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1.
Anticancer Res ; 39(11): 6231-6240, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704852

RESUMO

BACKGROUND/AIM: The present study aimed to prospectively examine the usefulness of interferon-gamma (IFN-γ) release (IGR) as a biomarker in non-small-cell lung cancer patients receiving immune checkpoint inhibitor treatment (ICI-Tx). PATIENTS AND METHODS: IGR was measured using enzyme-linked immunosorbent assay at four time points: within 14 days before ICI-Tx (T1), and 8±3 (T2), 22±7 (T3), and 43±7 (T4) days after ICI-Tx. RESULTS: Twenty-nine patients were divided into three groups based on IFN-γ levels in the IGR-positive control: Group-1 (n=8) with <10 IU/ml at T1, Group-2 (n=12) with a decrease in IFN-γ levels to <10 IU/ml at T3 and/or T4, and Group-3 (n=9) without changes in IFN-γ levels. Early progression and ICI-induced interstitial pneumonitis were frequently observed in Group-1 and Group-2, respectively. Group-3 exhibited more treatment cycles than the other groups. All three groups showed clear differences in clinical outcomes. CONCLUSION: IFN-γ levels could be a biomarker for ICI-Tx.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Interferon gama/metabolismo , Neoplasias Pulmonares/metabolismo , Linfócitos T/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Interferon gama/sangue , Tuberculose Latente/diagnóstico , Tuberculose Latente/etiologia , Tuberculose Latente/metabolismo , Doenças Pulmonares Intersticiais/etiologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Estudos Prospectivos , Linfócitos T/imunologia , Fatores de Tempo
2.
Rinsho Ketsueki ; 60(9): 1199-1204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597844

RESUMO

The treatment of follicular lymphoma (FL) continues to evolve. Those patients who present with minimal symptoms often are observed without therapy until significant progression occurs. When treatment is needed, initial options include single agent rituximab (R, anti-CD20), or various forms of chemoimmunotherapy including either R or the newer anti-CD20 monoclonal antibody obinutuzumab (O), with or without maintenance administration. Recent data suggest that the immunomodulatory agent lenalidomide can also be effective in combination with rituximab in both the upfront and relapsed setting. Patients with recurrent disease are frequently treated with chemoimmunotherapy or phosphoinositol-3-kinase (PI3K) inhibitors. Current information suggests that the most important prognostic feature of FL is the presence or absence of early progression (within 2 years of initial treatment/diagnosis). Ongoing efforts are focused on biomarkers to optimally match treatment to patient populations and further improve clinical outcomes.


Assuntos
Linfoma Folicular/terapia , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD20 , Humanos , Imunoterapia , Lenalidomida/uso terapêutico , Rituximab/uso terapêutico
3.
Drugs Today (Barc) ; 55(9): 575-585, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584574

RESUMO

Patients with metastatic triple-negative breast cancer (mTNBC) that has progressed on first-line therapy have a poor prognosis with limited therapeutic options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate (ADC) that has shown promising efficacy in mTNBC. SG is comprised of SN-38, the active metabolite of irinotecan, conjugated via a hydrolyzable linker to the humanized RS7 antibody targeting trophoblast cell surface antigen 2 (Trop-2), a glycoprotein that is expressed at high levels in many epithelial solid tumors. It has received breakthrough therapy status by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pretreated mTNBC. In this review, we summarize available data regarding the pharmacology, pharmacokinetics, safety and efficacy of SG and describe ongoing and future clinical studies investigating this agent.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antígenos de Neoplasias , Camptotecina/uso terapêutico , Moléculas de Adesão Celular , Feminino , Humanos , Estados Unidos , United States Food and Drug Administration
4.
Drugs Today (Barc) ; 55(9): 587-593, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584575

RESUMO

Generalized pustular psoriasis (GPP) is a severe psoriasis form that can be refractory to several systemic treatments. The role of interleukin (IL)-17/ T-helper 17 (Th17) axis inhibitors in the therapy of GPP is not fully established. The objective of this paper is to summarize the existing information on the efficacy and safety of secukinumab, ixekizumab and brodalumab in GPP. Articles published in the English language and derived from the databases MEDLINE (PubMed), Embase and Scopus were assessed for this study. Although the existing data on the potential therapeutic benefit of these agents in the treatment of GPP are encouraging, further studies are needed so as to provide sufficient evidence for their use in this serious condition.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Interleucina-17 , Psoríase/tratamento farmacológico , Receptores de Interleucina-17/antagonistas & inibidores , Humanos , Imunossupressores
5.
Medicine (Baltimore) ; 98(38): e17262, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31568001

RESUMO

BACKGROUND: This study will systematically investigate the efficacy and safety of the combination of pertuzumab, trastuzumab, and docetaxel (PTD) for treatment of patients with HER2-positive breast cancer (HER2-PBC). METHODS: A comprehensive literature search for this study will consist of 2 parts: electronic database records and gray literature. The electronic database literatures are searched from PubMed, EMBASE, Cochrane Library, Web of Science, Google Scholar, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All databases will be searched from inception up to the present. In addition, gray literatures, such as dissertations, ongoing trials, and so on, will also be searched. Two authors will independently read the records, extract data collection, and evaluate the risk of bias. RevMan V.5.3 software will be applied for statistical analysis. RESULTS: This study will summarize up-to-date evidence of PTD for patients with HER2-PBC via overall survival, complete response, cancer-specific survival, recurrence-free survival, disease-free survival, quality of life, and toxicities. CONCLUSION: This study will provide efficacy and safety of PTD for HER2-PBC.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Docetaxel/uso terapêutico , Genes erbB-2 , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Docetaxel/administração & dosagem , Feminino , Humanos , Trastuzumab/administração & dosagem , Resultado do Tratamento
6.
Internist (Berl) ; 60(10): 1059-1073, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31471629

RESUMO

Large-vessel vasculitis includes giant cell arteritis (GCA) and Takayasu arteritis (TA). GCA can affect persons from the age of 50 years and is more frequent among women. The disease course generally begins with an acute phase, with patients feeling very unwell and experiencing temporal headaches. Rapid diagnosis and treatment are necessary to reduce the risk of blindness. A suspected diagnosis must be confirmed by imaging, histology is optional. Initial treatment comprises oral prednisone. Recent studies have demonstrated inhibition of interleukin­6 with tocilizumab (TCZ) to be highly effective. Alternatively, methotrexate can be administered in a steroid-sparing approach. In contrast, TA onset is generally during childhood or adolescence, and begins with moderate systemic inflammation. The aorta and its main branches are affected. Treatment comprises steroids, disease-modifying antirheumatic drugs, and the tumor necrosis factor inhibitor infliximab or TCZ.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Arterite de Células Gigantes/tratamento farmacológico , Imunossupressores/administração & dosagem , Arterite de Takayasu/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Feminino , Células Gigantes , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Resultado do Tratamento
7.
Internist (Berl) ; 60(10): 1036-1042, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31485714

RESUMO

BACKGROUND: Monoclonal antibodies and fusion proteins were introduced into clinical rheumatology 20 years ago. Nowadays they are an established component of modern internal medical practice. OBJECTIVE: This article gives an overview of the breadth of biologics currently in clinical use. MATERIAL AND METHODS: Evaluation of published approval studies and guideline recommendations, discussion of the immunological principles and targets in the treatment with biologics. RESULTS: Monoclonal antibodies and fusion proteins for influencing cytokine signals, T­cell costimulation and B­cell function are the most important innovations in the treatment of rheumatological diseases. Nowadays they are indispensible for the treatment of moderate and severe disease courses of rheumatoid arthritis, spondylarthropathies and vasculitides. CONCLUSION: Although a cure or permanent freedom from symptoms in rheumatological autoimmune diseases is still not possible, much more favorable disease courses with less long-term limitations can be achieved by the early administration of biologics.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Infliximab/uso terapêutico , Reumatologia , Rituximab/uso terapêutico
8.
Internist (Berl) ; 60(10): 1032-1035, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31486861

RESUMO

Antibodies play an important role in the therapy of patients with hematological tumors and have become an established part of this therapy. By using the example of acute lymphoblastic leukemia (ALL), different antibodies with different mechanisms of action are described. The focus of this review is on the description of a bispecific antibody molecule and an immunoconjugate in the relapse of ALL. Although the antibodies have improved the treatment of patients with ALL, it still holds true that the therapy of patients can only be successfully carried out with a strategy that integrates different, mutually complementary schemes. The improvement of therapy can only be achieved through clinical studies with clearly defined protocols.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Leucemia/terapia , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Anticorpos Biespecíficos/uso terapêutico , Hematologia/tendências , Humanos , Rituximab/uso terapêutico
9.
Nervenarzt ; 90(10): 1055-1066, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31538208

RESUMO

Myasthenia gravis (MG) is an autoimmune disorder caused by antibodies against acetylcholine receptors (AChR) or other structural proteins of the neuromuscular junction. This diminishes cholinergic transmission, thus leading to exercise-induced fatigue and sometimes manifest muscle weakness, including the bulbar and ocular musculature. Whereas ocular MG is as a rule initially symptomatically treated with acetylcholine esterase inhibitors, generalized MG requires long-term immunosuppression. The thymus plays a particular role in the pathophysiology of AChR antibody-positive MG, which can also manifest as a paraneoplastic disorder in the context of a thymoma. This article reviews the basic and advanced treatment options of the different disease subtypes including plasma exchange and immunoglobulins for treatment in a myasthenic crisis. Recently, clinical approval of eculizumab, a complement inhibitor, enriched the pharmacological armamentarium for AChR antibody-positive MG patients not appropriately responding to immunosuppression alone.


Assuntos
Miastenia Gravis , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Imunoglobulinas/uso terapêutico , Imunossupressão , Miastenia Gravis/imunologia , Miastenia Gravis/terapia , Troca Plasmática , Timo/imunologia , Timo/patologia
11.
Lancet ; 394(10206): 1352-1363, 2019 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-31495497

RESUMO

BACKGROUND: No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. METHODS: We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770. FINDINGS: Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo. INTERPRETATION: Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD. FUNDING: MedImmune and Viela Bio.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/complicações , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
12.
Lancet ; 394(10205): 1286-1296, 2019 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-31533907

RESUMO

Over several decades, studies have described the progression of autoimmune diabetes, from the first appearance of autoantibodies until, and after, the diagnosis of clinical disease with hyperglycaemia and insulin dependence. Despite the improved management of type 1 diabetes with exogenous insulin, most patients do not meet clinical glycaemic goals, and diabetes remains an important medical problem that affects children and adults. Clinical and preclinical studies have suggested strategies to prevent the diagnosis of type 1 diabetes in people at risk, but the outcomes of previous clinical trials have not met their primary endpoints of disease prevention or delay. The results from the TN-10 teplizumab prevention trial show that the diagnosis of type 1 diabetes can be delayed by treatment with a FcR non-binding monoclonal antibody to CD3 in people at high risk for disease. This Series paper discusses how this clinical achievement raises new questions about for whom, and when, immunological strategies might be developed to prevent type 1 diabetes, and how to achieve this goal.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Anticorpos Monoclonais Humanizados/uso terapêutico , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/imunologia , Humanos
13.
Acute Med ; 18(3): 197-199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31536059

RESUMO

The advent of immunotherapy in oncology has led to the emergence of a new spectrum of adverse effects. A number of these have the potential to contribute to life-threatening outcomes; and therefore require prompt identification and aggressive treatment to optimise management. In this report, we describe a case of pembrolizumab-induced CTCAE (common toxicity criteria for adverse events) grade 4 myositis in a non-small cell lung cancer patient.


Assuntos
Adenocarcinoma de Pulmão , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Miosite , Adenocarcinoma de Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Miosite/induzido quimicamente
14.
Cancer Immunol Immunother ; 68(9): 1493-1500, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31501955

RESUMO

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.


Assuntos
Imunoterapia/métodos , Melanoma/metabolismo , Ligante OX40/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Ligante OX40/genética , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Sobrevida , Resultado do Tratamento
15.
Cochrane Database Syst Rev ; 8: CD012893, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31476018

RESUMO

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, and immune response modulation is the main treatment strategy to induce remission in active CD. Certolizumab pegol (CZP) is a tumor necrosis factor-alfa (TNF-α) inhibitor which regulates impaired immune response. OBJECTIVES: The primary objectives were to evaluate the efficacy and safety of CZP for the induction of remission in CD. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD group specialized register, trials registers and other sources from inception to 28 January 2019. Moreover, we contacted the pharmaceutical company that manufactures CZP. SELECTION CRITERIA: We included randomized controlled trials comparing CZP with placebo or no treatment in active CD patients. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. The main outcomes selected for GRADE analysis were clinical remission at week 8 (Crohn's Disease Activity Index [CDAI] ≤150), clinical response at week 8 (CDAI reduction ≥ 100 or clinical remission), and serious adverse events. The Mantel-Haenszel random-effects method was applied for the statistical analyses. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI). MAIN RESULTS: Four studies involving 1485 participants with moderate to severe CD met the inclusion criteria and were used in the meta-analyses. All studies included active CD patients with CDAI ranging from 220 to 450. Most patients were adults over 18 years of age. One study was identified as high risk of bias due to a non-identical placebo while the other studies were judged to be at low risk of bias.CZP (100 mg to 400 mg every 2 to 4 weeks) was shown to be superior to placebo for achieving clinical remission at week 8 (RR 1.36, 95% CI 1.11 to 1.66; moderate certainty evidence). The raw numbers of participants achieving clinical remission at week 8 were 26.9% (225/835) and 19.8% (129/650) in the CZP and the placebo groups, respectively.CZP was shown to be superior to placebo for achieving clinical response at week 8 (RR 1.29, 95% CI 1.09 to 1.53; moderate certainty evidence). In raw numbers, clinical response at week 8 was achieved in 40.2% (336/835) and 30.9% (201/650) of participants in the CZP and the placebo groups, respectively.In raw numbers, serious adverse events were observed in 8.7% (73/835) and 6.2% (40/650) of participants in the CZP and the placebo groups, respectively (RR 1.35, 95% CI 0.93 to 1.97; moderate certainty evidence). Serious adverse events included worsening Crohn's disease, infections, and malignancy. AUTHORS' CONCLUSIONS: Moderate certainty evidence suggests that CZP is effective for induction of clinical remission and clinical response in participants with active CD patients. It is uncertain whether the risk of serious adverse events differs between CZP and placebo as the 95% CI includes the possibility of a small decrease or doubling of events. Future studies are needed to evaluate the long-term efficacy and safety of CZP in CD patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Certolizumab Pegol/uso terapêutico , Doença de Crohn/tratamento farmacológico , Humanos , Fatores Imunológicos/uso terapêutico , Quimioterapia de Indução , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão
16.
N Engl J Med ; 381(13): 1215-1226, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31553834

RESUMO

BACKGROUND: Biologic therapies are widely used in patients with ulcerative colitis. Head-to-head trials of these therapies in patients with inflammatory bowel disease are lacking. METHODS: In a phase 3b, double-blind, double-dummy, randomized trial conducted at 245 centers in 34 countries, we compared vedolizumab with adalimumab in adults with moderately to severely active ulcerative colitis to determine whether vedolizumab was superior. Previous exposure to a tumor necrosis factor inhibitor other than adalimumab was allowed in up to 25% of patients. The patients were assigned to receive infusions of 300 mg of vedolizumab on day 1 and at weeks 2, 6, 14, 22, 30, 38, and 46 (plus injections of placebo) or subcutaneous injections of 40 mg of adalimumab, with a total dose of 160 mg at week 1, 80 mg at week 2, and 40 mg every 2 weeks thereafter until week 50 (plus infusions of placebo). Dose escalation was not permitted in either group. The primary outcome was clinical remission at week 52 (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). To control for type I error, efficacy outcomes were analyzed with a hierarchical testing procedure, with the variables in the following order: clinical remission, endoscopic improvement (subscore of 0 to 1 on the Mayo endoscopic component), and corticosteroid-free remission at week 52. RESULTS: A total of 769 patients underwent randomization and received at least one dose of vedolizumab (383 patients) or adalimumab (386 patients). At week 52, clinical remission was observed in a higher percentage of patients in the vedolizumab group than in the adalimumab group (31.3% vs. 22.5%; difference, 8.8 percentage points; 95% confidence interval [CI], 2.5 to 15.0; P = 0.006), as was endoscopic improvement (39.7% vs. 27.7%; difference, 11.9 percentage points; 95% CI, 5.3 to 18.5; P<0.001). Corticosteroid-free clinical remission occurred in 12.6% of the patients in the vedolizumab group and in 21.8% in the adalimumab group (difference, -9.3 percentage points; 95% CI, -18.9 to 0.4). Exposure-adjusted incidence rates of infection were 23.4 and 34.6 events per 100 patient-years with vedolizumab and adalimumab, respectively, and the corresponding rates for serious infection were 1.6 and 2.2 events per 100 patient-years. CONCLUSIONS: In this trial involving patients with moderately to severely active ulcerative colitis, vedolizumab was superior to adalimumab with respect to achievement of clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission. (Funded by Takeda; VARSITY ClinicalTrials.gov number, NCT02497469; EudraCT number, 2015-000939-33.).


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Adalimumab/efeitos adversos , Corticosteroides/uso terapêutico , Adulto , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Indução de Remissão/métodos
17.
Cochrane Database Syst Rev ; 9: CD013210, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513295

RESUMO

BACKGROUND: Crohn's disease (CD) is a chronic disease of the gut. About 75% of people with CD undergo surgery at least once in their lifetime to induce remission. However, as there is no known cure for the disease, patients usually experience a recurrence even after surgery. Different interventions are routinely used in maintaining postsurgical remission. There is currently no consensus on which treatment is the most effective. OBJECTIVES: To assess the effects and harms of interventions for the maintenance of surgically induced remission in Crohn's disease and rank the treatments in order of effectiveness. SEARCH METHODS: We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, and Embase from inception to 15 January 2019. We also searched reference lists of relevant articles, abstracts from major gastroenterology meetings, ClinicalTrials.gov, and the WHO ICTRP. There was no restriction on language, date, or publication status. SELECTION CRITERIA: We considered for inclusion randomised controlled trials (RCTs) that compared different interventions used for maintaining surgically induced remission in people with CD who were in postsurgical remission. Participants had to have received maintenance treatment for at least three months. We excluded studies assessing enteral diet, diet manipulation, herbal medicine, and nutritional supplementation. DATA COLLECTION AND ANALYSIS: Two review authors independently selected relevant studies, extracted data, and assessed the risk of bias. Any disagreements were resolved by discussion or by arbitration of a third review author when necessary. We conducted a network meta-analysis (NMA) using a Bayesian approach through Markov Chain Monte Carlo (MCMC) simulation. For the pairwise comparisons carried out in Review Manager 5, we calculated risk ratios (RR) with their corresponding 95% confidence intervals (95% CI). For the NMA, we presented hazard ratios (HR) with corresponding 95% credible intervals (95% CrI) and reported ranking probabilities for each intervention. For the NMA, we focused on three main outcomes: clinical relapse, endoscopic relapse, and withdrawals due to adverse events. Data were insufficient to assess time to relapse and histologic relapse. Adverse events and serious adverse events were not sufficiently or objectively reported to permit an NMA. We used CINeMA (Confidence in Network Meta-Analysis) methods to evaluate our confidence in the findings within networks, and GRADE for entire networks. MAIN RESULTS: We included 35 RCTs (3249 participants) in the review. The average age of study participants ranged between 33.6 and 38.8 years. Risk of bias was high in 18 studies, low in four studies, and unclear in 13 studies. Of the 35 included RCTs, 26 studies (2581 participants; 9 interventions) were considered eligible for inclusion in the NMA. The interventions studied included 5-aminosalicylic acid (5-ASA), adalimumab, antibiotics, budesonide, infliximab, probiotics, purine analogues, sulfasalazine, and a combination of sulfasalazine and prednisolone. This resulted in 30 direct contrasts, which informed 102 mixed-treatment contrasts.The evidence for the clinical relapse network (21 studies; 2245 participants) and endoscopic relapse (12 studies; 1128 participants) were of low certainty while the evidence for withdrawal due to adverse events (15 studies; 1498 participants) was of very low certainty. This assessment was due to high risk of bias in most of the studies, inconsistency, and imprecision across networks. We mainly judged individual contrasts as of low or very low certainty, except 5-ASA versus placebo, the evidence for which was judged as of moderate certainty.We ranked the treatments based on effectiveness and the certainty of the evidence. For clinical relapse, the five most highly ranked treatments were adalimumab, infliximab, budesonide, 5-ASA, and purine analogues. We found some evidence that adalimumab (HR 0.11, 95% Crl 0.02 to 0.33; low-certainty evidence) and 5-ASA may reduce the probability of clinical relapse compared to placebo (HR 0.69, 95% Crl 0.53 to 0.87; moderate-certainty evidence). However, budesonide may not be effective in preventing clinical relapse (HR 0.66, 95% CrI 0.27 to 1.34; low-certainty evidence). We are less confident about the effectiveness of infliximab (HR 0.36, 95% CrI 0.02 to 1.74; very low-certainty evidence) and purine analogues (HR 0.75, 95% CrI 0.55 to 1.00; low-certainty evidence). It was unclear whether the other interventions reduced the probability of a clinical relapse, as the certainty of the evidence was very low.Due to high risk of bias and limited data across the network, we are uncertain about the effectiveness of interventions for preventing endoscopic relapse. Whilst there might be some evidence of prevention of endoscopic relapse with adalimumab (HR 0.10, 95% CrI 0.01 to 0.32; low-certainty evidence), no other intervention studied appeared to be effective.Due to high risk of bias and limited data across the network, we are uncertain about the effectiveness of interventions for preventing withdrawal due to adverse events. Withdrawal due to adverse events appeared to be least likely with sulfasalazine (HR 1.96, 95% Crl 0.00 to 8.90; very low-certainty evidence) and most likely with antibiotics (HR 53.92, 95% Crl 0.43 to 259.80; very low-certainty evidence). When considering the network as a whole, two adverse events leading to study withdrawal (i.e. pancreatitis and leukopenia) occurred in more than 1% of participants treated with an intervention. Pancreatitis occurred in 2.8% (11/399) of purine analogue participants compared to 0.17% (2/1210) of all other groups studied. Leukopenia occurred in 2.5% (10/399) of purine analogue participants compared to 0.08% (1/1210) of all other groups studied. AUTHORS' CONCLUSIONS: Due to low-certainty evidence in the networks, we are unable to draw conclusions on which treatment is most effective for preventing clinical relapse and endoscopic relapse. Evidence on the safety of the interventions was inconclusive, however cases of pancreatitis and leukopenia from purine analogues were evident in the studies. Larger trials are needed to further understand the effect of the interventions on endoscopic relapse.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Crohn/prevenção & controle , Quimioterapia de Manutenção/métodos , Anti-Inflamatórios não Esteroides/uso terapêutico , Antimetabólitos/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Humanos , Imunossupressores/uso terapêutico , Meta-Análise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Indução de Remissão , Prevenção Secundária
18.
Arerugi ; 68(7): 869-873, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31406083

RESUMO

The two biologic therapies, anti-IgE (omalizumab) and anti-IL-5 antibodies (mepolizumab), are used in the treatment of severe pediatric asthma. We present here a case study of a 13-year-old girl with severe asthma who switched from omalizumab to mepolizumab therapy and achieved good control over her asthma. The patient was diagnosed with asthma at one year of age and presented with poor disease control, even while taking high doses of inhaled corticosteroids (ICS). As such, she was considered to have severe persistent asthma. At 10 years old, she began omalizumab therapy which improved asthma control. However, after two years of this therapy, she manifested frequent acute exacerbations. At 12 years old, she switched to mepolizumab and has since maintained good control of asthma. Additionally, total serum IgE levels and peripheral eosinophil counts decreased. As the underlying mechanisms of omalizumab and mepolizumab therapy are distinct, it is recommended to use either one if the other proves ineffective.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Substituição de Medicamentos , Omalizumab/uso terapêutico , Adolescente , Corticosteroides , Criança , Feminino , Humanos
19.
Cochrane Database Syst Rev ; 8: CD012448, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31425625

RESUMO

BACKGROUND: Kawasaki disease (KD) is an acute inflammatory vasculitis (inflammation of the blood vessels) that mainly affects children between six months and five years of age. The vasculitis primarily impacts medium-sized blood vessels, especially in the coronary arteries. In most children, intravenous immunoglobulin (IVIG) and aspirin therapy rapidly reduce inflammatory markers, fever, and other clinical symptoms. However, approximately 15% to 20% of children receiving the initial IVIG infusion show persistent or recurrent fever and are classified as IVIG-resistant. Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that plays an important role in host defence against infections and in immune responses. Several studies have established that blocking TNF-α is critical for obtaining anti-inflammatory effects in children with KD, thus, there is a need to identify benefits and risks of TNF-α blockers for the treatment of KD. OBJECTIVES: To evaluate the efficacy and safety of using TNF-α blockers (i.e. infliximab and etanercept) to treat children with Kawasaki disease. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 19 September 2018. We also undertook reference checking of grey literature. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared TNF-α blockers (i.e. infliximab and etanercept) to placebo or other drugs (including retreatment with IVIG) in children with KD, reported in abstract or full-text. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the study selection criteria, assessed risk of bias and extracted data. When necessary, we contacted study authors for additional information. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included five trials from 14 reports, with a total of 494 participants. All included trials were individual RCTs that examined the effect of TNF-α blockers for KD.Five trials (with 494 participants) reported the incidence of treatment resistance. TNF-α blockers reduced the incidence of treatment resistance (TNF-α blocker intervention group 30/237, control group 58/257; risk ratio (RR) 0.57, 95% confidence interval (CI) 0.38 to 0.86; low-certainty evidence).Four trials reported the incidence of coronary artery abnormalities (CAAs). Three trials (with 270 participants) contributed data to the meta-analysis, since we could not get the data needed for the analysis from the fourth trial. There was no clear difference between groups in the incidence of CAAs (TNF-α blocker intervention group 8/125, control group 9/145; RR 1.18, 95% CI 0.45 to 3.12; low-certainty evidence).Three trials with 250 participants reported the adverse effect 'infusion reactions' after treatment initiation. The TNF-α blocker intervention decreased infusion reactions (TNF-α blocker intervention group 0/126, control group 15/124; RR 0.06, 95% CI 0.01 to 0.45; low-certainty evidence).Two trials with 227 participants reported the adverse effect 'infections' after treatment initiation. There was no clear difference between groups (TNF-α blocker intervention group 7/114, control group 10/113; RR 0.68, 95% CI 0.33 to 1.37; low-certainty evidence).One trial (with 31 participants) reported the adverse effect 'cutaneous reactions' (rash and contact dermatitis). There was no clear difference between the groups for incidence of rash (TNF-α blocker intervention group 2/16, control group 0/15; RR 4.71, 95% CI 0.24 to 90.69; very low-certainty evidence) or for incidence of contact dermatitis (TNF-α blocker intervention group 1/16, control group 3/15; RR 0.31, 95% CI 0.04 to 2.68; very low-certainty evidence).No trials reported other adverse effects such as injection site reactions, neutropenia, infections, demyelinating disease, heart failure, malignancy, and induction of autoimmunity. AUTHORS' CONCLUSIONS: We found a limited number of RCTs examining the effect of TNF-α blockers for KD. In summary, low-certainty evidence indicates that TNF-α blockers have beneficial effects on treatment resistance and the adverse effect 'infusion reaction' after treatment initiation for KD when compared with no treatment or additional treatment with IVIG. Further research will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution. Further large high quality trials with timing and type of TNF-α blockers used are needed to determine the effects of TNF-α blockers for KD.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Pré-Escolar , Humanos , Fatores Imunológicos , Lactente , Ensaios Clínicos Controlados Aleatórios como Assunto , Vasculite/tratamento farmacológico
20.
Medicine (Baltimore) ; 98(33): e16834, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415404

RESUMO

RATIONALE: Pembrolizumab, an immune-checkpoint inhibitor (ICI), has been shown to be effective for treatment-naive patients with non-small cell lung cancer (NSCLC) and high expression of programmed death-ligand 1 (PD-L1). Therefore, treatment regimens containing pembrolizumab have become a standard therapy for these patients. However, the use of pembrolizumab is limited owing to the side effects of ICIs. PATIENT CONCERNS AND DIAGNOSES: The patient was a 65-year-old man with a left lung mass surrounded by interstitial shadow. The tumor was diagnosed as adenocarcinoma, cT4N3M0, stage IIIC, and the tumor cells showed high PD-L1 expression. It was unclear whether the interstitial shadow was interstitial lung disease (ILD) or lymphangitis carcinomatosa. INTERVENTIONS AND OUTCOMES: The patient received carboplatin and nab-paclitaxel, a less risky regimen for ILD, as the first-line therapy. Administration of 2 cycles of this regimen markedly improved both the tumor diameter and interstitial shadow. The interstitial shadow was clinically diagnosed as lymphangitis carcinomatosa and not ILD. Subsequently, the patient was treated with pembrolizumab, and the tumor showed much further shrinkage with no deterioration of the interstitial shadow. To date, the patient is alive with no complaints and no disease progression, and has continued pembrolizumab treatment for a total of 12 months. LESSONS: In patients at a high risk of ICI-related side effects, platinum-doublet chemotherapy may be permitted as the first-line therapy for NSCLC with high PD-L1 expression. However, if the risk associated with ICIs is resolved, early switching from chemotherapy to pembrolizumab might be desirable, even if the chemotherapy is effective.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Neoplasias Pulmonares/diagnóstico , Linfangite/diagnóstico , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma/tratamento farmacológico , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Linfangite/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Compostos de Platina/uso terapêutico
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