Oral methotrexate therapy was associated with significant reductions in knee osteoarthritis pain, stiffness, and functional impairment, compared with placebo at 6 months in the randomized, double-blind PROMOTE trial, Philip G. Conaghan, MD, PhD, reported at the OARSI 2019 World Congress.

Dr. Philip G. Conaghan, University of Leeds, England Bruce Jancin/MDedge News

Dr. Philip G. Conaghan

There is, however, an asterisk attached to these findings. “Despite a moderate standard effect size, the treatment effect was smaller than some of the thresholds for what is considered clinically meaningful,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.

That being said, the rheumatologist is convinced further investigation of methotrexate in osteoarthritis is warranted.

“I have to say that, unlike our earlier hydroxychloroquine trial, which was robustly negative with nothing more to say, I think there is a signal in this study. I need to understand the results of this trial better to understand if there is a subgroup we could treat with methotrexate. It’s a cheap drug, it’s readily available, and we’ve got a lot of experience with it,” noted Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.

The rationale for the 15-center PROMOTE trial is that synovitis is common in OA. Synovitis is associated with pain, methotrexate is the gold-standard treatment for synovitis in inflammatory forms of arthritis, and current treatments for OA are, to say the least, severely limited. Also, an earlier 30-patient, open-label pilot study of methotrexate in patients with painful knee OA conducted by Dr. Conaghan and coworkers suggested the drug was promising (Rheumatology [Oxford]. 2013 May;52[5]:888-92).

PROMOTE included 134 patients with symptomatic and radiographic knee OA who were randomized in double-blind fashion to 6 months of oral methotrexate at 10 mg titrated to a target dose of 25 mg/week or to placebo. All patients also received usual care with oral NSAIDs and/or acetaminophen. Their mean baseline knee pain on a 0-10 numeric rating scale was 6.6.

The primary endpoint, assessed at 6 months, was the difference between the two study arms in average knee pain during the previous week on a 0-10 scale. The score was 5.1 in the methotrexate group and 6.2 in the placebo arm, for a baseline-adjusted treatment difference of 0.83 points, which works out to a standard effect size of 0.36. When the data were reanalyzed after excluding the 15 patients who missed more than four doses of medication within any 3-month period, the between-group difference in pain scores increased to 0.95 points in favor of the methotrexate group.

A significant difference in favor of the methotrexate group was documented in the OARSI-OMERACT response rate at 6 months: 45% in the methotrexate group and 26% in the controls. Some secondary endpoints were positive as well, with statistically significant differences seen at 6 months in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness, WOMAC physical function, and several other endpoints. But there were no significant differences in WOMAC pain, SF-12 physical component or SF-12 mental component scores, or in an OA quality of life measure.

Differences between methotrexate, placebo groups at 6 months

The mean dose of methotrexate used in the study was about 17 mg/week. Dr. Conaghan said that if he could do the trial over again, he would have used subcutaneous methotrexate.

“It’s a more reliable way of getting a dose into people and probably of getting a slightly higher dose into people. In the rheumatoid arthritis world, we use a lot more subcutaneous methotrexate now than we did 10 years ago because it gets around a lot of the minor side effects and helps compliance,” he said.

One audience member suggested that one potentially useful way to zero in on a subgroup of knee OA patients likely to derive the most benefit from methotrexate would be to have screened potential study participants for comorbid fibromyalgia and exclude those with the disorder. Dr. Conaghan replied that the PROMOTE investigators did gather data on participants’ pain at sites other than the knee. That data can be used to identify those at increased likelihood of fibromyalgia, and he agreed that’s worth looking into.

Dr. Conaghan reported having no financial conflicts regarding PROMOTE, which was funded by the U.K. National Institute for Health Research and Versus Arthritis.

SOURCE: Conaghan PG et al. OARSI 2019, Abstract 86.