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: a key link between innate and adaptive immune responses in RA
by Dr Gordon Lam

Dr Lam was compensated and/or received an honorarium from Sanofi Genzyme in connection with this presentation. This content was jointly devloped by Dr Lam and Sanofi Genzyme.

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

before symptoms occur
(early, acute disease)

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

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

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

Understanding IL-6 as a Key
Mediator of the
Immune Response in RA

Interleukin-6, or IL-6, is integral to the body’s immune responses in rheumatoid arthritis, or RA.

In healthy individuals, the innate and adaptive immune responses that occur as a result of infection or injury produce IL-6. These increased IL-6 levels quickly return to baseline levels once the inflammation or trauma is resolved. However, in rheumatoid arthritis, IL-6 is persistently elevated.

In RA, the cells that produce IL-6 help to create a positive feedback loop that generates even more IL-6 and further stimulates the processes that contribute to chronic inflammation. The feedback loop of IL-6 has a role even before symptoms occur, and that role continues all the way through disease onset and progression.

Prior to RA symptom manifestation, IL-6 contributes to the differentiation of B cells into autoantibody-producing plasma cells, and autoantibodies have been found in rheumatoid arthritis patients 10 or more years prior to diagnosis.

At disease onset, IL-6 continues to contribute to chronic, systemic inflammation. It acts on multiple cell types, promoting: the differentiation of monocytes into macrophages, neutrophil migration to synovial fluid, and the differentiation of T cells.

IL-6 also influences disease progression and joint damage by contributing to pannus formation, activation of fibroblast-like synoviocytes, or FLSs, and activation and differentiation of osteoclasts. Elevated IL-6 levels correlate with both disease activity and radiographic progression of RA.

Serum levels of IL-6 have been found to be up to approximately 10 times higher in patients with rheumatoid arthritis compared to healthy controls. IL-6 levels in the joint fluid of patients with RA have been observed to be as much as 100- to 1000-fold higher than in patients without RA. Additionally, serum IL-6 is highest in the early morning hours in patients with rheumatoid arthritis, correlating with the peak of pain and stiffness affecting functional disability.

In summary, IL-6 stimulates multiple cellular processes throughout the course of disease, from before symptoms even appear through disease onset and progression.

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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