Our objective was to analyse the relationship between circulating cytokines, autoantibodies, acute phase reactants, and disease activity in DMARDs-naïve rheumatoid arthritis (RA) patients ( 𝑛 = 1 4 0 ). All cytokines were significantly higher in the RA cohort than in healthy controls. Moderate-to-strong positive intercorrelations were observed between Th1/Th2/macrophage/fibroblast-derived cytokines. RF correlated significantly with IL-1β, IL-2, IL-4, IL-10, IL-12, G-CSF, GM-CSF, IFN-γ, and TNF ( 𝑃 < . 0 0 0 1 ), and aCCP and aMCV with IL-1β, IL-2, IL-4, and IL-10 ( 𝑃 < . 0 0 0 2 ), while IL-6 correlated best with the acute phase reactants, CRP, and SAA ( 𝑃 < . 0 0 0 1 ). In patients with a DAS28 score of ≥5.1, IFN-γ, IL-1β, IL-1Ra, TNF, GM-CSF, and VEGF were significantly correlated ( 𝑃 < . 0 4 - . 0 0 1 ) with high disease activity (HDA). Circulating cytokines in RA reflect a multifaceted increase in immune reactivity encompassing Th1 and Th2 cells, monocytes/macrophages, and synovial fibroblasts, underscored by strong correlations between these cytokines, as well as their relationships with RF, aCCP, and aMCV, with some cytokines showing promise as biomarkers of HDA.