What Role Elevated IL-6 Can Play in RA

For U.S. Healthcare Professionals Only


Overproduction of interleukin-6 (IL-6) can contribute to systemic manifestations in rheumatoid arthritis (RA)1,2

Prolonged increase of serum IL-6 levels can cause numerous systemic manifestations of RA, including abnormal lipid metabolism, cardiovascular disease (CVD), anemia, osteoporosis, fatigue, mood disorders, pain, and morning stiffness.1-3

Metabolic Manifestations


  • Increased lipolysis of adipose tissue and adipocytes
  • Abnormal low-density lipoprotein (LDL) cholesterol metabolism, leading to decreased LDL cholesterol plasma levels
  • Low levels of total cholesterol, LDL cholesterol, and high-density lipoprotein cholesterol
Hepatic Manifestations

Acute-phase protein production and CVD1,2

  • Acute phase response can cause changes in systemic concentrations of certain plasma proteins (ie, increased C-reactive protein [CRP] and serum amyloid A synthesis) following alteration of protein synthesis within hepatocytes
  • Induction of CRP activates the complement system and may exacerbate tissue damage and lead to further complications (eg, CVD)
  • Systemic inflammation—associated proatherogenic changes can cause dysfunction of distant tissues (eg, adipose tissue, skeletal muscle, liver, and vascular endothelium), leading to insulin resistance, dyslipidemia, endothelial dysfunction, and increased oxidative activity
Cardiovascular Manifestations

Anemia of chronic inflammation1,2

  • Hypoferremia through induction of hepcidin, which prevents iron absorption, transport, and release
  • Decreased synthesis of hemoglobin
Hematologic Manifestations

Osteoporosis and osteopenia

  • Increased osteoclastogenesis1,2
    • Osteoclast differentiation
    • Secretion of matrix metalloproteinases
  • Reduced osteoblast activity1,2
  • Loss of generalized bone mineral density4
  • Increased risk of bone fractures1,2
Skeletal Manifestations


  • Anemia-related inadequate oxygen supply to tissues
  • Dysregulation of hypothalamo-pituitary-adrenal axis
    • Lack of sleep
    • Depression
Immunologic Manifestations


  • Auto-antibody production
  • Dysregulation of T cells and B cells
    • Activation and proliferation of Th17 cells
    • Differentiation of B-cells into antibody-producing plasma cells

Morning stiffness and IL-6

Serum IL-6 levels are highest in the early morning hours when patients with RA most often experience articular pain and stiffness, as well as functional disability.5

  • A study in which samples were taken every hour for 24 hours, serum IL-6 levels spiked dramatically in RA patients (n=5)—peaking in the early morning—compared to people without RA (n=5)5
  • A different study (n=16) of overnight variations in the concentrations of 9 different cytokines demonstrated that IL-6 was the only cytokine with significant variation over time in patients with RA6

Adapted from Crofford 1997.

Nearly 4X higher early morning levels of IL-6 in patients with RA5

IL-6 and articular manifestations of RA

Elevated IL-6 plays a central role in osteoclast activation, tissue damage, joint destruction, and bone loss.1,2

References: 1. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 5):v3-v11. 2. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49(1):15-24. 3. Gibbs JE, Ray DW. The role of the circadian clock in rheumatoid arthritis. Arthritis Res Ther. 2013;15(1):1-9. 4. Ota M, Yanagisawa M, Tachibana H, et al. A significant induction of neutrophilic chemoattractants but not RANKL in synoviocytes stimulated with interleukin 17. J Bone Miner Metab. 2015;33(1):40-47. 5. Crofford LJ, Kalogeras KT, Mastorakos G, et al. Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J Clin Endocrinol Metab. 1997;82(4):1279-1283. 6. Perry MG, Kirwan JR, Jessop DS, Hunt LP. Overnight variations in cortisol, interleukin 6, tumour necrosis factor alpha and other cytokines in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(1):63-68.