Toward a better understanding of methotrexate.

More is known about the metabolism, toxicity, pharmacokinetics, and clinical profile of methotrexate (MTX) than any other drug currently in use in either rheumatology or oncology. In the 56 years since Farber et al first described clinical remissions in children with acute leukemia after treatment with the folate antagonist aminopterin (1), antifolate drugs, dominated by MTX, have been used to treat millions of patients with malignant and autoimmune diseases. It is estimated that MTX is now prescribed to at least 500,000 patients with rheumatoid arthritis (RA) worldwide, making it by far the most commonly used disease-modifying antirheumatic drug (DMARD). Indeed, MTX is prescribed for more patients with RA than are all of the biologic drugs in current use combined. It is the most commonly studied and prescribed agent used in combination with other DMARDs, where clear additive therapeutic value is demonstrated (2–8). In spite of our collective experience and success with MTX in the last 20 years, the overall level of sophistication regarding the many issues and complexities associated with its use is surprisingly thin. Dogma about maximum weekly dosages, use in the elderly, monitoring with blood tests, and when to “give up” and add other agents to an MTX regimen is often invoked without rigorous scientific support. A sound understanding of the drug’s many cellular effects is sometimes viewed as irrelevant to its use for rheumatic disease. These behaviors and philosophies are understandable, since very busy clinicians often do not have the time or resources to research every nuanced publication describing the best way to conceptualize clinical decisions regarding the use of an agent such as MTX, which is supported by an enormous and often complex literature. It is the goal of this contribution to review the major and significant concepts regarding MTX metabolism which may be relevant to the treatment of rheumatic disease, not to summarize publications about its clinical effects. It will become apparent in the course of the discussion that most of what we know about the metabolism of MTX is derived from the oncology literature. Clinicians who have become familiar with the concepts presented should be better equipped to prescribe the drug in a more effective and rational manner. In addition, emerging insights into the role of naturally occurring genetic variations in cellular pathways of MTX metabolism hold promise for predicting both efficacy and toxicity of the drug. In spite of the real and perceived gaps in our understanding of the effects of MTX, at the time of this writing it remains a cornerstone for the treatment of RA and other rheumatic conditions, now and for the foreseeable future.