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2.
Gene ; 757: 144931, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640308

RESUMO

OBJECTIVE: The aim of this study is to investigate the role of close homolog of L1 (CHL1) on inflammatory bowel disease (IBD), and the correlation with the balance of Th17/Treg. METHODS: Dextran sodium sulfate (DSS)-induced IBD mice model was established. CHL1 knockout (KO) mice and CHL1 wild-type (WT) mice were subjected to DSS. CHL1 expression was detected using qRT-PCR. Weight was recorded daily, and disease activity index (DAI) score was assessed. The colon length and histological changes were measured. The number of neutrophils, macrophages and T cells was observed by immunohistochemistry. The expression of inflammatory cytokines and the proportion of Th17/Treg cells were detected by qRT-PCR and flow cytometry. The expression of RORγt, STAT3 and Foxp3 was detected by using immunohistochemistry and Western blot. RESULTS: CHL1 expression was upregulated in DSS-induced IBD mice. DSS-CHLl-KO mice exhibited less weight loss than the DSS-CHLl-WT mice. The DAI score and histological score were decreased in DSS-CHLl-KO mice compared with DSS-CHLl-WT mice, while colon length was increased. Number of neutrophils, macrophages and T cells, and expression of TNF-α, IL-6, IL-17A, IL-21 and IL-23 were decreased in DSS-CHLl-KO mice, while IL-10 expression was increased. Moreover, CHL1-deficient inhibited Th17 cells differentiation and promoted Treg cells differentiation in IBD mice. CHL1-deficient also inhibited the expression of RORγt and STAT3, and promoted the expression of Foxp3 in IBD mice. CONCLUSION: CHL1-deficient reduces the inflammatory response by regulating the balance of Th17/Treg in mice with IBD. CHL1 is expected to be a new target for the treatment of IBD.


Assuntos
Moléculas de Adesão Celular/genética , Doenças Inflamatórias Intestinais/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Moléculas de Adesão Celular/deficiência , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/citologia , Células Th17/citologia
3.
Aliment Pharmacol Ther ; 52(3): 459-470, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32598049

RESUMO

BACKGROUND: The association between NUDT15 polymorphisms and thiopurine-induced leucopenia is well known. AIM: To investigate the association between NUDT15 polymorphisms and time-to-leucopenia in paediatric patients with inflammatory bowel disease (IBD) receiving azathioprine and to determine the relationship between NUDT15 polymorphisms and 6-thioguanine nucleotide (6-TGN) levels. METHODS: This retrospective observational study included Korean paediatric patients with IBD who were treated with azathioprine and underwent NUDT15 and TPMT genotyping. Azathioprine doses were adjusted by regular thiopurine metabolite monitoring. Factors associated with time-to-leucopenia and the relationship between NUDT15 polymorphisms and 6-TGN levels were analysed. RESULTS: Among the 167 patients included, leucopenia was observed in 16% (19/119), 44% (20/45) and 100% (3/3) of the NUDT15 normal, intermediate and poor metabolisers respectively (P < 0.001). NUDT15 polymorphism was significantly associated with time-to-leucopenia (HR = 5.26, 95% CI = 2.74-10.09, P < 0.001). There was a positive association between 6-TGN levels and leucopenia among the NUDT15 intermediate/TPMT normal metabolisers (median 361.3 vs 263.8 pmol/8 × 108 RBC, P = 0.013). The most accurate 6-TGN cut-off level associated with leucopenia was 308.2 pmol/8 × 108 RBC (AUC = 0.742, 95% CI = 0.569-0.915, sensitivity 80.0%, specificity 72.7%, P < 0.001) in this subgroup. When the specificity was set to <15%, the 6-TGN cut-off level was 167.1 pmol/8 × 108 RBC (sensitivity 93.3%, specificity 13.6%). CONCLUSIONS: NUDT15 polymorphisms were associated with time-to-leucopenia during azathioprine treatment in Korean paediatric patients with IBD. In order to reduce the development of thiopurine-induced leucopenia (<15%) in NUDT15 intermediate metabolisers, adjustment of azathioprine doses should be based on a lower 6-TGN target level (<167.1 pmol/8 × 108 RBC).


Assuntos
Azatioprina/administração & dosagem , Nucleotídeos de Guanina/sangue , Imunossupressores/administração & dosagem , Doenças Inflamatórias Intestinais/tratamento farmacológico , Leucopenia/induzido quimicamente , Pirofosfatases/genética , Tionucleotídeos/sangue , Adolescente , Azatioprina/efeitos adversos , Criança , Feminino , Humanos , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/genética , Leucopenia/sangue , Leucopenia/genética , Leucopenia/prevenção & controle , Masculino , Metiltransferases/genética , Polimorfismo Genético
4.
PLoS One ; 15(5): e0233811, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470973

RESUMO

Crohn's disease (CD) and ulcerative colitis (UC) are characterized by overexpression of proinflammatory cytokines. We determined the association of serum levels of interleukin (IL)-6, soluble-IL-2-receptor (sIL-2R) and CRP as well as of faecal calprotectin (FC) values with disease activity in CD and UC patients. This prospective study included 145 CD and 84 UC patients. Serum proinflammatory biomarkers and FC levels were measured and demographic, clinical and endoscopic characteristics were collected. Uni- and multivariate statistical analyses were performed. Serum IL-6 and CRP levels as well as FC values of CD patients were associated with clinical and endoscopic remission. In multivariate analysis serum IL-6 levels remained significantly associated with clinical and endoscopic remission. FC levels were also associated with endoscopic remission in CD patients. CD patients under the threshold levels of 8.5 pg/mL and 5.5 pg/mL for serum IL-6 were in 70% and 66% in clinical and endoscopic remission, respectively. Serum sIL-2R, CRP levels and FC values of UC patients were associated in univariate analysis with clinical and endoscopic remission. In multivariate analysis CRP and FC values were associated with clinical remission and serum sIL-2R as well as FC levels with endoscopic remission. UC patients under the threshold levels of 759 IU/mL and 646 IU/mL for serum sIL-2R were in 76% and 76% in clinical and endoscopic remission, respectively. Beside CRP and FC, serum IL-6 levels in CD patients and sIL-2R levels in UC patients can be a further useful non-invasive biomarker to identify the disease activity status.


Assuntos
Doenças Inflamatórias Intestinais/sangue , Interleucina-6/sangue , Receptores de Interleucina-2/sangue , Adulto , Proteína C-Reativa/metabolismo , Endoscopia , Fezes/química , Feminino , Humanos , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Solubilidade , Estatísticas não Paramétricas
5.
Medicine (Baltimore) ; 99(17): e19693, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332611

RESUMO

BACKGROUND: microRNAs have drawn more attention due to their function on the inflammatory process. The association between microRNA-21 (miR-21) expression and risk of inflammatory bowel diseases (IBD) remain inconclusive. This study was aimed to acquire a more exact estimation of this relationship. METHODS: Relevant studies were identified through searching PubMed, Embase, Wanfang, and China National Knowledge Infrastructure database. Pooled standardized mean difference and 95% confidence intervals were calculated using a random-effect model. Publication bias test, sensitivity analysis and subgroup analysis were carried out. RESULTS: A total of 20 relevant articles comprising 540 patients with ulcerative colitis (UC), 459 patients with Crohn disease (CD) and 511 non-IBD controls were included in this analysis. The expression of miR-21 was significantly increased in colon tissue of both UC and CD patients compared with non-IBD controls. However, there were no significant differences between patients with UC and CD. Moreover, increased miR-21 expression was associated with disease activity status in UC patients, but not in CD patients. CONCLUSIONS: This meta-analysis demonstrates that the higher miR-21 expression in colon tissue is positively associated with the development of UC and CD, and miR-21 might serve as a disease marker of IBD.


Assuntos
Protocolos Clínicos , Doenças Inflamatórias Intestinais/genética , MicroRNAs/genética , Humanos , Doenças Inflamatórias Intestinais/sangue , Metanálise como Assunto , MicroRNAs/análise , MicroRNAs/sangue , Literatura de Revisão como Assunto
6.
Aliment Pharmacol Ther ; 51(11): 1087-1095, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32323356

RESUMO

BACKGROUND: The diagnosis of iron deficiency is based on ferritin and transferrin saturation (TfS) in inflammatory bowel disease (IBD) patients, yet guideline thresholds are not evidence-based. Soluble transferrin receptor (sTfR) is one of the best noninvasive tests in patients with inflammation. AIMS: To evaluate the accuracy of ferritin and/or TfS for diagnosing iron deficiency in IBD and identify the optimal thresholds of these parameters using sTfR as reference. METHODS: Two hundred and two patients (2072 samples) receiving at least one infusion of biologic (vedolizumab or infliximab) were included. RESULTS: In ulcerative colitis patients with C-reactive protein (CRP) <10 mg/L, optimal iron deficiency diagnostic performances were observed with ferritin and TfS thresholds of 65 µg/L (sensitivity of 0.78 and specificity of 0.76) and 16% (sensitivity of 0.79 and specificity of 0.90), respectively. For ulcerative colitis patients with CRP > 10 mg/L, the thresholds with the best diagnostic performance were 80 µg/L (sensitivity of 0.75 and a specificity of 0.82) for ferritin and 11% for TfS (sensitivity of 0.75 and a specificity of 0.82). There was no added value for combined ferritin and TfS. No ferritin or TfS threshold had good diagnostic performance in Crohn's disease patients (AUC for ferritin was 0.65 (95% CI 0.55-0.75) and the AUC for TfS was 0.70 (95% CI 0.61-0.78). CONCLUSION: Ferritin and TfS are reliable parameters for iron deficiency diagnosis only in ulcerative colitis patients, at thresholds different from current guidelines. In Crohn's disease patients, sTfR should be used given the poor diagnostic performance of ferritin and TfS.


Assuntos
Anemia Ferropriva/diagnóstico , Ferritinas/sangue , Doenças Inflamatórias Intestinais/sangue , Receptores da Transferrina/sangue , Transferrinas/sangue , Adolescente , Adulto , Anemia Ferropriva/sangue , Anemia Ferropriva/complicações , Produtos Biológicos/uso terapêutico , Biomarcadores/análise , Biomarcadores/sangue , Estudos de Coortes , Feminino , Ferritinas/análise , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Ferro/deficiência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Transferrinas/metabolismo , Adulto Jovem
7.
J Gastroenterol Hepatol ; 35(8): 1355-1364, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32285970

RESUMO

BACKGROUND AND AIM: Lipids play important roles in inflammation and may be involved in the pathophysiology of inflammatory bowel disease (IBD). Here, we evaluated the characteristics of the plasma lipid profile in patients with IBD. METHODS: Plasma samples were collected from 20 patients with Crohn's disease (CD), 20 patients with ulcerative colitis (UC), and 10 healthy volunteers (HVs) after overnight fasting. The subjects were men between 20 and 49 years of age with no history of hyperlipidemia. A total of 698 molecular species in 22 lipid classes were analyzed by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS: Lipid classes of lysophosphatidic acid, lysophosphatidylserine (LPS), phosphatidylserine (PS), and shingosine-1-phosphate (S1P) were significantly increased in UC patients compared with the HV. The LPS, PS, and S1P levels were significantly increased, while those of lysophosphatidylinositol and phosphatidylcholine were significantly decreased in CD patients compared with HV. Among PS species, the levels of PSacyl (PSa) 40:3, PSa 38:3, and PSa 42:4 were significantly higher in CD patients, both active and remissive stage, than in HV. The LPS 18:0 level was significantly higher in CD and UC patients compared with HV. PSa 40:3 and PSa 38:3 levels positively correlated with the Crohn's Disease Activity Index, erythrocyte sedimentation rate, and platelet count and negatively correlated with hemoglobin, hematocrit, and albumin levels in CD patients. CONCLUSION: The lipid profile in IBD patients exhibits significant alterations, and PS levels are associated with clinical disease activity in CD patients.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Doenças Inflamatórias Intestinais/diagnóstico , Lipidômica/métodos , Fosfatidilserinas/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Adulto , Biomarcadores/sangue , Colite Ulcerativa/sangue , Colite Ulcerativa/diagnóstico , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Lisofosfolipídeos/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
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
9.
Medicine (Baltimore) ; 99(10): e19359, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32150077

RESUMO

Monitoring anti-TNF agents in inflammatory bowel disease (IBD) patients may be helpful in optimizing outcomes. We aimed to evaluate potential correlations among demographic, clinical, laboratory, or imaging parameters, as well as serum levels of infliximab (IFX) and adalimumab (ADA) and their respective antibodies, in the clinical management of IBD patients.A cross-sectional study of 95 patients with Crohn's disease (CD) or ulcerative colitis (UC) in maintenance therapy with infliximab or adalimumab was performed. Drug trough levels and anti-drug levels were determined using ELISA-based assays.Regarding the serum IFX dosage, patients with higher relative C-reactive protein (CRP) levels had significantly lower relative serum IFX levels (<3 µg/mL) (P = .028). In contrast, higher concentrations of anti-IFX antibodies were found in patients who were not on concomitant immunomodulators (P = .022) and who had more biological-related adverse events (P = .001) and higher levels of CRP (P = .042). Serum CRP levels were also negatively correlated with IFX (CC = -0.315; P = .033) but positively correlated with the presence of IFX antibodies (CC = 0.327; P = .027). Serum albumin dosage showed a positive correlation with levels of both IFX (CC = 0.379; P = .004) and ADA (CC = 0.699; P = .003).Although anti-TNF-α trough levels and immunogenicity do not show a significant correlation with disease outcome, our results reinforce the use of combination therapy for patients treated with infliximab. Moreover, we confirmed the presence of significant associations between anti-TNF-α trough levels and immunogenicity with body mass index (BMI), the concomitant use of immunomodulators, the rates of side effects, and laboratory markers, including serum albumin and CRP.


Assuntos
Doenças Inflamatórias Intestinais/sangue , Fator de Necrose Tumoral alfa/análise , Adalimumab/análise , Adalimumab/sangue , Adalimumab/uso terapêutico , Adulto , Biomarcadores/análise , Biomarcadores/sangue , Índice de Massa Corporal , Proteína C-Reativa/análise , Estudos Transversais , Feminino , Humanos , Infliximab/análise , Infliximab/sangue , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue
10.
BMC Vet Res ; 16(1): 69, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32087719

RESUMO

BACKGROUND: Canine inflammatory bowel disease (IBD) is a group of chronic gastrointestinal (GI) disorders of still largely unknown etiology. Canine IBD diagnosis is time-consuming and costly as other diseases with similar signs should be initially excluded. In human IBD microRNA (miR) expression changes have been reported in GI mucosa and blood. Thus, there is a possibility that miRs may provide insight into disease pathogenesis, diagnosis and even treatment of canine IBD. The aim of this study was to determine the colonic mucosal and serum relative expression of a miRs panel in dogs with large intestinal IBD and healthy control dogs. RESULTS: Compared to healthy control dogs, dogs with large intestinal IBD showed significantly increased relative expression of miR-16, miR-21, miR-122 and miR-147 in the colonic mucosa and serum, while the relative expression of miR-185, miR-192 and miR-223 was significantly decreased. Relative expression of miR-146a was significantly increased only in the serum of dogs with large intestinal IBD. Furthermore, serum miR-192 and miR-223 relative expression correlated to disease activity and endoscopic score, respectively. CONCLUSION: Our data suggest the existence of dysregulated miRs expression patterns in canine IBD and support the potential future use of serum miRs as useful noninvasive biomarkers.


Assuntos
Doenças do Cão/sangue , Doenças Inflamatórias Intestinais/veterinária , MicroRNAs/genética , Animais , Biomarcadores/sangue , Colo/metabolismo , Doenças do Cão/genética , Doenças do Cão/metabolismo , Doenças do Cão/patologia , Cães , Feminino , Perfilação da Expressão Gênica/veterinária , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Masculino , MicroRNAs/metabolismo
11.
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
12.
J Vet Intern Med ; 34(1): 92-97, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31825538

RESUMO

BACKGROUND: T cells play a key role in the pathogenesis of chronic inflammatory enteropathy (CIE) in dogs. Cluster of differentiation 3 (CD3) antigen serves as a marker for T cells. In human medicine, Ki-67 is an indicator for cell growth but there are only a few studies in dogs with CIE. OBJECTIVE: To investigate Ki-67 in relation to T cells as a marker for CIE in dogs. ANIMALS: Eleven dogs with CIE and 6 healthy beagle controls (CO). METHODS: Retrospective case-control study. Dogs were clinically assessed by the Canine Chronic Enteropathy Clinical Activity Index (CCECAI). Duodenal mucosal biopsy samples were endoscopically obtained for histopathologic examination by means of the World Small Animal Veterinary Association score. Double-labeled immunofluorescence was used to investigate colocalization of Ki-67 and CD3 in epithelium and lamina propria (LP) of villi and crypts. RESULTS: Dogs with CIE had significantly higher clinical score (median, 5.0; interquartile range [IQR], 3-7) compared to CO (all 0; P < .001). The Ki-67/CD3 double-positive cells were significantly increased in the LP of the crypt region of CIE dogs (0.63 cells/mm2 ; IQR, 0-0.54) versus CO (0.08 cells/mm2 ; IQR, 0-0.26; P = .044). A significant correlation was found between CCECAI and the Ki-67/CD3 ratio in the LP of the crypt region (r = 0.670; P = .012) in dogs with CIE. CONCLUSIONS AND CLINICAL IMPORTANCE: The Ki-67/CD3 ratio is upregulated in the LP crypt region of dogs with CIE and it correlates with clinical severity. Therefore, Ki-67/CD3 could be a useful tool for detection of CIE.


Assuntos
Complexo CD3/sangue , Doenças do Cão/sangue , Doenças Inflamatórias Intestinais/veterinária , Antígeno Ki-67/sangue , Animais , Estudos de Casos e Controles , Cães , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/diagnóstico , Masculino , Estudos Retrospectivos
13.
J Pharm Biomed Anal ; 177: 112842, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31526960

RESUMO

BACKGROUND: Anti-drug-antibodies (ADA) against infliximab are frequently measured in patients receiving infliximab treatment with loss of response and undetectable infliximab concentrations. Different ADA bridging assays (1st generation, 2nd generation and ready-to-use kit) have been developed successively and were applied over the last 10 years, making comparison between ADA concentrations very challenging. A cutoff of 8 µg/ml was established to discriminate low from high ADA concentrations using the 1st generation ADA bridging assay. The objective of this study was to enable comparison of ADA concentrations determined with the different assays that were developed over the years. METHODS: 166 serum samples were collected from patients with inflammatory bowel disease treated with infliximab. 98 samples were measured simultaneously with the 1st and 2nd generation ADA assay, 67 serum samples were measured with the 2nd generation assay and the ready-to-use kit. RESULTS: From our ADA concentration comparison experiments, we deduced that the previously established cutoff of 8 µg/ml with the 1st generation ELISA has a similar impact as the cutoff of 374 ng/ml with the 2nd generation ELISA and a cutoff of 119 ng/ml in the ready-to-use ELISA kit. CONCLUSION: ADA concentrations measured with the different assays were compared and a cutoff concentration was determined for each of them to distinguish between low and high ADA concentrations. These cutoff concentrations may serve as a tool for clinicians to make treatment decisions for patients with a loss of response to infliximab and undetectable infliximab serum concentrations.


Assuntos
Anticorpos/sangue , Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/imunologia , Anticorpos/imunologia , Calibragem , Tomada de Decisão Clínica/métodos , Monitoramento de Medicamentos/instrumentação , Monitoramento de Medicamentos/normas , Resistência a Medicamentos , Ensaio de Imunoadsorção Enzimática/instrumentação , Ensaio de Imunoadsorção Enzimática/métodos , Ensaio de Imunoadsorção Enzimática/normas , Estudos de Viabilidade , Fármacos Gastrointestinais/administração & dosagem , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Infliximab/administração & dosagem , Sensibilidade e Especificidade
14.
Inflamm Bowel Dis ; 26(2): 263-270, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31247074

RESUMO

BACKGROUND: Increasing evidence supports the use of reactive therapeutic drug monitoring (TDM) in Crohn's disease (CD) and ulcerative colitis (UC) following secondary loss of response. It is still unknown if proactive TDM can improve clinical outcomes. METHODS: Consecutive patients completing infliximab (IFX) induction therapy were prospectively allocated into a proactive TDM protocol (pTDM). Before the fourth infusion and every 2 infusions, IFX trough levels and antidrug antibodies were measured using a drug-sensitive assay (Theradiag, Lisa Tracker). Treatment was proactively escalated aiming at an IFX trough level between 3 and 7 ug/mL (CD) and 5 and 10 ug/mL (UC). A retrospective cohort treated with IFX but without TDM served as the reference group. End points included the need for surgery, hospitalization, treatment discontinuation, and mucosal healing at 2 years of follow-up. RESULTS: Two hundred five patients were included, 56 in the proactive regimen. Treatment escalation was more common in pTDM patients (76.8% vs 25.5%; P < 0.001), who also required less surgery (8.9% vs 20.8%; P = 0.032) and presented higher rates of mucosal healing (73.2% vs 38.9%; P < 0.0001). Proactive TDM significantly decreased the odds of reaching any unfavorable outcome (odds ratio, 0.358; 95% confidence interval, 0.188-0.683; P = 0.002). CONCLUSIONS: Proactive TDM is associated with fewer surgeries and higher rates of mucosal healing than conventional non-TDM-based management.


Assuntos
Monitoramento de Medicamentos/métodos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/sangue , Infliximab/uso terapêutico , Membrana Mucosa/metabolismo , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Gerenciamento Clínico , Feminino , Seguimentos , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Cicatrização , Adulto Jovem
15.
Gut ; 69(2): 252-263, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31092589

RESUMO

OBJECTIVE: To study the role of α4ß7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4ß7 inhibition with regard to intestinal wound healing. DESIGN: We studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4ß7 integrin. RESULTS: Classical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4ß7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4ß7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4ß7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab. CONCLUSION: In addition to reported effects on lymphocytes, anti-α4ß7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Integrinas/fisiologia , Intestinos/patologia , Monócitos/fisiologia , Cicatrização/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Estudos de Casos e Controles , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Quimiotaxia de Leucócito/fisiologia , Feminino , Fármacos Gastrointestinais/farmacologia , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/fisiopatologia , Integrinas/antagonistas & inibidores , Integrinas/sangue , Mucosa Intestinal/metabolismo , Intestinos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Cicatrização/efeitos dos fármacos , Adulto Jovem
16.
J Gastroenterol Hepatol ; 35(8): 1302-1306, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31881552

RESUMO

BACKGROUND AND AIM: Therapeutic drug monitoring of infliximab (IFX) using the established laboratory-based enzyme-linked immunosorbent assay (ELISA) cannot produce results fast enough to allow IFX dose adjustments prior to each IFX infusion. We investigate the validity of IFX trough levels obtained through the Quantum Blue IFX (QB-IFX) rapid assay compared with the established ELISA. METHODS: Adult inflammatory bowel disease patients receiving maintenance IFX infusions at Middlemore Hospital and Dunedin Public Hospital were prospectively recruited from July to October 2016. Serum samples were stored at -40 °C until processed using QB-IFX by a clinician at Middlemore Hospital and a research staff at Dunedin Public Hospital strictly following the manufacturers' instructions in an open label fashion. RESULTS: Forty four inflammatory bowel disease patients were recruited. Median duration of IFX therapy was 21 months (interquartile range: 12-44). Overall, the correlation between ELISA and QB-IFX trough levels was 0.73 (95% confidence interval [CI]: 0.53-0.85). The sensitivity and specificity of a QB-IFX level < 7 in detecting an ELISA level < 7 were 0.79 (95% CI: 0.59-0.92) and 0.75 (95% CI: 0.48-0.93), respectively. Conversely, the sensitivity and specificity of a QB-IFX level < 2 detecting an ELISA level < 2 were 1.00 (95% CI: 0.52, 1.00) and 0.97 (95% CI: 0.85, 1.00), respectively. CONCLUSION: The QB-IFX had excellent sensitivity and specificity for IFX levels < 2 obtained with the established ELISA. Therefore, QB-IFX could be used for real time dosing decisions when the IFX level is low and dose escalation is required.


Assuntos
Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos/métodos , Ensaio de Imunoadsorção Enzimática , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/sangue , Humanos , Doenças Inflamatórias Intestinais/sangue , Infliximab/administração & dosagem , Quimioterapia de Manutenção
18.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(6): 740-748, 2020 Dec 30.
Artigo em Chinês | MEDLINE | ID: mdl-33423720

RESUMO

Objective To investigate the correlation between serum total 25-hydroxyvitamin D[T-25(OH)D]level and fecal microbiota in patients with inflammatory bowel disease(IBD). Methods Twenty-three patients with IBD completed the tests for serum T-25(OH)D,and the fecal microbiota was studied using V4 hypervariable region of 16S ribosomal RNA(rRNA)gene sequencing.According to serum T-25(OH)D level,the patients were divided into three groups including vitamin D normal group(n=5),vitamin D insufficiency group(n=5),and vitamin D deficiency group(n=13). Results There was no significant difference between these three groups in Alpha diversity or Beta diversity.Ternary pot at phylum level revealed that the abundance of Proteobacteria was the highest in the vitamin D deficiency group and Actinomycete was the highest in the vitamin D sufficiency group.Spearman correlation analysis showed that at the phylum level serum T-25(OH)D level was negatively correlated with the abundance of Proteobacteria(r=-0.445,P=0.033)and positively correlated with the abundance of Actinomycetes (r =0.447,P=0.033);at family level it was positively correlated with the abundance of Lachnospiraceae (r =0.414,P=0.049),Bifidobacteriaceae (r =0.468,P=0.024),Erysipelotrichacea (r =0.584,P=0.003),and Eggerthellaceae (r =0.507,P=0.014)and negatively correlated with the abundance of Aerococcaceae (r=-0.514, P=0.012);and at genus level it was positively correlated with the abundance of Blautia (r=0.459,P=0.028),Bifidobacterium (r=0.468,P=0.024),unidentified Erysipelotrichacea (r=0.485,P=0.019),Faecalitalea (r=0.544,P=0.007),Anaerostipes (r=0.475,P=0.022),Romboutsia (r=0.510,P=0.013),Flavonifractor (r=0.455,P=0.029),and Erysipelatoclostridium (r=0.617,P=0.002). Conclusions The fecal microbiota composition varies in IBD patients with different serum T-25(OH)D levels.The abundance of Proteobacteria increases and the abundance of Actinomyces decreases in IBD patients with vitamin D deficiency compared with IBD patients with normal vitamin D level.Serum T-25(OH)D level is negatively correlated with the abundance of some harmful bacteria(e.g.Proteobacteria)but is positively correlated with the abundance of some probiotics such as Lachnospiraceae,Bifidobacteriaceae,and Anaerostipes.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/microbiologia , Vitamina D/sangue , Bactérias/classificação , Fezes/microbiologia , Humanos , RNA Ribossômico 16S/genética
19.
Turk J Gastroenterol ; 30(12): 1025-1029, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31854307

RESUMO

BACKGROUND/AIMS: There is an increased tendency for thrombosis and thromboembolic complications in patients with inflammatory bowel disease (IBD). The aim of the present study was to determine the serum concentrations of thrombin-activatable fibrinolysis inhibitor (TAFI), tissue factor pathway inhibitor (TFPI) and a disintegrin and metalloproteinase with thrombospondin motif-13 (ADAMTS-13) in patients with IBD and to assess their possible role in the etiopathogenesis of the disease. MATERIALS AND METHODS: Thirty-four patients with IBD (23 ulcerative colitis and 11 Crohn's disease) and 20 healthy controls were included in the present study. TAFI, TFPI, and ADAMTS-13 concentrations were determined by enzyme-linked immunosorbent assay. RESULTS: Mean TAFI, TFPI, and ADAMTS-13 concentrations in the patient group were 17.75 ng/ml, 72.10 ng/ml, and 14.90 U/l, respectively. In the control group, these values were 117.10 ng/ml, 300 ng/ml, and 191.55 U/l, respectively. TAFI, TFPI, and ADAMTS-13 values were significantly lower in the patient group than in the control group (all p<0.01). CONCLUSION: TAFI, TFPI, and ADAMTS-13 levels were significantly lower in the patient group. These findings indicate the presence of a clear, multifactorial imbalance in the coagulation-fibrinolytic system in the patient group. It is also possible that this imbalance in the coagulation and fibrinolytic system may play a role in the still unclear etiopathogenesis of the disease.


Assuntos
Proteína ADAMTS13/sangue , Carboxipeptidase B2/sangue , Doenças Inflamatórias Intestinais/sangue , Lipoproteínas/sangue , Adulto , Feminino , Humanos , Doenças Inflamatórias Intestinais/etiologia , Masculino
20.
Cell ; 179(5): 1160-1176.e24, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31730855

RESUMO

Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Mucosa Intestinal/patologia , Antígenos CD/metabolismo , Apirase/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Morte Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Criança , Estudos de Coortes , Colo/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Dipiridamol/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença , Homeostase/efeitos dos fármacos , Humanos , Imunoglobulina G/sangue , Memória Imunológica , Inflamação/patologia , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/genética , Interferon Tipo I/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metilprednisolona/farmacologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo
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