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Introduction Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by autoantibody production, joint inflammation and bone destruction. Nearly 1/3 of RA patients with the active disease also exhibit a normal range of ESR and CRP. Here we assessed the performance and clinical significance of soluble CD24 (sCD24) as a biomarker of disease activity in RA.Methods A total of 269 RA patients, 59 primary Sjogren’s syndrome (SS) patients, 81 systematic lupus erythematosus (SLE) patients, 76 osteoarthritis (OA) patients and 97 healthy individuals (HC) were included in this study. Soluble CD24 in sera were detected by ELISA. Therefore, the concentration of sCD24 was analyzed in RA patients with different disease activity statuses.Results The sCD24 was significantly increased in RA (2970 pg/mL), compared to other rheumatic diseases (380-520 pg/mL) and healthy individuals (320 pg/mL). Moreover, sCD24 was elevated in 66.67% of early RA and 61.11% of seronegative RA patients. In addition, sCD24 was significantly correlated with the disease activity duration and inflammatory indicators. There was an increased sCD24 in 64.23% of RA patients with normal ESR and CRP.Conclusion The sCD24 could be an inflammatory biomarker in RA patients, especially in early and seronegative patients.