Persistently elevated levels of IL-6 in patients with RA are a key driver of articular and systemic manifestations that can significantly impact a patient’s quality of life1-7

Interleukin-6 (IL-6) exerts broad effects throughout the course of rheumatoid arthritis (RA), starting before symptoms occur and continuing through disease onset and progression.2,6,8 IL-6 is able to act directly on most cells through its unique dual signaling mechanism and activates several distinct downstream pathways.9-13 These effects go beyond the joints—adversely affecting multiple organ systems—and can impact patients’ quality of life.2,3,6,14-16

RA is more than a disease of the joints—it is associated with both articular and systemic manifestations that can significantly impact a patient’s quality of life.1-3 Manifestations of RA are driven by a network of pro-inflammatory cytokines, including IL-6.17-19

IL-6 is a multifunctional cytokine that regulates both innate and adaptive immunity. It also drives the diverse cellular processes involved in RA pathogenesis and progression.1,2,5,6,20,21 Persistently elevated levels of IL-6 have been shown to increase disease severity and promote the shift from acute to chronic inflammation.4-6

The unique dual signaling mechanism of IL-6 enables a broad range of biological activity, which can lead to chronic inflammation and diverse clinical manifestations.1,2,8,19,22,23 While cis-signaling is limited to certain cells, trans-signaling allows IL-6 to act directly on almost all other cell types.1,6,23

Utilizing dual signaling, IL-6 is able to activate 3 distinct downstream signaling pathways. Each pathway is believed to perform unique functions in RA pathogenesis.9-11

IL-6 plays a key role in the articular manifestations of RA such as morning stiffness, but it has also been shown to drive more systemic manifestations that are linked to a reduced quality of life for patients.2,3,6,14


Pathogenesis and manifestations of RA are driven by a network of pro-inflammatory cytokines17-19

Key network of pro-inflammatory cytokines like IL-6, IL-1, IL-8, IL-12 and TNF

Articular and systemic manifestations significantly affect multiple organ systems6,14-16

IL-6 plays a role in multiple systemic manifestations such as pain, fatigue, poor sleep, and effects on mental health, which impact a significant proportion of patients with RA and are often ranked as top concerns by patients.2,24-26

Effects of RA

  • Pain

    Articular Effects of RA

    Long-standing inflammation can cause morning stiffness and significant joint destruction1,14,23

  • Mental Health

    Neuroendocrine/Neurologic Effects of RA

    RA is associated with neuroendocrine/neurologic manifestations such as pain, fatigue, poor sleep, and effects on mental health, which are highly correlated with one another2,24,27

  • Sleep

    Cardiovascular Effects of RA

    RA is associated with increased risk of cardiovascular effects, including endothelial dysfunction, hypercoagulability, and atherogenesis15,16

  • Heart and Blood

    Metabolic Effects of RA

    Metabolic manifestations of RA include dyslipidemia and insulin resistance6,15

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.

Introducing IL-6: Effects Beyond the Joints in RA

In this video, we will give a brief overview of rheumatoid arthritis, or RA, and how interleukin-6, or IL-6, is implicated in the pathogenesis and progression of RA.

The physical impact of rheumatoid arthritis is wide-reaching. It is associated with articular and systemic manifestations, characterizing it as a disease beyond just the joints.

It is driven by a network of proinflammatory cytokines, including TNF, IL-1, and IL-6. IL-6 is one of the most abundant cytokines found in the serum and synovial fluid.

IL-6 signaling plays a key role in chronic inflammation and interactions between the innate and adaptive immune systems. Its unique dual-signaling mechanism allows it to signal via both membrane-bound and soluble receptors, explaining its pleiotropic effects.

This signaling activates 3 key proinflammatory pathways: JAK/STAT, MAP-kinase, and PI3-kinase.

Elevated and dysregulated IL-6 levels ultimately contribute to a multitude of RA manifestations that patients experience, including joint damage and morning stiffness, as well as the acute-phase response, pain, fatigue, poor sleep, mood disorders, and metabolic dysregulation.

In summary, rheumatoid arthritis is more than a disease of just the joints; persistently elevated IL-6 levels can play a key role in both the articular and systemic manifestations of RA that affect a patient’s quality of life.

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

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