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Rheumatoid arthritis prevention in arthralgia: fantasy or reality?

Abstract

The concept of a ‘window of opportunity’ in treating a disease assumes the existence of a time frame during which the trajectory of the disease can be effectively and permanently modified. In rheumatoid arthritis (RA), optimal timing of this period is presumed to be during the phase before arthritis is clinically apparent and disease is diagnosed. Several proof-of-concept trials of treatment during the ‘arthralgia’ phase of RA have been completed in the past 4 years, with the underlying notion that temporary treatment at this stage could prevent the development of RA or induce a sustained reduction in the burden of disease. This Review summarizes the results of these trials and reflects on the outcomes in relation to the patients’ perspectives. Overall, the majority of symptomatic at-risk individuals could benefit from a fixed period treatment, even if RA does not develop. Various factors must be taken into consideration when translating these findings into clinical practice. More evidence is needed to target the individuals at highest risk, and additional tools are needed to monitor treatment and guide decisions about whether treatment can be discontinued. Without these tools, there is a paradoxical risk of seemingly increasing the incidence of the disease and prolonging disease duration, which is the opposite of what the concept of intervening in the window of opportunity entails.

Key points

  • The therapeutic ‘window of opportunity’ in rheumatoid arthritis presumes that disease processes are less matured and more modifiable in the symptomatic pre-arthritis phase, fuelling the design of ‘prevention trials’.

  • Although the populations studied in these trials varied slightly, the at-risk individuals included those with a combination of symptoms (clinically suspect arthralgia), autoantibodies and subclinical inflammation on imaging.

  • The first ‘proof-of-concept’ prevention trials suggest that disease modification could be possible with temporary treatment initiated in an at-risk pre-arthritis phase.

  • Nonetheless, treatment in a symptomatic at-risk phase without clinical arthritis is not yet recommended by any treatment guideline.

  • Before findings can be implemented, validated tools are needed for risk stratification to guide treatment-start decisions and for monitoring (a ‘disease activity score for clinically suspect arthralgia’) to guide treatment-withdrawal decisions.

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Fig. 1: Conceptual difference between disease suppression and prevention.
Fig. 2: Duration of DMARD treatment for rheumatoid arthritis: current, ideal and worst-case scenarios.

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All authors researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. H.W.v.S. and A.H.M.v.d.H.-v.M. wrote the article.

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Correspondence to Hanna W. van Steenbergen or Annette H. M. van der Helm-van Mil.

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van Steenbergen, H.W., Cope, A.P. & van der Helm-van Mil, A.H.M. Rheumatoid arthritis prevention in arthralgia: fantasy or reality?. Nat Rev Rheumatol 19, 767–777 (2023). https://doi.org/10.1038/s41584-023-01035-y

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