Leflunomide Methotrexate

Rheumatoid arthritis Extension of double-blind, randomized, controlled trial 48 weeks Leflunomide + methotrexate continued (n = 96) and placebo -i- methotrexate switched to leflunomide 10 mg/ day + methotrexate (n = 96) American College of Rheumatology 20 response rate was 59% at 24 weeks and 55% at 48 weeks in patients maintained on leflunomide -i-methotrexate, and patients switched from placebo to leflunomide -i-methotrexate increased their American College of Rheumatology 20 response rates from 25% at 24 weeks to 57% at 48 weeks (23)... 

Chronic sarcoidosis Single-center experience 1 year Leflunomide 100 mg/day for 3 days, then 10-20 mg/day (n = 32 17 leflunomide and 15 leflunomide + methotrexate) Complete or partial responses in 13/17 leflunomide and in 12/15 leflunomide + methotrexate (32)... 

Low-dose methotrexate is used for treatment of rheumatoid arthritis despite side effects such as disorders of the gastrointestinal tract and the liver. Leflunomide is also approved for this indication, however, hepatoxicity limits its use as first option. 

Strand, V., Cohen, S., Schiff, M., et al. (1999) Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Archives of Internal Medicine. 159, 2542-2550. 

Leflunomide is an immunomodulatory dmg inhibiting dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine synthesis. It has also anti-inflammatory effects. Leflunomide is able to slow progression of the disease and to cause re-mission/relief of symptoms of rheumatoid arthritis and psoriatic arthritis such as joint tenderness and decreased joint and general mobility in patients. The combined use of leflunomide with methotrexate may... 

Azathioprine, cyclophosphamide, methotrexate, leflunomide Lymphocyte-specific cytotoxic agents Mycophenolate mofetil... 

Leflunomide is as effective as methotrexate in rheumatoid arthritis, including inhibition of bony damage. In one study, combined treatment with methotrexate and leflunomide resulted in a 46.2% ACR20 response compared with 19.5% in patients receiving methotrexate alone. 

When added to methotrexate background therapy, cyclosporine, chloroquine, hydroxychloroquine, leflunomide, infliximab, adalimumab, rituximab, and etanercept have all shown improved efficacy. In contrast, azathioprine, auranofin, or sulfasalazine plus methotrexate results in no additional therapeutic benefit. Other combinations have occasionally been used, including the combination of intramuscular gold with hydroxychloroquine. 

Cannon, G., Fox, R., Moreland, L., Olsen, N., Furst, D., Caldwell, )., Kaine, )., Sharp, )., Hurley, F., Loew-Friedrich, I. (1999). Treatment of active rheumatoid arthritis with Leflunomide compared with placebo and methotrexate. Arch. Intern. Med. 

Leflunomide has anti-inflammatory, immunosuppressive, and virustatic effects. Its efficacy has been demonstrated in patients with rheumatoid arthritis and psoriatic arthritis and other conditions in randomized, double-blind, placebo-controlled trials and other studies (8-32), and it was approved for treatment of adult rheumatoid arthritis in August 1998 (Table 1) (33). In three large phase III trials (US301, n = 482 MN301, n = 358 MN302, n = 999), leflunomide was as effective and well tolerated as methotrexate and sulfasalazine and superior to placebo (34). These data were confirmed by a meta-analysis (35,36). Leflunomide is therefore indicated for patients with rheumatoid arthritis who have failed first-line disease modifying anti-rheumatic drug therapy on the basis of efficacy, safety, and costs (36). It is effective as monotherapy and in combination with methotrexate or infliximab (6). 

However, the rate of adverse effects associated with leflunomide was significantly lower than with methotrexate and other disease-modifying antirheumatic drugs (DMARDs) in an analysis of 40 594 patients with rheumatoid arthritis (8,51). The incidences of adverse events per 1000 patient-years were as follows ... 

Rheumatoid arthritis Double-blind, randomized, controlled trial 12 months Leflunomide 100 mg/day for 3 days, thereafter 20 mg/day (n = 182) versus methotrexate 7.5-15 mg/ week (n = 180) versus placebo (n= 118) American College of Rheumatology response and success rates were leflunomide 52% and 41%, methotrexate 46% and 35%, and placebo 26% and 19% (9)... 

Rheumatoid arthritis Follow-up study 2 years Leflunomide (n = 98) versus methotrexate (n = 101) American College of Rheumatology 20, 50, and 70 response rates for leflunomide versus methotrexate were 79 versus 67%, 56 versus 43%, and 26 versus 20% (14)... 

Rheumatoid arthritis Double-blind randomized controlled trial 24 weeks Leflunomide 100 mg/day for 2 days, then 10 mg/day (n = 130) versus placebo (n = 133), both with methotrexate 10-25 mg/day American College of Rheumatology 20 rates at 24 weeks leflunomide -i- methotrexate 46% versus placebo -i- methotrexate 20% similar drug withdrawal and adverse events rates (18)... 

Pancytopenia, thrombocjdopenia, and anemia can occur during leflunomide treatment (21,66-68). The risk of pan-cjdopenia is increased when it is used in combination with methotrexate and in elderly patients. Its course can be fatal and the time of onset ranges from 11 days to 4 years (66). Anemia has been reported in renal transplant recipients (28). 

Leflunomide can cause abnormal liver function tests, but the risk of serious and non-serious hepatic adverse events is not higher than with methotrexate (71). In the MN301, US301, and MN302 trials, there were abnormal liver enzymes in 6-10% (9,10,12). The co-administration of methotrexate is a risk factor (18,72-74). According to the National Cancer Institute Common Toxicity Criteria, 8.9% of patients developed grade 2 or 3 hepato-toxicity within the first year, mainly within 6 months and in combination with methotrexate, after the start of leflunomide therapy based on liver enzyme determinations (72). The use of folate was also associated with less... 

Emery P, Breedveld FC, Lenunel EM, Kaltwasser JP, Dawes PT, Gomor B, Van Den Bosch F, Nordstrom D, Bjomeboe O, Dahl R, Horslev-Petersen K, Rodriguez De La Serna A, MoUoy M, Tikly M, Oed C, Rosenburg R, Loew-Friedrich I. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2000 39(6) 655-65. 

Cohen S, Cannon GW, Schiff M, Weaver A, Fox R, Olsen N, Furst D, Sharp J, Moreland L, Caldwell J, Kaine J, Strand V. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis Rheum 2001 44(9) 1984-92. 

Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, Luggen ME, Keystone E, Weisman MH, Bensen WM, Kaine JL, Ruderman EM, Coleman P, Curtis DL, Kopp EJ, Kantor SM, Waltuck J, Lindsley HB, Markenson JA, Strand V, Crawford B, Fernando I, Simpson K, Bathon JM. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002 137(9) 726-33. 

Chan J, Sanders DC, Dn L, PUlans PL Leflunomide-associated pancytopenia with or withont methotrexate. Ann Pharmacother 2004 38(7-8) 1206-ll. 

Gao JS, Wn H, Tian J. [Treatment of patients with jnvenile rheumatoid arthritis with combination of leflunomide and methotrexate.] Zhonghna Er Ke Za Zhi 2003 41(6) 435-8. 

Leflunomide has efficacy similar to that of methotrexate for treating rheumatoid arthritis. The drug may cause liver toxicity and is contraindicated in patients with pre-existing liver disease. Patients taking the drug should have ALT monitored monthly initially, and periodically thereafter as long as they continue treatment. 

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