Efforts to delay or prevent rheumatoid arthritis (RA) in individuals at high risk for the disease received a boost from the findings of a subgroup analysis of an older Dutch prevention trial involving methotrexate that were published recently in Arthritis & Rheumatology.

However, while the 22-patient subgroup analysis of the 2007 trial, called PROMPT (Probable RA: Methotrexate Versus Placebo Treatment), showed that 1 year of methotrexate prevented the development of rheumatoid arthritis in significantly more individuals at high risk for the disease than did placebo, hindsight has shown that most of these high-risk individuals actually had RA at baseline as defined by the 2010 American College or Rheumatology/European League Against Rheumatism classification criteria.

These new findings still show, however, the importance of risk stratification in future prevention efforts and solidify the evidence for the transition to earlier diagnosis and more aggressive treatment, said Jeffrey Sparks, MD, a rheumatologist at Brigham and Women’s Hospital, Boston, who was not involved in the study.

Even though the “landscape of RA has changed since this study was conceived, enrolled, and performed,” Dr. Sparks noted that the study provides evidence that today’s “standard of care really works” by making use of data that are unobtainable today.

“Nowadays, we wouldn’t be able to do a placebo-controlled trial in early RA because those patients need to be treated, but at the time, it was perfectly fine, based on the treatment landscape, to put these patients in a [placebo-controlled] trial,” he said in an interview.

“It also demonstrates that you really need to find high-risk individuals, because, if you recruit people who are never going to develop RA, you’re just diluting your effect, and you’re not going to find the difference in the groups based on that diluted effect when there could be a true effect in that special subgroup,” he added.

Senior study author Annette van der Helm-van Mil, MD, PhD, and her colleagues at Leiden (the Netherlands) University Medical Center performed the reanalysis after the initial finding that methotrexate had no preventative effect may have been falsely negative because the study included patients with a low risk of progressing to RA (Arthritis Rheumatol. 2017 Feb 19. doi: 10.1002/art.40062).

The research team said the initial results of the PROMPT trial showed that intervention with 1 year of 15 mg/week methotrexate in the “early period” of RA may result in longer-term benefits, particularly in patients who were anticitrullinated protein antibody (ACPA)–positive, but a 5-year follow-up study involving the same cohort and published in 2012 concluded methotrexate had no preventive effect on RA development.

In the reanalysis, the investigators defined 22 out of the trial’s 110 participants as high risk based on their score of 8 or higher on the Leiden prediction rule at baseline. Of those 22, 18 also fulfilled the 2010 classification criteria for RA.

This “definition of high risk [in the trial] very much coincided with the new classification criteria and reinforces the standard of care that patients with new diagnosed RA should be treated with DMARDs [disease-modifying antirheumatic drugs] front line,” Dr. Sparks said.

The Leiden prediction rule score is based on ACPA statuses, as well as age, sex, distribution of involved joints, number of swollen and tender joints, severity of morning stiffness, C-reactive protein level, and rheumatoid factor. In previous studies of patients with undifferentiated arthritis, a score of 8 or higher with the prediction rule had a positive predictive value of 84% in patients with undifferentiated arthritis, according to the investigators.

Based on a primary outcome of fulfilling the 1987 classification criteria for RA after 5 years of follow-up, the investigators found that 6 of 11 (55%) in the methotrexate arm developed RA, compared with all 11 patients in the placebo arm (P = .011). “A 1-year course of methotrexate was associated with an absolute risk reduction of 45% on RA development, resulting in a number needed to treat of 2.2 (95% [confidence interval], 1.3-6.2),” the authors wrote.

Furthermore, the time to the development of RA based on the 1987 criteria was longer with methotrexate than with placebo (median of 22.5 months vs. 3 months; P less than .001).

Drug-free remission was also achieved by 4 of 11 (36%) patients taking methotrexate, compared with none of the patients taking placebo (P = .027).

The beneficial effects of methotrexate were seen in ACPA-positive and ACPA-negative high-risk patients but not in patients without a high risk of RA.

For the patients who did not fulfill the 2010 RA criteria at baseline, only one of four of those in the placebo arm did go on to develop RA based on 1987 criteria, whereas only one of three who received methotrexate did.

Overall, the reanalysis of PROMPT trial data illustrates how “noninformative inclusions can blur highly relevant study outcomes, such as prevention of RA,” the study authors concluded.

“As trials are now being conducted to evaluate the efficacy of treatment initiated in the phase of arthralgia, the development of adequate risk prediction models are of importance in order to prevent false-negative study results in the future,” they added.

The PROMPT trial was supported by the Dutch Arthritis Foundation and the Netherlands Organisation for Scientific Research.

Methotrexate use justified for early RA, disease prevention