Background/Purpose: Subjects with clinically suspect arthralgia (CSA) are at risk for developing rheumatoid arthritis (RA) and therapeutic interventions may prevent or delay progression. Still, a better identification of potential progressors would minimize exposure to unnecessary treatment. CD4+CXCR5+PD-1hi follicular helper (Tfh) and CD4+ CXCR5-PD-1hi peripheral helper (Tph) T cells are implicated in RA pathogenesis; characterizing their profile in CSA can enhance our understanding of the RA preclinical stage. Therefore, our objective was to examine the frequencies of circulating Tfh (cTfh) and Tph (cTph) cells in CSA.

Methods: Prospective, non-interventional study in patients with CSA (EULAR definition). Immediately upon initial evaluation, peripheral blood was drawn from each patient and an age/gender-matched healthy control (HC). Ficoll-Hypaque isolated PBMCs were examined by cytometry. Patients were subsequently followed until RA onset or alternatively for up to 48 months.

Results: As compared with HC, patients with seropositive (RF and/or ACPA+) (n=32) but not seronegative (n=37) CSA demonstrated expanded baseline frequencies of cTfh and cTph cells. These frequencies were significantly higher in seropositive CSA patients who progressed to develop classified RA vs those who did not. A cTfh cell frequency > 0.66 predicted progression with a sensitivity of 72% and a specificity of 85%. At the time of RA onset, seropositive progressors (n=18) demonstrated a significant further increase of the cTph but not of the cTfh cell frequency.

Conclusion: Seropositive CSA patients demonstrate increased baseline cTfh and cTph cell frequencies. Higher baseline proportions of cTfh cells associate with progression. This may help identify patients who would benefit from therapeutic interventions directed at delaying or preventing RA onset.

Fig. 1. Frequency of circulating Tfh and Tph cells in HC, seronegative CSA (CSA S-) and seropositive CSA (CSA S+) subjects. A. Frequencies of cTfh (left) and cICOS+Tfh cells(right). B. Frequencies of cTph (left) and cICOS+cTph cells (right)

Figure 2. Relation of the baseline cTfh and cTph cell frequencies with the occurrence of progression to inflammatory arthritis in CSA patients. A-D. Baseline cTfh (A), ICOS+cTfh (B), cTph (C), and ICOS+cTph (D) cell frequencies, in CSA patients who did not progress (non-progressors, NP), vs CSA patients who progressed (progressors, P) to develop inflammatory arthritis. Bars in the left panels represent the median and interquartile range; whiskers represent the maximum and minimum values. *p < 0.05, Mann-Whitney test. The right panels show the ROC curves representing the relation of the baseline cTfh (A), ICOS+ cTfh (B), cTph (C) and ICOs+ cTph (D) cell frequencies with the occurrence of progression during the observation period (48 months) (ROC AUC and p values calculated with logistic regression analysis). E. Kaplan-Meier survival curves displaying the probability of progression-free follow-up, stratified using the optimal cTfh cut-off value for progression prediction obtained from the ROC curve.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/expansion-of-pd-1hi-tfh-and-tph-cells-in-the-peripheral-blood-of-seropositive-clinically-suspect-arthralgia-patients-association-with-progression-to-rheumatoid-arthritis/