Indications: Cyclosporine is approved for use in RA and retards the appearance of new bony erosions. Its usual dosage is 3–5 mg/kg per day divided into two doses. Anecdotal reports suggest that it may be useful in SLE, polymyositis and dermatomyositis, Wegener’s granulomatosis, juvenile chronic arthritis, and refractory eye involvement in Behçet disease.
4.
Adverse Effects: Leukopenia, thrombocytopenia, and, to a lesser extent, anemia are predictable. High doses can be cardiotoxic and neurotoxic, and sterility may occur after chronic dosing at antirheumatic doses, especially in women. Bladder cancer is very rare but must be looked for, even 5 years after cessation of use.
1.
Mechanism of Action: Leflunomide, another csDMARD, undergoes rapid conversion, both in the intestine and in the plasma, to its active metabolite, A77-1726. This metabolite inhibits dihydroorotate dehydrogenase, leading to a decrease in ribonucleotide synthesis and the arrest of stimulated cells in the G1 phase of cell growth. Consequently, leflunomide inhibits T-cell proliferation and reduces production of autoantibodies by B cells. Secondary effects include increases of IL-10 receptor mRNA, decreased IL-8 receptor type A mRNA, and decreased TNF-α–dependent nuclear factor kappa B (NF-κB) activation.
2.
Pharmacokinetics: Leflunomide is completely absorbed from the gut and has a mean plasma half-life of 19 days. Its active metabolite, A77-1726, has approximately the same half-life and is subject to enterohepatic recirculation. Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%.
3.
Indications: Leflunomide is as effective as methotrexate in RA, 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.
4.
Adverse Effects: Diarrhea occurs in approximately 25% of patients given leflunomide, although only about 3–5% of patients discontinue the drug because of this side effect. Elevation in liver enzymes can occur. Both effects can be reduced by decreasing the dose of leflunomide. Other adverse effects associated with leflunomide are mild alopecia, weight gain, and increased blood pressure. Leukopenia and thrombocytopenia occur rarely. This drug is contraindicated in pregnancy.
Methotrexate, a synthetic nonbiologic antimetabolite, is the first-line csDMARD for treating RA and is used in 50–70% of patients. It is active in this condition at much lower doses than those needed in cancer chemotherapy (see Chapter 54).
1.