Interleukin-6 Receptor Inhibitor Tocilizumab Research Articles

Trajectories and predictive significance of inflammatory parameters for clinical outcome in COVID-19 patients treated with tocilizumab.

The IL-6 receptor inhibitor tocilizumab reduces mortality and morbidity in severe cases of COVID-19 through its effects on hyperinflammation and was approved as adjuvant therapy. Since tocilizumab changes the levels of inflammatory markers, we aimed to describe these changes in patients treated with tocilizumab, analyse their value in predicting death and bacterial superinfection and determine their influence on mortality rates. A retrospective analysis of 76 patients who were treated with tocilizumab for severe COVID-19 in 2020 and 2021 was conducted. Inflammatory markers (IL-6, C-reactive protein (CRP), procalcitonin) were documented before and up to seven days after tocilizumab administration. The overall mortality was 25% and 53.8% in patients who required invasive respiratory support. Deceased patients had higher baseline IL-6 (p = 0.026) and peak IL-6 levels after tocilizumab vs those who survived (p < 0.0001). A peak IL-6 value > 1000pg/dl after tocilizumab administration was a good predictor of mortality (AUC = 0.812). Of the deceased patients 41.1% had a renewed CRP increase after an initial decrease following tocilizumab administration, compared to 7.1% of the surviving patients (p = 0.0011). Documented bacterial superinfections were observed in 35.5% (27/76) of patients, of whom 48.1% (13/27) died. CRP-decline and IL-6 increase after tocilizumab treatment occurs regularly. An increase of IL-6 levels exceeding tenfold of baseline IL-6 levels, an absolute peak of 1000pg/ml or a renewed increase of CRP are associated with higher mortality. Suppressed CRP synthesis can impede the diagnosis of bacterial superinfections, thus increasing the risk for complications.

Predictive and pharmacodynamic biomarkers for combination therapy in stage III-IV melanoma: A Simon phase II trial (NCT03999749).

222 Background: The evaluation of biomarkers that predict response and immune-related adverse events (irAEs) is crucial for optimizing melanoma treatment with Immune checkpoint inhibitors (ICIs). We report predictive and pharmacodynamic biomarkers for response and irAEs using high-dimensional flow cytometry in a phase II trial combining nivolumab (3 mg/kg), ipilimumab (1 mg/ml), and the IL-6 receptor inhibitor tocilizumab (4 mg/kg) in unresectable/advanced melanoma patients. Methods: We analyzed serum and blood from melanoma patients at baseline, weeks 7 and 37, categorized them by irAE severity and clinical response. Patients were categorized based on the severity of irAEs (grades 3-5) (TOX), the absence of toxicity or grades 1-2 irAE (NT), clinical benefit (CB), and non-clinical benefit (NCB). Immune monitoring regimen included ELISA for IL-6, gp130, IL-23, osteopontin, and Luminex oncological panel (LXSAHM-22). We employed multi-parametric flow cytometry panels to examine myeloid cells, cytotoxic T cells, and checkpoint protein expression on immune cells. We processed ~1 million PBMCs per sample using various antibodies, with data acquisition performed via Sony’s ID7000 cytometer. The data underwent quality control, normalization PBMCs per patient, concatenation, dimensionality reduction, and clustering in FlowJo. Results: Among the 70 patients administered treatment, we observed a best overall response rate of 57%. Grade 3-5 irAEs occurred in 22% of patients by week 24. Patients manifesting irAEs exhibited notably higher baseline Th17 cell counts (NT=181±18 vs. Tox=311±49, p&lt;0.01) and CD26+ Naive CD4 T-cell populations (NT=5838±801 vs. Tox=9632±1343, p&lt;0.04), suggesting their potential role as predictive markers for toxicity. Additionally, in vitro investigations led us to identify CD26 co-stimulation as a preliminary step in TH17 cell differentiation. Key pharmacodynamic markers included a significant elevation in Treg cells (NCB=1286±71 vs. CB=1492±95, p=0.02) and reduction in serum gp130 levels (NCB=104±5 vs. CB=83±5 ng/ml, p&lt;0.01) at week 7 in addition to IL-6 (NCB=7.5±1.5 vs. CB=4.6±1.1 pg/ml, p&lt;0.01) and osteopontin (NCB=95±15 vs. CB=25±3 ng/ml, p&lt;0.01) by week 37 when compared to baseline. Conclusions: Our findings suggest that Th17 cells can serve as a toxicity biomarker for combination therapy with ipilimumab, nivolumab and tocilizumab. Circulating Treg cells and serum osteopontin have emerged as promising pharmacodynamic biomarkers. Clinical trial information: NCT03999749 .

Dynamics of modified cardiovascular risk factors in patients with rheumatoid arthritis on the background of 5-year therapy with an interleukin 6 receptor inhibitor

The effect of an inhibitor of interleukin (IL) 6 receptors on the state of the cardiovascular system in patients with rheumatoid arthritis (RA) remains poorly understood, especially with its long-term use.The aim – to study the effect of therapy with the IL-6 receptor inhibitor tocilizumab (TCZ) on the dynamics of modifiable risk factors (RF), total cardiovascular risk (CVR), structural changes in the carotid arteries (CA) and the incidence of cardiovascular complications (CVC) in patients with rheumatoid arthritis during the 260-week follow-up period.Material and methods. The study included 37 patients with active RA (32 women and 5 men) with ineffectiveness and/or intolerance to disease modifying anti-rheumatic drugs (DMARDs); median age was 56 [48; 68] years, disease duration was 92 [49; 158] months; DAS28 (Disease Activity Score 28) – 6.2 [5.5; 6.7] points; all patients were seropositive for rheumatoid factor (RF), 86% – for antibodies to cyclic citrullinated peptide (ACCP). Patients received TCZ therapy 8 mg/kg intravenously every 4 weeks; after 192 [176; 210] weeks, 60% of patients switched to subcutaneous administration of the drug at a dose of 162 mg once a week. In 51% of patients with RA, TCZ monotherapy was performed, in 49% – combination therapy of TCZ with DMARDs. Statins were received by 17 (46%) patients, including 7 patients before and 10 after inclusion in the study. All patients underwent an assessment of traditional risk factors, the total cardiovascular risk was calculated using the mSCORE scale, atherosclerotic vascular lesions were assessed by the detection of atherosclerotic plaques (ASP) of CA. The observation period was 260.4 [251.5; 283.4] weeks.Results. After 260 weeks of TCZ therapy, RA remission was observed in 32 (86%) patients, low activity – in 5 (14%) patients. During the observation period, the frequency of modified RF and the total CVR did not change significantly, an increase in body mass index (BMI) by 11% was recorded, the number of patients with hypercholesterolemia and a reduced level of HDL cholesterol (C) decreased. In patients without statin therapy, there were no significant changes in the blood lipid spectrum. In the group of patients receiving statins, there was an increase in HDL-C by 43%, a decrease in cholesterol levels by 15%, atherogenic index (AI) by 56% (p&lt;0.01 in all cases) and associations between the dynamics of ∆cholesterol and ∆CRP (r=0.35; p=0.04), ∆LDL-C and ∆CRP (r=0.41; p=0.03). Significant structural changes in CA in RA patients by the end of 260 weeks of TCZ therapy were not identified. Initially, intima-media thickness (IMT) CA positively moderately correlated with age (r=0.7; p&lt;0.01), BMI (r=0.37; p&lt;0.01), systolic blood pressure (SBP) (r=0.62; p&lt;0.01) and weakly with lipid spectrum parameters – cholesterol (r=0.29; p&lt;0.01), LDL-C (r=0.36; p&lt;0.01). No new associations of IMT CA by the end of the observation, as well as the relationship of the IMT CA value with the indicators of RA activity and the ongoing therapy, were identified. By the end of the study, the distribution of patients by mSCORE value and CVR level did not change significantly. The incidence of CVC was 0,54 per 100 patient-years over a 260-week period of TCZ use. Conclusion. Against the background of long-term TCZ therapy in RA patients, there was no increase in CVR and significant structural changes in CA. It is necessary to dynamically monitor the blood lipid profile and CVR in RA patients receiving TCZ therapy. Statin therapy can successfully control dyslipidemia in RA patients who receive long-term TCZ.

Abstract 13873: Ischemic Time and Interleukin 6 Levels in Acute Myocardial Infarction

Introduction: Increased levels of the inflammatory cytokine interleukin 6 (IL-6) after percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) are associated with larger infarct size and decreased cardiac function. Early treatment with the IL-6 receptor inhibitor tocilizumab in STEMI patients resulted in less myocardial damage, especially in patients treated &gt;3 hours after symptom onset. However, the specific window of opportunity for IL-6 inhibition in STEMI patients remains to be investigated. Therefore, we studied IL-6 levels in STEMI patients varying in ischemic time (i.e. time from symptom onset to PCI), and its association with infarct size. Methods: In 369 STEMI patients IL-6 levels were measured at 24 hours post-PCI. Patients were categorized according to ischemic time (&lt;2 hours, 2-3 hours, 3-4 hours, 4-5 hours, &gt;5 hours). At 4 months, infarct size was assessed by magnetic resonance imaging. IL-6 levels were log transformed for statistical analysis. Results: IL-6 levels at 24 hours post-PCI increased from 9.2 ng/ml (IQR 5.2-16.7 ng/ml) in patients with symptom onset &lt;2 hours to 13.2 ng/ml (IQR 9.0-20.2 ng/ml) in patients with symptom onset between 4-5 hours (P trend =0.036), stabilizing in patients with symptom onset &gt;5 hours ( Figure 1A ). Higher IL-6 levels at 24 hours post-PCI were associated with larger infarct size in patients with symptom onset &lt;4 hours (&lt;2 hours: β 1.9, 95% CI 0.6-3.1, P=0.004; 2-3 hours: β 1.9, 95% CI 0.3-3.4, P=0.019; 3-4 hours: β 3.0, 95% CI 1.6-4.5, P&lt;0.001) ( Figure 1B ). Conclusions: IL-6 levels at 24 hours post-PCI are related to ischemic time. Moreover, higher IL-6 levels are associated with larger infarct size in patients with ischemic time shorter than 4 hours, suggesting a time dependent role of IL-6. This suggests that the window of opportunity for IL-6 inhibition in STEMI patients is within 4 hours of symptom onset. Randomized controlled trials are necessary to further establish this relationship.

Use of tocilizumab in the combination treatment of a COVID-19 patient with concomitant rheumatoid arthritis (a case report)

The aim is to familiarize practitioners with the clinical case of tocilizumab use in the combination treatment of the coronavirus disease (COVID-19) patient with concomitant rheumatoid arthritis. Materials and methods. The clinical case shows our own follow-up of COVID-19 clinical course in the patient with concomitant rheumatoid arthritis during combination treatment with the use of a recombinant humanized anti-interleukin-6 receptor monoclonal antibody tocilizumab. Results. The patient with a severe COVID-19 course, whose examination and treatment results are given in the article, was comorbid for rheumatoid arthritis. The cytokine storm development at the hospital stage was confirmed by an increase in markers of systemic inflammation: C-reactive protein, D-dimer, fibrinogen, an almost 50-fold increase in serum interleukin-6 level, as well as absolute and relative lymphocytopenia. Despite the anti-inflammatory therapy administered with systemic corticosteroids, the patient’s condition progressively worsened. After assessing the indications and contraindications, it was decided to use the interleukin-6 receptor inhibitor tocilizumab, followed by rapid clinical, laboratory and X-ray positive response to the treatment. The understanding of tocilizumab use in patients with COVID-19 at the current stage was formed based on the comparative analysis of our own clinical case data and the results of relevant clinical trials, world recommendations and guidelines. Conclusions. The use of recombinant humanized anti-interleukin-6 receptor monoclonal antibody tocilizumab in the combination treatment of severe COVID-19 with concomitant rheumatoid arthritis is pathogenetically based and decreases the main clinical and laboratory signs of cytokine storm, respiratory failure, improves chest x-ray findings and reduces the length of hospital stay. Further large randomized placebo-controlled trials including the population of patients with various comorbid conditions are needed to clarify conclusively the place and role of anti-cytokine drugs in the treatment of COVID-19 patients.

Impact of the Uncoupling Protein 1 on Cardiovascular Risk in Patients with Rheumatoid Arthritis.

Adiposity is strongly associated with cardiovascular (CV) morbidity. Uncoupling protein 1 (UCP1) increases energy expenditure in adipocytes and may counteract adiposity. Our objective was to investigate a connection between UCP1 expression and cardiovascular health in patients with rheumatoid arthritis (RA) in a longitudinal observational study. Transcription of UCP1 was measured by qPCR in the subcutaneous adipose tissue of 125 female RA patients and analyzed with respect to clinical parameters and the estimated CV risk. Development of new CV events and diabetes mellitus was followed for five years. Transcription of UCP1 was identified in 89 (71%) patients. UCP1 positive patients had often active RA disease (p = 0.017), high serum levels of IL6 (p = 0.0025) and were frequently overweight (p = 0.015). IL-6hiBMIhi patients and patients treated with IL6 receptor inhibitor tocilizumab had significantly higher levels of UCP1 compared to other RA patients (p < 0.0001, p = 0.032, respectively). Both UCP1hi groups displayed unfavorable metabolic profiles with high plasma glucose levels and high triglyceride-to-HDL ratios, which indicated insulin resistance. Prospective follow-up revealed no significant difference in the incidence of new CV and metabolic events in the UCP1hi groups and remaining RA patients. The study shows that high transcription of UCP1 in adipose tissue is related to IL6-driven processes and reflects primarily metabolic CV risk in female RA patients.

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction

BackgroundPrompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response. ObjectivesThis study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. MethodsThe ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. ResultsWe randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups. ConclusionsTocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703)

Exploring the Role of Interleukin-6 Receptor Inhibitor Tocilizumab in Patients with Active Rheumatoid Arthritis and Periodontal Disease.

Background: The aim of our study was to explore the influence of weekly subcutaneous administration of interleukin-6 (IL-6) receptor inhibitor tocilizumab (TCZ) on periodontal status in a local longitudinal study of patients with rheumatoid arthritis (RA) and periodontal disease (PD). Methods: We performed a 6-month prospective study in 51 patients with chronic periodontitis and moderate-to-severe RA starting TCZ in accordance with local recommendations. Extensive rheumatologic (clinical activity, inflammatory, serological biomarkers) and periodontal (visible plaque index, gingival index, bleeding on probing, probing pocket depth, clinical attachment loss) assessments were done. Changes in RA activity and periodontal status were reassessed after 3 and 6 months. Results: We demonstrated significant correlations between periodontal status, disease activity, and serologic biomarkers (p < 0.05). Tocilizumab significantly improved the gingival index scores and decreased the number of sites with bleeding on probing after only 3 months (p < 0.05), while the probing pocket depth significantly decreased after 6 months; overall, clinical attachment loss presented only slight changes without any statistical significance as well as teeth count and plaque levels (p > 0.05). Conclusion: IL-6 inhibition is able to improve periodontal outcomes in patients with RA and concomitant PD, which is essentially related to a dramatic decrease in serum inflammatory mediators.

Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial

SummaryBackgroundAlthough targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells—the target for rituximab—in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status.MethodsThis study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28.FindingsBetween Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI −11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [–1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [–5 to 10]) were not significantly different between treatment groups.InterpretationThe results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice.FundingEfficacy and Mechanism Evaluation programme from the UK National Institute for Health Research.

Interleukin-6 Receptor Inhibition in Acute St-Segment Elevation Myocardial Infarction: A Randomised Placebo-Controlled Trial

Background: Prompt myocardial revascularisation with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with acute ST segment elevation myocardial infarction (STEMI). However, as much as 50 % of the loss of viable myocardium may be attributed to the subsequent reperfusion injury and the associated inflammatory response. The aim of the ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction (ASSAIL-MI) trial was to evaluate the effect of interleukin-6 (IL-6) receptor inhibition on myocardial salvage in acute STEMI. Methods: The ASSAIL-MI trial was a randomised, double blind, placebo-controlled trial performed at three high-volume PCI centres in Norway. Patients admitted with STEMI within six hours of symptom onset were eligible if they had had no prior myocardial infarction. Consenting patients were randomised in a 1:1 fashion to receive a single infusion of the IL-6 receptor inhibitor tocilizumab or placebo during PCI. The primary endpoint was the myocardial salvage index as measured by cardiac magnetic resonance imaging three to seven days after randomisation. Findings: Between 16 th March 2017 and 10 th February 2020, 101 patients were randomised to tocilizumab and 98 patients were randomised to placebo. In the intention to treat analysis, the myocardial salvage index was 69 ± 19 % in patients allocated to tocilizumab and 64 ± 21 % in the placebo group (adjusted between-group difference 5.6 percentage points, 95 % confidence interval 0·0 – 11·3 percentage points, p = 0 · 04). There were 34 serious adverse events, 19 of which occurred in patients treated with tocilizumab and 15 in patients receiving placebo.Interpretation: Treatment with tocilizumab significantly improved myocardial salvage in patients presenting with acute STEMI. Funding: The South-Eastern Norway Regional Health Authority, the Central Norway Regional Health Authority, and Roche TM supported the trial. Roche™ provided the investigational medicinal products and an unrestricted grant. Trial registration number: ClinicalTrials.gov (NCT3004703). Funding Statement: The South-Eastern Norway Regional Health Authority, the Central Norway Regional Health Authority, and RocheTM supported the trial. Roche™ provided the investigational medicinal products and an unrestricted grant. Declaration of Interests: Dr Gullestad has received lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis and Amgen and has been a member of local advisory board in AstraZeneca and Boehringer Ingelheim. The other authors do not have conflicts of interest pertaining to this work. Ethics Approval Statement: The trial protocol was approved by the regional ethics committee (REK Sor-Ost 2016/1223), and all participants provided written informed consent. An independent data and safety monitoring board oversaw the safety of the trial. The trial was conducted in compliance with the declaration of Helsinki and with the rules outlined in the guidelines for Good Clinical Practice.

Subcutaneous tocilizumab treatment in patients with severe COVID-19-related cytokine release syndrome: An observational cohort study.

BackgroundPatients with severe coronavirus disease 2019 (COVID-19) have elevated levels of acute phase reactants and inflammatory cytokines, including interleukin-6, indicative of cytokine release syndrome (CRS). The interleukin-6 receptor inhibitor tocilizumab is used for the treatment of chimeric antigen receptor T-cell therapy–induced CRS.MethodsPatients aged 18 years or older with laboratory-confirmed COVID-19 admitted to the Annunziata Hospital in Cosenza, Italy, through March 7, 2020, who received at least one dose of tocilizumab 162 mg subcutaneously for the treatment of COVID-19–related CRS in addition to standard care were included in this retrospective observational study. The primary observation was the incidence of grade 4 CRS after tocilizumab treatment. Chest computed tomography (CT) scans were evaluated to investigate lung manifestations.FindingsTwelve patients were included; all had fever, cough, and fatigue at presentation, and all had at least one comorbidity (hypertension, six patients; diabetes, five patients; chronic obstructive lung disease, four patients). Seven patients received high-flow nasal cannula oxygen therapy and five received non-invasive mechanical ventilation for lung complications of COVID-19. No incidence of grade 4 CRS was observed within 1 week of tocilizumab administration in all 12 patients (100%) and within 2 days of tocilizumab administration in 5 patients (42%). The predominant pattern on chest CT scans at presentation was ground-glass opacity, air bronchograms, smooth or irregular interlobular or septal thickening, and thickening of the adjacent pleura. Follow-up CT scans 7 to 10 days after tocilizumab treatment showed improvement of lung manifestations in all patients. No adverse events or new safety concerns attributable to tocilizumab were reported.InterpretationTocilizumab administered subcutaneously to patients with COVID-19 and CRS is a promising treatment for reduction in disease activity and improvement in lung function. The effect of tocilizumab should be confirmed in a randomised controlled trial.

Case series of six kidney transplanted patients with COVID-19 pneumonia treated with tocilizumab.

Few reports described the outcome of kidney transplanted patients (KTs) affected by COVID‐19 treated with interleukin‐6 receptor inhibitor tocilizumab (TCZ). We report our case series of 6 KTs with COVID‐19 pneumonia who received TCZ: All were of male gender, with a mean age of 55.5 ± 8.4 years, a median time from transplantation of 3611 days (1465‐5757); 5/6 had cardiovascular comorbidities, 1/6 had diabetes, and 3/6 have one or more previous KTs. Four out of six patients died, at an average time of 9.75 ± 2.4 days after tocilizumab administration, 3/6 due to a coexistent septic shock. Two patients improved after TCZ and were discharged at 20 and 21 days, respectively; in both patient, a significant increase of total lymphocyte count was observed. In conclusion, KTs, where the role of peculiar factors such as chronic immunosuppression is still undetermined, represent a high‐risk group with significant COVID‐19‐associated mortality. The evaluation of the TCZ effect in COVID‐19 pneumonia requires controlled studies (ideally RCTs) in this specific population.

Time course of changes in the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with rheumatoid arthritis during therapy with an interleukin-6 receptor inhibitor

Objective : to investigate the impact of therapy with the interleukin-6 receptor inhibitor tocilizumab (TCZ) on the time course of changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with rheumatoid arthritis (RA) during a 12-month follow-up period. Subjects and methods . 31 RA patients (26 women and 5 men) with an inadequate response and/or intolerance to disease-modifying antirheumatic drugs (DMARDs) were included. Their median age was 54 [45; 61] years; the disease duration – 110 [62; 168] months; DAS28 – 6.2 [5.1; 7.1]; SDAI – 35.0 [23.9; 51.0], and CDAI – 30.0 [21.0; 42.0]. All the patients were seropositive for rheumatoid factor (RF), 84% – for anti-cyclic citrulinated peptide (anti-CCP) antibodies. Extra-articular manifestations were found in 54% of patients. Patients with chronic heart failure were not included. The RA patients were found to have a high frequency of traditional risk factors for cardiovascular diseases (CVD): hypertension (75%), dyslipidemia (61%), smoking (17%), overweight (61%), a family history of CVD (36%) , and hypodynamia (68%). Coronary heart disease was diagnosed in 11% of patients. The inefficacy of three or more NSAIDs was noted in 45% of cases; intolerance to previous therapy with NSAIDs was observed in 55%. The patients received TCZ at a dose of 8 mg/kg every 4 weeks: 39% received TCZ alone; 61% – in combination with methotrexate (MTX), the MTX median dose was 20 [18; 25] mg/week. The level of NT-proBNP was measured before and 12 months after TCZ therapy. Results and discussion . After 12 months of treatment with TCZ 54% of patients had disease remission (DAS28 <2.6), 46% – low disease activity (DAS28 <3.2). Median DAS28 value decreased from 6.2 [5.1; 7.1] to 2.7 [1.5; 3.3] (p<0.01), erythrocyte sedimentation rate (ESR) – from 38 [24; 54] to 8 [4; 16] mm/h (p<0.01), C-reactive protein (CRP) – from 27 [10; 49] to 0.5 [0.2; 0.7] mg/L (p<0.01) and NT-proBNP – from 75.8 [43.0; 100.7] to 37.8 [25.1; 78.5] pg/l (p=0.01), although the frequency of its increased values (≥100 pg/ml) remained unchanged (13%). There was a correlation of ΔNT-proBNP with ΔESR (r=0.43; p<0.05) and with ΔCRP (r=0.46; p<0.05). No association was found between ΔNT-proBNP, RA activity measures, RF, and anti-CCP. The level of NT-proBNP in patients treated with TCZ alone and in combination with MTX did not differ considerably. Conclusion . After 12 months of treatment to suppress RA activity, there was a decrease in NT-proBNP levels when TCZ was used alone and in combination with MTX. The lower concentration of NT-proBNP was associated with a reduction in acute phase measures (CRP and ESR). Control of RA activity results in the reduced damaging effect of inflammation on the myocardium.

A Phase II Study of the Interleukin-6 Receptor Inhibitor Tocilizumab in Combination With Ipilimumab and Nivolumab in Patients With Unresectable Stage III or Stage IV Melanoma

A Phase II Study of the Interleukin-6 Receptor Inhibitor Tocilizumab in Combination With Ipilimumab and Nivolumab in Patients With Unresectable Stage III or Stage IV Melanoma

Transforming growth factor-β dampens interleukin-6 signaling in chondrocytes by decreasing the interleukin-6 receptor

Purpose: Interleukin-6 (IL-6) is a pro-inflammatory cytokine present in increased levels in serum and synovial fluid from patients with osteoarthritis (OA) and is even considered to be predictive for disease progression. Previous studies implicate IL-6 in articular cartilage destruction, which is the main hallmark of OA. In contrast, transforming growth factor-β (TGF-β) is an important homeostatic regulator of cartilage that can decrease the catabolic effects of pro-inflammatory cytokines in chondrocytes. Multiple mechanisms of cross-talk between TGF-β and IL-6 are reported in other tissues. In this study, we investigated whether TGF-β is able to control IL-6 signaling in chondrocytes. Methods: Human primary chondrocytes and the human G6 chondrocyte cell line were stimulated with rhTGF-β1 (1.0 ng/ml). We determined mRNA expression levels of IL-6 and IL-6 receptor (IL-6R) using qPCR, measured IL-6 protein release using Luminex multianalyte technology and IL-6R protein levels by Western Blot. rhIL-1β was used as a positive control for IL-6 induction. Induction of signal transducer and activator of transcription (STAT)3 phosphorylation by TGF-β was determined using Western Blot, in presence of the IL-6R inhibitor Tocilizumab to study IL-6R dependency. Induction of suppressor of cytokine signaling (SOCS)3 gene expression was used as a read-out for IL-6/STAT3 mediated transcriptional activity. Results: TGF-β increased both IL-6 mRNA expression and protein release in G6 and primary chondrocytes. Moreover, we observed activation of the main IL-6R downstream signaling protein STAT3 after TGF-β exposure, which could be completely prevented by blockade of the IL-6R, suggesting IL-6 dependency. We further explored whether TGF-β mediated IL-6/p-STAT3 signaling resulted in activation of target genes, and measured expression of SOCS3, which is a well-known IL-6 target gene as well as an important regulator of IL-6 signaling. Surprisingly however, TGF-β did not increase SOCS3 expression, despite the increased IL-6 and p-STAT3 levels we observed in these cells. This unexpected finding suggests regulation of STAT3 mediated transcriptional activity by TGF-β. The effect of exogenously added rhIL-6 was also inhibited by TGF-β, as 6h pre-treatment with TGF-β prevented rhIL-6-induced SOCS3 expression. At the level of STAT3, TGF-β decreased the response to rhIL-6 as well, although p-STAT3 levels were not reduced to baseline level. This points towards a crucial role for TGF-β in the regulation of IL-6 effects upstream of STAT3. Interestingly, we observed decreased expression of the IL-6R in both primary and G6 chondrocytes after exposure to TGF-β, which might explain the decreased intracellular IL-6 signaling. This effect was not dependent on IL-6 itself, as IL-1β did not affect IL-6R expression, despite being a strong inducer of IL-6. Finally, we showed that rescuing IL-6R levels using soluble IL-6R dose-dependently restored induction of SOCS3 and p-STAT3 by rhIL-6 in the presence of TGF-β. This confirms that TGF-β inhibition of IL-6 effects is indeed dependent on reduced IL-6R levels. Conclusions: Our study reveals a novel, protective effect of TGF-β that could help preserve cartilage homeostasis under inflammatory conditions by dampening IL-6 signaling via IL-6R down regulation.

A New Hose to Extinguish the FIRES?

Tocilizumab Treatment for New Onset Refractory Status Epilepticus Jun JS, Lee ST, Kim R, Chu K, Lee SK. Ann Neurol. 2018;84(6):940-945. doi:10.1002/ana.25374.We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new-onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE.

The bidirectional crosstalk between metastatic uveal melanoma cells and hepatic stellate cells engenders an inflammatory microenvironment

Uveal melanoma is the most common primary ocular neoplasm in adults. It is peculiar for its hematogenous dissemination and its high propensity to spread to the liver. Current treatments rarely prolong patient survival. We hypothesized that metastatic uveal melanoma cells modulate the function of surrounding hepatic stellate cells to facilitate their own growth and survival. This study was conducted to investigate the role of the hepatic microenvironment on uveal melanoma aggressiveness. We demonstrated that the paracrine signaling of surrounding hepatic stellate cells have more transcriptional impact on metastatic uveal melanoma cells. Upregulated transcripts were linked to inflammation and included several interleukins. The uveal melanoma-stellate cell crosstalk induced as well the expression of transmembrane integrins. In addition, the interleukin-6 receptor inhibitor Tocilizumab did not reduce the growth of uveal melanoma cells. Our results provide evidence that inflammatory mediators are key players in the homing of uveal melanoma cells to the liver. The bidirectional crosstalk between uveal melanoma cells and hepatic stellate cells involved pro-fibrogenic interleukins. The inflammatory characteristics of the metastatic microenvironment might offer relevant therapeutic opportunities in uveal melanoma.

Tocilizumab treatment for new onset refractory status epilepticus.

We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE. Ann Neurol 2018;84:940-945.

Abstract 925: In silico models accurately predict in vivo response for IL-6 blockade in head and neck cancer

Abstract The purpose of this study is to create and validate a mathematical model describing the effect of interleukin-6 (IL-6) on head and neck cancer growth and cancer stem cell fraction. Head and Neck Squamous Cell Carcinoma (HNSCC) is the seventh most-common solid tumor with about 55,000 new cases diagnosed every year. Malignant features of HNSCC cells are derived from a shift towards more stem-like features, as postulated by the cancer stem cell (CSC) hypothesis. CSCs encompass a unique cellular subpopulation characterized by multipotency, uniquely high tumorigenic potential, and self-renewal. These cells function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Though they are an appealing conceptual target, CSC directed cancer therapies remain scarce. High levels of both serum IL-6 and tumor IL-6 receptor (IL-6R) expression are strongly correlated with poor patient survival. Endothelial cell-secreted IL-6 enhances the tumorigenic potential and self-renewal of head and neck CSCs. Furthermore, interruption of the IL-6 pathway results in a decreased fraction of HNSCC CSCs. Efficacy and optimal administration of the FDA approved rheumatoid arthritis IL-6R antibody Tocilizumab in HNSCC is not known. Here we used a multi-scale mathematical model that operates at the intracellular, molecular, and tissue level to investigate the impacts of endothelial cell-secreted IL-6 signaling on the crosstalk between tumor cells and ECs during tumor growth. This endothelial cell - tumor cell (EC-TC) model was used to study the effect of tocilizumab treatment on HNSCC, and particularly the CSC fraction. Our ordinary differential equation model is the first of its kind to include full occupancy dynamics between endothelial-cell produced IL-6, IL-6R, and the competitive IL-6R inhibitor Tocilizumab. In order to biologically validate the utility of our mathematical model, we performed a series of in-vivo experiments using HNSCC cell lines and human endothelial cells co-embedded in a porous scaffold and implanted in SCID mice flank. Tumor volumes were measured serially. CSC fraction was determined in HNSCC cell lines using flow cytometry for aldehyde dehydrogenase (ALDH) high/CD44 high proportion. Without artificial tuning to the laboratory data, our model provided superb predictive agreement to the decrease in tumor volumes observed in TCZ treated mice (r = 0.947, p &amp;lt; 0.0001), as well as a decrease in CSC fraction. This predictive in-silico framework can serve to rapidly evaluate dosing strategies for IL-6 pathway modulation, as well as providing the basis for proposing combination treatments with IL-6 blockade and cytotoxic or other targeted therapies. Citation Format: Fereshteh Nazari, Alexandra E. Oklejas, Jacques E. Nör, Alexander T. Pearson, Trachette L. Jackson. In silico models accurately predict in vivo response for IL-6 blockade in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 925.

PM2.5-induced oxidative stress increases intercellular adhesion molecule-1 expression in lung epithelial cells through the IL-6/AKT/STAT3/NF-\u03baB-dependent pathway

BackgroundEpidemiological studies have shown that ambient air pollution is closely associated with increased respiratory inflammation and decreased lung function. Particulate matters (PMs) are major components of air pollution that damages lung cells. However, the mechanisms remain to be elucidated. This study examines the effects of PMs on intercellular adhesion molecule-1 (ICAM-1) expression and the related mechanisms in vitro and in vivo.ResultThe cytotoxicity, reactive oxygen species (ROS) generation, and monocyte adherence to A549 cells were more severely affected by treatment with O-PMs (organic solvent-extractable fraction of SRM1649b) than with W-PMs (water-soluble fraction of SRM1649b). We observed a significant increase in ICAM-1 expression by O-PMs, but not W-PMs. O-PMs also induced the phosphorylation of AKT, p65, and STAT3. Pretreating A549 cells with N-acetyl cysteine (NAC), an antioxidant, attenuated O-PMs-induced ROS generation, the phosphorylation of the mentioned kinases, and the expression of ICAM-1. Furthermore, an AKT inhibitor (LY294002), NF-κB inhibitor (BAY11–7082), and STAT3 inhibitor (Stattic) significantly down-regulated O-PMs-induced ICAM-1 expression as well as the adhesion of U937 cells to epithelial cells. Interleukin-6 (IL-6) was the most significantly changed cytokine in O-PMs-treated A549 cells according to the analysis of the cytokine antibody array. The IL-6 receptor inhibitor tocilizumab (TCZ) and small interfering RNA for IL-6 significantly reduced ICAM-1 secretion and expression as well as the reduction of the AKT, p65, and STAT3 phosphorylation in O-PMs-treated A549 cells. In addition, the intratracheal instillation of PMs significantly increased the levels of the ICAM-1 and IL-6 in lung tissues and plasma in WT mice, but not in IL-6 knockout mice. Pre-administration of NAC attenuated those PMs-induced adverse effects in WT mice. Furthermore, patients with chronic obstructive pulmonary disease (COPD) had higher plasma levels of ICAM-1 and IL-6 compared to healthy subjects.ConclusionThese results suggest that PMs increase ICAM-1 expression in pulmonary epithelial cells in vitro and in vivo through the IL-6/AKT/STAT3/NF-κB signaling pathway.