Leflunomide rheumatoid arthritis

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. 

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. 

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... 

Leflunomide (Arava) is an isoxazole derivative approved for the treatment of rheumatoid arthritis in 1998. Limited data suggest that it is comparable in efficacy to sulfasalazine and produces fewer adverse effects. It has a faster onset of action (4 weeks) than other DMARDs. 

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. 

Maddison P, Kiely P, Kirkham B, et al. Leflunomide in rheumatoid arthritis recommendations through... 

Miceli-Richard C, Dougados M. Leflunomide for the treatment of rheumatoid arthritis. Expert Opin Pharma-cother. 2003 4 987-997. 

Leflunomide is a prodrug of an inhibitor of pyrimidine synthesis rather than purine synthesis. It is orally active, and the active metabolite has a long half-life of several weeks. Thus, the drug should be started with a loading dose, but it can be taken once daily after reaching steady state. It is approved only for rheumatoid arthritis at present, though studies are under way combining... 

Luhrmann, R. (1998). The mammalian homologue of Prpl6p is overexpressed in a cell line tolerant to Leflunomide, a new immunoregulatory drug effective against rheumatoid arthritis. RNA 4, 1007-1018. 

Smolen, J. S., Kalden, ). R., Scott, D. L., Rozman, B., Kvien.T. K., Larsen, A., Loew-Friedrich, I., Oed, C., Rosenburg, R. (1999). Efficacy and safety of Leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis a double-blind, randomised, multi-centre trial. Lancet 353, 259-266. 

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 selectively inhibits pyrimidine synthesis and prevents T-cell proliferation, which is thought to be important in the pathogenesis of rheumatoid arthritis. The onset of action is faster than other DMARDs, providing clinical benefit in 4-6 weeks. As the drug is retained in the body for 2 years, elimination therapy with either cholestyramine or activated charcoal may be necessary if a change to another DMARD is planned. 

An interesting application of this interaction is seen with the use of leflunomide (Arava) in the treatment of rheumatoid arthritis. Leflunomide can cause fetal harm if administered during pregnancy, and it has an active metabolite that can persist in the system for at least 2 years. If a woman of childbearing potential discontinues use of leflunomide, it is recommended that cholestyramine (8 g 3 times a day for 11 days) be used to accelerate the elimination of the drug and its active metabolite. 

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 ... 

The incidence of hypertension in patients with rheumatoid arthritis taking leflunomide 25 mg/day was 11% in a phase II trial (54). During phase III trials, there was new-onset hypertension in 2.1-3.7% (9,10). Increased sympathetic drive has been implicated in its pathogenesis, because leflunomide-induced hypertension is accompanied by an increased heart rate (55). However, this hypothesis remains to be tested. 

Rheumatoid arthritis Double-blind, randomized, controlled trial 24 weeks Leflunomide 50-100 mg/day for 1 day, then 5-25 mg/day (n = 300) versus placebo n = 102) Leflunomide 10 and 25 mg/day was significantly more effective than placebo (8)... 

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 Single-center experience 32 weeks Leflunomide 100 mg/day for 3 days, then 20 mg/day plus infliximab 3 mg/kg at 2, 4, 8, 16, and 24 weeks (n = 20) 11/20 withdrawn (four infliximab infusion reactions, one Stevens-Johnson syndrome) the other patients achieved American College of Rheumatology 20 and 70 response rates in >80% and 46% (17)... 

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)... 

Rheumatoid arthritis Multicenter experience 24 weeks Leflunomide 100 mg/day for 3 days, then 20 mg/day (n = 969) 191 withdrawn (107 adverse events, 26 lack of efficacy, 58 other reasons) 24% good and 45% moderate responses on the disease activity score, and 61%, 34%, and 9.6% achieved American College of Rheumatology 20, 50, and 70 response rates (19)... 

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)... 

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