Interleukin-6 Receptor Inhibitor Research Articles

A VERY PROLONGED AND ULTIMATELY FATAL COURSE OF COVID-19 IN A PATIENT WITH LYMPHOMA

TOPIC: Chest Infections TYPE: Global Case Reports INTRODUCTION: Recent data suggest that patients with advanced solid and hematologic malignancies are more likely to have prolonged SARS-CoV-2 viral shedding and poor outcomes with coronavirus disease 2019 (COVID-19) due to disease and therapy-related immunosuppression. We present a patient with lymphoma who had a very prolonged and ultimately fatal course of COVID-19 despite aggressive treatments. CASE PRESENTATION: A 39-year-old male was diagnosed with aggressive follicular lymphoma and received standard chemotherapy. Two years later, his disease recurs with transformation to diffuse large B-cell lymphoma and received Rituximab, Dexamethasone, Cytarabine, and Oxaliplatin and radiotherapy to T8-T10 for chord compression. Autologous hematopoietic stem cell transplant (HSCT) was planned but deferred because he tested positive for SARS-CoV-2 via nasopharyngeal (NP) swab RT-PCR. Over the next 12 months, he required hospitalization 7 times with fever, cough, progressive dyspnea, and diffuse lung opacities on chest radiograph. Chest CT revealed bilateral diffuse ground glass infiltrates. Bronchoscopy with BAL was positive for SARS-CoV-2 RT-PCR;lung biopsy revealed interstitial pneumonitis but negative for other infectious pathogens. Overtime, he tested 6 times positive and 2 times negative for SARS-CoV-2 by RT-PCR. He was treated with antimicrobials, convalescent plasma, Remdesivir, and corticosteroids. Cytoxan was subsequently added as a steroid sparing agent. He had 3 negative and 2 positive SARS-CoV-2 IgG serology tests. On this last admission, he presented with hypoxic respiratory failure requiring ICU admission and mechanical ventilation. IL-6 levels peaked at 244. The cycle threshold (CT) values were in the teens suspicious of active viral replication. In ICU he was treated with proned positioning and received vasopressors, Remdesivir, and another course of IV corticosteroids. A year from the COVID-19 diagnosis, the patient's family decided to focus care on comfort, and he expired. DISCUSSION: Per our knowledge we are describing the longest case that suffered with COVID 19. He had a slowly progressive disease and inconsistent SARS-CoV-2 RT-PCR tests. Our case highlights the challenges in managing lymphoma patients, who due to B-cell dysfunction and treatment depletion of B-cells, may act as persistent shedders and sources of transmission. They harbor dysfunctional CD8+ T cells and have an increased likelihood of virally induced lymphopenia and high mortality. The efficacy of corticosteroids and IL-6 receptor inhibitors to treat COVID-19 in patients with lymphoma is unknown. Although these treatments may be helpful in suppressing the 'cytokine storm', they can impede viral clearance. CONCLUSIONS: Our case suggests that regular viral load testing and prolonged courses of antiviral therapies and use of convalescent plasma may need to be considered in patients with lymphoma and protracted COVID-19. REFERENCE #1: Aries JA, et al. Clinical outcome of coronavirus disease 2019 in haemato-oncology patients. Br J Haematol 2020 REFERENCE #2: Hueso T, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood 2020;136:2290-95 REFERENCE #3: Ji Hoon Baang Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Replication in an Immunocompromised Patient J Infect Dis. 2020 Oct 22 : jiaa666. Published online 2020 Oct 22 DISCLOSURES: No relevant relationships by Alina Dulu, source=Web Response No relevant relationships by Anna Ford, source=Web Response Advisory Committee Member relationship with Jazz Pharmaceuticals Please note: $1-$1000 by Stephen Pastores, source=Web Response, value=Consulting fee Grant Support for Clinical Trial relationship with Biomerieux Please note: $5001 - $20000 by Stephen Pastores, source=Web Response, value=Grant/Research Support No relevant relationships by Kate Tayban, source=Web Response

The efficacy and safety of levilimab in severely ill COVID-19 patients not requiring mechanical ventilation: results of a multicenter randomized double-blind placebo-controlled phase III CORONA clinical study

Objective and designThe aim of this double-blind, placebo-controlled, phase III CORONA clinical trial was to evaluate the efficacy and safety of IL-6 receptor inhibitor levilimab (LVL) in subjects with severe COVID-19.SubjectsThe study included 217 patients. The eligible were men and non-pregnant women aged 18 years or older, hospitalized for severe COVID-19 pneumonia.Treatment206 subjects were randomized (1:1) to receive single subcutaneous administration of LVL 324 mg or placebo, both in combination with standard of care (SOC). 204 patients received allocated therapy. After the LVL/placebo administration in case of deterioration of symptoms, the investigator could perform a single open-label LVL 324 mg administration as the rescue therapy.MethodsThe primary efficacy endpoint was the proportion of patients with sustained clinical improvement on the 7-category ordinal scale on Day 14. All efficacy data obtained after rescue therapy administration were considered missing. For primary efficacy analysis, all subjects with missing data were considered non-responders.Results63.1% and 42.7% of patients in the LVL and in the placebo groups, respectively, achieved sustained clinical improvement on Day 14 (P = .0017). The frequency of adverse drug reactions was comparable between the groups.ConclusionIn patients with radiologically confirmed SARS-CoV-2 pneumonia, requiring or not oxygen therapy (but not ventilation) with no signs of other active infection administration of LVL + SOC results in an increase of sustained clinical improvement rate.Trail registrationThe trial is registered at the US National Institutes of Health (ClinicalTrials.gov; NCT04397562).

Favorable clinical response and drug retention of anti-IL-6 receptor inhibitor in rheumatoid arthritis with high CRP levels: the ANSWER cohort study

Objective Currently, biological disease-modifying anti-rheumatic drugs (bDMARDs) with different modes of action [tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), or cytotoxic T-lymphocyte antigen 4–immunoglobulin (CTLA4-Ig)] are used in clinical practice to treat rheumatoid arthritis (RA). However, it is unclear which type of bDMARD is the most efficacious for a specific clinical situation. C-reactive protein (CRP) is an acute-phase reactant driven by IL-6 signalling. Here, we aimed to establish whether therapeutic efficacy differs between IL-6Ri and other bDMARDs with alternative modes of action in RA patients according to their CRP level. Method RA patients treated with bDMARDs were enrolled from an observational multicentre registry in Japan. Patients were classified into three groups according to baseline CRP tertiles. The overall 3 year retention rates of each bDMARD category were assessed. The Clinical Disease Activity Index (CDAI) was also assessed before and 3, 6, and 12 months after bDMARD initiation. Results A total of 1438 RA patients were included and classified into three groups according to tertiles of baseline CRP levels (CRP1, 0–0.3; CRP2, 0.3–1.8; CRP3, 1.8–18.4 mg/dL). In CRP3, the overall 3 year drug retention rates were significantly higher for IL-6Ri than for TNFi and CTLA4-Ig (77.5 vs 48.2 vs 67.3, respectively). No significant difference was evident in terms of CDAI 12 months after bDMARD initiation in CRP1–CRP3. Conclusion IL-6Ri may be a favourable therapeutic option over TNFi and CTLA4-Ig in RA patients with high CRP levels.

Title Current Status of the Search for Biomarkers for Optimal Therapeutic Drug Selection for Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive synovitis. It is significantly associated with disability, impaired quality of life, and premature mortality. Recently, the development of biological agents (including tumor necrosis factor-α and interleukin-6 receptor inhibitors) and Janus kinase inhibitors have advanced the treatment of RA; however, it is still difficult to predict which drug will be effective for each patient. To break away from the current therapeutic approaches that could be described as a “lottery,” there is an urgent need to establish biomarkers that stratify patients in terms of expected therapeutic responsiveness. This review deals with recent progress from multi-faceted analyses of the synovial tissue in RA, which is now bringing new insights into diverse features at both the cellular and molecular levels and their potential links with particular clinical phenotypes.

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.

IL-6 Generated from Human Hematopoietic Stem and Progenitor Cells through TLR4 Signaling Promotes Emergency Granulopoiesis by Regulating Transcription Factor Expression.

Emergency granulopoiesis, also known as demand-adapted granulopoiesis, is defined as the response of an organism to systemic bacterial infections, and it results in neutrophil mobilization from reservoir pools and increased myelopoiesis in the bone marrow. Indirect and direct initiating mechanisms of emergency granulopoiesis have been hypothesized. However, the detailed mechanism of hyperactive myelopoiesis in the bone marrow, which leads to granulocyte left shift, remains unknown. In this study, we report that TLR4 is expressed on granulo-monocytic progenitors, as well as mobilized human peripheral blood CD34+ cells, which account for 0.2% of monocytes in peripheral blood, and ∼ 10% in bone marrow. LPS, a component of Gram-negative bacteria that results in a systemic bacterial infection, induces the differentiation of peripheral blood CD34+ cells into myelocytes and monocytes in vitro via the TLR4 signaling pathway. Moreover, CD34+ cells directly responded to LPS stimulation by activating the MAPK and NF-κB signaling pathways, and they produced IL-6 that promotes emergency granulopoiesis by phosphorylating C/EBPα and C/EBPβ, and this effect was suppressed by the action of an IL-6 receptor inhibitor. This work supports the finding that TLR is expressed on human hematopoietic stem and progenitor cells, and it provides evidence that human hematopoietic stem and progenitor cells can directly sense pathogens and produce cytokines exerting autocrine and/or paracrine effects, thereby promoting differentiation.

POS0606 DISEASE ACTIVITY AND PATIENTS-REPORTED OUTCOMES AFTER SWITCHING BETWEEN IL-6 RECEPTOR INHIBITORS AND JAK INHIBITORS: AN ANALYSIS FROM THE CORRONA REGISTRY

Background:Rheumatoid arthritis (RA) patients who fail therapy may be switched to any of the five classes of biological disease-modifying antirheumatic drugs (DMARDs) and targeted synthetic DMARDs, to meet treatment goals. Physicians may hesitate to switch between Janus Kinase inhibitors (JAKi) and interleukin-6 receptor inhibitors (IL-6Ri) since they both impact IL-6 signalling and due to limited data on switching between the two classes.Objectives:This retrospective, observational study based on the real-world Corrona RA registry aimed to describe the response in RA patients switching between IL-6Ri and JAKi.Methods:Adult RA patients who initiated either IL-6Ri or JAKi after November 2012 and had a six-month post-initiation follow-up visit were eligible. Patients in ‘Cohort A’ initiated an IL-6Ri following discontinuation of a JAKi and those in ‘Cohort B’ initiated a JAKi following discontinuation of an IL-6Ri. Disease activity measures and patient-reported outcomes (PROs) were evaluated at baseline and at six-month follow-up. Within each group, change from baseline was assessed for Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire (HAQ), pain, fatigue, tender joint count (TJC), swollen joint count (SJC), physician global assessment (MDGA), patient global assessment (PtGA) and morning stiffness duration. Proportion of patients achieving CDAI low disease activity (LDA), CDAI remission and minimal clinically important difference (MCID) for HAQ, pain, fatigue, MDGA, PtGA were assessed. Adjusted linear and logistic regression models were performed for between-group comparisons (Cohort A vs Cohort B) excluding initiators who switched therapy prior to six-month visit.Results:Cohorts A and B included 122 and 144 initiators, respectively. Patients who switched toIL-6Ri (vs JAKi) were younger (mean [SD] age, 56.2 [11.3] vs 58.9 [12.6] years), had higher baseline CDAI (23.2 [12.9] vs 20.2 [12.8]), had higher prior use of ≥2 csDMARDs (75% vs 65%), and were less likely to initiate therapy as monotherapy (44% vs 50%).In Cohort A, significant changes from baseline were observed for all continuous outcomes except HAQ and fatigue. In Cohort B, a significant improvement was observed only for patient-reported pain (Table 1).Table 1.Unadjusted Within-Group Change from Baseline to Six Months, Mean (95% CI), nOutcomesCohort A, N = 122Cohort B, N = 144CDAI-4.7 (-7.6, -1.9), 109-2.4 (-5.2, 0.4), 116HAQ-0.0 (-0.1, 0.1), 105-0.1 (-0.1, 0.0), 118Patient-reported pain-8.2 (-13.4, -3.0), 109-5.9 (-11.5, -0.2), 120Patient-reported fatigue-4.4 (-9.0, 0.2), 109-1.7 (-6.6, 3.3), 117TJC-1.6 (-3.0, -0.1), 112-1.2 (-2.6, 0.3), 117SJC-1.5 (-2.5, -0.4), 112-0.4 (-1.3, 0.6),117MDGA-10.9 (-15.6, -6.3), 112-4.3 (-8.7, 0.2), 117PtGA-6.0 (-11.2, -0.8), 109-4.8 (-10.5, 0.8), 120Morning stiffness durationa-1.3 (-2.2, -0.5), 109-0.1 (-1.1, 0.8), 118aAmong those reporting morning stiffness at baseline.In the adjusted between-group comparison (data not shown) of change from baseline, there were no significant differences in clinical outcomes between Cohorts A and B.In both cohorts, patients achieved CDAI LDA, CDAI remission, and MCIDs across other PROs (Figure 1). In the adjusted between-group comparison (data not shown), the results were similar with the exception of achievement of CDAI LDA among patients with moderate to high disease activity at baseline.Figure 1.Rates of CDAI LDA, CDAI Remission, and MCID for PROsa at Six MonthsConclusion:In general, in both cohorts a substantial proportion of patients achieved CDAI LDA and MCID across PROs. Despite some overlap of JAKi and IL-6Ri therapies’ on the IL-6 pathway, there are some distinct mechanisms of action which may result in meaningful improvements for a subset of patients.Acknowledgements:Amy Praestgaard (Sanofi) contributed to the interpretation of the statistical analysis for this abstract. Medical writing support for this abstract was provided by Nupur Chaubey (Sanofi).Disclosure of Interests:Anisha Dua Speakers bureau: AbbVie, Consultant of: Consulting/advisory board for AbbVie, Novartis, and Chemocentryx, Employee of: Board member of Vasculitis foundation and Chicago Rheumatism Society, Kerri Ford Shareholder of: Sanofi, Employee of: Sanofi, Stefano Fiore Shareholder of: Sanofi, Employee of: Sanofi. In addition, Stefano Fiore has a patent EP 19306553.9; USPTO #s 62/799,698; 62/851,474; 62/935,395 issued, Dimitrios A Pappas Shareholder of: Corrona LLC, Consultant of: Sanofi, AbbVie, Gtech, Roche Hellas, and Novartis, Employee of: Corrona LLC. Board of directors, Corrona Research Foundation, Judson Janak: None declared, Taylor Blachley: None declared, Carla Roberts-Toler: None declared, Kelechi Emeanuru: None declared, Joel Kremer Consultant of: AbbVie, Lilly, Novartis, Pfizer, BMS, Genentech, Regeneron, Sanofi, and Corrona, Grant/research support from: AbbVie, Lilly, Novartis, and Pfizer, Alan Kivitz Shareholder of: Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc., and Novartis, Speakers bureau: Celgene, Merck, Lilly, Novartis, Pfizer, Sanofi, Flexion, and AbbVie, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc. In addition, Alan Kivitz reports other from Altoona Center for Clinical Research, PC, during the conduct of the study.

Efficacy and safety of levilimab in combination with methotrexate in subjects with rheumatoid arthritis: Results of phase II AURORA study

Levilimab (LVL) is a monoclonal antibody against the interleukin-6 receptor (IL6R). The article presents data obtained during 56 weeks of the AURORA phase II study.Objective: to evaluate the efficacy safety and immunogenicity of LVL in methotrexate (MTX) resistant patients with active rheumatoid arthritis (RA).Materials and methods. 105 patients with active RA were randomized in a 1:1:1 ratio into two LVL or placebo groups. LVL was administered subcutaneously at a dose of 162 mg every week (QW) or every other week (Q2W). All patients received MTX. After evaluating the primary endpoint of 20% improvement in ACR criteria (ACR20) at week 12, patients in the placebo group were switched to LVL Q2W. The study duration was 56 weeks. The frequency, profile, degree and severity of adverse events were determined in each group for safety assessment. The immunogenicity of LVL was determined by the proportion of patients with identified binding and neutralizing antidrug antibodies. Results. LVL in both regimens was superior to placebo. At week 12, the incidence of ACR20 achievement was 77.1% (LVL QW), 57.1% (LVL Q2W), and 17.1% (placebo) with 95% confidence intervals [37.53; 82.54] (p<0.0001) and [19.08; 68.42] (p=0.003) for the effect difference between LVL and placebo groups. The clinical response, more pronounced in the LVL QW group, persisted until week 52 with an increase in the proportion of patients with ACR50/70, low activity and RA remission. The most common treatment-related adverse events were laboratory abnormalities (predominantly grade 1–2) such as neutropenia, elevated alanine aminotransferase, aspartate aminotransferase levels, hypercholesterolemia, and elevated triglyceride levels. Antidrug antibodies were not identified.Conclusion. In MTX-resistant patients with active RA, the efficacy of both LVL regimens at a dose of 162 mg in combination with MTX was significantly superior to MT monotherapy. LVL QW lead to highest treatment response. LVL has been shown to be well tolerated and low immunogenicity. LVL safety profile is similar to IL6R inhibitors.

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.

Downregulation of Renal MRPs Transporters in Acute Lymphoblastic Leukemia Mediated by the IL-6/STAT3/PXR Signaling Pathway.

PurposeConsidering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL.Subjects and MethodsALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).ResultsPlasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway.ConclusionInflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments.

Anti-cytokine treatments in Covid-19 disease: IL-6 receptor inhibitor (Tocilizumab) and IL-1 receptor antagonist (Anakinra)

Koronavirüs hastalığı 2019 (COVID-19) ilk kez Aralık 2019 tarihinde Çin'in Wuhan kentinde ortaya çıktı ve büyük bir küresel salgına neden oldu. Tüm dünyada halk sağlığı için önemli bir problem haline geldi. Hastalık geçirenlerin büyük çoğunluğu iyi bir prognoza sahip olmasına rağmen bazı hastalarda özellikle akciğeri etkileyen makrofaj aktivasyonu sendromuna (MAS) neden olmaktadır. Hastalığı geçiren bireylerde beklenen inflamasyon yanıtından hiperinflamasyona geçişte sitokin artış hızı ve sitokin miktarının rolü olduğu bilinmektedir. MAS gelişen hasta grubunda mortalite oranları yüksek seyretmektedir ve hastaların klinik ve laboratuvar bulgularında kısa sürede ortaya çıkan değişiklikler görülmektedir. Bu nedenle dinamik bir tedavi süreci ihtiyacı vardır. Özellikle solunum desteği ihtiyacı olan hastalarda glukokortikoid tedaviler önerilmektedir. Glukokortikoid yanıtı olmayan hastalarda anti-sitokin tedaviler gündeme gelmektedir. Anti-sitokin tedavilerden yararlanabilecek hasta grubunun doğru ve vaktinde tanımlanması, etkili ve güvenli bir tedavi planlanması açısından önem taşımaktadır.

Use of Vagus Nerve Stimulation and Vagal Maneuvers as Adjuvant Therapy for COVID-19 Patients

At present there is no effective specific antiviral drug to treat the ongoing COVID-19 pandemic that has already infected millions of individual and caused hundreds of thousand deaths worldwide. There is strong indication that a cytokine storm is responsible for the severity of COVID-19 patients. Pilot studies using IL-6 receptor inhibitors such as Tolicizumab have shown promising results. However, since the cytokine storm is a complex systemic inflammatory response involving multiple cytokines it can be hypothesized that a “paninhibition” of cytokines and/or cytokine receptors will be more effective. However, at the same time this strategy may cause more adverse effects. In this article, we propose the application of Vagus Nerve Stimulation (NVS) and/or some forms of vagal maneuvers as adjuvant therapies to prevent and/or mitigate the cytokine response in COVID-19 patients. This proposal is based on the ability of NVS and to decrease the production of IL-6 and other cytokines. The potential application of the diving response (one form of vagal maneuver), that has been shown to confer intrinsic resistance to inflammation in the blood of diving mammals, is also discussed as adjuvant therapy for COVID-19 patients. Doi: 10.28991/SciMedJ-2021-03-SI-2 Full Text: PDF

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)

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

BackgroundElevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.MethodsWe did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021.FindingsBetween March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group.InterpretationThis trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19.FundingSanofi and Regeneron Pharmaceuticals.

Safety of tocilizumab in COVID‐19 pregnant women and their newborn: A retrospective study

What is known and objectiveTocilizumab is an IL‐6 receptor inhibitor agent which has been proposed as a candidate to stop the inflammatory phase of infection by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). However, safety data of tocilizumab in pregnant women and their newborn are scarce. We aimed to describe maternal and neonatal safety outcomes associated with tocilizumab treatment in pregnant women with severe COVID‐19.MethodsThis is a retrospective study of severe COVID‐19 pregnant women, treated with tocilizumab in two Spanish hospitals between 1 March and 31 April 2020. Demographics, medical history, clinical and radiologic findings, treatment information and laboratory data of mothers and their newborns were collected from electronic medical records.Results and discussionA total of 12 pregnant women were identified to have received tocilizumab during pregnancy in the two hospitals. Median gestational age at admission was 27.7 weeks (interquartile range, 18.0–36.4). Most of them received lopinavir/ritonavir, azithromycin and hydroxychloroquine, two patients received corticosteroids and one received interferon beta 1B. All 12 pregnancies resulted in live births. Somatometric values were normal for all newborns, and evolution at 14 and 28 days was favourable for all of them. Hepatotoxicity was observed in 2 patients, which improved or resolved at discharge. Cytomegalovirus reactivation was detected in another patient who had also received corticosteroids for 15 days, causing a congenital infection in her newborn. Both hepatotoxicity and viral reactivation adverse events were classified as possibly related to tocilizumab administration according to Naranjo's causality algorithm.What is new and conclusionsIt does not appear that tocilizumab has detrimental effects for the mother and newborn. Close monitoring of infections should be considered, especially if other immunosuppressive agents are used.

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.

Repurposing approved drugs for cancer therapy.

BackgroundMany drugs approved for other indications can control the growth of tumor cells and limit adverse events (AE).Data sourcesLiterature searches with keywords ‘repurposing and cancer’ books, websites: https://clinicaltrials.gov/, for drug structures: https://pubchem.ncbi.nlm.nih.gov/Areas of agreementIntroducing approved drugs, such as those developed to treat diabetes (Metformin) or inflammation (Thalidomide), identified to have cytostatic activity, can enhance chemotherapy or even replace more cytotoxic drugs. Also, anti-inflammatory compounds, cytokines and inhibitors of proteolysis can be used to control the side effects of chemo- and immuno-therapies or as second-line treatments for tumors resistant to kinase inhibitors (KI). Drugs specifically developed for cancer therapy, such as interferons (IFN), the tyrosine KI abivertinib TKI (tyrosine kinase inhibitor) and interleukin-6 (IL-6) receptor inhibitors, may help control symptoms of Covid-19.Areas of controversyBetter knowledge of mechanisms of drug activities is essential for repurposing. Chemotherapies induce ER stress and enhance mutation rates and chromosome alterations, leading to resistance that cannot always be related to mutations in the target gene. Metformin, thalidomide and cytokines (IFN, tumor necrosis factor (TNF), interleukin-2 (IL-2) and others) have pleiomorphic activities, some of which can enhance tumorigenesis. The small and fragile patient pools available for clinical trials can cloud the data on the usefulness of cotreatments.Growing pointsBetter understanding of drug metabolism and mechanisms should aid in repurposing drugs for primary, adjuvant and adjunct treatments.Areas timely for developing researchOptimizing drug combinations, reducing cytotoxicity of chemotherapeutics and controlling associated inflammation.

Clinical laboratory and radiation parameters associated with different outcomes of severe new coronavirus infection (COVID­19) with pneumonia in patients receiving tocilizumab

ntroduction. Coronavirus infection 2019 (COVID-19) is characterized by high morbidity and mortality. Interleu- kin-6 receptor inhibitors, including tocilizumab, are used for the anti-inflammatory therapy of COVID-19. The aim of the study was to compare the clinical, lab and radia- tion characteristics of surviving and deceased patients with severe COVID-19 and pneumonia caused by SARS- CoV-2 who received tocilizumab and identify features that were associated with various outcomes. Methods. The medical records of 31 hospitalized COVID-19 pa- tients were stu died. All patients received a single dose of tocilizumab 400 mg. Two groups were created. Group 1 included 17 patients who were discharged with improve- ment, Group 2–14 fatal cases. The methods of parametric and nonparametric statistics were used for processing. Results. The condition of patients from Group 2 more often than in Group 1 was assessed as severe already at admission, p=0.022. Only 4 patients from Group 1 and all patients from Group 2 were allocated to the intensive care unit; the mechanical ventilation was used exclusively in group 2, p &lt;0.001. The groups differed in terms of the SpO2 le vel, p=0.023, and the concentration of C-reactive protein (CRP) at admission, p=0.047, as well as in the vo- lume of lung tissue damage, p=0.027. Tocilizumab was admi nistered to all patients within a comparable period from the onset of the disease. There was an increase in the neutrophil/lymphocyte ratio in peripheral blood (NLR) by the day of its administration in Group 2, p=0.026. The NLR le vel increased even more significantly within 5–7 days after administration, p=0.045 (p=0.007 compared to baseline). The NLR value in Group 2 changed insigni- ficantly. The blood ferritin level in patients from Group 1 by the day of tocilizumab administration was lower than in Group 2, p=0.014, and decreased after the treatment, p=0.01, in contrast to Group 2. The decrease in the CRP concentration after the appointment of tocilizumab in Group 1 was also significant, p=0.001. Conclusions. The deceased COVID-19 patients who received tocilizu- mab were characterized, compared with the survivors, by the initially more severe course of the disease, more pronounced hypoxemia, as well as the volume of lung tissue damage and laboratory abnormalities, inclu ding the le vels of NLR, CRP and ferritin. Monitoring of these in- dicators appears to be necessary to assess the course of COVID-19 and make a decision on the anti-inflammatory therapy with tocilizumab.

The role of IL-6 receptor inhibitor treatment in critical patient monitoring with COVID-19

Objectives: The COVID-19 disease can manifest itself with acute respiratory distress syndrome, renal failure, and septic shock in critically ill patients. There are opinions that there is a correlation between high IL-6 levels and disease severity. In our intensive care unit, we evaluated the changes in the laboratory data and radiological involvement severity of our patients who underwent tocilizumab treatment and examined the appropriate laboratory parameter in the treatment follow-up and its effect on survival. Methods: In the critical patient follow-up of COVID-19, 17 of the 23 patients treated with tocilizumab had a mortal course (Group 1) and the remaining 6 (Group 2) were. The C-reactive protein, lactate dehydrogenase, IL-6, D-dimer, procalcitonin, albumin, and ferritin values, which were routinely screened in our clinic on the day of tocilizumab treatment and the 5th day after, were recorded. Both the change between the two groups and the change between days 1 and 5 were analyzed. Results: A total of 23 patients (55.35 ± 13.31 years) were included in the study. The computed tomography severity score assessed at the intensive care unit admission was statistically significantly higher in Group 2. The procalcitonin and lactate dehydrogenase values measured on day 5 after tocilizumab were significantly lower in Group 2. On the 5th day after treatment, the levels of C-reactive protein, ferritin, chest X-rays, IL-6 and D-dimer statistically significantly changed compared to the first day of the treatment. In correlation with the decrease in PCT as of the 5th day after tocilizumab administration, an increasing tendency was observed in 28-day survival. Conclusion: This study demonstrated that tocilizumab treatment may positively contribute to the treatment by decreasing cytokine levels. PCT and LDH follow-up before and after treatment in critically ill patients who are receiving tocilizumab treatment can give an idea about survival.

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.