Shifting Perspectives: New Context for the Therapeutic Window of Opportunity in RA

The therapeutic window of opportunity is well-known in rheumatology, first described by researchers in 1992.¹ However, since that time, there have been dramatic changes in outcomes for patients with rheumatoid arthritis (RA).¹

Anette H. van der Helm-van Mil, MD, PhD, from the Department of Rheumatology at Leids University Medical Center in Leiden, The Netherlands, and Erasmus Medical Center in Rotterdam, The Netherlands, and colleagues, aimed to define the therapeutic window of opportunity in RA using the most recent data from current medical literature. Results of this viewpoint article were published in RMD Open.²

“We explored whether there was consensus in terms of the long-term outcomes that were considered to benefit from early treatment, as well as on the time period, expressed as disease duration, that was proposed to cover the window of opportunity,” Dr van der Helm-van Mil and colleagues noted.² “Second, we determined the level of evidence for the association between the timing of intervention and the disease outcomes.”

Literature Review

To construct these definitions, Dr van der Helm-van Mil and colleagues conducted a systematic literature review of 75 randomized controlled trials to evaluate the difference between early vs delayed RA treatment using disease-modifying antirheumatic drugs (DMARDs).² Patients with undifferentiated arthritis and arthralgia without clinically apparent arthritis were also included.²

A review was first conducted to determine the timing of the window of opportunity. Forty-nine percent of articles in the literature review did not include an exact duration of this timeframe; rather, general terms like “early,” or a disease phrase, such as “preceding radiographic damage” or “preceding RA development,” were used.² Articles that described the treatment window as the first 2 years following disease onset were primarily written and published in the 1990s and early 2000s²; articles that shortened that period to the first 12 weeks or 3 months following symptom onset were published after 2010.²

Among the articles included in the review, 35% described possible long-term treatment outcomes using general clinical terms like “sustained clinical benefits” or “better outcomes.”² The prevention or slowing of radiographic damaged and remission (clinical remission, Disease Activity Score remission, or drug-free remission) were the 2 most frequently mentioned outcomes.² In addition, 6 articles explained that treatment within the prescribed window of opportunity could result in a cure or RA prevention.²

“[T]he definition of the window of opportunity as was retrieved from the literature revealed that the concept has changed over time,” Dr van der Helm-van Mil and colleagues noted. “Whereas it was previously defined as a treatment period in the first 2 years after disease onset in which joint damage could be halted (‘old definition’), it is increasingly considered to represent a period before the diagnosis is established in which new treatment could potentially prevent RA development (‘new definition’).”²

Overview: Old vs New Perspectives

The initial definition of the therapeutic window of opportunity was a short time frame — approximately 2 years following diagnosis — in which clinicians could treat patients to remission before “irreversible damage” was done to joints.² In a 1992 paper, Peter T. Dawes, MD, and colleagues compared the onset of RA to that of a fire: “A fire that smolders and spreads slowly from room to room may ultimately cause more damage than a blaze which is rapidly extinguished.”¹

In the literature review conducted by Dr van der Helm-van Mil and colleagues,² 5 randomized controlled trials demonstrated a “significant benefit” in patients who initiated early DMARD treatment. Eight randomized controlled trials examined functional disability, and found that DMARD initiation in the early group (6-12 months before the delayed group) resulted in improved functional outcome.² Additional clinical studies have found that disease duration at the time of initiation of DMARD therapy is a “significant predictor of response to treatment.”^3,4

“We have … demonstrated that there is convincing evidence for this effect based on data from [randomized controlled trials],” the researchers wrote.² “Notably, earlier treatment resulted in absolute lower levels of radiographic joint destruction and in slower progression rates.”

In contrast to the old window, the new therapeutic window of opportunity includes patients currently in a phase prior to RA diagnosis or fulfilment of RA classification criteria — for example, patients with arthralgia without clinical arthritis or undifferentiated arthritis.² In these patients, the therapeutic window is a pre-RA phase in which “biologic processes could be halted and RA development prevented by very early treatment.”²

In the literature review,² Dr van der Helm-van Mil and colleagues found 1 randomized controlled trial that included seropositive patients with arthralgia. Patients in this trial randomly received either dexamethasone or placebo, and were followed for a median of 26 months, at which point there was “no difference in arthritis development between the 2 arms.”² Six articles, reporting data from 5 randomized controlled trials, focused on patients with undifferentiated arthritis. These trials compared DMARD and placebo therapies; none resulted in a significant difference in primary study outcome.² As such, the “new definition” remains unsupported by evidence from randomized controlled trials.²

Despite the lack of evidence from randomized controlled trials, clinical researchers have continued to examine the concept of pre-treatment for RA. Although it lacks a standardized definition,⁵ preclinical RA — and associated RA-related autoimmunity — can be identified by the presence of anti-citrullinated protein antibodies and rheumatoid factor in serum samples.⁶

Defining Challenges

“Interpreting data from studies addressing the concept of a window of opportunity is challenging,” the researchers wrote.²

One such challenge is the understanding of duration. According to Dr van der Helm-van Mil and collages, studies reporting on the so-called window of opportunity simply report the disease duration, and conclude that patients “with a disease duration of less than x months” are more likely to have improved outcomes compared with patients with a disease duration greater than x months.² However, the duration of when x months begins is often “inadequately” described.²

“Clearly, adopting different definitions of a starting point for the disease onset will lead to different durations of the therapeutic window,” the authors noted.²

Another challenge is determining when — or if — a window of opportunity is required to close. Is there a time after which intervention becomes comparatively ineffective? There is often limited discussion of why treatment durations were chosen, and only 1 study evaluated treatment timeframe and provided evidence that a confined treatment period is more likely than a simple “the earlier the better” explanation.^2,7,8

Karim Raza, PhD, and Andrew Filer, PhD, also probed this question, pointing out that opening the window in relation to the earliest “relevant” RA symptoms is “hugely challenging.”⁸ They suggest that future studies in this area address the length of the therapeutic window of opportunity in relation to different types of RA onset.⁸

Conclusions

“While the concept of a window of opportunity in RA is widely used, different definitions of this window exist,” Dr van der Helm-van Mil and colleagues concluded. “As there were relatively few trials performed in pre-RA phases, more research is needed to verify the new definition.”²

References

1. Dawes PT, Symmons DPM. Short-term effects of antirheumatic drugs. Baillières Clin Rheumatol. 1992;6(1):117-140.

2. Burgers LE, Raza K, van der Helm-van Mil AH. Window of opportunity in rheumatoid arthritis — definitions and supporting evidence: From old to new perspectives. RMD Open. 2019;5(1):e0008.

3. Nam JL, Emery P. Is there a place for initial treatment with biological DMARDs in the early phase of RA? Best Pract Res Clin Rheumatol. 2013;27(5):537-554.

4. Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 2000;43(1):22-29.

5. Marotte H. Determining the right time for the right treatment-application to preclinical rheumatoid arthritis. JAMA Netw Open. 2019;2(6):e195358.

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

 7. Nagy G, van Vollenhoven RF. Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now? Arthritis Res Ther. 2015;17:181.

 8. Raza K, Filer A. The therapeutic window of opportunity in rheumatoid arthritis: does it ever close? Ann Rheum Dis. 2015;74(5):793-794.