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Objectives The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6, IL-6 receptor and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome. Trial design A phase 3 prospective, multi-center, interventional, open label, 6-arm 2x2 factorial design study. Participants Subjects will be recruited at the specialized COVID-19 wards and/or ICUs at 16 Belgian participating hospitals. Only adult (≥18y old) patients will be recruited with recent (≤16 days) COVID-19 infection and acute hypoxia (defined as PaO2/FiO2 below 350mmHg or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation) and signs of systemic cytokine release syndrome characterized by high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those, who have not been on mechanical ventilation for more than 24 hours before randomisation. Patients should have had a chest X-ray and/or CT scan showing bilateral infiltrates within the last 2 days before randomisation. Patients with active bacterial or fungal infection will be excluded. Intervention and comparator Patients will be randomized to 1 of 5 experimental arms versus usual care. The experimental arms consist of Anakinra alone (anti-IL-1 binding the IL-1 receptor), Siltuximab alone (anti-IL-6 chimeric antibody), a combination of Siltuximab and Anakinra, Tocilizumab alone (humanised anti-IL-6 receptor antibody) or a combination of Anakinra with Tocilizumab in addition to standard care. Patients treated with Anakinra will receive a daily subcutaneous injection of 100mg for a maximum of 28 days or until hospital discharge, whichever comes first. Siltuximab (11mg/kg) or Tocilizumab (8mg/kg, with a maximum dose of 800mg) are administered as a single intravenous injection immediately after randomization. Main outcomes The primary end point is the time to clinical improvement defined as the time from randomization to either an improvement of two points on a six-category ordinal scale measured daily till day 28 or discharge from the hospital or death. This ordinal scale is composed of (1) Death; (2) Hospitalized, on invasive mechanical ventilation or ECMO; (3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; (4) Hospitalized, requiring supplemental oxygen; (5) Hospitalized, not requiring supplemental oxygen; (6) Not hospitalized. Randomisation Patients will be randomized using an Interactive Web Response System (REDCap). A 2x2 factorial design was selected with a 2:1 randomization regarding the IL-1 blockade (Anakinra) and a 1:2 randomization regarding the IL-6 blockade (Siltuximab and Tocilizumab). Blinding (masking) In this open-label trial neither participants, caregivers, nor those assessing the outcomes are blinded to group assignment. Numbers to be randomised (sample size) A total of 342 participants will be enrolled: 76 patients will receive usual care, 76 patients will receive Siltuximab alone, 76 patients will receive Tocilizumab alone, 38 will receive Anakinra alone, 38 patients will receive Anakinra and Siltuximab and 38 patients will receive Anakinra and Tocilizumab. Trial Status COV-AID protocol version 3.0 (15 Apr 2020). Participant recruitment is ongoing and started on April 4 th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. Trial registration The trial was registered on Clinical Trials.gov on April 1st, 2020 ( ClinicalTrials.gov Identifier: NCT04330638) and on EudraCT on April 3rd 2020 (Identifier: 2020-001500-41). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Background: The influences of exercising on cytokine response, fatigue and cardiorespiratory values are important aspects of rehabilitation in persons with multiple sclerosis (PwMS). Exercise performed within these programs is often practised in water but the effects of immersion on PwMS have not been systematically investigated. Objective: The objective of this study is to determine differences in cytokine and neurotrophin concentrations, fatigue and cardiorespiratory values in response to 3 week endurance training conducted on a cycle ergometer or an aquatic bike. Methods: A randomized controlled clinical trial was conducted in 60 MS patients (Expanded Disability Status Scale range 1.0–6.5). Resting serum levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), Interleukin-6, soluble receptor of IL-6 and tumor necrosis factor alpha, and concentrations in response to cardiopulmonary exercise test (CPET), fatigue and cardiorespiratory values were determined at entry and discharge. Subjects performed daily 30 minute training at 60% of VO2max. Results: Cytokines and neurotrophins showed no significant differences between groups over the training intervention. Within the water group BDNF resting and post-CPET concentrations (p<0.05) showed a significant increase and NGF tended to increase after the training intervention. Short-term effects on BDNF (CEPT) tended to increase at the start and significantly thereafter (p<0.05). No changes occurred in the land group. Other cytokines and fatigue scores remained unchanged over the training period. Cardiorespiratory values improved significantly over time within both groups. Conclusion: This study indicates that aquatic training activates BDNF regulation and can be an effective training method during rehabilitation in PwMS.

We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.

No data from controlled trials exists regarding the inflammatory response in patients with de novo heart failure (HF) complicating ST-elevation myocardial infarction (STEMI) and a possible role in the recovery of contractile function. We therefore explored the time course and possible associations between levels of inflammatory markers and recovery of impaired left ventricular function as well as levosimendan treatment in STEMI patients in a substudy of the LEvosimendan in Acute heart Failure following myocardial infarction (LEAF) trial. A total of 61 patients developing HF within 48 hours after a primary PCI-treated STEMI were randomised double-blind to a 25 hours infusion of levosimendan or placebo. Levels of IL-6, CRP, sIL-6R, sgp130, MCP-1, IL-8, MMP-9, sICAM-1, sVCAM-1 and TNF-α were measured at inclusion (median 22 h, interquartile range (IQR) 14, 29 after PCI), on day 1, day 2, day 5 and 6 weeks. Improvement in left ventricular function was evaluated as change in wall motion score index (WMSI) by echocardiography. Only circulating levels of IL-8 at inclusion were associated with change in WMSI from baseline to 6 weeks, r = ÷ 0.41 (p = 0.002). No association, however, was found between IL-8 and WMSI at inclusion or peak troponin T. Furthermore, there was a significant difference in change in WMSI from inclusion to 6 weeks between patients with IL-8 levels below, compared to above median value, ÷ 0.44 (IQR ÷ 0.57, ÷ 0.19) vs. ÷ 0.07 (IQR ÷ 0.27, 0.07), respectively (p < 0.0001). Levosimendan did not affect the levels of inflammary markers compared to control. High levels of IL-8 in STEMI patients complicated with HF were associated with less improvement in left ventricular function during the first 6 weeks after PCI, suggesting a possible role of IL-8 in the reperfusion-related injury of post-ischemic myocardium. Further studies are needed to confirm this hypothesis. ClinicalTrials.gov NCT00324766.

Tocilizumab is a recombinant humanized antihuman interleukin-6 receptor monoclonal antibody, which inhibits binding of IL-6 to its soluble (sIL-6R) and membrane-expressed (mIL-6R) receptors. The work investigated whether the observed decline in peripheral neutrophil and platelet counts after tocilizumab administration can be directly explained by tocilizumab IL-6R blockade, thus demonstrating the mechanism of tocilizumab action. Tocilizumab and total sIL-6R concentrations, neutrophil and platelet counts from 4 phase 3 studies in rheumatoid arthritis patients were available. Patients received 4 or 8 mg/kg tocilizumab intravenous infusions every 4 weeks for a total of 6 doses. A population approach was applied to describe the relationship between tocilizumab and sIL-6R concentrations and subsequent changes in neutrophil and platelet counts. Following tocilizumab administration, concentrations of total sIL-6R increased, while neutrophil and platelet counts declined. These changes were transient, with counts returning to their respective baseline levels soon after tocilizumab is eliminated from the body. Tocilizumab concentrations were described by a two compartment model with parallel linear and Michaelis–Menten elimination. The quasi-steady-state target-mediated drug disposition model described tocilizumab relationships to total sIL-6R, which allowed computation of unobserved unbound sIL-6R concentrations. The neutrophil counts were described as a direct function of unbound sIL-6R concentrations. The platelet counts were described by the transit-compartment life-span model with inhibition of production that depended on the unbound sIL-6R concentrations. Thus, the observed changes in sIL-6R, neutrophil, and platelet data are consistent with the tocilizumab mechanism of action and can be fully explained by tocilizumab binding to sIL-6R and mIL-6R.

Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for the proinflammatory properties of IL-6 and constitutes an attractive therapeutic target, but how the sIL-6R is generated in vivo remains largely unclear. Here, we use liquid chromatography-mass spectrometry to identify an sIL-6R form in human serum that originates from proteolytic cleavage, map its cleavage site between Pro-355 and Val-356, and determine the occupancy of all O- and N-glycosylation sites of the human sIL-6R. The metalloprotease a disintegrin and metalloproteinase 17 (ADAM17) uses this cleavage site in vitro, and mutation of Val-356 is sufficient to completely abrogate IL-6R proteolysis. N- and O-glycosylation were dispensable for signaling of the IL-6R, but proteolysis was orchestrated by an N- and O-glycosylated sequon near the cleavage site and an N-glycan exosite in domain D1. Proteolysis of an IL-6R completely devoid of glycans is significantly impaired. Thus, glycosylation is an important regulator for sIL-6R generation.

Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10⁻²²) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10⁻²²). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10⁻⁷). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.

IL-6 signaling is critical in the pathogenesis of several autoimmune diseases, including psoriasis and psoriatic arthritis. This study utilized Mendelian randomization (MR) analysis to investigate the genetic associations between IL-6 signaling, soluble IL-6 receptor (sIL-6R) levels, and psoriasis and its arthritis. Additionally, the therapeutic potential of IL-6R inhibitors was evaluated. The study methodology was validated through positive and negative control analysis, with further confirmation of genetic associations via Bayesian factor colocalization analysis. The MR results indicated that upregulation of IL-6 signaling was positively associated with psoriasis (P IVW = 0.008, 95% CI: 1.16–2.66), whereas elevated sIL-6R levels were negatively associated with psoriasis (P IVW < 0.001, 95% CI: 0.95–0.99). Positive control analysis showed that IL-6R inhibitors effectively reduced the risk of rheumatoid arthritis but increased the risk of atopic dermatitis. In contrast, negative control analysis revealed no significant therapeutic effect on seborrheic dermatitis. Using GWAS data from multiple databases, IL-6R inhibitors were identified as being associated with a reduced risk of psoriasis and psoriatic arthritis. Colocalization analysis highlighted the rs4129267 genetic variant as strongly linked to the therapeutic effects of IL-6R inhibitors on psoriasis ( P  < 0.001, 95% CI: 0.37–0.74). These findings underscore the crucial role of IL-6 signaling in the development of psoriasis and psoriatic arthritis and provide robust genetic evidence supporting the therapeutic potential of IL-6R inhibitors. By identifying genetic determinants of disease susceptibility and potential biomarkers of treatment response, this study provides valuable clinical insights and guidance for optimizing treatment strategies for psoriasis.

As the number of patients undergoing total joint replacement (TJR) surgery increases, so does the number of revision surgeries. One driver of implant failure and subsequent revision surgery is peri-implant osteolysis, which is driven by inflammation-mediated bone loss. IL-6 is an inflammatory cytokine that is elevated during the peri-operative period. Early elevations in IL-6 levels have been linked to osteolysis development. The current study asked whether there is genetic contribution to the IL-6-related peri-operative inflammatory reaction to TJR surgery. Patients undergoing primary TJR (total hip or total knee) provided pre-operative and post-operative blood samples for measurement of the circulating levels of IL-6 and the soluble IL-6 receptor (sIL-6r), as well as evaluation of allele status of three single nucleotide polymorphisms (SNPs) linked to IL-6 or sIL-6r levels - rs2069845, rs2228145, and rs4537545. Circulating sIL-6r levels were associated with allele status in the rs2228145 SNP. More interestingly, allele status in the rs2069845 SNP was associated with the change in circulating IL-6 levels following TJR surgery. Specifically, patients with the A,A allele had increasing levels of IL-6, while those harboring the G,A allele had decreasing levels of IL-6. While implant survival was not assessed, the critical role of IL-6 in peri-implant osteolysis suggests that the rs2069845 allele may influence orthopedic implant success. rs2069845 polymorphisms may be a useful patient-specific marker of inflammatory response to TJR surgery.

Signaling of the pleiotropic cytokine Interleukin-6 (IL-6) via its soluble IL-6R (sIL-6R) has been termed trans-signaling and is thought to be responsible for the pro-inflammatory properties of IL-6. The sIL-6R can be generated by alternative mRNA splicing or proteolytic cleavage of the membrane-bound IL-6R. However, which stimuli induce sIL-6R release and which endogenous signaling pathways are required for this process is poorly understood. Here, we show that activation of Toll-like receptor 2 (TLR2) on primary human peripheral blood mononuclear cells (PBMCs) and on the monocytic cell line THP-1 induces expression and secretion of IL-6 and the generation of sIL-6R. We show by flow cytometry that monocytes are a PBMC subset that expresses TLR2 in conjunction with the IL-6R and are the major cellular source for both IL-6 and sIL-6R. Mechanistically, we find that the metalloproteases ADAM10 and ADAM17 are responsible for cleavage of the IL-6R and therefore sIL-6R generation. Finally, we identify the Extracellular-signal Regulated Kinase (ERK) cascade as a critical pathway that differentially regulates both IL-6 and sIL-6R generation in monocytes.