Relationship Between Serum Interleukin-6 Levels, Systemic Immune-Inflammation Index, and Other Biomarkers Across Different Rheumatoid Arthritis Severity Levels

Abstract

Background Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation, pain, and progressive disability. Identifying biomarkers that accurately reflect disease severity is crucial for effective management. Interleukin-6 (IL-6) is a pro-inflammatory cytokine involved in the pathogenesis of RA, and the systemic immune-inflammation index (SII) is emerging as a useful marker of systemic inflammation. This study aims to explore the relationship between serum IL-6 levels, SII, and various biomarkers to better predict disease severity in RA patients. Objective To determine the relationship between serum IL-6 levels and the SII, along with various biomarkers, across different severity levels for predicting the severity of RA in patients. Methods This cross-sectional, observational study was conducted at the Mardan Medical Complex from January 2024 to August 2024, involving 67 RA patients. Clinical assessments included demographic data, disease activity (DAS28), pain (VAS), joint damage (Larsen score), and functional status (HAQ-DI). Serum IL-6 levels, along with other biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and the SII, were measured through fasting blood samples. Statistical analyses, including density plots, scatter plots, boxplots with ANOVA, and random forest models, were performed to explore associations between IL-6 and all other variables. Significance was set at p < 0.05. Results The study included 67 RA patients (mean age: 41.79 ± 10.51 years, 53.73% male). Elevated IL-6 levels (mean: 80.28 ± 35.27 pg/mL) were strongly associated with disease severity. Patients with DAS28 > 5.5 had IL-6 levels over 100 pg/mL, while those in remission had around 40 pg/mL. IL-6 levels correlated with joint damage (100 pg/mL in severe cases) and pain (over 120 pg/mL for severe pain). Patients with metabolic and cardiovascular comorbidities had the highest IL-6 levels, particularly with diabetes and hypertension (98.6 pg/mL) or cardiovascular disease (119.3 pg/mL). IL-6 correlated strongly with CRP (r = 0.65), ESR (r = 0.51), and SII (r = 0.62). Regression confirmed IL-6 as an independent predictor of severity (p < 0.001), with comorbidities being key predictors. Conclusion Elevated IL-6 and SII levels serve as critical markers for predicting the severity of RA. Addressing these markers may lead to more targeted and effective therapeutic strategies for managing disease progression.