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Autoimmune bullous diseases
Autoimmune Bullous Diseases Hossein C. Nousari, MD, and Grant J. Anhalt, MD Autoimmune bullous diseases are caused by autoantibodies directed against specific adhesion molecules of the skin and mucous membranes. This report describes new insights derived from studies that have defined precise molecular mechanisms of blister formation in these diseases, and shows how knowledge of these pathophysiologic mechanisms provides a rational approach to diagnosis and treatment. These diseases are divided into 2 categories, depending on whether blistering is intra-epidermal (pemphigus) or subepidermal (pemphigoid and epidermolysis bullosa acquisita [EBA]).
Intra-Epidermal There are 3 major forms of pemphigus: (1) pemphigus vulgaris (PV), (2) pemphigus foliaceus (PF), and (3) paraneoplastic pemphigus (PNP). All have blistering and ulceration of the skin or mucous membranes (or both), loss of epithelial intercellular adhesion (acantholysis), and the presence of pathogenic IgG autoantibodies directed against transmembrane desmosomal proteins, the desmogleins (Dsgs). Each type has distinct clinical and immunopathologic features. Another recently reported form called "IgA pemphigus" may not actually be pemphigus because evidence is lacking for in vivo pathogenicity of the IgA autoantibodies.
PemphigusVulgaris The most common form, PV, affects people primarily during the fourth and fifth decades of life. An immunogenetic predisposition for PV has been well established. Specific alterations in the hypervariable region of the [31 chain of HLA class II genes confer susceptibility to the disease. This has been linked to DRB 1"0402, a subtype of HLA-DR4. Among Ashkenazi Jews, more than 90% of PV patients carry the DRBI*0402 haplotype, which is rare in the general population. 1 On the other hand, the susceptibility for PV in other ethnic groups (including non-Ashkenazi Jews) is linked to a distinct but also rare DQB 1"0503 allele. Infectious agents, particularly herpes virus, have been implicated in triggering other human antoimmune diseases. Most PV patients present with Curr Probl Dermatol, January/February 2000
painful oral ulcerations, or oral lesions develop early in the course of the disease. The oral ulcers in PV have ill-defined borders and favor the posterior buccal mucosae and gingivae. However, any mucous membrane covered by stratified squamous epithelium can be affected. In many patients, lesions appear on mucous membranes as the only clinical manifestation of the disease. Skin lesions, when they appear, are fragile and vesiculobullous and favor the head and neck areas. Later, the lesions extend to the trunk and flexural areas (Figure 1). In severe cases, generalized involvement of the skin may occur. Untreated, the disease progresses relentlessly to death, usually from sepsis, within 5 years of onset. In PV, individual epithelial cells become rounded and lose their intercellular attachment (acantholysis), although attachment to the underlying basement membrane is not disrupted. Direct immunofluorescence of lesions shows consistent IgG and variable complement component 3 deposition on the epithelial cell surfaces without deposition along the basement membrane. In virtually all patients with active disease, indirect immunofluorescence of serum shows circulating IgG autoantibodies that specifically bind to stratified squamous epithelium. For all forms of pemphigus, the cutaneous manifestation can be reproduced by passively transferring human IgG autoantibodies into neonatal mice. 2 The PV antigen is Dsg3, a transmembrane desmosomal cadherin. Diagnosis of PV is established by the presence of (1) characteristic clinical findings, (2) histologic intra-epithelial acantholysis (shown by histologic studies), (3) in vivo-bound IgG autoantibodies on surfaces of affected epithelial cells (revealed by direct immunofluorescence), and (4) either circulating antiepithelial autoantibodies (shown by indirect immunofluorescence) or specific anti-Dsg3 autoantibodies (shown by immunochemical techniques). 3 The anti-Dsg3 autoantibodies cause the acantholysis in pemphigus, seemingly by down-regulating the adhesive function of the antigen. However, the mechanisms by which these autoantibodies induce acantholysis are unknown. The importance of Dsg3 in cellular adhesion of mucosal squamous epithelia was further 17
FIG 1. Pemphigus vulgaris patient with extensive areas of superficial cutaneous erosion on chest. (Nousari, HC)
revealed by the development of genetically engineered mice with a targeted disruption of the Dsg3 gene. 4 Mucosal lesions with the typical macroscopic, histologic, and electron microscopic characteristics of PV developed in these mice. These studies prove that if the Dsg3 molecule is "knocked out" genetically or by the binding of autoantibodies, keratinocytes fall apart. Although oral lesions developed in the Dsg3 knockout mice, skin lesions did not. Recent data may explain this observation. PV patients with blistering restricted to mucous membranes have autoantibodies only against Dsg3. However, those patients in which cutaneous lesions develop have been shown to have antibodies against both Dsg3 and Dsgl, the PF antigen. 5 This may be an example of "epitope spread," in which autoimmune diseases evolve, and in which patients, over time, make antibodies with new specificity, often against related or neighboring antigen molecules. It appears that disruption of Dsg3 alone by autoantibodies is sufficient to cause oral acantholysis, but autoantibodies must "knock out" 2 related adhesion molecules, Dsg3 and Dsgl, to induce blistering in skin. These findings also explain why some patients only have oral lesions, and why early diagnosis and treatment may prevent progression to skin and a more serious prognosis. These pathophysiologic mechanisms establish that the goal of therapy in pemphigus must be directed toward reducing synthesis of the autoantibodies. This is accomplished by the use ofsystemic corticosteroids, alone or, more frequently, in combination with immunosuppressive therapy. Topical therapies have no role in management. The mortality rate for PV is 5% 18
to 10%. Complications secondary to the use of highdose corticosteroids contribute to the current mortality rate, and dosages of prednisone exceeding 1 mg/kg (lean body weight)/day are not recommended. Combination therapy that includes early use of immunosuppressive drugs as steroid sparing agents is advised for cases that would otherwise require excessive doses of prednisone for control. We use the following treatment steps for mildly to more severely affected patients: (1) prednisone alone, (2) prednisone and a nonalkylating agent (azathioprine or mycophenolate mofetil), (3) prednisone and an alkylating agent (cyclophosphamide or chlorambucil), and (4) prednisone and an alkylating agent and shortterm plasmapheresis for immediate disease control. Prednisone alone controls only a minority of cases. The drug should be tapered to and maintained at 5 to 10 mg every other day within 9 to 12 months of initiation. If it is not possible to taper corticosteroids at this rate, combination therapy is indicated. Azathioprine should be used at an initial dosage of 3 to 4 mg/kg/day because lower dosages are less effective at inhibiting autoantibody synthesis. This dosage is maintained for 18 to 24 months, during which prednisone is tapered to 5 mg every other day. Both the efficacy of the drug and the patient's predisposition to severe adverse effects of the drug appear to be mediated by the activity of the enzyme thiopurine methyttransferase. If the activity of this enzyme is low in a patient, the level of azathioprine for a given dose may be high, raising the risk of severe cytopenias. Conversely, a patient with a greater amount of this enzyme may require higher doses for full therapeutic effect. 6 Mycophenolate mofetil (35 to 45 mg/kg/day) has shown promising results in patients with moderate disease and in patients unable to tolerate azathioprine. 7 The most effective agent for control of pemphigus is cyclophosphamide at 2 to 3 mg/kg/day. Because of its numerous toxic effects, it is reserved for refractory or severe cases. Rapid improvement of an aggressive disease can be achieved only by physical removal of circulating autoantibodies by plasmapheresis. This approach must be used with cyclophosphamide to blunt rebound flares that occur after plasmapheresis is stopped. Other immunomodulatory agents such as methotrexate, cyclosporine, immunoglobulin (intravenous), and gold have shown inconsistent results in PV patients. The goals of immunosuppressive therapy are to enhance effectiveness and reduce toxicity. 8 In organ Curr Probl Dermatol, January/February 2000
FIG 2. Pemphigus foliaceus patient with annular scaly erosions on abdomen.
FIG 3. Paraneoplastic pemphigus patient with lichenoid eruption and superficial ruptured blisters on chest.
transplantation and treating autoimmune diseases, these goals are better accomplished with combined therapy. Immunotherapy with altered peptide ligands (Dsg3 and Dsgl) might be an appealing therapeutic alternative. The radical elimination of autoreactive lymphocytes with immunoablative therapy and a high dose of cyclophosphamide, with or without stem cell rescue, may have a place in the therapy for PV. Selective plasmapheresis or immunoapheresis with adsorbing columns of Dsg3 and Dsgl could be an attractive way of rapidly removing pathogenic PV antibodies.
and central Brazil and Colombia and is strongly associated with 4 HLA DRB1 haplotypes DRBI*0404, 1402, 1406, and 1401.11 Unlike all other forms of pemphigus, this disease may occur in multiple family members. Although results of epidemiologic studies are consistent with an environmental agent being causative, the precise agent has not been identified. PF can also occur as a consequence of the administration of certain drugs, most frequently D-penicillamine. Drug-induced pemphigus does not usually disappear when patients stop taking the drug. When the condition is initiated, it behaves like idiopathic pemphigus. Therapy for PF differs from that for PV only in that treatment can be less aggressive, because this form of pemphigus has lower rates of morbidity and mortality.
Pemphigus Foliaceus PF differs from PV in several ways. First, lesions appear only on skin, blisters are superficial (Figure 2), and mucous membranes are never affected in PF. Second, acantholytic blistering occurs only high in the epidermis, just below the cornified outer layer. Third, autoantibodies target only Dsgl. It is now known why lesions have this specific localization. Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsgl is important to cell adhesion, and no protective redundancy of adhesion molecules occurs by co-expression of Dsg3.9 PF is of significant interest because an environmental agent is known to precipitate autoimmunity in 2 forms of the disease. There is an endemic form of PF, called "fogo selvagem." The immunopathologic behavior of this variant is identical to that of PF in North America and Europe, but its epidemiologic characteristics are different. 1° The variant occurs frequently in southwestern Curr Probl Dermatol, January/February 2000
Paraneoplastic Pemphigus PNP develops exclusively in the context of a known or occult neoplasm, 12 most frequently a B-cell lymphoproliferative disorder. These conditions include (in order of decreasing frequency) non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Castleman's disease, thymoma, Waldenstri3m's macroglobulinemia, and spindle cell sarcoma. Painful mucous membrane ulcerations, polymorphous blistering, and lichenoid skin lesions develop in all patients (Figure 3). The acantholytic blistering seen in PNP is caused by autoantibodies against Dsg3 and Dsgl. These autoantibodies are present in all PNP patientsJ 3 These patients also have autoantibodies that act as serologic markers for the disease; they also have autoantibodies against a complex group of sequence-related proteins 19
FIG 4. IgA pemphigus patient with grouped pus-filled blisters on posterior neck.
called plakin proteins (and a 170-kD protein still not characterized). Plakin proteins connect the intermediate filaments of the cytoskeleton with transmembrane desmosomal and hemidesmosomal proteins. The plakin antigens include desmoplakins I and II, bullous pemphigoid (BP) 230 antigen (Ag), envoplakin, periplakin, and plectin. The presence of antiplakin antibodies is the basis for serologically differentiating PV and PE To evaluate sera from these patients, the antigen specificity should be established, preferably by immunochemical techniques such as immunoprecipitation. When associated with a malignant neoplasm, PNP is progressive and almost always fatal within 2 years. Once initiated, the autoimmunity moves forward independently of the underlying neoplasm. However, when PNP is associated with a benign neoplasm such as a benign thymoma or localized Castleman's disease and the tumor is completely excised, the autoimmune disease disappears during the next 6 to 12 months. PNP is the only form of pemphigus in which an internal organ can be affected by autoimmune injury. Progressive respiratory failure caused by puhnonary involvement constitutes the terminal event in approximately 30% of these patients. This complication first manifests itself as obstructive disease affecting both large and small airways. Endobronchial biopsies show acantholytic changes of the respiratory epithelium and deposition of autoantibodies on the surfaces of bronchial epithelial cells. 14 Treatment of PNP has not improved since its description. There is no single optimal therapy, but a
20
FIG 5. Bullous pemphigoid patient with tense and ruptured blisters arising from urticarial plaques on lateral arm,
combination of moderate-dose corticosteroids and cyclosporine provides some palliation. High-dose cyclophosphamide without stem cell rescue was used with success in 1 patient, is Interleukin-6 has been implicated in the pathogenesis of autoimmune diseases, as shown by the elevated levels of interleukin-6 in the sera of PNP patients] 6 This may be taker} into consideration in devising therapy for PNE For example, the preparation and use of monoclonal anti-interleukin-6 antibodies is one way in which cytokines could be manipulated for use in the treatment of PNP.
IgA Pemphigus IgA pemphigus is an uncommon intra-epidermal vesicopustular disease that may clinically and histologically mimick subcorneal pustular dermatosis (Figure 4), PF, and even PV. Patients with all these conditions have IgA antibodies bound to the surfaces of their epidermal cells. However, no studies have shown the in vivo pathogenicity of these IgA autoantibodies. Autoantibodies against desmocollins I have been described in a subset of patients with the subcorneal pustular dermatosis type. These patients usually respond to dapsone, retinoids, or prednisone.
Curr Probl Dermatol, January/l:ebruary 2000
Subepidermal Bullous Pemphigoid Occurring most often in elderly patients, BP is the most common autoimmune blistering skin disease. Oral lesions are rare; when they appear, they are transient and relatively asymptomatic. Skin lesions are typically pruritic, and may first present as urticarial plaques of the trunk and extremities (Figure 5). Subsequently, tense blisters arise, sometimes producing an extensive eruption. Despite the sometimes dramatic appearance of blistering, the morbidity and mortality rates of BP are much lower than in pemphigus. This difference occurs for several reasons. In BR mucosa is not involved, spontaneous remission tends to occur, and patients respond rapidly to therapy. The pathophysiologic mechanisms responsible for this benign course are described below. The sera of BP patients are able to recognize 2 hemidesmosomal antigens. The first one identified was a 230-kD antigen called BP Agl or BP230 Ag. The second was a 180-kD protein called BP Ag2 or BP180 Ag, a transmembrane hemidesmosomal antigen. The BP230 Ag is an intracellular platkin protein. The BPI80 Ag is a unique transmembrane protein with a short noncollagenous ectodomain that lies adjacent to the plasma membrane and a long collagenous ectodomain that interacts with anchoring proteins of the basement membrane. Although 2 antigens are recognized by autoantibodies, only antibodies against the BPI80 Ag have proved to induce blistering in animals. The pathogenic epitopes are at the noncollagenous ectodomain of the BP180 Ag in a motif called NC16A. Unlike pemphigus antibodyinduced cell detachment, in which antibody binding to the cell adhesion molecule directly induced cellular detachment, BP antibodies induce a cascade of inflammatory events that are requisite to blister formation. The production of blisters occurs only after the sequence of antibody binding to the BP180 Ag, complement activation, 17 and polymorphonuclear cell infiltration is completed, is These experimental data help to explain clinical observations about the disease and provide a rational basis for treatment of BR The blistering in BP patients often ceases within 24 to 48 hours of instituting corticosteroid therapy because reducing antibody synthesis is not necessary to halt blistering in BR This is in contrast to pemphigus, and can be explained by the effect of cortico-
Curt Probl Dermatol, January/February 2000
FI6 6. Cicatricial pemphigoid patient with erythematous-based uJcerations on inferior labial mucosa. Borders of ulcerations are welldefined.
steroids at multiple sites in the inflammatory cascade. Several immunomodulatory drugs have been used in treating BE Prednisone is the most useful, because it has anti-inflammatory and immunomodulatory effects, and is often rapidly effective at a dosage of 0.5 mg/kg/ day. In mild cases of BP, anti-inflammatory drugs such as dapsone or certain antibiotics may have steroidsparing effects. In cases of moderate severity, azathioprine at a dosage of 2 to 3 mg/kg or mycophenolate mofetil at a dosage of 30 mg/kg/day can be effective. More aggressive treatment with plasmapheresis and cyclophosphamide is rarely required, but when needed these treatments are effective.
Gestational Pemphigoid Gestational pemphigoid, a blistering disease also known as herpes gestationis, is immunologically similar to BR However, it occurs during the late second or third trimester of pregnancy and lesions disappear promptly after delivery. In this disease, autoantibodies are directed almost exclusively against the NC 16A epitope of BP180.19 Gestational pemphigoid is of interest because autoantibody production can be induced by pregnancy, molar pregnancies, ovarian tumors, and challenge with oral estrogens. The mechanisms of this hormonal induction are unknown. Prednisone is the "gold standard" therapy for this disease.
Cicatricial Pemphigoid Cicatricial pempbigoid (CP) is a subepithelial blistering disease that involves (almost exclusively) tile
21
IgA Pemphigoid IgA pemphigoid (linear IgA bullous disease) occurs in preschool children and adults. The condition is characterized by the presence of pruritic vesicobullous lesions distributed over the trunk. Mucosal involvement may be present or absent. A transient druginduced variant was recently reported in association with vancomycin and several other drugs. 21 Immunofluorescence studies show a linear deposition of IgA along the basement membrane in both entities. This disease may represent several different conditions mediated by a single immunoglobulin isotype. One of the most common autoantigens in this disease, the 120-kD lamina lucida antigen, formerly identified as a 97-kD antigen, is the entire collagenous component and part of the NC16A ectodomain of the BP180 antigen. 22 Prednisone alone or in conjunction with dapsone is usually effective in the treatment of this disease.
Epidermolysis Bullosa Acquisita FIG 7. Epidermoiysis bullosa acquisita patient with ruptured bullae and areas of scarring on lateral thigh and buttock.
mucous membranes and leads to scarring and dysfunction of the affected organs. The immunohistologic features of CR though similar to those of BR are distinguished by 2 characteristics: (1) a predominance of scarring mucosal lesions (Figure 6) and (2) the presence of circulating autoantibodies (detectable by conventional immunochemical techniques) directed against the basement membrane in only a minority of patients. The autoantibodies (in patients who have them) display activity against a wide variety of basement membrane components,;° including (but not limited to) BP180 Ag and BP130 Ag, laminin-5, and type VII collagen. However, CP patients present in different ways that cannot be explained by different reactivities with specific antigens. Azathioprine, dapsone, and corticosteroids (topical and systemic) are effective in cases i~vithmild to moderate oral, nasal, and anogenital involvement as well as cutaneous disease. However, in refractory, life-threatening cases, or when lesions involve the conjunctiva or pharyngoesophageal and tracheobronchial mucosae, more aggressive treatment with cyclophosphamide and prednisone should be applied early to prevent severe morbidity and occasional mortality.
22
EBA is an uncommon subepithelial blistering disease characterized by the presence of scarring lesions, predominantly in areas of trauma (Figure 7). Blisters occur beneath the lamina densa of the basement membrane. Immunologic studies indicate that EBA patients have IgG autoantibodies reactive against various epitopes of type VII collagen, the most dominant of those found in fibronectin-like repeating units within the molecule. 23 These repeating units bind the ~33 chain of laminin-5, so perturbation of the NCl-laminin 5 interaction may contribute to the pathogenesis of the disease. An association between EBA and HLA-DR2 has been reported. In unusual circumstances, subepidermal blisters develop in patients with systemic lupus erythematosus, the result of development of autoantibodies against type VII collagen or other mechanisms. This condition is known as bullous systemic lupus erythematosus. This disease and EBA have similar immunopathologic and genetic features, but they differ in some histologic and therapeutic characteristics. Inflammatory bowel disease is the most common disease associated with EBA. A significant number of patients with Crohn's disease have circulating antibodies against the NC 1 domain of type VII collagen, but the disease develops in only a few of such patients. More data are necessary to explain this phenomenon. EBA is probably the most refractory of the subepidermal autoimmune bullous diseases, and prednisone,
Curr Probl Dermatol, )anuary/February 2000
azathioprine, alkylating agents, and cyclosporine are presumably the most effective drugs. Anecdotal reports of the use of other anti-inflammatory medications and plasmapheresis have appeared.
Dermatitis Herpetiformis Dermatitis herpetiformis (DH) is a peculiar inflammatory skin disease usually included among autoimmune subepidermal blistering diseases, although no autoantigen has been identified in the skin of a patient. DH is an uncommon IgA-mediated bullous disease with a mean age of onset occurring in the fourth decade. Primary lesions consist of pruritic papulovesicles on extensor surfaces. Although most patients have histologic evidence of a gluten-sensitive enteropathy, only approximately 10% are symptomatic. An association with HLA haplotypes DQ (alpha 1"0501, beta l*02/alpha 1"03, beta 1"0302) has been reported. Ultrastructural and immunochemical studies have shown IgA immunocomplex deposition around fibrillin, the most important protein of the microfibrils in the upper dermis. IgA anti-endomisial antibodies are the most specific and sensitive antibodies found in DH and glutensensitive enteropathy. Recent studies show that the antigen of these antibodies is the tissue transglutaminase (TGase). TGase is a calcium-dependent enzyme that catalyzes the transamidation of specific bound glutamine residues. TGase selectively deamidates gluten peptides, which in turn results in a strongly enhanced T-cell stimulatory activity leading to amplification of the gluten-specific T-cell responses. This deamidation creates an epitope in gliadin that binds efficiently to DQ2 and is recognized by gut-derived T cells. This generation of epitopes by enzymatic modification is a new mechanism that may be relevant for breaking tolerance and initiation of the gastrointestinal and cutaneous diseaseY Several proteases are responsible for the degradation of the basement membrane in DH lesions. Restriction of gluten and antineutrophil drugs such as dapsone and sulfapyridine are the "gold standards" of therapy. A retrospective study shows that a gluten-free diet appears to protect against the development of lymphoma in DH patients. 25
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bility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptide in PV. Proc Natl Acad Sci USA 1995;92:11935-9. Anhalt GJ, Labib RS, Vorhees JJ, et al. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med 1982;306:1189-96. Lenz P, Amagai M, Volc-Platzer B, et al. Desmoglein-3 ELISA: a pemphigus vulgaris-specific diagnostic tool. Arch Dermatol 1999;135:143-8. Koch PJ, Mahoney MG, Ishikawa H, et al. Targeted disruption of the PV antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to PV. J Cell Biol 1997;137:1091-102. Ding X, Aoki V, Mascaro JM, et al. Mucosal and mucocutaneous (generalized) pemphigus vulgaris show distinct autoantibody profiles. J Invest Dermatol 1997;109:592-6. Snow IL, Gibson LB. The role of genetic variation in thiopurine methyltransferase activity and efficacy and/or side effects of azathioprine in dermatologic patients. Arch Dermatol 1995;131:193-7. Nousari HC, Sragovich A, Kimyai-Asadi A, et al. Mycophenolate mofetfl in autoimmune and inflammatory skin disorders. J Am Acad Dermatol 1999;40:265-8. Kahan BD. The three fates of immunosuppression in the next millennium: selectivity, synergy, and specifcity. Transplant 1996;9:527-34. Mahoney MY, Wang Z, Rothenberger K, et al. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest 1999; 103:461-8. Rock B, Martins CR, Theofilopoulos AN, et al. The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus. N Engl J Med 1989;320:1463-9. Moraes ME, Feruandez-Vina M, V. Stasny P, et al. An epitope in the third hypervariable region of the DRB 1 gene is involved in the susceptibility to endemic pemphigus foliaceus (fogo selvagem) in the three different Brazilian populations. Tissue antigens 1997;49:35-40. Anhalt GJ, Kim S-C, Stanley IR, et al. Paraneoplastic pemphigus. An autoirnmune mucocutaneous disease associated with neoplasia. N Engl J Med 1990;323:1729-35. Amagai M, Nishikawa T, Nousari HC, et al. Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice. J Clin Invest 1998;102:775-82. Nousari HC, Deterding R, Wojtczack HA, et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med 1999;340:1406-10. Nousari HC, Brodsky RA, Jones Ri, et al. Immunoablative high-dose cyclophosphamide without stem cell rescue in paraneoplastic pemphigus: report of a case and review of this new therapy for severe autoimmune disease. J Am Acad Dermatol 1999;40:750-4. Nousari HC, Kimyai-Asadi A, Anhalt GJ. Elevated serum levels of interleukin-6 in paraneoplastic pemphigus. J Invest Dermatol 1999;112:396-8. Liu Z, Giudice GJ, Swartz SJ, et al. The role of complement
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in experimental bullous pemphigoid. J Clin Invest 1995;95: 1539-44. Liu Z, Guidice GJ, Zhou X, et al. A major role for neutrophils in experimental bullous pemphigoid. J Clin Invest 1997; 100:1256-63. Giudice GJ, Emery DJ, Zelickson BD, et al. Bullous pemphigoid and herpes gestationis autoantibodies recognize a common noncollagenous site on the BP 180 ectodomain. J Immunol 1993;151:5742-50. Shimizu H, Masunaga T, Ishiko A, et al. Autoantibodies from patients with cicatricial pemphigoid target different sites in epidermal basement membrane. J Invest Dermatol 1995;104:370-3. Nousari HC, Kimyai-Asadi A, Caeiro JP, et al. Clinical, demographic, and immunopathologic features of vancomycinassociated linear IgA bullous disease. Medicine 1999;78:1-8.
22. Zone JJ, Taylor TB, Meyer U, et al. The 97 kDa linear IgA bullous disease antigen is identical to a portion of the extracellular domain of the 180 Wa bullous pemphigoid antigen, BPAg2. J Invest Dermatol 1998;110:207-10. 23. Jones DA, Hunt III SW, Prisayanh PS, et al. Immunodominant autoepitopes of type VII collagen are short, paired peptide sequences within the fibronectin type III homology region of the noncollagenous (NC 1) domain. J Invest Dermatol 1995;104:231-5. 24. Molberg 0, Mcadam SN, Komer R, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 1998;4;7137. 25. Lewis HM, Renaula TL, Garioch JJ, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis. Br J Dermatol 1996;135:363-7.
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Intra-Epidermal There are 3 major forms of pemphigus: (1) pemphigus vulgaris (PV), (2) pemphigus foliaceus (PF), and (3) paraneoplastic pemphigus (PNP). All have blistering and ulceration of the skin or mucous membranes (or both), loss of epithelial intercellular adhesion (acantholysis), and the presence of pathogenic IgG autoantibodies directed against transmembrane desmosomal proteins, the desmogleins (Dsgs). Each type has distinct clinical and immunopathologic features. Another recently reported form called "IgA pemphigus" may not actually be pemphigus because evidence is lacking for in vivo pathogenicity of the IgA autoantibodies.
PemphigusVulgaris The most common form, PV, affects people primarily during the fourth and fifth decades of life. An immunogenetic predisposition for PV has been well established. Specific alterations in the hypervariable region of the [31 chain of HLA class II genes confer susceptibility to the disease. This has been linked to DRB 1"0402, a subtype of HLA-DR4. Among Ashkenazi Jews, more than 90% of PV patients carry the DRBI*0402 haplotype, which is rare in the general population. 1 On the other hand, the susceptibility for PV in other ethnic groups (including non-Ashkenazi Jews) is linked to a distinct but also rare DQB 1"0503 allele. Infectious agents, particularly herpes virus, have been implicated in triggering other human antoimmune diseases. Most PV patients present with Curr Probl Dermatol, January/February 2000
painful oral ulcerations, or oral lesions develop early in the course of the disease. The oral ulcers in PV have ill-defined borders and favor the posterior buccal mucosae and gingivae. However, any mucous membrane covered by stratified squamous epithelium can be affected. In many patients, lesions appear on mucous membranes as the only clinical manifestation of the disease. Skin lesions, when they appear, are fragile and vesiculobullous and favor the head and neck areas. Later, the lesions extend to the trunk and flexural areas (Figure 1). In severe cases, generalized involvement of the skin may occur. Untreated, the disease progresses relentlessly to death, usually from sepsis, within 5 years of onset. In PV, individual epithelial cells become rounded and lose their intercellular attachment (acantholysis), although attachment to the underlying basement membrane is not disrupted. Direct immunofluorescence of lesions shows consistent IgG and variable complement component 3 deposition on the epithelial cell surfaces without deposition along the basement membrane. In virtually all patients with active disease, indirect immunofluorescence of serum shows circulating IgG autoantibodies that specifically bind to stratified squamous epithelium. For all forms of pemphigus, the cutaneous manifestation can be reproduced by passively transferring human IgG autoantibodies into neonatal mice. 2 The PV antigen is Dsg3, a transmembrane desmosomal cadherin. Diagnosis of PV is established by the presence of (1) characteristic clinical findings, (2) histologic intra-epithelial acantholysis (shown by histologic studies), (3) in vivo-bound IgG autoantibodies on surfaces of affected epithelial cells (revealed by direct immunofluorescence), and (4) either circulating antiepithelial autoantibodies (shown by indirect immunofluorescence) or specific anti-Dsg3 autoantibodies (shown by immunochemical techniques). 3 The anti-Dsg3 autoantibodies cause the acantholysis in pemphigus, seemingly by down-regulating the adhesive function of the antigen. However, the mechanisms by which these autoantibodies induce acantholysis are unknown. The importance of Dsg3 in cellular adhesion of mucosal squamous epithelia was further 17
FIG 1. Pemphigus vulgaris patient with extensive areas of superficial cutaneous erosion on chest. (Nousari, HC)
revealed by the development of genetically engineered mice with a targeted disruption of the Dsg3 gene. 4 Mucosal lesions with the typical macroscopic, histologic, and electron microscopic characteristics of PV developed in these mice. These studies prove that if the Dsg3 molecule is "knocked out" genetically or by the binding of autoantibodies, keratinocytes fall apart. Although oral lesions developed in the Dsg3 knockout mice, skin lesions did not. Recent data may explain this observation. PV patients with blistering restricted to mucous membranes have autoantibodies only against Dsg3. However, those patients in which cutaneous lesions develop have been shown to have antibodies against both Dsg3 and Dsgl, the PF antigen. 5 This may be an example of "epitope spread," in which autoimmune diseases evolve, and in which patients, over time, make antibodies with new specificity, often against related or neighboring antigen molecules. It appears that disruption of Dsg3 alone by autoantibodies is sufficient to cause oral acantholysis, but autoantibodies must "knock out" 2 related adhesion molecules, Dsg3 and Dsgl, to induce blistering in skin. These findings also explain why some patients only have oral lesions, and why early diagnosis and treatment may prevent progression to skin and a more serious prognosis. These pathophysiologic mechanisms establish that the goal of therapy in pemphigus must be directed toward reducing synthesis of the autoantibodies. This is accomplished by the use ofsystemic corticosteroids, alone or, more frequently, in combination with immunosuppressive therapy. Topical therapies have no role in management. The mortality rate for PV is 5% 18
to 10%. Complications secondary to the use of highdose corticosteroids contribute to the current mortality rate, and dosages of prednisone exceeding 1 mg/kg (lean body weight)/day are not recommended. Combination therapy that includes early use of immunosuppressive drugs as steroid sparing agents is advised for cases that would otherwise require excessive doses of prednisone for control. We use the following treatment steps for mildly to more severely affected patients: (1) prednisone alone, (2) prednisone and a nonalkylating agent (azathioprine or mycophenolate mofetil), (3) prednisone and an alkylating agent (cyclophosphamide or chlorambucil), and (4) prednisone and an alkylating agent and shortterm plasmapheresis for immediate disease control. Prednisone alone controls only a minority of cases. The drug should be tapered to and maintained at 5 to 10 mg every other day within 9 to 12 months of initiation. If it is not possible to taper corticosteroids at this rate, combination therapy is indicated. Azathioprine should be used at an initial dosage of 3 to 4 mg/kg/day because lower dosages are less effective at inhibiting autoantibody synthesis. This dosage is maintained for 18 to 24 months, during which prednisone is tapered to 5 mg every other day. Both the efficacy of the drug and the patient's predisposition to severe adverse effects of the drug appear to be mediated by the activity of the enzyme thiopurine methyttransferase. If the activity of this enzyme is low in a patient, the level of azathioprine for a given dose may be high, raising the risk of severe cytopenias. Conversely, a patient with a greater amount of this enzyme may require higher doses for full therapeutic effect. 6 Mycophenolate mofetil (35 to 45 mg/kg/day) has shown promising results in patients with moderate disease and in patients unable to tolerate azathioprine. 7 The most effective agent for control of pemphigus is cyclophosphamide at 2 to 3 mg/kg/day. Because of its numerous toxic effects, it is reserved for refractory or severe cases. Rapid improvement of an aggressive disease can be achieved only by physical removal of circulating autoantibodies by plasmapheresis. This approach must be used with cyclophosphamide to blunt rebound flares that occur after plasmapheresis is stopped. Other immunomodulatory agents such as methotrexate, cyclosporine, immunoglobulin (intravenous), and gold have shown inconsistent results in PV patients. The goals of immunosuppressive therapy are to enhance effectiveness and reduce toxicity. 8 In organ Curr Probl Dermatol, January/February 2000
FIG 2. Pemphigus foliaceus patient with annular scaly erosions on abdomen.
FIG 3. Paraneoplastic pemphigus patient with lichenoid eruption and superficial ruptured blisters on chest.
transplantation and treating autoimmune diseases, these goals are better accomplished with combined therapy. Immunotherapy with altered peptide ligands (Dsg3 and Dsgl) might be an appealing therapeutic alternative. The radical elimination of autoreactive lymphocytes with immunoablative therapy and a high dose of cyclophosphamide, with or without stem cell rescue, may have a place in the therapy for PV. Selective plasmapheresis or immunoapheresis with adsorbing columns of Dsg3 and Dsgl could be an attractive way of rapidly removing pathogenic PV antibodies.
and central Brazil and Colombia and is strongly associated with 4 HLA DRB1 haplotypes DRBI*0404, 1402, 1406, and 1401.11 Unlike all other forms of pemphigus, this disease may occur in multiple family members. Although results of epidemiologic studies are consistent with an environmental agent being causative, the precise agent has not been identified. PF can also occur as a consequence of the administration of certain drugs, most frequently D-penicillamine. Drug-induced pemphigus does not usually disappear when patients stop taking the drug. When the condition is initiated, it behaves like idiopathic pemphigus. Therapy for PF differs from that for PV only in that treatment can be less aggressive, because this form of pemphigus has lower rates of morbidity and mortality.
Pemphigus Foliaceus PF differs from PV in several ways. First, lesions appear only on skin, blisters are superficial (Figure 2), and mucous membranes are never affected in PF. Second, acantholytic blistering occurs only high in the epidermis, just below the cornified outer layer. Third, autoantibodies target only Dsgl. It is now known why lesions have this specific localization. Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsgl is important to cell adhesion, and no protective redundancy of adhesion molecules occurs by co-expression of Dsg3.9 PF is of significant interest because an environmental agent is known to precipitate autoimmunity in 2 forms of the disease. There is an endemic form of PF, called "fogo selvagem." The immunopathologic behavior of this variant is identical to that of PF in North America and Europe, but its epidemiologic characteristics are different. 1° The variant occurs frequently in southwestern Curr Probl Dermatol, January/February 2000
Paraneoplastic Pemphigus PNP develops exclusively in the context of a known or occult neoplasm, 12 most frequently a B-cell lymphoproliferative disorder. These conditions include (in order of decreasing frequency) non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Castleman's disease, thymoma, Waldenstri3m's macroglobulinemia, and spindle cell sarcoma. Painful mucous membrane ulcerations, polymorphous blistering, and lichenoid skin lesions develop in all patients (Figure 3). The acantholytic blistering seen in PNP is caused by autoantibodies against Dsg3 and Dsgl. These autoantibodies are present in all PNP patientsJ 3 These patients also have autoantibodies that act as serologic markers for the disease; they also have autoantibodies against a complex group of sequence-related proteins 19
FIG 4. IgA pemphigus patient with grouped pus-filled blisters on posterior neck.
called plakin proteins (and a 170-kD protein still not characterized). Plakin proteins connect the intermediate filaments of the cytoskeleton with transmembrane desmosomal and hemidesmosomal proteins. The plakin antigens include desmoplakins I and II, bullous pemphigoid (BP) 230 antigen (Ag), envoplakin, periplakin, and plectin. The presence of antiplakin antibodies is the basis for serologically differentiating PV and PE To evaluate sera from these patients, the antigen specificity should be established, preferably by immunochemical techniques such as immunoprecipitation. When associated with a malignant neoplasm, PNP is progressive and almost always fatal within 2 years. Once initiated, the autoimmunity moves forward independently of the underlying neoplasm. However, when PNP is associated with a benign neoplasm such as a benign thymoma or localized Castleman's disease and the tumor is completely excised, the autoimmune disease disappears during the next 6 to 12 months. PNP is the only form of pemphigus in which an internal organ can be affected by autoimmune injury. Progressive respiratory failure caused by puhnonary involvement constitutes the terminal event in approximately 30% of these patients. This complication first manifests itself as obstructive disease affecting both large and small airways. Endobronchial biopsies show acantholytic changes of the respiratory epithelium and deposition of autoantibodies on the surfaces of bronchial epithelial cells. 14 Treatment of PNP has not improved since its description. There is no single optimal therapy, but a
20
FIG 5. Bullous pemphigoid patient with tense and ruptured blisters arising from urticarial plaques on lateral arm,
combination of moderate-dose corticosteroids and cyclosporine provides some palliation. High-dose cyclophosphamide without stem cell rescue was used with success in 1 patient, is Interleukin-6 has been implicated in the pathogenesis of autoimmune diseases, as shown by the elevated levels of interleukin-6 in the sera of PNP patients] 6 This may be taker} into consideration in devising therapy for PNE For example, the preparation and use of monoclonal anti-interleukin-6 antibodies is one way in which cytokines could be manipulated for use in the treatment of PNP.
IgA Pemphigus IgA pemphigus is an uncommon intra-epidermal vesicopustular disease that may clinically and histologically mimick subcorneal pustular dermatosis (Figure 4), PF, and even PV. Patients with all these conditions have IgA antibodies bound to the surfaces of their epidermal cells. However, no studies have shown the in vivo pathogenicity of these IgA autoantibodies. Autoantibodies against desmocollins I have been described in a subset of patients with the subcorneal pustular dermatosis type. These patients usually respond to dapsone, retinoids, or prednisone.
Curr Probl Dermatol, January/l:ebruary 2000
Subepidermal Bullous Pemphigoid Occurring most often in elderly patients, BP is the most common autoimmune blistering skin disease. Oral lesions are rare; when they appear, they are transient and relatively asymptomatic. Skin lesions are typically pruritic, and may first present as urticarial plaques of the trunk and extremities (Figure 5). Subsequently, tense blisters arise, sometimes producing an extensive eruption. Despite the sometimes dramatic appearance of blistering, the morbidity and mortality rates of BP are much lower than in pemphigus. This difference occurs for several reasons. In BR mucosa is not involved, spontaneous remission tends to occur, and patients respond rapidly to therapy. The pathophysiologic mechanisms responsible for this benign course are described below. The sera of BP patients are able to recognize 2 hemidesmosomal antigens. The first one identified was a 230-kD antigen called BP Agl or BP230 Ag. The second was a 180-kD protein called BP Ag2 or BP180 Ag, a transmembrane hemidesmosomal antigen. The BP230 Ag is an intracellular platkin protein. The BPI80 Ag is a unique transmembrane protein with a short noncollagenous ectodomain that lies adjacent to the plasma membrane and a long collagenous ectodomain that interacts with anchoring proteins of the basement membrane. Although 2 antigens are recognized by autoantibodies, only antibodies against the BPI80 Ag have proved to induce blistering in animals. The pathogenic epitopes are at the noncollagenous ectodomain of the BP180 Ag in a motif called NC16A. Unlike pemphigus antibodyinduced cell detachment, in which antibody binding to the cell adhesion molecule directly induced cellular detachment, BP antibodies induce a cascade of inflammatory events that are requisite to blister formation. The production of blisters occurs only after the sequence of antibody binding to the BP180 Ag, complement activation, 17 and polymorphonuclear cell infiltration is completed, is These experimental data help to explain clinical observations about the disease and provide a rational basis for treatment of BR The blistering in BP patients often ceases within 24 to 48 hours of instituting corticosteroid therapy because reducing antibody synthesis is not necessary to halt blistering in BR This is in contrast to pemphigus, and can be explained by the effect of cortico-
Curt Probl Dermatol, January/February 2000
FI6 6. Cicatricial pemphigoid patient with erythematous-based uJcerations on inferior labial mucosa. Borders of ulcerations are welldefined.
steroids at multiple sites in the inflammatory cascade. Several immunomodulatory drugs have been used in treating BE Prednisone is the most useful, because it has anti-inflammatory and immunomodulatory effects, and is often rapidly effective at a dosage of 0.5 mg/kg/ day. In mild cases of BP, anti-inflammatory drugs such as dapsone or certain antibiotics may have steroidsparing effects. In cases of moderate severity, azathioprine at a dosage of 2 to 3 mg/kg or mycophenolate mofetil at a dosage of 30 mg/kg/day can be effective. More aggressive treatment with plasmapheresis and cyclophosphamide is rarely required, but when needed these treatments are effective.
Gestational Pemphigoid Gestational pemphigoid, a blistering disease also known as herpes gestationis, is immunologically similar to BR However, it occurs during the late second or third trimester of pregnancy and lesions disappear promptly after delivery. In this disease, autoantibodies are directed almost exclusively against the NC 16A epitope of BP180.19 Gestational pemphigoid is of interest because autoantibody production can be induced by pregnancy, molar pregnancies, ovarian tumors, and challenge with oral estrogens. The mechanisms of this hormonal induction are unknown. Prednisone is the "gold standard" therapy for this disease.
Cicatricial Pemphigoid Cicatricial pempbigoid (CP) is a subepithelial blistering disease that involves (almost exclusively) tile
21
IgA Pemphigoid IgA pemphigoid (linear IgA bullous disease) occurs in preschool children and adults. The condition is characterized by the presence of pruritic vesicobullous lesions distributed over the trunk. Mucosal involvement may be present or absent. A transient druginduced variant was recently reported in association with vancomycin and several other drugs. 21 Immunofluorescence studies show a linear deposition of IgA along the basement membrane in both entities. This disease may represent several different conditions mediated by a single immunoglobulin isotype. One of the most common autoantigens in this disease, the 120-kD lamina lucida antigen, formerly identified as a 97-kD antigen, is the entire collagenous component and part of the NC16A ectodomain of the BP180 antigen. 22 Prednisone alone or in conjunction with dapsone is usually effective in the treatment of this disease.
Epidermolysis Bullosa Acquisita FIG 7. Epidermoiysis bullosa acquisita patient with ruptured bullae and areas of scarring on lateral thigh and buttock.
mucous membranes and leads to scarring and dysfunction of the affected organs. The immunohistologic features of CR though similar to those of BR are distinguished by 2 characteristics: (1) a predominance of scarring mucosal lesions (Figure 6) and (2) the presence of circulating autoantibodies (detectable by conventional immunochemical techniques) directed against the basement membrane in only a minority of patients. The autoantibodies (in patients who have them) display activity against a wide variety of basement membrane components,;° including (but not limited to) BP180 Ag and BP130 Ag, laminin-5, and type VII collagen. However, CP patients present in different ways that cannot be explained by different reactivities with specific antigens. Azathioprine, dapsone, and corticosteroids (topical and systemic) are effective in cases i~vithmild to moderate oral, nasal, and anogenital involvement as well as cutaneous disease. However, in refractory, life-threatening cases, or when lesions involve the conjunctiva or pharyngoesophageal and tracheobronchial mucosae, more aggressive treatment with cyclophosphamide and prednisone should be applied early to prevent severe morbidity and occasional mortality.
22
EBA is an uncommon subepithelial blistering disease characterized by the presence of scarring lesions, predominantly in areas of trauma (Figure 7). Blisters occur beneath the lamina densa of the basement membrane. Immunologic studies indicate that EBA patients have IgG autoantibodies reactive against various epitopes of type VII collagen, the most dominant of those found in fibronectin-like repeating units within the molecule. 23 These repeating units bind the ~33 chain of laminin-5, so perturbation of the NCl-laminin 5 interaction may contribute to the pathogenesis of the disease. An association between EBA and HLA-DR2 has been reported. In unusual circumstances, subepidermal blisters develop in patients with systemic lupus erythematosus, the result of development of autoantibodies against type VII collagen or other mechanisms. This condition is known as bullous systemic lupus erythematosus. This disease and EBA have similar immunopathologic and genetic features, but they differ in some histologic and therapeutic characteristics. Inflammatory bowel disease is the most common disease associated with EBA. A significant number of patients with Crohn's disease have circulating antibodies against the NC 1 domain of type VII collagen, but the disease develops in only a few of such patients. More data are necessary to explain this phenomenon. EBA is probably the most refractory of the subepidermal autoimmune bullous diseases, and prednisone,
Curr Probl Dermatol, )anuary/February 2000
azathioprine, alkylating agents, and cyclosporine are presumably the most effective drugs. Anecdotal reports of the use of other anti-inflammatory medications and plasmapheresis have appeared.
Dermatitis Herpetiformis Dermatitis herpetiformis (DH) is a peculiar inflammatory skin disease usually included among autoimmune subepidermal blistering diseases, although no autoantigen has been identified in the skin of a patient. DH is an uncommon IgA-mediated bullous disease with a mean age of onset occurring in the fourth decade. Primary lesions consist of pruritic papulovesicles on extensor surfaces. Although most patients have histologic evidence of a gluten-sensitive enteropathy, only approximately 10% are symptomatic. An association with HLA haplotypes DQ (alpha 1"0501, beta l*02/alpha 1"03, beta 1"0302) has been reported. Ultrastructural and immunochemical studies have shown IgA immunocomplex deposition around fibrillin, the most important protein of the microfibrils in the upper dermis. IgA anti-endomisial antibodies are the most specific and sensitive antibodies found in DH and glutensensitive enteropathy. Recent studies show that the antigen of these antibodies is the tissue transglutaminase (TGase). TGase is a calcium-dependent enzyme that catalyzes the transamidation of specific bound glutamine residues. TGase selectively deamidates gluten peptides, which in turn results in a strongly enhanced T-cell stimulatory activity leading to amplification of the gluten-specific T-cell responses. This deamidation creates an epitope in gliadin that binds efficiently to DQ2 and is recognized by gut-derived T cells. This generation of epitopes by enzymatic modification is a new mechanism that may be relevant for breaking tolerance and initiation of the gastrointestinal and cutaneous diseaseY Several proteases are responsible for the degradation of the basement membrane in DH lesions. Restriction of gluten and antineutrophil drugs such as dapsone and sulfapyridine are the "gold standards" of therapy. A retrospective study shows that a gluten-free diet appears to protect against the development of lymphoma in DH patients. 25
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