"Although the relatively small number of patients due to the premature termination of this trial precludes definite conclusions on the relative potency of LEF compared to MTX, the data confirm the potential for LEF for the prevention of relapses in WG," writes Dr. Metzler, rheumatologist at the University Hospital of Schleswig-Holstein, in Luebeck, Germany.
Higher rate of major relapse among MTX users halts study early
Fifty-four patients with generalized WG who had remissions and no disease activity for at least 3 months after induction therapy with oral cyclophosphamide (2 mg/kg) and prednisone were randomly assigned to 2 years of either oral LEF at 30 mg/d (n = 26) or oral MTX starting with 7.5 mg/wk reaching 20 mg/wk after 8 weeks (n = 28). The primary endpoint was the incidence of relapses. Secondary outcome parameters were Disease Extension Index (DEI), Birmingham Vasculitis Activity Score (BVAS), SF-36, cANCA-titre, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).
The study was stopped after 21 months of follow-up because 13 of 28 patients in the MTX arm relapsed, seven of whom suffered rapidly progressive glomerulonephritis, pulmonary hemorrhage, and cerebral granuloma. Six of 26 patients in the LEF arm relapsed, one of whom suffered a new pulmonary granuloma after a median of 7 months.
The significantly higher incidence of major relapses in the MTX arm (P = .037) forced the early termination of the trial. Patients still taking oral MTX after the study was stopped were asked to switch to parenteral application of MTX or to LEF.
Higher rate of side effects among LEF users
In the LEF group, four patients were withdrawn because of hypertension (n = 2), peripheral neuropathy (n = 1), and leucopenia (n = 1). All adverse events were reversible after stopping LEF therapy.
Assessing for disease activity, WG patients in both arms had median DEI and BVAS of 0 at randomization. Although, patients who suffered a relapse showed an increase in median DEI to 4 in the LEF arm and an increase of 3.5 in the MTX arm. There was a parallel increase in BVAS from 0 at baseline to 7.5 in the LEF arm and from 0 to 10.5 in the MTX arm.
Five of the MTX patients who had a major relapse showed a 1- to 4-fold increase in ANCA-titre. By contrast, ANCA-titre levels remained stable in LEF patients who had a major relapse.
More study of optimal remission-maintenance agents needed
"The disappointing results for MTX must be weighted against the low rate of side effects that had not led to any treatment-related withdrawal in the MTX group," the study authors write. They suggest that the high rate of relapse among MTX users may be related to the low starting does of MTX and lower bioavailability of oral MTX dosing.
"Further studies testing other dosing regimens of lower doses of LEF are needed to confirm these promising results in larger patient cohorts. [F]urther comparative studies of existing maintenance treatments including azathioprine, MTX, leflunomide and mycophenolate mofetil are [also] warranted," the researchers conclude.
One small, randomized study vs years of practice
"This is a complicated issue because it weighs the results of one randomized study of 54 patients against years of clinical practice in which MTX has been a standard agent for remission-maintenance for the treatment of WG," Philip Seo, MD, MHS, assistant professor of medicine at The Johns Hopkins University School of Medicine, and co-director of The Johns Hopkins Vasculitis Center, both in Baltimore, Maryland, told CIAOMed.
Dr. Seo said that this study positions LEF as a promising alternative to MTX for remission maintenance. "The fact that the group treated with leflunomide experienced approximately half as many flares as the group treated with methotrexate is intriguing. The fact that the leflunomide-treated group also experienced twice as many adverse events is, of course, concerning." He pointed out that many of the adverse events listed have been previously associated with LEF and, therefore, are not completely unexpected.
"In clinical practice, we know that some patients who are maintained on MTX will experience disease relapse," Dr. Seo added. "This study highlights the fact that the optimal therapy for this disease is still uncertain and gives us further impetus to continue to explore new options and treatment strategies."
"I think that leflunomide would be a logical choice for remission maintenance in a patient with WG who cannot tolerate either MTX or azathioprine, [but] whether leflunomide supplants these agents will largely depend on what happens to these patients over the next several years. In particular, it will be important to establish that the reduced flare rate seen in the leflunomide-treated group is not a transient benefit. It will also be important to demonstrate that the adverse event rate does not climb with prolonged follow-up," Dr. Seo warned.
Table 1. Wegener's Granulomatosis Relapses: LEF vs MTX
|
Treatment |
Relapses |
P vs MTX |
|
LEF |
6/26 |
P = .09 |
|
Major relapses |
1 (1 new pulmonary granuloma and infiltration) |
P = .037 |
|
Minor relapses |
5 (3 ENT granulomas, 2 episcleritis |
|
|
MTX |
13/28 |
|
|
Major relapses |
7 (4 renal, 2 new pulmonary infiltrates and hemoptysis, 1 cerebral granulomatous mass) |
|
|
Minor relapses |
6 (3 ENT granulomas, 1 arthritis, 1 constitutional symptoms |
|
Adapted from Metzler C, et al. Rheumatology. 2007 May 22; [Epub ahead of print].
Table 2. Adverse Events: Leflunomide vs MTX in Wegener's Granulomatosis
|
Adverse Events |
Leflunomide (n = 26) |
MTX (n = 28) |
|
Total adverse events |
34 |
17 |
|
Severe side effects/withdrawal |
4 |
0 |
|
infections |
13 |
12 |
Adapted from Metzler C, et al. Rheumatology. 2007 May 22; [Epub ahead of print].
Reference
1. Metzler C, Miehle N, Manger K, et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis. Rheumatology. 2007 May 22; [Epub ahead of print].
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