Interleukin-6 Receptor Inhibitor Research Articles

Tocilizumab therapy in COVID-19 patients

A severe pneumonia-associated respiratory syndrome caused by the new coronavirus 2 (SARS‑CoV‑2) was identified in December 2019 as Coronavirus Disease 2019 (COVID-19). It has spread rapidly and has become a worldwide health challenge. Some patients experienced severe complications, including acute respiratory distress syndrome (ARDS), and have even progressed to an intensive care unit (ICU) admission and death. Research has reported that pathogenic T cells and inflammatory monocytes prompt an inflammatory storm with large amounts of interleukin 6. Consequently, IL-6 receptor inhibitors have been repurposed to treat COVID-19, but their exact role in treatment remains unclear. Tocilizumab (TCZ), a monoclonal antibody against IL-6, emerged as an alternative treatment in COVID-19 patients with ARDS syndrome. Therefore, the authors hypothesise that tocilizumab might be effective in decreasing the inflammatory storm and reducing mortality in COVID-19 severe cases. This observational retrospective study explored the use of a single dose of tocilizumab 400 mg intravenous infusion for an hour in COVID-19 patients. The results showed that tocilizumab could not improve the parameters related to mortality rates, such as IL-6 levels, leukocytes, C-reactive protein (CRP), Neutrophil-to-lymphocyte ratio (NLR), and ferritin. IL-6 levels increased after tocilizumab administration.

Treatment of childhood-onset Takayasu arteritis: switching between anti-TNF and anti-IL-6 agents.

Biologics are new treatment alternatives in Takayasu arteritis (TA), although data in childhood are limited. The aim of this study was to share our experience in seven childhood-onset TA patients who received a TNF-α inhibitor (adalimumab) or an IL-6 receptor inhibitor (tocilizumab) and the effect of switching therapy. We retrospectively evaluated the medical treatment records of seven patients with TA, followed between August 2005 and January 2021 at the Pediatric Rheumatology Department of Hacettepe University Faculty of Medicine. The median age of patients was 14 (IQR 4) years, and six were female. All of the patients had severe disease and high acute-phase reactants. The patients initially received only steroids or steroids+CYC. Prednisone was decreased, and biologic agents were started once the acute phase reactants decreased, and the Indian Takayasu Activity Score (ITAS) returned to normal. Initially, four patients received tocilizumab (TCZ) [median 25.5 (IQR 41) months] and three patients received adalimumab (ADA) [median 13 (IQR 31) months]. However, due to the progression of MR angiography findings or persistent elevation in acute-phase reactants, the biologic agents were switched from TCZ to ADA in four patients and from ADA to TCZ in three patients. The patients' median follow-up time after changing was 50 (IQR 77) months, and median ITAS was evaluated as '0' after 2 (IQR 4) months. In conclusion, both TNF-α and IL-6 inhibitors are effective alternatives in treating patients with childhood-onset TA. However, prospective randomized controlled trials are needed for the comparison of their effectiveness.

Analysis of hematological parameters in rheumatoid arthritis patients receiving biological therapy: contribution to prevention of avoidable hematological complications

Administration of biological therapy (BT) in rheumatoid arthritis (RA) patients is often associated with hematological complications, which result in switching among therapies. Thus, there is an instant need for suitable screening parameters that will help to individualize the therapy and minimize the onset of adverse effects. We analyzed the hematological profile of 99 RA patients receiving TNFα (Adalimumab - ADA, Golimumab - GOL, Etanercept - ETA) or IL-6 receptor (Tocilizumab - TCZ) inhibitors in order to find possible indicators to improve personalization of RA therapy. BTs significantly affect the levels of observed hematological parameters. In contrast to TNF-α inhibitors, TCZ normalized almost all monitored hematological parameters to values of healthy donors. Only GOL from the TNF-α inhibitors studied, was able to normalize neutrophil counts, as well as platelet indicators. Importantly, effects on the blood parameters (e.g. lymphocytes or platelet count) differ even within the same therapeutic group (anti-TNFα). Variable effects of individual biological agents in RA treatment point to importance to evaluate the patient's hematological profile to improve the selection of suitable BT. It will help to personalize the administration of BT and prevent unnecessary switching from an effective therapy just because of provocation of avoidable hematological complications.

Preferable outcome of Janus kinase inhibitors for a group of difficult-to-treat rheumatoid arthritis patients: from the FIRST Registry

BackgroundsTreatment of difficult-to-treat rheumatoid arthritis (D2T RA) is one of the greatest unmet needs in rheumatology. This study aims to find out preferable treatment options for a group of D2T RA patients who are refractory to multiple biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs).MethodsData were obtained from patients enrolled in the FIRST Registry who started either TNF inhibitor (TNFi), interleukin-6 receptor inhibitor, cytotoxic T-lymphocyte–associated antigen-4 immunoglobulin, or Janus-kinase inhibitor (JAKi) in the period of August 2013 to December 2020. Those who failed to ≥ 2 and ≥ 3 b/tsDMARDs were categorised as D2T RA and very D2T RA (vD2T RA), respectively. Change in Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire Disability Index were compared among the groups using propensity-based inverse probability treatment weighted (IPTW) method.ResultsOf 2128 cases included, 353 were categorised as D2T RA. Among the D2T RA, 106 were identified as vD2T RA. JAKi showed a significant improvement in CDAI in the patients with D2T RA and vD2T RA, compared to IPTW-adjusted patients treated with the other 3 regimens. Latent class analysis of the trajectories of treatment response revealed that the proportion of a group of patients who showed poor response was lower among the JAKi subgroup than among those with other subgroups. This superiority of JAKi was more apparent among methotrexate- and glucocorticoid-free individuals. The hazard ratio of severe adverse events was comparable among the four treatment subgroups in both the D2T RA and b/tsDMARD-naïve groups.ConclusionsThis study compared responsiveness to different classes of b/tsDMARDs among D2T RA and vD2T RA patients who were refractory to multiple b/tsDMARDs. The results suggest JAKi is a preferable treatment choice for this type of D2T RA.

Childhood-onset Takayasu arteritis.

Takayasu arteritis is a rare chronic granulomatous large vessel vasculitis that predominantly affects the aorta and its branches. The purpose of this review is to unite the current knowledge regarding the pathophysiology, cause, and epidemiology as well as diagnosis, prognosis, and treatment of this condition in children. Although the etiopathogenesis is not fully understood, studies suggest an autoimmune basis for the disease as well as a genetic predisposition. It is a disease primarily affecting young women with up to a third of cases with onset in childhood. There are distinct features of childhood-onset Takayasu arteritis (cTA) that merit this separate review. Diagnostic criteria and clinical manifestations are unique in pediatric patients with renovascular hypertension being the most prevalent presentation. Traditional treatments involving high-dose corticosteroids and cytotoxic agents are being reconsidered for less toxic contemporary biologic agents. Current algorithms for treatment include early introduction of corticosteroid-sparing agents, such as methotrexate or mycophenolate as well as tumor necrosis factor-alpha (TNF-α) inhibitor (infliximab, adalimumab) and/or interleukin-6 (IL-6) receptor inhibitor (tocilizumab). Early diagnosis of cTA with goals to develop effective and well tolerated treatment paradigms are essential to improve the long-term prognosis of this rare and devastating disease.

Effect of Interleukin 6 on Scleral Fibroblast Proliferation, Differentiation, and Apoptosis Involved in Myopic Scleral Remodeling

Introduction: Scleral hypoxia (HO) is present in myopic eyes, and interleukin (IL)-6 is increased in the aqueous humor of patients with high myopia. The aim of this study was to investigate the effects of IL-6 on scleral fibroblast proliferation, differentiation, and apoptosis under conditions of HO and the possible role of IL-6 in myopic scleral remodeling. Methods: Primary human scleral fibroblasts (HSFs) were cultured using a tissue mass adherent method. First, cells were cultured under conditions of HO (2% O2) or normoxia (NO, 20% O2) for different times. A quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence were used to detect the expression of IL-6 in HSFs. Next, cells were divided into five groups: NO, HO, HO plus IL-6, HO plus IL-6 receptor inhibitor (IL6RI), and HO plus IL-6 and IL6RI. The groups were treated separately for 72 h. Cell counting kit-8 assay and flow cytometry were used to detect cell proliferation and apoptosis, respectively. Western blotting and qRT-PCR were used to detect the expression of various genes in the transforming growth factor-β1/Smad2/matrix metalloproteinase-2 pathway; these methods and immunofluorescence were also used to detect transdifferentiation of HSFs. Results: HO resulted in upregulation of IL-6 expression in HSFs. Compared with NO, HO resulted in diminished cell proliferation and increased apoptosis and differentiation in HSFs; the above trend was further enhanced by the addition of IL6RI. Compared with the HO group, the addition of IL-6 led to a decrease in cell proliferation and an increase in apoptosis and differentiation of HSFs; the above trends showed opposite changes after the addition of both IL-6 and IL6RI. Additionally, IL-6 and IL6RI exerted opposite regulatory effects on the transforming growth factor-β1/Smad2/matrix metalloproteinase-2 pathway under conditions of HO. Conclusion: HO caused HSFs to overexpress IL-6. IL-6 has a role in scleral remodeling in myopic eyes through affecting the proliferation, differentiation, and apoptosis of HSFs.

Предикторы достижения ремиссии при терапии генно-инженерными биологическими препаратами (тоцилизумабом и канакинумабом) детей с системным ювенильным идиопатическим артритом: когортное исследование

Therapy with biologicals at the onset of systemic juvenile idiopathic arthritis (sJIA) ensures faster achievement of inactive disease or remission in more patients compared to standard treatment. Identification of predictors of early response to biologicals is necessary to increase treatment efficacy in children with sJIA. Objective. To develop a model for predicting treatment outcomes with different biologicals in sJIA patients. Materials and methods. We analyzed medical records of sJIA patients who received tocilizumab or canakinumab and were admitted to the Department of Rheumatology between July 2009 and February 2021. Predicted outcomes included inactive disease after 12 months of therapy with biologicals (according to C. Wallace criteria and JADAS71) and drug-free remission (without biologicals) for at least 6 months. Potential predictors comprised patient demographic and clinical characteristics, such as sJIA activity, CHAQ index, concomitant therapy, treatment outcomes after 1 and 3 months of therapy, etc. (115 parameters in total). Independent predictors were chosen using multivariate binary logistic regression. Results. This study included 250 patients receiving tocilizumab and 73 patients receiving canakinumab. After 12 months of tocilizumab therapy, 179 patients (76%) achieved inactive disease according to C. Wallace criteria and 170 patients (72%) achieved remission according to JADAS71 index. Drug-free remission (for at least 6 months without biologicals) was registered in 51 patients (20%) from the tocilizumab group. In the canakinumab group, inactive disease according to C. Wallace criteria, remission according to JADAS71, and drug-free remission were achieved in 58 (79%), 58 (79%), and 10 (14%) patients, respectively. Duration of morning stiffness at sJIA onset, dynamics of the duration of morning stiffness after 1 and 3 months of treatment, disease activity evaluated by a physician using the 100-mm visual analog scale (VAS) after one month of therapy, and patientreported overall well-being evaluated using VAS after 3 months of therapy were found to be the predictors of achieving remission according to C. Wallace criteria in the tocilizumab group. The following factors were significantly associated with remission according to JADAS71 index: duration of morning stiffness at sJIA onset and upon treatment initiation, VAS score evaluated by a physician after 1 and 3 months, and number of painful joints after 3 months. We also found several predictors of achieving drug-free remission, including lymphocyte count at disease onset, therapy with glucocorticoids (GCs) and its duration by the time of biological initiation, ESR upon treatment initiation, 50% improvement according to ACR pediatric criteria after 1 month, administration of systemic GCs after 1 month, ESR dynamics by 3 months, and number of joints with limited motion after 3 months. In the canakinumab group, the following factors were associated with remission according to C.Wallace criteria and JADAS71: duration of morning stiffness at treatment initiation, number of biologicals received in the past, 30% improvement according to pediatric ACR criteria after 1 month, and presence of joints with limited motion after 3 months; the predictors of drug-free remission included previous treatment with tocilizumab, number of active joints, and patient-reported overall well-being evaluated using VAS at treatment initiation, dynamics of the number of joints with active arthritis after 1 and 3 months, dynamics of JADAS71 after 1 month, lymphadenopathy after 1 month, and dynamics of patient-reported overall well-being after 3 months. Conclusion. Treatment in the past, characteristics of joint syndrome before and 1–3 months following treatment initiation, dynamics of laboratory parameters and VAS scores of disease activity (both patient-reported and physician-rated) were independent predictors of remission in sJIA patients during therapy with tocilizumab and canakinumab. Key words: systemic juvenile idiopathic arthritis, remission, predictors, biologicals, interleukin-1b inhibitor, interleukin-6 receptor inhibitor, tocilizumab, canakinumab

Colony-Stimulating Factor-1 Receptor and Interleukin-6 Receptor Inhibition Prevents Conversion of cDC2s Into Tumor-Induced DC3s

Colony-Stimulating Factor-1 Receptor and Interleukin-6 Receptor Inhibition Prevents Conversion of cDC2s Into Tumor-Induced DC3s

SARS-CoV-2 in coronary blood from thrombus aspiration in a patient with myocardial infarction

SARS-CoV-2 in coronary blood from thrombus aspiration in a patient with myocardial infarction

Overcoming sunitinib resistance with tocilizumab in renal cell carcinoma: Discordance between in vitro and in vivo effects

Sunitinib is one of the first-line multi-tyrosine kinase inhibitors for metastatic renal cell carcinoma, and resistance to sunitinib continues to be a limiting factor for the successful treatment. As interleukin-6 (IL-6) is overexpressed in sunitinib-resistant cells, the purpose of this study was to explore the potential of IL-6 inhibition with tocilizumab, an IL-6 receptor inhibitor, to overcome resistance. In vitro, two sunitinib-resistant renal cell carcinoma cell lines (Caki-1 and SN12K1) were treated with tocilizumab. A mouse subcutaneous xenograft model was also used. Cell viability was studied by MTT assay, and apoptosis by morphology and ApopTag. Expression of IL-6, vascular endothelial growth factor (VEGF), and Bcl-2 was analyzed by qPCR. In vitro, tocilizumab induced significant cell death, and reduced the expression of IL-6, VEGF, and Bcl-2 in sunitinib-resistant cells. However, the in vitro findings could not be successfully translated in vivo, as tocilizumab did not decrease the growth of the tumors.

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 >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 (<2 hours, 2-3 hours, 3-4 hours, 4-5 hours, >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 <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 >5 hours ( Figure 1A ). Higher IL-6 levels at 24 hours post-PCI were associated with larger infarct size in patients with symptom onset <4 hours (<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<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.

Early Cytomegalovirus Reactivation after Allogenic Bone Marrow Transplantation Is Associated with the Loss of Recipient-Derived Humoral Immunity and Is Reduced By IL-6 Inhibition

Background:Interleukin-6 (IL-6) promotes the differentiation of pathogenic T cells and represents a dominant pathway of cytokine-dysregulation and graft-versus-host disease (GVHD). Cytomegalovirus (CMV) reactivation is a common and life-threatening infectious complication following allogenic bone marrow transplantation (BMT). The role of T cell immunity is long-established, and our group recently demonstrated that CMV strain-specific immunoglobulins (Ig) are critical in preventing CMV reactivation in preclinical models (Martins JP et al, Science 2019).Methods and Results:In a phase I/II clinical trial (Kennedy GA et al, Lancet Onc. 2014), we observed unexpectedly low rates of CMV reactivation following IL-6 receptor (IL-6R) blockade with tocilizumab (TCZ) compared to historical control (8/35 vs 20/43, P < 0.05). We used our preclinical models of murine CMV (MCMV) reactivation to pursue the mechanisms. We transplanted bone marrow (BM) and T cells from naïve B6 donors into CMV-latently infected B6D2F1 recipients and monitored MCMV reactivation. Ablation of IL-6R in donor T cells (using B6 CD4 cre x IL-6R fl/fl transgenic mice; IL-6R -/-) significantly reduced MCMV reactivation 5 weeks after BMT, as measured by plasma viremia and infectious viral loads in the liver (Fig 1A).Next, we examined the contribution of donor T and B cells to the suppression of MCMV reactivation by IL-6R inhibition. At 2 - 3 weeks after BMT and prior to MCMV reactivation, cytokine (IFNɣ/TNF) secretion from CD4 + T cells (in response to MCMV infected DC) was not detectable; MCMV m38 tetramer + CD8 T cells were present at very low frequencies (< 0.1% of CD8 T cells) which were not altered by IL-6R ablation. The frequency of CXCR-5 +PD-1 + T FH cells was comparable or lower in IL-6R -/- vs wild-type (WT) T cells after BMT. Transplant of BM from B6.μMT mice (unable to generate mature B cells and plasma cells) did not increase MCMV viremia (Fig 1B), excluding a role for donor B cells. Thus, early MCMV reactivation in the presence of IL-6 is independent of MCMV-specific T cells and donor B cells.To study the effects of IL-6 on recipient-derived humoral immunity we quantified MCMV-specific IgG in plasma after BMT and found that levels were significantly higher in recipients of IL-6R -/- T cells (Fig 1C). Furthermore, MCMV-IgG levels in plasma correlated with MCMV viremia (r = - 0.72, P < 0.0001) and viral loads in liver (r = - 0.68, P < 0.0001). MCMV-IgG2a, which can only be generated by B6D2F1 recipients, was significantly higher in recipients of IL-6R -/- T cells, confirming that differences in humoral responses were of recipient-origin. To define relevant mechanisms, we examined the kinetics of IgG after BMT by monitoring the loss of murine IgG (transferred on day 0) in plasma (Fig 1D). Recipients of IL-6R -/- T cells showed significantly slower loss of IgG than recipients of WT T cells, with or without GVHD prophylaxis with cyclosporine (CSA). Thus, ablation of IL-6 signaling in donor T cells is associated with reduced loss of recipient IgG and protection from MCMV reactivation, an outcome which seems independent of the effects of IL-6 on GVHD.We correlated our findings with data from a recent randomized, placebo-controlled, double-blind phase III clinical trial of TCZ administration on Day -1 of BMT (Kennedy GA et al, Blood 2021). TCZ reduced CMV reactivation in at risk seropositive BMT recipients of volunteer unrelated donor grafts regardless of acute GVHD (all at risk recipients, TCZ vs. control: 12/26 vs 21/28, P = 0.03; at risk without grade 2-4 GVHD, TCZ vs control: 6/18 vs 9/13, P = 0.03). TCZ did not alter the frequency of B cells or the frequency and function of HCMV-specific CD8 + T cells, quantified by HCMV-pMHC tetramer-staining and HCMV peptide-specific cytokine (IFNγ/TNF) secretion. In contrast, levels of HCMV-specific IgG at day +30 in HCMV-seropositive recipients were significantly higher in the TCZ versus control group (Fig 1E). Consistent with our preclinical studies, the level of HCMV-IgG significantly and inversely correlated with early HCMV reactivation (within 35 days) after transplant.Conclusion:These data confirm the importance of recipient-derived humoral immunity in controlling early CMV reactivation in clinical BMT recipients. Critically, we demonstrate the ability of IL-6R blockade to maintain protective humoral responses until effective donor-derived adaptive immunity can be generated. [Display omitted] DisclosuresBoeckh: Merck: Consultancy, Research Funding; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; GSK: Consultancy. Hill: Generon corporation: Consultancy; NapaJun Pharma: Consultancy; Compass Therapeutics: Research Funding; Syndax Pharmaceuticals: Research Funding; Applied Molecular Transport: Research Funding; iTeos Therapeutics: Consultancy, Research Funding; Roche: Research Funding; Neoleukin Therapeutics: Consultancy.

Anti-inflammatory potential of λ-carrageenan by inhibition of IL-6 receptor: in silico study

In some cases, the immune system in COVID-19 patients leads to the release of excess cytokine production (cytokine storm), which will potentially develop into pneumonia. Interleukin 6 (IL-6) plays the role of pro-inflammatory cytokine, it is a receptor mediated signalling system. Macroalgae is well known as a source of valuable bioactive substances with potential biological activities. Among them is the sulphated polysaccharide lambda-carrageenan λ-CGN which has been reported as an anti-inflammatory agent. However, its mechanism of action against IL-6 production is currently unknown. This study aims to predict potential molecular mechanisms of λ-CGN chemical compound against IL-6 expression through in silico study. Chemical compound of λ-CGN and target protein in this study were obtained from the pubchem and protein data bank (PDB). The molecular docking prediction was conducted with PyRx software, the result is λ-CGN compound showing strong binding energy to bind target protein IL-6 receptor with the value of -5.9 kcal/mol. Based on the results of in silico study, the sulphated polysaccharide λ-CGN potentially inhibits IL-6R expression by binding ligand pocket with six conventional hydrogen bonds (amino acid residus: His256, His 257, Trp 219, Arg 231, and Asp 221) and two carbon hydrogen bonds (amino acid residus: THR 218 and GLN 220). Binding with these amino acid residues potentially contributes to IL-6 receptor structural change which could result in functional change. Hence, further studies related to in vitro and in vivo investigations would be interesting to further understand the inhibitory mechanism of λ-CGN against IL-6.

Tocilizumab suppresses the pro-carcinogenic effects of breast cancer-associated fibroblasts through inhibition of the STAT3/AUF1 pathway.

Active breast cancer-associated fibroblasts (CAFs), the most influential cells in breast tumor microenvironment, express/secrete high levels of the proinvasive/metastatic interleukin-6 (IL-6). Therefore, we have tested here the effect of the IL-6 receptor (IL-6R) inhibitor tocilizumab (TCZ; Actemra) on different active breast CAFs. We have shown that TCZ potently and persistently suppresses the expression of various CAF biomarkers, namely α-SMA, SDF-1 as well as the STAT3 pathway and its downstream target AUF1. TCZ also inhibited the proliferation, migration and invasion abilities of active breast CAF cells. Additionally, TCZ repressed the ability of CAF cells in promoting epithelial-to-mesenchymal transition, and enhancing the migratory/invasive and proliferative capacities of breast cancer cells in vitro. Importantly, these findings were confirmed in orthotopic humanized breast tumors in mice. Furthermore, TCZ suppressed the expression of the pro-angiogenic factor VEGF-A and its transactivator HIF-1α in CAF cells, and consequently inhibited the angiogenic-promoting effect of active CAFs both in vitro and in orthotopic tumor xenografts. These results indicate that inhibition of the IL-6/STAT3/AUF1 pathway by TCZ can normalize active breast CAFs and suppress their paracrine pro-carcinogenic effects, which paves the way toward development of specific CAF-targeting therapy, badly needed for more efficient breast cancer treatments.

The IL-6R and Bmi-1 axis controls self-renewal and chemoresistance of head and neck cancer stem cells

Despite major progress in elucidating the pathobiology of head and neck squamous cell carcinoma (HNSCC), the high frequency of disease relapse correlates with unacceptably deficient patient survival. We previously showed that cancer stem-like cells (CSCs) drive tumorigenesis and progression of HNSCC. Although CSCs constitute only 2–5% of total tumor cells, CSCs contribute to tumor progression by virtue of their high tumorigenic potential and their resistance to chemo-, radio-, and immunotherapy. Not only are CSCs resistant to therapy, but cytotoxic agents actually enhance cancer stemness by activating transcription of pluripotency factors and by inducing expression of Bmi-1, a master regulator of stem cell self-renewal. We hypothesized therapeutic inhibition of interleukin-6 receptor (IL-6R) suppresses Bmi-1 to overcome intrinsic chemoresistance of CSCs. We observed that high Bmi-1 expression correlates with decreased (p = 0.04) recurrence-free survival time in HNSCC patients (n = 216). Blockade of IL-6R by lentiviral knockdown or pharmacologic inhibition with a humanized monoclonal antibody (Tocilizumab) is sufficient to inhibit Bmi-1 expression, secondary sphere formation, and to decrease the CSC fraction even in Cisplatin-resistant HNSCC cells. IL-6R inhibition with Tocilizumab abrogates Cisplatin-mediated increase in CSC fraction and induction of Bmi-1 in patient-derived xenograft (PDX) models of HNSCC. Notably, Tocilizumab inhibits Bmi-1 and suppresses growth of xenograft tumors generated with Cisplatin-resistant HNSCC cells. Altogether, these studies demonstrate that therapeutic blockade of IL-6R suppresses Bmi-1 function and inhibits cancer stemness. These results suggest therapeutic inhibition of IL-6R might be a viable strategy to overcome the CSC-mediated chemoresistance typically observed in HNSCC patients.

CASE OF MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN (MIS-C) PRESENTING WITH RASH AND SHOCK

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Multisystem inflammatory syndrome in children (MIS-C) is a multisystem inflammatory disorder sharing the clinical features of Kawasaki disease (KD) and toxic shock syndrome. CASE PRESENTATION: A 19-year-old male with no known past medical history presented to the emergency room with myalgia, headache, fever, photophobia, and rash on bilateral upper and lower extremities for more than one week. He tested positive for SARS-CoV-2 by RT-PCR 6 weeks prior to the presentation. Symptoms worsened with the development of a maculopapular skin rash, high-grade fevers, diarrhea, and vomiting. On admission he was afebrile (97.6 °F), had tachycardia (133/min) and tachypnea (48/min) along with hypotension (78/33 mmHg), and saturating 85% on 4L/min. Lab abnormalities included WBC of 28.2 k/uL with 55% bands, procalcitonin 42.91 ng/mL, lactic acid 4 mmol/L, BUN 65 mg/dl, serum creatinine 7 mg/dl and elevated D-dimer of 3.1 mg/L. Cardiac labs were remarkable for proBNP 76,275 pg/mL, and peak troponin 31.10ng/mL in 12 hours. EKG consistent with myopericarditis. CT scan of the abdomen/pelvis found edema of the cecum and ascending colon with pericolonic fat stranding of ascending colon possible mesenteric adenitis. He initially required 3 vasopressors to maintain his MAP>65mmHg. Echocardiography revealed a left ventricle ejection fraction (LVEF) of 20% with moderate global hypokinesis of the left ventricle. Cardiac catheterization revealed elevated wedge pressure and had clean coronaries with no aneurysms. MIS-C was suspected and was started on 1g/kg IVIG, high dose aspirin, methylprednisolone, and anakinra. Rash dissipated in days after starting steroids. His LVEF recovered to 55-60% prior to discharge from the hospital. He was kept on Anakinra, continued for 4 weeks till normalization of ferritin. DISCUSSION: MIS-C is a rare sequela of COVID-19 manifesting 2-8 weeks after the initial SARS-CoV-2 infection. In severe cases, cardiac involvement leads to cardiogenic shock. The echocardiographic findings of myocarditis and pericarditis have been frequently reported[1]. Inflammatory markers including ESR, C-reactive protein, ferritin, and IL-6 are reported to be elevated in all the cases [2]. Though its pathogenesis is not well defined, proposed hypotheses include hyper-immune response, macrophage activation, and T cell stimulation with a delayed cytokine storm. Various case have reported clinical outcomes with the use of intravenous immunoglobulin, corticosteroids, IL-1 inhibitor (anakinra), or IL-6 receptor inhibitor (tocilizumab) [3]. However, further research is needed to define clinical predictors and treatment modalities to manage MIS-C. CONCLUSIONS: Our case emphasizes the complexity of MIS-C with multisystem involvement, and it highlights a timely use of IVIG, high dose aspirin, anakinra, and methylprednisolone as potential therapeutics for this hyperinflammatory condition. REFERENCE #1: Alsaied T, Tremoulet AH, Burns JC, et al. Review of Cardiac Involvement in Multisystem Inflammatory Syndrome in Children. Circulation. 2021;143(1):78-88. doi:10.1161/CIRCULATIONAHA.120.049836 REFERENCE #2: Abrams JY, Godfred-Cato SE, Oster ME, et al. Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2: A Systematic Review [published online ahead of print, 2020 Aug 5]. J Pediatr. 2020;226:45-54.e1. doi:10.1016/j.jpeds.2020.08.003 REFERENCE #3: Tanner T, Wahezi DM. Hyperinflammation and the utility of immunomodulatory medications in children with COVID-19. Paediatr Respir Rev. 2020;35:81-87. doi:10.1016/j.prrv.2020.07.003 DISCLOSURES: No relevant relationships by Faran Ahmad, source=Web Response No relevant relationships by Sunil Nair, source=Web Response No relevant relationships by Sanu Rajendraprasad, source=Web Response

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.