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.

Serum Amyloid A Is a Biomarker of Disease Activity and Health-Related Quality-of-Life in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

“…In the ROC analysis, SAA was revealed to be moderately accurate (AUROC 0.7-0.9) in discriminating poor and high HRQoL as well as in assessing disease activity [ 27 ]. In line with our observation, it was reported that SAA correlates with HRQoL measures in systemic sclerosis and could be a predictor of patient-reported outcome response in patients with rheumatoid arthritis [ 28 , 29 ]. However, the HRQoL in patients with chronic diseases could be influenced by multiple factors such as disease severity and the use of medications such as glucocorticoids [ 30 – 32 ].…”

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

“…Levels of soluble IL-6 receptor were not associated with differential response with sarilumab versus placebo or adalimumab (data not shown). Changes in other biomarkers that were assessed in these studies have been discussed previously (18,19).…”

“…Analyses were performed using continuous and categorical biomarker variables, with patients grouped into tertiles according to baseline IL-6 or CRP level (high, medium, or low) (Supplementary Table 1, available on the Arthritis & Rheumatology website at http://onlin elibr ary.wiley.com/doi/10.1002/art.41299/ abstract). Additional biomarkers were assessed in both studies (18,19).…”

Lipoprotein(a) and Its Potential Association with Thrombosis and Inflammation in COVID-19: a Testable Hypothesis

“…An acute increase in Lp(a)-OxPL may then predispose to acute thrombotic events by tilting the balance of coagulation to a prothrombotic state by inhibiting natural fibrinolysis et al [40], the anti-TNFalpha antibody (adalimumab) did not affect Lp(a) levels, showing a specific effect to IL-6 on Lp(a) biology as opposed to a generalized proinflammatory effect [40]. In addition, sarilumab another anti-IL-6R mAb has been shown to lower Lp(a) by 41% compared with 2.8% for adalimumab [57]. Both tocilizumab and sarilumab have completed phase 2 trials in severe COVID-19 patients, and phase 3 trials are currently underway.…”