Tocilizumab Group Research Articles

Impact of tocilizumab on anti-CD19 chimeric antigen receptor T-cell therapy in B-cell acute lymphoblastic leukemia.

Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T-cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T-cell therapy. In total, 93 patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving humanized anti-CD19 CAR T cells were recruited from May 2016 to November 2022. Forty-five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab. The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event-free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immuneeffector cell-associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells. Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS.

Serial electrical impedance tomography course in different treatment groups; The MaastrICCht cohort

PurposeTo describe the effect of dexamethasone and tocilizumab on regional lung mechanics over admission in all mechanically ventilated COVID-19 patients. Materials and methodsDynamic compliance, alveolar overdistension and collapse were serially determined using electric impedance tomography (EIT). Patients were categorized into three groups; no anti-inflammatory therapy, dexamethasone therapy, dexamethasone + tocilizumab therapy. The EIT variables were (I) visualized using polynomial regression, (II) evaluated throughout admission using linear mixed-effects models, and (III) average respiratory variables were compared. ResultsVisual inspection of EIT variables showed a pattern of decreasing dynamic compliance. Overall, optimal set PEEP was lower in the dexamethasone group (−1.4 cmH2O, −2.6; −0.2). Clinically applied PEEP was lower in the dexamethasone and dexamethasone + tocilizumab group (−1.5 cmH2O, −2.6; −0.2; −2.2 cmH2O, −5.1; 0.6). Dynamic compliance, alveolar overdistension, and alveolar collapse at optimal set PEEP did not significantly differ between the three groups. ConclusionOptimal and clinically applied PEEP were lower in the dexamethasone and dexamethasone + tocilizumab groups. The results suggest that the potential beneficial effects of these therapies do not affect lung mechanics favorably. However, this study cannot fully rule out any beneficial effect of anti-inflammatory treatment on pulmonary function due to its observational nature.

Investigation into effects of tocilizumab and epoetin beta in rats with experimental sciatic nerve injury model

ObjectiveTo investigate the effects of tocilizumab (TCZ), epoetin beta (EPO), and their combination on nerve regeneration in a sciatic nerve injury model. Materials and methodMale Sprague-Dawley rats were divided into (-) negative control, sham, TCZ, EPO ((+) positive control), and TCZ+EPO groups. The TCZ group received TCZ (8 mg/kg intraperitoneal) immediately after surgery. On day 14th, the EPO group received EPO (5000 IU/kg, intraperitoneal); the TCZ+EPO group received TCZ (8 mg/kg, intraperitoneal), EPO (5000 IU/kg, intraperitoneal), and TCZ (8 mg/kg, intraperitoneal) post-surgery. Motor and sensory functions were assessed pre and post-surgery. Lipid peroxidation and oxidative stress parameters were evaluated biochemically in the serum, and sciatic nerve tissue was evaluated histopathologically using haematoxylin-Eosin and Masson trichrome staining. ConclusionsTCZ and EPO decreased nerve injury effects by increasing motor and sensory conduction velocities of the sciatic nerve. Biochemically, TCZ and EPO significantly increased Superoxide Dismutase, Catalase, and Glutathione peroxidase 4 levels while decreasing Lipid Peroxidation levels (p=0.001). Histopathologically, neuronal degeneration following nerve injury was decreased in the groups receiving TCZ and EPO (p=0.001). EPO and TCZ attenuate the adverse effects of nerve injury. However, the TCZ+EPO treatment favoured biochemical activities over tissue and functional activities. This has been confirmed functionally, biochemically, and histopathologically.

Tocilizumab treatment in COVID-19 patients: therapy's side effects and effect on mortality.

This study aimed to determine the effect of tocilizumab use on mortality and the potential side effects in COVID-19 patients. The intensive care patients were divided into the tocilizumab group and the control group. Hemogram, biochemistry, acute phase reactant values, age, gender, comorbidity, and culture results were recorded on the 0th, 3rd, 7th, and 14th days. Factors affecting mortality between and within the groups and side effects were examined. 32.14% of the patients were female, and 67.85% were male. The tocilizumab group had high alanine aminotransferase and potassium on day 3. On day 7, low levels of platelet, glucose, international normalized ratio, prothrombin time, and active partial thromboplastin time levels were observed. Procalcitonin, C-reactive protein, and fibrinogen levels were low on days 3 and 7. The relationship between the tocilizumab treatment and mortality was statistically not significant, although the APACHE score was low. In the tocilizumab group, the presence of additional disease and reproduction in culture significantly increased mortality. Despite the risks of side effects, tocilizumab was used in COVID-19 treatment since it is an interleukin-6 blocker. Although the first publications stated that the treatment could decrease the mortality rate, later meta-analyses did not support these results. Our study also found that using tocilizumab did not make a difference in long-term mortality. We also observed that the known side effects were seen in short-term use.

Tocilizumab Reduces Lung Injury in a Rat Lung Ischemia and Reperfusion Model.

In this study, the effect of tocilizumab (TCZ) on lung tissue in lung ischemia-reperfusion (I/R) injury in rats was investigated. A total of 24 Wistar rats were divided into 4 equal groups, with 6 rats in each group: Left lung I/R was applied to I/R groups. In the I/R groups, the left lung hilum was clamped for 45 minutes, and then the clamp was removed and reperfused for 120 minutes. In the TCZ groups, 4 mg/kg and 8 mg/kg of TCZ were administered intraperitoneally to the rats 30 minutes before surgery. The tumor necrosis factor-alpha mean value was not statistically significant between the groups (P = .091). Statistically significant results were observed between group I/R-TCZ (8 mg/kg) and group I/R for catalase. (P = .005). Statistically significant results were observed between group I/R-TCZ (8 mg/kg) and group I/R for malondialdehyde. (P = .009). The difference in total ischemia score between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R was statistically significant (P < .001). In terms of alveolar hemorrhage, there was a statistically significant difference between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R (P = .01 and P = .002, respectively). There was a statistically significant difference between group I/R-TCZ (8 mg/kg) and group I/R in terms of neutrophil accumulation (P = .01). In terms of interstitial edema, there was a statistically significant difference between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R (P = .006 and P = .001, respectively). In terms of pulmonary edema, there was a statistically significant difference between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R (P = .01 and P = .009, respectively). Lung tissue may be affected by I/R injury and this damage can be reversed with the use of TCZ.

The association between tocilizumab therapy and the development of thrombosis in critically ill patients with COVID-19: a multicenter, cohort study

The use of tocilizumab for the management of COVID-19 emerged since it modulates inflammatory markers by blocking interleukin 6 receptors. Concerns regarding higher thrombosis risk while using tocilizumab were raised in the literature. The aim of this study is to investigate the association between tocilizumab therapy and the development of thromboembolic events in critically ill COVID-19 patients. A propensity score-matched, multicenter cohort study for critically ill adult patients with COVID-19. Eligible patients admitted to ICU between March 2020 and July 2021 were categorized into two sub-cohorts based on tocilizumab use within 24 h of ICU admission. The primary endpoint was to assess the incidence of all thrombosis cases during ICU stay. The secondary endpoints were 30-day mortality, in-hospital mortality, and the highest coagulation parameters follow-up (i.e., D-dimer, Fibrinogen) during the stay. Propensity score matching (1:2 ratio) was based on nine matching covariates. Among a total of 867 eligible patients, 453 patients were matched (1:2 ratio) using propensity scores. The thrombosis events were not statistically different between the two groups in crude analysis (6.8% vs. 7.7%; p-value = 0.71) and regression analysis [OR 0.83, 95% CI (0.385, 1.786)]. Peak D-dimer levels did not change significantly when the patient received tocilizumab (beta coefficient (95% CI): 0.19 (− 0.08, 0.47)), while there was a significant reduction in fibrinogen levels during ICU stay (beta coefficient (95% CI): − 0.15 (− 0.28, − 0.02)). On the other hand, the 30-day and in-hospital mortality were significantly lower in tocilizumab-treated patients (HR 0.57, 95% CI (0.37, 0.87), [HR 0.67, 95% CI (0.46, 0.98), respectively). The use of tocilizumab in critically ill patients with COVID-19 was not associated with higher thrombosis events or peak D-dimer levels. On the other hand, fibrinogen levels, 30-day and in-hospital mortality were significantly lower in the tocilizumab group. Further randomized controlled trials are needed to confirm our findings.

Investigation of the Effectiveness of Tocilizumab on COVID-19 Patients: A Retrospective Study

Background: Tocilizumab (TCZ), an interleukin-6 receptor inhibitor, has been considered a potential treatment for severe COVID-19 cases. However, data on its effectiveness remain limited. Objectives: This study aims to evaluate the outcomes of using TCZ in patients with severe COVID-19 during the fifth wave of the pandemic. Methods: This retrospective cohort study was conducted on 114 patients with severe COVID-19 who were hospitalized in the ICU at Sayyad Shirazi Hospital in Gorgan, Iran, during the fifth wave. The patients were divided into two groups: 57 received TCZ along with standard treatment (remdesivir and corticosteroids), while 57 received only standard treatments. Results: The mean age of the participants was 53.02 ± 17.29 years, with 54.4% being female. The mean length of hospitalization was 20.16 ± 17.30 days. Statistical analysis showed no significant differences regarding age (P = 0.34), gender (P = 0.25), or length of hospitalization (P = 0.84). Additionally, 43.9% of the participants had underlying health conditions, with no significant difference in their distribution (P = 0.70). The intubation rate was 3.5% in the TCZ group compared to 5.3% in the control group, with no significant association between the two groups (P = 0.64). Mortality rates were 47.4% (27 patients) in the TCZ group and 56.1% (32 patients) in the control group, with statistical analysis revealing no significant difference between the two groups (P = 0.34). However, in patients aged 60 years and older, the mortality rate was significantly higher in the control group than in the TCZ group (P = 0.03). Conclusion: The use of TCZ in severe COVID-19 patients hospitalized in the ICU was associated with a reduced mortality risk among patients aged 60 years and older.

Baseline absolute monocyte count predicts lung function decline among patients with systemic sclerosis-associated interstitial lung disease: A post hoc analysis from the focuSSced trial

ObjectiveInterstitial lung disease (ILD) is the leading cause of death in adults with systemic sclerosis (SSc). The identification of biomarkers to predict progression of SSc-ILD is an important unmet need. The purpose of this study was to determine whether an elevated baseline absolute monocyte count (AMC) is associated with a decline in forced vital capacity (FVC) at 48 weeks among participants with SSc-ILD enrolled in the phase 3 focuSSced trial. MethodsWe performed a post-hoc analysis of the focuSSced trial, a multicenter, double-blind, randomized, placebo-controlled trial of adults with diffuse cutaneous SSc for ≤ 60 months. Participants received subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks. We examined the relationship between baseline AMC and FVC at 48 weeks using a General Linear Model adjusted for potential confounders. ResultsThe 136 participants with SSc-ILD in focuSSced were included in this study. Among participants assigned to the placebo group, there was a statistically significant inverse association between baseline AMC and change in FVC from baseline at week 48 in both unadjusted (β coefficient -0.539, 95 % CI -1.032 to -0.047, p-value=0.032) and multivariable-adjusted (β coefficient -0.573, 95 % CI -1.086 to -0.060, p-value=0.029) models. Among participants with SSc-ILD assigned to the tocilizumab group, there was no statistically significant association between baseline AMC and change in FVC from baseline at week 48 in unadjusted or fully adjusted models. ConclusionAMC may be a biomarker of disease progression in SSc-ILD, especially in those with early SSc with elevated circulating inflammatory markers. These results should be validated in other SSc-ILD cohorts.

Efficacy and Safety of Tocilizumab Treatment in Tunisian Critically Ill COVID‐19 Patients

Background. COVID‐19 is the major cause of serious acute respiratory complications, leading to strong perturbation of cytokine release and high levels of interleukin‐6. In this work, we assessed the efficacy and safety of Tocilizumab in Tunisian patients with severe COVID‐19. Materials and Methods. We enrolled in this retrospective study 255 critically ill patients in the intensive care unit of the military hospital of Tunis. These patients were categorized into a standard group (n = 148) and a Tocilizumab group (n = 107). Medical records were gathered and analyzed between September, 2020 and September, 2021. Results. No significant difference was detected in clinical and biological parameters at admission between the two studied groups. Interestingly, we revealed here a significant improvement in respiratory parameters as well as biological findings such as hemoglobin (p = 0.001), platelets (p = 0.005), CRP (p = 0.0001), fibrinogen (p = 0.0001), and creatinine (p = 0.002). Regarding the Simplified Acute Physiology Score II and 28‐day mortality, we showed a significant decrease of these two parameters following 48 hr of drug administration (p = 0.0001, respectively). No significant difference between the two groups regarding complications except the renal failure and the need for renal replacement therapy, which are higher in the standard group as compared to patients treated with Tocilizumab (p = 0.02; p = 0.0001, respectively). Conclusions. Treatment with TCZ seems to be safe and effective in reducing the mortality rate in severe COVID‐19 patients.

The use of prognostic scales to assess the effectiveness of the use of anti-cytokine drugs in patients with moderate and severe course of a new coronavirus infection

The aim. To analyze the effectiveness of the use of anti-cytokine drugs (tocilizumab, olokizumab and sarilumab) in a single-center retrospective cohort study based on the prediction of clinical outcomes using prognostic scales, with a single administration in patients with moderate to severe course of a new coronavirus infection.Materials and methods. The retrospective cohort study included three groups of patients with single administration of tocilizumab (65 patients), olokizumab (56 patients) and sarilumab (26 patients). All patients were treated in a repurposed infectious diseases hospital for patients with COVID-19 on the basis of Аlexandro-Mariinskaya Regional Clinical Hospital in the period January- August 2021. Upon admission to the hospital and 2 days after administration of the drug, patients were predicted the severity of the course and outcome using prognostic scales: 4C Mortality Score, COVID-GRAM, SHOCS-COVID.Results. A comparative analysis of the effectiveness of the use of anti-cytokine drugs using the 4C Mortality Score scale revealed a further deterioration in the prognosis of clinical outcome in the groups receiving tocilizumab (p = 0,002) and sarilumab (p = 0,031). When using the COVID-GRAM predictive scale, further deterioration of the prognosis was also noted in the tocilizumab (p = 0,004) and olokizumab (p = 0,005) groups. The SHOCS-COVID scale showed a further deterioration in the prognosis in the tocilizumab group (p = 0,001).Conclusion. The use of drugs based on monoclonal antibodies against IL-6 and its receptors in patients with moderate to severe COVID-19 did not reveal significant positive dynamics in changing the prognosis of clinical outcome 2 days after administration of these drugs.

Comparing tocilizumab biosimilar BAT1806/BIIB800 with reference tocilizumab in patients with moderate-to-severe rheumatoid arthritis with an inadequate response to methotrexate: a phase 3, randomised, multicentre, double-blind, active-controlled clinical trial

Biosimilars provide an opportunity to address unmet medical need by expanding access to biological treatments. This study aimed to show equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles of a proposed tocilizumab biosimilar BAT1806/BIIB800, to reference tocilizumab, in participants with rheumatoid arthritis with an inadequate response to methotrexate. This phase 3, multicentre, randomised, double-blind, active-controlled, equivalence study comprised a 24-week initial treatment period (results reported here) and a 24-week secondary treatment period. Participants were recruited at 54 centres across five countries (China, Ukraine, Poland, Georgia, and Bulgaria). Patients with active rheumatoid arthritis with an inadequate response to methotrexate were randomly assigned (1:1:2) to receive reference tocilizumab up to week 48, or reference tocilizumab up to week 24 followed by BAT1806/BIIB800 up to week 48 (the two reference tocilizumab groups were analysed as a single group in this analysis), or BAT1806/BIIB800 up to week 48 (the BAT1806/BIIB800 group), administered by intravenous infusion once every 4 weeks at a starting dose of 8 mg/kg. The primary endpoint was the proportion of participants who had a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 (for the European Medicines Agency [EMA]) or week 24 (for the US Food and Drug Administration [FDA] and China National Medical Products Administration [NMPA]) using prespecified equivalence margins (95% CI -14·5 to +14·5 [EMA], 90% CI -12·0 to +15·0 [FDA], and 95% CI -13·6 to +13·6 [NMPA]). The International Council for Harmonisation E9(R1) estimand framework, with strategies for addressing intercurrent events, was implemented for the efficacy evaluations with expected differences as per the predefined equivalence margins. This trial is registered at ClinicalTrials.gov (NCT03830203) and EudraCT (2018-002202-31), and is closed to new participants. Between Dec 19, 2018, and Jan 5, 2021, we randomly assigned 621 participants: 309 to the reference tocilizumab group and 312 to the BAT1806/BIIB800 group. The mean age was 50·5 years (SD 12·0), 534 (86%) were women, 87 (14%) were men, and 368 (59%) were White. For the primary estimands, estimated ACR20 response rates were 64·8% in the reference tocilizumab group and 69·0% in the BAT1806/BIIB800 group (treatment difference 4·1% [95% CI -3·6 to 11·9]) at week 12, and 67·9% in the reference tocilizumab group and 69·9% in the BAT1806/BIIB800 group (treatment difference 1·9% [90% CI -4·0 to 7·9; 95% CI -5·2 to 9·1]) at week 24. All confidence intervals were contained within the predefined equivalence margins. Comparable pharmacokinetic and immunogenicity profiles were observed for the reference tocilizumab and BAT1806/BIIB800 groups. Adverse events were reported by 201 (65%) participants in the reference tocilizumab group and 206 (66%) in the BAT1806/BIIB800 group; 196 (63%) participants in the reference tocilizumab group and 201 (64%) participants in the BAT1806/BIIB800 group reported a treatment-emergent adverse event. Five participants had a fatal event (reference tocilizumab n=1; BAT1806/BIIB800 n=4). BAT1806/BIIB800 showed equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles as reference tocilizumab. Bio-Thera Solutions and Biogen.

Comparative effectiveness of tocilizumab vs standard care in patients with severe COVID-19-related pneumonia: a retrospective cohort study utilizing registry data as a synthetic control

BackgroundThe 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.MethodsThis 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.ResultsFor 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).ConclusionsTocilizumab 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.

Metabolism in resuscitated out-of-hospital cardiac arrest and the effect of Tozilizumab

Abstract Background Out-of-Hospital Cardiac Arrest (OHCA) is a leading cause of death. The mortality and morbidity for initially comatose patients remain high even after successful resuscitation. The conquest of attenuating the damage caused by ischemia and reperfusion is ongoing. In a double-blinded clinical trial, comatose resuscitated OHCA patients (n=80) were randomized 1:1 to receive tocilizumab (interleukin-6 receptor antagonist) or placebo at arrival to the intensive care unit to reduce systematic inflammation (Figure 1). Tocilizumab markedly reduced the immunological response invested by high-sensitive C-reactive-protein and white blood count and further significantly lowered both troponin and NT-pro-BNP levels. Aim To describe circulating metabolites in out-of-hospital cardiac arrest patients and how tocilizumab affects the metabolism. Methods Accordingly, using ultra-performance-liquid-mass-spectrometry, we detected more than 3000 plasma metabolites in samples from arrival at the hospital (before tocilizumab infusion) and 48 hours later. We had prespecified 61 metabolites for quantification. Results The level of poly-unsaturated free fatty acids was associated with activated partial thromboplastin time (rho=0.77), while metabolites from the tricarboxylic acid cycle were associated with time to return of spontaneous circulation (rho=0.32) and interleukin-6 levels (rho=0.37) upon arrival. Furthermore, medium- and long-chain acylcarnitines were associated with increasing age (rho=0.32), eGFR (rho=-0.46), and NT-pro-BNP level (rho=0.47) Tocilizumab treatment increased the levels of several amino acids and free fatty acids more than 1.5 times (Figure 2). A possible interpretation would suggest a downregulated systemic protein synthesis in the tocilizumab group, possibly due to reduced systemic inflammation. Conclusion In this study, we have described the alterations in metabolites following OHCA and, for the first time, described the effect of tocilizumab on metabolism in critically ill patients.IMICA TrialVolcano Plot - Effect of tocilizumab

Neurofilament Light Chain levels during admission after out-of-hospital cardiac arrest is associated with cognitive performance at 3-months follow-up

Abstract Background Patients who are resuscitated from out-of-hospital cardiac arrest (OHCA) and hospitalized in coma are at high risk of mortality or brain injury with consequent cognitive impairment, and new therapy are wanted. Biomarkers of brain injury, including Neuron-specific enolase (NSE) and Neurofilament light chain (NfL), predict mortality from cerebral injury. However, prognostication of cognitive dysfunction after discharge in OHCA survivors is challenging. Montreal Cognitive Assessment (MoCA) is a recommended standardized cognitive function testing which is used in the months following OHCA. Nevertheless, prognostic methods assessed in the initial phase of admittance which identify patients at risk of developing cognitive impairment are needed. Purpose To investigate the effect of tocilizumab administered at admission after OHCA on cognitive performance assessed by MoCA at 3-month follow-up, and to investigate the association to time-to-ROSC, and NSE as well as NfL levels during index admission with MoCA at follow-up. Methods The IMICA trial evaluated tocilizumab for reducing systemic inflammation after OHCA and randomized 80 comatose adult patients at admission to an infusion of either tocilizumab (8mg/kg, maximum 800mg) or placebo. NSE at 48 hours was measured as part of routine biochemistry based on serum samples, and NFL at 48 hours was measured in serum samples from the biobank. Time-to-ROSC was reported from pre-hospital data and cognitive performance at 3 months follow-up were assessed by the MoCA test. The association between MoCA and time-to-ROSC, NSE and NfL was assessed by Spearman’s correlation analyses. Results At follow-up, 35 patients had a MoCA test performed, while 28 patients were deceased, and 17 were alive without having an available MoCA score. There was no difference in MoCA scores at follow-up in the tocilizumab group compared to placebo group (p=0.72), and therefore results for both groups were pooled for analyses. NfL was found to be inversely correlated with MoCA score, r = -0.49, p = 0.003 (Figure), while there were no correlations with MoCA for time-to-ROSC or NSE (p = 0.46 and p = 0.34). Conclusions NfL measured at 48 hours after admission was inversely correlated with cognitive performance at 3 months for survivors of OHCA.

Prophylactic Tocilizumab to Prevent Cytokine Release Syndrome (CRS) with Teclistamab Administration

Introduction: Teclistamab is a T-cell redirecting bispecific antibody that targets both CD3 on the T-cell surface and B-cell maturation antigen (BCMA) expressed on myeloma cells. Teclistamab gained accelerated approval for RRMM patients that had previously been treated with 4 prior lines of therapy including a PI, IMID and a CD38 monoclonal antibody. This approval was based on the results of the MajesTEC-1 study demonstrating an ORR of 63%. Cytokine release syndrome (CRS), a known complication of T-cell engaging therapies, occurred in 72% patients which required a REMS program to monitor the patients in hospital for 48 hours post both priming doses and the target dosing. Several approaches are in place to minimize the risk of CRS to allow for the administration of teclistamab safely as an outpatient. We have evaluated the role of administering tocilizumab prophylactically to mitigate the incidence and the severity of CRS. Methods: A total of 48 patients were admitted to the Emory University hospital from December 2022 until July 2023 as mandated by REMS program for teclistamab step-up dosing followed by the first full dose at least 48 hours apart (0.06, 0.3, and 1.5mg/kg) with premeds per institutional guidelines (Benadryl 50 PO, Tylenol 650 PO, and Dexamethasone 16mg PO 30 minutes prior to each dose). Upon evaluation of our first 15 patients, the median time to CRS from the administration of the first-priming dose was 48 hours. We subsequently administered tocilizumab 8mg/kg IV over an hour (max dose of 800 mg) prophylactically at 44 hours (4 hours prior to the second step-up dose level) for the next 33 patients. CRS was graded per the American Society for Transplantation and Cellular Therapy criteria and managed according to institutional guidelines. Results: The median age of the patients was 66 years (range, 44-82). All patients were IMID, PI and CD38 mab refractory. The rate of all grade CRS amongst the entire cohort was 21 of 48 patients (43.8%). CRS occurred in 10 of the 33 patients (30.3%) who received prophylactic tocilizumab, compared to 11 of 15 (73.3%) of patients that did not. The majority the events in the prophylactic tocilizumab group are grade 1 [8 (24.2%)]. 1 patient had grade 2 and another had grade 3 CRS (patient with an aggressive relapse at time of teclistamab administration, requiring 3 doses of tocilizumab every 8 hours). The median number of tocilizumab doses was 1 (range, 1-3). The median duration of CRS was 1 day (range, 1-3). 1 dose of steroids (outside of premeds) was administered in the 1 patient who experienced grade 3 CRS but in no additional patients treated with prophylactic tocilizumab. Concurrent immune effector cell neurotoxicity syndrome (ICANS) was also decreased with the incorporation of prophylactic tocilizumab (20% vs 6.1%, respectively). All ICANS in the prophylactic cohort were grade 1 and managed symptomatically. The median duration of ICANS was 1 day. The non-prophylactic cohort experienced 3 of 15 (20%) patients with readmissions, with 1 additional patient going to hospice. None of the patients in the prophylactic cohort were readmitted to the hospital within 14 days of discharge. Conclusion: Prophylactic tocilizumab prior to the second priming dose has decreased the incidence and severity of CRS in heavily refractory RRMM patients receiving teclistamab. These results are lower in absolute incidence and severity when compared to the MajesTEC-1 trial where CRS was seen in 72% of patients. Prophylactic tocilizumab prevented usage of steroids, prevented dose delays, prevented readmission to the hospital, and possibly reduced the occurrence of ICANS. These data make a case for early incorporation of prophylactic tocilizumab and support outpatient administration of teclistamab in most patients.

Long-term effect of tocilizumab on mortality, readmissions, persistent symptoms and lung function in SARS-CoV-2 patients 1 year after hospital discharge: A matched cohort study

BackgroundTocilizumab is presumed to be an effective and safe treatment for severe SARS-Cov-2, but its usefulness has not been investigated yet for long-term outcomes. This study aimed to evaluate the influence of tocilizumab on mortality in patients with SARS-CoV-2 throughout the year following discharge. MethodsA retrospective observational analysis was performed on electronic medical records of patients with SARS-CoV2 who were discharged from our hospital after surviving the first wave in March-April 2020. Logistic regression was used to analyse the effect of tocilizumab on mortality, as the main outcome, and propensity-score analysis to further validate their effect. Secondary outcomes were readmissions, persistent symptoms and lung function evolution. Patients were selected by matching their individual propensity for receiving therapy with tocilizumab, conditional on their demographic and clinical variables. ResultsA total of 405 patients were included in the mortality study (33.6 % were treated with tocilizumab) and 390 were included in the assessment of persistent symptoms. After propensity-score analysis, no association between tocilizumab use and 1-year overall mortality was found (HR= 2.05, 95 % CI: 0.21–19.98). No differences regarding persistent symptoms (OR= 1.01 95 %CI 0.57–1.79), nor lung function parameters (forced vital capacity: coefficient -0.16 95 %CI -0.45 to 0.14) were found throughout the year follow-up between control and tocilizumab group. ConclusionsThe administration of tocilizumab in patients with SARS-CoV-2 did not show any effect on long-term mortality. Identically, no association were found regarding readmissions, persistent symptoms or lung function evolution and tocilizumab administration in our cohort of patients after 1 year follow-up.

Evaluation of Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio in Covid-19 Patients Treated with Tocilizumab Due to Cytokine Storm

Background/Aims: There is a significant increase in proinflammatory cytokine levels in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients entering cytokine storm. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), also increase in inflammatory diseases. The aim was to evaluate the NLR and PLR of coronavirus disease 2019 (COVID-19) patients receiving tocilizumab (TCZ) due to cytokine storm. Materials and Methods: In this retrospective, cross-sectional study conducted in between March and December 2020, adult patients with laboratory-confirmed COVID-19 were analyzed Results; The mean age of 519 patients included in the study was 61.6 ± 17.0 years, with male predominance (64.7%). 70.7% of patients had at least one type of comorbidity and the most common comorbid conditions were chronic obstructive pulmonary disease (45.9%) and asthma (28.7%). 399 patients who were given TCZ (group 1) and 120 patients who were not given TCZ (group 2) were evaluated. Compared with group 2, group 1 had more male predominance and they were older (p&amp;lt;0.001). The mortality rate, which was found to be 48.6% in group 1, was approximately twice as high in the intensive care unit (ICU). NLR and PLR were significantly higher and lymphopenia was more prominent in group 1, especially in ICU patients than group 2 (p&amp;lt;0.001). Conclusion: High NLR, PLR and lymphopenia was more common in critically ill Covid-19 patients. Therefore, they may be used as a marker to predict poor prognosis. It can be suggested to treat these patients more aggressively in the initial period.

The use of Tocilizumab in COVID-19 critically ill patients with renal impairment: a multicenter, cohort study

Tocilizumab (TCZ) is recommended in patients with COVID-19 who require oxygen therapy or ventilatory support. Despite the wide use of TCZ, little is known about its safety and effectiveness in patients with COVID-19 and renal impairment. Therefore, this study evaluated the safety and effectiveness of TCZ in critically ill patients with COVID-19 and renal impairment. A multicenter retrospective cohort study included all adult COVID-19 patients with renal impairment (eGFR˂60 mL/min) admitted to the ICUs between March 2020 and July 2021. Patients were categorized into two groups based on TCZ use (Control vs. TCZ). The primary endpoint was the development of acute kidney injury (AKI) during ICU stay. We screened 1599 patients for eligibility; 394 patients were eligible, and 225 patients were included after PS matching (1:2 ratio); there were 75 TCZ-treated subjects and 150 controls. The rate of AKI was higher in the TCZ group compared with the control group (72.2% versus 57.4%; p = 0.03; OR: 1.83; 95% CI: 1.01, 3.34; p = 0.04). Additionally, the ICU length of stay was significantly longer in patients who received TCZ (17.5 days versus 12.5 days; p = 0.006, Beta coefficient: 0.30 days, 95% CI: 0.09, 0.50; p = 0.005). On the other hand, the 30-day and in-hospital mortality were lower in patients who received TCZ compared to the control group (HR: 0.45, 95% CI: 0.27, 0.73; p = 0.01 and HR: 0.63, 95% CI: 0.41, 0.96; p = 0.03, respectively). The use of TCZ in this population was associated with a statistically significantly higher rate of AKI while improving the overall survival on the other hand. Further research is needed to assess the risks and benefits of TCZ treatment in critically ill COVID-19 patients with renal impairment.

Tocilizumab in ICU-admitted COVID-19 Patients: A Retrospective Study.

Severe and critically-ill COVID-19 patients are characterized by a severe inflammatory response. Pharmacologic inhibition of acute-phase inflammatory pathways such as IL-6 receptor inhibitor, Tocilizumab (TCZ) may improve patient outcomes in these cases. Consequently, the therapeutic benefit of TCZ was evaluated in this study. We evaluated intravenous tocilizumab in severe and critically ill adult COVID-19 patients who met pre-defined stringent CRS criteria. A single-center, prospective, observational cohort study was carried out among consecutive adult (≥18 years of age) in-patients with COVID-19 between March 20, 2020 and March 20, 2021. In total, 354 patients were included in our study. Mortality and time to hospital discharge were compared between patients who received tocilizumab treatment (n = 177) and those who did not (n = 177). A total of 354 patients were analyzed whereas 177 patients were included in each group. In those receiving TCZ, all-cause mortality was significantly reduced, corresponding to an adjusted hazard ratio (HR) of 0.57, (95% confidence interval (CI): 0.43-0.76; P < 0.001). Furthermore, time to discharge was significantly improved in the TCZ group (HR: 1.66; 95%CI: 1.17-2.36, P = 0.004). Invasive mechanical ventilation was not statistically different among the study groups after adjusting for confounding variables (HR: 1.38; 95%CI: 0.89-2.14; P = 0.139). Dosing frequency was independent of survival status (P = 0.676). The use of TCZ in ICU-hospitalized patients resulted in improved patient survival and reduced duration of hospitalization. Further studies are needed to confirm the efficacy of TCZ in severe and critical COVID-19 cases.

Tocilizumab Is Associated with Increased Risk of Fungal Infections among Critically Ill Patients with COVID-19 and Acute Renal Failure: An Observational Cohort Study.

Does treatment with tocilizumab increase the risk of a fungal infection in critically ill patients with coronavirus-19? Numerous therapies have been evaluated as possible treatments for coronavirus-2019 caused by severe acute respiratory syndrome coronavirus-2. Tocilizumab is a humanized monoclonal antibody directed against the interleukin-6 receptor that has found a role as a therapy for patients with severe coronavirus-19 pneumonia. The immunomodulatory effects of tocilizumab may have the unintended consequence of predisposing recipients to secondary infections. We sought to assess the risk of invasive fungal disease and the therapeutic impact of tocilizumab on the hospital length of stay, duration of mechanical ventilation, and intensive-care-unit length of stay in critically ill patients with severe coronavirus-19 pneumonia. Records of critically ill patients with coronavirus-2019 admitted from March to September 2020 at our institution were reviewed. The risk for fungal infections, intensive-care-unit length of stay, hospital length of stay, and duration of mechanical ventilation in those that received tocilizumab in addition to standard coronavirus-2019 treatments was assessed. Fifty-six critically ill patients treated with dexamethasone and remdesivir for coronavirus-2019 were included, of which 16 patients also received tocilizumab. The majority of the cohort was African American, Asian, or of other ethnic minorities (53.6%). Invasive fungal infections occurred in 10.7% of all patients, and infection rates were significantly higher in the tocilizumab group than in the control group (31.2% vs. 2.5%, risk difference [RD] = 28.8%, p < 0.01). The increased risk in the tocilizumab group was strongly associated with renal replacement therapy. There was a dose-response relationship between the risk of fungal infection and number of tocilizumab doses received, with 2.5% of infections occurring with zero doses, 20% with a single dose (RD = 17.5%), and 50% with two doses (RD = 47.5%) (trend test p < 0.001). In addition, ICU LOS (23.4 days vs. 9.0 days, p < 0.01), the duration of mechanical ventilation (18.9 vs. 3.5 days, p = 0.01), and hospital length of stay (LOS) (29.1 vs. 15.5, p < 0.01) were increased in patients that received tocilizumab. Repurposed immunomodulator therapies, such as tocilizumab, are now recommended treatments for severe coronavirus-2019 pneumonia, but safety concerns remain. In this early pandemic cohort, the addition of tocilizumab to dexamethasone was associated with an increased risk of fungal infection in those that were critically ill and received renal replacement therapy. Tocilizumab use was also associated with increased ICU and hospital LOSs and duration of mechanical ventilation.