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High Serum Interleukin-6 Is Associated With Severe Progression of Rheumatoid Arthritis and Increased Treatment Response Differentiating Sarilumab From Adalimumab or Methotrexate in a Post Hoc Analysis


Arthritis Rheumatol. 2020 Apr 28. doi: 10.1002/art.41299. Online ahead of print.

Anita Boyapati 1, Sergio Schwartzman 2, Jérôme Msihid 3, Ernest Choy 4, Mark C Genovese 5, Gerd R Burmester 6, Gordon Lam 7, Toshio Kimura 1, Jonathan Sadeh 8 9, David M Weinreich 1, George D Yancopoulos 1, Neil M H Graham 1

Author Information

1. Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA.

2. Rheumatology, Hospital for Special Surgery, New York, New York, USA, Tarrytown.

3. Real World Evidence Generation, Sanofi, Chilly-Mazarin, France.

4. Rheumatology and Translational Research, CREATE Centre, Cardiff University School of Medicine, Cardiff, UK.

5. Division of Immunology and Rheumatology, Stanford University Medical Center, Palo Alto, California, USA.

6. Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany.

7. NorthEast Rheumatology, Atrium Health, Charlotte, North Carolina, USA.

8. Immunology and Inflammation, Sanofi, Bridgewater, New Jersey, USA.

9. Sanofi Genzyme, Bridgewater, NJ, USA.


Objectives: The development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin-6 (IL-6) levels; however, the utility of IL-6 as a predictor of treatment response is unclear. The objective of this study was to investigate, by post hoc analysis, whether baseline IL-6 levels could predict sarilumab treatment responses in two phase III studies.

Methods: Serum IL-6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every two weeks (Q2W) (MONARCH, NCT02332590) or sarilumab 150 or 200 mg+methotrexate (n = 401 and n = 396, respectively) or placebo+methotrexate (n = 397) Q2W (MOBILITY, NCT01061736). Efficacy and patient-reported outcomes were compared between and within groups according to IL-6 tertile using linear and logistic regression.

Results: In MONARCH, patients with high baseline IL-6 (n = 100; all ≥3×upper limit of normal) had higher disease activity at baseline than those with low IL-6 (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high baseline IL-6 than patients with low baseline IL-6. In MOBILITY, patients with high IL-6 (n = 398) had higher disease activity and joint damage at baseline than those with low IL-6 (n = 397), were more likely to have joint progression, and had less clinical improvement over 52 weeks' treatment with placebo+methotrexate compared with sarilumab 150/200 mg+methotrexate. Baseline IL-6 and C-reactive protein were both predictive of outcomes. Safety profiles were similar between defined IL-6 tertiles.

Conclusion: IL-6 may be a prognostic marker of disease progression and severity, and patients with high IL-6 may be likely to benefit from sarilumab compared with adalimumab or methotrexate. Prospective validation is warranted to confirm the results of these post hoc analyses.