IL-6 and IL-21 in Rheumatoid Arthritis

Gustavo Carbone¹, Augusta Wilson¹, Sean Diehl², Janice Bunn³, Sheldon Cooper⁴ and Mercedes Rincon⁵, ¹Rheum & Clinical Imm Unit, University of Vermont College of Medicine, Burlington, VT, ²Immunobiology, University of Vermont College of Medicine, ³Mathematics and Statistics, University of Vermont, Burlington, VT, ⁴Rheum & Clinical Imm Unit, Univ Vermont College of Med, Burlington, VT, ⁵Immunobiology, University of Vermont College of Medicine, Burlington, VT

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Antibodies, interleukins (IL), rheumatoid arthritis (RA) and tocilizumab

Session Information

Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Interleukin-6 (IL-6) levels are known to be increased in patients with rheumatoid arthritis (RA). Tocilizumab, a monoclonal antibody to the IL-6 receptor (IL-6R), reduces disease activity in RA, although its mechanisms of action remain unclear. IL-6 has been shown to regulate cytokine production by CD4 T cells during activation. The objective of this study was to determine if treatment with tocilizumab altered the phenotype and cytokine production by CD4 T cells in patients with rheumatoid arthritis.

Methods: RA patients who entered a six-month open-label Phase III clinical study of tocilizumab (ACT-STAR), also consented to enter an accompanying laboratory study. Clinical parameters were obtained at each study visit. Additional blood specimens were obtained prior to the first treatment (baseline, visit 1), second infusion (visit 2), fourth infusion (visit 4), and 1 month after the sixth infusion (visit 7). CD4 CD45RA (naïve) and CD4 CD45RO (memory/activated) cells were isolated from peripheral blood of RA patients at the above time points. Production of IL-2, IL-21, IFNg, and IL-17 upon activation in vitro was determined. In addition, serum was also collected to determine the levels of specific immunoglobulins.

Results: There was significant reduction in tender and swollen joint counts, and DAS28 scores with tocilizumab treatment. The relative frequency of naïve and memory CD4 T cells was not altered over the treatment period. There was no change in the production of any of the examined cytokines by CD45 RA naïve T cells during the study. In contrast, there was a marked reduction of IL-21 production by memory/activated CD4 T cells with tocilizumab treatment. In addition, tocilizumab treatment led to a profound decrease in the levels of IgG4-specific anti-CCP autoantibodies. We also show that IL-21 is a powerful inducer of IgG4 production by B cells.

Conclusion: Treatment of RA with tocilizumab selectively lowers both the production of IL-21 by the memory/activated CD4 T cell population and serum IgG4-specific autoantibody levels. Since IL-21 promotes IgG4 production by B cells, these results suggest that IL-21 may play a role in B cell activation in patients with RA, and blockade of IL-6 may down-regulate this pathway.

Disclosure:

G. Carbone,
None;

A. Wilson,
None;

S. Diehl,
None;

J. Bunn,
None;

S. Cooper,
None;

M. Rincon,
None.

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