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1.
Lancet Haematol ; 7(6): e456-e468, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32359506

RESUMO

BACKGROUND: The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation. METHODS: In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (ISS), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1·3 mg/m2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m2 administered orally on days 1-4) and prednisone (60 mg/m2 administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m2), stratified by site and ISS disease stage. In centres with a double HSCT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1·3 mg/m2 either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment. FINDINGS: Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60·3 months (IQR 52·2-67·6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56·7 months [95% CI 49·3-64·5] vs 41·9 months [37·5-46·9]; hazard ratio [HR] 0·73, 0·62-0·85; p=0·0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42·1 months (IQR 32·3-49·2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58·9 months [54·0-not estimable] vs 45·5 months [39·5-58·4]; HR 0·77, 0·63-0·95; p=0·014). The most common grade ≥3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]). INTERPRETATION: This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. FUNDING: Janssen and Celgene.


Assuntos
Quimioterapia de Consolidação/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Transplante Autólogo/métodos , Administração Intravenosa , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/epidemiologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Infecções/induzido quimicamente , Infecções/epidemiologia , Injeções Subcutâneas , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Masculino , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Proteínas do Mieloma/análise , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Plasmocitoma/patologia , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia , Transplante Autólogo/mortalidade
2.
PLoS One ; 15(5): e0232102, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437367

RESUMO

Cigarette smoke exposure is a risk factor for many pulmonary diseases, including Chronic Obstructive Pulmonary Disease (COPD). Cigarette smokers are more prone to respiratory infections with more severe symptoms. In those with COPD, viral infections can lead to acute exacerbations resulting in lung function decline and death. Epithelial cells in the lung are the first line of defense against inhaled insults such as tobacco smoke and are the target for many respiratory pathogens. Endocytosis is an essential cell function involved in nutrient uptake, cell signaling, and sensing of the extracellular environment, yet, the effect of cigarette smoke on epithelial cell endocytosis is not known. Here, we report for the first time that cigarette smoke alters the function of several important endocytic pathways in primary human small airway epithelial cells. Cigarette smoke exposure impairs clathrin-mediated endocytosis and fluid phase macropinocytosis while increasing caveolin mediated endocytosis. We also show that influenza virus uptake is enhanced by cigarette smoke exposure. These results support the concept that cigarette smoke-induced dysregulation of endocytosis contributes to lung infection in smokers. Targeting endocytosis pathways to restore normal epithelial cell function may be a new therapeutic approach to reduce respiratory infections in current and former smokers.


Assuntos
Caveolinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Infecções/patologia , Pulmão/citologia , Fumaça/efeitos adversos , Tabaco/química , Regulação para Cima/efeitos dos fármacos , Suscetibilidade a Doenças , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Humanos , Infecções/induzido quimicamente , Infecções/virologia , Tabaco/efeitos adversos
3.
Hematol Oncol ; 38(3): 318-325, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32239673

RESUMO

Infections during first-line therapy for DLBCL are often associated with chemotherapy dose reductions and increased mortality. Systemic infections have also been suggested as beneficial promotors of immunological responses. However, whether there is an association between the timing of an infectious episode and outcome during treatment has not yet been clarified. We investigated how the occurrence and timing of infectious episodes during the first line of treatment for "de novo" DLBCL influenced patient outcome. We used data on DLBCL patients from the Danish Lymphoma Registry, the Danish National Patient Registry, and the Danish National Pathology Registry. Infections were categorized according to type (ICD-10) and time of occurrence after treatment start. "Early" infections were defined as occurring between days 7 and 42 and "late" infections between days 100 and 150 from treatment start. Patients experiencing both "early and late" infections were categorized separately. We used multivariable Cox regression and Kaplan-Meier estimates to assess the association between infections and survival adjusting for NCCN-IPI, sex, comorbidity, and rituximab treatment. We identified 3546 patients, median age 65 years (IQR 56,73). Infectious episodes occurred in 1171 (33%) patients, of which 666 had "early," 303 "late," and 202 both "early and late" events. Patients without registered infections had a 5-year overall survival (OS) rates of 74%. Those with "early," "late," or "early+late" had 5-year OS of 65%, 62%, and 53%, respectively. Compared with patients without any registered infections, hazard rate ratios (HR) were 1.24 (95% CI 1.05-1.47), 1.32 (95% CI 1.06-1.63), and 1.59 (95% CI 1.27-2.00), respectively, in the multivariable model. We observed that infectious episodes during first-line treatment for "de novo" DLBCL occurred in 44% of the patients. Irrespective of timing, patients with infectious episodes had an inferior outcome compared to those without. Outcome patterns were similar for patients registered with sepsis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Infecções/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Infecções/induzido quimicamente , Infecções/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Rituximab/administração & dosagem , Taxa de Sobrevida , Vincristina/administração & dosagem
4.
PLoS One ; 15(3): e0229973, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163477

RESUMO

PURPOSE: To describe patterns of utilization, survival and infectious events in patients treated with rituximab at the University Hospital of Siena (UHS) to explore the feasibility of combining routinely collected administrative and hospital-pharmacy data for examining the real-world use of intravenous antineoplastic drugs. METHODS: A retrospective, longitudinal cohort study was conducted using data from the Hospital Pharmacy of Siena (HPS) and the Regional Administrative Database of Tuscany (RAD). Patients aged ≥18 years with ≥1 rituximab administration recorded between January 2012 and June 2016 were identified in the HPS database. Anonymized patient-level data were linked to RAD. Rituximab utilization during the first year of treatment was described using HPS. Hospital diagnoses of adverse infectious events that occurred during the first year of follow-up and four-year survival were observed using RAD. RESULTS: A total of 311 new users of rituximab were identified: 264 patients received rituximab for non-Hodgkin's lymphoma (NHL) and 47 were treated for chronic lymphocytic leukemia (CLL). Among new users with one complete year of follow-up (n = 203) over 95% received rituximab as the first-line treatment, and approximately 70% of them received 5-8 doses. No patient in the CLL group received >8 administrations. Four-year survival was approximately 70% in both CLL and NHL patients. Sepsis was the most frequent infectious event observed (5.1%). CONCLUSION: HPS and RAD provided complementary information on rituximab utilization, demonstrating their potential for future pharmacoepidemiological studies on antineoplastic medications administered in the Italian hospital setting. Overall, this general description of the real-world utilization of rituximab in patients treated for NHL and CLL at UHS was in line with treatment guidelines and current knowledge on the rituximab safety profile.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Uso de Medicamentos/estatística & dados numéricos , Infecções/epidemiologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/administração & dosagem , Administração Intravenosa , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adolescente , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Infecções/induzido quimicamente , Infecções/imunologia , Itália/epidemiologia , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Estudos Longitudinais , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Serviço de Farmácia Hospitalar/estatística & dados numéricos , Estudos Retrospectivos , Rituximab/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
5.
Ann Rheum Dis ; 79(6): 760-770, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32033941

RESUMO

OBJECTIVES: To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). METHODS: An SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures. RESULTS: Forty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1-3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6-4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors. CONCLUSION: Data obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Infecções/induzido quimicamente , Perfuração Intestinal/induzido quimicamente , Produtos Biológicos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Herpes Zoster/induzido quimicamente , Humanos , Neoplasias/induzido quimicamente , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Medicamentos Sintéticos/efeitos adversos , Tromboembolia Venosa/induzido quimicamente
6.
Ann Rheum Dis ; 79(4): 460-463, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033935

RESUMO

BACKGROUND: In rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes. OBJECTIVES: To determine if inclusion of patients on background GC use influenced efficacy and safety outcomes of RA randomised clinical trials on initiation of tocilizumab (TCZ) or adalimumab (ADA) or methotrexate (MTX) monotherapy. METHODS: Data of four double-blind RA randomised controlled trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with in total four TCZ, one ADA and two MTX monotherapy arms were analysed. Analyses of covariance of changes from baseline to week 24 in efficacy endpoints and radiographic progression up to week 104 were performed, correcting for relevant covariates. Incidence rates of serious adverse events (SAEs) were assessed. RESULTS: No statistically significant differences were found in efficacy parameters between background GC users and non-GC users, except for less radiographic progression associated with GC usage in one MTX arm. SAE rates were not statistically significantly different between GC users and non-GC users in the treatment arms. CONCLUSION: No effect of including patients on background GC treatment on efficacy and safety trial outcomes was found, with the exception of reduced radiological joint damage in one MTX arm.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Glucocorticoides/uso terapêutico , Adalimumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/fisiopatologia , Quimioterapia Combinada , Humanos , Infecções/induzido quimicamente , Metotrexato/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
7.
Gastroenterology ; 158(3): 562-572.e12, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31470005

RESUMO

BACKGROUND & AIMS: Maintenance treatment with vedolizumab, a monoclonal antibody that inhibits the gut-selective α4ß7 integrin, is administered intravenously. Some patients might prefer a subcutaneous formulation of vedolizumab for maintenance treatment. Subcutaneous vedolizumab was investigated as maintenance treatment in patients with moderately to severely active ulcerative colitis. METHODS: We performed a phase 3, double-blind, double-dummy trial at 141 sites in 29 countries from December 18, 2015 through August 21, 2018. Patients with moderately to severely active ulcerative colitis received open-label treatment with intravenous vedolizumab 300 mg at weeks 0 and 2. At week 6, patients with clinical response were randomly assigned maintenance treatment with subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo. The primary end point was clinical remission at week 52, which was defined as a total Mayo score of ≤2 and no subscore >1. RESULTS: Among the randomized 216 patients, clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively (subcutaneous vedolizumab vs placebo: Δ32.3%; 95% confidence interval, 19.7%-45.0%; P < .001). The subcutaneous vedolizumab group also had greater endoscopic improvement and durable clinical response at week 52 compared with placebo (both P < .001). The incidence of injection-site reactions was more frequent in patients given subcutaneous vedolizumab (10.4%) than intravenous vedolizumab (1.9%) or placebo (0%); these were not treatment limiting, most were mild, and none resulted in discontinuation. Subcutaneous and intravenous vedolizumab safety profiles were otherwise similar. CONCLUSIONS: Subcutaneous vedolizumab is effective as maintenance therapy in patients with moderately to severely active ulcerative colitis who had a clinical response to intravenous vedolizumab induction therapy. It has a favorable safety and tolerability profile. ClinicalTrials.gov ID: NCT02611830; EudraCT 2015-000480-14.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Administração Intravenosa , Adulto , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Colite Ulcerativa/diagnóstico por imagem , Colonoscopia , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/imunologia , Fármacos Gastrointestinais/farmacocinética , Humanos , Infecções/induzido quimicamente , Reação no Local da Injeção/etiologia , Injeções Subcutâneas , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Indução de Remissão
8.
Ann Rheum Dis ; 79(2): 285-291, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31672774

RESUMO

OBJECTIVE: To examine whether initiation of interleukin (IL)-17, IL-12/23 or tumour necrosis factor (TNF) inhibitor is associated with an increased risk of serious infection among real-world psoriasis (PsO) or psoriatic arthritis (PsA) patients. METHODS: We assembled a retrospective cohort of commercially insured adults in the USA diagnosed with PsO or PsA between 2015 and 2018. Exposure was dispensation for IL-17 (ixekizumab or secukinumab), IL-12/23 (ustekinumab) or TNF (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab). The outcome was infection requiring hospitalisation after biologic initiation. Incidence rates (IRs) per 100 person-years were computed, and hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models, adjusted for inverse probability of treatment-weighted propensity scores. RESULTS: A total of 11 560 new treatment episodes were included. Overall, 190 serious infections (2% of treatment episodes) were identified in 9264 person-years of follow-up. Class-specific IRs were similar among IL-17 and TNF, yet significantly lower for IL-12/23. After adjustment for propensity scores, there was no increased risk with IL-17 compared with either TNF (HR=0.89, 95% CI 0.48 to 1.66) or IL-12/23 (HR=1.12, 95% CI 0.62 to 2.03). By contrast, IL-23/23 were associated with a lower risk of infections than TNF (HR=0.59, 95% CI 0.39 to 0.90). CONCLUSIONS: Relative to TNF and IL-17, IL-12/23 inhibitors were associated with a reduced risk of serious infection in biologic-naïve patients with PsO or PsA. In biologic-experienced individuals, there was no difference in infection risk across TNF, IL-17 or IL-12/23 inhibitors.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Produtos Biológicos/efeitos adversos , Imunossupressores/efeitos adversos , Infecções/induzido quimicamente , Psoríase/tratamento farmacológico , Adulto , Artrite Psoriásica/imunologia , Produtos Biológicos/imunologia , Feminino , Humanos , Imunossupressores/imunologia , Infecções/imunologia , Interleucina-12/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , Estudos Retrospectivos , Fatores de Risco , Inibidores do Fator de Necrose Tumoral/efeitos adversos
9.
Pediatrics ; 144(6)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31699831

RESUMO

OBJECTIVES: Proton pump inhibitors (PPIs) are often used in pediatrics to treat common gastrointestinal disorders, and there are growing concerns for infectious adverse events. Because CYP2C19 inactivates PPIs, genetic variants that increase CYP2C19 function may decrease PPI exposure and infections. We tested the hypothesis that CYP2C19 metabolizer phenotypes are associated with infection event rates in children exposed to PPIs. METHODS: This retrospective biorepository cohort study included individuals aged 0 to 36 months at the time of PPI exposure. Respiratory tract and gastrointestinal tract infection events were identified by using International Classification of Diseases codes in the year after the first PPI mention. Variants defining CYP2C19 *2, *3, *4, *8, *9, and *17 were genotyped, and all individuals were classified as CYP2C19 poor or intermediate, normal metabolizers (NMs), or rapid or ultrarapid metabolizers (RM/UMs). Infection rates were compared by using univariate and multivariate analyses. RESULTS: In all, 670 individuals were included (median age 7 months; 44% girls). CYP2C19 NMs (n = 267; 40%) had a higher infection rate than RM/UMs (n = 220; 33%; median 2 vs 1 infections per person per year; P = .03). There was no difference between poor or intermediate (n = 183; 27%) and NMs. In multivariable analysis of NMs and RM/UMs adjusting for age, sex, PPI dose, and comorbidities, CYP2C19 metabolizer status remained a significant risk factor for infection events (odds ratio 0.70 [95% confidence interval 0.50-0.97] for RM/UMs versus NMs). CONCLUSIONS: PPI therapy is associated with higher infection rates in children with normal CYP2C19 function than in those with increased CYP2C19 function, highlighting this adverse effect of PPI therapy and the relevance of CYP2C19 genotypes to PPI therapeutic decision-making.


Assuntos
Citocromo P-450 CYP2C19/genética , Infecções/induzido quimicamente , Infecções/genética , Fenótipo , Inibidores da Bomba de Prótons/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Lactente , Infecções/diagnóstico , Masculino , Estudos Retrospectivos , Fatores de Risco
10.
Facial Plast Surg Clin North Am ; 27(4): 565-570, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31587774

RESUMO

This article discusses complications that may occur after procedures on the lips, specifically focusing on injectable fillers. Evidence-based guidelines and suggested methods to manage these complications are presented in a systematic format.


Assuntos
Técnicas Cosméticas/efeitos adversos , Preenchedores Dérmicos/efeitos adversos , Edema/induzido quimicamente , Doenças Labiais/induzido quimicamente , Transtornos da Pigmentação/induzido quimicamente , Equimose/induzido quimicamente , Granuloma de Corpo Estranho/induzido quimicamente , Granuloma de Corpo Estranho/cirurgia , Humanos , Infecções/induzido quimicamente , Lábio , Rejuvenescimento
11.
Ann Rheum Dis ; 78(10): 1305-1319, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31350269

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of the oral Janus kinase (JAK) inhibitor peficitinib versus placebo in Japanese patients with rheumatoid arthritis (RA). METHODS: In this multicentre, double-blind, parallel-group, placebo-controlled phase III study, patients with RA and inadequate response to methotrexate (MTX) were randomised 1:1:1 to placebo, peficitinib 100 mg once daily or peficitinib 150 mg once daily with MTX for 52 weeks. Based on baseline randomisation, at week 12, non-responders receiving placebo were switched to peficitinib until the end of treatment; the remaining patients were switched to peficitinib at week 28. Primary efficacy variables were American College of Rheumatology (ACR)20 response rate at week 12/early termination (ET) and change from baseline in van der Heijde-modified total Sharp score (mTSS) at week 28/ET. RESULTS: 519 patients were randomised and treated. Significantly more (p<0.001) peficitinib (58.6%, 100 mg; 64.4%, 150 mg) than placebo (21.8%) recipients achieved ACR20 response at week 12/ET. Significantly lower (p<0.001) mean changes from baseline in mTSS at week 28/ET occurred in peficitinib (1.62, 100 mg; 1.03, 150 mg) than placebo (3.37) recipients. Peficitinib was associated with haematological and biochemical parameter changes, and increased incidence of serious infections and herpes zoster-related disease. One death from suicide occurred in a patient in the placebo group after switching to peficitinib 100 mg. CONCLUSIONS: In Japanese patients with RA and inadequate response to MTX, peficitinib demonstrated significant superiority versus placebo in reducing RA symptoms and suppressing joint destruction. Peficitinib had an acceptable safety and tolerability profile, with no new safety signals compared with other JAK inhibitors. TRIAL REGISTRATION NUMBER: NCT02305849.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Imunossupressores/administração & dosagem , Inibidores de Janus Quinases/administração & dosagem , Niacinamida/análogos & derivados , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adulto , Idoso , Antirreumáticos/efeitos adversos , Método Duplo-Cego , Substituição de Medicamentos , Feminino , Herpes Zoster/induzido quimicamente , Humanos , Imunossupressores/efeitos adversos , Infecções/induzido quimicamente , Inibidores de Janus Quinases/efeitos adversos , Japão , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Índice de Gravidade de Doença , Resultado do Tratamento
12.
Ann Rheum Dis ; 78(10): 1320-1332, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31350270

RESUMO

OBJECTIVES: To investigate the efficacy and safety of peficitinib, an oral Janus kinase inhibitor, in patients with rheumatoid arthritis (RA). METHODS: In this double-blind phase III study, patients with RA and an inadequate response to prior disease-modifying anti-rheumatic drugs (DMARDs) were randomised to peficitinib 100 mg once daily, peficitinib 150 mg once daily, placebo or open-label etanercept for 52 weeks' treatment; placebo-treated patients were switched at week 12 to peficitinib 100 or 150 mg once daily. The primary endpoint was American College of Rheumatology (ACR)20 response at week 12/early termination (ET). Secondary endpoints (assessed throughout) included ACR20, ACR50 and ACR70 response, changes from baseline in disease activity scores (DAS)28 and ACR core parameters, adverse events (AEs) and changes in clinical or laboratory measurements. RESULTS: In total, 507 patients received treatment. ACR20 response rates at week 12/ET were significantly higher in the peficitinib 100 mg (57.7%) and 150 mg (74.5%) groups versus placebo (30.7%) (p<0.001). ACR50/70 response rates were also higher for both peficitinib doses versus placebo. Improvements in ACR response were maintained until week 52. Changes from baseline in DAS28-C-reactive protein/erythrocyte sedimentation rate and the ACR core set were significantly greater for both peficitinib doses versus placebo at week 12/ET (p<0.001). AE incidence was similar across treatment arms. Incidence of serious infection and herpes zoster-related disease was higher with peficitinib versus placebo, but with no clear dose-dependent increase. CONCLUSIONS: In patients with RA and inadequate response to DMARDs, peficitinib 100 mg once daily or 150 mg once daily was efficacious in reducing RA symptoms and was well tolerated compared with placebo. TRIAL REGISTRATION NUMBER: NCT02308163.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Imunossupressores/administração & dosagem , Inibidores de Janus Quinases/administração & dosagem , Niacinamida/análogos & derivados , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adulto , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/sangue , Sedimentação Sanguínea/efeitos dos fármacos , Proteína C-Reativa/efeitos dos fármacos , Método Duplo-Cego , Substituição de Medicamentos , Feminino , Herpes Zoster/induzido quimicamente , Humanos , Imunossupressores/efeitos adversos , Infecções/induzido quimicamente , Inibidores de Janus Quinases/efeitos adversos , Japão , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Índice de Gravidade de Doença , Resultado do Tratamento
13.
Eur J Cancer Care (Engl) ; 28(5): e13125, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31222826

RESUMO

OBJECTIVE: To examine risk of emergency hospital admission and survival following adjuvant chemotherapy for early breast cancer. METHODS: Linked data from New South Wales population-based and clinical cancer registries (2008-2012), hospital admissions, official death records and pharmaceutical benefit claims. Women aged ≥18 years receiving adjuvant chemotherapy for early-stage operable breast cancer in NSW public hospitals were included. Odds ratios (OR) for emergency hospitalisation within 6 months following chemotherapy initiation were estimated using logistic regression and survival using Kaplan-Meier and Cox proportional hazards methods. RESULTS: A total of 3,950 women were included and 30.6% were hospitalised. The most common principal diagnosis at admission was neutropenia (30.8%). Women receiving docetaxel/carboplatin/trastuzumab (TCH) and docetaxel/cyclophosphamide (TC) were the most frequently hospitalised. After adjustment for demographic and clinical factors, the increased risk of hospitalisation for TCH and TC remained compared with doxorubicin/cyclophosphamide 3-weekly (OR 1.71, 95% confidence interval [CI] 1.24-2.37 and OR 1.47, 95% CI 1.17-1.85 respectively). Five-year overall survival was similar for women who were (92.2%, 95% CI 90.7-93.8) and were not hospitalised (93.1%, 95% CI 92.1-94.1). CONCLUSION: Emergency hospitalisations following chemotherapy for early breast cancer were relatively common, especially following docetaxel-containing protocols. Further examination of reasons for admission is needed to inform actions to improve patient safety.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Febre/epidemiologia , Hospitalização/estatística & dados numéricos , Infecções/epidemiologia , Neutropenia/epidemiologia , Taxa de Sobrevida , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Neutropenia Febril Induzida por Quimioterapia/etiologia , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Docetaxel/administração & dosagem , Emergências , Feminino , Febre/induzido quimicamente , Humanos , Infecções/induzido quimicamente , Estimativa de Kaplan-Meier , Modelos Logísticos , Mastectomia , Mastectomia Segmentar , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , New South Wales/epidemiologia , Razão de Chances , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Trastuzumab/administração & dosagem
14.
CMAJ ; 191(25): E680-E688, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235489

RESUMO

BACKGROUND: Most patients with polymyalgia rheumatica or giant cell arteritis are treated with glucocorticoid therapy in primary care. We estimated dose-response risks of infection for this population in England. METHODS: We conducted a retrospective record-linkage study involving a cohort of people with polymyalgia rheumatica or giant cell arteritis registered in family practices across England (1998-2017). Estimates of first occurring infection per level of time-variant current and cumulative dose were obtained using Kaplan-Meier methods and multilevel proportional-hazards Cox models. RESULTS: Of 39 938 patients attending 389 family practices, 22 234 (55.7%) had at least 1 infection over a median follow-up period of 4.8 years, with 5937 (26.7%) requiring hospital admission and 1616 (7.3%) dying within 7 days of diagnosis. Cumulative risks of all-cause infection were 18.3% (95% confidence interval [CI] 17.9%-18.7%) at 1 year, 54.7% (95% CI 54.1%-55.2%) at 5 years and 76.9% (95% CI 76.2%-77.5%) at 10 years. Lower respiratory tract infections, conjunctivitis and herpes zoster were the most commonly diagnosed infections. The increases in adjusted hazard ratios (HRs) for all-cause infection per 5 mg prednisolone-equivalent daily dose increase and per 1000 mg cumulative dose increase in the last year from the patient's end date of follow-up were 1.13 (95% CI 1.12-1.14) and 1.50 (95% CI 1.49-1.52), respectively. Adjusted HRs associated with periods of current glucocorticoid versus no glucocorticoid use ranged from 1.48 (95% CI 1.39-1.57) for fungal to 1.70 (95% CI 1.60-1.80) for bacterial infection. Stepwise dose-related associations were found for bacterial, viral, parasitic and fungal infections, irrespective of patient age, duration of underlying chronic disease and baseline vaccination status. INTERPRETATION: We quantified the excess risk of all-cause, bacterial, viral, parasitic and fungal infection conferred by oral glucocorticoids in people with polymyalgia rheumatica or giant cell arteritis and found strong dose responses for all types, even at daily doses of less than 5 mg prednisolone.


Assuntos
Arterite de Células Gigantes/tratamento farmacológico , Glucocorticoides/efeitos adversos , Infecções/induzido quimicamente , Polimialgia Reumática/tratamento farmacológico , Prednisolona/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Inglaterra/epidemiologia , Feminino , Glucocorticoides/administração & dosagem , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Infecções/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco
15.
Expert Opin Drug Saf ; 18(8): 733-744, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173698

RESUMO

Objectives: To examine agreement between the FDA Adverse Event Reporting System (FAERS) and observational studies in common infections for tumor necrosis factor inhibitors (TNFi's). Methods: Using MedDRA® preferred terms, all infection cases in FAERS with each TNFi were retrieved using EvidexTM. Observational studies reporting TNFi-related infections were identified from PubMed (OS-PM) and ClinicalTrials.gov (OS-CT). Infections with a reporting rate of ≥2% (based on percentage of total number of infections) from each data source were compiled. Fleiss's kappa and Cohen's kappa (κ) were calculated to determine agreement across all three sources and between each two sources. Results: A total of 163,789 FAERS infection cases, 53 OS-PM studies and 52 OS-CT studies were identified. The Fleiss' kappa that comparing all 3 data sources demonstrated lack of agreement. Significant moderate agreements were found between FAERS and OS-CT for etanercept and adalimumab, respectively (κ = 0.53, p = 0.02; κ = 0.56, p = 0.02), but no agreements (κ < 0) when comparing FAERS vs. OS-PM or OS-CT vs. OS-PM. Conclusion: For common TNFi-related infections, passive (FAERS) and active (observational studies) pharmacovigilance results are similar between FAERS vs. OS-CT for etanercept and adalimumab but dissimilar across the 3 sources. Our findings suggest incorporating both active and passive pharmacovigilance methods in post-marketing drug safety assessment.


Assuntos
Fatores Imunológicos/efeitos adversos , Infecções/epidemiologia , Farmacovigilância , Vigilância de Produtos Comercializados/métodos , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Doenças Autoimunes/tratamento farmacológico , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Humanos , Fatores Imunológicos/administração & dosagem , Infecções/induzido quimicamente , Vigilância de Produtos Comercializados/estatística & dados numéricos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Estados Unidos , United States Food and Drug Administration
16.
Rheumatology (Oxford) ; 58(10): 1755-1766, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30982883

RESUMO

OBJECTIVES: To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors. METHODS: We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach. RESULTS: Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates. CONCLUSION: The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk. SYSTEMATIC REVIEW REGISTRATION NUMBER: Prospero 2017 CRD4201707879.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Herpes Zoster/epidemiologia , Infecções/epidemiologia , Inibidores de Janus Quinases/efeitos adversos , Adulto , Azetidinas/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Herpes Zoster/induzido quimicamente , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Incidência , Infecções/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas/efeitos adversos
17.
Curr Opin Neurol ; 32(3): 305-312, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30985373

RESUMO

PURPOSE OF REVIEW: A variety of high-efficacy disease-modifying therapies (DMTs) are available for the treatment of multiple sclerosis (MS). After evaluation and approval by regulatory agencies, DMTs are likely to be administered to patients whose characteristics differ from those enrolled in clinical trials. This may contribute to the emergence of unexpected adverse events observed in the real-world setting. Higher age may be a relevant factor that could change the benefit-risk balance of DMTs, as it may associate with lower efficiency and higher frequency of adverse events. RECENT FINDINGS: The absolute and relative number of patients with MS who reach the age of 55 and higher increases. Growing evidence demonstrates lower efficacy of DMTs in older persons with MS. Specific risks during DMTs for MS, such as the risk of developing progressive multifocal leukoencephalopathy (PML) or the outcome following PML, have been associated with age. It is hypothesized that age-related and therapy-induced alterations to the immune system may have (super)additive effects, resulting in an acceleration of physiological immunosenescence and inflamm-aging. SUMMARY: In this article, we review the risks of high-efficacy DMTs in MS with a specific focus on age-related efficacy and risks, including opportunistic infections, malignancies, and autoimmune reactions.


Assuntos
Fatores Imunológicos/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Humanos , Fatores Imunológicos/uso terapêutico , Infecções/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Neoplasias/induzido quimicamente , Fatores de Risco
19.
Horm Behav ; 110: 90-97, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30826308

RESUMO

Seasonal changes in day length enhance and suppress immune function in a trait-specific manner. In Siberian hamsters (Phodopus sungorus) winter-like short days (SDs) increase blood leukocyte concentrations and adaptive T cell dependent immune responses, but attenuate innate inflammatory responses to simulated infections. Thyroid hormone (TH) signaling also changes seasonally and has been implicated in modulation of the reproductive axis by day length. Immunologically, TH administration in long days (LD) enhances adaptive immune responses in male Siberian hamsters, mimicking effects of SDs. This experiment tested the hypothesis that T3 is also sufficient to mimic the effects of SD on innate immune responses. Adult male hamsters housed in LDs were pretreated with triiodothyronine (T3; 1 µg, s.c.) or saline (VEH) daily for 6 weeks; additional positive controls were housed in SD and received VEH, after which cytokine, behavioral, and physiological responses to simulated bacterial infection (lipopolysaccharide; LPS) were evaluated. SD pretreatment inhibited proinflammatory cytokine mRNA expression (i.e. interleukin 1ß, nuclear factor kappa-light-chain-enhancer of activated B cells). In addition, the magnitude and persistence of anorexic and cachectic responses to LPS were also lower in SD hamsters, and LPS-induced inhibition of nest building behavior was absent in SD. T3 treatments failed to affect behavioral (food intake, nest building) or somatic (body mass) responses to LPS in LD hamsters, but one CNS cytokine response to LPS (e.g., hypothalamic TNFα) was augmented by T3. Together these data implicate thyroid hormone signaling in select aspects of innate immune responses to seasonal changes in day length.


Assuntos
Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Phodopus , Síndrome de Resposta Inflamatória Sistêmica/patologia , Tri-Iodotironina/farmacologia , Animais , Anorexia/induzido quimicamente , Anorexia/metabolismo , Anorexia/patologia , Peso Corporal/fisiologia , Cricetinae , Modelos Animais de Doenças , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Comportamento de Doença/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Infecções/induzido quimicamente , Infecções/metabolismo , Infecções/patologia , Lipopolissacarídeos , Masculino , Phodopus/metabolismo , Fotoperíodo , Reprodução/efeitos dos fármacos , Estações do Ano , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia
20.
J Crohns Colitis ; 13(9): 1148-1157, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30809631

RESUMO

BACKGROUND AND AIMS: The Observational Postmarketing Ulcerative colitis Study [OPUS] was conducted to obtain the first long-term [5 years] safety data assessing treatment with originator infliximab versus conventional therapies in patients with ulcerative colitis [UC] in real-world clinical practice. METHODS: The OPUS registry was a prospective, non-randomised, observational study that measured adverse events in nine prespecified categories of interest in UC patients whose treatment with either originator infliximab or conventional therapy [defined as initiation or dose-increase of corticosteroids and/or immunosuppressants] was determined by their treating physician. RESULTS: Data for 2239 patients were available: N = 1180 enrolled to conventional therapy [including N = 296 who switched to originator infliximab during follow-up] and N = 1059 enrolled to originator infliximab. Patients in the originator infliximab group, compared with the conventional therapy group, had more severe disease at baseline, based on partial Mayo score [PMS]: 46.0% of patients in the originator infliximab group had severe disease (PMS of 7-9 [out of 9]), compared with 30.5% in the conventional therapy group. In adjusted time-to-event analyses, enrolment into the originator infliximab group was associated with a higher risk of serious infection (hazard ratio = 1.98 [95% confidence interval: 1.34, 2.91; p <0.001]) compared with enrolment into the conventional therapy group. No notable risk differences between groups were identified for haematological disorder, autoimmune disorder, malignancy/lymphoproliferative disorder, hepatobiliary disorder or fatality. CONCLUSIONS: UC patients treated with infliximab had higher risk for serious infection, compared with conventional therapies. No new safety concerns were observed with originator infliximab in the OPUS registry. [ClinicalTrials.gov: NCT00705484.].


Assuntos
Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infliximab/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Europa (Continente) , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Infecções/induzido quimicamente , Infliximab/efeitos adversos , Masculino , Vigilância de Produtos Comercializados , Estudos Prospectivos , Sistema de Registros
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