Methotrexate (MTX), an anti-metabolite that inhibits purine pathways, has been the hallmark of standard of care for many years in the treatment of rheumatoid arthritis (RA). However, many RA patients continue to have active disease despite maximal doses of methotrexate. Recent studies indicate that combinations of disease-modifying anti-rheumatic drug (DMARD) therapy can provide improved clinical benefit for those patients who continue to have active disease despite methotrexate.
In contrast to methotrexate, leflunomide is a DMARD that inhibits pyrimidine pathways. Kremel et al. (Ann Intern Med 2002;137:726-733) investigated the potential efficacy of this combination of DMARDs in RA.
263 patients 18 to 75 years of age with active RA taking stable doses of methotrexate were randomized into a 24 week double-blind placebo-controlled trial to determine the safety and efficacy of leflunomide and MTX and versus placebo and MTX. Patients were required to take 1 mg of folate daily and also permitted to continue stable doses of corticosteroids at 10 mg or less daily. Subjects were randomized to receive either placebo or 10mg of leflunomide daily following a two day loading dose of 100mg. Persistent adverse events at 10mg daily would allow for a dose adjustment from daily to every other day. Following at least eight weeks of study treatment and if tolerated, daily dosing was increased to 20 mg with persistent active disease. However, if the increase in dose resulted in significant adverse effects the dose was decreased to 10 mg daily. Furthermore, a dosage adjustment or discontinuation of treatment therapy was permitted if liver enzymes (ALT and AST) were elevated at twice the upper limit of normal.
The primary outcome was the American College of Rheumatology criteria (ACR20) for 20 % clinical improvement at week 24. Secondary outcomes were the ACR50 and ACR70. Safety measures included adverse event reports, laboratory assessments for blood chemistry, liver function, urinalysis, and physical examination.
130 patients received treatment with leflunomide and methotrexate and 133 subjects were randomized to placebo and methotrexate. The response rate of ACR20 criteria (P<0.001) at week 24 was 46.2% and 19.5% for the leflunomide and placebo groups respectively. Additionally, the ACR50 (P<0.001) response rates were 26.2% and 6.0% for the leflunomide and placebo groups respectively at week 24. Furthermore, the ACR70 (P<0.0155) response rates were 10% and 2.3 % for the leflunomide and placebo groups respectively. Statistical significance was reached.
The most common adverse events, mild to moderate in intensity, were diarrhea, upper respiratory infection, nausea, headache, rash dizziness, and alopecia. The frequency of infections was less in the leflunomide (40.8%) group than in the placebo (51.9%) group. Discontinuations of treatment in the leflunomide group were more commonly due to of adverse events whereas discontinuations in the placebo group were more often from lack of efficacy. Liver enzyme elevations were more frequent in the first three months of treatment. 31.5% of leflunomide treated patients, compared to 6.8% of placebo treated patients experienced abnormal ALT levels, whereas 16.9% vs. 4.5% (placebo vs. leflunomide) displayed abnormal AST levels. Mild LFT elevations association with leflunomide frequently returned to normal range without any dose adjustment. However, three leflunomide-treated patients and two placebo-treated patients were discontinued from the study due to persistent elevations in liver function values. There were no observed cases of leukopenia or neutropenia.
Combination treatment with leflunomide and methotrexate was generally well tolerated and resulted in statistically significant improvement in RA, in comparison to placebo and methotrexate. Therefore, combination therapy of leflunomide with methotrexate suggests a possible alternative for those patients with persistent active RA who fail methotrexate monotherapy. Vigilant monitoring of liver function should continue during combination therapy with appropriate dosage adjustments as needed. Further long-term observations are necessary to establish long-term clinical efficacy and safety of this DMARD combination.
The original open-label study of MTX and leflunomide suggested more liver toxicity than was actually seen in this double-blind, placebo-controlled study. The dosing regimen in this study was conservative in that the loading dose was 200 rather than 300 mg, and chronic dosing began at 10 mg qd. This may be the reason for less liver toxicity, or simply because larger numbers of patients were studied in this protocol. The present results are encouraging but they are short-term. Also, there are no x-ray data to confirm that the combination of MTX and leflunomide is superior to MTX alone, in terms of suppressing radiographic progression.