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Elevated IL-6 perpetuates chronic synovitis and bone and cartilage erosion.1-3*
*Based on preclinical, ex-vivo, and clinical data.
Evaluation of synovial fluid from patients with RA determined a higher ratio of nuclear factor
IL-6 can affect the RANKL/OPG ratio and effector T-cell proliferation by stimulating:
Consequently, the increased number of T cells expressing RANKL increases the ratio of RANKL to OPG and enhances osteoclast function.4 This results in increased bone resorption, resulting in reduced bone mineral density in patients with RA.4,5
Elevated IL-6 signaling also inhibits bone regeneration by affecting osteogenesis.1
Increased bone resorption activity is associated with RA and causes articular damage and systemic bone loss.1
Adapted from Choy 2012.
Schematic view of a normal joint (A) and a joint affected by RA (B)2
IL-6 activates and increases proliferation of FLS, correlating with articular damage in RA.1,2,5
Under normal conditions, FLS secrete proteins that help build the extracellular collagen network, which is responsible for cushioning in joints.7
Adapted from Ota 2015 and Kimura 2010.
IL-6 and the positive feedback loop
Elevated IL-6 signaling increases articular destruction in RA1
Overproduction of IL-6 can contribute to systemic manifestations, including hypolipidemia, acute-phase protein production, cardiovascular disease, anemia of chronic inflammation, osteoporosis and osteopenia, fatigue, autoimmunity, and morning stiffness.1,9,10
References: 1. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49(1):15-24. 2. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 5):v3-v11. 3. Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233(1):233-255. 4. Haynes DR, Crotti TN, Loric M, Bain GI, Atkins GJ, Findlay DM. Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatology (Oxford). 2001;40(6):623-630. 5. Ota M, Yanagisawa M, Tachibana H, et al. A significant induction of neutrophilic chemoattractants but not RANKL in synoviocytes stimulated with interleukin 17. J Bone Miner Metab. 2015;33(1):40-47. 6. Page G, Miossec P. RANK and RANKL expression as markers of dendritic cell-T cell interactions in paired samples of rheumatoid synovium and lymph nodes. Arthritis Rheum. 2005;52(8):2307-2312. 7. Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol. 2013;9(1):24-33. 8. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40(7):1830-1835. 9.Crofford LJ, Kalogeras KT, Mastorakos G, et al. Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J Clin Endocrinol Metab. 1997;82(4):1279-1283. 10. Perry MG, Kirwan JR, Jessop DS, Hunt LP. Overnight variations in cortisol, interleukin 6, tumour necrosis factor alpha and other cytokines in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(1):63-68.