Distinct Cytokine Patterns Associated With Rheumatoid Arthritis Disease Activity

• Zainab Abd Mohammed

  Department of Biotechnology, College of Science, University of Diyala, Diyala

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by systemic inflammation and joint destruction, driven in part by dysregulated cytokine activity. Specific Background: Pro-inflammatory and anti-inflammatory cytokines are central to RA pathogenesis, yet their potential as reliable predictors of disease activity remains underutilized in routine clinical practice. Knowledge Gap: Traditional RA activity markers lack specificity regarding immune pathways, and the diagnostic value of cytokine profiling, especially in relation to sex-based differences, remains unclear. Aim: This study aimed to evaluate serum levels of IL-6, TNF-α, IL-1β, IL-10, and IFN-γ in RA patients versus healthy controls, and assess their correlation with disease activity. Results: RA patients exhibited significantly elevated IL-6, TNF-α, IL-1β, and IFN-γ, and reduced IL-10 (p<0.001). Cytokine levels positively (or inversely for IL-10) correlated with disease activity, with ROC analysis confirming their diagnostic utility. Novelty: The study highlights gender-specific cytokine variations, notably higher IL-6 and lower IL-10 in females, providing insight into sex-based immunopathology. Implications: These findings support cytokine profiling as a promising tool for RA diagnosis and activity monitoring, and underscore the need for personalized, cytokine-targeted therapeutic strategies.
Highlight :

• Cytokine markers predict RA activity – Elevated IL-6, TNF-α, IL-1β, and IFN-γ correlate with disease severity.

• IL-10 is a key anti-inflammatory marker – Lower levels are linked to worse RA outcomes.

• ROC analysis confirms diagnostic value – IL-6 had the highest diagnostic accuracy (AUC = 0.91).

Keywords : Rheumatoid Arthritis, Cytokines, IL-6, TNF-α, Biomarkers

[1] N. Kondo, T. Kuroda, and D. Kobayashi, "Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis," International Journal of Molecular Sciences, 2021.

[2] S. Alivernini, G. S. Firestein, and I. B. McInnes, "The Pathogenesis of Rheumatoid Arthritis," Immunity, 2022.

[3] Q. Ding, W. Hu, R. Wang, Q. Yang et al., "Signaling Pathways in Rheumatoid Arthritis: Implications for Targeted Therapy," Signal Transduction and Targeted Therapy, 2023.

[4] A. Markovics, K. S. Rosenthal, K. Mikecz, R. E. Carambula et al., "Restoring the Balance Between Pro-Inflammatory and Anti-Inflammatory Cytokines in the Treatment of Rheumatoid Arthritis: New Insights From Animal Models," Biomedicines, 2021.

[5] A. Tylutka, L. Walas, and A. Zembron-Lacny, "Level of IL-6, TNF, and IL-1beta and Age-Related Diseases: A Systematic Review and Meta-Analysis," Frontiers in Immunology, 2024.

[6] S. K. Dhar, K. Vishnupriyan, S. Damodar, S. Gujar et al., "IL-6 and IL-10 as Predictors of Disease Severity in COVID-19 Patients: Results From Meta-Analysis and Regression," Heliyon, 2021.

[7] A. A. Hamad, H. M. Mustafa, and O. A. Mohsein, "Detection of the Levels of Immune Cytokines (IL-4, IL-5, TNF-alpha) in School-Age and Preschoolers With an Ascaris Lumbricoides Infection," Journal of Parasitic Diseases, vol. 48, no. 4, pp. 782–787, 2024.

[8] M. Wei and C. Q. Chu, "Prediction of Treatment Response: Personalized Medicine in the Management of Rheumatoid Arthritis," Best Practice and Research: Clinical Rheumatology, 2022.

[9] M. Colina and G. Campana, "Precision Medicine in Rheumatology: The Role of Biomarkers in Diagnosis and Treatment Optimization," Journal of Clinical Medicine, 2025.

[10] J. M. Guthridge, C. A. Wagner, and J. A. James, "The Promise of Precision Medicine in Rheumatology," Nature Medicine, 2022.

[11] N. Deol, V. Nuno, M. Schuman, and C. Contreras, "An Osteopathic Approach to Complex Regional Pain Syndrome (CRPS)," AAO Journal, 2021.

[12] S. S. Taylor, N. Noor, I. Urits, A. Paladini et al., "Complex Regional Pain Syndrome: A Comprehensive Review," Pain and Therapy, 2021.

[13] L. Meert, "Unravelling the Role of and the Interrelation Between Somatosensory Function and Metabolic Factors in Chronic (Postsurgical) OA Pain," unpublished, 2024.

[14] N. A. Abdulmuttaleb, M. Q. Mohammed, and O. A. Mohsein, "Exploring the Connection Between Inflammatory Cytokines, Hypertension, and Diabetes in Angina Patients," Cytokines, vol. 14, no. 15, p. 16, 2024.

[15] L. Zhang, R. Zhang, and L. Li, "Effects of Probiotic Supplementation on Exercise and the Underlying Mechanisms," Foods, 2023.

[16] K. Onnheim, S. Huang, A. S. Holmertz et al., "Rheumatoid Arthritis Chondrocytes Produce Increased Levels of Pro-Inflammatory Proteins," Cartilage Open, 2022.

[17] S. Shufang and X. Xiaojiao, "Pro-Inflammatory Cytokine IL-21 Correlates With the Reactive Oxygen Species and 25-Hydroxy Vitamin D in Rheumatoid Arthritis Patients," Immunity, [n.d.].

[18] Z. K. Abbas et al., "Immunological Biomarkers and Their Role in the Diagnosis and Prognosis of Leishmaniasis: A Case–Control Study," Tropical Parasitology, vol. 15, no. 1, pp. 33–41, 2025.

[19] J. Xiao, R. Wang, W. Zhou, X. Cai et al., "LncRNA NEAT1 Regulates the Proliferation and Production of the Inflammatory Cytokines in Rheumatoid Arthritis Fibroblast-Like Synoviocytes by Targeting miR-204-5p," Human Cell, 2021.

[20] S. Nirenjen, J. Narayanan, T. Tamilanban et al., "Exploring the Contribution of Pro-Inflammatory Cytokines to Impaired Wound Healing in Diabetes," Frontiers in Immunology, 2023.

[21] Q. Lu, Z. Zhu, C. Tan, H. Zhou et al., "Changes of Serum IL-10, IL-1beta, IL-6, MCP-1, TNF-alpha, IP-10 and IL-4 in COVID-19 Patients," Journal of Clinical Laboratory Analysis, 2021.

[22] H. Islam, G. S. Jackson, J. S. Yoon et al., "Sex Differences in IL-10’s Anti-Inflammatory Function: Greater STAT3 Activation and Stronger Inhibition of TNF-alpha Production in Male Blood Leukocytes ex vivo," American Journal of Physiology: Cell Physiology, 2022.

[23] N. Subramanian, B. Tavira, K. Hofwimmer et al., "Sex-Specific Regulation of IL-10 Production in Human Adipose Tissue in Obesity," Frontiers in Immunology, 2022.

[24] K. Dissanayake, C. Jayasinghe, P. Wanigasekara et al., "Potential Applicability of Cytokines as Biomarkers of Disease Activity in Rheumatoid Arthritis: ELISPOT-Based Evaluation of TNF-alpha, IL," PLoS One, 2021.

[25] A. M. A. Faqri et al., "The Role of Cytokines in Autoimmune Diseases: Pathogenesis and Therapeutic Implications," Central Asian Journal of Medical and Natural Sciences, vol. 6, no. 3, pp. 852–873, 2025.

[26] H. Wang, R. Zhang, J. Shen, Y. Jin et al., "Circulating Level of Blood Iron and Copper Associated With Inflammation and Disease Activity of Rheumatoid Arthritis," Biological Trace Element Research, 2023.

[27] C. Liu, D. Chu, K. Kalantar-Zadeh, and J. George, "Cytokines: From Clinical Significance to Quantification," Advances in Clinical Chemistry, 2021.

[28] A. E. R. Kartikasari, C. S. Huertas, A. Mitchell et al., "Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis," Frontiers in Immunology, 2021.

[29] S. Shekhar, A. K. Yadav, A. Khosla, and P. R. Solanki, "Interleukins Profiling for Biosensing Applications: Possibilities and the Future of Disease Detection," ECS Sensors Plus, 2022.