Leflunomide in rheumatoid arthritis

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

Maddison P, Kiely P, Kirkham B, Lawson T, Moots R, Proudfoot D, Reece R, Scott D, Sword R, Taggart A, Thwaites C, Williams E. Leflunomide in rheumatoid arthritis recommendations through a process of consensus. Rheumatology (Oxford) 2005 44(3) 280-6. 

Rozman B. Clinical experience with leflunomide in rheumatoid arthritis. Leflunomide Investigators Group. J Rheumatol Suppl 1998 53 27-32. 

Fox RI, Herrmann ML, Frangou CG, et al. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol 1999 93 198-208. 

Bird P, Griffiths H, Tymms K, NichoUs D, Roberts L, Arnold M, et al. The SMILE study - safety of methotrexate in combination with leflunomide in rheumatoid arthritis. J Rheumatol March 2013 40(3) 228-35. 

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. 

Kiely PD, Johnson DM. Infliximab and leflunomide combination therapy in rheumatoid arthritis an open-label study. Rheumatology (Oxford) 2002 41(6) 631-7. 

Coblyn JS, Shadick N, Hehgott S. Leflunomide-associated weight loss in rheumatoid arthritis. Arthritis Rheum 2001 44(5) 1048-51. 

Hansen KE, Cush J, Singhal A, Cooley DA, Cohen S, Patel SR, Genovese M, Sundaramurthy S, Schiff M. The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis. Arthritis Rheum 2004 51(2) 228-32. 

B-lymphocytes. It is currently approved for use in rheumatoid arthritis. Bioavailability is 80% after oral administration. Leflunomide is metabolized in the liver to the active metabolite A77,1726. Biliary recirculation of A77,1726 contributes to the long half-life of 15 to 18 days. Adverse effects noted with leflunomide in solid-organ transplantation studies include skin rash, anemia, and elevated liver enzymes. 

Answer B. Leflunomide, used in rheumatoid arthritis, inhibits dihydro-orotic acid dehydrogenase >4 formation of UMP ->4- de novo synthesis of ribonucleotides — arrest of lymphocytes in the GI phase. Glucocorticoids do not decrease expression of lipoxygenase, but by preventing arachidonate formation they decrease activity of the pathway. Misoprostol, used in NSAID-induced GI ulcers, activates receptors colchicine decreases microtubular polymerization ketorolac is a potent NSAID but a nonselective inhibitor of cyclooxygenases. 

Ans B Leflunomide, used in rheumatoid arthritis, inhibits dihydro-orotic... 

Leflunomide This drug inhibits dihydroorotic acid dehydrogenase, an enzyme involved in ribonucleotide synthesis. Leflunomide arrests lymphocytes in the Gj phase of the cell cycle. Leflunomide is used in rheumatoid arthritis. The drug causes alopecia, rash, and diarrhea. 

Bohanec Grabar P, Rozman B, Tomsic M, Suput D, Logar D, Dolzan V. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Chn Pharmacol 2008 64(9) 871-6. 

Suissa S, Hudson M, Ernst P. Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis. Arthritis Rheum 2006 54 1435-1439. 

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. 

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. 

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 52 weeks Leflunomide 100 mg/day for 3 days, then 20 mg/day n = 501) versus methotrexate 7.5-15 mg/day n = 498) Both drugs effective, although methotrexate resulted in significantly greater improvement in tender and swollen joint counts compared with leflunomide (12)... 

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 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)... 

Adverse effects of leflunomide on the skin in patients with rheumatoid arthritis include alopecia (9-17%), rash (11-12%), pruritus (5-6%), dry skin (3%), and eczema (1-3%) (9,10,12). Single cases of an erythema multiforme-like drug eruption (82), exfoliative dermatitis (83), a lichenoid drug reaction (84), and skin ulceration (85) have been reported. 

In the treatment of rheumatoid arthritis leflunomide can cause a vasculitis, and acute necrotizing vasculitis is rare but serious (47,86). 

The administration of infliximab after or simultaneously with leflunomide seems to be safe and effective in patients with rheumatoid arthritis (20,94,95). 

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