The Role of
IL-6 in RA

Persistently elevated levels of IL-6 are
correlated with disease severity and progression1-4

Many cytokines, including IL-6, play an important role in inflammatory responses and diseases. Under normal physiologic conditions, IL-6 performs many functions, including vital pro-inflammatory functions in response to infection or injury.5,6 However, persistently elevated IL-6 levels contribute to chronic inflammation, which can help promote the pathologic conditions observed in autoimmune and chronic inflammatory conditions such as RA.1-3

 

IL-6 causes a cycle of inflammation beneath
the surface7

Increased IL-6 levels causes a shift from acute to chronic inflammation

RA is a chronic, progressive disease that involves an ongoing cycle of inflammation in which immune cells infiltrate the synovium in response to cytokines.7-9 These activated immune cells then produce more pro-inflammatory cytokines, which leads to more cell activation and cytokine production.10-13

IL-6 is one of the most abundant cytokines
in patients with RA14-16

  • IL-6 is nearly 2x as abundant as any other cytokine in the synovium14-16
  • Elevated IL-6 has been associated with disease activity, articular destruction, and systemic manifestations3,9,17,18

Chronically elevated IL-6 levels in serum and synovial fluid in healthy individuals vs RA patients15,19,20

RA patients have 10 times the normal levels of IL-6 in serum and 100-1000 times the normal levels of IL-6 in synovial fluid.
RA patients have 10 times the normal levels of IL-6 in serum and 100-1000 times the normal levels of IL-6 in synovial fluid.

Serum IL-6 levels are highest in the early morning hours, correlating with the peak of articular pain and stiffness, as well as functional disability9

Joint pain and stiffness show a circadian variation, with greater prominence in the early morning9*

In RA patients, IL-6 levels peak during the early morning, when symptoms like joint symptoms and pain are most prominent

In patients with RA, IL-6 levels peak during the early morning, potentially correlating with symptom prominence9*

In RA patients, IL-6 levels peak during the early morning, when symptoms like joint symptoms and pain are most prominent

*These graphs originated from multiple data sources and are summarized in Cutolo et al 2008.9

IL-6 exerts broad effects throughout the course of RA3,10,21

Starts
before symptoms occur
(early, acute disease)

Long before RA symptoms emerge, IL-6 can stimulate autoantibody production by inducing B-cell differentiation3

Drives
cellular processes at onset

IL-6 contributes to the chronic systemic inflammation observed at disease onset through its actions on multiple cell types, including monocytes, neutrophils, and T cells3,10,22

Continues
through disease onset and progression (advanced, chronic disease)

As RA progresses, IL-6 contributes to pannus formation and ultimately joint damage through its actions on osteoclasts and fibroblast-like synoviocytes3,7,21,23

References: 1. Raimondo MG, Biggioggero M, Crotti C, Becciolini A, Favalli EG. Drug Des Devel Ther. 2017;11:1593-1603. 2. Jones SA. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol. 2005;175(6):3463-3468. 3. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49(1):15-24. 4. Hambardzumyan K, Saevarsdottir S, Bolce R, et al. A multi-biomarker disease activity (MBDA) score and the 12 individual biomarkers in early rheumatoid arthritis patients relate differently to clinical response and radiographic progression: results from the SWEFOT trial. Poster presented at the EULAR Annual European Congress of Rheumatology Meeting; June 12-15, 2013; Madrid, Spain. 5. McInnes IB. Cytokines. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR, eds. Kelley’s Textbook of Rheumatology. Vol 1. 9th ed. Elsevier/Saunders; 2013:369-381. 6. Tanaka T, Kishimoto T. Targeting interleukin-6: all the way to treat autoimmune and inflammatory diseases. Int J Biol Sci. 2012;8(9):1227-1236. 7. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 5):v3-v11. doi:10.1093/rheumatology/kes113. 8. Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2012;122(4):143-159. 9. Cutolo M, Straub RH, Buttgereit F. Circadian rhythms of nocturnal hormones in rheumatoid arthritis: translation from bench to bedside. Ann Rheum Dis. 2008;67(7):905-908. 10. Choy EHS, Calabrese LH. Neuroendocrine and neurophysiological effects of interleukin 6 in rheumatoid arthritis. Rheumatology (Oxford). 2018;57(11):1885-1895. 11. Irwin MR, Olmstead R, Carrillo C, et al. Sleep loss exacerbates fatigue, depression, and pain in rheumatoid arthritis. Sleep. 2012;35(4):537-543. 12. Rohleder N, Aringer M, Boentert M. Role of interleukin-6 in stress, sleep, and fatigue. Ann N Y Acad Sci. 2012;1261:88-96. 13. Vgontzas AN, Bixler EO, Lin H-M, Prolo P, Trakada G, Chrousos GP. IL-6 and its circadian secretion in humans. Neuroimmunomodulation. 2005;12(3):131-140. 14. Choy E. Clinical experience with inhibition of interleukin-6. Rheum Dis Clin North Am. 2004;30(2):405-415. 15. Raimondo MG, Biggioggero M, Crotti C, Becciolini A, Favalli EG. Drug Des Devel Ther. 2017;11:1593-1603. 16. Colmegna I, Ohata BR, Menard HA. Current understanding of rheumatoid arthritis therapy. Clin Pharmacol Ther. 2012;91(4):607-620. 17. Sattar N, McCarey DW, Capell H, McInnes IB. Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation. 2003;108(24):2957-2963. 18. Gonzalez-Gay MA, Gonzalez-Juanatey C, Martin J. Rheumatoid arthritis: a disease associated with accelerated atherogenesis. Semin Arthritis Rheum. 2005;35(1):8-17. 19. Richardson D, Pearson RG, Kurian N, et al. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):R43. 20. Robak T, Gladalska A, Stepień H, Robak E. Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. Mediators Inflamm. 1998;7(5):347-353. 21. Yoshida Y, Tanaka T. Interleukin 6 and rheumatoid arthritis. Biomed Res Int. 2014;2014:698313. 22. Chomarat P, Banchereau J, Davoust J, Palucka AK. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol. 2000;1(6):510-514. 23. Jung SM, Kim KW, Yang CW, Park SH, Ju JH. Cytokine-mediated bone destruction in rheumatoid arthritis. J Immunol Res. 2014;2014:263625.