Several trials have explored interventions to potentially delay or prevent the progression to clinically apparent rheumatoid arthritis (RA) in high-risk groups, but despite some encouraging trends, none had previously met their primary end points. Two new successful trials in abatacept, APIPPRA and ARIAA, are the first to convincingly demonstrate the potential of this preventive approach, but more research is needed.1,2
Prevention in Rheumatology
Historically, management of RA and other inflammatory diseases in rheumatology has focused on secondary prevention (e.g., preventing severe joint erosion) in patients already presenting with clinically apparent, full-blown disease. The diagnosis of RA is a clinical one, but most diagnosed patients also meet the 2010 EULAR/ACR classification criteria, including synovitis of one or more joints, usually evaluated via swollen joints on clinical exam.3 Researchers have begun exploring early interventions in some high-risk patients who don’t fully qualify for a diagnosis of RA.
Dr. Holers
V. Michael Holers, MD, the Smyth Professor of Rheumatology at the University of Colorado School of Medicine, Aurora, shares an analogy between RA and the treatment of cardiovascular disease, which formerly included stroke and heart attack management with few preventive interventions: “We are trying to identify a kind of statin or blood pressure-lowering analog in the at-risk population [for RA] that would stop patients from developing the equivalent of a heart attack—joint inflammation and synovitis.”
The rheumatology community has historically embraced the dictum, “Don’t treat a lab test,” and some
Dr. Deane
physicians have expressed skepticism and safety concerns about potential prevention trials, partly because of potential differences in the risk/benefit ratio in this population, says Kevin Deane, MD, PhD, a professor of medicine in the Division of Rheumatology, University of Colorado. Dr. Deane holds the William P. Arend endowed chair in rheumatology research.
Jeffrey A. Sparks, MD, MMSc, an associate professor of medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital, Boston, points out that the field has already significantly moved toward treating clinically diagnosed RA earlier and more aggressively, which has greatly benefited patient outcomes. “This approach is trying to turn back the clock even more,” he says.
Dr. Sparks
High-Risk/Pre-RA Populations Defined
A complex variety of factors ultimately leads to the development of clinically apparent RA. Some individuals possess genes that place them at higher risk. These may interact with environmental and other factors, such as obesity, smoking, periodontitis, viral infections or hormones, to increase the risk of clinically apparent RA.4
The pathophysiology is incompletely understood, but some individuals develop autoantibodies characteristic of RA, rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA). The presence of such antibodies puts individuals at increased risk of disease development, although some test positive for such antibodies without symptoms for many years, and individuals with seronegative RA never develop such antibodies.5
Some individuals eventually develop joint symptoms but without clear-cut synovitis that can be identified on exam. For some, these symptoms can be quite significant, potentially affecting their employment. A subset of these individuals have subclinical joint inflammation (e.g., low levels of inflammation that can be detected on ultrasound or magnetic resonance imaging [MRI]), although this is sometimes transient.6
Most individuals who eventually develop seropositive RA go through this initial period of elevated antibodies and joint symptoms before they develop clinically apparent RA with synovitis. These early stages (before clinically apparent RA) involve limited systemic inflammation, which in some patients is followed by expansion of innate and adaptive immune responses and consequent tissue injury.5
The terminology surrounding these disease states will probably evolve and become more formalized. A EULAR study group suggested that the term “pre-RA” should be used only retrospectively to describe any of these earlier phases of disease in someone who has developed clinically apparent RA, but the term is also sometimes applied non-retrospectively.7
Some groups prefer the term preclinical RA to describe people who, to varying degrees, are at high risk of progression to clinically apparent RA. Individuals can also be described as being at high risk for RA, which can be quantified via scoring systems.8 EULAR has defined a phenotype based on clinical characteristics, clinically suspected arthralgia (CSA), which is characterized by joint symptoms without clinically apparent synovitis.9
Existing intervention trials in patients at high risk for clinically defined RA have used slightly different criteria for inclusion (e.g., in terms of whether joint pain must be present, antibody positivity and imaging criteria). These differences can complicate interpretation and comparisons among studies.10
High-Risk RA/Pre-RA Trials
Several trials have explored whether early interventions in groups at high risk for RA may delay or prevent the development of clearly apparent synovitis and the definite diagnosis of RA as defined by current classification criteria. They have also explored the effectiveness of decreasing existing symptom burden in such patients. But before APIPPRA and ARIAA, none had met their clinical end points.1,2
Dr. Deane was lead investigator on the StopRA trial, which examined symptomatic or asymptomatic patients positive for ACPA and without synovitis on clinical exam, giving hydroxychloroquine for 12 months and evaluating at three years.11
“We thought hydroxychloroquine was an important drug to study because rheumatologists commonly already use it in some patients who might have aches and pains and may be antibody positive,” says Dr. Deane. “But it doesn’t look like it works to prevent future rheumatoid arthritis.”
Dr. Emery
Another important study, TREAT EARLIER, looked at methotrexate as a one-year intervention. Methotrexate did not prevent onset of RA at 24 months, although it did improve patient-reported outcomes.12
Paul Emery, CBE, FLSW, FRCP, FRCPE, FMedSci, Versus Arthritis Professor at the Leeds Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds, U.K., points out that although this study didn’t meet its primary outcome, it did show delayed onset of RA in the subset of patients who were positive for ACPA. He also adds that many in the field believe that seronegative RA is distinct from seropositive RA in its pathophysiology and should be considered separately.
Trials in Abatacept: APIPPRA & ARIAA
The APIPPRA study follows up on an abatacept study led by Dr. Emery.1,13 Abatacept is a co-stimulation modulator attenuating naive T cell activation and downstream production of cytokines, and evidence points to a potential role for T cells in the initiation of the immunopathology associated with RA.13
APIPPRA is a phase 2b, randomized controlled study in at-risk individuals positive for ACPA who had joint pain but no synovitis on exam. This multi-center study included 110 patients assigned to receive weekly injections of 125 mg of abatacept weekly and 103 patients to placebo. The treatment group received abatacept for 12 months, with another 12-month follow-up period off the study drug. The clinical end point was RA as defined by EULAR/ACR 2010 criteria or clinical synovitis in three or more joints.1
At 12 months, 29% of patients in the placebo group had progressed to RA, compared with 6% of those in the abatacept group. At 24 months, one year after treatment cessation, 37% of patients in the placebo group had progressed to rheumatoid arthritis, compared with 25% in the abatacept group, meeting the study’s primary end point.1 Importantly, in ad hoc exploratory analyses yet to be published, participants with the highest levels of ACPA or an extended autoantibody profile at study initiation were more likely to remain arthritis free at 24 months.14
Abatacept was also associated with improvements in pain scores, functional well-being and quality of life-measurements during treatment, as well as lower scores of subclinical synovitis determined by ultrasound. These effects were not sustained beyond the treatment period, but this might be partly because APIPPRA did not remove patients from the study who had developed RA, unlike, for example, TREAT EARLIER and ARRIA, which showed sustained improvements in patient-reported outcomes after treatment cessation.1,2,12
Dr. Cope
APIPPRA lead investigator, Andrew P. Cope, BSc, MBBS, PhD, FRCP, HFEA, Versus Arthritis professor of rheumatology and head of the Centre for Rheumatic Diseases at King’s College London, points out that the modest differences in participant-reported outcomes may partly be due to challenges of evaluation in patients with lower symptom burden; measures such as the Disease Activity Score-28 have not been validated in this population and may not be appropriate in it.
Overall, the results from APIPPRA complement those of the ARIAA study, which looked at abatacept given for six months to patients with joint pain, positive ACPA and subclinical joint inflammation at baseline. ARIAA demonstrated improvements in synovitis, tenosynovitis and/or osteitis via MRI in 57% of patients in the abatacept group vs. 31% of patients in the placebo group, and these effects were maintained one year after stopping treatment.2
“Some of the earlier prevention trials had promising signals related to either quality of life measures or improved biomarkers,” says Dr. Sparks, “but having these two trials that truly show that we could delay onset—I think is a real proof of principle that this is possible.”
Dr. Cope and colleagues are soon to complete long-term follow up of the APIPPRA trial cohort for an additional four to eight years (based on time of accrual), which should yield more information about long-term potential impacts on prevention vs. delay of RA onset.
Critiques & Considerations
Dr. Sparks points out that some in the field are still skeptical about these sorts of preventive investigations in patients at high risk of RA. “Did these patients just have RA the whole time? That’s the critique given.”
Questions about whether patients “really have” RA can trend toward the philosophical. On one hand, although the classification criteria are particularly helpful for research studies, RA is ultimately a clinical diagnosis. Dr. Sparks points out that variations exist in the way rheumatologists assess synovitis by exam, particularly for borderline cases. Some rheumatologists may also assess synovitis by ultrasound or by MRI, but not all do, which can influence interpretation and add to variation in assessment.
This is one reason researchers establish narrow and specific groups in clinical trials, such as in APIPPRA. Disease in patients may exist on a pathogenic spectrum with RA, and some cases eventually progress to full-blown disease. However, Dr. Cope argues that it’s misleading to characterize these patients as having early RA. “We see people in clinic without swelling in their joints on clinical exam or ultrasound. If you stick to the classification for the disease, they [don’t] fulfill it.”
Dr. Emery acknowledges concerns of potential overtreatment. But he contends that targeting specific subgroups most appropriate for potential interventions could improve the risk/benefit ratio. For example, although about 50% of patients with inflammatory joint pain and positive antibodies go on to develop clinically defined RA, this rate is higher when other factors are considered, including high-titer autoantibodies, early morning stiffness and increased erythrocyte sedimentation rates.8
Some have also critiqued prevention studies by arguing that they may simply be temporarily suppressing disease rather than truly changing the disease trajectory. But even if further studies show that these agents don’t ultimately prevent RA, they still may help decrease some patients’ joint damage and improve their quality of life.
Dr. Cope notes that the field may move ultimately toward a different model of treatment, with cycles of treatment holidays and periods of treatment if symptoms return. With this on/off approach, clinicians may be able to limit symptom burden and prevent patients from developing clinical synovitis and fully qualifying for an RA diagnosis.
Current Approaches
Studies like APIPPRA may help inform future guidelines for patients at high risk for RA.
“In five or 10 years, I suspect we will have a much clearer definition of this at-risk phase, which will inform potential treatment based on symptom burden, clinical exam, autoantibodies, imaging and, probably, other [factors] as well,” says Dr. Cope. “Then we’ll be in a much better place to assess who needs treatment and who doesn’t.”
The best approach for managing a patient at high risk for RA is currently unknown. Clinicians need to use an individualized, shared decision-making approach with patients, which may vary based on many factors.
From a practical standpoint, abatacept is currently unlikely to be an available treatment option for most patients in the U.S. or the U.K. outside clinical studies. Dr. Sparks notes that it’s reasonable to monitor closely and not treat with any disease-modifying anti-rheumatic drug (DMARD) in these patients. He shares that he probably wouldn’t consider hydroxychloroquine due to results of the StopRA study. “If I were going to use a DMARD, it would probably be methotrexate,” he says. “Even if it doesn’t delay RA onset, it will help reduce joint pain and improve quality of life.”
Dr. Deane also notes that although we don’t yet have approved interventions to prevent future RA, it’s important to carefully monitor individuals who are at-risk for future disease, educate them to come back for reevaluation if their symptoms escalate and encourage risk reduction strategies, e.g., through quitting smoking and perhaps following a Mediterranean-type diet. These aren’t proven to prevent RA in trials, but they still may help with autoimmunity and have other health benefits.
Moving Forward
Drs. Holers and Deane are co-leaders of SERA (Studies of the Etiologies of Rheumatoid Arthritis). The multi-center collaboration is examining factors and pathophysiological processes leading to RA by prospectively following individuals at risk for RA, including individuals who are ACPA positive or first-degree relatives of patients with RA.
Dr. Holers notes that prior to the onset of synovial inflammation, the disease seems to be driven by mechanisms that aren’t fully identified and don’t seem to be addressed by current RA therapies, such as methotrexate, B cell depletion or hydroxychloroquine.10 Research will continue to explore therapies already approved by the U.S. Food & Drug Administration for RA in this population.
To work toward prevention on a deeper level, the field will need to learn more about this early pathophysiology and find new therapeutic strategies for intervention, a key part of the overall SERA project.
Dr. Cope also notes that researchers are beginning to explore other high-risk rheumatology populations who may benefit from a preventive approach, such as patients at high risk of developing systemic lupus erythematosus or psoriatic arthritis.
“I think the paradigm [may] change,” says Dr. Deane. “If we have the right lab tests and learn to properly understand and apply them, we [may] be able to screen people at risk for disease and intervene to stop them from getting sick in the first place.”
Ruth Jessen Hickman, MD, a graduate of the Indiana University School of Medicine, is a medical and science writer in Bloomington, Ind.
References
- 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.
- Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569–2581.
- Deane KD, Demoruelle MK, Kelmenson LB, et al. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017 Feb;31:3–18.
- Deane KD, Holers VM. Rheumatoid arthritis pathogenesis, prediction, and prevention: An emerging paradigm shift. Arthritis Rheumatol. 2021 Feb;73(2):181–193.
- Di Matteo A, Duquenne L, Cipolletta E, et al. Ultrasound subclinical synovitis in anti-CCP-positive at-risk individuals with musculoskeletal symptoms: An important and predictable stage in the rheumatoid arthritis continuum. Rheumatology (Oxford). 2022 Aug;61(8):3192–3200.
- Gerlag DM, Raza K, van Baarsen LG, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: Report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis. 2012 May;71(5):638–641.
- Duquenne L, Hensor EM, Wilson M, et al. Predicting inflammatory arthritis in at-risk persons: Development of scores for risk stratification. Ann Intern Med. 2023 Aug;176(8):1027–1036.
- Van Steenbergen HW, Aletaha D, Beaart-van de Voorde LJJ, et al. EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis. Ann Rheum Dis. 2017 Mar;76(3):491–496.
- Van der Helm-van Mil AHM. Preventive interventions in individuals at risk for rheumatoid arthritis: State of the art and perspectives. Joint Bone Spine. 2023 Jul;90(4):105543.
- Deane K, Holers V, Striebich C, et al. Hydroxychloroquine does not prevent the future development of rheumatoid arthritis in a population with baseline high levels of antibodies to citrullinated protein antigens and absence of inflammatory arthritis: Interim analysis of the StopRA trial [abstract]. Arthritis Rheumatol. 2022;74 (suppl 9):1604.
- Krijbolder DI, Verstappen M, van Dijk BT, et al. Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): A randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet. 2022 Jul;400(10348):283–294.
- Emery P, Durez P, Dougados M, et al. Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: A clinical and imaging study of abatacept (the ADJUST trial). Ann Rheum Dis. 2010 Mar;69(3):510–516.
- Cope A, Jasenecova M, Vasconcelos J, et al. Abatacept in individuals at risk of developing rheumatoid arthritis: Results from the Arthritis Prevention in the Preclinical Phase of RA with Abatacept (APIPPRA) trial [abstract]. Ann Rheum Dis. 2023;82:86.
