What role elevated IL-6 may have in RA

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Elevated IL-6 plays a central role in the articular manifestations of rheumatoid arthritis (RA)1-4

Elevated interleukin-6 (IL-6) perpetuates chronic synovitis1,5,6*

  • Activates pro-inflammatory cells and mediators within the joints, such as neutrophils, macrophages, fibroblast-like synoviocytes (FLSs), T cells, and B cells4,7-13

  • Degrades cartilage by activating FLSs and chondrocytes to release cathepsins and matrix metalloproteinases (MMPs)14-18

  • Stimulates osteoclastogenesis and osteoclast activity, leading to structural damage through bone resorption. There is also evidence that IL-6 and/or soluble IL-6 receptor (sIL-6R) is implicated in the regulation of osteoclast precursors in the bone marrow (hematopoietic stem cells) before and during inflammatory arthritis3,4,10,18-20

*Based on pre-clinical, ex-vivo, and clinical data.

Effects of elevated IL-6 signaling on bone metabolism in RA

RA leads to increased bone destruction. In the clinical evaluation of synovial fluid from patients with RA, it was determined that the ratio of receptor activator of nuclear factor kappa-ß ligand (RANKL) to osteoprotegerin (OPG) reflects osteoclast function, and a higher ratio of RANKL to OPG is correlated to osteoclast hyperactivity and bone resorption in RA joints.1,9,19,21-24

IL-6 can affect the RANKL/OPG ratio through 2 mechanisms during RA inflammation by directly stimulating25,26:

  • Osteoblasts to increase expression of RANKL, which can be bound by osteoclasts and drive their activation

  • Th17 cells, which produce IL-17. IL-17 levels are significantly higher in the synovial fluid of patients with RA

IL-6 induces macrophages/monocytes to produce IL-1 and tumor necrosis factor-α (TNF-α). IL-17, IL-1, and TNF-α all stimulate effector T-cell proliferation and activation, which contribute to tissue damage in RA. Importantly, these newly formed, activated T cells can express RANKL.27

Therefore, the increased number of T cells expressing RANKL increases the ratio of RANKL to OPG and enhances osteoclast function.28

This increased osteoclast function shifts the balance of bone resorption/formation toward resorption, resulting in reduced bone mineral density in patients with RA. Elevated IL-6 signaling also inhibits bone regeneration by affecting osteogenesis.1,10,19,29,30

Increased bone resorption activity is associated with RA and translates to articular bone damage and systemic bone loss.31-33

Adapted from Choy 2012.

Normal Joint and Joint Affected by RA

Schematic view of a normal joint (a)
and a joint affected by RA (b)

IL-6–activated fibroblast-like synoviocytes may play a key role in chronic inflammation and joint destruction in RA17,34,35

IL-6 activates and increases proliferation of FLSs of the synovial intimal, or inner lining.2,9,35,36 The invasive properties of FLSs have been shown to correlate with radiologic and histological damage in RA.37

Under normal conditions, FLSs secrete proteins that help build the extracellular collagen network, which is responsible for cushioning in joints.35 In RA, however, FLSs:

  • Promote inflammatory cell recruitment and activation, as well as angiogenesis, through expression of immunomodulating cytokines and mediators, including IL-62,9,17,36

  • Are the main effectors of cartilage breakdown because of their unique invasive properties and production of large amounts of MMPs15,17

  • Contribute to bone erosion and systemic osteoporosis through secretion of factors such as RANKL, which promote osteoclast differentiation, survival, and activity38,39

IL-6 is both produced by and activates FLSs.2,9,34,36

  • IL-6 forms a positive feedback loop through its effects on FLS and Th17 cells26,34

  • Th17 cells produce IL-17, which contributes to RA pathogenesis26,34

  • Th17 activates synoviocytes to produce more IL-6, creating a positive feedback loop26,40
FLS (Fibroblast-Like Synoviocyte)

FLS

Adapted from Ota 2014 and Kimura 2010.

IL-6 and the positive feedback loop26,40-44

Morning stiffness and IL-6

Serum IL-6 levels are at their highest in the early morning hours when patients with RA most often experience articular pain and stiffness, as well as functional disability.45-47

  • In one study, samples were taken every hour over a 24-hour period in 5 patients with RA and 5 without45

  • Serum IL-6 levels spiked dramatically in RA patients—peaking in the early morning—compared to people without RA45

Adapted from Crofford 1997.

Early morning levels of IL-6: nearly 4 times higher in patients with RA45

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