What Role Elevated IL-6 Can Play in RA

For U.S. Healthcare Professionals Only


Elevated interleukin-6 (IL-6) plays a central role in the articular manifestations of rheumatoid arthritis (RA)1

Elevated IL-6 perpetuates chronic synovitis and bone and cartilage erosion.1-3*

  • Activates pro-inflammatory cells and mediators within the joints
  • Degrades cartilage by activating fibroblast-like synoviocytes (FLS) and chondrocytes to release cathepsins and matrix metalloproteinases (MMPs)
  • Stimulates osteoclastogenesis and osteoclast activity, leading to structural damage through bone resorption

*Based on preclinical, ex-vivo, and clinical data.

Role of IL-6 in osteoclast activation, tissue damage, joint destruction, and bone loss

Evaluation of synovial fluid from patients with RA determined a higher ratio of nuclear factor kappa-β ligand (RANKL) to osteoprotegerin (OPG) is associated with osteoclast hyperactivity and bone resorption in RA joints.4

IL-6 can affect the RANKL/OPG ratio and effector T-cell proliferation by stimulating:

  • Osteoblasts to increase expression of RANKL, which drives osteoclast activation1,2
  • Th17 cells to produce IL-17, which lead to effector T-cell proliferation and activation, contributing to tissue damage1,2,5
  • Macrophages/monocytes to produce IL-1 and tumor necrosis factor-α (TNF-α), which stimulate effector T-cell proliferation and activation leading to tissue damage1,2,5,6
    • Newly formed, activated T cells can express RANKL on osteoblasts

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

Normal Joint and Joint Affected by RA

Adapted from Choy 2012.

Schematic view of a normal joint (A) and a joint affected by RA (B)2

IL-6–activated FLS may play a key role in chronic inflammation and joint destruction in RA1,2

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

In RA, FLS2,7

  • Promote inflammatory cell recruitment and activation, as well as angiogenesis, through expression of immunomodulating cytokines and mediators, including IL-6
  • Are the main effectors of cartilage breakdown because of their unique invasive properties and production of large amounts of MMPs
  • Contribute to bone erosion and systemic osteoporosis through secretion of factors, such as RANKL, which promote osteoclast differentiation, survival, and activity

IL-6 is both produced by and activates FLS2,5

  • IL-6 forms a positive feedback loop through its effects on FLS and Th17 cells
  • Th17 cells produce IL-17, which contributes to RA pathogenesis
  • Th17 activates synoviocytes to produce more IL-6, creating a positive feedback loop
FLS (Fibroblast-Like Synoviocyte)

Adapted from Ota 2015 and Kimura 2010.

IL-6 and the positive feedback loop

Elevated IL-6 signaling increases articular destruction in RA1

IL-6 and systemic manifestations of RA

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.