Methotrexate—an affordable, established drug for rheumatoid arthritis—may also be helpful for patients suffering from osteoarthritis (OA) of the hand, a recent study reports.1
Treatment of hand OA and inflammation with 20 mg of methotrexate for six months had a moderate, but potentially clinically meaningful, effect on reducing pain and stiffness in patients with symptomatic hand OA, Australian researchers write in The Lancet. They add that their study is proof of concept that methotrexate may have a role in the management of hand osteoarthritis with an inflammatory phenotype.
Hand OA makes daily activities, such as dressing and eating, difficult and reduces quality of life. According to the Arthritis Foundation, the condition is common among older adults, and even more so in women, with symptoms typically starting around the time of menopause. About half of all women and one-quarter of all men will experience the stiffness and pain of hand OA by age 85.2 About half of these patients have inflamed joints, associated with significant damage.
“At the moment, if a person goes to the doctor with hand osteoarthritis, treatments are very limited and do not work well. Often patients are told there is nothing much to offer them,” says senior author Flavia Cicuttini, PhD, MSc, head of the Musculoskeletal Research Unit at Monash University and head of rheumatology at The Alfred Hospital, Melbourne, Australia. “The results of our study support a potential role for methotrexate in the management of hand osteoarthritis and inflammation.”
The Reason for Research
Hand OA was previously seen as a primarily degenerative condition, not an inflammatory one. This old thinking limited treatments to pain relief with paracetamol or such medications as naproxen or celecoxib, says Dr. Cicuttini. However, research involving imaging has since found inflammation in patients with hand OA, despite normal blood tests, she notes in an interview. “This inflammation is associated with pain and very significant joint damage. For these reasons, and the huge unmet need, there have been many trials to see if the anti-tumor necrosis factors (TNF) and other biological agents work. While very effective in conditions such as rheumatoid arthritis, they are also very expensive and have not worked [for hand OA],” she says.
Dr. Cicuttini and her co-authors “decided to test methotrexate because we know it is effective in inflammatory arthritis. Its mode of action is broader than the more selective anti-TNF agents which have revolutionized the management of rheumatoid arthritis and other inflammatory conditions.”
A previous study of methotrexate in hand OA found no benefit.3 But the study was in a subgroup of patients who had erosive OA—which involves cartilage damage and bone erosion in the hand joints—a different population from those described in the recent study, whose disease was not as advanced, Dr. Cicuttini noted. However, in her previous methotrexate trials and studies examining TNF-alpha inhibitors in hand OA, some evidence suggested reduced inflammation with less joint damage.
The Study
The randomized, double-blind, placebo-controlled trial assessed whether methotrexate given once a week reduced pain, compared to a placebo, and improved function in patients with symptoms of hand OA and synovitis.
The researchers followed patients taking methotrexate for six months to see whether they had significantly less pain and stiffness, compared with the placebo patients. Methotrexate patients took 10 mg by mouth once per week for the first four weeks and took 20 mg weekly in the same way for the rest of the study, plus folic acid to reduce drug side effects.
The primary outcome was pain measured by the visual analog scale (VAS), a well-established way to measure self-reported pain intensity. VAS consists of a 100 mm line, with two end points representing 0 ( or no pain) and 10 (for pain as bad as it could possibly be). Patients reported their current level of pain by placing a mark on the line.
The patients were recruited between 2017 and 2022, although the trial—intended originally as a two-year study—paused temporarily in 2020 due to the COVID-19 pandemic and concerns about potentially infected patients taking methotrexate. The study included 97 patients aged 40–75, 70% of whom were women. The participants had experienced pain in their hand joints most days for the previous three months. According to the paper, the patients’ VAS scores were at least 40 mm in the week prior to beginning participation. Patients had OA confirmed in at least one joint, and many had inflammation visible on magnetic resonance imaging (MRI). The researchers excluded patients with gout, psoriasis, evidence of rheumatoid arthritis (e.g., rheumatoid factor, the presence of anti-cyclic citrullinated peptides, elevated inflammatory markers), and patients who would be harmed by methotrexate or MRI.
After six months, patients who took methotrexate had less pain and lower VAS scores than those patients who took placebo. The mean reduction in VAS scores was 15.2 mm for the methotrexate group, vs. 7.7 mm for the placebo group. Additionally, the methotrexate patients had greater reductions in another pain index, the Australian Canadian (AUSCAN) Osteoarthritis Hand Index. But there were no differences in other secondary outcomes, including mean AUSCAN score, scores on two other pain assessments, and grip strength.
The researchers reported that patients tolerated methotrexate well. No patients had serious adverse events from treatment, although 10% of the patients on the drug did discontinue it. Four patients also discontinued the placebo. The methotrexate and placebo groups had similar incidences of adverse events, none of which required change in medication dosage or dropping out of the study.
“Our results suggest that targeting inflammation is important and works, and that it can be done with a medication, such as methotrexate, that has a broader action than the more selective medications, such as the anti-TNF [agents], which have not worked,” says Dr. Cicuttini.
The paper notes study limitations. They include the low initial dose of methotrexate and failure to target the inflammatory phenotype of hand osteoarthritis, since only 29 of a possible 1,024 joints had evidence of synovitis, where an effect of methotrexate might be expected.
Using Methotrexate
Dr. Cicuttini says methotrexate is a well-tolerated treatment. The most common side effects are nausea and mouth ulcers, which can be reduced with use of the vitamin folic acid. However, using methotrexate does require blood monitoring to check for effects on the liver function or reduced white blood cells or platelets.
“Although it’s the most commonly used drug around the world for inflammatory arthritis, some of the methotrexate side effects are potentially serious and need monitoring. And that adds hassle for health systems, doctors, and patients, although most people cope with the side effects pretty well,” says Professor Philip Conaghan, MBBS, PhD, director, National Institute for Health and Care Research, Leeds Biomedical Research Centre, Leeds Teaching Hospitals, and professor of musculoskeletal medicine at University of Leeds, U.K.
“It would overwhelm health systems if we gave methotrexate to everyone with hand OA,” he says. “So you need a clear understanding of which subgroup of patients you should give it to. No one knows that very well yet.”
Dr. Conaghan adds that the study shows methotrexate works for hand OA pain, but it does not show significant improvement in function. Function primarily means grip strength, which relies on muscles, he explains. “This drug is never going to give you stronger muscles, so the drug does not remove the need to teach people exercises to get their function back.”
“For the first time in many years, in an imaging-proven inflammatory group of hand OA patients, we’ve seen a reduction in pain with methotrexate, full stop,” he says. “But it’s not feasible to send everyone off for MRIs and ultrasounds.” He called the study “clearly very important as a proof of concept,” and for more understanding of the subset of hand OA patients for whom methotrexate will be a useful, everyday clinical therapy.
The paper also calls for more clinical trials to establish whether the effects of 20 mg of methotrexate once weekly extend beyond six months and whether it improves structural outcomes in individuals with hand OA and synovitis over longer periods.
To that end, Dr. Cicuttini says she will soon start a new study of methotrexate in patients with hand OA. The recently published six-month study showed a reduction in pain, but because methotrexate is a slow-acting agent, the forthcoming 12-month study will follow approximately 150 similar patients. The goal is to figure out which patients continue to benefit from it.
Although Dr. Conaghan says he would hold off prescribing methotrexate for hand OA pending further positive research results, Dr. Cicuttini says rheumatologists can discuss the drug with some patients, considering their individual disease and treatment options.
Deborah Levenson is a writer and editor based in College Park, Md.
References
- Wang Y, Jones G, Keen HI, et al. Methotrexate to treat hand osteoarthritis with synovitis (METHODS): An Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial. Lancet. 2023 Nov;402(10414):1764–1772.
- Osteoarthritis of the hands. Arthritis Foundation. 2021 Oct 14. https://www.arthritis.org/diseases/more-about/osteoarthritis-of-the-hands.
- Ferrero S, Wittoek R, Allado E, et al. Methotrexate treatment in hand osteoarthritis refractory to usual treatments: A randomised, double-blind, placebo-controlled trial. Semin Arthritis Rheum. 2021 Aug;51(4):831–838.
