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
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.
For more specifics on these fascinating findings, we interviewed the corresponding authors, who were kind enough to share their take.
Interviewees were:
- Gary Firestein, MD, distinguished professor of medicine, University of California, San Diego;
- Kevin Deane, MD, professor, medicine-rheumatology, University of Colorado Anschutz, Aurora;
- Troy Torgerson, MD, PhD, director, experimental immunology, Allen Institute for Immunology, Seattle; and
- Mark Gillespie, PhD, assistant investigator, Allen Institute for Immunology, Seattle.
Interview
The Rheumatologist (TR): How would you summarize your findings?
Dr. Kevin Deane
Dr. Deane: Prior studies have demonstrated that individuals who have elevated blood levels of ACPAs are at high risk for the future development of full-blown RA, which can also be called clinical RA. However, not all ACPA-positive, at-risk individuals get clinical RA. In addition, the biology that drives a transition from an at-risk state to clinical RA isn’t fully understood.
With this study, we evaluated ACPA-positive individuals, a portion of whom developed clinical RA during the approximately seven years of the study. We were able to deeply evaluate the immune system across time as these at-risk individuals ‘converted’ to clinical RA. The key findings were that there are multiple immune system abnormalities in T and B cells, as well as systemic inflammation, even prior to the onset of clinical RA.
Going forward, we plan to build on these findings to develop improved ways to predict future RA and target specific biologic processes to improve our current therapies for RA, as well as to ultimately prevent RA.
Dr. Gary Firestein
Dr. Firestein: Clinicians often encounter patients with family histories of RA or an isolated positive test, like anti-cyclic citrullinated protein (anti-CCP) antibody. Currently, there is little guidance on how to proceed beyond watchful waiting.
Our study provides a road map for the immunological changes that occur as someone moves from asymptomatic autoimmunity to RA. As we continue to dissect these pathways, newer tests will hopefully be available that will help determine who has the greatest risk of progression and perhaps even the best ways to prevent RA.
TR: Integrative multiomics is likely a new concept to most of our readers. How is this technology changing the rheumatology research landscape?
Dr. Troy Torgerson
Dr. Torgerson: Multiomics describes an approach of utilizing a variety of omic assays (transcript-omics, prote-omics, etc.) to broadly, deeply and simultaneously measure many aspects of a biological system. Integrative means trying to correlate the biology observed in one ome with that observed in a second, third or fourth ome.
Each of these omic assays generates large datasets, so integration involves using computational algorithms and powerful computing platforms to bring together the disparate pieces of data to create a systemwide view of human immunity in the setting of disease. Tools to do this type of analysis at scale in humans have become available relatively recently, facilitating our ability to do systems immunology to generate a more complete picture of immune-mediated diseases, such as RA. Our hope is that this approach will yield new insights, as described in our paper, that will provide opportunities for early, targeted interventions.
Dr. Mark Gillespie
Dr. Gillespie: Multiomics approaches allow us to profile the various molecular features of a system in a mostly unbiased manner. For instance, to understand the state of a cell, which can provide clues as to its function, we can profile that cell’s transcriptome or proteome—the molecular changes occurring inside that cell. Making these measurements independently gives us one level of information, but processing and interpreting them together in an integrative manner provides deeper insights into the identity of this cell, what it may be doing, what other cells it may be communicating with and what might be going wrong in autoimmune diseases like RA.
By applying integrative multiomics approaches in rheumatology research, we can generate a more comprehensive, system-level view of the disease-relevant changes. These changes may represent critical drivers of disease pathology or important biomarkers of disease onset or progression—information that can provide the future basis for more personalized therapeutics and/or prevention strategies.
TR: What should practicing rheumatologists take away from these findings?
Dr. Deane: At a high-level, this study again demonstrated that ACPA-positive individuals are at high risk for developing clinical RA. While more work needs to be done, we plan in the near future to translate the findings from this study into actionable prediction models, and ultimately preventive interventions for RA, that can be used in the routine clinical care of individuals who are at risk for RA.
Importantly, while RA is one of the more common chronic autoimmune diseases, it’s still relatively rare because it only affects about 1% of the population. As such, people who are at risk for RA because of ACPA positivity are also relatively rare—although such individuals are seen in rheumatology clinics periodically.
To help the next generation of studies on the prediction and prevention of RA, we need networks of rheumatologists and people who are at risk for RA to participate in research studies. To help in this area, a new study that has evolved from this collaborative effort between the Allen Institute, University of California, San Diego and University of Colorado Anschutz is called StopRA: National. It offers opportunities for rheumatologists and people who are ACPA positive across the U.S. to participate remotely in a research study to learn more about how RA develops. More information about StopRA: National can be found at https://tinyurl.com/w8aaz45k.
TR: What does this work add to the goal of preventing RA before clinically active disease ensues? How far off do you think we are from achieving that goal?
Dr. Firestein: One of the challenges with RA prevention is that the markers for identifying at-risk individuals are not specific enough to make therapeutic decisions. A positive anti-CCP test is helpful, but only about a third of those people will ultimately transition to clinical RA. Therefore, testing therapeutic agents for prevention is difficult because most of the patients will never develop the disease.
Our new data can provide insights that will hopefully lead to better biomarkers that identify those individuals at the greatest risk. In addition, the pathways identified could help us identify which agents might work the best in those individuals. We know that there is a diversity of responses to targeted treatments, and we currently rely on trial and error for optimizing therapy. If we understand the mechanisms of disease for an individual, we might be able to tailor the therapy more precisely.
TR: This study looked at ACPA-positive individuals. Are we any closer to understanding the immunobiology of seronegative RA?
Dr. Firestein: We have typically viewed seronegative RA as a different disease, with distinct pathogenic mechanisms and genetics. Even though the distribution of joints, clinical presentations and responses to some therapies can be similar, we would need to do a separate study with the seronegative group to understand its trajectory and pathways.
TR: What research needs to be done next?
Dr. Gillespie: We need a deeper understanding of the molecular mechanisms that control the development of autoimmune diseases. Specifically in RA, we need to understand what is driving differences in ACPA-positive individuals who transition to clinical RA and in those who do not transition. It’s likely there are multiple routes to get to clinical disease, which emphasizes the importance of developing new integrative omics technologies.
It’s also important for us to validate these findings and predictions in new cohorts, such as StopRA: National. As mentioned earlier in this interview, understanding mechanisms leads to more precise therapies and better predictive models.
Conclusion
Thanks to this work, we’re many steps closer to understanding why seropositive RA develops and what we might do to prevent it. Inflammatory disease begins well before we see synovitis on exam, and a better understanding of what’s brewing before the storm could lead to the development of preventive therapies. We look forward to big data research from this group and others in the near future.
Samantha C. Shapiro, MD, is a clinician educator who is passionate about the care and education of rheumatology patients. She writes for both medical and lay audiences and practices telerheumatology.
References
- Kelmenson LB, Wagner BD, McNair BK, et al. Timing of elevations of autoantibody isotypes prior to diagnosis of rheumatoid arthritis. Arthritis Rheumatol. 2020 Feb;72(2):251–261.
- Nielen MMJ, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis Rheum. 2004 Feb;50(2):380–286.
- Rantapää-Dahlqvist S, de Jong BAW, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003 Oct;48(10):2741–2749.
- Gerlag DM, Safy M, Maijer KI, et al. Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: The PRAIRI study. Ann Rheum Dis. 2019 Feb;78(2):179–185.
- Cope AP, Jasenecova M, Vasconcelos JC, et al. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): A randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial. Lancet. 2024 Mar;403(10429):838–849.
- Rech J, Tascilar K, Hagen M, et al. Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): A randomised, international, multicentre, double-blind, placebo-controlled trial. Lancet. 2024 Mar;403(10429):850–859.
- He Z, Glass MC, Venkatesan P, 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 Sep 24; 17(817):eadt7214.
