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1.
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
2.
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
3.
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
5.
Clin Biochem ; 74: 73-75, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31669514

RESUMO

BACKGROUND: Infliximab (IFX) is a monoclonal antibody used to treat patients with inflammatory bowel disease (IBD). For IFX therapeutic drug monitoring (TDM), the most commonly used analysis is enzyme-linked immunosorbent assays (ELISA) which do not allow results to be provided in real-time. The aim of this study was to compare the in-house ELISA (Promonitor IFX) with the much faster assay Quantum Blue® IFX (QB) for quantification of serum IFX concentration among IBD patients in maintenance IFX therapy. METHODS: We studied 30 serum samples from outpatients in IFX maintenance therapy at Copenhagen University Hospital Hvidovre, Denmark. Samples were used to compare IFX measurements from Promonitor IFX with QB. Therapeutic intervals of <3 µg/mL, 3-7 µg/mL and >7 µg/mL were equally covered. Differences were evaluated using Bland-Altman plots and Student t-test. Correlation was evaluated using x,y-plot and Pearson's correlation coefficient. The intermediate imprecision (CV%) of QB was measured at two levels (3 µg/mL and 7 µg/mL). For qualitative comparison, weighted kappa statistics (κ) were determined after stratification of results by therapeutic interval. RESULTS: Promonitor IFX and QB were strongly correlated (r = 0.92, p < 0.001). The mean difference between Promonitor IFX and QB was -0.57 µg/mL (p = 0.2). The CV% of QB was 16.3% at 3 µg/mL and 16.7% at 7 µg/mL. Classification of results according to therapeutic interval showed almost perfect agreement (κ = 0.81). CONCLUSIONS: QB is a suitable alternative to Promonitor IFX for TDM in patients treated with IFX for IBD. The results revealed a strong correlation between methods, in particular at lower IFX concentrations, representing the most interesting clinical range. When the samples were stratified according to the therapeutic interval, an almost perfect agreement between the methods was observed.


Assuntos
Monitoramento de Medicamentos/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Fármacos Gastrointestinais/sangue , Doenças Inflamatórias Intestinais/sangue , Infliximab/sangue , Sistemas Automatizados de Assistência Junto ao Leito , Dinamarca , Fármacos Gastrointestinais/uso terapêutico , Hospitais Universitários , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Pesquisa Qualitativa
6.
Medicine (Baltimore) ; 98(38): e17208, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567972

RESUMO

Ulcerative colitis (UC) and Crohn disease (CD) are the most common forms of inflammatory bowel disease (IBD). Because these subtypes of IBD are characterized by periods of activity and remission, an understanding of the modulation of biochemical markers with the clinical features of IBD or its treatment, may be useful for determining the correct treatment protocol.This study aimed to evaluate the serum levels of 27 protein biomarkers to determine their association with IBD, correlation with clinical findings of disease, and modulation according to the pharmacologic therapy.A case-control study was carried out in Zacatecas, Mexico. The 27 protein profiles of serum from 53 participants (23 UC, 11 CD, and 19 controls) were evaluated using the Pro Human Cytokine 27-Plex immunoassay (Bio-Rad).Considering the controls as a reference, the group with IBD endoscopic activity showed higher serum levels of granulocyte colony-stimulating factor (G-CSF), interleukin 1 receptor antagonist (IL-1Ra), and platelet-derived growth factor BB (PDGF-BB) (P < .05). Interferon-induced protein 10 (IP-10) was associated with extraintestinal symptoms of disease (P = .041). Both PDGF-BB and interleukin 6 (IL-6) showed the strongest correlations with clinical features of IBD. Levels of IL-6, IL-7, and monocyte chemoattractant protein 1 were higher with 5-aminosalicylic acid (5-ASA) + Azathioprine therapy than controls (P < .05). Combined therapy with 5-ASA + Adalimumab led to the strongest changes in marker modulation: IL-4, IL-5, IL-15, and PDGF-BB, were upregulated (P < .05).Elevated serum levels of G-CSF, IL-1Ra, and PDGF-BB were associated with IBD endoscopic activity, and of IP-10 with extraintestinal manifestations of IBD. Combined therapy of 5-ASA + Adalimumab produced significant upregulation of IL-4, IL-5, IL-15, and PDGF-BB. This information may be useful for deciding on the course of pharmacologic therapy for patients with IBD and for generating new therapy alternatives to improve the outcome of patients with IBD.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Doenças Inflamatórias Intestinais/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Adalimumab/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Azatioprina/uso terapêutico , Becaplermina/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocina CXCL10/sangue , Feminino , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Interleucina-6/sangue , Masculino , Mesalamina/uso terapêutico , Pessoa de Meia-Idade , Receptores de Interleucina-1/sangue
7.
J Vet Intern Med ; 33(5): 1995-2004, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31496004

RESUMO

BACKGROUND: The cause of low serum vitamin D concentrations in dogs with chronic inflammatory enteropathy (CIE) is not well understood. OBJECTIVE: Improve understanding of pathogenesis of low serum vitamin D concentrations in dogs with CIE by comparing several clinical, clinicopathologic, and histologic variables between CIE dogs with low and normal serum 25-hydroxyvitamin D concentrations (25[OH]D). ANIMALS: Fifteen dogs with CIE and low serum 25[OH]D concentrations; 15 dogs with CIE and normal serum 25(OH)D concentrations. METHODS: Prospective cohort study. Clinical and clinicopathologic variables were compared between groups. Correlations between serum 25(OH)D concentration and histopathologic variables were assessed. RESULTS: Dogs with CIE and low serum 25(OH)D concentrations had higher canine chronic enteropathy clinical activity index scores (P = .003), lower serum α-tocopherol (P < .001), cholesterol (P < .001), and albumin (P < .001) concentrations and higher serum C-reactive protein (P = .004) concentrations compared to CIE dogs with normal serum 25(OH)D concentrations. Serum concentrations of vitamin D-binding protein (VDBP) were not different between groups (P = .91). Duodenal morphologic and inflammatory histopathological scores (P = .002 and P = .004, respectively) and total histopathological scores in duodenum and combined duodenum and ileum negatively correlated with serum 25(OH)D concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: The pathogenesis of low serum vitamin D concentrations in dogs with CIE is likely multifactorial. Fat malabsorption deserves further study in dogs with low serum vitamin D concentration and CIE. Loss of VDBP does not appear to be an important cause of low serum vitamin D concentration in dogs with CIE.


Assuntos
Doenças do Cão/patologia , Doenças Inflamatórias Intestinais/veterinária , Vitamina D/análogos & derivados , Animais , Proteína C-Reativa/análise , Colesterol/sangue , Estudos de Coortes , Doenças do Cão/sangue , Cães , Feminino , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/patologia , Masculino , Estudos Prospectivos , Albumina Sérica/análise , Tocoferóis/sangue , Vitamina D/sangue , Proteína de Ligação a Vitamina D/sangue
8.
Gastroenterology ; 157(5): 1338-1351.e8, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31401142

RESUMO

BACKGROUND & AIMS: Some patients develop anti-drug antibodies (ADAs), which reduce the efficacy of infliximab, a monoclonal antibody against tumor necrosis factor (TNF), in the treatment of immune-mediated diseases, including inflammatory bowel diseases. ADAs arise inconsistently, and it is not clear what factors determine their formation. We investigated features of the immune system, the infliximab antibody, and its complex with TNF that might contribute to ADA generation. METHODS: C57BL/6 mice were given injections of infliximab and recombinant human TNF or infliximab F(ab')2 fragments. Blood samples were collected every 2-3 days for 2 weeks and weekly thereafter for up to 6 weeks; infliximab-TNF complexes and ADAs were measured by enzyme-linked immunosorbent assay (ELISA). Intestinal biopsy and blood samples were obtained from patients having endoscopy who had received infliximab therapy for inflammatory bowel diseases; infliximab-TNF complexes were measured with ELISA. Infliximab-specific plasma cells were detected in patient tissue samples by using mass cytometry. We studied activation of innate immune cells in peripheral blood mononuclear cells (PBMCs) from healthy donors incubated with infliximab or infliximab-TNF complexes; toll-like receptors (TLRs) were blocked with antibodies, endocytosis was blocked with the inhibitor PitStop2, and cytokine expression was measured by real-time polymerase chain reaction and ELISAs. Uptake of infliximab and infliximab-TNF complexes by THP-1 cells was measured with confocal microscopy. RESULTS: Mice given increasing doses of infliximab produced increasing levels of ADAs. Blood samples from mice given injections of human TNF and infliximab contained infliximab-TNF complexes; complex formation was associated with ADA formation with an area under the curve of 0.944 (95% confidence interval, 0.851-1.000; P = .003). Intestinal tissues from patients, but not blood samples, contained infliximab-TNF complexes and infliximab-specific plasma cells. Incubation of PBMCs with infliximab-TNF complexes resulted in a 4.74-fold increase in level of interleukin (IL) 1ß (IL1B) messenger RNA (P for comparison = .005), increased IL1B protein secretion, and a 2.69-fold increase in the expression of TNF messenger RNA (P for comparison = 0.013) compared with control PBMCs. Infliximab reduced only IL1B and TNF expression. Antibodies against TLR2 or TLR4 did not block the increases in IL1B or TNF expression, but endocytosis was required. THP-1 cells endocytosed higher levels of infliximab-TNF complexes than infliximab alone. CONCLUSIONS: In mice, we found ADA formation to increase with dose of infliximab given and concentration of infliximab-TNF complexes detected in blood. Based on studies of human intestinal tissues and blood samples, we propose that infliximab-TNF complexes formed in the intestine are endocytosed by and activate innate immune cells, which increase expression of IL1B and TNF and production of antibodies against the drug complex. It is therefore important to optimize the infliximab dose to a level that is effective but does not activate an innate immune response against the drug-TNF complex.


Assuntos
Anticorpos/sangue , Fragmentos Fab das Imunoglobulinas/imunologia , Doenças Inflamatórias Intestinais/imunologia , Infliximab/imunologia , Intestinos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Estudos de Casos e Controles , Endocitose , Feminino , Humanos , Imunidade Inata , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/administração & dosagem , Injeções Intravenosas , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Células THP-1 , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo
9.
Pathology ; 51(6): 634-639, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31466865

RESUMO

Traditionally anti-neutrophil cytoplasmic antibodies (ANCA) are used to subtype patients with inflammatory bowel disease (IBD) and to predict primary sclerosing cholangitis (PSC). The clinical utility of this testing in the Australian context is not known. Our retrospective, cross-sectional study looked at the results of ANCA testing performed during routine clinical review and aimed to retrospectively review (1) the distribution of different ANCA subtypes for IBD patients, (2) the temporal change of ANCA status, and (3) the predictive value of ANCA for PSC. Sixty-four IBD patients attending our hospital gastroenterology clinic between 2012 and 2016 had at least one ANCA test requested. Surprisingly, >80% of the IBD patients in our cohort who underwent ANCA testing had a positive ANCA result and a significant proportion had positive PR3 antibodies. However, no specific ANCA pattern predicted a specific IBD subtype or clinical course. Pairing ANCA and anti-Saccharomyces cerevisiae (ASCA) did not add value in subtyping IBD for these patients. Our study suggests that there is little value in ordering an ANCA for patients with IBD.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Doenças Inflamatórias Intestinais/imunologia , Adolescente , Adulto , Idoso , Austrália , Criança , Estudos Transversais , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
10.
J Trace Elem Med Biol ; 55: 121-126, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31345349

RESUMO

INTRODUCTION: Inflammatory bowel disease (IBD), a chronic inflammatory disorder of gastrointestinal tract, arises from complex interaction between genetics, environment, gut microbiota and mucosal immune response. Along with clinical, endoscopic and radiological evaluation various biomarkers are needed as an additional diagnostic tool, as well as to predict disease course and therapeutic outcomes. AIM: The aim of this study was to evaluate clinical value of essential trace elements (ETEs) serum concentration profile in the assessment of pediatric IBD diseases development. MATERIALS AND METHODS: Concentration of five ETEs: iron (Fe), zinc (Zn), copper (Cu), manganese (Mn) and selenium (Se) in serum of 41 children with newly diagnosed IBD (27 CD and 14 UC) and 20 healthy controls were determined by inductively coupled plasma mass spectrometry (ICP-MS) and atomic fluorescence spectrometry (AFS) at the moment of diagnosis and after one year of treatment. RESULTS: The obtained results revealed significant differences in serum concentration profile of studied ETEs' for IBD pediatric patients and healthy controls. Decrease of iron, zinc and selenium and increase of copper and manganese serum concentration were observed in IBD patients at the time of diagnosis. The changes were reversible and after one year of treatment the studied ETEs serum concentration profile resembled much more that observed for healthy controls. Correlations between studied ETEs levels within cases (IBD, CD, UC) were also found to be different from those in healthy controls (HC). CONCLUSION: Although much more studies are required on the subject our results demonstrate a clinical value of ETEs serum concentration profile in pediatric IBD patients regarding disease development.


Assuntos
Progressão da Doença , Doenças Inflamatórias Intestinais/sangue , Oligoelementos/sangue , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Doenças Inflamatórias Intestinais/diagnóstico , Masculino , Estudos Prospectivos
11.
Gut ; 68(10): 1893-1899, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31227590

RESUMO

The two major forms of inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated conditions characterised by an increased production of pro-inflammatory cytokines that act as critical drivers of intestinal inflammation. Anti-cytokine therapy has been shown to improve clinical outcomes in IBD. Janus kinases (JAKs) are tyrosine kinases that bind different intracellular cytokine receptors, leading to phosphorylation of signal transducer and activation of transcription molecules implicated on targeted gene transcription. Four isoforms of JAKs have been described: JAK1, JAK2, JAK3 and TYK2. Oral JAK inhibitors (JAKi) have been developed as synergic anti-cytokine therapy in IBD, showing different selectivity towards JAK isoforms. Tofacitinib, a pan-JAK inhibitor, has been recently approved for the treatment of moderate-to-severe UC. With the aim of improving the benefit: risk ratio of this drug class, several second-generation subtype-selective JAKi are under development. However, whether selective inhibition of JAK isoforms is associated with an increased clinical efficacy and/or a better safety profile remains debatable. The aim of this review is to critically review the preclinical and clinical data for the differential selectivity of JAK inhibitors and to summarise the potential clinical implications of the selective JAK inhibitors under development for UC and CD.


Assuntos
Imunossupressores/uso terapêutico , Imunoterapia/métodos , Doenças Inflamatórias Intestinais/terapia , Janus Quinases/sangue , Biomarcadores/sangue , Citocinas/sangue , Humanos , Doenças Inflamatórias Intestinais/sangue , Janus Quinases/efeitos dos fármacos
12.
Nat Commun ; 10(1): 2686, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217423

RESUMO

Inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis. Each disease is characterized by a diverse set of potential manifestations, which determine patients' disease phenotype. Current understanding of phenotype determinants is limited, despite increasing prevalence and healthcare costs. Diagnosis and monitoring of disease requires invasive procedures, such as endoscopy and tissue biopsy. Here we report signatures of heterogeneity between disease diagnoses and phenotypes. Using mass cytometry, we analyze leukocyte subsets, characterize their function(s), and examine gut-homing molecule expression in blood and intestinal tissue from healthy and/or IBD subjects. Some signatures persist in IBD despite remission, and many signatures are highly represented by leukocytes that express gut trafficking molecules. Moreover, distinct systemic and local immune signatures suggest patterns of cell localization in disease. Our findings highlight the importance of gut tropic leukocytes in circulation and reveal that blood-based immune signatures differentiate clinically relevant subsets of IBD.


Assuntos
Citometria de Fluxo/métodos , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Leucócitos/imunologia , Espectrometria de Massas/métodos , Adulto , Idoso , Biópsia , Separação Celular , Colonoscopia , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , Intestinos/imunologia , Intestinos/patologia , Masculino , Pessoa de Meia-Idade , Exacerbação dos Sintomas , Adulto Jovem
13.
Mediators Inflamm ; 2019: 5256460, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31148945

RESUMO

The associations between serum total bilirubin (sTB) levels, inflammatory marker levels, and disease activity are not well understood in patients with inflammatory bowel disease (IBD). The present study investigated the association between sTB levels and disease activity in patients with IBD. We conducted a retrospective study with a total of 242 consecutive patients with Crohn's disease (CD) and 211 consecutive patients with ulcerative colitis (UC). The Crohn's Disease Activity Index (CDAI) score was used to assess disease activity in patients with CD and the Mayo score of patients with UC. 255 clinically healthy subjects comprised the control group, which come from the same geographic area as the IBD group. We retrieved the clinical and laboratory parameters of patients with IBD from the medical records. Patients with IBD displayed significantly lower sTB levels than controls. sTB levels were negatively associated with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC), and hemoglobin (Hb) levels in patients with IBD. Additionally, there was a negative association between sTB levels and the CDAI score of patients with CD. sTB levels were also negatively associated with the Mayo score of patients with UC. IBD patients had lower sTB levels when compared with controls, and there was a negative correlation between sTB levels and disease activity in patients with IBD. Increased reactive oxygen species production in IBD is likely to be responsible for increased consumption of bilirubin in patients with IBD, leading to further intestinal injury. Reducing oxidative stress may be therapeutic for these patients.


Assuntos
Bilirrubina/sangue , Colite Ulcerativa/sangue , Doenças Inflamatórias Intestinais/sangue , Adulto , Proteína C-Reativa/metabolismo , Feminino , Hemoglobinas/metabolismo , Humanos , Complexo Antígeno L1 Leucocitário/sangue , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Estudos Retrospectivos
14.
Artigo em Inglês | MEDLINE | ID: mdl-31152640

RESUMO

The active metabolite of azathioprine, 6-thioguanine nucleotide (6-TGN) is the main component responsible for the immunosuppressive effect in treatment of inflammatory bowel disease (IBD). The aim of this study was to assess the correlation between the concentration of 6-thioguanine nucleotide and disease activity, azathioprine-related adverse effects and time duration of treatment in patients with inflammatory bowel disease. Thirty-four patients were included in this study. Type of disease, gender, time duration of therapy and adverse effects were recorded. Metabolite concentration was determined by high performance liquid chromatography. Twenty-one percent of patients have experienced an adverse effect, with leucocytopenia most commonly occurring (42.9%). More adverse effects were registered when patients were treated with azathioprine in a period of less than 3 months in comparison to the group of patients that have been under therapy between 3-12 months and more than 12 months (p˂0.05). Most of the patients that presented any adverse effect had high 6-TGN concentration (>450 pmol/8x108 Er). The mean value of 6-TGN metabolite concentration in IBD patients treated with azathioprine was 437.46 pmol/8x108 Er ± 198.82 pmol/8x108. The time duration of azathioprine treatment did not have any significant impact on the achieved 6-TGN concentration (p>0.05).Twenty patients (58.9%) had achieved remission after therapy initiation with azathioprine. More alertness is recommended to clinicians towards patients in the first 3 months of the therapy. Our study demonstrated that higher 6-TGN concentration is associated with azathioprine toxicity.


Assuntos
Azatioprina/efeitos adversos , Nucleotídeos de Guanina/metabolismo , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Tionucleotídeos/metabolismo , Adulto , Azatioprina/uso terapêutico , Monitoramento de Medicamentos/métodos , Feminino , Nucleotídeos de Guanina/sangue , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tionucleotídeos/sangue , Fatores de Tempo
15.
BMC Gastroenterol ; 19(1): 83, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159802

RESUMO

BACKGROUND: Patients with inflammatory bowel disease (IBD) present with reduced serum insulin-like growth factor I (IGF-I). Anti-inflammatory treatment with prednisolone or infliximab ameliorates symptoms and increases circulating IGF-I, but prednisolone induces catabolism, whereas infliximab may promote protein synthesis. Recently, stanniocalcin-2 (STC2) was discovered as a novel inhibitor of the enzyme pregnancy-associated plasma protein-A (PAPP-A), which modulates IGF-I activity. PAPP-A can cleave IGF binding protein-4 (IGFBP-4), upon which IGF-I is liberated. We hypothesized that prednisolone and infliximab exert different effects on levels of STC2, PAPP-A, and IGFBP-4, thereby explaining the distinct metabolic effects of prednisolone and infliximab. METHODS: Thirty-eight patients with active IBD treated with either prednisolone (n = 17) or infliximab (n = 21) were examined before and after 7 days of treatment. Circulating levels of IGF-I, IGF-II, IGFBP-3, PAPP-A, and STC2 were measured by immunoassays. Intact IGFBP-4 and two IGFBP-4 fragments were determined by a novel immunoassay. Bioactive IGF was assessed by cell-based IGF receptor activation assay. Concentrations of IGFBP-4, PAPP-A, and STC2 on day 0 and 7 were compared to healthy control subjects. RESULTS: Following seven days of prednisolone treatment, total and bioactive IGF-I were increased (p < 0.001 and p < 0.05, respectively). Upon infliximab treatment, total IGF-I levels were augmented (p < 0.05), yet IGF bioactivity remained unaltered. Intact IGFBP-4 and the two IGFBP-4 fragments generated upon cleavage by PAPP-A were all decreased following treatment with either prednisolone or infliximab (all p < 0.05). PAPP-A levels were only increased by infliximab (p = 0.005), whereas the inhibitor STC2 did not respond to any of the treatments. CONCLUSION: IGF-I and IGFBP-4 concentrations were markedly altered in patients with IBD and near-normalized with disease remission following treatment with prednisolone or infliximab. Thus, IGFBP-4 may modulate IGF bioavailability in IBD. The effect of immunosuppression did not appear to extend beyond the regulation of IGF and IGFBP-4, as neither PAPP-A nor STC2 were discernibly affected. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00955123 . Date of registration: August 7, 2009 (retrospectively registered).


Assuntos
Glicoproteínas/sangue , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/farmacocinética , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Prednisolona/farmacocinética , Proteína Plasmática A Associada à Gravidez/efeitos dos fármacos , Adulto , Disponibilidade Biológica , Feminino , Humanos , Imunossupressão , Quimioterapia de Indução , Doenças Inflamatórias Intestinais/sangue , Masculino
16.
Vet J ; 248: 37-41, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31113560

RESUMO

Human studies have shown an association between certain platelet indices and active inflammatory bowel disease when compared to healthy controls. The objectives of this retrospective study were to determine if any platelet indices differ between dogs with chronic enteropathies and healthy age- and sex-matched control dogs and are predictive of the severity of chronic enteropathy based on canine chronic enteropathy clinical activity index (CCECAI) scores. Medical records for 22 chronic enteropathy-positive dogs and 22 healthy control dogs were reviewed for historical and physical examination findings, platelet indices, and histologic diagnoses of chronic enteropathy. Platelet indices were compared between the groups, and an association between platelet indices and CCECAI scores in dogs with chronic enteropathy was investigated. Chronic diarrhea and weight loss were common clinical signs associated with chronic enteropathy. Lymphoplasmacytic enteritis was the most common histologic diagnosis. Only one platelet index, platelet component distribution width (P = 0.045), was found to be significantly different between the groups. For predicting severity of disease, determined by CCECAI score, statistically significant differences in indices associated with higher scores were platelet count (P = 0.024) and platelet dry mass distribution width (P = 0.036). Only platelet component distribution width showed potential in characterizing dogs with chronic enteropathy compared to normal dogs. Elevated platelet count and decreased platelet dry mass distribution width had a significant effect on total CCECAI scores. These findings suggest further investigation into the utility of platelet indices as predictors of disease presence and severity in dogs with chronic enteropathy is warranted.


Assuntos
Plaquetas/fisiologia , Doenças do Cão/sangue , Doenças Inflamatórias Intestinais/veterinária , Animais , Biomarcadores , Cães , Feminino , Doenças Inflamatórias Intestinais/sangue , Masculino , Registros , Estudos Retrospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença
17.
PLoS One ; 14(5): e0217238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120977

RESUMO

OBJECTIVES: Vitamin D deficiency predicts unfavorable disease outcomes in inflammatory bowel disease. Endogenous vitamin D synthesis is affected by seasonal factors including sunlight exposure, raising the question whether seasonality determines the risk of vitamin D deficiency and may mask other clinical risk factors. METHODS: Univariable and multiple regression analyses were performed in a retrospective cohort of 384 patients to determine risk factors for vitamin D deficiency. Since the observed 25-hydroxyvitamin D [25(OH)D] concentrations followed a sinusoidal pattern over the year, all 25(OH)D concentrations were normalized for the predicted variability of the respective day of analysis based on a sinusoidal regression analysis of 25(OH)D test results obtained in more than 86,000 control serum samples. RESULTS: Vitamin D deficiency was highly prevalent in patients with Crohn's disease or ulcerative colitis (63% and 55%, respectively) and associated with winter/spring seasons. After normalization of 25(OH)D concentrations for the day of analysis, vitamin D deficiency was associated with histories of complications related to inflammatory bowel disease, surgery, smoking and ongoing diarrhea while initial disease manifestation during adulthood, ongoing vitamin D supplementation and diagnosis of ulcerative colitis vs. Crohn's disease appeared to be protective. Multiple regression analyses revealed that vitamin D deficiency was associated with disease activity in Crohn's disease and anemia in ulcerative colitis patients. Only few deficient patients achieved sufficient 25(OH)D concentrations over time. However, increasing 25(OH)D concentrations correlated with improved Crohn's disease activity. CONCLUSIONS: Vitamin D deficiency was highly prevalent in patients with Crohn's disease and ulcerative colitis and dependent on the season of the year. Following normalization for seasonality by sinusoidal regression analysis, vitamin D deficiency was found to be associated with parameters of complicated disease course while increasing 25(OH)D concentrations over time correlated with reduced activity of Crohn's disease.


Assuntos
Doenças Inflamatórias Intestinais/sangue , Vitamina D/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Doença de Crohn/sangue , Doença de Crohn/complicações , Suplementos Nutricionais , Feminino , Alemanha/epidemiologia , Humanos , Doenças Inflamatórias Intestinais/complicações , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Estações do Ano , Vitamina D/administração & dosagem , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Adulto Jovem
18.
J Vet Intern Med ; 33(4): 1602-1607, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31111561

RESUMO

BACKGROUND: Lymphocytic-plasmacytic enteritis is the common form of idiopathic inflammatory bowel disease (IBD) in dogs. In human IBD, disturbances of amino acid metabolism have been demonstrated to be involved in the pathophysiology of IBD. Therefore, plasma amino acid profile might represent a novel marker of human IBD. OBJECTIVES: To determine the plasma amino acid profiles of dogs with IBD and its usefulness as a novel marker of IBD in dogs. ANIMALS: Fasting blood plasma was obtained from 10 dogs with IBD and 12 healthy dogs. METHODS: All IBD dogs were prospectively included in this study, and heparinized blood samples were collected. The plasma concentrations of 21 amino acids were determined using the ninhydrin method. The relationships among the plasma amino acid concentrations and plasma C-reactive protein (CRP) concentration, canine chronic enteropathy clinical activity index (CCECAI), and overall World Small Animal Veterinary Association (WSAVA) score were investigated. RESULTS: Median concentration (nmol/mL) of methionine [46.2; range, 30.0-59.3], proline [119.4; range, 76.7-189.2], serine [115.1; range, 61.4-155.9], and tryptophan [17.4; range, 11.9-56.3]) were significantly lower than in control dogs [62.6; range, 51.0-83.6, 199.1; range, 132.5-376.7, 164.3; range, 124.7-222.9, and 68.3; range, 35.7-94.8, respectively]. A negative correlation was identified between the plasma serine concentration and CCECAI (r s = -.67, P = .03), but there were no correlations between plasma amino acid concentrations and CRP concentration or overall WSAVA score. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma serine concentration might represent a novel maker of IBD in dogs.


Assuntos
Aminoácidos/sangue , Doenças do Cão/sangue , Doenças Inflamatórias Intestinais/veterinária , Animais , Biomarcadores/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Cães , Feminino , Doenças Inflamatórias Intestinais/sangue , Masculino , Serina/sangue , Índice de Gravidade de Doença
19.
Dig Dis ; 37(6): 444-450, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31039560

RESUMO

BACKGROUND: Adalimumab (ADA) is an anti-tumor necrosis factor agent that has been shown to be effective in inducing and maintaining remission in adult patients with inflammatory bowel disease. The relationship between the ADA trough levels and clinical efficacy has been demonstrated, but there is variability in the definition of the most suitable range for its clinical applicability. SUMMARY: A review of published studies during the last 5 years on ADA serum levels and its relationship with the clinical outcome was performed. The studies selected included 7 observational studies, a systematic review, a meta-analysis and a post hoc analysis of a clinical trial. The reported ADA levels that discriminate patients in clinical remission from those with active disease range from 4.5 to 8 µg/mL. This therapeutic range varies when considering endoscopic remission (7.5 to >13.9 µg/mL). Although the sample of patients with ulcerative colitis is small, a tendency to reach higher levels of ADA is observed in both clinical and endoscopic remission. Key Messages: The optimal therapeutic cut-off point of serum ADA levels ranges from 4.5-5 to 12 µg/mL, where ADA levels are associated with an adequate clinical monitoring of the disease during maintenance therapy. These ranges vary according to the target, suggesting levels of 4.8 µg/mL as the cut-off for clinical remission and levels ≥7.5 µg/mL for mucosal healing/endoscopic response. Controlled prospective studies are required to determine the optimal therapeutic interval of ADA serum levels both as induction and as maintenance therapy.


Assuntos
Adalimumab/sangue , Adalimumab/uso terapêutico , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Endoscopia , Humanos , Publicações , Resultado do Tratamento
20.
Medicine (Baltimore) ; 98(18): e15233, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045762

RESUMO

Patients with inflammatory bowel disease have an increased risk of vitamin D deficiency and this may impact upon the disease activity. This study explored the association between serum vitamin D levels and inflammatory bowel disease in a Chinese population.Sixty-five patients with ulcerative colitis (UC) and 50 with Crohn's disease (CD) were investigated between January 2015 and December 2016 at the Kunshan Second People's Hospital, China. A control group of 120 healthy volunteers was also selected. Serum vitamin D levels were detected and compared between groups and among patients with different disease activity.The serum vitamin D levels in the UC (10.27 ±â€Š4.05 ng/mL) and CD (11.13 ±â€Š3.96 ng/mL) groups were lower than in the control group (12.96 ±â€Š5.18 ng/mL) (P < .05). In the UC group, during the moderate (9.21 ±â€Š3.26 ng/mL) and severe (7.58 ±â€Š3.81 ng/mL) periods, serum vitamin D levels were significantly lower compared with during remission (12.18 ±â€Š3.69 ng/mL) and the mild period (11.35 ±â€Š4.08 ng/mL) (P < .05). In the CD group, serum vitamin D levels were significantly lower during the moderate (10.28 ±â€Š3.57 ng/mL) and severe (8.52 ±â€Š3.72 ng/mL) periods compared with remission (13.97 ±â€Š5.61 ng/mL) (P < .05).Patients with UC and CD are both prone to vitamin D deficiency. Serum vitamin D was significantly lower with aggravating disease status. Therefore, vitamin D may be involved in the development of inflammatory bowel disease in a Chinese population.


Assuntos
Doenças Inflamatórias Intestinais/sangue , Deficiência de Vitamina D/etiologia , Vitamina D/sangue , Adulto , China/epidemiologia , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/fisiopatologia , Doença de Crohn/sangue , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/fisiopatologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico
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