Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis

Abstract

Objective. To examine the safety and pharmacokinetics of and clinical response to leflunomide, a de novo pyrimidine synthesis inhibitor, when administered to patients with active rheumatoid arthritis (RA) who have been receiving long-term methotrexate therapy.Methods. This was an open-label, 52-week study in which 30 patients with RA that remained active despite therapy with methotrexate at 17 ؎ 4 mg/week (mean ؎ SD) for >6 months were given leflunomide, 10-20 mg/day. Patients were assessed for adverse effects, pharmacokinetic measurements of leflunomide and methotrexate, and clinical response by American College of Rheumatology (ACR) 20% response criteria.Results. Twenty-three patients completed 1 year of treatment. No significant pharmacokinetic interactions between leflunomide and methotrexate were noted. This combination therapy was generally well tolerated clinically, with the exception of elevations of liver enzyme levels. Seven patients withdrew from the treatment regimen: 2 withdrawals were voluntary, 3 were due to persistent elevation of plasma transaminase levels, and 2 were due to lack of efficacy. Of the patients, 16 (53%) met ACR 20% response criteria. Two met ACR criteria for remission after 1 year.

Efficacy and safety of leflunomide alone and in combination with methotrexate in the treatment of refractory rheumatoid arthritis

“…Efficacy ranging from 50 to 87% with monotherapy using various assessment criteria, have been observed in studies in different situations to date, irrespective of the absence of the loading dose. [5][6][7][11][12][13][14][15][16][17] Hematological and biochemical parameters showed no significant change. Few patients had liver enzyme elevation, though it did not reach significance and only one had to discontinue.…”

“…Earlier studies have shown liver enzyme elevation, which subsequently normalized. [6,7,[15][16][17] Twenty four (29%) patients dropped out of the study and an adverse event was observed in 15 patients, of which five withdrew. Skin reactions observed were more of type B adverse event, which were unpredictable.…”

“…[17] Leflunomide has shown adverse 10% and total withdrawal in up to 23%. [7,[15][16]19] expected to be minimum. Further, including events in up to 79%, withdrawal due to There was 32 and 63% patients showing refractory patients alone will give the efficacy adverse events in up to 22%, hepatic enzyme more than 1.2 times the basal hepatic in pragmatic situations, which is the more elevation in up to 11%, withdrawal due to enzyme increase.…”

Guidelines for the management of rheumatoid arthritis: 2002 Update

“…The combinations of infliximab, etanercept, or leflunomide with MTX have all been studied in patients who had a partial response to MTX, and the combinations were found to be beneficial (93,94,(130)(131)(132).…”

Current use of glucocorticoids in patients with rheumatoid arthritis in Germany

“…A recent international multicenter study demonstrated that ϳ60% of 1,399 patients with rheumatoid arthritis (RA) take a mean glucocorticoid dosage of 6.6 mg/day of prednisone equivalent (12). This figure appears to be even higher in the US, reaching ϳ70%, whereas the corresponding figure for Europe is lower (only ϳ25%) when taken from recent clinical trials (13)(14)(15). However, glucocorticoid use in routine practice might differ from use in clinical trials because trial participants do not represent the full patient spectrum.…”