Introduction T-cells are thought to be key players in the initiation and progression of rheumatoid arthritis (RA). Earlier we showed that already at the seropositive at-risk stage uninflamed synovial tissue contains T-cell infiltrates.¹ In another study we showed that inflamed synovium harbours expanded T-cell clones.²

Objectives Following up on these observations, we longitudinally investigated whether the expanded T-cell clones found in the inflamed synovial tissue at onset of RA are already present in the at-risk stage.

Methods Next-Generation Sequencing of the TCRβ repertoire was performed on 20 randomly selected individuals with elevated IgM-RF and/or ACPA levels. Ten individuals did not develop RA during at least 3 years of follow-up, and 10 individuals did. Peripheral blood and synovial tissue samples were analysed during the at-risk phase and, for individuals that developed RA, again after RA onset. T-cell clones were identified by their unique TCRβ sequence.³ For each sample 3,570 TCRβ sequences were analysed.

Results During the at-risk phase the TCRβ repertoire in the synovium is characterised by expanded clones. This is observed both in at-risk individuals that did and did not develop RA. Interestingly, a higher impact of expanded clones inversely correlated with a longer disease-free follow-up time (p=0.02). During progression to RA, the at-risk TCRβ repertoire is largely maintained in the tissue. Further characterisation of the synovial CDR3 sequences showed no significant differences between clones that were maintained in the tissue during progression to clinical disease and clones that were uniquely present in the at-risk phase or at RA onset.

Conclusions Expanded T-cell clones are present in the synovial tissue in the at-risk phase regardless of future development of RA, and are maintained after onset of clinical disease. The resemblance in TCRβ repertoires indicates that the process leading to disease – at least at the T-cell level – constitutes a smooth development. Elucidating the role of these synovial T cells (resident memory, regulatory or autoreactive) might help understanding the earliest pathogenic events in RA.

References

1. . de Hair MJ, et al. Arthritis Rheum2014.

2. . Klarenbeek PL, et al. Ann Rheum Dis2012.

3. . Klarenbeek PL, et al. Immunol Lett2010.

Acknowledgements MED, NdV, DMG and PPT received support from BTCURE, a research project from the Innovative Medicines Initiative Joint Undertaking (grant no 115142–2), NdV from the Dutch Arthritis Foundation, and from ZonMw, the Netherlands Organisation for Health Research and Development, in the program 2Treat (Grant 436001001).

Disclosure of interest None declared