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The potentially life-threatening antineutrophil cytoplasm antibody (ANCA) vasculitides, including Wegener granulomatosis (WG) and microscopic polyangitis (MPA), can be brought into remission with high doses of corticosteroids and cyclophosphamide, but long-term therapy with these agents is associated with multiple toxic effects. Therefore, less-toxic therapies for maintaining remission are needed. Both methotrexate and azathioprine have been suggested as possibilities, but few if any reports of their relative effect and toxicity are available.
Investigators performed a prospective open-label trial comparing 2 mg/kg/day of azathioprine with 25 mg/week of methotrexate in 125 patients whose WG or MPA was in remission. The patients were assigned to treatment with either azathioprine or methotrexate for 12 months; the mean follow-up period was 29±13 months. Methotrexate recipients were given folic acid or folinic acid 48 hours after each weekly dose. In addition, patients with WG received trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for pneumocystis.
Adverse reactions were noted in 29 azathioprine recipients and 35 methotrexate recipients; relapses occurred in 23 patients in the azathioprine group and 21 in the methotrexate group. The authors conclude that these agents have no substantive differences. One male methotrexate recipient (age, 75) developed aplasia complicated by septicemia within 2 months of starting therapy and died. The authors do not specify whether he had WG and was thus receiving TMP-SMX prophylaxis. By the end of the analysis, three patients had developed cancer (ovarian adenocarcinoma in a methotrexate recipient; and lung adenocarcinoma in 1 azathioprine recipient and breast carcinoma in another).
Pagnoux C et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med 2008 Dec 25; 359:2790.
Comment
Azathioprine and methotrexate appear to be similarly effective for maintaining remission in patients with severe vasculitis. Although few dermatologists direct the therapy of such patients, we are often involved in evaluating their skin lesions, so knowing the therapeutic options is important. I wonder whether folate therapy lessened the effectiveness of methotrexate and whether TMP-SMX prophylaxis was associated with the death in the methotrexate recipient. However, many of these patients were exposed to concomitant TMP-SMX and methotrexate without ill effect, suggesting that our dogma that this combination is unsafe is not well founded.