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

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