Methotrexate, one of the first drugs developed based on a specific chemical structure, turns out to have many different uses aside from that for which it was designed, treatment of cancer and related malignancies. A variety of pharmacologic actions explain the effects of methotrexate on RA and other inflammatory diseases, but the action for which there is the greatest amount of evidence is the promotion of adenosine release, which mediates the antiinflammatory effects of low-dose methotrexate via adenosine receptors.
Practice Implications for Methotrexate Use
The role of adenosine and its receptors in the actions of methotrexate suggests that ingestion of caffeine, an adenosine receptor antagonist, should be reduced or avoided in treating patients with RA. As noted previously, prospective studies demonstrate that caffeine ingestion diminishes the likelihood that methotrexate will be efficacious for the treatment of RA. In these studies, the effect of caffeine on the response to methotrexate was modest due, most likely, to caffeine’s relatively low affinity for adenosine receptors and its highly variable metabolism. Indeed, a large retrospective study of patients who had been on methotrexate for more than two years failed to show an effect of caffeine ingestion on the response to methotrexate.23 It should be noted that, in this study, many of the patients who experienced a poor response to methotrexate may have already been prescribed other therapies for their RA by the time the study was performed; this situation could have led to an enrichment of caffeine unresponsive patients in the cohort of patients studied.
The implication of these studies is that if patients with RA achieve a good response to methotrexate despite continued caffeine ingestion, there is no reason to stop their usage of coffee or caffeine-containing soft drinks; however, if the patients are not responding to methotrexate, it might be useful (if the patients tolerate it) to try abstaining from caffeine use for several weeks before adding another antirheumatic agent.
As has been well documented, the bioavailability of methotrexate diminishes at higher doses of the drug, a phenomenon most likely due to the fact that methotrexate is taken up from the gut by saturable transporters, which may be affected by luminal pH and other factors.24,25 In contrast, administration of either split dose or subcutaneous methotrexate leads to more reliable bioavailability of high doses of the drug; thus, for those patients who require higher doses of methotrexate to manage their RA, splitting oral doses of methotrexate or administering the drug subcutaneously might enhance patient responses to the drug.26-28
Acknowledgments
This work was supported by grants from the National Institutes of Health (AR56672, AR56672S1, and AR54897), the NYU-HHC Clinical and Translational Science Institute (UL1RR029893), and the Vilcek Foundation.
