Concomitant Prednisone Could Limit Methotrexate Side Effects in RA

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The addition of low-to-moderate doses of prednisone to methotrexate therapy in patients with rheumatoid arthritis (RA) has the potential to significantly lessen side effects associated with methotrexate, a new study suggests.

The findings could mean patients are able to stay on methotrexate longer and on higher doses.

“This might specifically be of interest in patients where the maximum MTX (methotrexate) dose is limited by side-effects, given that prednisone is tolerated well, and other measures to reduce side-effects (such as subcutaneous administration or addition of folic acid) have insufficient effect,” wrote corresponding author Matthijs S. van der Leeuw, M.Sc., of the University Medical Center Utrecht in the Netherlands, and colleagues.

The results could also have implications for payers. Both methotrexate and prednisone are available in generic form. If the combination of the two allows patients to stay on methotrexate longer, it could delay the need for such patients to use higher-cost disease-modifying anti-rheumatic drugs (DMARDs). The report was published in the journal BMC Rheumatology.

Methotrexate is the first-line treatment for most patients with RA, but van der Leeuw and colleagues said patients are typically given a disease-modifying anti-rheumatic drug (DMARD) in addition to methotrexate if they do not achieve remission, or if their remission reverses.

Yet, despite being the “anchor” of RA treatment, van der Leeuw and colleagues said methotrexate comes with significant side effects, including nausea, vomiting, abdominal pain, elevated liver enzymes, loss of appetite and ulcers of the digestive tract. Between 10% to 37% of patients eventually discontinue methotrexate treatment as a result of side effects, previous research has shown.

The CAMERA-II trial, which was published in 2020, showed that adding prednisone to methotrexate led to reduced disease activity and radiographic progression, compared to adding placebo. In addition, the data also seemed to indicate that prednisone might also decrease rates of common methotrexate side effects.

But van der Leeuw and colleagues said the dynamic dosing of methotrexate in that study made it difficult to draw clear conclusions about whether it was prednisone — or factors such as dosing —that decreased side effects.

In search of clearer understanding, van der Leeuw and colleagues re-examined the study’s data, conducting a post-hoc analysis to figure out if prednisone could be credited with reducing side effects.

The investigators used an estimation model to calculate the occurrence of common methotrexate side effects over time, controlling for disease activity, dosage and other possible causes of adverse events.

They also compared those results to a similar study that found adding Actemra (tocilizumab) to methotrexate reduced side effects. The latter analysis was designed to see whether any effect was specific to prednisone.

The analysis showed that prednisone significantly reduced the risk of methotrexate side effects. Adding prednisone led to an odds ratio for side effects of 0.54 (95% confidence interval [CI] 0.38-0.77; p=0.001). In particular, they said prednisone decreased the risk of nausea and elevated alanine transaminase (ALT)/aspartate transaminase (AST).

In the analysis of the earlier Actemra study, the investigators found no difference in side effects between the tocilizumab-methotrexate arm and the methotrexate monotherapy arm. They added that the mean dose of methotrexate used in the CAMERA-II trial was higher than the mean dose in the tocilizumab study, suggesting prednisone allowed for higher methotrexate dosing.

The exact reasons why prednisone seems to alleviate side effects is unknown, but one possibility, the authors said, is that methotrexate, “induces a low-grade inflammatory response in the liver, leading to elevation of liver enzymes which can be inhibited by prednisone, but not by tocilizumab.”

Van der Leeuw and colleagues said it is also unclear what the long-term implications of concomitant methotrexate and prednisone might be. For instance, they said it is not known whether physicians could taper prednisone at a certain point, or whether low-to-moderate doses of prednisone would be needed indefinitely. If they are latter, they said, “the protective effect of prednisone should of course be weighed against its possible long-term toxicity and comorbidity, which remains a topic of discussion and has been extensively reviewed by others.”