Millions of people around the world suffer from rheumatoid arthritis, an autoimmune disorder that causes debilitating joint swelling and pain. Researchers have been looking for ways to identify those who are at risk of developing rheumatoid arthritis to help stop the disease before it causes pain and improve patient outcomes. To do this, they first need to understand how rheumatoid arthritis develops.
In a recent multi-year study, researchers from multiple institutions joined forces to study the molecular profiles of patients with rheumatoid arthritis, those at risk of developing the disease, and people without the disease.1 The researchers found that about 30 percent of at-risk individuals developed rheumatoid arthritis within a few years. They reported, for the first time, that at-risk patients who developed rheumatoid arthritis showed signs of whole-body inflammation years before the onset of the disease. The researchers’ findings, published in Science Translational Medicine, reveal more early biomarkers for rheumatoid arthritis which may lead to ways to prevent, rather than treat, the disease.
“Overall, we hope this study raises awareness that rheumatoid arthritis begins much earlier than previously thought and that it enables researchers to make data-driven decisions on strategies to disrupt disease development,” said Mark Gillespie, an immunologist at the Allen Institute and a coauthor of the study, in a statement.
Physicians typically diagnose rheumatoid arthritis by testing patients’ blood for the presence autoantibodies, specifically anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF). Researchers previously reported that in about 30 to 60 percent of cases, ACPA and RF can be present in the blood years before individuals experience symptoms of rheumatoid arthritis, suggesting their utility as biomarkers for an early diagnosis.2-6 However, scientists didn’t know how individuals progressed from the at-risk stage to the manifestation of joint inflammation and pain, which is known as clinical rheumatoid arthritis.
Ziyuan He and Mark Gillespie, immunologists at the Allen Institute, look for early immunological signs of rheumatoid arthritis.
Jenny Burns
In the present study, Gillespie and his collaborators sought to understand this transition. The researchers recruited 45 ACPA-positive “at-risk” individuals who had not yet developed clinical rheumatoid arthritis, 11 patients with early-stage clinical disease, and 38 ACPA-negative individuals who represented the healthy group. Then they profiled the participants’ blood plasma using transcriptomics, proteomics, and flow cytometry.
The researchers found hundreds of proteins that were enriched in at-risk individuals relative to their healthy counterparts. Many of these proteins were already known to be involved in inflammatory pathways, suggesting that there are indeed molecular changes that may allow researchers to identify people who are at risk of developing rheumatoid arthritis and that these changes are likely associated with systemic inflammation.
After about one-and-a-half years after the start of the study, 16 of the 45 at-risk individuals (36 percent) progressed to clinical rheumatoid arthritis. The researchers denoted this population as “converters.” To better understand the early progression of rheumatoid arthritis, the researchers paired converters’ samples from before and after their diagnosis. Through this analysis, they found transcriptional changes that indicated the activation and expansion of helper T cells, which stimulate the production of antibodies.
The researchers also attempted to find transcriptomic signatures in circulating immune cells that could distinguish between converters and non-converters. However, they could only find a few transcripts that were differentially enriched between the two populations. The team proposed that this was due to the heterogeneity between patients and that their study was likely not large enough to pick up on subtler trends.
“We expect that going forward the findings from this study will support additional studies to identify ways to better predict who will get rheumatoid arthritis, identify potential biologic targets for preventing rheumatoid arthritis, as well as identify ways to improve treatments for those with existing rheumatoid arthritis,” said Kevin Deane, a rheumatologist at the University of Colorado Anschutz and coauthor of the study.
- He et al. Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation. Sci Transl Med. 2025
- Rantapää-Dahlqvist S, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48(10):2741-2749.
- Nielen MM, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50(2):380-386.
- Kelmenson LB, et al. Timing of elevations of autoantibody isotypes prior to diagnosis of rheumatoid arthritis. Arthritis Rheumatol. 2020;72(2):251-261.
- Duquenne L, et al. Predicting inflammatory arthritis in at-risk persons: development of scores for risk stratification. Ann Intern Med. 2023;176(8):1027-1036.
- Bergstedt DT, et al. Antibodies to citrullinated protein antigens, rheumatoid factor isotypes and the shared epitope and the near-term development of clinically-apparent rheumatoid arthritis. Front Immunol. 2022;13:916277.
