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Factors that predicted failure of methotrexate therapy among patients with inflammatory polyarthritis included younger age and more active disease, a U.K. registry study found.

In a multivariate analysis of 431 patients enrolled from 2000 to 2008 in the , those who were younger at the time of symptom onset (age 50 versus 58) were more likely to have stopped methotrexate because of a lack of efficacy (HR 0.97, 95% CI 0.96-0.99, P<0.001), according to Suzanne M.M. Verstappen, PhD, of the University of Manchester, and colleagues.

In addition, early failure because of a lack of efficacy was more likely among those with higher Disease Activity Scores in 28 joints at baseline (4.37 versus 3.82, HR 1.23, 95% CI 1.05-1.43, P=0.008), the researchers reported online in .

Currently, methotrexate is the first choice among disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis, but not all patients respond or tolerate the drug, and time spent on an ineffective medication may provide a window of opportunity for joint destruction to occur.

Previous studies looking for factors that helped predict success with methotrexate have had conflicting results, with only some suggesting that baseline disease activity was predictive, and others finding that baseline functional status, shared epitope positivity, and smoking were associated with lack of efficacy. In addition, most of the studies investigating methotrexate failure were conducted before 2000, so there is a need for up-to-date "real-world" information to help guide treatment choices in today's treat-to-target milieu.

Accordingly, to investigate the rates of stopping methotrexate treatment, the reasons why, and contributory factors, Verstappen and colleagues analyzed data from a primary care inception cohort of patients with early inflammatory polyarthritis who were starting their first DMARD. Patients who went on to receive a second DMARD were considered efficacy failures.

During 1,608 patient-years of follow-up, 16% of patients stopped their methotrexate because of adverse events, and 33%, because of a lack of efficacy.

The most common adverse events leading to treatment failure involved the gut, in 37% of patients.

Among patients who added or switched to a second DMARD, the median time to the change was 514 days.

On multivariate analysis an additional predictor was being rheumatoid factor positive, which was protective against early methotrexate failure because of an adverse event, but was independently associated with failure because of a lack of efficacy after considering the competing risks (HR 0.34, 95% CI 0.20-0.59, P<0.001).

In a Kaplan-Meier analysis, the probabilities of continuing on methotrexate treatment at years 2 and 5 were 82% (95% CI 0.79-0.86) and 72% (95% CI 0.67-0.76), respectively.

In a subgroup analysis of patients who fulfilled the criteria of the American College of Rheumatology and the European League Against Rheumatism for rheumatoid arthritis, the probability of remaining on methotrexate at years 2 and 5 was higher, at 85% and 77%, respectively.

These methotrexate survival rates were higher than what has been seen in previous studies. In , the 5-year survival rate of those on methotrexate was only 45%, although this cohort included individuals who had previously not responded to other DMARDs. And in , the 5-year probability of remaining on methotrexate was 57.1%.

In addition, in Stockholm also found that younger patients were less likely to respond to methotrexate, similar to what was observed in the current study.

"It is not clear whether younger patients are genuinely less responsive to methotrexate or whether they are more likely than older patients to move onto combination DMARD therapy in order to achieve complete control of disease activity," Verstappen and colleagues wrote.

Female sex was associated with methotrexate failure in the univariate analysis and trended toward significance in the multivariate model. Possible explanations for this, the researchers said, included the influence of hormonal factors on methotrexate metabolism and differences between men and women in disease activity and pain processing.

The authors concluded that patients exhibiting the factors identified as being associated with methotrexate failure may benefit from combination therapy as first-line treatment.

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