DMARDs Ineffective Against Osteoarthritis, Study Finds

Lara C. Pullen, PhD

July 02, 2018

Disease-modifying antirheumatic drugs (DMARDs) do not offer patients with osteoarthritis (OA) clinically significant pain relief relative to placebo, according to a meta-analysis.

Monica S.M. Persson, a graduate student at the University of Nottingham, United Kingdom, and colleagues published results from the first meta-analysis of conventional and biologic DMARDs for OA June 16 in Rheumatology.

The researchers analyzed results from 11 randomized controlled trials (RCTs) that were published as conference abstracts and scientific papers. The RCTs included 1205 participants; half of the trials (757 participants) evaluated conventional DMARDs and half (448 participants) evaluated biologics.

Although DMARDs were statistically superior to placebo [effect size (ES), 0.18; 95% confidence interval [CI], 0.03 - 034], the difference was not clinically significant (0.5 ES threshold). The investigators also saw no statistically significant differences in subanalyses of high-quality trials (ES, 0.11; 95% CI, –0.06 to 0.28), biologics (ES, 0.16; 95% CI, –0.02 to 0.34), or conventional DMARDs (ES, 0.24; 95% CI, –0.05 to 0.54).

DMARDs and Arthritis

In general, DMARDs target the innate immune response via interleukin (IL)-1, the adaptive immune response via tumor necrosis factor (TNF), or overall inflammation (eg, methotrexate). Whereas results from in vitro studies and animal models have suggested that biologic DMARDs could be useful in the treatment of OA, RCTs indicate that they do not provide a clear benefit over placebo.

"We have followed the literature on this and realized that trials were largely negative," Persson told Medscape Medical News. "However, our study has, for the first time, fully examined and quantified the efficacy of the drugs in OA using meta-analysis."

Not only did the investigators find that DMARDs were ineffective for OA, they also found no difference in efficacy between anti–IL-1 and anti-TNF biologics. The same held true for different joint sites and OA subtypes, with no statistically significant differences in any of the subanalyses.

"It's really interesting," Lindsey A. MacFarlane, MD, MPH, a rheumatologist at Brigham and Women's Hospital, Boston, Massachusetts, told Medscape Medical News. "I don't know if I am surprised," she added.

Causes of Osteoarthritis

OA tends to result from wear and tear. That said, "Over the past few years, people have gotten interested in the role of inflammation in osteoarthritis," explained MacFarlane.

The authors have interpreted their findings, however, to mean that inflammation may not be a prime driver for OA pain.

"There is much debate about the role of inflammation in OA — some believe that inflammation is a primary driver of structural change and pain in OA, whilst others believe that any inflammation that is present is part of the repair process of the joint that is triggered largely by mechanical or metabolic drivers," explained Persson. "DMARDs can effectively manage arthritis that is driven by primary injurious inflammation (eg, rheumatoid arthritis) that both damage joints and cause pain. Our findings would suggest that such primary inflammation is not a key driver of OA pain."

Nevertheless, a body of literature not only has made the connection between inflammation and pain but also suggests that inflammation plays a role in OA pain. In addition, clinicians know that patients with OA have inflammation. They see the inflammation in the joint when they image it via MRI.

Despite this, MacFarlane believes that physicians generally recognize that DMARDs are not particularly helpful against OA, and thus most providers don't prescribe them to patients with OA.

Clinical experience thus suggests that the inflammation of OA differs from the inflammation of rheumatoid arthritis.

Inflammation and Osteoarthritis

MacFarlane explained her interest in the intersection of obesity, inflammation, and osteoarthritis, noting that studies of hand OA have revealed an increased incidence in individuals who are obese.

The location of OA in the hand of individuals who are obese suggests that the OA results not from increased mechanical load associated with obesity, such as would be seen in the knee. Instead, the increased incidence of hand OA may be associated with obesity in another way, perhaps through inflammation.

Moreover, "there is a lot of literature to suggest that inflammation matters in OA," emphasized MacFarlane. However, she acknowledged that pain is multifactorial and that although individuals with inflammation tend to have more pain, the relationship is not absolute.

In some patients, inflammation may drive pain. Other patients appear to have additional factors that are major contributors to the sensation of pain. All patients with OA, however, represent an unmet medical need.

"The field is really begging for treatments that will halt the progression of disease," emphasized MacFarlane. Patients with OA do not yet have such options.

Physicians thus treat OA by recommending such measures as weight reduction, dietary changes, nonsteroidal anti-inflammatory drugs, and, occasionally, local injections of corticosteroids. Ultimately, however, many patients will choose to have their joints replaced.

In this landscape, researchers seek not only solutions for their patients but also answers to their many unresolved questions. "The lack of a clinically meaningful effect [from DMARDs] suggests that inflammation is not a major risk factor for pain in OA," explained Persson.

"I wouldn't shut the door on inflammation and osteoarthritis," countered MacFarlane.

Multiple authors report various financial relationships with companies. A complete list of disclosures is available on the journal website. MacFarlane has consulted for Flexion Therapeutics.

Rheumatology. Published online June 16, 2018. Abstract

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