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3.
Int J Colorectal Dis ; 36(10): 2081-2092, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34467414

RESUMO

BACKGROUND: The effect of preoperative vedolizumab (VDZ) therapy on postoperative complications in inflammatory bowel disease (IBD) patients is still controversial. This meta-analysis aims to review postoperative complications of IBD patients who preoperatively received VDZ. METHODS: A meta-analysis of the available literature was performed. Studies of IBD patients who received VDZ and non-VDZ therapy (including anti-TNF-α agents, non-biological therapy, other biological agents, ustekinumab, and placebo) before surgery were included. Primary outcomes included overall complications, infectious complications, and non-infectious complications. RESULTS: Twelve studies with 1925 IBD patients were enrolled, among which 709 patients received VDZ treatment. The results show that, compared with non-VDZ treatment, there is no significant difference in the incidence of overall complications (OR = 1.25, p = 0.43) for adult IBD patients treated with VDZ preoperatively, the incidence of infectious complications (OR = 0.49, p = 0.001) decreases, but the risks of all surgical site infection (SSI) (Crohn's disease (CD): OR = 2.97, p < 0.001), superficial surgical site infection (sSSI) (OR = 2.24, p = 0.02), and ileus (OR = 2.16, p < 0.001) increase. The risk of mucocutaneous separation (MCS) (OR = 4.69, p = 0.03) with VDZ is also higher than non-VDZ. Two studies involved pediatric patients and showed no difference in ileus (OR = 0.55, p = 0.55). CONCLUSIONS: Overall, compared with non-VDZ treatment, preoperative use of VDZ is relatively safer in adult IBD patients, which does not increase the risk of overall postoperative complications and reduces the occurrence of infectious complications. But, it increases the risk of all SSI and sSSI in infectious complications and the incidence of ileus and MCS in non-infectious complications. Due to lack of sufficient data, the safety of VDZ in pediatric patients is uncertain and requires further study.


Assuntos
Doenças Inflamatórias Intestinais , Inibidores do Fator de Necrose Tumoral , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Criança , Fármacos Gastrointestinais/efeitos adversos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos
4.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360781

RESUMO

To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8+ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3+ T cells before the second cycle of treatment. The percentage of CD8+ effector memory (CD8+CD45RA-CD45RO+CCR7-) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4+ (CD4+CD38+HLADR+) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Inibidores de Checkpoint Imunológico/administração & dosagem , Melanoma , Nivolumabe/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Citometria de Fluxo , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Memória Imunológica/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/imunologia
5.
N Engl J Med ; 385(8): 683-694, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34407342

RESUMO

BACKGROUND: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence. METHODS: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred. CONCLUSIONS: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nefrectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida
6.
Drug Saf ; 44(9): 987-998, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34374967

RESUMO

INTRODUCTION: The safety profile of remdesivir, conditionally approved for COVID-19, was limited at its 2020 introduction. Adverse drug reactions (ADRs) for medicines are collected in VigiBase, the WHO Global Database of Individual Case Safety Reports (ICSRs). OBJECTIVE: This study aimed to provide a descriptive analysis of COVID-19 ICSR data focusing on remdesivir, including a disproportionality analysis (DA) of ADRs. METHODS: A dedicated algorithm enabled retrieval of all COVID-19 treatment-specific ICSRs. A severity algorithm based on co-reported medicines and symptoms enabled selection of tocilizumab with its well established safety profile as comparator for remdesivir. Descriptive statistics were used for general ICSR demographics for all COVID-19-specific medicines, remdesivir and tocilizumab individually and furthermore to present treatment patterns of medicines co-reported with remdesivir. A COVID-19 indication-focused DA was deployed to minimize confounding from underlying polysymptomatic disease. RESULTS: 14,574 COVID-19-related ICSRs were entered into VigiBase during 2020. Remdesivir was the most common medicine reported. Of 4944 remdesivir ICSRs, where tocilizumab was not co-reported, 93% described remdesivir as the sole suspect medicine. Sixty percent of ICSRs concerned males, median age was 63 years and the majority originated from the Americas (72%). In 1089 (21%) of remdesivir ICSRs, data indicated severe/critical disease. Co-reported medicines peaked during the first 3 days of remdesivir treatment. The DA for the established tocilizumab and the new remdesivir were mainly in line with the safety profiles for both medicines but suggested new safety concerns. The most reported ADRs for remdesivir represented liver dysfunction, kidney injury, death and bradycardia. CONCLUSION: Global COVID-19-related ADR reporting proved useful in providing information on ADRs as well as on treatment patterns in this patient group. Indication-focused disproportionality analysis, together with the use of a comparator with a known safety profile, proved effective in identifying known safety information and suggested new safety concerns for remdesivir.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Alanina/análogos & derivados , Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Alanina/efeitos adversos , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antivirais/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores Sexuais , Fatores Socioeconômicos , Organização Mundial da Saúde , Adulto Jovem
7.
Eur Cytokine Netw ; 32(1): 8-14, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34346869

RESUMO

Cytokine release syndrome is a serious complication of the new coronavirus infection (COVID-19). The aim of the study was to assess effectiveness and safety of the IL-17 antagonist nekatimab for its treatment. The retrospective study included COVID-19 patients with C-reactive protein levels >60 mg/L. Patients received either netakimab (group NET), IL-6 antagonist tocilizumab (group TOC) or no anti-cytokine treatment (group CON). Forty-four patients were enrolled in the NET group, 27 patients in the TOC group, and 47 patients in the CON group. Mortality was lower in the NET group than in TOC and CON groups (2.3% vs. 14.8% and 31.9%; p = 0.018 and p < 0.001). NET group patients required intensive care unit admission (6.8% vs. 25.9% and 46.3%; p = 0.025 and p < 0.001) and mechanical ventilation (4.6% vs. 22.2% and 31.9%; p = 0.022 and p = 0.002) less frequently than patients of the TOC and CON groups. After 7-10 days of anti-cytokine drug administration, a reduction in lung lesion volume (p = 0.016) and an increase in the proportion of patients who did not need oxygen support (p = 0.005) or stayed in prone position (p = 0.044) was observed in the NET group only group; C-reactive protein levels were the same in the TOC and NET groups (p = 0.136) and lower in the CON group (p < 0.001 and p = 0.005). IL-6 levels decreased in the NET group (p = 0.005) and did not change in the TOC group (p = 0.953). There was no difference in the incidence of side effects between groups. The IL-17 antagonist netakimab is effective and safe in the treatment of cytokine release syndrome in COVID-19.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , COVID-19/tratamento farmacológico , Interleucina-17/antagonistas & inibidores , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Proteína C-Reativa/metabolismo , COVID-19/sangue , COVID-19/virologia , Estudos de Casos e Controles , Humanos , Interleucina-17/metabolismo , Interleucina-6/sangue , Pulmão/patologia , Pulmão/virologia , SARS-CoV-2/fisiologia , Resultado do Tratamento
8.
Cochrane Database Syst Rev ; 7: CD012997, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34219224

RESUMO

BACKGROUND: Haemolytic uraemic syndrome (HUS) is a common cause of acquired kidney failure in children and rarely in adults. The most important risk factor for development of HUS is a gastrointestinal infection by Shiga toxin-producing Escherichia coli (STEC). This review addressed the interventions aimed at secondary prevention of HUS in patients with diarrhoea who were infected with a bacteria that increase the risk of HUS. OBJECTIVES: Our objective was to evaluate evidence regarding secondary preventative strategies for HUS associated with STEC infections. In doing so, we sought to assess the effectiveness and safety of interventions as well as their potential to impact the morbidity and death associated with this condition. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 November 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Studies were considered based on the methods, participants, and research goals. Only randomised controlled trials were considered eligible for inclusion. The participants of the studies were paediatric and adult patients with diarrhoeal illnesses due to STEC. The primary outcome of interest was incidence of HUS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified four studies (536 participants) for inclusion that investigated four different interventions including antibiotics (trimethoprim-sulfamethoxazole), anti-Shiga toxin antibody-containing bovine colostrum, Shiga toxin binding agent (Synsorb Pk: a silicon dioxide-based agent), and a monoclonal antibody against Shiga toxin (urtoxazumab). The overall risk of bias was unclear for selection, performance and detection bias and low for attrition, reporting and other sources of bias. It was uncertain if trimethoprim-sulfamethoxazole reduced the incidence of HUS compared to no treatment (47 participants: RR 0.57, 95% CI 0.11-2.81, very low certainty evidence). Adverse events relative to this review, need for acute dialysis, neurological complication and death were not reported. There were no incidences of HUS in either the bovine colostrum group or the placebo group. It was uncertain if bovine colostrum caused more adverse events (27 participants: RR 0.92, 95% CI 0.42 to 2.03; very low certainty evidence). The need for acute dialysis, neurological complications or death were not reported. It is uncertain whether Synsorb Pk reduces the incidence of HUS compared to placebo (353 participants: RR 0.93, 95% CI 0.39 to 2.22; very low certainty evidence). Adverse events relevant to this review, need for acute dialysis, neurological complications or death were not reported. One study compared two doses of urtoxazumab (3.0 mg/kg and 1.0 mg/kg) to placebo. It is uncertain if either 3.0 mg/kg urtoxazumab (71 participants: RR 0.34, 95% CI 0.01 to 8.14) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) reduced the incidence of HUS compared to placebo (very low certainty evidence). Low certainty evidence showed there may be little or no difference in the number of treatment-emergent adverse events with either 3.0 mg/kg urtoxazumab (71 participants: RR 1.00, 95% CI 0.84 to 1.18) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) compared to placebo. There were 25 serious adverse events reported in 18 patients: 10 in the placebo group, and 9 and 6 serious adverse events in the 1.0 mg/kg and 3.0 mg/kg urtoxazumab groups, respectively. It is unclear how many patients experienced these adverse events in each group, and how many patients experienced more than one event. It is uncertain if either dose of urtoxazumab increased the risk of neurological complications or death (very low certainty evidence). Need for acute dialysis was not reported. AUTHORS' CONCLUSIONS: The included studies assessed antibiotics, bovine milk, and Shiga toxin inhibitor (Synsorb Pk) and monoclonal antibodies (Urtoxazumab) against Shiga toxin for secondary prevention of HUS in patients with diarrhoea due to STEC. However, no firm conclusions about the efficacy of these interventions can be drawn given the small number of included studies and the small sample sizes of those included studies. Additional studies, including larger multicentre studies, are needed to assess the efficacy of interventions to prevent development of HUS in patients with diarrhoea due to STEC infection.


Assuntos
Diarreia/complicações , Infecções por Escherichia coli/terapia , Síndrome Hemolítico-Urêmica/prevenção & controle , Prevenção Secundária/métodos , Escherichia coli Shiga Toxigênica , Adulto , Animais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Viés , Bovinos , Criança , Colostro/imunologia , Diarreia/microbiologia , Diarreia/terapia , Síndrome Hemolítico-Urêmica/epidemiologia , Humanos , Incidência , Compostos de Organossilício/efeitos adversos , Compostos de Organossilício/uso terapêutico , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Trissacarídeos/efeitos adversos , Trissacarídeos/uso terapêutico
9.
Cytokine ; 146: 155627, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34237556

RESUMO

BACKGROUND: One of the main pathophysiological mechanisms underlying the severe course of COVID-19 is the hyper-inflammatory syndrome associated with progressive damage of lung tissue and multi-organ dysfunction. IL-17 has been suggested to be involved in hyper-inflammatory syndrome. OBJECTIVE: To evaluate the efficacy and safety of the IL-17 inhibitor netakimab in patients with severe COVID-19. STUDY DESIGN: In our retrospective case-control study we evaluated the efficacy of netakimab in hospitalized patients with severe COVID-19 outside the intensive care unit (ICU). Patients in the experimental group were treated with standard of care therapy and netakimab at a dose of 120 mg subcutaneously. RESULTS: 171 patients with severe COVID-19 were enrolled in our study, and 88 of them received netakimab. On the 3 day of therapy, body temperature, SpO2/FiO2, NEWS2 score, and CRP improved significantly in the netakimab group compared to the control group. Other clinical outcomes such as transfer to ICU (11.4% vs 9.6%), need for mechanical ventilation (10.2% vs 9.6%), 28-day mortality (10.2% vs 8.4%), did not differ between the groups. CONCLUSION: In hospitalized patients with severe COVID-19, anti-IL-17 therapy might mitigate the inflammatory response and improve oxygenation, but do not affect the need for mechanical ventilation and mortality.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/terapia , Hospitalização/estatística & dados numéricos , Pacientes Internados/estatística & dados numéricos , Interleucina-17/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , COVID-19/complicações , COVID-19/virologia , Estudos de Casos e Controles , Diarreia/induzido quimicamente , Dispneia/induzido quimicamente , Feminino , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-17/imunologia , Interleucina-17/metabolismo , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Respiração Artificial , Estudos Retrospectivos , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Resultado do Tratamento
10.
Front Immunol ; 12: 606056, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220792

RESUMO

Context: Immune-related adverse events frequently take place after initiation of immune checkpoint inhibitors (ICI) therapy. The thyroid gland is the endocrine organ most commonly affected by ICI therapy, the pathological mechanism is still poorly understood. Case Description: A 60-year old Upper Austrian male melanoma patient under pembrolizumab therapy received thyroidectomy because of a suspicious FDG avid thyroid nodule. Histopathology showed a pattern comparable with thyroiditis de Quervain. The inflammatory process consisted predominantly of T lymphocytes with a dominance of CD4+ T helper cells. In addition CD68+ histiocytes co-expressing PD-L1 were observed. Conclusion: Clusters of perifollicular histiocytes expressing PD-L1 were observed in this case of pembrolizumab induced thyroiditis - probably induced by the former ICI therapy. This finding might indicate the initial target for the breakdown of self tolerance. In context with other data the immunological process seems to be driven by CD3+ lymphocytes infiltrating the thyroid.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Histiócitos/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/métodos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Glândula Tireoide/patologia , Tireoidite/diagnóstico , Anticorpos Monoclonais Humanizados/uso terapêutico , Movimento Celular , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Melanoma/complicações , Melanoma/diagnóstico , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/diagnóstico , Glândula Tireoide/imunologia , Tireoidectomia , Tireoidite/etiologia
11.
BMC Neurol ; 21(1): 257, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215196

RESUMO

BACKGROUND: Erenumab, a monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor, is registered for migraine prevention. Compared to other conventional migraine prevention medicines (i.e. topiramate, betablockers and amitriptyline) erenumab has better tolerability. Impaired hemostasis has not been reported previously. Here, we report the first case of an increased tendency to bruise in a migraine patient treated with erenumab. CASE PRESENTATION: A 41-year old female migraine patient was treated with erenumab for 12 months, which led to a significant reduction of headache and migraine days. Three months after treatment start, she experienced increased tendency to bruise leading to extreme ecchymosis after 4 months treatment. Platelet counts and aggregation, thromboelastography, activated partial thromboplastin time (APTT) and international normalized ratio (INR) were all normal. Thorough interview revealed intake of fish oil supplements for many years prior to treatment. The increased tendency to bruise subsided after discontinuation of fish oil supplements. CONCLUSION: The combination of fish oil supplements and erenumab may cause increased tendency to bruise. Erenumab has no effect on the platelets per se but may cause impaired wound healing by suppression of CGRP. Thus, small and unnoticeable bruises may be aggravated instead in patients with tendency to bruise caused by for instance fish oil supplements.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Equimose/induzido quimicamente , Óleos de Peixe , Transtornos de Enxaqueca/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Feminino , Óleos de Peixe/efeitos adversos , Óleos de Peixe/uso terapêutico , Humanos
12.
BMJ Case Rep ; 14(7)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290006

RESUMO

This case report concerns a 63-year-old man affected by metastatic undifferentiated liposarcoma. After receiving pembrolizumab as a second-line treatment in a clinical trial, the patient experienced an immune-mediated myocarditis, myositis and myasteniform syndrome. The last two adverse events showed significant clinical relevance in terms of severity, duration and the required specific treatment.Initial treatment approach consisted in pulses of 1 g of methylprednisolone, followed by 2 mg/kg/day, with clinical improvement. After 12 days, the immune-mediated myasteniform syndrome worsened, with dysphagia, dysphonia, bilateral palpebral ptosis and respiratory difficulty. Due to the refractoriness to glucocorticoid treatment, it was decided to initiate intravenous immunoglobulin at 2 g/kg, followed by 2 mg/kg every 4 weeks once discharged and mycophenolate 500 mg/12 hours, in order to reduce the dose of glucocorticoids.After 2 months, the patient presented an optimal clinical evolution, without muscular weakness and referred to an improvement in dysphagia and speech.


Assuntos
Anticorpos Monoclonais Humanizados , Miosite , Anticorpos Monoclonais Humanizados/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Masculino , Metilprednisolona , Pessoa de Meia-Idade , Miosite/induzido quimicamente
13.
JAMA ; 326(3): 230-239, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34283183

RESUMO

Importance: Effective treatments for patients with severe COVID-19 are needed. Objective: To evaluate the efficacy of canakinumab, an anti-interleukin-1ß antibody, in patients hospitalized with severe COVID-19. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020. Intervention: Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227) or placebo (n = 227). Main Outcomes and Measures: The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations. Results: Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, -3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54; P = .29). COVID-19-related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of -2.3% (95% CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo. Conclusions and Relevance: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29. Trial Registration: ClinicalTrials.gov Identifier: NCT04362813.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Respiração Artificial/estatística & dados numéricos , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Proteína C-Reativa/análise , COVID-19/mortalidade , COVID-19/terapia , Terapia Combinada , Método Duplo-Cego , Feminino , Ferritinas/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hospitalização , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento
14.
Ann Clin Transl Neurol ; 8(8): 1738-1744, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34240579

RESUMO

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , COVID-19/fisiopatologia , Fatores Imunológicos/farmacologia , Interferons/farmacologia , Esclerose Múltipla/tratamento farmacológico , Rituximab/farmacologia , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , COVID-19/epidemiologia , Feminino , França/epidemiologia , Humanos , Fatores Imunológicos/efeitos adversos , Interferons/efeitos adversos , Itália/epidemiologia , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Análise Multivariada , Fatores de Proteção , Estudos Retrospectivos , Fatores de Risco , Rituximab/efeitos adversos , Índice de Gravidade de Doença
16.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281247

RESUMO

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before-after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.


Assuntos
Hiperlipoproteinemia Tipo II/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/análise , LDL-Colesterol/sangue , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/genética , Itália , Lipoproteínas LDL/análise , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , NADPH Oxidase 2/análise , NADPH Oxidase 2/sangue , Pró-Proteína Convertase 9/genética
18.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200673

RESUMO

Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe immune-related (ir) adverse events (AEs). Here, we report the clinical and immune-biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Autoimunidade , Antígenos HLA/imunologia , Miastenia Gravis/patologia , Miosite/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Humanos , Masculino , Miastenia Gravis/induzido quimicamente , Miastenia Gravis/imunologia , Miosite/induzido quimicamente , Miosite/imunologia , Prognóstico
19.
BMJ Case Rep ; 14(7)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266818

RESUMO

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening adverse drug reaction with a mortality rate of 10%. Interstitial nephritis, pneumonitis, myocarditis, meningitis, thyroiditis and pancreatitis are major causes of morbidity and mortality in this syndrome. Cessation of offending medication is paramount. There is paucity in high quality prospective studies guiding the treatment of DRESS, and there are no published therapeutic clinical trials in the treatment of corticosteroid refractory hypersensitivity myocarditis. The authors present a unique case of ciprofloxacin-induced DRESS with concurrent thyroiditis and refractory eosinophilic myocarditis that required mepolizumab and multiple immunosuppressants for successful treatment.


Assuntos
Síndrome de Hipersensibilidade a Medicamentos , Miocardite , Tireoidite , Anticorpos Monoclonais Humanizados/efeitos adversos , Humanos , Miocardite/induzido quimicamente , Miocardite/tratamento farmacológico , Estudos Prospectivos
20.
BMJ Case Rep ; 14(7)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266820

RESUMO

Pembrolizumab is a selective anti-PD-L1 humanised monoclonal antibody approved by the Food and Drug Administration for treating multiple cancers, including cervical cancer, non-small cell lung cancer (NSCLC), renal cell carcinoma, bladder cancer, and squamous head and neck cancer. Pneumonitis is a rare but known complication of pembrolizumab treatment for NSCLC. The median time frame of its appearance is 2.8 months. However, we present a case of pneumonitis appearing within 48 hours. The patient presented with rapidly progressive respiratory failure, and imaging demonstrated diffuse bilateral patchy involvement of the upper lung lobe and pre-hilar regions, which likely indicate pneumonitis. Because of likely grade 3 pneumonitis, he was treated with steroids and showed immediate improvement of symptoms. Repeated CT imaging showed resolution of bilateral patchy infiltrates. He was discharged to the rehabilitation unit. Rapid recognition of pneumonitis as a side effect of pembrolizumab is important because early treatment can help prevent respiratory failure and possible death.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pneumonia/induzido quimicamente
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