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2.
N Engl J Med ; 383(16): 1511-1521, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33053283

RESUMO

BACKGROUND: Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with abatacept, a T-cell costimulation modulator, in patients with rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (DMARDs) are unclear. METHODS: In this 24-week, phase 3, double-blind, controlled trial, we randomly assigned patients in a 1:1 ratio to receive oral upadacitinib (15 mg once daily) or intravenous abatacept, each in combination with stable synthetic DMARDs. The primary end point was the change from baseline in the composite Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP; range, 0 to 9.4, with higher scores indicating more disease activity) at week 12, assessed for noninferiority. Key secondary end points at week 12 were the superiority of upadacitinib over abatacept in the change from baseline in the DAS28-CRP and the percentage of patients having clinical remission according to a DAS28-CRP of less than 2.6. RESULTS: A total of 303 patients received upadacitinib, and 309 patients received abatacept. From baseline DAS28-CRP values of 5.70 in the upadacitinib group and 5.88 in the abatacept group, the mean change at week 12 was -2.52 and -2.00, respectively (difference, -0.52 points; 95% confidence interval [CI], -0.69 to -0.35; P<0.001 for noninferiority; P<0.001 for superiority). The percentage of patients having remission was 30.0% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P<0.001 for superiority). During the treatment period, one death, one nonfatal stroke, and two venous thromboembolic events occurred in the upadacitinib group, and more patients in the upadacitinib group than in the abatacept group had elevated hepatic aminotransferase levels. CONCLUSIONS: In patients with rheumatoid arthritis refractory to biologic DMARDs, upadacitinib was superior to abatacept in the change from baseline in the DAS28-CRP and the achievement of remission at week 12 but was associated with more serious adverse events. Longer and larger trials are required in order to determine the effect and safety of upadacitinib in patients with rheumatoid arthritis. (Funded by AbbVie; SELECT-CHOICE Clinicaltrials.gov number, NCT03086343.).


Assuntos
Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Proteína Coestimuladora de Linfócitos T Induzíveis/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Abatacepte/efeitos adversos , Administração Oral , Antirreumáticos/efeitos adversos , Artrite Reumatoide/sangue , Proteína C-Reativa/análise , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Infusões Intravenosas , Análise de Intenção de Tratamento , Inibidores de Janus Quinases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Indução de Remissão
4.
Front Immunol ; 11: 1844, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903555

RESUMO

With the onset of the global pandemic in 2020 of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), there has been increasing research activity around certain disease-modifying drugs that are used for the management of inflammatory disorders such as rheumatoid arthritis, spondyloarthrosis, psoriatic arthritis, systemic lupus erythematosus, and inflammatory bowel disease for managing coronavirus symptoms. In the conditions mentioned, many people are on long-term treatment with agents including hydroxychloroquine, tumor necrosis factor alpha (TNFα) inhibitor drugs, other biologic agents such as monoclonal antibodies to IL-6 and Janus kinase inhibitors including baricitinib and tofacitinib, which are used to control inflammatory responses in their respective auto-immune condition. There is emerging data that immunomodulatory drugs could be protective at reducing certain features of SARS-CoV-2 and improving recovery. In addition, it is important to understand if subjects being treated with the immunomodulatory agents described have a less severe SARS-CoV-2 infection, as they are deemed some protection from their immunomodulatory treatment, or if they develop infections similar to non-immunocompromised patients. There is a huge unmet clinical need to advise patients responsibly about whether they should remain on their immunomodulatory treatment or not in light of Covid-19 infection. In this article we will discuss potential treatment options for SARS-CoV-2 using immunomodulatory drugs and at what stage of the condition they may be beneficial. Viable treatment options during the global coronavirus pandemic are a much-needed and an intensely active area of research.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Colchicina/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/sangue , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Pessoa de Meia-Idade , Pandemias , Fatores de Risco , Fator de Necrose Tumoral alfa/antagonistas & inibidores
5.
Am J Chin Med ; 48(6): 1263-1277, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907358

RESUMO

In December 2019, a novel coronavirus SARS-CoV-2, causing the disease COVID-19, spread from Wuhan throughout China and has infected people over 200 countries. Thus far, more than 3,400,000 cases and 240,000 deaths have occurred worldwide, and the coronavirus pandemic continues to grip the globe. While numbers of cases in China have been steadying, the number of infections outside China is increasing at a worrying pace. We face an urgent need to control the spread of the COVID-19 epidemic, which is currently expanding to a global pandemic. Efforts have focused on testing antiviral drugs and vaccines, but there is currently no treatment specifically approved. Traditional Chinese medicine (TCM) is grounded in empirical observations and the Chinese people use TCM to overcome these sorts of plagues many times in thousands of years of history. Currently, the Chinese National Health Commission recommended a TCM prescription of Qing-Fei-Pai-Du-Tang (QFPDT) in the latest version of the "Diagnosis and Treatment guidelines of COVID-19" which has been reported to provide reliable effects for COVID-19. While doubts about TCM still exist today, this review paper will describe the rationalities that QFPDT is likely to bring a safe and effective treatment of COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Cloroquina/uso terapêutico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Combinação de Medicamentos , Humanos , Indóis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Lopinavir/uso terapêutico , Medicina Tradicional Chinesa , Pandemias , Pneumonia Viral/imunologia , Ritonavir/uso terapêutico
6.
Front Immunol ; 11: 1648, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754159

RESUMO

Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure. The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19. Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate. In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult). Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease. In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy. Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Cuidados Críticos/métodos , Citocinas/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Corticosteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Tomada de Decisão Clínica/métodos , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Estado Terminal , Células Endoteliais/metabolismo , Feminino , Humanos , Hospedeiro Imunocomprometido , Interleucina-6/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Masculino , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Fatores Sexuais , Trombose
7.
Paediatr Respir Rev ; 35: 81-87, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32792288

RESUMO

The rapid spread of SARS-CoV-2 infection globally coupled with the relatively high case-fatality rate has led to immediate need for therapeutic intervention to prevent and treat COVID-19 disease. There is accumulating evidence that morbidity and mortality in COVID-19 may be exacerbated by a dysregulated host immune response resulting in significant hyperinflammation and cytokine release. The aim of this review is to describe the basis for the immune dysregulation caused by SARS-CoV-2 infection and to examine current investigations into immunomodulatory therapies aimed at targeting the excessive host immune response.


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo Antígeno-Anticorpo/imunologia , Betacoronavirus , Criança , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/fisiopatologia , Síndrome da Liberação de Citocina/terapia , Humanos , Imunização Passiva/métodos , Imunoglobulinas Intravenosas/uso terapêutico , Inflamação/imunologia , Inflamação/fisiopatologia , Inflamação/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Receptores de Interleucina-6/antagonistas & inibidores , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Síndrome de Resposta Inflamatória Sistêmica/terapia
8.
Brasília; s.n; 12 ago. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1117983

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 13 artigos e 10 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Avaliação da Tecnologia Biomédica , Ivermectina/uso terapêutico , Imunoglobulinas/uso terapêutico , Vacina BCG/uso terapêutico , Colchicina/uso terapêutico , Estudos Transversais , Estudos de Coortes , Azitromicina/uso terapêutico , Ritonavir/uso terapêutico , Lopinavir/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Telmisartan/uso terapêutico , Hidroxicloroquina/uso terapêutico
9.
Dermatol Online J ; 26(3)2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32609446

RESUMO

With recent advancements in the understanding of vitiligo pathogenesis, Janus kinase (JAK) inhibitors have emerged as a promising new treatment modality, but their effects remain incompletely elucidated. Tofacitinib, an oral JAK 1/3 inhibitor approved for the treatment of rheumatoid arthritis, has previously been shown to induce significant re-pigmentation in vitiligo. However, as with other novel targeted therapies, cutaneous adverse effects have been observed. We report a 36-year-old woman with a history of rheumatoid arthritis, refractory to multiple pharmacotherapies, who was initiated on tofacitinib and subsequently developed progressive depigmented patches consistent with new-onset vitiligo. Although definitive causation cannot be established in this case without additional studies, it is important to note that many targeted therapies have the potential to induce paradoxical effects, that is, the occurrence or exacerbation of pathologic conditions that have been shown to respond to these medications. Paradoxical findings with other targeted therapies include the occurrence of melanoma during treatment with BRAF inhibitors, keratoacanthomas with PD-1 inhibitors, vitiligo and psoriasis with TNF-alpha inhibitors, and hidradenitis suppurativa with various biologic agents. Although JAK inhibitors hold therapeutic promise in the treatment of inflammatory skin disorders, further research is warranted to more fully comprehend their effects.


Assuntos
Inibidores de Janus Quinases/efeitos adversos , Piperidinas/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Vitiligo/induzido quimicamente , Adulto , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Feminino , Hidradenite Supurativa/induzido quimicamente , Humanos , Inibidores de Janus Quinases/uso terapêutico , Ceratoacantoma/induzido quimicamente , Melanoma/induzido quimicamente , Piperidinas/uso terapêutico , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico
10.
Front Immunol ; 11: 1311, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32676080

RESUMO

Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.


Assuntos
Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Interferon gama/genética , Interleucina-17/genética , Inibidores de Janus Quinases/uso terapêutico , Pneumonia Viral/patologia , Pirazóis/uso terapêutico , Animais , Células Cultivadas , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/sangue , Citocinas/imunologia , Antígeno HLA-DR3/genética , Intestino Delgado/imunologia , Intestino Delgado/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Knockout , Pandemias , Pneumonia Viral/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/imunologia
11.
Front Immunol ; 11: 1439, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655577

RESUMO

In December 2019, following a cluster of pneumonia cases in China caused by a novel coronavirus (CoV), named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infection disseminated worldwide and, on March 11th, 2020, the World Health Organization officially declared the pandemic of the relevant disease named coronavirus disease 2019 (COVID-19). In Europe, Italy was the first country facing a true health policy emergency, and, as at 6.00 p.m. on May 2nd, 2020, there have been more than 209,300 confirmed cases of COVID-19. Due to the increasing number of patients experiencing a severe outcome, global scientific efforts are ongoing to find the most appropriate treatment. The usefulness of specific anti-rheumatic drugs came out as a promising treatment option together with antiviral drugs, anticoagulants, and symptomatic and respiratory support. For this reason, we feel a duty to share our experience and our knowledge on the use of these drugs in the immune-rheumatologic field, providing in this review the rationale for their use in the COVID-19 pandemic.


Assuntos
Betacoronavirus/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Imunidade Adaptativa/efeitos dos fármacos , Adulto , Anticoagulantes/uso terapêutico , Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Hidroxicloroquina/uso terapêutico , Imunidade Inata/efeitos dos fármacos , Interleucina-1/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/etiologia
12.
Cytokine Growth Factor Rev ; 54: 51-62, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32636055

RESUMO

Ruxolitinib is the first approved JAK1 and JAK2 inhibitor, and is known to interfere with the JAK / STAT signaling pathway, one of the critical cellular signaling pathways involved in the inflammatory response. This review presents an overview of SARS-CoV-2 and the COVID-19 pandemic, and then focuses on the potential efficacy of ruxolitinib in this infection. The potential targets of ruxolitinib were determined by using genetic alterations that have been reported in COVID-19 patients. The potential effectiveness of ruxolitinib is suggested by evaluating the interactions of these potential targets with ruxolitinib or JAK/STAT pathway.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pirazóis/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Humanos , Pandemias , Pneumonia Viral/patologia , Fatores de Risco , Fatores de Transcrição STAT/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
13.
Rheumatol Int ; 40(9): 1353-1360, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32654078

RESUMO

As of June 10th 2020 about 7.2 million individuals have tested positive for, and more than 410,000 have died due to COVID-19. In this review we outline the pathophysiology that underpins the potential use of anti-rheumatic therapies for severe COVID-19 infection and summarize the current evidence regarding the risk and outcome of COVID-19 in patients with systemic autoimmune diseases. Thus far there is no convincing evidence that any disease-modifying anti-rheumatic drug (conventional synthetic, biologic or targeted synthetic) including hydroxychloroquine, may protect against severe COVID-19 infection; answers about their possible usefulness in the management of the cytokine storm associated with severe COVID-9 infection will only arise from ongoing randomized controlled trials. Evidence on COVID-19 risk and outcome in patients with systemic autoimmune diseases is extremely limited; thus, any conclusions would be unsafe and should be seen with great caution. At present, the risk and severity (hospitalization, intensive care unit admission and death) of COVID-19 infection in people with autoimmune diseases do not appear particularly dissimilar to the general population, with the possible exception of hospitalization in patients exposed to high glucocorticoid doses. At this stage it is impossible to draw any conclusions for differences in COVID-19 risk and outcome between different autoimmune diseases and between the various immunomodulatory therapies used for them. More research in the field is obviously required, including as a minimum careful and systematic epidemiology and appropriately controlled clinical trials.


Assuntos
Antirreumáticos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Betacoronavirus , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Humanos , Inibidores de Janus Quinases/uso terapêutico , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Fatores de Risco , Índice de Gravidade de Doença , Inibidores do Fator de Necrose Tumoral/uso terapêutico
14.
Lancet ; 396(10244): 110-120, 2020 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-32653055

RESUMO

BACKGROUND: Vitiligo is a chronic autoimmune disease resulting in skin depigmentation and reduced quality of life. There is no approved treatment for vitiligo repigmentation and current off-label therapies have limited efficacy, emphasising the need for improved treatment options. We investigated the therapeutic potential of ruxolitinib cream in patients with vitiligo and report the efficacy and safety results up to 52 weeks of double-blind treatment. METHODS: We did a multicentre, randomised, double-blind, phase 2 study for adult patients with vitiligo in 26 US hospitals and medical centres in 18 states. Patients with depigmentation of 0·5% or more of their facial body surface area (BSA) and 3% or more of their non-facial BSA were randomly assigned (1:1:1:1:1) by use of an interactive response technology system to receive ruxolitinib cream (1·5% twice daily, 1·5% once daily, 0·5% once daily, or 0·15% once daily) or vehicle (control group) twice daily on lesions constituting 20% or less of their total BSA for 24 weeks. Patients in the control group in addition to patients in the 0·15% once daily group who did not show a 25% or higher improvement from baseline in facial Vitiligo Area Scoring Index (F-VASI) at week 24 were re-randomised to one of three higher ruxolitinib cream doses (0·5% once daily, 1·5% once daily, 1·5% twice daily). Patients in the 0·5% once daily, 1·5% once daily, or 1·5% twice daily groups remained at their original dose up to week 52. Patients, investigators, and the study sponsor (except members of the interim analysis and primary endpoint analysis data monitoring teams) remained masked to treatment assignment throughout the study. The primary endpoint was the proportion of patients achieving a 50% or higher improvement from baseline in F-VASI (F-VASI50) at week 24, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03099304. FINDINGS: Between June 7, 2017, and March 21, 2018, 205 patients were screened for eligibility, 48 were excluded and 157 patients (mean age, 48·3 years [SD 12·9]; 73 [46%] male and 84 [54%] female) were randomly assigned to either an intervention group or the control group. 32 (20%) of 157 were assigned to the control group, 31 (20%) to the 0·15% once daily group, 31 (20%) to the 0·5% once daily group, 30 (19%) to the 1·5% once daily group, and 33 (21%) to the 1·5% twice daily group. F-VASI50 at week 24 was reached by significantly more patients given ruxolitinib cream at 1·5% twice daily (15 [45%] of 33) and 1·5% once daily (15 [50%] of 30) than were treated with vehicle (one [3%] of 32). Four patients had serious treatment-emergent adverse events (one patient in the 1·5% twice daily group developed subdural haematoma; one patient in the 1·5% once daily group had a seizure; one patient in the 0·5% once daily group had coronary artery occlusion; and one patient in the 0·5% once daily group had oesophageal achalasia), all of which were unrelated to study treatment. Application site pruritus was the most common treatment-related adverse event among patients given ruxolitinib cream (one [3%] of 33 in the 1·5% twice daily group; three [10%] of 30 in the 1·5% once daily group; three [10%] of 31 in the 0·5% once daily group; and six [19%] of 31 in the 0·15% once daily group)with three [9%] of 32 patients showing application site pruritis in the control group. Acne was noted as a treatment-related adverse event in 13 (10%) of 125 patients who received ruxolitinib cream and one (3%) of 32 patients who received vehicle cream. All treatment-related adverse events were mild or moderate in severity and similar across treatment groups. INTERPRETATION: Treatment with ruxolitinib cream was associated with substantial repigmentation of vitiligo lesions up to 52 weeks of treatment, and all doses were well tolerated. These data suggest that ruxolitinib cream might be an effective treatment option for patients with vitiligo. FUNDING: Incyte.


Assuntos
Inibidores de Janus Quinases/uso terapêutico , Pirazóis/uso terapêutico , Vitiligo/tratamento farmacológico , Adulto , Estudos de Casos e Controles , Método Duplo-Cego , Feminino , Humanos , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Creme para a Pele/administração & dosagem , Resultado do Tratamento
15.
Ann Rheum Dis ; 79(7): 988-990, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-545713
16.
Ugeskr Laeger ; 182(25)2020 06 15.
Artigo em Dinamarquês | MEDLINE | ID: mdl-32584762

RESUMO

Severely afflicted patients with the COVID-19 may become in need of mechanical ventilation. The cause of acute respiratory failure is a massive hyperinflammation in the lungs, and treatment with glucocorticoids is not recommended by the WHO. A rare haematological disease, the virus-associated haemophagocytic lymphohistiocytosis syndrome (HLS), is associated with high mortality and a similar hyperinflammation syndrome. Janus kinase (JAK) 1/2 inhibitor treatment is highly efficacious in HLS. In this review, we discuss the rationales and perspectives for using JAK1/2 inhibitors in severely afflicted patients with COVID-19 pneumonia.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/virologia , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , Humanos , Pandemias
17.
Ann Rheum Dis ; 79(7): 988-990, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32503857
18.
Biosci Trends ; 14(3): 161-167, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32536632

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a serious public health threat to the whole world, and the number of infected is still rising dramatically at this moment. Several studies have confirmed that cytokine storms play a critical role in causing a case to worsen from mild to severe or critical. The current treatment for cytokine storms is limited, so the international medical community is focusing on a specific and effective remedy. Jaktinib hydrochloride is a broad spectrum JAK inhibitor. It can inhibit cytokine-induced immune activation by multiple mechanisms and also slow viral proliferation by inhibiting AAK1 without causing unacceptable toxicity. Jaktinib hydrochloride has great potential for the treatment of patients with coronavirus disease 2019 (COVID-19).


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia
19.
J Mol Med (Berl) ; 98(6): 789-803, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494931

RESUMO

To date, there is no licensed treatment or approved vaccine to combat the coronavirus disease of 2019 (COVID-19), and the number of new cases and mortality multiplies every day. Therefore, it is essential to develop an effective treatment strategy to control the virus spread and prevent the disease. Here, we summarized the therapeutic approaches that are used to treat this infection. Although it seems that antiviral drugs are effective in improving clinical manifestation, there is no definite treatment protocol. Lymphocytopenia, excessive inflammation, and cytokine storm followed by acute respiratory distress syndrome are still unsolved issues causing the severity of this disease. Therefore, immune response modulation and inflammation management can be considered as an essential step. There is no doubt that more studies are required to clarify immunopathogenesis and immune response; however, new therapeutic approaches including mesenchymal stromal cell and immune cell therapy showed inspiring results.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Corticosteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , Vacina BCG/uso terapêutico , Betacoronavirus/genética , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Humanos , Imunização Passiva/métodos , Imunoterapia Adotiva/métodos , Inibidores de Janus Quinases/uso terapêutico , Transplante de Células-Tronco Mesenquimais/métodos , Nanomedicina/métodos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Inibidores de Serino Proteinase/uso terapêutico
20.
Cardiorenal Med ; 10(5): 277-287, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32599589

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged in Wuhan, Hubei-China, as responsible for the coronavirus disease 2019 (COVID-19) and then spread rapidly worldwide. While most individuals remain asymptomatic or develop only mild symptoms, approximately 5% develop severe forms of COVID-19 characterized by acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) that usually require intensive-care support and often yield a poor prognosis. SUMMARY: The pathophysiology of COVID-19 is far from being completely understood, and the lack of effective treatments leads to a sense of urgency to develop new therapeutic strategies based on pathophysiological assumptions. The exaggerated cytokine release in response to viral infection, a condition known as cytokine release syndrome (CRS) or cytokine storm, is emerging as the mechanism leading to ARDS and MOF in COVID-19, thus endorsing the hypothesis that properly timed anti-inflammatory therapeutic strategies could improve patients' clinical outcomes and prognosis. Key Messages: The objective of this article is to explore and comment on the potential role of the promising immunomodulatory therapies using pharmacological and nonpharmacological approaches to overcome the dysregulated proinflammatory response in COVID-19.


Assuntos
Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/terapia , Pneumonia Viral/terapia , Síndrome do Desconforto Respiratório do Adulto/terapia , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Antagonistas dos Receptores CCR5/uso terapêutico , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Inibidores Enzimáticos/uso terapêutico , Oxigenação por Membrana Extracorpórea , Anticorpos Anti-HIV/uso terapêutico , Hemoperfusão , Humanos , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunomodulação , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Lesão Pulmonar/imunologia , Lesão Pulmonar/terapia , Transplante de Células-Tronco Mesenquimais , Insuficiência de Múltiplos Órgãos , Pandemias , Troca Plasmática , Plasmaferese , Pneumonia Viral/imunologia , Receptores de Interleucina-6/antagonistas & inibidores , Síndrome do Desconforto Respiratório do Adulto/imunologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico
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