Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis

Rheumatology (Oxford). 2007 Jul;46(7):1087-91. doi: 10.1093/rheumatology/kem029. Epub 2007 May 22.


Objectives: Results from open-label trials suggest that methotrexate (MTX) and leflunomide (LEF) are effective for maintenance of remission in Wegener's granulomatosis (WG), but data from randomized controlled clinical trails are not yet available.

Methods: In this multicentre, prospective randomized controlled clinical trial, patients with generalized WG were treated either with oral LEF 30 mg/day or oral MTX (starting with 7.5 mg/week reaching 20 mg/week after 8 weeks) for 2 yrs following induction of remission with cyclophosphamide. The primary endpoint was the incidence of relapses. Secondary outcome parameters were DEI, BVAS, SF-36, cANCA-titre, ESR and CRP.

Results: Fifty-four patients were included in the study, 26 in the LEF-limb, 28 in the MTX-limb. In the LEF-group, six patients relapsed after a median time of 7 months, thereof one major relapse with a new pulmonary manifestation. In the MTX-group, 13 relapses occurred in 6 months, of which seven were major: rapidly progressive glomerulonephritis (n = 4), pulmonary haemorrhage (n = 2) and one cerebral granuloma. The significantly higher incidence of major relapses in the MTX-limb (P = 0.037) led to premature termination of the study. In the LEF-limb, four patients were withdrawn due to hypertension (n = 2), peripheral neuropathy (n = 1) and leucopenia (n = 1).

Conclusion: LEF at a dosage of 30 mg/day appears to be effective in the prevention of major relapses in WG, however, this is associated with an increased frequency of adverse events. Further studies testing other dosing regimens of lower doses of LEF are needed to confirm these promising results in larger patients cohorts.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antibodies, Antineutrophil Cytoplasmic / blood
  • C-Reactive Protein / analysis
  • Cyclophosphamide / therapeutic use
  • Drug Administration Schedule
  • Female
  • Glomerulonephritis / chemically induced
  • Granulomatosis with Polyangiitis / blood
  • Granulomatosis with Polyangiitis / drug therapy*
  • Hemoptysis / chemically induced
  • Humans
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use
  • Isoxazoles / administration & dosage*
  • Isoxazoles / adverse effects
  • Isoxazoles / therapeutic use
  • Leflunomide
  • Leukopenia / chemically induced
  • Male
  • Methotrexate / administration & dosage*
  • Methotrexate / adverse effects
  • Methotrexate / therapeutic use
  • Middle Aged
  • Prospective Studies
  • Recurrence
  • Remission Induction
  • Treatment Outcome


  • Antibodies, Antineutrophil Cytoplasmic
  • Immunosuppressive Agents
  • Isoxazoles
  • Cyclophosphamide
  • C-Reactive Protein
  • Leflunomide
  • Methotrexate