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
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
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
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.