Cytokine and chemokine profile in rheumatoid arthritis patients with and without interstitial lung disease: a systematic review and meta-analysis integrating demographic, serological, and clinical comparisons

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe extra-articular complication of RA, contributing significantly to morbidity and mortality. Despite its impact, the immunological mechanisms driving RA-ILD remain poorly understood. This systematic review and meta-analysis aims to define a distinct immunological signature for RA-ILD and evaluate its associations with demographic, serological, and clinical parameters. Following PRISMA guidelines, we searched PubMed, Scopus, and Web of Science for studies comparing cytokine and chemokine levels in RA-ILD vs. RA patients without ILD. Eligible studies measured these molecules in biological samples and were published in English. Data were extracted on study characteristics, cytokine/chemokine levels, and clinical, serological, and demographic parameters. Meta-analyses used standardized mean differences for continuous outcomes and risk differences for dichotomous outcomes, with heterogeneity assessed via I2 and Cochran's Q tests. Narrative synthesis explored correlations due to heterogeneous reporting. From 2000 articles, 15 studies involving 3,433 patients (715 RA-ILD, 2,718 RA-no ILD) were included. RA-ILD patients exhibited elevated levels of six chemokines (CCL2, CCL4, CCL18, CXCL8, CXCL10, SDF-1α) and 11 cytokines (IL-1α, IL-4, IL-6, IL-11, IL-13, IL-18, IL-23, IL-33, IL-36α, IL-36γ, TGF-β), with reduced IL-22, forming a distinct immunological profile. RA-ILD patients had elevated anti-CCP, CRP, and RF levels, indicating heightened autoimmunity and greater disease activity. Correlations linked IL-13 and TGF-β to disease severity, while IL-22 and IL-36γ showed protective roles. This meta-analysis establishes a pioneering cytokine and chemokine profile distinguishing RA-ILD from RA, offering potential for early diagnosis and monitoring. Complementary demographic, serological, and clinical findings underscore RA-ILD's distinct pathogenesis.