Methotrexate Side Effects, Intolerance Common in Arthritis Patients

January 03, 2014

By Will Boggs MD

NEW YORK (Reuters Health) Jan 03 - Rheumatoid arthritis and psoriatic arthritis patients commonly develop gastrointestinal side effects and intolerance to methotrexate therapy, researchers from the Netherlands report.

Methotrexate is the first-choice disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA) and psoriatic arthritis (PsA) due to its low cost, efficacy, and safety profile. But gastrointestinal adverse effects can lead to its discontinuation in up to 12% of patients after six months to two years of treatment, the researchers note in Arthritis Research & Therapy, online December 18.

Dr. Maja Bulatovic Calasan from University Medical Center, Wilhelmina Children's Hospital in Utrecht and colleagues used the Methotrexate Intolerance Severity Score (MISS) -- previously validated in juvenile idiopathic arthritis patients -- to determine the prevalence of methotrexate intolerance in a cross-sectional study of 291 RA/PsA patients. The patients had low-to-moderate DAS-28 and were treated with methotrexate for at least three months.

The researchers defined methotrexate intolerance as having an MISS of at least 6 points, including at least one anticipatory, associative, or behavioral symptom.

Gastrointestinal symptoms emerged during methotrexate treatment in 123 (42.3%) of the patients, with nausea affecting 32.0%, abdominal pain 11.3% and vomiting 6.5%, the teams reports.

Nearly one in 10 patients (8.6%) developed nausea in anticipation of treatment, and 11.0% had nausea even when thinking about the drug.

Behavioral symptoms were common, with 13.1% reporting restlessness, 10.0% reporting irritability, and 4.5% refusing to take the medication.

Overall, 32 patients (11.0%) met criteria for methotrexate intolerance (median, 9 points), including 10.4% of RA patients and 14.3% of PsA patients.

The most common symptoms in the patients with methotrexate intolerance were anticipatory (56.3%) and associative (53.1%) nausea, followed by anticipatory (37.5%) and associative (34.4%) abdominal pain. One in six intolerant patients (15.6%) even had anticipatory vomiting, compared with none of the tolerant patients.

Most of these symptoms represent a classical conditioning response to physical symptoms after methotrexate, the authors say.

Methotrexate intolerance was significantly higher in patients receiving parenteral (20.6%) than in patients receiving oral (6.2%) methotrexate.

On multivariate analysis, older patients were less likely than younger patients to have methotrexate intolerance, whereas patients with higher physician's global assessment of disease activity and those receiving parenteral methotrexate were more likely than others to have methotrexate intolerance.

"As persisting methotrexate intolerance could have a negative impact on patients' quality of life and hamper the use of methotrexate, RA and PsA patients on methotrexate should be monitored with the MISS for early detection of methotrexate intolerance," the authors conclude. "This would create a window of opportunity to intervene timely and avoid incompliance and discontinuation of an otherwise efficacious treatment."

Dr. Clive A. Kelly from Gateshead Health in the UK has studied the use of methotrexate extensively. He told Reuters Health that methotrexate intolerance might be reduced by regular folic acid before and after methotrexate and by using split doses 12 hours apart.

"Subcutaneous therapy is often tolerated if oral therapy isn't," he told Reuters Health by email, urging doctors to "explore patients' wishes and choose a solution for them, with them."

Dr. Calasan did not respond to a request for comments.


Arthr Res Ther 2013.


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