Impact on
Manifestations

IL-6 manifestations can diminish patient quality of life1-3

IL-6 contributes to many of the inflammatory activities within the synovium, resulting in debilitating articular manifestations such as morning stiffness and joint destruction.4,5 More importantly, elevated IL-6 also results in many systemic manifestations that may affect patient quality of life.2-5 IL-6 promotes expression of C-reactive protein and hepcidin, acute-phase proteins that are a key part of the acute- phase response seen in many patients with RA.4

LISTEN NOW:
The wide-reaching effects of pain and IL-6 in rheumatoid arthritis
by Ms Amanda Mixon

Speakers received an honorarium from Sanofi Genzyme in connection with these presentations. This content was jointly developed by speakers and Sanofi Genzyme.

RA is more than a disease of the joints

Systemic manifestations of IL-6 and RA include: osteoporosis, osteopenia, anemia, acute-phase response (e.g. elevated CRP), cardiovascular risk, metabolic dysregulation (e.g. Insulin resistance, dyslipidemia), fatigue, mental health effects and pain. Articular manifestations of IL-6 and RA include: morning stiffness and joint destruction.
LISTEN NOW:
Elevated IL-6 as a contributor to cardiovascular effects in patients with RA
by Dr Leonard Calabrese

Uncovering the systemic effects of elevated IL-62,4,6-9

  • Pain

    Pain

    IL-6 helps mediate pain through direct action on the nociceptive system2

  • Mental Health

    Mental Health

    IL-6 can affect mental health and cause fatigue via its action on the hypothalamic-pituitary-adrenal axis2

  • Sleep

    Sleep

    IL-6 has been linked to sleep disruption2,7

  • Heart and Blood

    Heart and Blood

    IL-6 contributes to numerous changes in cardiovascular and hematologic parameters commonly seen in patients with RA6,8

  • Matabolism

    Metabolism

    IL-6 can affect lipid metabolism, thereby contributing to metabolic manifestations of RA such as dyslipidemia and insulin resistance4,6,8,9

LISTEN NOW:
Beyond the joints: systemic manifestations of IL-6 elevation in rheumatoid arthritis
by Dr Grace Wright

IL-6 effects on bone resorption

In addition to articular and systemic effects, elevated IL-6 can affect bone resorption.1,4 Elevated IL-6 signaling favors osteoclast over osteoblast function, promoting bone resorption that may manifest as both articular and systemic bone loss.4,5

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

Schematic view of a normal joint compared to a joint affected by RA
Adapted from Choy, 2012.1
LISTEN NOW:
Bone resorption: a manifestation of RA mediated by elevated IL-6
by Dr Robin Dore
LISTEN NOW:
The role of IL-6 in HPA-axis–related manifestations in RA
by Dr Sanjay Chabra

Recognizing the Role of
Elevated IL-6 in Articular
and Systemic
Manifestations of RA

In this video, we will discuss how the dysregulation of interleukin-6, or IL-6, is a key contributor to articular and systemic manifestations of rheumatoid arthritis, or RA, that can significantly affect quality of life.

Elevated IL-6 causes common articular manifestations of RA, including morning stiffness and joint destruction. IL-6 levels tend to peak in the early morning, which correlates with when many rheumatoid arthritis patients feel the most debilitating joint pain and stiffness.

In the joints, the synovium becomes thick and inflamed with excess immune cells that cause progressive damage to the bones and cartilage, also known as joint destruction. These immune cells, via IL-6–mediated actions, contribute to pannus formation, the activation of fibroblast-like synoviocytes, and the activation and differentiation of osteoclasts. In RA, the usual balance between bone formation and resorption is disrupted, and there’s an increase in osteoclast differentiation and activity that results in greater bone resorption.

Conversely, osteoblast differentiation and activity are inhibited by IL-6, resulting in reduced bone formation. This imbalance may lead to articular and systemic bone loss.

Systemic manifestations are the effects of IL-6 that occur throughout the body, outside of the joints. Pain, fatigue, mood changes, and poor sleep affect a significant proportion of patients with rheumatoid arthritis and are often ranked as top concerns.

There are significant positive correlations among these manifestations, which are likely to mutually influence each other and suggest the possibility of a common mechanism. This is possible because IL-6 plays a dominant role in the stimulation of the HPA axis by acting upon all 3 levels: the hypothalamus, pituitary gland, and adrenal glands.

Another systemic manifestation of RA is the acute-phase response, during which IL-6 stimulates hepatocytes and promotes the production of acute-phase proteins, including CRP and hepcidin. Elevated CRP and hepcidin levels may indicate systemic inflammation and chronic disease. Increased levels of CRP may affect cardiovascular parameters, and increased levels of hepcidin may contribute to reduced iron levels and result in decreased hemoglobin synthesis and anemia.

Elevated IL-6 may also increase cardiovascular risk in patients with rheumatoid arthritis. IL-6 promotes the production of CRP, which contributes to oxidative stress and endothelial dysfunction.

Other markers of CV risk are the hematologic changes seen in platelet and fibrinogen production. Metabolic dysregulation is also affected by IL-6. Dyslipidemia in patients with RA is unconventional and is often referred to as the “lipid paradox”. Patients with rheumatoid arthritis can have lower lipid levels but paradoxically higher CVD risk than those without.

Elevated insulin resistance is also common in patients with RA because IL-6 affects metabolic processes in the liver, muscle tissue, pancreas, and adipose tissue.

Chronic dysregulation of IL-6 has widespread effects in patients with rheumatoid arthritis, driving not only the articular manifestations observed in the joints, but also many of the systemic manifestations that can impact quality of life.

To find out more about IL-6, please browse additional videos in this series on RAandIL6.com. This video was brought to you by Sanofi Genzyme and Regeneron Pharmaceuticals.

References: 1. 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. 2. Choy EHS, Calabrese LH. Neuroendocrine and neurophysiological effects of interleukin 6 in rheumatoid arthritis. Rheumatology (Oxford). 2018;57(11):1885-1895. 3. Malm K, Bergman S, Andersson ML, Bremander A, Larsson I. Quality of life in patients with established rheumatoid arthritis: a phenomenographic study. SAGE Open Med. 2017;5:2050312117713647. 4. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49(1):15-24. 5. 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. 6. 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. 7. 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. 8. Gonzalez-Gay MA, Gonzalez-Juanatey C, Martin J. Rheumatoid arthritis: a disease associated with accelerated atherogenesis. Semin Arthritis Rheum. 2005;35(1):8-17. 9. Kerekes G, Nurmohamed MT, González-Gay MA, et al. Rheumatoid arthritis and metabolic syndrome. Nat Rev Rheumatol. 2014;10(11):691-696.