Disease-modifying antirheumatic drugs

Abstract

Disease-modifying antirheumatic drugs (DMARDs) are commonly used to treat patients with rheumatoid arthritis (RA). DMARDs most frequently used include hydroxychloroquine, sulfasalazine and methrotrexate. However, azathioprine, penicillamine, gold compounds, cyclosporine and combination therapy are also used. Hydrochloroquine inhibits antigen presentation by increasing pH within acidic vesicles. It is oxidized to three metabolites and has a terminal half-life of 40 days. Hydroxychloroquine is the least toxic DMARD and is moderately effective. Sulfasalazine has a potent immunomodulatory effect on lymphocytes. It is metabolized to sulfapyridine and 5-aminosalacylic acid in the bowel. Sulfasalazine is more effective than hydroxychloroquine, but not as well tolerated, with approximately 20% of patients stopping the drug secondary to gastrointestinal side effects. Currently, methotrexate is the most popular DMARD. It inhibits dihydrofolate reductase and also enhances release of adenosine, which inhibits neutrophil function. Methotrexate undergoes intracellular metabolism and remains within cells for a prolonged period. Methotrexate's most common toxicities include gastrointestinal upset, mucosal ulcerations and elevated liver enzymes. Because of its high degree of efficacy and reasonable tolerability, patients stay on methotrexate longer than any other DMARD. Azathioprine, penicillamine and gold compounds have all been shown to be effective in the treatment of RA. Small trials comparing these drugs failed to show significant differences in their clinical efficacies. These drugs are somewhat less well tolerated by patients than the first three mentioned. Cyclosporine is an important drug in organ transplantation and is increasingly used in autoimmune disease, including RA. Its most important side effect is renal toxicity and it is generally used as salvage therapy or in combination therapy. Combination therapy has become more popular with the realization that RA may not be the benign disease it was once thought to be. Some combinations are more effective than single drug therapy and may be warranted in patients with aggressive disease.