The initiation of disease-modifying antirheumatic drugs (DMARDs) promptly after the diagnosis of rheumatoid arthritis (RA) been shown to substantially boost outcomes. Researchers have described this phenomenon as a “window of opportunity” that is open for a limited time. Although there is disagreement on the duration of the window of opportunity in RA, some researchers describe it as lasting only 12 weeks after symptom onset.1 Treatment within the window of opportunity is associated with better therapeutic responses to DMARDs, lower measures of disease activity, and the avoidance of permanent joint damage. Even a delay of as little as 8 to 9 months in starting appropriate therapy with DMARDs has been shown to have a negative impact on disease parameters years later.2 Today, researchers are exploring whether there is another window of opportunity in which drug treatment in patients at high risk for RA might prevent the development of clinically apparent disease.

Strategies for preventing or delaying the onset of RA have been facilitated by a growing understanding of both the autoimmune and inflammatory changes that take place prior to the onset of classifiable RA and the environmental and genetic risk factors that predispose individuals to the disease. The observation that RA-associated biomarkers, such as rheumatoid factor and anticyclic citrullinated peptide (anti-CCP) antibodies are elevated years before the diagnosis of clinically classifiable RA has allowed patients to be selected for clinical trials and eventual preventive treatment.3-5

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To date, trials of glucocorticoids, conventional synthetic DMARDs, and biologic DMARDs for the prevention or delay of RA symptoms in patients with preclinical RA have yielded varied results.6 The randomized, placebo-controlled Prevention of RA by Rituximab trial investigated the B-cell depleting monoclonal antibody rituximab in patients with arthralgia (but without clinical evidence of arthritis) and with positivity for both anti-CCP and rheumatoid factor. Results demonstrated that a single intravenous dose of rituximab did not prevent the development of RA; however, patients in the rituximab arm experienced a significant delay in arthritis development of 12 months compared with those who received placebo.7 In the Steroids In Very Early Arthritis trial, intramuscular injections of glucocorticoids over 3 weeks prevented 1 in 10 patients with very early inflammatory polyarthritis from having progression to RA.8 Another prevention trial, Strategy to Prevent the Onset of Clinically Apparent Rheumatoid Arthritis (StopRA ) trial, is currently underway. StopRA is designed to determine whether hydroxychloroquine, a relatively benign drug already used successfully in the treatment of RA and other diseases, can safely prevent RA in individuals at high risk for future RA resulting from high titer elevations of anti-CCP3.9

Balancing between the risks and benefit of preventive treatment for RA is likely to be challenging. Kevin Deane, MD, PhD, Associate Professor of Medicine at the University of ColoradoSchool of Medicine and principal investigator for the StopRA trial, told Rheumatology Advisor that patients with anti-CCP over a certain threshold have a 30% to 50% risk for the disease developing within 3 to 5 years. Given the inability to precisely determine in which patients full-blown disease will eventually develop, patients at risk for RA may be reluctant to consider the use of medications carrying adverse effects and uncertain benefit in the absence of symptoms.10,11 Authors of a recent review summarizing the adverse events that occurred in trials for the prevention of RA concluded that the risk for serious adverse events, defined as episodes requiring hospitalization or resulting in death, with the use of conventional synthetic or biologic DMARDs was small. “If such therapies prove effective at preventing or considerably delaying the onset of RA, incorporating patient preferences as well as robust quantification of benefits/harms would be vital,” they wrote.6

“We would ideally want to get to the point where we’re screening people in the general population to find those who are at risk, just by doing routine bloodwork — similar to cardiovascular prevention, where people get their cholesterol checked even if they feel fine, and then are treated based on the results,” Dr Deane told Rheumatology Advisor. However, he noted that many people in the preclinical phase of RA are not entirely asymptomatic and may indeed realize discernable benefits from preventive treatment. “Some of these individuals may have some aches or pains or stiffness or joint symptoms but not have any defined inflammatory arthritis on examination. They may have more fatigue and an increased range of mood disorders in this early period. Even though they may not have full-blown arthritis, their immune system can be telling them something that hey, things aren’t right, there’s something wrong.

“More research is needed to learn more and find the way to predict risk more accurately and also to identify what treatments can be beneficial,” noted Dr Deane. “But there’s a range of things people may be able to do to help prevent RA, ranging from low-potency, low-risk drugs, to ones with higher risk. Researchers are still figuring out how to determine what is the risk for each patient, what’s the right intervention and what risk will each patient be willing to take. Meanwhile, there are likely lifestyle interventions that can be beneficial for those who feel they’re at risk for RA because they have a family member with RA, or who know that they have these blood markers. Weight loss and exercise are important. Patients may benefit from sticking to an immune health diet, like the Mediterranean diet. Smoking cessation is beneficial because smoking is a risk factor for getting RA. These are things everybody can do now. Beyond that we are going to have to wait to see what drugs work and what the risk and benefits are.

Quotes have been lightly edited for clarity.

References

1. van Nies JAB, Krabben A, Schoones JW, Huizinga TWJ, Kloppenburg M, van der Helm-van Mil AHM. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis. 2014;73(5):861-870.

2. O’Dell JR. Treating rheumatoid arthritis early: a window of opportunity? Arthritis Rheum. 2002;46(2):283-285.

3. Deane K. Can rheumatoid arthritis be prevented? Best Pract Res Clin Rheumatol. 2013;27(4):467-485.

4. Deane KD. Preclinical rheumatoid arthritis and rheumatoid arthritis prevention. Curr Rheumatol Rep. 2018;20(8):50.

5. Mankia K, Emery P. A new window of opportunity in rheumatoid arthritis: targeting at-risk individuals. Curr Opin Rheumatol. 2016;28(3):260-266

6. Costello R, David T, Jani M. Impact of adverse events associated with medications in the treatment  and prevention of rheumatoid arthritis. Clin Ther. 2019;41(7):1376-1396.

7. 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;78(2):179-185.

8. Verstappen SMM, McCoy MJ, Roberts C, Dale NE, Hassell AB, Symmons DPM. Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial. Ann Rheum Dis. 2010;69(3):503-509.

9. ClinicalTrials.gov, Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis (StopRA). NCT02603146. https://clinicaltrials.gov/ct2/show/NCT02603146. Updated September 2, 2019. Accessed September 23, 2019.

10. Mosor E, Stoffer‐Marx M, Steiner G, et al. I would never take preventive medication! Perspectives and information needs of people who underwent predictive tests for rheumatoid arthritis [published online February 2, 2019]. Arthritis Care Res. doi:10.1002/acr.23841

11. Falahee M, Finckh A, Raza K, Harrison M. Preferences of patients and at-risk individuals for preventive approaches to rheumatoid arthritis. Clin Ther. 2019;41(7):1346-1354.