A new autoimmune bullous disease entity which is characterized by immunoglobulin (Ig)G autoantibodies to a 200-kDa dermal protein was first described in 1996 by Zillikens et al.1 The identity of the 200-kDa protein was not identified for a long time. However, it has recently been identified as laminin-γ1 subunit, and the name of anti-laminin-γ1 pemphigoid was proposed.2 Laminin-γ1 was detected in approximately 90% patients with anti-p200 pemphigoid.2 The target antigen of the remaining 10% patients has not yet been identified.2 In this report, we describe a rare case of subepidermal blistering disease associated with psoriatic erythroderma. We diagnosed this case as anti-laminin-γ1 pemphigoid by various immunological techniques.
A 59-year-old Japanese man visited us because of widespread pruritic bullous skin lesions and erythema on the entire body of 1-week duration as well as fever and general malaise. He had a past history of psoriasis vulgaris, and was treated with the topical glucocorticosteroid of very strong class alone for more than 10 years. On examination, multiple tense bullae and erosions with erythema similar to the skin lesions of bullous pemphigoid were seen on the entire body, accompanied with psoriatic erythroderma (Fig. 1). Neither apparent scar formation nor mucosal lesion was seen. Laboratory examinations revealed elevated white blood cell count (13.3 × 103/mm3), marked leukocytosis (77.4%) and high level of C-reactive protein (5.6 mg/dL). Histopathology of the skin taken from a bullous lesion showed subepidermal blistering with infiltration of abundant neutrophils and fibrin deposit (Fig. 2a). Infiltration of lymphocytes and neutrophils was also found in the upper dermis. Another skin biopsy from a pustule on the leg revealed subcorneal neutrophilic infiltration forming Munro’s microabscess (Fig. 2b). These lesions were negative for fungi and bacteria by KOH examination and bacterial culture, respectively. Direct immunofluorescence showed linear deposits of IgG (Fig. 2c) and C3 at the dermoepidermal junction. Indirect immunofluorescence using 1 mol/L NaCl-split normal human skin as a substrate showed circulating IgG autoantibodies binding to the dermal side of the artificial split (Fig. 3a). Immunoblotting with epidermal and dermal extracts of normal human skin was performed using methods described elsewhere.3 The control anti-laminin-γ1 pemphigoid serum (lane 2) and the patient’s serum (lane 3) reacted with a 200-kDa protein in dermal extract (Fig. 3b). In immunoblotting of dermal extract, most epidermolysis bullosa acquisita sera also show an approximately 200-kDa protein band. However, this band is seen slightly above the p200 band, and can be easily distinguished from the p200.
In contrast, the patient’s serum did not react with the 290-kDa epidermolysis bullosa acquisita antigen (type VII collagen) in dermal extract. The patient’s serum did not react with BP230 or BP180 in epider-mal extract (data not shown). From the above results, this patient was diagnosed as having anti-laminin-γ1 pemphigoid in association with psoriatic erythroderma. Oral prednisolone 30 mg daily was first given. However, because new blisters still appeared and pustule formations were observed on the legs, cyclosporine 150 mg daily was added. Cyclosporine was quite effective, and the skin lesions of the patient disappeared in a short period.
Immunopathologically, anti-laminin-γ1 pemphigoid is characterized by linear deposits of IgG and C3 along the dermoepidermal junction, as detected by direct immunofluorescence of the perilesional skin biopsy specimens. Indirect immunofluorescence demonstrates circulating IgG autoantibodies reacting with the dermal side of 1 mol/L NaCl-split normal human skin. The target dermal 200-kDa antigen for these antibodies was thought to be important for cell matrix adhesion. Ultrastructural studies localized the 200-kDa protein to the lower portion of lamina lucida of the epidermal basement membrane zone. While the 200-kDa protein was demonstrated to be immunologically distinct from all major autoantigens of the dermoepidermal junction, including BP230, BP180, α6β4 integrin (mucous membrane pemphigoid), laminin-332 (mucous membrane pemphigoid) and type VII collagen (epidermolysis bullosa acquisita), little is known about its structure and biochemical properties.1,4 Finally, Dainichi et al.2 have recently identified the 200-kDa protein as laminin-γ1 by proteomics techniques, and proposed the name of anti-laminin-γ1 pemphigoid.
Dilling et al.5 evaluated 29 cases of anti-laminin-γ1 pemphigoid with regard to clinicopathological features and immunological findings. Notably, 14 of 29 cases had coexisting psoriasis in their analysis. Although anti-laminin-γ1 pemphigoid cases associated with psoriasis were frequently reported,3,6–8 the mechanism of concurrence of anti-laminin-γ1 pemphigoid and psoriasis is still unclear. Some anti-laminin-γ1 pemphigoid cases were reported to occur with exacerbation of the preceding psoriasis, such as pustular psoriasis.3,7 In some cases with coexistent psoriasis vulgaris and bullous disease, the bullous lesions were thought to be induced by anti-psoriatic treatment, such as psoralen and ultraviolet A therapy.4 These facts suggest that severe psoriasis itself may promote the occurrence of anti-laminin-γ1 pemphigoid. In our case, psoriatic erythroderma may also be the cause of the appearance of the bullous lesions. To our knowledge, there are few previous reports of psoriatic erythroderma associated with anti-laminin-γ1 pemphigoid.
The histology of subepidermal blisters with neutrophils in anti-laminin-γ1 pemphigoid may mimic that of linear IgA bullous disease or dermatitis herpetiformis. However, bullous pemphigoid-like subepidermal bullae also contained numerous neutrophils in the previous cases with anti-laminin-γ1 pemphigoid.8 Yasuda et al.8 suggested that infiltration of neutrophils was predominant in anti-laminin-γ1 pemphigoid, while infiltration of eosinophils was predominant in bullous pemphigoid.
The patients of anti-laminin-γ1 pemphigoid were treated with various therapies including oral corticosteroid, minocycline, dapsone and cyclosporine, and they showed favorable response to the most treatments.5 Despite severe widespread blistering skin lesions and psoriatic erythroderma, the present case showed a relatively good response to prednisolone and cyclosporine. While the course of anti-laminin-γ1 pemphigoid is variable, our case remained in remission after tapering of immunosuppressive medication. Treatment with oral prednisolone for the patient with bullous skin disease and psoriasis requires special attention, because it might cause transformation into pustular psoriasis.