Oral methotrexate added to usual analgesia reduces pain, stiffness in knee osteoarthritis
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Key takeaways:
- Methotrexate plus usual analgesia significantly outperformed placebo in knee OA pain reduction at 6 months.
- The difference between treatments decreased over time and was similar at 12 months.
Oral methotrexate in combination with usual analgesics significantly reduced knee osteoarthritis pain and stiffness, and improved function, vs. placebo, according to data published in Annals of Internal Medicine.
“Current pharmacologic treatments for OA are limited by lack of efficacy,” Sarah R. Kingsbury, PhD, of the Leeds Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds, in the United Kingdom, and colleagues wrote.
“The disease-modifying anti-rheumatic drug methotrexate is the standard-of-care treatment of inflammatory arthritis,” she added. “Small clinical and experimental studies suggest that methotrexate could be a potential treatment for persons with [knee OA (KOA)] symptoms.”
To examine the effects of methotrexate on knee OA, Kingsbury and colleagues conducted a multicenter, randomized, double-blind, placebo-controlled trial. Across 15 U.K. secondary care musculoskeletal clinics, 207 adults with knee OA (mean age, 60.9 years) were randomly assigned to receive either oral methotrexate once weekly, with a 6-week escalation from 10 mg to 25 mg, or a matched placebo, while continuing their usual analgesia.
Eligible participants were those who demonstrated radiographic changes, reported knee pain on most days within the last 3 months, and had an inadequate response to their current medication. The primary endpoint was average past-week knee pain at 6 months, assessed with a zero-to-10 scale. The researchers assessed longer-term response at a 12-month follow-up visit.
According to the researchers, the methotrexate group demonstrated a statistically significant reduction in mean knee pain score at 6 months, from 6.4 (standard deviation [SD], 1.8) at baseline to 5.1 (SD, 2.32). Compared with placebo, methotrexate also yielded significantly better improvement in the Western Ontario and McMaster Universities Osteoarthritis Index stiffness (mean difference, 0.6 points; 95% CI, 0.01-1.18) and function (mean difference, 5.01; 95% CI, 1.29-8.74) scores at 6 months.
In terms of numerical pain score, methotrexate outperformed placebo at 6 months (mean difference, 0.79; 95% CI, 0.08-1.51). However, this difference decreased over time, and by 12 months the regimens appeared to perform similarly.
According to the researchers, the decreased benefit of methotrexate over time may be attributable to diminishing doses, higher loss to follow-up in the methotrexate group, or the confounding effect of background analgesic use.
“Oral methotrexate added to usual care showed statistically significant reduction in KOA pain, WOMAC stiffness and function, and a composite patient responder index,” Kingsbury and colleagues wrote. “Further work is required to understand adequate methotrexate dosing, whether benefits are greater in those with elevated systemic inflammation levels, and to consider cost effectiveness before introducing this therapy for a potentially large population.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Methotrexate, an antimetabolite cancer drug, has a long history in rheumatoid arthritis, although rheumatologists were somewhat hesitant at first to use a cancer drug in that disease.
It was used as a first-line treatment in RA only 10% of the time from 1980 to 1984, and then 26% of the time from 1985 to 1989. Its use first appeared in the literature in 1951, when Richard Gubner, MD, a cardiologist in Brooklyn, N.Y., reported the use of aminopterin, the precursor of methotrexate, in RA and psoriasis with good effect. This was an open-label trial and, surprisingly, there was no further interest in this compound or its successor for almost 30 years.
The first placebo-controlled trial of methotrexate in RA was reported by Michael Weinblatt, MD, and colleagues in the New England Journal of Medicine in 1985, preceded by a successful open-label trial in 1980 by Robert Willkens, MD, in Seattle. At that time, in the early 1980s, Ted Pincus, MD, related that severe RA had similar mortality to malignancy and three-vessel coronary disease. This context gave comfort to rheumatologists that aggressive treatment was needed — and methotrexate was reasonable and had been proven to work.
We now have this article about the use of methotrexate in symptomatic knee osteoarthritis and, again, rheumatologists will be hesitant to use it.
Pincus and colleagues published a 2019 article in Clinical and Experimental Rheumatology suggesting that OA is as severe as RA. This was based on studies use VAS Pain scales and HAQ scores. Similar levels of disability and earnings losses have also been reported for RA and OA.
Although methotrexate is used to decrease inflammation in RA, the present article focuses on pain reduction in OA, as well as WOMAC stiffness and function, and a composite patient responder index. It is interesting that the initial dose of methotrexate used was 25 mg orally per week. You might have assumed that a dose this high would not be needed for pain relief, compared with what is needed for inflammation in RA. The mean dosage did decrease over the year-long study, as dose reductions were made to tolerance.
The authors showed a statistically significant reduction in pain at 6 and 9 months, but the effect was lost at 12 months. No synovial changes were seen between groups by MRI.
The authors admit that the use of methotrexate in symptomatic knee OA is not ready for “prime time.” I guess many of us are wondering what we are doing with the drug in OA to begin with. We will wait and see.
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