15-Deoxyspergualin in Patients with Refractory ANCA-Associated Systemic Vasculitis

Abstract

ABSTRACT. The combination of cyclophosphamide (CYC) and oral corticosteroids is effective in the majority of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AASV), but it carries substantial risk of drug-related morbidity and mortality. New regimens are desired, especially in refractory cases. The immunosuppressant 15-deoxyspergualin (DSG) is effective in experimental autoimmune disease and transplantation as well as in acute kidney transplant rejection in humans. To assess the efficacy and safety of DSG, an open label multicenter trial was conducted in patients with AASV who were either unresponsive or had contraindications for standard immunosuppressants. Included were 19 cases of Wegener granulomatosis and one case of microscopic polyangiitis. Nine of them had received CYC shortly before study entry without apparent therapeutic success. DSG (0.5 mg/kg per d) was given for 2 to 3 wk until the WBC count dropped to 3000/μl followed by a rest until at least a WBC of 4000/μl was reached again. This was repeated up to six cycles. During the study, no other immunosuppressants besides steroids were allowed. Disease improvement during treatment with DSG was achieved in 70% of cases (six cases of complete remission; eight cases of partial remission). Leucopenia occurred in each patient in a regular pattern during the cycles and was transient without exception. No mortality or septicemia was observed. Mild to moderate infections mainly in the respiratory tract were observed but resolved under adequate treatment without sequel. It is concluded that treatment with DSG is successful in patients with refractory Wegener granulomatosis under careful monitoring of WBC count. E-mail: rainer.birck@med5.ma.uni-heidelberg.de

A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis

“…We evaluated the role of ANCA and B cell levels as predictors of relapse and re-treatment. ANCA was present in just over one-half of the patients at the time of initial treatment, consistent with ANCA positivity in other cohorts of patients with refractory AAV (34,35). Levels of MPO and PR3 ANCA fell following rituximab treatment; however, clinical remissions occurred to the same extent in both ANCA-positive and ANCA-negative patients, and relapses were preceded by an increase in ANCA levels in only a few patients.…”

In vivoeffects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis

“…Nevertheless, it is believed that ANCA production is, at least partly, T celldependent. Because DSG treatment decreases ANCA titre, as we have shown previously [3,4], this could indicate that activation of autoreactive T cells is also impaired by DSG, either directly or by influencing antigen presentation. However, direct proof for this assumption has to be established.…”

“…At the nadir, treatment was discontinued for at least 2 weeks to allow leucocyte count to recover (WBC at least 4000/ml). Treatment was then resumed in the same manner [3].…”

“…Therefore, new treatment strategies are warranted, particularly in frequent relapsing or refractory patients and in those suffering from side effects of cyclophosphamide. Previously we have reported that treatment with the immunosuppressive drug 15-deoxyspergualin is successful in patients with refractory WG [3] and may also have beneficial effects during long-term treatment [4]. 15 laterosporus.…”

Orbital inflammatory disease management

“…The combination of cyclophosphamide and corticosteroids is still commonly used for induction therapy of orbital GPA. Although not specifically evaluated for orbital GPA, methotrexate, azathtioprine, mycophenolate mofetil, and 15-deoxyspergualin (an immunomodulatory synthetic analog of bacteria-derived spergualin) have also been shown to assist in inducing remission [72][73][74][75][76].…”