Leflunomide is used for the management of the signs and symptoms of rheumatoid arthritis to improve physical function, and to retard structural damage associated with the disease in adults with moderate to severe active rheumatoid arthritis.
Leflunomide is being evaluated to determine whether the drug may have a possible role in patients undergoing transplantation, and leflunomide is designated an orphan drug by the US Food and Drug Administration (FDA) for prevention of acute and chronic rejection in solid organ transplant recipients.
Rheumatoid Arthritis in Adults
Leflunomide is used for the management of the signs and symptoms of rheumatoid arthritis in adults to improve physical function and to retard structural damage associated with the disease. Current data suggest that leflunomide is as effective as methotrexate or sulfasalazine for the management of rheumatoid arthritis in adults and may be a suitable alternative for these disease-modifying antirheumatic drugs (DMARDs); however, long-term experience with leflunomide is limited and the exact role of the drug in the management of rheumatoid arthritis remains to be determined. Leflunomide generally is well tolerated; however, serious hepatic reactions have occurred rarely in patients receiving the drug.
(See Cautions: Hepatic Effects.)Leflunomide has been used concomitantly with methotrexate in a limited number of adults with rheumatoid arthritis.
Pharmacologic therapy for rheumatoid arthritis usually consists of combinations of nonsteroidal anti-inflammatory agents (NSAIAs), DMARDs, and/or corticosteroids. The ultimate goal in managing rheumatoid arthritis is to prevent or control joint damage, prevent loss of function, and decrease pain. Although NSAIAs may be useful for initial symptomatic treatment of rheumatoid arthritis, these drugs do not alter the course of the disease or prevent joint destruction. DMARDs have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health-care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy. DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs. DMARDs commonly used in the treatment of rheumatoid arthritis include etanercept, hydroxychloroquine, infliximab, leflunomide, methotrexate, and sulfasalazine. Less frequently used DMARDs include azathioprine, cyclosporine, minocycline, penicillamine, and/or oral or injectable gold compounds. The role of anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, in the management of rheumatoid arthritis remains to be established.
While many factors influence the choice of a DMARD, methotrexate has substantially greater long-term efficacy than other DMARDs and is used as the initial or anchor DMARD in many patients with rheumatoid arthritis. Because residual inflammation generally persists in patients receiving maximum dosages of a single DMARD, many rheumatoid arthritis patients are candidates for combination therapy to achieve optimum control. Although the most effective combination regimen of DMARDs has not been determined, regimens that have been found efficacious in clinical studies include combinations of methotrexate and cyclosporine, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, or infliximab.
Low-dose oral corticosteroids and local injection of corticosteroids are effective in relieving symptoms in patients with active rheumatoid arthritis. In addition, limited evidence indicates that low-dose corticosteroids slow the rate of joint damage.
Clinical evaluations of leflunomide have shown that usual dosages of the drug are more effective than placebo and as effective as methotrexate or sulfasalazine in the management of rheumatoid arthritis in adults. Response to leflunomide generally occurs 1 month after initiation of therapy and maximum improvement is achieved within 3-6 months. Durable responses have been maintained for up to 24 months in patients receiving leflunomide. Therapy with leflunomide reduces the number of swollen joints, pain, and duration of morning stiffness, improves the quality of life, and reduces disease activity as assessed by laboratory measures (i.e., ESR, CRP). In addition, leflunomide was more effective than placebo and as effective as methotrexate or sulfasalazine in retarding radiographic evidence of disease progression.
Therapy with a Single Disease-modifying Antirheumatic Drug
Leflunomide has been evaluated for the management of rheumatoid arthritis in adults with active disease (American Rheumatism Association criteria for rheumatoid arthritis with American College of Rheumatology [ACR] functional class I, II, III or IV) in a placebo-controlled phase 2 study and in 3 double-blind, placebo- and active-controlled phase 3 studies (studies US301, MN301, and MN302). Most adults included in these studies had received prior therapy with a DMARD; however, patients were required to discontinue DMARD therapy 28-30 days prior to study enrollment. Patients receiving stable dosages of NSAIAs and/or prednisone (10 mg daily or less) at study enrollment could continue such agents during these studies.
ACR criteria for a 20% improvement (ACR 20 response) in measures of disease activity was used as the principal measure of clinical response in studies evaluating the efficacy of leflunomide. An ACR 20 response is achieved if the patient experiences a 20% improvement in tender and swollen joint count, and a 20% or greater improvement in a least 3 of the following criteria: patient pain assessment, patient global assessment, physician global assessment, patient self-assessed disability, or laboratory measures of disease activity (i.e., ESR or CRP level). ACR 50 and ACR 70 responses are defined using the same criteria with a level of improvement of 50 and 70%, respectively. The Sharp Score, a composite score of erosions and joint space narrowing in hands, wrists, and forefeet, was used as the principal measure of structural damage.
In study US301, 482 adults with rheumatoid arthritis (mean age: 54 years, mean disease duration: 6.7 years, mean number of DMARDs that failed: 0.8) were randomized to receive leflunomide (100 mg once daily for 3 days, then 20 mg once daily), methotrexate (7.5-20 mg once weekly), or placebo. All patients received folic acid 1 mg twice daily (to decrease methotrexate toxicity). At 12 months, an ACR 20 (intent-to-treat analysis) was achieved in 52% of patients receiving leflunomide, and an ACR 50 or 70 was achieved in 34 or 20%, respectively. An ACR 20 was observed at month 12 in 46 or 26% of patients receiving methotrexate or placebo, respectively; an ACR 50 was observed in 23 or 8%, respectively, and an ACR 70 was observed in 9 or 4% of patients, respectively. Evaluation at 12 months indicated that leflunomide therapy was associated with greater decreases in the number of tender joints (from 15.5 at baseline to 7.8), number of swollen joints (from 13.7 at baseline to 7), pain (from 5.9 at baseline to 3.7), HAQ disability index (from 1.3 at baseline to 0.85), ESR (from 38.4 mm/hour at baseline to 32.1), CRP (from 2.08 mg/dL at baseline to 1.46 mg/dL), and greater improvement in physician and patient assessments than placebo; improvement in these parameters in patients receiving leflunomide was essentially the same as that in patients receiving methotrexate. Radiographic analysis at month 12 indicated that leflunomide or methotrexate therapy was associated with less disease progression than placebo. Data from an extension of study US301 indicate that clinical and radiographic improvement observed in patients receiving leflunomide or methotrexate at 12 months was maintained at 24 months.
In study MN302, 999 adults with rheumatoid arthritis (mean age: 58 years, mean disease duration: 3.75 years, mean number of DMARDs that failed: 1.1) were randomized to receive leflunomide (100 mg daily for 3 days, then 20 mg daily) or methotrexate (7.5-15 mg weekly). Analysis at month 12 indicated that more patients receiving methotrexate achieved an ACR 20 than patients receiving leflunomide; the ACR 20 response rate in patients receiving leflunomide in this study was similar to the response rate reported in study US301. Improvements in the number of tender or swollen joints, pain, ESR, CRP, and physician and patient assessments observed in leflunomide-treated patients in study MN302 were similar to those observed in study US301. At month 12, disease progression as assessed by radiographic analysis in patients receiving leflunomide was similar to that in patients receiving methotrexate.
In study MN301, 358 adults with rheumatoid arthritis (mean age: 58.3-58.9 years, mean disease duration: 5.7-7.6 years, 40-53% had not received prior therapy with a DMARD) were randomized to receive leflunomide (100 mg daily for 3 days, then 20 mg daily), sulfasalazine (dose increased to 2 g daily over 1-4 weeks), or placebo. At 24 weeks, an ACR 20 or ACR 50 was achieved in 48 or 30%, respectively, of patients receiving leflunomide. An ACR 20 was observed at 24 weeks in 44 or 29% of patients receiving sulfasalazine or placebo, respectively; an ACR 50 was observed in 30 or 14%, respectively. Radiographic analysis at week 24 indicated that leflunomide or sulfasalazine therapy was associated with less disease progression than placebo.
Physical functioning and disability were assessed using the Health Assessment Questionnaire (HAQ) and the general health-related quality-of-life questionnaire SF-36. Leflunomide therapy was associated with greater improvement from baseline in all 8 HAQ Disability Index subscales (dressing, arising, eating, walking, hygiene, reach, grip, activities) and the SF-36 physical component summary score compared with placebo; in addition, leflunomide was at least as effective as methotrexate as measured by the HAQ Disability Index. Improvements in HAQ and SF-36 were maintained over 2 years.
Combination Therapy with Methotrexate
Leflunomide has been used concomitantly with methotrexate in a limited number of adults with rheumatoid arthritis, and there is some evidence from clinical studies that addition of leflunomide may be useful in patients who have a suboptimal response to methotrexate. However, additional study is needed to clarify the role of leflunomide in combination with methotrexate versus other therapies (e.g., changing from methotrexate to another DMARD, adding a DMARD other than leflunomide) in patients who have not responded adequately to methotrexate. Although some data from patients with rheumatoid arthritis who received leflunomide in combination with methotrexate indicate that the adverse effect profile in patients receiving concomitant therapy with the drugs is similar to that in patients receiving either leflunomide or methotrexate, increased serum concentrations of liver enzymes are frequently observed in such patients. In addition, serious hepatic reactions have occurred in patients receiving leflunomide in combination with methotrexate. The manufacturer of leflunomide states that concomitant use with methotrexate has not been adequately studied in controlled settings.
(See Cautions: Precautions and Contraindicationsand see Drug Interactions: Methotrexate.)
Solid Organ Transplantation
Results of studies in animal models of transplantation indicate that leflunomide may provide some benefits when used in conjunction with other drugs for prevention of allograft rejection. There also is evidence from in vitro studies using human fibroblasts and endothelial cells infected with cytomegalovirus (CMV) that leflunomide's active metabolite (A77 1726; commercially available as teriflunomide) has antiviral activity against CMV. Leflunomide has been evaluated in a limited number of renal or hepatic transplant recipients. Experience with leflunomide in these patients indicates that the drug possesses substantial immunosuppressive potency. Although safety and efficacy of leflunomide in transplant recipients have not been established, the drug is designated an orphan drug by FDA for the prevention of acute and chronic rejection in recipients of solid organ transplants.