The TNF inhibitors have shown dramatic efficacy in the treatment of RA. Careful studies have shown significant improvements in function, lessening the number of swollen and tender joints and a slowing of the radiographic progression of disease. These medications have been used safely and effectively with more traditional DMARDs as well. The most common toxicities are injection site reactions, but they are also associated with increased infection risk, including TB and other opportunistic organisms and drug-induced lupus.

Reference: Hochberg MC (ed). Rheumatology, 3rd ed. St. Louis, Mosby, 2003

The newest options for the treatment of RA are anti-cytokine regimens. Three preparations (etanercept [Enbrel], infliximab [Remicade], and adalimunmab [Humira]) target TNF-α and one targets IL-1R (anakinra [Kineret]). All of these options are given parenterally and are fairly expensive. Anakinra, although proven efficacious, requires daily injections and has a slower onset of action and is therefore used less frequently.

Reference: Harris ED, Budd RC, Firestein GS, et al (eds): Kelley’s Textbook of Rheumatology, 7th ed. Philadelphia, W.B. Saunders, 2005

Answer:
Immunosuppressive drugs have been shown to be effective DMARDs in RA. To a large degree their use is restricted by their toxicities. Chlorambucil and cyclophosphamide are generally reserved for severe disease including the development of extra-articular features such as vasculitis. Azathioprine has been studied in RA, but its greater toxicity risk and lack of efficacy advantage over methotrexate make it a less common therapeutic choice. Cyclosporine has been used in the treatment of RA with good effect. Unfortunately, when used as a single agent, the doses required confer a high risk of hypertension and renal insufficiency. It has been used synergistically in combination with methotrexate, allowing lower doses of each drug.

Reference: Hochberg MC (ed). Rheumatology, 3rd ed. St. Louis, Mosby, 2003

Sulfasalazine is an easy to use and well-tolerated medication. Some studies have shown it to be as effective as methotrexate as a DMARD. It is used more frequently in Europe than in the U.S.

Leflunomide (Arava) has been available for a number of years. It is known to inhibit pyrimidine synthesis and thereby alter T-cell function. Studies show it to be about as effective as methotrexate. It must be monitored as closely as methotrexate since its toxicities are remarkably similar. The rate of diarrhea and hair loss may be a bit higher with leflunomide, but it does not have the risk of pulmonary reaction.

Reference: Harris ED, Budd RC, Firestein GS, et al (eds): Kelley’s Textbook of Rheumatology, 7th ed. Philadelphia, W.B. Saunders, 2005

In the U.S, methotrexate remains the cornerstone of treatment for RA. Its exact mechanism of action is unclear, but its anti-folate effect contributes to its effect as a potent anti-inflammatory agent. It has a more rapid onset of action than many of the older DMARDs. Although it has many potential toxicities, most are reversible when the drug is stopped. These include bone marrow suppression, stomatitis, nausea, alopecia and hepatic toxicity. Idiopathic pulmonary hypersensitivity is perhaps the most dangerous side effect and must be dealt with promptly to avoid serious impairments. Because of these toxicities, methotrexate must be monitored carefully.

Reference: Hochberg MC (ed). Rheumatology, 3rd ed. St. Louis, Mosby, 2003

Hydroxychloroquine (Plaquenil) is pretty well the uniquely used antimalarial medication in the U.S. (over chloroquine [Aralen] and quinacrine [Atabrine]). Antimalarial medications are believed to be weak, have a slow onset of action, and are generally used in mild disease or in combination with other DMARDs.

Reference: Hochberg MC (ed). Rheumatology, 3rd ed. St. Louis, Mosby, 2003

NSAIDs, including aspirin, decrease platelet aggregation by inhibiting the COX. Acetylated salicylates (such as aspirin) irreversibly destroy this enzyme, whereas other NSAIDs (including nonacetylated salicylates) allow the return of normal enzyme function once the drug level has dropped. Because COX-2 does not regulate platelet aggregation, newer COX-2 NSAIDs have little effect on platelet function.

Reference: Koopman WJ (ed): Arthritis and Allied Conditions: A Textbook of Rheumatology, 15th ed. Philadelphia, Lippincott Williams & Wilkins, 2005.