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1.
Medicine (Baltimore) ; 99(29): e21226, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702894

RESUMO

Decreased trough level of infliximab (TLI) is associated with diminished efficacy in patients with Crohn disease (CD). We examined whether TLI at 14 weeks subsequent to the start of infliximab (IFX) treatment would impact long-term clinical course.Serum IFX levels and antibodies to IFX (ATI) at 14 and 54 weeks after IFX administration were measured in 12 patients with mild to moderate CD. We examined patient background, clinical severity, blood test values, and the relationship between ATI and TLI up to 108 weeks.We compared the group with TLI < 3 µg/mL at 14 weeks (TLI(14) < 3 group) the group with TLI > 3 µg/mL (TLI(14) ≥ 3 group). Patients in the TLI(14) ≥ 3 group were significantly more likely to use immunomodulators before IFX treatment induction (P = .01). At 54 weeks, 2 cases of ATI production were observed in the TLI(14) < 3 group, but no ATI production was observed in the TLI(14) ≥ 3 group. TLI in the TLI(14) ≥ 3 group at 54 weeks was significantly higher than in the TLI(14) < 3 group (6.5 µg/mL vs 1.0 µg/mL; P < .01). Although CD activity index and serum albumin values in the TLI(14) ≥ 3 group at 14, 54, and 108 weeks significantly improved compared to baseline, these improvements were not observed in the TLI(14) < 3 group. The remission maintenance rate at 108 weeks evaluated with the Kaplan-Meier method was significantly higher in the TLI(14) ≥ 3 group than the TLI(14) < 3 group (100% vs 33.3%; P = .02).The TLI 14 weeks after IFX treatment in patients with CD affects long-term outcome.


Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infliximab/uso terapêutico , Adolescente , Adulto , Idoso , Estudos de Coortes , Doença de Crohn/sangue , Progressão da Doença , Feminino , Fármacos Gastrointestinais/farmacocinética , Humanos , Infliximab/farmacocinética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Adulto Jovem
2.
PLoS One ; 15(4): e0231796, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287314

RESUMO

BACKGROUND: Antimicrobial peptide expression is associated with disease activity in inflammatory bowel disease (IBD) patients. IBD patients have abnormal expression of elafin, a human elastase-specific protease inhibitor and antimicrobial peptide. We determined elafin expression in blood, intestine, and mesenteric fat of IBD and non-IBD patients. METHODS: Serum samples from normal and IBD patients were collected from two UCLA cohorts. Surgical resection samples of human colonic and mesenteric fat tissues from IBD and non-IBD (colon cancer) patients were collected from Cedars-Sinai Medical Center. RESULTS: High serum elafin levels were associated with a significantly elevated risk of intestinal stricture in Crohn's disease (CD) patients. Microsoft Azure Machine learning algorithm using serum elafin levels and clinical data identified stricturing CD patients with high accuracy. Serum elafin levels had weak positive correlations with clinical disease activity (Partial Mayo Score and Harvey Bradshaw Index), but not endoscopic disease activity (Mayo Endoscopic Subscore and Simple Endoscopic Index for CD) in IBD patients. Ulcerative colitis (UC) patients had high serum elafin levels. Colonic elafin mRNA and protein expression were not associated with clinical disease activity and histological injury in IBD patients, but stricturing CD patients had lower colonic elafin expression than non-stricturing CD patients. Mesenteric fat in stricturing CD patients had significantly increased elafin mRNA and protein expression, which may contribute to high circulating elafin levels. Human mesenteric fat adipocytes secrete elafin protein. CONCLUSIONS: High circulating elafin levels are associated with the presence of stricture in CD patients. Serum elafin levels may help identify intestinal strictures in CD patients.


Assuntos
Colite Ulcerativa/sangue , Doença de Crohn/complicações , Elafina/sangue , Obstrução Intestinal/diagnóstico , Gordura Abdominal/citologia , Gordura Abdominal/metabolismo , Adipócitos/metabolismo , Adulto , Estudos de Casos e Controles , Linhagem Celular , Colite Ulcerativa/patologia , Colo/diagnóstico por imagem , Colo/patologia , Colonoscopia , Constrição Patológica/sangue , Constrição Patológica/diagnóstico , Constrição Patológica/etiologia , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Elafina/metabolismo , Feminino , Fibroblastos , Voluntários Saudáveis , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Obstrução Intestinal/sangue , Obstrução Intestinal/etiologia , Obstrução Intestinal/patologia , Masculino , Cultura Primária de Células , Estudos Prospectivos , Índice de Gravidade de Doença
3.
N Z Med J ; 133(1511): 61-70, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32161422

RESUMO

AIM: Patients with inflammatory bowel disease (IBD), Crohn's disease (CD) or ulcerative colitis (UC) are at risk of low vitamin D owing to reduced absorption, medication-associated sunlight exposure restrictions and/or increased requirements due to inflammation. This study aimed to determine if the serum vitamin D concentration of New Zealand IBD patients relates to disease activity and differs from controls. METHOD: Data concerning demographics, sunlight exposure, vitamin D supplementation and disease activity were collected using a retrospective questionnaire. Serum vitamin D concentrations were measured in dried blood spots and validated against blood samples in a participant sub-group. RESULTS: Vitamin D concentration was significantly increased by supplementation (82.8 v 66.4nmol/L, p<0.001) and sunlight exposure while on holiday (75.2 v 63.7nmol/L, p<0.001). Patients with CD who reported active disease in the last year had significantly lower vitamin D concentrations (68.6 v 84.6nmol/L, p=0.008) than those who reported remaining in remission. CONCLUSION: In this cohort of New Zealand residents, mean vitamin D of patients with IBD was not different from controls. In patients with CD, recent disease activity was significantly associated with lower vitamin D. The use of vitamin D supplementation may have implications for reducing disease activity occurrence in patients with CD.


Assuntos
Doenças Inflamatórias Intestinais/epidemiologia , Deficiência de Vitamina D/epidemiologia , Vitamina D/análogos & derivados , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/sangue , Colite Ulcerativa/epidemiologia , Doença de Crohn/sangue , Doença de Crohn/epidemiologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Vitamina D/sangue , Deficiência de Vitamina D/sangue
4.
Z Gastroenterol ; 58(5): 439-444, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045954

RESUMO

BACKGROUND AND AIM: The role of therapeutic drug monitoring (TDM) in ustekinumab (UST) therapy for Crohn's disease (CD) has not been established, as only few studies have analyzed the relationship between UST serum concentrations and clinical outcome. In this pilot study, we retrospectively examined the potential of UST-concentrations (cUST) 8 weeks after induction (cUSTw8) to predict clinical response at week 16. METHODS: Serum samples and clinical data from patients (n = 72) with moderate to severely active CD who received intravenous induction with UST were retrospectively analyzed. cUST were quantitated using liquid chromatography-tandem mass spectrometry (LC-MSMS). A receiver-operating characteristic (ROC) curve and area under ROC curve (AUROC) was computed to analyze the predictive potential of cUSTw8 for clinical response at week 16 and to determine the minimal therapeutic UST trough concentration. RESULTS: Forty-four patients (61 %) achieved clinical response to UST therapy at week 16. cUSTw8 was moderately effective to predict clinical response with a minimal therapeutic cUSTw8 of 2.0 mg/l (AUC 0.72, p = 0.001). CONCLUSION: Trough concentrations of UST 8 weeks after induction predict clinical response to therapy in week 16 with moderate sensitivity and specificity. TDM using LC-MSMS could prove beneficial in personalized UST therapy of patients with CD by identifying individuals with subtherapeutic concentrations who might benefit from dose escalation.


Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Fatores Imunológicos/farmacologia , Ustekinumab/uso terapêutico , Biomarcadores/análise , Cromatografia Líquida , Doença de Crohn/sangue , Fármacos Dermatológicos/sangue , Humanos , Fatores Imunológicos/administração & dosagem , Projetos Piloto , Curva ROC , Estudos Retrospectivos , Espectrometria de Massas em Tandem , Resultado do Tratamento , Ustekinumab/sangue
6.
PLoS One ; 15(1): e0227306, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929564

RESUMO

The inflammatory bowel diseases (IBD), which include mainly Crohn's disease (CD) and ulcerative colitis (UC), are common chronic inflammatory conditions of the digestive system. The diagnosis of IBD relies on the use of a combination of factors including symptoms, endoscopy and levels of serum proteins such as C-reactive protein (CRP) or faecal calprotectin. Currently there is no single reliable biomarker to determine IBD. Galectins are a family of galactoside-binding proteins that are commonly altered in the circulation of disease conditions such as cancer and inflammation. This study investigated serum galectin levels as possible biomarkers in determining IBD and IBD disease activity. Levels of galectins-1, -2, -3, -4, -7 and -8 were analysed in 208 samples from ambulant IBD patients (97 CD, 71 UC) patients and 40 from healthy people. Disease activity was assessed using Harvey-Bradshaw Index for CD and simple clinical colitis activity index for UC. The relationship of each galectin in determining IBD and IBD disease activity were analysed and compared with current IBD biomarker CRP. It was found that serum level of galectin-1 and -3, but not galectins-2, -4, -7 and -8, were significantly higher in IBD patients than in healthy people. At cut-off of 4.1ng/ml, galectin-1 differentiated IBD from healthy controls with 71% sensitivity and 87% specificity. At cut-off of 38.5ng/ml, galectin-3 separated IBD from healthy controls with 53% sensitivity and 87% specificity. None of the galectins however were able to distinguish active disease from remission in UC or CD. Thus, levels of galectins-1 and -3 are significantly elevated in both UC and CD patients compared to healthy people. Although the increased galectin levels are not able to separate active and inactive UC and CD, they may have the potential to be developed as useful biomarkers for IBD diagnosis either alone or in combination with other biomarkers.


Assuntos
Colite Ulcerativa/sangue , Doença de Crohn/sangue , Galectina 1/sangue , Galectina 3/sangue , Adulto , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Feminino , Galectinas/sangue , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/patologia , Masculino , Pessoa de Meia-Idade
7.
World J Gastroenterol ; 26(2): 246-265, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31988587

RESUMO

BACKGROUND: Non-invasive criteria are needed for Crohn's disease (CD) diagnosis, with several biomarkers being tested. Results of individual diagnostic test accuracy studies assessing the diagnostic value of pancreatic autoantibodies-to-glycoprotein-2 (anti-GP2) tests for the diagnosis of CD appear promising. AIM: To systematically review and meta-analyze evidence on the diagnostic accuracy of anti-GP2 tests in patients with suspected/confirmed CD. METHODS: An electronic search was conducted on PubMed, Cochrane-CENTRAL and grey literature (CRD42019125947). The structured research question in PICPTR format was "Population" including patients with symptoms akin to CD, the "Index test" being anti-GP2 testing, the "Comparator" involved standard CD diagnosis, the "Purpose of test" being diagnostic, "Target disorder" was CD, and the "Reference standard" included standard clinical, radiological, endoscopical, and histological CD diagnostic criteria. Quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool and hierarchical models were employed to synthesize the data. RESULTS: Out of 722 studies retrieved, 15 were meta-analyzed. Thirteen studies had industry-related conflicts-of-interest, and most included healthy donors as controls (spectrum bias). For the combination of IgA and/or IgG anti-GP2 test, the summary sensitivity was 20% (95% confidence interval: 10%-29%) at a median specificity of 97%. If the test was applied in 10000 suspected patients, 9669 would be true negatives and in 26, the diagnosis would be missed. In this hypothetical cohort, the anti-GP2 would fail to produce a diagnosis for 81.3% of the positive cases. Low summary points of sensitivity and high specificity were estimated for the IgG or IgA anti-GP2 test. Analogous results were observed when the analyses were restricted using specific cut-offs, or when ulcerative colitis patients were used as comparators. CONCLUSION: Anti-GP2 tests demonstrate low sensitivity and high specificity. These results indicate that caution is required before relying on its diagnostic value. Additionally, the need for improving the methodology of diagnostic test accuracy studies is evident.


Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Doença de Crohn/diagnóstico , Glicoproteínas de Membrana/imunologia , Autoanticorpos/imunologia , Biomarcadores/sangue , Doença de Crohn/sangue , Doença de Crohn/imunologia , Humanos , Sensibilidade e Especificidade
8.
Gastroenterology ; 158(3): 515-526.e10, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31711925

RESUMO

BACKGROUND & AIMS: Noninvasive tests to measure endoscopic activity in patients with Crohn's disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. METHODS: We developed a test to measure 13 proteins in blood (ANG1, ANG2, CRP, SAA1, IL7, EMMPRIN, MMP1, MMP2, MMP3, MMP9, TGFA, CEACAM1, and VCAM1), called the endoscopic healing index [EHI], using samples from 278 patients with CD from a multinational training cohort. We validated the test using 2 independent cohorts of patients with CD: 116 biologic-naive patients with early-stage CD (validation cohort 1) and 195 biologic-exposed patients with chronic CD (validation cohort 2). The ability of the test to identify patients with active disease vs patients in remission (defined as a simple endoscopic score for CD of ≤2 and ≤1 in each segment, or a total CD endoscopic index of severity score <3) was assessed by using area under receiver operating characteristic curve (AUROC) analysis. The diagnostic accuracy of the test was compared with that of measurement of serum C-reactive protein (CRP) and fecal calprotectin. RESULTS: The EHI scores range from 0 to 100 units; higher scores indicate more severe CD activity, based on endoscopy findings. The EHI identified patients in remission with an AUROC of 0.962 in validation cohort 1 (95% confidence interval, 0.942-0.982) and an AUROC of 0.693 in validation cohort 2 (95% confidence interval, 0.619-0.767), regardless of CD location or phenotype. A cutoff value of 20 points identified patients in remission with the highest level of sensitivity (97.1% in validation cohort 1 and 83.2% in validation cohort 2), with specificity values of 69.0% and 36.6%, respectively. A cutoff value of 50 points identified patients in remission with the highest level of specificity (100% in validation cohort 1 and 87.8% in validation cohort 2), with sensitivity values of 37.3% and 30.0%, respectively. The EHI identified patients in remission with a significantly higher AUROC value than the test for CRP (0.876, P < .001 in validation cohort 1 and 0.624, P = .109 in validation cohort 2). In analysis of patients with available FC measurements, the AUROC value for the EHI did not differ significantly from that of measurement of FC (AUROC, 0.950 for EHI vs AUROC, 0.923 for FC; P = .147 in validation cohort 1 and AUROC, 0.803 for EHI vs AUROC, 0.854 for FC; P = .298 in validation cohort 2). CONCLUSIONS: We developed an index called the EHI to identify patients with CD in endoscopic remission based on blood levels of 13 proteins. The EHI identified patients with resolution of endoscopic disease activity, with good overall accuracy, although with variation between the 2 cohorts assessed. The EHI AUROC values were comparable to measurement of FC and higher than measurement of serum CRP. The test might be used in practice to assess endoscopic activity in patients with CD.


Assuntos
Colonoscopia , Doença de Crohn/diagnóstico , Fármacos Gastrointestinais/administração & dosagem , Infliximab/administração & dosagem , Índice de Gravidade de Doença , Adulto , Biomarcadores/sangue , Proteína C-Reativa/análise , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/patologia , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Fezes/química , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Complexo Antígeno L1 Leucocitário/análise , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Recidiva , Indução de Remissão/métodos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
9.
Gut ; 69(3): 473-486, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31167813

RESUMO

OBJECTIVE: Pregnancy may affect the disease course of IBD. Both pregnancy and IBD are associated with altered immunology and intestinal microbiology. However, to what extent immunological and microbial profiles are affected by pregnancy in patients with IBD remains unclear. DESIGN: Faecal and serum samples were collected from 46 IBD patients (31 Crohn's disease (CD) and 15 UC) and 179 healthy controls during first, second and third trimester of pregnancy, and prepregnancy and postpartum for patients with IBD. Peripheral blood cytokine profiles were determined by ELISA, and microbiome analysis was performed by sequencing the V4 region of the bacterial 16S rRNA gene. RESULTS: Proinflammatory serum cytokine levels in patients with IBD decrease significantly on conception. Reduced interleukin (IL)-10 and IL-5 levels but increased IL-8 and interferon (IFN)γ levels compared with healthy controls were seen throughout pregnancy, but cytokine patterns remained stable during gestation. Microbial diversity in pregnant patients with IBD was reduced compared with that in healthy women, and significant differences existed between patients with UC and CD in early pregnancy. However, these microbial differences were no longer present during middle and late pregnancy. Dynamic modelling showed considerable interaction between cytokine and microbial composition. CONCLUSION: Serum proinflammatory cytokine levels markedly improve on conception in pregnant patients with IBD, and intestinal microbiome diversity of patients with IBD normalises during middle and late pregnancy. We thus conclude that pregnancy is safe and even potentially beneficial for patients with IBD.


Assuntos
Colite Ulcerativa/sangue , Colite Ulcerativa/microbiologia , Doença de Crohn/sangue , Doença de Crohn/microbiologia , Citocinas/sangue , Microbioma Gastrointestinal , Complicações na Gravidez/sangue , Complicações na Gravidez/microbiologia , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Fezes/microbiologia , Feminino , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-5/sangue , Interleucina-8/sangue , Gravidez , Complicações na Gravidez/imunologia , Trimestres da Gravidez/sangue , Trimestres da Gravidez/imunologia
10.
Gastroenterology ; 158(1): 189-199, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600487

RESUMO

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies. METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58). CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449.


Assuntos
Adalimumab/imunologia , Doença de Crohn/terapia , Cadeias alfa de HLA-DQ/genética , Infliximab/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Adulto , Alelos , Doença de Crohn/sangue , Feminino , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
11.
Inflamm Bowel Dis ; 26(1): 103-111, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31184366

RESUMO

BACKGROUND: Therapeutic drug monitoring (TDM) is increasingly performed for Infliximab (IFX) in patients with Crohn's disease (CD). Reactive TDM is a cost-effective strategy to empiric IFX dose escalation. The cost-effectiveness of proactive TDM is unknown. The aim of this study is to assess the cost-effectiveness of proactive vs reactive TDM in a simulated population of CD patients on IFX. METHODS: We developed a stochastic simulation model of CD patients on IFX and evaluated the expected health costs and outcomes of a proactive TDM strategy compared with a reactive strategy. The proactive strategy measured IFX concentration and antibody status every 6 months, or at the time of a flare, and dosed IFX to a therapeutic window. The reactive strategy only did so at the time of a flare. RESULTS: The proactive strategy led to fewer flares than the reactive strategy. More patients stayed on IFX in the proactive vs reactive strategy (63.4% vs 58.8% at year 5). From a health sector perspective, a proactive strategy was marginally cost-effective compared with a reactive strategy (incremental cost-effectiveness ratio of $146,494 per quality-adjusted life year), assuming a 40% of the wholesale price of IFX. The results were most sensitive to risk of flaring with a low IFX concentration and the cost of IFX. CONCLUSIONS: Assuming 40% of the average wholesale acquisition cost of biologic therapies, proactive TDM for IFX is marginally cost-effective compared with a reactive TDM strategy. As the cost of infliximab decreases, a proactive monitoring strategy is more cost-effective.


Assuntos
Doença de Crohn/tratamento farmacológico , Doença de Crohn/economia , Monitoramento de Medicamentos/economia , Fármacos Gastrointestinais/economia , Infliximab/economia , Estudos de Coortes , Simulação por Computador , Análise Custo-Benefício , Doença de Crohn/sangue , Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/sangue , Humanos , Infliximab/sangue , Anos de Vida Ajustados por Qualidade de Vida , Índice Terapêutico do Medicamento
12.
Bratisl Lek Listy ; 120(12): 924-928, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31855052

RESUMO

OBJECTIVES: The aim of this study was to investigate the relationship between thromboxane levels and oxidative stress in children with Crohn´s disease (CD), and examine the effect of natural polyphenolic compounds on thromboxane levels. METHODS: This study involved 14 children suffering from CD and 15 healthy controls. Patients were receiving the polyphenolic extract Pycnogenol for 10 weeks. Plasma levels of the static and dynamic forms of thromboxane B2 as well as their metabolite 11-dehydro thromboxane B2 in urine were determined. RESULTS: In comparison to controls, CD patients had significantly higher levels of the static and dynamic forms of thromboxane B2. Pycnogenol decreased the level of the dynamic form of thromboxane B2 after 10 weeks of administration. CONCLUSIONS: Paediatric Crohn's disease is associated with higher thromboxane levels. Our results indicate that Pycnogenol administration reduces thromboxane levels, which may positively influence some clinical symptoms of CD such as thromboembolic episodes (Tab. 3, Ref. 49).


Assuntos
Doença de Crohn/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/farmacologia , Tromboxanos/sangue , Adolescente , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Feminino , Flavonoides/administração & dosagem , Humanos , Masculino , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem
13.
World J Gastroenterol ; 25(41): 6273-6288, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31749597

RESUMO

BACKGROUND: Increasing evidence demonstrates that by acting as microRNA sponges modulating gene expression at the transcriptional or post-transcriptional level, circular RNAs (circRNAs) participate in the pathogenesis of a variety of diseases and are considered ideal biomarkers of human disease. AIM: To examine the expression of circRNA_103516 in inflammatory bowel disease (IBD) and its associations with clinical phenotypes and inflammatory cytokines. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with IBD, healthy controls (HCs), and patient controls (PCs). Expression of circRNA_103516 and hsa-miR-19b-1-5p was assessed by quantitative reverse transcription-polymerase chain reaction. Crohn's disease activity index (CDAI), Mayo score, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) were measured. To assess the inflammatory cytokines tumour necrosis factor α (TNF-α), interferon-γ (IFN-γ), and interleukin-10 (IL-10), blood samples were analysed by flow cytometry. RESULTS: Ninety Crohn's disease (CD) and 90 ulcerative colitis (UC) patients, 80 HCs, and 35 PCs were included in the study. CircRNA_103516 was upregulated in CD and UC patients compared with HCs and PCs (P < 0.05). The area under the curve of circRNA_103516 for diagnosing CD and UC was 0.790 and 0.687, respectively. In addition, circRNA_103516 levels were increased in active CD and UC compared with remittent groups (P = 0.027, P = 0.045). Furthermore, in CD, circRNA_103516 correlated positively with CDAI (P < 0.001), CRP (P < 0.001), ESR (P < 0.001), TNF-α (P < 0.001), and IFN-γ (P < 0.001) and negatively correlated with IL-10 (P = 0.006). In UC patients, circRNA_103516 correlated with Mayo score (P < 0.001), CRP (P < 0.001), ESR (P < 0.001), TNF-α (P < 0.001), IFN-γ (P =0.011), and IL-10 (P = 0.002). Additionally, circRNA_103516 correlated positively with stricturing (P = 0.018) and penetrating (P = 0.031) behaviour. Moreover, hsa-miR-19b-1-5p correlated negatively with circRNA_103516 in CD. CONCLUSION: CircRNA_103516 levels in PBMCs can be considered an ideal candidate biomarker for diagnosing IBD. Dysregulation of circRNA_103516 may participate in the molecular mechanism of IBD through hsa-miR-19b-1-5p sponging.


Assuntos
Colite Ulcerativa/sangue , Doença de Crohn/sangue , Citocinas/metabolismo , RNA Circular/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/análise , Colite Ulcerativa/genética , Doença de Crohn/genética , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Leucócitos Mononucleares/citologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Fenótipo , Curva ROC , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
14.
Int J Colorectal Dis ; 34(12): 2185-2188, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31705193

RESUMO

AIM: Bowel resection in Crohn's disease still has a high rate of complications due to risk factors including immune suppression, malnutrition and active inflammation or infection at the time of operating. In this study, we use serological levels and inflammatory markers to predict the potential of complications in patients undergoing resections for complicated Crohn's disease. METHODS: All patients undergoing laparoscopic bowel resection for Crohn's disease from 5th of November 2012 to 11th of October 2017 were included in this retrospective observational study. Patients were divided into 4 groups scoring 0, 1, 2 or 3 depending on their pre-operative haemoglobin concentration (Hb), C-reactive protein (CRP) and albumin (Alb) where 1 point was given for an abnormal value in each as detailed in the definitions. They were then grouped into a low risk group comprised of those scoring 0 and 1, and a high risk group for those scoring 2 and 3 and data was collected to compare outcomes and the incidence of septic complications. RESULTS: Seventy-nine patients were included. Eleven (13.9%) and 2 (2.5%) patients had 2 or 3 abnormal values of CRP, Alb and Hb and were categorized as high risk. High risk patients had a significantly higher rate of post-operative septic complications (30.7%) compared with low risk patients (10.6%) p value < 0.0001. CONCLUSION: Pre-operative CRP, haemoglobin and albumin can serve as predictors of septic complications after surgery for Crohn's disease and can therefore be used to guide pre-operative optimisation and clinical decision-making.


Assuntos
Anemia/epidemiologia , Proteína C-Reativa/análise , Doença de Crohn/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Hipoalbuminemia/epidemiologia , Mediadores da Inflamação/sangue , Laparoscopia/efeitos adversos , Sepse/epidemiologia , Adulto , Anemia/sangue , Anemia/diagnóstico , Biomarcadores/sangue , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Feminino , Hemoglobinas/análise , Humanos , Hipoalbuminemia/sangue , Hipoalbuminemia/diagnóstico , Incidência , Masculino , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sepse/sangue , Sepse/diagnóstico , Albumina Sérica Humana/análise , Fatores de Tempo , Resultado do Tratamento , Reino Unido/epidemiologia
15.
PLoS One ; 14(10): e0222952, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618209

RESUMO

BACKGROUND: Presenting features of inflammatory bowel disease (IBD) are non-specific. We hypothesized that mRNA profiles could (1) identify genes and pathways involved in disease pathogenesis; (2) identify a molecular signature that differentiates IBD from other conditions; (3) provide insight into systemic and colon-specific dysregulation through study of the concordance of the gene expression. METHODS: Children (8-18 years) were prospectively recruited at the time of diagnostic colonoscopy for possible IBD. We used transcriptome-wide mRNA profiling to study gene expression in colon biopsies and paired whole blood samples. Using blood mRNA measurements, we fit a regression model for disease state prediction that was validated in an independent test set of adult subjects (GSE3365). RESULTS: Ninety-eight children were recruited [39 Crohn's disease, 18 ulcerative colitis, 2 IBDU, 39 non-IBD]. There were 1,118 significantly differentially (IBD vs non-IBD) expressed genes in colon tissue, and 880 in blood. The direction of relative change in expression was concordant for 106/112 genes differentially expressed in both tissue types. The regression model from the blood mRNA measurements distinguished IBD vs non-IBD disease status in the independent test set with 80% accuracy using only 6 genes. The overlap of 5 immune and metabolic pathways in the two tissue types was significant (p<0.001). CONCLUSIONS: Blood and colon tissue from patients with IBD share a common transcriptional profile dominated by immune and metabolic pathways. Our results suggest that peripheral blood expression levels of as few as 6 genes (IL7R, UBB, TXNIP, S100A8, ALAS2, and SLC2A3) may distinguish patients with IBD from non-IBD.


Assuntos
Colite Ulcerativa/diagnóstico , Colo/patologia , Doença de Crohn/diagnóstico , Perfilação da Expressão Gênica/métodos , Mucosa Intestinal/patologia , Adolescente , Biomarcadores/sangue , Biomarcadores/metabolismo , Biópsia , Criança , Colite Ulcerativa/sangue , Colite Ulcerativa/patologia , Colo/diagnóstico por imagem , Colonoscopia , Doença de Crohn/sangue , Doença de Crohn/patologia , Estudos de Viabilidade , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Masculino , Estudos Prospectivos , Reprodutibilidade dos Testes
16.
World J Gastroenterol ; 25(38): 5850-5861, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31636477

RESUMO

BACKGROUND: Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes? AIM: To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes. METHODS: Patients' clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured. RESULTS: A total of 411 Crohn's disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively. CONCLUSION: The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.


Assuntos
Doença de Crohn/tratamento farmacológico , Nucleotídeos de Guanina/sangue , Imunossupressores/efeitos adversos , Leucopenia/diagnóstico , Mercaptopurina/efeitos adversos , Pirofosfatases/genética , Tionucleotídeos/sangue , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Variação Biológica da População/genética , Biomarcadores/sangue , Criança , Doença de Crohn/sangue , Doença de Crohn/imunologia , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Prognóstico , Valores de Referência , Estudos Retrospectivos , Adulto Jovem
17.
Clin Lab ; 65(9)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532084

RESUMO

BACKGROUND: The rhesus (Rh) system is the second most important blood group system after ABO, with highly immunogenic antigens. Although the anti-E Rh antibody has been reported to cause hemolytic disease of the newborn and delayed hemolytic transfusion reactions, acute hemolytic transfusion reactions (AHTR) have been rarely reported. METHODS: Peripheral blood (PB) samples were screened for irregular antibodies using a commercial ID-Diacell I - II antibody screening Panel (Bio-Rad Laboratories, Glattbrugg, Switzerland) and ID-cards "LISS/Coombs" (Bio-Rad, Switzerland). The antibody was confirmed using ID DiaPanel, an antibody identification panel (Bio-Rad, Switzerland). Rh phenotyping was performed for RhC/c and RhE/e antigens using an immediate-spin tube test with monoclonal anti-C, -c, -E, and -e (OrthoClinical Diagnostics, High Wycombe, UK) in saline-filled test-tubes. RESULTS: The patient was negative for antibody screening test before transfusion. After receiving a total of 6 units of cross-matching negative RBC transfusion, the antibody screening test result increased to 2+ after showing traces and the antibody was confirmed as anti-E Rh antibody. The Rh phenotype of the patient was C (+), c (+), E (-), and e (+). In addition, we verified that all the six units of RBCs transfused were E (+) except for the two units transfused before surgery. CONCLUSIONS: Here is an unusual case of an AHTR due to the anti-E Rh antibody after E-positive RBC transfusion in a patient with Crohn's disease. Because anemia is common in patients with Crohn's disease, it is important to determine the cause of the anemia and necessary to examine the Rh phenotype before transfusions because of the high need for transfusion due to any cause. Awareness of this possibility will ensure safe blood transfusion with special care to screen for antibodies and perform Rh phenotyping, thereby minimizing morbidity and preventing potential mortality.


Assuntos
Antígenos de Grupos Sanguíneos/imunologia , Doença de Crohn/terapia , Transfusão de Eritrócitos/métodos , Sistema do Grupo Sanguíneo Rh-Hr/imunologia , Reação Transfusional/sangue , Adulto , Doença de Crohn/sangue , Doença de Crohn/imunologia , Humanos , Masculino , Reação Transfusional/imunologia
18.
Arab J Gastroenterol ; 20(3): 135-140, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31563476

RESUMO

BACKGROUND AND STUDY AIMS: Non-invasive biomarkers of inflammatory bowel diseases (IBD) are of critical importance. Here, we evaluated the S100A8 and S100A9 mRNA expression, as the heterodimers of calprotectin, in the blood leucocytes of IBD patients to find how their expression associates with the disease characteristics. PATIENTS AND METHODS: In this cross-sectional study, 59 IBD patients and 30 healthy subjects were included. The flare and remission phases of disease were identified in 46 and 13 patients, respectively. Blood leucocytes were isolated, and the S100A8 and S100A9 mRNA expression were evaluated in the isolated leucocytes using relative quantification real-time PCR. RESULTS: The mean S100A8 and S100A9 mRNA expression were significantly higher in IBD patients than in the controls (p = 0.03 and p = 0.02, respectively). The mean S100A8 and S100A9 mRNA expression were significantly higher in the flare phase of the disease compared with the remission phase (p = 0.01 and p = 0.007, respectively). S100A8 distinguished IBD patients from controls with the sensitivity and specificity of 73% and 64%, and flare phase of disease from remission with the sensitivity and specificity of 67% and 62%. On the other hand, S100A9 distinguished IBD patients from controls with the sensitivity and specificity of 81% and 70%, and flare phase of disease from remission with the sensitivity and specificity of 68% and 64%. CONCLUSION: The S100A8 and S100A9 mRNA are differentially expressed in blood leucocytes of IBD patients compared to healthy controls as well as active versus quiescent disease. Thus, they can be potentially used as a blood-based biomarker in the monitoring of IBD.


Assuntos
Calgranulina A/genética , Calgranulina B/genética , Colite Ulcerativa/sangue , Doença de Crohn/sangue , RNA Mensageiro/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Leucócitos , Masculino , Pessoa de Meia-Idade , Curva ROC , Exacerbação dos Sintomas
19.
Gastroenterology ; 157(6): 1584-1598, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513797

RESUMO

BACKGROUND & AIMS: T-regulatory (Treg) cells suppress the immune response to maintain homeostasis. There are 2 main subsets of Treg cells: FOXP3 (forkhead box protein 3)-positive Treg cells, which do not produce high levels of effector cytokines, and type 1 Treg (Tr1) cells, which are FOXP3-negative and secrete interleukin (IL) 10. IL10 is an anti-inflammatory cytokine, so Tr1 cells might be used in the treatment of inflammatory bowel diseases. We aimed to develop methods to isolate and expand human Tr1 cells and define their functions. METHODS: We obtained blood and colon biopsy samples from patients with Crohn's disease or ulcerative colitis or healthy individuals (controls). CD4+ T cells were isolated from blood samples and stimulated with anti-CD3 and anti-CD28 beads, and Tr1 cells were purified by using an IL10 cytokine-capture assay and cell sorting. FOXP3-positive Treg cells were sorted as CD4+CD25highCD127low cells from unstimulated cells. Tr1 and FOXP3-positive Treg cells were expanded, and phenotypes and gene expression profiles were compared. T cells in peripheral blood mononuclear cells from healthy donors were stimulated with anti-CD3 and anti-CD28 beads, and the suppressive abilities of Tr1 and FOXP3-positive Treg cells were measured. Human colon organoid cultures were established, cultured with supernatants from Tr1 or FOXP3-positive cells, and analyzed by immunofluorescence and flow cytometry. T84 cells (human colon adenocarcinoma epithelial cells) were incubated with supernatants from Tr1 or FOXP3-positive cells, and transepithelial electrical resistance was measured to determine epithelial cell barrier function. RESULTS: Phenotypes of Tr1 cells isolated from control individuals vs patients with Crohn's disease or ulcerative colitis did not differ significantly after expansion. Tr1 cells and FOXP3-positive Treg cells suppressed proliferation of effector T cells, but only Tr1 cells suppressed secretion of IL1B and tumor necrosis factor from myeloid cells. Tr1 cells, but not FOXP3-positive Treg cells, isolated from healthy individuals and patients with Crohn's disease or ulcerative colitis secreted IL22, which promoted barrier function of human intestinal epithelial cells. Tr1 cell culture supernatants promoted differentiation of mucin-producing goblet cells in intestinal organoid cultures. CONCLUSIONS: Human Tr1 cells suppress proliferation of effector T cells (adaptive immune response) and production of IL1B and TNF by myeloid cells (inmate immune response). They also secrete IL22 to promote barrier function. They might be developed as a cell-based therapy for intestinal inflammatory disorders.


Assuntos
Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Interleucina-10/metabolismo , Mucosa Intestinal/patologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Biópsia , Comunicação Celular/imunologia , Proliferação de Células , Células Cultivadas , Colite Ulcerativa/sangue , Colite Ulcerativa/terapia , Colo/citologia , Colo/imunologia , Colo/patologia , Doença de Crohn/sangue , Doença de Crohn/terapia , Feminino , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Voluntários Saudáveis , Humanos , Interleucina-10/imunologia , Interleucinas/imunologia , Interleucinas/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante
20.
Medicine (Baltimore) ; 98(33): e16622, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415355

RESUMO

OBJECTIVE: This study aimed to investigate the correlation of serum Jun-amino-terminal kinase (JNK) pathway-associated phosphatase (JKAP) level with disease risk, severity, inflammation, and treatment response to tumor necrosis factor (TNF)-α inhibitor in Crohn disease (CD) patients. METHOD: Ninety-six active CD patients and 90 healthy controls (HCs) were consecutively enrolled. Serum JKAP level of participants was determined via enzyme-linked immunosorbent assay (ELISA). In CD patients, C-reactive protein (CRP), erythrocyte sedimentation rate, Crohn disease activity index (CDAI), and inflammatory cytokine levels (determined by ELISA) were recorded. All CD patients underwent infliximab (IFX) treatment for 12 weeks, then treatment response (defined as decrement of CDAI ≥70) was assessed at week 12 (W12). RESULTS: Serum JKAP level in CD patients was lower compared to HCs, and it disclosed a good predictive value for decreased CD risk; meanwhile, it was negatively correlated with CRP level, CDAI score, TNF-α, interleukin (IL)-6, and IL-17 levels in CD patients. Sixty-eight (70.8%) patients achieved treatment response to IFX at W12, and JKAP level was increased at W12 compared to baseline. Interestingly, baseline JKAP level in response patients was decreased compared to nonresponse patients, and it exhibited a good predictive value for decreased treatment response to IFX, multivariate logistic regression revealed that JKAP was an independent factor for predicting reduced IFX response. CONCLUSION: Circulating JKAP expression correlates with decreased disease risk, activity, and inflammation level, and it could be served as a novel biomarker for predicting reduced clinical response to TNF-α inhibitor in CD patients.


Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Sistema de Sinalização das MAP Quinases/fisiologia , Monoéster Fosfórico Hidrolases/sangue , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Doença de Crohn/sangue , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Inflamação , Infliximab/uso terapêutico , Masculino , Fatores de Risco , Resultado do Tratamento
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