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Background: The severity of coronavirus disease 2019 (COVID-19) infections has led to the development of several therapeutic agents, with tocilizumab becoming increasingly used to treat patients with COVID-19-related pneumonia. This study compared the use of tocilizumab treatment with the standard of care (SOC) to determine its efficacy against severe COVID-19-related pneumonia in Japan. Methods: This retrospective cohort study was designed to evaluate the efficacy of tocilizumab in two different databases: the JA42434 single-arm study and COVID-19 Registry Japan (COVIREGI-JP), with a synthetic control group from the COVIREGI-JP cohort as a benchmark for the tocilizumab group. The study's primary objective was to evaluate the efficacy of tocilizumab in treating severe COVID-19-related pneumonia compared to the SOC among patients included in the above two databases. The SOC group was extracted as the synthetic control group using exact matching and a propensity score matching in sequence per subject. As a secondary objective, the efficacy of tocilizumab compared to the SOC was evaluated exclusively among patients included in the COVIREGI-JP database. In each objective, the primary endpoint was defined as the time to discharge or the status of awaiting discharge. Results: For the primary endpoint, the hazard ratio (HR) of the tocilizumab group against the SOC group was 1.070 (95% confidence interval [CI]: 0.565–2.028). The median time from Study Day 1 to discharge or the state of awaiting discharge was 15 days in the tocilizumab group and 16 days in the SOC group. The HRs for the secondary endpoints, namely, time to improvement in the clinical state, time to clinical failure, and time to recovery, were 1.112 (95% CI: 0.596–2.075), 0.628 (95% CI: 0.202–1.953), and 1.019 (95% CI: 0.555–1.871), respectively. Similarly, the HR of the primary endpoint for the secondary objective was 0.846 (95% CI: 0.582–1.230). Conclusions: Tocilizumab did not demonstrate a positive effect on time to discharge or the state of awaiting discharge. Furthermore, no statistically significant differences in other clinical outcomes, such as time to improvement in the clinical state, time to clinical failure, and time to recovery, were observed among the groups. [ABSTRACT FROM AUTHOR]

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Introduction: Patients with adult-onset Still's disease (AOSD) are at risk of developing macrophage activation syndrome (MAS), a life-threatening condition. Some cases of MAS have been reported following the use of biological agents, highlighting the need to identify contributing factors. This study aims to examine the characteristics of MAS in patients with AOSD treated with anakinra (ANA) or tocilizumab (TCZ). Methods: A systematic search was conducted across four online databases to identify studies reporting the incidence rates of MAS in patients with AOSD treated with ANA or TCZ. Meta-analysis was performed using a random-effects model and the generic inverse variance method to estimate the pooled incidence rates. The difference in incidence rates of MAS between TCZ and ANA was assessed. Additionally, we analyzed laboratory data and clinical features of AOSD cases at our institution, stratifying them into two groups: those who developed MAS after TCZ administration and those who did not. Results: Of the 455 screened articles, we included five ANA and six TCZ studies. The pooled incidence rates of MAS were 1.50% (95% confidence interval [CI], 0–3.36) for ANA (345 patients) and 14.01% (95% CI 4.51–23.51) for TCZ (94 patients). MAS incidence was significantly higher in the TCZ group (P = 0.01). Among the 17 patients from our institution, the six patients who developed MAS had significantly higher white blood cell and neutrophil counts, as well as elevated levels of lactate dehydrogenase, C-reactive protein, and ferritin before TCZ induction (P < 0.05). Conclusions: In patients with AOSD, the manifestation of MAS is influenced by multiple causative factors. Consequently, the administration of TCZ should be approached with caution, particularly in patients exhibiting elevated inflammatory markers. Trial Registration: This study was registered with the Clinical Trial Registry of the University Hospital Medical Information Network (Japan) as UMIN000049243. [ABSTRACT FROM AUTHOR]

Objectives: Novel coronavirus-19 (COVID-19) has led to over 6 million fatalities globally. An estimated 75% of COVID-19 patients who require critical care admission develop acute respiratory distress syndrome (ARDS) needing invasive mechanical ventilation (IMV) and/or extracorporeal membrane oxygenation (ECMO). Due to prolonged ventilation requirements, these patients often also require tracheostomy. We performed a review of clinical outcomes in COVID-19 patients on ECMO at a high-volume tertiary care center in Hamilton, Ontario, Canada. Methodology: We performed a retrospective case series, including 24 adult patients diagnosed with COVID-19 who required IMV, veno-venous (ECMO), and tracheostomy. All patients were included from April to December 2021. We extracted demographic and clinical variables pertaining to the tracheostomy procedure and ECMO therapy. We performed descriptive statistical analyses. This study was approved by the Hamilton Integrated Research Ethics Board (14217-C). Results: We included 24 consecutive patients with COVID-19 who required tracheostomy while undergoing ECMO therapy. The mean age was 49.4 years [standard deviation (SD): 7.33], the majority of patients were male (75%), with mean body mass index of 32 (SD: 8.81). Overall mortality rate was 33.3%. Percutaneous tracheostomy was performed most frequently (83.3%) and, similar to open tracheostomy, was associated with a low rate of perioperative bleeding complications. Within surviving patients, the mean time to IMV weaning and decannulation was 60.2 (SD: 24.6) and 49.4 days (SD: 21.8), respectively. Conclusion: Percutaneous tracheostomy appears to be safe in COVID-19 patients on ECMO and holding anticoagulation 24 hours prior to and after tracheostomy may limit bleeding events in these patients. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) is one of the cytokines implicated in murine and human SLE. Only a few small studies have investigated IL-6 inhibition in human SLE. Currently, there are no studies registered in clinicaltrials.gov to assess the IL-6 targeted therapy in SLE, yet its role in the future remains to be defined. This narrative review analyses these and potential areas of future studies with IL-6 targeted therapy in SLE. [ABSTRACT FROM AUTHOR]

Les pneumopathies interstitielles diffuses sont fréquentes au cours de la sclérodermie systémique et sont associées à une morbi-mortalité importante. Dans cette revue, nous proposons de synthétiser les principaux facteurs de risque de survenue de l'atteinte interstitielle pulmonaire, ses modes de présentations cliniques, et radiologiques, et ses modalités évolutives, hétérogènes au cours de la sclérodermie. Nous synthétisons les principales données de la littérature concernant les thérapeutiques actuellement proposées, immunosuppressives/immunomodulatrices et anti-fibrosantes. Enfin, les perspectives thérapeutiques pour l'avenir sont présentées. Interstitial lung diseases are common during the course of systemic sclerosis and associated with significant morbidity and mortality. In this review, we propose to synthetize the risk factors for interstitial lung involvement development, its principal clinical and radiological features, and the evolutionary trajectories, which are highly heterogeneous. We synthesize the main data regarding the currently proposed therapies, immunosuppressive/immunomodulatory and anti-fibrotic. Finally, the therapeutic perspectives for the future are presented. [ABSTRACT FROM AUTHOR]

We report the case of a 58-year-old patient with a multiple myeloma who experienced an inflammatory shoulders and hands pain with progressive irreducible fingers retractions. After further examinations, the diagnoses of associated paraneoplastic polymyalgia rheumatica and palmar fasciitis were made, revealing at the same time a relapse of his haemopathy. The inclusion of these two pathologies under the same diagnostic label cannot be excluded. Despite the use of corticosteroids at an appropriate dose, symptomatic improvement could only be noted following tocilizumab treatment, suggesting a potential role of the interleukin-6 in the pathophysiology of paraneoplastic palmar fasciitis. [ABSTRACT FROM AUTHOR]

Background: Inflammatory cytokines are related to the occurrence and development of hepatocellular carcinoma (HCC). Objectives: Interleukin 6 (IL-6) is associated with the occurrence and prognosis of HCC, while Dicer inhibits HCC; accordingly, we checked whether Dicer regulates HCC by modulating the IL-6 pathway. Methods: The HCC cells of SMMC-7721 transfected with Dicer overexpression (pCMV-Dicer) and control (pCMV-NC) lentivirus were divided into 3 groups: The SMMC-7721, pCMV-NC, and pCMV-Dicer groups. The assays of cell proliferation, migration, and invasion were performed using cell counting, wound scratch, and transwell chamber assay. The IL-6 level was measured by flow cytometry bead-based immunoassays. All statistical analyses were analyzed using SPSS version 21 by the student t test and 1-way analysis of variance (ANOVA). Results: Dicer inhibited the secretion of IL-6 from HCC cells, as well as the growth of HCC related to proliferation, migration, and invasion. IL-6 incubation with pCMV-NC cells increased proliferation (from 24 hours to 72 hours; P < 0.05), migration (P = 0.008), and invasion (P = 0.85). In addition, IL-6 could reverse the inhibitory effect of Dicer on HCC cells related to proliferation (P < 0.01) and migration (P= 0.006) when incubated with pCMV-Dicer cells, whereas an IL-6 blocker of tocilizumab could enhance the Dicer-induced inhibition related to proliferation (P < 0.05), migration (P = 0.007), and invasion (P= 0.001) when incubated with pCMV-Dicer cells. Furthermore, Dicer could increase the inhibition efficiency of apatinib on HCC treatment by their cooperation in IL-6 downregulation. Conclusions: Dicer could inhibit HCC by the IL-6 pathway, which would be a potential target for HCC treatment. The Dicer inducer might be an enhancer of apatinib for HCC treatment. [ABSTRACT FROM AUTHOR]

Aims: The results of randomized clinical trials evaluating the effects of tocilizumab in patients with patients are inconsistent. We aimed to investigate the reliability of pre-treatment levels of prognostic nutritional index (PNI), C-reactive protein (CRP)/albumin ratio (CAR), systemic immune-inflammatory index (SII), interleukin-6 (IL-6), and lactate dehydrogenase (LDH) as treatment response biomarkers in hospitalized coronavirus disease-2019 (COVID-19) patients who were administered tocilizumab. Methods: Adult patients hospitalized for COVID-19 confirmed by severe acute respiratory syndrome-coronavirus-2 polymerase chain reaction and administered tocilizumab because of rapid clinical worsening despite receiving standard care were retrospectively included. Patients who received steroids, anakinra, or IVIG before tocilizumab and had missing data were excluded. Treatment effectiveness was evaluated with the improvement in the clinical status on an eight-category ordinal scale at 28 days of tocilizumab administration. Results: One hundred and thirty-three COVID-19 patients with a mean age of 62.64±13.66 years and consisting of 93 (69.9%) males were included. At 28 days of tocilizumab administration, 99 (74.4%) patients improved. Improved patients after tocilizumab treatment had significantly lower IL-6, LDH, SII, CAR, and higher PNI. To predict the effectiveness of tocilizumab, IL-6 had the highest area under the curve (AUC) value (AUC=0.782), followed by LDH (AUC=0.761), PNI (AUC=0.696), SII (AUC=0.671), CAR (AUC=0.682), and CRP (AUC=0.643). The cut-off level was 143.12 pg/mL for IL-6 (sensitivity=84.85%, specificity=64.71%), 460U/L for LDH (sensitivity=71.72%, specificity=73.75%), 31.35 for PNI (sensitivity=79.80%, specificity=55.88%), 3895.92 for SII (sensitivity=90.91%, specificity=47.06%), and 61.15 for CAR (sensitivity=67.68%, specificity=61.76%). Conclusions: In COVID-19 patients with clinically worsening disease, the administration of tocilizumab in the early stage of the hyperinflammatory state may improve the prognosis. Pre-treatment inflammatory biomarker levels may predict tocilizumab response. [ABSTRACT FROM AUTHOR]

To describe the efficacy and safety of subcutaneous tocilizumab (SC-TCZ) in a cohort of juvenile idiopathic arthritis (JIA) patients with refractory uveitis. Retrospective observational monocentric study including patients with JIA-associated uveitis treated with SC-TCZ. Thirteen patients were enrolled. The rate of uveitis flare/year per each patient was 1.6 ± 2.0 on the last bDMARDs before SC-TCZ, while it decreased to 0.4 ± 0.7 on SC-TCZ. Nine out of thirteen patients (69%) required the introduction of SC-TCZ only for active uveitis at baseline. Among these patients, five (56%) achieved complete treatment response. No uveitis relapses were observed in patients (4/13, 31%) requiring the introduction of SC-TCZ for active arthritis during follow-up (30.48 ± 21.6 months). Overall, SC-TCZ was safe, and no side effects were observed during the treatment. SC-TCZ can be effective and safe in patients with JIA and uveitis recalcitrant to several bDMARDs. [ABSTRACT FROM AUTHOR]

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disorder with potential for life-threatening complications in pregnancy. Recently, biologic therapeutics have been increasingly used for treatment of AOSD, but there is little available data on the treatment of AOSD in pregnancy. Here we report a 23-year-old primigravid patient with a history of AOSD who presented at 20 weeks of gestation with fever, arthralgias, rash, fatigue, and highly elevated ferritin, concerning for AOSD flare. She was treated with tocilizumab, an interleukin-6 receptor antagonist, with rapid clinical and laboratory improvement; however, she underwent iatrogenic preterm delivery at 34 weeks of gestation for fetal distress, which was attributed to placental injury. In a subsequent pregnancy, she was treated with tocilizumab throughout and had an uncomplicated term delivery with normal labs and no AOSD flare. This case highlights that the use of tocilizumab may be effective to reduce the risk of AOSD flare during pregnancy. [ABSTRACT FROM AUTHOR]

A young female patient with Takayasu arteritis presented with unstable angina due to bilateral coronary artery involvement. Steroid pulse therapy and subsequent prednisolone administration were started, but early coronary artery bypass grafting was required because of the multiple angina attacks at rest, with a prednisolone dose of 22.5 mg (0.45 mg/kg/day). Since the left internal thoracic artery which was grafted to the left anterior descending artery resulted in graft failure a few days after the surgery, the immunosuppressive therapy was intensified with the addition of tocilizumab and methotrexate. After controlling the disease activity, coronary ostial angioplasty using external iliac artery grafts was successfully performed, with a prednisolone dose of 15 mg (0.3 mg/kg/day). Ten months after the operation, the patient has been free from chest pain. The present case demonstrated the importance of adequate preoperative immunosuppressive therapy, even when early surgical intervention is required. There are no established treatment regimens for immunosuppressive management in cases of Takayasu arteritis (TAK) requiring immediate surgical intervention. Even when early surgery is required, it is important to reduce disease activity with appropriate preoperative immunosuppressive therapy using steroids in addition to biological agents, such as tocilizumab. Coronary ostial angioplasty is the effective surgical revascularization technique for TAK with coronary artery involvement. [ABSTRACT FROM AUTHOR]

Purpose: Tocilizumab, a monoclonal IL-6 receptor blocker, is an effective agent for severe-to-critical cases of COVID-19; however, its target patients for the optimum use need to be detailed. We performed a systematic review and meta-analysis to define its effect among severely ill but non-intubated cases with COVID-19. Methods: We searched PubMed, Scopus, Web of Science, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Medrxiv, and Biorxiv until February 13, 2022, for non-intubated cases, and included randomized-controlled trials (RCT) based on bias assessment. The primary outcomes were the requirement of invasive mechanical ventilation and mortality. Random effect and fixed-effect models were used. The heterogeneity was measured using the χ2 and I2 statistics, with χ2p ≤ 0.05 and I2 ≥ 50% indicating the presence of significant heterogeneity. We registered the study to the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42021232575. Results: Among 261 articles, 11 RCTs were included. The pooled analysis of the 11 RCTs demonstrated that the rate of mortality was significantly lower in the tocilizumab group than in the control group (20.0% and 24.2%, OR: 0.84, 95% CI 0.73–0.96, and heterogeneity I2 = 0%. p = 0.82.). The mechanical ventilation rate was lower in the tocilizumab group than the control group (27% vs 35.2%, OR: 0.76, 95% CI 0.67–0.86, and heterogeneity I2 = 6%. p = 0.39). Conclusion: Among non-intubated severe COVID-19 cases, tocilizumab reduces the risk of invasive mechanical ventilation and mortality compared to standard-of-care treatment. [ABSTRACT FROM AUTHOR]

Giant cell arteritis (GCA) is a chronic vasculitis that primarily affects the elderly, and can cause visual impairment, requiring prompt diagnosis and treatment. The global impact of the coronavirus disease 2019 (COVID-19) pandemic has been substantial. Although vaccination programs have been a key defense strategy, concerns have arisen regarding post-vaccination immune-mediated disorders and related risks. We present a case of GCA after COVID-19 vaccination with 2 years of follow-up. A 69-year-old woman experienced fever, headaches, and local muscle pain two days after receiving the COVID-19 vaccine. Elevated inflammatory markers were observed, and positron emission tomography (PET) revealed abnormal uptake in the major arteries, including the aorta and subclavian and iliac arteries. Temporal artery biopsy confirmed the diagnosis of GCA. Treatment consisted of pulse therapy with methylprednisolone, followed by prednisolone (PSL) and tocilizumab. Immediately after the initiation of treatment, the fever and headaches disappeared, and the inflammation markers normalized. The PSL dosage was gradually reduced, and one year later, a PET scan showed that the inflammation had resolved. After two years, the PSL dosage was reduced to 3 mg. Fourteen reported cases of GCA after COVID-19 vaccination was reviewed to reveal a diverse clinical picture and treatment response. The time from onset of symptoms to GCA diagnosis varied from two weeks to four months, highlighting the challenge of early detection. The effectiveness of treatment varied, but was generally effective similarly to that of conventional GCA. This report emphasizes the need for clinical vigilance and encourages further data collection in post-vaccination GCA cases. [ABSTRACT FROM AUTHOR]

As of May 3, 2023, the Coronavirus disease 2019 (COVID-19) pandemic has resulted in more than 760 million confirmed cases and over 6.9 million deaths. Several patients have developed pneumonia, which can deteriorate into acute respiratory distress syndrome. The primary etiology may be attributed to cytokine storm, which is triggered by the excessive release of proinflammatory cytokines and subsequently leads to immune dysregulation. Considering that high levels of interleukin-6 (IL-6) have been detected in several highly pathogenic coronavirus-infected diseases, such as severe acute respiratory syndrome in 2002, the Middle East respiratory syndrome in 2012, and COVID-19, the IL-6 pathway has emerged as a key in the pathogenesis of this hyperinflammatory state. Thus, we review the history of cytokine storm and the process of targeting IL-6 signaling to elucidate the pivotal role played by tocilizumab in combating COVID-19. [ABSTRACT FROM AUTHOR]

A 7 years old girl diagnosed as case of juvenile idiopathic arthritis since the age of 1.5 years, generalized onset with systemic presentation is complicated by secondary nephrotic syndrome. Renal biopsy showing amyloidosis. Patient has severe disease course being complicated by sever flare ups of disease symptoms and body swelling. Since onset of disease patient got NSAIDs, methotrexate, steroids, anti TNF inhibitors with no or partial response. After diagnosis with secondary nephrotic syndrome due to secondary amyloidosis patient is started on intravenous tocilizumab. There is improvement of patient symptoms.

BackgroundIn COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated.MethodsAdults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615.FindingsBy day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference -0·5% [95% CI -9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase-quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti-SARS-CoV-2 antibodies at day 60.InterpretationThere was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments.FundingF. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

Abstract Immune‐checkpoint inhibitors (ICIs) have changed the management of advanced cancers. However, patients with pre‐existing autoimmune diseases (ADs) have usually been excluded from clinical trials of ICIs due to concerns about exacerbation of AD. Here, we combined ICIs with selective immunosuppressant treatment in a metastatic lung adenocarcinoma patient with active pre‐existing polymyalgia rheumatica (PMR). Remarkably, the strategy led to durable response and no exacerbation of PMR. Thus, we provide the first clinical evidence of treating metastatic cancer with ICIs and concomitant use of tocilizumab and hydroxychloroquine for active pre‐existing PMR.

Xiaojing Zhong,&ast; Tongtong Xu,&ast; Tianhao Li,&ast; Nana Luo, Nan Luo, Pingsheng Hao Author Affiliations Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pingsheng Hao, Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, 39 Shi-Er-Qiao Road, Jinniu District, Chengdu, Sichuan, 610072, People’s Republic of China, Tel +86138 8196 5024, Fax +86-28-87732407, Email hpswl@126.comAbstract: Adult-onset Still’s disease (AOSD) is considered a rare autoimmune inflammatory disorder with an unclear etiology and pathogenesis.The main clinical manifestations of this disease are high fever, joint pain, and transient skin lesions. Physical examination may reveal hepatomegaly, splenomegaly, and lymphadenopathy, while laboratory tests show abnormalities such as elevated white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum ferritin (SF). The lack of specific diagnostic markers contributes to a relatively high rate of clinical misdiagnosis and missed diagnoses.In terms of treatment, glucocorticoids have always been the cornerstone medication, but some patients exhibit suboptimal responses to conventional drug therapy, making disease control challenging. However, as our understanding of the pathogenesis continues to grow, novel therapeutic approaches targeting various cytokines have been gradually identified. In this report, we present a case of successful treatment of recurrent AOSD with tocilizumab (TCZ), along with a concise review of innovative treatment strategies for AOSD based on literature retrieval.Keywords: AOSD, tocilizumab, treatment, interleukin-6 inhibitors

Takayasu’s disease (nonspecific aortoarteritis) is a granulomatous inflammation of the aorta and its main branches with a progressive course and development of severe ischemic disorders. The difficulty of diagnosis and the possibility of applying various methods of pathogenetic anti-inflammatory treatment of Takayasu’s arteritis make it expedient to study a clinical case. The analysis of a clinical case of a patient with Takayasu’s arteritis with manifestation of the disease in the form of general inflammatory syndrome and manifestations of severe cerebral ischemia due to bilateral stenotic carotid artery lesion was performed. The patient has been under observation since September 2017 up to the present time, various methods of pharmacotherapy and surgical correction were used in her therapy. The dynamics of clinical symptomatology of Takayasu’s arteritis and clinical results of step therapy with high doses of methylprednisolone, bolus administration of cyclophosphan followed by long-term oral cyclophosphan administration were analyzed. In the course of treatment, the patient underwent carotid angioplasty. Due to the unstable effect of the therapy, the patient was administered intravenous infusions of IL-6 blocker tocilizumab, which led to remission of the disease. The presented clinical case demonstrates the important diagnostic value of vascular imaging methods in early diagnosis and control of the disease course and the effectiveness of IL-6 inhibitors in achieving and maintaining remission of Takayasu’s arteritis.

Abstract Introduction Patients with adult-onset Still’s disease (AOSD) are at risk of developing macrophage activation syndrome (MAS), a life-threatening condition. Some cases of MAS have been reported following the use of biological agents, highlighting the need to identify contributing factors. This study aims to examine the characteristics of MAS in patients with AOSD treated with anakinra (ANA) or tocilizumab (TCZ). Methods A systematic search was conducted across four online databases to identify studies reporting the incidence rates of MAS in patients with AOSD treated with ANA or TCZ. Meta-analysis was performed using a random-effects model and the generic inverse variance method to estimate the pooled incidence rates. The difference in incidence rates of MAS between TCZ and ANA was assessed. Additionally, we analyzed laboratory data and clinical features of AOSD cases at our institution, stratifying them into two groups: those who developed MAS after TCZ administration and those who did not. Results Of the 455 screened articles, we included five ANA and six TCZ studies. The pooled incidence rates of MAS were 1.50% (95% confidence interval [CI], 0–3.36) for ANA (345 patients) and 14.01% (95% CI 4.51–23.51) for TCZ (94 patients). MAS incidence was significantly higher in the TCZ group (P = 0.01). Among the 17 patients from our institution, the six patients who developed MAS had significantly higher white blood cell and neutrophil counts, as well as elevated levels of lactate dehydrogenase, C-reactive protein, and ferritin before TCZ induction (P

Background: Tocilizumab is a well-practiced strategy to manage cytokine release syndrome (CRS) after chimeric antigen receptor T cell (CAR-T) therapy. However, varied efficiency in CRS mitigation by tocilizumab has been reported to highlight affecting variables such as tumor types and timing of the administration. Objective: The objective of this study is to identify different curative effect between diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL) by early use of tocilizumab for prophylaxis and treatment of CRS. Methods: By retrospectively summarizing our institution's experience with a CAR-T clinical trial targeting CD19, 11 cases were analyzed: 5 DLBCL, and 6 ALL. The two groups were compared with patient characteristics, CRS information and clinical outcomes. 3 patients were pretreated with tocilizumab for prophylaxis and the rest were treated with tocilizumab at CRS diagnosis. Results: CRS occurred in 81.8% of patients (9/11), grade 3 or higher occurred in 55.6% of the CRS patients (5/9). The two group were similar in patient characteristics, CAR-T and CRS profile. However, tocilizumab produced much better efficacy against CRS in DLBCL group compared with ALL group (80% versus 16.7%, P ​= ​0.08). Conclusions: Despite the statistical was non-significant, possibly due to small case pool and bias was unavoidable, our analysis suggested that early use of tocilizumab was more effective for DLBCL than ALL in the prophylaxis and treatment of CRS. A treatment algorithm for management of CRS with regard to DLBCL and ALL is proposed, which may extend to other local or systemic malignancies and warrant further investigation.

Pathogenesis of lung injury in COVID-19 is not completely understood, leaving gaps in understanding how current treatments modulate the course of COVID-19. Neutrophil numbers and activation state in circulation have been found to correlate with COVID-19 severity, and neutrophil extracellular traps (NETs) have been found in the lung parenchyma of patients with acute respiratory distress syndrome (ARDS) in COVID-19. Targeting the pro-inflammatory functions of neutrophils may diminish lung injury in COVID-19 and ARDS. Neutrophils were isolated from peripheral blood of healthy donors, treated ex vivo with dexamethasone, tocilizumab and intravenous immunoglobulin (IVIG) and NET formation, oxidative burst, and phagocytosis were assessed. Plasma from critically ill COVID-19 patients before and after clinical treatment with IVIG and from healthy donors was assessed for neutrophil activation-related proteins. While dexamethasone and tocilizumab did not affect PMA- and nigericin-induced NET production ex vivo, IVIG induced a dose-dependent abrogation of NET production in both activation models. IVIG also reduced PMA-elicited reactive oxygen species production, but did not alter phagocytosis. COVID-19 patients were found to have elevated levels of cell-free DNA, neutrophil elastase and IL-8 as compared to healthy controls. Levels of both cell-free DNA and neutrophil elastase were lower 5 days after 4 days of daily treatment with IVIG. The lack of impact of dexamethasone or tocilizumab on these neutrophil functions suggests that these therapeutic agents may not act through suppression of neutrophil functions, indicating that the door might still be open for the addition of a neutrophil modulator to the COVID-19 therapeutic repertoire.

Coronavirus disease-2019 (COVID-19) has become a global pandemic and a health problem of epic proportions. The disease is mild in the majority of cases. Respiratory symptoms predominate and acute respiratory distress syndrome (ARDS) is the commonest complication associated with the disease. Chest X-ray plays an important role in the initial evaluation and follow-up of COVID-19 disease at different stages, more so, in resource-limited settings. It is useful to monitor disease progression and possibly to exclude other unusual causes of dyspnea. In this case series, we present a rare manifestation in COVID-19-positive patients: spontaneous pneumothorax and pneumomediastinum associated with the cytokine release syndrome (CRS) which was successfully managed at COVID care intensive care unit. [ABSTRACT FROM AUTHOR]

Background: Coronavirus Disease-2019 (COVID-19) has posed formidable challenges to healthcare systems. Exploring novel biomarkers that can provide valuable prognostic insights, particularly in critically ill patients, has a significant importance. Against this backdrop, our study aims to elucidate the associations between serum chloride levels and clinical outcomes. Methods: A total of 499 patients were enrolled into the study. The serum chloride levels of patients upon hospital admission were recorded and then categorized into three groups (hypochloremia, normochloremia, and hyperchloremia) for the evaluation of clinical outcomes. Additionally, serum C-reactive protein, procalcitonin, and D-dimer measurements were recorded for further evaluation. Results: A total of 390 (78.1%) patients tested positive for COVID-19 via polymerase chain reaction testing. Non-contrast thorax computed tomography scans were indicative of COVID-19 compatibility for all patients. A total of 210 (42%) patients were female and 289 (58%) were male. A total of 214 (42.8%) patients necessitated tocilizumab intervention; 250 (50.1%) were at an intensive care unit (ICU), with 166 (66.4%) of them receiving tocilizumab. A total of 65 (13%) patients died, 40 (61.5%) of whom received tocilizumab; 41 (63%) were in the ICU. Serum chloride levels upon admission were markedly lower and elevated D-dimer levels were apparent in tocilizumab users, patients requiring ICU care, and patients who died. Conclusions: our findings provide robust evidence supporting the value of serum chloride levels as a prognostic biomarker in critically ill COVID-19 patients.

Circular (circ) RNAs are non-coding RNAs with important functions in the nervous system, cardiovascular system, and cancer. Their role in atherosclerosis and myocardial infarction (MI) remains poorly described. We aim to investigate the potential circRNAs in immune cells during atherogenesis and examine the most regulated during MI and the modulation by interleukin (IL)-6 receptor inhibition by tocilizumab. Wild-type (WT) and ApoE−/− mice were fed an atherogenic diet for 10 weeks, and the circRNA profile was analyzed by circRNA microarray. Whole blood from patients with ST-elevated MI (STEMI) and randomized to tocilizumab (n = 21) or placebo (n = 19) was collected at admission, 3–7 days, and at 6 months, in addition to samples from healthy controls (n = 13). Primers for human circRNA were designed, and circRNA levels were measured using RT-qPCR. mRNA regulation of predicted circRNA targets was investigated by RNA sequencing. The expression of 867 circRNAs differed between atherogenic and WT mice. In STEMI patients, circUBAC2 was significantly lower than in healthy controls. CircANKRD42 and circUBAC2 levels were inversely correlated with troponin T, and for circUBAC2, an inverse correlation was also seen with final infarct size at 6 months. The predicted mRNA targets for circUBAC2 and circANKRD42 were investigated and altered levels of transcripts involved in the regulation of inflammatory/immune cells, apoptosis, and mitochondrial function were found. Finally, tocilizumab induced an up-regulation of circANKRD42 and circUBAC2 3–7 days after percutaneous coronary intervention. CircRNA levels were dysregulated in STEMI, potentially influencing the immune system, apoptosis, and mitochondrial function.

Pulmonary drug delivery offers a minimally invasive and efficient method for treating lung conditions, leveraging the lungs’ extensive surface area and blood flow for rapid drug absorption. Nebulized therapies aim to deliver drugs directly to the lung tissue. This study investigates the histological impact of nebulized tocilizumab—a monoclonal antibody targeting IL-6, traditionally administered intravenously for rheumatoid arthritis and severe COVID-19—on a murine model. Thirty BALB/c mice were nebulized with tocilizumab (10 mg, 5 mg, and 2.5 mg) and six controls were nebulized with saline solution. They were euthanized 48 h later, and their organs (lungs, nasal mucosa, and liver) were analyzed by a microscopic histological evaluation. The results indicate that all the mice survived the 48 h post-nebulization period without systemic compromise. The macroscopic examination showed no abnormalities, and the histopathological analysis revealed greater lung vascular changes in the control group than in the nebulized animals, which is attributable to the euthanasia with carbon dioxide. Additionally, increased alveolar macrophages were observed in the nebulized groups compared to controls. No significant histological changes were observed in the liver, indicating the safety of nebulized tocilizumab. In conclusion, these findings suggest the potential of nebulized tocilizumab for treating pulmonary inflammation, warranting further research to establish its efficacy and safety in clinical settings.

TAFRO syndrome is an inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly. Despite great advancements in research on the TAFRO syndrome in the last decade, its diagnosis and treatment are still challenging for most clinicians because of its rarity and severity. Since the initial proposal of the TAFRO syndrome as a distinct disease entity in 2010, two independent diagnostic criteria have been developed. Although these are different in the concept of whether TAFRO syndrome is a subtype of idiopathic multicentric Castleman disease or not, they are similar except for the magnitude of lymph node histopathology. Because there have been no specific biomarkers, numerous diseases must be ruled out before the diagnosis of TAFRO syndrome is made. The standard of care has not been fully established, but interleukin-6 blockade therapy with siltuximab or tocilizumab and anti-inflammatory therapy with high-dose corticosteroids are the most commonly applied for the treatment of TAFRO syndrome. The other immune suppressive agents or combination cytotoxic chemotherapies are considered for patients who do not respond to the initial treatment. Whereas glowing awareness of this disease improves the clinical outcomes of patients with TAFRO syndrome, further worldwide collaborations are warranted.

IntroductionTo study metabolic signatures can be used to identify predictive biomarkers for a patient's therapeutic response.ObjectivesWe hypothesized that the characterization of a patients' metabolic profile, utilizing one-dimensional nuclear magnetic resonance (1H-NMR), may predict a response to tocilizumab in patients with rheumatoid arthritis (RA).Methods40 active RA patients meeting the 2010 ACR/EULAR classification criteria initiating treatment with tocilizumab were recruited. Clinical outcomes were determined at baseline, and after six and twelve months of treatment. EULAR response criteria at 6 and 12 months to categorize patients as responders and non-responders. Blood was collected at baseline and after six months of tocilizumab therapy. 1H-NMR was used to acquire a spectra of plasma samples. Chenomx NMR suite 8.5 was used for metabolite identification and quantification. SPSS v.27 and MetaboAnalyst 4.0 were used for statistical and pathway analysis.ResultsIsobutyrate, 3-hydroxybutyrate, lysine, phenylalanine, sn-glycero-3-phosphocholine, tryptophan and tyrosine were significantly elevated in responders at the baseline. OPLS-DA at baseline partially discriminated between RA responders and non-responders. A multivariate diagnostic model showed that concentrations of 3-hydroxybutyrate and phenylalanine improved the ability to specifically predict responders classifying 77.1% of the patients correctly. At 6 months, levels of methylamine, sn-glycero-3-phosphocholine and tryptophan tended to still be low in non-responders.ConclusionThe relationship between plasma metabolic profiles and the clinical response to tocilizumab suggests that 1H-NMR may be a promising tool for RA therapy optimization. More studies are needed to determine if metabolic profiling can predict the response to biological therapies in RA patients.

Abstract Background The IL-6R antibody tocilizumab has been proven effective in treating Takayasu arteritis (TA). However, some patients show silent vascular stenosis progression (VSP) despite treatment with tocilizumab. The aim of the study was to explore the related risk factors of VSP in patients treated with tocilizumab. Methods Patients receiving tocilizumab were enrolled from the prospective living ongoing East China Takayasu Arteritis cohort. Their medical information was uniformly recorded with a homogenized evaluation method. Magnetic resonant angiography or computed tomographic angiography was employed to monitor VSP during the follow-up period, and Cox regression analysis was performed to explore the related risk factors. Results Thirty-eight patients were enrolled, among whom 18 (47.4%) experienced VSP, and seven and three patients experienced new and worsened vascular ischemic symptoms and events (VISE) during follow-up, respectively. The median period for VSP occurrence was 6.9 months during follow-up. Patients with VSP showed higher levels of baseline complement 3 (C3) than those in the patients without VSP. Multivariate Cox regression analysis revealed baseline C3 level (hazard ratio [HR] = 7.05, 95% confidence interval: 1.50–33.07, p = 0.013) was independently associated with VSP, with a cut-off value of 1.22 g/L. Conclusions 47.4% of TA patients treated with tocilizumab would suffer VSP. A high C3 level is a risk factor for VSP in TA patients receiving tocilizumab, which may facilitate the option of tocilizumab in the future.

Hemophagocytic lymphohistiocytosis (hemophagocytic syndrome, HLH, HPS) is the group of severe life-threatening and hardly diagnosing conditions caused by the immune dysregulation because of systemic inflammatory response with non-controlled proliferation and activation of T-cells, monocytes and macrophages with accumulation in target organs and the development of multiple organ failure. HLH are includes primary (monogenic) and secondary forms associated with various conditions, such as infections, immunopathological, oncohematological diseases. The severity of the condition, association with infections makes these diseases potentially lethal and requiring intensive care. In many critically ill patients in the intensive care unit, the presence of hemophagocytic syndrome remains unrecognized and is often interpreted as generalized infection, sepsis, systemic inflammatory response syndrome, multiple organ failure. Such patients require special attention, timely diagnosis and treatment. Nowadays, we have got a big group of drugs, which can pointwise block one or another pathogenesis pathway, but for a quick and correct choice, we need clear algorithms for deciding on the use of this group of targeted therapy. The article presents the history of the study of the issue and modern approaches to the diagnosis and treatment of these conditions in critically ill patients.

En 2019, en China se detectaron casos de una nueva patología causada por una variante desconocida, de la familia de los coronavirus, la cual presentó síntomas leves o incluso pacientes asintomáticos, se denominó SARS-CoV-2, pudiendo evolucionar a un síndrome de dificultad respiratoria aguda (SDRA), esto debido a la probable falta de tratamientos oportunos y adecuados para controlar el síndrome de liberación de citoquinas, siendo la interleucina-6 (IL-6), la causante principal para el desarrollo de un SDRA. El Tocilizumab, un anticuerpo monoclonal anti interleucina-6 ha sido estudiado; esto con el fin de intentar en pacientes que presentaban un cuadro de SDRA no lleguen a presentar un cuadro más grave, como necesitar una unidad de cuidados intensivos o ventilación mecánica. Por lo que se planteó, como objetivo determinar la relación entre disminución de la letalidad y la administración del fármaco Tocilizumab en pacientes con SDRA. Se utilizó una búsqueda en los motores PubMed y BVS y en las bases de datos Medline y LILACS. La búsqueda arrojó unas revisiones sistemáticas, dos revisiones sistemáticas más metaanálisis y dos ensayos clínicos aleatorios. La evidencia consultada demostró que Tocilizumab no provee un beneficio significativo en pacientes que fueron administrados con Tocilizumab en comparación con los grupos control.

Abstract Purpose The efficacy of tocilizumab in refractory chronic noninfectious uveitis has been previously reported, but no data comparing intravenous and subcutaneous tocilizumab in uveitis are available. Results We report a case series of patients with chronic noninfectious uveitis with incomplete efficacy of subcutaneous tocilizumab, improved after switching to intravenous routes. Improvement of visual acuity was observed with intravenous tocilizumab for all patients. Half of the patients could stop corticosteroids. Rapid efficacy of intravenous tocilizumab was observed, between 2 and 3 months. Conclusion In uveitis, tocilizumab administration could be optimized by a switching from a subcutaneous to an intravenous administration route.

Abstract Background Our aim was to compare the efficacy of rituximab, tocilizumab, and abatacept in individuals with rheumatoid arthritis (RA) refractory to treatments with MTX or TNFi agents. Methods We searched 6 databases until January 2023 for phase 2–4 RCTs evaluating patients with RA refractory to MTX or TNFi therapy treated with rituximab, abatacept, and tocilizumab (intervention arm) compared to controls. Study data were independently assessed by two investigators. The primary outcome was considered as achieving ACR70 response. Results The meta-analysis included 19 RCTs, with 7,835 patients and a mean study duration of 1.2 years. Hazard ratios for achieving an ACR70 response at six months were not different among the bDMARDs, however, we found high heterogeneity. Three factors showing a critical imbalance among the bDMARD classes were identified: baseline HAQ score, study duration, and frequency of TNFi treatment in control arm. Multivariate meta-regression adjusted to these three factors were conducted for the relative risk (RR) for ACR70. Thus, heterogeneity was attenuated (I2 = 24%) and the explanatory power of the model increased (R2 = 85%). In this model, rituximab did not modify the chance of achieving an ACR70 response compared to abatacept (RR = 1.773, 95%CI 0.113–10.21, p = 0.765). In contrast, abatacept was associated with RR = 2.217 (95%CI 1.554–3.161, p

Abstract Background COVID-19, an emerging disease raised as a pandemic, urgently needed treatment choices. Some options have been confirmed as lifesaving treatments, but long-term complications must be clearly illustrated. Bacterial endocarditis is a less frequent disease among patients infected with SARS_COV_2 compared to other cardiac comorbidities in these patients. This case report discusses bacterial endocarditis as a potential adverse effect after administering tocilizumab, corticosteroids, and COVID-19 infection. Case presentation In the first case, a 51-year-old Iranian female housewife was admitted to the hospital with fever, weakness, and monoarthritis symptoms. The second case is a 63-year-old Iranian woman who is a housewife admitted with weakness, shortness of breath, and extreme sweating. Both cases tested positive for Polymerase chain reaction (PCR) less than one month ago and were treated with tocilizumab and corticosteroid. Both patients were suspected of infective endocarditis. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in the blood cultures of both patients. The diagnosis of endocarditis is confirmed for both cases. Cases are subjected to open-heart surgery, a mechanical valve is placed, and they are treated with medication. In subsequent visits, their condition was reported to be improving. Conclusion Adjacent to cardiovascular inclusion as COVID-19 disease complications, secondary infection taken after the organisation of immunocompromising specialists can result in basic maladies and conditions counting infective endocarditis.

Abstract Objectives Donor haematopoietic stem cell transplantation treats leukaemia by inducing graft‐versus‐leukaemia (GVL) immunity. However, this benefit is often mitigated by graft‐versus‐host disease (GVHD), which is reduced by post‐transplant cyclophosphamide (PTCy) alone or combined with tocilizumab (TOC) in humanised mice. This study established a preclinical humanised mouse model of GVL and investigated whether PTCy alone or combined with TOC impacts GVL immunity. Methods NOD‐scid‐IL2Rγnull mice were injected with 2 × 107 human peripheral blood mononuclear cells (hPBMCs) on day 0 and with 1 × 106 THP‐1 acute myeloid leukaemia cells on day 14. In subsequent experiments, mice were also injected with PTCy (33 mg kg−1) or Dulbecco's phosphate buffered saline (PBS) on days 3 and 4, alone or combined with TOC or control antibody (25 mg kg−1) twice weekly for 28 days. Clinical signs of disease were monitored until day 42. Results Mice with hPBMCs from three different donors and THP‐1 cells showed similar survival, clinical score and weight loss. hCD33+ leukaemia cells were minimal in mice reconstituted with hPBMCs from two donors but present in mice with hPBMCs from a third donor, suggesting donor‐specific GVL responses. hPBMC‐injected mice treated with PTCy alone or combined with TOC (PTCy + TOC) demonstrated prolonged survival compared to control mice. PTCy alone and PTCy + TOC‐treated mice with hPBMCs showed minimal hepatic hCD33+ leukaemia cells, indicating sustained GVL immunity. Further, the combination of PTCy + TOC reduced histological damage in the lung and liver. Conclusion Collectively, this research demonstrates that PTCy alone or combined with TOC impairs GVHD without compromising GVL immunity.