The Natural Sequence in Which Subclinical Inflamed Joint Tissues Subside or Progress to Rheumatoid Arthritis: A Study of Serial MRIs in the TREAT EARLIER Trial

Doortje I. Krijbolder*, Xanthe M.E. Matthijssen, Bastiaan T. van Dijk, Hanna W. van Steenbergen, Debbie M. Boeters, Annemiek Willemze, Anne A. Schouffoer, Annette H.M. van der Helm-van Mil

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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The natural trajectory of clinical arthritis progression at the tissue level remains elusive. We hypothesized that subclinical inflammation in different joint tissues (synovitis, tenosynovitis, osteitis) increases in a distinct temporal order in patients with clinically suspect arthralgia (CSA) who develop rheumatoid arthritis (RA) and subsides in a different sequence when CSA spontaneously resolves. 


We studied 185 serial magnetic resonance images (MRIs) from CSA patients with subclinical joint inflammation from the placebo arm of the TREAT EARLIER trial: 52 MRIs from 21 RA progressors (MRIs conducted at 1 year before, at 4 months before, and upon RA development), and 133 MRIs from 35 patients with spontaneous resolution of pain (MRIs conducted at baseline and at 4, 12, and 24 months). MRIs were scored for osteitis, synovitis, and tenosynovitis. We used cross-lagged models to evaluate 2 types of time patterns between pairs of inflamed tissues: a simultaneous pattern (coinciding changes) and a subsequent pattern (inflammatory changes in 1 tissue preceding changes in another tissue). 


In patients who developed RA, synovitis, tenosynovitis, and osteitis increased simultaneously. Increasing osteitis occurred in the final 4 months before RA diagnosis, following incremental tenosynovitis and synovitis changes during the 1 year to 4 months before diagnosis (P < 0.01). In anti–citrullinated protein antibody (ACPA)-positive and ACPA-negative patients who progressed to RA, osteitis increased just before RA development. In patients with pain resolution, simultaneous decreases in synovitis, tenosynovitis, and osteitis occurred, with tenosynovitis decreasing in the first 4 months after CSA onset preceding decreasing synovitis and osteitis during 4–12 months (P = 0.02 and P < 0.01). 


We identified natural sequences of subclinical inflammation in different joint tissues, which deepens our understanding of clinical arthritis and RA development. During RA progression, increasing osteitis followed previous increases in tenosynovitis and synovitis. During pain resolution, tenosynovitis decreased first, followed by decreasing synovitis and osteitis.

Original languageEnglish
Pages (from-to)1512-1521
Number of pages10
JournalArthritis and Rheumatology
Issue number9
Early online date24 Apr 2023
Publication statusPublished - Sept 2023

Bibliographical note

Funding Information:
We thank G. Kracht for assistance in preparing the MRIs for Figure 3.

Funding Information:
Supported by a ZonMW grant (programma translationeel onderzoek), by the European Research Council under the European Union's Horizon 2020 research and innovation programme (starting grant, agreement number 714312), and by the Dutch Arthritis Society.

Publisher Copyright:
© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.


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