More than half of juvenile idiopathic arthritis (JIA) patients treated with methotrexate monotherapy stop taking it for a variety of reasons two years after beginning treatment, and about a third experience one or more adverse reactions, a study shows.

Most of these adverse reactions were related to gastrointestinal problems, which then caused some of these patients to discontinue the treatment. A majority of patients who stopped taking the medication did so because it proved ineffective.

These findings show that to guide treatment decisions and management planning, it is critical to predict juvenile arthritis patients who will respond to methotrexate monotherapy and who will experience adverse reactions.

The study, “Methotrexate persistence and adverse drug reactions in patients with juvenile idiopathic arthritis,” was published in the journal Rheumatology.

Methotrexate monotherapy is the current recommended first-line treatment for JIA. This conventional synthetic disease-modifying anti-rheumatic medication is an effective treatment with a good safety profile.

Still, it is estimated that up to a third of JIA patients do not respond to methotrexate treatment, and still others cannot tolerate the medication. Intolerance and nausea with methotrexate monotherapy have been repeatedly reported, occurring in up to nearly 3 in 4 treated patients.

Treatment persistence is a good proxy for treatment effectiveness and tolerance. The occurrence of adverse reactions to treatment can influence therapy continuation. Even so, data on how long patients remain on methotrexate therapy are sparse and variable.

Researchers from the University of Manchester wanted to gain a better understanding on how long JIA patients stayed on methotrexate monotherapy and the occurrence of and factors associated with adverse reactions to the treatment. To do so, they took advantage of two of the largest prospective observational studies of children and young people with JIA receiving methotrexate therapy in the U.K.

In total, 577 patients took part in the study, of whom 68% were female. The median age at methotrexate treatment start was 9 years old, median disease duration was less than one year, and median therapy persistence was approximately one year.

Within two years of starting treatment, 310 (54%) patients were no longer receiving methotrexate monotherapy. Reasons for methotrexate monotherapy discontinuation reported by the physicians included:

• treatment ineffectiveness (60%), usually leading to biologic therapy supplementation (52%)
• an adverse event (25%)
• remission (8%)
• patient or family decision (3%)

During the first two years of follow-up, about a third of the participants experienced at least one adverse reaction on methotrexate monotherapy. The first adverse reaction to treatment generally occurred at a little more than half a year (0.6 years) after starting treatment.

Of the patients with an adverse reaction to methotrexate treatment, most had an adverse reaction from one category (84%) and the remaining had an adverse reaction from two (15%) except for three patients who had an adverse reaction from three or more categories. Most patients with at least one adverse reaction had:

• gastrointestinal problems (68%), mostly nausea and vomiting
• elevated liver enzymes (26%)
• rash (10%)
• psychological symptoms (3%; mostly anxiety)
• hypersensitivity to methotrexate treatment (2%)

Importantly, about 1 in 6 of those with gastrointestinal problems permanently discontinued methotrexate monotherapy. Gastrointestinal adverse reactions were less likely in patients with polyarticular rheumatoid factor positive JIA (defined by the presence of more than four affected joints during the first six months of the disease) than in polyarticular rheumatoid factor negative JIA participants and those with a higher physician global assessment of disease activity at the start of methotrexate therapy.

When analyzing only participants with gastrointestinal adverse reactions, the researchers found that the likelihood of gastrointestinal adverse reactions could be predicted by the patient’s age at the start of methotrexate treatment. The likelihood that a patient would experience a gastrointestinal adverse reaction increased by 10% with every year of age.

“This supports the opinion that methotrexate is considered an effective and safe first-line [disease-modifying antirheumatic] treatment for patients with JIA,” the researchers wrote.

However, further studies are needed to investigate the potential for simultaneous treatments with methotrexate monotherapy and to predict the likelihood of experiencing an adverse reaction.

“As clinical factors alone cannot fully predict the occurrence of adverse [methotrexate treatment] reactions, further biological studies, including genetic markers, should be undertaken to continue to search for predictors of adverse methotrexate [treatment] effects,” the team concluded.