Abstract
Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review, we examine multiple hypotheses to explain the mechanism of methotrexate efficacy in RA. These include folate antagonism, adenosine signaling, generation of reactive oxygen species (ROS), decrease in adhesion molecules, alteration of cytokine profiles, and polyamine inhibition amongst some others. Currently, adenosine signaling is probably the most widely accepted explanation for the methotrexate mechanism in RA given that methotrexate increases adenosine levels and on engagement of adenosine with its extracellular receptors an intracellular cascade is activated promoting an overall anti-inflammatory state. In addition to these hypotheses, we examine the mechanism of methotrexate in RA from the perspective of its adverse effects and consider some of the newer genetic markers of methotrexate efficacy and toxicity in RA. Lastly, we briefly discuss the mechanism of additive methotrexate in the setting of TNF-α inhibitor treatment of RA. Ultimately, finding a clear explanation for the pathway and mechanism leading to methotrexate efficacy in RA, there may be a way to formulate more potent therapies with fewer side effects.
Highlights
There has been development of numerous new targeted therapies for rheumatoid arthritis (RA) in recent years, methotrexate has remained the “anchor drug” for most patients since the late 1980s [1]
One study found that a particular missense SNP in aminoimidazole-4carboxamide ribonucleotide (AICAR) transformylase (ATIC) was a significant predictor of methotrexate response whereas there were no significant differences in SNPs found in dihydrofolate reductase (DHFR) and folylpolyglutamate synthase (FPGS) genes [48]
In studies of adalimumab plus methotrexate treatment, authors have found that development of anti-drug antibodies against the anti-TNFs were significantly reduced with addition of methotrexate along with improved efficacy of therapy [53, 55, 56]
Summary
There has been development of numerous new targeted therapies for rheumatoid arthritis (RA) in recent years, methotrexate has remained the “anchor drug” for most patients since the late 1980s [1]. The efficacy of low doses of methotrexate used in RA patients is unaffected by the administration of folic acid and it is almost invariably part of the RA medication regimen to minimize the unwanted methotrexate side effects [4] This indicates that inhibition of purine metabolism is unlikely to be the major mechanism of methotrexate in RA and that another element must be accounting for efficacy of methotrexate in RA patients. Methotrexate in RA is usually effective at doses ranging from 15–25mg and it is often initiated as monotherapy It can be used with other disease modifying anti-rheumatic drugs (DMARDs) such as hydroxychloroquine and sulfasalazine. It is thought that the polyglutamated form of methotrexate is responsible for its DMARD activity and the following sections will highlight some of the different hypotheses regarding the methotrexate mechanism with variable amounts of evidence
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