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Preventing progression from arthralgia to arthritis: targeting the right patients

Key Points

  • Early treatment initiation in patients with clinically manifest rheumatoid arthritis (RA) is associated with improved disease outcomes; hence, disease modulation in pre-arthritis phases might prevent the occurrence of clinical arthritis

  • The inclusion of patients with a low risk of developing RA might dilute possible preventive effects and result in false-negative results in preventive trials

  • Although a symptomatic phase typically precedes clinical arthritis in patients who develop RA, arthralgia is common and is not specific enough to identify patients at risk of developing RA

  • The EULAR definition of 'arthralgia suspicious for progression to RA', which identifies patients with arthralgia at risk of developing RA, is a good starting position for preventive trial participant selection

  • Adequate stratification of patients with arthralgia at risk of developing RA requires a combination of clinical, serological and imaging markers


Early treatment is associated with improved outcomes in patients with rheumatoid arthritis (RA), suggesting that a 'window of opportunity', in which the disease is most susceptible to disease-modifying treatment, exists. Autoantibodies and markers of systemic inflammation can be present long before clinical arthritis, and maturation of the immune response seems to coincide with the development of RA. The pre-arthritis phase associated with symptoms such as as joint pain without clinical arthritis (athralgia) is now hypothesized to fall within the aforementioned window of opportunity. Consequently, disease modulation in this phase might prevent the occurrence of clinically apparent arthritis, which would result in a persistent disease course if untreated. Several ongoing proof-of-concept trials are now testing this hypothesis. This Review highlights the importance of adequate risk prediction for the correct design, execution and interpretation of results of these prevention trials, as well as considerations when translating these findings into clinical practice. The patients' perspectives are discussed, and the accuracy with which RA development can be predicted in patients presenting with arthralgia is evaluated. Currently, the best starting position for preventive studies is proposed to be the inclusion of patients with an increased risk of RA, such as those identified as fulfilling the EULAR definition of 'arthralgia suspicious for progression to RA'.

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Figure 1: Rheumatoid arthritis development over time in relation to the level of inflammation.
Figure 2: Different approaches for identifying individuals at risk of developing rheumatoid arthritis.


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The authors of this Review are supported by grants from the Netherlands Organization for Health Research and Development (Vidi grant) and European Research Council (ERC Starting grant). The funding sources had no role in the writing of the manuscript.

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All authors wrote the article, provided substantial contributions to discussions of its content, and undertook review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Tom W. J. Huizinga.

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The authors declare no competing financial interests.

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van Steenbergen, H., da Silva, J., Huizinga, T. et al. Preventing progression from arthralgia to arthritis: targeting the right patients. Nat Rev Rheumatol 14, 32–41 (2018).

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