Other Drugs for Rheumatoid Arthritis Therapy
The following drugs are not commonly used as first-line treatments of rheumatoid arthritis, either because they lack the efficacy of other drugs or because they pro-duce more serious side effects or both. They do, how-ever, remain useful in specific clinical situations and in individuals in whom more conservative therapies have failed.
Serious adverse effects are produced by long-term, high-dose exposure to the corticosteroids; therefore, these drugs are not agents of choice for the treatment of rheumatic disease. In general, the use of low-dose corti-costeroids avoids significant side effects (e.g. fluid re-tention, osteoporosis, GI bleeding, immunosuppression) but does not completely control the disease. However, for patients whose disease is refractory to other agents or who cannot tolerate the side effects of other DMARDs, a corticosteroid such as prednisone may be used to control symptoms. Low-dose corticosteroids may also be used as an alternative to more toxic DMARDs in pregnant, elderly, or debilitated individu-als. Intraarticular injection of corticosteroids can con-trol acute inflammation of a specific joint without caus-ing systemic side effects. High-dose steroids can control severe systemic manifestations of autoimmune disease, such as iritis, pericarditis, nephritis, or vasculitis. Following discontinuation of corticosteroid treatment, rebound joint deterioration is common.
The immunosuppressive drugs are used in rheumatoid arthritis and certain other autoimmune conditions that are refractory to less toxic treatments. Azathioprine (Imuran) is a prodrug that is metabolized to a purine antimetabolite. Its disease-modifying activity results from the inhibition of lym-phocyte proliferation and secretion of certain cytokines. This drug is used in the treatment of rheumatoid arthri-tis, lupus nephritis, and psoriatic arthritis. Cyclosporine (Sandimmune, Neoral) is used in refractory rheumatoid arthritis, psoriasis, and inflammatory bowel disease. It acts by blocking the transcriptional activation of many genes involved in the first phase of T cell activation. Cyclophosphamide (Cytoxan) is an alkylating agent that was used in severe rheumatoid in the past but is seldom used today because of its severe bladder toxic-ity, bone marrow toxicity, and carcinogenicity.
The tetracycline antibiotic minocycline (Minocin) is modestly effective in the treatment of rheumatoid arthritis and is generally well tolerated. Radiographic evidence of its efficacy as a DMARD is lacking, al-though clinical symptoms do abate. It can be useful in the treatment of early, mild disease.
Penicillamine (Cuprimine) can be used to treat acute, severe rheumatoid arthritis, producing reductions in joint pain, edema, and stiffness. The response to penicil-lamine is usually delayed (4–12 weeks), and remissions can last several months after withdrawal of treatment. Radiographic evidence of this drug’s efficacy is limited; thus, penicillamine is seldom used to treat rheumatoid arthritis. The mechanism of action of penicillamine is unknown, but some evidence suggests that it may in-volve the inhibition of angiogenesis, synovial fibroblast proliferation, or transcriptional activation. Because penicillamine can chelate copper and promote its ex-cretion, it is used to treat Wilson’s disease (hepatolen-ticular degeneration) and has also been used in mercury and lead intoxication.
Penicillamine is readily absorbed from the GI tract and is rapidly excreted in the urine, largely as the intact molecule. Gradually increasing its dose minimizes side effects, which necessitate discontinuance of penicil-lamine therapy in perhaps one-third of patients. The most common side effects are maculopapular pruritic dermatitis, GI upset, loss of taste sensation, mild to oc-casionally severe thrombocytopenia and leukopenia, and mild proteinuria, which at times may progress to the nephritic syndrome. Discontinuance of therapy usu-ally results in a rapid disappearance of side effects.
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