Cicatricial pemphigoid

CONTINUING

MEDICAL EDUCATION

Cicatricial pemphigoid Thomas E. Fleming, MD, and Neil J. Korman, MD, PhD Cleveland, Ohio Cicatricial pemphigoid (CP) is a heterogeneous group of rare, chronic, subepithelial blistering disorders of the mucous membranes and, occasionally, the skin, which can have serious and rarely fatal consequences. The most common clinical features are desquamative gingivitis, oral erosions, and conjunctival fibrosis. Skin lesions occur less frequently and may present as widespread vesicles and bullae, as in bullous pemphigoid (BP). In some patients, the scarring can be a source of significant morbidity because it can result in odynophagia, strictures of the upper aerodigestive tract, or corneal opacities leading to eventual blindness. This article is a comprehensive review and discusses clinical, pathologic, and pathophysiologic aspects of this group of disorders collectively known as CP. (J Am Acad Dermatol 2000;43:571-91.)

Learning objective: At the conclusion of this learning activity, participants should be familiar with the clinical spectrum of CP, the histopathologic and immunopathologic characteristics, the differential diagnosis, the treatment, and the natural history of the disease. Furthermore, this learning activity should facilitate early diagnosis of CP and should promote the idea that the involvement of other specialists, including ophthalmologists, otolaryngologists, gastroenterologists, and oral medicine specialists, as appropriate, will aid in providing these patients with the highest quality of care.

C

icatricial pemphigoid (CP) is a disease phenotype that consists of a group of subepithelial blistering diseases involving primarily mucosal surfaces and, occasionally, the skin. Over the years this disease has been referred to by many names, including benign mucous membrane pemphigoid, cicatricial pemphigoid, oral pemphigoid, and ocular pemphigoid. The name benign mucous membrane pemphigoid, which was coined by Lever in 1953, was used to differentiate patients with this disease who, unlike patients with pemphigus, did not die from their disease. This confusing and misleading term should be eliminated from future use because the potentially severe ocular and esophageal disease that these patients may have is certainly not benign. Recent studies, using sophisticated immunopathologic and immunochemical techniques, have revealed that CP actually consists of several distinct subgroups.1 The first group includes patients with antiepiligrin CP.2 These patients are immunochemi-

From the Department of Dermatology, Case Western Reserve University. Supported by National Institutes of Health grant R29 AR41008. Reprint requests: Neil J. Korman, PhD, MD, Department of Dermatology, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: [email protected]. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/2/107248 doi:10.1067/mjd.2000.107248

Abbreviations used: BMZ: BP: CP: DIF: EBA: IIF: LABD: SLE:

basement membrane zone bullous pemphigoid cicatricial pemphigoid direct immunofluorescence epidermolysis bullosa acquisita indirect immunofluorescence linear IgA bullous dermatosis systemic lupus erythematosus

cally distinct in that they have circulating IgG autoantibodies that bind to the dermal side of salt-split skin and recognize epiligrin, now known as laminin-5. These patients lack other distinguishing clinical features that separate them from other CP variants. Although antiepiligrin CP has been considered a small subgroup of CP, a recent report suggests that among patients with CP, those with antiepiligrin CP may comprise a higher percentage than previously thought.3 Some of the patients with anti-laminin-5 CP may occasionally also have antibodies directed against laminin6.4 The other major groups that form the CP spectrum have been delineated in a large study of 123 patients with immune-mediated subepithelial blistering diseases who were categorized on the basis of clinical and immunopathologic features.1 The first distinct group of patients has pure ocular disease in the 571

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absence of skin, oral, or other mucous membrane disease and are characterized as having pure ocular pemphigoid. In this study, the investigators found that these patients rarely had circulating IgG antibodies and had negative serologic reactivity to bullous pemphigoid (BP) antigens or other defined basement membrane zone (BMZ) antigens. Recently, one group demonstrated that many patients with predominantly ocular pemphigoid have IgG antibodies directed against the β4 integrin,5 while another group of patients have been found to have circulating IgA antibodies that react with an uncharacterized 45 kd antigen.6 The next distinct group of patients defined in this large study are those who have mucosal disease along with skin lesions. These patients have circulating IgG antibodies, have serologic reactivity to BP antigens, and have been classified as having anti-BP antigen mucosal pemphigoid. Another variant within the CP phenotype is oral pemphigoid. This variant includes patients who have disease limited to the oral cavity with no skin or other mucosal involvement.7 These patients all had linear BMZ deposits of complement and immunoglobulin on direct immunofluorescence (DIF), but none of the patients whose sera were tested displayed any circulating antibodies by indirect immunofluorescence (IIF). Patients with oral pemphigoid had a very benign course and were able to be successfully treated with either topical therapy or dapsone. The last group within the CP phenotype is a heterogeneous group that includes patients who have involvement of multiple different mucosal surfaces without skin disease. Whether any of these variants within the CP phenotype are pathomechanistically distinct remains the subject for future study.

HISTORY A chronic blistering disease associated with eye involvement was described in 1794 by Wichmann.8 In 1858, Cooper9 reported a patient with erosions and scarring of the conjunctivae and transient nonscarring blisters of the skin. Other reports of similar patients were published in the late 1800s.10,11 In 1911, Thost12 distinguished this disease from pemphigus and suggested the name “benign mucosal pemphigoid.” However, until the mid 1900s it continued to be classified as a variant of pemphigus and was known primarily as pemphigus conjunctivae or ocular pemphigus. In the 1940s and 1950s, Civatte13 and Lever14 separated this disorder from pemphigus on a histopathologic basis. Lever15 reported 30 cases in 1953 and suggested the name “benign mucous membrane pemphigoid.” A clinical variant that affects the head and neck was described by Brunsting and Perry16 in 1957. In his discussion of Brunsting and Perry’s 7 cases, some of which had

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no mucosal involvement, Lever16 suggested that “cicatricial pemphigoid” may be a more appropriate name. In the early 1960s, the term cicatricial pemphigoid began to appear in the literature.17,18 Our knowledge of the various patterns of this disease was extended by Hardy et al,19 who in 1971 published clinical and laboratory data for a series of 81 patients. Immunofluorescence studies were first performed in the early 1970s when Bean et al20 and Heydenreich, From, and Diederichsen21 demonstrated the presence of tissue-bound immunoglobulins and complement components in a linear pattern at the BMZ. The existence of circulating antibodies was first demonstrated by Dantzig22 and was, shortly thereafter, confirmed by Bean.23 The immunofluorescence findings suggested an autoimmune origin. Recent investigations have centered around the identification of the antigens involved in this disease and are discussed later in this review. These studies demonstrate that CP should be considered a disease phenotype consisting of a group of subepithelial blistering diseases involving primarily mucosal surfaces and occasionally the skin.

EPIDEMIOLOGY CP is a rare condition and the exact incidence and prevalence are unknown. It has been estimated that the incidence of CP is between 1 in 12,000 and 1 in 20,000 in the general population and 1 in 20,000 to 1 in 40,000 patients seen by ophthalmologists.24 However, because of the difficulty with diagnosis, especially in the early stages, CP may be more common than has previously been recognized.25 The disease generally affects older persons, typically those who are between 60 and 80 years of age, although cases occurring in childhood have been reported.26-29 Using compiled data from 16 clinical series that included a total of 457 patients, Ahmed and Hombal30 calculated the mean age at 62 years. In a series reported by Laskaris, Sklavounou, and Stratigos,31 the mean age was 66 years. No geographic or racial predilection has been reported, but there is a female predominance. The female-to-male ratio has been estimated at 2.27:130 and 1.5:1.31 Several studies have looked at HLA associations in CP. Mondino, Brown, and Rabin32 reported an association with HLA-B12 in patients with ocular CP, but later studies failed to confirm that association. Zaltas, Ahmed, and Foster,33 in a study of 70 patients with ocular CP, reported statistically significant associations with HLA-DR4, -DR5, -DQw3, -A2, -B8, -B35, and -B49. In addition, complement types SC32, SC41, and SC42 were more prevalent in patients with ocular CP than in control subjects. Nayar et al34 also found associations with HLA-DR4

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Fig 1. Desquamative gingivitis seen in CP patient with significant oral mucosal disease.

Fig 2. Severe blisters and erosions on the palate in a patient with CP.

and -DQw3 in patients with CP. In 1991, Ahmed et al,35 using restriction fragment length polymorphism analysis, showed that HLA-DQw3 is an allele of HLA-DQw7, subtyped HLA-DQB1*0301. Using polymerase chain reaction, two groups of investigators have demonstrated an increased incidence of the HLA-DQB1*0301 allele in patients with ocular CP, having found it in 76% to 90% of patients with ocular CP and 68% in patients with oral CP.36,37 Chan, Hammerberg, and Cooper38 recently reported that the relative risk of ocular CP in persons with the DQB1*0301 allele is 8.0, whereas the relative risk of oral disease only (excluding ocular disease) is 3.5. On the basis of these studies, the DQB1*0301 allele appears to be a marker for increased susceptibility to ocular CP.

Severe mucosal injury may also be a precipitating factor in the development of CP. Chan et al49 reported 5 cases of ocular CP that occurred after severe ocular inflammatory injury as a result of StevensJohnson syndrome. It is possible that the mucosal injury from Stevens-Johnson syndrome resulted in the availability of epithelial BMZ antigens for immune processing and presentation.

ETIOLOGY It has been suggested that in CP, as in other autoimmune diseases, an environmental factor combined with genetic susceptibility leads to the development of autoantibodies. The environmental “trigger” may be a virus or drug that has some structural similarity to an endogenous antigen within the BMZ. Antibodies to the exogenous hapten then cross-react with the endogenous antigen, causing autoimmune disease. Supporting an autoimmune pathogenesis is a study by Nayar et al34 in which patients with CP were shown to have a higher prevalence of other autoimmune diseases. Drug-induced CP has been reported, supporting the idea that an environmental agent can be involved in the pathogenesis of this disease.39 The use of topical glaucoma medications,40-45 practolol,46 and clonidine47 has been demonstrated to cause a CPlike disease. Further support for an environmental factor comes from a case report of monozygotic twins who were discordant for CP.48

CLINICAL MANIFESTATIONS CP is a chronic blistering disease of the mucous membranes and, less often, the skin. The primary lesion is a vesicle or bulla, and this evolves to become an erosion or ulcer that heals with scarring. The areas of involvement are highly variable. In 1986, Ahmed and Hombal30 summarized the lesion distribution for a total of 457 patients in their meta-analysis of 16 prior clinical reports. The reported sites of involvement were oral mucosa (85%), conjunctiva (64%), skin (24%) , pharynx (19%), external genitalia (17%), nasal mucosa (15%), larynx (8%), anus (4%), and esophagus (4%). Oral lesions Whereas 85% of patients have oral involvement, the specific sites affected are gingiva (64%) (Fig 1), buccal mucosa (58%), palate (26%) (Fig 2), alveolar ridge (16%), tongue (15%), and lower lip (7%).31,50 The most frequent oral manifestation is desquamative or erosive gingivitis.25,51-53 In mild cases it is characterized by gingival erythema and edema. Moderate to severe involvement is manifested by paresthesias and desquamation with blisters, erosions, and ulcers. Patients may complain of bleeding gums after brushing their teeth, and mild trauma from chewing may cause desquamation. Loose, nonadherent gingiva can frequently be peeled off in large pieces. In a study of patients with desquama-

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Fig 3. Early ocular inflammation in a patient with CP revealing conjunctival injection, early symblepharon formation, and forniceal shortening.

Fig 4. Late ocular disease in a patient with CP showing more pronounced symblepharon formation along with ankyloblepharon formation.

tive gingivitis followed up over several years, Rogers, Sheridan, and Nightingale54 found that 36 of 41 patients had a subepithelial blister and immunofluorescence findings consistent with CP. Of these 36 patients, 18 went on to develop extragingival and extraoral lesions consistent with CP. Two patients were diagnosed with pemphigus, and one each was diagnosed with lichen planus, contact stomatitis, and epidermolysis bullosa acquisita (EBA). Active gingival ulcers can be debilitating, but often the process is slowly progressive and relatively asymptomatic. Over time, inflammation within the adjacent soft tissues can lead to periodontal ligament damage and loss of bone mass, necessitating dental extractions.51,55 In addition to the gingiva, other areas of the oral cavity can be involved. Vesicles quickly give rise to erosions, and pain is minimal unless there is secondary infection. Lesions that occur on the tongue are usually seen on the lateral and ventral surfaces.51 Healing is very slow, and there is a tendency toward scar formation, including adhesions. During the healing phase, the fibrosis is often manifested as white, reticulated striations that resemble lichen planus.52 Erosions of the hard and soft palate, uvula, tonsils, tongue, and lips tend to be persistent and difficult to treat because of constant trauma in the mouth and secondary infection from oral flora.

only one eye. Ocular CP begins as a nonspecific, chronic conjunctivitis, and patients complain of burning, irritation, tearing, and mucus production.15,52,53,55,56 Periods of exacerbation and remission are typical, with eventual progression to subepithelial conjunctival fibrosis. Conjunctival vesicles are rare.15,55 Over time, the conjunctivae become scarred, and adhesions called symblephara form between the bulbar and palpebral conjunctivae (Fig 3). The inferior fornix becomes shortened and symblepharon formation increases to the point that the eyelids become firmly attached to the globe, inhibiting its movement. At later stages, the eyelids grow together and the conjunctival sac is obliterated (ankyloblepharon)15,55,56 (Fig 4). The anatomy of the eyelid becomes disturbed, and the fibrosis can lead to abnormal lash orientation (trichiasis) and entropion formation.55 Inflammation and fibrosis can also lead to destruction of the tear ducts and glands, and the lack of tear secretion leads to xerosis. Trichiasis, entropion, and xerosis lead to superficial corneal trauma and, in some cases, corneal ulceration.55,56 Conjunctival scarring may result in the inability to close the eyelids completely, thereby increasing the ocular exposure. Eventual keratinization of the surface epithelium leads to corneal opacities. Growth of granulation tissue (corneal pannus) on the surface of the cornea contributes to the development of corneal opacities in some patients. This process eventually leads to blindness in uncontrolled disease. Several staging systems have been developed for ocular CP. The modified Foster staging system57 (Table I) combines elements of the earlier Foster staging system55 and the Mondino staging system.24 It is helpful in monitoring disease progression.

Ocular lesions The conjunctiva is the second most frequent site of involvement and is often the only site affected. The vast majority of cases are bilateral, although the disease often begins unilaterally and progresses to the other eye within several years. 55,56 Pseudopemphigoid, a mimic of CP that may occur because of the topical application of numerous ocular preparations, 40-44 most commonly affects

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Table I. Modified Foster staging system for ocular cicatricial pemphigoid

Table available in print version only

Fig 5. Very late ocular disease in a patient with CP along with crusted erosions on periocular skin.

Skin lesions Two types of skin lesions have been described. The first type consists of recurrent vesicles and bullae, similar to those seen in BP, which rupture and heal without significant scarring15,55,58 (Fig 5). The second type, known as localized CP of the BrunstingPerry type, is localized to the head and neck and consists of flaccid blisters surrounded by patches of erythema15,16,55 (Fig 6). The blisters are often grouped in discrete circumscribed plaques and may be pruritic. Mucosal involvement is not always present. After a prolonged healing phase, smooth, atrophic scars remain (Fig 7). On the scalp, the scarring is manifested as cicatricial alopecia. CP with disseminated skin involvement has also been reported.28,59-62 However, the skin lesions of CP tend to be relatively transient in nature, whereas the skin lesions in BP tend to be longer lasting. Classification based on antigenic specificity of the autoantibodies may be necessary to determine whether such patients have BP with mucosal involvement or oral mucosal pemphigoid with skin involvement. Upper aerodigestive tract lesions Nasal lesions have been associated with extensive involvement of the upper aerodigestive tract in most cases. In a series of 33 patients with nasal involvement,63 crusted ulcerations on the septum or turbinates were typical, crusting and airway obstruction were noted in 76%, and mild pain occurred in 50%. Epistaxis and fibrous adhesions between neighboring mucosal surfaces were also reported.

Fig 6. Scalp lesions consisting of blisters on a erythematous base along with large erosions in a patient with Brunsting-Perry pemphigoid. (Courtesy of Robert Jordon, MD, Houston, Tex.)

Nasopharyngeal involvement can lead to stenosis and nasal obstruction. If severe, the obstruction can cause sleep apnea.63 Pharyngeal involvement is typically manifested by ulcerations on the posterior or lateral pharynx, dysphagia, and odynophagia.30,63 In patients with involvement of the larynx, the earliest manifestation is hoarseness. This may be transient initially, but becomes permanent as the disease progresses.63,64 Laryngeal erosions and adhesions may be seen on examination.15,64 Once scarring of the larynx occurs, it is permanent. If laryngeal involvement is severe, life-threatening stenosis may result, requiring tracheostomy.65

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Fig 7. Scarring alopecia with residual erythema on the scalp in a patient with CP. (Courtesy of Grant Anhalt, MD, Baltimore, Md.)

Fig 8. Erosion on penile shaft of a patient with CP. (Courtesy of Grant Anhalt, MD, Baltimore, Md.)

Esophageal disease is also manifested by erosions, dysphagia, odynophagia, and, in some cases, strictures and stenosis.15,63,66 In early esophageal involvement, symptoms may be mild and easily overlooked. An early manifestation of esophageal involvement is the sticking of food to the throat, requiring smaller bites along with liquid in order for the patient to swallow. Accordingly, a careful history for heartburn and dysphagia should be elicited by the physician. A barium study and/or upper endoscopy may be indicated.

ic lesions tend to have a heavy infiltrate and often demonstrate fibrosis in the upper dermis.15 The histopathologic findings can be indistinguishable from those of BP; however, in CP the inflammatory cell infiltrate tends to be more diffuse with fewer eosinophils.65 Fibrosis, present in the more developed lesions of CP, can be a helpful distinguishing feature, because BP lesions are nonscarring. Biopsy specimens of the conjunctiva demonstrate the histopathologic characteristics of epithelial metaplasia, reduced numbers of goblet cells in some patients, a lymphocytic plasma cell and mast cell infiltrate of the substantia propria, and fibrosis of the substantia propria.55,71-73 Foster,55 in a study of 130 patients with ocular CP, was the first to report the increased numbers of mast cells. They were seen in large numbers around venules and were often degranulating.

External genital and anal lesions Vesicles and erosions of the glans penis and foreskin or labia majora and labia minora can lead to fibrosis and adhesion formation15,29 (Fig 8). Complications include urethral stenosis and narrowing of the vaginal orifice.19 Scarring in these areas may require surgical intervention. Anal vesicles and erosions can lead to scarring and, in severe cases, stricture formation.15,25 The most common symptoms are spasm and pain on defecation, but limitations of function are rare.19

HISTOPATHOLOGY Light microscopy On light microscopy, the histopathologic findings in CP are nonspecific. Similar findings can be seen in BP, EBA, and linear IgA bullous disease. The typical histologic appearance is that of a subepidermal bulla and a diffuse, perivascular, mixed inflammatory cell infiltrate composed primarily of lymphocytes and histiocytes with scattered neutrophils and eosinophils.13-15,55,65-70 Oral lesions typically show plasma cells but rarely show eosinophils.65,67 In early lesions the infiltrate is mild, whereas chron-

Electron microscopy Ultrastructural studies using electron microscopy have demonstrated that the BMZ may be on either the dermal or the epidermal side of the blister, or it may be split, with components of the BMZ on both sides.66,70 At the edge of the bullae, basal keratinocytes show edema, loss of hemidesmosomes, and loss of tonofilaments.66 Foster55 used electron microscopy to study conjunctival biopsy specimens and found that the basal lamina was discontinuous, focally thickened, and focally duplicated. The lamina propria was thickened and infiltrated with inflammatory cells. In the substantia propria, there was a marked increase in ground substance, disorganized collagen fibrils, and thickened vascular basement membranes. With the use of scanning electron microscopy, it was also

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Table II. Immunofluorescence patterns of autoimmune blistering diseases DIF Immunoreactants

Results

Pattern

IIF on monkey esophagus

IIF on salt-split skin

IIF autoantibodies

IgG, C3 IgA C3 IgG IgA, IgM IgA Other IgG C3, IgA, IgM IgG C3 IgA IgM IgG C3

80%-100% Occasional 100% 50%-90% Occasional 100% Occasional 100% Occasional 100% 80%-100% 60%-70% 50% 100% 25%-50%

Linear band at BMZ

5%-25%

IgG, IgA

Linear band at BMZ

70%

50%-80% Epidermal or dermal 90% Epidermal

Linear band at BMZ

30%-50%

IgA

Linear band at BMZ

50%

Linear band at BMZ

Often pos

80%-90% Epidermal or dermal >50% Dermal Often pos Dermal

Cell surface

80%-90% Cell surface

Neg

IgG

IgG, C3

100%

Cell surface and occasional linear band at BMZ

90%-100%

Occasional pos

IgG

CP BP

LABD EBA Bullous eruption of SLE Pemphigus vulgaris/ foliaceus Paraneoplastic pemphigus

IgG

IgG IgG

Neg, Negative; pos, positive.

demonstrated that patients with active disease have a thick, amorphous sheet of mucinlike material covering the conjunctivae.74

IMMUNOFLUORESCENCE DIF In approximately 80% to 100% of patients with the clinical characteristics of CP, DIF studies using perilesional skin or mucosa show a linear, continuous band at the BMZ, most often with IgG and C3, and with IgA to a lesser degree20,75-82 (Fig 9). A comparison of the immunofluorescence patterns of the major autoimmune blistering disorders is shown in Table II. The presence of linear IgA deposits at the BMZ, along with IgG and C3, is more commonly seen in CP than in BP and can occasionally be a helpful clue in distinguishing these two entities. Positive DIF has also been observed in the BMZ of submucosal mucous glands.83 The best results for DIF examination are obtained from perilesional mucosal specimens, but perilesional skin specimens may also be of value. Technical difficulties can sometimes lead to loss of mucosal epithelium, rendering the DIF study impossible to interpret. In these circumstances, detached gingival epithelium, obtained by gently rubbing erythematous mucosa, has been found to be a useful substrate for DIF.84 Buccal mucosal biopsy for DIF, even in the absence of oral disease, is more useful than a skin biopsy in patients

with pure ocular disease and helps to avoid the morbidity of a conjunctival biopsy. DIF findings in CP are not specific. BP, herpes gestationis, EBA, and systemic lupus erythematosus (SLE) can all display identical DIF patterns, and further evaluation is necessary. Although it is technically more difficult, immunoperoxidase staining has been shown to be even more sensitive than DIF in patients with CP.85 DIF is essential for the diagnosis of CP and must be done to document the immunopathologic results. IIF Early IIF studies in CP either failed to show circulating antibodies20,75,86 or showed that only a small percentage of patients (5%-25%) had low titer (1:101:40) circulating IgG anti-BMZ antibodies.22,23,78,87-90 Several investigators have shown that the sensitivity of IIF can be increased by using 1.0 mol/L salt-split skin or mucosa. Kelly and Wojnarowska,91 using 1.0 mol/L salt-split normal human skin or normal human mucosa tissue as a substrate, found that 50% of the patients they studied had circulating IgG antibodies that bound to the epidermal side of salt-split skin and mucosa. Sarret et al88 obtained positive IIF results for circulating anti-BMZ IgG and/or IgA antibodies in 100% of 11 patients studied using 1.0 mol/L salt-split normal human skin as a substrate. In contrast to previous studies, Sarret and colleagues included only patients with active disease, obtained

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Fig 9. DIF of perilesional mucosa from a patient with CP revealing linear deposits of IgG at the epithelial submucosal BMZ.

serum at a time when patients had all stopped taking immunosuppressive medications, and used undiluted serum in the assay. Clinical subsets of CP also vary in their IIF sensitivity. Chan et al1 performed IIF using salt-split skin and found positive results in 81% of 16 patients with combined skin and mucosal disease, 18% of 17 patients with mucosal disease only, and 7% of 14 patients with ocular disease only. However, Ahmed et al92 used conventional IIF methods and obtained positive results in 6 of 12 patients with ocular CP. When sera from these same patients were tested by radioimmunoassay, circulating antiBMZ antibodies were detected in 100%. Thus it appears that patient selection and laboratory methods greatly influence the sensitivity of IIF. We have found that along with circulating IgG antibodies directed against the BMZ, circulating IgA is also sometimes found in patients with CP. Although most patients with CP have antibodies that bind to the epidermal side of salt-split skin, patients with antilaminin-5 CP have IgG antibodies that bind to the dermal side of salt-split skin.2 Because some patients with CP have very low titer circulating antibodies, we recently developed a technique that utilizes concentrated serum as the substrate in a salt-split IIF study.93 This methodology allowed us to detect very low titer antibodies in patients with suspected but previously unproven autoimmune-mediated diseases of the mucous membranes (Fig 10). This concentrated serum IIF assay may therefore prove to be a valuable tool in improving the diagnostic evaluation of patients with suspected CP. In the evaluation of patients with suspected CP, we recommend that IIF studies be performed with the use of salt-split skin and that the presence of both IgG and IgA antibodies be evaluated. An analysis of IgG subclasses in 14 patients with CP was performed by Bernard et al94 with an indirect

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Fig 10. IIF of concentrated serum from a patient with CP assayed on 1.0 mol/L salt-split human epidermis reveals the presence of a circulating IgG antibody that binds to the epidermal side of the blister cavity. Serum from this patient was negative for circulating IgG antibodies when previously assayed utilizing unconcentrated serum.

competitive enzyme-linked immunosorbent assay with monoclonal antibodies. They identified IgG4 and IgG1 as the predominant subclasses, with all complement-fixing sera containing IgG1 and all noncomplement-fixing sera containing only IgG4.

IMMUNOELECTRON MICROSCOPY Examination of lesional skin or mucosa by immunoelectron microscopy (IEM) has not been studied in a large series to date. Several smaller series using standard IEM have revealed two patterns of immune deposits: one in the area of the lower lamina lucida and lamina densa79,95,96 and another in the area of the hemidesmosomes and basal keratinocyte cytoplasm.96,97 Bédane et al98 performed indirect IEM with salt-split normal human skin as a substrate and, in 7 of 8 patients, found continuous deposits over the lamina densa and adjacent, regularly spaced, clumped deposits in the lamina lucida. There was clearly separation between the deposits and the basal keratinocytes. This pattern was in contrast to that seen in BP by the same investigators. In BP, staining was seen intracellularly within basal keratinocytes in the area of the hemidesmosomes. Furthermore, for staining to occur with BP sera, the substrate required treatment with saponin, a detergent that permeates plasma membranes, whereas the staining pattern seen with CP sera was the same with or without saponin treatment. This study demonstrated that the target epitope or epitopes in CP are extracellular and are different from those of BP. Shimizu et al96 separated a group of 5 patients with CP into two subsets based on IIF: those with IgG binding to the dermal side of salt-split skin and

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those with IgG binding to the epidermal side. On immunoelectron microscopic examination, studies from the group that had shown IgG binding to the dermal side demonstrated IgG autoantibodies at the lower lamina lucida at its interface with the lamina densa. In the other (epidermal) group, IgG autoantibodies localized to the hemidesmosomes and the junction between the hemidesmosomes and the basal keratinocyte plasma membranes. In addition, the first group (dermal) immunoprecipitated epiligrin (laminin 5), whereas the second (epidermal) group had a negative immunoprecipitation study. These studies emphasize the heterogeneity that is present within the spectrum of CP.

IMMUNOCHEMISTRY The use of immunochemical techniques, including immunoblotting and immunoprecipitation, to characterize the autoantigens targeted by CP sera has clearly demonstrated the heterogeneity of the CP phenotype. There is strong evidence that implicates laminin-5 (epiligrin),2,99-101 BP pemphigoid antigen II (BP180),102-104 and the β4-integrin5,105,106 in different clinical subsets of CP. The earliest immunochemical studies demonstrated that patients with CP had circulating IgG antibodies that recognized either the 230-kd BP antigen (BP230) or the 180-kd BP antigen (BP180), or both.90,102,107,108 There is some controversy on this point because recent studies evaluating large numbers of patients revealed that CP patients with BP antibodies tend to have skin lesions, and their disease should therefore be characterized as a variant of BP.1 Balding et al103 presented convincing evidence that some patients with CP have autoantibodies to BP180 (96%). They constructed 4 bacterial fusion proteins using various segments of BP180, and used immunoblotting to determine reactivity of CP sera with these fusion proteins. The results demonstrated at least two antigenic sites on the extracellular domain of BP180 against which CP autoantibodies are directed. One is located in the noncollagenous domain, and the other is located near the carboxy terminus. An ultrastructural study using both BP and CP autoantibodies revealed that the CP autoantibodies directed against BP180 localized to the lower lamina lucida and lamina densa, whereas the BP autoantibodies directed against BP180 localized to the upper lamina lucida immediately below the hemidesmosome.104 This study demonstrates that although patients with BP and CP may both have IgG autoantibodies directed against the same BP180 molecule, these antibodies recognize different epitopes on BP180 found on distinct sites of the epidermal BMZ. Patients with CP may also have IgA autoanti-

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bodies directed against BP180, and these IgA autoantibodies appear to react against different epitopes than do the IgG autoantibodies.109 Further studies will be necessary to clarify the role of IgA autoantibodies in the pathogenesis of CP. Laminin-5 (formerly epiligrin, kalinin, nicein, and BM600) is an adhesion molecule consisting of α3, β3, and γ2 laminin subunits.110 It is localized to anchoring filaments within the lamina lucida111 and is a ligand for α3β1 and α6β4 integrins.112,113 The first report identifying laminin-5 as a target in some patients with CP was published in 1992.99 The investigators showed that IgG anti-BMZ autoantibodies from 3 patients immunoprecipitated a distinct set of polypeptides from human keratinocyte culture media of 170, 145, 125, and 95 kd. The immunoprecipitation pattern was identical to that of laminin-5 (then known as epiligrin and BM600). Under nonreducing conditions, these polypeptides remain disulfide-linked to form complexes of 400 and 440 kd.11,114 In later experiments, it was shown that the autoantibodies from patients with antiepiligrin CP bind the α3 subunit of laminin-5.100 Another group of investigators reported immunoprecipitation of both laminin-5 and laminin-6 by autoantibodies from patients with anti-laminin-5 CP.4 Because laminin-5 and laminin-6 share the same α3 subunit,110 it appears likely that they are cotargets for the autoantibodies. Although some studies suggest that patients with anti-laminin-5 autoantibodies may represent a minority of patients with CP,2,101 further work will be necessary to clarify this point. One case of CP has been reported in which the patient had developed autoantibodies against both laminin-5 and BP180.115 The development of a simultaneous autoimmune response directed against these two distinct BMZ molecules is fascinating and it suggests a possible role for epitope spreading. A group led by Foster and Ahmed detected binding to proteins of 230, 205, 160, and 85 kd on immunoblot analysis in 10 of 11 sera from patients with ocular CP.105 When the tissue lysates were first preabsorbed with BP sera and then tested with ocular CP sera, only binding to the 205-kd protein was observed.106 Purified IgG from these sera recognized a cDNA clone from a human keratinocyte library that had complete homology with the cytoplasmic domain of β4-integrin, and antibodies to β4-integrin recognized the same 205-kd antigen on immunoblotting.5 Integrins are a large group of heterodimeric transmembrane proteins that serve as receptors for extracellular matrix and cell surface proteins. The β4-integrin subunit is associated with the α6 subunit and this α6β4 integrin functions as an integral part of the epidermal hemidesmosome.116 These important studies provide substantial

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evidence that autoantibodies to β4-integrin may be pathogenic in some patients with ocular CP. Ghohestani et al117 identified a 168-kd mucosal antigen on immunoblotting that was recognized by sera from 4 of 6 CP patients with marked mucosal involvement. The antigen, M168, is a component of normal human BMZ that localizes to the epidermal side of salt-split skin and appears to be strongly expressed in buccal mucosa. In a study of patients with purely ocular disease, Smith et al6 demonstrated IgA binding to a 45-kd antigen by immunoblotting. Sera from these patients did not react with the 97-kd linear IgA bullous dermatosis (LABD) antigen, BP180, or BP230. Additional studies will be necessary to further identify and characterize these 168- and 45-kd antigens.

PATHOPHYSIOLOGY In CP, as in BP and other acquired blistering diseases, the precise mechanisms by which epidermal detachment occurs are unknown. However, there are substantial data to suggest that the autoantibodies target adhesion molecules within the BMZ, interfering with their structural integrity and function. With respect to anti-laminin-5 CP, there is in vitro and in vivo evidence that autoantibodies interfere with the adhesion function of laminin-5, causing detachment of keratinocytes from the BMZ. As discussed earlier in this article, laminin-5 localizes to the area of the anchoring filaments and is a ligand for two other adhesion molecules, the α3β1 and α6β4 integrins. This suggests that laminin-5 is associated with, or is a component of, the anchoring filament complex. Rousselle et al111 reported that in cell cultures of human keratinocytes, the addition of monoclonal antibodies directed against the α3 subunit of laminin-5 causes the cells to round up and detach. Incubation of skin fragments with this same antibody caused extensive epidermal detachment. Evidence that laminin-5 plays an important role as an adhesion molecule within the BMZ is also demonstrated in patients with Herlitz-type junctional epidermolysis bullosa. This severe, often lethal, inherited, subepidermal blistering disease affecting the skin, mouth, larynx, esophagus, and other epithelial-lined structures118 has been linked to mutations in the gene that encodes for the γ2 subunit of laminin-5.119,120 BP180 also appears to function as an adhesion molecule, possibly forming part of the anchoring filament complex along with laminin-5. A study by Bédane et al104 provided evidence that BP180 spans the lamina lucida and interacts with the lamina densa. In this study, the investigators showed that the target domain is at the carboxy terminus of BP180, near the lamina densa. This is in contrast to

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BP in which the target domain is located in the upper lamina lucida, subjacent to the hemidesmosome complex.104,121 The difference in target epitopes in patients with CP and BP may help to explain the fact that lesions in BP are nonscarring, whereas in CP they often heal with scarring. Possibly, in CP the BMZ is disrupted at a location deeper than in BP, resulting in an inflammatory response in the area of the lamina densa and papillary dermis. However, further investigation will be necessary to determine the precise mechanism by which scarring occurs in patients with CP. A potential role for the β4 integrin in the pathophysiology of CP has recently been demonstrated. In a human conjunctiva organ culture system, anti-β4 integrin antibodies, like ocular CP IgG antibodies, were capable of causing BMZ separation.122 These findings suggest a possible important role for the β4 integrin as an autoantigen in the subgroup of patients with ocular CP. A recent study investigating the role of costimulatory molecules found up-regulated expression of the costimulatory molecule B7-1 in the epithelium of patients with ocular CP, whereas the costimulatory molecule B7-2 was up-regulated in the conjunctival substantia propria of patients with active ocular CP.123 Increased numbers of Langerhans cells were identified in both the epithelium and substantia propria, and increased numbers of CD28+ T cells were found in the substantia propria. The interaction between B7-2 and CD28 may contribute to the chronic immune activation seen in these patients.

DIFFERENTIAL DIAGNOSIS Subepithelial blistering of the mucous membranes can occur in several other conditions besides CP, including BP, EBA, LABD, the bullous eruption of SLE, and anti-p105 pemphigoid. We will also discuss two other entities that, although they do not typically reveal subepithelial blisters, are important to include in the differential diagnosis: paraneoplastic pemphigus and pseudopemphigoid. BP BP is an autoimmune blistering disease characterized by tense bullae that develop on normal or erythematous skin.124,125 Although there are clinical and histologic similarities between BP and CP, there are also significant differences in most cases. Lesions in BP are nonscarring unless they become traumatized or infected. BP primarily affects the skin, and the most common sites of involvement are the lower abdomen, groin, and flexor surfaces of the extremities. Mucous membrane lesions occur in 10% to 40% of patients with BP, almost always affect the oral mucosa, and are

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usually not the presenting symptom. Age at onset is similar to that of CP, typically 65 to 75 years. BP tends to persist for months to years with periods of exacerbation and remission. Response to corticosteroid therapy is generally good, although occasionally, steroidsparing immunosuppressive therapy is required. Histologically, BP is characterized by a subepidermal blister, eosinophilic spongiosis, and a mixed, perivascular and interstitial inflammatory cell infiltrate.124,126 Eosinophils are usually more prominent than in CP. DIF shows a linear deposition of IgG in 50% to 90% and a linear deposition of C3 in 100% of specimens. IIF studies reveal the presence of circulating IgG antibodies that bind to the epidermal side of salt-split skin in approximately 90% of patients. Immunoblotting and immunoprecipitation studies have shown that there are two target antigens in BP.124 The first is BP230, a 230-kd polypeptide located at the hemidesmosome plaque within the basal keratinocyte cytoplasm. The mechanism by which autoantibodies become exposed to this intracellular antigen is unknown. The second antigen is BP180, discussed above as one of the target antigens in CP. BP180 is a transmembrane protein that appears to extend from the hemidesmosome to the lamina densa. EBA EBA is an acquired autoimmune blistering disease. This uncommon disease is found most frequently in middle age and can have two major clinical presentations.127-132 In “classic” EBA, noninflammatory blisters and erosions develop at sites of trauma that heal with scarring and milia. The disease is often localized, involving areas prone to superficial trauma such as the dorsal hands and arms, elbows, knees, and tops of the feet. A second, perhaps more common,132 presentation is a widespread eruption of inflammatory blisters on erythematous skin involving flexural surfaces. This is the BP-like phenotype. Mucous membranes are involved in approximately 50% of EBA cases,133,134 and nail dystrophy may be present. As in CP, patients may have oral, ocular, genital, esophageal, or laryngeal involvement. Conjunctival and corneal scarring may lead to blindness. Rare cases of EBA occurring in children have been reported.135,136 Treatment is extremely difficult, and patients are often resistant to systemic steroids and immunosuppressive drugs, with the possible exception of cyclosporine.132 Histopathologically, EBA is characterized by a subepidermal blister with a perivascular and interstitial mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, neutrophils, and eosinophils. Noninflammatory lesions have a sparse dermal infiltrate, whereas inflammatory

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lesions tend to have an abundance of neutrophils at the dermoepidermal junction.131 DIF studies on perilesional skin show a broad, intense band of IgG in all patients. Occasionally, C3, IgM, and IgA are also identified. Circulating autoantibodies are identified by IIF in about 50% of patients and are usually IgG. When IIF is performed with the use of salt-split skin, the sensitivity is increased and IgG is identified on the dermal side of the specimen.137 This method differentiates EBA from BP, herpes gestationis, and most cases of CP in which the immunoreactants localize either to the epidermal side or to both dermal and epidermal sides of the specimen.132 On immunoblots, polypeptides of 290 and 145 kd have been detected in BMZ extracts by EBA antibodies.138 The 290-kd antigen has been identified as type VII collagen, a component of anchoring fibrils,139,140 whereas the 145-kd antigen appears to be a degradation product of the same molecule. LABD LABD, also known as linear IgA disease, is a subepidermal blistering disease that until recently was considered a variant of dermatitis herpetiformis.141 In adults, the average age at onset is 60 to 65 years.142 Chronic bullous disease of childhood is the same disease as adult LABD.142 Patients with LABD typically have clinical features that mimic BP and/or dermatitis herpetiformis. The usual presentation is that of generalized tense bullae on normal or erythematous skin, often in herpetiform clusters.143,144 Skin lesions are common and are nonscarring. Pruritus is variable. Lesions of the oral mucous membranes are frequently seen, but ocular involvement is much rarer.145-147 Patients with conjunctival involvement experience scarring of the conjunctivae with symblepharon formation that can be indistinguishable clinically from ocular CP. These patients require aggressive therapy with systemic corticosteroids along with immunosuppressives to control their disease and prevent progression to blindness. Histologically, the findings in LABD are nonspecific. There is a subepidermal blister with a mixed inflammatory cell infiltrate composed of lymphocytes, neutrophils, and eosinophils.143,147 Papillary microabscesses are seen in about 60% of specimens.143 On DIF, a linear band of IgA deposits can be demonstrated along the BMZ of perilesional or nonlesional skin, and the diagnosis of LABD is dependent on this finding.145,148 Other immunoreactants, such as C3 and IgG, have occasionally been reported, but linear IgA at the BMZ is the most prominent.143,145 Circulating low-titer IgA antibodies that

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usually bind to the epidermal side of salt-split skin are found in some patients.143,145 Investigations into the target antigens involved in LABD have demonstrated that autoantigens of 97 kd,149-152 285 kd,153,154 and 290 kd155 may be involved. Recently, the 97-kd antigen has been characterized as an anchoring filament protein that is recognized by monoclonal antibody 123.156 Radioimmunoprecipitation studies showed that this 97-kd protein is secreted as a 120-kd peptide from keratinocyte cell cultures, and immunoaffinity studies now reveal that this 97-kd protein is actually identical to a portion of the BPAG2.157 Monoclonal antibody 123 induces blistering in human skin, providing evidence that autoantibodies are pathogenic in LABD.156 The LABD antibodies directed against a 285/290-kd protein appear to represent an IgA antibody response against type VII collagen.158 Immunoelectron microscopic studies in LABD have demonstrated IgA deposits in the lamina lucida as well as in the sub–lamina densa zone.150,159,160 These studies further emphasize the two immunopathologic phenotypes of LABD.

findings of other primary lupus lesions, such as epidermal atrophy, basement membrane thickening, and vacuolization of the basal cell layer, are absent.132 DIF of perilesional skin demonstrates immunoreactants in the BMZ, upper dermis, or, occasionally, in the dermal venules.132,165 IgG and C3 are seen in nearly all cases, IgA in two thirds, and IgM in half. The DIF pattern is a broad, linear band in the majority of specimens, but in some a granular, mixed linear-granular, thready, or fibrillar pattern is seen. IIF performed on normal skin is rarely positive. With salt-split skin, autoantibodies bind to the dermal side,164,165 as in EBA. On immunoelectron microscopy, deposits are identified on and beneath the lamina densa,164,165 a pattern identical to that of EBA. Immunoblotting studies have identified the target antigen as type VII collagen, the same 290-kd molecule that is a component of anchoring fibrils and is involved in the pathogenesis of EBA.132 It is unknown why lesions of bullous SLE are generally nonscarring whereas those of EBA heal with scarring and milia.

Bullous SLE Bullous SLE is an acquired subepidermal blistering disease occurring uncommonly in patients with SLE.132,161-164 Clinically, patients present with a widespread, nonscarring, vesiculobullous eruption consisting of erythematous macules, plaques, and blisters on erythematous skin. There is a tendency toward involvement of sun-exposed areas, but nonsun-exposed skin may be affected as well. Oral mucosa and pharyngeal involvement are seen in some patients. Bullous SLE affects all ages and races, but most patients have been young black women. The activity of the skin disease does not necessarily correlate with the activity of systemic manifestations. Although bullous SLE can be chronic, it often resolves within a year or so. It is usually dramatically responsive to dapsone, but prednisone and/or immunosuppressive agents may be necessary in the unusual patient who is unresponsive to dapsone. Histopathologic findings include a subepidermal blister with a mixed inflammatory cell infiltrate, including neutrophils, at the dermoepidermal junction and a sparse perivascular lymphocytic infiltrate.132,164 Neutrophilic microabscesses are often seen in the dermal papillae, thereby making the histologic findings indistinguishable from those found in dermatitis herpetiformis. Focal vacuolar degeneration of the basal cell layer has been reported,164 but it is unclear whether these patients had bullous SLE or other cutaneous manifestations of lupus, such as leukocytoclastic vasculitis, which can also present with bullae. Generally, in bullous SLE, the histologic

Paraneoplastic pemphigus Paraneoplastic pemphigus is an autoimmune syndrome that occurs in patients with an underlying malignancy, usually lymphoreticular in origin.166 It is characterized by ocular and oral blisters and erosions that can be similar to those seen in CP but are often more severe. Generalized skin lesions may also resemble toxic epidermal necrolysis, lichen planus, BP, or erythema multiforme. Paraneoplastic pemphigus is a rapidly progressive condition leading to death in the majority of patients who have an associated malignant neoplasm but may resolve in patients who have an associated benign neoplasm that is surgically removed.167 Histologic features of both pemphigus vulgaris and erythema multiforme may be present, and rarely the histologic examination may show features of pemphigoid.168 Immunofluorescence studies show the presence of circulating and tissue-bound IgG antibodies in paraneoplastic pemphigus that bind to the cell surface of stratified squamous epithelia in a pattern indistinguishable from pemphigus antibodies. These circulating IgG antibodies also recognize the cell surface of simple epithelia, such as liver and heart, as well as transitional epithelia such as bladder. In contrast, pemphigus IgG antibodies only recognize the cell surface of stratified squamous epithelia. The circulating antibodies in paraneoplastic pemphigus recognize a complex of epidermal proteins that includes a 250-kd protein (desmoplakin I), the 230-kd BP antigen (BPAG1), a 210-kd protein (envoplakin), a 190-kd protein (periplakin), and an as yet uncharacterized 170-kd protein.167,169 Although the origin of

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this disease is poorly understood, it is thought that it may result from the combination of both a cellular and humoral immune response to tumor antigens with overlapping reactivity to normal components of skin and other epithelia. Anti-p105 pemphigoid Anti-p105 pemphigoid, a new clinical entity, was described in a patient who presented with a nonscarring dermatosis characterized by the sudden onset of severe bullae and erosions of the skin and oral mucous membranes. Histologic examination demonstrated subepidermal blister formation along with neutrophilic dermal papillary infiltration, and immunopathologic examination revealed linear deposits of IgG and C3 along the epidermal BMZ. More extensive immunochemical characterization revealed that this patient had circulating IgG antibodies directed against a novel component of the epidermal BMZ, a 105-kd molecule that had not been previously identified.170 With the report of a second patient with antibodies directed against this 105-kd molecule,171 this entity has become known as anti-p105 pemphigoid. Pseudo-ocular CP Pseudo-ocular CP is an entity well known to the ophthalmologist as a scarring ocular disease that may be difficult to distinguish from ocular CP.44 Patients develop pseudo-ocular CP, which only involves the eyes and most commonly only one eye, as an unusual complication of the long-term use of topical eyedrops, usually for glaucoma treatment. The most commonly implicated agents include pilocarpine, echothiophate iodide, idoxuridine, timolol, and epinephrine.44 Unfortunately, the histologic and immunopathologic characteristics of pseudo-ocular CP can be indistinguishable from ocular CP. One study demonstrates that there are immunochemical differences between idiopathic ocular CP and pseudo-ocular CP.172 Many cases of pseudo-ocular CP tend to be self-limiting and nonprogressive after the offending drug is stopped, but some patients will have progressive ocular disease despite discontinuation of the offending medication. In these cases, aggressive systemic therapy will be required.

TREATMENT AND PROGNOSIS The treatment of patients with CP is predicated upon the extent and severity of disease, with careful consideration given to the involved tissues. All therapeutic regimens used in the treatment of patients with CP are empiric and are based on clinical experience. Mild disease limited to the oral cavity can often be managed with topical therapies with the occa-

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sional use of systemic corticosteroids during exacerbations. More advanced disease involving other mucous membranes generally requires the judicious use of systemic corticosteroids combined with immunosuppressive agents for their purported steroid-sparing effects. Surgery may occasionally be required for severe scarring involving the conjunctivae, esophagus, or larynx. It is crucial that this surgical intervention be forestalled until the disease is well controlled. Otherwise, it is probable that surgery will result in more severe scarring. Local therapy The treatment of oral CP requires careful attention to good hygiene and avoidance of trauma. Ahmed, Kurgis, and Rogers53 have stressed the importance of debridement of dead mucosal tissue to help prevent infection. In addition, they have outlined a regimen for the adjunctive use of hydrogen peroxide, elixir of dexamethasone, and elixir of diphenhydramine. These agents are diluted 1:4 or 1:6 and are used separately several times daily for rinsing the mouth (without swallowing). For severe mouth pain, Muzyka, Greenberg, and Glick173 recommend the use of an oral rinse containing the local anesthetics dyclonine and viscous lidocaine along with diphenhydramine elixir. Therapy with potent topical corticosteroids is often helpful in oral disease. Fluocinonide 0.05%, desoximethasone 0.25%, or clobetasol 0.05% gels or ointments may be used twice daily. Compounding with Orabase may facilitate adherence to the mucosal surface. After application, the patient should not take anything by mouth for 1 hour to allow for adequate absorption. When used under dentures, there is an occlusive effect that increases potency. However, patients must be very careful with the use of their dentures because minor trauma can lead to the development of new erosions. A vinyl prosthesis which fits over the teeth and nearby gingiva may be fabricated by a dentist to facilitate application of the corticosteroid preparation.174 Potent topical steroids may also be of some benefit when applied to skin lesions, and corticosteroid sprays and inhalers may be helpful in nasal, pharyngeal, and esophageal disease. Corticosteroid injections can be of significant benefit in recalcitrant lesions of both skin and mucous membranes and triamcinolone acetonide 5 to 10 mg/mL every 2 to 4 weeks has been used with success.53,174 Cetacaine spray or viscous lidocaine may be used for local anesthesia within the oral cavity, and injections should be directed toward the papillary dermis, close to the dermoepidermal junction. A treatment session should be limited to a maximum of 40 mg. Topical cyclosporine has been

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reported to be of some benefit in the treatment of oral mucosal disease of CP with 2 of 2 patients showing significant reduction in gingival erythema and 1 of 2 patients showing complete healing after 4 weeks of treatment.175 In ocular CP, topical corticosteroids are ineffective in controlling the progression of disease.55 Although intralesional corticosteroid injections may produce short-term remission, their use is limited by the lack of long-term benefit and the adverse consequence of cataract formation. Frequent lubrication is important in ocular CP, as is attention to eyelid hygiene.53 A potentially useful topical therapy for ocular CP is cyclosporine. Of 4 patients with ocular CP studied, two had a favorable response, whereas the other two showed no improvement.176 Blood levels of cyclosporine were unmeasurable. Although this report suggests that topical therapy may occasionally be of some value in the treatment of patients with ocular CP, we believe that all patients with ocular CP require systemic therapy. Systemic therapy Systemic medications used in the treatment of CP include anti-inflammatory and immunosuppressive agents. Indications for systemic therapy include ocular involvement, laryngeal involvement, esophageal involvement, or the presence of oral or cutaneous disease unresponsive to less aggressive topical measures. Although oral CP can usually be managed with topical therapy, there are occasional patients who have severe oral disease with relentless gingivitis leading to loosening of the teeth, which needs to be treated with systemic therapy. This may include oral corticosteroids alone or along with dapsone to suppress the immune response and to prevent major dental problems, including the loss of teeth. Systemic corticosteroids are used in the treatment of patients with CP because of their potent anti-inflammatory and immunosuppressive effects. However, because of the potential for significant toxicities, including osteoporosis, avascular necrosis, hypertension, diabetes mellitus, peptic ulcer disease, cataract formation, psychosis, suppression of the hypothalamic-pituitary-adrenal axis, infection, and pseudotumor cerebri, it is imperative to limit the long-term use of systemic corticosteroids. In an attempt to minimize toxicity, patients can often be tapered to an every-other-day dosage of prednisone, which will decrease the incidence of many side effects, with the exception of osteoporosis and cataract formation. Because long-term use of systemic corticosteroids can lead to so many adverse sequelae, steroid-sparing agents are often used in an attempt to minimize the steroid dosage. Although

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no controlled clinical trials have proven the usefulness of these agents, significant clinical experience supports this approach. Rogers, Seehafer, and Perry177 reported at least partial control of the inflammatory activity in 20 of 24 patients with CP treated only with dapsone. Control of disease activity was achieved in 2 to 12 weeks in these patients who had a mix of oral, ocular, and other involved sites. It is important to note that in this classic and regularly cited study of CP, only 12 of 24 patients had both histologic and immunofluorescence findings that were diagnostic for CP. Patients who are to be treated with dapsone must have a screening glucose 6-phosphate dehydrogenase level to ensure that they will not have severe hemolysis when given dapsone. Toxicities of dapsone include hemolysis, leukopenia, dapsone hypersensitivity syndrome, hepatitis, nephrotoxicity, and peripheral neuropathy. Patients who are treated with dapsone require frequent monitoring of the white blood cell count for the first 4 months because the risk of agranulocytosis, which occurs in approximately 1 in 400 patients,178 appears to be greatest 8 to 12 weeks after the initiation of therapy.179 In addition, all patients being treated with dapsone require regular monitoring of the red blood cell count, liver and renal function, and urinalyses along with testing for peripheral neuropathy, especially in those patients who are treated with high doses of dapsone for long periods. One of the major morbidities in CP is ocular involvement. Patients with ocular CP are often referred from and managed in consultation with an ophthalmologist. The most worrisome physical signs are a rapidly progressive conjunctival inflammation with significant scarring. These patients require aggressive therapy to prevent the destruction of the meibomian glands and mucous glands, which play an important role in ocular function. All patients with ocular disease require systemic therapy, although there is some disagreement regarding the specifics of therapy. Unfortunately, at the present time there are no controlled double-blind clinical trials that address this issue. Some experts recommend the use of dapsone with or without concomitant corticosteroids as a reasonable first-line therapy for patients with moderate ocular disease. Tauber, de la Maza, and Foster180 reported that when dapsone was used as the initial chemotherapeutic agent in a group of patients with clinical and immunopathologic features diagnostic for CP, all of whom had ocular disease and 38% of whom had extraocular involvement, 31 of 69 patients (45%) had their ocular disease controlled. In this study, when dapsone was used as the initial agent for the treatment of moder-

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ately active CP, only 2% of patients failed to have their ocular disease controlled. In contrast, when patients have more severe ocular disease or rapidly progressive disease, the combination of oral corticosteroids along with cyclophosphamide is indicated.181 This stepwise approach to treatment is not always adhered to because many dermatologists and ophthalmologists who treat ocular CP do so only infrequently. Because of the severe morbidity that uncontrolled ocular CP is known to cause, many clinicians treating ocular CP recommend that all patients be treated aggressively at the outset with the combination of prednisone and cyclophosphamide. This may be due in part to a lack of familiarity with the criteria used to grade severity in ocular CP. We have therefore included in Table I the details of the modified Foster system for staging of ocular CP. Significant experience with the combination of cyclophosphamide and corticosteroids in patients with severe and/or progressive ocular CP demonstrates that approximately 75% of these patients experience a prolonged remission after 18 to 24 months of treatment.182 However, there are significant risks with this therapy, including hemorrhagic cystitis, bone marrow suppression, increased risk of infections, and, most worrisome of all, a significantly increased risk of the development of malignancy. Bladder carcinomas and lymphomas are the most frequently reported malignancies in patients treated with cyclophosphamide.182,183 Recently, the use of pulse cyclophosphamide along with corticosteroids has been reported to also be a successful treatment in a few patients with ocular CP.184 Whether this form of therapy will prove to be as efficacious and perhaps less toxic than oral cyclophosphamide is not known at this time. Azathioprine has also been used in the treatment of patients with ocular CP with some degree of success.181 Important toxicities to be aware of in patients treated with azathioprine are bone marrow suppression (including acute bone marrow failure), gastrointestinal distress, hepatotoxicity, increased risk of infection, and increased risk of malignancy, particularly lymphomas.185 Patients who have involvement of the skin or genitalia may be managed with either topical or, occasionally in the more severe cases, systemic corticosteroids. Other major morbidities in CP occur when patients have esophageal or laryngotracheal involvement, and there is good consensus that these patients should be treated aggressively with the combination of prednisone and cyclophosphamide to prevent the potentially life-threatening complications of asphyxiation and esophageal stenosis. Other therapies reported to be of potential value in the treatment of CP include sulfapyridine,186,187

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minocycline,188 intravenous immunoglobulin,189-191 and subconjunctival mitomycin.192 Of these, intravenous immunoglobulin appears the most promising for recalcitrant CP. In a recent study of 10 patients with progressive, otherwise treatment-resistant ocular CP, intravenous immunoglobulin therapy was shown to be safe and effective therapy.191 Treatment of patients with CP requires very careful clinical and laboratory monitoring by physicians familiar with the numerous potential toxicities of the medications that are to be used. These patients should be cared for jointly by a dermatologist experienced in the use of these potent medications and an internist who can assist in the management of any side effects that may occur as a result of treatment. It is very important for physicians caring for patients with CP to be attuned to the potential toxicities of the aggressive treatment modalities utilized. In some cases, the side effects of treatment can be worse than the disease. Surgical therapy The management of CP involves not only the control of the disease process but the restoration of function in cases in which severe deformities are present. In patients with ocular CP, entropion, trichiasis, symblepharon formation, and keratinization of the cornea develop. Esophageal strictures develop in patients with esophageal CP, and laryngeal strictures develop in patients with laryngeal CP. It is critical that surgical intervention not occur in CP until the disease is fully controlled by medical therapy because more inflammation will be created with further scarring if surgery is performed while the disease is still clinically active. If surgical procedures that injure mucosal epithelium, such as lysis of conjunctival adhesions, dilatation of the esophagus, or resection of laryngeal stenosis, become necessary, then the level of immunosuppression should be increased for a period of at least 2 weeks after the procedure. Because CP is a disease that affects multiple mucous membranes, it is imperative to develop a close working relationship with the appropriate specialist (ophthalmologist, otolaryngologist, or gastroenterologist) to obtain optimal care for these patients. Although dilation of the esophagus or resection of laryngeal stenosis can be performed by most gastroenterologists or otolaryngologists, surgical treatment of ocular CP can be very challenging, requiring ophthalmologists with significant expertise in this area. Mucous membrane grafts,193,194 corneal grafts,195 and a new advanced technique utilizing allograft limbal transplantation, amniotic membrane transplantation, and tarsorrhaphy followed by the use of serum-derived tears196 are some of the spe-

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cialized procedures that have been used with varying degrees of success in the surgical treatment of ocular CP. In patients with severe tracheal involvement, an elective tracheostomy should be considered in order to prevent asphyxiation. The use of portable voice translational computers can be helpful in assisting such patients with speech. Prognosis The heterogeneous group of disorders collectively classified as CP are chronic, often progressive, and potentially fatal. When a patient with CP is initially diagnosed, it is important to recognize that this is a serious and potentially devastating disease due to severe laryngeal, tracheal, oral, esophageal, or ocular laryngeal involvment. Repeated laryngeal or tracheal ulceration, scarring, and adhesion formation may lead to asphyxiation and death. Severe esophageal disease leading to strictures, webs, or complete obstruction may also result in serious, life-threatening complications. Progressive ocular CP may result in xerosis, entropion, trichiasis, symblepharon formation, keratopathy with neovascularization, and eventual blindness. The presence of serious secondary complications, such as recurrent infection and malnutrition, complicates the collection of mortality data, and such data are currently lacking with respect to CP. The potentially devastating course is of sufficient concern that multispecialty evaluation and aggressive therapy should be initiated early. However, in many patients, even aggressive immunosuppressive therapy is ineffective, and the disease progresses to the frustration of both the physician and the patient. Dermatologists who specialize in blistering diseases find CP among the most difficult to control. It is not uncommon in patients with refractory disease to see a temporary response to one drug or another followed by a relapse. In other patients, however, longterm remissions can be achieved. Neumann, Tauber, and Foster197 found that about one third of patients with CP maintained a prolonged period of remission after treatment with one or more immunosuppressive agents. In addition, they found that patients with less severe disease are less likely to progress and are more likely to respond to treatment. Although little is known about the factors that may determine disease progression, two groups of investigators identified several potential prognostic factors. Elder et al198 found that persistent epithelial defects, limbal inflammation, and ongoing conjunctival inflammation were associated with poor visual prognosis, whereas systemic involvement and ocular involvement were not associated. Setterfield et al199

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showed that the combination of an initial clinical score and initial IIF findings can be useful in identifying patients at high risk for severe disease. Patients with IIF studies positive for both IgG and IgA had the highest likelihood of requiring treatment with systemic medications. Titers of circulating IgG and IgA also appear to correlate with disease activity200 and therefore may be useful in the assessment and management of CP. Despite these recent advances, disease progression remains poorly understood, and further investigation into the pathophysiology of CP will likely be necessary to allow us to better identify prognostic factors. Often overlooked by dermatologists is the fact that visual impairment, chronic pain, difficulty in eating, and other physical aspects of the disease can have a major impact on the patient’s quality of life. In addition, the emotionally draining effects of dealing with a chronic disease can be psychologically difficult. The dermatologist should actively participate in and coordinate necessary supportive measures, including family education and social services involvement when appropriate. REFERENCES 1. Chan LS, Yancey KB, Hammerberg C, Soong HK, Regezi JA, Johnson K, et al. Immune-mediated subepithelial blistering diseases of mucous membranes: pure ocular cicatricial pemphigoid is a unique clinical and immunopathological entity distinct from bullous pemphigoid and other subsets identified by antigenic specificities of autoantibodies. Arch Dermatol 1993;129:448-55. 2. Domloge-Hultsch N, Anhalt GJ, Gammon WR, Lazarova Z, Briggaman R, Welch M, et al. Antiepiligrin cicatricial pemphigoid: a subepithelial bullous disorder. Arch Dermatol 1994;130:1521-9. 3. Leverkus M, Schmidt E, Lazarova Z, Bröcker EB, Yancey KB, Zillikens D. Antiepiligrin cicatricial pemphigoid: an underdiagnosed entity within the spectrum of scarring autoimmune subepidermal bullous diseases? Arch Dermatol 1999;135: 1091-8. 4. Chan LS, Majmudar AA,Tran HH, Meier F, Schaumburg-Lever G, Chen M, et al. Laminin-6 and laminin-5 are recognized by autoantibodies in a subset of cicatricial pemphigoid. J Invest Dermatol 1997;108:848-53. 5. Tyagi S, Bhol K, Natarajan K, Livir-Rallatos C, Foster CS, Ahmed AR. Ocular cicatricial pemphigoid antigen: partial sequence and biochemical characterization. Proc Natl Acad Sci U S A 1996;93:14714-9. 6. Smith EP, Taylor TB, Meyer LJ, Zone JJ. Identification of a basement membrane zone antigen reactive with circulating IgA antibody in ocular cicatricial pemphigoid. J Invest Dermatol 1993;101:619-23. 7. Mobini N, Nagarwalla N, Ahmed AR. Oral pemphigoid: subset of cicatricial pemphigoid? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:37-43. 8. Wichmann JE. Ideen zur diagnostik: beobachtenden aerzten mitgetheilet. Hanover, Germany: Helwing; 1794. p. 89-92. 9. Cooper W. Pemphigus of the conjunctiva. Ophthal Hosp Rep 1858;1:155-7.

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139. Woodley DT, Burgeson RE, Lunstrum G, Bruckner-Tuderman L, Reese MJ, Briggaman RA. Epidermolysis bullosa acquisita antigen is the globular carboxyl terminus of type VII procollagen. J Clin Invest 1988;81:683-7. 140. Lapiere JC, Woodley DT, Parente MG, Iwasaki T, Wynn KC, Christiano AM, et al. Epitope mapping of type VII collagen: identification of discrete peptide sequences recognized by sera from patients with acquired epidermolysis bullosa. J Clin Invest 1993;92:1831-9. 141. Leonard JN, Wright P, Williams DM, Gilkes JJH, Haffenden GP, McMinn RMH, et al. The relationship between linear IgA disease and benign mucous membrane pemphigoid. Br J Dermatol 1984;110:307-14. 142. Wojnarowska F, Marsden RA, Bhogal B, Black MM. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults: a comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatol 1988;19:792-805. 143. Leonard JN, Haffenden GP, Ring NP, McMinn RMH, Sidgwick A, Mowbray JF, et al. Linear IgA disease in adults. Br J Dermatol 1982;107:301-16. 144. Peters MS, Rogers RS. Clinical correlations of linear IgA deposition at the cutaneous basement membrane zone. J Am Acad Dermatol 1989;20:761-70. 145. Kelly SE, Frith PA, Millard PR, Wojnarowska F, Black MM. A clinicopathological study of mucosal involvement in linear IgA disease. Br J Dermatol 1988;119:161-70. 146. Chan LS, Regezi JA, Cooper KD. Oral manifestations of linear IgA disease. J Am Acad Dermatol 1990;22:362-5. 147. Webster GF, Raber I, Penne R, Jacoby RA, Beutner EH. Cicatrizing conjunctivitis as a predominant manifestation of linear IgA bullous dermatosis. J Am Acad Dermatol 1994;30: 355-7. 148. Wilson BD, Beutner EH, Kumar V, Chorzelski TP, Jablonska S. Linear IgA bullous dermatosis: an immunologically defined disease. Int J Dermatol 1985;24:569-74. 149. Zone JJ, Taylor TB, Kadunce DP, Meyer LJ. Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest 1990;85:812-20. 150. Haftek M, Zone JJ, Taylor TB, Kowalewski C, Chorzelski TP, Schmitt D. Immunogold localization of the 97-kD antigen of linear IgA bullous dermatosis (LABD) detected with patients’ sera. J Invest Dermatol 1994;103:656-9. 151. Ishiko A, Shimizu H, Masunaga T, Hashimoto T, Dmochowski M, Wojnarowska F, et al. 97-kDa linear IgA bullous dermatosis (LAD) antigen localizes to the lamina lucida of the epidermal basement membrane. J Invest Dermatol 1996;106:739-43. 152. Dmochowski M, Hashimoto T, Bhogal BS, Black MM, Zone JJ, Nishikawa T. Immunoblotting studies of linear IgA disease. J Dermatol Sci 1993;6:194-200. 153. Wojnarowska F, Whitehead P, Leigh IM, Bhogal BS, Black MM. Identification of the target antigen in chronic bullous disease of childhood and linear IgA disease of adults. Br J Dermatol 1991;124:157-62. 154. Wojnarowska F, Allen J, Collier P. Linear IgA disease: a heterogeneous disease. Dermatology 1994;189(Suppl 1):52-6. 155. Hashimoto T, Ishiko A, Shimizu H,Tanaka T, Dodd HJ, Bhogal BS, et al. A case of linear IgA bullous dermatosis with IgA anti-type VII collagen autoantibodies. Br J Dermatol 1996;134:336-9. 156. Marinkovich MP, Taylor TB, Keene DR, Burgeson RE, Zone JJ. LAD-1, the linear IgA bullous dermatosis autoantigen, is a novel 120-kDa anchoring filament protein synthesized by epidermal cells. J Invest Dermatol 1996;106:734-8. 157. Zone JJ, Taylor TB, Meyer LJ, Petersen MJ.The 97 kDa linear IgA bullous disease antigen is identical to a portion of the extra-

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158.

159.

160.

161.

162.

163.

164.

165.

166.

167. 168. 169.

170.

171.

172.

173.

174.

175. 176.

cellular domain of the 180 kDa bullous pemphigoid antigen, BPAg2. J Invest Dermatol 1998;110:207-10. Hashimoto T, Ishiko A, Shimizu H,Tanaka T, Dodd HJ, Bhogal BS, et al. A case of linear IgA bullous dermatosis with IgA anti-type VII collagen autoantibodies. Br J Dermatol 1996;134:336-9. Kárpáti S, Stolz W, Meurer M, Krieg T, Braun-Falco O. Ultrastructural immunogold studies in two cases of linear IgA dermatosis: are there two distinct types of this disease? Br J Dermatol 1992;127:112-8. Bhogal BS, Wojnarowska F, Marsden RA, Das A, Black MM, McKee PH. Linear IgA bullous dermatosis of adults and children: an immunoelectron microscopic study. Br J Dermatol 1987;117:289-96. Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestations of systemic lupus erythematosus. Br J Dermatol 1996;135:35562. Roholt NS, Lapiere JC, Wang JI, Bernstein LJ, Woodley DT, Eramo LR. Localized linear bullous eruption of systemic lupus erythematosus in a child. Pediatr Dermatol 1995;12:138-44. Yell JA, Allen J, Wojnarowska F, Kirtschig G, Burge SM. Bullous systemic lupus erythematosus: revised criteria for diagnosis. Br J Dermatol 1995;132:921-8. Gammon WR, Briggaman RA. Bullous eruption of systemic lupus erythematosus. In: Wojnarowska F, Briggaman RA, editors. Management of blistering diseases. London: Chapman and Hall Medical; 1990. p. 263-75. Gammon WR, Woodley DT, Dole KC, Briggaman RA. Evidence that anti-basement membrane zone antibodies in bullous eruption of systemic lupus erythematosus recognize epidermolysis bullosa acquisita autoantigen. J Invest Dermatol 1985; 84:472-6. Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, et al. Paraneoplastic pemphigus: an autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 1990; 323:1729-35. Korman NJ. Paraneoplastic pemphigus: a distinctive autoimmune syndrome. Med Surg Dermatol 1995;2:3-6. Horn TD, Anhalt GJ. Histologic features of paraneoplastic pemphigus. Arch Dermatol 1992;128:1091-5. Kiyokaya C, Ruhrberg C, Nie Z, Karashima T, Mori O, Nishikawa T, et al. Envoplakin and periplakin are components of the paraneoplastic pemphigus antigen complex. J Invest Dermatol 1998;111:1236-8. Chan LS, Fine JD, Briggaman RA, Woodley DT, Hammerberg C, Drugge RJ, et al. Identification and partial characterization of a novel 105-kDalton lower lamina lucida antoantigen associated with a novel immune-mediated subepidermal blistering disease. J Invest Dermatol 1993;101:262-7. Cotell SL, Lapiere JC, Chen JD, Iwasaki T, Krusinski PA, Chan LS, et al. A novel 105-kDa lamina lucida autoantigen: association with bullous pemphigoid. J Invest Dermatol 1994;103:78-83. Bhol K, Mohimen A, Neumann R,Yunis J, Foster S,Yunis EJ, et al. Differences in the anti-basement membrane zone antibodies in ocular and pseudo-ocular cicatricial pemphigoid. Curr Eye Res 1996;15:521-32. Muzyka BC, Greenberg MS, Glick MG. Management of oral manifestations of mucous membrane pemphigoid. J Geriatr Dermatol 1994;2:105-9. Lee MS,Wakefield PE, Konzelman JL, James WD. Oral insertable prosthetic device as an aid in treating oral ulcers. Arch Dermatol 1991;127:479-80. Eisen D, Ellis CN, Voorhees JJ. Topical cyclosporine for oral bullous disorders. J Am Acad Dermatol 1990;23:936-7. Holland EJ, Olsen TW, Ketcham JM, Florine C, Krachmer JH, Purcell JJ, et al. Topical cyclosporin A in the treatment of anterior segment inflammatory disease. Cornea 1993;12:413-9.

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177. Rogers RS, Seehafer JR, Perry HO. Treatment of cicatricial (benign mucous membrane) pemphigoid with dapsone. J Am Acad Dermatol 1986;6:215-23. 178. Hornsten P, Keisu M, Wiholm B.The incidence of agranulocytosis during treatment of dermatitis herpetiformis with dapsone as reported in Sweden, 1972 through 1988. Arch Dermatol 1990;126:919-22. 179. Raizman MB, Fay AM, Weiss JS. Dapsone-induced neutropenia in patients treated for ocular cicatricial pemphigoid. Ophthalmology 1994;101:1805-7. 180. Tauber J, de la Maza MS, Foster CS. Systemic chemotherapy for ocular cicatricial pemphigoid. Cornea 1991;10:185-95. 181. Foster CS, Wilson LA, Ekins MB. Immunosuppressive therapy for progressive ocular cicatricial pemphigoid. Ophthalmology 1982;89:340-53. 182. Korman NJ. Update on the use of cyclophosphamide in the management of pemphigus, bullous pemphigoid and cicatricial pemphigoid. Med Surg Dermatol 1998;5:1-6. 183. Talar-Williams C, Hijazi Y,Walther M, Linehan WM, Hallahan CW, Lubensky I, et al. Cyclophosphamide induced cystitis and bladder cancer in patients with Wegener Granulomatosis. Ann Intern Med 1996;124:477-84. 184. Pandya AG, Warren KJ, Bergstresser PR. Cicatricial pemphigoid successfully treated with pulse intravenous cyclophosphamide. Arch Dermatol 1997;133:245-7. 185. Korman NJ. Update on the use of azathioprine in the management of pemphigus and bullous pemphigoid. Med Surg Dermatol 1996;3:209-13. 186. Rogers RS. Dapsone and sulfapyridine therapy of pemphigoid diseases. Australas J Dermatol 1986;27:58-63. 187. Elder MJ, Leonard J, Dart JKG. Sulfapyridine: a new agent for the treatment of ocular cicatricial pemphigoid. Br J Ophthalmol 1996;80:549-52. 188. Poskitt L, Wojnarowska F. Minimizing cicatricial pemphigoid orodynia with minocycline. Br J Dermatol 1995;132:784-9. 189. Urcelay ML, McQueen A, Douglas WS. Cicatricial pemphigoid treated with intravenous immunoglobulin. Br J Dermatol 1997;137:467-84.

190. Bohn J, Benfeldt E, Dabelsteen E, Menne T. Treatment of ocular cicatricial pemphigoid with intravenous gammaglobulin. Acta Derm Venereol (Stockh) 1998;78:316-7. 191. Foster CS, Ahmed AR. Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: a preliminary study. Ophthalmol 1999;106:2136-43. 192. Donnenfeld ED, Perry HD, Wallerstein A, Caronia RM, Kanellopoulos AJ, Sforza PD, et al. Subconjunctival mitomycin C for the treatment of ocular cicatricial pemphigoid. Ophthalmology 1999;106:72-9. 193. Heiligenhaus A, Shore JW, Rubin PAD, Foster CS. Long-term results of mucous membrane grafting in ocular cicatricial pemphigoid: implications for patient selection and surgical considerations. Ophthalmology 1993;100:1283-8. 194. Shore JW, Foster CS, Westfall CT, Rubin PA. Results of buccal mucosal grafting for patients with medically controlled ocular cicatricial pemphigoid. Ophthalmol 1992;99:383-95. 195. Tugal-Tutkun I, Akova YA, Foster CS. Penetrating keratoplasty in cicatrizing conjunctival diseases. Ophthalmology 1995;102:576-85. 196. Tsubota K, Satake Y, Ohyama M, Toda I, Takano Y, Ono M, et al. Surgical reconstruction of the ocular surface in advanced ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Am J Ophthalmol 1996;122:38-52. 197. Neumann R, Tauber J, Foster CS. Remission and recurrence after withdrawal of therapy for ocular cicatricial pemphigoid. Ophthalmology 1991;98:858-62. 198. Elder MJ, Bernauer W, Leonard J, Dart JKG. Progression of disease in ocular cicatricial pemphigoid. Br J Ophthalmol 1996;80:292-6. 199. Setterfield J, Shirlaw PJ, Kerr-Muir M, Neill S, Bhogal BS, Morgan P, et al. Mucous membrane pemphigoid: a dual circulating antibody response with IgG and IgA signifies a more severe and persistent disease. Br J Dermatol 1998;138:602-10. 200. Setterfield J, Shirlaw PJ, Bhogal BS, Tilling K, Challacombe SJ, Black MM. Cicatricial pemphigoid: serial titres of circulating IgG and IgA antibasement membrane antibodies correlate with disease activity. Br J Dermatol 1999;140:645-50.

Answers to CME examination Identification No. 800-110

October 2000 issue of the Journal of the American Academy of Dermatology

Questions 1-33, Fleming TE, Korman NJ. J Am Acad Dermatol 2000;43:571-91.

1. 2. 3. 4. 5. 6. 7. 8. 9.

e d e c c a b a c

10. 11. 12. 13. 14. 15. 16. 17. 18.

b e c e d e b b c

19. 20. 21. 22. 23. 24. 25. 26. 27.

d e a e c e a c d

28. 29. 30. 31. 32. 33.

c d e e a e

CME examination Identification No. 800-110

Instructions for Category I CME credit appear in the front advertising section. See last page of Contents for page number.

Questions 1-33, Fleming TE, Korman NJ. J Am Acad Dermatol 2000;43:571-91.

Directions for questions 1-33: Give single best response. 1. Cicatricial pemphigoid (CP) is a heterogeneous group of disorders that may cause which of the following? a. Skin erosions with scarring b. Ocular erosions, fibrosis, and eventual blindness c. Desquamative gingivitis d. Esophageal strictures e. Any of the above 2. Distinct CP phenotypes include each of the following except a. ocular disease only b. predominantly ocular disease c. mucosal disease along with skin lesions d. generalized skin disease without mucosal involvement e. oral disease only 3. CP has been referred to by many different names. This includes each of the following except a. benign mucous membrane pemphigoid b. oral pemphigoid c. ocular pemphigoid d. pemphigus conjunctivae e. pemphigus vegetans 4. Several distinct immunochemical subgroups of CP have been described in which circulating autoantibodies recognize different antigens. These include each of the following antigens except a. 180-kd bullous pemphigoid (BP180) b. laminin-5 c. type VII collagen d. β4-integrin e. an uncharacterized 45-kd antigen 5. CP typically affects persons in the age range a. 20 to 40 years b. 40 to 60 years c. 60 to 80 years d. older than 80 years e. no age predilection has been determined 6. Which of the following is true with regard to CP? a. There is a female predominance. b. There is a male predominance. c. There is a predominance in the Caucasian population. d. The highest incidence is in the United States and Canada. e. b, c, and d

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7. The cause of CP a. is related to an environmental agent in most cases b. is unknown, although there is some evidence supporting an autoimmune pathogenesis c. is related to severe mucosal injury in most cases d. is thought to be Epstein-Barr virus e. is thought to be herpes simplex virus 8. In CP, the most frequent site of involvement is a. oral mucosa b. conjunctivae c. skin d. larynx e. esophagus 9. The most frequent oral manifestation of CP is a. erosions of the palate b. vesicles of the buccal mucosa c. desquamative gingivitis d. erosions of the lower lip e. painful tongue ulcerations 10. With regard to ocular CP, each of the following is true except a. ocular CP often begins as a nonspecific, chronic conjunctivitis. b. conjunctival vesicles are usually present in early disease. c. over time, adhesions called symblephara form between the bulbar and palpebral conjunctivae. d. in later stages, fibrosis can lead to abnormal lash orientation (trichiasis). e. blindness may result from severe ocular CP. 11. The modified Foster staging system for ocular CP considers each of the following except a. subconjunctival scarring and fibrosis b. degree of forniceal shortening c. percentage of horizontal involvement by symblephara d. presence of ankyloblephara and a frozen globe e. presence of trichiasis and entropion 12. The Brunsting-Perry variant of CP a. affects the trachea and larynx b. is a nonscarring variant affecting only the skin c. is localized to the head and neck d. usually results in blindness e. always affects some mucosal surface

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13. On light microscopy, the histopathologic findings in CP are similar to those of a. BP b. epidermolysis bullosa acquisita c. linear IgA bullous disease d. a and b e. a, b, and c 14. Ultrastructural studies of a blister in CP have demonstrated that the basement membrane zone (BMZ) is a. on the epidermal side of the blister b. on the dermal side of the blister c. split, with components of the BMZ on both sides d. a, b, or c may be true in any given patient e. a or b may be true in any given patient 15. In patients with clinical characteristics of CP, direct immunofluorescence (DIF) studies using perilesional skin or mucosa are positive in a. 0% to 25% b. 25% to 50% c. 40% to 50% d. 60% to 70% e. 80% to 100% 16. Positive DIF studies in patients with CP, which typically show a linear, continuous band at the BMZ, most commonly have the following reactant(s): a. IgA b. IgG and C3 c. IgA and C3 d. IgA and IgG e. IgA and IgM 17. Each of the following statements regarding DIF studies in CP is true except a. DIF is essential for the diagnosis of CP. b. the presence of IgA deposits at the BMZ is more common in BP than in CP. c. BP, epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, and herpes gestationis may have an identical DIF pattern. d. immunoperoxidase staining is more sensitive than DIF in documenting the presence of immunoreactants at the BMZ. e. the best results for DIF examination are obtained from perilesional mucosal specimens. 18. Regarding indirect immunofluorescence (IIF) studies in patients with CP, each of the following statements is true except a. the sensitivity of IIF can be increased by using saltsplit normal human skin or mucosa as a substrate. b. clinical subsets of CP vary in their IIF sensitivity. c. circulating IgA antibodies are found most commonly. d. in patients with suspected CP, IIF studies should evaluate the presence of both IgG and IgA antibodies. e. using concentrated serum as the substrate in a salt-split IIF study may allow for the detection of very low titer antibodies.

CME examination 593

19. Immunochemical studies have shown that some patients with CP have circulating antibodies that recognize BP180 (the 180-kd BP antigen). These patients a. have only circulating IgA antibodies directed against the 180-kd BP antigen (BP180), whereas patients with BP have only IgG antibodies directed against BP180 b. have autoantibodies that recognize a different epitope on BP180 than the one recognized by autoantibodies from patients with BP c. have autoantibodies that localize to the lower lamina lucida and lamina densa d. b and c e. a, b, and c 20. Another name for the adhesion molecule laminin-5 is a. epiligrin b. BM600 c. kalinin d. nicein e. all of the above have been used. 21. Clinical differences between CP and BP include each of the following except a. the average age at onset is much earlier for BP than CP. b. BP typically affects the skin primarily, whereas CP typically affects mucous membranes primarily. c. when mucosal involvement occurs in BP, it is usually not the presenting symptom. d. skin lesions in CP tend to be somewhat transient, whereas in BP they are longer lasting. e. lesions in BP are nonscarring unless they have become traumatized or infected, whereas lesions in CP are usually scarring. 22. The clinical differential diagnosis of CP includes which of the following? a. Epidermolysis bullosa acquisita b. Linear IgA bullous dermatosis c. Paraneoplastic pemphigus d. a and b e. a, b, and c 23. Each of the following is true of pseudo-ocular CP except a. pseudo-ocular CP may be difficult to distinguish from CP both clinically and histopathologically. b. pseudo-ocular CP most commonly affects just one eye. c. the most commonly implicated agents in the origin of pseudo-ocular CP are beta-blockers taken orally. d. immunochemical differences between pseudoocular CP and ocular CP have been demonstrated. e. many cases of pseudo-ocular CP are self-limited and nonprogressive after the offending drug is discontinued. 24. Local therapy for mild oral CP includes which of the following? a. Potent topical corticosteroids

594 CME examination

b. c. d. e.

Topical cyclosporine Topical anesthetics Debridement of dead mucosal tissue All of the above

25. Systemic medications that have been helpful in patients with CP include each of the following except a. etretinate b. dapsone c. intravenous immunoglobulin d. cyclophosphamide e. minocycline 26. Important potential toxicities of dapsone include each of the following except a. hepatitis b. hemolysis c. thrombocytosis d. peripheral neuropathy e. leukopenia 27. Systemic regimens that have been used in the initial treatment of ocular CP include a. prednisone along with dapsone b. dapsone alone c. prednisone along with cyclophosphamide d. a, b, and c e. a and c 28. Patients with CP who are at risk for potentially lifethreatening complications include those with a. ocular disease b. anogenital disease c. laryngotracheal disease d. skin disease e. a, b, and c 29. Patients at risk for life-threatening complications should be treated aggressively. Although there have been no large clinical studies to guide therapy, the most reasonable approach based on clinical experience to date is the use of a. prednisone alone with the addition of other agents for treatment failures b. prednisone along with sulfapyridine c. cyclosporine d. prednisone along with cyclophosphamide e. dapsone

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30. In the surgical management of CP it is essential to a. initiate surgery early in the course of disease b. refer to appropriate specialist, if possible one with experience managing patients with CP, to obtain optimal care c. control the disease fully with medical therapy before surgical intervention d. a, b, and c e. b and c 31. The factors that determine disease severity in CP a. are poorly understood b. are related to the age of the patient, with older patients having more severe disease c. may include titers of circulating IgG and IgA d. a, b, and c e. a and c 32. Disease progression in CP a. is poorly understood b. can be predicted based on the initial response to prednisone c. can be effectively controlled in almost all patients with immunosuppressive medications d. is slow in patients with ocular CP e. a, b, and c 33. Complications of CP include a. infection b. malnutrition c. chronic pain d. psychologic or emotional difficulties e. all of the above