Study: Inflammation Starts Earlier Than You Think

Rheumatoid arthritis (RA) is increasingly understood as a disease that begins well before the onset of clinically apparent synovitis. Anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are often detectable, on average, three to five years earlier.^1-3 Individuals who are ACPA positive but asymptomatic are considered at risk for developing RA, and this stage has become the focus of prevention-oriented research.

Initial clinical trials aimed at identi­fying therapies that could prevent the development of full-blown RA have shown mixed results. Single-dose rituximab delayed, but did not pre­vent, RA in the PRAIRI study.⁴ Abatacept showed promise, reducing progression to clinical RA in the ARIAA and APIPPRA trials.^5,6

Overall, progress toward effective preemptive treatment is slow. Why? Because we have lacked a detailed immunobiological understanding of what’s happening during the at-risk (pre-RA) period—until now.

In September 2025, He et al. published a groundbreaking article characterizing the pathogenesis of the at-risk stage of RA in ACPA-positive individuals.⁷

Summary of Research

He et al. used integrative multiomics (see below) to longitudinally profile at-risk individuals who were ACPA positive. They studied blood samples from a prospective, longitudinal cohort of 45 at-risk people (defined as clinically healthy, ACPA-positive individuals), 11 people with early clinical RA and 38 ACPA-negative healthy controls for a mean follow-up of approximately 18 months. The goal was to better understand and reveal the immune features associated with the at-risk stage of RA, as well as the immune changes that accompany progression to clinically active disease.⁷

During the study, 36% of healthy, ACPA-positive individuals progressed to clinical RA. Progression to clinical RA was determined clinically, with a rheumatologist or trained study nurse identifying one or more swollen joints consistent with inflammatory arthritis.

In brief, the authors were able to show that in ACPA-positive individuals, inflammatory disease begins well before the development of synovitis on exam. Inflammation is brewing long before the person or provider realizes it.

He et al. observed signs of widespread inflammation and early activation in naïve T and B cells in these individuals. As some of them progressed to clinical disease, their immune systems showed an increase in proinflammatory atypical B cells and activated memory CD4 T cells that could support B cell responses, even though ACPA levels in the blood didn’t rise. Epigenetic changes in naïve CD4 T cells also indicated they were primed to become effector cells able to assist B cells.