Rheumatoid arthritis methotrexate therapy

E. Treatment guidelines suggest the use of DMARDs early in the course of rheumatoid arthritis to slow the joint deterioration associated with the disease. Methotrexate is the DMARD of choice for people with moderate to severe forms of rheumatoid arthritis. Although NSAIDs can decrease methotrexate clearance, NSAIDs can be safely used with the low doses of methotrexate used in the therapy of rheumatoid arthritis. Methotrexate is highly teratogenic and should not be used by women who are or may become pregnant. 

FIGURE 4-1. Algorithm for treatment of rheumatoid arthritis. (DMARD, diseasemodifying antirheumatic drug MIX, methotrexate NSAID, nonsteroidal antiinflammatory drug Rx, therapy.)... 

Kumagai, K., Hiyama, K., Oyama, T., Maeda, H., and Kohno, N. (2003) Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. International Journal of Molecular Medicine. 11, 593-600. 

Keystone, E. C., Kavanaugh, A. E., Sharp, J. T., et al. (2004) Radiographic, cUnical, and functional outcomes of treatment with adaUmumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy a randomized, placebo-controUed, 52-week trial. Arthritis and Rheumatism. 50, 1400-1411. 

Severe reactions Because of the possibility of severe toxic reactions (which can be fatal), fully inform patients of the risks involved and assure constant supervision. Deaths Use methotrexate only in life-threatening neoplastic diseases, or in patients with psoriasis or rheumatoid arthritis (RA) with severe, recalcitrant, disabling disease that is not adequately responsive to other forms of therapy. Deaths have occurred with the use of methotrexate in malignancy, psoriasis, and RA. Closely monitor patients for bone marrow, liver, lung, and kidney toxicities. 

Two recently introduced biological therapies were designed to interfere with the inflammatory cascade initiate by TNF-a. Etanercept (Enbrel) is indicated for the treatment of moderate to severe rheumatoid arthritis in individuals over age 4. Infliximab in conjunction with methotrexate (Remicade) is approved for use by adults in the treatment of rheumatoid arthritis. It is also indicated for therapy of Crohn s disease. Over the short term, the efficacy of these drugs in the treatment of rheumatoid arthritis appears to be superior to that of methotrexate alone however, their ability to prevent bone erosion for longer than 24 months must be further studied. The cost of both drugs is significantly higher than that of the other DMARDs. 

Anakinra (Kineret) is the first antirheumatic agent that acts by blocking the action of IL-1. This drug was recently approved for the treatment of moderately to severely active rheumatoid arthritis in adults who have not responded to therapy with one or more DMARDs. Anakinra may be used alone or in combination with DMARDs other than the TNF antagonists. Clinical trials have shown anakinra to be more effective than placebo, either alone or in conjunction with methotrexate. 

The most recent treatment paradigm calls for earher, more aggressive treatment of rheumatoid arthritis. DMARDs are frequently employed along with NSAIDs in the initial treatment of the disease. The COX-2 inhibitors are often used because they are less likely to cause serious GI toxicity than are the nonspecihc COX inhibitors. The usual DMARD of choice for patients with mild rheumatoid arthritis is hydroxychloroquine or sulfasalazine methotrexate is used for those with moderate to serious disease. Other DMARDs are used if these agents are poorly tolerated or do not produce suf-hcient response. Combination therapy of methotrexate and another agent is also used to treat disease that is not responsive to individual DMARDs. 

Methotrexate is approved for use in severe disabling psoriasis recalcitrant to other less toxic treatments. The standard regimen is similar to low-dose therapy used for the treatment of rheumatoid arthritis (see Chapter 36). Although toxicities are similar to those described in the treatment of other diseases, hepatic cirrhosis and unexpected pancytopenia are of special concern given the chronicity of treatment. 

Gerards AH et al Cyclosporine A monotherapy versus cyclosporine A and methotrexate combination therapy in patients with early rheumatoid arthritis A double blind randomised placebo controlled trial. Ann Rheum Dis 2003 62 291. [PMID 12634224]... 

A 43-year-old woman developed cavitary lung tuberculosis after she received methotrexate and glucocorticoid pulse therapy for rheumatoid arthritis (321). 

Penicillamine (Cuprimine), a derivative of penicillin, is officially classified as a chelating agent that is often used in the treatment of heavy metal intoxication (e.g., lead poisoning). In addition, this drug has been used in patients with severe rheumatoid arthritis, and seems to be as effective as other DMARDs such as methotrexate, sulfasalazine, and gold therapy.68 98 Penicillamine, however, tends to be substantially more toxic than other DMARDs, and is therefore used rarely in the treatment of specific patients with rheumatoid arthritis.68... 

In general, these drugs are more toxic and are usually reserved for patients who have not responded to more traditional DMARDs such as methotrexate. Drugs with immunosuppressant activity may also be used in combination with more traditional DMARDs to provide optimal benefits in certain patients. Combination drug therapy in rheumatoid arthritis is addressed in the next section. 

The disease-modifying agents used in rheumatoid arthritis are associated with a number of side effects that could influence rehabilitation. Some of these drugs, such as the gold compounds and methotrexate, may cause headache and nausea, which may be bothersome during the therapy session. Joint pain and swelling may also occur with drugs such as methotrexate and peni-... 

Morgan SL, et al. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm,low dose methotrexate therapy for rheumatoid arthritis implications for cardiovascular disease prevention. J Rheumatol 1998 25(3) 44l-446. 

Furst DE. Practical clinical pharmacology and drug interactions of low-dose methotrexate therapy in rheumatoid arthritis. Br J Rheumatol 1995 34(suppl 2) 20-25. 

Rau R, Schleusser B, Herborn G, Karger T. Longterm combination therapy of refractory and destructive rheumatoid arthritis with methotrexate (MTX) and intramuscular gold or other disease modifying antirheumatic drugs compared to MTX monotherapy. J Rheumatol 1998 25(8) 1485-92. 

A comprehensive review discusses the therapeutic management of RA (Turesson and Matteson, 2004). Epidemiological studies link extra-articular rheumatoid arthritis manifestations with premature mortality and support aggressive anti rheumatoid therapies for those patients. Cyclophosphamide is favored in patients with systemic rheumatoid vasculitis and methotrexate in those cases with other manifestations of extra-articular rheumatoid arthritis (Turesson and Matteson, 2004). Cyclophosphamide and TNFa inhibitors such as infliximab have some positive success in treatment resistant vasculitis associated with RA (Unger et al., 2003). However, TNFa inhibitors have also been associated with the opposite effect, an induction of extra articular rheumatoid arthritis so their use should be used only in specific cases when close monitoring is in place. 

Blanco R, Martinez-Taboada VM, Gonzalez-Gay MA, Armona J, Fernandez-Sueiro JL, Gonzalez-Vela MC, Rodriguez-Valverde V. Acute febrile toxic reaction in patients with refractory rheumatoid arthritis who are receiving combined therapy with methotrexate and azathioprine. Arthritis Rheum 1996 39(6) 1016-20. 

Tishler M, Caspi D, Fishel B, Yaron M. The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 1988 31(7) 906-8. 

Leflunomide has anti-inflammatory, immunosuppressive, and virustatic effects. Its efficacy has been demonstrated in patients with rheumatoid arthritis and psoriatic arthritis and other conditions in randomized, double-blind, placebo-controlled trials and other studies (8-32), and it was approved for treatment of adult rheumatoid arthritis in August 1998 (Table 1) (33). In three large phase III trials (US301, n = 482 MN301, n = 358 MN302, n = 999), leflunomide was as effective and well tolerated as methotrexate and sulfasalazine and superior to placebo (34). These data were confirmed by a meta-analysis (35,36). Leflunomide is therefore indicated for patients with rheumatoid arthritis who have failed first-line disease modifying anti-rheumatic drug therapy on the basis of efficacy, safety, and costs (36). It is effective as monotherapy and in combination with methotrexate or infliximab (6). 

Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, Luggen ME, Keystone E, Weisman MH, Bensen WM, Kaine JL, Ruderman EM, Coleman P, Curtis DL, Kopp EJ, Kantor SM, Waltuck J, Lindsley HB, Markenson JA, Strand V, Crawford B, Fernando I, Simpson K, Bathon JM. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002 137(9) 726-33. 

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