The disease-modifying anti-rheumatic drug methotrexate, the first line of defense against rheumatoid arthritis symptoms, is administered as a weekly pill or a shot. Many patients find it helps keep their symptoms under control for years, but up to a quarter may discontinue taking methotrexate within the first year. A new study, published in Arthritis Research & Therapy, examines the reasons oral methotrexate may fail for those patients.

Between 2000 and 2008, Suzanne Verstappen, of University of Manchester, and colleagues studied 431 early inflammatory polyarthritis patients — meaning the disease impacted at least five joints — from the UK-based Norfolk Arthritis Register. If the drug failed, patients self-reported whether it was due to “adverse event,” “inefficacy,” or another reason.

The researchers found that younger patients, as well as those whose disease was more active, were likelier to stop taking methotrexate due to ineffectiveness. “Such patients may require combination therapy as a first-line treatment,” the researchers write.

In the study, 82 percent of the polyarthritis patients remained on methotrexate after two years. At the five-year mark, 72 percent were still taking the drug. The rest of the patients — the 18 and 28 percents respectively — either switched to another disease-modifying anti-rheumatic drug or added a second DMARD.

Prior studies associated factors, such as female gender, smoking histories, and longer duration of the disease, with methotrexate’s ineffectiveness. There was a need for a new study, the scholars write, as previous research examined patients before the year 2,000, but not after. In the past decade, a “treat to target” approach to rheumatoid arthritis, combining methotrexate with other therapies, has become more popular.

“Knowledge of predictors of methotrexate failure should enable early identification of individuals who are at increased risk of methotrexate inefficacy or adverse events and appropriate adjustment in treatment,” the authors write.