Refractory Epidermolysis Bullosa Acquisita with Chronic Graft-versus-Host Disease Successfully Treated with Rituximab

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Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous disease (AIBD) of the skin and mucous membranes caused by autoantibodies against type VII collagen, which is a major component of the anchoring fibrils in the basement membrane zone (BMZ)¹. The clinical features are blisters on trauma-prone areas that heal with formation of atrophic scars. Rarely, AIBD accompanied by graft-versus-host disease (GvHD) is reported²,³. Herein, we present a case of refractory EBA with chronic GvHD (cGvHD) successfully treated with rituximab. A 41-year-old male presented with pruritic and painful erythematous patches and tense bullae over his whole body, accompanied by an oral ulcer (Fig. 1A). He had a history of acute myeloid leukemia with allogeneic peripheral blood stem cell transplantation (PBSCT) and oral, ocular, and liver cGvHD started 9 months after PBSCT. Corneal biopsy showed epithelial denudation with inflammation and fibrosis in stroma and lip biopsy revealed peri-ductal lymphocyte infiltration with atrophy and fibrosis (Fig. 2A, B). Treatment with prednisolone 5~30 mg/day and mycophenolic acid 500 mg~2 g/day showed improvement in cGvHD. Cornea improved with additional amniotic membrane transplantation. Three years after PBSCT, multiple bullae developed on the whole body. Hematologist supposed the lesion as bullous GvHD. However, he was referred for skin biopsy as he was refractory to immunosuppressant. Biopsy revealed subepidermal bulla with mild perivascular lymphohistiocytic infiltration in upper dermis (Fig. 2C, D). Direct immunofluorescent test showed immunoglobulin G (IgG) 3 and C3 infiltration in the dermoepidermal junction (Fig. 2E, F). Indirect immunofluorescent analysis revealed serum IgG infiltration on the dermal side of the dermoepidermal junction (Fig. 2G). As the patient was refractory to the treatment, and the lesions left atrophic scars including nail dystrophy, the patient was diagnosed as EBA (Fig. 1B). Rituximab was administered at a dose of 1,000 mg twice daily with a two-week interval. After a gradual taper of immunosuppressant and during 36 months of follow-up, the patient remained in clinical remission (Fig. 1B). The exact pathophysiology for development of AIBD after GvHD is not well known. The basement membrane and basal layer destruction that occurs in GvHD could give rise to AIBD through development of circulating autoantibodies to basement membrane components, and reduced self-tolerance may also induce anti-BMZ-antibody production²,³,⁴. Additional factors, certain HLA-types or microchimerism, are thought to be required for AIBD development²,³,⁴. Anti-CD20 antibody (rituximab) is a chimeric mouse/human monoclonal antibody for treatment of B cell malignancies. Recently, there are studies suggesting that rituximab is effective for cGvHD, where B cells play an important role in the development and maintenance⁵. Few case of AIBD accompanied by cGvHD has been reported previously (Supplementary Table 1). In particular, EBA followed by GvHD is rare and it is meaningful to note that rituximab was successfully used in a patient with refractory EBA associated with cGvHD. AIBD and bullous GvHD manifest similar clinical features. Though it is difficult to distinguish two diseases clinically, biopsies and immunofluorescent tests can produce an accurate diagnosis⁴. Although rare, AIBD should be in the differential diagnosis for patients with cGvHD with skin blisters, and rituximab can be considered a therapeutic option.

Fig. 1. (A) Erythematous patches and large tense bullae with erosion over the whole body (B) 36 months after treatment with rituximab, the patient showed clinical remission with formation of atrophic including nail dystrophy. We received the patient’s consent form about publishing all photographic materials.

Fig. 2. In corneal biopsy, denudation of epithelium with chronic inflammation and fibrosis in the stroma was observed (A: H&E, ×100) and in lip biopsy, periductal lymphocyte infiltration with atrophy and fibrosis was observed with no epidermis included (B: H&E, ×100). Skin biopsy revealed subepidermal bulla with mild perivascular lymphohistiocytic infiltration in the upper dermis (C: H&E, ×100; D: H&E, ×200). Direct immunofluorescence (IF) test showed (E) immunoglobulin G (IgG) 3 and (F) C3 infiltration in the dermoepidermal junction (E, ×200; F, ×200). Indirect IF test on 1 M NaCl split skin revealed serum IgG infiltration on the dermal side of the dermoepidermal junction (G, ×200).

SUPPLEMENTARY MATERIALS

Supplementary data can be found via http://anndermatol.org/src/sm/ad-20-332-s001.pdf.

Supplementary Table 1

Autoimmune blistering diseases after stem cell transplantation