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

Abstract

Objective The development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin‐6 (IL‐6) levels; however, the utility of IL‐6 as a predictor of treatment response is unclear. This study was undertaken to investigate, by post hoc analysis, whether baseline IL‐6 levels are predictive of sarilumab treatment responses in 2 phase III studies. Methods Serum IL‐6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every 2 weeks (in the MONARCH trial; ClinicalTrials.gov identifier: NCT02332590) or sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks plus methotrexate (MTX) (n = 401, n = 396, and n = 397, respectively) (in the MOBILITY trial; ClinicalTrials.gov identifier: NCT01061736). Efficacy and patient‐reported outcomes were compared between and within groups according to IL‐6 tertile using linear and logistic regression. Results In MONARCH, patients with high baseline IL‐6 levels (all ≥3 times the upper limit of normal; n = 100) had higher disease activity at baseline than those with low IL‐6 levels (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high compared to those with low baseline IL‐6 levels. In MOBILITY, compared to patients with low IL‐6 levels (n = 397), patients with high IL‐6 levels (n = 398) had higher disease activity and joint damage at baseline, were more likely to have joint progression, and had less clinical improvement over 52 weeks’ treatment with placebo plus MTX compared to sarilumab 150 mg or 200 mg plus MTX. Baseline IL‐6 and C‐reactive protein levels were both predictive of outcomes. Safety profiles were similar between defined IL‐6 tertiles. Conclusion IL‐6 may be a prognostic marker of disease progression and severity, and patients with high IL‐6 levels may be likely to benefit from sarilumab compared to adalimumab or MTX. Prospective validation is warranted to confirm the results of these post hoc analyses.

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

“…The beneficial effects of sarilumab versus adalimumab on HRQoL were greater in patients with high IL-6 levels at baseline indicating that among adult RA patients with moderate-to-severely active RA who have had an inadequate response or intolerance to one or more DMARDs, high IL-6 levels may predict greater improvements in PROs/HRQoL than low IL-6 levels. These findings support previous analyses which have shown that across various endpoints, patients with elevated baseline IL-6 levels compared with those without responded better to sarilumab compared with methotrexate or adalimumab [36].…”

“…A separate post hoc analysis of clinical endpoints evaluated in the MONARCH RCT [36] demonstrated that patients with high serum IL-6 levels prior to treatment with sarilumab or adalimumab had increased baseline disease activity, joint damage, pain, and lower patient global assessment and HRQoL scores, and less likely to benefit from TNFi therapies. Furthermore, patients with high versus normal IL-6 levels reported lower responses to placebo plus methotrexate or adalimumab compared with sarilumab treatment [36].…”

“…First, the number of patients in each IL-6 tertile was modest; hence, prospective validation in larger cohorts is warranted to confirm the findings. Furthermore, while we have observed that baseline IL-6 levels predict greater improvements in PROs/HRQoL, it will be important to also assess the indirect effects of improvement of disease activity or other clinical endpoints [36] on PROs and to compare them in terms of magnitude and effect size in the different IL-6 tertiles.…”

Comparison of the drug retention and reasons for discontinuation of Tumor Necrosis Factor Inhibitors and Interleukin-6 Inhibitors in patients with Elderly-onset Rheumatoid Arthritis-the ANSWER cohort study

“…In the present study, the median baseline CRP was signi cantly higher in the IL-6i as compared to the TNFi (1.74 mg/dL versus 1.02 mg/dL; p = 0.02). Several studies have found RA patients with high IL-6 levels had a greater response to IL-6i compared to TNFi [27][28][29][30]. Most recently, a post hoc analysis by Boyapati et al evaluated whether baseline IL-6 levels are predictive of sarilumab treatment responses in 2 phase III studies [29].…”

The cholinergic anti-inflammatory pathway in chronic kidney disease—review and vagus nerve stimulation clinical pilot study

“…Interestingly, circulating IL-6 and IL-17 in RA patients have been shown to correlate with depression symptoms, which is a condition also known to be associated with reduced HRV [ 51 , 109 , 110 ]. Furthermore, the use of an IL-6 inhibitor in RA seems to have a more significant clinical effect on patients with higher levels of circulating IL-6 [ 111 ].…”