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New Drugs for Rheumatoid Arthritis: Are They Better?

Am Fam Physician. 1999 Feb 15;59(4):1029-1030.

Consultants for The Medical Letter for Drugs and Therapeutics reviewed three new drugs for the treatment of rheumatoid arthritis. Leflunomide, which inhibits pyrimidine synthesis, and etanercept, which blocks action of tumor necrosis factor, have recently been labeled by the U.S. Food and Drug Administration (FDA) for use in rheumatid arthritis. A third drug, infliximab, which also blocks tumor necrosis factor, was previously labeled for treatment of Crohn's disease.

Leflunomide is an oral drug considered as a possible alternative to methotrexate for first-line treatment of rheumatoid arthritis. The active metabolite of leflunomide inhibits the enzyme required for synthesis of pyrimidine nucleotide. It has an antiproliferative effect on T cells in vitro and an anti-inflammatory effect in animals. The active drug is metabolized and excreted in urine and feces. It has a half-life of about 14 days.

Unpublished 12-month study data indicate that after one year, an improvement of greater than 20 percent in tender and swollen joints occurred in 41 percent of patients treated with leflunomide in a dosage of 20 mg per day; in 35 percent treated with methotrexate in a dosage of 7.5 to 15 mg per week; and in 19 percent of those given placebo. Another study demonstrated that more patients improved with leflunomide therapy than with sulfasalazine or placebo.

Leflunomide inhibits CYP2C9, which could lead to an increase in serum concentrations of many drugs, including ibuprofen, tolbutamide and diclofenac. Concurrent use of cholestyramine leads to rapid decreases in serum levels of leflunomide. Adverse effects include diarrhea and reversible alopecia. The drug is carcinogenic and teratogenic in animals and is contraindicated in pregnancy. The oral dosage of leflunomide is 100 mg daily for three days followed by a maintenance dosage of 10 to 20 mg daily. The cost to the pharmacist is about $1,600 for a six-month prescription of leflunomide at a dosage of 10 to 20 mg per day.

Etanercept is an injectable drug marketed for use alone or with methotrexate for patients with active disease that is refractory to methotrexate or other antirheumatic drugs. Infliximab is given intravenously and, presumably, it will also be marketed for use in refractory disease. Etanercept is a recombinant version of soluble human tumor necrosis factor receptor, and infliximab is an anti-tumor necrosis factor monoclonal antibody. Both bind to tumor necrosis factor and prevent its binding to cell surface receptors. A single subcutaneous 25-mg dose of etanercept has a half-life of about five days compared with a single infusion of infliximab, which has a half-life of about 10 days.

Randomized trials of patients with refractory disease demonstrated improvement in symptoms in 75 percent of patients undergoing therapy with etanercept, compared with 14 percent of control subjects. In a similar trial, infliximab improved symptoms in refractory patients up to 79 percent of the time, compared with 8 percent of the time in control subjects.

Reactions at the injection site are common with etanercept. Patients treated with the drug have developed auto-antibody markers, but no autoimmune disease developed after one year of therapy. Some patients undergoing therapy with infliximab developed hypersensitivity reactions. The dosage of etanercept is 25 mg subcutaneously twice a week, and the wholesale price for a six-month supply would be $6,300. Infliximab is given intravenously in dosages of 3 or 10 mg per kg, repeated at about four- to 12-week intervals. The cost of three doses would be about $3,500 to $10,500 for a 60-kg (132-lb) patient.

The Medical Letter consultants conclude that leflunomide improves the signs and symptoms of rheumatic arthritis and slows the progression of disease but offers no clear advantages over better known and less expensive drugs such as methotrexate. Etanercept and infliximab appear to decrease symptoms in active disease that is refractory to other drugs, but whether they slow disease progression is unknown. It is not known at this time whether the latter two drugs will increase the incidence of other autoimmune diseases, serious infections or malignancy.

Medical Letter consultants. New drugs for rheumatic arthritis. Med Lett Drugs Ther. November 20, 1998;40 (1040):110–2.


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