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.