokines orneurokines released locally. These cytokines also cause up-regulation of adhesion molecule expression, leading to the substantial leucocyte infiltratecharacteristic of the histological appearances of autoimmune urticaria.The organ selectivity of anti-FceRIa autoantibodies is puzzling. Human lungmast cells express FceRIa but patients with anti- FceRI autoantibodies get urticaria without pulmonary symptoms. If complement is involved in evoked histamine release by anti- FceRIa autoantibodies, then this anomaly is explicablesince dermal but not lung mast cells express complement receptors. Alternatively, local cytokine and micro-circulatory differences between lung andskin may restrict access of the autoantibodies to tissue mast cells in the lungs.There is also functional heterogeneity between dermal and lung mast cells(Lowman et al. 1988). However, the reasons for fact that lung mast cells are evidently ‘ring fenced’ against FceRI and anti-IgE autoantibodies remain obscure. Clinical and Histological FeaturesDetailed comparative reviews of the symptoms, clinical presentation and natural history of autoimmune and non-autoimmune chronic urticaria have failedto reveal differences sufficiently distinctive to be of diagnostic value (Sabroeet al. 1999a). However, the disease does tend to run a more aggressive andprotracted course in patients who possess anti-FcRI autoantibodies than thosewithout an autoimmune etiology. Patients with autoimmune urticaria also tendto be less responsive to routine antihistamine treatment than non-autoimmunepatients. Again, the difference is not so conspicuous as to be useful as a discriminating marker for an autoimmune etiology.Sabroe et al. have also recently reported that the peripheral blood basophilleucocyte count is greatly reduced in patients with anti-FceRIa autoantibodiescompared with patients who did not have these antibodies (Sabroe et al. 1998).This is not an original observation; Rorsman (1961) noted almost 45 years’ agothat chronic urticaria was associated with basopenia in some patients withchronic ‘idiopathic’ (but not physical) urticaria. The fate of the cells is of interest; degranulation or destruction in the peripheral blood is an obvious possibility. Indeed, Kaplan’s group found the increase of basophils in skin ofchronic idiopathic urticaria with or without autoantibodies as well as T cells,eosinophils and neutrophils (Ying et al. 2002). The alternative of redistribution into the lesional skin of chronic urticaria may account for the basopenia.Sabroe (1999b) recently carried out a detailed histological study of skinbiopsy material from patients with autoimmune and non-autoimmune urticaria. No significant differences were found apart from reduced numbers ofactivated eosinophils (EG2+) in lesional skin of autoimmune patients in whichthe wheal biopsied was more than 12 hours old. There is no vasculitis in autoimmune urticaria. More recently Kaplan’s group also found no difference Chronic Urticaria as an Autoimmune Disease 323 in either the numbers of inflammatory cells or the pattern of cytokine expressions between patients with and without autoantibody (Ying et al. 2002). DiagnosisAs pointed out above, there are no clinical or histological features which canbe used as a paradigm in diagnosis (Sabroe et al. 1999a). The cornerstone ofdiagnosis is clearly detection of anti-FceRIa or anti-IgE autoantibodies in serum of patients with chronic urticaria. However, we have found the autologousserum skin test to be a useful screening procedure. As recently describedand characterised (Sabroe et al. 1999c), this test is based upon the originalfinding by Grattan (1986) that the serum of some patients with chronic ‘idiopathic’ urticaria would cause a red wheal upon autologous injection into thepatient’s uninvolved skin. This test has now been optimised for sensitivity andspecificity (Sabroe et al. 1999c).Autologous serum, collected during exacerbation of the chronic urticaria,is injected into uninvolved skin of the forearm in volume 0.05 ml. An equalvolume of phosphate-buffered saline acts as a vehicle control. The local response is measured at 30 minutes and is deemed positive if the wheal is redin colour and at least 1.5 mm diameter greater than the saline control (Fig. 7).This autologous serum skin test (ASST) is positive in about 40 per cent of patients with chronic idiopathic urticaria (Table 2). In this test, false negativereactions are rare, but false positives may occasionally occur and some of thesera probably contain other wheal-producing mediators including the ‘mastcell specific’ factor. This non-immunoglobulin mediator retained by 3 KDultrafiltration membranes was reported by us (Kermani et al. 1995) and appears to be present in about eight per cent of patients with chronic urticaria.It requires further characterisation.There is one study that showed no correlation between ASST and clinical features in chronic idiopathic urticaria, except for the frequency of complication with angioedema (Nettis et al. 2002).However, ASST shows a reasonable concordance with in vitro measurementsof serum anti-FceRI or anti-IgE autoantibodies, which also significantly correlated with clinical severities (Zweiman et al. 1996; Sabroe et al. 1999a).A positive autologous serum skin screening test requires confirmation byin vitro analysis for anti-FceRIa and anti-IgE autoantibodies. The current goldstandard consists of demonstration by bioassay that either blood basophils ordermal mast cells release histamine or other mediators upon incubation withthe patient’s serum. Low IgE basophils predominantly detect anti-FceRI autoantibodies, whereas high IgE basophils detect anti-IgE autoantibodies and antiFceRI autoantibodies that are non-competitive with IgE. Low IgE basophilsmay be directly obtained from low IgE (1 IU/ml) donors or prepared by lacticacid treatment of ordinary donors’ leukocytes. To distinguish between the twotypes of autoantibody, it is desirable to carry out inhibition experiments utilising human recombinant a-chain and monoclonal IgE. However, for practical 324 Michihiro Hide and Malcolm W. Greaves Fig. 7. Autologous Serum Skin Test. PBS = Phosphate-buffered saline; serum: undiluted0.05 ml. Both serum and plasma show positive results at 30 min purposes, this is usually unnecessary. In our hands, 25 per cent of chronic idiopathic urticaria sera can be confirmed to contain anti-FceRIa autoantibodies, whereas about five percent have anti-IgE autoantibodies (Niimi et al.1996, Sabroe et al. 1999a).As high as 76 per cent of chronic idiopathic urticaria patients were foundto have anti-FceRIa autoantibodies by Kaplan’s group using a rat basophilicleukaemia cell line expressing a-chain of human FcRI, which integrates chimeric FceRI with endogenous rat b and g chains of the receptor and using release of b-hexosaminidase as an indicator of cell degranulation (RBL-48) (Tonget al. 1997). This figure is even higher than that they observed by humanbasophils (52%). In our hands, however, the sensitivities of RBL-48 cell andother cell lines expressing human FceRIa for anti-FceRIa antibodies are notas high as human basophils obtained from healthy donors (unpublished Chronic Urticaria as an Autoimmune Disease 325 observation). Further studies with standardized conditions may be necessaryto establish the usability of RBL cells expressing human FceRIa.Some investigators have used immunoassays (immunoblotting, ELISA,immunoprecipitation) (Fiebiger et al. 1995, 1998; Sabroe et al. 1998; Kikuchiand Kaplan 2001). These assays measure immunoreactive FceRIa autoantibodies and show false positives when compared with bioassays. False positivesare particularly prone to occur in autoimmune diseases including Sjögren’ssyndrome, dermatomyositis, pemphigus and pemphigoid (Fiebiger et al. 1998).However, unlike the anti-FceRIa autoantibodies in urticaria which are of subtype IgG1 and IgG3, these antibodies are predominantly of the IgG2 and IgG4subtypes. More important, they are non-functional, being inactive (non-histamine-releasing) against basophil leucocytes. Kikuchi and Kaplan (2001)showed no correlation between positive histamine release activity and immunoblotting in sera of patients with chronic urticaria. The ELISA, though initially promising, has not yet confirmed expectations in terms of specificity anddemonstration of linearity between level of antibody and immunoreactivity.Horn et al (1999) detected substantial amount of anti-FceRIa antibodies in serafrom healthy donors and demonstrated that these antibodies are cross-reactive with tetanus toxoid by ELISA. He used recombinant protein consistingof two moieties of the extracellular part of human FceRIa flanking one moiety of human serum albumin. Although the affinities of such autoantibodiesagainst the recombinant FceRIa were low (3.4x10–6 and 7.1x10–7 M), healthydonor sera containing these autoantibodies showed histamine release activity as well as sera of patients with chronic idiopathic urticaria, using basophilstreated with IL-3. They recently cloned anti-FceRIa autoantibodies from healthydonors and patients with chronic idiopathic urticaria. Both autoantibodieshad the same amino acid sequence and showed the activity of histamine release from basophils that were not occupied by IgE (Pachlopnik et al. 2004).On the other hand, immunoreactivity against FceRIa in ELISA studied byFiebiger et al (1998) and that in immunoblotting by the authors (Sabroe et al.2002) were significantly correlated with basophil histamine release activities(p<0.0001, x2; data were re-calculated by the authors). Moreover, recent studies of IgE and FceRIa revealed that cross linkage between FceRI and FcgRIImay inhibit histamine release from human mast cells and basophils (Tam etal. 2004) and binding of certain types of monomeric IgE could activate FceRIby itself (Pandey et al. 2004). It is feasible that autoantibodies against FceRIcould mimic either of such functions. Taken together, the overall assessmentof functional autoantibodies with histamine releasing assay using humanbasophils, or possibly mast cells, should be the gold standard for the detection of pathological autoantibodies.Recently published values for anti-FceRIa autoantibodies incidences and positive reactions in autologous serum skin test in chronic urticaria are listed inTable 2.A better screening test than ASST is badly needed. Rapid flow cytophotometric methods for enumeration of circulating blood basophils offer prospects Asero et al(2001) Horn et al(1999) Sabroe et al(1999) ASST4) 3) ASST 205/306(67%) 55/155(35%)ELISA(sFceRIa) 21/21(100%)9)5/21(9.5%) 34/53 (64%) 20/121 (17%)19/87 (22%)of ASST+ 1/21(4.7%)9) HBHR (IL-3+) 6HBHR6 54/155 (35%) 31/68 (48%)28/65 (46%)HBHR6 HBHR8foreskin-MC HR 6 Western blot(sFceRIa) 39/86 (45%)33/50 (66%)of autoAb+6/36 (17%)of autoAb- Ferrer et al(1998) 6) HBHR (IL-3+) ELISA(sFceRIa) Fiebiger et al(1998) 106/281 (38%) 26/50 (52%)38/50 (76%) HBHR6RBL cells Tong et al(1997) Niimi et al(1996) 21/70 (30%)anti-FceRIa12/13 anti-IgE 1/13 12/32 (37%) 14/25 (56%) HBHR6 Western blot(sFceRIa) HBHR6 Zweiman et al(1996) 98/163(60%) 20/25(80%) Bioassay 47/163 (29%)anti-FceRIa 38 (23%)anti-IgE 9 (6%) 2) ASST ASST1) Immunoassay HBHR6) Fiebiger et al(1995) Grattan et al(1991) Skin test Table 2. Prevalence of Anti-FceRI Autoantibodies in Chronic Idiopathic Urticaria 326Michihiro Hide and Malcolm W. Greaves 27/78(35%) 81/180(45%) 4) 5) Sabroe et al(2002) Hide et al(unpublishedresults) 3 32/78(41%)HR+ 20HR- 12 Determined as positive if flare diameter is ³ 5 mm than saline control OR serum-induced flare is larger than the flare induced by intradermalinjection of 20ml of 10mg/ml histamine at 30 min Human basophil histamine release in the presence (if noted) or absence of IL-3 b-hexosaminidase release from rat basophilic leukemia cell line transfected with human FceRIa Histamine release from isolated foreskin mast cells When criteria for “positive” was set so as to exclude all data of all healthy controls 5 6 7 8 9 Histamine release from skin slices Determined as positive if wheal-and-flare area is ³ 50% of the reaction induced by a prick test with 10 mg/ml histamine at 15 and 40 min 4 10 Determined as positive if diameter of wheal with flare is ³ 2 mm than saline control at 30 min Determined as positive if diameter of wheal plus redness is ³ 1.5 mm than saline control at 30 min. The condition was determined to obtain theoptimal sensitivity and specificity for the identification of patients with histamine-releasing activity 15/25 (60%)of ASST+anti-FceRIa11/25 anti-IgE4/25 27/78 (35%)31/78 (40%) 3 HBHR6 HBHR6skin sliceMC HR10 111/260 (43%) 2 Determined as positive if wheal volume ³ 10 mm than saline control at 60 min Western blot(sFceRIa) HBHR6 Western blot(sFceRIa) 122/260(47%) Bioassay Immunoassay 1 ASST ASST 42/102(41.2%) 3) ASST Nettis et al(2002) Kikuchi andKaplan(2001) Skin test Table 2. Prevalence of Anti-FceRIa Autoantibodies in Chronic Idiopathic Urticaria Chronic Urticaria as an Autoimmune Disease327 328 Michihiro Hide and Malcolm W. Greaves of an effective test, since basophil numbers are usually greatly reduced inantibody-positive patients (Sabroe et al. 1998). Treatment of Autoimmune UrticariaThe routine treatment of autoimmune chronic urticaria is essentially the sameas that for non-autoimmune urticaria. All patients with chronic urticaria shouldreceive antihistamines commencing with a low-sedation antihistamine suchas loratidine 10 mg, cetirizine 10 mg, evastine 10 mg or fexofenadine 60 to180 mg, (in Japan, fexofenadine is licensed for 120 mg; 60 mg each in morning and evening) usually administered in the morning. Since pruritus is mainlya problem in the evening and at night, it is useful to give a second dose of thesame antihistamine in the evening or before retiring for the night. This represents a total daily dosage in excess of the licensed recommended dosage.In patients troubled by severe nocturnal pruritus, a sedative antihistaminesuch as hydroxyzine 25 mg may be indicated. However, patients should bewarned that impairment of cognitive function may be a problem the following morning (Pirisi 2000).Patients with autoimmune chronic urticaria may respond poorly to theabove antihistamine regime. Systemic steroids are unsuitable as long termtreatment for chronic urticaria although short tapering courses may be usefulto meet specific contingencies. In patients with recalcitrant autoimmunechronic urticaria which is causing significant disability, cyclosporin may beeffective (Grattan et al. 2000). The dosage for an average adult is 3–4 mg/kg/day and one of us (MWG) usually prescribe this dosage for two–three months.There is rarely a rebound withdrawal. About one-third of patients remain inremission after cyclosporin has been withdrawn; one-third relapse but onlymildly and one-third relapse to their former pretreatment level of disease activity and may have to be recontinued on cyclosporin. Chronic autoimmuneurticaria is not a licensed indication for cyclosporine and the usual precautions regarding renal function, blood pressure monitoring and unwanted interactions with other concurrently administered drugs metabolised via thecytochrome P450 enzyme pathway have to be considered.We have previously reported positive results using more aggressive formsof immunotherapy including intravenous immunoglobulin (O’Donnell et al.1998) and plasmapheresis (Grattan et al. 1992) in selected patients with autoimmune urticaria. We ought to emphasise that these treatment modalitiesare temporary symptom relieving rather than curative. Nevertheless, it is noteworthy that histamine releasing activities of the patients had decreased ordiminished in accordance with urticarial symptoms after the treatments, endorsing the pathological role of autoantibodies and rationale for immunotherapies for chronic autoimmune urticaria.More selective immunotherapeutic strategies are on the horizon. These include administration of humanised structure-based peptides representing the Chronic Urticaria as an Autoimmune Disease 329 antibody-binding sites on the a-chain. This development will be dependenton epitope mapping, and should enable induction of desensitisation in antiFceRI-positive individuals. Alternatively down regulation of the FceRI population density on mast cells could be achieved by administration of anti-IgEantibodies reactive with the C3 domain of the IgE heavy chain (MacGlashanet al. 1987). Development of tolerance to the alpha chain of FceRI might alsobe possible by oral administration (Weiner 1997). ReferencesAdachi J, Aoki T, Yamatodani A (1994) Demonstration of sweat allergy in cholinergic urticaria. J Dermatol Sci 7: 142–149Adams DD (1988) Long-acting thyroid stimulator: how receptor autoimmunity was discovered. J Autoimmunity 1: 3–9Asero R, Tedeschi A, Lorini M, Salimbeni R, Zanoletti T, Miadonna A (2001) Chronic urticaria: novel clinical and serological aspects. Clin Exp Allergy 31: 1105–1110Bentley-Phillips CB, Black AK, Greaves MW (1976) Induced tolerance in cold urticariacaused by cold-evoked histamine release. Lancet ii: 63–66Black AK, Lawlor F, Greaves MW (1996) Consensus meeting on the definition of physicalurticarias and urticarial vasculitis. Clin Exp Dermatol 21: 424–426Black, AK, Physical and Cholinergic Urticarias. In: Urticaria and Angioedema. Eds MalcolmW Greaves, Allen P Kaplan. Marcel Dekker, New York, (2004) chapter 8, pp171 – 214Burova GP, Mallet AI, Greaves MW (1998) Is Helicobacter pylori a cause of chronic urticaria?Br J Dermatol 139 (Suppl): 42Caproni M, Volpi W, Macchia D, Giomi B, Manfredi M, Campi P, Cardinali C, D’Agata A,Fabbri P. (2003) Infiltrating cells and related cytokines in lesional skin of patients withchronic idiopathic urticaria and positive autologous serum skin test. Exp Dermatol 2:621–628Commens CA, Greaves MW (1978) Tests to establish the diagnosis in cholinergic urticaria.Brit J Dermatol 98: 47–51Erbagci Z (2002) The leukotriene receptor antagonist montelukast in the treatment of chronicidiopathic urticaria: a single-blind, placebo-controlled, crossover clinical study. J AllergyClin Immunol 110: 484–848Fagiolo U, Kricek F, Ruf C, Peserico A, Amadori A, Cancian M.(2000) Effects of complementinactivation and IgG depletion on skin reactivity to autologous serum in chronic idiopathicurticaria. J Allergy Clin Immunol 106: 567–572Ferrer M, Kinet JP, Kaplan AP (1998) Comparative studies of functional and binding assaysfor IgG anti-FceRIah (a-subunit) in chronic urticaria. J Allergy Clin Immunol 101: 672–676Fiebiger E, Maurer D, Holubar H, Reininger B, Hartmann G, Woisetschlager M, Stingl G(1995) Serum IgG autoantibodies directed against the alpha chain of FceRI: a selectivemarker and pathogenetic factor for a distinct subset of chronic urticaria patients. J Clin Invest 96: 2606–2612Fiebiger E, Hammerschmid F, Stingl G, Maurer D (1998) Anti-FceRIa autoantibodies in autoimmune-mediated disorders. J Clin Invest 101: 243–261Fung-Leung W-P, Sousa-Hitzien JD, Ishaque A (1996) Transgenic mice expressing the human high affinity immunoglobulin (Ig)E receptor a chain, respond to human IgE in mastcell degranulation and allergic reactions. J Exp Med 183: 49–56Grattan CEH, Wallington TB, Warin RP (1986) A serological mediator in chronic idiopathicurticaria: a clinical immunological and histological evaluation. Br J Dermatol 114: 583–590Grattan CEH, Francis DM, Hide M, Greaves MW (1991) Detection of circulating histamine releasing autoantibodies with functional properties of anti-Ig

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Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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37

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(1992) Cutaneous responses to vasoactive intestinal polypeptide in chronic idiopathic urticaria.Lancet. 339:91–93Tam SW, Demissie S, Thomas D, Daeron M (2004) A bispecific antibody against human IgEand human FcRII that inhibits antigen-induced histamine release by human mast cellsand basophils. Allergy 59: 772–780Tong LJ, Balakrishnan G, Kochan JP, Kinet J-P, Kaplan AP (1997) Assessment of autoimmunity in chronic urticaria. J Allergy Clin Immunol 99: 461–465Wedi B, Wagner S, Werfil T, Mann MP, Kapp A (1998) Prevalence of Helicobacter pylori-associated gastritis in chronic urticaria. Int Arch Allergy Immunol 116: 288–294Weiner HL (1997) Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 18: 335–343Wolfrom E, Chene G, Boisseau H, Beylot C, Geniaux M, Taleb A (1995) Chronic urticaria andToxocara canis. 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J InvestigDermatol Symp Proc. 6: 123–127 11 Lichen Planus, Lichenoid Eruptions andCutaneous Graft-Versus-Host-ReactionMiklós Simon Jr. IntroductionLichen planus (LP) is a noncontagious, inflammatory, pruritic, papular mucocutaneous disease of unknown etiology that most commonly affects middleaged adults. In 1869 Erasmus Wilson described the cutaneous “leichen planus”in 50 case histories and recorded oral lesions in 3 of his patients (Wilson, 1869).Weyl and Wickham noted the surface markings on the papules and pointedout the importance of these marks in establishing the clinical diagnosis of LP(Weyl, 1885; Wickham, 1895). After Neumann, Weyl, Caspary, and Poór, Darierdescribed the histopathology of LP (Darier, 1909), the only important addition has been the demonstration of “colloid bodies” at the dermoepidermaljunction by Thyresson and Moberger (1957). The direct immunofluorescencefindings in LP have been extensively studied for the first time by Barthelmesand Haustein (1970) and Baart de la Faille Kuyper and Baart de la Faille (1974),respectively.LP has a worldwide distribution. The prevalence of LP in the general population is of the order of 0.9 to 1.2% (Scully & El-Kom, 1985). It appears initially during the fifth or sixth decade and affect women preferentially. LP ofchildhood is unusual, but familial cases have been observed (Copeman, 1978).A weak association with HLA-A3, B8, B16, B35 and a significantly increasedHLA-DR1 (DRB1* 0101) antigen frequency has been reported in patients withidiopathic LP (Simon jr et al, 1984; Powell et al, 1986; La Nasa et al, 1995). Inaddition, TNF-a and IFNg polymorphisms contributing to susceptibility to LPwere described, very recently (Carrozzo et al, 2004).The cause of LP is unknown. Evidence points to the possibility that analteration of epidermal cell antigens (bacterial/viral infections, contact sensitizers, trauma etc.) induces a cell-mediated immune response similar to thatseen in cutaneous graft-versus-host-reaction (cGVHR). Drugs may induce lichenoid eruptions (LDE). LDE (probably an allergic type IV reaction) produces 334 Miklós Simon Jr. mucocutaneous lesions that are clinically and histologically indistinguishablefrom (idiopathic) LP. LDE usually appear as a symmetric eruption on the trunkand extremities and sometimes fail to exhibit classic Wickham striae. Medications commonly associated with the development of LDE are antimalarials,gold, penicillamine, methyldopa, b-blockers, angiotensin-converting enzymeinhibitors, spironolactone, lithium, cinnarizine, nonsteroidal anti-inflammatory drugs, thiazide, phenothiazine derivatives, allopurinol, tetracycline, andsulfonylurea agents (Ellgehausen et al, 1998).There have been several reports of patients with LP in association with autoimmune disorders, notably with systemic lupus erythematosus, thymoma,myasthenia gravis, dermatomyositis, ulcerative colitis, primary biliary cirrhosis, chronic active hepatitis, pemphigus vulgaris, dermatitis herpetiformis, bullouspemphigoid, alopecia areata, vitiligo, Sjögren’s syndrome, morphea, andsystemic sclerosis suggesting there may also be an immunological basis forclassical LP (Simon jr, 1985). Immune PathogenesisDirect immunofluorescence studies of lesional and uninvolved skin in patientswith LP demonstrated an irregular deposition of fibrin and complement alongthe dermoepidermal junction, especially in the dermal papillary region andaround hair follicles, in the active papular lesions. The colloid bodies fluoresced brightly with IgM and with other immunoglobulins and complementcomponents (Barthelmes & Haustein, 1970; Baart de la Faille-Kuyper & Baartde la Faille, 1974; Simon jr et al, 1983). In 1984, Olsen et al described an LPspecific antigen (LPSA) found by indirect immunofluorescence in the granular or spinous layer of the epidermis of lesional tissue (Olsen et al, 1984). Thecirculating anti-LPSA antibodies are more likely to be markers of the diseasethan to be causative.In 1975 Touraine et al (1975) and Saurat et al (1975) reported a lichenoideruption that occurred in two men who had received allogenic bone marrowtransplants from their sisters. It now seems likely that this lichenoid tissue reaction is a later and more chronic manifestation of a GVHR in which the target appears to be the basal cell layer of the epidermis. The clinical pictureand the histologic and direct immunofluorescence findings were essentiallythe same as those in idiopathic LP. Immunopathological investigations oflesional skin in these patients revealed intraepidermal a predominance ofCD3+CD8+CD11a+CD16+CDw137+T-lymphocytes and a net-like specific positive staining when exposed to HLA-DR, CD54, CD36, CD21, CD16, and CD1monoclonal antibodies, recently (Simon jr & Hunyadi, 1992; Anasetti, 2004). Cutaneous GVHR occurs most commonly in patients undergoing bone marrowtransplantation, after solid organ transplant, but is also seen in fetuses ob- Lichen Planus, Lichenoid Eruptions and cGVHR 335 taining maternal leukocytes via maternal-fetal transfusion and in bloodtransfusions transplanting immunocompetent cells into immunodeficient recipients. The precise pathophysiology of GVHR is not known. However, several studies demonstrate that acute GVHR occurring in humans is inducedby donor T-lymphocytes reactive against recipient cells expressing differenttissue antigens. On the other hand, T-cells recognizing host-specific antigensare present in the blood and the skin of patients with chronic GVHR (Aractingi& Chosidow, 1998). A significant association between polymorphism of TNF-a,IFN-g, IL-10, and IL-6 and the development of severe GVHR has been demonstrated, recently (Takahashi et al, 2000; Cavet et al, 2001).The pathologic process in LP is a cell-mediated response localized to thedermoepidermal junction and characterized by degeneration of keratinocytesin the basal layer and disruption of the basement membrane. The basementmembrane zone is an interface composed of epidermal basal cell surfaceglycoproteins, laminin, fibronectin, type IV collagen, and supporting mesenchymal extracellular proteoglycans. These proteins and oligosaccharides maybe identified immunohistochemically by monospecific antibodies and highaffinity lectins, respectively.The earliest features of LP are changes in, and close to the epidermal basalcell layer, which may occur in the absence of demonstrable changes in thedermis. Studies concerning the evolution of lesions of LP demonstrated, thatone of the first observable changes is the appearance of Langerhans cells (Ragaz& Ackerman, 1981). Shortly after appearance of Langerhans cells basalkeratinocytes undergo flattening and hydropic changes, their nuclei are injured at an early phase of the mitotic cycle. These basal cell changes in LPare accompanied by a dense mononuclear inflammatory T-lymphocyte infiltrate subepidermal and at the dermoepidermal interface, the location of whichmakes a relationship to the basal epithelial changes highly likely.In the course of examining keratinocyte-lymphocyte interactions in vitroNickoloff et al (1988) reported prominent adherence by both allogeneic andautologous T-lymphocytes and monocytes to cultured keratinocytes after pretreatment of keratinocytes with IFNg. The binding of these mononuclear cellsto IFNg-treated keratinocytes involves the lymphocyte function-associatedantigen-1 (LFA-1) molecule on T-cells and the intercellular adhesion molecule-1 (ICAM-1) induced by IFNg or TNF-a on keratinocytes (Griffiths et al,1989). Biopsy specimens from lesional skin of LP patients exhibited intraepidermal specific positive staining when exposed to ICAM-1 (CD54), HLA-DR,NF-kappaB, CXCL9, 10, 11, CD1, and CD120a antibodies (Malmnäs Tjernlund,1980; Simon jr, 1988; Griffiths et al, 1989; Simon jr & Gruschwitz, 1997; Iijimaet al, 2003; Santoro et al, 2003). CD54 expression in lesional keratinocytes inLP, similar to that in various cutaneous inflammatory conditions (LangeWantzin et al, 1988; Griffiths et al, 1989), may be an important initiator ofkeratinocyte-lymphocyte interaction, whereas HLA-DR expression in keratinocytes seems to be more important in postadherence antigenic recognitionand/or presentation to activated T-lymphocytes (Messadi et al, 1988). 336 Miklós Simon Jr. In LP, the cellular infiltrate is predominantly composed of T-lymphocytesand monocytes as detected by hetero- and monoclonal antibodies, nonspecific esterase, lysosyme, and, selectively by peanut agglutinin lectin (Walker,1976). The role of these T-lymphocytes, probably antigen activated T-cells,is not quite clear, however, autoradiographic investigations revealed a threeto four times higher lymphoblast proliferation rate in LP lesions than in psoriasis or contact dermatitis (Lachapelle & De la Brassine, 1973). Langerhanscells in the epidermis and subepidermal may also be identified with the useof light microscopy by formalin resistent sulfhydril dependent nucleosidetriphosphatase, ultrastructurally by the presence of Birbeck’s granules, immunohistochemically by monoclonal antibodies or S-100 calf brain protein. Theirparticipation in LP, and close vicinity to the T-lymphocytes, combined withlocal and systemic release of various cytokines (e.g. TNF-a, IL-6, IFNg) both inthe skin and in the serum, would seem to provide antigen processing activityand the induction of a hypersensitivity reaction (Giannotti et al, 1983; Soehnchen et al, 1992). In addition, soluble mediators of cell damage produced byT-cells may induce keratinocyte apoptosis and formation of colloid bodies.Examinations of different lymphocyte subpopulations in cutaneous inflammatory infiltrate of active LP revealed the existence of T-lymphocytes ofboth the CD4+ and the CD8+ phenotype. In early phases of LP lesions thelymphocytes observed in close contact with large, non-lymphoid cells wereidentified as CD4+T-cells (Bhan et al, 1982). In the late phases of LP lesionsintraepidermal lymphocytes almost constantly exhibited CD8-positivity (Simon jr & Keller, 1984). The dermoepidermal interface, from the pathogeneticpoint of view probably the most important zone, showed a predominance ofHLA-DR+CD25+LFA-1+TNF–R+CCR5+CXCR3+CCL5+CXCL10+CD3+CD8+TCRgd+- Fig. 1. Typical purple polygonal papules of LP Lichen Planus, Lichenoid Eruptions and cGV

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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38

HR 337 T-lymphocytes (Malmnäs Tjernlund, 1980; Simon jr & von den Driesch, 1994;Gadenne et al, 1994; Simon jr & Gruschwitz, 1997; Iijima et al, 2003).Immunological characterization of different T-lymphocyte subpopulationsin peripheral blood of LP patients, by means of the indirect immunofluorescence technique using monoclonal antibodies, clearly documented a reducedpercentage of the CD8+T-cell subset, normal pan T-, CD4+T-, and B-lymphocyte values as compared with the controls (Simon jr & Keller, 1984). The phytohemagglutinin response of lymphocytes from LP patients was in the samerange as that of healthy controls (Cerni et al, 1976).A markedly diminished, to the severity of the disease related natural killercell activity against K562 target cells was revealed in patients with extensiveerosive LP of oral mucosa, generalized acute eruptive and moderate cutaneous LP as compared with that of patients with non-erosive LP of oral mucosaand healthy controls. Interleukin-2 failed to restore completely reduced natural killer cell activities in all groups of patients investigated (Simon jr et al, 1989).The in vitro effect of peripheral blood lymphocytes on syngeneic oral epithelial cells using a modified 51Cr release macro-assay in patients with LPresulted as a substantial lymphocytotoxicity in comparison to the controls.This positive lymphocytotoxicity is probably generated by sensitized effectorlymphocytes via specific recognition of foreign antigenic structures on syngeneic oral target cells (Simon jr et al., 1983). Similar results were found usingCD8+ T-cell lines and clones cultured from LP lesions against autologous lesional keratinocytes, recently (Sugerman et al, 2000). These findings may be regarded as a functional evidence for the pathogenetic role of CD8+ cytotoxicT-cells in the course of LP. Clinical FeaturesLichen Planus, Lichenoid EruptionsThe cutaneous lesions of LP consist of pruritic faintly erythematous to violaceous, flat-topped, polygonal papules, occasionally showing central umbilication. A thin, transparent scale may be discerned atop the lesions. A networkof fine white lines or puncta referred to as Wickham striae is present in manywell-developed papules (Fig. 1).LP lesions are usually distributed symmetrically, the disease tends to involve the flexural areas (wrists, arms, legs) preferentially. The thighs, lumbararea, trunk, neck, and the dorsal surfaces of the hands with the nails may alsobe affected. The face and scalp are usually spared in classic LP. Inverse LPaffects the axillae, groin, and inframammary regions. Nail changes includelongitudinal ridging and splitting of the nail plate, onycholysis, pterygiumformation, or complete loss of the nail plate. Mucous membranes are in morethan half of the patients additional sites of involvement. Erosive mucosal LP 338 Miklós Simon Jr. is extremely painful often pursues a chronic course with little tendency tospontaneous resolution. It may predispose to squamous cell carcinoma, butthe risk is fairly low. In generalized LP, the eruption often spreads within 1–3month from onset of the disease. Koebner’s isomorphic response (LP develops at the site of exogenous irritation) is common (Fox & Odom, 1985; Boyd &Neldner, 1991). Clinical VariantsSeveral distinctive variants of LP need to be recognized, since lack of characteristic skin changes in these cases makes the clinical diagnosis difficult. Theprototypic papule of LP can be altered/modified in morphology, configuration or anatomic distribution.Linear LP. Linear group of typical LP papules, usually on the extremities. Thelinear pattern may develop secondary to trauma, in zosteriform or segmentalarrangement or even in the site of healed herpes zoster.Annular LP. Annular lesions develop from a ring of typical LP papules thatprogress peripherally and produce central clearing. Annular lesions are common on the penis and scrotum but may occur on the trunk or extremities.Bullous LP. Rare variant of LP characterized by the development of bullae onpreexisting LP papules. The bullae, which appear mostly on the extremitieswith mild constitutional symptoms, usually resolve in a few month. Bullae arising from normal skin in LP patients are more characteristic of lichen planuspemphigoides, which is a unique condition with circulating IgG autoantibodies reacting to 180- and/or 200-kDa antigen within the basement membrane zone.Erosive/ulcerative LP. This is a very rare variant of LP presenting with chronic,painful bullae and ulcerations of the soles of the feet, and sometimes of themucous membranes, associated with cicatricial alopecia of the scalp and permanent loss of the toenails. The lesions on the feet tend not to heal and havea definite risk of development of a squamous cell carcinoma in the chroniculcerations.Hypertrophic LP. The extensor sides of the shins and interphalangeal jointsare preferentially affected with highly pruritic, lichenified, violaceous, or hyperpigmented plaques (LP verrucous). The lesions are often symmetric, sometimesshow accentuated, elevated follicle swellings and chalky hyperkeratoses. Scarring occurs after healing of the lesions. Malignant degeneration is not uncommon.Atrophic LP. In some cases, atrophy of LP papules may produce sharply demarcated, whitish, atrophic maculae. These lesions can coalesce and form largerplaques most common on the trunk or lower extremities. This LP variant is Lichen Planus, Lichenoid Eruptions and cGVHR 339 Fig. 2. Reticular LP in buccal mucosa rare and needs to be distinguished from lichen sclerosus et atrophicus andguttate morphea.Follicular LP. This form of LP may occur alone or simultaneously with othermucocutaneous changes of LP. It forms isolated or aggregated, pinheadsized, red papules, which carry a conical acuminated hyperkeratosis (LP acuminatus). Sites of predilection include the trunk, neck, sacral region, and theproximal extremities. Follicular LP of the scalp also occurs in an isolated formand leads to scarred alopecia (LP follicularis decalvans). This condition affects women more than men. Perifollicular erythema and acuminate keratotic plugs are characteristic features. The symptom combination of follicularLP on the trunk and on the scalp with nail dystrophy has been described asLassueur-Graham-Little syndrome.Actinic LP. This variant is more common in the tropics, especially in childrenand young adults, on sun-exposed parts of the body such as the face, theback of the hands, the lower forearms, and the chest. The extremely pruriticpapular lesions are hyperpigmented with violaceous-brown color, which frequently show annular configuration. The course is subacute, and the condition tends to heal spontaneously.Mucosal LP. LP can affect the mucosal sites of mouth, glans penis, vulva, vagina, collum uteri, anus, conjunctiva, nose, larynx, trachea, esophagus, stomach, urethra, bladder, and tympanic membrane.Oral LP is present in some 60–70% of dermatological patients with LP. As thesole manifestation of the disease, it makes up 15% to 35% of the patient populace. The buccal mucosa (bilateral) and the tongue are most often affected 340 Miklós Simon Jr. Fig. 3. Disseminated lichenoid GVHR but the gums, floor of the mouth, palate, and lips have also been documented.The mucosal lesions consist of lacy, reticulated white streaks (Fig. 2), whitepapules and plaques, and erythematous, atrophic or ulcerated patches withpainful, burning sensations.Particular clinical forms are characteristic for certain regions of the oralmucosa. Reticular LP is the most common type. It affects the buccal mucosapredominantly. The margins of the tongue show generally lace-like and/orerosive LP, the dorsal surface exhibits usually round, white plaques or smoothatrophic areas. Most cases of carcinoma appear to arise in patients with longstanding erosive LP of the tongue or buccal mucosa. Gingival involvement ofLP may potentially lead to the picture of desquamative gingivitis (Scully &El-Kom, 1985).Lesions of the male genitalia are observed in about 25% of cases. Theglans penis is most commonly affected, exhibiting annular lesions frequently.Similar changes can occur on the scrotal skin as well. Occasionally, the glanspenis has erosive lesions and is the only site of LP involvement (Alinovi et al,1983). The female genitalia demonstrate generally patches of leukoplakia orerythroplakia, with variable atrophy. Desquamative vaginitis is most commonly due to LP. The labia minora agglutinate and vaginal adhesions, in association with burning pain, may prevent sexual intercourse (Edwards &Friedrich jr, 1988; Soper et al, 1988). Lichen Planus, Lichenoid Eruptions and cGVHR 341 Fig. 4. Erosive buccal lesions in a patient with lichenoid GVHR Cutaneous Graft-Versus-Host-Reaction (cGVHR)Mucocutaneous lesions of GVHR occur in 20 to 80% of posttransplant casesafter marrow infusion. There are two forms: in the acute form the cutaneouseruption begins between the fifth and fiftieth day, in the chronic form two tosix months after grafting. Some patients experience both forms of cGVHR,sequentially (Harper, 1987).In acute cGVHR the eruption generally begins with tender erythematousmacules on the upper trunk, neck, hands, and feet. As a cGVHR evolves, thedistribution of erythematous macules increases, becoming confluent overbroad body surfaces. At later stages, erythroderma may ensue. Generalizederythroderma with bullae formation and desquamation portend a poor prognosis. The clinical picture of subepidermal bullae with a necrotic roof in thesepatients greatly resembles toxic epidermal necrolysis. Oral and/or ocular involvement in acute cGVHR may occur but are less common then in chroniccGVHR (Volc-Platzer, 1992; Aractingi & Chosidow, 1998).The incidence of a chronic cGVHR, divided artificial into lichenoid andsclerodermoid forms, is roughly 25%. This two forms of chronic cGVHR clearlyoverlap in many patients.In the lichenoid form, which may also occur soon after transplantation, erythematous to violaceous polygonal papules appear acrally and may be seenon the palms and soles. In addition, lichenoid cGVHR favors the ears, periorbitalregion, trunk, buttocks, hips, and thighs as well. In some cases lichenoidpapules can occur around hair follicles. LP-like cGVHR can also affect thenails, with onychatrophia and pterygium. The disseminated lichenoid eruptionin chronic cGVHR is clinically indistinguishable from LP (Fig. 3). Pruritus and 342 Miklós Simon Jr. postinflammatory hyperpigmentation are also present. Oral involvement istypical, with white lacy patches and/or painful erosions on the tongue andbuccal mucosa (Fig. 4).The sclerodermoid form of a chronic cGVHR greatly resembles sclerodermawith variably distributed, hyper- and/or hypopigmented, somewhat atrophicplaques. Some patients develop only few sclerodermoid plaques, other onesdevelop widespread disease associated with alopecia, chronic cutaneousischemia with ulceration, joint contractures and debilitating fasciitis. Of note,acrosclerosis and Raynaud phenomenon are uncommon in chronic sclerodermatous GVHR, in contrast to systemic sclerosis. The mucosa of the gums,palate, and lips can become atrophic and occasionally ulcerate. Sicca symptoms often accompany the sclerodermoid form due to diminished salivary andlacrimal output (Volc-Platzer, 1992; Aractingi & Chosidow, 1998).Despite the apparent simplicity of the traditional classification of GVHRinto acute and chronic phases, defined as number of days after transplantation, this separation is not that precise. The lichenoid chronic GVHR may beobserved as early as day 30 after transplantation and acute GVHR may appear/persist after day 100 in some cases. Moreover, atypical variants of cGVHR havebeen described that do not fit into this diagnostic classification either. DiagnosisThe diagnosis of LP, LDE, cGVHR rests on the combination of anamnesticdata, clinical, histopathologic, and immunofluorescence/immunohistochemical findings. Special immunophenotypic and T-cell receptor genotypic analyses are sometimes required to define the underlying pathology manifestingas lichenoid dermatitis more precisely.The clinical differential diagnosis of lichenoid dermatoses, depending onthe manifestation of the disease, involves generalized granuloma annulare,psoriasis guttata, papular sarcoid, lichen amyloidosus, scabies, pityriasis rosea,pityriasis rubra pilaris, and papular secondary syphilis. Mucous membranelesions may be confused with leukoplakia, mucous patches of syphilis, candidiasis, oral hairy leukoplakia, lupus erythematosus, chronic ulcerative stomatitis, paraneoplastic pemphigus, and cicatricial pemphigoid. TherapyLichen Planus, Lichenoid EruptionsApart from the very rare instances of possible malignant transformation (ulcerative LP, LP verrucosus, erosive/atrophic mucosal LP), LP is a benign diseasewith spontaneous remissions and exacerbations. Consequently, any treatment Lichen Planus, Lichenoid Eruptions and cGVHR 343 strategy must be safe and unlikely to aggravate the disease. Avoidance of potentially provocative medications (Ellgehausen et al, 1998), unless absolutelyrequired, and minimizing trauma to skin and mucosal tissues are recommended. Patients with actinic LP must be protected by sunscreens. Oral erosive/atrophic LP lesions are painful and are frequently associated with poororal hygiene. For these patients, good oral hygiene (the use of an antibacterial mouthwash e.g. chlorhexidine) and regular professional dental care needto be encouraged.Evaluating the efficacy of different forms of treatment in cutaneous LP isdifficult since LP tends to regress spontaneously after varying amounts of time.A large variety of topical and systemic therapies are available, and this rangeof options may be attributed to the chronicity, symptomatology, and variableresponsiveness of the disease. In mild cases, treatment should be symptomatic: antihistamines for pruritus and topical glucocorticoids for their antipruritic and anti-inflammatory effects. Severe, acute cases may benefit from atapered course of systemic glucocorticoids or retinoids for two to eight weeks.Relapses may occur, however, chronic systemic glucocorticoid use should beavoided. Narrowband UVB, ultraviolet A1, PUVA photochemotherapy (or bathPUVA) solely or combined with systemic retinoids may have beneficial effectin such cases. Systemic cyclosporine administration has many side effects, therefore it should be considered as a drug of last resort. Hypertrophic LP may alsobenefit from intralesional glucocorticoids, or topical glucocorticoids underocclusion, or tar preparations. Ulcerative and hypertrophic LP of the palmsand soles is frequently disabling and uncomfortable. Use of split-thicknessskin grafts to cover these lesions has been proved an effective way to manage such patients (Lendrum, 1974; Simon jr, 1990; Simon jr & Hunyadi, 1990;Simon jr & von den Driesch, 1994; Boyd, 2000; Saricaoglu et al, 2003; Polderman et al, 2004).Non-erosive LP of mucous membranes generally does not need any treatment and may resolve spontaneously. Erosive oral and/or genital LP can beexceptionally difficult to control, but may respond to high potency topical glucocorticoids (in Orabase or intralesional), topical retinoic acid (tretinoin orisotretinoin gel), cyclosporine or tetracycline rinses, and topical tacrolimus(FK-506) (Hodgson et al, 2003). 308-nm UVB excimer laser showed encouraging results in these patients, recently (Kollner et al, 2003). Topical anaesthetics also provide symptomatic benefit for patients who have difficulty witheating and chewing. Newer antifungal agents may be useful in mucosalLP with evidence of Candida colonization.Systemic treatment with oral glucocorticoids and retinoids may be considered for particularly severe erosive mucosal LP lesions, but remissions areshort-lived and the risk of serious side-effects is high. Nevertheless, oral glucocorticoids may be of value in the management of acute episodes, when topicalor intralesional glucocorticoids alone failed to achieve adequate control. Inrecalcitrant cases, steroid sparing agents such as azathioprine, mycophenolate mofetil, methotrexate or cyclosporine are generally added. Anecdotal 344 Miklós Simon Jr. reports have suggested improvement in mucosal erosive LP with a numberof systemic agents including griseofulvin, dapsone, hydroxychloroquine,low-molecular-weight heparin, and thalidomide. The administration of lowdose cyclophosphamide for the treatment of severe oral LP, unresponsive tothe aforementioned therapies, appears to induce remissions that are sustained. Extracorporeal photochemotherapy has recently been examined forthe treatment of erosive LP, mainly involving oral and vulvar tissues. All patients experienced complete remission, and some have showed a durable response. Surgical excision, CO2 laser, Nd: YAG laser, and cryotherapy haveall been used for treatment of recalcitrant mucosal LP. In general, surgery isreserved for removal of dysplastic areas in patients at high risk. Patients under a great deal of stress frequently show improvement when their emotionalenvironment is altered (Boyd, 2000; Setterfield et al, 2000). Cutaneous Graft-Versus-Host-Reaction(cGVHR)The best way of treating (c)GVHR is to prevent it from occurring by irradiatingblood products before transfusion. Patients receiving allogeneic transplantsare placed on methotrexate, cyclosporine, or both before marrow infusion.Recent data indicate that FK-506 is more effective than cyclosporine in theprevention of GVHR when each drug is used in combination with methotrexate(Hiraoka et al, 2001).If acute GVHR has already occurred, initial therapy usually includes systemic glucocorticoids. Anti-thymocyte globulin, azathioprine, mycophenolatemofetil, pentostatin, cyclosporine, FK-506, and monoclonal antibodies, directedagainst effector cell populations (CDw52, CD25) or cytokines (TNF-a), mayalso be used separately or in combination. Narrowband UVB, PUVA or extracorporeal photochemotherapy may be useful in the treatment of patients withacute cGVHR. Keratinocytes treated with UV-A and UV-B are known to produce immunosuppressive cytokines. Depletion and morphologic alterationsof dendritic cells also occur (Queen et al, 1989; Aubin et al, 1995; Hale et al,1996; Richter et al, 1997; Dall’Amico & Zacchello, 1998; GrundmannKollmann et al, 2002).Chronic GVHR is treated similar to acute GVHR. Glucocorticoids, cyclosporine, azathioprine, mycophenolate mofetil, and methotrexate are administered in various combinations, depending on the severity of the disease.Tacrolimus ointment, pimecrolimus cream or PUVA treatment generally control widespread lichenoid GVHR effectively (Volc-Platzer et al, 1990; Choi &Nghiem, 2001). Mucous membrane manifestations may improve with thesetherapies as well. It is unclear whether PUVA (or bath PUVA) is able to reverse the cutaneous changes in sclerodermatous GVHR (Aubin et al, 1995).Ultraviolet A1 phototherapy may be considered as an appropriate approach Lichen Planus, Lichenoid Eruptions and cGVHR 345 for these patients (Calzavara Pinton et al, 2003). Extracorporeal photochemotherapy has also been reported as beneficial (Greinix et al, 2000). SummaryLichenoid dermatoses encompass, based on the microscopic pattern of inflammation and skin response, a significant group of dermatologic conditions whosepathophysiologic mechanisms are unclear. Lichen planus (LP), the prototype,is an inflammatory disorder with characteristic purple, polygonal, pruriticpapules of the skin and may be accompanied by mucosal lesions. There aremany similar clinical variants described, ranging from lichenoid drug eruptions (LDE) to association with other diseases such as the cutaneous graftversus-host-reaction (cGVHR). This chapter delineates some of the recentaspects of the etiopathogenesis, clinical manifestations and treatment modalities of LP, LDE, and cGVHR. ReferencesAlinovi A, Barella PA, Benoldi D (1983) Erosive lichen planus involving the glans penis alone.Int J Dermatol. 22: 37–38Anasetti C (2004) Advances in the prevention of graft-versus-host disease after hematopoieticcell transplantation. Transplantation 77: S79-S83Aractingi S, Chosidow O (1998) Cutaneous graft-versus-host disease. Arch Dermatol 134:602–612Aubin F, Brion A, Deconinck E, Plouvier E, Herve P, Humbert P, Cahn JY (1995) Phototherapyin the treatment of cutaneous graft-versus-host disease. Our preliminary experience in resistant patients. Transplantation 59: 151–155Baart de la Faille-Kuyper EH, Baart de la Faille H (1974) An immunofluorescence study of lichen planus. Br J Dermatol. 90: 365–371Barthelmes H, Haustein UF (1970) Nachweis von Fibrinablagerungen beim Lichen ruberplanus mit Hilfe der Immunfluoreszenzhistologie. 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management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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39

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ClinExp Dermatol 25: 176–182Simon jr M, Reimer G, Schardt M, Hornstein OP (1983) Lymphocytotoxicity for oral mucosa inlichen planus. Dermatologica 167: 11–15Simon jr M, Unterpaintner F, Reimer G (1983) Immunphänomene bei Lichen ruber – eineimmunfluoreszenzmikroskopische Studie. Z Hautkr 58: 121–128Simon jr M, Djawari D, Schönberger A (1984) HLA antigens associated with lichen planus.Clin Exp Dermatol 9: 435Simon jr M, Keller J (1984) Subpopulations of T lymphocytes in peripheral blood and in skinlesions in lichen ruber planus. Dermatologica 169; 112–116Simon jr M (1985) Lichen ruber planus aus immunologischer Sicht. Zbl Hautkr 150: 699–708Simon jr M (1988) Lesional keratinocytes express OKM5, Leu-8 and Leu-11b antigens in lichen planus. Dermatologica 177: 152–158Simon jr M, Hunyadi J, Fickentscher H, Hornstein OP (1989) Basic and interleukin-2-augmented natural killer cell activity in lichen planus. 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Arch Dermatol Res 284: 27Soper DE, Patterson JW, Hurt WG, Fantl JA, Blaylock WK (1988) Lichen planus of the vulva.Obstet Gynecol. 72: 74–76Sugerman PB, Satterwhite K, Bigby M (2000) Autocytotoxic T-cell clones in lichen planus. BrJ Dermatol 142: 449–456 348 Miklós Simon Jr. Takahashi H, Furukawa T, Hashimoto S, Suzuki N, Kuroha T, Yamazaki F, Inano K,Takahashi M, Aizawa Y, Koike T (2000) Contribution of TNF-alpha and IL-10 genepolymorphisms to graft-versus-host disease following allo-haematopoietic stem cell transplantation. Bone Marrow Transplant 26: 1317–1323Thyresson N, Moberger G (1957) Cytologic studies in lichen ruber planus. Acta DermVenereol (Stockholm) 37: 191–204Touraine R, Revuz J, Dreyfus B, Rochant H, Mannoni P (1975) Graft-versus-host-reaction andlichen planus. Br J Dermatol 92: 589Volc-Platzer B (1992) “Graft-versus-host disease” (GvHD). Hautarzt 43: 669–677Volc-Platzer B, Hönigsmann H, Hinterberger W, Wolff K (1990) Photochemotherapy improves chronic cutaneous graft-versus-host disease. J Am Acad Dermatol 23: 220–228Walker DM (1976) Identification of subpopulations of lymphocytes and macrophages in theinfiltrate of lichen planus lesions of skin and oral mucosa. Br J Dermatol 94: 529–534Weyl A (1885) Bemerkungen zum Lichen planus. Dtsch Med Wschr 11: 624–626Wickham LF (1895) Sur un signe pathognomonique du lichen de Wilson (lichen plan). Strieset ponctuations grisâtres. Annls Derm Syph Paris 6: 517–520Wilson E (1869) On leichen planus. J Cut Med 3: 117–132 12 Small Vessel VasculitidesPeter Lamprecht and Wolfgang L. Gross IntroductionVasculitis of small blood vessels of the skin, i.e. arterioles, capillaries and venules, is found in cutaneous leukocytoclastic vasculitis (CLA) as well as in systemic vasculitides. CLA is restricted to the skin, whereas ANCA-associatedand several immune complex-mediated systemic vasculitides are characterized by an involvement of – predominantly – small vessels affecting variousorgans including the skin.Primary systemic vasculitides, where no underlying disease or agent isknown, are to be distinguished from secondary vasculitides, i.e. secondary toother diseases of either autoimmune or other origin. ANCA-associated andimmune complex-mediated vasculitides are the major immunopathogeneticcategories which involve small vessels (Table. 1) (for review: Gross 2003). PathophysiologyANCA-Associated VasculitidesSubstantial evidence from in vitro experiments and animal models supportsthe view, that anti-neutrophil cytoplasmic antibodies (ANCA) have a role inthe immunopathogenesis of Wegener’s granulomatosis (WG) and microscopicpolyangiitis (MPA), giving rise to the “ANCA-cytokine sequence theory”(Figure 1) (Gross et al. 1991). The target autoantigens proteinase 3 (PR3) andmyeloperoxidase (MPO) are expressed on the cell surface of neutrophil granulocytes and monocytes after priming with TNF-a or IL-1 (Falk et al. 1988,Jenne et al. 1990, Falk et al. 1990, Csernok et al. 1990). ANCA directed againstthese enzymes of neutrophil azurophilic granula (PR3-ANCA and MPO-ANCA)induce activation of primed neutrophil granulocytes, which degranulate andrelease reactive oxygen radicals and lytic enzymes subsequently. PR3- and 350 Peter Lamprecht and Wolfgang L. Gross Table 1. Small vessel vasculitides affecting the skinPrimary systemic vasculitis ANCA-associated vasculitis1. Wegener’s granulomatosis (WG)2. Microscopic vasculitis (MPA)3. Churg-Strauss syndromeImmune complex-mediated primary systemicvasculitis1. Cutaneous leukocytoklastic angiitis (CLA)2. Henoch-Schönlein purpura (HSP)3. Essential cryoglobulinemic vasculitis (ECV) Secondary systemic vasculitis Immune complex-mediated secondary systemicvasculitis1. Rheumatoid vasculitis (RV)2. HCV-associated CV3. Secondary vasculitis or CV in SLE, Sjögren’ssyndrome and other connective tissue diseases4. Secondary vasculitis or CV in infectiousdiseases, e.g. bacterial endocarditis5. Paraneoplastic vasculitis Abbreviations: ANCA = anti-neutrophil cytoplasmic antibody; HCV = hepatitis C virus;SLE = systemic lupus erythematosus Fig. 1. ANCA-cytokine sequence theory: Cytokine primed polymorphonuclear leukocytes(PMN) translocate and express intracytoplasmic proteinase 3 (PR3) or myeloperoxidase(MPO) on their cell surface. PR3 or MPO become accessible to anti-neutrophil cytoplasmicantibodies (ANCA). ANCA bind via Fc and Fab proportions to PMN. Activated PMN adhereto endothelial cells via adhesion molecule interaction and release oxygen radicals (ROS) andother substances. As a consequence endothelial damage is found (update and review byCsernok and Gross 2000) Small Vessel Vasculitides 351 MPO-ANCA bind to surface-expressed PR3 or MPO via F(ab’)2 and Fcg receptor (FcgRIIa or FcgIIIb). Binding of ANCA to PR3 or MPO as well as to theFcg receptor is necessary for full activation (Csernok et al. 1990, Porges et al.1994, Kocher et al. 1998). ANCA-activated neutrophil granulocytes up-regulate gene expression of inflammatory mediators and release cytokines such asIL-8 and leukotrienes (Grimminger et al. 1996, Yang et al. 2002). Productionof IL-8 by ANCA stimulated neutrophils and monocytes within the intravascular department and/or endothelial cells may frustrate transendothelialleukocyte migration and favor premature degranulation with subsequentendothelial damage (Cockwell et al. 1999). Moreover, ANCA also favor firmadhesion of rolling neutrophil granulocytes and promote their migration invitro (Radford et al. 20001). Pauci-immune, necrotizing vasculitis is seen as aresult of the complex interaction of ANCA, neutrophil granulocytes and endothelial cells. An in vivo animal model has provided further support of thepivotal role of ANCA and neutrophil granulocytes for the induction of vasculitis(Xiao et al. 2002).The inciting agent(s) triggering the aforementioned pathophysiologicalcascade in ANCA-associated vasculitides are still unknown. Staphylococcusaureus nasal carriage is associated with the activity of WG in the upper respiratory tract. A prophylaxis with trimethoprim/sulfmethooxazole results ina significant reduction in the relapse rate (Stegeman et al. 1996). B-cell superantigens such as staphylococcal protein A might play a role in the expansionof autoreactive PR3 producing B-cells residing within granulomatous lesionsof the respiratory tract (Voswinkel et al. 2002). One hypothesis suggests thata polypeptide translated from the antisense DNA strand of PR3 or to a mimicof this peptide may induce anti-idiotypic PR3-ANCA production (Pendergraftet al. 2004). Granulomatous Lesions in WG and CSSWegener’s granulomatosis (WG) and Churg Strauss syndrome (CSS) arecharacterized by small vessel vasculitis and necrotizing granulomatous lesions in the respiratory tract and other locations, e.g. the orbita and the skin(Lamprecht and Gross 2004). Granulomatous lesions in WG are made up ofCD4+ (-positive) and CD8+ T-cells, monocyte derived tissue macrophages, giant cells, B-cells, and neutrophil granulocytes surrounding a necrotic center.Peripheral blood T-cells and monocytes produce Th1-type cytokines in WG,but they secrete higher amounts of IFNg during the initial disease stage (localized WG) as compared to generalized WG. A subset of circulating T-cellslacking the co-stimulatory molecule CD28 is expanded in WG. The expansion of CD28– T-cells is already evident in early disease, i.e. localized WG restricted to the respiratory tract (Lamprecht et al. 2003). The expansion of CD28–T-cells correlates with organ involvement. Circulating peripheral blood aswell as CD4+CD28– T-cells within granulomatous lesions are a major source 352 Peter Lamprecht and Wolfgang L. Gross of Th1-type cytokine secretion and may favor recruitment of T-cells andmonocytes into granulomatous lesions (Komosci et al. 2002, Lamprecht et al.2003). Th1-type CD28– T-cells subset display features of effector memoryT-cells (Lamprecht et al. 2003, Lamprecht et al. 2004). Moreover, a subset ofautoreactive PR3-specific T-cells producing TNF-a can be detected in WG(Winek et al. 2004). These studies suggest that an aberrant Th1-type dominated immune response might play a role during initiation of WG, whereasadditive Th2-type cytokine production may play a role during late diseasestages (Komocsi et al. 2002, Sneller 2002, Lamprecht et al. 2003, Lamprechtand Gross 2004). Granulomatous lesions in CSS consist of lymphocytes, macrophages and eosinophils. A predominance of the Th2 cytokine profile is seenin Churg Strauss syndrome (Fujioka et al. 1998, Tsukadaira et al. 1999, Kieneet al. 2001). Immune Complex-Mediated VasculitidesDeposition or in situ formation of immune complexes in the vessel wall mayresult in the subsequent evolution of vasculitis. Additional factors such as thesize of the complexes, composition, charge, complement activation, hydrostatic pressure on the wall and efficiency or ineffectivity of reparative mechanisms determine, whether the initial lesion will eventually progress to anecrotizing vasculitis (for review: Gross 2003). Immune complexes formed inantigen excess circulate until the aforementioned factors contribute to theirdeposition in blood vessel walls. Activation of neutrophils, up-regulation ofendothelial adhesion molecules and cytokine release facilitate further leukocyte recruitment. The membrane attack complex of complement plays a significant role in altering the endothelial cell membrane integrity. Activatedneutrophils release proteolytic enzymes, especially collagenases and elastases, along with free oxygen radicals that further damage the vessel wall(Claudy 1998).Cryoglobulinemic vasculitis (CV) is an immune complex-mediated vasculitis predominately affecting small vessels. Cryoglobulins are cold-precipitablemonoclonal or polyclonal immunoglobulins. Cryoglobulins can induce colddependent activation of complement and hypocomplementemia, followedby leukocyte attraction and vessel damage (Wei et al. 1997). The skin is frequently involved. CV is usually found in the presence of type II cryoglobulinemia, i.e. mixed monoclonal IgMk and polyclonal IgG cryoglobulinemia.The monoclonal IgM component often (>75%) has rheumatoid factor activity(for review: Lamprecht et al. 1999). The non-enveloped HCV core protein isa constitutive component of type II cryoglobulins and might contribute tocryoprecipitation in hepatitis C virus (HCV)-associated CV. Binding of HCVcore protein to the globular domain of the C1q receptor on the surface of bothleukocytes and endothelial cells may favor the interaction of HCV core proteincontaining type II cryoglobulin and endothelial cells (Sansonno et al. 2003). Small Vessel Vasculitides 353 Fig. 2. Immune complex vasculitis. A. Clinical presentation with petechial purpura of thelower legs. B. Histopathology with diapedesis of erythrocytes and fragmentation of neutrophilgranulocytes. C. Depositis of immune complexes around dermal blood vessels detected bydirect immunofluorescence microscopy Clinical Classification and AppearanceClassificationANCA-associated, pauci-immune vasculitides (WG, MPA, CSS) and immunecomplex-mediated vasculitides (CLA, HSP, ECV) comprise the group of primary systemic vasculitides affecting predominantly small vessels accordingto the definition of the Chapel Hill Consensus (CHC) conference (Jennette etal. 1994). Whereas the CHC nomenclature gives names and definitions ofprimary systemic vasculitides, the American College of Rheumatology (ACR) 354 Peter Lamprecht and Wolfgang L. Gross classification criteria distinguish selected vasculitides from each other on thebasis of criteria with high level sensitivity and specificity (Hunder et al. 1990).Neither the CHC nomenclature nor the ACR classification criteria can betaken as diagnostic criteria. Some authors consider the ACR classification oflimited value for the diagnosis of vasculitis (Rao et al. 1998). Clinical Appearance: SkinThe typical aspect of CLA and skin involvement in systemic small vessel vasculitides is the palpable purpura (for review: Csernok and Gross 2000). Purpurais a manifestation mainly of postvenule capillary vasculitis. The lower limbsare most frequently affected by the palpable purpura due to the higher hydrostatic pressure in these vessels (Hautmann et al. 1999). Hydrostatic pressure may also account for the accentuation of the purpura during the day seenin some patients. Petechiae may occur secondary to widespread capillarydamage. Urticaria vasculitis results from a progression of the small vessel vasculitis to fibrinoid necrosis of postcapillary venules, i.e. necrotizing vasculitis.Urticaria typically persists for more than 24 hours in these cases (Schur 1993).Small hemorrhages with slightly nodular character at the tips of the fingers (Osler’s nodes) and on the palms, especially on the thenar eminences(Janeway lesions) are seen in secondary immune complex-mediated smallvessel vasculitides in infectious endocarditis. These lesions indicate an important differential diagnosis with regard to the etiology of vasculitis (Schuret al. 1993). Pyoderma gangrenosum or dermatitis ulcerosa may be encountered in several systemic diseases, e.g. inflammatory bowel diseases, and insmall vessel vasculitides (Powell et al. 1985).Nailfold splinter hemorrhages and infarcts are vasculitic manifestationsmainly of arterioles and small arteries. The vasculitis may progress and include small arteries causing cutaneous ulcers and acral necrosis. Pathologicexamination often reveals fibrinoid necrosis and thrombosis with little inflammatory infiltration. Vasospasm of dermal ascending arterioles with hyperperfusion of unaffected vessels gives rise to livedo reticularis. Progression to livedovasculitis may result in purpura, cutaneous nodules and ulceration predominantly of the lower extremities (Schur 1993). Clinical Appearance: Systemic VasculitisConstitutional signs such as malaise, weight loss, fever, arthralgia and myalgia may proceed other symptoms of systemic vasculitis. Multi-organ involvement may be found in every systemic small vessel vasculitis. However,mono- or oligosymptomatic courses may be encountered at times. Vasculitidesdiffer with respect to the preferential involvement of distinct vascular areas(Table. 2): Pulmonary-renal syndrome is more likely in WG and MPA, whereas Small Vessel Vasculitides 355 Table 2. Typical aspects of ANCA-associated vasculitides (WG, MPA, CSS) and immunecomplex-mediated vasculitides (CLA, CV, sec. SVV in SLE, RV)Vasculitis Clinical findings Laboratory findings Histology WG Starts in the upperrespiratory tract,pulm.-renal syndr. Compl. « or ,C-ANCA,PR3-ANCA Granulomatous lesions,pauci-imm. vasc. MPA Pulm-renal syndr. Compl. « or ,P-ANCA,MPO-ANCA Pauci-imm. vasc. CSS Asthma, pulmonaryinfiltration, PNP,cardiac involvement Eosinophilia,compl. « or ,less often: ANCA Pauci-imm. vasc.,eosinophilinfiltration CLA Purpura Compl. « or ¯ Leukocyt. vasculitis ECV, HCV-ass.CV Purpura, arthralgia,weakness, PNP, GN Compl. ¯, RF,Imm. compl. vasc.cryoglobulin,HCV-ab., HCV-RNA Sec. vasculitis inSLE Purpura, PNP, GN,cerebral vasculitis Compl. ¯, ANA, dsImm. compl. vasc.DNA ab., anti-Sm ab. RV Purpura, ulcers, PNP HSP Purpura, arthralgia,GN, abdominal pain Compl. ¯, RFCompl. ¯, IgA − Imm. compl. vasc.Imm. compl. vasc.with IgA ANCA = anti-neutrophil cytoplasmic antibody (Immunofluorescence patterns: C-ANCA =cytoplasmic pattern ANCA, P-ANCA = perinuclear pattern ANCA; ELISA: PR3-ANCA =proteinase 3 ANCA, MPO = myeloperoxidase ANCA), WG = Wegener’s granulomatosis,MPA = microscopic polyangiitis, CSS = Churg Strauss syndrome, CLA = cutaneousleukocytoclastic angiitis, CV = cryoglobulinemic vasculitis (ECV = essential CV, HCV-ass.CV = hepatitis C virus associated CV), sec. = secondary, GN = glomerulonephritis, PNP =polyneuropathy, RA = rheumatoid arthritis, SVV = small vessel vasculitis, SLE = sytemiclupus erythematosus, RV = rheumatoid vasculitis, ab. = antibody, Imm. compl. vasc. =immune complex-mediated vasculitis, Compl. = complement, ANA = antinuclear ab.,ds-DNA ab. =double strand DNA ab, Leukocyt. vasc. = leukocytoclastic vasculitis, Immunecompl.–med. vasc. = immune complex-mediated vascultis other diseases such as systemic lupus erythemtosus (SLE) less often cause thissyndrome. Purpura and renal involvement are common in CV, polyneuropathyand gastrointestinal vasculitis in CV and CSS, and cardiac involvement inCSS. Proceeding nasal obstruction, crusting, epistaxis and/or otitis mediaand mastoiditis is usually found in WG. Episcleritis is often seen in WG andMPA. Asthma bronchiale, eosinophilia and pulmonary infiltrations togetherwith cardiac involvement and/or polyneuropathy are frequently seen in CSS.Severe renal disease is less frequent in CSS compared to WG and MPA.Neuropathy and cardiac disease are frequently encountered in severe CSS. 356 Peter Lamprecht and Wolfgang L. Gross Coronary arteritis and myocarditis are the principle causes of morbidity andmortality in CSS (Jennette and Falk 1997; Savage et al. 1997). CSS may evolveover a period of time starting with allergic rhinitis, asthma bronchiale. Thereafter, a hypereosinophilic syndrome with infiltrative eosinophilic disease,e.g. eosinophilc pneumonia and gastroenteritis will ensue, and finally smallvessel vasculitis with granulomatous lesions is seen in CSS (Lanham et al.1984). The triad of arthralgia, purpura and weakness (so-called Meltzer’s triad)is frequently seen in essential CV (ECV) and in HCV-associated CV. CV frequently involves the kidneys and peripheral nerves (Ferri et al. 1991). Purpura,cutaneous ulcers and polyneuropathy in a patient with long-standing rheumatoid arthritis (RA) is suggestive of rheumatoid vasculitis (RV). Purpura, arthritis, and abdominal pain in a child with a nephritic sediment is found inHenoch-Schönlein purpura (HSP). HSP has a peak incidence at the age offive years. The disease often begins after an upper respiratory tract infection(Jennette and Falk 1997; Savage et al. 1997).Small vessel vasculitides may affect different structures within the sameorgan or body region giving rise to a variety of symptoms: Affection of theear in WG may include sensoneurinal deafness due to vasculitis of the innerear and/or cochlear nerve, otitis media, and mastoiditis. CSS and CV maycause abdominal pain due to gastro-intestinal vasculitis or vasculitis of thegall bladder. Renal involvement in immune complex-mediated vasculitismay result in mesangioproliferative and other forms of glomerulonephritis,whereas focal and segment necrotizing glomerulonephritis is more commonin ANCA-associated vasculitis (Jennette and Falk 1997). Renal vas

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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40

culitis ofsmall and medium sized renal arteries is seen at least in one third of the patients with cryoglobulinemic glomerulonephritis (D’Amico 1998). Pulmonarysmall vessel vasculitis may result in dyspnoea, cough, hemoptysis due to either bronchial ulcerations or frank hemorrhagic alveolitis. Full-blown pulmonary-renal syndrome will cause renal and respiratory failure. Centralnervous involvement may cause cranial nerve palsies, seizures, stroke andother symptoms. Cardiac involvement may be indicated by arrhythmias dueto coronariitis or myocarditis, pericardial effusion, and angina pectoris (Savage et al. 1997).Secondary vasculitides in SLE and other connective tissue diseases orrheumatoid arthritis are usually proceeded by typical symptoms of their underlying autoimmune disease. Thus, rheumatoid vasculitis is usually encountered after previous long-lasting rheumatoid arthritis. In case of unusual symptomconstellations paraneoplastic vasculitis, secondary vasculitis in infectious diseases such as bacterial endocarditis, and drug-induced vasculitides shouldbe excluded. It has to be kept in mind, that small vessel vasculitides are alsoseen in primary immunodeficiencies, e.g. bare lymphocyte syndrome (TAPdeficiency and others), CVID, hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), and tumor necrosis factor receptor-associated periodicsyndrome (TRAPS) (Sais et al. 1996, Moins-Teisserenc et al. 1999, Lamprechtet al. 2004). Small Vessel Vasculitides 357 DiagnosisClinical ParametersA detailed patient history, physical examination and focused laboratory investigation are vital in diagnosing vasculitic disorders. The goals of the workup include identification of a cause of the disease and/or the underlyingimmunopathogenetic mechanism, classification of the disease, and determination of the disease activity and extent. The latter is all the more importantas stage-adapted therapy and assessment of the treatment’s efficacy are onlypossible if there are uniform and reproducible measures of the extent and activity of organ involvement in the vasculitic disease. A prerequisite for this isa standardized evaluation of the clinical, radiological and laboratory findingsby an interdisciplinary team of expert physicians (internal medicine, neurology, ophthalmology, dermatology, radiology etc.) (Gross et al. 2000).A detailed patient history and physical examination should give rise to apreliminary diagnosis. CLA requires a detailed drug history as drugs causeca. 10% of vasculitic skin lesions. Drugs that have been implicated are penicillins, aminopenicillins, sulfonamides, allopurinol, thiazides, hydantoins andpropylthiouracil (Jennette and Falk 1997). Laboratory TestsLaboratory tests are used to ascertain the type of vasculitis. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) indicate inflammation.Low complement levels are seen in immune complex-mediated vasculitidesincluding CV, whereas normal or elevated complement levels are found inANCA-associated vasculitides (Gross et al. 2000). Furthermore, low complement levels may indicate hereditary complement deficiencies, which maycause SLE-like diseases with secondary vasculitides. C-ANCA are stronglyassociated with “classic” WG. The principle target antigen for C-ANCA inWG is PR3 (Csernok et al. 1990, Jenne et al. 1990). Only few WG patients(<5%) have a P-ANCA with MPO specificity. In PR3-ANCA positive WG ahigher disease extent is seen as compared to MPO-ANCA positive WG (Schönermarck et al. 2000). ANCA-negative WG is rarely encountered (Lamprechtet al. 2000). Combing the detection of C-ANCA resp. P-ANCA in IFT andPR3-ANCA resp. MPO-ANCA in ELISA yields a high sensitivity and specificity for WG and MPA (Hagen et al. 1998). Despite their high sensitivity andspecificity, C-ANCA and PR3-ANCA may be found in other diseases thanWG, e.g. subacute bacterial endocarditis or severe CV (Choi et al. 2000). RFmay be found in various conditions such as RV, CV and endocarditis. Autoantibodies, e.g. ANA, ds-DNA antibodies, anti Sm, anti SSA, anti-SSB etc.,will be seen in secondary vasculitides in SLE, Sjögren’s syndrome and other 358 Peter Lamprecht and Wolfgang L. Gross connective tissue diseases. Low level autoantibodies such as ANA may alsobe found in CV. ANA may be seen in RV and a variety of other diseases. Serum levels of IgA are elevated in half of the patients with HSP. As infectionsmay cause secondary vasculitis, HBV, HCV, HIV, and bacterial infectionsshould be excluded. Serial blood cultures may be necessary (Gross et al. 2000).ALT and AST may not necessarily be elevated in HCV-associated CV (Lamprecht et al. 1999). Procalcitonin may help to differentiate between autoimmune diseases and bacterial infections and sepsis (Moosig et al. 1998). Additional DiagnosticsEchocardiography should rule out vegetations on the leaves. Primary immunodeficiencies also have to be considered. Quantitative assessment of immunoglobulin classes including IgD, lymphocyte subpopulations, standardizedcutaneous tests for various T-cell specific antigens, complement levels, MHCclass I and II expression, tests for the assessment of the functional status ofvarious neutrophils, lymphocytes etc., and moleculargenetic analysis of mutations of the MEFV-gene (Familial Mediterranean fever), MVK-gene (HIDS),or TNFRSF1A-gene (TRAPS) may be necessary in selected patients (Baumertet al. 1992, Moins-Teisserenc et al. 1999, Lamprecht et al. 2004).Arteriogramms are helpful in identifying vasculitis of medium-sized arteries, e.g. renal, coronar or intestinal vessels, or even larger arteries. These vascular areas may sometimes be involved in addition to the small vessel vasculitis.The definite diagnosis of vasculitis is dependent on the demonstration ofvascular involvement by biopsy. Biopsy specimen should be obtained fromclinically involved tissue. Applying immunohistochemistry is helpful in distinguishing immune complex mediated from pauci-immune (ANCA-associated)vasculitides (Gross et al. 2000). TherapyCutaneous Leukocytoclastic Vasculitis(CLA)CLA is usually limited to a single episode that resolves spontaneously withinweeks or a few months. Approximately 10% will have recurrent disease atintervals of months to years. Drugs that could cause the disease should bestopped. Oral corticosteroid therapy is indicated in severe cutaneous disease.Progressive, steroid resistant CLA is rarely encountered and may necessitateadditional immunosuppressive therapy such as azathioprine. Critical reevaluation of the diagnosis should also take place in such cases (Jennette andFalk 1997). Small Vessel Vasculitides 359 ANCA-Associated VasculitisInduction of remission is achieved with combined oral corticosteroids andoral cyclophosphamide in life threatening conditions and severe, progressive vasculitis in WG, MPA and CSS. Oral cyclophosphamide at 2mg/kg/dayis preferentially used in severe conditions (”Fauci’s scheme” or”NIH standard”), whereas cyclophosphamide i.v. (15mg/kg every 3 weeks) may onlybe expected as a successful alternative in less severe disease (ReinholdKeller et al. 1994). Reduction of the corticosteroid dose should be startedcarefully as cyclophosphamide therapy becomes effective after 7–10 days.Tapering of corticosteroids is aimed at reaching the lowest effective dose after having achieved a stable remission for more than three months. Dosesshould at least range below the so-called “Cushing” level at this time in order to prevent adverse effects (Savage et al. 1997).About 5% of patients remain resistant to “Fauci’s scheme”. A transientincrease of the cyclophosphamide dose to 4mg/kg for approximately two weeksand subsequent reduction on the basis of the patients leukocyte count mayovercome the initial therapy resistance in some patients (Schmitt and Gross1998). In cases resistant to conventional therapy high dose intravenous immunoglobulin may be effective (Jayne et al 2000). T-cell directed biologicals,such as anti-thymocyte globulin (ATG) and humanized monoclonal antibodies to CD4 and CD52 have been reported to induce remission in small caseseries, but adverse effects may be substantial (Schmitt et al. 2004). 15-deoxyspergualin proved to be efficient in the treatment of refractory WG in anothersmall case series (Birck et al. 2003). Both the chimeric monoclonal antiTNF-a antibody infliximab and the human soluble p75 TNF-a receptor fusionprotein etanercept have been successfully applied in patients with refractoryWG (Stone et al. 2000; Lamprecht et al. 2002).Corticosteroids and cyclophosphamide predispose patients to serious adverse effects. Cyclophosphamide causes premalignant hemorrhagic cystitis,ovarian and testicular failure and myelodysplastic syndrome (Hoffman et al.1992; Reinhold-Keller et al. 2000). Mesna is beneficial in avoiding hemorrhagiccystitis (Reinhold-Keller et al. 2000). Less toxic treatment is highly desirable.However, only patients with non-life threatening WG or MPA may be treatedsafely with methotrexate (0,3 mg/kg/week i.v.) and corticosteroids for the induction of remission (Langford et al 2000). Azathioprine can be used for themaintenance of remission after induction of remission with cyclophosphamide(Jayne et al. 2003). Methotrexate and leflunomide may be alternatives for themaintenance of remission in WG and MPA (deGroot et al. 1996, Metzler etal. 2004). Nasal S. aureus carriage is associated with activity of WG in the upper respiratory tract. A prophylaxis with trimethoprim/sulfmethooxazole results in a significant reduction in the relapse rate (Stegeman et al. 1996).Mupirocin ointment is also used for the reduction of nasal S. aureus carriage.CSS is often controlled with high-dose corticosteroid treatment. Refractory and relapsing disease may require addition of a cytotxic drug similar to 360 Peter Lamprecht and Wolfgang L. Gross the treatment of WG and MPA (Jennette and Falk 1997). Interferon-a (IFN-a)therapy has been reported to induce remission in CSS and substantial reduction of the prednisolone requirement in patients who had attained incompleteremission with cyclophosphamide or methotrexate. The mechanism of actionof IFN-a in CSS has not been clearly established, but switch in the cytokineprofile as well as down-regulation of IgE receptors on eosinophils and lymphocytes may be relevant (Tatsis et al. 1998; Metzler et al. 2000). Cryoglobulinemic VasculitisEssential CV, i.e. non-infection or other disease related CV, is treated similarto the treatment protocol for WG and MPA. Plasma pheresis has been recommended in life-threatening conditions, progressive glomerulonephritis andpolyneuropathy (Lamprecht et al. 1999). Severe, progressive vasculitis andlife-threatening conditions of HCV-associated CV may also be treated withoral cyclophosphamide and corticosteroids (“Fauci’s scheme”) for the induction of remission. Plasmapheresis may be added (D’Amico 1998). The monoclonal anti-CD20 antibody rituximab targeting B-cells has been shown to beefficacious in severe HCV-associated CV (Zaja et al. 2003). IFN-a and ribavirinare applied in less severe disease in order to attempt HCV elimination(Donada et al. 1998). However, caution is recommended for the treatment ofpolyneuropathy with IFN-a (Ferri et al. 1993). Addition of corticosteroids maybe beneficial in controlling cutaneous vasculitis despite the risk of delayedvirus elimination and easier evolution of escape-mutants from immune surveillance (Dammacco et al 1994). Secondary CV in infectious endocarditisshould be controlled by antibiotic treatment and valve replacement if indicated. Transient addition of corticosteroids may be necessary in order to control vasculitic manifestations, e.g. glomerulonephritis (Choi et al. 2000). Henoch-Schönlein PurpuraHSP has a good prognosis in general. Pulmonary disease, rapidly progressive renal failure and peripheral polyneuropathy are uncommon (Jennette andFalk 1997). Adult onset HSP is rare. Corticosteroids and azathioprine may bebeneficial in patients with progressive renal insufficiency (Bergstein et al. 1998). Miscellaneous Secondary VasculitidesRV shows histopathological similarities to polyarteritis nodosa and requiresequally aggressive therapy. Intermittent intravenous bolus cyclophosphamideplus methylprednisolone for the induction of remission has been demonstratedto improve healing of vasculitic lesions including leg ulcers and neuropathy. Small Vessel Vasculitides 361 Bolus therapy result in a lower incidence of relapse and a lower mortalitycompared with other treatments. Comparatively high doses of cyclophosphamide (15–20mg/kg per bolus) and short treatment intervals (14 and 21 days)are necessary to control the often aggressive course of the disease (Scott andBacon 1984). Although there are no controlled studies for the maintenance ofremission in RV, practical considerations suggest to treat the patient withDMARDS used in RA, preferably methotrexate.Secondary vasculitis in SLE is treated with intermittent intravenous boluscyclophosphamide and corticosteroids according to the Austin’s scheme. Theoriginal Austin’s scheme included monthly intermittent intravenous boluscyclophosphamide (0,5–1,0g/m2 body surface area) plus low-dose oral prednisolone (starting with up to 0,5mg/kg per day) (Austin et al. 1986; Boumpaset al. 1991). Secondary vasculitides in other connective tissue diseases aretreated analogous to the Austin’s scheme in SLE.Secondary vasculitis in bacterial endocarditis is treated similar to secondary CV due to endocarditis (see 12.4.3). Paraneoplastic vasculitis may require treatment similar to the treatment protocol for WG and MPA for thevasculitic manifestations, e.g. cutaneous ulcers, acral necrosis, or polyneuropathy. Therapy of the underlying neoplasm is essential for the control of thevasculitis. Rheumatic symptoms and vasculitis secondary to primary immunodeficiencies may improve upon intravenous immunoglobulin administration in some disease conditions, e.g. CVID (Sais et al. 1996; Gause et al. 2000)and in TAP deficiency (Gadola et al. 2000). SummarySmall vessel vasculitides affecting the skin are seen in primary systemicvasculitides, i.e. the ANCA-associated vasculitides (WG, MPA, CSS) and theimmune complex-mediated vasculitides (ECV, HSP, CLA). Secondary immunecomplex-mediated vasculitides, e.g. in SLE and other connective tissue diseases, paraneoplastic conditions, and in infectious diseases, also frequentlyinvolve small vessels of the skin. Diagnosis is made upon a detailed patienthistory, physical examination, focused laboratory investigation, and demonstration of vasculitis by biopsy. Stage-adopted therapy aims at inducing andmaintaining remission of the respective vasculitis. Treatment of underlyingdiseases may be necessary in secondary vasculitides. ReferencesAustin HA 3d, Klippel JH, Balow JE, le Riche NG, Steinberg AD, Plotz PH, Decker JL (1986)Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl JMed 314: 614–619 362 Peter Lamprecht and Wolfgang L. Gross Bergstein J, Leiser J, Andreoli SP (1998) Response of crescentic Henoch-Schoenlein purpuranephritis to corticosteroid and azathioprine therapy. Clin Nephrol 49: 9–14Birck R, Warnatz K, Lorenz HM, Choi M, Haubitz M, Grunke M, Peter HH, Kalden JR, GobelU, Drexler JM, Hotta O, Nowack R, Van der Woude FJ (2003) 15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis: A six-month open-label trialto evaluate safety and efficacy. J Am Soc Nephrol 14, 440–447Boumpas DT, Yamada H, Patronas NJ, Scott D, Klippel JH, Balow JE (1991) Pulse cyclophosphamide for severe neuropsychiatric lupus. Q J Med 81: 975–984Baumert E, Schlesier M, Wolff-Vorbeck G, Peter HH (1992) Alterations in lymphocyte subsetsin variable immunodeficiency syndrome. Immun Infekt 20: 73–75Choi HK, Lamprecht P, Niles JL, Gross WL, Merkel PA (2000) Subacute bacterial endocarditiswith positive C-ANCA and antiproteinase 3 antibodies. Arthritis Rheum 43: 226–231Claudy A (1998) Pathogenesis of leukocytoclastic vasculitis. Eur J Dermatol 8: 75–79Cockwell P, Brooks CJ, Adu D, Savage COS (1999) Interleukin-8: pathogenetic role in antineutrophil cytoplasmic autoantibody-associated glomerulonephritis. Kidney Int 55: 852–863Csernok E, Lüdemann J, Gross WL, Bainton DF (1990) Ultrastructural localization of proteinase 3, the target antigen of anticytoplasmic antibodies circulating in Wegener’s granulomatosis. Am J Pathol 137: 1113–1120Csernok E, Trabandt A, Müller A, Wang GC, Moosig F, Paulsen J, Schnabel A, Gross WL(1999) Cytokine profiles in Wegner’s granulomatosis. Predominance of type 1 (Th1) in thegranulomatous inflammation. Arthritis Rheum 42: 742–750Csernok E, Gross WL (2000) Primary vasculitides and vasculitis confined to the skin: clinicalfeatures and new pathogenic aspects. Arch Dermatol Res 292: 427–436.Dammacco F, Sansonno D, Han JH, Shyamala V, Cornacchiulo V, Iacobelli AR, Lauletta G,Rizzi R (1994) Natural interferon-alpha versus its combination with 6-methyl-prednisolone in the therapy of type II mixed cryoglobulinemia: a long-term, randomized, controlled study. Blood 84: 3336–3343D’Amico G (1998) Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis. Kidney Int 54: 650–671deGroot K, Reinhold-Keller E, Tatsis E, Paulsen J, Heller M, Nolle B, Gross WL (1996) Therapy for the maintenance of remission in sixty-five patients with generalized Wegener’sgranulomatosis. Methotrexate versus trimethoprim/sulfamethoxazole. Arthritis Rheum39: 2052–2061deGroot K, Haubitz M, Haller H (2000) ANCA-assoziierte Vaskulitiden. Neue Konzepte undStrategien in der Therapie. Internist 41: 1112–1119Donada C, Crucitti A, Donadon V, Chemello L, Alberti A (1998) Interferon a and ribavirincombination therapy in patients with chronic hepatitis C and mixed cryoglobulinemia.Blood 92: 2983–2984Falk RJ, Jennette JC (1988) Anti-neutrophil cytoplasmic autoantibodies with specificity formyeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 318: 1651–1657Falk RJ, Terrell RS, Charles LA, Jennette JC (1990) Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc NatlAcad Sci USA 87: 4115–4119Ferri C, Greco F, Longombardo G, Palla P, Moretti A, Marzo E, Fosella PV, Pasero G,Bombardieri (1991) Antibodies to hepatits C virus in patients with mixed cryoglobulinemia. Arthritis Rheum 34: 1606–1610Ferri C, Marzo E, Longombardo G, Lombardini F, La Civita L, Vanacore R, Liberati AM, GerliR, Greco F, Moretti A (1993) Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood 81: 1132–1136Fujioka A, Yamamoto T, Takasu H, Kawano K, Masuzawa M, Katsuoka K, Jinno S (1998) Theanalysis of mRNA expression of cytokines from skin lesions in Churg-Strauss syndrome. JDermatol 25:171–177Gadola SD, Moins-Teisserenc HT, Trowsdale J, Gross WL, Cerundolo V (2000) TAP deficiency syndrome. Clin Exp Immunol 121: 173–178Gause A, Inderrieden DC, Laas R, Arlt AC, Gross WL (2000) Common variable immunodeficiency (CVID) and inclusion body myositis. Immunobiology 202: 199–203 Small Vessel Vasculitides 363 Grimminger F, Hattar K, Papavassilis C, Temmesfeld B, Csernok E, Gross WL, Seeger W,Sibelius U (1996) Neutrophil activation by anti-proteinase 3 antibodies in Wegener’sgranulomatosis: role of exogenous arachidonic acid and leukotrien B4 generation. J ExpMed 184: 1567–1572Gross WL, Csernok E, Schmitt WH (1991) Antineutrophil cytoplasmic autoantibodies: immunobiolgical aspects. Klin Wochenschr 69: 558–566Gross WL, Trabandt A, Reinhold-Keller E (2000) Diagnosis and evaluation of vasculitis.Rheumatology 39: 245–252Gross WL (2003) Immunopathogenesis of vasculitis. In: Klippel JH, Dieppe PA (eds) Rheumatology. 3rd ed. Mosby, London, chapter 7.19, p. 1–8Hagen EC, Daha MR, Hermans J, Andrassy K, Csernok E, Gaskin G, Lesavre P, Ludemann J,Rasmussen N, Sinico RA, Wiik A, van der Woude FJ (1998) Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis.EC/BCR Project for ANCA Assay Standardization. Kidney Int 53: 743–753Hautmann G, Campanile G, Lotti TM (1999) The many faces of cutaneous vasculitis. ClinDermatol 17: 515–531Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, FauciAS (1992) Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 116:488–498Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, Leavitt RY, Lie JT,Lightfoot RW Jr, Masi AT, McShane DJ, Michel BA, Mills JA, Stevens MB, Wallace SL,Zvaifler NJ (19990) The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum 33: 1065–1067Jayne DR, Chapel H, Adu D, Misbah S, O’Donoghue D, Scott D, Lockwood CM (2000) Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent diseaseactivity. QJM 93: 433–439Jayne D, Rasmussen N, Andrassy K, Bacon PA, Cohen Tervaert JW, Dadoniene J, EkstrandA, Gaskin G, Gregorini G, deGroot K, Gross WL, Hagen EC, Mirapeix E, Pettersson E,Siegert C, Sinico A, Tesar V, Westman K, Pusey C, for the European Vasculitis StudyGroup (2003) A randomized trial of maintenance therapy for vasculitis associated withantineutrophil autoantibodies. N Engl J Med 349: 36–44Jenne DE, Tschopp J, Lüdemann J, Utech B, Gross WL (1990) Wegener’s autoantigen decoded. Nature 346: 520.Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS,Hunder GG, Kallenberg CG, McCluskey RT, Sinico A, Rees AJ, van Es LA, Waldherr R,Wiik A (1994) Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 37: 187–192Jennette JC, Falk R. (1997) Small-vessel vasculitis. N Engl J Med 337: 1512–1523Kallenberg CG, Cohen Tervaert JW (2000) New treatments of ANCA-associated vasculitis.Sarcoidosis Vasc Diffuse Lung Dis 17: 125–129Kiene M, Csernok E, Müller A, Metzler C, Trabandt A, Gross WL (2001) Elevated IL-4 andIL-13 production by T-cell lines in Churg-Strauss syndrome. Arthritis Rheum 44: 469–473Kocher M, Edberg JC, Fleit HB, Kimberly RP (1998) Antineutrophil cytoplasm antibodiespreferentially engage Fc gammaRIIIb on human neutrophils. J Immunol 161: 6909–6914Komocsi A, Lamprecht P, Csernok E, Müller A, Holl-Ulrich K, Seitzer U, Moosig F, SchnabelA, Gross WL (2002) Peripheral blood and granuloma CD4+CD28- T-cells are a majorsource of IFNg and TNF-a in Wegener’s granulomatosis. Am J Pathol 160: 1717–1724Langford CA, Talar-Williams C, Sneller MC. Use of methotrexate and glucocorticoids in thetreatment of Wegener’s granulomatosis. Long-term renal outcome in patients with glomerulonephritis. Arthritis Rheum 43: 1836–1840Lamprecht P, Gause A, Gross WL (1999). Cryoglobulinemic vasculitis. Arthritis Rheum 42:2507–2516Lamprecht P, Trabandt A, Gross WL (2000) Clinical and immunological aspects of Wegener’sgranulomatosis (WG) and other syndromes resembling WG. Isr Med Assoc J 2: 621–626Lamprecht P, Voswinkel J, Lilienthal T, Nölle B, Heller M, Gross WL, Gause A (2002) Effectiveness of TNF-a blockade with infliximab in refractory Wegener’s granulomatos

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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0, 0, 0 ]

41

is.Rheumatology 41: 1303–1307 364 Peter Lamprecht and Wolfgang L. Gross Lamprecht P, Erdmann A, Müller A, Csernok E, Reinhold-Keller E, Holl-Ulrich K, Feller AC,Brühl H, Gross WL (2003a) Heterogeneity of CD4+ and CD8+ memory T cells in localizedand generalized Wegener’s granulomatosis. Arthritis Res Ther 5: R25-R31Lamprecht P, Brühl H, Erdmann A, Holl-Ulrich K, Csernok E, Seitzer U, Mack M, Feller AC,Reinhold-Keller E, Gross WL, Müller A (2003b) Differences in CCR5 expression on peripheral blood CD4+CD28– T-cells and in granulomatous lesions between localized andgeneralized Wegener’s granulomatosis. Clin Immunol 108: 1–7Lamprecht P, Gross WL (2004) Wegener’s granulomatosis. Herz 29: 47–56Lamprecht P, Müller A, Gross WL (2004a) CD28- T-cells display features of effector memoryT-cells in Wegener’s granulomatosis. Kidney Int 65:1113.Lamprecht P, Moosig F, Adam-Klages S, Mrowietz U, Csernok E, Kirrstetter M, AhmadiSimab K, Schröder JO, Gross WL (2004b) Small vessel vasculitis and relapsing panniculitisin tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Ann Rheum Disin pressLanham JG, Elkon KB, Pusey CD, Hughes GR (1984) Systemic vasculitis with asthma andeosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore)63: 65–81Ludviksson BJ, Sneller MC, Chua KS, Talar-Williams C, Langford CA, Ehrhardt RO, FauciAS, Strober W (1998) Active Wegener’s granulomatosis is associated with HLA-DR+CD4+T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10. JImmunol 160: 3602–3609Metzler C, Tatsis E, Gause A, Gross WL (2000) Long-term treatment of Churg-Strauss syndrome with interferon-a. Arthritis Rheum 43 (Suppl): S369Metzler C, Fink C, Lamprecht P, Gross WL, Reinhold-Keller E (2004) Maintenance of remission with leflunomid in Wegener’s granulomatosis. Rheumatology 43: 315–320Moins-Teisserenc HT, Gadola SD, Cella M, Dunbar PR, Exley A, Blake N, Baycal C, LambertJ, Bigliardi P, Willemsen M, Jones M, Buechner S, Colonna M, Gross WL, Cerundolo V(1999) Association of a syndrome resembling Wegener’s granulomatosis with low surfaceexpression of HLA class-I molecules. Lancet 354: 1598–1603Moosig F, Csernok E, Reinhold-Keller E, Schmitt W, Gross WL (1998) Elevated procalcitoninlevels in active Wegener’s granulomatosis. J Rheumatol 25: 1531–1533Müller A., Trabandt A, Glöckner-Hofmann K, Seitzer U, Csernok E, Schönermarck U, FellerAC, Gross WL (2000) Localized Wegener’s granulomatosis: predominance of CD26 andIFNg expression. J Path 192: 113–120Pendergraft WE, Preston GA, Shah R, Tropsha A, Carter CW, Jennette JC, Falk RJ (2004)Autoimmunity is triggered by cPR3(105–201), a protein complementary to human autoantigen proteinase 3. Nature Med 10: 72–79Porges AJ, Redecha PB, Kimberly WT, Csernok E, Gross WL, Kimberly RP (1994) Antineutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gammaRIIa. J Immunol 153: 1271–1280Powell FC, Schroeter AL, Su WPD, Perry HO (1985) Pyoderma gangrenosum: A review of 86patients. Q J Med 55: 173–82Radford DJ, Luu NT, Hewins P, Nash GB, Savage CO (2000) Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelialcells. Arthritis Rheum 44: 2851–2861Rao JK, Allen NB, Pincus T (1998) Limitations of the 1990 American College of Rheuamtologyclassification criteria in the diagnosis of vasculitis. Ann Intern Med 129: 345–352Reinhold-Keller E, Kekow J, Schnabel A, Schmitt WH, Heller M, Beigel A, Duncker G, GrossWL (1994) Influence of disease manifestation and antineutrophil cytoplasmic antibody titer on the response to pulse cyclophosphamide therapy in patients with Wegener’sgranulomatosis. Arthritis Rheum 37: 919–924Reinhold-Keller E, Beuge N, Latza U, de Groot K, Rudert H, Nolle B, Heller M, Gross WL(2000) An interdisciplinary approach to the care of patients with Wegener’s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum 43: 1021–1032Sais G, Vidaller A, Servitje O, Jucgla A, Peyri J (1996) Leukocytoclastic vasculitis and common variable immunodeficiency: successful treatment with intravenous immune globulin. J Allergy Clin Immunol 98: 232–233. Small Vessel Vasculitides 365 Sansonno D, Lauletta G, Nisi L, Gatti P, Pesola F, Pansini N, Dammacco F (2003) Non-enveloped HCV core protein as constitutive antigen of cold-precipitable immune complex intype II mixed cryoglobulinemia. Clin Exp Immunol 133: 275–282Savage COS, Harper L, Adu D (1997) Primary systemic vasculitis. Lancet 349: 553–558Schmitt WH, Gross WL (1998) Vasculitis in the seriously ill patient: diagnostic approachesand therapeutic options in ANCA-associated vasculitis. Kidney Int Suppl 64: S39–44Schmitt WH, Hagen EC, Neumann I, Nowack R, Flores-Suarez LF, Van der Woude FJ, for theEuropean Vasculitis Group (2004) Treatment of refractory Wegener’s granulomatosiswith antithymocyte globulin (ATG): An open study in 15 patients. Kidney Int 65: 1440–1448Schönermarck U, Lamprecht P, Csernok E, Gross WL (2000) Prevalence and spectrum ofrheumatic diseases associated with PR3-ANCA and MPO-ANCA. Rheumatology in press.Schur PH (1993) Clinical features of SLE. In: Kelley WN, Harris ED Jr, Ruddy S, Sledge CB(eds) Textbook of Rheumatology, Volume 2. WB Saunders Company, Philadelphia London Toronto Montreal Sydney Tokyo, pp 1017–1042Scott DG, Bacon PA (1984) Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med 76: 377–384Sneller MC (2002) Granuloma formation, implications for the pathogensis of vasculitis.Cleveland Clin J Med 69(Suppl. 2): SII-40-SII43Stegeman CA, Cohen Tervaert JW, de Jong PE, Kallenberg CGM (1996) Trimethoprimsulfmethoxazole (Co-trimoxazole) for the prevention of relapses in Wegener’s granulomatosis. N Engl J Med 335: 16–20Stone JH for the WGET investigators (2000) Etanercept in Wegner’s granulomatosis (WG):Design of a randomized, multi-center trial. Clin Exp Immunol 120 (Suppl 1): 72Tatsis E, Schnabel A, Gross WL (1998) Interferon-alpha treatment of four patients with theChurg-Strauss syndrome. Ann Intern Med 129: 370–374Tsukadaira A, Okubo Y, Kitano K, Horie S, Momose T, Takashi S, Suzuki J, Isobe M,Sekiguchi M (1999) Eosinophil active cytokines and surface analysis of eosinophils inChurg-Strauss syndrome. Allergy Asthma Proc 20: 39–44Voswinkel J, Müller A, Lamprecht P, Gause A, Gross WL (2002) Does ANCA formation resultfrom an antigen-triggered immune response in Wegener’s endonasal inflamed tissue?(Abstract) Cleveland Clin. J. Med. 69-Supl.2: SII-159.Wei G, Yano S, Kuroiwa T, Hiromura K, Maezawa A (1997) Hepatitis C virus (HCV)-inducedIgG-IgM rheumatoid factor (RF) complex may be the main causal factor for cold-dependent activation of complement in patients with rheumatic disease. Clin Exp Immunol107:83–88.Winek J, Müller A, Csernok E, Gross WL, Lamprecht P (2004) Frequency of proteinase 3(PR3)-specific autoreactive T-cells determined by cytokine flow cytometry in Wegener’sgranulomatosis. J Autoimmun 22: 79–85Xiao H, Heeringa P, Hu P, Liu Z, Zhao M, Aratani Y, Maeda N, Falk RJ, Jennette JC (2002)Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 110: 955–963Yang JJ, Preston GA, Alcorta DA, Waga I, Munger WE, Hogan SL, Sekura SB, Phillips BD,Thomas RP, Jennette JC, Falk RJ (2002) Expression profile of leukocyte genes activatedby anti-neutrophil cytoplasmic autoantibodies (ANCA). Kidney Int 62: 1638–1649.Zaja F, De Vita S, Mazzaro C, Sacco S, Damiani D, De Marchi G, Michelutti A, Baccarani MFanin R, Ferraccioli G (2003). Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 101: 3827–3834 13 VitiligoKarin U. Schallreuter IntroductionVitiligo (from vitula (latin) = calf, vitium (latin) = mistake) is an acquired idiopathic epidermal pigment loss which can occur anywhere on the body. Thecause of this ancient disease is still unknown.The incidence of vitiligo worldwide has not been accurately determined,but studies in Europe indicate that 0.5% of the population may be affected,meanwhile in India reports of 4–8% have been suggested (Ortonne and Bose1993). Even if the lower value is correct, vitiligo must be regarded as one skindisease confronting Dermatologists worldwide (Ortonne and Bose 1993). Thisdisabling depigmentation disorder was recognised thousands of years ago.Several hypotheses have been put forward for the depigmentation processbut none of them can conclusively explain the plethora of clinical and basicscientific data (Ortonne and Bose 1993, LePoole et al. 1993a). The clinical signature of the disease is the loss of constitutive pigment from the skin, and mostpublications account for this by either showing a decreased number of functioning melanocytes or the complete absence of these cells in the depigmented epidermis (Ortonne and Bose 1993, LePoole et al. 1993a, LePoole et al.1993b, Xie et al. 1999). A recent study by Tobin et al proved that melanocytesare still present, even in long standing vitiligo (Tobin et al. 2000). There hasbeen much debate over, how melanocytes lose their functionality and viability, and certainly the most popular hypothesis is still selective autoimmunityto melanocytes. Clinical Picture and ClassificationThe typical lesion of vitiligo has a chalk white colour without any other epidermal changes and varies in size and location. 368 Karin U. Schallreuter Vitiligo can be diagnosed by demonstrating a distinct fluorescence in thedepigmented epidermis when it is exposed to Wood’s light (UVA 351 nm),whereas leucodermas of other origin do not fluoresce (Schallreuter et al. 1994a).A comparison of vitiligo and a laser induced leucoderma is shown in Figure 1.The disease has several characteristic patterns but can involve the entireskin surface.–– ––– Focal vitiligo is characterised by the appearance of one or more isolatedmacules anywhere on the body.Segmental vitiligo is characterised by unilateral appearance in dermatomal or almost dermatomal distribution. Rarely this form can be mixedwith generalised vitiligo (Figure 2).Generalised vitiligo (vitiligo vulgaris) is characterised by symmetricaldistribution of white areas anywhere on the integument.Acrofacial vitiligo involves distal digits and acrofacial as well as genitoanal areas.Universal vitiligo describes depigmentation in > 80% of the entire integument. The disease can involve mucosal surfaces as well as palms and soles. Activevitiligo is often associated with pruritus in the freshly depigmenting skin(Schallreuter, unpublished results). Koebnerisation has been observed in morethan 40% of patients (Ortonne and Bose 1993). Fig. 1. Differential diagnosis of clinical leucoderma upon WOOD’s light (351 nm)examination A. Vitiligo vulgaris: i. Clinical picture; ii. N.B. Presence of bluish fluorescence ischaracteristic for vitiligo. B. Laser induced leucoderma: i. Clinical picture; ii. N.B. Absence of anyfluorescence under WOOD’s light Vitiligo 369 Fig. 2. Segmental vitiligo mixed with generalised vitiligo (vulgaris). A. Before treatment. B.After treatment with low dose narrowband UVB activated pseudocatalase (PC-KUS). NB:The repigmentation of segmental vitiligo is considerably slower! Pathomechanisms – a Critical AnalysisI. Autoimmunity in VitiligoOver the past, a variety of techniques have been used in the detection of antibodies to melanocytes in patients with vitiligo. These include indirect immunofluorescence, immunoprecipitation, immunoblotting and complementdependent cytolysis of melanocytes (Naughton et al. 1983a, Naughton et al.1983b, Naughton et al. 1986a, Naughton et al. 1986b, Galbraith et al. 1988,Norris et al. 1988, Harning et al. 1991, Cui et al. 1992, Cui et al. 1993). Theseantibodies are believed to be important in the progress of the disease, becausethey have been found to be cytotoxic to melanocytes under in vitro conditions (Norris et al. 1988, Cui et al. 1993). The presence of anti-melanocyte antibodies has been correlated with the activity of skin depigmentation (Naughtonet al. 1986a, Harning et al. 1991). Recent work has focused on attempts toidentify specific antibodies against melanocytes in vitiligo (Cui et al. 1992).Since several of the antigens are not specific and can cross-react, most attention has been given to antibodies reacting with proteins specific for melanocytes. In this context, research has focused on the detection of antibodies againsttyrosinase and tyrosinase related proteins 1 and 2 (TRP-1 and TRP-2) (Songet al. 1994, Baharav et al. 1996, Kemp et al. 1997a, Kemp et al. 1997b, Kempet al. 1998 and Okamato et al. 1998). Since tyrosinase is a glycoprotein whichis extremely stable to proteolytic digestion, it appeared to be a good candidate for the elicitation of an immune response (Wood and Schallreuter 1991,Laskin and Piccinini 1996). In addition, tyrosinase, TRP-1 and TRP-2 areregarded as melanosome specific as well as being key proteins in the controlof pigmentation. TRP-1 is a melanosomal membrane associated protein whichhas 43% sequence homology to tyrosinase and it controls both the activity andstability of this key enzyme in melanogenesis (Halaban and Moellmann 1990,Orlow et al. 1993). Halaban and Moellmann were the first to demonstrate 370 Karin U. Schallreuter that TRP-1 has catalase/peroxidase activities and these authors suggested thatit functions by protecting tyrosinase from oxidative degradation (Halabanand Moellmann 1990). In this context, it has been established that H2O2 is apotent competitive inhibitor of human tyrosinase and that superoxide anionradical is a preferred substrate for this enzyme compared to molecular oxygen (Wood and Schallreuter 1991). Thus, melanogenesis has been consideredas anti-oxidant defence mechanism protecting the melanocyte against oxidative stress (Wood et al. 1999). Jimbow et al reported that melanocytes established from the perilesional skin of patients with vitiligo expressed a TRP-1containing 11 additional amino acids at the C-terminal end of its sequenceand this sequence was identical to murine TRP-1 (Jimbow et al. 2001). Theinitial transcript for human and murine TRP-1 shows 93% sequence homology(Boissy et al. 1998). However, post-translational processing via an unidentified protease occurs in the human system producing a protein lacking 11 residues from the C-terminal. It has been proposed that this protease appears tobe either lost, inhibited or inactivated in vitiligo (Jimbow et al. 2001). Interestingly, in vitiliginous melanocytes the murine form of TRP-1 is expressedand this protein loses its function for protecting melanosome integrity due todefective interactions with both tyrosinase as well as the melanosome chaperonecalnexin (Manga et al. 2000, Jimbow et al. 2001). Animal models lacking active TRP-1 develop an adaptive autoimmune response to melanocytes, thusproviding an example to support a potential role for H2O2 in fostering an immune response (Austin and Boissy 1995, Rutault et al. 1999).To date the results obtained on tyrosinase antibodies in vitiligo are controversial. Xie et al could not confirm the presence of antibodies to tyrosinasein 54 patients’ sera (Xie et al. 1999). These authors reported a non-specificprotein comigrating with tyrosinase at 62 kD (Xie et al. 1999). Therefore, itwas concluded that this protein most likely gave false positive results as reported by Song et al (Song et al. 1994, Xie et al. 1999). Very recently Kemp etal have re-examined the antibodies and this group delineated epitope regionson tyrosinase reacting with these antibodies (Kemp et al. 1999). Accordingly,three epitope regions were found in the centre of the tyrosinase molecule(i.e. amino acids 240–255, 289–294 and 295–300) and two others towards theC-terminal end (i.e. amino acids 435–447 and 461–479). The centrally locatedepitopes had sequence homology with regions of TRP-1 and TRP-2, whichconsequently could explain the cross reactivity observed for these closely related proteins (Kwon 1993, Yokoyama et al. 1994). Two of the five patientsexamined cross-reacted with both TRP-1 and TRP-2 and one patient reactedonly with the 289–294 and 295–300 regions of tyrosinase (Kemp et al. 1999).Two patients reacted only with tyrosinase 435–447 and 461–479 and did notrecognise TRP-1 or TRP-2 (Kemp et al. 1999). Based on these results, it canbe concluded that multiple autoantibodies to tyrosinase occur in vitiligo. However, the frequency of tyrosinase antibody expression in this disease remainsextremely low (i.e. = 5%). Whether these anti-tyrosinase antibodies can account for the progress of vitiligo in these few patients remains currently Vitiligo 371 unanswered. Similar low frequencies for TRP-1 and TRP-2 were found in vitiligopatients (i.e. 3 out of 53) (Kemp et al. 1997, Kemp et al. 1998). Based on thislow expression, it is very likely that tyrosinase, TRP-1 and TRP-2 antibodiesdo not play a major role in vitiligo and that other melanocyte autoantigensmust be more significant targets. It should be recognised that during the period from 1994 to 1999 autoantibodies to tyrosinase in vitiligo have lost theirscientific significance from 61% down to 0–5% (Song et al. 1994, Kemp et al.1999, Xie et al. 1999). In conclusion, it seems unconvincing that autoantibodiesto tyrosinase, TRP-1 and TRP-2 account for the loss of functioning melanocytes in this disease. Moreover, recently three membrane associated antigenshave been detected at the cell surface of melanocytes with molecular weightsof 90, 75 and 40 kD, in addition to the non-specific 62 kD protein that comigrates with tyrosinase (Xie et al. 1999). However, the structure/function ofthese proteins and their specificity to the melanocyte requires more rigorousexamination before they can be unambiguously proved to be part of the postulated autoimmune response in vitiligo. A critical analysis of all data published and a reevaluation of 320 patients with vitiligo failed to support theinvolvement of classical autoimmunity in vitiligo. However, there are indeedincreased thyroid peroxidase (TPO) antibody levels compared to controls. Avery recent study failed to link these results to the clinical outcome of vitiligoand to autoimmune thyroiditis (M Hashimoto) (J Diehle, Medical Thesis, U ofHamburg, 2004).Hence, the question remains “Are there specific autoantigens in the depigmentation disorder vitiligo?” II. The Neural HypothesisIt is believed that neurochemical mediators released from nerve endings cancause destruction of MC’s. Its has been proposed that some intermediates orend products of catecholamines destroy the pigment (reviewed in Nordlundet al. 1988). Neural factors were thought to be involved in 30% of patientswith vitiligo. III. The Self Destruction HypothesisBased on both laboratory and clinical experiments melanin precursor toxicity was implicated for the loss of pigment cells. The melanocyte synthses melanin by the oxidation of L-tyrosine via L-dopa to L-dopaquinone.Subsequently, L-dopaquinone oxidises through several steps into a variety of indoles and free radicals. These phenolic compounds can damage MC’sin vitro and in vivo (Boissy and Manga 2004). 372 Karin U. Schallreuter IV. Virus and VitiligoRecently Grimes et al have proposed a viral aetiology for this disease (Grimeset al. 1996, Grimes et al. 1999). Using PCR techniques, cytomegalovirus (CMV)and Epstein Barr virus (EBV) have been detected in the epidermis of patientswith this disorder. Based on these findings, the authors suggested a viral induced patho-mechanism. Since this study was undertaken in California thedirect association of CMV with vitiligo is difficult to assess, since 85% of thepopulation in California test positive for CMV but the incidence of vitiligo isonly approximately 0.5%. A recent study re-examined the hypothesis of viralinduced disease on 72 patients with vitiligo compared to healthy controls (n= 70). The outcome showed no direct evidence for CMV, Herpes virus I/IIand varicella virus using PCR techniques in skin biopsies as well as in the serum from these patients (Würfel et al. 2000). However, even these findingscannot exclude a viral involved ‘hit/run’ mechanism, despite there is no direct evidence for virus detection in loco or in serum. In fact, it has beenshown in animal models that virus infection can trigger an autoimmune response due to molecular mimicry of viral peptide sequences activating subsets of T-cells. This hypothesis could support viral induced T-cells as a targetagainst melanocytes. In these models the virus causing autoimmunity escapes detection after the onset of the disease (Herrath and Oldstone 1996,Morse et al. 1999). In this context, it is noteworthy that viruses can attract aninfiltrate of leukocytes and macrophages leading to the ‘oxygen burst’ concomitant with the production of reactive oxygen species (ROS), such as superoxide anion radical (O2-) and hydrogen peroxide (H2O2). V. Oxidative Stress in VitiligoNowadays there is accumulating evidence that vitiligo is a disease affectingthe entire epidermis, although most of the studies have concentrated on themelanocyte (Schallreuter et al. 1999a, Schallreuter 1999b). In addition to theloss of functioning melanocytes, the keratinocytes and Langerhans cells aredisturbed in this disease (Nordlund and Ortonne 1992, Tobin et al. 2000). Ithas been demonstrated by various investigators that the entire epidermis ofpatients shows signs for oxidative stress yielding various degrees of vacuolation in all epidermal cells including dilation of the rough endoplasmic reticulum in melanocytes (Moellmann et al. 1982, Bhawan and Bhutani 1983, Boissyet al 1991, Nordlund and Ortonne 1992, Schallreuter et al, 1999a, Schallreuter 1999b, Tobin et al 2000). This oxidative stress can continue even in melanocytes and keratinocytes cultured under in vitro conditions unless thesecultures are protected by anti-oxidant enzymes for instance catalase (Medranoand Nordlund 1990, Schallreuter et al. 1999a). The proof of oxidative stress invitiligo has been accomplished ‘in vivo’ by measuring hydrogen peroxide (H2O2)directly in the depigmented epidermis by non-invasive Fourier Transform Vitiligo 373 (FT) Raman spectroscopy, where H2O2 yields a distinctive peak due to the O– O stretch at 875 cm–1 (Schallreuter et al. 1999a). This epidermal H2O2 can beremoved by a synthetic catalyst that oxidises H2O2 to O2 and H2O, thus mimicking the reaction catalysed by natural catalase. The active catalyst is a nar23- 2row band UVB-activated bis MnIII (EDTA) (HCO ) complex and has beennamed ‘pseudocatalase’ (Schallreuter et al. 1995a). Pseudocatalase can arrest the progress of the disease in 95% of all patients and initiates repigmentation in approximately 60% of those treated topically with this modality(Schallreuter et al. 1995a, Schallreuter 1999a). The biochemical basis for theaccumulation of H2O2 in patients with vitiligo has been the target of much research. Initially it was shown that these patients have low levels of catalasein their entire epidermis (Schallreuter et al. 1991). However, although catalaselevels are decreased, the expression of catalase mRNA remains unaltered inthese patients (Schallreuter et al. 2004). These early data were confirmed,showing that melanocytes established from the non-lesional skin of thesepatients contained lower than normal catalase activities (Maresca et al. 1997).These in

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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42

vitro results were in agreement with increased epidermal H2O2 levels (mM range) in vivo. Under these conditions this reactive oxygen speciescan inactivate catalase by degradation of the porphyrin active site after concentrations exceeding Vmax levels (Aronoff 1965). In the presence of low catalaselevels, glutathione peroxidase functions as a back up enzyme for the efficient removal of H2O2. In this context, it has been shown that these enzymeactivities are also compromised in this patient group (Beazley et al. 1999).Several investigators have reported the presence of a cellular infiltrate inthe perilesional skin of patients with vitiligo (Ortonne and Bose 1993). Thepresence of this infiltrate indicates the likelihood of the biological ‘oxygenburst’ leading to the generation of superoxide anion radical (O2-) from O2 viaNADPH-oxidase (Darr and Fridovich 1994, Marks et al. 1996, Stark 1998). In anormal inflammatory reaction O2- concentrations increase up to 20 fold. Afterdisproportionation this concentration would produce a 10 fold increase inH2O2 (Darr and Fridovich 1994). The perilesional border in vitiligo frequentlycontains an infiltrate but the numbers of infiltrating neutrophils and macrophages as well as T-cells are usually very low or even absent in long lastingdisease. Therefore, it is very difficult to assess the H2O2 contribution derivingfrom this perilesional infiltrate. Indeed, cells in the perilesional epidermis invitiligo show the same degree of vacuolation (i.e. lipid peroxidation) as cellsin both lesional and non-lesional skin (Schallreuter et al. 1999a, Tobin et al.2000). However, recently it has been shown that H2O2 can activate peripheral blood dendritic cells by upregulating surface markers known to be involved in T-cell interactions (Rutault et al. 1999). This H2O2 driven processpromotes interaction with MHC class II molecules (DQ and DR) as well ascostimulatory molecules CD 40 and CD 86 (Rutault et al. 1999). After exposing dendritic cells in culture to H2O2 these cells promote T-cell proliferationcompared to untreated controls lacking H2O2 exposure (Rutault et al. 1999).The effect of H 2O 2 can be blocked in vitro upon the addition of the anti- 374 Karin U. Schallreuter oxidant N-acetyl cysteine (Rutault et al. 1999). In the same context, it has beenshown that solar simulated irradiation upregulates epidermal Langerhanscell B7.1 and B7.2 costimulatory molecules (Laihia and Jansen 1997). It hasbeen shown in vivo and in vitro that H2O2 is generated by UVB (311 nm) andUVA using FT-Raman spectroscopy (Schallreuter et al. 1999a). Therefore itcan be concluded that H2O2 could modulate the response of epidermal Langerhans cells and other dendritic cells in vitiligo (Laihia and Jansen 1997, Schallreuter et al. 1999a, Tobin et al. 2000). These data could directly link oxidativestress from H2O2 to the onset of an adaptive immune response (Laihia andJansen 1997). Moreover, these results may also be a rationale that the immune response in vitiligo is most likely a secondary event linked to oxidativestress with an overproduction of H2O2 in the skin.To date a plethora of studies have recognised several sources and consequences of H2O2 in vitiligo:1. Defective de novo synthesis/recycling and regulation of the essentialcofactor (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (Schallreuter et al.1994a, Schallreuter et al. 1994b).– Induction of GTP-CH1 (rate limiting step for de novo 6BH4 synthesis(Shimizu et al. 2003).– Deactivation of pterin-4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR). (Both enzymes are involved in 6BH4recycling). (Schallreuter et al. 2001, Hasse et al. 2004).2. Increased epidermal monoamine oxidase A activities (Schallreuter et al.1996a).3. Increased NADPH-oxidase activities from the activation of neutrophilsand macrophages that can sometimes be observed in the perilesionalinfiltrate in vitiligo (Darr and Fridovich 1994).4. Increased TNFa production (Moretti et al. 2002).5. Photo-oxidation of epidermal 6-biopterin and sepiapterin (Rokos et al.2002).6. Increased inducible nitric oxide synthase (Schallreuter et al. 1999b).7. Deactivation of acetylcholinesterase (Schallreuter et al. 2004).8. Oxidation of epidermal albumin (Rokos et al. 2004). VI. Pteridines in VitiligoIn 1994 it was finally discovered that the fluorescent compounds present invitiliginous epidermis were oxidised pterins (Schallreuter et al. 1994a, Schallreuter et al. 1994b) (Figure 1). This accumulation of oxidised pterins arosefrom the recognition that these patients have a defective de novo synthesis/recycling/regulation of the essential cofactor (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4) (Schallreuter et al. 1994a, Schallreuter et al. 1994b) (Figure 3). Defective recycling of 6BH4 causes accumulation of its abiogenic isomer Vitiligo 375 Fig. 3. Defective 6BH4 synthesis leading to 7BH4 production in vitiligo. Both epidermalmelanocytes and keratinocytes have the full capacity for de novo synthesis/recycling of 6BH4(Schallreuter et al. 1994a, Schallreuter et al. 1994b). The rate limiting step for the de novosynthesis of 6BH4 is GTP-cyclohydrolase I (GTP-CH-I) which is regulated by H2O2 (Shimizu etal. 2003). This enzyme is also controlled by L-phenylalanine (positive feedback) via theGTP-CH-I feedback regulatory protein (GFRP), as well as several cytokines (TNFa, IL-2,IFNg, MGF). 6BH4 down regulates GTP-CH-I via GFRP. Furthermore, 6BH4 is the essentialcofactor (a) for phenylalanine hydroxylase to metabolise L-phenylalanine to L-tyrosine inmelanocytes and keratinocytes, and (b) for tyrosine hydroxylase to convert L-tyrosine toL-dopa in catecholamine biosynthesis in epidermal keratinocytes and melanocytes. It isalso a regulator of tyrosinase activity in melanocytes, inhibiting the enzyme by an allostericmechanism. The recycling of 6BH4 is catalysed by the rate-limiting pterin-4a-carbinolaminedehydratase (PCD) via quinonoid dihydropterin (qBH2) and its reduction by dihydropteridinereductase (DHPR) in the presence of NADH. If 6BH4 is overproduced, as in vitiligo, then4a-hydroxy-BH4 is non-enzymatically converted to high levels of 7BH4, which in turn inhibitphenylalanine hydroxylase, yielding a compromised L-tyrosine supply 7BH4 and it was shown that molar concentrations of 7BH4 inhibit phenylalanine hydroxylase (PAH) thus preventing the turnover of L-phenylalanineto L-tyrosine resulting in a build up of L-phenylalanine in the epidermis (Davis et al. 1992). This build up has been indeed demonstrated in vivo by FTRaman Spectroscopy (Schallreuter et al. 1998). Only recently it has been discovered that H2O2 deactivates the rate limiting recycling enzyme pterin-4acarbinolamine dehydratase (PCD) because H2O2 alters directly the structureof this bifunctional protein (Schallreuter et al. 2001). The deactivation ofPCD by H2O2 as observed in vivo and in vitro could contribute to the immuneresponse considering that lymphocytes and dendritic cells do express PCDand produce H2O2 themselves via NADPH oxidase (Darr and Fridovich 1994, 376 Karin U. Schallreuter Marks et al. 1996 and Stark 1998). Consequently, the build up of H2O2 wouldbe autocatalytic. Furthermore, it should be noted that H2O2 rapidly oxidises6BH4 to 6-biopterin and this oxidation product has been shown to be cytotoxic to melanocytes with an LC50 = 10–7 M (Schallreuter et al. 1994c). Furtherinvestigation demonstrated the presence of pterin 6-carboxylic acid as the final oxidation product of 6-biopterin and other pterins. This photo-oxidationcoincides with the generation of H2O2 (Rokos et al. 2002). Hence, defectivepterin synthesis coupled to oxidative stress can directly influence melanocyte populations and integrity in vitiligo primarily due to the cytotoxicity of6-biopterin and other oxidised pterins. Only very recently it was demonstratedthat epidermal H2O2 travels to the vascular system and there it can influencethe cholinergic pathway via acetylcholine esterase (Schallreuter et al. 2004).It also has been shown that dihydropteridine reductase, the last step in 6BH4recycling, can be deactivated in peripheral blood cells by H2O2 in the mmolarrange (Hasse et al. 2004). VII. Catecholamines in VitiligoThe presence of increased levels of 6BH4 and low levels of L-tyrosine invitiligo provides ideal conditions for increased activity of tyrosine hydroxylase (TH), the key enzyme for catecholamine biosynthesis (Schallreuter et al.1995b). Both keratinocytes and melanocytes express TH isoform I, the mostactive of the four different isoforms of this enzyme (Schallreuter et al. 1995b,Marles et al. 2003). In this context it has been reported that patients with active vitiligo have elevated levels of noradrenaline in skin and plasma, as wellas high levels of catecholamine metabolites in their urine (Schallreuter et al.1994b, Morrone et al. 1992). Increased noradrenaline synthesis in the epidermis of these patients causes the induction of the catecholamine degradingenzymes monoamine oxidase A (MAO-A) and catecholamine-O-methyltransferase (COMT) (LePoole et al. 1994, Schallreuter et al. 1996a). MAO-Aproduces H2O2 as a reaction product from the oxidation of noradrenaline, andtherefore the increased expression of epidermal MAO-A yields severe oxidative stress (Schallreuter et al. 1996a). VIII. Calcium Homeostasis and Oxidative Stress in VitiligoThe influence of oxidative stress on calcium uptake/efflux has been knownfor a long time (Marks et al 1996). Earlier studies on the transport of isotopically labelled calcium with keratinocytes and melanocytes established fromthe depigmented epidermis of patients with vitiligo revealed a significantdecrease in the rates for calcium uptake in these cells (Schallreuter et al. 1988,Schallreuter et al. 1996b). Several investigators have shown that the extracellular concentration of calcium, which controls the kinetics for its uptake Vitiligo 377 and efflux, strongly influences melanogenesis in melanosomes. Recently ithas been confirmed that L-phenylalanine transport and its intracellular turnover to L-tyrosine is a calcium dependent process in normal human melanocytes (Schallreuter et al. 1999c). This essential amino acid is actively transportedin these cells via the well established L-phenylalanine/sodium/calcium ATP-aseantiporter system described previously for the active transport of neutral aminoacids (Schallreuter et al. 1999c). Since the majority of eumelanin is synthesised in melanocytes from the autocrine conversion of L-phenylalanine toL-tyrosine via PAH, then the perturbation of calcium homeostasis in thesecells from these patients could also play a crucial role in the loss of pigmentin vitiliginous melanocytes (Schallreuter et al. 1996b, Schallreuter et al. 1999c).In this context it is noteworthy that epidermal calcium homeostasis also relies on both the adrenergic and cholinergic signal transduction. Only recentlyit was shown that acetylcholinesterase, the degrading step for acetylcholineis also deactivated by H2O2 (Schallreuter et al. 2004). IX. Genetic and/or Environmental Factors in VitiligoThe application of FT-Raman spectroscopy for in vivo analysis of the depigmented epidermis indicates that all untreated patients contain higher thannormal levels of H2O2 by following the peak at 875 cm-1 (Schallreuter et al. 1999a).In addition, all patients have more total phenylalanine in their depigmentedskin at 1004 cm–1, measured also in vivo by the same method, compared totheir pigmented skin (Schallreuter et al. 1998). This defect in phenylalaninemetabolism has been recognised also in the systemic turnover of L-phenylalanine in this patient group (n>1000) after receiving an oral loading with thisessential amino acid (Schallreuter et al. 1998). Interestingly all patientsshowed a normal rate for the phenylalanine turnover compared to controls,but 40% of the patients tested, revealed pathological L-phe/L-tyr ratios similar to phenylketonurea heterozygotes (Schallreuter et al. 1998). In this context, it is interesting that approximately 35–40% of the patients have a positivefamily history for vitiligo, strongly suggesting a genetic predisposition forthis disease (Ortonne and Bose 1993). However, to date there is no evidencefor any mutation on the PAH gene in vitiligo. The defective recycling of 6BH4via pterin 4a-carbinolamine dehydratase (PCD) suggested the possibility ofa polymorphism in this gene (Schallreuter et al. 1994a, Schallreuter et al. 1994b),but recent studies have shown that PCD is directly deactivated by H2O2(Schallreuter et al. 2001). Examination of the sequence of the PCD gene revealed only wild type enzyme (Schallreuter et al. 2001). Another report onvitiligo suggested that this disease is caused by a mutation in GTP-cyclohydrolase I (GTP-CH-I), the rate limiting enzyme for 6BH4 synthesis (De la FuenteFernandez 1997), but this result could not be substantiated (Blau et al. 1996,Schallreuter and Blau 1997). An attempt to search for a possible mutation inthe regulatory protein GFRP revealed wild type sequence for the 6BH4 binding 378 Karin U. Schallreuter domain (KUS, unpublished results). Whether the polymorphism in the catalasegene of affected individuals can account for vitiligo needs to be substantiated (Casp et al. 2002). Only recently the involvement of chromosome 17 hasbeen invoked where special autoimmunity alleles are implicated (Spritz et al.2004). However, so far this finding was only shown in one family.Therefore a genetic analysis may be more feasible for those patients whohave both autoimmune disorders and vitiligo indicating a true subset of thedisease. In our hands the majority of the patients (> 4000) only have vitiligo. No Increased Risk for Skin Cancer in VitiligoIt is generally accepted that the cutaneous pigment protects against the development of skin cancers despite the sun protection factor (SPF) for this melanin is only ranging between 2–5. Since patients with vitiligo lack this protectivemechanism, it would be anticipated that affected individuals run a higherrisk for skin cancer. Surprisingly, these patients even with long standingvitiligo (>47 years duration) have no evidence for increased photodamage suchas actinic keratosis and solar elastosis as well as increased numbers of basalcell and squamous cell carcinoma (Calanchini–Postizzi and Frenk 1987, Schallreuter et al. 2002).The reason for this paradox response in vitiligo is still unknown. Recentlyan increased epidermal functioning p53 has been detected, but this increasedp53 is not associated with apoptosis in these patients (Schallreuter et al. 2003).In this context it should be noted that p53 can be induced by mmolar levels ofH2O2 (Vile GF 1997). Hence, this scenario could be valid in vitiligo. The question remains, whether p53 is induced as a direct protective mechanism inprevention of skin cancer in this disease which could be an interesting newconcept to explain the observed paucity of solar induced damage and skincancer. Further work is needed to gain more insight into these interestingobservations. Newer Treatment ConceptsBased on the evidence provided there is no doubt that epidermal generation/accumulation of H2O2 plays a central role in vitiligo.This concept is in agreement with the clinical observation where patientswith this disorder, regardless of the time of onset and duration of the disease,age, gender and skin phototype respond to a topically applied pseudocatalase (PC-KUS) with a loss of epidermal and systemic H2O2 accumulation concomitant with repigmentation (Schallreuter et al. 1999a; Schallreuter et al. 2001,Hasse et al. 2004; Schallreuter et al. 2004) (Figure 5). Vitiligo 379 Fig. 4. Epidermal oxidative stress in acute vitiligo. Toluidine blue staining. NB: The extensivevacuolation (V) is based on lipid peroxidative damage due to H2O2 (Tobin et al. 2000) Fig. 5. Extensive facial vitiligo in skin phototype VI (Fitzpatrick Classification). A. Beforetreatment. B. After treatment with low dose narrowband UVB activated pseudocatalase(PC-KUS) 380 Karin U. Schallreuter If vitiligo would fit the criteria of an autoimmune disease, one would expect that the treatment is more successful after the introduction of topical orsystemic immunosuppressive drugs. However, the published clinical resultsare rather disappointing. Even the use of systemic as well as local corticosteroids failed to control the disease in the majority of patients. Topical application of tacrolimus and pimecrolimus as recent local treatment modalities areeffective in the repigmentation of facial vitiligo but fail the management ofother body areas. Apart from pseudocatalase (PC-KUS) the most promisingtreatment at the present time seems to be the use of narrowband UVB (311nm)with increasing doses twice or 3 times per week at least over 1 year. The precise mechanism of action remains to be established (Westerhof et al. 1999,Hamzavi et al. 2004). SummaryWhat did we learn? Despite autoimmunity is still the favoured hypothesis forvitiligo, the evidence to date does not support that vitiligo belongs into thegroup of primary autoimmune diseases. The low frequency of vitiligo antibodies specific for melanocytes could most likely be caused by the influenceof H2O2 on the immune system as a secondary response. To date there is accumulating evidence that other autoimmune phenomena in association withvitiligo are a rather random event.In the light of epidermal and systemic H2O2 accumulation, it is tempting tospeculate that environmental (exogenous) or systemic (endogenous) triggerfactors could be the mechanisms for the ‘hit’ that increases H2O2 productionvia NADPH-oxidase in the microenvironment. This could tip the balance andcause the initial loss of constitutive pigmentation due to the generation ofhydroxyl radicals (OH•) from H2O2 via the UV-catalysed Haber-Weiss reaction(Darr and Fridovich 1994). However, in the subsequent process of the disease,the origin of H2O2 derives from various sources, which could well foster the‘run’ mechanism, where H2O2 activates T-cell proliferation with consequentactivation of T-cell clones (Rutault et al. 1999, LePoole et al. 2004). A cellularinfiltrate in the perilesional skin in active vitiligo can contribute to a temporaryoxygen burst yielding H2O2. However, vacuolation/lipid peroxidation, expected to be exacerbated by the oxygen burst, is not different in the perilesionalskin compared to lesional skin and the normally pigmented epidermis. Allcompartments can have the same extent of vacuolation (Tobin et al. 2000) (Figure 4). Moreover, many of the described mechanisms are perturbed and areobserved in both the lesional and non lesional skin of patients with vitiligoindicating that the entire skin participates in the depigmentation process.Despite that our knowledge on vitiligo has improved, there is still no complete concept in understanding of those factors underlying the initiation ofthis disease. Future work is needed to get a better picture which allows the Vitiligo 381 development of a more effective treatment or even cure of this ancient disfiguring disease. ReferencesAronoff S (1965) Catalase: kinetics of photo-oxidation. Science 150: 72–73Austin LM, Boissy RE (1995) Mammalian tyrosinase related protein-1 is recognised byautoantibodies from vitiliginous Smyth chickens. Am J Pathol 146:1529–1541Baharav E, Merimski O, Shoenfeld Y, Zigelman R, Gilbrud B, Yecheskel G, Youinou P,Fishman P (1996) Tyrosinase as an autoantigen in patients with vitiligo. Clin Exp Immunol105: 84–88Beazley WD, Gaze DC, Panske A, Panzig E, Schallreuter KU (1999) Serum selenium levelsand glutathione peroxidase activities in vitiligo. Br J Dermatol 141: 301–303Bhawan J, Bhutani LK (1983) Keratinocyte damage in vitiligo. J Cutaneous Path 10: 207–212Blau N, Barnes I, Dhondt JL (1996) International database of tetrahydrobiopterin deficiences.J Inherit Metab Dis 19: 8–14Boissy R, Liu YY, Medrano EE, Nordlund JJ (1991) Structural aberration of the roughendoplasmic reticulum and melanosome compartmentalisation in long term cultures ofmelanocytes from vitiligo patients. J Invest Dermatol 97: 395–404Boissy RE, Sakai C, Zhao H, Kobayashi T, Hearing VJ (1998) Human tyrosinase related protein-1 (TRP-1). Exp Dermatol 7: 198–204Boissy RE, Manga P (2004) On the etiology of contact/occupational vitiligo. Pigment Cell Res17: 208–14Calanchini-Postizzi E, Frenk E (1987) Long-term actinic damage in sun-exposed vitiligo andnormally pigmented skin. Dermatologica 174: 266–71Casp CB, She JX, McCormack WT (2002) Genetic association of the catalase gene (CAT) withvitiligo susceptibility. Pigment Cell Res 15: 62–6Cui J, R Harning, M Henn, J-C Bystryn (1992) Identification of pigment cells antigens definedby vitiligo antibodies. J Invest Dermatol 98: 162–165Cui J, Arita Y, Bystryn J-C (1993) Cytolytic antibodies to melanocytes in vitiligo. J InvestDermatol 100: 812–815Cui J, Chen D, Misfeldt ML, Swinfard RW, Bystryn J-C (1995) Antimelanoma antibodies inswine with spontaneously regressing melanoma. Pigment Cell Res 8: 60–63Darr D, Fridovich I (1994) Free radicals in cutaneous biology. J Invest Dermatol 102: 671–675Davis MD, Ribeiro P, Tipper J, Kaufman S (1992) 7-Tetrahydrobiopterin, a naturally occurring analogue of tetrahydrobiopterin, is a cofactor for and a potential inhibitor of the aromatic amino acid hydrolases. Proc Natl Acad Sci USA 89: 10108–10113De la Fuente-Fernandez R (1997) Mutations in GTP-cyclohydrolase I gene and vitiligo. Lancet 350: 640Diehle J (2004) Med Thesis, University of Hamburg, GermanyGalbraith GM, Miller D, Emerson DL (1988) Western blot analysis of serum antibody reactivity with human melanoma cell antigens in alopecia areata and vitiligo. Clin ImmunolImmunopathol 48: 317–324Grimes PE, Sevall JS, Vojdani A (1996) Cytomegalovirus DNA identified in skin biopsy specimens of patients with vitiligo. J Am Acad Dermatol 1996; 35:21–26Grimes PE, Elkadi T, Sanders, J (1999) Epstein-Barr virus infection in patients with vitiligo(abstr). J Invest Dermatol 112: 604Halaban R, Moellmann GE (1990) Murine and human b-locus pigmentation genes encode aglycoprotein (gp75) with catalase activity. Proc Nat Acad Sci USA 1990 87:4809–4813Hamzavi I, Jain H, Mclean D, Shapiro J, Zeng H, Lui H (2004) Parametric modelling ofnarrowband UVB phototherapy for vitiligo using a novel quantitative tool: the VitiligoArea Scoring Index. Arch Dermatol 140: 677–83Harning R, Cui J, Bystryn J-C (1991) Relation between the incidence and level of pigment cellantibodies and disease activity in vitiligo. J Invest Dermatol 97: 1078–1080 382 Karin U. Schallreuter Hasse S, Gibbons NC, Rokos H, Marles LK, Schallreuter KU (2004) Perturbed 6-tetrahydrobiopterin recycling via decreased dihydropteridine reductase in vitiligo: more evidence forH2O2 stress. J Invest Dermatol 122: 307–313Herrath MG, Oldstone MB (1996) Virus induced autoimmune disease. Curr Opin Immunol 8:878–885Jimbow K, Chen H, Park JS, Thomas P (2001) Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase related protein in vitiligo. Br J Dermatol144: 55–65Kemp EH, Gawkrodger DJ, MacNeil S, Watson PF, Weetman AP (1997a) Detection oftyrosinase autoantibodies in vitiligo patients using 35S-labelled recombinant humantyrosinase in a radioimmunoassay. J Invest Dermatol 109: 69–73Kemp EH, Gawkrodger DJ, Watson PF, Weetman AP (1997b) Immunoprecipitation of melanogenic enzyme autoantigens with vitiligo sera: evidence for cross-reactive autoantibodies to tyrosinase and tyrosinase-related protein-2 (TRP-2). Clin Exp Immunol 109:495–500Kemp EH, Waterman, Gawkrodger DJ, Watson PF, Weetman AP (1998) Autoantibodies totyrosinase-related protein-1 (TRP-1) detected in the sera of vitiligo patients using a quantitative radiobinding assay. Br J Dermatol 139: 798–805Kemp EH, Waterman EA, Gawkrodger DJ, Watson PF, Weetman AP (1999) Identification ofepitopes on tyrosinase which are recognised by autoantibodies from patients with vitiligo.J Invest Dermatol 1

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Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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43

13: 267–271Kwon BS (1993) Pigmentation genes: the tyrosinase gene family and the pmel17 gene family.J Invest Dermatol 100: 134S-140SLaihia JK, Jansen CT (1997) Upregulation of human epidermal Langerhans cell B7–1 andB7–2 costimulatory molecules in vivo by solar stimulating irradiation. Eur J Immunol 27:984–989Laskin JD, Piccinini LA (1986) Tyrosinase isozyme heterogeneity in differentiating B16/C3melanoma. J Biol Chem 261: 16626–16635LePoole IC, Das PK, van den Wijngaard RM, Bos JD, Westerhof W (1993a) Review of theetiopathomechanism of vitiligo: A convergence theory. Exp Dermatol 2: 146–153LePoole IC, van dan Wijngaard RM, Westerhof W, Dutrieux RP, Das PK (1993b) Presence orabsence of melanocytes in vitiligo lesions: an immunohistochemical investigation. J Invest Dermatol 100: 816–822LePoole C, Wijngaard Van den, Smit NPM, Oosting J, Westerhof W, Pavel S (1994) Catechol-O-methyl transferase in vitiligo. Arch Dermatol Res 286: 81–86Le Poole IC, Wankowicz-Kalinska A, van der Wijngaard RMJGJ, Nickoloff BJ, Das PK (2004)Autoimmune aspects of depigmentation in vitiligo. J Invest Dermatol Symp Proc 9: 68–72Manga P, Sato K, Ye L, Beerman F, Lamoreux ML, Orlow SJ (2000). Mutational analysis of themodulation of tyrosinase by tyrosinase related proteins 1 and 2 in vitro. J Pigment Cell Res13: 364–374Maresca V, Roccella M, Roccella F, Camera E, Del Porto G, Passi S, Grammatico P, Picardo M(1997) Increased sensitivity to peroxidative agents as a possible pathogenic factor ofmelanocyte damage in vitiligo. J Invest Dermatol 109: 310–313Marks DB, Marks AD, Smith CM (1996) Oxygen metabolism and oxygen toxicity. In: BasicMedical Biochemistry: A Clinical Approach. 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Biochim Biophys Acta 1217: 317–321 14 Alopecia areataPia Freyschmidt-Paul, Kevin McElwee and Rolf Hoffmann Classification and Clinical AppearanceAlopecia areata (AA) is the symptomless loss of hair in either small circumscribed patches (Fig. 1), which may remain discrete or may expand into totalloss of all scalp (Fig. 2) and even body hairs. AA is a common human diseasewith a lifetime risk of 1.7% in the general population. It is characterized by areversible patchy hair loss most commonly involving the scalp although otherregions of the head, including eyelashes and beard, may also be affected.The typical patient with AA notes the sudden appearance of circular patch ofhair loss. Areas of activity in the lesion may be indicated by the presence of“exclamation mark” hairs (Fig. 3) which are usually 2–4mm long and mayhave a dark expanded tip and a depigmented root. The disease may sometimes lead to complete scalp baldness (Alopecia areata totalis) or even totalbody hair loss (Alopecia areata universalis). AA of the neck is called the ophiasis Fig. 1. Patchy alopecia areata: two small round bald patches in a child 386 Pia Freyschmidt-Paul et al. Fig. 2. Alopecia areata totalis. In this example the whole scalp is affected type. AA may be observed at any age with no sex predominance. AA is morelikely to occur in adolescents. AA is not life-threatening but rather psychologically and socially disturbing.The course of AA is unpredictable and typically characterized by phasesof acute hair loss followed by spontaneous hair regrowth and waxing and waning of the lesions. However, in severe forms hair loss can persist for manyyears. Very often AA shows a mild clinical course with only few small baldpatches, and hair regrowth after some weeks or months. However, the severe forms are usually chronic. The prognosis for AA is defined by the age atdisease onset, duration, nails signs, the extent of hair loss and the presence Alopecia areata: Classification and Appearance 387 Fig. 3. Exclamation mark hairs at advancing edge of patch of alopecia areata of atopic dermatitis. This means that a patient with AA universalis for manyyears, with a first episode of AA during childhood, associated nail changesand atopic dermatitis has only a small chance to experience hair regrowth.Except the nails, which may show typical signs of AA such as small pits,red spotted lunulae or verticular ridging (Fig.4), no other organs are affectedby this disease. Sometimes small nail pits are the first signs of a developingAA and hair loss may occur later. Only exeptionally nails may fall off (Onychomadesis) due to a severe nail AA. Sometimes all nails are affected. Nailinvolvement is usually associated with wide spread AA. There are some publications which describe the association of AA with other autoimmune diseasessuch as Vitiligo or Type 1 diabetes mellitus. However, there is considerabledebate about the practical value of those observations. In our view only Hashimotos thyroiditis tends to be more common in AA.As hair loss is sudden, hair regrowth occurs without any indicators. Theinitial hair regrowth after an episode of AA is often white due to a delay inrepigmentation of hairs. Interestingly, the last hairs to be affected by AA arewhite hairs, explaining how scalp hair can appear to become white overnight. DiagnosisThe clinical history of abrupt onset of patchy hair loss, the lack of infection,black dots, exclamation mark hairs, are all suggestive of the diagnosis of AAand in most cases the diagnosis of AA can be made clinically. There is noblood test to confirm or to rule out the diagnosis. In rare cases differential diagnosis such as chronic discoid lupus erythematosus, Lichen planopilaris, syphilis, traction alopecia, metastasis to the scalp, mycosis fungoides or alopecia 388 Pia Freyschmidt-Paul et al. Fig. 4. Mild nail dystrophy in alopecia areata with pitting and ridging mucinosa must be taken into consideration. Especially in AA of the diffuse typeit might be difficult to make the diagnosis. Then a scalp biopsy is indicated. HistopathologyHistopathological features of AA include peri- and intrafollicular lymphocytic infiltrates involving only anagen hair follicles with subsequent miniaturization of these follicles. The lymphocytic infiltrate is located around the hairbulb with some lymphocytes invading the hair follicle (Fig. 5). Destructionof hair follicles or scarring usually does not occur in AA and therefore hairregrowth is possible at any timepoint of the disease, either spontaneously or Alopecia areata: Classification and Appearance 389 Fig. 5. Histology of alopecia areata. Lymphocytes are clustered around the hair bulb andextend into the dermal papilla (LM x 100) due to a successful treatment. The process usually involves terminal hairs butcan affect vellus hairs as well. Molecular Genetics –the Present KnowledgeAA has been proposed to be an autoimmune disease based on several indirect observations in humans and animal models of the disease (McElwee et al. 390 Pia Freyschmidt-Paul et al. 1999c). Genetic influence has been clearly demonstrated in most other autoimmune diseases and one would expect that AA is no exception. AA is clearlya complex disease, it does not segregate according to the rules of Mendelianinheritance (Van der Steen et al. 1992a; Shellow et al. 1992; Colombe et al. 1995;Sharma et al. 1996a). As with other autoimmune diseases, AA is most likely apolygenic disorder where susceptibility is dictated by several major genes andthe phenotype may be modified by numerous minor genes. Rodent ModelsIsolated examples of AA have been identified in several species. However,the limited characterization or availability of these examples restricts theirusefulness in any genetic research for AA (McElwee et al. 1998b). Two rodent models have been developed and characterized for use in AA research,the Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse (Michieet al. 1991; Sundberg et al. 1994). Both models are inbred strains. Despitetheir inbred nature, rodents may have a wide variety of hair loss presentations from isolated patches, or diffuse AA, to near universal hair loss. AA inboth rodent models has been shown to be an autosomal polygenic trait withpartial phenotype penetrance by analysis of breeding programs.The DEBR, originally a hybrid between BDIX and Wistar rats, has beenintercrossed for over 35 generations. Two separate inbred DEBR sub-strainsexist, one black hooded and the other brown, but with similar AA phenotypeproperties. Hair loss is associated with a primarily CD4+ and CD8+ lymphocyte cell infiltrate of anagen stage hair follicles and production of hair folliclespecific antibodies (Zhang and Oliver 1994, McElwee et al. 1996). Spontaneous expression of AA develops in 42% of individuals with onset from 7 monthsof age in both males and females. Hair loss typically first develops in symmetrical bald patches on the flanks. Multiple patches may develop to affectthe head, dorsal and ventral skin with approximately 15% of affected individuals reaching a near universal hair loss state. DEBR have been cross bredwith PVG/OlaHsd rats yielding 21% affected F1 offspring (Oliver, personalcommunication) suggesting PVG/OlaHsd rats contain few AA susceptibilitygenes. PVG/OlaHsd rats may be one of several strains suitable for use in anintercross or backcross breeding strategy to identify AA susceptibility andseverity modifying genes by linkage disequilibrium.C3H/HeJ mice have existed as a unique inbred strain at the Jackson Laboratory since 1947, but onset of the AA phenotype was first observed in several individuals of a C3H/HeJ mouse colony in 1993. The mouse breedingpattern permitted tracing the genetic history of the affected mice to a singlebreeding pair at generation F198 (Sundberg et al. 1994), suggesting a geneticmodification of the strain in one parent. The frequency of spontaneous AAexpression in aged mice, up to 18 months old, increased to approximately 20% Alopecia areata: Classification and Appearance 391 in 3–4 generations for over 300 mice evaluated (Sundberg et al. 1994). Bothmales and females are affected with initially ventral hair loss typically developing in females from 6 months and in males from 10 months of age. Hairloss may progress to the dorsal surface and reach near universal loss in 10%of affected individuals. Histopathology shows all affected anagen stage hairfollicles to be affected by non-scaring focal inflammation of primarily CD4++and CD8 lymphocytes and hair follicle specific autoantibodies are present ata high titer (Tobin et al. 1997; Freyschmidt-Paul et al. 1999).Recent studies have demonstrated that all adult C3H/HeJ mice are susceptible to AA. Grafting skin from spontaneous AA affected mice to normalhaired C3H/HeJ mice consistently promotes onset of AA 8–10 weeks aftergrafting (McElwee et al. 1998a). Skin grafts from AA affected mice to the histocompatible C3H/OuJ and C3HeB/FeJ inbred strains promotes AA onset witha similar phenotype and pathology, but in only 40% of graft recipients (McElweeet al. 1998a). Crosses between C3H/HeJ mice with AA and mice from theclosely related strain with no history of age associated alopecia, yielded F1and subsequent generation mice with an AA expression frequency of 10–12%(Sundberg et al. 1994). The AA induction technique suggests that while inbred C3H/HeJ mice may all be genetically susceptible, the AA phenotypemust be activated. It is possible that the environment provides a trigger forinitial disease onset. The apparent reduced susceptibility of the C3H/OuJand C3HeB/FeJ strains to AA suggest that these strains carry fewer AA susceptibility genes as compared to the C3H/HeJ strain. The segregation pattern of phenotypes suggests that AA in laboratory mice is under the controlof one or more dominant gene alleles.A preliminary backcross study between C3H/HeJ mice and C57BL6/J micesuggested a tentative locus for susceptibility on mouse Chromosome 6 (37cM,1 recombinant/24 alleles with D6MIT230 is 4.2 cM, p = 3×10–6, 95% confidenceinterval of the distance is 0.1–21.1 cM) (McElwee et al. 1999a). Within thisregion are numerous immunoglobulin genes, a gene for cytokine TGFa, aswell as genes for the lymphocyte surface markers CD8 and Ly36. The mouselocus corresponds to human chromosome region 2p13. Thus, this region maybe worthy of close attention within a genome wide screen. C3H/HeJ micecross bred with C57/BL6J mice yield 7% of affected F1 generation mice (10%affected females, 2% affected males) and intercross studies with C57BL6/Jmice are in progress with up to 13 candidate gene loci under investigationsupporting the hypothesis that AA is a polygenic disease (Sundberg et al. 2003). Human EpidemiologyThere is a higher incidence of AA in genetically related individuals. This suggests that at least some people are genetically predisposed to develop AA.The triggers for the onset of AA may be environmental, but the resistance of 392 Pia Freyschmidt-Paul et al. the AA lesion to treatment, its persistence and regression, and its extent overthe body may be influenced by the presence and interaction of multiple genes.Several studies suggest that AA has a genetic basis (Van der Steen et al. 1992a;Colombe et al. 1995). AA with similar times of onset or similar hair loss patterns has been reported in monozygotic twins (Hendren 1949; Weidman etal. 1956; Bonjean et al. 1968; Stankler 1979; Cole and Herzlinger 1984; Scerriand Pace 1992; Alsaleh et al. 1995). Families with several generations of AAaffected individuals also suggest AA may be a genetically determined disease (Shelton and Hollander 1942; Goldshtein and Chipizhenko 1978; Hordinskyet al. 1984; Valsecchi et al. 1985; Van der Steen et al. 1992a; Sharma et al.1996a; Sharma et al. 1996b).Epidemiological studies provide basic evidence for AA susceptibilitygenes. Numerous studies suggest AA may be more frequently expressed ingenetically related individuals. Typically, 10 to 20% of patients with AA Table 1. Incidence of alopecia areata in reported epidemiological studiesPercentage withfamily history Geographic location Source 3% UK Barber 1921 20% UK Brown 1929 20% France Sabouraud 1929 19% UK Anderson 1950 10% USA Muller and Winkelmann 1963 3.4% Italy Olivetti and Bubola 1965 6.3% Portugal Bastos Araujo

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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44

and Poiares Baptista 1967 25% UK Cunliffe et al. 1969 17% Sweden Gip et al. 1969 27% USA Sauder et al. 1980 24% UK Friedmann 1981 11% Belgium De Weert et al. 1984 6.6% Germany Lutz and Bauer 1988 18% Netherlands De Waard 1989 11.4% Germany Gollick and Orfanos 1990 16% Germany Van der Steen et al. 1992 42% USA Shellow et al. 1992 11.5% Korea Ro Bi 1995 9% India Sharma et al. 1996a 12.4%* India Sharma et al. 1996b *Children aged 16 or younger Alopecia areata: Classification and Appearance 393 indicate at least one other affected family member (Table 1). In contrast, thelifetime risk of AA expression in the general population has been suggestedto be 1.7% (Safavi et al. 1995). Familial incidence may be significantly higherthan reported in epidemiological studies as the marked psycho-social consequences of hair loss inhibit some individuals from seeking diagnosis. In addition, some may not be aware of their hair loss if it is limited or develops in anarea not immediately visible to the individual.A strong association has been observed between AA and trisomy 21(Down’s syndrome). In 1000 patients and 1000 control subjects, Du Vivier andMunro observed 60 cases of trisomy 21 individuals with AA versus 1 control(Du Vivier and Munro 1975). Carter and Jegasothy identified 19 cases of AAin 214 trisomy 21 affected patients and the statistical relationship is furthersupported in other studies (Wunderlich and Braun-Falco 1965; Carter andJegasothy 1976). The genetic mutation for autoimmune polyendocrinopathysyndrome type 1 (AIRE, autoimmune regulator gene) (Finnish-GermanAPECED Consortium 1997) is also associated with a 29 to 37% prevalence ofAA (Betterle et al. 1998). These studies suggest that candidate gene loci forAA susceptibility may be present on human chromosome 21.Associations of AA with other autoimmune diseases have also been reported. Between 7% and 27% of AA affected patients may also have a thyroiddisease, including goiter presence, myxedema and Hashimoto’s thyroiditis(Cunliffe et al. 1969; Milgraum et al. 1987; Shellow et al. 1992; Puavilai et al.1994). Co-expression of vitiligo and AA has also been reported at between4% and 9% (Muller and Winkelmann 1963; Main et al. 1975). However, thestatistical significance of these disease associations when compared to appropriate control populations has been disputed elsewhere (Salamon et al. 1971;Gollick and Orfanos 1990; Schallreuter et al. 1994). Numerous case reportsdetail concordant presence of AA with other autoimmune diseases, such asdiabetes and myasthenia gravis, although the statistical significance is unknown (McElwee et al. 1998b). HLA GenesHuman leukocyte antigen (HLA) genes on human chromosome 6 code forthe major histocompatibility complex (MHC) proteins that are important inpresentation of antigens and self recognition by immune cells. MHC class Iantigens comprise the HLA-B, HLA-C and HLA-A loci in this order. MHCclass II is coded by genes in the HLA-D region that is subdivided into geneclusters HLA-DP, HLA-DQ, and HLA-DR (Vogel and Motulsky 1997). MHC+class I antigens are expressed on almost all nucleated cells. CD8 lymphocyteshave the capacity to recognize cellular antigens presented in association withMHC class I via their T cell receptors. In contrast, MHC class II antigens arenormally expressed on antigen presenting cells (APCs), such as macrophages 394 Pia Freyschmidt-Paul et al. and Langerhans’ cells, and expression may be induced on other nucleatedcells during inflammatory processes such as AA (Messenger and Bleehen1985; Bröcker et al. 1987). CD4+ lymphocytes may recognize antigen plus MHCclass II complexes on APCs. Different MHC proteins may have superior presenting properties for particular antigens compared to other MHC complexesand consequently some antigen plus MHC complexes will be more effective intheir activation of lymphocytes than others. In part, this may determine theability of lymphocytes to respond to the hair follicle antigen(s) targeted in AA andmay define how potent an immune response against a particular antigen will be.Genetic research into other autoimmune diseases has shown HLA encoding alleles to segregate with specific disease phenotypes. However, inconsistent results have been found with analysis of HLA class I haplotypes of theA and B series and AA. Some studies report statistically significant associations, but other studies found no HLA class I association (Kuntz et al. 1977;Zlotogorski et al. 1990). HLA-A2, B40 and Aw32, B18 have each been reportedas associated with AA (Hordinsky et al. 1984; Valsecchi et al. 1985). Associations between HLA-B12 in Finnish patients, HLA-B18 in Israelis, B13 and B27in Russians have also been suggested (Kianto et al. 1977; Hacham-Zadeh etal. 1981; Averbakh and Pospelov 1986).Genetic analysis studies in AA have primarily focused on the HLA-Dgenes (MHC class II encoding) as the most likely region for genes that regulate susceptibility, severity of, or resistance to disease (Duvic et al. 1991). Consistent associations have been observed between class II haplotypes and AAincluding DR4 (Friedman 1985; Frentz et al. 1986; Orecchia et al. 1987; Duvicet al. 1991; de Andrade et al. 1999), DR5 (Friedman 1985; Frentz et al. 1986;Orecchia et al. 1987), DR6 (de Andrade et al. 1999), DR7 (Averbakh andPospelov 1986) and broad antigen DQ3 (Welsh et al. 1994; Colombe et al. 1995;Colombe et al. 1999). More recent research has shown allele DRB1*1104(DR11) to be present with significant increased expression in patients withAA (Colombe et al. 1995; Colombe et al. 1999) and this was confirmed in otherstudies (Morling et al. 1991; Welsh et al. 1994; Duvic et al. 1995). AlleleDRB1*0401 (DR4) was strongly associated with AA totalis and universalis subgroups (Colombe et al. 1999). DQB1*0301 (DQ7 by serology) was also significantly expressed only in association with AA totalis and universalis (Colombeet al. 1995; Duvic et al. 1995; Colombe et al. 1999). Other studies implicate otherDQB1 alleles, DQB1*302, DQB1*601, and DQB1*603, in AA (de Andrade et al.1999). The current consensus is that AA in humans has a genetic basis, but is notalways in a familial aggregation (Van der Steen et al 1992; Colombe et al. 1995).It has been suggested that the HLA gene products, the MHC antigens,could be important for the presentation of an unknown AA antigen. Aberrant expression of MHC proteins within AA affected hair follicles is frequentlyfound, but the question of its true significance remains (Messenger and Bleehen1985; Bröcker et al. 1987). There are many more alleles that code for otherfactors within, and outside of, the immune system that may be vital in the development of AA. Alopecia areata: Classification and Appearance 395 Non HLA GenesThe HLA gene region is likely to be only one of several gene loci involved inAA, but limited research has been conducted in other areas of the genome.One investigation has shown an association between AA and allele 2 polymorphism for the IL-1rn gene on human chromosome 2 that codes for the IL-1receptor antagonist (Tarlow et al. 1994). Results indicated allele 2 was present in 41% of controls versus 44% in individuals with patchy AA, 66% of thosewith alopecia totalis and 77% of alopecia universalis affected individuals(Tarlow et al. 1994). Allele 2 is known to influence IL-1b production. Galbraithet al. identified the IL-1b-1,2 genotype as significantly increased in frequencyfor individuals with extensive, but not patchy, AA further suggesting that thesevere form of disease may be associated with increased IL-1b production(Galbraith et al. 1999).Genes for immunoglobulin heavy (Gm) and light (Km) chain genotypeson human chromosome 14 have also been implicated in AA susceptibility(Galbraith et al. 1984; Galbraith and Pandey 1989) with the suggestion thatIL-1b (IL-1b -1,2) and light chain (KM-1,3) genotypes may interact to increaseAA susceptibility (Galbraith et al. 1999). TNFa gene polymorphisms, or adjacent genes in the HLA region may also influence AA susceptibility (Galbraithand Pandey 1995; Cork et al. 1996). Involvement of all these gene loci, assusceptibility or severity modifying genes, is consistent with an autoimmunepathogenesis of AA. ConclusionsRodent model research has shown that AA is an immune mediated diseaseand strongly suggests that the mechanism is autoimmune in nature (McElweeet al. 1999c). It is probable that AA susceptibility and severity modifyinggenes will primarily be involved in the immune system, but other susceptibility genes may control hair follicle function. From observation in humansand animal models, AA can be described as an polygenic disease with a variablespectrum of severity. While previous research studies have understandablyfocused on the HLA region and identification of marker genes segregatingwith the AA phenotype, there is a clear need for genome wide analysis to define further candidate susceptibility, severity modifying, and possibly resistance gene loci. Human population analysis suggests potential gene loci maybe located on chromosomes 2, 6, 14, and 21 (Du Vivier and Mundo 1975;Colombe et al. 1995; Duvic et al. 1995; Galbraith et al. 1999). Careful categorization of DNA samples based on phenotypic presentation of hair loss in theindividual will be important for defining sub-categories of AA. It might be possible to define specific alleles with association to particular AA phenotypessuch as patchy AA, AA totalis, or AA universalis. 396 Pia Freyschmidt-Paul et al. TherapyVarious methods to treat AA have been described, but for many of them onlyanecdotal reports exist and the alleged treatment success might be attributedto spontaneous remission. Because of the high rate of spontaneous hairregrowth in AA, the only treatments that can be regarded as evidence-basedare those proven to be effective either after exclusion of spontaneous remission by treating every patient on one half of the scalp only or in a doubleblind, placebo controlled study including a very large number of patients.Furthermore, studies evaluating treatments for AA should preferably includepatients with AA totalis, AA universalis and extensive patchy AA (> 25%scalp hair loss) persisting longer than 3 months, because these patients havea worse prognosis than patients with limited patchy AA. These patients arealso the ones who are most in need of an effective treatment. Any treatmenthas to be suitable for long-term therapy, because AA is a disease that canpersist for many years or even life. Hence, all therapeutic approaches showing severe side-effects are inappropriate for AA in the long run. Immunosuppressive TreatmentsCorticosteroidsTopical, intralesional, and systemic corticosteroids have been used for thetreatment of AA with different rates of success and side effects. Topical CorticosteroidsTopical treatment of AA with corticosteroid creams, ointments or lotions isfrequently used. However, only two placebo-controlled studies reported atreatment response (Pascher et al. 1970; Leyden and Kligman 1972), but bothstudies do not fulfill the criteria for evidence based treatment of AA (40% ofdrop outs in the first study, patients with only limited AA in the second study).Furthermore, both studies were performed in the 1970s and they have notbeen confirmed by others over the last 30 years (Weitgasser 1968; Verbov1973; Lehnert 1974; Montes 1977). Only one placebo-controlled study withan appropriate number of patients has been performed to date, but the rateof treatment success was not statistically significant (Charuwichitatrana et al.2000).The failure of topical corticosteroids is most likely due to the insufficientpenetration of topically applied drugs dissolved in ointments, creams or lotions to the hair bulb. Improved penetration by occlusive treatment has beentried without success (Lehnert 1974) or with a response rate of only 17,8% Alopecia areata: Therapy 397 (Tosti et al. 2003). Considering the lack of treatment response and the sideeffects of topically applied corticosteroids, we conclude that topical corticosteroids are not an effective method of treating AA. Intralesional CorticosteroidsIntralesional injections of corticosteroid crystal suspensions, primarily triamcinolone acetonide, have been used for the treatment of AA for more than 40years (Kalkoff and Macher 1958). Several studies reported hair regrowth atthe site of injection in the majority of cases (Kalkoff and Macher 1958; Orentreich et al. 1960; Porter and Burton 1971; Fülöp and Vajda 1971; Abell andMunro 1973; Frentz 1977). Most of these studies tried to exclude spontaneoushair regrowth by comparing the injected sites of the scalp with non-injectedareas, especially in alopecia totalis. However, in practice it is impossible totreat the whole scalp by intralesional injections of corticosteroids and so thistreatment is only indicated in patchy AA with longstanding bald areas. Apartfrom the sometimes painful procedure of injection, permanent skin atrophycan occur after injection. Taken together, intralesional injection of corticosteroids is a reasonable treatment in exceptional, selected cases of longstanding small patches of AA, but has potentially significant side effects. Systemic CorticosteroidsAA has been treated with systemic corticosteroids since 1952 (Dillaha andRothman 1952). Whereas initially corticosteroids were applied orally daily orevery other day for several months, this approach is obsolete today. The dosesthat are required to maintain hair regrowth in AA are between 30 and 150mg prednisolone daily, giving rise to unacceptable side effects such as hypertension, diabetes, immunosuppression, osteoporosis and susceptibility tothrombosis.Since 1975 several authors have performed pulsed administration of corticosteroids in single doses, given once monthly in order to reduce the sideeffects of corticosteroids to an acceptable level, but all studies which notedhair regrowth, were uncontrolled and the majority of patients had patchy AA(Perriard-Wolfensberger et al. 1993; Sharma 1996; Friedli et al. 1998; Sharmaand Muralidhar 1998; Seiter et al. 2001). Moreover, other studies reported atreatment failure after corticosteroid pulse therapy (Burton and Shuster 1975;Schulz et al. 1996). Controlled studies should be conducted to prove the efficacy and long-term value of this treatment. In particular, the efficacy in interrupting acute phases of rapid hair loss by pulsed administration of oralcorticosteroids should be investigated. According to the data currently available, pulsed administration of corticosteroids for AA cannot be recommended. 398 Pia Freyschmidt-Paul et al. PUVASeveral studies have been performed on the treatment of AA with PUVA using either oral application of 8-methoxypsoralen (8-MOP) with ultraviolet Aradiation (UVA) of the scalp or the whole body, or topical application of 8-MOPand UVA radiation on the scalp, including one study with topical applicationof psoralen via the PUVA-turban (Larkö and Swanbeck 1983; Claudy andGagnaire 1983; Lassus et al. 1984; Mitchell and Douglass 1985; Healy andRogers 1993; Taylor and Hawk 1995; Behrens-Williams et al. 2001). Some investigations seemed to show good results (Claudy and Gagnaire 1983; Lassuset al. 1984; Healy and Rogers 1993; Taylor and Hawk 1995; Behrens-Williamset al. 2001, Whitmont and Cooper 2003), but there were no controls in any ofthe studies. Moreover, there were a high number of AA recurrences in mostof the studies (between 30% and 50% of successfully treated patients) afterinitial hair regrowth that strongly decreases the efficacy of PUVA treatmentfor AA (Claudy and Gagnaire 1983; Lassus et al. 1984; Healy and Rogers 1993;Taylor and Hawk 1995). This high number of relapses is most likely due tothe fact that regrown hair inhibits the UVA light from reaching the skin.Technical improvement such as a comb emitting UVA light have been tried,but so far no results have been reported. Unfortunately, a continuous hairregrowth after the initial response has to be actively maintained for severalyears in most cases of AA. With regard to the increased risk of skin malignancies after long-term PUVA therapy, PUVA therapy cannot be recommendedfor AA even if technical improvement like a UVA-comb should ultimatelyprove to be effective. Immunomodulatory TreatmentsDiphenylcyclopropenone and Squaric Acid DibutylesterAA has been treated with contact sensitizers for more than 25 years. Dinitrochlorobenzene (DNCB) was the first sensitizer that was used for the treatment of AA (Happle and Echternacht 1977), but because it has been shownto be mutagenic in the Ames test, it can no longer be used (Happle 1979, 1985).Today diphenylcyclopropenone (DCP) or squaric acid dibutylester (SADBE),that are not mutagenic in the Ames test, are widely used in European statesand in Canada. TreatmentTreatment with contact sensitizers is preceded by sensitization of the patientwith 2% DCP solution on a small area of the scalp. Two weeks later, treatment is initiated by application of a 0.001% DCP solution, followed by weekly Alopecia areata: Therapy 399 application of increasing concentrations of DCP until a mild eczematous reaction is obtained. In this way, an appropriate eliciting concentration of DCPfor each patient is identified. This concentration has to be applied once aweek to induce a mild eczematous reaction that is characterized by itchingand erythema, without blistering or oozing. SADBE is used in those patientswho become tolerant to DCP. It is applied in the same way and shows a similar rate of response.Initial hair regrowth is usually visible after 8–12 weeks. Treatment has tobe continued once weekly until complete hair regrowth is obtained. Treatment intervals are then decreased and eventually treatment may be discontinued. However, if a relapse occurs after discontinuation of therapy, treatmentcan be restarted immediately to stop further progression of AA and inducerenewed hair growth. Treatment should initially always be applied on onehalf of the scalp and the other side left untreated to exclude a spontaneoushair regrowth coincidental to treatment initiation. Treatment is continued onboth sides only after the treated side has shown a response in the form of betterhair growth on the treated side (Fig. 1). Side EffectsA mild eczematous reaction and enlargement of retroauricular lymph nodesare desired reactions and inherent to treatment. They are usually well tolerated if the patients are informed that these reactions are desirable for the therapeutic effect. Undesired side effects are noted in 2–5% of patients (Hoffmannand Happle 1996). Vesicular or bullous reactions sometimes occur at the Fig. 6. Treatment of AA with a contact sensitizer: Unilateral contact dermatitis after applicationof a contact sensitizer on the left side of the scalp (a); unilateral hair growth on the treated side(b); complete hair growth after treatment of both sides (c) 400 Pia Freyschmidt-Paul et al. beginning of treatment before the individual appropriate concentration hasbeen determined. Dissemination of allergic contact dermatitis, urticarial orerythema multiforme-like reactions may occur (Perret et al. 1990) but canbe successfully treated with topical corticosteroids. Pigmentary disturbancessuch as postinflammatory hyperpigmentation with spotty hypopigmentation(“dyschromia in confetti”) have been observed, especially in patients withdark skin, but resolved within 1 year after discontinuation of treatment inmost cases (van der Steen and Happle 1992; Hoffmann and Happle 1996).Apart from these acute and subacute side effects, no long-term side effectshave been reported after 20 years of DCP (23 years of SADBE) treatment worldwide of about 10,000 patients, including children. However, it should be bornein mind that DCP and SADBE are not approved therapeutic substances. StudiesMore than 25 studies have been performed to test the efficacy of AA treatment with a contact sensitizer. The most significant controlled studies arelisted in Table 2. In contrast to corticosteroid and PUVA treatment studies,the majority of contact sensitizer treatment studies were controlled, most ofthem using an untreated side of the scalp as a control. When comparing therates of response obtained in various therapeutic modalities, one should bearin mind that spontaneous regrowth is excluded in these controlled, withinpatient studies, but not in the uncontrolled ones. The response rate of treatment with a contact sensitizer varies between 29% and 78% (see Table 1).The differences may be explained in part by the different extent and duration of AA prior to treatment in the patients of each study, and in part by differences in the method of treatment. However, the median response rate ofall studies is 49%, rendering contact sensitizers an effective therapeutic toolfor AA. Mode of ActionThe mode of action of the treatment with contact sensitizers is so far poorlyunderstood. It has been shown that treatment with a contact sensitizer changesthe composition and localization of the perifollicular infiltrate in humans andin the C3H/HeJ mouse-model for AA (Happle et al. 1986; Freyschmidt-Paulet al. 1999). In both, mice and men, the localization of the inflammatory infiltrate shows a shift from peribulbar before treatment to the upper dermis aftertherapy. However, in human AA the CD4:CD8 ratio changes from 4:1 beforeto 1:1 after therapy, while in mice successful treatment with a contact sensitizeris associated with an increase in the number of CD4+ cells and a decrease inthe number of CD8+ cells. Hoffmann et al. demonstrated that after treatmentwith a contact sensitizer the mRNA-expression of IFNg is reduced while theexpression of IL-10 is increased (Hoffmann et al. 1994). Whether this is due DCPDCPDCPDCPDCPDCPDCPDCPSADBESADBESADBESADBE Steen van der, et al., 1991 Macdonald Hull et al., 1991 Macdonald Hull et al., 1991 Hoting et Boehm, 1992 Gordon et al., 1996 Schuttelaar et al., 1996 Weise et al., 1996 Cotellessa et al., 2001 Wiseman et al., 2001 Happle et al., 1980 Case et al., 1984 Caserio 1987 Micali et al., 1996 129 2 11 26 113 14 43 10 12 11 33 4 78 0 8 18 8 5 Patchy AA 8 5 10 27 35 42 22 16 36 20 45 8 32 20 8 37 22 AA totalis 0 7 0 0 0 40 0 0 14 0 0 29 14 0 1 0 0 AA universalis Clinical form of AA (number ofpatients) ULT, unilateral treatment, untreated side serves as control DCPDCP Monk, 1989 DCPDCP DCP Happle et al., 1984 Macdonald Hull and Norris, 1988 DCP Happle et al., 1983 Ochsendorf et al., 1988 ContactSensitizer Reference Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Yes (ULT) Controlledstudy 137 14 21 53 148 56 105 26 children 48 45 78 12 children 139 14 28 27 45 27 Number ofpatients Table 2. Treatment of AA with Contact Sensitizers, Controlled Studies Including Patients with Severe, Longstanding AA 64% 29% 52% 70% 77,9% 48% 48% 32% 38% 51% 55% 33% 50.4% 43% 29% 37% 58% 68% Cosmeticallyacceptable hairregrowth Alopecia areata: Therapy401 402 Pia Freyschmidt-Paul et al. to a Th1-Th2 shift or whether it is caused by the introduction of regulatoryT-cells with a type 2 cytokine profile is the object of current investigations.Immunohistochemical studies furthermore have shown in humans and in theC3H/HeJ mouse-model of AA, that treatment with a contact sensitizer reduces the aberrant expression of MHC-I and MHC-II molecules on the lowerhair follicle epithelium (Bröcker et al. 1987; Freyschmidt-Paul et al. 1999).From these data it can be concluded that treatment with a contact sensitizerrestores the immune privilege of the lower hair follicle epithelium. Other TreatmentsIrritant Contact Dermatitis – AnthralinWhile treatment of AA with an allergic contact dermatitis has been proven tobe effective, treatment of AA with an irritant contact dermatitis has neverbeen shown to be successful in a controlled study. In a half-side controlledstudy, using 0.1% anthralin that resulted in a mild irritant contact dermatitis,no difference between treated and untreated side was observed (Nelson andSpielvogel 1985). Therefore, anthralin cannot be recommended for the treatment of AA. MinoxidilBecause the antihypertensive agent minoxidil causes hypertrichosis as a sideeffect, Weiss et al. attempted to use it as a treatment for various forms of hairloss, including alopecia areata (Weiss et al. 1984). But all studies that claimsuccessful treatment of AA with minoxidil did not fulfill the criteria of evidence based treatment of AA (Weiss et al. 1984, Fiedler-Weiss et al. 1986,Price 1987a, b; Ranchoff et al. 1989)Six other placebo-controlled studies performed by various groups did notshow a statistically significant difference between the hair growth of patientstreated with the placebo or with minoxidil (Frentz 1984; Maitland et al. 1984;Vanderveen et al. 1984; White and Friedmann 1985; Vestey and Savin 1986;Fransway and Muller 1988). In three of these studies cosmetically acceptablehair regrowth was not even observed in any patient (Vanderveen et al. 1984;White and Friedmann 1985; Fransway and Muller 1988). In summary, minoxidilis not useful in the treatment of AA. SummaryAlopecia areata is regarded as a T-cell mediated autoimmune disease that isdirected against a so far unknown autoantigen of the hair follicle. There is a Alopecia areata: Therapy 403 genetic predisposition to develop alopecia areata, whereas environmental triggers have not yet been identified. The diagnosis can be established by characteristic clinical features including severe forms such as alopecia areata totalisand universalis. Nail changes may help confirm the diagnosis. In some caseshistopathological examination may be necessary, whereas other laboratoryinvestigations are unnecessary. Because of the high rate of spontaneous remission, the efficacy of a rational treatment for AA has to be proven in controlled studies. An ideal treatment should be highly effective but associatedwith only minor side effects. According to the rules of evidence-based medicine, treatment with

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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45

a contact sensitizer is at present the most effectivetreatment of alopecia areata showing only mild side effects. However, it is atime-consuming and in some cases ineffective therapeutic approach, whichis why it is necessary to develop new, more specific forms of treatment. 404 Pia Freyschmidt-Paul et al. PathogenesisThe complete pathogenesis picture for AA has yet to be determined. However, recent research has made much progress in our understanding of thedisease mechanism. There is numerous circumstantial evidence in support ofthe notion that AA is fundamentally an inflammation driven disease and maybe autoimmune in nature. Observation of a peri- and intra-follicular inflammation of the target anagen hair follicle primarily by T lymphocytes in bothhumans and animal models is the most compelling morphological evidence(Perret et al. 1984; Ranki et al. 1984; Zhang et al. 1994; Sundberg et al. 1994).In addition to a lymphocytic infiltrate there is increased presence of antigenpresenting cells such as macrophages and particularly Langerhans cellsaround, and sometimes within, dystrophic hair follicles (Wiesner-Menzel andHapple, 1984; Zhang et al. 1994). Furthermore, inflammatory markers include up regulation of ICAM and ELAM expression on the endothelium ofblood vessels closely associated with affected hair follicles (Nickloff andGriffiths 1991; McDonagh et al. 1993; Zhang et al. 1994). Changes in cytokinelevels, particularly activating cytokines such as IL-2 and IFNg, have beennoted during AA inflammation with corresponding alteration of cytokineconcentrations after successful topical counter irritant therapy (Hoffmann etal. 1994). MHC class I and II expression on hair follicle epithelial structuresnormally devoid of MHC expression is associated with hair follicle inflammation and AA (Bröcker et al. 1987; McDonagh et al. 1993). Certain MHCclass II haplotypes seem to be associated with predisposal of the individualtowards AA, a common observation in autoimmune diseases (Duvic et al. 1991;Colombe et al. 1999). Hair follicle specific IgG autoantibodies have been foundin increased concentrations in the peripheral blood of AA affected individuals compared to normal, non-affected humans (Tobin et al. 1994a, Tobin etal. 1994b). AA may respond to a range of immunomodulatory treatments(Hoffmann and Happle, 1999). All these and other circumstantial evidence(McElwee et al. 1999c; McElwee et al. 2002b) are of some assistance in understanding the pathogenesis of AA. However, detailed characterization andfunctional studies are required to demonstrate the significance of these circumstantial observations and to elucidate disease mechanisms. Primarily dueto ethical limitations, functional studies cannot readily be conducted in humans. Consequently, animal models of human AA are required. Immune System TargetsAA is generally believed to have an autoimmune pathogenesis (Paus et al.1993; McDonagh and Messenger, 1996). While the evidence in support ofthis idea is compelling, the primary requirement to prove the autoimmune Alopecia areata: Pathogenesis 405 nature of AA, to identify a self antigen as the primary target that can initiatethe disease mechanism and lead to development of the phenotype, has yet tobe proven. Without this evidence, AA can only be described as a putative autoimmune disease. Using a SCID-human model of AA, Gilhar et al claimedmelanogenesis related antigens to be inciting agents for the activation ofpathogenic cells involved in AA (Gilhar et al. 2001). Circumstantially, thereare several claimed cases of selective pigmented hair loss and white hair survival in AA affected individuals (Plinck et al. 1993; Messenger and Simpson,1997; Camacho, 1997). Much has been made of this observed phenomenonin defining potential targets of inflammation in AA. However, there are manymore unreported examples of AA affected individuals losing both pigmentedand non-pigmented hair and in a mouse model of AA white hair can be successfully targeted by inflammatory cells (McElwee et al. 2001a).While it is quite possible for melanocyte derived antigens to be involvedin AA, they need not be the primary agents in precipiting disease onset.Downstream of the disease activation event it is likely that the phenomena ofepitope spreading (Chan et al. 1998) results in the targeting of numerous antigenic epitopes from diverse sources within the hair follicles. Logically, onewould expect the primary target for follicular inflammation to be a key component in hair fiber production, the targeting of which would lead to growthcessation. While follicular dermal papilla cells may be a candidate source ofthe primary antigenic target for inflammatory cells (Nutbrown et al. 1996),the most likely source of the primary inciting agent are follicular keratinocytes. Circumstantial evidence in support of this view includes the identification of hair follicle specific autoantibodies which target keratinocyte derivedepitopes and that intra-follicular penetrating inflammatory cells in humansand animal models primarily take up residence in keratinocyte comprisedroot sheath and matrix locations (McElwee et al. 2003b). However, beyondthese speculations, little is known about the nature of the antigenic targetson which inflammatory cells focus in AA. It is quite possible that differentclinical AA presentations may be associated with different antigenic epitopetargeting patterns. The Humoral Immune System in AAAutoantibodies against hair follicle antigens have been identified in both humans and animal models of AA with significantly increased frequency compared to the general population. Tobin et al, demonstrated production ofantibodies with heterogeneous targeting of hair follicle structures and similar heterogeneity of morphological targeting has been found in mouse andrat models of AA (McElwee et al. 1996a; Tobin et al. 1997). Trichohyalin andspecific keratins, have been defined as targets for some of the antibodies(Tobin et al. 2003). The diversity of autoantibody production with no consistent 406 Pia Freyschmidt-Paul et al. structure targeting observed in serum samples from different patients,suggests autoantibodies are not the dominant factor in AA development.Other evidence also supports this view with time line evaluation studies on amouse model for AA indicating cellular targeting for the follicle occurs priorto an upregulation in genes associated with antibody production (Carroll etal. 2002). Transfer of serum from AA patients to skin in a SCID-human modelalso failed to regenerate the disease phenotype (Gilhar et al. 1992). However, this does not invalidate antibody investigation. Autoantibodies in serum from AA patients may hold important clues to the targets for cellularinflammation in AA. Autoantibodies may yet be shown to play a secondaryrole in the disease pathogenesis. One small study involving the transfer ofequine AA-derived antibodies to normal haired mice promoted an increasein telogen state hair follicles, although no apparent development of cellularinflammation was induced and systemic AA did not develop (Tobin et al. 1998).Autoantibodies then may play a secondary role accentuating the chronic disease state but it seems unlikely they are the primary mediators of AA. The Cellular Immune System in AAIn many autoimmune diseases and animal models of autoimmune diseaselymphocytes are identified as the primary disease mediator. Most commonly,CD4+ lymphocytes have been identified as the primary pathogenic cell subset retaining the ability to transfer many autoimmune diseases, but other subsets including CD8+ cells have also been identified as important in diseasepathogenesis (eg. Ablamunits et al. 1999; Huseby et al. 2001). The predominantly CD4+ and CD8+ lymphocyte inflammation of hair follicles suggests thesecells to be the primary instigators of the disease phenotype in AA. Depletingthe inflammatory cell number with immunosuppressive therapies reinforcesthe general view that these cells hold the key to hair growth inhibition in AA(Freyschmidt-Paul et al. 2001). In rodent models this has been taken a stepfurther with the selective removal of CD4+ or CD8+ cells by injections monoclonalantibodies. Depletion of one or other lymphocyte population permits hairregrowth, but with replacement of the depleted cell population the AA phenotype redevelops (McElwee et al. 1996b; McElwee et al. 1999b; Carroll etal. 2002).Recent cell subset transfer studies have further characterized the importance of CD4+ and CD8+ lymphocytes in AA. Human AA-affected, skin-derived cells have been shown to reinduce inflammatory hair loss in xenograftsof previously AA affected skin grafted to scid/scid mice (Gilhar et al. 1998).Separation of CD4+ and CD8+ cell subsets and their transfer to this model suggested each cell type alone was not capable of reinducing hair loss, but incombination hair loss redeveloped (Gilhar et al. 2002). In C3H/HeJ mice subcutaneous injection of CD8+ cells led to the rapid development of localized Alopecia areata: Pathogenesis 407 hair loss at the site of injection but no further development of hair loss. Incontrast, injection of CD4+/CD25- cells resulted in little localized hair loss butsuccessful transfer of the disease systemically with the development of multiple alopecia patches (McElwee et al. in press). Thus, it is the CD4+/CD25cell population in the C3H/HeJ mouse model that retains the capacity totransfer the systemic AA phenotype to naive hosts and most likely promotesAA via promotion of APC activity and subsequent stimulation of hair follicleautoreactive CD8+ cells. This pathogenic activity defines the CD4+/CD25- cellpopulation as a key component of AA and a prime target for the develop+ment of therapeutic strategies. CD8 cells, although apparently the primaryeffectors of the actual hair loss phenotype, are largely under the control ofCD4+/CD25- cells. Mechanisms of Cellular Action on the Hair FollicleIt seems then that the cellular immune system is the principal promoter ofAA. The question remains how might leukocytes act on hair follicles to promote hair loss. Studies so far implicate a combination of mechanisms. Cytotoxicity may be mediated through Fas – Fas ligand (FasL) interaction. Thebinding of Fas expressed on target cells by FasL on activated lymphocytesleads to apoptosis of the Fas expressing cell. This mechanism of tissue destruction is not MHC restricted and has the potential to damage innocent bystander cells not directly targeted by the pathogenic lymphocyte clones. Fas –FasL signaling is also believed to promote antigen presentation (Siegel et al.2000). In the C3H/HeJ mouse model for AA, Fas and FasL are significantlydifferentially expressed in skin infiltrating lymphocytes and Fas is highly expressed on human and mouse dystrophic hair follicle keratinocytes (Bodemeret al. 2000; McElwee et al. 2002a; Freyschmidt-Paul et al. 2003). Histocompatible mice deficient in Fas or FasL are comparatively resistant to the induction of AA. This resistance was in part localized to the skin as Fas and FasLdeficient skin transplanted to AA affected mice resisted immune activity andcontinued to grow hair (Freyschmidt-Paul et al. 2003). The possibility of anautocrine and paracrine action of Fas and FasL within and between hair follicle keratinocytes may add to the action of the inflammatory infiltrate and mayexplain why FasL deficient hair follicles were also relatively resistant to AA.Perforin, produced by cytotoxic cells, is a potent mediator of cell lysis(Russell and Ley, 2002). For perforin induced lysis of target cells to occur, theT cell receptor of an autoreactive cell must ligand with the relevant antigenicpeptide presented in conjunction with MHC on the target cell. Whether perforinmediated cell destruction occurs in AA is unknown, but the presence of highlyactivated CD8+ cells within dystrophic hair follicles and the high expressionof MHC molecules on hair follicle keratinocytes circumstantially suggestsMHC restricted, perforin mediated, tissue damage could occur. Granzymes, 408 Pia Freyschmidt-Paul et al. that may gain access to target cells via perforin or induce apoptosis independent of perforin through binding cell surface receptors (Motyka et al. 2000),have been identified as highly expressed in human AA (Bodemer et al. 2000;Carroll et al. 2002). Inducible nitric oxide synthase expression is apparentduring mouse AA development which may suggest a role for nitric oxide indisease pathogenesis (McElwee, personal observations).Lymphocytes need not have close contact with hair follicle keratinocytesto exert an effect. Cytokines such as TNFa may have a negative impact onthe survival of hair follicle keratinocytes in AA (Janssen et al. 2003). IFNg mayinhibit cell proliferation and promote keratinocyte expression of MHC molecules that will aid other inflammatory mechanisms (Schroder et al. 2004).Other cytokines may negatively regulate keratinocyte cell proliferation andencourage hair follicles to truncate their growth cycle and enter a telogenresting state (Randall, 2001). Overall, cytokines may be significant modulators of hair follicle disruption. Disease Modulating FactorsWhile the fundamental mechanism of AA is essentially self contained it islikely there are exterior factors that influence the disease course. Thus farvarious, candidate genetic influences have been identified in human and rodent model AA (described elsewhere). In addition, epigenetic factors arealso probably involved in determining an individual’s susceptibility to AA.Epigenetic factors may be both susceptibility and severity modifiers of AAand act in two ways: They may modify an individual’s general susceptibilityto a disease activation event. Alternatively, they may be involved in determining the future prognoses for hair loss in terms of extent, hair loss pattern,duration or chronicity of disease, and/or resistance to treatment, once onsetof overt hair loss has been initiated.Recently, using the C3H/HeJ mouse model, interferon gamma (IFNg) hasbeen identified as a key player in precipitating onset of hair loss (FreyschmidtPaul et al. 2004). Injecting IFNg into mice known to be genetically susceptibleto AA brings forward the time at which AA onset develops and increases thefrequency of mice expressing the AA while transgenic knockout mice genetically deficient in IFNg are incapable of developing AA. In the real world,IFNg expression is increased in response to a variety of insults, particularlyinfectious agents (Schroder et al. 2004). It is generally accepted that an infectious agent might promote autoimmune disease onset through mimicry ofantigenic epitopes (Wucherpfennig, 2001). If an infectious agent expressesantigens that are similar to self antigens found naturally in hair follicles thenexposure to the pathogen may elicit a cross reactivity to the to the hair folliclelocated antigens. However, the knowledge that IFNg is involved in diseasedevelopment suggests that there need not be a specific relationship between Alopecia areata: Pathogenesis 409 pathogen-expressed antigens and hair follicle antigens. Rather, responses tothe general “viral load” might play a key role in AA for some (Stewart andSmoller, 1993; Kissler et al. 2001). It is conceivable then that an individualgenetically susceptible to AA might experience onset of hair loss subsequentto infectious agent exposure or exposure to any other factor that promotes inan increase in IFNg. Chronic exposure or cumulative exposure to multiplepathogens may increase the level of susceptibility to disease onset.Increased levels of IFNg alone are unlikely to induce AA onset in any oneindividual. If this were true, AA would be expressed with a much higher frequency within the population than is the case. It is likely that multiple genetic and epigenetic factors must interact correctly for actual disease onset tooccur. Rodent model research has shown that hormones can influence thedegree of susceptibility to AA induction. Ovariectomized mice had a relatively reduced rate of AA development compared to estradiol supplementedmice. In contrast mice supplemented with testosterone were fully resistant toAA development compared to gonadectomized mice (McElwee et al. 2001b).Hormonal influence in humans is suggested by old case reports assertingtemporary hair growth in AA affected women during the late stages of pregnancy or improvement with onset of menopause (Sabouraud 1913, LévyFranckel 1925, Walker 1950). Model research has also shown that increaseddietary soy oil content can reduce AA susceptibility (McElwee et al. 2003a).While this is of little practical value in understanding human AA, it demonstrates the potential influence of environmental factors on AA susceptibility.To protect against inappropriate immune system activation, and to calmdown activated immune cells after a pathogenic challenge has been cleared,immune regulatory mechanisms are exploited. CD4+/CD25+ cells have beenidentified as one of probably several lymphocyte regulatory cell subsets thatcan restrain pathogenic cell activity. CD4+/CD25+ cells are essential for maintaining homeostasis, are able to suppress the induction of autoimmune disease,suppress CD4+/CD25– cells, and can inhibit the effector function of autoreac+tive CD8 cells (Suri-Payer et al. 1998; Gao et al. 1999; Annacker et al, 2001).Little is currently known about immune regulatory mechanisms in human AA.Recent studies in the skin graft induced AA mouse model revealed thatCD4+/CD25+ cell levels drop significantly on activation of AA and prior to theonset of overt hair loss (Zöller et al. 2002). In contrast, sham grafted mice areable to maintain CD4+/CD25+ cell numbers and quickly recover normal inflammatory cell numbers after injury. This apparent active depression of regulatory cells in AA challenged mice may be a key factor in AA susceptibility.++CD4 /CD25 cells or CD8 cells from AA affected mice transferred to unaffected mice can induce some form of AA, but if CD4+/CD25+ cells are addedto the mixture the disease onset is partially inhibited (McElwee et al. in press).This indicates the potential importance of regulatory cell failure in AA development. Why regulatory cells fail to appropriately restrain onset of AA is notknown but further examination of CD4+/CD25+ cells and other regulatorycells may reveal significant insights into AA susceptibility and development. 410 Pia Freyschmidt-Paul et al. There are likely other epigenetic factors that modulate AA. Stress hasbeen suggested as a potential instigator of autoimmune diseases possiblythrough glucocorticoid modulation of inflammatory cytokine expression(Elenkov and Chrousos, 2002). Stress has also been postulated as a potentialinfluence on AA development although the evidence is only circumstantial(Mehlman and Griesemer, 1968; Colon et al. 1991; Liakopoulou et al, 1997;Kavak et al, 2002). AA frequency and severity is apparently associated witha greater frequency of allergies as compared to the general population (Muller and Winkelmann, 1963; Ikeda, 1965; Penders, 1968; De Waard-van derSpek et al. 1989; Weise et al. 1996). Whether there is a direct relationshipwhereby an allergic response is capable of increasing immune system sensitivity and instability such that AA susceptibility increases, or whether theincreased frequency of allergies in AA patients is merely a reflection of genetically determined immune system sensitivity remains to be determined. Otherpromoters of the immune system in autoimmune diseases may include drugsand toxins (Bigazzi, 1994; Elkayam et al. 1999; Holsapple, 2002). In principle,one or more of these factors may modulate the immune system in AA, but inpractice little is known about the effects of environmental stimuli on AA inrodent models or humans.With time and changes in epigenetic factors that may influence AA, sothe degree of susceptibility to AA will fluctuate. While an individual may havea genetic susceptibility to AA that may be regarded as an unmovable baseline, additional epigenetic factors may increase or depress overall AA susceptibility. Only if an individual receives multiple signals that cumulativelyincrease the susceptibility to disease above a threshold level for expressionwill an episode of AA actually develop. This may also help explain why thepresentation of the AA phenotype is so varied. Individuals with chronic extensive AA, versus those with an isolated AA patch, may have a dominantgenetic susceptibility to disease and relatively minor epigenetic modificationof this genetic susceptibility. In others who whose AA waxes and wanes, orwho present with multiple episodes of AA expression and remission may bemore greatly impacted by epigenetic factors and their changing influencewith time. Disease InitiationWe still do not know the disease phenotype precipitating event, but one hypothesis is that AA develops in susceptible individuals due to a failure in hairfollicle immunoprotection. Anagen stage hair follicles are regarded as immuneprivileged sites (Westgate et al. 1991; Paus et al. 1999), but follicle immunoprotection is likely only transient due to the nature of the hair follicle cycle.Research suggests the onset of catagen is associated with an infiltration ofimmune cells, candidate antigen presenting cells (Parakkal, 1969; Westgate Alopecia areata: Pathogenesis 411 et al. 1991; Paus, 1996; Eichmüller et al. 1998). Regression of the hair folliclein catagen involves high levels of apoptosis and significant remodeling of thelower transient portion of the hair follicle (Weedon and Strutton, 1981; Lindneret al. 1997). It is possible then that the immune system is constantly exposedto low levels of hair follicle derived antigens as hair follicles cycle throughcatagen and given the ability of dendritic cells to present apoptosis derivedantigens. Autoimmune disease is not regarded as an all or nothing event.Rather, there are degrees of autoreactivity and a threshold level above whichovert autoimmune disease is induced (Ludewig et al. 2001; McElwee et al.2001b). A reflection of this may be the low level of hair follicle specific antibodies found in some humans and rodents in the absence of overt AA (Tobinet al. 1994a; Tobin et al. 1994b; Tobin et al. 1997). If however, catagen regression became disordered and the immune cell infiltrate associated withcatagen inappropriately presented antigenic peptides in association with expression of costimulatory molecules, antigen presentation to the immunesystem might breach the threshold for stimulation of autoreactive cells. In agenetically susceptible individual, resident in a permissible environment,AA might follow. SummaryOverall, we still cannot claim AA is an autoimmune disease with completeconfidence, but all the evidence produced so far points in that direction andprovides compelling supporting evidence. Circumstantial evidence from observing the state of humans with AA has been supplemented with indirect,functional evidence from a variety of animal models. In the near future, animal model and human genome screening will likely define loci involved inAA susceptibility and resistance. With further research, the contribution ofspecific genes to the disease onset may provide much information on the disease pathogenesis. ReferencesAbell E, Munro DD (1973) Intralesional treatment of alopecia areata with triamcinoloneacetonide by jet injector. Br J Dermatol 88: 55–9Ablamunits V, Elias D, Cohen IR (1999) The pathogenicity of islet-infiltrating lymphocytes inthe non-obese diabetic (NOD) mouse. Clin Exp Immunol 115: 260–7Alsaleh QA, Nanda A, al-Hasawi F, el-Kashlan M (1995) Concurrent appearance of alopeciaareata in siblings. Pediatr Dermatol 12: 285–6Anderson I (1950) Alopecia areata: A clinical study. Br Med J 2: 1250–2.Andrade M de, Jackow CM, Dahm N, Hordinsky M, Reveille JD, Duvic M (1999) Alopeciaareata in families: Association with the HLA locus. J Invest Dermatol Symp Proc 4: 220–3Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A(2001) CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through theproduction of IL-10. J Immunol 166: 3008–18 412 Pia Freyschmidt-Paul et al. Averbakh EV, Pospelov LE (1986) HLA antigens in patients with alopecia areata. VestnDermatol Venerol 1: 24–6Barber HW (1921) Alopecia areata. Br J Dermatol and Syph 33: 1–14Bastos Araujo A, Poiares Baptista A (1967) Algunas consideracions sobre 300 casos de pelada.Trabalhos da Sociedad Portugesa de Dermatologia e Venereolagia 25: 135–41Behrens-Williams S, Leiter U, Schiener R, Weidmann M, Peter RU, Kerscher M (2001) ThePUVA-turban as a new option of applying a dilute psoralen solution selectively to thescalp of patients with alopecia areata. J Am Acad Dermatol 44: 248–252Betterle C, Greggio NA, Volpato M (1998) Clinical review 93 Autoimmune polyglandularsyndrome type 1. J Clin Endocrinol Metab 83: 1049–55Bigazzi PE (1994) Autoimmunity and heavy metals. Lupus 3:449–53Bodemer C, Peuchmaur M, Fraitaig S, Chatenoud L, Brousse N, De Prost Y (2000) Role ofcytotoxic T cells in chronic alopecia areata. J Invest Dermatol 114: 112–6Bonjean M, Prime A, Avon P. Pelade chez deux jumeaux homozygotes (sic) (1968) Lyon Med219: 1852–3Bröcker EB, Echternacht-Happle K, Hamm H, Happle R (1987) Abnormal expression of class Iand class II major histocompatibility antigens in alopecia areata: Modulation by topicalimmunotherapy. J Invest Dermatol 88: 564–8Brown WH (1929) The aetiology of alopecia areata and its relationship to vitiligo and possiblyscleroderma. Br J Dermatol and Syph 41: 299–323Burton JL, Shuster S (1975) Large doses of glucocorticoid in the treatment of alopecia areata.Acta Derm Venereol (Stockh) 55: 493–6Camacho F Anagenic and telogenic effluvia (1997) In: Trichology: Diseases of the pilosebaceous follicle, Camacho F, Montagna W, eds.; Aula Medica Group: Madrid pp.387–96Carroll JM, McElwee KJ, E King L, Byrne MC, Sundberg JP (2002) Gene array profiling andimmunomodulation studies define a cell-mediated immune response underlying thepathogenesis of alopecia areata in a mouse model and humans. J Invest Dermatol 119:392–402Carter DM, Jegasothy BV (1976) Alopecia areata and Down syndrome. Arch Dermatol 112:1397–9Case PC, Mitchell AJ, Swanson NA, Vanderveen EE, Ellis CN, Headington JT (1984) Topicaltherapy of alopecia areata with squaric acid dibutylester. J Am Acad Dermatol 10:447–51Caserio RJ (1987) Treatment of alopecia areata with squaric acid dibutylester. 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management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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46

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management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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47

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Br JDermatol 133: 914–8Tobin DJ, Orentreich N, Bystryn JC (1994a) Autoantibodies to hair follicles in normal individuals. Arch Dermatol 130: 395–6 Alopecia areata: Pathogenesis 419 Tobin DJ, Orentreich N, Fenton DA, Bystryn JC (1994b) Antibodies to hair follicles in alopecia areata. J Invest Dermatol 102: 721–4Tobin DJ, Sundberg JP, King LE Jr, Boggess D, Bystryn JC (1997) Autoantibodies to hair follicles in C3H/HeJ mice with alopecia areata-like hair loss. J Invest Dermatol 109: 329–33Tobin DJ, Alhaidari Z, Olivry T (1998) Equine alopecia areata autoantibodies target multiplehair follicle antigens and may alter hair growth. A preliminary study. Exp Dermatol 7:289–97Tobin DJ (2003) Characterization of hair follicle antigens targeted by the anti-hair follicle immune response. J Investig Dermatol Symp Proc 8: 176–81Tosti A, Piraccini B, Pazzaglia M, Vincenzi C (2003) Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis. J Am Acad Dermatol 49: 96–98Valsecchi R, Vicari O, Frigeni A, Foiadelli L, Naldi L, Cainelli T (1985) Familial alopeciaareata – genetic susceptibility or coincidence? Acta Derm Venereol 65: 175–7Van der Steen PH, Baar van JMJ, Perret C, Happle R (1991) Treatment of alopecia areata withdiphenylcyclopropenone. J Am Acad Dermatol 24: 253–7Van der Steen P, Traupe H, Happle R, Boezeman J, Strater R, Hamm H (1992a) The geneticrisk for alopecia areata in first degree relatives of severely affected patients. Acta DermVenereol (Stockh) 72: 373–5Van der Steen PH, Happle R (1992b) Dyschromia in confetti as a side effect of topicalimmunotherapy with diphenylcyclopropenone. Arch Dermatol 128: 518–20Van der Veen EE, Ellis CN, Kang S, Case P, Headington JT, Voorhees JJ, Swanson NA (1984)Topical minoxidil for hair regrowth. J Am Acad Dermatol 11: 416–421Verbov J (1973) Steroid solution treatment of alopecia areata. Arch Derm 108:135Vestey JP, Savin JA (1986) A trial of 1% minoxidil used topically for severe alopecia areata.Acta Derm Venereol (Stockh) 66: 179–80Vogel F, Motulsky AG (1997) Human Genetics: Problems and Approaches. 3rd ed. Berlin:Springer-Verlag, 223–6Walker SA, Rothman S (1950) Alopecia areata. A statistical study and consideration of endocrine influences. J Invest Dermatol 14: 403–413Weedon D, Strutton G (1981) Apoptosis as the mechanism of the involution of hair follicles incatagen transformation. Acta Derm Venereol 61: 335–9Weidman AI, Zion LS, Mamelok AE (1956) Alopecia areata occurring simultaneously in identical twins. Arch Dermatol 74: 424–6Weise K, Kretzschmar L, John SM, Hamm H (1996) Topical immunotherapy in alopeciaareata: anamnestic and clinical criteria of prognostic significance. Dermatology 192:129–133Weiss VC, West DP, Fu TS, Robinson LA, Cook B, Cohen RL, Chambers DA (1984) Alopeciaareata treated with topical minoxidil. Arch Dermatol 120: 457–63Weitgasser H (1968) Erfahrungen mit einer Triamcinolon-Tinktur bei entzündlichen Dermatosen. Z Hautkr 43: 505–8Welsh EA, Clark HH, Epstein SZ, Reveille JD, Duvic M (1994) Human leukocyte antigen-DQB1*03 alleles are associated with alopecia areata. J Invest Dermatol 103: 758–63Westgate GE, Craggs RI, Gibson WT (1991) Immune privilege in hair growth. J InvestDermatol 97: 417–420White SI, Friedmann PS (1985) Topical minoxidil lacks efficacy in alopecia areata. ArchDermatol 121: 591Whitmont K, Cooper A (2003) PUVA treatment of alopecia areata totalis and universalis: aretrospective study. Australas J Dermatol 44: 106–109Wiseman MC, Shapiro J, MacDonald N, Lui H (2001) Predictive model for immunotherapy ofalopecia areata with diphencyprone. Arch Dermatol 137: 1063–1068Wucherpfennig KW (2001) Mechanisms for the induction of autoimmunity by infectiousagents. J Clin Invest 108: 1097–104Wunderlich C, Braun-Falco O (1965) Mongolismus und Alopecia areata. Med Welt 10: 477–81Zandman-Goddard G, Shoenfeld Y (2002) HIV and autoimmunity. Autoimmun Rev 1: 329–37Zhang JG, Oliver RF (1994) Immunohistological study of the development of the cellular infiltrate in the pelage follicles of the DEBR model for alopecia areata. Br J Dermatol 130:405–14 420 Pia Freyschmidt-Paul et al. Zlotogorski A, Weinrauch L, Brautbar C (1990) Familial alopecia areata: No linkage withHLA. Tissue Antigens 36: 40–1Zöller M, McElwee KJ, Engel P, Hoffmann R (2002) Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopeciaareata. J Invest Dermatol 118: 983–92 15 Novel Therapeutic Approaches inAutoimmune Skin DisordersSybille Thoma-Uszynski and Rüdiger Eming IntroductionThe medical management of autoimmune skin disorders is complex. At present,the mainstay of therapy of most of the previously characterized autoimmuneskin diseases is based on mid- to long-term administration of immunosuppressive drugs. Although therapeutic immunosuppression took away the fatality of many autoimmune skin disorders, there are several pitfalls associatedwith longterm immunosuppression. Under this light, there is an urgent needto incorporate novel efficient therapeutic applications which harbor fewer sideeffects in the medical management of autoimmune skin diseases.Immunological tolerance and breakdown of or escape from self-toleranceare incompletely understood. Deeper insight into immune mechanisms of selftolerance should extend the possibilities for specific therapeutic interventions in autoimmune diseases. Principally, therapeutic strategies are targetedto distinct steps in the sequence of events which lead to a misbalance in immune function and/or break of tolerance and eventually to overt autoimmunedisease. These include bone marrow ablation, general immunosuppression,modulating autoantigen recognition, cytokine function, autoantibody production and degradation, gene transcription or inhibiting cellular immune responses. During the past several years the development of biologic agents(biologics) interfering with key steps in the immunopathogenesis of autoimmune diseases have profoundly changed the way of treating autoimmunedisorders. This chapter reviews the most recent developments and the corresponding clinical applications. Immunomodulatory Drug DevelopmentRecent drug development extended the spectrum of anti-inflammatory and/orimmunosuppressive pharmaceuticals. 422 Sybille Thoma-Uszynski and Rüdiger Eming Mycophenolic AcidMycophenolic acid (MPA), an immunosuppressive agent that blocks lymphocyte purine synthesis (Lipsky 1996), had been introduced into the managmentof psoriasis, but now becomes increasingly popular for other clinical applications, including autoimmune bullous skin disorders, such as pemphigus vulgaris(PV) and bullous pemphigoid (BP) (Bohm et al. 1997; Enk and Knop 1999;Grundmann-Kollmann et al. 1999). One recent study applied it as monotherapyin PV and BP and disease activity was successfully suppressed (GrundmannKollmann et al. 1999). Mimouni et al. conducted a historical prospective studyincluding 31 patients with PV and 11 pemphigus foliaceus (PF)-patients,evaluating the role of MPA as a corticosteroid-sparing agent (Mimouni et al.2003). Complete remission was achieved in 71% and 45% of the patients withPV and PF, respectively. The authors considered MPA as an effective andwell tolerated adjuvant in the treatment of patients with pemphigus (Mimouniet al. 2003). Powell et al. confirmed these conclusions by evaluating the efficacy and safety of mycophenolate mofetil (MMF) combined with glucocorticosteroids in a group of 17 pemphigus patients (Powell et al. 2003). In thisstudy, treatment with MMF was an effective steroid-sparing immunosuppressant to 12 of the 17 patients (Powell et al. 2003). Recent studies demonstrate good responses to treatment with MMF in various nephrological autoimmune disorders. Filler et al. reported effective treatment of pediatric patientswith vasculitis and connective tissue disease involving the kidney, i.e. SLE,antiphospholipid antibody syndrome or Wegener granulomatosis (Filler etal. 2003). Contreras et al. showed that for patients with proliferative lupus nephritis maintenance therapy with MMF or azathioprine (AZA) seems to be moreefficacious and safer than i.v.-cyclophosphamide treatment (Contreras et al.2004). A recent study by Budde et al. with renal transplant patients demonstrated that MMF can safely be converted to enteric-coated mycophenolate sodium without compromising the safety and efficacy of the drug(Budde et al. 2004). This enteric-coated formulation reduces the adverse effects in the upper gastrointestinal tract compared to MPA. The current status ofMPA as a promising compound in the dermatological field is reviewed byFrieling and Luger (Frieling and Luger 2002). Immunosuppressive MacrolidesImmunosuppressive macrolides represent a new class of substances whichmodulate inflammatory processes. They can be topically applied and are potential alternatives to corticosteroid therapy. Tacrolimus (FK506)The macrolide lactone tacrolimus (FK506), introduced into transplantationmedicine for prevention of allograft rejection, is now also applied for treat- Novel Therapeutic Approaches in Autoimmune Skin Disorders 423 ment of inflammatory skin disorders such as atopic eczema, psoriasis, pyodermagangrenosum, Behcet’s disease, alopecia areata and lichen planus (Assmannet al. 2000). Functionally similar, but structurally different to cyclosporin A,FK506 binds to immunophilins and this complex specifically inhibits calcineurinephosphatase and early gene expression after T cell stimulation, but with a 10to 100 fold stronger immunosuppressive potency than cyclosporin A (Sawadaet al. 1987).It has been shown that topical application of FK506 has a wide spectrumof effects including reduced expression of costimulatory molecules on immunocompetent cells and cytokine production in the skin (Homey et al. 1998). Ithas been used to treat patients with systemic sclerosis with moderate success(Morton and Powell 2000). A cohort of recent case reports demonstrated thesuccessful topical treatment of different autoimmune blistering disorderswith tacrolimus, including vesicular pemphigoid (Chuh et al. 2004), cases oflocalized pemphigoid (Chu et al. 2004; Ko et al. 2004) and labial pemphigusas reported by Hodgson et al. (2003). Vecchietti et al. reported the case of apatient with CD20+ follicular non Hodgkin’s lymphoma developing paraneoplastic pemphigus with severe stomatitis and painful ulceration on the dorsumof the tongue (Vecchietti et al. 2003). In addition to treatment with monoclonalanti-CD20 antibody (Rituximab®), the patient was given an oral suspensionof tacrolimus 0,03%, three 5-min rinses per day. The mucosal lesion clearedwithin six weeks and relapses of mucosal ulcerations responded well to reintroduction of a two week course of topical tacrolimus. (Vecchietti et al. 2003).Furthermore, effective topical treatment of Hailey-Hailey´s disease (Rabeniet al. 2003; Sand et al. 2003) and recalcitrant chronic discoid lupus erythematosus (CDLE) (Walker et al. 2003) with tacrolimus have recently been described.Thus the current results may prove tacrolimus a useful adjunct in the topicaltreatment of a variety of cutaneous autoimmune disorders. Sirolimus (Rapamycin)Sirolimus (Rapamycin) is another macrolide which also binds to immunophilins.In contrast to cyclosporin A and tacrolimus, the sirolimus FKBP12 complex inhibits the mammalian target of rapamycin and interferes with cell cycling events. Ascomycin (ASM 981)Another related macrolactam derivative, ASM 981 or ascomycin has beenspecifically developed for the treatment of inflammatory skin diseases. It inhibits via complex formation with FKBP12 calcineurin phosphatase and genetranscription. Thereby, it suppresses Th1 and Th2 cytokine production,downmodulates release of proinflammatory mast cell mediators and of note,also decreases the release of the proinflammatory cytokine, TNF-a (Grassberger et al. 1999). 424 Sybille Thoma-Uszynski and Rüdiger Eming This new generation of macrolid derivatives represents a class of T celldependent immunosuppressive agents. Their application in dermatologyholds great potential to more specifically influence immune dysregulation indistinct autoimmune disorders and warrants controlled clinical trials. LeflunomideLeflunomide is a new immunomodulatory drug which had been approvedfor treatment of rheumatoid arthritis (RA) (Prakash and Jarvis 1999). Thespecific mode of action is not clear; it presumably inhibits the mitochondrialenzyme dihydro-orotate dehydrogenase and subsequently, pyrimidine biosynthesis with suppressive effects on cytotoxic T cells and antibody production. In addition, leflunomide exerts an antiinflammatory action throughinhibition of leucotriene B4 (LTB4) formation and chemotaxis (Chong et al.1999). Furhermore, it is an antiproliferative agent (Kurtz et al. 1995). One recent study suggests that it also blocks TNF-a receptor signaling (Manna etal. 2000). Leflunomide has been successfully applied and shown to be of particular value in critical situations where steroids are contraindicated andother steroid-sparing agents are not tolerated (Nousari and Anhalt 2000). Itsefficacy and safety profile make it a potential agent for hyperproliferativeand inflammatory dermatoses (Herrmann et al. 2000). Lately, however, reports on substantial liver toxicity contributed to concerns regarding its handling, particular if applied as part of a combination therapy with potentialadditive or synergistic toxic effects (Weinblatt et al. 2000; Emery et al. 2000).Lately, also cystic macular edema has been reported as a severe adverseevent after administration of leflunomide (Barak et al. 2004). Antigen Specific Approaches for Therapy ofAutoimmune DiseasesThe ideal treatment for autoimmune diseases would be to induce long lasting autoantigen specific tolerance. A precondition for such treatment is thatthe disease-associated autoantigens are well characterized. This holds truefor only few, mostly organ-specific autoimmune diseases such as myasteniagravis (MG), Hashimoto’s disease, autoimmune diabetes mellitus or the autoimmune skin diseases BP and PV (Stanley 1989; Patrick 1990). Therapy by Autoantigen AdministrationSeveral experimental animal models of autoimmune disease are established.In these models, autoantigens are used to induce the autoimmune disease Novel Therapeutic Approaches in Autoimmune Skin Disorders 425 such as MBP for experimental autoimmune encephalitis (EAE), insulin forautoimmune diabetes mellitus, acetylcholine receptor (AchR) for experimental autoimmune myasthenia gravis (EAMG), and thyroglobulin for experimental autoimmune thyroiditis, and others. Depending on the dose androute of administration, exogenous administration of proteins that usuallyrepresent self-antigens can lead to tolerance induction and prevention of autoimmune disease. This paradoxical use of self-antigens to treat autoimmune disease has been verified in the aforementioned experimental animalmodels as well.The antigen is delivered either via a tolerizing route, e.g. via oral/intestinal or nasal mucosa, or in a tolerogenic form, e.g. as soluble peptide MHCcomplex. Systemic administration (intraperitoneal, intravenous or subcutanousinjection) of high dose peptide or monomeric protein can induce clonal deletion,clonal anergy or immune deviation (Liblau et al. 1997). Examples of systemicantigen immunotherapy in experimental autoimmune disease are reviewedby Libleau and colleagues (Liblau et al. 1997).Experimental proof of that principle had been brought about by Chen etal. who tolerized mice via oral administration of myelin basic protein (MBP).Isolated T cell clones from the mesenteric lymph nodes showed a Th2-typecytokine pattern and induced suppression of EAE. Thus mucosa-associatedregulatory T cells are generated upon an oral vaccination approach (Chen etal. 1994).Distinct mechanisms are involved during antigen-induced tolerance. Highdose antigen administration leads to antigen-induced T cell apoptosis via FasLor TNF-a-dependent pathways. Continuous presence of antigen can lead to Tcell hyporesponsiveness or clonal anergy. Low dose antigen administrationcan induce regulatory T cells which secrete anti-inflammatory cytokines,such as IL-4, IL-10 or TGF-b and suppress APC and/or effector T cell function and possibly compete with effector T cells for antigen presentation.The administration of the random peptide copolymer glatiramer acetate(Copaxone) is another related approach. Previously shown to be partially effective in multiple sclerosis (MS) it was thought to suppress autoreactiveT cells specifically (Johnson et al. 2000). A recent study, however, revealedthat the T cell receptor (TCR) is engaged in a degenerate, antigen-non specific way and immune function is altered by induction of cross-reactive regulatory Th2 responses with bystander suppressor effects on APC and/or effectorT cells in MS patients (Duda et al. 2000). Although shown in MS, it could be apotent agent also for other autoimmune diseases which are alleviated upon aTh2 shift.Antigen-specific immune therapy has not made it yet to broad clinical application. Although neither significant toxicity nor exacerbation of autoimmunedisease had overshadowed recent and ongoing clinical trials, a clear clinicalefficacy could not yet been demonstrated (Faria and Weiner 1999). 426 Sybille Thoma-Uszynski and Rüdiger Eming Modified Antigens to Induce ToleranceAltered Peptide LigandsThe TCR interacts with the peptide MHC-complex with high specificity. Theon/off time of such interaction determines which co-stimulatory moleculesparticipate in the immunologic synapse with functional consequences onsubsequent T cell activation. According to this “strength of signal theory”there is either full T cell activation, partial activation or T cell anergy. Full vs.partial T cell activation may lead to an opposite cytokine profile, e.g. Th1 vs.Th2, a phenomenon called immune deviation. An altered peptide ligand (APL)has slightly changed residues of an immunodominant self-epitope which impair the T cell strength of signal (Fig. 1). Thus a single TCR can productivelyrecognize a large continuum of related ligands (Kersh and Allen 1996a). Thisflexibility is crucial for T cell development and harbors the possibility for bothbeneficial and harmful effects on peripheral T cells (Kersh and Allen 1996b). Fig. 1. Natural peptide ligands and altered peptide ligands (APL). The T cell receptor of anautoreactive T cell is fully stimulated by its natural ligand. Slight modification of the naturalpeptide ligand results in an APL. Interaction of an APL with the autoreactive T cell can lead topartial activation with a possible shift of the cytokine profile or to T cell anergy, both desiredeffects regarding therapeutic intervention in states of autoimmunity Novel Therapeutic Approaches in Autoimmune Skin Disorders 427 The APL strategy has been applied in several animal models of autoimmune diseases, and EAE being a well established animal model of MS inparticular: A single TCR antagonistic peptide has been shown to inhibit EAE(Kuchroo et al. 1994). A single amino acid shift of a myelin basic protein peptide produced an APL which mediated immune deviation by changing thecytokine profile towards a protective Th2 or Th0 pattern while retaining crossreactivity to the native peptide (Nicholson et al. 1995).Recently, first phase II clinical trials in humans applied the APL approach.One

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Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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48

study compared the APL of MBP to placebo. The APL-treated groupwas clinically stable and fine analysis revealed that lesions were reduced involume and number. The APL induced a regulatory type 2 T helper cell response that cross-reacted with the native peptide (Kappos et al. 2000). Thesecond phase II clinical trial to treat MS with an MBP peptide (aa 83–99)derived APL induced an exacerbation of the disease in three individuals, andthe trial had therefore to be halted (Bielekova et al. 2000). In two of the threepatients, clinical worsening could be attributed to the APL as immunologicalstudies demonstrated the encephalitogenic potential of the APL peptide (aa83–99).Although principally appealing to modulate the fine tuning of the immunologic synapse by APL, severe considerations arise from these first clinicalexperiences. In light of an individual T cell repertoire in the outbred humanpopulation, the functional effects of APLs seem unpredictable and problematic. Complementary PeptidesAccording to the molecular recognition theory, peptides encoded by theantisense RNA are designated as complementary or antisense peptides, caninteract with the natural peptide due to their hydropathic complementarity(Blalock 1990). Antibodies raised against complementary peptides of a ligandcan recognize its receptor, thus antibodies against complementary peptidesposses the ability to bind antibodies against sense or natural peptides (Aragaet al. 1996). Proof of principle had been given by animal models of AMG andEAE (Araga and Blalock 1994; Araga et al. 1996, 1999, 2000). These studiesshowed that a complementary peptide vaccine approach resulted in T cellanergy and blocking of T cell help in particular (Araga et al. 1999, 2000). Thecomplementary peptide approach has also been shown to alter B cell-mediated autoimmune diseases by induction of anti-idiotypic antibodies to pathogenic autoantibodies (Smith et al. 1987; Araga and Blalock 1994). One recentstudy based on the molecular recognition theory aimed to develop a complementary peptide vaccine to BP (Nie et al. 1999). Choosing the extracellular noncollagenous immunodominant NC16A domain of BP180, the putative majorBP autoantigen, to derive complementary peptides from, failed however todemonstrate binding to the natural peptides. Thus the targeted epitope was 428 Sybille Thoma-Uszynski and Rüdiger Eming not eligible for complementary peptide vaccine development for BP (Nie etal. 1999). This result does not preclude that other yet undefined BP180 epitopescan be targeted using the complementary peptide approach. Tolerogenic Dendritic CellsDendritic cells (DC) are the most powerful antigen presenting cells and initiate immune responses after uptake, processing and presentation of foreignantigen. In addition to their eminent role in host defense, DC are also heldresponsible in triggering autoimmune diseases by presenting autoantigensto autoreactive T cells (Ludewig et al. 1998, 1999; Link et al. 1999; Drakesmith et al. 2000). Several immuntherapeutic strategies utilize the antigenpresenting capacity of DC, such as DC vaccine for treatment of cancer or infection. Recent attempts included also to modify DC function such that subsequent T cell activation would be inhibited or downregulated. For instance,monocyte-derived human DC cultured in the absence of IL-4 and in thepresence of low concentrations of GM-CSF were maturation-resistant and induced hyporesponsiveness of T cells and prolonged cardiac allograft survival(Lutz et al. 2000).Appropriate cytokine treatment can convert immunogenic into tolerogenicDC (Drakesmith et al. 2000). IL-10-treated DC had a reduced allostimulatorycapacity and induced a state of T cell anergy (Steinbrink et al. 1997, 1999). Incontrast to cytokine treatment which halts DC maturation, it has been shownrecently that also fully mature DC are able to induce anergy in T cell clonesreactive with thyroid peroxidase antigen and are able to process and presentan immunodominant epitope with antagonistic altered peptide features(Quaratino et al. 2000). Recently, DC that take up apoptotic cells were described to induce peripheral tolerance to self antigens (Huang et al. 2000;Sauter et al. 2000).More and more functional properties are ascribed to cytokines, chemokines and other factors within the network of immune regulation. One suchfactor is the neuropeptide alpha-melanocyte stimulating hormone (a-MSH)which has been shown to exert anti-inflammatory effects by antagonizingIL-1, IL-6 and TNF-a (Becher et al. 1999). a-MSH signals via the melanocortinreceptor 1 (MC-1R) which is present on both monocytes and DC. Indicativefor the potentially anti-inflammatory and/or immunosuppressive role of a-MSHis the observation that it downregulates the expression of the co-stimulatorymolecules CD86 and CD40 on monocyte-derived DC (Becher et al. 1999).Although the term DC defines a heterogeneous population with differentfunctional properties ranging from powerful to poor T cell activators, thereare therapeutic possibilities emerging to functionally modulate DC into mediators of tolerance in T cell-dependent autoimmune diseases (Fig. 2). Novel Therapeutic Approaches in Autoimmune Skin Disorders 429 Fig. 2. Immunogenic and tolerogenic dendritic cells (DC). Immunogenic DC can be derivedfrom monocytes by in vitro culture in the presence of a cytokine cocktail, usually containingGM-CSF and IL-4. Addition of TNF-a or LPS induces complete maturation. Variations of thecytokine cocktail in terms of content and concentration of the cytokines can modify theresulting DC regarding maturation state and immunogenicity. Depicted are cytokinecombinations in the presence of which tolerogenic DC have been generated Modulating the Effector Phase of Autoimmune DiseasesSince many autoimmune diseases share common effector pathways of inflammation it is a rational strategy to target this effector phase. Attempts to neutralize proinflammatory cytokines in conditions where these cytokines representpathogenic key elements, are promising and most clinical experience hasbeen collected regarding TNF-a. Inhibition of TNF-a SynthesisTNF-a mediates inflammatory effects by acting on multiple target cells andby inducing cascades of other cytokines such as IL-1, IL-6 and IL-8 facilitating leukocyte chemotaxis and angiogenesis. Elevated serum levels are detectable in many autoimmune diseases including RA, Crohn’s disease andMS. Ways to neutralize a cytokine include alteration of cytokine transcription/translation, administration of monoclonal antibodies against the cytokine orcytokine receptor, soluble cytokine receptors or nonactivating cytokineantagonists. In humans, TNF-a neutralization has been accomplished by in- 430 Sybille Thoma-Uszynski and Rüdiger Eming Table 1. Immunomodulatory and Anti-Inflammatory Mode of Action of ThalidomideInhibition of TNF-a production by monocytes/macrophagesReduced TNF-a mRNA half-lifeInhibition of IL-12 productionInhibition of leukocyte chemotaxisReduced phagocytosis by polymorphonuclear granulocytesIncreased IL-4 and IL-5 synthesis by mononuclear cellsInhibition of IFN-g production by mononuclear cells Table 2. Dermatological Disorders that are Responsive to Treatment with ThalidomideDisorder Initial therapeuticdaily dose Reference Erythema nodosum leprosum 400 mg Iyer et al. 1971 Stomatitis aphthosa 200–400 mg Brodthagen 1985,Grinspan 1985 Behcet‘s disease 100–400 mg Ghate and Jorizzo 1999 Cutaneous lupus erythematosus 100–400 mg Ordi-Ros et al. 2000,Kyriakis et al. 2000 Systemic lupus erythematosus 100–400 mg Khamashta et al. 2000 Prurigo nodularis 400 mg Warren et al. 1998,Daly and Shuster 2000 Pyoderma gangrenosum 200–400 mg Federman and Federman 2000 HIV-associated symptoms 200–400 mg Berger et al. 1995,Herranz et al. 1998 hibitors of cytokine production, monoclonal antibodies and genetically engineered soluble TNF-receptors.Thalidomide, a sedative drug originally introduced for sleep disordershas been among the first drugs known to exert anti-inflammatory action byinhibition of TNF-a synthesis (Calabrese and Fleischer 2000). There are additional effects exerted by thalidomide on immune function that are still incompletely understood (Table 1). Thalidomide reduces neutrophil phagocytosisand inhibits monocyte phagocytosis. A major immunomodulatory effect ofthalidomide is the selective, but incomplete inhibition of TNF-a productionby human monocytes. This effect is presumably the consequence of a significantly reduced half-life of TNF-a mRNA (Moraes et al. 2000).Since TNF-a is a major proinflammatory cytokine, the inhibition of thiscytokine by thalidomide may explain its effectiveness in a variety of inflammatory disorders. Conditions such as lepromatous leprosy which are highlyresponsive to thalidomide (FDA approval for this indication) are character- Novel Therapeutic Approaches in Autoimmune Skin Disorders 431 ized by elevated serum TNF-a levels. Relief of the symptoms is accompaniedby a decrease of serum TNF-a levels. There are, however, disastrous examples that demonstrate that thalidomide does not always reduce overall TNF-asynthesis. A double-blinded randomized study in drug-induced toxic epidermal necrolysis, a condition characterized by most severe epidermolysis ofskin and mucosa and elevated TNF-a concentrations in skin lesions and serum showed that treatment with thalidomide significantly increased the riskof a fatal outcome of this disorder. Patients with toxic epidermal necrolysishad even elevated TNF-a serum levels upon treatment with thalidomide (Wolkenstein et al. 1998).Apart from leprosy, thalidomide has been successfully applied in Behcet’sdisease and HIV-associated aphthosis, cutaneous and systemic lupus erythematosus and prurigo syndromes (Table 2). Removal or Inhibition of Pathogenic AutoantibodiesA key feature and pathogenetic hallmark of many autoimmune skin disorders is the formation of autoantibodies that interfere with the function of thetarget antigen. Autoimmune bullous skin disorders, such as pemphigus vulgaris(PV) and bullous pemphigoid (BP), are well characterized by the presence ofdistinct disease-precipitating antibodies. Removal of pathogenic autoantibodies contributes to reduced disease activity. PV as a paradigmatic disorder ofantibody-mediated autoimmunity correlates in intensity with the concentration of circulating autoantibodies. Moreover, transfer of the patients’ autoantibodies into mice reproduces the characteristic pathology of this disorder(Amagai et al. 1994, 1995). For more than 25 years, attempts have been madeto reduce levels of circulating autoantibodies as a therapeutic strategy (Fig. 3). PlasmapheresisPlasmapheresis has been one of the mainstays in the treatment of pemphigusfor several years but has not yet developed into a first-line therapy of autoimmune disases. This is greatly due to limited patient numbers which do not allowthe appropriate conduction of controlled clinical trials to confirm a statistically proven benefit (Schneider 1996). Plasmapheresis has been applied totreat a series of autoimmune diseases: In PV, BP, and severe epidermolysisbullosa acquisita (EBA), plasmapheresis led to a substantial steroid sparingeffect of immunosuppressive therapy (Sondergaard et al. 1995, 1997; Yamadaet al. 1997; Egan et al. 2000; Turner et al. 2000). Plasmapheresis has provenbeneficial in systemic lupus erythematosus, particularly in lupus nephritis(Wallace 1999; Braun et al. 2000), and also in systemic sclerosis (Dau andCallahan 1994) and dermatomyositis (Bennington and Dau 1981; Dau 1994).Unfortunately, plasmapheresis does not only remove pathogenic antibodiesbut also causes a significant loss of additional plasma components. 432 Sybille Thoma-Uszynski and Rüdiger Eming Fig. 3. Mechanism of action of intravenous immunoglobulin (IVIG) therapy. The intracellularFcRn receptor in endothelial cells binds pinocytosed IgG at acid pH in the endosome andredirects it to the neutral pH at the cell surface. Unbound IgG is degraded in the lysosome. Instates of hypergammaglobulinemia, FcRn becomes saturated, and lysosomal degradation isincreased. This IgG depleting mechanisms contributes to degradation of pathogenic IgG(autoantibodies) during high dose IVIG therapy. Therapeutic approaches targeting the FcRnwith either synthetic ligands or neutralizing mAb would predict the same IgG depletingcatablism without the risks and costs associated with IVIG therapy. Figure adapted from Yuand Lennon 1999 ImmunoadsorptionSeveral models demonstrated that selective adsorption of pathogenic autoantibodies may prevent the experimental induction of autoimmune bullousskin disorders of the pemphigus group. Amagai et al. demonstrated thatpemphigus sera can be depleted from IgG reactive with the autoantigens ofPV, desmoglein 3 and pemphigus foliaceus, desmoglein 1, by preadsorptionof the sera over immobilized protein A (Amagai et al. 1994, 1995). The IgGautoantibody-depleted sera no longer induced pemphigus-like blisters uponpassive transfer into newborn mice.Immunoadsorption is a novel therapeutic strategy aimed at removing distinct protein components from the patient’s plasma. Similarly to leukapheresis,peripheral blood from the patient is collected and separated by centrifugation into plasma and cellular components. The plasma fraction is then subjected to passage over an affinity column coated with protein A sepharose,peptides with IgG binding capacity, tryptophane-PVA or phenylalaninePVA. The most important advantages of adsorption apheresis over unselectiveplasma exchange (i.e. plasmapheresis) are: Novel Therapeutic Approaches in Autoimmune Skin Disorders ––– 433 Selective removal of pathogenic plasma proteins (i.e. antibodies, cytokines)No loss of essential plasma proteinsNo requirement for adequate protein replacement The tremendous costs of immunoadsorption, however, exceed those of unselective plasma exchange by a factor greater than 2. The different adsorbents currently available for therapeutic trials have distinct adsorption profilesand may be selectively utilized to remove distinct antibody subtypes (Ikonomovet al. 1992). Immunoadsorption has been successfully employed for the removalof circulating autoantibodies in systemic lupus erythematosus (Kutsuki et al.1998; Gaubitz et al. 1998). Recently, immunoadsorption has been successfullyemployed in the treatment of recalcitrant pemphigus vulgaris and pemphigusfoliaceus (Luftl et al. 2003; Eming et al. [submitted]). Single yet unpublishedcase reports suggest a beneficial effect of immunoadsorption in severe pemphigoid gestationis and EBA. High Dose Intravenous ImmunoglobulinsModifying the immune system by repeated intravenous administration of highdose intravenous immunoglobulins has become an attractive therapeutic option to treat cases of autoimmune disorders that are resistant to conventionalimmunosuppressive drug regimens. The underlying mechanism of such treatment, however, remained obscure until recently. Immunoglobulins may exert immunomodulatory effects by several ways. These include Fc receptorblockade, regulatory capacity of anti-idiotypic antibodies or cytokine modulation via effectors on cytokine synthesis (Yu and Lennon 1999). An accelerated rate of IgG catabolism has been proposed to be the most likely mechanismin mediating the beneficial action of intravenous immunoglobulins in antibody-dependent autoimmune disorders (Ghetie and Ward 1997; Yu andLennon 1999). A specialized intracellular Fc receptor, FcRn, is abundantlyexpressed in endothelial cells and binds pinocytosed IgG in an pH-dependent manner, namely only in the acidic endosome. IgG is released whenendosomic transport vesicles reach the neutral pH of the cell surface. Unbound IgG is transfered to lysosomes for rapid degradation. FcRn becomessaturated in states of hypergammaglobulinemia, resulting in an increased rateof IgG catabolism. IgG depletion via FcRn receptor saturation convincinglyexplains the temporary benefit of intravenous immunoglobulin therapy inantibody-mediated autoimmune diseases. Based on this mechanism, a therapeutic strategy would be to target FcRn, e.g. by neutralizing antibodies orsynthetic ligands to decrease levels of circulating pathogenic autoantibodies(Yu and Lennon 1999). These fundamental insights into IgG catabolism harbor great potential for therapeutic intervention at the effector level (Fig. 4).Intravenous immunoglobulins have been highly beneficial in restoring therapeutic responsiveness to standard immunosuppressive treatment in disorders that were otherwise refractory (Table 3). Intravenous immunoglobulins 434 Sybille Thoma-Uszynski and Rüdiger Eming Fig. 4. Therapeutical effect of infliximab (anti-TNF-a) in an inflammatory skin disorder. Apatient with recalcitrant subcorneal pustular dermatosis (Sneddon-Wilkinson) respondedpromptly to infliximab therapy. Shown are pre-(left) and posttreatment (right) fotographs ofthe patient’s neck. Disseminated pustules completely resolved after a single course oftreatment and the patient remained in stable remission for several months (provided by Dr. C.Voigtländer, Erlangen, Germany) may be highly effective in therapy-refractory PV, linear IgA bullous dermatosis (incl. chronic bullous disease of childhood), EBA and mucous membranepemphigoid. In drug-induced toxic epidermal necrolysis, a condition characterized by extensive and uncontrolled epidermal necrolysis of large skin areas, immediate treatment with intravenous immunoglobulins resulted in adramatic beneficial response in some patients (Viard et al. 1998). This effectseems to be mediated by the anti-apoptotic action of anti-Fas IgG in the immunoglobulin preparations preventing apoptotic keratinocyte death. Targeting Immune Cells in Autoimmune DiseasesBiologicsBiologic agents or “biologics” represent a new group of substances includingmonoclonal antibodies, fusion and recombinant proteins possessing biological activity. These proteins can either be isolated from animal tissues or nowa- Novel Therapeutic Approaches in Autoimmune Skin Disorders 435 Table 3. Dermatological Disorders Treated with Intravenous ImmunoglobulinsDisorder Therapeutic Trial Reference Dermatomyositis Double-blind,placebo-controlled Dalakas 1998 Pemphigus vulgaris Open Harman and Black 1999;Sibaud et al. 2000 Epidermolysis bullosa Open Kofler et al. 1997 Bullous Pemphigoid Open Harman and Black 1999 Linear IgA bullous dermatosis Open Letko et al. 2000 Mucous Membrane Pemphigoid Open Foster and Ahmed 1999 Toxic epidermal necrolysis Open Viard et al. 1998 Chronic (autoimmune) urticaria Open O’Donnell et al. 1998 Lupus erythematosus Open Hundt et al. 2000;Viertel et al. 2000;Enk and Knop 2000 Morphea Open Wollina et al. 1998 Systemic sclerosis Open Levy et al. 2000 Pyoderma gangrenosum Single case Dirschka et al. 1998 Vasculitides Open Jayne et al. 2000;Ong and Benson 2000 days commonly be synthesized by biotechnological methods, i.e. recombinantDNA techniques. The use of biologics in other specialties, i.e. hematooncology(erythropoietin, GM-CSF) or organ transplantation (anti-CD25-antibodies) hasbeen known for years. The more defined understanding of the pathophysiology of autoimmune diseases has led to the therapeutical use of biologics inchronic inflammatory disorders like RA or Crohn’s disease (Feldman et al.1998). More recently, in the dermatological field psoriasis serves as a modelfor a chronic, T cell mediated (auto-) immune disease which has been an important subject for new therapeutic strategies using biologics (Gottlieb andBos 2002). With regard to the immunpathophysiology of psoriasis the immunologic strategies of biologics aim at inhibition of T cell activation, depletionof activated T cells, inhibition of T cell adhesion and inhibition of proinflammatory cytokines. Regarding therapy of inflammatory autoimmune diseasesantibodies which target B cells and autoantibody-producing plasma cells areof particular interest.Most of the listed biologics are being investigated in clinical trials (phaseI-III) for the treatment of moderate to severe plaque psoriasis. Alefacept andefalizumab are approved for the treatment of moderate to severe plaque psoriasis, whereas infliximab is approved for psoriatic arthritis, Crohn’s disease 436 Sybille Thoma-Uszynski and Rüdiger Eming Table 4. Biologic therapies and their sites of actionSubstances Target Type Company Inhibition of T cell activationAlefacept (LFA3TIP)CD2-LFA-3-interactionCTLA4-Ig (BMS 188667) CD80/CD86 costimulationIDEC 114CD80 costimulation fusion proteinchimeric fusion proteinprimatized mAb Biogen IDECBristol Myers SquibbBiogen IDEC humanized IgG1 mAb Genentech/XOMA Inhibition of T cell migrationEfalizumab (hu1124) CD11a(LFA-1-ICAM-interaction)CDP 850E-selectinBimosiamose (TBC-1269) anti-pan-selectinEfomycine MP- and E-selectin humanized mAbsmall moleculesamll molecule CelltechEncysive IL-2R fusion protein Ligand CD2CD3CD3CD4CD4CD25CD25 humanized mAbmurine IgG2a mAbhumanized mAbhuman mAbhumanized IgG4 mAbchimeric IgG1 mAbhumanized IgG1mAb CD20 chimeric IgG1 mAb Roche humanized IgG1 mAb ILEX Reduction of activated T cellsDAB398IL-2(denileukin diftitox)Siplizumab/MEDI-507OKT3VisilizumabHuMax-CD4OKTcdr4aBasiliximabDaclizumab MedimmuneCilag Lab.PDLGenmab A/SIMUCLONENovartisRoche Depletion of B cellsRituximab Depletion of lymphocytesCampath-1H/Alemtuzumab CD52 Blocking the activity of inflammatory cytokinesInfliximabAtlizumabEtanerceptABX-IL8HuZAF/Fontolizumab TNFaIL-6RTNFaIL-8IFNg chimeric IgG1 mAbhumanized mAbfusion proteinhuman mAbhumanized mAb Centocor/EssexRoche/ChugaiWyethAbgenixPDL and rheumatoid arthritis and etanercept is approved for the treatment ofpsoriatic and rheumatoid arthritis. Basiliximab and daclizumab are indicatedfor the prophylaxis of acute organ rejection in patients receiving renal transplants. Rituximab is being used for the treatment of low-grade B cell nonHodgkin’s lymphoma. For simplification, each substance is listed in one categoryonly. Note that some biologics have multiple effects, i.e. efalizumab also inhibits T cell activation. Novel Therapeutic Approaches in Autoimmune Skin Disorders 437 Inhibition of T cell activationAlefacept Alefacept is a fully human, recombinant fusion protein consisting of the extracellular domain of the leucocyte function-associated antigen type 3 (LFA-3)fused to the Fc-portion of human IgG1. It is produced by recombinant DNAtechnology in a Chinese Hamster Ovary (CHO) mammilian expression system (Biogen IDEC 2003). By effectively blocking the interaction between CD2which is highly expressed on memory effector T cells and LFA-3 expressedon APC, alefacept inhibits the activation of effector T cells. Treatment withalefacept also reduces the number of CD4/CD45 RO-positive memory T cellsthrough binding of its Fc-portion to FcgIII-receptors on natural killer cells(NK cells) or macrophages. This leads to the induction of a granzyme B-mediated apoptosis preferentially in CD4/CD45 RO-positive memory T cells(Ellis et al., 2001). Recent studies by Gordon et al. revealed a relationship between the decrease in circulating CD4+ memory T lymphocytes and the improvement of the psoriatic skin lesions (Gordon et al. 2003). Since January2003, alefacept is approved by the FDA for the treatment of moderate to severe plaque psoriasis. The treatment regimen is a course of 12 weekly injections (15 mg i.m./week) followed by a 12 week treatment free observationperiod (Biogen Idec 2003). The results of two phase III trials show that aftertwo i.v.- or i.m.-alefacept courses, respectively about 40% of the patientsshowed a ³ 75% reduction in their PASI-scores (Krueger et al. 2002; Lebwohlet al. 2003). The response to alefacept was durable, since the median duration of a > 50% reduction in PASI was 216 days for patients who initiallyachieved a 75% reduction in PASI (Krueger and Callis 2003). Alefacept is reported to be well tolerated both by i.v. and i.m. administration with a consistent safety profile in the clinical trials (Gordon et al. 2003). Commonlyreported infections in patients treated with alefacept were similar to those inpatients receiving placebo. In both phase III studies there did not appear to be acorrelation between infections and CD4+ cell counts below 250 cells/ml(Ortonne 2003 and Krueger et al. 2003). Kraan et al reported that alefacepttreatment in psoriatic arthritis shows promising results (Kraan et al. 2002). Efalizumab Efalizumab (hu 1124, anti-CD11a) is a humanized IgG1 version of the murineanti-human CD11a monoclonal antibody MHM24 (Werther et al. 1996). CD11aand CD18 are subunits of the lymphocyte b2-integrin LFA-1 that primarilybinds to the intercellular adhesion molecules ICAM-1 ICAM-2 and ICAM-3expressed on leukocytes, epithelial cells including keratinocytes and endothelial cells (Janeway et al. 2001). The main function of integrins on the cellsurface of T lymphocytes is to mediate cell adhesion with APC, endothelial 438 Sybille Thoma-Uszynski and Rüdiger Eming cells and extracellular matrix. In vitro studies by Werther et al. showed thatby blocking the LFA-1–ICAM-1 interaction, efalizumab inhibits key pathogenic steps in psoriasis like T cell activation, T cell extravasation and T celladhesion to keratinocytes (Werther et al. 1996). In two

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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49

recent phase III trialswith s.c. administered efalizumab nearly 1100 psoriatic patients had been randomized to treatment with an initial conditioning dose of 0,7 mg/kg in weekone followed by weekly doses of efalizumab 1 mg/kg or 2 mg/kg or placebo.Compared to the placebo group, in which 3,4% achieved PASI 75, 29% ofthe patients in the 1 mg/kg group and 28% in the 2 mg/kg group achieved a³ 75% reduction in their PASI-score (Gordon et al. 2002). The clinical improvement correlated with sustained efalizumab levels in the serum, T cell CD11asaturation and down modulation, decreased epidermal and dermal T cellcounts, histologic improvement and increased counts of circulating lymphocytes (Menter et al. 2001). FDA approved efalizumab for the treatment ofmoderate to severe psoriasis in October 2003. At present, safety data for 2762patients treated during 13 clinical trials are available, showing a good safetyprofile for efalizumab (Leonardi et al. 2004). Long term results based on treatment for up to 24 months revealed no new common (> 5% of the patients) adverse events. The incidence of serious infection or malignancy in efalizumabtreated patients was low and similar to the placebo group (Leonardi et al. 2004). CTLA-4Ig/IDEC-114 In addition to antigen-induced signals, the proliferation and differentiationof T cells requires a second signal provided by costimulatory molecules onAPC. A well characterized costimulatory pathway includes CD28 on T cellsbinding to the costimulatory molecules B7–1 (CD80)/B7–2 (CD86) on activatedAPC. Another T cell surface receptor for CD80/CD86, CTLA-4 (CD152) inhibits T cell activation (Abbas et al. 2000). CTLA-4Ig and IDEC-114 are biologicals targeting these costimulatory signals by binding to CD80 and CD86on APC, thus inhibiting T cell activation. IDEC-114 is a primatized anti-humanCD80 monoclonal antibody blocking the CD28-CD80 ligation without affecting the CD80-CTLA-4-interaction (Schopf 2001). Gottlieb et al. presenteddata on a single-dose phase I/II trial with 24 psoriatic patients who were administered IDEC-114 in i.v.-doses ranging from 0,05–15 mg/kg. IDEC-114demonstrated mild clinical and histologic improvements in patients of thehigher-dose groups (Gottlieb et al. 2000). A follow-up study (multiple dose,phase I/II) showed a PASI 50% reduction in 40% of the observed patients.The maximal clinical effect was observed 12 weeks after the last infusion(IDEC 2001). CTLA-4 Ig is a fusion protein composed of the extracellular domain of CTLA-4 (CD152) and the Fc domain of human IgG1. In an open phaseI/II dose escalation trial CTLA-4Ig showed a dose dependent improvementin psoriatic patients. In the high dose group (50 mg/kg) about 90% of thestudy patients experienced a 50% PASI reduction (Abrams et al. 2000). An Novel Therapeutic Approaches in Autoimmune Skin Disorders 439 earlier study by Abrams et al. indicated a decreased ability of the treated patients to mount T cell dependent antibody responses (Abrams et al. 1999).Currently, CTLA-4Ig is being investigated in other inflammatory disorderssuch as rheumatoid arthritis or organ transplantation (Gottlieb and Bos 2002). Depletion of Activated T LymphocytesInterleukin-2 Interleukin-2 (IL-2) is the principal cytokine which is secreted by antigenactivated T lymphocytes in the early phase of antigen recognition. IL-2 functionsas an autocrine growth and differentiation factor for the T cells. Its high affinityreceptor consists of the three non-covalently associated subunits IL-2Ra (CD25),IL-2Rb (CD122) and IL-2Rg (CD132). The TCR-dependent activation of naiveT cells leads to the upregulation of the a chain (CD25) which then enables Tcells to respond to low concentration of IL-2 through their high affinity receptor. Therefore, CD25 is also considered an early activation marker for T cells.This is the rationale for using anti-CD25 monoclonal antibodies or denileukindiftitox (DAB389IL-2) which is composed of recombinant IL-2 and part of diphteriatoxin. All three substances aim at eliminating pathogenic T cells. Basiliximab Basiliximab is a chimeric monoclonal antibody consisting of the heavy andlight chain of the variable region of the murine anti-human CD25 antibodyRFT5 and the heavy chain and k-light chain of the Fc region of human IgG1.Basiliximab specifically binds to the IL-2 receptor (IL-2R) with high affinity(Amlot et al. 1995). Binding of basiliximab to the IL-2R prevents further binding of IL-2 to the receptor. This way basiliximab inhibits IL-2-dependent proliferation of antigen-activated T cells (Onrust et al. 1999). Since May 1998basiliximab is approved for the prevention of acute organ rejection afterallogeneic renal transplantation. It is combined with other immunosuppressive drugs as cyclosporin or corticosteroids. So far, in different case reportsbasiliximab has been reported to treat severe recalcitrant psoriasis in combination with cyclosporin (Owen et al. 2000; Bell et al. 2002). Kaegi and Heyerdemonstrated the successful treatment of a 29-year old patient with severeatopic dermatitis with two i.v.-infusions of basiliximab (20 mg/infusion) together with low-dose cyclosporin (150 mg/d) (Kaegi and Heyer 2001). Daclizumab Daclizumab is the humanized variant of the murine anti-human CD25 monoclonal antibody MAT (murine anti TAC). In vitro studies demonstrated a high 440 Sybille Thoma-Uszynski and Rüdiger Eming affinity of daclizumab for the alpha chain (CD25) of the human IL-2R (Queenet al. 1989; Junghans et al. 1990). Daclizumab shows a dose dependent inhibition of the IL-2-dependent proliferation of human T cells. An open phase IIclinical trial by Krueger et al. included 19 psoriatic patients who underwenttreatment with four cycles of daclizumab, initially 2 mg/kg and 1 mg/kg, respectively at weeks 2, 4, 8 and 12 (Krueger et al. 2000). Daclizumab showeda moderate clinical improvement with a mean PASI reduction of 30%. In astudy by Willenbacher et al. daclizumab was used to treat 16 patients withgrade III-IV graft-vs.-host disease (GvHD) (Willenbacher et al. 2001). Asonly nine patients showed a clinical response and three patients died of serious infections, daclizumab demonstrated a limited effectiveness when usedas a monotherapy. Denileukin diftitox (DAB389-IL-2) This recombinant fusion protein contains human IL-2 linked to a portion ofthe diphteria toxin molecule. Activated T lymphocytes expressing the highaffinity IL-2R internalize denileukin diftitox by receptor mediated endocytosis. The intracellular release of the diphteria toxin blocks the protein-synthesisof the T cells and finally leads to cell death (Martin et al. 2001). Currentlydenileukin diftitox is approved for the treatment of cutaneous T cell lymphoma.Martin et al. demonstrated results of a dose-escalation trial with 35 psoriaticpatients who were given 12 infusions of denileukin diftitox over a peroid ofeight weeks. Seven out of 15 patients in the high dose group (5 ìg/kg) showeda minimal PASI reduction of 50% (Martin et al. 2001). The dose dependentadverse effects included fever/chills, asthenia, myalgia and rush. Siplizumab (Medi-507) CD2 is a 50 kD glycoprotein containing two extracellular Ig domians and it isexpressed on more than 90% of mature T cells, NK cells and up to 70% ofthymocytes (Abbas et al. 2000). Binding of CD2 to its principal ligand LFA-3(CD58) on APC increases the strength of adhesion between T lymphocytesand APC. There is further evidence that the CD2-LFA-3 interaction enhancesTCR-mediated activation of T cells (Abbas et al. 2000). Siplizumab (Medi-507)is a humanized anti-CD2 monoclonal IgG1 antibody which is currently investigated for its efficacy in the treatment of moderate to severe psoriasis. In threephase I/II trials, siplizumab was administered as a single i.v.-dose, eight weeklyi.v.-infusions or as 12 weekly s.c.-doses (Langley et al. 2001). In the high dosegroups (5–7 mg in the s.c.-group or 40 mg/kg in the i.v.-study) more than 55%of the patients showed at least a 50% reduction in PASI, while 33% of the patients experienced a 75% PASI reduction (Langley et al. 2001). With a maximum 12h post-dose, the number of circulating T lymphocytes in the peripheral Novel Therapeutic Approaches in Autoimmune Skin Disorders 441 blood decreased by 50%. Siplizumab was considered generally safe andwell tolerated. The side effects included fever/chills and flu-like symptoms(MedImmune, R&D pipeline, available at http://www.medimmune.com). Depletion of B LymphocytesRituximab Arising from haematopoietic stem cells, B lymphocytes pass through different maturation steps. Finally, mature B cells give rise to plasma cells producing immunoglobulins. The surface markers CD19 and CD20 appear early inthe B cell development and remain present until the stage of mature B cells.Rituximab (anti-CD20) is a chimeric IgG1k monoclonal antibody with murinevariable region and human constant regions, recognizing human CD20. In1997 rituximab was the first mAb to be approved for the treatment of relapsedor refractory, low-grade B cell follicular non-Hodgkin’s lymphoma (NHL) bythe FDA. In lymphoma patients receiving the standard regimen with fourweekly treatments of 375 mg/m2, profound B cell depletion is observed andsustained for 6–9 months (Gorman et al. 2003). Thus rituximab seems to bepromising for the treatment of antibody-mediated autoimmune diseases. Inpatients with systemic lupus erythematosus (SLE) significant B cell depletioncorrelated with clinical improvement (Anolik et al. 2003). In an open studyincluding five patients with refractory dermatomyositis, all patients reportedmarked improvement in both muscle strength and dermatitis within 1–3 months.The clinical improvement sustained for at least six months (Levine 2003). Thereare several recent reports indicating successful treatment of autoimmunebullous disorders with rituximab. Cooper et al. (2003) and Herrmann et al.(2003) reported good clinical responses in patients with severe PV upontreatment with rituximab (Coopet et al. 2003; Herrmann et al. 2003). Borradoriet al reported the rapid improvement of paraneoplastic pemphigus in a 61year-old woman with CD20+ follicular non Hodgkin’s lymphoma grade I, aftera regimen with rituximab 375 mg/m2 once a week for four weeks (Borradoriet al. 2001). Another case report showed rapid clinical response to rituximabin a patient with treatment-resistant pemphigus foliaceus (Goebeler et al. 2003). Inhibition of Lymphocyte Migration and ExtravasationTo eliminate (auto-) antigens in the effector phase of an (auto-) immune response, memory and effector T cells home to the sites of inflamed peripheraltissues, i.e. to inflamed dermis. Among the adhesion molecules which areimportant for leukocyte recruitment, selectins (E- and P-selectin) are expressedon activated endothelium and initiate leukocyte recruitment by binding tooligosaccharides (sialyl LewisX) on the cells surface of circulating leukocytes.Therefore selectins are considered as crucial targets for interrupting the 442 Sybille Thoma-Uszynski and Rüdiger Eming initiation and perpetuation of a T cell mediated, inflammatory (auto-) immune response. CDP850 CDP 850 is a humanized anti-E-selectin monoclonal antibody. Bhushan et al.performed a randomized clinical trial including nine psoriatic patients withmoderate to severe chronic plaque psoriasis. While nine patients received 20mg/kg CDP850 as a single i.v. infusion, four control patients received placebo infusions (Bhushan et al. 2002). Eight weeks post infusion, there was nosignificant reduction in PASI from baseline for the CDP850 treated groupcompared to the placebo group. These results demonstrate that blockade ofE-selectin alone does not have sufficient impact on the treatment of psoriasis, probably due to alternative pathways for leukocyte adherence to endothelium (Bhushan et al. 2002). Bimosiamose (TBC1269)/Efomycine M Both compounds are so called small molecules and as anti-pan-selectins theymay overcome the ineffectiveness of monoclonal antibodies directed againstsingle adhesion molecules. Preliminary data from recent clinical pilot studieson psoriatic patients treated with bimosiamose strongly suggest an effectiverole in the treatment of psoriasis (Friedrich et al. 2003). Schon et al. presenteddata in the psoriasis-SCID-mouse model showing that efomycine M effectively inhibits leukocyte recruitment and thus alleviates cutaneous inflammatory responses (Schon et al. 2002). This substance is currently in furtherclinical development. Neutralization of TNF-a by Monoclonal AntibodiesRecently, several recombinant antibodies and receptor agonists have beenintroduced to block bioactive TNF-a in rheumatological disorders and inflammatory bowel disease. In fact, these antibodies have contributed to the recentrenaissance of antibody therapy in general. Infliximab, a chimeric mousehuman IgG1 monoclonal antibody (mAb) against TNF-a has been provenhighly effective in several clinical trials in RA (Elliott et al. 1994a; Elliott et al.1994b). The Crohn’s disease study group demonstrated that anti-TNF-a wasa potent therapy in gastrointestinal and cutaneous Crohn’s disease (Targanet al. 1997; Geyer et al. 2000). Recent studies evaluated infliximab for treatment of ankylosing spondylitis and found significant improvement of clinicaland laboratory parameters (Van den Bosch et al. 2000a, 2000b; Brandt et al.2000). Novel Therapeutic Approaches in Autoimmune Skin Disorders 443 Etanercept is a dimeric molecule consisting of two human p75 sTNFRextracellular domains attached to the Fc portion of human IgG1. By now,extensive experience has been collected with etanercept in the treatmentof adult RA (Weinblatt et al. 1999). It has been demonstrated that particularlyearly phase treatment is clinically very effective in preventing irreversiblebone destruction (Bathon et al. 2000). In addition, the pediatric rheumatologycollaborative study group recently reported that anti-TNF-a therapy withetanercept in children with polyarticular juvenile RA is a save and efficienttherapy with a high clinical response rate (Lovell et al. 2000).Potential dermatological indications for treatment with anti-TNF-a antibodies include recalcitrant psoriasis arthritis (Maini et al. 1999) and plaquepsoriasis where first clinical trials are initiated, pyoderma gangraenosum andother conditions with elevated TNF-a levels. A recent study demonstratedthat infliximab was highly efficient in the treatment of psoriatic plaques thatwere otherwise unresponsive to concomitant treatment with methotrexate(Oh et al. 2000; Ogilvie et al. 2001). Infliximab was also highly effective in recalcitrant subcorneal pustular dermatosis (Sneddon-Wilkinson) (Fig. 5), a skindisorder characterized by disseminated pustules which is associated with RAand inflammatory bowel disease (Voigtländer et al. 2001). Pyoderma gangrenosum is yet another disorder that may be highly responsive to treatmentwith anti-TNF-a antibodies as observed in a single case with a chronic re- Fig. 5. Immune intervention in autoantibody-mediated skin disorders. Circulating pathogenicautoantibodies cause loss of integrity of the skin by interfering with adhesion moleculefunction in autoimmune blistering diseases of the pemphigus and pemphigoid group. Removalof these antibodies by several techniques allows reconstitution of epidermal or dermal/epidermal adhesion. These therapeutical approaches may be also useful to removeautoantibodies or proinflammatory cytokines in other skin autoimmune diseases such assystemic scleroderma, lupus erythematosus and dermatomyositis 444 Sybille Thoma-Uszynski and Rüdiger Eming fractory course (Jenne et al. 2004). Recently, the administration of infliximabwas highly effective in chronic disseminated granuloma annulare (Hertl etal. 2005) and a case of therapy-refractory pemphigus vulgaris. Jacobi et al.reviewed the current therapeutic applications for the two TNFa inhibitorsinfliximab and etanercept in inflammatory skin disorders (Jacobi et al. 2003). Inhibition of Other Pro-Inflammatory CytokinesAttempts to neutralize other proinflammatory cytokines included IL-1 (Campion et al. 1996; Bresnihan et al. 1998; Jiang et al. 2000) and IL-6 (Yoshizakiet al. 1998) with encouraging results for RA.Since TNF-a blockade also affects circulating levels of TNF-dependentcytokines such as IL-1 and IL-6 it seems currently superior to inhibit this keycytokine to stop autoaggressive inflammatory responses.To modulate inflammatory responses, other anti-inflammatory cytokineshave been administered with therapeutic intention: IL-10 has been used successfully in psoriasis (Asadullah et al. 1998, 1999). Although IL-10 leads to asignificant clinical response rate, its use may be restricted to severe forms ofpsoriasis due to potential immunosuppressive side effects of systemic IL-10administration. The immunomodulatory cytokine IL-11 had been administered to patients in Crohn’s disease (Sands et al. 1999). The clinical responserate was moderate in this short term trial, the therapeutic potential of IL-11appears limited due to its thrombocytopoietic properties. In an open-labelphase I dose-escalation clinical trial, Trepicchio et al. reported significantimprovement in seven out of twelve psoriasis patients treated with oprelevkin(recombinant humanized IL-11). There was a correlation between the clinical response and a decrease in proinflammatory cytokines (Trepicchio et al.1999). Peptide T is an octapeptide from the V2 region of gp120 of HIV.Raychaudhuri et al. demonstrated its immunmodulatory effects leading to anupregulation of IL-10 and a decrease of IFNg and IL-2 production (Raychaudhuri et al. 1999). Due to this anti-inflammatory effect, peptide T showed clinical improvement in psoriatic patients in several clinical trials (Gulliver et al.1999). Moreover, Talme et al. demonstrated by immunohistology that peptide T treated psoriasis patients showed decreased dermal lymphocytic infiltrates (Talme et al. 1995). Keratinocyte-derived IL-8 is involved in leukocyterecruitment to inflammed dermis (Barker et al. 1991; Biasi et al. 1998) andangiogenesis which is also a prominent characteristic of chronically inflammedskin (Nickoloff et al. 1994). ABX-IL8 is a fully humanized anti-IL-8 IgG 2monoclonal antibody that has been used for treating psoriasis patients (Lohneret al. 1999). In dose-escalating clinical trials ABX-IL8 was well tolerated andgenerally safe. So far its clinical efficacy in improving psoriasis is moderateso that its further clinical development in the field of psoriasis had been discontinued. IL-4 is considered the principal cytokine promoting the develop- Novel Therapeutic Approaches in Autoimmune Skin Disorders 445 ment of Th2-type effector T cells. Its capacity to counterbalance Th1-dominated,proinflammatory immune responses led to the use of IL-4 in clinical trials.Recently, twenty psoriasis patients devided into five groups received increasing doses of IL-4 over six weeks. 18 patients receiving higher doses ofIL-4 showed a statistically significant PASI reduction of 60 to 80% in thisstudy (Ghoreschi et al. 2003). Extracorporeal PhotopheresisPhotopheresis is a leukapheresis-based therapy with ultraviolett A (UVA) irradiation of ex-vivo isolated peripheral blood mononuclear cells (PBMC) plussystemically administered 8-methoxypsoralen (8-MOP). After UVA-irradiation, the PBMC are re-infused into the patients. The ECP procedure consistsof several steps: first, a portion of PBMC is collected and secondly, incubatedwith 8-MOP; alternatively, 8-MOP is administered systemically and third,followed by UVA irradiation. Fourth, the UVA-irradiated PBMC are reinfusedintravenously (Andreu et al. 1994). ECP is usually well tolerated with onlyminor side effects (Perotti et al. 1999; Salvaneschi et al. 2000). The molecularmode of action of 8-MOP/UVA is the formation of DNA and RNA photo adducts(i.e. thymidine dimers) leading to an alteration of DNA and protein synthesis.The immunological basis for the responses of patients to photopheresis ispresumably due to the induction of anti-clonotypic immunity directed againstpathogenic clonal T cell populations. Treatment-induced apoptosis of pathogenic T cells and activation of antigen presenting cells may be critical in thistherapeutic process (Rook et al. 1999).In addition to cutaneous T cell lymphoma (CTCL) (Bisaccia et al. 2000),the treatment modality of ECP has been applied to several autoimmune diseases (Table 5), including RA, systemic sclerosis (Schwartz et al. 1997), SLE(Knobler 1994) and PV (Wollina et al. 1999). Several case reports and caseseries suggest efficacy of ECP, but few controlled studies have been conducted to test this hypothesis (Owsianowski et al. 1996). Immunoablation and Stem Cell TransplantationImmunoablation and subsequent autologous or allogenic hematopoietic stemcell transplantation (HSCT) has emerged as a recent treatment modality forsevere autoimmune diseases (Marmont 2000). Insight into a response of autoimmune disorders to immunoablation and subsequent stem cell transplantioncomes from animal models and patient cases with concomitant malignancies(Passweg et al. 1999). 446 Sybille Thoma-Uszynski and Rüdiger Eming Table 5. Extracorporeal Photopheresis in Dermatological DisordersDisorder Trial Reference Chronic graft versus host disease Open Dall’Amico et al.1997 PV, BP Open Wollina et al. 1999 Epidermolysis bullosa acquisita Open Gordon et al. 1997 SLE Open Richter et al. 1998 Systemic sclerosis Open Krasagakis et al. 1998 MS Double-blind,placebo-controlled Rostami et al. 1999 First clinical trials or cases have been reported for progressive MS (Fassaset al. 2000; Burt et al. 1998), systemic lupus erythematosus (SLE) (Burt et al.1999a, 2000), RA (Burt et al. 1999b; Snowden et al. 1999) and chronic autoimmune thrombocytopenia (Pavletic 1997; Skoda et al. 1997). The mechanismof remission of autoimmune disease is not entirely clear. There is ongoingdebate whether dose-intense immunosuppression, as performed with nonmyeloablative conditioning is sufficient to induce remission. Under currentview, although autologous stem cell transplants are associated with a lowercomplication rate, allogeneic stem cell grafts seem preferable for treatmentof autoimmune diseases in order not to reintroduce the autoimmunity intothe recipient (Burt and Traynor 1999b). An allograft provides a new stem cellsource, and a controlled graft versus host effect could further contribute tomodulation and eradication of autoreactive lymphocytes.Overall, immunoablation followed by HSCT is an aggressive treatmentand should be reserved for a carefully selected patient collective. Precise preand posttransplant assessment of the immune system should unravel furtherdetails on tolerance and immunity. It remains to be determined whether thistherapy can induce true long-term peripheral tolerance and whether the curative efficacy weighs out the treatment-associated risks. Summary and ConclusionsTremendous progress has been made in understanding autoimmune processesand autoimmune diseases. Novel therapies begin to emerge and techniquesin use for some time have been refined and enrich the spectrum of treatmentmodalities. New immunomodulatory drugs currently help to reduce corticosteroid induced morbidity, but are also applied as monotherapy. These includemycophenolic acid, immunosuppressive macrolides and leflunomide. Novel Therapeutic Approaches in Autoimmune Skin Disorders 447 Antigen specific immunotherapy includes oral, mucosal or systemic autoantigen delivery and tolerance induction. Modified antigens are administeredin form of altered peptide ligands or complementary peptides. As antigenspecific therapy in perfection appears the use of tolerogenic dendritic cellsas mediators of specific tolerance induction.The effector phase of an autoimmune disease involves production of autoantibodies and release of proinflammatory cytokines. Therapeutic approachesare aimed at removing these compounds from the circulation and includeplasmapheresis, immunoadsorption, high dose intravenous immunoglobulintherapy, and most potently, TNF-a blockade.Dysregulated cellular immune responses in autoimmune diseases are targeted by antibody therapy to eliminate distinct cell populations, by extracorporeal photopheresis and, most aggressively, by immunoablation followedby hematopoietic stem cell transplantation. In this scenario, the use of biologicswill help to more specifically modulate crucial events in the effector phase ofan inflammatory autoimmune response. This can be achieved by the inhibition of proinflammatory cytokines such as TNF-a and costimulatory moleculesrequired for T cell activation.Based on increasing knowledge about tolerance and immunity, new horizons for therapeutic intervention are visible. ReferencesAdair JR, Athwal DS, Bodmer MW, Bright SM, Collins AM, Pulito VL, Rao PE, Reedman R,Rothermel AL, Xu D (1994) Humanization of the murine anti-human CD3 monoclonal antibody OKT3. Hum Antibodies Hybridomas 5: 41–47Amagai M, Hashimoto T, Shimizu N, Nishikawa T (1994) Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced bybaculovirus. J Clin Invest 94: 59–67Amagai M, Hashimoto T, Green KJ, Shimizu N, Nishikawa T (1995) Antigen-specific immunoadsorption of pathogenic autoantibodies in pemphigus foliaceus. J Invest Dermatol104: 895–901Andreu G, Leon A, Heshmati F, Tod M, Menkes CJ, Baudelot J, Laroche L (1994) Extrac

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Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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50

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management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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N Engl J Med 340: 227–228 Subject IndexAcantholysis 47Acanthosis 293ACE inhibitors 177, 207Acetylcholine esterase 376Acid Blockers 207Acitretin 218, 302Acral annular plaques 209Acrodermatitis chronica atrophicans 173Acrodermatitis continua suppurativahallopeau 303Acrosclerosis 249Acute cutaneous lupus erythematosus 183,188Acute guttate psoriasis 298Acute urticaria 309Adenocarcinomas 78Alefacept 220, 436, 437Allergic contact dermatitis 400, 402Allergic rhinitis 356Alopecia areata 145, 385, 420– totalis 385–386, 395– universalis 385, 395Alopecia mucinosa 387Altered peptide ligand (APL) 426American College of Rheumatology 174,184, 209, 353Amyloidosis 172Anagen hair follicle 404ANCA-associated vasculitides 351, 355,357, 361ANCA-associated vasculitis 359ANCA-cytokine sequence theory 350Anchoring fibrils 109, 117, 119Anemia 196Anetoderma 274Angioedema 310, 313, 317, 329Angiokeratomas 232Annular erythema 208, 274Anthralin 300, 402Anti-FceRIa autoantibodies 321–323Antibiotics 74Antibodies 193, 246, 369, 380Antibody-antigen complexes 80 Antibody-dependent cellular cytotoxicity187, 204Anticardiolipin antibodies 201, 213, 248,274Anticentromere antibodies 145Anticoagulants 256Anti-Cytokines 178Anti-DNA-antibodies 194Anti-double-stranded DNA antibodies 213,219Anti-endomysium autoantibodies 97Anti-FceRI autoantibodies 321, 324–325Anti-fibrillin-1 antibody 248Antigen specific immunotherapy 425, 447Antigen spreading 49Antihistamines 311, 328Anti-IgE autoantibodies 320, 321, 322Anti-La/SSB 204, 213Antimalarials 144, 152, 196, 206, 217, 240Anti-melanocyte antibodies 369Anti-neutrophil cytoplasmic antibodies(ANCA) 274, 350, 355Antinuclear antibodies 1, 172, 193, 198,212, 238, 267, 275, 277–278Antinuclear matrix antibody 248Antiphospholipid antibodies 145, 218,248Antiphospholipid antibody syndrome 422Antiplatelets 256Anti-Ro/SS-A antibodies 194, 204, 213,265, 278Anti-Scl 70, 145Anti-Sm 213Anti-TNF-a antibodies 17, 303, 443Anti-U1 RNP antibody 213, 246Aplastic anemia 144, 217Apoptosis 186, 263Arteriogramms 358Arthralgias 145,

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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52

209, 356Arthritis 170, 209–210Arthropod reaction 77Ascomycin (ASM 981) 423Asthma bronchiale 356 458 Subject Index Atopic childhood eczema 291Atopic dermatitis 387, 423Atrophoderma 140Atrophy 165, 168Atypical pneumonia 192Auspitz sign 298Autoantibodies 1, 6, 13, 16, 46, 71, 80, 110,123, 127, 138, 146, 165, 212, 246, 325,328, 431–433Autoantigens 10, 424Autoimmune bullous diseases 95, 122Autoimmune bullous skin disorders 95,122, 119, 422, 431–432Autoimmune diabetes 425Autoimmune pathogenesis 404Autoimmune polyendocrinopathysyndrome type 1 210, 393Autoimmune thrombocytopenia 74, 446Autoimmune thyroiditis 100, 210, 371Autoimmune urticaria 309, 320, 322, 328Autologous serum skin test 321Autoreactive B cells 1, 9Autoreactive lymphocytes 8, 13Autoreactive T cells 9, 74, 81, 425–426, 428Azathioprine 79, 197, 219, 239, 358 B cell dysregulation 138B cell receptor 2B cell tolerance 10B Lymphocytes 441b4 integrin 78Basement membrane zone 71, 102, 119,124Basiliximab 436, 439Bath-PUVA 176Behcet's disease 431, 450Beta Blockers 207b-haemolytic streptococci 294, 297Biologics 421, 434Biopsy 358Biostatistics 25Blaschko's lines 142Bone marrow 2, 166Bone marrow transplant 178BP188 1, 57, 76, 78, 81, 84BP238 76, 78, 81, 84Breast Implants 34–35Brunsting-Perry pemphigoid 109Bullous morphea 141Bullous pemphigoid 39, 71, 102, 109, 122,422, 431, 435, 446Bullous SLE 116C3H/HeJ mouse-model 400Calcinosis 235, 240–241Calcitriol 150Calcium channel blockers 175, 207 Calcium Homeostasis 376Captopril 57, 74Cardiac involvement 355Catalase 373Catecholamines 376CD11a 437CD4+/CD25+ cells 409Celiac disease 105Cell-mediated cytotoxicity 204Cell-substrate adhesion 85Cellular infiltrate 373CENP antibodies 169, 172Central Tolerance 3Chapel Hill Consensus 353Chemokine receptors 295Chemotaxis 424Chilblain lupus 190, 198Chlorambucil 79, 239Chloroquine 196, 216, 240Cholinergic Urticaria 312Chronic active hepatitis 11Chronic bullous disease of childhood 115,434Chronic cutaneous lupus erythematosus183–187, 188, 190–191, 196–197Chronic cutaneous lupus erythematosus– ACR criteria 191– American College of Rheumatology 183– ANA 194– Annular erythema 192– Anti-SS-A antibodies 187, 193– Antinuclear antibodies 194– Antiphospholipid syndrome 194– Anti-Ro/SS-A 186– Arthralgia 191–192– Autoantibodies 186– CDLE 186, 188– Chilblain 190– Chilblain lupus 194– Classification 183– Clinical Appearance 187– Cytokines 186– Diagnosis 186, 192– Direct Immunofluorescence 193– ELISA 194– Generalized DLE 188, 194– Hypertrophic DLE 188– Kaposi-Irgang disease 189– Keratinocyte apoptosis 186– Lipathrophy 190– Localized form of DLE 188– Lupus band test 193– Lupus panniculitis 189, 194– Lupus pernio 190–191– Lupus profundus 189–190– Lupus tumidus 191–192– Mucous membrane involvement 191 Subject Index– Nephritis 189– Papular mucinosis 192– Pathogenesis 185– Photosensitivity 186–187, 191–192– Polymorphous light eruption 191– Raynaud's phenomenon 192– SCLE 183–184, 186–187, 195– Serological Tests 194– T helper 2 response 187– Therapeutic options 195– Ultraviolet radiation 186Chronic discoid lupus erythematosus 189,387, 423Chronic graft versus host disease 344, 446Chronic idiopathic urticaria 316–317, 318,320, 325–326, 329Chronic plaque psoriasis 294, 298, 303Chronic ulcerative stomatitis 342Chronic urticaria 310, 319, 323Chronic urticaria– Anti-FceRIa autoantibodies 320–324– Aquagenic urticaria 314– Arthralgia 314– Autoantibodies 319– Autoimmune chronic urticaria 319– Autologous Serum Skin Test 324– Cholinergic urticaria 312–313– Classification 309– Cold agglutinin 313– Cold urticaria 313– Cryoglobulins 313– Delayed pressure urticaria 314– Dermographism 310– Eosinophils 314– Food additive-evoked 314– Food provocation 312– H1-antihistamines 318– Helicobacter pylori 317, 319– High affinity IgE receptors 319– Histamine 317– Oral steroids 318– Physical urticaria 310, 314– Solar urticaria 314– Systemic steroids 328– Treatment 328– Urticaria vasculitis 310, 315– Vibratory angioedema 314Chronic urticaria 309Churg Strauss syndrome 351–352Cicatricial pemphigoid 74, 78, 102, 109Ciclosporine 79Clofazimine 197Clonal anergy 425Coal tars 301Cochrane review 27Colchicine 104, 126Collagen 149, 178 459 – bundles 135, 167– degradation 167– metabolism 138– synthesis 153, 167– vascular diseases 165– collagenase I 149– collagenous domain 112Colloid bodies 334, 336Complement 137, 206, 320Complementary peptides 427Congenital heart block 265, 276Connective tissue growth factor 167Contact dermatitis 77Contact sensitizers 398, 400–401Contact urticaria 309Contraceptives 73Corticosteroid pulse therapy 397Corticosteroids 16, 144, 176, 219, 235, 241,256, 359C-reactive protein 357CREST syndrome 248Crohn's disease 117, 211, 442Cryoglobulin 278, 352Cryoglobulinemic vasculitis 274, 352, 360Cryptic epitopes 265Cutaneous calcinosis 173Cutaneous Graft-Versus-Host-Reaction333, 343, 344Cutaneous leukocytoclastic vasculitis 349,358Cutaneous lupus erythematosus 183, 187,204, 217, 430Cutaneous sclerosis 209Cutaneous T cell lymphoma (CTCL) 445Cutaneous vasculitis 274Cyclophosphamide 79, 177, 197, 239, 256,268, 359–360Cyclosporin A 104, 127, 153, 175, 219, 239,256, 279–280, 302Cytolysis of melanocytes 369Cytomegalovirus infection 166, 372Cytotoxic T cells 204 Daclizumab 436, 439Dapsone 102, 104, 196Deep morphea 143Delayed pressure urticaria 310Dendritic cells 428Denileukin diftitox 440Depigmentation process 367Dermal capillaries 293Dermal-epidermal junction 95, 102, 212Dermatitis herpetiformis Duhring 77, 96–95– Autoantibodies 102– Autoimmune disorders 100– Celiac disease 95, 97 460 Subject Index – Clinical presentation 95, 100– Diagnosis 100– Direct immunofluorescence microscopy100– Endomysium 97, 99– Gluten 97, 100, 105– Histopathology 101– IgA 99–100, 102, 105– Immunofluorescence microscopy 100,102– Neutrophils 102– Therapy 102– Tissue transglutaminase 97Dermatomyositis 34, 45, 74, 170, 174, 230,234, 236, 239, 242, 261, 325, 432, 435,441– Amyopathic dermatomyositis 230, 232,236– Anti-Ro (SS-A) 238– Arthralgias 234– Calcinosis 235– Cardiopulmonary involvement 235, 238,240– Classification 229– Corticosteroids 239– Cutaneous Manifestations 230– Cytokines 229– Diagnosis 237– Drug-Induced DM 237– Dysphagia 234– Electromyography 237– Facial erythema 230– Gottron's papules 230–231– Heliotrope rash 230– Immunofluorescence microscopy 233– Immunosuppressive agents 239–240– Intravenous immune globulin 239– Malignancy 236, 238, 240– Muscle involvement 234, 237– Myopathy 229, 233– Myositis 229, 239– Myositis-specific antibodies (MSAs) 238– Photosensitivity 231, 233– Polymyositis 229, 233, 235– Pulmonary involvement 235– Systemic corticosteroids 239– Systemic Features 234– Therapy 239Dermoepidermal basement membrane 57,60Dermographism 310Desmogleins 1, 3, 14, 46, 49–50, 57, 432Desquamation 297Diabetes 393Digital ulceration 179Dihydrofolate reductase 302Dinitrochlorobenzene 398 Diphenylcyclopropenone 398Direct immunofluorescence microscopy 75,334Discoid lupus erythematosus 198Disease Modulating Factors 408Distal dysphagia 235Distal interphalangeal arthritis 299Dithranol 300Diuretics 207DNA-topoisomerase I 172Down's syndrome 393D-penicillamine 57, 74, 152, 237Drug-induced lupus erythematosus 145,208Drug-induced pemphigus 45–46Drug-induced toxic epidermal necrolysis434Dyshidrosiform pemphigoid 72 Echocardiography 358Efalizumab 220, 303, 436–437Efomycine 442Electromyogram 229Endothelial adhesion molecules 352Endothelin-1 175, 249Endothelium 137, 166, 351Enteropathy 97Environmental factors 170, 206, 294, 377Envoplakin 50Enzyme linked immunosorbent assays 76,123Eosinophilc pneumonia 356Eosinophilia 144–146, 355Eosinophilic fasciitis 144, 172Eosinophils 82Eotaxin 82Epidemiology 25–27, 39, 133, 203, 391– Analytic 25–26– Autoimmune skin disorders 25– BP 39– Bullous pemphigoid 38– Case series 25– Case-control studies 36, 38, 40, 50– Case-control study 26, 31– Chronic discoid lupus erythematosus28–29– Cohort studies 26– Control group 26– Controlled trials 27– Cross-sectional studies 26– Dermatomyositis 36– Descriptive 25–26, 28– Etiology 25– Evidence Based Medicine 27– Incidence 26, 28, 32, 38– Morbidity 26 Subject Index––––––––––– Morphea 32Mortality 26Odds-ratio 26Ordinary review 27Population 26Prevalence 26, 28, 32–33, 38Risk Factors 25–26, 29, 32, 38Smoking 31SSc 33–34, 36–37Systematic review 27Systemic lupus erythematosus 28–29,32, 34, 36– Systemic sclerosis 32–33Epidermal atrophy 212Epidermal cell antigens 333Epidermal keratinocytes 46, 48, 63Epidermal transglutaminase 101Epidermal-dermal junction 100Epidermolysis bullosa acquisita 77, 102,109, 131, 435, 446– Anchoring fibrils 109–110, 112–113,117–118, 120– Autoantibodies 112, 115, 117–119,122–123– Basement membrane zone 109– BP-like presentation 114– Brunsting-perry pemphigoid 115– Bullous SLE 111, 116–117, 122–123, 128– Classical EBA 114– Clinical manifestations 113– Clinical presentation 113, 119– Colchicine 126– Collagen 109– CP 115– Crohn's disease 117– Diagnosis 118– Direct immunofluorescence 118– Direct salt split skin immunofluorescence121– EBA 109–110, 112–113, 115–116,118–120, 122, 125–126, 434– Electron microscopy 119– ELISA 119, 123– Etiology 110– Hemidesmosomes 110– Histology 119– IgA 115–116– Immune adsorption 127– Immunoblot analysis 123– Immunoelectron microscopy 120– Immunoglobulins 127– Immunosuppressive agents 126– Incidence 110– Indirect immunofluorescence 119– LABD-like presentation 115– Lamina densa 110, 125– Lamina lucida 118 461 ––––––– Pathogenesis 110–111, 118Photopheresis 127Salt-split skin 121Suction split immunofluorescence 125Systemic glucocorticoids 126Therapy 125Type VII collagen 110–113, 115–117,122–125, 127– Western blot analysis 122Epithelial hyperplasia 297Epitope 81, 405Epstein Barr virus 266, 372Erythema 188Erythema annulare centrifugum 211, 278Erythema gyratum repens 209, 211Erythema multiforme 56, 208, 400Erythemato-squamous plaques 298Erythematous papules 95Erythroderma 72, 209Erythrodermic psoriasis 299Esophageal dysfunction 249Esophageal involvement 145Etanercept 219, 436, 443Exclamation mark hairs 385, 387Experimental autoimmune encephalitis425Experimental autoimmune myastheniagravis 425Experimental autoimmune thyroiditis 425Extracellular matrix synthesis 139,166Extracorporeal photochemotherapy 127,153, 175, 344Extracorporeal photopheresis 445–446Extraglandular symptoms 275 Facial erythema 249Fas ligand 407Fauci's scheme 359–360Fc receptor 433FceRI 321, 324, 329FcRn 433–434Fibrillar collagens 167Fibrillarin 172Fibrillin 1 146, 248Fibroblasts 138Fibronectin 112Fibrotic process 168, 178Finger tip ulcerations 175Fingernails 298Fixed urticaria 77Flexual psoriasis 298Fluorescent overlay antigen mapping 125Focal vitiligo 368Fodrin 265Follicular inflammation 404Follicular plugging 209 462 Subject Index Foxp3 6Free oxygen radicals 352Fumaric acid esters 302–303 Gastrointestinal vasculitis 355Gene loci 291Generalised vitiligo 368–369Generalized disease 196Generalized morphea 134, 137, 141Generalized pustular psoriasis vonZumbusch 299Genetics 291Gestational pemphigoid 73Gingival involvement 340Gingival telangiectasia 232Glandular cells 262Glatiramer acetate 425Glomerulonephritis 360Glucocorticosteroids 195Glucose-6-phosphate deficiency 196Glucose-6-phosphate dehydrogenase 217Gluten 105Gluten sensitive enteropathy 211Gluten-free diet 105–106Gold 197Graft-versus-Host-Reaction 344Granular IgA deposits 100Granuloma annulare 211, 444Granulomatous lesions 351, 356Granzyme 262Gutatte psoriasis 292Guttate morphea 139 H2-blockers 178Haemopoetic stem cell 178Hair follicle 404, 407Hair follicle antigens 405, 409Hair regrowth 396–397H-antihistamines 317Hashimoto's thyroiditis 74, 145, 393Helicobacter pylori 316Hemidesmosomes 84, 120Hemifacial atrophy 143Hemolytic anemia 196Hemorrhagic cystitis 359Henoch-Schönlein purpura 360Hereditary angioedema 210Herpes gestationis 73High affinity IgE receptor 320High dose intravenous immunoglobulins62, 433HIV-associated aphthosis 431HLA class II alleles 45–46, 74, 205, 319, 394Human leukocyte antigen 393Hydroxychloroquine 153, 196, 216, 239 Hypereosinophilic syndrome 356Hypergammaglobulinemia 146, 433Hyperglobulinemic purpura 273, 275, 278Hyperpigmentation 188Hypertension 177Hypertrophic DLE 198Hypothyroidism 276 Idiopathic inflammatory myopathies 229IgA antibodies 105IgA gammopathies 58IgE-mediated diseases 17IgE receptor 320IgG catabolism 433Ignorance 5, 7Immune complex-mediated vasculitides349, 352–353, 361Immune deviation 425–426Immune pathogenesis 334Immune phenomena 248Immunoablation 445Immunoadsorption 62, 432–433Immunodominant 81, 426Immunoglobulin 1–2, 7, 9–10, 14–15, 120Immunohistochemistry 358Immunological tolerance 421Immunomodulatory treatments 86, 398,404, 421Immunopathogenesis 213, 421Immunophilins 423Immunosuppression 147, 254, 301, 421Immunosuppressive macrolides 422Immunosuppressive therapy 62, 150, 241,396Immunotherapy 425Incidence 26, 28, 134Inclusion body myositis 230, 240Indirect immunofluorescence 75Infectious agents 10Inflammatory alveolitis 177Inflammatory bowel disease 117, 126, 442Inflammatory infiltrate 166, 295Infliximab 436, 442–444Inhibition of pathogenic autoantibodies431Insulin-resistance 233a6b4 integrin 85Intercellular adhesion molecule-1 335Interferon-a 175Interferon-g 7, 153Interferons 197Interleukin-1 52Interleukin-2 439Interleukin-8 102Intermittent urticaria 309Interstitial pneumonitis 235 Subject IndexIntimal hyperplasia 166Intra-epidermal microabscesses 298Intrafollicular lymphocytic infiltrates 388Intralesional corticosteroids 397Intrathymic selection 4Intravenous immunoglobulin 127, 219, 328,359, 433–434Irritant contact dermatitis 402Ischemic injury 136Isotretinoin 218 Jo-1 antibodies 172, 235Joint contractures 144Junctional adhesion complexes 84Juvenile DM 237–238 Keratinocyte 186, 204, 294–295, 297, 336Keratoacanthoma 188Keratoconjunctivitis sicca 267Kidney failure 179Koebner's isomorphic response 186, 188,191, 338, 368 LABD antigen 78, 116Laboratory tests 357Lamina densa 125Lamina lucida 102, 120–122Laminin 265Laminin-5 78, 81, 85, 122Laminin-6 78Langerhans cells 335, 372, 374, 404Leflunomide 359, 424Leucocyte function-associated antigentype 3 437Leucoderma 368Leukaemia 144Leukocyte attraction 352Leukocytoclastic vasculitis 274–275, 278Leukopenia 212Lichen planopilaris 387Lichen planus 11, 145, 188, 231, 333, 337,342, 423Lichen sclerosus 139, 145Lichenoid dermatoses 244, 334, 342, 345Light microscopy 75Lilac ring 139, 142Linear IgA bullous dermatosis 77, 95, 97,110, 434Linear morphea 142, 145Lipatrophy 190Lipodystrophy 233Lipopolysacharides 12Livedo vasculitis 354Local inflammation 82 463 Localized morphea 148Localized scleroderma 133, 135, 151, 172,176Low complement levels 357L-phenylalanine 375Lupus 315Lupus band test 193, 214Lupus erythematosus 74, 100, 145, 183,203, 230, 245, 435– Lupus nephritis 422, 431– Lupus panniculitis 190, 193, 196, 198,209– Lupus profundus 190– Lupus-like syndrome 219Lyme borreliosis 136Lymph drainage 175Lymphocytic infiltrate 191, 267–

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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53

268, 404Lymphocytic perivascular infiltrates 165Lymphoma 105Lysyl pyridinoline 167Lytic enzymes 349 Macrolides 422Malar erythema 231Malar rash 183, 278Mast cells 15, 322Matrix metalloproteinase 82MCTD 245, 249, 252Mechanic hands 173Mechanobullous disease 114, 126Melanocyte autoantigens 371Melanogenesis 370Melanosome 370, 377Meltzer's triad 356Membrane thickening 166Memory T cells 1Metalloproteinases 176, 262Methemoglobulinemia 196Methotrexate 79, 150, 152, 197, 206, 219,239–240, 302, 359–361, 4438-Methoxypsoralen 302, 398Methylprednisolone 219MHC class II 110, 404Microchimerism 166Microscopic polyangiitis 349Microvascular injury 166Milia formation 114Mimicry 408Minoxidil 402Mixed connective tissue disease 245, 247,250, 255Mixed connective tissue disease (MCTD)– Alarcon-Segovia's criteria 252– Anticardiolipin antibody 248– Anti-casein kinase II (CKII) antibody246 464–––– Subject Index Anti-DNA antibody 246Anti-EC antibody 247Anti-HSP 70kDa antibody 246Anti-human endogenous retrovirus(HERV) p30gag ant 248– Anti-U1snRNP autoantibodies 245– Arthritis 250– Autoantibodies 246–301– Classification 252–254– Clinical appearance 249–250– CREST syndrome 248– Criteria 252–255– Diagnostic criteria 250, 252– Endothelin-1 247– Esophageal dysfunction 249– Etiopathogenesis 245– HLA class II 247, 249– Immunological aberrations 247– Leukocytopenia 249– Myositis 250– Nonsteroidal anti-inflammatory drugs 254– Pericarditis 249– Pleuritis 249– Prognosis 256– Pulmonary hypertension 248, 250, 256– Raynaud's phenomenon 250– Sausage-like fingers 249– Sharp's criteria 252– Survival rate 252– Systemic corticosteroids 254– T cell characteristics 247– The Research Committee of theJapanese Ministry 252– Therapy 254– Thrombocytopenia 249Mixed cryoglobulinemia 274Molecular mimicry 11, 246 296, 372Monoamine oxidase A 374Monocytes 349Monozygotic twins 392Morbilliform exanthem 209Morning stiffness 192Morphea 133, 136, 150, 152, 154, 435Morphea en plaque 134Mucocutaneous lesions 48, 341Mucosal inflammation 262Mucous membrane pemphigoid 434–435Multiple sclerosis 425Munro microabscesses 293Muscle biopsy 229Muscle disease 234Muscle weakness 176Mutilating psoriatic arthritis 299Myalgia 170Myasthenia gravis 393Mycophenolate mofetil 79, 127, 219, 239,302 Mycophenolic acid 422Myelin basic protein (MBP) 425Myelodysplastic syndrome 359Myeloperoxidase 349Myenteric nerve plexus 177Myocardial fibrosis 178Myopathy 230, 240Myositis 236, 240Myxedema 393 Nail involvement 387–388Nail pits 387Nailfold capillary dilatation 169Nailfold splinter hemorrhages 354Nasolabial folds 209Necrotizing vasculitis 351Neonatal lupus 274, 276Nephropathy 152, 175, 210Neurological disorders 192Neutrophil elastase 82Neutrophilic granulocytes 293, 298, 349,351Non HLA genes 395Non steroidal anti-inflammatory agents176, 207Nuclear antigens 264 Oedema 168Oesophagus 177Onychomadesis 387Ophiasis 385Oral cavity 72Ortho-hyperkeratosis 293Overlap syndrome 172, 174, 176Oxidative stress 370, 372, 376, 379 Palmoplantar pustular psoriasis 299Palpable purpura 274, 354Panniculitis 233Pansclerotic morphea 144Papillary dermis 102, 295Papular mucinosis-like lesions 234Parakeratosis 293Paraneoplastic dermatosis 210Paraneoplastic pemphigus 45, 77, 342, 441Paraneoplastic vasculitis 356Parry–Romberg syndrome 143Passive transfer 52Patchy hair loss 385Pathogenesis 187, 294Pathogen associated molecular pattern 7Pathogenic autoantibodies 431Pauci-immune vasculitides 353, 358PBL-SCID mouse model 53 Subject IndexPemphaxin 49Pemphigoid 325Pemphigoid gestationis 73, 110Pemphigoid nodularis 72Pemphigus 45, 325, 431–432Pemphigus– a9 acetylcholine receptor 50– Acantholysis 46, 48, 52, 57, 63– Animal models 52–53– Antinuclear Ab 58– Auto-Ab 56– Autoantigens 61– Autoreactive B cells 51, 53– Autoreactive T cells 51–52– Azathioprin 62– B cell lymphoma 56– BP238 50, 57– Castleman's tumor 56– CD4+ T lymphocytes 51– Cholinergic receptor 50– Clinical phenotype 53, 54– Cyclophosphamide 62– Cyclosporin A 62– Desmocollins 47, 50, 58– Desmoglein 3-deficient mouse 52– Desmoplakins I 50, 57– Direct Immunofluorescence microscopy57, 60– Drug-induced pemphigus 57– Dsg1 53, 55, 57, 61, 63– Dsg3 47–48, 51, 53, 55, 57, 61– ELISA 58, 61– Envoplakin 57– Epidemiology 45– Epitopes 48– Etiopathogenesis 46– Fogo selvagem 55– Gastrointestinal disease 58– Glucocorticoids 61– Hallopeau type 60– HD1/plektin 50, 57– Histopathology 60– HLA-DQb1*0503 51– HLA-DRb1*0410 46, 51– HLA-DRb1*1409 46– IgA pemphigus 58– Immunological diagnosis 59– Immunosuppression 62– Immunosuppressive agents 62– Immunosuppressive therapy 62– Incidence 45– Indirect immunofluorescence microscopy60– Interferon-g 57– Intraepidermal neutrophilic dermatosis58– Intravenous immunoglobins 62 ––––––––––––– 465 Lung epithelium 56Lymphoma 45Methotrexate 62Monoclonal IgA gammopathies 58Mucosal involvement 54, 58Mycophenolate mofetil 62Nuclear antigens 50Oral lesions 54, 57Paraneoplastic pemphigus 56Pathogenic auto-Ab 51PBL-SCID Mouse 53Pemphaxin 50Pemphigus erythematosus (SenearUsher) 58– Pemphigus foliaceus 54, 56– Pemphigus herpetiformis 58– Pemphigus sebor rhoicus 56– Pemphigus vegetans 58– Pemphigus vulgaris 54, 56– Penicillamine 45– Periplakin 50, 57– Plasmapheresis 62– Rare pemphigus variants 58– Subcorneal pustular dermatosis 58– Therapy 61– Thymoma 56– Type Neumann 58Pemphigus erythematosus 50Pemphigus foliaceus 45, 432, 441Pemphigus variants 61Pemphigus vulgaris 14, 16, 45, 52, 422, 435Penicillin 153Peptide MHC complex 425–426Perforin 262, 407Pericarditis 250Perifollicular infiltrate 400Peripheral tolerance 3, 5, 428Periplakin 50Perniotic lupus 190Phenylalanine metabolism 375, 377Phenytoin 153Phosphodiesterase-inhibitors 175Phospholipase C 48Photochemotherapy 301–302Photodynamic therapy 153Photopheresis 175Photo-protective clothing 215Photoprovocation 194Photosensitivity 192, 206, 214Phototherapy 301Physiotherapy 175Pimecrolimus 196, 380Pityriasiform lesions 209Plaque morphea 134, 137, 139, 147Plaque psoriasis 435, 443Plaque-like mucinosis 233Plasmapheresis 127, 152, 321, 431 466 Subject Index Plasminogen activator 48, 82–83Plectin 81, 85Pleuritis 249PM-Scl complex 170, 172PM-Scl overlap syndrome 173Poikiloderma 231–232Polymorphic light eruption 211Polymyositis 170–171, 174, 236–237, 240,245Polyneuropathy 355, 360Porphyria cutanea tarda 114, 172, 211Postinflammatory hyperpigmentation400PR3-specific T-cells 352Precursor T cells 2Prednisolone 254Pregnancy 73Pretibial pemphigoid 72Prevalence 26, 34, 133Prognostic markers 80Progressive systemic scleroderma– Alveolitis 177– ANA 172– Anti centromer (CENP-B) antibodies169– Anti-DNA-topoisomerase I antibodies169– Anti-ds DNA antibodies 172– Antifibrotic agents 175– Arthralgia 176– Autoantibodies 165, 171–172– Autoantibody profile 171– Calcinosis 175– Cardiac involvement 178– Clinical presentation 168, 172– Collagen synthesis 167, 175, 178– Collagens 167, 175, 180– Dermatohistopathology 174– Diagnosis 171– Diffuse cutaneous SSc (dSSc) 168–169– D-penicillamine 175– Extracellular matrix 166–167– Gastrointestinal Involvement 177– HLA gene 165– Immune dysregulation 165– Immunosuppressive agents 175– Incidence 168– Interferon-g 175– Limited cutaneous SSc (lSSc) 168–169– Methotrexate 175– Mixed connective tissues disease(MCTD) 170– Musculosceletal involvement 176– Overlap syndromes 170– Physical therapy 174– Pulmonary involvement 170, 175, 177– Quality of life 168 – Raynaud's syndrome 166, 169–170, 172,175, 178– Renal involvement 176– Sclerodactily 172– Scleroderma-like syndromes 170, 173– Scleromyositis (PM-Scl-associated) 170– Skin involvement 175– Synthetase syndrome 170– Systemic lupus erythematosus 172, 178– Systemic sclerosis sine scleroderma169– TGF-beta 167, 178– Therapy 174, 178– UV radiation 176– Vascular pathology 166Propanolol 57Prostacycline 175, 177, 254Prostaglandin 254Proteases 48, 104Proteinase 3 349Proton pump inhibitors 177Prurigo 77Pruritic eruption 95Pseudocatalase 373Pseudolymphoma 276Psoralens 149, 302Psoriasis 17, 231, 298, 423, 435, 444– Psoriasis arthritis 443– Psoriasis cum pustulatione 299– Psoriasis vulgaris 291– Psoriasis-subtypes 292– Psoriatic arthritis 299– Psoriatic autoantigens 296– Psoriatic skin lesions 295–296– Psoriatic spondylarthritis 299– PSORS1 292– PSORS2 292– Psychosocial situation 168Pteridines 374Pulmonary embolism 248Pulmonary fibrosis 179Pulmonary hypertension 250Pulmonary involvement 56, 177Pulse methylprednisolone therapy 239Purpura 278, 355–356Pustular arthroosteitis 299Pustular psoriasis 299, 303PUVA 149, 176Pyoderma gangrenosum 354, 423, 430,435, 443 Quinacrine hydrochloride 216 Radiation 136Rashes 278 Subject IndexRaynaud's phenomenon 133, 166, 171,342Raynaud's syndrome 169Receptor type 1 antagonists 175Regulatory T cell 6, 17, 296Relaxin 175Renal involvement 176, 355Repigmentation 378Respiratory failure 56Retinoids 197Retrovirus 248Rheumatoid arthritis 74, 145, 171, 178, 210,219, 246, 267, 424, 447Rheumatoid factor 213, 275, 352Rheumatoid vasculitis 356Risk factor 29, 31Rituximab 220, 360, 436, 441RNA Polymerase I, III 172Ro autoantigen 204Ro/SS-A 211, 214Rodnan skin score 146, 168, 175 Salicylic acid 301Salivary glands 261–262, 264Salt split skin immunofluorescence 121Scabies 77Scl-70 172SCLE 192–193, 204, 208–209, 211,213–216, 233Scleroderma 133, 138, 170, 176, 230, 250,261, 342– Scleroderma adultorum Buschke 172– Scleroderma overlap syndromes 170– Sclerodermiform genodermatoses 173– Scleromyositis 170– Scleromyxoedema 172– Sclerosis 136, 142, 144– Sclerotic lesions 142– Secondary immune complex-mediatedvasculitides 356, 361Secondary epitopes 81Segmental vitiligo 368–369Self antigens 428Self MHC molecules 265Self-tolerance 421Self-antigens 4, 11Self-reactive T and B Cells 9Shulman Syndrome 144Sicca symptoms 192, 268, 270Silica dust 170Siplizumab 440Sirolimus (Rapamycin) 423Sjogren's syndrome 100, 192, 210–211,248, 261, 265, 271–273, 278-280, 281,283, 285, 287, 289– Antibodies 265 467 – Anti-cardiolipin antibodies 276– Apoptosis of glandular epithelial cells264– Arthralgia 275, 280– Arthralgias– Arthritis 275– Autoantibodies 264, 267, 276– Autoantigens 264– Central nervous system involvement274– Complete heart block 265– Cutaneous manifestations 271– Differential diagnosis 277– Dyspareunia 276– Environmental agents 266– Epidemiology 267– European (EEC) criteria 261, 267– Extraglandular manifestations 273, 275– Extra-glandular symptoms 280– Fatigue 276– Genetic factors 277– Hepatitis C infection 274– HLA associations 277– Hypergammaglobulemic purpura 273– Lacrimal glands 266– Leukopenia 275– Lymphoma 278– Mucosal surface abnormalities 268– Myalgias 275– Myositis 275– Nephritis 277–278– Pathogenesis 261– Peripheral neuropathy 273– Pulmonary involvement 274– Salivary gland 264, 271– San Diego criteria 261– Sialadenitis 264– Sicca symptoms 267, 278– SS-A 264, 276– SS-B 264– Therapeutic principles 279– T-lymphocytes 262– Vasculitis 277– Xerostomia 267Sjogren's syndrome 34, 174, 315Skin cancer 378Skin fragility 112, 114, 117Skin involvement 137Skin prick testing 310Skin sclerosis 146Skin thickness 149Skin-infiltrating T cells 149SLE 110, 177, 183, 191, 197, 209, 220, 248,252, 277–279, 446Small vessel vasculitides 209, 361Soluble CD4 receptor 137Spinous cell carcinoma 188 468 Subject Index Spliceosome 247Squaric acid dibutylester 398SS-A 265, 267, 274SS-A antigens 265SS-B 267, 267, 274SSc 165–166, 168, 171–172, 175–178, 248,252Staphylococcus aureus 351Stem Cell transplantation 445Steroids 206Stomach 177Stratified epithelia 71Streptococcal antigens 294, 297Streptococcal infections 11Subacute cutaneous lupus erythematosus188, 196, 233– ACLE 203, 209– ACR 209– Acute cutaneous LE 203– Alopecia 209– ANA 212, 221– Antimalarials 216– Autoantibodies 204, 212– CCLE 203– Chronic cutaneous LE 203– Clofazimine 219– Cutaneous manifestations 208– Dapsone 218– Definition 203– Differential diagnosis 211– Direct immunofluorescence 213– DLE 208–209– Environmental factors 206– Epidemiology 203– Etiology 204– Exfoliative erythroderma 209– Histopathology 212– HLA-DR3 205– Immunoglobulin 219– Immunoglobulins 213– La/SS-B autoantibodies 212– Laboratory findings 211– Livedo reticularis 209– Local corticosteroids 215– Local therapy 214– Nephritis 209– Nonlesional lupus band test 214– Photosensitivity 206– Prognosis 220– Progressive generalized poikiloderma209– Raynaud's phenomenon 209– Retinoids 218– Ro/SS-A autoantibody 211, 213, 221– Serological findings 213– SLE 220– Smoking 217 – Systemic corticosteroids 219– Systemic disease 209– Systemic therapy 216– Thalidomide 217– Ultraviolet A-1 phototherapy 220– UV light 204– UVA protection 215Subcorneal pustular dermatosis(Sneddon-Wilkinson) 443Subcutaneous amyloid 274Subcutaneous morphea 143Subepidermal bullous diseases 102, 118,122, 341Sublamina densa zone 118–121Sulfmethooxazole 351, 359Sulphapyridine 104Sulphasalazine 153Sun protection factor 215Sunlight induced papulonodular mucinosis209Superantigens 3Superficial morphea 141Susceptibility haplotypes 46Sweet's syndrome 211Symmetric psoriatic polyarthritis 299Systemic disease 194Systemic glucocorticoids 63, 152, 343,397Systemic lupus erythematosus 13, 171,183, 203, 261, 334, 355, 446, 430–431,433, 441Systemic sclerosis 33, 133–134, 146, 165,172, 245, 423, 431, 435, 445–446Systemic therapy 302Systemic vasculitides 349, 353–354, 361 T cell anergy 426, 428T cell epitopes 11T cell receptor (TCR) 1, 4, 425–426T cells 404, 425T helper (Th) cells 8Tacrolimus (FK506) 153, 196, 380, 422Tazarotene 301T-B cell Interactions 2, 16TCR 265, 296Telangiectasia 231Th1 cytokines 82Th2 cytokines 82Thalidomide 196, 430–431Therapy 79, 279Throat infection 294, 300Thrombocytopenia 144, 212Thromboembolisms 248Thrombosis 192, 218Thymic maturation 2Thymus 2, 265 Subject IndexTissue hypoxia 166Tissue injury 296TNF-a 353, 429, 442TNF-a gene polymorphisms 395TNF-a receptor 424, 430TNF-a-antagonists 303Tobacco use 214Toenails 298Tolerance 3, 10, 16, 264, 421, 424–426Tolerogenic dendritic cells (DC) 428–429Toll-like receptors 7Tonsillectomy 300Topical calcipotriol 150Topical corticosteroids 79, 147, 396Topical tacrolimus 215Topical therapy 300Topoisomerase 265Toxic pustuloderma 218Traction alopecia 387Transforming growth factor-b 167Transglutaminase 97, 105Trauma-induced blisters 112Trichohyalin 405Trimethoprim 351, 359Tumor necrosis factor-a 52Tumor necrosis factor-b, 356Type I collagen 167Type I diabetes mellitus 100, 270Type VII collagen 78, 109–112, 115,117–118, 122–123Type XVII collagen 76Tyrosinase 369Tyrosinase antibodies 370 469 U1-RNA-70 kDa protein complex 172, 246Ultraviolet A radiation 147, 398Universal vitiligo 368Urticaria 309Urticarial plaques 97Urticarial vasculitis 274, 315, 318, 354UV exposure 214UV light 204UVA1 176UV-B spectrum 301 Vascular inflammation 229Vascular system 165Vasculitis 77, 275, 277, 349, 357–358, 435Vasodilatators 254, 256Verrucous DLE 188Vessel damage 352Virus infections 186Vitamin D analogues 150, 301Vitiligo 100, 145, 367, 383– acrofacial 368Vulvar pemphigoid 72 Weakness 356Wegener's granulomatosis 349, 351, 422Wickham striae 337 Xeropthalmia 261Xerostomia 261,

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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54

267X-linked chronic granulomatous disease 211 Springer and the EnvironmentW E AT S PRINGER FIRMLY BELIEVE THAT AN INTERnational science publisher has a special obligation tothe environment, and our corporate policies consistently reflect this conviction.W E ALSO EXPECT OUR BUSINESS PARTNERS – PRINTERS ,paper mills, packaging manufacturers, etc. – to committhemselves to using environmentally friendly materials and production processes.T HE PAPER IN THIS BOOK IS MADE FROM NO - CHLORINEpulp and is acid free, in conformance with international standards for paper permanency. <|end|>

management

Michael Hertl - Autoimmune Diseases of the Skin. Pathogenesis. Diagnosis, Management-Springer (2005).txt

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