Autoimmune blistering skin diseases

Reviews

Autoimmune Blistering Skin Diseases STEPHANIE COTELL, MD,* NEHA D. ROBINSON, MD,* AND LAWRENCE S. CHAN, MD*'I" Emergency physicians, at the front line of patient care, are often confrontedwith a wide variety of dermatologicconditions.Prompt recognition is essential, especially for the autoimmune blistering skin diseases, many of which have considerable morbidity and mortality. Therefore, an accurate diagnosis is imperative for appropriate referral and initiation of therapy. This review article provides a concise yet thorough discussion of the clinical presentation, incidence, differential diagnosis and management of the commonly encountered autoimmune blistering skin diseases, some of which include pemphigus, bullous pemphigoid, and epidermolysis bullosa acquisita. (Am J Emerg Med 2000;18:288-299. Copyright © 2000 by W.B. Saunders Company) The autoimmune blistering skin diseases are a group of diseases characterized by small and large blisters during the active period of disease and are mediated by autoantibodies targeting skin components. These diseases are chronic and should be distinguished from other nonautoimmune blistering skin diseases of short duration which have typical clinical features such as herpes simplex, poison ivy, bullous erythema mulfiforme, or toxic epidermal necrolysis. Mortality and significant morbidity may be associated with these diseases. Although they have chronic clinical courses, their onset can be relatively rapid. Emergency physicians, at the front line of patient care, will inevitably encounter these diseases. Therefore, the objective of this report is to enhance the emergency physician's awareness of the general clinical recognition of these diseases, provide suggestions for the initiation of therapy, and aid in referral to the appropriate specialists. In general, the autoimmune blistering skin diseases are caused by circulating and tissue bound autoanfibodies to skin proteins, leading to blister formation. These diseases are categorized by the level at which the blister occurs in the skin into two major groups: pemphigus and pemphigoid. Pemphigus is characterized by a loss of epidermal cell adhesion resulting in intraepidermal blisters with a thin flaccid roof. Pemphigoid is characterized by a loss of adhesion below the basal epidermal cells resulting in From the *Department of Dermatology, Northwestern University Medical School, Chicago, IL, and the l-Medicine Service, Section of Dermatology, Lakeside Division, VA Chicago Health Care System, Chicago, IL. Manuscript received June 7, 1999, accepted June 17, 1999. Address reprint requests to Lawrence S. Chan, MD, Department of Dermatology, Tarry 4-721, Mail Code T225, 300 E. Superior Street, Chicago, IL 60611-3010. E-mail address: larrychan @nwu.edu Key Words: Blistering skin diseases, pemphigus, pemphigoid, autoimmune. Copyright © 2000 by W.B. Saunders Company 0735-6757/00/1803-0013510.00/0 doi:l 0.1053/J E .2000.6320 288

subepidermal blisters with a thick "tense" roof. It is important to obtain an accurate diagnosis for patients with autoimmune blistering diseases, because treatment often requires long-term immunosuppressive therapy, which in itself can lead to a host of undesirable side effects. The use of immunosuppressive therapy, however, has dramatically decreased the morbidity and mortality of some of these diseases. This review article will discuss the clinical features, incidence, differential diagnosis, clinical course and treatment options for the commonly encountered autoimmune blistering skin diseases. PEMPHIGUS GROUP Essential facts: Pemphigus vulgaris is a life-threatening blistering disease of skin and mucous membranes, with the majority of patients initially presenting with oral lesions. Patients appear very ill and require immediate treatment with systemic corticosteroids. Other pemphigus subsets are clinically less severe. Clinical Features and Incidence The term pemphigus describes a group of autoimmune intraepidermal blistering diseases characterized clinically by superficial blisters and erosions of the skin and/or mucous membranes (especially the mouth). 1,2 Pemphigus is classified into two major forms: the deeper and more serious form, pemphigus vulgaris (and a minor variant pemphigus vegetans), and the superficial and more benign form, pemphigus foliaceus (and two minor variants pemphigus erythematosus and pemphigus herpetiformis). Myasthenia gravis and/or thymoma have been associated with pemphigus.

Pemphigus Vulgaris Pemphigus vulgaris is the most common and most dramatic type of pemphigus. Patients generally present in their fifth to sixth decade with superficial blisters and erosions involving all skin surfaces, as well as mucous membranes. Patients with extensive disease often appear very ill. The primary lesion is a flaccid blister, which may occur on normal or erythematous skin (Table 1). The blisters are fragile and rupture easily leaving erosions which may increase in size by peripheral extension. This characteristic finding in pemphigus patients can be elicited by applying lateral pressure to normal appearing skin at the periphery of an active lesion. The resulting shearing away of the epidermis, known as Nikolsky sign, is characteristic, but not diagnostic, of an intraepidermal blistering process. Erosions

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TABLE 1. Clinical Features of Autoimmune Blistering Skin Diseases

Disease

Characteristic Skin Manifestations

Age

Pemphigus vulgaris

Midadulthood

Generalized flaccid blisters and erosions

Pemphigus foliaceus

Midadulthood

Paraneoplastic pemphigus Bullous pemphigoid

Variable

Cicatricial pemphigoid

Elderly

Pemphigoid gestations

2nd-3rd trimester of pregnancy

Epidermolysis bullosa acquisita

Midadutthood

Linear IgA bullous dermatosis

Midadulthood

Chronic bullous disease of childhood

Early Childhood

Bullous systemic lupus erythematosus

Midadulthood

Crusted erosions on chest, back, and central face Variable presentation with skin and mucosal involvement Tense blisters or urticarial plaques, often on flexor surfaces Tense blisters primarily on face and scalp heal with scarring Pruritic urticarial papules and plaques which progress to tense blisters, begins on abdomen Tense blisters on non-inflamed skin over trauma prone extensor surfaces (elbows, knees, dorsal hands). Fragile skin heals with milia and scarring Blisters and erosions clinically similar to bullous pemphigoid or dermatitis herpetiformis, but less symmetrical Annular erythematous patches with peripherally arranged blisters, "string of pearls" appearance Widespread tense blisters that heal without scarring

Elderly

from ruptured blisters lead to crusted lesions, which if properly treated will heal without scarring. Because of the superficial nature of the blisters, erosions or crusted lesions may be the only presenting lesions (Fig 1). In approximately 50% to 70% of patients, oral lesions are the initial clinical presentation, and may precede the skin lesions by an average of 5 months. If oral involvement is not present initially, most patients will develop oral lesions during the clinical course of their disease. Lesions are commonly seen on the buccal, palatine, and gingival mucosa and appear as erosions, caused by the fragility of the blisters. These erosions may spread to involve the pharynx and larynx with resulting hoarseness. The oral erosions may be excruciatingly painful, and patients may be unable to eat or drink, which contributes to the malnutrition and extreme debilitation seen in untreated patients. Although oral mucous membrane lesions are the most common, involvement of other mucosa with painful erosions may occur, including conjunctival, rectal,

Extracutaneous Manifestations Oral mucosal erosions; rarely, thymoma and myasthenia gravis Typically none Cancer, most commonly lymphoma Typically none Oral mucosal and ocular erosions and scarring, scarring alopecia ÷ / - fetal morbidity or mortality

Rare association with diabetes mellitus, Crohn's disease, systemic lupus erythematosus Cancer (mainly lymphoma)

Typically none

Signs and symptoms of SLE

urethral, cervical, labial and esophageal mucous membranes. ~,a Physicians encountering patients with skin blisters or erosions should carefully examine patients' mucous membranes to make an accurate diagnosis. Pemphigus vulgaris has an incidence of 0.1 to 0.5 cases per 100,000 per year. The prevalence of pemphigus vulgaris is equal in men and women, and there is an increased prevalence in people of Mediterranean and Jewish descent. Pemphigus vulgaris is a sporadic disease, although there have been isolated reports of the disease occurring in families.

Pemphigus Vegetans Pemphigus vegetans is a minor variant of pemphigus vulgaris in which lesions initially resemble those of pemphigus vulgaris, but as they heal, they form verrucous, vegetative plaques that may be studded with small pustules. These lesions tend to occur in the intertriginous areas (groin, axillae, and creases of neck) and on the scalp or face (Fig 2). The laboratory findings, cause, and treatment of pemphigus vegetans are the same as those of pemphigus vulgaris. These patients, however, do not have as poor a prognosis as those with the classic form of pemphigus vulgaris.

Pemphigus Foliaeeus

FIGURE 1. Erosions in a patient with pemphigus vulgaris.

The other major form of pemphigus is pemphigus foliaceus, also referred to as superficial pemphigus, caused by the location of the blister just below the stratum corneum of the epidermis. Patients present with recurrent crusted superficial erosions in a seborrheic distribution (central face, neck, chest, or upper back). In contrast to pemphigus vulgaris, oral

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lyte and water loss, and debilitation. With current immunosuppressive therapy, mortality is now approximately 5% and is usually caused by complications from therapy. Long-term remissions are rare and many patients require therapy for life.

Diagnosis and Differential Diagnosis

FIGURE 2. Characteristic vegetative lesion in the axilla of a patient with pemphigus vegetans. lesions are uncommon and Nikolsky's sign is not inducible. Pemphigus foliaceus also occurs with equal frequency in men and women, although there is no ethnic predominance in people of Mediterranean or Jewish descent.

Pemphigus Erythematosus Pemphigus erythematosus, also known as Senear-Usher syndrome, is a localized form of pemphigus foliaceus in which there are clinical and/or serological features suggestive of coexistent lupus erythematosus. Patients have facial lesions typical of lupus erythematosus, as well as other skin manifestations of pemphigus foliaceus, with a positive antinuclear antibody and a positive lupus band test (deposits of immunoglobulin or complement, or both, at the dermalepidermal junction [DEJ]). 1

Pemphigus Herpetiformis Pemphigus herpetiformis is a disease originally described as having a combination of the clinical features of dermatitis herpetiformis (pruritic blister) and the immunopathologic features of pemphigus. 3 In most cases, patients have pruritic symptoms. Histology usually reveals a subcorneal blister with an inflammatory cell infiltrate composed of eosinophils and/or neutrophils.

Drug-Induced Pemphigus In rare instances, clinical and immunological features suggestive of pemphigus (mainly foliaceus) may be induced by drugs, most commonly D-penicillamine (5% of penicillamine users) and captopril. Both D-penicillamine and captopril have highly reactive sulfhydryl residues that can reduce disulfide bonds, leading to blister formation. Most, but not all, of these patients go into remission when the offending drug is discontinued. 1A careful drug history should be taken when evaluating patients with blistering diseases to rule out a drug-induced cause.

A diagnosis of pemphigus should be based on a combination of the following clinical, histological, and immunopathologic findings: (1) Clinical findings of flaccid blisters and erosions on skin and/or oral mucosa (for vulgaris subtype) and crusted erosions in a seborrheic distribution (for foliaceus subtype), (2) Histological examination of lesional skin showing a characteristic intraepidermal vesicle and acantholysis (loss of epidermal cell adhesion), (3) Direct immunofluorescence of normal-appearing perilesional skin showing a characteristic pattern of lgG deposition in a network-like pattern on keratinocyte cell surfaces.4 Indirect immunofluorescence using patients' sera showing circulating IgG autoantibodies bound to the epidermal cell surfaces of normal skin or monkey esophagus in approximately 75% of patients with active disease (Fig 3, Table 2). When only oral lesions are present, the differential diagnosis includes apthous stomatitis, erythema multiforme, herpes simplex, erosive lichen planus, and cicatricial pemphigoid. When oral and cutaneous lesions are present, the differential diagnosis includes the following: StevensJohnson syndrome/toxic epidermal necrolysis (acute, lifethreatening diseases), and other autoimmune blistering diseases including bullous pemphigoid, linear IgA buUous dermatosis, and epidermolysis bullosa acquisita. For further confirmation, immunoblotting studies using patients' sera against epidermal proteins can be performed. Patients with the vulgaris subtype have autoantibodies against a 130kD cadherin protein, desmoglein 3; whereas, patients with the foliaceus subtype have circulating autoantibodies against desmoglein 1, a 160kD demosomal protein. 5,6

Treatment Acute treatment in the emergency department consists of supportive care with IV fluids and appropriate antibiotics for streptococcus and staphylococcus coverage when secondary infection is suspected, while testing to determine an accurate diagnosis is performed. Long-term therapy for pemphigus is

Clinical Course Pemphigus vulgaris is a chronic, severely debilitating disease, which has a grave prognosis if untreated. Before the introduction of an effective treatment with oral corticosteroids, the mortality was 50% at 2 years and 100% by 5 years. Common causes of death were sepsis, malnutrition, electro-

FIGURE 3. Indirect immunofluorescence using serum from a pemphigus vulgaris patient showing IgG antibodies bound to the epidermal cell surfaces of monkey esophagus (magnification×40).

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TABLE2. Pathological and Immunopathological Features of Autoimmune Blistering Skin Diseases Disease Pemphigus vulgaris

Pemphigus foliaceus

Paraneoplastic pemphigus

Histology Suprabasilar acantholysis with vesicle formation, eosinophilic infiltrate Subcorneal or intragranular clefts with acantholysis and eosinophils Suprabasilar acantholysis with dyskeratotic cells and basal cell vacuolization

Bullous pemphigoid

Subepidermal blister with eosinophils + / - neutrophils Cicatricial pemphigoid Subepidermal blister with mixed infiltrate of eosinophils, neutrophils, lymphocytes and plasma cells. Fibrosis present if scarring present clinically Pemphigoid gestaVariable features; may tionis resemble BP; eosinophils along DEJ are most consistent feature Epidermolysis bullosa Subepidermal blister with acquisita variable inflammatory infiltrate Linear IgA bullous Subepidermal blister with dermatosis papillary dermal neutrophilic microabscesses Bullous systemic Subepidermal blister with lupus erythemaneutrophils tosus

Direct Immunofluorescence

Indirect Immunofiuorescence

Autoantigen(s)

IgG, C3, or both on keratinocyte cell surfaces

IgG autoantibodies against Desmoglein 3 keratinocyte cell surfaces

IgG, C3 or both on keratinocyte cell surfaces

IgG autoantibodies against keratinocyte cell surfaces

Desmoglein 1

IgG, C3 or both on keratinocyte cell surfaces ( + / - on DEJ)

IgG autoantibodies against keratinocyte cell surfaces

IgG, C3 or both in linear arrangement along DEJ

IgG autoantibodies against epithelial BMZ

Desmoptakin I and II, BP antigen 1, Envoplakin, Periplakin, Desmoglein 1 and 3, and a 170kD antigen BP antigen 1 and 2

IgG, C3, (occasionally IgA) in linear arrangement along DEJ

IgG or IgA autoantibodies against epithelial BMZ

BP antigen 2 (in some cases), laminin 5 or laminin 6 (few cases)

C3, rarely IgG, in linear arrangement along DEJ

Complement activating IgG autoantibodies against epithelial BMZ

BP antigen 2

IgG in linear arrangement along DEJ

IgG autoantibodies against epithelial BMZ

Type VII collagen

IgA in linear arrangement along DEJ

IgA autoantibodies against epithelial BMZ

BP antigen 2

IgG, IgA, IgM and C3 in linear arrangement along DEJ

IgG autoantibodies against epithelial BMZ

Type VII collagen

Abbreviations: DEJ, dermal-epidermal junction; BMZ, basement membrane zone.

directed at decreasing autoantibody synthesis because disease severity correlates with titers of autoantibodies. The first line of treatment is oral corticosteroids with the later addition of an immunosuppressive agent, such as azathioprine or cyclophosphamide, to offer a steroid-sparing effect. If complete remission is achieved with a two-drug regimen, the dosage of the second immunosuppressive drug is maintained while the oral corticosteroid is slowly tapered and eventually discontinued, at which point careful tapering of the other drug is attempted. Some patients have responded to treatment with prednisone along with low-dose weekly methotrexate, chlorambucil, cyclosporine, gold therapy, and plasmapheresis (Table 3). I

ParaneoplasticPemphigus Essential facts: Paraneoplastic pernphigus is a potentially fatal blistering disease of the skin and mucous membranes associated with an underlying neoplasm, most commonly lymphoma. Severe mucositis is a hallmark of the disease. The disease may be associated with significant morbidity and mortality, especially respiratory failure. Removal of a benign neoplasm improves skin lesions, but in patients with a malignancy, aggressive use of systemic immunosuppression is necessary,

Paraneoplastic pemphigus is an autoimmune blistering disease associated with an occult or confirmed underlying neoplasm. Clinically, patients are ill-appearing with polymorphous skin lesions including papules, blisters and erosions, as well as mucosal blisters and erosions (Fig 4). 7 The disease generally occurs in middle-aged adults in a wide ethnic distribution. The most common associated malignancies include (in order of decreasing frequency) non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Castleman's disease, thymoma, spindle cell neoplasms, and Waldenstrom's macroglobulinemia. In most cases, the neoplasm is present before the development of paraneoplastic pemphigus. 8 In the emergency department, physicians should perform a careful history and physical examination to detect the presence of an underlying malignancy, which may help establish the diagnosis. Histopathologic findings include intraepidermal acantholysis, basal cell vacuolization, and dyskeratotic cells. Direct imrnunofluorescence demonstrates IgG and complement deposition along the cell surface of keratinocytes often with linear/granular complement deposition along the basement membrane zone. Indirect immunofluorescence reveals circulating IgG antibodies which bind to the cell surface of skin and mucosa in a pattern similar to that of pemphigus, but in

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TABLE3. Therapeutic Options forAutoimmune Blistering Skin Diseases First Line Treatment

Alternative Treatment

Pemphigus (generalized)

Prednisone (1-2.5 mg/kg/day), azathioprine

Pemphigus (localized)

Potent topical corticosteroids

Bullous permpNgoid (generalized)

Prednisone (0.75-1.25 mg/kg/ day)

Bullous pemphigoid (localized)

Potent topical corticosteroids, tetracycline (2 g/day) and niacinamide (1.5-2 g/day) Prednisone (1 mg/kg/day), azathioprine, dapsone Dapsone

Pulsed corticosteroids, cyclosporine, cyclophosphamide, methetrexate, gold Prednisone (decreased dosage or alternate day therapy) Azathioprine, tetracycline and niacinamide, dapsone, cyclephosphamide, methotrexate, sulfapyridine, pulsed corticosteroids, plasmapheresis Prednisone (0.5-0.75 mg/kg/day)

Disease

Cicatricial pemphigoid (generalized) Cicatricial pemphigoid (localized) Pemphigoid gestationis Epidermolysis bullosa acquisita Linear IgA bullous dermatosis Chronic bullous disease of childhood Bullous systemiclupus e~them~osus

Adjunct Treatment Ultrapotent topical corticosteroids

Potent topical steroids

Cyclophosphamide Prednisone (0.5-0.75 mg/kg/day)

Potent topical corticosteroids

Photopheresis, potent topical corticosteroids

Dapsone

Cyclophosphamide, cyclosporine, methotrexate, gold, colchicine, IV lg Prednisone, sulfapyridine, colchicine, IFN-alpha Prednisone, sulfapyridine

Dapsone

Prednisone (1.0 mg/kg/day)

Prednisone (0.5-1 mg/kg/day) Prednisone (1 mg/kg/day), azathioprine, dapsone, avoid trauma Dapsone

addition bind to simple, columnar and transitional epithelia. Circulating autoantibodies recognize the following epidermal antigens by immunoprecipitation: Desmoplakin I and II, Bullous pemphigoid antigen 1 (BP230), Envoplakin, Periplakin, Desmoglein 1 and 3, and an undetermined 170-kd antigen. 7,8 Once a diagnosis of paraneoplastic pemphigus is made, treatment is very difficult. Removal of a benign neoplasm substantially improves the skin disease. In cases of malignancy, aggressive use of systemic corticosteroids, followed by cyclophosphamide, azathioprine, cyclosporine, or plasmapheresis should be used. Although the skin lesions may improve with therapy, the mucosal lesions are often resistant. Respiratory failure, clinically resembling bronchiolitis obliterans, is often the cause of death among patients. 9

PEMPHIGOID GROUP The term pemphigoid ("pemphigus-like") describes a group of autoimmune subepidermal blistering skin diseases characterized clinically by thick-walled, tense blisters and histologically by a separation between the epidermis and dermis at the skin basement membrane. In general, patients have a more benign course than those with pemphigus vulgaris, the most common pemphigus variant. Pemphigoid consists of a group of diseases each with distinct clinical features, and therefore, will be discussed under the following separate headings: bullous pemphigoid, pemphigoid gestations, cicatricial pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis and bullous systemic lupus erythematosus.

Bullous Pemphigoid Essential facts: Bullous pemphigoid is a nonscarring, blistering disease of the skin with rare mucous membrane involvement. Clinical features include tense blisters with a predilection for intertriginous skin areas (neck, groin, axillae). The disease is associated with low morbidity and mortality, and responds well to oral corticosteroids. Clinical Featuresand Incidence

FIGURE 4. Mucosal erosions in a patient with paraneoplastic pemphigus.

Bullous pemphigoid is a relatively benign, subepidermal blistering disease characterized by large, tense blisters that may occur anywhere on the skin, but with a predilection for the lower abdomen, flexor surfaces of the extremities, and inner or anterior thighs (Fig 5). 1°,11The blisters may occur on

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FIGURE 5. Typical tense blisters in a patient with bullous pemphigoid. erythematous or normal-appearing skin. Unlike pemphigus vulgaris, ruptured blisters do not expand peripherally, and the Nikolsky sign is negative. Mucous membrane lesions are uncommon, occurring in about 10% to 35% of patients and are almost always limited to the oral mucosa. A minority of patients may present with only localized lesions, usually on the lower legs or head and neck. The disease may go on to become generalized or may remain localized. The blisters and erosions heal with hyperpigmentation but without scarring. In addition to, or instead of blisters, patients may have urticarial plaques, eczematous patches, or just generalized pruritus. These changes may precede the blisters by several months. Patients are generally elderly, with the majority over 60 years of age at presentation. Bullous pemphigoid occurs more frequently than pemphigus vulgaris, although the exact incidence is unknown. 11There is no known racial, ethnic, or gender predominance.

Clinical Course Unlike pemphigus, bullous pemphigoid is often a selflimited disease lasting from months to years, and the patient may only require treatment for a finite time period. Approximately half of treated patients will go into remission within 2.5 to 6 years of onset of disease; however, individuals may have active disease for as long as 10 years or more. Unlike pemphigus, bullous pemphigoid antibody titers do not correlate with disease severity by immunofluorescence.11

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skin reveals linear deposits of IgG and C3 at the basement membrane (Fig 6). 12Indirect immunofluorescence examination shows circulating autoantibodies in 60% to 70% of patient's sera. When skin split by 1M NaC1 is used as a substrate, indirect immunofluorescence reveals antibodies bound to the epidermal side (the roof) of the split (Fig 7). 13 This pattern of immunofluorescence is useful to distinguish bullous pemphigoid from epidermolysis bullosa acquisita, in which circulating autoantibodies bind to the dermal side (the base) of salt-split skin. The target antigens of the bullous pemphigoid antibodies are two hemidesmosome-associated proteins, BPAgl (230 kd) and BPAg2 (180 kd), and have been well-characterized. 14.15

Treatment The mainstay of therapy for bullous pemphigoid is oral corticosteroids, and most patients will have a relatively rapid response to therapy. Steroid-sparing immunosuppressive agents, such as azathioprine, can be used along with corficosteroids. Dapsone or sulfapyridine are effective treatments in patients whose biopsy specimens show a predominantly neutrophilic infiltrate within the blister cavity. Other therapies for severe generalized disease include pulsed corticosteroids, cyclophosphamide, cyclosporine, and methotrexate. Recently, several investigators have reported success using a regimen of tetracycline (2 g per day) with niacinamide (1.5 to 2.5 g per day). This therapy may be useful for patients in whom steroids are contraindicated. Localized disease is successfully managed with highpotency topical steroidsJ 1

Pemphigoid Gestationis (Herpes Gestationis) Essential facts: Pemphigoid gestationis is a self-limited blistering disease occurring only during pregnancy or the postpartum period. Patients present with pruritic urticarial papules/plaques which progress to tense blisters on the abdomen. Associated fetal morbidity is controversial. Treatment includes topical or systemic corticosteroids and antihistamines.

Clinical Features and Incidence

Diagnosis and Differential Diagnosis

Pemphigoid gestationis, originally termed herpes gestatiohis, is a pruritic, blistering disease with clinical features

The differential diagnosis of bullous pemphigoid includes several subepidermal blistering diseases: cicatricial pemphigoid, epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, bullous drug eruption, linear IgA bullous dermatosis, dermatitis herpetiformis, and pemphigoid gestationis. Bullous pemphigoid can be easily distinguished from bullous drug eruption, linear IgA bullous dermatosis, dermatitis herpetiformis, and pemphigus vulgaris by histology and immunofluorescence. The scarring manifestation distinguishes cicatricial pemphigoid and epidermolysis bullosa acquisita from bullous pemphigoid. The findings of systemic lupus distinguish bullous systemic lupus erythematosus from bullous pemphigoid. Histological examination of a lesional biopsy of bullous pemphigoid shows a subepidermal blister with an eosinophil-rich inflammatory infiltrate. Direct immunofluorescence of perilesional

FIGURE 6. Direct immunofluorescence of a perilesional skin biopsy from a bullous pemphigoid patient showing IgG deposition at the basement membrane zone (magnification ×40).

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Histological examination can be variable, but the presence of eosinophils along the basement membrane appears to be the most constant feature and may resemble bullous pemphigold. Direct immunofluorescence is much more specific than histology and consistently shows linear C3 deposits along the basement membrane zone with additional IgG deposits detected in about 30% to 40% of patients. Immunofluorescence with salt-split skin reveals the immunoreactants to be on the epidermal side, similar to the findings with bullous pemphigoid. Pemphigoid gestationis is mediated by IgG autoantibodies that recognize BPAg2 (BP230).16,18 FIGURE 7. Salt-split indirect immunofluorescence using serum from a bullous pemphigoid patient showing circulating IgG antibodies bound to the epidermal side of the split (magnification x40). resembling bullous pemphigoid that occurs during pregnancy or in the immediate postpartum period. Because the disease is not related to the herpes virus infection, "pemphigoid gestationis" is a better term for the disease. Pemphigoid gestationis usually begins during the second or third trimester and presents as extremely pruritic urticarial papules and plaques on the abdomen that progress within days to form tense blisters which may become generalized. 16 The blisters can occur within urticarial plaques or on normal-appearing skin. Mucosal surfaces and the face are usually not involved. In 50% of cases, the lesions begin on the abdomen, whereas in the other 50%, lesions may begin in an atypical distribution. The degree of pruritus may seem out of proportion to the physical findings. The incidence of pemphigoid gestationis has been estimated to be 1 in 50,000 deliveries. This disease can occur in any pregnancy of an individual, but it occurs more often in early pregnancies and the disease tends to be more severe with later pregnancies. Nevertheless, there have been reports of disease-free pregnancies in women with a history of pemphigoid gestationis. 16

Clinical Course Although the disease is self-limited for a particular episode (generally resolving 1 to 6 months postpartum), recurrences have occurred with menstruation and with use of oral contraceptives. In 75% of patients, the disease will flare at the time of delivery. In others, the disease will flare shortly after giving birth. Ten percent of newborns experience transient mild cutaneous involvement which resolves on its own within weeks. It is controversial as to whether there is any increased fetal morbidity or mortality associated with this disease. A recent study showed a slight tendency for small-for-gestational-age births and prematurity with 16% of spontaneous deliveries associated with the disease occurring before 36 weeks (compared with 2% in normal controls) and 32% before 38 weeks (compared with 11% in normal controls). 17

Diagnosis and Differential Diagnosis The urticarial phase of the disease may be confused with pruritic urticarial papules and plaques of pregnancy, but the progression to blisters generally clarifies the diagnosis.

Treatment This disorder generally abates rapidly with delivery. Treatment is geared towards relieving pruritus and suppressing blister formation. Topical steroids are usually not effective in clearing the disease, but may be adequate in partially controlling the disease until delivery. Antihistamines may be used in conjunction with topical or systemic steroids. After consulting with the patients' obstetrician, systemic steroids are the mainstay of therapy, and are tapered during the postpartum period. The use of systemic steroids does not adversely affect the fetus, but infants born to mothers on prolonged high doses of systemic steroids should be monitored for adrenal insufficiency. Although the pruritus and blisters are problematic, this disease poses minimal risk to mother or child, and there is no role for induction of labor to halt the disease process. 16

Cicatricial Pemphigoid Essential facts: Cicatricial pemphigoid is a scarring, inflammatory blistering disease of mucous membranes with or without minimal skin involvement. Although nonfatal, involvement of ocular mucosa is an emergency, and should be treated aggressively with immunosuppression and/or surgical intervention to prevent irreversible ocular scarring and blindness.

Clinical Features and Incidence Cicatricial pemphigoid is a devastating immune-mediated subepidermal blistering disease primarily involving mucous membranes. 19 Lesions occur primarily on the oral mucosa and conjunctiva and heal with disfiguring scars, which may lead to permanent loss of function around the eyes and mouth. This disease is also known as "benign mucous membrane pemphigoid," but the disability and morbidity that result from this scarring disorder make cicatricial pemphigoid a more appropriate name (cicatricial = scarring). Patients with cicatricial pemphigoid present with mucous membrane lesions with the oral and ocular mucosae being the most frequently involved. Involvement of other mucosal surfaces may occur, such as the mucosae of the anogenital region, esophagus, larynx, and pharynx. Less often, patients will have cutaneous involvement as well. Oral lesions occur in most patients and begin as blisters that quickly break open, leaving slowly healing erosions. Patients can also present with a desquamative gingivitis that is typical of this disease, but this feature can also be seen with other blistering diseases of the oral cavity. Lesions may occur on any

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mucosal surface of the mouth including the buccal mucosa and soft and hard palates. At the early stage, lesions may be painful and resemble those of pemphigus vulgaris, but the scarring which follows at sites of healing in cicatricial pemphigoid does not occur with pemphigus vulgaris. 19 Ocular involvement is seen with approximately 61% to 80% of patients and presents as a conjunctival irritation which may be bilateral. Patients complain of a burning sensation or dryness of their eyes. Vesicles and erosions are rarely seen in the conjunctiva; rather, lesions present as a conjunctivitis with a violaceous hue and subconjunctival fibrosis. As the disease progresses, further fibrosis occurs causing an adhesion of the conjunctivae with symblepharon and ankloblepharon formation (fibrous tracts that fuse the bulbar and palpebral conjunctivae). As the conjunctiva contract, inversion of the eyelid margins (entropion) occurs which leads to inversion of lashes on to the corneal surface (trichiasis). This can lead to corneal scarring with eventual loss of vision. Blindness is the most devastating consequence of ocular involvement and was noted in up to one third of patients with ocular involvement followed for an average of 6 years. 19 Cutaneous lesions occur in anywhere from 10% to 40% of patients with cicatricial pemphigoid. Two types of lesions occur--scarring lesions which develop from blisters localized to the head and neck (Brunsting-Perry cicatricial pemphigoid) or nonscarring lesions which appear as vesicles and bullae on the trunk and extremities. 19 The incidence and prevalence of cicatricial pemphigoid are not known. There is no racial or geographic predominance, although the disease occurs slightly more frequently in women than men with a ratio of 1.5:1.

Clinical Course The clinical course of cicatricial pemphigoid is variable with some patients having limited disease with mild scarring and others having extensive scarring with loss of their functional abilities. Blindness and airway obstruction are the most serious complications of this disease.

Diagnosis and Differential Diagnosis A diagnosis of cicatricial pemphigoid should be based on the following criteria: (1) Clinical finding of a chronic blistering disease with erosions, predominantly of mucous membranes, which heal with scarring, (2) Histological examination of lesional skin showing a subepidermal blister with a mixed inflammatory infiltrate, (3) Direct immunofluorescence of perilesional skin or mucosal biopsies showing IgG and C3 and/or IgA (rare) in a linear pattern along the basement membrane. Immunoblotting studies show that autoantibodies from some patients with cicatricial pemphigoid bind to BPAg2. 2° Another subset of cicatricial pemphigoid patients has autoantibodies to the anchoring filament proteins, laminin-5 and laminin-6. 2m2 Because of the broad clinical presentation, the differential diagnosis early in the clinical course of this disease may be extensive including herpetic gingivostomatitis, erosive lichen planus, pemphigus vulgaris, paraneoplastic pemphigus, and erythema multiforme major. Differential diagnosis of the ocular lesions may include viral conjunctivitis, ocular

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rosacea, and ocular pseudopemphigoid (from use of topical eye medications which are toxic to the ocular epithelium). In patients who have both skin and mucous membrane involvement, the differential should be broadened to include epidermolysis bullosa acquisita and linear IgA bullous dermatosis.

Treatment Treatment of cicatricial pemphigoid depends on the organs involved and the extent and severity of involvement. In patients who have both skin and mucosal disease, the skin lesions usually respond quickly to immunosuppressive treatment, whereas the mucosal lesions are often resistant. For limited involvement of oral mucosa, good oral hygiene with antibacterial washes, topical anesthetics, and topical corticosteroids may be sufficient. Intralesional corticosteroids may be helpful for persistent erosions. Systemic therapy with oral corticosteroids, dapsone, cyclophosphamide, or azathioprine is necessary for patients with severe or progressive ocular or laryngeal disease. Once the disease begins to improve, tapering of the corticosteroids should be attempted. Patients may require moderately high doses for control of this disease while it is active, and they must be monitored carefully for the side effects of long-term systemic corticosteroids.19 The treatment of cicatricial pemphigoid may require a team approach with a variety of specialists, including ophthalmologists, dermatologists, dentists, and otolaryngologists, to participate in the patients' care. Surgical intervention may be undertaken to improve the scarring associated with this disease, but should only be attempted when control of the disease is obtained. Removal of the entropic eye lashes may be indicated for preventing corneal irritation and scarring. Surgery during the active stage of the disease may trigger more inflammation and further scarring with resulting flare of the disease. 19

Epidermolysis Bullosa Acquisita Essential facts: Epidermolysis bullosa acquisita is a scarring blistering disease of skin primarily over traumaprone extensor surfaces and mucous membranes. Skin fragility is significant, affecting patients' daily activities; therefore, avoidance of trauma and local wound care are important. Systemic corticosteroids are effective in the treatment of inflammatory forms of the disease.

Clinical Features and Incidence Epidermolysis bullosa acquisita is an immune-mediated, scarring, subepidermal blistering disorder affecting the skin and mucous membranes, predominantly on trauma-prone areas. 23 Most patients have tense blisters and erosions over trauma-prone extensor surfaces such as the knuckles, dorsal hands, elbows, knees, and ankles (Fig 8). Lesions heal with scarring and milia formation. Inflammatory changes with erythema are limited. This presentation may mimic that of porphyria cutanea tarda or a form of nonimmune-mediated hereditary epidermolysis bullosa (if the patient has a childhood onset of disease). The disease is characterized by

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tion of the patient's autoantibodies' reactivity to the target antigen (type VII collagen) by immunoblotting (or immunoprecipitation) .24

Treatment

FIGURE 8. Blisters, scarring and milia on a trauma-prone area of a patient with epidermolysis bullosa acquisita. significant skin fragility, often prohibiting patients from being able to perform their daily tasks. Most patients with this disease have oral mucosal lesions which may involve the buccal, gingival, palatal, nasal, conjunctival and esophageal mucosae. Furthermore, nail dystrophy and alopecia are sometimes observed. 23 This disease has a worldwide distribution and is slightly more common in blacks and women. The average age of onset is about 50 years of age, but it has been reported in children. Children with the disease are often misdiagnosed as having the inherited forms of dystrophic epidermolysis bullosa.

Clinical course This disease tends to run a chronic course with episodes of partial remissions and exacerbations. In some patients, the severity of the disease decreases with time, but spontaneous resolution seldom occurs.

Diagnosis and Differential Diagnosis The diagnosis is based on the clinical findings of an acquired subepidermal blistering disorder which characteristically results in milia and scars in trauma-prone sites. The absence of family history for bullous disorders will distinguish this disease from inherited forms of dystrophic epidermolysis bullosa. True and pseudoforms of porphyria cutanea tarda must also be considered in the differential diagnosis. Patients with epidermolysis bullosa acquisita, however, do not have the characteristic facial hypertrichosis, photodistributed lesions, scleroderma-like changes, or abnormal urine porphyrin studies seen in porphyria. It must also be differentiated from bullous pemphigoid, a nonscarring disease. Histological examination shows a subepidermal blister with a variable inflammatory infiltrate. The degree of inflammation in the biopsy specimen reflects the degree of inflammation clinically. Direct immunofluorescence of perilesional skin shows IgG deposits at the dermal-epidermal junction in all cases, a pattern similar to that seen with bullous pemphigoid skin. A helpful test to distinguish epidermolysis bullosa acquisita from bullous pemphigoid is indirect immunofluorescence on salt-split skin in which epidermolysis bullosa acquisita sera bind to the dermal side of the split (Fig 9), in contrast to bullous pemphigoid sera which bind the epidermal side of the split (Fig 7). 13,23 The most definitive diagnostic criteria are the demonstra-

Treatment is difficult as patients typically respond poorly to systemic corticosteroids and standard immunosuppressive agents that are helpful in other blistering diseases. Because trauma plays a key role in this disease and patients have increased skin fragility, they should be instructed to avoid vigorous rubbing of their skin and the use of harsh soaps and hot water. They should use local care for open wounds and seek medical attention if an infection develops. For patients with predominantly inflammatory disease, prednisone may be helpful; whereas, for patients with predominantly noninflammatory disease, the response to systemic steroids is often minimal. Other treatments which have been efficacious include dapsone, cyclosporine, colchicine, and photophoresis. 23 Linear IgA Bullous Dermatosis/Chronic BulIous Disease of Childhood Essential facts: Linear IgA bullous dermatosis is a pruritic blistering disease characterized by tense blisters or asymmetrically grouped herpetiform lesions. Chronic bullous disease of childhood has a distinct appearance of annular erythematous patches with peripheral blisters resembling a "string of pearls" configuration. Both diseases respond quickly to dapsone and sulfapyridine.

Clinical Features and Incidence Linear IgA bullous dermatosis is a subepidermal blistering disease which occurs in adults and is characterized clinically by tense blisters resembling lesions of bullous pemphigoid, or grouped lesions in a herpetiform pattern resembling dermatitis herpetiformis. However, the lesions are scattered and not as symmetrical as in dermatitis herpetiformis. Mucous membrane lesions may occur and pruritus is variable. Definitive diagnosis is made by immunofluorescence which reveals linear deposition of IgA along the dermal-epidermal junction. 25 In the United States, the incidence has not been reported,

FIGURE 9. Salt-split indirect immunofluorescence using serum from a patient with epidermolysis bullosa acquisita showing circulating IgG antibodies bound to the dermal side of the split (magnification ×40)

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but the prevalence in Utah has been estimated to be 0.6 per 100,000 adults. The average age of onset is greater than 60 years of age, but it can present at any time throughout adult life. A slight increase in incidence of woman over men has been noted in some series. Chronic bullous disease of childhood is a subepidermal blistering disease occurring in young children with a distinct clinical appearance, but similar direct immunofluorescence findings to adults with linear IgA bullous dermatosis. Clinically, children present with annular and serpiginous erythematous patches with blisters arranged peripherally giving rise to a dramatic "string of pearls" appearance (Fig 10). Individuals with chronic bullous disease of childhood usually present before age 10 (generally ages 2 to 6). The incidence is similar in boys and girls. 25 Patients with both diseases have circulating autoantibodies against a 97-kDa basement membrane zone protein demonstrable in some, but not all patients. 26 This 97-kDa target antigen is now determined to be BPAg2 (BP180). Because of these similarities, linear IgA bullous dermatosis and chronic bullous disease of childhood may be the same disease occurring in different age groups.

Clinical Course The usual course is characterized by persistence for several years and then spontaneous remission. For children with this disease, remission generally occurs within 2 years. Appropriate therapy can control all symptoms.

Diagnosis and Differential Diagnosis Linear IgA bullous dermatosis may be difficult to distinguish clinically from dermatitis herpetiformis and bullous pemphigoid, but can be distinguished from both of these by direct immunofluorescence which reveals linear IgA deposition along the basement membrane in perilesional skin. Histological examination of a lesional biopsy shows a subepidermal blister with neutrophilic microabscesses in the dermal papillae, similar to dermatitis herpetiformis.

Treatment Most patients with linear IgA bullous dermatosis will respond to treatment with dapsone or suplfapyridine in 48 to 72 hours. In rare patients, it may be necessary to add i!!!!i!~i; i

FIGURE 10. Annular, erythematous plaques with peripherally arranged blisters ("string of pearls" appearance) in a patient with chronic bullous disease of childhood.

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prednisone to control symptoms. Most cases of chronic bullous disease of childhood respond to either dapsone of sulfapyridine. It is recommended that initial therapy begin with sulfapyridine, because the side effects are less significant than those with dapsone. Other medications such as colchicine and interferon-alpha (INF-e0 are effective in some cases. 25

Bullous Systemic Lupus Erythematosus Bullous systemic lupus erythematosus is a rare subset of systemic lupus. Patients with this disease meet the criteria for systemic lupus as defined by the American Rheumatological Association (ARA). In addition, they have a widespread vesiculobullous eruption (resembling bullous pemphigoid) which is unrelated to the severity of the systemic lupus. Histologically, there is a subepidermalblister with a predominantly neutrophilic infiltrate. Direct immunofluorescence shows linear IgG, IgA, IgM, and C3 along the basement membrane. Indirect immunofluorescence shows that patients' circulating autoantibodies bind to the dermal side of salt-split skin. The patients' autoantibodies target type VII collagen, identical to that seen with epidermolysis bullosa acquisita. 27 However, lesions usually heal without scarring. Patients respond quickly to therapy with dapsone or corticosteroids? 8

DERMATITIS HERPETIFORMIS Essential facts: Dermatitis herpetiformis is an extremely pruritic blistering disease primarily of the skin presenting with symmetrically grouped lesions on the extensor surfaces. The disease is associated with a gluten-sensitive enteropathy. Sulfa drugs, such as dapsone or sulfapyridine, can result in a rapid resolution of symptoms.

Clinical Features and Incidence Dermatitis herpetiformis is a chronic, relapsing, intensely pruritic papulovesicular eruption with symmetrically grouped lesions, primarily on the extensor surfaces. 29 Dermatitis herpetiformis usually presents in the second or third decade, but may occur at any age. Patients typically present with symmetric, grouped or herpetiform (grouped blisters resembling herpes zoster) erythematous papules, urticarial plaques, or small blisters on extensor surfaces of the elbows, knees, shoulders, and buttocks. Patients commonly have scalp or posterior neck lesions. Mucosal surfaces are usually spared. The lesions are intensely pruritic or have a burning sensation. Some patients can predict the onset of new lesions by a preceding localized stinging or pruritic sensation. This disease is associated with a gluten-sensitive enteropathy which is identical to, but usually less severe than, celiac disease. A diet overloaded with gluten or iodides (seafood) can often precipitate a flare of the eruption. As a result of the gluten-sensitive enteropathy, some patients may develop steatorrhea, abnormal D-xylose absorption, or anemia caused by iron or folate deficiency; most patients are asymptomatic, however.29 The true incidence of dermatitis herpetiformis is not known, but in Sweden and Finland, the incidence is between 0.86 and 1.45 in 100,000 per year. In Anglo-Saxon and

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Scandinavian populations the prevalence is between 10 and 39 per 100,000. Dermatitis herpetiformis is much less common in blacks and Asians. A slight predilection in men is seen with a ratio of approximately 3:2. Strictly speaking, dermatitis herpetiformis is not an autoimmune disease because its target antigen has not been found. It is better considered an immune-mediated disease pending future research results.

Clinical Course Patients with this disease typically have a chronic course with exacerbations and remissions, although long-lasting remissions are rare. If patients follow a gluten-free diet, however, the skin and gastrointestinal abnormalities often remit. Dermatitis herpetiformis may be associated with an increased risk for gastrointestinal lymphomas and other malignancies.

Diagnosis and DifferentialDiagnosis Dermatitis herpetiformis may be confused with a number of other diseases because of its polymorphous presentation. The differential diagnosis includes papular urticaria, scabies, bullous pemphigoid, pemphigoid gestationis, neurotic excoriations, erythema multiforme, folliculitis, and linear IgA bullous dermatosis. Histological examination of lesional skin shows neutrophilic microabscesses within dermal papillae and subepidermal cleft formation. Histological examination of the small intestine shows villous atrophy and a lymphocytic infiltrate in the lamina propria. A definitive diagnosis depends on finding granular IgA deposition along the papillary dermis (as opposed to a linear pattern of IgA along the basement membrane in linear IgA bullous dermatosis) by direct immunofluorescence of nonlesional skin. 3°

Treatment Patients respond promptly to treatment with dapsone or sulfapyridine. With a starting dose of 100 mg of dapsone, most patients will be asymptomatic within 24 hours and new lesions no longer appear after 1 to 2 days of therapy. This rapid response to sulfa medication helps to confirm the diagnosis. Conversely, the lesions readily resurface within a few days of discontinuation of the sulfa medication. Although dapsone can suppress the skin lesions, it does not treat the gastrointestinal symptoms or reverse the pathological findings in the gut. The main complication of dapsone therapy is hemolysis, which occurs to some degree in all patients, but can be dangerous for patients with glucose-6phosphate dehydrogenase deficiency. Other dose-related side effects include toxic hepatitis, cholestatic jaundice, psychiatric symptoms, and sensory and motor neuropathy. An idiosyncratic reaction with aplastic anemia or an infectious mononucleosis-like syndrome may occur at any dose. 29 Sulfapyridine can be used for patients who cannot tolerate dapsone, who are glucose-6-phosphate dehydrogenase deficient, or who have cardiac disease. However, sulfapyridine is poorly absorbed from the gastrointestinal tract and is less effective at suppressing the skin lesions. Complications which may occur with sulfapyridine are similar to side effects seen with other sulfa drugs, including nephrolithiasis.

Another treatment option is strict adherence to a glutenfree diet that requires substantial self-discipline and effort to maintain patient compliance. Gluten is present in barley, rye, oats, and wheat, but rice and corn do not contain gluten. Not only does this form of therapy spare the patient the side effects of dapsone and sulfapyridine, but it also reverses the gut abnormalities. Patients need to be educated, often with the assistance of a nutritionist, if they are to succeed with this diet. Patients should also be informed that unlike the rapid response seen with dapsone or sulfapyridine, it may take greater than a year of avoiding gluten before they will see results from strict adherence to the diet. Patients who comply with this diet in addition to taking dapsone or sulfapyridine will require lower medication doses to suppress their disease. 29

REFERENCES 1. Stanley JR: Pemphigus, in Freedberg IM, Eisen AZ, Wolff K, et al (eds): Fitzpatrick's Dermatology in General Medicine. New York, NY, McGraw-Hill, 1999, pp 654-666 2. Lever WF (ed): Pemphigus and Pemphigoid. Springfield, IL, Charles C. Thomas, 1965 3. Jablonska S, Chorzelski T, Beutner EH, et al: Herpetiform pemphigus, a variable pattern of pemphigus. Int J Dermato11975;14: 353-359 4. Beutner EH, Lever WF, Witebsky E, et al: Autoantibodies in pemphigus vulgaris: Response to an intercellular substance of epidermis. JAMA 1965; 192:682-688 5. Amagai M, Klaus-Kovtun V, Stanley JR: Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 1991;67:869-877 6. Eyre RW, Stanley JR: Human autoantibodies against a desmosomal protein complex with a calcium-sensitive epitope are characteristic of pemphigus foliaceus patients. J Exp Med 1987;165:17191724 7. Anhalt GJ, Kim SC, Stanley JR, et al: Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 1990;323:1729-1735 8. Robinson ND, Hashimoto T, Amagai M, et al: The new pemphigus variants. J Am Acad Dermatol 1999;40:649-671 9. Nousari HC, Deterding R, Wojtczack H, et al: The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med 1999;340:1406-1410 10. Lever WF: Pemphigus. Medicine 1953;32:1-123 11. Stanley JR: Bullous Pemphigoid, in Freedberg IM, Eisen AZ, Wolff K, et al (eds): Fitzpatrick's Dermatology in General Medicine. New York, NY, McGraw-Hill, 1999, pp 666-671 12. Jordon RE, Beutner EH, Witebsky E, et al: Basement zone antibodies in bullous pemphigoid. JAMA 1967;200:751-756 13. Gammon WR, Briggaman RA, Inman AO, et al: Differentiating anti-lamina lucida and anti-sublamina densa anti-BMZ antibodies by indirect immunofluorescence on 1.0 M sodium chloride-separated skin. J Invest Dermatol 1984;82:139-144 14. Stanley JR, Hawley-Nelson P, Yuspa SH, et al: Characterization of bullous pemphigoid antigen: A unique basement membrane protein of stratified squamous epithelia. Cell 1981;24:897-903 15. Labib RS, Anhalt GJ, Patel HP, et al: Molecular heterogeneity of the bullous pemphigoid antigens as detected by immunoblotting. J Immuno11986;136:1231-1235 16. Katz Sl: Herpes GestatioNs (Pemphigoid Gestationis), in Freedberg IM, Eisen AZ, Wolff K, et al (eds): Fitzpatrick's Dermatology in General Medicine. New York, NY, McGraw-Hill, 1999, pp 686-689 17. Shornick JK, Black MM: Fetal risks in herpes gestationis. J Am Acad Dermato11992;26:63-68 18. Giudice GJ, Emery DJ, Zelickson BD, et al: Bullous pemphi-

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gold and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain. J Immuno11993;151: 5742-5750 19. Yancey KB: Cicatricial Pemphigoid, in Freedberg IM, Eisen AZ, Wolff K, et al (eds): Fitzpatrick's Dermatology in General Medicine. New York, NY, McGraw-Hill, 1999, pp 674-679 20. Chan LS, Yancey KB, Hammerberg C, et ah Immunemediated 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 specificity of autoantibodies. Arch Dermatol 1993;129:448-455 21. Domloge-Hultsch N, Gammon WR, Briggaman RA, et ah Epiligrin, the major human keratinocyte integrin ligand, is a target in both an acquired autoimmune and an inherited subepidermal blistering skin disease. J Clin Invest 1992;90:1628-1633 22. Chan LS, Majmudar AA, Tran HH, et ah Laminin-6 and laminin-5 are recognized by autoantibodies in a subset of cicatricial pemphigoid. J Invest Dermatol 1997;108:848-853 23. Woodley DT, Gammon WR, Briggaman RA: Epidermolysis Bullosa Acquisita, in Freedberg IM, Eisen AZ, Wolff K, et al (eds): Fitzpatrick's Dermatology in General Medicine. New York, NY, McGraw-Hill, 1999, pp 702-709 24. Woodley DT, Briggaman RA, O'Keefe EJ, et al: Identification of

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the skin basement-membrane autoantigen in epidermolysis bullosa acquisita. N Engl J Med 1984;310:1007-1013 25. Hall RP: Linear IgA Dermatosis and Chronic Bullous Disease of Childhood, in Freedberg IM, Eisen AZ, Wolff K, et al (eds): Fitzpatrick's Dermatology in General Medicine. New York, NY, McGraw-Hill, 1999, pp 680-685 26. Zone JJ, Taylor TB, Kadunce DID, et ah Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear IgA bullous dermatosis. J Clin Invest 1990;85:812820 27. Gammon WR, Woodley DT, Dole KC, et ah Evidence that anti-basement membrane zone antibodies in bullous eruption of systemic lupus erythematosus recognize epidermolysis bullosa acquisita autoantigen. J Invest Dermatol 1985;84:472-476 28. Sontheimer RD: Lupus Erythematosus, in Freedberg IM, Eisen AZ, Wolff K, et al (eds): Fitzpatrick's Dermatology in General Medicine. New York, NY, McGraw-Hill, 1999, pp 2002 29. Katz SI: Dermatitis Herpetiformis, in Freedberg IM, Eisen AZ, Wolff K, et al (eds): Fitzpatrick's Dermatology in General Medicine. New York, NY, McGraw-Hill, 1999, pp 709-715 30. Hall RP, Lawley T J: Characterization of circulating and cutaneous IgA immune complexes with dermatitis herpetiformis. J Immunol 1985; 135:1760-1765