High levels of interleukin-6 in patients with rheumatoid arthritis are associated with greater improvements in health-related quality of life for sarilumab compared with adalimumab

Abstract

Background Increased levels of cytokines, including interleukin-6 (IL-6), reflect inflammation and have been shown to be predictive of therapeutic responses, fatigue, pain, and depression in patients with rheumatoid arthritis (RA), but limited data exist on associations between IL-6 levels and health-related quality of life (HRQoL). This post hoc analysis of MONARCH phase III randomized controlled trial data evaluated the potential of baseline IL-6 levels to differentially predict HRQoL improvements with sarilumab, a fully human monoclonal antibody directed against both soluble and membrane-bound IL-6 receptor α (anti-IL-6Rα) versus adalimumab, a tumor necrosis factor α inhibitor, both approved for treatment of active RA. Methods Baseline serum IL-6 levels in 300/369 randomized patients were categorized into low (1.6–7.1 pg/mL), medium (7.2–39.5 pg/mL), and high (39.6–692.3 pg/mL) tertiles. HRQoL was measured at baseline and week (W)24 and W52 by Short Form 36 (SF-36) physical/mental component summary (PCS/MCS) and domain scores, Functional Assessment of Chronic Illness Therapy -fatigue, and duration of morning stiffness visual analog scale (AM-stiffness VAS). Linear regression of changes from baseline in HRQoL (IL-6 tertile, treatment, region as a stratification factor, and IL-6 tertile-by-treatment interaction as fixed effects) assessed predictivity of baseline IL-6 levels, with low tertile as reference. Pairwise comparisons of improvements between treatment groups were performed by tertile; least squares mean differences and 95% CIs were calculated. Similar analyses evaluated W24 patient-level response on minimum clinically important differences (MCID). Results At baseline, patients with high versus medium or low IL-6 levels (n = 100, respectively) reported worse (nominal p < 0.05) SF-36 MCS and role-physical, bodily pain, social functioning, role-emotional domain, and AM-stiffness VAS scores. There was a greater treatment effect with sarilumab versus adalimumab in high tertile versus low tertile groups in SF-36 PCS, physical functioning domain, and AM-stiffness VAS (nominal interaction p < 0.05). PCS improvements ≥MCID were higher in high (odds ratio [OR] 6.31 [2.37, 16.81]) versus low (OR 0.97 [0.43, 2.16]) tertiles with sarilumab versus adalimumab (nominal interaction p < 0.05). Adverse events between IL-6 tertiles were similar. Conclusions Patients with high baseline IL-6 levels reported better improvements in PCS, physical functioning domain, and AM-stiffness scores with sarilumab versus adalimumab and safety consistent with IL-6R blockade. Trial registration NCT02332590. Registered on 5 January 2015

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

“…Biomarkers for prediction of therapeutic response A total of 20 reports (including three conference abstracts) investigating the applicability of predictors of treatment success and outcome of bDMARDs selectively targeting the IL-6 pathway were included. Different variables including CRP, 158 serum IL-6 concentration, [159][160][161][162] baseline anticitrullinated peptide antibody status, 163 type I interferon signalling and metallothionein proteins 164 as well as cellular and synovial, [165][166][167] cardiac, [168][169][170][171] genetic markers, 172 173 parameters of bone metabolism 174 and body mass index [175][176][177] were evaluated as possible predictors of clinical outcomes. Investigated biomarkers and detailed results are listed in online supplemental table S5.1 and S5.2, respectively.…”

Systemic Administration of Neutral Electrolyzed Saline as a Novel Treatment for Rheumatoid Arthritis Reduces Mechanical and Inflammatory Damage to the Joints: Preclinical Evaluation in Mice

“…Besides, a significant correlation was found between serum IL-6 levels and the synovitis grading, suggesting a direct correlation between IL-6 production and disease severity. Interleukin-6 (IL-6) is overproduced in the joints of patients with rheumatoid arthritis, suggesting that IL-6 production is a crucial factor in the pathogenesis of the disease [ 27 , 28 ].…”

“…It has been previously postulated that blocking or inhibiting IL-6 is a valuable strategy for treating RA since there is a clear association between IL-6 levels and the quality of life in RA patients [ 27 , 28 ]. In that sense, and according to the findings in the animal model of this study, the administration of NES was beneficial in modulating IL-6 levels, which correlated with a reduction in joint damage, especially for the group treated with the highest dose of NES (NES40).…”

Proinflammatory cytokines and their receptors as druggable targets to alleviate pathological pain

“…251 Sarilumab also had beneficial effects on stiffness and pain in patients with RA. 311,312 Satralizumab did not affect pain or fatigue in NMOSD patients. 369 These outcomes, together with the general tolerability and safety of IL-6 biologics, support their suitability as potentially promising novel and effective pain therapies.…”