Correspondence

Co-Trimoxazole in Wegener's Granulomatosis

N Engl J Med 1996; 335:1769-1770December 5, 1996

Article

To the Editor:

In their study of treatment with co-trimoxazole (trimethoprim–sulfamethoxazole) to prevent relapses of Wegener's granulomatosis (July 4 issue),1 Stegeman et al. do not report the cumulative doses of cyclophosphamide and prednisolone in their two groups of patients during the study period. Although this omission does not undermine their conclusion, it is relevant because the information may shed light on the mechanism by which co-trimoxazole prevents relapses. If, as Stegeman et al. speculate, co-trimoxazole either prevents infections that would have triggered relapses or has a direct antiinflammatory effect, then one would expect a lower cumulative dose of immunosuppressive agents in the co-trimoxazole group than in the placebo group. An alternative hypothesis, however, is that the occurrence of infection influenced the dose of cyclophosphamide or prednisolone. In this case, the lower infection rate in the co-trimoxazole group might have allowed treatment with a higher cumulative dose of immunosuppressive agents, which could explain the lower frequency of relapses. These alternative hypotheses have very different implications for further studies of co-trimoxazole in patients with Wegener's granulomatosis.

Andrew Weir, M.B., B.S.
Marc Lipman, M.R.C.P.
Jo Congleton, M.R.C.P.
Royal Brompton Hospital, London SW3 6NP, United Kingdom

1 References

1
Stegeman CA, Cohen Tervaert JW, de Jong PE, Kallenberg CGM. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. N Engl J Med 1996;335:16-20
Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Weir et al. argue that the reduction in the number of relapses of Wegener's granulomatosis in the co-trimoxazole group may be explained by the more frequent reductions in the doses of cyclophosphamide and prednisolone in the placebo group as a result of the higher number of infectious episodes in that group. However, our results cannot be explained by differences in immunosuppressive-drug treatment between the two groups. First, the patients were treated according to a protocol1 in which the daily dose of cyclophosphamide was reduced by 25 mg every three months and prednisolone was reduced by 5 mg every two to four weeks. Immunosuppressive therapy was interrupted or reduced because of opportunistic infections or leukopenia in only three patients in the co-trimoxazole group and in only four in the placebo group. Second, the two groups did not differ with respect to the relative numbers of patients taking cyclophosphamide or prednisolone who were still at risk for a relapse during the study.

During the first year of the study, the mean (±SE) doses of immunosuppressive agents received by all the patients, including those who had relapses, were 27±6 mg of cyclophosphamide per day and 4±1 mg of prednisolone per day in the co-trimoxazole group, as compared with 34±6 mg of cyclophosphamide per day and 5±1 mg of prednisolone per day in the placebo group (P = 0.44 and P = 0.60, respectively). During the second year, because of the difference in the numbers of patients who had relapses, the doses of both cyclophosphamide and prednisolone tended to be lower in the co-trimoxazole group than in the placebo group (12±4 vs. 20±4 mg of cyclophosphamide per day, P = 0.17; and 2±1 vs. 4±1 mg of prednisolone per day, P = 0.11).

The absence of significant differences in immunosuppressive-drug therapy in the two groups supports our conclusion that the lower number of relapses of Wegener's granulomatosis during co-trimoxazole treatment was caused by a possible antimicrobial action of co-trimoxazole itself.

Coen A. Stegeman, M.D.
Jan Willem Cohen Tervaert, M.D.
Cees G.M. Kallenberg, M.D.
University Hospital, 9713 EZ Groningen, the Netherlands

1 References

1
Cohen Tervaert JW, Huitema MG, Hene RJ, et al. Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet 1990;336:709-711
CrossRef | Web of Science | Medline

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