Cicatricial pemphigoid: immunopathogenesis and treatment

Dermatologic Therapy, Vol. 15, 2002, 382±388 Printed in the United States
All rights reserved

Copyright # Blackwell Publishing, Inc., 2002

DERMATOLOGIC THERAPY ISSN 1396-0296

Cicatricial pemphigoid: immunopathogenesis and treatment ZELMIRA LAZAROVA*

&

KIM B. YANCEYy

*Department of Dermatology, Johns Hopkins University, Baltimore, Maryland, and y Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin

ABSTRACT: Cicatricial pemphigoid (CP) is a chronic, autoimmune, subepidermal blistering disease of mucous membranes and skin that has a tendency to scar and result in tissue destruction. Recent studies demonstrate that CP is a heterogeneous disease in which patients can resemble each other clinically, histologically, and immunopathologically, but have autoantibodies that target different autoantigens in the epidermal basement membrane. Accordingly CP is now considered to be a disease phenotype rather than a single nosologic entity. CP can be associated with substantial morbidity, and in rare instances, mortality. Currently the management of patients with CP is grounded in clinical experience rather than the results of large randomized trials. This article discusses recent advances in the understanding of this disorder's pathophysiology and treatment. KEYWORDS: autoimmunity, basement membrane, bullous disease, pemphigoid, therapy.

Cicatricial pemphigoid (CP) or mucous membrane pemphigoid (MMP) refers to a group of rare, chronic autoimmune blistering disorders of mucous membranes and skin. Common clinical features include oral mucosal erosions, desquamative gingivitis, and cicatrizing conjunctivitis. Other mucous membranes such as the esophageal, laryngeal, genital, and rectal mucosa may be affected as well (1 ± 3). Scarring of mucous membranes is common, hence the designation of this disorder as cicatricial (i.e., scarring) pemphigoid (4). Severely affected individuals may develop adhesions and strictures in the conjunctival, laryngeal, esophageal, and urogenital mucosa. Examples of such complications in the eye include symblepharon, ankyloblepharon, ectropion, entropion, and/or corneal opacities that may lead to blindness. Skin lesions develop in approximately one-third of patients with CP Address correspondence and reprint requests to: Zelmira Lazarova, MD, Department of Dermatology, Immunodermatology Laboratory, Johns Hopkins University, 720 Rutland Ave., Ross Building, Room 771, Baltimore, MD 21205, or email: [email protected].

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and tend to predominate on the scalp, face, shoulders, and upper trunk. Such lesions are typically characterized as small scattered vesiculobullae that burst soon after formation and evolve into crusted erosions. Less commonly, lesions present as widespread vesicles and bullae that resemble those seen in patients with bullous pemphigoid (BP). Immunopathologic and immunohistochemical studies demonstrated that patients with CP have in situ deposits of immunoreactants in epithelial basement membranes (5 ± 9). Circulating antibasement membrane autoantibodies have been detected in the serum of many patients using sensitive test substrates and state-of-the-art immunofluorescence microscopy techniques. Indeed, anti-basement membrane autoantibodies are believed to be responsible for the immunopathogenesis of this disease (see below). Of interest is that recent studies have shown that autoantibodies from CP patients that resemble each other clinically, histologically, and immunopathologically may target different autoantigens in epidermal basement membrane (10 ± 14). These observations led to the concept that cicatricial

Cicatricial pemphigoid

pemphigoid is not a single nosologic entity, but rather a disease phenotype consisting of a group of subepithelial blistering disorders that predominate on mucosal surfaces. Currently the management of patients with CP is grounded in clinical experience rather than randomized controlled trials. The immunopathogenesis and treatment of CP is summarized in this article.

Epidemiology Cicatricial pemphigoid is a rare disorder. Although its exact incidence and prevalence are unknown, the annual incidence of new cases per million people in France and Germany has been calculated to be 1.16 and 0.87, respectively (15,16). Because early cases are often not accurately identified, some have suggested that CP may actually be more common. Females are affected 1.5 ± 2 times more often than males. The disease generally affects older people, with a mean age of onset in the early to mid-60s. As is true for other autoimmune disorders, certain class II major histocompatibility complex (MHC) haplotypes are overrepresented in patients with CP. There is general agreement that the HLA-DQB1*0301 allele is significantly increased in frequency among patients with ocular CP (17 ±20). Moreover, one study has suggested that this same allele is a marker for susceptibility for both the oral and ocular forms of CP and that common amino acid residues at positions 71± 77 of the DQB1 protein are found in such patients (10).

Etiology The immunogenetic considerations outlined above are of relevance to theories concerning the immunopathogenesis of CP and other autoantibody-mediated diseases. In brief, the predominance of the HLA-DQB1*0301 allele among patients with CP suggests that the expression of this haplotype on these patients' antigenpresenting cells influences the ability of the latter to present certain epitopes to autoreactive T cells. Antibody (in this case autoantibody) responses to protein antigens are T-cell dependent; the latter are thought to regulate immune responses. While the exact mechanism(s) responsible for the initiation of autoimmunity in CP and other organ-specific autoimmune diseases is unknown, it is currently thought that these disorders result from immunologic responses to foreign antigens that cross-react with

determinants in the host. Molecular mimicry is the term applied to pathologic events where a susceptible host (i.e., a host expressing a certain immunogenetic profile) encounters an environmental factor or infectious agent with antigenic determinants that resemble those of the host. If such determinants elicit an immune response that cross-reacts with the host, ``tolerance'' to self is broken and disease ensues. In CP, the stimulus for developing an autoimmune response could be a virus or drug with structural similarity to an antigen present in epidermal basement membrane.

Laboratory findings Histopathology Light microscopy studies of lesional skin or mucosa from patients with CP characteristically demonstrate subepidermal blister formation. A dermal leukocytic infiltrate composed of eosinophils and neutrophils may be seen in early skin and mucosal lesions. Lymphocytes, histiocytes, and plasma cells predominate in established mucosal lesions (21 ± 23); a lichenoid infiltrate may be observed. Older lesions often demonstrate lamellar fibrosis in which collagen bundles are ordered parallel to the surface of the epithelium. Electron microscopy Ultrastructural studies have shown that blisters in patients with CP develop within the lower lamina lucida (24 ± 26). Patients with a mucosalpredominate subepidermal bullous disease who demonstrate blister formation in the sublamina densa region often represent the mucosal form of epidermolysis bullosa acquisita (27). Immunofluorescence microscopy Direct immunofluorescence microscopy of perilesional mucosa or skin from patients with CP characteristically shows continuous deposits of immunoreactants in epithelial basement membranes. Such immunoreactants typically consist of IgG, C3 (the third component of complement), and/or IgA (28,29). IgM and fibrin are found to a lesser degree. Splitting patient tissue samples with 1 M NaCl increases the sensitivity of direct immunofluorescence microscopy studies by facilitating the identification of immunoreactants as well as their distribution in situ (10,13).

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Indirect immunofluorescence microscopy studies using intact skin usually find low titer IgG (or IgA) anti-basement membrane autoantibodies. The sensitivity of indirect immunofluorescence microscopy can be increased significantly by using 1 M salt-split skin as a test substrate (10,13). In studies of the latter, the majority of patients with CP have autoantibodies that bind the epidermal side of this substrate; a minority of patients react with both sides or only the dermal side. While one study suggested that using mucosal tissue as a test substrate improved the sensitivity of indirect immunofluorescence microscopy studies of sera from CP patients, other studies did not reach the same conclusion.

Pathogenesis Immunochemical studies of sera from patients with CP found that individuals who resembled each other clinically, histologically, and immunopathologically often had circulating autoantibodies directed against different antigens in epidermal basement membrane. Accordingly, CP is regarded as a disease phenotype rather than a single nosologic entity. Patients with this phenotype can be segregated by the reactivity of their autoantibodiesÐan approach that has the potential to identify differences among such patients. To date, considerable data support the idea that CP autoantigens include bullous pemphigoid antigen 2 (BPAG2), laminin 5, integrin subunit b4, and a 168 kDa mucosal antigen. Rare patients with epidermolysis bullosa acquisita can present with disease that is mucosal predominant and mimics CP (27). Current evidence suggests that the most common (i.e., ``major'') CP autoantigen is bullous pemphigoid antigen 2 (BPAG2) (30). BPAG2 (also known as collagen XVII) is a type II transmembrane protein associated with hemidesmosomeanchoring filament complexes in epidermal basement membrane. The intracellular domain of BPAG2 is associated with hemidesmosomes; its extracellular domain comprises anchoring filaments and extends across the lamina lucida to the lamina densa (i.e., the basement membrane proper) (31,32). Immunoblot studies of bacterial recombinants corresponding to various segments of BPAG2 showed that patients with CP tend to bind the carboxyl terminus (i.e., distal extracellular domain) of BPAG2 as well as the NC16a portion of this protein (a site positioned just outside the plasma membrane of basal keratino-

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cytes) (33). These immunoblot findings were substantiated by ultrastructural studies showing that IgG autoantibodies from CP patients tend to localize to the lower lamina lucida, where the distal extracellular domain of BPAG2 resides in epidermal basement membrane (34). Since most patients with BP recognize an epitope adjacent to the plasma membranes of basal keratinocytes, the reactivity of autoantibodies from patients with CP to the distal portion of BPAG2 is thought to contribute to the tendency of such patients to develop scars. The latter hypothesis has not yet been substantiated in organ culture studies in vitro or animal modeling experiments in vivo. Patients with one form of CP have IgG antibasement membrane autoantibodies against heterotrimeric adhesion protein localized to the lamina lucida± lamina densa interface in epidermal basement membrane (35). Because initial studies showed that this autoantigen is present in the extracellular matrix of cultured keratinocytes and is immunoreactive with antibodies directed against a protein called epiligrin, this form of CP is called antiepiligrin CP (36). Additional studies have shown that epiligrin is identical to laminin 5 (a3b3g2) and that most of these patients have IgG4 autoantibodies directed against the a subunit of this protein (37 ±40). Because this subunit of laminin 5 is immunologically cross-reactive with the a subunit of laminin 6 (a3b1g1), autoantibodies from most patients with antiepiligrin CP also bind this laminin isoform (39,41). Passive transfer of experimental antilaminin 5 IgG (or Fab fragments) to neonatal BALB/c mice induced noninflammatory subepidermal blisters of the skin and mucous membranes independent of complement activation or mast cell degranulation (42,43). Moreover, experimental as well as patient antilaminin 5 IgG induced noninflammatory, subepidermal blisters in grafts of human skin on immunodeficient mice, demonstrating the pathogenic role of these antibodies in vivo (44). Studies by Mohimen et al. (45) found that sera from patients with ocular CP bound a 205 kDa protein in extracts of COLO and SCABER tumor cell lines. Purified IgG from one such patient bound a cDNA clone corresponding to the cytoplasmic domain of integrin subunit b4 (46). Recently, using a human conjunctiva organ culture system, these investigators demonstrated that experimental antibodies against integrin subunit b4 (presumably like IgG autoantibodies from patients with ocular CP) cause subepithelial blister formation in vitro (47).

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In immunoblot studies, Ghohestani et al. (48) found four of six serum samples from patients with CP that bound a 168 kDa polypeptide in mucosal extracts (M168). Of interest is that all of these patients had buccal mucosal involvement, autoantibodies against the epidermal side of 1 M salt-split skin, and no evidence of reactivity to proteins in extracts of epidermis or dermis (48). This incompletely characterized autoantigen apparently is not related to bullous pemphigoid antigen 1, BPAG2, or laminin 5.

Disease associations A recent study regarding a cohort of 35 patients with antiepiligrin CP indicated that such individuals have an increased relative risk for solid cancer (49). More specifically, 10 patients in this cohort had solitary solid cancers (3 lung, 3 stomach, 2 colon, 2 endometrial). Eight patients developed cancer after the onset of CP (six within a year, seven within 14 months). The time between blister onset and cancer diagnosis was between ‹14 months in 9 of 10 patients. Eight patients with cancer died during follow-up; all deaths were related to cancer and occurred within 21 months. Antiepiligrin CP has an increased relative risk for malignancy that approximates that for adults with dermatomyositis. As is true for the latter individuals, the risk for cancer in patients with antiepiligrin CP is particularly high in the first year of disease.

Management Cicatricial pemphigoid is a chronic and locally progressive disorder that rarely remits spontaneously (50 ± 52). Treatment of all subsets of this disease is dictated by the site of involvement and its relative severity. There is no evidence that one particular subset of CP (e.g., antiepiligrin CP) is specifically responsive to a given therapeutic intervention. Therapeutic regimens for patients with CP are largely derived from clinical experience rather than clinical trials. What follows is an overview of interventions typically applied to patients with mild, moderate, and severe forms of CP. Mild disease is often limited to the mouth. In such patients (as well as in patients with more severe disease), it is important to maintain good dental practices in order to minimize loss of

gingival tissue and/or teeth. Such complications often develop as a direct complication of CP or as a consequence of poor dental hygiene due to the pain and bleeding that follows routine brushing, flossing, or cleaning of teeth in patients with oral mucosal involvement. Dental devices that use forced water or ultrasound to clean teeth represent alternative, and often less painful, ways for patients with CP to maintain oral hygiene. For patients with mild oral mucosal involvement, topical glucocorticosteroids (cream, ointment, or gel) or ``swish and spit'' elixirs of dexamethasone are often useful. The effectiveness of topical glucocorticosteroids in such patients is enhanced by applying these agents under occlusion with dental appliances that fit snugly over the patient's gingiva. Application of topical glucocorticosteroids to the oral mucosa and gingiva is particularly effective when the medication is applied just before bed, since secretions generally diminish during sleep. For sites of chronic disease on the labial or buccal mucosa or the anterior hard palate, intralesional triamcinolone acetonide (10 mg/ml, 0.25 ± 0.5 ml/site) can be used as a more aggressive measure. Topical tetracycline and topical cyclosporine have also been reported to be of benefit in some patients with oral mucosal disease (53,54). Some authors have recommended topical anesthetics for treatment of mouth pain in patients with cicatricial pemphigoid. Examples of agents used for such purposes include viscous lidocaine, dyclonine, and/or diphenhydramine elixir. Many patients dislike the numbness that results from widespread application of such agents. Moreover, such anesthetic agents (particularly if introduced into the pharyngeal or hypopharyngeal areas) can impair swallowing and facilitate aspiration. Patients with mild to moderate nasal involvement usually require irrigation to promote removal of crust and dried secretions that often clog nasal passages, promote sinusitis, and cause discomfort. Such irrigation should be performed with isotonic saline or tap water once or twice each day. Bulb syringes, plastic syringes, or forced water toothbrushes (the latter commercially available with nasal irrigation fittings) are useful for nasal irrigation. Topical applications of a nasal mucosal lubricant (e.g., Ponaris spray or Ponaris drops) may help diminish crust formation when applied after irrigation. Even mild disease affecting the conjunctival mucosa typically requires the management of a qualified ophthalmologist and systemic agents. Unfortunately intraocular topical glucocorticosteroids typically have little effect on

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CP. Recent preliminary studies have suggested that tacrolimus (55), topical cyclosporine A (56), and subconjunctival mitomycin (57) may improve ocular CP; additional experience with these agents is of interest. Lubrication of ocular mucosal surfaces and good eye hygiene are important for the management of ocular CP. Most patients with moderately severe CP or disease that involves the ocular mucosa require treatment with dapsone alone or in conjunction with systemic glucocorticosteroids (58 ± 61). Doses of dapsone that are routinely applied in such cases range from 100 to 200 mg by mouth each day. Higher doses are sometimes used, though they are more commonly associated with side effects, such as peripheral neuropathy. The dose of glucocorticosteroids employed with dapsone in such patients ranges from 20 to 40 mg of prednisone each morning. Cicatricial pemphigoid is regarded to be severe if ocular, laryngeal, or urogenital epithelia are scarred, since involvement of such sites can result in tissue destruction and/or loss of function. Most patients with severe CP require treatment with systemic glucocorticosteroids (e.g., prednisone) at doses of approximately 1 mg/kg/day, as well as additional immunosuppressives (e.g., cyclophosphamide, azathioprine, mycophenolate mofetil) (62,63). While there is no formalized regimen for such cases, the goals of this approach include bringing CP under control promptly, limiting daily doses of systemic glucocorticosteroids, and achieving a sustained remission of disease (62,63). One favored regimen for control of severe CP consists of beginning patients on prednisone at a dose of 1 mg/kg/day in conjunction with cyclophosphamide at a dose of 1 ± 2 mg/kg/day. The dose of the latter agent is adjusted to keep the patient's peripheral blood leukocyte count just above 3000/ml (a target that generally maintains the neutrophil count at approximately 1500/ml and thus avoids severe leukopenia and its associated risk of infection). At the initiation of this regimen, prednisone is administered together with cyclophosphamide; subsequently the former agent is gradually tapered, then discontinued. For example, a patient may begin this regimen at 60 mg of prednisone each morning and have this agent tapered at 5 mg intervals weekly until a dose of 20 mg each morning is reached. At that time, the daily morning prednisone dose is decreased by approximately 2.5 mg each week over a period of approximately 10 weeks until the patient is maintained on cyclophosphamide alone. The approximate time to achieve discontinuation of

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prednisone in such patients is 6 months. After patients are maintained on daily cyclophosphamide for an additional 6 ± 12 months, attempts are made to discontinue this agent. Numerous complications can be encountered with this regimen; those of particular concern include bone marrow suppression, hemorrhagic cystitis, and cancer (specifically urinary bladder cancer and lymphoma). Experience suggests that a number of patients with severe disease who have followed this regimen achieve sustained remission. Pulse doses of intravenous cyclophosphamide have been used in small numbers of patients to achieve control of CP with possibly fewer complications (64). In an effort to avoid adverse side effects and complications produced by immunosuppressive regimens, several groups have recently treated patients with moderate to severe CP with intravenous immunoglobulin (IVIg) (65 ±67). The usual dose of IVIg in such patients has been 2 g/kg body weight/cycle divided over approximately 3 days administered every 2 ± 6 weeks for 4 ±6 months. Plasmapheresis followed by IVIg represents another application of this agent. While such preliminary studies are encouraging, additional experience with this expensive biotherapeutic is required to critically evaluate its effectiveness. The reader is referred to recent reviews describing in additional detail systemic management of patients with advanced CP as well as those patients who develop complications requiring surgical intervention (50 ±52). Patients with severe CP generally require the attention of several physicians (e.g., dermatologists, ophthalmologists, otolaryngologists, urologists) who have an interest and expertise in the diagnosis and management of this rare mucosal disease.

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