Methotrexate rheumatoid arthritis

Low-dose methotrexate is used for treatment of rheumatoid arthritis despite side effects such as disorders of the gastrointestinal tract and the liver. Leflunomide is also approved for this indication, however, hepatoxicity limits its use as first option. 

Adalimumab (Humira ) is a folly human anti-TNF monoclonal antibody that is mainly used in combination with methotrexate to treat rheumatoid arthritis in adults [3]. Meanwhile, it is also used against arthritis of psoriasis and ankylosing spondylitis. Its therapeutic value in Crohn s disease is under clinical trial. 

The miscellaneous drugp are used to treat a variety of musculoskeletal disorders. Ffenicillamine, methotrexate (MTX), and hydroxychloroquine are used to treat rheumatoid arthritis in patients who have had an insufficient therapeutic response to or are intolerant of other antirheumatic drugp such as the sailcylates and NSAIDs. The Summary Drug Table Drug s Used to Tream Musculoskeletal Disorders provides additional information about these and other drug s. One compound, hylan G-F 20, listed in the Summary Drug Table is not used for rheumatoid arthritis, but rather, for osteoarthritis knee pain. It is a viscous, elastic... 

Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001 344( 12) 907—916. Cronstein BN. Low-dose methotrexate A mainstay in the treatment of rheumatoid arthritis. Pharmcol Rev 2005 57(2) 163—172. 

The answer is c. (Katzung, pp 608-609, 932-9.13.) Methotrexate is classified as an anti metabolite with therapeutic uses in cancer chemotherapy and as an immunosuppressive agent indicated in the treatment of severe active classical rheumatoid arthritis. Leucovorin is related to methotrexate in that it is an antagonist of its actions. It can supply a source of reduced folate for the methylation reactions that are prevented by methotrexate. 

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

In a Phase la study in healthy volunteers, ARRY-438162 was well tolerated up to 20mg/kg q.d. oral dose. There was a dose proportional increase in plasma concentration and decrease in the production of IL-1 ft, TNFa, IL-6 and pERK in the ex-vivo-stimulated whole blood from drug treated volunteers. Array has initiated a Phase lb study of ARRY-438162 in combination with methotrexate in rheumatoid arthritis patients with the goals of assessing safety, tolerability, pharmacokinetics (PK), biomarkers and initial signs of efficacy. 

Kremer, I.M., and Phelps, C.T. (1992) Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 mo. Arthritis and Rheumatism. 35, 138-145. 

Strand, V., Cohen, S., Schiff, M., et al. (1999) Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Archives of Internal Medicine. 159, 2542-2550. 

Bathon, J.M., Martin, R.W., Fleischmann, R.M., et al. (2001) A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. New England Journal of Medicine. 343,1586-1593. 

Dervieux, T., Lein, D.O., Park, G., et al. (2003) Single nucleotide polymorphisms in the folate/ purine synthesis pathway predict methotrexate s effects in rheumatoid arthritis [abstract]. Arthritis and Rheumatism. 48(suppl. 9), S438. 

Haagsma, C. J., Blom, H. J., van Riel, P. L., et al. (1999) Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 58, 79-84. 

Berkun, Y., Levartovsky, D., Rubinow, A., et al. (2004) Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Annals of the Rheumatic Diseases. 63, 227-231. 

Urano, W., Taniguchi, A., Yamanaka, H., et al. (2002) Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics. 12, 183-190. 

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. 

Wessels, J. A., de Vries-Bouwstra, J. K., Heijmans, B. T., et al. (2006) Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis ami Rheumatism. 54,1087-1095. 

Maini, R. N., Breedveld, E. C., Kalden, J. R., et al. (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis and Rheumatism. 41, 1552-1563. 

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. 

Ranganathan, P., Culverhouse, R., Marsh, S., et al. (2004) Single nucleotide polymorphism profiling across the methotrexate pathway in normal subjects and patients with rheumatoid arthritis. Pharmacogenomics. 5, 559-569. 

For rheumatoid arthritis, the pharmacogenomics of three major diseasemodifying antirhenmatic drags (methotrexate, azathioprine, and sulfasalazine) and one class of biologic antirhenmatic drags (the tumor necrosis factor antagonists) are discnssed in detail. 

The first-line agents in the treatment of rheumatoid arthritis are non-steroidal anti-inflammatory drugs such as diclofenac. Diclofenac and indometacin, another NSAID, tend to have similar activity hov/ever, indometacin has a higher incidence of side-effects and therefore diclofenac is more appropriate for initial treatment. Sodium aurothiomalate is classified as a disease-modifying antirheumatic drug and is used as a second-line treatment in rheumatoid arthritis, but has been superseded by methotrexate, administered v/eekly. Paracetamol is often indicated in the management of osteoarthritis. Local intra-articular injections of dexamethasone may be administered for the relief of soft-tissue inflammatory conditions. 

Presumably, any cytotoxic substance that destroys bone marrow and lymphoid tissue may be used as an immunosuppressant. Among these drugs, the most widely used primarily for autoimmune diseases are vincristine, methotrexate, and cytarabine. However, their use should be considered experimental. Only methotrexate is seriously and sufficiently recognized as an initial drug for treating rheumatoid arthritis. 

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. 

Rheumatoid arthritis (RA moderate to severe) In combination with methotrexate for reducing the signs and symptoms and inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA who have had an inadequate response to methotrexate. 

Leflunomide is an immunomodulatory dmg inhibiting dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine synthesis. It has also anti-inflammatory effects. Leflunomide is able to slow progression of the disease and to cause re-mission/relief of symptoms of rheumatoid arthritis and psoriatic arthritis such as joint tenderness and decreased joint and general mobility in patients. The combined use of leflunomide with methotrexate may... 

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