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1.
EBioMedicine ; 51: 102567, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31901853

RESUMO

BACKGROUND: Intestinal coeliac auto-antibodies are the marker of coeliac disease (CD). Since the determination of these antibodies is still not widely available, we used immunoassays to identify the most suitable technology for revealing intestinal auto-antibodies in the wide clinical spectrum of CD. METHODS: Intestinal auto-antibodies have been prospectively investigated in CD suspected children using two immunoassays: intestinal-deposits of IgA anti-tissue transglutaminase antibodies (anti-tTG) and biopsy-culture IgA anti-endomysium (AEA). Intestinal IgM antibodies have been determined in IgA-deficient subjects. FINDINGS: Two-hundred and twenty-one suspected CD patients were enrolled. Intestinal antibodies were tested positive for both assays in classical CD patients (n = 178) with villous atrophy and positive serum-CD antibodies, potential CD patients (n = 16) with normal intestinal mucosa and positive serum-CD antibodies, and pre-potential CD patients (n = 14) with normal intestinal mucosa and negative serum-CD antibodies. In 13/221 with normal intestinal mucosa, negative CD-serum antibodies and negative intestinal antibodies CD has been excluded. All classical, 14/16 potential and 11/14 pre-potential CD patients on gluten-free diet (GFD) improved their symptoms. In 9/11 pre-potential patients intestinal antibodies disappeared on GFD. Both assays were negative in 69/71 control subjects. The two assays showed high diagnostic sensitivity (100%) and specificity (99%). INTERPRETATION: Intestinal CD-antibodies make prompt diagnosis in the wide clinical spectrum of CD reducing the delay in diagnosis and treatment, especially in pre-potential CD patients. The easy handling biopsy culture assay is an effective diagnostic tool which should be carried out by any gastroenterology unit to recognize all CD clinical manifestations. FUNDING: Interreg Central-Europe, IRCCS "Burlo Garofolo".

2.
J Pediatr Gastroenterol Nutr ; 70(2): 211-217, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31978019

RESUMO

OBJECTIVES: Parents have a central role in the management of children with inflammatory bowel disease (IBD). Alterations in parental psychological well-being may affect the patient's health-related quality of life (HRQoL). This study aimed to evaluate the correlation between maternal and paternal distress, anxiety, depression and pain catastrophizing and the HRQoL of patients with IBD. METHODS: Children with IBD ages 8 to 18 years and their parents were prospectively recruited. Children answered questionnaires on HRQoL while parents completed an assessment of distress, anxiety, depression, and pain catastrophizing. Univariate and multivariate regression models analysis were used to evaluate correlations between parental measures and patient's HRQoL and between the factors related to children health and parental psychological suffering. RESULTS: One hundred patients (45 Crohn disease, 55 ulcerative colitis), 90 mothers and 62 fathers were enrolled. Parents had high levels of distress while anxiety, depression, and pain catastrophizing levels were relatively low. Parental distress had the most substantial correlation with children's HRQoL and was associated with patients' disease activity and recent flares. On multivariate regression analysis, parental factors explained less than 20% of the variance in the children's HRQoL scores. Mothers suffered from psychological alterations more frequently than fathers, but the parental inter-rater agreement was strong in regards to distress and anxiety. CONCLUSIONS: Parental distress is high and correlates with the HRQoL of children with IBD. Interventions aimed at evaluating and managing parental distress should be considered during the management of children with IBD.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31703041

RESUMO

OBJECTIVES: Parents have a central role in the management of children with inflammatory bowel disease (IBD). Alterations in parental psychological well-being may affect the patient's health-related quality of life (HRQoL). This study aimed to evaluate the correlation between maternal and paternal distress, anxiety, depression and pain catastrophizing and the HRQoL of patients with IBD. METHODS: Children with IBD aged 8-18 years and their parents were prospectively recruited. Children answered questionnaires on HRQoL while parents completed an assessment of distress, anxiety, depression and pain catastrophizing. Univariate and multivariate regression models analysis were used to evaluate correlations between parental measures and patient's HRQoL and between the factors related to children health and parental psychological suffering. RESULTS: One hundred patients (45 Crohn's disease, 55 ulcerative colitis), 90 mothers and 62 fathers were enrolled. Parents had high levels of distress while anxiety, depression and pain catastrophizing levels were relatively low. Parental distress had the most substantial correlation with children's HRQoL and was associated with patients' disease activity and recent flares. On multivariate regression analysis, parental factors explained less than 20% of the variance in the children's HRQoL scores. Mothers suffered from psychological alterations more frequently than fathers, but the parental inter-rater agreement was strong in regards to distress and anxiety. CONCLUSIONS: Parental distress is high and correlates with the HRQoL of children with IBD. Interventions aimed at evaluating and managing parental distress should be considered during the management of children with IBD.

4.
Int J Mol Sci ; 20(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652976

RESUMO

BACKGROUND: The long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of GAS5 in regulating MMP2 and MMP9 expression in pediatric patients with IBD and in vitro. METHODS: In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and GAS5, MMP2, and MMP9 were quantified by TaqMan assay. The expression of GAS5 and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of GAS5 was assessed by overexpressing the lncRNA and evaluating the MMPs levels. RESULTS: Real-time PCR results demonstrated a downregulation of GAS5 and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of GAS5 while an increase of MMPs was observed. Overexpression experiments showed that higher levels of GAS5 lead to a decrease of both enzymes. CONCLUSION: These results provide new information about the role of GAS5 in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs.

5.
Inflamm Bowel Dis ; 2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31375816

RESUMO

BACKGROUND AND AIMS: Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients' management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis. METHODS: Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008-2017 who underwent a genetic workup were collected. RESULTS: Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT. CONCLUSION: A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients' management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.

6.
J Pediatr Gastroenterol Nutr ; 69(4): e99-e104, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31335840

RESUMO

OBJECTIVES: Inflammatory bowel disease (IBD) can be particularly challenging during the pediatric age with a relevant impact on patient's health-related quality of life (HRQoL). Disease activity accounts for only a small part of the variability in HRQoL, and psychological factors can play a significant role. We aimed to evaluate the impact of patient's distress and pain catastrophizing on children and adolescents with IBD. METHODS: We prospectively recruited children aged 8 to 18 with IBD and recorded demographic and disease characteristics. Patients answered questionnaires on HRQoL (IMPACT III), distress (distress thermometer [DT]), and pain catastrophizing (Pain Catastrophizing Scale-Children [PCS-C]). Univariate and multivariate regression models analysis were used to evaluate correlations between patients' characteristics, disease activity, distress, pain catastrophizing, and HRQoL. RESULTS: Seventy-one patients were enrolled (median age 13.6, 49.3% Crohn disease, 50.7% ulcerative colitis). Median HRQoL, DT, and PCS-C scores were 78.6 (interquartile range 68.0-87.1), 3.0 (1.0-5.0), and 12.0 (4.0-23.0), respectively. Patient's distress and pain catastrophizing levels significantly correlated with HRQoL. Pain catastrophizing had the strongest impact on HRQoL (Spearman correlation coefficient, ρ = 0.73), followed by distress (ρ = 0.67), and ulcerative colitis severity (ρ = 0.67). The DT and the PCS-C scores were significantly associated (ρ = 0.46). CONCLUSIONS: Distress and pain catastrophizing have a significative impact on HRQoL in young patients with IBD. Physicians should recognize the role of these psychological factors and consider cognitive-behavioral therapy to optimize the patient's health.

7.
United European Gastroenterol J ; 7(6): 759-766, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31316780

RESUMO

Background: Very few data regarding the use of infliximab in children with very early-onset inflammatory bowel disease (VEO-IBD) have been reported. Objective: We aimed to assess the efficacy and the safety of infliximab in children with VEO-IBD compared with older children. Methods: Children treated with infliximab were identified within the Italian IBD registry. The primary outcome was the rate of clinical remission at weeks 14 and 54. Secondary outcomes included the proportion of partial clinical response, treatment duration, and incidence of adverse events. Results: Forty-two children with VEO-IBD were compared with 130 children with IBD. Despite significantly higher infliximab withdrawals in VEO-IBD patients during induction (42.9% vs 7.7% p < 0.01), remission rates at week 14 were similar (28.6% vs 43.8%, p = 0.10). At week 54 fewer VEO-IBD children were in remission (15.8% vs 54.3%, p < 0.01). The treatment duration was shorter in VEO-IBD (median 12.0 vs 18.4 months, p < 0.01). During the induction phase, adverse events were more common in the VEO-IBD group (p < 0.01). Conclusion: Compared with older children, VEO-IBD patients have higher rates of infliximab failures, lower remission rates at one year, and more often experience adverse events during induction.

8.
Clin Immunol ; 207: 10-17, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279857

RESUMO

Autoimmune enteropathy (AIE) is a rare condition that may affect pediatric and adult patients, frequently associated with primary immunodeficiencies. We performed a retrospective study on clinical and histological findings from 40 AIE patients. Histological presentation showed a prevalent celiac disease pattern (50%), followed by the mixed pattern (35%), independently of age, chronic active duodenitis (10%), and GVHD-like pattern (5%). Patients with primary immunodeficiencies (24/40) presented mainly with the celiac disease pattern (72.2% versus 22.2%; p < .0001), while patients without primary immunodeficiencies presented with a mixed histological pattern (61.1% versus 13.6%; p < .0001). Our study shows that the prevalent histological presentation is the celiac disease-like pattern, independently of age, and, for the first time, that the histological presentation of AIE differs significantly between patients with and without primary immunodeficiencies. These findings may be helpful for more precise and timely diagnosis and management of this rare disorder.

9.
J Pediatr Gastroenterol Nutr ; 69(4): 474-479, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31149938

RESUMO

OBJECTIVES: Therapeutic drug monitoring is becoming increasingly important in clinical decision-making in children with inflammatory bowel disease (IBD). However, enzyme-linked immunosorbent assay (ELISA) assays do not allow results to be provided in real-time. We sought to compare 2 point-of-care (POC) devices for quantification of serum infliximab concentration with 2 validated ELISA assays in children with IBD. METHODS: We studied 32 serum samples from 19 children with IBD treated with infliximab. Serum samples were collected immediately before drug infusion (trough level). Infliximab was measured using 2 POC infliximab assays, Quantum Blue (POC IFX/QB) and Rida Quick (POC IFX/RQ), and 2 ELISA assays: Lisa-Tracker (used as primary reference), and Promonitor (used as second control). Intraclass correlation coefficient (ICC) was assessed for quantitative comparison. Qualitative analysis was also performed to evaluate whether POC assays would correctly classify infliximab serum according to a target window (between 3 and 7 µg/mL). RESULTS: ICC was 0.82 and 0.87 for POC IFX/QB and POC IFX/RQ with the primary reference ELISA assay, respectively; ICC between the 2 ELISA assays was 0.87. Classification of results according to therapeutic intervals showed good agreement between pairs of assays, with kappa of 0.67 and 0.80 for POC IFX/QB and POC IFX/RQ, respectively, with reference ELISA, and 0.81 between the 2 ELISAs. Accuracy of POC assays was better for drug levels <3 µg/mL. CONCLUSIONS: POC infliximab assays showed good agreement with traditional ELISA assays. POC devices may represent a viable option for real-time therapeutic drug monitoring in children treated with infliximab.

10.
Genes (Basel) ; 10(4)2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987408

RESUMO

The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn's disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio and 30% decrease in clinical efficacy. GSTA1 variant (12.8% of patients) showed a trend (p = 0.049, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics.


Assuntos
Azatioprina/farmacocinética , Glutationa Transferase/genética , Imunossupressores/farmacocinética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Variantes Farmacogenômicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Azatioprina/administração & dosagem , Biotransformação , Feminino , Deleção de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunossupressores/administração & dosagem , Doenças Inflamatórias Intestinais/genética , Masculino , Metiltransferases/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Resultado do Tratamento , Adulto Jovem
11.
J Matern Fetal Neonatal Med ; : 1-5, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30983441

RESUMO

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E cell-mediated gastrointestinal food allergy that primarily presents in infancy, as early as the first hours of life. FPIES is often misdiagnosed as sepsis, severe gastroenteritis, abdominal surgical emergency or even metabolic, neurologic, or cardiac disorders. METHODS: We report two neonatal cases of cow's milk protein (CMP)-induced FPIES masquerading as surgical diseases. Our purpose is to highlight the diagnostic difficulties in FPIES in this age group and to provide further evidence of the important role played by the prenatal environment in the development of allergic diseases. RESULTS: Case 1 is a 2-day-old boy born at 35th + 5 weeks of gestation admitted to our Neonatal Intensive Care Unit (NICU) for bloody diarrhea who started presenting apnea, crying, pallor, jaundice, and abdominal tenderness. Case 2 is a 3-day-old boy born at 38th +5 weeks of gestation admitted to our NICU for repeated bilious vomiting. Both patients were administered infant formula in the first hours of life, thereafter they received only breast milk. In both cases, CMP allergy was finally suspected and an extensively hydrolyzed formula was administered with the resolution of symptoms. A diagnosis of CMP-induced FPIES was made. CONCLUSIONS: FPIES is a heterogeneous disorder. Severe forms of FPIES could be mistaken for surgical diseases, such as necrotizing enterocolitis. A trial of food elimination should be considered whenever diagnostic tests are inconclusive. FPIES must be suspected even in breastfed infants.

12.
Biologics ; 13: 13-21, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30655661

RESUMO

Background: Adalimumab (Ada) treatment is an available option for pediatric Crohn's disease (CD) and the published experience as rescue therapy is limited. Objectives: We investigated Ada efficacy in a retrospective, pediatric CD cohort who had failed previous infliximab treatment, with a minimum follow-up of 6 months. Methods: In this multicenter study, data on demographics, clinical activity, growth, laboratory values (CRP) and adverse events were collected from CD patients during follow-up. Clinical remission (CR) and response were defined with Pediatric CD Activity Index (PCDAI) score ≤10 and a decrease in PCDAI score of ≥12.5 from baseline, respectively. Results: A total of 44 patients were consecutively recruited (mean age 14.8 years): 34 of 44 (77%) had active disease (mean PCDAI score 24.5) at the time of Ada administration, with a mean disease duration of 3.4 (range 0.3-11.2) years. At 6, 12, and 18 months, out of the total of the enrolled population, CR rates were 55%, 78%, and 52%, respectively, with a significant decrease in PCDAI scores (P<0.01) and mean CRP values (mean CRP 5.7 and 2.4 mL/dL, respectively; P<0.01) at the end of follow-up. Steroid-free remission rates, considered as the total number of patients in CR who were not using steroids at the end of this study, were 93%, 95%, and 96% in 44 patients at 6, 12, and 18 months, respectively. No significant differences in growth parameters were detected. In univariate analysis of variables related to Ada efficacy, we found that only a disease duration >2 years was negatively correlated with final PCDAI score (P<0.01). Two serious adverse events were recorded: 1 meningitis and 1 medulloblastoma. Conclusion: Our data confirm Ada efficacy in pediatric patients as second-line biological therapy after infliximab failure. Longer-term prospective data are warranted to define general effectiveness and safety in pediatric CD patients.

13.
J Pediatr Gastroenterol Nutr ; 68(4): 547-551, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30499881

RESUMO

OBJECTIVES: Available data indicate that liver involvement is present in a significant proportion of children with celiac disease (CD) at the diagnosis (elevated transaminases 15%-57%, autoimmune liver disease 1%-2%). We sought to evaluate prevalence, clinical course, and risk factors for liver involvement in a large cohort of children with CD. METHODS: Children (age 0-18 years) diagnosed with CD from March 2010 to April 2016 were enrolled. Liver involvement was considered to be present when alanine transaminase (ALT) levels were >40 U/L (hypertransaminasemia [HTS]). Patients with HTS were re-evaluated after at least 12 months of a gluten-free diet. RESULTS: CD was diagnosed in 806 patients during the study period; of these, ALT levels were available for 700 patients (86.9%), and were elevated in 27 (3.9%, HTS group); median ALT and aspartate transaminase levels in the HTS group were 57 U/L (interquartile range 49-80 U/L) and 67 U/L (interquartile range 53-85 U/L), respectively. Younger age, malabsorption symptoms, and low hemoglobin or ferritin were significantly more common in the HTS group at univariate analysis. At multivariate analysis, only age ≤4.27 years correlated with risk of liver involvement (odds ratio 3.73; 95% confidence interval: 1.61-8.66). When retested on a gluten-free diet, all but 3 patients normalized ALT levels; of these, 1 was diagnosed with sclerosing cholangitis. CONCLUSIONS: Liver involvement in celiac children is now less frequent than previously reported, possibly due to changing CD epidemiology. Younger age is the only risk factor. Associated autoimmune liver disease is rare.

14.
Minerva Pediatr ; 71(1): 39-46, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30021413

RESUMO

Celiac disease is a common immune-mediated disease, that may present, after gluten ingestion, with various and heterogeneous symptoms that can vary according to patients' age. The diagnostic screening test is serum anti-tissue transglutaminase IgA level. In doubt cases, antiendomysium IgA and the antideamidated gliadin peptides IgG could be useful to confirm the suspicion, before a biopsy will be perform. Since 2012, guidelines have made it possible to avoid the biopsy in symptomatic pediatric patients with high levels of antitransglutaminase IgA, positivity to antiendomysium IgA, and with HLA DQ2 or DQ8. In all other cases duodenal biopsy is still mandatory to confirm the diagnosis. The therapy of celiac disease is a lifelong gluten free diet. In children prognosis of celiac disease is good, without complications. Here we review and discuss the present literature about celiac disease in childhood.


Assuntos
Doença Celíaca/diagnóstico , Dieta Livre de Glúten , Glutens/efeitos adversos , Biópsia , Doença Celíaca/dietoterapia , Criança , Proteínas de Ligação ao GTP/imunologia , Humanos , Imunoglobulina A/sangue , Programas de Rastreamento/métodos , Prognóstico , Transglutaminases/imunologia
15.
J Pediatr Gastroenterol Nutr ; 68(1): 37-44, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30211845

RESUMO

OBJECTIVES: Anti-tumor necrosis factor antibodies have led to a revolution in the treatment of inflammatory bowel diseases (IBD); however, a sizable proportion of patients does not respond to therapy. There is increasing evidence suggesting that treatment failure may be classified as mechanistic (pharmacodynamic), pharmacokinetic, or immune-mediated. Data regarding the contribution of these factors in children with IBD treated with infliximab (IFX) are still incomplete. The aim was to assess the causes of treatment failure in a prospective cohort of pediatric patients treated with IFX. METHODS: This observational study considered 49 pediatric (median age 14.4) IBD patients (34 Crohn disease, 15 ulcerative colitis) treated with IFX. Serum samples were collected at 6, 14, 22 and 54 weeks, before IFX infusions. IFX and anti-infliximab antibodies (AIA) were measured using enzyme linked immunosorbent assays. Disease activity was determined by Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index. RESULTS: Clinical remission, defined as a clinical score <10, was obtained by 76.3% of patients at week 14 and by 73.9% at week 54. Median trough IFX concentration was higher at all time points in patients achieving sustained clinical remission. IFX levels during maintenance correlated also with C-reactive protein, albumin, and fecal calprotectin. After multivariate analysis, IFX concentration at week 14 >3.11 µg/mL emerged as the strongest predictor of sustained clinical remission. AIA concentrations were correlated inversely with IFX concentrations and directly with adverse reactions. CONCLUSIONS: Most cases of therapeutic failure were associated with low serum drug levels. IFX trough levels at the end of induction are associated with sustained long-term response.

16.
Gastrointest Endosc ; 88(3): 521-526, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29807020

RESUMO

BACKGROUND AND AIMS: Anti-tissue transglutaminase antibodies (anti-tTG) have simplified celiac disease (CD) diagnosis. However, in atypical forms of CD, intestinal biopsy sampling is still required. This prospective study investigates whether histologic analysis of the duodenal bulb combined with intestinal IgA anti-tTG deposit immunoassay makes CD diagnosis possible in at-risk children with low concentrations of serum anti-tTG. METHODS: Histologic and intestinal IgA anti-tTG deposit immunoassays were used. RESULTS: Two hundred forty-five symptomatic children positive for serum anti-tTG (>7 U/mL) were enrolled and divided into 3 groups: extensive duodenal atrophy (n = 209), with IgA anti-tTG deposits throughout the duodenum and high serum anti-tTG concentrations (157 ± 178 U/mL); bulb duodenal atrophy (n = 22), with widespread IgA anti-tTG deposits in 9 and in the bulb alone in 13 and low serum anti-tTG concentrations (13.9 ± 8.7 U/mL); and normal duodenum (n = 14), with widespread IgA anti-tTG deposits in 8 and in the bulb alone in 6 and low serum anti-tTG concentrations (10.6 ± 6.2 U/mL). All patients in the first 2 groups were diagnosed with CD and 8 from the third group. All improved after 1 year of gluten-free diet. Bulb duodenal analysis led to a 12% (30/245) increase in CD diagnosis. No CD-related lesions were observed in the 30 control subjects. CONCLUSIONS: In children at risk for CD, bulb duodenum biopsy sampling is essential to identify villous atrophy and detect IgA anti-tTG deposits even in absence of intestinal lesions. These mucosal autoantibodies could well represent a new standard for diagnosing CD.


Assuntos
Doença Celíaca/diagnóstico , Duodeno/imunologia , Imuno-Histoquímica/métodos , Adolescente , Autoanticorpos/análise , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doença Celíaca/sangue , Doença Celíaca/imunologia , Criança , Pré-Escolar , Duodeno/química , Feminino , Humanos , Imunoglobulina A/análise , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Lactente , Masculino , Estudos Prospectivos , Transglutaminases/análise , Transglutaminases/antagonistas & inibidores , Transglutaminases/sangue , Transglutaminases/imunologia
17.
Int J Mol Sci ; 19(5)2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29738455

RESUMO

The aim of this research was the identification of novel pharmacogenomic biomarkers for better understanding the complex gene regulation mechanisms underpinning glucocorticoid (GC) action in paediatric inflammatory bowel disease (IBD). This goal was achieved by evaluating high-throughput microRNA (miRNA) profiles during GC treatment, integrated with the assessment of expression changes in GC receptor (GR) heterocomplex genes. Furthermore, we tested the hypothesis that differentially expressed miRNAs could be directly regulated by GCs through investigating the presence of GC responsive elements (GREs) in their gene promoters. Ten IBD paediatric patients responding to GCs were enrolled. Peripheral blood was obtained at diagnosis (T0) and after four weeks of steroid treatment (T4). MicroRNA profiles were analyzed using next generation sequencing, and selected significantly differentially expressed miRNAs were validated by quantitative reverse transcription-polymerase chain reaction. In detail, 18 miRNAs were differentially expressed from T0 to T4, 16 of which were upregulated and 2 of which were downregulated. Out of these, three miRNAs (miR-144, miR-142, and miR-96) could putatively recognize the 3’UTR of the GR gene and three miRNAs (miR-363, miR-96, miR-142) contained GREs sequences, thereby potentially enabling direct regulation by the GR. In conclusion, we identified miRNAs differently expressed during GC treatment and miRNAs which could be directly regulated by GCs in blood cells of young IBD patients. These results could represent a first step towards their translation as pharmacogenomic biomarkers.


Assuntos
Biomarcadores , Glucocorticoides/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , MicroRNAs/genética , Adolescente , Criança , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Masculino , Receptores de Glucocorticoides/genética , Transcriptoma/efeitos dos fármacos
18.
J Crohns Colitis ; 12(7): 870-879, 2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29518184

RESUMO

Background and Aims: Ocular extraintestinal manifestations [O-EIMs] are known complications of Crohn's disease [CD], ulcerative colitis [UC], and inflammatory bowel disease unclassified [IBD-U]. However, data on their prevalence in children are scarce and there are no clear recommendations on what follow-up should be offered. We aimed to review available data on O-EIMs in children. Methods: In January 2018, we performed a systematic review of published English literature using PubMed and EMBASE databases and disease-specific queries. Results: Fifteen studies [7467 patients] reported data on O-EIMs prevalence in children. Overall prevalence of O-EIMs was 0.62-1.82%. Uveitis was the most common O-EIM. Meta-analysis showed that children with CD are at increased risk of O-EIMs as compared with children with UC and IBD-U (odds ratio [OR] 2.70, 95% confidence interval [CI] 1.51-4.83). Five studies [357 patients] reported data on ophthalmological screening in asymptomatic children: mild asymptomatic uveitis was identified in a variable proportion of patients [1.06-23.1%], more frequently in male patients with CD and colonic involvement. No evidence of ocular complications from untreated uveitis was detected. A total of 23 case reports [24 patients] were identified. Conclusions: Data on O-EIMs in children are scarce. Prevalence of O-EIMs is lower than in adults but may be underestimated because of the possibility of asymptomatic uveitis; however, the long-term significance of this condition is unknown. Children with CD may be at increased risk of O-EIMs. No recommendations on routine ophthalmological examination can be made, but a low threshold for ophthalmological referral should be maintained. Larger studies in paediatric IBD populations are needed.


Assuntos
Colite Ulcerativa/complicações , Doença de Crohn/complicações , Oftalmopatias/epidemiologia , Adolescente , Catarata/epidemiologia , Catarata/etiologia , Criança , Pré-Escolar , Oftalmopatias/etiologia , Humanos , Prevalência , Uveíte/epidemiologia , Uveíte/etiologia
19.
Paediatr Drugs ; 20(2): 165-171, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29214394

RESUMO

OBJECTIVES: Anti-tumor necrosis factor alpha (anti-TNF-α) agents are generally well tolerated, yet they can be associated with serious adverse events (SAEs) in a minority of patients. We examined the incidence of SAEs in a pediatric referral center for chronic rheumatologic and gastroenterological inflammatory disorders. METHODS: Retrospective analysis of SAEs occurring during treatment with anti-TNF-α agents in patients with juvenile idiopathic arthritis (JIA) (n = 78)  or pediatric-onset inflammatory bowel disease (IBD) (n = 105) seen at the Institute for Maternal and Child Health IRCCS "Burlo Garofolo" in Trieste, Italy, between June 2001 and February 2016. Only SAEs grade 3-5 according to the Common Terminology Criteria for Adverse Events version 4.03 and/or requiring definitive therapy discontinuation were reported. RESULTS: Total anti-TNF-α exposure was 390.5 patient-years (PYs). The overall incidence rate of SAEs for etanercept was 4.14/100 PYs. Four patients developed uveitis, two had anxiety disorders, one had a serious zoster infection, and one developed TNF-α antagonist-induced lupus-like syndrome (TAILS). The overall incidence rate of SAEs for infliximab was 22.49/100 PYs. The most common SAEs were anaphylactoid reactions (n = 18), followed by infectious events (n = 9) and TAILS (n = 3). The overall incidence rate of SAEs for adalimumab was 4.71/100 PYs (two infectious SAEs). No malignancies or deaths were observed. A greater incidence rate of infectious SAEs was observed in IBD patients receiving infliximab compared to JIA patients receiving etanercept (8.11 vs 0.52 per 100 PYs). CONCLUSIONS: Anti-TNF-α therapy was generally well tolerated. SAEs leading to anti-TNF-α discontinuation were rare and non-fatal. Infliximab was associated with the highest incidence of SAEs. Infectious SAEs were more frequently observed in IBD patients treated with infliximab than in JIA patients receiving etanercept.


Assuntos
Artrite Juvenil/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/efeitos adversos , Adolescente , Antirreumáticos/uso terapêutico , Criança , Pré-Escolar , Etanercepte/efeitos adversos , Feminino , Humanos , Incidência , Infliximab/efeitos adversos , Masculino , Estudos Retrospectivos , Adulto Jovem
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