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Use of methotrexate in the treatment of rheumatoid arthritis

Joel M Kremer, MD
Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Deputy Editor
Paul L Romain, MD


Methotrexate (MTX) is a designer compound that was first used for the treatment of rheumatoid arthritis (RA) and psoriasis in 1951 [1]. It emerged at the same time as glucocorticoids, however, and received little attention in the therapy of rheumatic diseases until retrospective reports appeared in the early 1980s [2,3]. Short-term placebo-controlled prospective studies in the mid-1980s demonstrated its potent efficacy and superiority to placebo in patients with chronic severe RA, and long-term open prospective studies then showed that the response was sustained and that toxicity was manageable. These insights have led to the metamorphosis of MTX into its present status as the dominant slow-acting drug to treat patients with RA.

The pharmacology of MTX and its use in the treatment of RA will be reviewed here. MTX has also been used effectively in a variety of other mostly rheumatic diseases including ankylosing spondylitis, Felty's syndrome, inclusion body myositis, reactive arthritis, and granulomatosis with polyangiitis (Wegener's). These disorders, as well as the major side effects of MTX, are discussed separately. (See "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)


Methotrexate (MTX) can be given by oral, intramuscular, and subcutaneous routes. Oral MTX is variably absorbed in the dose range used to treat rheumatoid arthritis (RA). Serum levels of MTX consistently increase when the drug is administered parenterally, which is not the case for oral ingestion of doses of 15 mg or greater administered all at one time [4,5]. This difference in absorption may have therapeutic implications, as some patients may respond better to parenteral therapy, presumably because more drug reaches the circulation (see 'Parenteral therapy' below). This difference in drug levels between parenteral and oral administration may be more pronounced at higher doses within the usual therapeutic range.

As an example, a 7.5 mg weekly dose is absorbed better than a 15 to 20 mg dose [4]. Bioavailability (f) is defined as the ratio of oral drug absorption divided by intravenous drug absorption. Since f may drop off by a mean of 13.5 percent as the dose of MTX is increased from a starting dose of 7.5 mg to the typical maintenance weekly doses employed in RA, a patient may do better clinically when switched from oral (PO) to intramuscular (IM) or subcutaneous (SC) administration of the same dose of the drug (see 'Parenteral therapy' below). At a 17.5 to 20 mg weekly dose of MTX, for example, a 13.5 percent difference in f between the PO and IM routes of administration is equivalent to one full 2.5 mg MTX tablet. As the variation in the confidence intervals for the drop-off in f extends to 27 percent, selected patients may have an even greater difference in f between parenteral and oral dosing.

At higher doses, decreased bioavailability may be even more pronounced. This was illustrated in a pharmacokinetic analysis of 15 patients taking more than 25 mg/week of MTX (mean of 30 mg/week); the ratio of oral to subcutaneous absorption was decreased by approximately one-third [6].

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Literature review current through: Nov 2017. | This topic last updated: Nov 28, 2017.
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