Interleukin-6: Pathophysiology and Clinical Implications in Rheumatoid Arthritis

The Pathophysiology of IL-6 in RA

There is an imbalance in the production of IL-6 in patients with RA,⁸ resulting in elevated levels of IL-6 in serum and synovial fluid.³ A correlation between the fluctuation in IL-6 levels and RA disease activity was established in one study,¹⁴ while a different study found the reduction in IL-6 levels during the first 12 months of treatment with DMARDs to be a prognostic marker for clinical outcome in patients with RA.¹⁵

In RA, IL-6 signaling triggers a cascade of local and systemic inflammatory events including joint inflammation, osteoclast activation and bone resorption, and chronic synovitis.¹⁶ One of the mechanisms implicated in joint destruction is the IL-6-mediated stimulation of endothelial cells to produce IL-8 and monocyte chemoattractant protein-1 (MCP-1), which in turn stimulates the expression of adhesion molecules and leads to leukocyte accumulation in affected joints.¹⁷   

Furthermore, IL- 6 induces excess production of vascular endothelial growth factor (VEGF), causing enhanced angiogenesis and vascular permeability of synovial tissue in patients with RA.¹⁸ It also has the capability to trigger an increase in the synthesis of acute-phase proteins — C-reactive protein, fibrinogen, serum amyloid A, and haptoglobin — causing systemic responses such as fever, anemia, and asthenia.¹⁹ 

Another important feature of IL-6 is its ability to promote autoantibody production and cause an imbalance between 2 types of T cells: type 17 T helper (T₁₇H) and T_REG.⁸ While T₁₇H are involved in the pathophysiology of RA and other inflammatory diseases through production of inflammatory cytokines such as TNF, IL-17, IL-21, IL-22, and IL-26, the role of T_REG is to inhibit T-cell activation and suppress proinflammatory cytokine production.³

A 2012 study found increased levels of T₁₇H and decreased levels of T_REG in the peripheral blood of patients with RA; this imbalance was corrected by inhibiting the function of IL-6.²⁰

Further confirming the role of IL-6 in chronic inflammation and arthritis, an animal model study published in 1999 found transgenic mice deficient in IL-6 to be resistant to antigen-induced experimental arthritis.²¹

Developing IL-6 Receptor Inhibitors for RA

The realization that IL-6 is implicated in many pathologic features of RA has prompted the search for IL-6-blocking agents as therapeutic options for RA. The result of this effort is tocilizumab, the first human monoclonal antibody designed to bind to IL-6R and block IL-6 signaling.

Tocilizumab works by binding to membrane-bound IL-6R as well as S-IL6R and blocking both IL-6 classic and trans-signaling.⁸ Tocilizumab is effective as monotherapy as well as in combination with methotrexate.¹ Clinical trials conducted worldwide have confirmed tocilizumab’s efficacy and safety, leading to its approval for the treatment of RA in more than 100 countries.⁸

The AMBITION trial (ClinicalTrials.gov identifier: NCT00109408) compared the efficacy and safety of tocilizumab monotherapy vs methotrexate monotherapy in patients with moderate or severe RA and found tocilizumab monotherapy to be more effective in patients with early RA.²² Tocilizumab monotherapy was superior to methotrexate monotherapy in patients who had failed prior therapy with methotrexate or other biological agents.²² A large study analyzing cumulative safety data from multiple clinical trials found infections to be the most common adverse event of tocilizumab treatment.²³

Encouraged by the demonstrated effectiveness of tocilizumab, researchers continue to explore IL-6 blockade as a therapeutic strategy for RA, chronic inflammatory and autoimmune diseases, and cancer.  

Sarilumab is a novel IL-6R inhibitor that has been shown to improve disease activity and physical function among patients with RA with an inadequate response to methotrexate or TNF inhibitors.²⁴ A phase 3 trial (ClinicalTrials.gov Identifier: NCT02332590) recently examined the superiority of sarilumab monotherapy compared with adalimumab monotherapy in patients who were either intolerant of or inappropriate candidates for methotrexate therapy.²⁵ Sarilumab was found to be more effective than adalimumab at improving DAS28-ESR at 24 weeks (DAS28-ESR change from baseline, −3.28 vs −2.20; P <.0001). In addition, significantly more patients in the sarilumab group had American College of Rheumatology 20/50/70 response rates than those in the adalimumab group (P ≤.0074 for all comparisons).  The US Food and Drug Administration (FDA) has since approved sarilumab injection to treat adults with moderate to severe RA.²⁶

A combination of sarilumab and DMARDs administered for 24 weeks was shown to effectively reduce fasting glucose and glycosylated hemoglobin in patients with RA, with or without diabetes, in a study presented at the American College of Rheumatology 2017 Annual Meeting, held November 3-8 in San Diego, California.²⁷ Further research presented at the meeting showed that sarilumab administered every 2 weeks is associated with improvements in physical function in adults with RA that are similar to those achieved with adalimumab.²⁸