ROME — Methotrexate-induced gastrointestinal side effects in juvenile idiopathic arthritis patients are extremely common—and even more so with parenteral than with oral therapy, suggesting the nausea has a psychological basis that might be amenable to cognitive-behavioral therapy, according to findings of a Dutch study.
“This was a surprise. In daily practice, many doctors say that if you're intolerant to an oral medication and there's a subcutaneous alternative, you switch to subcutaneous, of course. And we did. And we found the methotrexate intolerance score was higher in the subcutaneous than [in] the oral group,” Dr. Nico M. Wulffraat said. Methotrexate intolerance was unrelated to the drug dose, disease activity or duration, JIA subtype, or treatment duration. The only predictor in this study was the route of administration.
Hepatotoxicity and hematologic abnormalities are the methotrexate side effects most physicians are preoccupied with, even though they occur in only a minority of pediatric patients and are often mild and transient.
In contrast, GI side effects (chiefly nausea and vomiting) were a significant problem for 55% of the 283 JIA patients in the study. The rate was 50% among those on oral therapy and 69% in youths on injectable methotrexate, reported Dr. Wulffraat, a pediatric rheumatologist at Wilhelmina Children's Hospital in Utrecht, the Netherlands.
“This is very clinically relevant. In a large proportion of patients these side effects end in early discontinuation of otherwise effective therapy,” he observed. “There is a lot of refusal to take the medication among our small children. And many schoolchildren say their weekends are ruined. That's because most boys and girls take the drug on Fridays, knowing they're going to feel bad for several days, and they don't want it to affect school.”
These pervasive GI symptoms in JIA patients are best viewed as a psychological side effect of methotrexate. Anticipatory nausea and anxiety figure prominently in the clinical picture. And the fact that the symptoms occur so frequently with parenteral therapy argues against direct mucosal toxicity as the mechanism.
Asked if early introduction of antiemetic agents in conjunction with methotrexate helps curb the GI side effects, Dr. Wulffraat explained that although pediatric oncologists routinely use this strategy when prescribing nausea-inducing chemotherapeutic agents, he hasn't found it effective in the setting of methotrexate for JIA.
However, based on a favorable pilot study he and his coworkers conducted (Clin. Exp. Rheumatol. 2007;25:480-5), Dr. Wulffraat and coinvestigators have launched an ongoing, large, multicenter, randomized clinical trial in which Dutch and German methotrexate-treated JIA patients with anticipatory nausea are being randomized to one of three study arms: continuation on methotrexate as before, switching the route of administration, or continuing the medication while receiving cognitive-behavioral therapy. The goal is to establish whether psychotherapy can help patients with JIA stay on this effective, cheap, and safe drug.
Disclosures: The study is funded by the Dutch League Against Rheumatism and Medac, a German manufacturer of methotrexate. Dr. Wulffraat reported having no conflicts of interest.
These side effects can end in an early discontinuation of otherwise effective therapy.
Source DR. WULFFRAAT