PMID- 32264972 OWN - NLM STAT- MEDLINE DCOM- 20210111 LR - 20210111 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 22 IP - 1 DP - 2020 Apr 7 TI - Sarilumab and adalimumab differential effects on bone remodelling and cardiovascular risk biomarkers, and predictions of treatment outcomes. PG - 70 LID - 10.1186/s13075-020-02163-6 [doi] LID - 70 AB - BACKGROUND: Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in the pathogenesis of rheumatoid arthritis. Sarilumab is a human monoclonal antibody that binds membrane-bound and soluble IL-6 receptor-alpha to inhibit IL-6 signalling. The aim of this study was to compare the effects of sarilumab and adalimumab (a tumour necrosis factor alpha inhibitor) monotherapy on levels of circulating biomarkers associated with the acute-phase response, bone remodelling, atherothrombosis, anaemia of chronic disease and markers purported to reflect synovial lymphoid and myeloid cell infiltrates, as well as the potential of these biomarkers to differentially predict clinical and patient-reported outcomes with sarilumab vs. adalimumab. METHODS: In this post hoc analysis, serum samples were analysed at baseline and prespecified post-treatment timepoints up to week 24 in adults with moderate-to-severe active rheumatoid arthritis intolerant of or inadequate responders to methotrexate from the MONARCH trial (NCT02332590). RESULTS: Greater reductions in C-reactive protein (CRP; - 94.0% vs. -24.0%), serum amyloid A (SAA; - 83.2% vs. -17.4%), total receptor activator of nuclear factor-kappaB ligand (RANKL; - 18.3% vs. 10.5%) and lipoprotein (a) (- 41.0% vs. -2.8%) were observed at week 24 with sarilumab vs. adalimumab, respectively (adjusted p < 0.0001). Greater increases in procollagen type 1 N-terminal propeptide (P1NP) were observed with sarilumab vs. adalimumab at week 24 (22.8% vs. 6.2%, p = 0.027). Patients with high baseline SAA, CRP and matrix metalloproteinase-3 (MMP-3) were more likely to achieve clinical efficacy, including American College of Rheumatology 20% improvement criteria and Disease Activity Score (28 joints)-CRP < 3.2, and report improvements in patient-reported outcomes, including Health Assessment Questionnaire-Disability Index and pain visual analogue scale, with sarilumab than adalimumab. CONCLUSION: Sarilumab was associated with greater positive effects on bone remodelling and decreases in biomarkers of the acute-phase response, synovial inflammation and cardiovascular risk vs. adalimumab. High baseline concentrations of SAA, CRP and MMP-3 are predictive of clinical and patient-reported outcome responses to sarilumab treatment and prospective validation is warranted to confirm these results. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02332590. Registered on 5 January 2015. FAU - Gabay, Cem AU - Gabay C AD - University Hospitals of Geneva, Geneva, Switzerland. FAU - Burmester, Gerd R AU - Burmester GR AD - Charite - University Medicine Berlin, Berlin, Germany. FAU - Strand, Vibeke AU - Strand V AD - Stanford University, Palo Alto, CA, USA. FAU - Msihid, Jerome AU - Msihid J AD - Sanofi, Chilly-Mazarin, France. FAU - Zilberstein, Moshe AU - Zilberstein M AD - Sanofi Genzyme, Bridgewater, NJ, USA. FAU - Kimura, Toshio AU - Kimura T AD - Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. FAU - van Hoogstraten, Hubert AU - van Hoogstraten H AD - Sanofi Genzyme, Bridgewater, NJ, USA. FAU - Boklage, Susan H AU - Boklage SH AD - Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. FAU - Sadeh, Jonathan AU - Sadeh J AD - Sanofi Genzyme, Bridgewater, NJ, USA. FAU - Graham, Neil M H AU - Graham NMH AD - Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. FAU - Boyapati, Anita AU - Boyapati A AD - Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. anita.boyapati@regeneron.com. LA - eng SI - ClinicalTrials.gov/NCT02332590 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20200407 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Biomarkers) RN - 9007-41-4 (C-Reactive Protein) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - FYS6T7F842 (Adalimumab) RN - NU90V55F8I (sarilumab) SB - IM MH - Adalimumab/*therapeutic use MH - Adult MH - Aged MH - Antibodies, Monoclonal, Humanized/*therapeutic use MH - Arthritis, Rheumatoid/blood/*drug therapy/pathology MH - Biomarkers/*blood MH - Bone Remodeling/*drug effects MH - C-Reactive Protein/analysis MH - Cardiovascular Diseases/blood/*prevention & control MH - Double-Blind Method MH - Female MH - Humans MH - Male MH - Matrix Metalloproteinase 3/blood MH - Middle Aged MH - Prospective Studies MH - Treatment Outcome PMC - PMC7137491 OTO - NOTNLM OT - Acute-phase response OT - Biologic disease-modifying antirheumatic drug OT - Biomarkers OT - Bone remodelling OT - Cardiovascular risk OT - Rheumatoid arthritis OT - Sarilumab OT - Synovial inflammation COIS- CG received research grants from AB2 Bio, Pfizer and Roche and consulting fees or other remuneration from AB2 Bio, AbbVie, Bristol Myers Squibb, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB. GRB has received research grants from AbbVie, Pfizer, UCB and Roche and consulting fees or other remuneration from AbbVie, Lilly, MSD, Pfizer, Sanofi, Roche and UCB. VS received consulting fees from AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Celltrion, CORRONA, Crescendo, Genentech/Roche, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Sandoz, Sanofi and UCB. JM is an employee of Sanofi and may hold stock and/or stock options in the company. MZ and HvH are employees of Sanofi Genzyme and may hold stock and/or stock options in the company. JS is a former employee of Sanofi Genzyme and may hold stock and/or stock options in the company and is currently employed by Bristol Myers Squibb. TK, SHB, NMHG and AB are employees of Regeneron Pharmaceuticals, Inc. and may hold stock and/or stock options in the company. EDAT- 2020/04/09 06:00 MHDA- 2021/01/12 06:00 PMCR- 2020/04/07 CRDT- 2020/04/09 06:00 PHST- 2019/08/08 00:00 [received] PHST- 2020/03/27 00:00 [accepted] PHST- 2020/04/09 06:00 [entrez] PHST- 2020/04/09 06:00 [pubmed] PHST- 2021/01/12 06:00 [medline] PHST- 2020/04/07 00:00 [pmc-release] AID - 10.1186/s13075-020-02163-6 [pii] AID - 2163 [pii] AID - 10.1186/s13075-020-02163-6 [doi] PST - epublish SO - Arthritis Res Ther. 2020 Apr 7;22(1):70. doi: 10.1186/s13075-020-02163-6.