Endoplasmic reticulum stress and apoptosis-associated biomarkers in rheumatoid arthritis: an exploratory case-control...

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction, leading to functional disability and reduced quality of life. Beyond classical inflammatory pathways, increasing evidence indicates that endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) contribute to immune dysregulation and chronic inflammation in RA. However, the clinical relevance of circulating ER stress-related biomarkers in RA remains insufficiently defined. This study aimed to evaluate serum levels of ER stress-related and apoptosis-associated markers in patients with RA, to assess their ability to discriminate RA from healthy individuals, and to explore their associations with inflammatory parameters and disease activity. This observational case-control study was conducted between 2021 and 2022 at the Rheumatology Clinic of Sivas Cumhuriyet University Faculty of Medicine Hospital. This observational case-control study included 35 patients with RA and 31 age- and sex-matched healthy controls. Serum levels of GRP78, eIF2α, ATF4, CHOP, caspase-3, and caspase-9 were measured using enzyme-linked immunosorbent assay. Disease activity was assessed using the Disease Activity Score-28 (DAS28). Statistical analyses included group comparisons, receiver operating characteristic curve analysis, and Spearman correlation analyses. A total of 67 participants (35 RA, 32 controls) were included. GRP-78, ATF4, eIF2α, caspase-3, and caspase-9 levels were significantly higher in RA patients (all p < 0.01), whereas CHOP levels were comparable between groups (p = 0.103). Caspase-3 demonstrated the highest discriminatory performance (AUC = 0.774, 95% CI: 0.656-0.891; p < 0.001). Caspase-3 and caspase-9 remained independently associated with RA in multivariable analysis. No significant correlations were observed between ER stress markers and DAS28 scores. Circulating ER stress-related apoptotic markers, particularly caspase-3 and caspase-9, were found to be associated with rheumatoid arthritis and may represent exploratory candidate biomarker signals reflecting the potential involvement of ER stress-apoptosis pathways in disease pathophysiology.