The standard approach to the treatment for rheumatoid arthritis (RA) includes the early initiation of disease-modifying antirheumatic drugs (DMARDs) based on the presumption that there is a window of opportunity in which treatment is likely to be more effective in limiting disease progression. Various retrospective studies have identified RA-related autoantibodies and inflammatory markers months or years before symptoms appear.1-4 Such findings suggest that the “disease process is evolving long before the disease becomes clinically detectable,” wrote the authors of a review published in January 2018 in Nature Reviews Rheumatology.5
In light of these developments, there has been a growing interest in preventive trials to investigate the possibility that initiating treatment in the pre-arthritis phases could prevent the onset of the disease. This concept “raises questions concerning how to accurately identify individuals in the pre-arthritis phases, how to avoid overtreatment, and how to manage patients that are presumed to be at risk of [RA] developing,” according to the paper.5 The authors state that the European League Against Rheumatism (EULAR) terminology for preclinical RA phases would serve as a reasonable starting point for use in future research.
The EULAR Study Group for Risk Factors for RA was created to facilitate research pertaining to the preclinical period of RA. The group recommends that prospective studies use different descriptors for subgroups of patients in varying phases of preclinical RA.6 Participants should be described as having either genetic risk factors for RA, environmental risk factors for RA, systemic autoimmunity associated with RA, symptoms without clinical arthritis (arthralgia), or unclassified arthritis. These terms may be combined for an individual patient as applicable.
For additional perspectives on the topic, Rheumatology Advisor interviewed 3 experts: Susan M. Goodman, MD, rheumatologist at the Hospital for Special Surgery, New York, and associate professor of medicine at Weill Cornell Medical College, New York; Christine Peoples, MD, rheumatologist and clinical assistant professor of medicine at the University of Pittsburgh Medical Center; and Joshua F. Baker, MD, MSCE, rheumatologist and assistant professor of rheumatology and epidemiology in the Perelman School of Medicine at the University of Pennsylvania.
Rheumatology Advisor: Can you elaborate on this hypothesized window of opportunity for arthritis prevention?
Dr Goodman: The window of opportunity describes an early period after recognition of RA when the most favorable outcomes appear possible. This theory makes the assumption that there is a process that is critical to the pathophysiology of RA that is switched on after which disease modification and response to treatment becomes much harder. When researchers have analyzed the relationship between symptom duration and achieving drug-free remission, shorter duration of symptoms at the time treatment was initiated did predict a better response.7 This finding has been confirmed in multiple studies, demonstrating decreased radiographic progression and greater likelihood of achieving remission with early treatment.8,9
Early initiation of DMARDs has now become the accepted standard of care and has been included in the recommendations of the American College of Rheumatology and EULAR for treatment of RA.10,11 However, these studies and recommendations are for patients with clinical evidence of RA, not preclinical findings such as arthralgia or autoantibodies, where interventions are aimed at preventing the development of clinical disease in the pre-arthritis phase.
Dr Peoples: It is well established that early treatment of RA results in improved outcomes. Is the general concept that earlier is better enough in terms of treatment, or can we take it a step further with a defined period of time in which early treatment can be capitalized upon? Many rheumatologists recognize a unique window of opportunity when the disease is readily amenable to disease-modifying treatment.
While additional clinical study is needed, 2 large clinical cohorts examined by van Nies et al in 2015 suggested that there is a finite period of time (within the first 6 months or less) in which this window of opportunity exists.7 During this defined period of time, the disease may not be fully established and there is an opportunity to achieve a robust response with DMARDs.
Dr Baker: Patients with RA tend to do better if we recognize the disease early and get them better more quickly. This has stemmed from the idea that if we could identify the disease process before the arthritis starts, perhaps we could prevent the disease from ever really occurring. This is an exciting idea because we are starting to be able to identify people who are at risk for RA. However, we are not particularly good at it yet.
Rheumatology Advisor: What is the recommended approach for early identification of patients with arthralgia in whom clinical arthritis may be prevented?
Dr Goodman: The benefit of intervention at the pre-arthritis stage is not proven, although it is supported by animal models, where treating with immunosuppressant medications as arthritis is induced in animals decreased the severity of the arthritis.12
There have been 2 studies of intervention in the pre-arthritis stage to attempt to prevent the development of RA. In one trial, rituximab was given, delaying the onset of clinical arthritis, and the other trial used dexamethasone injections without changing the onset of arthritis.13,14 The difficulty with this approach is that the accurate recognition of pre-arthritis is difficult, and the optimal candidates, optimal timing, and optimal intervention are not known, so overtreatment is a potential problem.
Dr Peoples: There are several challenges that exist in identifying those patients with arthralgia and/or symptoms that suggest possible arthritis before definite RA develops. The EULAR definition of arthralgia suspicious for progression to RA can be used as one guideline to help identify those patients at risk for RA developing. In an ideal setting, patients would be promptly identified who have arthralgias with certain characteristics and then evaluated by a rheumatologist in a timely manner.
However, patients may or may not be aware of what joint symptoms should cause enough concern to be evaluated by their primary care provider. Certain patients may be more aware of the implications of joint pain compared with others. For example, if a patient’s close relative has RA, then that may prompt the patient to seek evaluation earlier.
Primary care providers need a strategy to identify those patients with arthralgia who should be referred to a rheumatologist. Education at the primary care level along with health care systems that prioritize relationships with primary care providers and specialists can improve the timely referrals to rheumatologists. Improved access to rheumatology specialist care is also an important part of evaluating those patients with arthralgia at risk for progression to RA.
Dr Baker: There is no consensus about how to approach this in clinic. The problem with treating everyone in whom arthritis might possibly develop is that many people in whom the disease might never have developed would end up getting treated inappropriately. In addition, it is probably not a good idea to test every single person with joint pain for evidence of RA. Therefore, the best approach is not clear. Many of us will initiate some form of therapy if there are positive blood tests and characteristic symptoms in a young person; however, there is not an agreed upon approach to testing or management.
Rheumatology Advisor: What are other top takeaways for clinicians?
Dr Goodman: Only a small percentage of those with arthralgia will go on to have RA develop, increasing the challenge of studying this important group. EULAR has defined patients with “arthralgia suspicious for progression to RA” to facilitate further study. Although patients diagnosed with RA have nonspecific symptoms and positive serologies prior to clinical RA developing, much more study is needed so that the appropriate people can be targeted for intervention prior to the development of clear disease.
Dr Peoples: RA is a complex disease that can present early on in different ways in different patients. One major goal is to identify those patients with joint symptoms who are at risk for progression to RA. Fostering relationships between primary care providers and rheumatologists can facilitate identification of those patients at risk for RA developing. Exploring different ways to deliver rheumatology specialist care is also important so that patients with arthralgia can be evaluated early with subsequent follow up if needed.
Additional study is needed on the window of opportunity concept and how best to identify those patients with arthralgia at risk for progression to RA. Fortunately, both of these topics are the focus of several ongoing clinical studies.
- Rantapää-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48(10):2741-2749.
- Sokolove J, Bromberg R, Deane KD, et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis.PLoS One. 2012;7(5):e35296.
- van de Stadt LA, Bos WH, Meursinge Reynders M, et al. The value of ultrasonography in predicting arthritis in auto-antibody positive arthralgia patients: a prospective cohort study. Arthritis Res Ther. 2010;12(3):R98.
- Nam JL Hensor EM, Hunt L, Conaghan PG, Wakefield RJ, Emery P. Ultrasound findings predict progression to inflammatory arthritis in anti-CCP antibody-positive patients without clinical synovitis. Ann Rheum Dis. 2016;75:2060-2067.
- van Steenbergen HW, da Silva JAP, Huizinga TWJ, van der Helm-van Mil AHM. Preventing progression from arthralgia to arthritis: targeting the right patients.Nat Rev Rheumatol. 2018;14(1):32-41.
- Gerlag, DM, Raza K, van Baarsen LGM, 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;71(5):638-641.
- van Nies JAB, Tsonaka R, Gaujoux-Viala C, Fautrel B, van der Helm-van Mil AHM. Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden Early Arthritis Clinic and ESPOIR cohorts. Ann Rheum Dis. 2015;74(5):806-812.
- Lukas C, Combe B, Ravaud P, Sibilia J, Landew R, van der Heijde D. Favorable effect of very early disease-modifying antirheumatic drug treatment on radiographic progression in early inflammatory arthritis: Data from the Étude et Suivi des polyarthrites indifférenciées récentes (study and followup of early undifferentiated polyarthritis).Arthritis Rheum. 2011;63(7):1804-1811.
- Kyburz D, Gabay C, Michel BA, Finckh A; physicians of SCQM-RA. The long-term impact of early treatment of rheumatoid arthritis on radiographic progression: a population-based cohort study.Rheumatology (Oxford). 2011;50(6):1106-1110.
- Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.Ann Rheum Dis. 2017;76(6):960-977.
- Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis.Arthritis Rheumatol. 2016;68(1):1-26.
- Dekkers JS, Schoones JW, Huizinga TW, Toes RE, van der Helm-van Mil AH. Possibilities for preventive treatment in rheumatoid arthritis? Lessons from experimental animal models of arthritis: a systematic literature review and meta-analysis. Ann Rheum Dis. 2017;76(2):458-467.
- Bos WH, Dijkmans BAC, Boers M, van de Stadt RJ, van Schaardenburg D. Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial.Ann Rheum Dis. 2010;69(3):571-574.
- Gerlag DM, et al. 2016 ACR/ARHP Annual Meeting Abstract Supplement. Arthritis Rheumatol. 2016;68 Suppl 10:1-4550.