Anti-epiligrin cicatricial pemphigoid with IgG autoantibodies to the beta and gamma subunits of laminin 5

Anti-epiligrin cicatricial pemphigoid is an autoimmune subepithelial blistering disorder of mucous membranes and skin. By immunoblot analyses, sera of most patients with antiepiligrin cicatricial pemphigoid have been shown to react specifically with the alpha3 chain of laminin 5. We describe the first patient with anti-epiligrin cicatricial pemphigoid in whom circulating IgG autoantibodies directed against the beta3 and gamma2-chains of laminin 5 were detected. Treatment with oral prednisolone was beneficial in controlling the disease.     

Transient Cutaneous Vesicles in a Teenager: The Final Piece to a Puzzle

Abstract: Cicatricial pemphigoid is a chronic blistering disease that predominantly affects the mucous membranes. It has a peak occurrence in the seventh decade. Pediatric cicatricial pemphigoid is a rare entity, with fewer than 20 cases reported. We report an 18-year-old man who was recently diagnosed with cicatricial pemphigoid after six years of diagnostic uncertainty.     

Mucous membrane pemphigoid: clinical aspects, immunopathological features and therapy

More than 50 years have passed since Civatte, Lever, and others described the clinical and histopathological characteristics of mucous membrane pemphigoid (synonym: cicatricial pemphigoid). This enigmatic, relapsing, and often eventually progressive subepithelial blistering disorder of the mucous membranes and skin continues to challenge investigators trying to understand the pathogenesis of the disease and prevent its progression. Mucous membrane pemphigoid typically begins in late adulthood and has a variable prognosis. Fifty percent of patients will develop esophageal and ocular lesions that heal with secondary atrophy leading to stenosis of the upper aerodigestive tract and blindness in uncontrolled disease. Recent progress has been made in understanding the cause, the immunological components, and the pathologic process of mucous membrane pemphigoid. The short-term clinical and pathological manifestations of disease activity have been reduced by new therapies, although the degree of long-term benefit from these treatments awaits further study.     

Epidermolysis bullosa acquisita with combined features of bullous pemphigoid and cicatricial pemphigoid.

Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal blistering disease associated with autoantibodies against type VII collagen. The classical or mechanobullous form of EBA is characterized by skin fragility, trauma-induced blisters and erosions with mild mucous membrane involvement and healing with scars. Furthermore, bullous-pemphigoid-like and cicatricial pemphigoid-like features have been described. We report a patient who developed a bullous skin disease with upper airway obstruction requiring tracheotomy. The diagnosis of EBA was established by immunoblot, showing a band at 290 kD (collagen VII), and NaCl-split skin immunofluorescence (IgG deposition at the floor of the split). This case presented with clinical features of both bullous pemphigoid and cicatricial pemphigoid which to our knowledge is the first report of such a combination in EBA. The patient also presented tracheal involvement that has never been described either.     

New and emerging therapies in the treatment of blistering diseases

The autoimmune vesiculobullous diseases of the skin and mucous membranes are a fascinating group of diseases characterized by blisters of the skin and mucous membranes. These diseases are among the most intriguing, well-characterized, and potentially serious skin diseases known. In recent years, there has been major progress made in the understanding of their pathophysiology, in the development of new diagnostic techniques and of new therapeutic approaches. These advances have placed the autoimmune blistering diseases of the skin and mucous membranes at the forefront of dermatologic advances in the late twentieth century. This article discusses several of the most important autoimmune blistering disease, including bullous pemphigoid, mucous membrane pemphigoid (formerly known as cicatricial pemphigoid), epidermolysis bullosa acquisita, linear IgA bullous dermatosis, pemphigus and paraneoplastic pemphigus, with particular emphasis on the use of new and emerging therapeutic approaches.     

The use of chemically split tissue in the detection of circulating anti-basement membrane zone antibodies in bullous pemphigoid and cicatricial pemphigoid

Human skin and mucous membranes were used to detect circulating auto-antibodies by indirect immunofluorescence in 20 patients with bullous pemphigoid and eight with cicatricial pemphigoid. The tissue substrate was used intact and after chemical separation through the basement membrane zone (BMZ) by incubation with I M NaCl. Chemically split skin and oral mucosa provided a more sensitive assay for demonstrating circulating anti BMZ antibodies. Use of a battery of substrates increased the number of positives in bullous pemphigoid from 30% detected on monkey oesophagus to 100% (tissue battery). In cicatricial pemphigoid there was an increase in the proportion of positive sera from 13% (monkey oesophagus) to 88% (tissue battery). In addition, a different class of antibody was frequently detected on split tissue substrate suggesting that new antigens are exposed by this procedure.     

Dual diagnosis of Pemphigus and pemphigoid. Retrospective review of thirty cases in the literature.

BACKGROUND: Pemphigus and pemphigoid are two distinct groups of autoimmune blistering diseases. There are many reports of the simultaneous presence of clinical and serological features of both diseases in the same patient. OBJECTIVE: This study is a retrospective review of the present literature on reports of patients with features of both pemphigus and pemphigoid. We recommend that these patients be considered as having a dual diagnosis. METHODS: A review of the English language, peer-reviewed literature was conducted on patients described with features of pemphigus and pemphigoid. Available data on clinical profile, histology, immunopathology, treatment, follow-up and outcome were studied in 30 patients. They were divided into three groups: (1) bullous pemphigoid and pemphigus vulgaris, (2) mucous membrane or cicatricial pemphigoid and pemphigus vulgaris and (3) bullous pemphigoid and pemphigus foliaceus. RESULTS: In all three groups, most patients had a clinical phenotype resembling both diseases. In 17 patients with bullous pemphigoid and pemphigus vulgaris, 83% had a skin biopsy consistent with bullous pemphigoid, 70% had direct immunofluorescence studies typical of bullous pemphigoid and sera of 83% had antibodies typical of pemphigus vulgaris on indirect immunofluorescence. In 10 patients with mucous membrane or cicatricial pemphigoid and pemphigus vulgaris, a histology of mucous membrane pemphigoid was reported in 60% of the patients, direct immunofluorescence studies typical of mucous membrane pemphigoid were reported in 70% of the patients and in 80%, autoantibodies characteristic of pemphigus vulgaris were observed. In 3 patients with bullous pemphigoid and pemphigus foliaceus, the histologies were consistent with bullous pemphigoid, direct immunofluorescence was typical of pemphigus foliaceus and their sera had both autoantibodies. The majority of the 30 patients required long-term high-dose corticosteroids and immunosuppressive agents to control their disease. Three patients with bullous pemphigoid and pemphigus vulgaris (18%) died due to effects of prolonged immunosuppression. CONCLUSION: We characterize a group of patients who have clinical, histological and immunopathological features of bullous or mucous membrane or cicatricial pemphigoid with serological features of pemphigus. These patients did not achieve a prolonged clinical remission by conventional therapy. It is possible that early identification of these patients may improve their prognosis.     

Autoimmune subepidermal blistering diseases in Uganda: correlation of autoantibody class with age of patients

BACKGROUND: No data are available on the incidence and immunoreactivity of autoimmune subepidermal blistering skin diseases in East Africa. METHODS: All patients with frank blisters/erosions on the skin and/or mucous membranes that attended the Department of Dermatology at Mbarara University, Uganda, from May 2000 to June 2002, were investigated. The diagnosis was based on the clinical presentation and on the presence of circulating autoantibodies detected by indirect immunofluorescence microscopy on 1 m NaCl-split human skin and by Western blotting of recombinant and cell-derived forms of BP180, BP230, and type VII collagen. RESULTS: Twenty-two patients with autoimmune subepidermal blistering skin disorders were identified, including nine with bullous pemphigoid (41%), four with linear immunoglobulin A (IgA) disease (18%), three with mucous membrane pemphigoid (14%), two with linear IgG/IgA bullous dermatosis (9%), and one each with cicatricial pemphigoid and epidermolysis bullosa acquisita (5%). In addition, two patients with immunoreactivity to both the epidermal and dermal side of salt-split skin by indirect immunofluorescence microscopy, who were unreactive to type VII collagen, were provisionally diagnosed as "mixed pemphigoid" (9%). In patients with subepidermal blistering diseases, IgG reactivity correlated significantly with old age, whereas younger patients preferentially developed IgA autoantibodies (P = 0.024). CONCLUSIONS: The age of patients with autoimmune subepidermal blistering diseases appears to influence the immunoglobulin class of autoantibodies. The high frequency of IgA autoantibodies in Ugandan patients may be explained by the age distribution of the Ugandan population.     

Antiepiligrin (laminin 5) cicatricial pemphigoid associated with an underlying gastric carcinoma producing laminin 5

Although bullous pemphigoid and cicatricial pemphigoid are sometimes associated with malignancy, it remains uncertain whether such an association is pathogenetically related or just a coincidence attributable to the advanced age of the patients. We report a 61-year-old patient with antiepiligrin (laminin 5) cicatricial pemphigoid (AeCP) associated with an advanced gastric carcinoma. The gastric carcinoma cells in this patient were shown to produce laminin 5 by immunofluorescence microscopy, and the patient's serum contained autoantibodies directed against laminin 5 on immunoprecipitation. Furthermore, the blistering symptoms and the titre of antibasement membrane zone antibodies coordinately changed with the resection and subsequent relapse of the gastric cancer. These observations suggest that the gastric carcinoma producing laminin 5 may have induced the production of autoantibodies to this laminin, which were pathogenic to the skin and mucous membranes in this patient. This report demonstrates a link between this autoimmune subepithelial blistering disease and malignancy. It is of interest and potential great importance to examine other cases of AeCP for such a potential association.     

Anti-p200 pemphigoid responding to dapsone

Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease. Clinical presentation is similar to standard bullous pemphigoid (BP) but mucous membranes and cephalic lesions are more frequent. Histology and direct immunofluorescence (IF) are identical to BP but indirect IF discloses linear deposits of immunoglobulin G (IgG) on the dermal side of artificial salt-split skin. Specific diagnosis is based on western immunoblotting that shows circulating IgG recognizing a 200-kDa protein localized on the dermal extract. The 200-kDa antigen was recently identified as laminin γ1. Anti-p200 pemphigoid should be considered before all atypical or topical steroid-resistant bullous disease, as well as mucous membranes pemphigoid or epidermolysis bullosa acquisita. Dapsone appears to be the most effective treatment and should be used as the first option in combination with topical steroids. In this report, we describe the case of a patient with a typical clinical and immunopathological anti-p200 pemphigoid, responding to a combination of topical steroids and dapsone.     

Treatment of cicatricial pemphigoid with mycophenolate mofetil as a steroid-sparing agent.

BACKGROUND: Cicatricial pemphigoid (CP) is a rare autoimmune bullous disease that affects the skin and mucous membranes. It commonly ends by serious complications such as blindness, stenosis, and stricture formation and is difficult to treat. Mycophenolate mofetil has been reported to be effective in the treatment of pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid either as monotherapy or as a steroid-sparing agent. OBJECTIVE: Our purpose was to evaluate the effectiveness of mycophenolate mofetil as a steroid-sparing agent in treating patients with CP. METHODS: Three patients with CP were treated with mycophenolate mofetil and prednisolone. RESULTS: All 3 patients responded very well to the therapy. None of them showed relapse of the disease for a follow-up period of 6 to 14 months after complete cessation of mycophenolate mofetil and prednisolone. No side effects were seen. CONCLUSION: Mycophenolate mofetil appears to be a safe and effective steroid-sparing agent in the treatment of CP.     

Pemphigoid gestationis with predominant involvement of oral mucous membranes and IgA autoantibodies targeting the C-terminus of BP180

Pemphigoid gestationis (PG) is an autoimmune pregnancy-associated subepidermal blistering disease. It usually affects skin and, rarely, mucous membranes. In the vast majority of patients with PG, the autoimmune response is directed to the membrane-proximal NC16A domain of the 180-kd bullous pemphigoid (BP) antigen (BP180) and is mediated by IgG1 and IgG3 autoantibodies. We report the case of a patient with PG associated with extensive lesions on oral mucous membranes. Immunoblotting studies demonstrated the presence of circulating IgA autoantibodies in the patient's serum that were exclusively directed to a 49 amino acid stretch on the C-terminal portion of the BP180 ectodomain located 800 amino acids downstream from NC16A. This C-terminal stretch of BP180 has previously been demonstrated to localize to the lamina lucida/lamina densa interface and to be recognized by IgG and IgA antibodies in a subgroup of patients with cicatricial pemphigoid as well as by IgG autoantibodies in some BP sera. Our patient's lesions healed without scarring within 6 weeks after delivery of a healthy child. The findings in this patient extend the clinical and immunopathologic spectrum of PG.     

Blistering disorders: diagnosis and treatment

Blistering diseases are a heterogeneous group of disorders that can affect either skin and mucous membrane, or both, varying in presentation, clinical course, pathohistology, immunopathology and treatment. Not infrequently the diagnosis is delayed. This can result in severe, and sometimes fatal consequences. Although these diseases are rare, it is very important to make an accurate diagnosis based on a combination of clinical profile and laboratory observations. A brief review is presented of the following bullous diseases: pemphigus, paraneoplastic pemphigus, bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis, linear IgA bullous disease, porphyria cutanea tarda, and subcorneal pustular dermatitis. Their clinical, pathohistologic and immunopathologic features and recommendations for therapy are discussed.     

Cicatricial pemphigoid presenting with unusual palmar involvement, successfully treated with a combination of nicotinamide and tetracycline

Cicatricial pemphigoid is a rare subepidermal blistering disease, mainly of elderly women, that primarily involves mucous membranes. Oral, ocular or genital mucous membranes are most frequently involved and skin involvement is less frequent. We report a case of Cicatricial pemphigoid with extensive cutaneous involvement, including unusual bilateral palmar involvement. Clinical improvement has been achieved with a combination of topical steroids, oral nicotinamide and tetracycline.     

Childhood cicatricial pemphigoid confined to the vulva

Cicatricial pemphigoid or benign mucous membrane pemphigoid is an autoimmune bullous disease predominantly affecting the mucosal surfaces and healing with scar formation. Localized cicatricial pemphigoid of the vulva in children is rare. We present a child with this rare condition who was initially investigated on suspicion of her being subjected to child sexual abuse, and discuss its management.     

Disseminated cicatricial pemphigoid in a child and in an adult. Ultrastructural diagnostic criteria and differential diagnosis with special reference to acquired epidermolysis bullosa

Summary The first case of an infant affected with a rare, disseminated variant of benign cicatricial pemphigoid is described, showing the same ultrastructural features of initial blister formation as an adult patient. These consist in edematous changes within the superficial dermis caused by vesiculation or dissolution of cellular and noncellular connective tissue elements, coalescing into subepidermal blisters. Differential diagnosis excludes other nonhereditary bullous disorders because of the ultrastructure of the dermo-epidermal junction in nascent blisters and in perilesional skin. In spite of evident clinical, histological, and immunohistological similarities as well as controversial and confusing immunological studies, acquired epidermolysis bullosa can be clearly separated from our case by a diagnostic hallmark on the electron-microscopical level, i.e., band-like IgG depositions beneath the basal lamina. This is demonstrated in comparing the two cases of disseminated cicatricial pemphigoid with three patients suffering from acquired epidermolysis bullosa, thus providing evidence that disseminated cicatricial pemphigoid and acquired epidermolysis bullosa are two distinct nosologic entities.     

Pemphigoid variants affecting the skin

Pemphigoid diseases are autoimmune subepidermal blistering diseases affecting the skin and mucous membranes, which are caused by autoantibodies targeting structural hemidesmosomal proteins or hemidesmosome‐associated proteins. Variants of pemphigoid can be differentiated based on targeted antigens and clinical aspects. In this review, we will discuss pemphigoid variants that predominantly affect the skin, and provide clinicians with clues to diagnosis.     

Oesophageal involvement in cicatricial pemphigoid

Four cases of cicatricial pemphigoid complicated by oesophageal involvement are presented. All patients suffered dysphagia but repeated radiological studies were required for confirmation of oesophageal ulceration, webs and strictures. A combination of systemic drug therapy and oesophageal dilatation were necessary for the suppression of symptoms. The clinical and immunopathological features, management and complications of oesophageal involvement in cicatricial pemphigoid are discussed. Dermatologists should be aware of these features and make regular inquiries about swallowing difficulties in patients with cicatricial pemphigoid to guide appropriate investigations and treatment     

Mucous gland basement membrane immunofluorescence in cicatricial pemphigoid

Three patients are described with cicatricial pemphigoid and positive immunofluorescence findings in the basement membrane zone of mucous glands of the pharynx, mouth, and nose. These findings appear to be unique to cicatricial pemphigoid.     

U-serrated immunodeposition pattern differentiates type VII collagen targeting bullous diseases from other subepidermal bullous autoimmune diseases

BACKGROUND: Epidermolysis bullosa acquisita (EBA) can be differentiated from other subepidermal bullous diseases by sophisticated techniques such as immunoelectron microscopy, salt-split skin antigen mapping, fluorescence overlay antigen mapping, immunoblot and enzyme-linked immunosorbent assay. OBJECTIVES: To determine whether the diagnosis can also be made by routine direct immunofluorescence microscopy. METHODS: We studied frozen skin biopsies from 157 patients with various subepidermal immunobullous diseases. RESULTS: We found three distinct 'linear' fluorescence patterns at the basement membrane zone: true linear, n-serrated and u-serrated. The true linear pattern, often seen in conjunction with either the n- or the u-serrated pattern, was found in any subepidermal immunobullous disease with nongranular depositions. In bullous pemphigoid, mucous membrane pemphigoid, antiepiligrin cicatricial pemphigoid, p200 pemphigoid and linear IgA disease the n-serrated pattern was found, corresponding with depositions located in hemidesmosomes, lamina lucida or lamina densa. However, in EBA and bullous systemic lupus erythematosus the u-serrated staining pattern was seen, corresponding with the ultralocalization of type VII collagen in the sublamina densa zone. The diagnosis of EBA with IgG or IgA autoantibodies directed against type VII collagen was confirmed by immunoelectron microscopy, salt-split skin antigen mapping, fluorescence overlay antigen mapping or immunoblotting. CONCLUSIONS: Using this pattern recognition by direct immunofluorescence microscopy we discovered several cases of EBA which would otherwise have been erroneously diagnosed as a form of pemphigoid or linear IgA disease.