Case of epidermolysis bullosa acquisita with concomitant anti‐laminin‐332 antibodies

Subepidermal autoimmune blistering disease including bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid, anti‐laminin‐γ1 pemphigoid, linear immunoglobulin A bullous disease and epidermolysis bullosa acquisita (EBA), are all characterized by direct immunofluorescence microscopy or immunoglobulin deposition on the basement membrane zone. Among them, EBA is a rare acquired subepidermal autoimmune blistering disease of the skin and mucous membranes reactive with type VII collagen, a major component of the epidermal basement membrane zone. Anti‐laminin‐332‐type mucous membrane pemphigoid has pathogenic autoantibodies against laminin‐332, which is a basement membrane heterotrimeric protein composed of α3, β3 and γ2 laminin chains. We describe a 73‐year‐old Japanese man presenting with multiple, annular, tense blisters on the lower legs and oral lesions. Despite the severe clinical manifestations, the disease was successfully controlled by combination therapy of oral prednisolone and mizoribine. This case was confirmed to have autoantibodies to both type VII collagen and laminin‐332 α3 chain by indirect immunofluorescence of 1 mol NaCl‐split normal human skin, various immunoblot analyses and enzyme‐linked immunosorbent assays. This case was a rare case of EBA with concomitant anti‐laminin‐332 antibodies.     

Frequency of IgA antibodies in pemphigus, bullous pemphigoid and mucous membrane pemphigoid

Circulating and bound IgA antibodies can be found in the autoimmune blistering diseases, but their prevalence, clinical relevance and target antigens remain unknown. Thirty-two patients with pemphigus, 73 with bullous pemphigoid and 28 with mucous membrane pemphigoid were studied retrospectively. Direct immunofluorescence (DIF) analysis of IgG, IgA, IgM and C3 was carried out for all cases. Sera were studied by standard indirect immunofluorescence, indirect immunofluorescence on salt-split skin, immunoblotting for bullous pemphigoid and mucous membrane pemphigoid and ELISA for pemphigus. With DIF, we found IgA autoantibodies in 22 of all 133 cases. Circulating IgA antibodies to skin were detected in 2 of 3 IgA-DIF-positive patients with pemphigus, in 3 of 6 with bullous pemphigoid, and in 6 of 13 with mucous membrane pemphigoid. We confirm that the IgA reactivity is more frequently associated with mucous membrane involvement, especially in cases without critical involvement (5/8). The role of IgA and its antigenic specificity in these diseases remain unclear.     

Cicatricial pemphigoid with circulating autoantibodies to beta4 integrin, bullous pemphigoid 180 and bullous pemphigoid 230

Cicatricial pemphigoid is a heterogeneous group of autoimmune subepidermal blistering diseases associated most commonly with autoantibodies to bullous pemphigoid (BP)180 and less frequently with those to laminin 5 or type VII collagen. In addition, a few cases have been described with autoantibodies to the beta4 subunit of alpha6beta4 integrin. We describe a patient with extensive disease of ocular, oral, pharyngeal, laryngeal and genital mucous membranes that healed with scarring of conjunctivae. IgG autoantibodies bound to the dermal-epidermal junction on direct immunofluorescence (IF) microscopy and to the epidermal side of 1 mol L(-1) NaCl-split skin on indirect IF microscopy. Our patient's circulating IgG recognized a 205-kDa protein in extracts of 293T cells transfected with the beta4 subunit of alpha6beta4 integrin and in the cell extract of DJM-1 cells. Our patient's IgG and IgA autoantibodies also reacted with full-length BP180 derived from epidermal extracts and the ectodomain of BP180 (LAD-1) derived from culture supernatant of keratinocytes. In addition, a weak IgG reaction with BP230 was noted. The disease rapidly responded to dexamethasone-cyclophosphamide pulse therapy, and immunoblot reactivity to both beta4 integrin and BP180 decreased according to disease activity.     

Bullöses Pemphigoid

Pemphigoid diseases are a group of autoimmune disorders characterized by subepidermal blistering and autoantibodies against structural proteins of the dermal-epidermal junction. In bullous pemphigoid, the most common subepidermal blistering autoimmune disease, antibodies are directed against the hemidesmosomal antigens BP180 (collagen type XVII) and BP230. Bullous pemphigoid typically presents with severe pruritus and tense blisters accompanied by erosions and crusts in elderly patients. Diagnostic landmarks are the detection of linear IgG and/or C3 deposits at the dermo-epidermal junction by direct immunofluorescence microscopy of a perilesional biopsy and the detection of serum autoantibodies by indirect immunofluorescence microscopy on human salt-split skin and ELISA employing recombinant immunodominant fragments of BP180 and BP230. Treatment options include topical (class IV) and/or systemic corticosteroids, frequently combined with immunomodulatory agents like dapsone and tetracyclines or immunosuppressants such as methotrexate and azathioprine.     

Mucous membrane pemphigoid with immunoglobulin G autoantibodies against full-length and 120-kDa ectodomain of BP180

Mucous membrane pemphigoid (MMP) is a rare autoimmune, subepidermal, bullous disease characterized by erosive lesions on the mucous membranes and skin. MMP reacts with various target antigens including BP180, laminin-332, β4 integrin, α6 integrin or type VII collagen. We present a 67-year-old male MMP patient who had lesions on the oral and ocular mucous membranes and facial skin. By immunoblot analyses, immunoglobulin G autoantibodies in the patient's sera reacted with full-length BP180 and the 120-kDa ectodomain of BP180 (LAD-1).     

Mapping of epitopes on the BP180 ectodomain targeted by IgA and IgG autoantibodies in patients with the lamina lucida-type of linear IgA disease

Abstract Linear IgA disease (LAD) is an autoimmune subepidermal blistering skin disease characterized by the linear deposition of IgA at the dermoepidermal junction. Serum from patients with LAD most commonly contains autoantibodies that are directed against the hemidesmosomal transmembrane glycoprotein BP180 (type XVII collagen). Various antigenic sites on the extracellular domain of this anchoring filament protein have been shown to be targeted by autoantibodies in different autoimmune bullous skin diseases, including bullous pemphigoid and cicatricial pemphigoid (CP). However, little is known about epitopes on BP180 recognized by autoantibodies in LAD. In this study, we used three recombinant GST fusion proteins, together roughly covering the entire BP180 ectodomain, to characterize the autoimmune response in serum from patients with LAD. Interestingly, we found both IgA and IgG reactivity to all three portions of the BP180 ectodomain. The strongest reactivity was observed with the C-terminal portion of BP180. This is also the major region recognized by autoantibodies in patients with CP. This finding correlates with the observation that there may be significant overlap of the clinical and immunopathological findings in LAD and CP. Received: 21 August 2000 / Revised: 8 November 2000 / Accepted: 13 December 2000     

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.     

Subepidermal blasenbildende Autoimmundermatose mit linearen Ablagerungen von IgA und IgG

A 29-year-old female patient with an autoimmune subepidermal blistering disease had linear deposits of both IgA and IgG at the basement membrane zone. Clinically, the patient presented with tense blisters on the face, trunk, extremities and oral mucosa. Histologically, we found a subepidermal blister formation and a predominantly neutrophilic infiltrate. Direct immunofluorescence showed linear deposits of IgA along the basement membrane zone, as well as linear deposits of IgG and C3 as typically found in bullous pemphigoid. Indirect immunofluorescence demonstrated circulating IgA and IgG autoantibodies. This case extends previous reports on a subgroup of patients with subepidermal blistering diseases characterized by the presence of both IgA and IgG anti-basement membrane antibodies. These patients reveal clinical, histological and immunopathological features of linear IgA disease and bullous 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.     

Association between the subepidermal autoimmune blistering diseases linear IgA disease and the pemphigoid group and inflammatory bowel disease: two case reports and literature review

We report two patients with subepidermal autoimmune blistering diseases and inflammatory bowel disease (IBD) [one with linear IgA disease (LAD) and ulcerative colitis (UC), and the other with mucous membrane pemphigoid (MMP) and Crohn disease (CD)], and present a review of all previously reported cases. We reviewed the literature, and found 48 cases of patients with autoimmune blistering diseases and IBD. The blistering diseases were LAD (25 patients), bullous pemphigoid (BP) (21), MMP (1) and pemphigoid gestationis (1), while the IBD types comprised UC (40) and CD (8). We describe the clinical and immunopathological features and demographic characteristics of the patients. In all but one case, the diagnosis of IBD predated the development of the skin condition. The association was more common with LAD than BP. The immunopathogenesis of IBD and autoimmune blistering diseases is discussed and a link between them hypothesized, namely, that the presentation of multiple antigens to the immune system during the unregulated inflammation in the bowel wall results in excitation of the immune system and recognition of autologous antigens.     

Acquired subepidermal bullous diseases associated with psoriasis: a clinical, immunopathological and immunogenetic study

Summary Clinical, immunopathological and immunogenetic studies of four patients with a subepidermal bullous disease associated with psoriasis were carried out to determine the true nature of the blistering disease and to investigate further the relationship between psoriasis and acquired subepidermal bullous diseases. Autoantibodies in all four patients bound to the epidermal side of salt-split skin by indirect immunofluorescence and detected the major bullous pemphigoid (BP) antigens by immunoblotting. One had additional IgA autoantibodies binding an epidermal polypeptide of 270/280 kDa and another had circulating IgA autoantibodies which detected both BP and epidermolysis bullosa acquisita (EBA) antigens. All patients had active psoriasis at the onset of the bullous disease. Three patients were being treated with tar when blisters developed: one patient also received UVB radiation and experienced a relapse after exposure to sunlight. HLA phenotypes in three patients were determined. All the patients responded well to methotrexate. These findings demonstrate that BP is the subepidermal bullous disease most associated with psoriasis. Changes at the basement membrane zone in psoriasis may be responsible for the heterogeneous antibody response and may trigger the bullous disease, as may antipsoriatic treatment including tar and UV radiation. However, common immunogenetic mechanisms may play a crucial part in this disease association.     

Pemphigoid with antibodies to laminin γ1, BP180 and BP230, associated with psoriasis vulgaris: Successful disease control with cyclosporin

Both anti‐laminin γ1 pemphigoid and bullous pemphigoid are autoimmune subepidermal blistering diseases. The former is rare and characterized by autoantibodies to laminin γ1, a 200‐kDa dermal protein, while the latter is common among the elderly and characterized by autoantibodies to BP180 and BP230, both of which are hemidesmosomal proteins. We experienced a 69‐year‐old Japanese male patient with blister formation secondary to erythrodermic psoriasis, which was successfully treated with cyclosporin. The histopathology of erythema corresponded with psoriasis and that of a blistering lesion showed infiltration of neutrophils and eosinophils in and around the subepidermal blisters. Patient immunoglobulin G antibodies labeled both the epidermal and dermal sides of 1 mol/L NaCl‐split human skin by indirect immunofluorescent microscopy and recognized laminin γ1, BP180 and BP230 by immunoblotting. To the best of our knowledge, this is the first report of coexistence of psoriasis and atypical pemphigoid with these three autoantibodies.     

Linear IgA Bullous Dermatosis of Childhood with Autoantibodies to a 230 kDa Epidermal Antigen

Abstract: Linear IgA bullous dermatosis (LABD) is an autoimmune, subepidermal disease defined on the basis of direct immunofluorescence findings. However, more recent techniques used to study bullous dermatoses suggest that LABD may be heterogeneous. A patient with LABD of childhood (chronic benign disease of childhood, CBDC) was studied by indirect immunofluorescence on salt-split skin and by Western blot in an attempt to characterize the involved autoantigen. This young girl's periorificial (mouth, genitalia), erythematovesicular lesions were diagnosed initially as herpes simplex. Histologic examination revealed eosinophilic spongiosis, suggesting the diagnosis of an autoimmune blistering disease. Direct immunofluorescence showed an exclusive linear IgA deposit at the dermoepidermal junction. Indirect immunofluorescence revealed circulating IgA autoantibodies that reacted with the epidermal side of saltsplit skin; these reacted by Western blot with a 230 kDa epidermal antigen, as in bullous pemphigoid. This case, fulfilling the diagnostic clinical and direct immunofluorescence criteria for LABD/CBDC, seems to represent IgA bullous pemphigoid. It further underscores the nosologic heterogeneity of LABD, which probably includes, apart from bullous pemphigoid, epidermolysis bullosa acquisita and cicatricial pemphigoid.     

Autoantibodies in a subgroup of patients with linear IgA disease react with the NC16A domain of BP1801

Linear IgA disease is an autoimmune subepidermal blistering disease characterized by IgA deposits at the cutaneous basement membrane zone. IgA antibodies from linear IgA disease sera react with antigens of 97 kDa (LABD97) and 120 kDa (LAD-1), both of which appear to be fragments of the extracellular domain of bullous pemphigoid 180 (type XVII collagen). The aim of this study was to determine whether linear IgA disease sera react with the immunodominant region of BP180 (NC16A domain), which is a major target of IgG autoantibodies produced by patients with bullous pemphigoid. Indeed, 11 of 50 linear IgA disease sera were found to contain IgA autoantibodies that recognized a recombinant form of NC16A by immunoblotting. The same sera also reacted with NC16A by enzyme-linked immunosorbent assay. An epitope mapping analysis uncovered four linear IgA disease-associated epitopes located within the 45 amino acid N-terminal stretch of NC16A, all of which were previously identified as antigenic sites targeted by bullous pemphigoid autoantibodies. Eight of the linear IgA disease sera that were reactive with NC16A also recognized LAD-1 secreted by the SCC-25 cell line, and five sera recognized BP180 extracted from keratinocytes. Linear IgA disease sera depleted of reactivity to NC16A by immunoadsorption continued to react with both the LAD-1 antigen and BP180 by immunoblotting and with the basement membrane zone by indirect immunofluorescence microscopy. Our results demonstrate that IgA autoantibodies from a subset of linear IgA disease patients react with the same sites on BP180 that are targeted by IgG autoantibodies in bullous pemphigoid.     

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.     

IgG autoantibodies from a lichen planus pemphigoides patient recognize the NC16A domain of the bullous pemphigoid antigen 180

Lichen planus pemphigoides (LPP) most likely encompasses a heterogeneous group of subepidermal autoimmune blistering disorders occurring in association with lichen planus. We describe the case of a 49-year-old patient with features characteristic of LPP. Direct immunofluorescence microscopy studies demonstrated linear deposits of C3 along the cutaneous basement membrane, while circulating IgG autoantibodies directed against the epidermal side of skin separated by 1 M NaCl were detected. The patient's serum contained IgG autoantibodies immunoblotting a recombinant form of bullous pemphigoid antigen 180 (BP180), but not the COOH-terminus of BP230. By using deletion mutants, it was found that IgG reactivity was restricted to the NC16A domain of BP180, the region harboring the major antigenic sites targeted by IgG autoantibodies from patients with the bullous pemphigoid group of disorders. Our findings provide support to the idea that a subset of patients with LPP have a distinct form of bullous pemphigoid associated with lichen planus.     

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.     

Acquired skin disease of hemidesmosomes.

The hemidesmosome is a membrane-associated supramolecular dermal epidermal complex linking the cytoskeleton of the basal keratinocyte to structures within the papillary dermis. Different components of this complex have been identified as autoantigens in autoimmune bullous skin diseases. Some of the autoantigens have been characterized at the molecular level. Little is known, however, about the factors that initiate the production of autoantibodies. By histopathology, acquired skin diseases of hemidesmosomes show subepidermal blisters and by direct immunofluorescence, linear deposits of IgG, C3 or IgA at the dermal epidermal junction. Bullous pemphigoid (BP) is the most common acquired disease of hemidesmosomes. Two proteins, BP180 and BP230, have been identified as primary targets of autoantibodies in BP. In addition, pemphigoid/herpes gestationis, lichen planus pemphigoides, cicatricial pemphigoid and linear IgA disease are characterized by an immune response to BP180. Laminin 5 is another well-characterized anchoring filament-lamina densa component of hemidesmosomes. Patients with autoantibodies to laminin 5 show the clinical phenotype of cicatricial pemphigoid. Other acquired skin diseases of the hemidesmosomes reveal autoantibodies to a plectin-like protein, the beta4 subunit of alpha6beta4 integrin, uncein and a not yet characterized 168 kDa protein. Recently, diseases with autoantibodies to 105 and 200 kDa proteins of the lower lamina lucida have been reported. The association of these autoantigens with hemidesmosomes still needs to be demonstrated. Finally, anchoring fibrils associate with the dermal epidermal anchoring complex. The major structural component of anchoring fibrils is type VII collagen, the autoantigen of epidermolysis bullosa acquisita.     

Relapse‐associated autoantibodies to BP180 in a patient with anti‐p200 pemphigoid

Anti‐p200 pemphigoid and bullous pemphigoid (BP) are autoimmune subepidermal blistering diseases characterized by autoantibodies to a 200‐kDa dermal antigen (p200) and two hemidesmosomal proteins (BP180 and BP230), respectively. We report a 70‐year‐old man with haemorrhagic blisters, widespread crusted erosions, and the immunopathological characteristics of anti‐p200 pemphigoid. Treatment with doxycycline, topical corticosteroids and immunoadsorption led to rapid clinical remission. However, 19 weeks later, a relapse occurred with generalized itchy urticarial erythema and tense blisters. At this time, both strong dermal and epidermal IgG staining was detected by indirect immunofluorescence microscopy on salt‐split skin, and autoantibodies against both p200 and the 16th noncollagenous (NC16A) domain of BP180 were found. Interestingly, the relapse was associated not only with the detection of autoantibodies to a second autoantigen (BP180), but also with an altered clinical phenotype. This case was a unique occasion to directly monitor the emergence of intermolecular epitope spreading during the course of an autoimmune bullous disorder.     

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.