Long-term Prospective Study Confirms Methotrexate Survival Advantage in RA

In a prospective study lasting a quarter century, the use of methotrexate was associated with increased lifespan for patients with rheumatoid arthritis (RA). This has been suggested often before, but the new report about methotrexate and RA resolves numerous questions arising from the "vast changes" in use of the medication for this condition over that period.

The study was initiated in the early 1980s by rheumatologist James Fries of Stanford University, and analyzed the relationship between functional status, medication use, and outcomes. It may lay to rest concerns that the apparent reduction in mortality risk could be due to the facts that:

♦  doctors were more likely to describe the drug to patients with more severe RA but fewer comorbidities, especially early on, and

♦  methotrexate is usually withdrawn some time before death, making the drug appear safer than it is.

Beginning in 1981, the study recruited patients diagnosed with RA from 10 North American rheumatology. Based on questionnaires mailed every 6 months and more careful followup in the case of death, investigators followed 5,626 patients for 25 years.

To adjust for selection bias that might skew mortality outcomes, the researchers calculated a propensity-to-treat score, a prediction based on clinical and demographic characteristics of how likely an individual was to receive the medication.

The results resoundingly confirm prior studies, finding methotrexate use for RA associated with a 70% reduction in mortality (or a mere 5% less after adjusting for the propensity to treat). The mortality risk  was not affected by likelihood to withdraw methotrexate shortly before death. The reduction in mortality risk set in only after about a year's duration, but did not change with long-term use.

It isn't clear whether this outcome is due to improvement in functional status, and whether it would also pertain to biological modifiers. In any case, it argues for adding other medications rather than switching away from methotrexate if monotherapy fails, say the authors, as the drug "may still carry a survival benefit."

The study was "completely innovative" for its time, said lead author Mary Chester Wasko MD of the Allegheny Singer Research Institute in Pittsburgh (who joined the team midway through the project). Electronic medical records may make this kind of analysis routine in the future, she observed, but this information is credited to extraordinary commitments from thousands of RA patients.