Sarilumab and adalimumab differential effects on bone remodelling and cardiovascular risk biomarkers, and predictions of treatment outcomes

Abstract

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-α 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-κB 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.

Keywords: Acute-phase response; Biologic disease-modifying antirheumatic drug; Biomarkers; Bone remodelling; Cardiovascular risk; Rheumatoid arthritis; Sarilumab; Synovial inflammation.

Conflict of interest statement

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.

Figures

Fig. 1

Correlations between baseline biomarkers. CRP, C-reactive protein; CXCL13, chemokine (C-X-C motif) ligand 13; Lp(a), lipoprotein (a); MMP-3, matrix metalloproteinase-3; OPG, osteoprotegerin; P1NP, procollagen type 1 N-terminal propeptide; RANKL, receptor activator of nuclear factor-κB ligand; SAA, serum amyloid A; sICAM-1, soluble intercellular adhesion molecule-1; TIBC, total iron-binding capacity

Fig. 2

Median percentage changes from baseline in biomarkers through week 24. Median percentage changes from baseline in biomarkers of a, b the acute-phase response (CRP and SAA), c–f bone remodelling (P1NP, OC, total RANKL and OPG), g synovial inflammation (MMP-3) and h atherothrombosis (Lp [a]). *Adjusted p < 0.05; **adjusted p < 0.01 vs. adalimumab; ***adjusted p < 0.0001 vs. adalimumab (Benjamini–Hochberg procedure). CRP, C-reactive protein; Lp(a), lipoprotein (a); MMP-3, matrix metalloproteinase-3; OC, osteocalcin; OPG, osteoprotegerin; P1NP, procollagen type 1 N-terminal propeptide; Q, quartile; q2w, every 2 weeks; RANKL, receptor activator of nuclear factor-κB ligand; SAA, serum amyloid A

Fig. 3

Proportions of patients whose biomarker values returned to normal reference ranges at week 24. Proportions of patients with biomarker serum concentrations exceeding the reference range at baseline that normalized to within reference range at week 24. ***Nominal p < 0.0001 vs. adalimumab (X2 test). CRP, C-reactive protein; Lp(a), lipoprotein (a); OC, osteocalcin; OPG, osteoprotegerin; P1NP, procollagen type 1 N-terminal propeptide; q2w, every 2 weeks; RANKL, receptor activator of nuclear factor-κB ligand; SAA, serum amyloid A

Fig. 4

Odds ratios for achieving efficacy endpoints at week 24 by baseline biomarker tertile. Odds ratios (sarilumab vs. adalimumab) for achieving ACR20, ACR50 and DAS28-CRP

Fig. 5

Changes from baseline in PROs at week 24 by baseline biomarker tertile. LS mean differences in changes from baseline between sarilumab and adalimumab at week 24 by baseline biomarker tertile in a HAQ-DI and b pain VAS. *Nominal biomarker-by-treatment interaction vs. low tertile. Low, medium and high subgroups are based on biomarker tertile values in overall treatment groups (see Table S3 for tertile ranges). CI, confidence interval; CXCL13, chemokine (C-X-C motif) ligand 13; HAQ-DI, Health Assessment Questionnaire-Disability Index; LS, least squares; MMP-3, matrix metalloproteinase-3; NS, not significant at 5%; P1NP, procollagen type 1 N-terminal propeptide; SAA, serum amyloid A; VAS, visual analogue scale