AA Amyloidosis Secondary to Horton's Disease Complicated by Pulmonary Fibrosis: A Very Challenging Diagnosis and Therapy

AA amyloidosis is a classic and serious complication of many chronic inflammatory processes, whether of infectious, autoimmune, or neoplastic origin. It is frequently complicated by kidney damage, often in the form of a nephrotic syndrome. Giant cell arteritis is a common inflammatory arteritis in the elderly; however, it rarely causes AA amyloidosis. We report a rare case of Horton disease causing AA amyloidosis in an elderly patient with history of myopericarditis and repeated episodes of congestive heart failure. Patient was treated initially with dual therapy based on corticosteroids and anti TNF therapy (Tocilizumab) associated with heart failure therapy recommended by the European society of cardiology (ESC 2021 guidelines on Heart Failure). The initial outcome was favorable but later complicated by the involvement of the lungs; pulmonary fibrosis, responsible for repeated episodes of pleural effusion non controlled in spite of high dose of loop diuretics and repeated pleural punction. Patient died shortly after her second hospitalization due to respiratory insufficiency.

Utilización precoz de tocilizumab en pacientes internados con COVID-19 grave y crítica: un estudio multicéntrico en la Provincia de Buenos Aires / Early use of tocilizumab in hospitalized patients with severe and critical COVID-19 in the Province of Buenos Aires: a multicentric study

Resumen Introducción: El objetivo principal del estudio fue evaluar la mortalidad en los pacientes con COVID-19 graves y críticos, que recibieron tocilizumab (TCZ) -un antagonista monoclonal del receptor de IL-6- de forma temprana vs. tardía. Métodos: Cohorte retrospectiva multicéntrica de pacientes >18 años internados con COVID-19 desde el 1/7/2021-1/8/2022, con 5-7 puntos de gravedad inicial (GI) según Escala de la OMS. Se consideró adminis tración temprana o tardía a la infusión de TCZ ≤ ó > a 48 h del ingreso. Las variables de resultado fueron mortalidad a 28 días y cambio de la GI. Los factores relacionados con la mortalidad fueron evaluados con regresión de Cox. Resultados: Se incluyeron 266 pacientes, 159(60%) varones; edad 58(± 15); con hipertensión arterial (43%), obesidad (37%) y diabetes (27%);70 presentaban GI = 5 (oxígeno suplementario), 143 GI = 6 (ventilación no inva siva o cánula nasal de alto flujo) y 53 GI = 7 (ventilación mecánica invasiva). La mortalidad a 28 días fue 42%, asociada independientemente a: edad, obesidad, GI, días entre la internación y administración del TCZ, y días entre la fecha de inicio de síntomas y el TCZ. La mortalidad para GI 5, 6 y 7 fue 26%, 39% y 72%, respectivamente; 76% y 62% de los pacientes permanecieron estables o mejoraron la GI a los días 3 y 7 de la infusión de TCZ. La mortalidad a 28 días fue 39% (TCZ temprano) vs. 57% (TCZ tardío); p = 0.02; HR = 0.63[0.41-0.99, p = 0.05]). Discusión: Estos resultados apoyan la administración temprana de TCZ en pacientes con COVID-19 grave y crítica.

Abstract Introduction: Tocilizumab (TCZ), an IL-6 receptor antagonist monoclonal antibody is warranted in severe and critically-ill COVID-19 patients. The objective was to evaluate 28-day mortality of patients with severe or critical COVID-19 treated with early vs delayed TCZ. Methods: Multicenter, retrospective cohort study in cluding patients>18 years hospitalized between 7/1/2021- 8/1/2022 with confirmed COVID-19, with 5, 6 and 7 points of WHO Ordinal Initial Severity Scale [SS]. Early or late administration was considered if TCZ was administered before or after 48 hours from admission. Outcomes were28-day mortality and change of SS. Factors related to 28-day mortality were evaluated with Cox regression. Results: 266 patients were included, 159(60%) male; aged 58(± 15); frequent comorbidities were hypertension (42%), obesity (37%) and diabetes (27%). Seventy patients had a SS = 5 (Supplemental O2), 143 had SS = 6 (NIV/ HFNC), and 53 had SS = 7 (IMV). 28-day mortality was 42%(112/266); predictors were age, obesity, higher SS, days between hospitalization and TCZ administration, and fewer days between symptoms onset and TCZ. Mortality of SS 5, 6 and 7 was 26%, 39% and 72% respectively. Com pared with baseline SS points, 76% and 62% of patients remained stable or improved on days 3 and 7 since TCZ administration. 28-day mortality was lower when TCZ was administered before 48 hours (39% vs 57%; p = 0.02; HR = 0.63;[0.41-0.99, p = 0.05]). Discussion: This study supports the early use of TCZ in patients with severe or critical COVID-19.

Effectiveness and safety of tocilizumab for COVID-19: a systematic review and meta-analysis of randomized clinical trials

ABSTRACT BACKGROUND: Tocilizumab is an anti-human interleukin 6 receptor monoclonal antibody that has been used to treat coronavirus disease 2019 (COVID-19). However, there is no consensus on its efficacy for the treatment of COVID-19. OBJECTIVE: To evaluate the effectiveness and safety of tocilizumab for treating COVID-19. DESIGN AND SETTING: Systematic Review of randomized controlled trials (RCTs), Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil. METHODS: We searched MEDLINE via PubMed, EMBASE, CENTRAL, and IBECS for RCTs published up to March 2021. Two authors selected studies and assessed the risk of bias and the certainty of the evidence following Cochrane Recommendations. RESULTS: Eight RCTs with 6,139 participants were included. We were not able to find differences between using tocilizumab compared to standard care on mortality in hospitalized patients with COVID-19 (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.84 to 1.13; 8 trials; 5,950 participants; low-certainty evidence). However, hospitalized patients under tocilizumab plus standard care treatment seemed to present a significantly lower risk of needing mechanical ventilation (risk ratio = 0.78; 95% CI 0.64−0.94 moderate-certainty of evidence). CONCLUSIONS: To date, the best evidence available shows no difference between using tocilizumab plus standard care compared to standard care alone for reducing mortality in patients with COVID-19. However, as a finding with a practical implication, the use of tocilizumab in association to standard care probably reduces the risk of progressing to mechanical ventilation in those patients. REGISTRATION: osf.io/qe4fs.

Rituximab, a Safer Option for Rheumatoid Arthritis: A Comparison of the Reported Adverse Events of Approved Monoclonal Antibodies

Monoclonal antibodies (mAbs), which are commonly used to treat rheumatoid arthritis (RA), have been linked to a variety of adverse events (AEs). The objective of the study was to compare the safety profiles of six FDA approved mAbs (sarilumab, tocilizumab, adalimumab, golimumab, infliximab, and rituximab) marketed for the treatment of RA. A systematic review of the literature was conducted using the databases PubMed, Cochrane Library, and Science Direct. The manuscript comprised a total of 23 clinical studies. The percentage of patients who had AEs was calculated and presented using box-whisker and forest plots. Infections and infestations were found to be the most common AEs in RA patients treated with mAbs. Raised alanine aminotransferase (ALT), aspartate aminotransferase (AST), upper respiratory tract infection (URTI), and nasopharyngitis were frequently reported. The most common AEs were reported with adalimumab. The highest percentage of patients reporting AEs was associated with golimumab (52%), while rituximab had the fewest AEs (4.9%). In conclusion, rituximab appears to be a safer treatment option for RA as it is found to be associated with a lower risk of AEs, particularly respiratory infections.

Caracterización de eventos adversos a hidroxicloroquina, ivermectina, azitromicina y tocilizumab en pacientes hospitalizados por COVID-19 en un hospital del Seguro Social de Salud del Perú / Characterization of adverse events to hydroxychloroquine, ivermectin, azithromycin and tocilizumab in patients hospitalized due to COVID-19 in a Peruvian Social Health Insurance hospital

Objetivos. Caracterizar los eventos adversos (EA) asociados a hidroxicloroquina (HQ), azitromicina (AZI), tocilizumab (TOB) e ivermectina (IVM) prescritos como «fuera de etiqueta» en el tratamiento de pacientes hospitalizados por la COVID-19. Materiales y métodos. Se realizó un análisis secundario transversal de la base de datos del sistema de farmacovigilancia del Seguro Social de Salud del Perú (EsSalud) de las notificaciones de EA a HQ, AZI, TOB e IVM provenientes del Hospital Nacional Edgardo Rebagliati Martins de abril a octubre del 2020. Se revisaron las historias clínicas digitales, se estimaron las tasas de reporte de EA y se evaluaron sus características por tipo de fármaco, tiempo de aparición, tipo por órgano-sistema afectado, gravedad y causalidad. Resultados. Se identificaron 154 notificaciones que describen un total de 183 EA posiblemente relacionados con HQ, AZI, TOB e IVM, siendo 8% la tasa de reporte de EA. La mediana de tiempo de aparición de EA fue de 3 días (RIC: 2-5). La mayoría fueron cardiovasculares, destacándose la prolongación del intervalo QT. Se observaron EA hepatobiliares principalmente asociados a TOB. La mayoría de los casos fueron moderados, no obstante, el 10,4% fue grave. Conclusiones. Se identificaron EA potencialmente asociados al uso de HQ, AZI, TOB e IVM contra la COVID-19, siendo los más frecuentes los de tipo cardiovasculares. A pesar de que la AZI, HQ e IVM poseen perfiles conocidos de seguridad, su empleo en la COVID-19 podría incrementar la aparición de EA por los factores de riesgo propios de esta infección. Se sugiere reforzar la vigilancia, especialmente, de TOB.

Objective. To characterize the adverse events (AEs) related to the off-label use of hydroxychloroquine (HQ), azithromycin (AZI), tocilizumab (TOB) and ivermectin (IVM) for the treatment of COVID-19 in hospitalized patients. Materials and Methods. We conducted a secondary cross-sectional analysis of the Peruvian Social Health Insurance (EsSalud) pharmacovigilance system database of AE notifications to HQ, AZI, TOB and IVM in the Edgardo Rebagliati Martins National Hospital from April to October 2020. Information was collected from digital medical records. We estimated AE reporting rates and evaluated their characteristics by drug type, time of occurrence, type by the affected organ-system, severity and causality. Results. We identified 154 notifications describing a total of 183 AE possibly related to HQ, AZI, TOB and IVM; the reporting rate was 8%. The median time of AE occurrence was 3 days (IQR: 2-5). Most were cardiovascular events; prolongation of the QT interval was the most frequent. Hepatobiliary AEs were mainly associated with TOB. Most cases were moderate, however, 10.4% were severe. Conclusions. We found AEs potentially associated with the use of HQ, AZI, TOB and IVM against COVID-19; cardiovascular events were the most frequent. Although AZI, HQ and IVM have known safety profiles, their use against COVID-19 could increase the occurrence of AE due to the risk factors inherent to this infection. Surveillance systems must be improved, especially those for TOB.

Efficacy and safety of five monoclonal antibodies in preventing relapse of neuromyelitis optica spectrum disorders：network meta-analysis / 中国药房

OBJECTIVE To indirectly compare and evaluate the efficacy and safety of rituximab， tocilizumab， eculizumab， inebilizumab and satralizumab in preventing the relapse of neuromyelitis optica spectrum disorders， so as to provide reference for clinical drug use. METHODS Retrieved from Embase， Medline， PubMed， CNKI， ClinicalTrials. gov， UMIN Clinical Trials Registry and Chinese Clinical Trial Registry， randomized controlled trials （RCTs） about five monoclonal antibodies （trial group） versus placebo or other therapeutic scheme （control group） were collected during the inception to Apr. 2022. Two reviewers independently screened literature， extracted data， and assessed the quality of included literature with Cochrane risk bias assessment tool. OpenBUGS software was used for network meta-analysis. In terms of safety， Chi-square test was performed for adverse events （AEs） in trial group and control group. RESULTS A total of 7 RCTs were included， involving 793 patients. The results of surface under the cumulative ranking curve （SUCRA） showed the order of capabilities decreasing relapse risk was： eculizumab＞ rituximab＞inebilizumab＞satralizumab； the order of capabilities reducing the annual recurrence rate was： eculizumab＞ satralizumab； the order of capabilities improving the progress of disability was： eculizumab＞satralizumab＞inebilizumab＞ rituximab＞tocilizumab. In terms of safety， the results of χ2 test showed that there were no statistically significant differences in the risk of total AEs and serious AEs in each study between trial groups and control groups （P＞0.05）； the incidence of infusion reaction， nausea and vomiting in rituximab group， and that of upper respiratory tract infection in eculizumab group were significantly higher than placebo group （P＜0.05）. CONCLUSIONS The effect of eculizumab is more optimal in three outcomes； in terms of improving the progress of disability， eculizumab， satralizumab and inebilizumab are more effective than the other two drugs； in terms of safety， there are significant goldenmoonsp@163.com differences in some AEs with different grades and individual AEs， but it is not found that they are inconsistent with the 学。E-mail：liyingpds@126.com reported results of the existing literature and drug instructions.

Compared efficacy of rituximab, abatacept, and tocilizumab in patients with rheumatoid arthritis refractory to methotrexate or TNF inhibitors agents: a systematic review and network meta-analysis

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 < 0.001) for ACR70 compared to tocilizumab. Conclusion We found high heterogeneity among studies comparing rituximab, abatacept, and tocilizumab. On multivariate metaregressions, if the conditions of the RCTs were similar, we estimate that abatacept could increase the chance of reaching an ACR70 response by 2.2-fold compared to tocilizumab. Key messages Abatacept could increase the chance of reaching an ACR70 response by 2.2-fold compared to tocilizumab.

From publications to every day clinical practice: tocilizumab in patients with severe COVID-19 / De las publicaciones a la práctica cotidiana: tocilizumab en pacientes con COVID-19 grave

Abstract Introduction: there is evidence on the effectiveness and safety of tocilizumab (TZC) used in combination with systemic corticosteroids for severe SARS-CoV-2 pneumonia treatment. The purpose of this study was to describe epidemiological, clinical, and laboratory features as well as clinical outcome of patients receiving this combination therapy compared with those receiving only corticosteroids. Methods: a retrospective cohort study, which included adults with severe SARS-CoV-2 pneumonia, was conducted between March and August 2021. Enrolment included 101 patients, 46 with corticosteroids and 55 with corticosteroids plus tocilizumab. Results: median age was 58 years old and 63.9% were females. High blood pressure was present in 36.1% and obesity in 54.6%. Survival in the cohort was 81.4%, with a median hospital stay of 19.0 days. Secondary infections were present in 47.4% of the cohort. Patients in the TZC group had a lower C reactive protein (CRP) at discharge, lower rate of multiple organ failure, better functional status at discharge and shorter hospital stay. In a bivariate analysis, no differences were found in mortality rate and secondary infections occurrence. When assessing clinical status as per WHO Ordinal Scale there was a significant difference in its variability from wors ening to discharge (or 14 days), evidencing a better functional status in patients receiving TCZ. Discussion: we were able to demonstrate its efficacy in reducing inflammatory biomarkers and a trend towards fewer days of hospitalization, with no impact on mortality.

Resumen Introducción: existe evidencia sobre la efectividad y seguridad de tocilizumab (TZC) utilizado en combinación con corticosteroides sistémicos para el tratamiento de la neumonía grave por SARS-CoV-2. El propósito de este estudio fue describir las características epidemiológicas, clínicas y de laboratorio, así como el resultado clínico de los pacientes que recibieron esta terapia combinada en comparación con los que recibieron solo corticosteroides. Métodos: se realizó un estudio de cohorte retrospectivo, que incluyó adultos con neumonía grave por SARS-CoV-2, entre marzo y agosto de 2021. Se incluyeron 101 pacientes, 46 con corticosteroides y 55 con corticosteroides más tocilizumab. Resultados: la mediana de edad fue de 58 años y el 63.9% eran mujeres. La hipertensión arterial estuvo presente en el 36.1% y la obesidad en el 54.6%. La supervivencia en la cohorte fue del 81.4%, con una mediana de estancia hospitalaria de 19.0 días. Las infecciones secundarias estuvieron presentes en el 47.4% de la cohorte. Los pacientes del grupo TZC tenían valores menores de pro teína C reactiva (PCR) al alta, una tasa más baja de insuficiencia multiorgánica, un mejor estado funcional al alta y una estancia hospitalaria más corta. En un análisis bivariado, no se encontraron diferencias en la tasa de mortalidad y la ocurrencia de infecciones secundarias. Al evaluar el estado clínico según la Escala Ordinal de la OMS hubo una diferencia significativa en su variabilidad desde el empeoramiento hasta el alta (o 14 días), evidenciando un mejor estado funcional en los que recibieron TCZ. Discusión: pudimos demostrar su eficacia en la reducción de biomarcadores inflamatorios y una tendencia a menos días de hospitalización, sin impacto en la mortalidad.

Highlights of clinical and laboratory parameters among severe COVID-19 patients treated with tocilizumab: a retrospective observational study

ABSTRACT BACKGROUND: Coronavirus disease 2019 (COVID-19) can cause cytokine release syndrome (CRS), which leads to high mortality rates. Tocilizumab suppresses CRS by blocking the signal transduction of interleukin-6 (IL-6). OBJECTIVE: To evaluate the clinical and laboratory parameters associated with mortality among patients receiving tocilizumab treatment. DESIGN AND SETTING: Retrospective observational study conducted in the chest disease departments of two different training and research hospitals in the center of Ankara, Turkey. METHODS: Patients who were hospitalized and treated with tocilizumab in September 2020 were retrospectively analyzed. Their laboratory parameters and clinical characteristics were obtained from the hospital information system database. Comparative analyses were performed between the patients who died and the ones who survived. RESULTS: A total of 58 patients who received tocilizumab treatment were included in this study, among whom 35 (60.3%) died. There was no difference between the mortality and survival groups in terms of white blood cell (WBC), neutrophil, lymphocyte, ferritin or C-reactive protein (CRP) levels detected on admission. WBC, lymphocyte, neutrophil and CRP levels measured on the third and fifth days after tocilizumab administration were found to be significantly lower in the survival group (P < 0.05). In multiple logistic regression analysis, age and oxygen saturation were determined to be independent risk factors for mortality. CONCLUSION: Persistently high WBC, CRP and neutrophil levels and low lymphocyte levels could be considered to be valuable indicators of mortality among COVID-19 patients treated with tocilizumab. Age and low oxygen saturation are independent risk factors for mortality among patients receiving tocilizumab treatment.

Strike Omicron before you Captures It !

Omicron is currently shaking the world to its core. The disease is mainly transmitted via the respiratory route when people inhale droplets and small airborne particles (that form an aerosol) that infected people exhale as they breathe, talk, cough, sneeze, or sing. “UK becomes first country in Europe to pass 1,50,000 COVID deaths Omicron clouds forecasts for Covid end game.Omicron is a variant of nSARS-CoV-2 that has been identified initially in COVID19 patients in Botswana and South Africa. The chief of the World Health Organization (WHO), Tedros Adhanom Ghebreyesus, has said that the combination of Delta and Omicron variants of coronavirus is driving a tsunami of COVID-19 cases. The statement came as record new cases were reported from the United States and countries across Europe. France recorded the highest ever daily numbers in Europe for the second consecutive day, at 208,000 new cases.Vaccines offer strong protection from serious illness.

Tocilizumab is useful for coronavirus disease 2019 patients: the key point is timing

SUMMARY OBJECTIVE: In coronavirus disease 2019, a rapidly progressive inflammatory process is considered to be the main cause of organ damage and mortality. Therefore, the importance of anti-inflammatory treatments such as tocilizumab is increasing. METHODS: A total of 107 patients who received tocilizumab between March 2020 and March 2021 were included in the study. The primary termination point was mortality. We compared surviving and deceased patients by the stage of the disease and where the drug was given (service or intensive care unit). RESULTS: The mean age was 60.8±14.6 years (minimum 29 years, maximum 96 years). According to the WHO staging system, 16 (15%) patients had moderate, 47 (43.9%) patients had severe, 44 (41.1%) patients had a critical illness. Although all patients were admitted to the service, 26 (24.3%) patients received tocilizumab in the intensive care unit. Of 107 patients, 80 (74.7%) survived and 27 (25.2%) died. Mortality was found to be significantly higher in critical patients (96.3%), severe patients (3.7%), and moderate patients (0%) (p<0.001). Peripheral oxygen saturation measured at admission was found to be significantly lower in patients who died. The initial saturations (p=0.008) were found to have independent effects on mortality. CONCLUSION: The results showed that tocilizumab is an effective treatment option for coronavirus disease 2019 disease and reduces mortality, but the key point is timing.

Eficacia terapéutica y seguridad del tocilizumab en COVID-19 / Therapeutic efficacy of tocilizumab in COVID-19

A la fecha, excepto los glucocorticoides, ningún otro tratamiento farmacológico ha demostrado disminución de la mortalidad en pacientes con COVID-19 grave-crítico. Con el objetivo de discutir su utilidad en la terapéutica, se realizó una revisión y lectura crítica de los estudios publicados más significativos sobre el uso de tocilizumab.Se llevó adelante una búsqueda en las principales bases de datos bibliográficas priorizando la inclusión de revisiones sistemáticas y ensayos clínicos aleatorizados controlados (ERC) que analizaran el efecto del tocilizumab en COVID-19 en diferentes puntos de valoración.Se incluyeron 5 ERC y 4 metaanálisis en la evaluación, todos ellos incluyeron pacientes con COVID-19 confirmado y mayoritariamente graves-críticos. El punto de valoración principal (PVP) fue la mortalidad a los 28 días y como resultado secundario de relevancia, la progresión a ventilación mecánica invasiva (VMI). Se analizó, además, la seguridad de la intervención, fundamentalmente a nivel de la ocurrencia de infecciones secundarias.Del análisis surge que la mayor posibilidad de beneficio parece estar circunscripta a pacientes con enfermedad grave-crítica, que reciben corticoides, con marcadores de inflamación elevados (PCR >10 mg/dL) y enfermedad rápidamente progresiva. Existe alto grado de certeza respecto del impacto del tocilizumab en evitar la progresión a VMI, con una pequeña magnitud del efecto y moderado grado de certeza respecto de su impacto en la mortalidad; además de que resultó una medicación segura

Up until now, other than corticosteroids, no other pharmacological treatment has shown a decrease in mortality rate in patients with severe-critical COVID-19. In order to discuss its place in therapy, a review and critical reading of the most significant published studies on the use of tocilizumab was carried out.Search was done in the main bibliographic databases, prioritizing the inclusion of systematic reviews and randomized controlled clinical trials (RCTs); that analyzed the effect of tocilizumab on COVID-19 at different endpoints.5 RCTs and 4 meta-analysis were considered in the evaluation, all of them including patients with confirmed COVID-19 and predominantly severe-critical illness. The primary endpoint was 28-day all-cause mortality and, as a secondary outcome of relevance, progression to invasive mechanical ventilation. The safety of the intervention was also analyzed, mainly the occurrence of secondary infections.From our analysis it appears that the greatest possibility of benefit seems to be limited to patients with severe-critical illness, who receive corticosteroids, with high markers of inflammation values (CRP> 10 mg/dL) and rapidly progressive disease. There is high certainty regarding the impact of tocilizumab in preventing progression to IMV, with a small effect size and moderate certainty regarding its impact on mortality. Moreover, it was a well-tolerated and safe medication

Tocilizumab for COVID-19 treatment. an argentine report / Tocilizumab en el tratamiento de COVID-19. Informe argentino

Abstract Recently it has been demonstrated the clinical effectiveness of tocilizumab (TCZ) associated with systemic steroids for the treatment of severe SARS-CoV-2 pneumonia with rapid progression. The objective of this work was to describe the epidemiological, clinical, laboratory and evolution characteristics of the patients who received this treatment. Between March and June 2021, TCZ was administered in a cohort study of adults with severe SARS-CoV-2 pneumonia, in a private hospital in the City of Buenos Aires; 30 patients were included, 63% men, middle age 55 years. Obesity (33%), arterial hypertension (26%) and diabetes (25%) were the most frequent comorbidities. We found associated infections during hospitalization in half of the cohort, within them, pneumonia associated with mechanical ventilation was the most frequent and methicillin-sensitive Staphylococcus aureus, the most prevalent germ. Patients with secondary infections had a higher requirement for invasive mechanical ventilation (IMV) (100% vs. 19% p < 0.001) and more days of hospitalization (median 23 vs. 15 p = 0.009). Of the entire cohort, seven who died during hospitalization had the highest requirement for IMV (100% vs. 43% p = 0.010) and secondary infections (100% vs. 35%, p = 0.006). In this relatively young cohort of patients with severe or critical SARS-CoV-2 pneumonia, obesity does not appear to be a predisposing factor for superinfection or death. The presence of secondary infections, organ failure and shock are presented as probable factors of worse evolution, as well as the requirement of IMV.

Resumen Recientemente se demostró la efectividad clínica del tocilizumab (TCZ) asociado a esteroides sistémicos para el tratamiento de la neumonía grave por SARS-CoV-2 con rápida progresión. El objetivo de este trabajo fue describir las caracterís ticas epidemiológicas, clínicas, de laboratorio y evolución de los pacientes que recibieron este tratamiento. Entre marzo y junio, 2021, se realizó un estudio de cohorte en un sanatorio privado de la Ciudad de Buenos Aires en adultos con neumonía grave por SARS-CoV-2 que recibieron TCZ. Se incluyeron 30 pacientes, hombres 63%, mediana edad 55 años, obesidad (33%), hipertensión arterial (26%) y diabetes (25%) fueron las comorbilidades más frecuentes. Encontramos infecciones asociadas durante la hospitalización en la mitad de la cohorte, den tro de ellas, la neumonía asociada a la ventilación mecánica fue la más frecuente y el Staphylococcus aureus meticilino sensible, el germen más prevalente. Los enfermos con infecciones secundarias tuvieron un mayor requerimiento de ventilación mecánica invasiva (VMI) (100% vs. 19% p < 0.001) y más días de internación (me diana 23 vs. 15 p = 0.009). De la totalidad de la cohorte, siete que fallecieron durante la internación tuvieron el mayor requerimiento de VMI (100% vs. 43% p = 0.010) e infecciones secundarias (100% vs. 35%, p = 0.006). En esta cohorte relativamente joven de pacientes con neumonía grave o crítica por SARS-CoV-2, la obesidad no parece ser un factor predisponente para sobreinfección o muerte. La presencia de infecciones secundarias, falla orgánica y shock se presentan como probables factores de peor evolución, como así también el requerimiento de VMI.

LC-MS/MS method for the quantitation of serum tocilizumab in rheumatoid arthritis patients using rapid tryptic digestion without IgG purification / 药物分析学报

The quantitation of serum tocilizumab using liquid chromatography tandem-mass spectrometry(LC-MS/MS)method has not been widely applied in clinical settings because of its time-consuming and costly sample pretreatments.The present study aimed to develop a validated LC-MS/MS method for detecting serum tocilizumab by utilizing immobilized trypsin without an immunoglobulin G purification step and evaluate its applicability in the treatment of rheumatoid arthritis(RA)patients administered intrave-nously or subcutaneously with tocilizumab.The tocilizumab-derived signature peptide was deciphered using a nano-LC system coupled to a hybrid quadrupole-orbitrap mass spectrometer.The serum tocili-zumab was rapidly digested by immobilized trypsin for 30 min.The chromatographic peak of the signature peptide and that of the internal standard were separated from the serum digests for a total run time of 15 min.The calibration curve of serum tocilizumab concentration was linear with a range of 2-200 μg/mL.The intra-and inter-day accuracy and relative standard deviation(RSD)were 90.7％-109.4％and＜10％,respectively.The serum tocilizumab concentrations in the RA patients receiving intravenous and subcutaneous injections were 5.8-28.9 and 2.4-63.5 pg/mL,respectively.The serum tocilizumab concentrations using the current method positively correlated with those using the enzyme-linked immunosorbent assay,although a systematic error was observed between these methods.In conclu-sion,a validated LC-MS/MS method with minimal sample pretreatments for monitoring serum tocili-zumab concentrations in RA patients was developed.

Evaluation of the Validity of Vial Sizes for the Efficient Use of Tocilizumab Formulations / 医薬品情報学

Objective: Tocilizumab and infliximab are biologic drugs that are widely used for the treatment of rheumatoid arthritis (RA). The dosage of these injectable RA drugs is calculated based on body weight. However, injectable RA drugs are used only once due to stability and sterility concerns. For expensive biologic drugs, drug disposal wastage needs to be reduced. Tocilizumab is approved in three vial sizes: 80, 200, and 400 mg. In this study, we evaluated the validity of these tocilizumab vial sizes to help resolve the issue of excess residual drug.Methods: A log-normal distribution was assumed for body weight, and 10,000 hypothetical cases were created using the programming language R. We analyzed the average wasted dose rate per vial (%) by gender after considering different vial size combinations.Results: The average wasted dose rate per vial of tocilizumab was estimated to be 3.7% for males and 4.7% for females.Conclusion: The three vial sizes of 80, 200, and 400 mg are reasonable for tocilizumab. The average wasted dose rate per vial of infliximab was estimated to be 17.7% for males and 22.6% for females. The average wasted dose rate per vial was lower for tocilizumab than infliximab. Tocilizumab is administered in a dose range of 200 to 1,100 mg with three different vial sizes in multiples of 40 mg. However, infliximab is administered in a dose range of 50 to 400 mg with a single vial size of 100 mg. Multiple vial sizes should be prepared to ensure the efficient use of limited medical resources. It is also expected that the method employed for this hypothetical case model will be applied to other drugs for which disposal wastage is a problem and used to set appropriate vial size combinations.

Cytokine storm secondary to coronavirus disease-19 pneumonia in a preterm pregnancy: A management and bioethical dilemma / Philippine Journal of Obstetrics and Gynecology

@#A 27‑year‑old primigravida at 26 weeks’ age of gestation presented with difficulty of breathing, nonproductive cough, and generalized body malaise. Coronavirus disease‑19 (COVID‑19) infection was confirmed by a positive reverse transcription‑polymerase chain reaction. She was diagnosed with severe COVID‑19 pneumonia with progressive oxygen desaturation requiring intubation and intensive care unit admission. The management and bioethical dilemma involved the use of investigational therapeutic interventions for compassionate use, with unknown effects to the fetus, namely remdesivir, tocilizumab, dexamethasone, and hemoperfusion to manage the cytokine storm and prolong pregnancy or to terminate the pregnancy hoping that it might improve the deteriorating condition of the patient. A multidisciplinary approach and family conference to solve the dilemma resulted in a successful outcome.

Tocilizumab or glucocorticoids treatment for patients with SARS-CoV-2 pneumonia: An observational study

Abstract Objective To estimate the effect of tocilizumab or glucocorticoids in preventing death and intubation in patients hospitalized with SARS-CoV-2 pneumonia. Methods This was a retrospective cohort study enrolling all consecutive patients hospitalized at Reggio Emilia AUSL between February the 11th and April 14th 2020 for severe COVID-19 and treated with tocilizumab or glucocorticoids (at least 80 mg/day of methylprednisolone or equivalent for at least 3 days). The primary outcome was death within 30 days from the start of the considered therapies. The secondary outcome was a composite outcome of death and/or intubation. All patients have been followed-up until May 19th 2020, with a follow-up of at least 30 days for every patient. To reduce confounding due to potential non-comparability of the two groups, those receiving tocilizumab and those receiving glucocorticoids, a propensity score was calculated as the inverse probability weighting of receiving treatment conditional on the baseline covariates. Results and conclusion Therapy with tocilizumab alone was associated with a reduction of deaths (OR 0.49, 95% CI 0.21-1.17) and of the composite outcome death/intubation (OR 0.35, 95% CI 0.13-0.90) compared to glucocorticoids alone. Nevertheless, this result should be cautiously interpreted due to a potential prescription bias.

Clinical and ultrasonic remission of rheumatoid arthritis after being treated uith tocilizumab for three months / 中华风湿病学杂志

Objective:To observe the changes of relevant clinical indicators and ultrasound pre-sentations in rheumatoid arthritis (RA) patients after being treated with tocilizumab for 3 months and explore the efficacy and safety of tocilizumab in the treatment of RA.Methods:Clinical data, laboratory and ultrasound examinations and medications of RA patients who met inclusion criteria in our hospital from Jan-uary 2017 to September 2020 were included and their data were analyzed retrospectively, and the efficacy and safety of tocilizumab and the ultrasound assessment of disease remission were analyzed. Paired sample t test, Wilcoxon signed-rank test, χ2 test or Fisher's exact probability test were used for comparative analysis. Results:① Compared with baseline data, morning stiffness duration of patients treated with tocilizumab for 3 months [60(30, 120) min vs 0(0, 10) min, Z=-6.19, P<0.001], disease activity score of 28 joints-erythrocyte sedimentation rate (DAS28-ESR) [(4.6±1.5) vs (3.2±1.2), t=6.83, P<0.001], disease activity score of 28 joints-C-reactive protein (DAS28-CRP) [(4.2±1.4) vs (2.8±1.1), t=7.14, P<0.001], swollen joint count (SJC) [2(1, 7) vs 0(0, 2), Z=-4.31, P<0.001], tender joints count (TJC) [6(2, 13.5) vs 2(0,4), Z=-5.16, P<0.001], gray scale score (GS) [4.5(2, 6) vs 1(0, 3), Z=-5.86, P<0.001], intra-synovial blood flow energy Doppler (PD) [2(1, 3) vs 0(0, 0), Z=-5.38, P<0.001], white blood cell (WBC) [6.6(4.9, 8.4)×10 9/L vs 5.7(4.9, 7.3)×10 9/L, Z=-2.83, P=0.005], hemoglobin (Hb) [119(104, 131) g/L vs 123(113, 136) g/L, Z=-2.82, P=0.007], ESR [32(14.5, 50) mm/1 h vs 19 (10, 30) mm/1 h, Z=-3.31, P=0.001], CRP [11.40(3.02, 25.80) mg/L vs 3.49(1.30, 11.82) mg/L, Z=-2.78, P=0.004], D-dimer (D-D) [0.93(0.47, 2.07) mg/L vs 0.43(0.21, 0.80) mg/L, Z=-3.77, P<0.001] were significantly improved, and the difference was statistically significant. ② The serum levels of interleukin (IL)-2 [2.08(1.43, 2.76) pg/ml vs 1.21(0.54, 2.08) pg/ml, Z=-2.67, P=0.008], IL-6 [22.40(5.13, 67.27) pg/ml vs 14.63(5.27, 27.71) pg/ml, Z=-2.81, P=0.005], IL-10 [(2.53±0.68) pg/ml vs (1.74±0.74) pg/ml, t=2.60, P=0.017] were significantly changed, while serum levels of IL-4 [1.63(1.08, 3.38) pg/ml vs 1.33(0.97, 2.59) pg/ml, Z=-0.89, P=0.374], tumor necrosis factor (TNF) -α [4.04(1.41, 10.45) pg/ml vs 1.62(0.84, 3.79) pg/ml, Z=-1.92, P=0.056], IL-17 [4.68(1.67, 6.72) pg/ml vs 3.15(1.81, 5.29) pg/ml, Z=-0.53, P=0.594] were not significantly changed from baseline data. ③ There was poor consistency between ultrasonic response and DAS28-ESR response, simplified disease activity Index (SDAI) response and clinical disease activity index (CDAI) response ( Kappa coefficient: 0.142, 0.142, 0.191), but no consistency between ultrasonic response and DAS28-CRP response (Kappa coefficient: -0.015) were found. Receiver operating characteristic (ROC) curve showed that ultrasound was not statistically significantly different in assessing the remission of RA, indicating subclinical synovitis remained in ultrasound examination even though clinically remission could be reached based on the above scoring indexes in RA patients. ④ In terms of adverse reactions, neutrophils (NEU) of patients after 3 months' tocilizumab treatment [4.47(2.77, 5.39)×10 9/L vs 3.76(2.98, 4.74)×10 9/L, Z=-2.77, P=0.006], platelet count (PLT) [(291±84)×10 9/L vs (254±70)×10 9/L, t=4.76, P<0.001] were significantly decreased, high-density lipoprotein-cholesterol (HDL-C) [(1.22±0.27) mmol/L vs (1.39±0.34) mmol/L, t=3.12, P=0.003], low density lipoprotein-cholesterol (LDL-C) [(1.96±0.66) mmol/L vs (2.19±0.84) mmol/L, t=3.15, P=0.003], triglyceride (TG) [0.85(0.68, 1.08) mmol/L vs 0.93(0.71, 1.25) mmol/L, Z=-2.36, P=0.018] and total cholesterol (TC) [(4.18±1.04) mmol/L vs (4.52±1.16) mmol/L, t=3.33, P=0.002] were significantly different from baseline. Among 65 patients, 5 patients (7.7%) had transaminase abnormality, but returned to normal after symptomatic treatment. Conclusion:Tocilizumab treatment can effectively suppress the inflammatory reactions, improve the clinical symptoms and prognosis of patients, however, patients who judged as clinical remission according to the current clinical commonly scores may still have subclinical active disease, ultrasound results should be included as one criteria for disease remission assessment and take into consideration when adjusting treatrnent.

Research progress of novel drug therapy for antibody-mediated rejection in kidney transplantation / 中华泌尿外科杂志

Antibody-mediated rejection (AMR) is the primary factor affecting the long-term prognosis of kidney transplant recipients and kidney allograft. Currently, there is no universally recognized or approved drug for the treatment of AMR. Therefore, more novel drug studies and clinical trials are urgently needed in order to change the long-term prognosis of kidney transplant recipients. Based on the core principles of prevention and treatment of AMR, this paper discusses the mechanism and efficacy of several new types of drugs of most concern in the treatment of AMR from three aspects: removing donor specific antibody, blocking antibody-mediated and complement-mediated tissue damage, and inhibiting the proliferation and activation of antibody-producing cells. These emerging drugs have shown potential in preventing and treating AMR and improving the prognosis of recipients, which is expected to change the dilemma of AMR treatment in the future and provide more effective treatment options for improving the long-term prognosis of kidney transplant recipients.

A case of febrile infection-related epilepsy syndrome in children successfully treated with tocilizumab and literature review / 中华神经科杂志

Objective:To report a case of tocilizumab successfully used in a child with febrile infection-associated epilepsy syndrome (FIRES), and to provide a new idea for the treatment of FIRES in children.Methods:The diagnosis and treatment of 1 case of FIRES admitted in Children′s Hospital Affiliated to Zhengzhou University on February 15, 2021 were described, and the prognosis and follow-up of the child were evaluated. At the same time, the literatures on tocilizumab in the treatment of children′s FIRES were reviewed.Results:A 5-year-old case of FIRES was reported. The child was extremely refractory to immunotherapy and anti-seizure medicines, anesthetics and ketogenic diet. So he was treated with tocilizumab (each time 4 mg/kg) at the 36th day and 43rd day, and epileptic seizures were controlled 10 days after the 2nd doses of tocilizumab. During a follow-up of 10 months, his epileptic seizures were controlled and the cognitive behavior and speech function were well recovered. At present, only 3 cases of FIRES in children have been reported all over the world. All the seizures were well controlled and no obvious adverse reactions were observed.Conclusions:FIRES is a rare refractory epilepsy syndrome, resistant to many kinds of anti-seizure medicines or even anesthetic agents, which is difficult to treat and has poor prognosis. Preliminary trials have shown that tocilizumab is effective and well tolerated in children with FIRES. It may be a potential therapeutic modality for children with FIRES.