With the discovery of autoantibodies and other risk factors for rheumatoid arthritis (RA), researchers developed clinical trials to see whether the disease can be prevented entirely. In the past 10 years, a number of these trials have concluded, with variable results.
While some trials demonstrated no effect at all, others showed that medical intervention can delay the onset of disease in certain populations and even reduce the rates of progression to RA. These completed trials also offer researchers the chance to identify opportunities to improve RA prevention trials moving forward.
“We’re looking at all that data and trying to figure out what the next step is going to be,” said Kevin Deane, MD, PhD, a professor of medicine and a rheumatologist at the University of Colorado School of Medicine, Aurora.
Key lessons include the need for improved risk stratification tools and better understanding of RA pathogenesis, he said.
The Research So Far
All RA prevention trials except for one have been completed and/or published within the past decade, bringing valuable insights to the field. (See chart below.)
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Atorvastatin (STAPRA) and hydroxychloroquine (StopRA) proved ineffective in preventing the onset of RA, and both trials were stopped early. Rituximab and methotrexate (MTX) both delayed the onset of RA, but the effect disappeared by the end of the follow-up periods.
However, the 2-year results from the TREAT EARLIER trial showed that compared with patients given placebo, those given MTX showed improved MRI-detected joint inflammation, physical functioning, and reported symptoms.
The 4-year analysis of the trial further risk stratified participants and found that MTX showed a preventive effect in anti–citrullinated protein antibody (ACPA)–negative participants at an increased risk for RA.
Abatacept also showed promise in preventing RA in two separate trials. In the ARIAA trial, compared with placebo, 6 months of treatment with abatacept reduced MRI inflammation and symptoms and lowered the rates of progression to RA. This treatment effect lessened during the 1-year follow-up period, but the difference between the two groups was still significant at 18 months.
In the APIPPRA trial, 12 months of treatment with abatacept improved subclinical inflammation and quality-of-life measures in participants and reduced the rates of progression to RA through another 12 months of observation. However, during this post-treatment follow-up period, the treatment effect began to diminish.
While there have been some promising findings — not only in disease prevention but also in disease modification — these studies all looked at different patient groups, noted Kulveer Mankia, MA, DM, an associate professor and consulting rheumatologist at the Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds in England.
“You have disparate, different inclusion criteria in different studies, all of which take years to complete,” he said. For example, while the TREAT EARLIER trial recruited patients with joint pain and subclinical joint inflammation via MRI, regardless of autoantibody status, the APIPPRA trial enrolled patients that were both ACPA+ and rheumatoid factor (RF)+ with joint pain.
“You’re left extrapolating as to whether [these interventions] will work in different at-risk populations,” he said.
Even with specific inclusion criteria in each study, there can still be heterogeneity in risk within a study group, Deane said. In the TREAT EARLIER study, 18%-20% of participants ultimately developed RA over the study period, which is lower than expected.
“While it seemed like a pretty high-risk group, it wasn’t as high risk as we thought,” he said, “and that’s why we’ve gone back to the drawing board.”