T-cell subset biomarkers across the rheumatoid arthritis disease continuum: from clinical utility to adoption in daily practice

The biomarker potential of CD4+T cell subsets (naive, regulatory (Treg), inflammation-related cells (IRC)) in patients with rheumatoid arthritis (RA) has been described. OBJECTIVE: This article investigates the dynamic changes in these biomarkers across the RA disease continuum from at-risk to drug-induced remission. METHODS: T cell subset biomarker data were acquired using flow cytometry. Multiple group comparison were performed using ANOVA test (with Bonferroni correction). RESULTS: In individuals at-risk of RA, longitudinal analysis showed that IRC frequencies increased just prior to onset of clinical synovitis, while naïve T cell frequencies reduced in those progressing to clinical synovitis, but increased in non-progressors. The use of naïve/IRC data improved the accuracy of RA classification, especially in ACPA-negative patients. A distinct T cell biomarker signature was observed in late-onset RA (>60 years old vs <59). In untreated RA, the predictive value of naïve T cell frequencies for methotrexate response was confirmed. For patients on methotrexate, naïve T cells increased only between 6-12 months and only when in remission. IRC and Treg showed no consistent change. In patients treated with TNF inhibitors, naïve T cell frequency increased independently of response, whilst sustained IRC reductions and Treg increases were seen in remission. Once in stable clinical remission, only naive frequencies increased with the length of remission on conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), whilst only Treg increased over time in TNF inhibitor-induced remission. CONCLUSION: These studies validated that T cell subset measurements are independent from other currently used biomarkers, highlighting differences in the impact of drug modes of action on the three T cell subsets. There is still an unmet need for biomarkers to predict response to TNF-inhibition in early RA.