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Successful treatment of recalcitrant Wegener's granulomatosis of the skin with tacrolimus (PrografTM)

SIR, Wegener’s granulomatosis (WG) is characterized by the triad of necrotizing and granulomatous inflammation of the respiratory tract, glomerulonephritis and vasculitis. In a subset of patients, ulcerated necrotizing lesions are restricted to the skin and the upper respiratory tract for many years without pulmonary or renal involvement (superficial variant). Biopsies of WG lesions show a granulomatous inflammatory process with epithelioid cells, Langerhans cells, and foreign-body giant cells destroying small vessels, along with an inflammatory perivascular exudate and fibrin deposition in small arteries, capillaries and venules. Although the disease resembles an infectious process, no causative agent has been isolated. The characteristic histological changes suggest that immunological hypersensitivity is involved in the pathogenesis. WG is highly associated with the presence of cytoplasmic immunofluorescent pattern antineutrophil cytoplasmic antibodies (c-ANCA). Two-thirds of patients are male, mostly in their third to fifth decade. Differential diagnosis of WG includes polyarteritis nodosa, systemic lupus erythematosus, pyoderma gangrenosum, immunocomplex vasculitis, T-cell-mediated vasculitis, mid-line granuloma, Churg–Strauss syndrome and, in cases with renal involvement, rapidly or slowly progressive glomerulonephritis. WG is a chronic disease requiring continuous immunosuppressive medication for adequate control. Systemic corticosteroids are the treatment of choice. To limit undesirable side-effects, azathioprine, cyclophosphamide, methotrexate and ciclosporin are established alternatives in the immunosuppressive treatment of WG. A 52-year-old woman with biopsy-proven WG of the upper respiratory tract presented at our department with a 2-year history of recurring nodules and ulcers localized to both lower legs and the gluteal region. Clinical investigation revealed a necrotic ulcer, 13 cm in diameter, with an inflammatory margin localized to the lower left leg (Fig. 1a) and a second ulcer, 6 cm in diameter, localized to the right gluteal region. Earlier systemic treatment with corticosteroids had led to slow healing of the ulcers, but after dose reduction, ulceration exacerbated again. Treatment with methotrexate 25 mg weekly, azathioprine 1 mg kg for 6 months and ciclosporin 5 mg kg for 6 months was unable to control the disease. Topical application of tacrolimus ointment (Protopic ; Fujisawa) was beneficial, but not sufficient. Laboratory investigations revealed a positive autoantibody profile with c-ANCA (titre 1 : 160) and decreased complement factor C4 (33%) as a sign of systemic vasculitis. Erythrocyte sedimentation rate was elevated at 56 mm in the first hour. Other blood parameters including antinuclear antibodies, full blood count, electrolytes, liver enzymes, creatinine and protein electrophoresis were within normal limits. Intralesional skin biopsy revealed a granulomatous inflammation of subcutaneous small arteries consistent with the diagnosis of WG of the skin. Because of the clinical improvement after topical application of tacrolimus in this patient we decided to start systemic treatment with tacrolimus (Prograf ; Fujisawa) 0Æ1 mg kg daily in addition to oral prednisolone (initial dose 100 mg daily). Under this regimen the clinical picture improved greatly in a short period of time. Prednisolone was reduced gradually and finally withdrawn, while tacrolimus treatment was continued. The ulcers disappeared completely within 2 months (Fig. 1b) without appearance of new lesions during a follow-up period of 6 months. Severe side-effects were not noticed. Tacrolimus or FK506 is a macrolide lactone discovered in 1984. It is derived from the fungus Streptomyces tsukubaensis. Tacrolimus binds an immunophilin called FK-binding protein (FKBP), which is important for signal transduction in T lymphocytes. The FKBP–tacrolimus complex impedes the activity of calcineurin by blocking a Ca binding site and in this way suppresses several important T-cell activation genes such as the cytokine interleukin 2.