Levels of CXCL9, CXCL10, and CXCL11 Reflect Pulmonary and Multi-Organ Severity in GRADS

Background Sarcoidosis is a granulomatous disease with heterogeneous clinical manifestations and limited reliable biomarkers to support disease assessment and management. The IFN-γ–inducible chemokines, CXCL9, CXCL10, and CXCL11, are involved in sarcoidosis pathophysiology and have been associated with pulmonary abnormalities and multi-organ involvement. This study aimed to replicate these associations in a large, multicenter sarcoidosis cohort. Methods Chemokine levels were measured by ELISA in serum samples from the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) cohort (n=353). Cross-sectional associations with percent predicted FVC, FEV1, DLCO, chest radiographic Scadding stage, and number of involved organs were assessed with multivariable linear and Poisson regression modeling with adjustment for immunosuppression, enrollment site, relevant demographics, and smoking, where applicable. Additional analyses evaluated the same associations with 12 other clinical blood tests. Results Higher levels of all three chemokines were associated with lower percent predicted pulmonary function values, with CXCL11 showing the largest effect sizes (−9.9 to −11.6% per 10-fold increase). All three chemokines were also associated with higher Scadding stage, again largest for CXCL11 (31.4% increase per category), and greater organ number, largest for CXCL11 (59% increase per 10-fold increase). In contrast, none of the other blood tests demonstrated consistent associations across all clinical features. Conclusions These results replicate and extend prior observations that CXCL9, CXCL10, and CXCL11 are associated with the degree of pulmonary impairment, radiographic extent, and total organ involvement in sarcoidosis. Prospective studies are needed to define their role in longitudinal monitoring and clinical decision-making.