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June 13, 2026Open Access

Soluble IL-2 receptor and memory Treg profiles differentiate early rheumatoid arthritis from undifferentiated arthritis at initial presentation

XZXiaoyu ZiShanxi Medical University YSYifang ShiShanxi Medical University YZYicong ZhaoShanxi Medical University

Key Points

The aim is to differentiate early rheumatoid arthritis from undifferentiated arthritis using immune profiling.
Enrolled 83 treatment-experienced RA, 49 treatment-naïve RA, 51 seropositive undifferentiated arthritis patients, and 60 healthy controls.
Profiled peripheral lymphocyte subsets and serum cytokines with flow cytometry and bead arrays.
Utilized LASSO regression to develop a classifier with bootstrap resampling for internal validation.
Identified distinct immune profiles between TN-RA and UA.
Constructed an eight-feature immune signature with an AUC of 0.959 (95% CI: 0.923–0.995) for distinguishing TN-RA from UA.
sIL-2R and IL-6 were significant contributors indicating their important roles in rheumatoid arthritis.

Abstract

Background Rheumatoid arthritis (RA) is a significant global health issue. Early diagnosis remains clinically challenging, particularly in patients with inflammatory arthritis who do not yet fulfill 2010 ACR/EULAR classification criteria (undifferentiated arthritis, UA). Methods This retrospective study enrolled 83 treatment-experienced RA (TE-RA), 49 treatment-naïve RA (TN-RA), and 51 seropositive UA patients, as well as 60 healthy controls. Peripheral lymphocyte subsets and serum cytokines were profiled using flow cytometry and bead arrays. Least absolute shrinkage and selection operator (LASSO) regression was utilized to develop an immune-based derivation-stage classifier for distinguishing TN-RA from UA, with internal validation by bootstrap resampling (B = 1000). Results Immunophenotypic analysis identified distinct immune profiles between TN-RA and UA at initial presentation. TN-RA was characterized by IL-2 signaling exhaustion (elevated sIL-2R, decreased IL-2), systemic inflammation (elevated IL-6, IFN-γ, and TNF-α), and compensatory memory Treg expansion (increased CD45RO+ Tregs). In contrast, UA exhibited a Th17/Treg imbalance with relatively preserved Th2 and Th17 responses. An eight-feature immune signature (sIL-2R, IL-6, CD45RO+ Tregs, CD45RO+ Treg%, IFN-γ, Th17/Treg ratio, Th2, Th17%) discriminated TN-RA from UA with an optimism-corrected AUC of 0.959 (95% CI: 0.923–0.995), adjusted for age, sex, BMI, and disease duration. sIL-2R and IL-6 were the strongest contributors, consistent with their central roles in RA pathophysiology. Conclusions In the present study, an immune-based derivation-stage classifier showed potential for distinguishing TN-RA from UA at initial presentation. The IL-2-Treg axis perturbation represents a potential pathophysiological distinction, with sIL-2R as a candidate biomarker. These findings suggest that objective immune profiling may inform clinical decision-making when conventional criteria are inconclusive.

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