Case of subepidermal autoimmune bullous disease with psoriasis vulgaris reacting to both BP180 C‐terminal domain and laminin gamma‐1

A number of cases of psoriasis vulgaris developing bullous skin lesions have been diagnosed as either bullous pemphigoid with antibodies to the 180‐kDa bullous pemphigoid antigen (BP180) non‐collagenous 16a (NC16a) domain or anti‐laminin‐γ1 (p200) pemphigoid. We report a case of subepidermal bullous disease with psoriasis vulgaris, showing antibodies to both BP180 C‐terminal domain and laminin‐γ1. A 64‐year‐old Japanese man with psoriasis vulgaris developed exudative erythemas and tense bullae on the whole body but he did not have mucosal involvement. The blistering lesion showed subepidermal blisters histopathologically. In indirect immunofluorescence of 1 mol/L NaCl‐split skin, immunoglobulin (Ig)G antibodies reacted with both the epidermal and dermal side. Immunoblotting showed positive IgG with recombinant protein of BP180 C‐terminal domain and 200‐kDa laminin‐γ1 in normal human dermal extract.     

A subepidermal blistering disease with histopathological features of dermatitis herpetiformis and immunofluorescence characteristcs of bullous pemphigoid: a novel subepidermal blistering disease or a variant of bullous pemphigoid?

A 64-year-old man presented with a bullous eruption which clinically and histopathologically resembled dermatitis herpetiformis. However, direct immunofluorescence analysis showed IgG deposits at the basement membrane zone, indicating a relationship with bullous pemphigoid or epidermolysis bullosa acquisita. Indirect immunofluorescence studies on salt-split skin showed binding of IgG mainly on the dermal side of the blister. Immunoblot analysis revealed a novel 200 kDa dermal antigen that could be associated with a major pathogen in this blistering a disease. The histopathological similarity to dermatitis herpetiformis and the immunofluorescence findings indicating bullous pemphigoid or epidermolysis bullosa acquisita seem typical of a distinct subepidermal blistering disease characterized by this 200 kDa antigen. However, the pathogenetic role of autoantibodies against this antigen should be further elucidated before confirming whether this case represents a novel subepidermal blistering disease or a special variant of bullous pemphigoid.     

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.     

Possible paraneoplastic syndrome case of bullous pemphigoid with immunoglobulin G anti‐BP180 C‐terminal domain antibodies associated with psoriasis and primary macroglobulinemia

A 61‐year‐old Japanese man developed bullous skin lesions during topical therapy for psoriasis vulgaris. Physical examination demonstrated numerous tense bullae and scaly erythemas on the trunk and extremities. Histopathology of the skin biopsy demonstrated subepidermal bullae and lymphocytic infiltration with eosinophils in the dermis. Direct immunofluorescence revealed linear deposits of immunoglobulin (Ig)G, IgA and C3 along the basement membrane zone. Indirect immunofluorescence of 1 mol/L NaCl‐split skin showed IgG reactivity with both epidermal and the dermal sides. IgM reactivity with both the epidermal and dermal sides was also detected. Enzyme‐linked immunosorbent assays showed negative results for both BP180 and BP230. Immunoelectrophoresis of serum and bone marrow aspiration revealed underlying primary macroglobulinemia with M‐proteinemia of IgM‐κ type. Immunoblot analysis revealed IgG, but not IgM, antibodies to recombinant protein of BP180 C‐terminal domain. We diagnosed the present case as bullous pemphigoid with IgG anti‐BP180 C‐terminal domain autoantibodies associated with primary macroglobulinemia and psoriasis vulgaris. Systemic administration of prednisolone 30 mg/day resulted in dramatic improvement of both bullous and psoriatic skin lesions. When the bullous and psoriatic lesions relapsed, DRC chemotherapy (dexamethasone, rituximab and cyclophosphamide) for macroglobulinemia was performed. Then, the psoriatic lesions improved and the bullous lesions disappeared. We suggested that the present case may be paraneoplastic syndrome of bullous pemphigoid associated with primary macroglobulinemia and psoriasis vulgaris.     

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.     

Coexistence of psoriasis and an unusual IgG-mediated subepidermal bullous dermatosis: identification of a novel 200-kDa lower lamina lucida target antigen

Summary Bullous pemphigoid (BP) is characterized by autoantibodies against 230- and 180-kDa hemidesmosomal antigens located in the most superficial layers of the basement membrane zone (BMZ). Histologically. there is a predominance of eosinophils in the infiltrate. In a psoriatic patient, we identified an unusual autoimmune subepidermal bullous eruption which clinically resembled BP, but which was characterized by IgG autoantibodies against a novel 200-kDa lower lamina lucida component, Histologically there was a predominance of neutrophils in the infiltrate.
Direct immunofluorescence showed linear immunoglobulin (Ig)G and C3 deposition at the BMZ. The patient's IgG autoantibodies bound exclusively to the dermal side of salt-split normal human skin. Indirect immunogold electron microscopy showed a marked deposition of IgG at the lower lamina lucida and minimal deposition at the hemidesmosomes. Immunoblot analysis identified a unique 200-kDa autoantigen in dermal extracts and a faint band of the 230-kDa BP antigen in epidermal extracts. The patient responded dramatically well to cyclosporin A.
Although the patient's serum also reacted slightly with the 230-kDa BP antigen, there were significant findings different from the usual immunopathological changes of BP. These included finding a novel 200-kDa lower lamina lucida target antigen, the binding of IgG autoantibodies exclusively to the dermal side of the split skin and a predominance of neutrophils in blister infiltrate. The IgG autoantibodies against the 200-kDa lamina lucida target antigen seemed to play a major role in the pathogenesis of this unique autoimmune subepidermal dermatosis.     

Drug-induced bullous pemphigoid with dermal fluorescence on salt-split skin

The immunological features of drug-induced bullous pemphigoid appear to be similar to those of idiopathic bullous pemphigoid (BP), with presence of circulating and tissue-bound antibodies showing anti-basement membrane zone specificity. We describe a 28-year-old woman who developed a widespread blistering eruption with marked involvement of the mucous membranes shortly after commencing treatment with oral flucloxacillin. The eruption gradually cleared following drug withdrawal and treatment with oral corticosteroids. Indirect immunofluorescence showed circulating IgG anti-basement membrane zone (BMZ) antibody and C3 which bound to the dermal aspect of salt-split skin, and direct immunofluorescence (IMF) of perilesional skin showed a linear band of C3 at the BMZ. Western immunoblotting of the patient's serum showed positive reactivity with a 180 kDa antigen in epidermal extracts and no reactivity with dermal extracts. The dermal-binding pattern on indirect IMF with salt-split skin only occurs in a minority of patients with BP and has not been described previously in a drug-induced case.     

IgA basement membrane zone autoantibodies in bullous pemphigoid detect epidermal antigens of 270–280 kDa, 230 kDa, and 180 kDa molecular weight by immunoblotting

Bullous pemphigoid (BP) is an acquired subepidermal blistering disease characterized by circulating IgG autoantibodies binding to the 230 and 180 kDa hemidesmosomal proteins. Associated basement membrane zone (BMZ) autoantibodies of the IgA class have been reported in few BP patients. The incidence and clinical relevance of these IgA antibodies, as well as their target antigens are unknown. Sera of 26 patients with BP were analysed for circulating IgG- and IgA-anti-BMZ autoantibodies by indirect immunofluorescence on salt-split human skin. All of the patients had circulating IgG autoantibodies and, in addition, nine (35%) also had circulating anti-BMZ IgA antibodies, that bound to the epidermal side of salt-split skin. By immunoblotting, IgA antibodies in seven of nine sera recognized either the 180 kDa, the 230 kDa, or both BP antigens. Moreover, IgA anti-BMZ antibodies in seven sera also detected an epidermal protein of 270-280 kDa. IgA antibodies did not identify specific bands on immunoblots of dermal extracts. There was no clinical difference between BP patients with or without circulating anti-BMZ-IgA.     

Heterogeneity of Brunsting-Perry type pemphigoid: a case showing blister formation at the lamina lucida, immune deposition beneath the lamina densa and autoantibodies against the 290-kD polypeptide along the lamina densa

An otherwise healthy 31-year-old man presented with multiple, vesicular, subepidermal blistering on the head, face, chest and oral cavity, leaving shallow scar formation, typical of Brunsting-Perry type pemphigoid. Direct immunofluorescence showed linear deposition of immunoglobulin (Ig)G and C3 along the basement membrane zone (BMZ), and indirect showed anti-BMZ autoantibodies (IgG, >40×) reacting with the dermal side under the salt-split study. Immunofluorescence staining for type IV collagen and laminins, as well as routine electron microscopy, demonstrated that the cleavage level of the blister was intra-lamina lucida. The immunoperoxidase method applied to lesional skin demonstrated IgG deposits along the lamina densa. The post-embedding immunogold method demonstrated that the autoantibodies against BMZ reacted with the lamina densa and the dermis just beneath it. Immunoblot studies demonstrated that the autoantibodies reacted with the 290-kD polypeptide (suggesting type VII collagen) when dermal extract was used as the substrate. The patient was treated with combination therapy consisting of 30 mg prednisolone, 900 mg nicotinamide and 750 mg tetracycline, and the number of newly forming blisters decreased. We concluded that Brunsting-Perry type pemphigoid, a rare autoimmune blistering disease, includes cases showing characteristics of epidermolysis bullosa acquisita as well as bullous pemphigoid. This case showed discrepancy between the blistering level (intra-lamina lucida) and location of antigen (lamina densa and sub-lamina densa areas).     

A case of epidermolysis bullosa acquisita with autoantibody to anti-p200 pemphigoid antigen and exfoliative esophagitis

BACKGROUND: Some cases of a subepidermal blistering disease associated with autoantibodies to more than two antigens have been reported. OBSERVATION: A 52-year-old Japanese woman had pruritic blisters on almost the whole body as well as erosive lesions in the oral cavity and esophagus. A histological finding was subepidermal bullae. Direct immunofluorescence (IF) revealed a linear deposition of IgG, IgM and C3 at the epidermal basement membrane zone (BMZ). Indirect IF using human skin split by 1 M NaCl as a substrate showed IgG antibody reactive with the dermal side. By immunoblot analysis using normal human dermal extract, the 200-kDa and 290-kDa bands were detected. Indirect IF did not show any anti-BMZ antibody activity, when using the skin of the patient with recessive dystrophic epidermolysis bullosa as a substrate. CONCLUSION: We regarded our case as epidermolysis bullosa acquisita with autoantibody to anti-p200 pemphigoid antigen. This is the second case in the literature associated with autoantibodies to these two 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.     

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.     

Childhood bullous pemphigoid successfully treated with diaminodiphenyl sulfone

Bullous pemphigoid (BP) is an acquired autoimmune blistering disease which predominantly affects the elderly. It is rare in children and infants. We reported a 14-year-old girl presenting with a month history of relapsing tense bullae on the face and extremities. Histopathological examination of the lesional skin revealed a subepidermal bulla with infiltration of eosinophils, neutrophils, and lymphocytes. Direct immunofluorescence showed linear deposits of IgM and C3 at the basement membrane zone. Indirect immunofluorescence using normal human skin sections as a substrate detected IgG anti-basement membrane zone antibodies in the patient's serum and that using 1M NaCl split skin sections showed that the patient's antibodies bound to the epidermal side of the split skin. Immunoblot analysis using normal human epidermal extracts demonstrated the presence of autoantibodies against the 230-kDa BP antigen. Furthermore, the patient's serum reacted with the recombinant protein of the NC16a domain of the 180-kDa BP antigen by immunoblot analysis and enzyme-linked immunosorbent assay. Our patient showed significant improvement of the skin lesions with systemic administration of diaminodiphenyl sulfone.     

Epidermolysis bullosa acquisita with ultraviolet radiationsensitivity

A 37-year-old male patient developed a bullous eruption and erythematous plaques mainly in exposed areas following prolonged sun exposure. In addition, blisters were noted on oral and nasal mucous membranes. Histopathological examination of a lesional skin biopsy revealed a subepidermal blister. Linear deposition of IgG and C3 at the epidermal basement membrane zone was revealed by direct immunofluorescence microscopy of a perilesional skin biopsy. Indirect immunofluorescence on 1 mol/L salt-split skin showed binding of autoantibodies to the dermal side of the split. Immunoblot analysis of dermal extracts demonstrated that the patient's serum contained IgG antibodies against type VII collagen, whereas no reaction was seen with epidermal extracts or by enzyme-linked immunosorbent assay using a recombinant form of bullous pemphigoid 180. Standardized ultraviolet (UV) radiation provocation induced blistering with both UVA (13.5 J/cm2) and UVB (0. 04 J/cm2) within 24 h clinically and histologically. External and systemic UV-protective medication and nine cycles of high dosage immunoglobulins given intravenously (1.2 g/kg body weight over 2-3 days every 4 weeks) resulted in the cessation of blister formation. To the best of our knowledge, this is the first report of a case of epidermolysis bullosa acquisita with sensitivity to UV.     

Bullous pemphigoid in association with cutaneous lesions specific to a myelodysplastic syndrome

Specific cutaneous lesions are a rare occurrence in myelodysplastic syndromes (MDS). The concurrent association of blistering skin lesions similar to those in bullous pemphigoid (BP), even though a rare event, suggests that BP may be a paraneoplastic syndrome. We report an 86-year-old man who had a refractory anaemia with excess bone marrow blasts in transformation, who developed a generalized pruritic blistering eruption. Immunohistopathological tests showed subepidermal blisters with linear deposits of IgG and C3 along the basement membrane zone of the epidermis surrounding a tumoral dermal infiltrate of CD13+ and CD15+ cells. Immunoblotting studies using epidermal extracts revealed circulating IgG antibodies against three protein bands: a 210–215 kDa band. a 180kDa band which co-migrated with the BP 180 antigen, and a 190kDa band. The tumour infiltrate may have revealed antigenic determinants which led to the onset of BP. The concept of paraneoplastic pemphigoid remains to be either confirmed or invalidated by further epidemiological studies.     

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.     

Subepidermal blistering disease with autoantibodies against a novel dermal 200-kDa antigen

A number of autoimmune subepidermal blistering diseases are characterized by the distinct autoantigens of the cutaneous basement membrane zone. Recently, a few cases with autoantibodies against a novel 200-kDa dermal protein have been reported. We collected nine cases of subepidermal blistering disease with IgG antibodies against this 200-kDa antigen. In this report, we describe the clinical and immunological appearances in these cases. Five cases showed bullous pemphigoid-like features, one case resembled dermatitis herpetiformis, and another case showed mixed features of bullous pemphigoid and linear IgA bullous dermatosis. It was interesting to note that psoriasis coexisted in four cases. By indirect immunofluorescence on 1 M NaCl split skin, IgG antibodies from all sera reacted with the dermal side of the split. By immunoblot analysis, IgG antibodies recognized a 200-kDa protein of dermal extract. IgG affinity-purified antibodies on the 200-kDa immunoblot membrane stained the dermal side of 1 M NaCl split skin. Various examinations suggested that the 200-kDa antigen is not identical to any chains of laminins-1, -5 or -6. This autoimmune subepidermal blistering disease against the dermal 200-kDa protein may form a new distinct entity, which often associates with psoriasis.     

Childhood bullous pemphigoid treated by i.v. immunoglobulin

Bullous pemphigoid is an acquired autoimmune subepidermal blistering disorder mostly seen in the elderly. Childhood bullous pemphigoid is very rare. For the first time we report a case of childhood bullous pemphigoid associated with infantile eczema. Two weeks after a routine vaccination, a 3.5-month-old boy with infantile eczema developed a generalized blistering disorder. Histopathology revealed a subepidermal blister. Direct immunofluorescence showed linear depositions of C3 along the basement membrane zone. Indirect immunofluorescence studies demonstrated the presence of circulating immunoglobulin G antibodies directed against the epidermal side of salt-split skin. Enzyme-linked immunosorbent assay demonstrated serum level of anti-BP180 antibody elevated. The patient was successfully treated by high-dose i.v. immunoglobulin.     

Penicillin-induced anti-p200 pemphigoid: an unusual morphology

We report here a case of a 52-year-old woman with erythema gyratum repens-like lesions appearing during anti-p200 pemphigoid, probably induced by oral penicillin. The diagnosis of anti-p200 pemphigoid was made by the presence of in vivo bound and circulating IgG anti-basement membrane zone auto-antibody reactive with the dermal side of salt-split skin and with 200 kDa protein in dermal extract on Western immunoblot. Laser scanning confocal microscopic study disclosed the localization of IgG at the lamina lucida-lamina densa border. Skin lesions responded poorly to high dose of prednisone and the combination of prednisone and dapsone. When methotrexate was added, skin lesions healed within 3 weeks. To our knowledge, erythema gyratum repens-like lesions have not been described previously in this disorder. Thus, we have expanded the clinical morphological spectrum of patients with anti-p200 pemphigoid and first described a patient whose disorder was probably drug-induced.     

Histopathology of anti-p200 pemphigoid

Anti-p200 pemphigoid is an autoimmune subepidermal blistering disease characterized by circulating and tissue-bound antibodies against a 200-kd glycoprotein (p200) of the human dermis. We reviewed 10 lesional biopsies from seven patients with anti-p200 pemphigoid in an attempt to define typical histopathologic features of this disease. All biopsy specimens showed subepidermal blistering and a moderate to dense inflammatory infiltrate in the upper dermis. Immunohistochemical analysis localized type IV collagen to the dermal side of the blister, suggesting that split formation occurred within the lamina lucida of the cutaneous basement membrane. The inflammatory infiltrate was composed almost exclusively of neutrophils in six biopsies and contained a mixture of neutrophils and eosinophils in the remaining four. In three specimens, microabscess formation in the papillary dermis adjacent to the blister cavity was noted. Neutrophilic and eosinophilic spongiosis was found in five and three biopsies, respectively. We conclude that histopathology of anti-p200 pemphigoid is characterized by subepidermal blistering and a superficial inflammatory infiltrate, which is usually dominated by neutrophils but occasionally contains significant numbers of eosinophils. While this microscopic picture mimics that of linear IgA disease, dermatitis herpetiformis, or bullous pemphigoid, it should also alert a histopathologist to the possibility of anti-p200 pemphigoid and prompt immunofluorescence and immunoblotting studies for definite diagnosis or exclusion of this autoimmune subepidermal blistering disease.