Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Trimethoprim-sulfamethoxazole reduced relapses in Wegener granulomatosis

ACP J Club. 1996 Nov-Dec;125:67. doi:10.7326/ACPJC-1996-125-3-067


Source Citation

Stegeman CA, Tervaert JW, De Jong PE, Kallenberg CG, for the Dutch Co-Trimoxazole Wegener Study Group. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. N Engl J Med. 1996 Jul 4;335:16-20. [PubMed ID: 8637536]


Abstract

Objective

To evaluate the effectiveness of trimethoprim-sulfamethoxazole (TMP-SMX) in preventing relapses in patients with Wegener granulomatosis in remission.

Design

Randomized, double-blind, placebo-controlled trial with 24-month follow-up.

Setting

Clinical practices throughout the Netherlands.

Patients

81 patients (median age 57 y, 72% men) with Wegener granulomatosis who were in complete remission with or without treatment with corticosteroids or cyclophosphamide. Exclusion criteria were history of adverse reaction to TMP-SMX or its components, impaired renal function, or current receipt of long-term antibiotics or TMP-SMX. All patients were included in the analysis.

Intervention

41 patients were allocated to TMP-SMX, 160 mg of trimethoprim and 800 mg of sulfamethoxazole, and 40 patients were allocated to placebo twice daily for 24 months in addition to their usual medication. Other antimicrobial therapy deemed necessary by the attending physicians was allowed for no longer than 6 consecutive weeks.

Main outcome measures

Disease activity, compliance with study treatment, side effects, and evidence of infections.

Main results

TMP-SMX was stopped in 8 patients (20%) after a median of 43 days (range 6 to 125 d) because of side effects. The median level of compliance was 98% in both treatment groups. At the 24-month follow-up, 82% of patients in the TMP-SMX group were in remission compared with 60% of patients in the placebo group {P = 0.02}*. The annual number of infectious episodes per patient was lower in the TMP-SMX group than in the placebo group (median 0.0 vs 1.0; range 0.0 to 3.0 vs 0.0 to 3.8, P < 0.001). Fewer respiratory (P = 0.005) and nonrespiratory tract infections (P = 0.05) occurred in the TMP-SMX group than in the placebo group.

Conclusion

Prolonged treatment with trimethoprim-sulfamethoxazole reduced the number of nasal and upper airway relapses in patients with Wegener granulomatosis in remission.

Sources of funding: Dutch Kidney Foundation and Roche Pharma Ltd., Switzerland (study medication).

For article reprint: Dr. C.A. Stegeman, Department of Internal Medicine, University Hospital, Oostersingel 59, 9713 EZ Groningen, The Netherlands. FAX 31-50-361-3312.

*Numbers calculated from data in article.


Table. Trimethoprim-sulfamethoxazole (TMP-SMX) for Wegener granulomatosis†

Outcome TMP-SMX Placebo RBI (95%CI) NNT (CI)
Remission at 24 m 82% 60% 38% (45 to 90) 4 (2 to 30)

†Abbreviations defined in Glossary. RBI, NNT, and CI calculated from data in article.


Commentary

For more than a decade, a therapeutic benefit of TMP-SMX in Wegener granulomatosis has been suggested by anecdotal reports that typically conclude by calling for controlled trials. In this well-designed trial from the Dutch Co-trimoxazole Wegener Study Group, patients had a broad spectrum of disease and the investigators used well-defined clinical outcome criteria and carefully monitored compliance and adverse effects.

The mechanism of the beneficial effect of TMP-SMX in this condition is unknown. Immunosuppressive and anti-inflammatory effects have been suggested but remain unproved. Of interest is a recent report by the same investigators (1) that showed an association between nasal carriage of Staphylococcus aureus and of Wegener granulomatosis relapses. Future studies should explore whether eradication of nasal S. aureus by TMP-SMX is associated with protection from relapses.

In this study, TMP-SMX did not reduce relapses that involved the kidneys, lungs, or other organs. A recent study (2), although not as methodologically rigorous as this one, did not support using TMP-SMX (relapse occurred in 42% of treated patients vs 29% of untreated patients). None of these patients was receiving cyclophosphamide or corticosteroids, whereas more than half of the Dutch patients were.

The decision to use TMP-SMX must be individualized. Until further studies become available, it may be reasonable to use TMP-SMX in patients who are still receiving immunosuppressive agents and in those with nasal and upper respiratory tract disease as the primary illness. Adverse effects may limit long-term treatment. It is uncertain whether patients who have been in remission for many years really benefit from TMP-SMX.

Jeffrey S. Berns, MD
The Graduate HospitalPhiladelphia, Pennsylvania, USA


References

1. Stegeman CA, Tervaert JW, Sluiter WJ, et al. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med. 1994;120:12-7.

2. Reinhold-Keller E, De Groot K, Rudert H, et al. Response to trimethoprim/sulfamethoxazole in Wegener's granulomatosis depends on the phase of disease. Q J Med. 1996;89:15-23.