Rheumatoid arthritis: A study in Science Translational Medicine maps immune system changes that precede rheumatoid arthritis (RA), raising hopes for earlier detection and prevention in individuals at risk.
Rheumatoid arthritis, an autoimmune disease with no cure, often shows elevated autoantibodies years before joint pain and swelling appear, but many antibody-positive individuals never develop the disease, complicating prevention efforts.
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Researchers followed 45 “at-risk” participants (autoantibody-positive, symptom-free), 11 people with early clinical RA, and 38 healthy controls. Sixteen at-risk participants later converted to clinical RA. At baseline, both converters and non-converters already showed systemic inflammation: higher circulating inflammatory proteins and an increased number of pro-inflammatory immune cells (including monocytes), compared with healthy controls. However, no baseline gene or protein signature cleanly distinguished those who would progress.
The turning point emerged just before diagnosis. In converters, B and T lymphocytes shifted toward an activated, pro-inflammatory state, with gene-expression patterns resembling those in early RA. Investigators identified an activated memory B-cell subset characteristic of clinical RA and an expansion of CD4+ “helper” T cells that promote B-cell activation, changes consistent with a ramp-up in autoantibody production. Naïve CD4 T cells also showed regulatory changes that prime them to become effector cells, suggesting the immune system is “pre-wired” for a pathogenic response before joints become swollen.
“Most people who are at-risk for RA never develop the disease. That makes prevention studies difficult because some individuals who do not need therapy will be treated,” said senior author Gary Firestein, MD (University of California, San Diego). Co-author Kevin Deane, MD (University of Colorado Anschutz) said the new immune profile could “directly support new ways to predict RA” and help identify targets for preemptive therapies. Mark Gillespie, PhD (Allen Institute), added that at-risk individuals “look and feel healthy,” yet display “widespread inflammation and signs of immune activity,” including B and T-cell changes that foreshadow disease.
Background data underscore the need for earlier action. Although disease-modifying anti-rheumatic drugs can slow progression once RA is diagnosed, 5–27% of patients do not respond, and relapses are common. Autoantibodies (ACPA/RF) can appear 3–5 years before symptoms, but only 30–60% of antibody-positive people progress, highlighting why more precise biomarkers are needed. Small trials of prevention strategies (for example, abatacept in at-risk individuals) hint that early immune modulation could delay or prevent onset.
The authors say larger, prospective cohorts will be required to validate the immune signatures, develop practical blood tests, and test targeted interventions that “reset” immunity before permanent joint damage occurs.
