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Abstract
Introduction Interleukin-6 (IL-6) orchestrates formation of an inflammatory pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a human monoclonal antibody blocking the IL-6Rα. In TARGET (NCT01709578), a phase 3 study in adults with moderate-to-severe RA and inadequate response or intolerance to tumour necrosis factor inhibitors, subcutaneous sarilumab 200 mg or 150 mg every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) significantly reduced disease activity versus placebo plus csDMARDs.
Methods Circulating levels of biomarkers associated with synovial inflammation (matrix metalloproteinase 3 (MMP-3), collagen type I MMP-cleaved fragment (C1M), collagen type III MMP-cleaved fragment (C3M)), myeloid (soluble intercellular adhesion molecule 1 (sICAM-1), IL-8 and calprotectin) and lymphoid activation (chemokine, CXC motif, ligand 13 (CXCL13), CXCL10, B cell-activating factor) and bone remodelling (receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin and osteocalcin) were evaluated in patients from a TARGET substudy.
Results Sarilumab significantly decreased C1M, C3M, CXCL13, MMP-3 and total RANKL levels at week 24 versus placebo; some markers were significantly suppressed at week 2 and normalised to levels in healthy controls. Levels of sICAM-1 were predictive of disease activity score by C-reactive protein and clinical disease activity index low disease activity (LDA) response in the sarilumab 200 mg q2w group at week 12. A trend was observed in which patients with lower sICAM-1 levels at baseline had better response compared with patients with higher sICAM-1.
Conclusions Sarilumab plus csDMARDs decreased circulating biomarkers of synovial inflammation and bone resorption; sICAM-1 was predictive of achieving LDA with sarilumab.
Trial registration number NCT01709578; Post-results.
- rheumatoid arthritis
- treatment
- dmards (biologic)
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Footnotes
Contributors AB, JM and CG contributed to the design of the study; JM and AB contributed to data acquisition; and all authors contributed to data analysis and interpretation. AB, JM, MZ and CG contributed to drafting the manuscript, and all authors were involved in revising it critically for important intellectual content. All authors approved the final version to be published.
Funding This study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.
Competing interests CG has received consulting fees from Roche, Merck, AbbVie, Pfizer, Bristol-Myers Squibb, Sanofi and AB2 Bio. JM, MZ and CP are employees of Sanofi R&D and may hold stock and/or stock options in the company. YL is an employee of Sanofi Genzyme and may hold stock and/or stock options in the company. NMHG and AB are employees of Regeneron Pharmaceuticals, Inc, and may hold stock and/or stock options in the company.
Patient consent Not required.
Ethics approval The protocol was approved by the appropriate ethics committees/institutional review boards.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.