Leflunomide, rheumatoid arthritis treatment

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. 

Jaimes-Hemandez J, Robles-San Roman M, Suarez-Otero R, Davalos-Zugasti ME, Arroyo-Borrego S. Rheumatoid arthritis treatment with weekly leflunomide an open-label study. J Rheumatol 2004 31(2) 235-7. 

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 (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. 

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

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. 

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). 

A 54-year-old woman with rheumatoid arthritis developed an interstitial pneumonia 2 weeks after the end of a 6-week course of treatment with leflunomide (60). 

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

A 49-year-old man with resistant rheumatoid arthritis took leflunomide 100 mg/day for 3 days. His international normalized ratio (INR) had been stable for 1 year while he was taking warfarin, and 2 days before starting treatment with leflunomide it was 3.4. After he took the second dose of leflunomide, he developed gross hematuria. His INR had risen to 11, and warfarin was withdrawn. The hematuria resolved spontaneously several hours later, but his INR remained raised for the next 2 days, even though he had stopped taking warfarin. He was given intravenous vitamin K 1 mg on the third day, and 12 hours later the INR fell to 1.9. 

Usually, overdosage and adverse events can be managed by dosage reduction, the addition of colestyramine, and symptomatic therapy (36). However, in one study in patients with rheumatoid arthritis, leflunomide 10 mg/ day compared with 20 mg/day was associated with less efficacy and more adverse events leading to treatment withdrawal (24). Colestyramine 3x8 g/day for 11 days is recommended to wash out leflunomide, if A77 1726 plasma concentrations do not fall to 0.02 mg/1 or less, additional colestyramine is advised. Without this washout procedure, it can take up to 2 years to reach A77 1726 plasma concentrations of 0.02 mg/1. Oral activated charcoal 50 g every 6 hours for 24 hours also reduced plasma A77 1726 concentrations (80). 

Mladenovic V, Domljan Z, Rozman B, Jajic I, Mihajlovic D, Dordevic J, Popovic M, Dimitrijevic M, Zivkovic M, Campion G, et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-... 

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. 

Scott DL, Smolen JS, Kalden JR, van de Putte LB, Larsen A, Kvien TK, Schattenkirchner M, Nash P, Oed C, Loew-Friedrich I European Leflunomide Study Group. Treatment of active rheumatoid arthritis with leflunomide two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis 2001 60(10) 913-23. 

Nyugen M, Kabir M, Ravaud P. Short-term efficacy and safety of leflunomide in the treatment of active rheumatoid arthritis in everyday clinical use. Chn Drug Invest 2004 24(2) 103-12. 

Hoi A, Littlejohn GO. Aminotransferase levels during treatment of rheumatoid arthritis with leflunomide in clinical practice. Ann Rheum Dis 2003 62(4) 379. 

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. 

Strand V, Cohen S, Schiff M, et al. Treatment of active rheumatoid arthritis widi leflunomide compared with placebo and mefliotrexate. Leflunomide Rheumatoid Arfluitis Investigators Group. Arch Intern Med 1999 159 2542-2550. 

Herrmann, M. L., Schleyerbach, R., and Kirschbaum, B. J. (2000) Leflunomide an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology 47, 273-289. 

Leflunomide is an antirheumatic agent. It is an isoxazole immunomodulatory agent that inhibits dihydro-orotate dehydrogenase and has antiproliferative and antiinflammatory activity. It is indicated in the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms and to retard structural damage. 

Leflunomide (Arava) is a pyrimidine-synthesis inhibitor indicated for the treatment of adults with rheumatoid arthritis. This drug has found utility in the treatment of polyo-mavirus nephropathy seen in immunosuppressed renal transplant recipients and is increasingly being used for that purpose. There are no studies showing efficacy, however, compared with control patients treated with withdrawal or reduction of immune-suppression alone in BK virus nephropathy. The drug inhibits dihydro-orotate dehydrogenase in the de novo pathway of pyrimidine synthesis. It is hepa-totoxic and can cause fetal injury when administered to pregnant women. 

Newer drugs that have become available for the treatment of rheumatoid arthritis include the COX-2 inhibitors, etanercept, infliximab, and leflunomide (see Chapter 36). 

Phenylbutazone has been utilised for some time in the treatment of severe arthritis, which, incidentally, afflicted such notables as Casanova, Goethe, and Luther. Leflunomide is used in the therapy of autoimmune diseases, such as active rheumatoid arthritis. Celecoxib is the first to market of a number of selective cycloxygenase 2 (COX 2) inhibitors which show great promise as anti-inflammatory and analgetic agents, without the undesirable side effects associated with other nonsteroidal anti-inflammatories. There are many pyrazole dyestuffs - the food colourant tartrazine is one such substance. 

Weinblatt ME, Kremer Coblyn JS, Maier AL, Helfgott SM, Mcnell M, Byrne VM, Kay-makcianMV, Sttand V. Pharmacokinetics, safety, and efficacy of combination treatment with methottexate and leflunomide in patients widi active rheumatoid arthritis. Ar iritis Rheum... 

Respiratory A 52-year-old woman with psoriatic arthritis developed pneumonitis after taking leflunomide for 5 months [63 ]. Several cases of acute interstitial pneumonitis complicating leflunomide treatment for rheumatoid arthritis have been described in Japanese populations, but this complication appears to be extremely rare in the Western hemisphere. 

The factors associated with a poor prognosis in leflunomide-induced lung injury have been studied in 22 patients with rheumatoid arthritis, of whom 9 died and 13 recovered [39 ]. The patients who died tended to have pre-existing interstitial pneumonia (8/9 vs. 6/13). The loading and maintenance doses, the serum concentration of the leflunomide metabolite A771726, and the duration of treatment did not differ between the groups. The patients who died had more frequent hypoxemia and mechanical ventilation, had a high serum CRP concentration (190 vs. 100 mg/1), and had a low albumin concentration (27 versus 33 g/1). The lymphocyte count was persistently low in those who died, but recovered in those who survived. 

Musculoskeletal Polymyositis occurred in a 53-year-old woman after leflunomide treatment for rheumatoid arthritis [47" ]. 

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. 

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