New research published in Rheumatology International has identified elevated circulating markers of endoplasmic reticulum (ER) stress and apoptosis in patients with rheumatoid arthritis (RA), with caspase-3 and caspase-9 showing independent associations with the disease. The findings add to growing evidence that cellular stress pathways may contribute to the pathophysiology of RA beyond the conventional focus on inflammation.
Although dysregulated immune and inflammatory pathways are central to RA, increasing evidence suggests that ER stress and activation of the unfolded protein response (UPR) may also influence immune-cell function, inflammatory signalling and tissue injury. ER stress occurs when misfolded or unfolded proteins accumulate within the endoplasmic reticulum, triggering cellular mechanisms designed to restore protein homeostasis. Persistent or excessive ER stress can activate pathways leading to apoptosis.
To investigate the relationship between these pathways and RA, researchers conducted an observational case-control study at the Rheumatology Clinic of Sivas Cumhuriyet University Faculty of Medicine Hospital between 2021 and 2022. The study included 35 patients with RA and 32 age- and sex-matched healthy controls. Serum concentrations of six biomarkers associated with ER stress and apoptosis were measured, including glucose-regulated protein 78 (GRP78), eukaryotic initiation factor 2 alpha (eIF2α), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), caspase-3 and caspase-9. Disease activity among patients with RA was assessed using the Disease Activity Score-28 (DAS28).
The analysis showed significantly higher serum concentrations of GRP78, ATF4, eIF2α, caspase-3 and caspase-9 in patients with RA compared with healthy controls. All of these differences reached statistical significance (p < 0.01). In contrast, serum CHOP concentrations did not differ significantly between the two groups (p = 0.103).Among the biomarkers examined, caspase-3 demonstrated the greatest ability to distinguish patients with RA from healthy controls. Receiver operating characteristic analysis showed an area under the curve of 0.774 (95% confidence interval [CI], 0.656–0.891; p < 0.001).
Multivariable analysis provided further evidence for the potential relevance of apoptosis-related pathways. Both caspase-3 and caspase-9 remained independently associated with RA after adjustment for other variables included in the analysis. Caspases are key components of programmed cell death, with caspase-9 involved primarily in the intrinsic mitochondrial pathway and caspase-3 acting as a major downstream executioner caspase. Their elevation may therefore reflect increased apoptotic activity or altered regulation of cell-death pathways in RA.
Despite the differences observed between patients and controls, the researchers did not identify significant correlations between the measured ER stress-related biomarkers and DAS28 scores. This suggests that circulating concentrations of these markers may not directly reflect the current level of clinical disease activity. Consequently, their potential role may be more closely related to underlying disease mechanisms than to routine monitoring of inflammatory activity.
The findings are consistent with the emerging concept that persistent ER stress and an inadequately resolved UPR may contribute to chronic autoimmune inflammation. In RA, sustained cellular stress could potentially affect immune-cell activation, cytokine production, synovial-cell function and tissue homeostasis. However, the present study cannot determine whether ER stress and apoptosis are causes of RA, consequences of chronic inflammation or part of a reciprocal process.
Overall, the study provides further evidence that ER stress and apoptosis-related pathways are altered in patients with RA and identifies caspase-3 and caspase-9 as potential biomarkers worthy of further investigation. Larger prospective studies involving diverse patient populations will be needed to determine whether these markers can improve RA diagnosis, provide information about disease prognosis or predict treatment response. If validated, biomarkers reflecting cellular stress and apoptosis could potentially complement conventional inflammatory markers and contribute to a broader understanding of the molecular mechanisms underlying RA.
Reference
Isık BY, Babayigit A, Dogan HO, Sahin A. Endoplasmic reticulum stress and apoptosis-associated biomarkers in rheumatoid arthritis: an exploratory case-control study. Rheumatol Int. 2026 Jul 14;46(8):202.