WASHINGTON, D.C.—People seek—or don’t seek—an evaluation with a rheumatologist for many reasons, and seeing what we can glean from such situations helps inform us about the phases of, and risk factors for, autoimmune disease. At ACR Convergence 2024, the session Risk Stratification for Future Rheumatoid Arthritis provided insights into this topic and enlightened the audience with international data.
Clinically Suspect Arthralgias
The first speaker was Annette van der Helm-van Mil, MD, PhD, Medical Delta Professor, Erasmus Medical Center, Rotterdam, The Netherlands, and professor of rheumatology, Leiden University Medical Center, The Netherlands. She discussed work from several papers over the past few years on patients who are at risk for rheumatoid arthritis (RA). It is understood that, during the transition to developing RA, patients may pass through a phase that entails the presence of symptoms without clinically apparent synovitis. Understanding this, EULAR created a task force that sought to define the clinical characteristics of patients with arthralgias who should be considered at risk for RA.
The task force, comprising 18 rheumatologists, three health professionals, two patients, a methodologist and a research fellow, developed a list of parameters characteristic of clinically suspect arthralgia (CSA), selected the most important parameters and evaluated 50 patients as having CSA or not having CSA. (They also indicated their confidence in this judgment.) This was followed by a validation phase, in which rheumatologists collected patients with and without CSA from their clinics.
A multivariable model was then used to determine the seven most important parameters. These were: symptom duration less than one year, metacarpophalangeal (MCP) joint symptoms, morning stiffness lasting more than an hour, early morning predominance of symptoms, RA in a first-degree relative, difficulty making a fist and positive MCP squeeze test.1
Such work has been helpful in informing the evaluation of at-risk patients, particularly with regard to clinical trials looking toward preventing the onset of clinical RA.
Variables in Identifying Patients
The second speaker was Kevin Deane, MD, PhD, a professor who holds the William P. Arend Endowed Chair in Rheumatology Research, University of Colorado School of Medicine, Aurora. Dr. Deane began by discussing the multiple ways to identify patients who are at risk for RA. Some patients seek evaluation for arthralgias and others may be identified via population-based means (i.e., being concerned by a family history of RA, learning about arthritis at a health fair or being found to have abnormal lab studies).
Dr. Deane noted the way a patient comes to attention should affect the determination of whether they are at risk. For example, an arthralgia-first approach may miss patients with mild symptoms or may identify patients who have only recently noticed and/or become concerned about symptoms but clearly have had long-standing disease unbeknownst to them. Dr. Deane further explained that patients who progress from at risk for RA to clinically diagnosed RA may have different trajectories, with symptoms progressing in a linear fashion for some and others experiencing peaks and values in joint pain until symptoms ultimately become more persistent.
An important subject that both Dr. van der Helm-van Mil and Dr. Deane discussed is weighing the risks of RA with the risks of intervention. By this they mean that if a patient is considered at risk for the disease, the clinician or researcher making this determination must decide what the next step is. Should this patient be actively treated? What are the potential side effects of such treatment? What if a patient has poor access to specialized care—in such a scenario, is the at-risk label simply superfluous? Nevertheless, Dr. Deane is hoping to build on the work of the EULAR group and use population-based approaches, such as health fair screenings, to identify at-risk patients and better understand their course over time. He did tell the audience that if they know of population-based cohorts they think would be relevant to study, they should contact him directly to discuss being a part of this project.
APIPPRA Study
The third and final speaker was Andrew Cope, MD, a professor who holds the AR UK Chair in Rheumatology, King’s College London, U.K., and he discussed the Abatacept in Individuals at High Risk of Rheumatoid Arthritis (APIPPRA) study. The aim of this study was to treat patients who were in the preclinical phase and prevent the development of RA. In the study, researchers recruited adults who had inflammatory joint pain and tested positive for antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor.
The 213 participants from The Netherlands and the U.K. were then randomized to receive either abatacept or placebo for 12 months and were followed up for another 12 months. After 12 months, about 30% of participants in the placebo group had RA or inflammation in three or more joints compared with 6% of people who received abatacept. Those receiving abatacept also reported improvements in pain, well-being and quality of life, as well as less joint inflammation during treatment. At 24 months of follow up, 25% of participants in the abatacept group had developed RA compared with 37% in the placebo group. The authors of the study thus argued that therapeutic intervention during the at-risk phase of RA is feasible, although treatment beyond 12 months may be required to prevent progression.2
Dr. Cope also discussed what is being learned at the epigenetic level about patients who are at risk for RA. In looking at these patients, it appears that chromatin signatures associated with progression to RA map to loci associated with the CD28 co-stimulation pathway. Specifically, Dr. Cope showed that two areas on chromosome 1 implicated in this pathway are linked to the gene PTPN22, which for nearly 20 years has been of interest to understanding the genetic risk factors for autoimmunity. (In 2004, researchers reported that a single-nucleotide polymorphism C1858T [rs2476601] in the PTPN22 gene was associated with type 1 diabetes, RA and systemic lupus erythematosus) 3. By looking at epigenetic modifications—DNA methylation, histone modification, chromosome remodeling, RNA interference—that affect and regulate the function and characteristics of genes, we may be able to better understand why some patients who are at risk for RA progress to disease and others do not.
In Sum
All three speakers in the session provided valuable insights into a timely topic. In 2024, the goal is not just to treat patients with RA, but it is also to identify those at risk for the disease and, perhaps, prevent its onset altogether.
References
- van Steenbergen HW, Aletaha D, Beaart-van de Voorde LJet al. EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis. Ann Rheum Dis. 2017 Mar;76(3):491-496.
- 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 2;403(10429):838–849. 3.
- Mustelin T, Bottini N, Stanford SM. The contribution of PTPN22 to rheumatic disease. Arthritis Rheumatol. 2019 Apr;71(4):486-495.
Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
