Rheumatoid arthritis

New review of MTX adverse events can inform patients when starting therapy


Gastrointestinal events remain the most commonly reported adverse events in patients starting methotrexate therapy for rheumatoid arthritis, according to a new review and pooled analysis. The analysis also identified several factors associated with treatment discontinuation and the risk of elevated liver enzymes.

“Identifying predictors of adverse events can help individualise therapy, promote adherence, and subsequently improve effectiveness,” wrote study authors led by Dr Suzanne Verstappen, of the University of Manchester, in Rheumatology. “The evidence of association is not always conclusive or consistent across studies and therefore, uncertainty exists regarding the predictors of these adverse events.”

The researchers also pointed out that previous studies of methotrexate toxicity were often limited to randomised controlled trial settings, leaving out real-world patient experience. Their new pooled analysis included 34 RCTs and 12 observational studies, encompassing 10,122 patients starting methotrexate either as monotherapy or in combination with other conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).

In the RCTs, the pooled prevalence of total adverse events was 80.1%, compared with only 23.1% in observational studies. However, more patients in observational studies discontinued methotrexate therapy due to adverse events (15.5%) compared to those in RCTs (6.7%).

The much higher incidence in RCTs is likely due to closer monitoring of adverse events in that setting, the authors wrote, and by higher adherence to therapy following stringent trial protocols.

The pooled prevalence of GI adverse events was 32.7%, with nausea reported as the most common such adverse event (19.0%). This was followed by abdominal pain (9.3%) and diarrhoea (8.0%). The pooled prevalence of elevated liver enzymes was 15.1%.

Other commonly reported adverse events included mucocutaneous adverse events in 24.7% of patients in RCTs, neurological adverse events in 24.7%, and pulmonary adverse events in 30.7%. The prevalence of pneumonitis/interstitial lung disease was only 0.09%, based on data from 11 RCTs.

“The pooled prevalence of alopecia was low (6.3%), potentially reducing patients’ concerns when starting methotrexate,” the authors noted.

Five studies (three RCTs and two observational studies) were used to examine predictors of adverse events and methotrexate discontinuation. In one study, rheumatoid factor positivity was found to be associated with a lower risk of methotrexate discontinuation due to adverse events , with a hazard ratio of 0.37 (95% CI, 0.21-0.64). Health Assessment Questionnaire score and female gender were associated with increased discontinuation risk. In another study, increased body mass index and decreased creatinine clearance were associated with a higher risk of discontinuation due to adverse events .

“Patients report that they do not receive enough information regarding adverse events from their rheumatologists, and the anxiety surrounding starting treatment might be lessened if patients had more information about the adverse events associated with methotrexate,” the authors wrote, adding that this could improve adherence to treatment.

“Identified predictors of MTX related adverse events may help to optimise drug therapy in patients likely to experience these adverse events early in the course of treatment, but the results of these predictors should be interpreted with caution and further research is required to investigate the predictors of adverse events .”

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