RESUMO
An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
Assuntos
Colectomia/estatística & dados numéricos , Colite Ulcerativa/cirurgia , Doença de Crohn/cirurgia , Locos de Características Quantitativas , Transcriptoma , Bancos de Espécimes Biológicos , Estudos de Coortes , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/genética , Colo/metabolismo , Colo/patologia , Colo/cirurgia , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Conjuntos de Dados como Assunto , Progressão da Doença , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Prognóstico , Medição de Risco , Reino UnidoRESUMO
BACKGROUND & AIMS: The evolution of complicated pediatric Crohn's disease (CD) in the era of anti-tumor necrosis factor (aTNF) therapy continues to be described. Because CD progresses from inflammatory to stricturing (B2) and penetrating (B3) disease behaviors in a subset of patients, we aimed to understand the risk of developing complicated disease behavior or undergoing surgery in relation to aTNF timing and body mass index z-score (BMIz) normalization. METHODS: Multicenter, 5-year longitudinal data from 1075 newly diagnosed CD patients were analyzed. Descriptive statistics, univariate and stepwise multivariate Cox proportional hazard regression (CPHR), and log-rank analyses were performed for risk of surgery and complicated disease behaviors. Differential gene expression from ileal bulk RNA sequencing was correlated with outcomes. RESULTS: Stricturing complications had the largest increase: from 2.98% to 10.60% over 5 years. Multivariate CPHR showed aTNF exposure within 3 months from diagnosis (hazard ratio [HR], 0.33; 95% CI, 0.15-0.71) and baseline L2 disease (HR, 0.29; 95% CI, 0.09-0.92) to be associated with reduced B1 to B2 progression. For children with a low BMIz at diagnosis (n = 294), multivariate CPHR showed BMIz normalization within 6 months of diagnosis (HR, 0.47; 95% CI, 0.26-0.85) and 5-aminosalicyclic acid exposure (HR, 0.32; 95% CI, 0.13-0.81) were associated with a decreased risk for surgery while B2 (HR, 4.20; 95% CI, 1.66-10.65) and B2+B3 (HR, 8.24; 95% CI, 1.08-62.83) at diagnosis increased surgery risk. Patients without BMIz normalization were enriched for genes in cytokine production and inflammation. CONCLUSIONS: aTNF exposure up to 3 months from diagnosis may reduce B2 progression. In addition, lack of BMIz normalization within 6 months of diagnosis is associated with increased surgery risk and a proinflammatory transcriptomic profile.
Assuntos
Doença de Crohn , Criança , Humanos , Índice de Massa Corporal , Fatores de Risco , Doença de Crohn/complicações , Fator de Necrose Tumoral alfa , Constrição Patológica/etiologia , Necrose , Progressão da Doença , Estudos RetrospectivosRESUMO
AIM: To investigate whether a structured yoga program improves health-related quality of life (HRQOL) and self-efficacy in pediatric patients receiving care for inflammatory bowel disease (IBD). METHODS: IBD patients who were 10-17 years old participated in a 12 week, in-person yoga intervention at two clinical sites. Outcomes were measured at time of consent (T0), start of yoga (T1), and completion of yoga (T2) and 3 months after yoga completion (T3) using the IMPACT-III, Pediatric Quality of Life Inventory (PedsQL), and General Self Efficacy (GSE) scales. RESULTS: Seventy-eight patients were enrolled. Fifty-six patients completed nine or more classes. 73.2% had Crohn's disease and 26.8% ulcerative colitis or IBD-unclassified. A significant increase in IMPACT-III was seen from T1 to T3 (mean change of 5.22, SD = 14.33, p = 0.010), in the PedsQL (mean change = 2.3, SD = 10.24, p = 0.050), and GSE (mean change = 1, SD = 3.60, p = 0.046). 85.2% of patients reported yoga helped them to control stress. Long-term data was available for 47 subjects with 31.9% (n = 15) continuing to practice yoga one to 3 years after study completion. CONCLUSION: This structured 12-week yoga program showed significant improvements in HRQOL and general self-efficacy, particularly 3 months after classes were concluded suggesting that yoga's benefits may persist. Yoga is a safe and effective adjunct to standard medical care to improve QOL and self-efficacy in youth with IBD.
Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Yoga , Adolescente , Criança , Humanos , Colite Ulcerativa/terapia , Doenças Inflamatórias Intestinais/terapia , Estudos Prospectivos , Qualidade de VidaRESUMO
OBJECTIVES: To assess the efficacy, safety, immunogenicity, and pharmacokinetics through 240 weeks of ustekinumab treatment in paediatric patients from the long-term extension (LTE) of the phase 1, double-blind UniStar trial. METHODS: Paediatric patients with moderately to severely active Crohn's disease (CD) were randomised 1:1 and stratified by body weight (<40 or ≥40 kg) to low- or high-dose intravenous ustekinumab followed by a subcutaneous maintenance dose at Week 8. At Week 16, patients were eligible to enter the LTE at the discretion of the investigator and continued maintenance dosing every 8 weeks up to Week 240. RESULTS: Of the 34 patients who entered the LTE, 25 patients with evaluable data completed Week 48, and 41.2% (14/34) achieved clinical remission at Week 48. Among the 24 patients with Week-0 C-reactive protein (CRP) levels ≥3 mg/L, 29.2% (7/24) achieved normalisation of CRP at Week 48, while imputing missing data as failures. Through Week 240, the most common adverse events were infections (n = 28) and gastrointestinal disorders (n = 26). The most common serious adverse event was worsening of CD (n = 6). Only one patient had detectable antibodies to ustekinumab. Median serum ustekinumab concentrations remained consistent through Week 48, were detectable through Week 224, and trended lower in patients <40 kg. CONCLUSIONS: Efficacy and pharmacokinetics through 1 year and safety and immunogenicity through 4 years of ustekinumab treatment in paediatric patients with CD were generally comparable to those previously reported in adults.
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Doença de Crohn , Ustekinumab , Humanos , Ustekinumab/uso terapêutico , Ustekinumab/administração & dosagem , Doença de Crohn/tratamento farmacológico , Masculino , Feminino , Criança , Adolescente , Método Duplo-Cego , Resultado do Tratamento , Índice de Gravidade de Doença , Indução de Remissão/métodos , Proteína C-Reativa/análiseRESUMO
Non-caseating granulomas may indicate a more aggressive phenotype of Crohn disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing was performed on peripheral blood-derived DNA from 17 pediatric patients with GCD and 19 with non-GCD (NGCD), and from an independent validation cohort of 44 GCD and 19 NGCD cases. PLINK (a tool set for whole-genome association and population-based linkage analyses) analysis was used to identify single nucleotide polymorphisms (SNPs) differentiating between groups, and subgroup allele frequencies were also compared to a public genomic database (gnomAD). The Combined Annotation Dependent Depletion scoring tool was used to predict deleteriousness of SNPs. Human leukocyte antigen (HLA) haplotype findings were compared to a control group (n = 8496). PLINK-based analysis between GCD and NGCD groups did not find consistently significant hits. gnomAD control comparisons, however, showed consistent subgroup associations with DGKZ , ESRRA , and GXYLT1 , genes that have been implicated in mammalian granulomatous inflammation. Our findings may guide future research and precision medicine.
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Doença de Crohn , Criança , Humanos , Doença de Crohn/complicações , Sequenciamento do Exoma , Predisposição Genética para Doença , Granuloma/genética , Granuloma/patologia , Fenótipo , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
INTRODUCTION: While fecal calprotectin (FC) is used to assess disease activity in ulcerative colitis (UC) there are little data concerning the role of serial FC levels at diagnosis in predicting clinical course. We sought to determine whether FC at diagnosis or early change following therapy predicts clinical outcomes in pediatric UC.Methods: Children with newly diagnosed UC were treated with standardized regimens of mesalamine or corticosteroids (CS). CS tapering and escalation to additional therapy or colectomy were by protocol. Patients with baseline or week 4 or week 12 FC levels were included in the analysis. Our primary outcome was CS-free remission on mesalamine at week 52. We compared the prognostic value of a baseline FC as well as a change in FC by week 4 or week 12 in predicting clinical outcomes. RESULTS: The study included 352 children (113 initial mesalamine, 239 initial CS, mean age 12.6âyears) with UC. At Week 52, 135 (38.3%), 84 (23.8%), and 19 (5.4%) children achieved CS-free remission, needed anti-tumor necrosis factor therapy or had colectomy respectively. Baseline FC was not associated with CS-free remission at week 52. However, both week 4 (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.901.00) and week 12 FC levels (OR 0.91, 95% CI 0.87-0.96) were associated with outcomes, with the latter having a stronger association with CS-free remission. Patients with a >75% decrease by 12âweeks, had a 3-fold increased likelihood of CS-free remission at 1âyear. DISCUSSION: Longitudinal changes in FC may predict 1âyear outcomes better than values at diagnosis in children with a new diagnosis of UC.
Assuntos
Colite Ulcerativa , Complexo Antígeno L1 Leucocitário , Biomarcadores/análise , Criança , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Fezes/química , Humanos , Complexo Antígeno L1 Leucocitário/análise , Mesalamina/uso terapêutico , Indução de Remissão , Resultado do TratamentoRESUMO
BACKGROUND: Research on the utilization and effectiveness of antitumor necrosis factor (TNF) biologics in children with very early onset inflammatory bowel disease (VEOIBD) is urgently needed. Here we describe anti-TNF use and durability in a multicenter cohort. METHODS: We performed a retrospective cohort study of patients diagnosed with VEOIBD (<6 years) between 2008 and 2013 at 25 North American centers. We performed chart abstraction at diagnosis and 1, 3, and 5 years after diagnosis. We examined the rate of initiation and durability of infliximab and adalimumab and evaluated associations between treatment durability and the following covariates with multivariate Cox proportional hazard regression: age at diagnosis, sex, disease duration, disease classification, and presence of combined immunomodulatory treatment versus monotherapy. RESULTS: Of 294 children with VEOIBD, 120 initiated treatment with anti-TNF therapy and 101 had follow-up data recorded [50% Crohn disease (CD), 31% ulcerative colitis (UC), and 19% IBD unclassified (IBD-U)]. The cumulative probability of anti-TNF treatment was 15% at 1 year, 30% at 3 years, and 45% at 5 years from diagnosis; 56 (55%) were treated between 0 and 6 years old. Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years. The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children. Children with UC/IBD-U had lower durability than those with CD (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06-0.51; P = 0.001). CONCLUSIONS: Utilization and durability of anti-TNF in VEOIBD is relatively high and comparable with older children. Having Crohn disease (compared with UC/IBD-U) is associated with greater durability.
Assuntos
Produtos Biológicos , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Adalimumab/uso terapêutico , Adolescente , Produtos Biológicos/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Necrose , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfaRESUMO
INTRODUCTION: Pediatric-specific quality standards for endoscopy are needed to define best practices, while measurement of associated indicators is critical to guide quality improvement. The international Pediatric Endoscopy Quality Improvement Network (PEnQuIN) working group was assembled to develop and define quality standards and indicators for pediatric gastrointestinal endoscopic procedures through a rigorous guideline consensus process. METHODS: The Appraisal of Guidelines for REsearch and Evaluation (AGREE) II instrument guided PEnQuIN members, recruited from 31 centers of various practice types representing 11 countries, in generating and refining proposed quality standards and indicators. Consensus was sought via an iterative online Delphi process, and finalized at an in-person conference. Quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. RESULTS: Forty-nine quality standards and 47 indicators reached consensus, encompassing pediatric endoscopy facilities, procedures, endoscopists, and the patient experience. The evidence base for PEnQuIN standards and indicators was largely adult-based and observational, and downgraded for indirectness, imprecision, and study limitations to "very low" quality, resulting in "conditional" recommendations for most standards (45/49). CONCLUSIONS: The PEnQuIN guideline development process establishes international agreement on clinically meaningful metrics that can be used to promote safety and quality in endoscopic care for children. Through PEnQuIN, pediatric endoscopists and endoscopy services now have a framework for auditing, providing feedback, and ultimately, benchmarking performance. Expansion of evidence and prospective validation of PEnQuIN standards and indicators as predictors of clinically relevant outcomes and high-quality pediatric endoscopic care is now a research priority.
Assuntos
Endoscopia Gastrointestinal , Melhoria de Qualidade , Adulto , Criança , Consenso , HumanosRESUMO
INTRODUCTION: There is increasing international recognition of the impact of variability in endoscopy facilities on procedural quality and outcomes. There is also growing precedent for assessing the quality of endoscopy facilities at regional and national levels by using standardized rating scales to identify opportunities for improvement. METHODS: With support from the North American and European Societies of Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN and ESPGHAN), an international working group of the Pediatric Endoscopy Quality Improvement Network (PEnQuIN) used the methodological strategy of the Appraisal of Guidelines for REsearch and Evaluation (AGREE) II instrument to develop standards and indicators relevant for assessing the quality of facilities where endoscopic care is provided to children. Consensus was reached via an iterative online Delphi process and subsequent in-person meeting. The quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach. RESULTS: The PEnQuIN working group achieved consensus on 27 standards for facilities supporting pediatric endoscopy, as well 10 indicators that can be used to identify high-quality endoscopic care in children. These standards were subcategorized into three subdomains: Quality of Clinical Operations (15 standards, 5 indicators); Patient and Caregiver Experience (9 standards, 5 indicators); and Workforce (3 standards). DISCUSSION: The rigorous PEnQuIN process successfully yielded standards and indicators that can be used to universally guide and measure high-quality facilities for procedures around the world where endoscopy is performed in children. It also underscores the current paucity of evidence for pediatric endoscopic care processes, and the need for research into this clinical area.
Assuntos
Gastroenterologia , Melhoria de Qualidade , Criança , Consenso , Endoscopia Gastrointestinal/métodos , HumanosRESUMO
INTRODUCTION: High-quality pediatric gastrointestinal procedures are performed when clinically indicated and defined by their successful performance by skilled providers in a safe, comfortable, child-oriented, and expeditious manner. The process of pediatric endoscopy begins when a plan to perform the procedure is first made and ends when all appropriate patient follow-up has occurred. Procedure-related standards and indicators developed to date for endoscopy in adults emphasize cancer screening and are thus unsuitable for pediatric medicine. METHODS: With support from the North American and European Societies of Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN and ESPGHAN), an international working group of the Pediatric Endoscopy Quality Improvement Network (PEnQuIN) used the methodological strategy of the Appraisal of Guidelines for REsearch and Evaluation (AGREE) II instrument to develop standards and indicators relevant for assessing the quality of endoscopic procedures. Consensus was sought via an iterative online Delphi process and finalized at an in-person conference. The quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. RESULTS: The PEnQuIN working group achieved consensus on 14 standards for pediatric endoscopic procedures, as well as 30 indicators that can be used to identify high-quality procedures. These were subcategorized into three subdomains: Preprocedural (3 standards, 7 indicators), Intraprocedural (8 standards, 18 indicators), and Postprocedural (3 standards, 5 indicators). A minimum target for the key indicator, "rate of adequate bowel preparation," was set at ≥80%. DISCUSSION: It is recommended that all facilities and individual providers performing pediatric endoscopy worldwide initiate and engage with the procedure-related standards and indicators developed by PEnQuIN to identify gaps in quality and drive improvement.
Assuntos
Gastroenterologia , Melhoria de Qualidade , Adulto , Criança , Consenso , Endoscopia Gastrointestinal/métodos , HumanosRESUMO
INTRODUCTION: High-quality pediatric endoscopy requires reliable performance of procedures by competent individual providers who consistently uphold all standards determined to assure optimal patient outcomes. Establishing consensus expectations for ongoing monitoring and assessment of individual pediatric endoscopists is a method for confirming the highest possible quality of care for such procedures worldwide. We aim to provide guidance to define and measure quality of endoscopic care for children. METHODS: With support from the North American and European Societies of Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN and ESPGHAN), an international working group of the Pediatric Endoscopy Quality Improvement Network (PEnQuIN) used the methodological strategy of the Appraisal of Guidelines for REsearch and Evaluation (AGREE) II instrument to develop standards and indicators relevant for assessing the quality of endoscopists. Consensus was sought via an iterative online Delphi process and finalized at an in-person conference. The quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. RESULTS: The PEnQuIN working group achieved consensus on 6 standards that all providers who perform pediatric endoscopy should uphold and 2 standards for pediatric endoscopists in training, with 7 corresponding indicators that can be used to identify high-quality endoscopists. Additionally, these can inform continuous quality improvement at the provider level. Minimum targets for defining high-quality pediatric ileocolonoscopy were set for 2 key indicators: cecal intubation rate (≥90%) and terminal ileal intubation rate (≥85%). DISCUSSION: It is recommended that all individual providers performing or training to perform pediatric endoscopy initiate and engage with these international endoscopist-related standards and indicators developed by PEnQuIN.
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Colonoscopia , Melhoria de Qualidade , Ceco , Criança , Colonoscopia/educação , Endoscopia Gastrointestinal , Humanos , ÍleoRESUMO
INTRODUCTION: High-quality procedure reports are a cornerstone of high-quality pediatric endoscopy as they ensure the clear communication of procedural events and outcomes, guide patient care and facilitate continuous quality improvement. The aim of this document is to outline standardized reporting elements that achieved international consensus as requirements for high-quality pediatric endoscopy procedure reports. METHODS: With support from the North American and European Societies of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN and ESPGHAN), an international working group of the Pediatric Endoscopy Quality Improvement Network (PEnQuIN) used Delphi methodology to identify key elements that should be found in all pediatric endoscopy reports. Item reduction was attained through iterative rounds of anonymized online voting using a 6-point scale. Responses were analyzed after each round and items were excluded from subsequent rounds if ≤50% of panelists rated them as 5 ("agree moderately") or 6 ("agree strongly"). Reporting elements that ≥70% of panelists rated as "agree moderately" or "agree strongly" were considered to have achieved consensus. RESULTS: Twenty-six PEnQuIN group members from 25 centers internationally rated 63 potential reporting elements that were generated from a systematic literature review and the Delphi panelists. The response rates were 100% for all three survey rounds. Thirty reporting elements reached consensus as essential for inclusion within a pediatric endoscopy report. DISCUSSION: It is recommended that the PEnQuIN Reporting Elements for pediatric endoscopy be universally employed across all endoscopists, procedures and facilities as a foundational means of ensuring high-quality endoscopy services, while facilitating quality improvement activities in pediatric endoscopy.
Assuntos
Gastroenterologia , Melhoria de Qualidade , Criança , Consenso , Técnica Delphi , Endoscopia Gastrointestinal , HumanosRESUMO
BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.
Assuntos
Corticosteroides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Mesalamina/uso terapêutico , Adolescente , Biomarcadores/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. METHODS: We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. RESULTS: We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. CONCLUSIONS: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.
Assuntos
Doença de Crohn/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana/métodos , Adolescente , Fatores Etários , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença de Crohn/sangue , Progressão da Doença , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Inflamação/genética , Masculino , América do Norte , Medição de Risco , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
OBJECTIVES: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis. METHODS: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (<65) and total Mayo score, severe (10-12) versus not severe (<10); mucosal disease by Mayo endoscopic subscore, severe (3) versus not severe (<3); and extensive disease versus not extensive (left-sided and proctosigmoiditis). RESULTS: Mean age was 12.7 years; 49.6% (nâ=â212) were girls, and 83% (nâ=â351) were Caucasian. Severe total Mayo score was present in 28% (nâ=â120), mean PUCAI score was 49.8â±â20.1, and 33% (nâ=â142) had severe mucosal disease with extensive involvement in 82% (nâ=â353). Classification and regression trees identified white blood cell count, erythrocyte sedimentation rate, and platelet count (PLT) as the set of 3 best blood laboratory tests to predict disease extent and severity. For mucosal severity, albumin (Alb) replaced PLT. Classification models for PUCAI and total Mayo provided sensitivity of at least 0.65 using standard clinical cut-points with misclassification rates of approximately 30%. CONCLUSIONS: A combination of the white blood cell count, erythrocyte sedimentation rate, and either PLT or albumin is the best predictive subset of standard laboratory tests to identify severe from nonsevere clinical or mucosal disease at diagnosis in relation to objective clinical scores.
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Colite Ulcerativa , Sedimentação Sanguínea , Criança , Colite Ulcerativa/diagnóstico , Colonoscopia , Feminino , Humanos , Contagem de Leucócitos , Masculino , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: Avoiding fibrostenotic complications is of paramount concern in the management of Crohn's disease (CD). We sought to investigate the association of candidate biomarkers of fibrosis collected at diagnosis with the future development of fibrostenotic CD. METHODS: Using the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort, a multicenter prospective observational pediatric inception cohort, subjects with an inflammatory phenotype (B1) at diagnosis who later converted to a stricturing phenotype (B2) within 3 years were compared with those who remained B1. Serum collected at diagnosis underwent both parallel reaction monitoring-targeted proteomic analysis and conventional enzyme-linked immunosorbent assay for 10 candidate biomarkers of intestinal fibrosis. Cox proportional hazard regression was used for multivariable analysis of time-dependent outcomes. RESULTS: In 116 subjects 58 subjects with verified B1 phenotype at diagnosis who later converted to B2 disease were compared with 58 subjects who remained B1 over 3 years of follow-up. Extracellular matrix protein 1 (ECM1) levels in the upper quartile (hazard ratio [HR] 3.43, 95% confidence limit [CL] 1.33, 8.42) were associated with future fibrostenotic disease. ASCA IgA (HR 4.99, 95% CL 1.50, 16.68) and CBir levels (HR 5.19, 95% CL 1.83, 14.74) were also associated with future intestinal fibrostenosis, although ECM1 continued to demonstrate independent association with conversion to B2 even with adjustment for serologies in multivariable analysis (HR 5.33, 95% CL 1.29, 22.13). CONCLUSIONS: ECM1 and other biomarkers of fibrosis may aid in determining the risk of uncomplicated inflammatory disease converting to B2 stricturing phenotypes in children with CD. Prospective validation studies to verify test performance and optimize clinical utilization are needed before clinical implementation.
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Doença de Crohn , Proteínas da Matriz Extracelular/sangue , Intestinos , Proteômica/métodos , Biomarcadores/sangue , Criança , Constrição Patológica/diagnóstico , Constrição Patológica/etiologia , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Progressão da Doença , Feminino , Fibrose , Humanos , Inflamação/sangue , Intestinos/imunologia , Intestinos/microbiologia , Intestinos/patologia , Masculino , Medição de Risco/métodosRESUMO
Patients with inflammatory bowel disease have adopted medical jargon terms of "flare" and "remission," but what they mean by these terms is ill-defined and may have implications for nurse-patient communication and treatment expectancy. The aim of this study was to elicit patients' understanding of "flare" and "remission." Individuals with self-reported inflammatory bowel disease were recruited through social media. A web-based survey, with closed and open-ended questions, was administered. Conventional content analysis was used to evaluate respondents' perceptions of jargon terms. A word cloud was generated to augment analysis by visualization of word use frequency. A majority of the 34 respondents had a symptom-focused understanding and described these terms as alternating states. Various symptoms were understood to signify "flare," which was largely attributed to lifestyle factors. Corroborated by the word cloud, there was rare mention of inflammation or tissue damage. This study demonstrates that an understanding of "flare" and "remission" by patients with inflammatory bowel disease is largely symptom-based. The role of inflammation, medication failure, and targets of inflammatory bowel disease treatment beyond symptom control are not currently well known to patients with inflammatory bowel disease. To create a shared understanding of symptoms and treatment goals between the patient and the nurse, patient education on emerging expectations of inflammatory bowel disease care should be prioritized.
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Progressão da Doença , Conhecimentos, Atitudes e Prática em Saúde , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/fisiopatologia , Medidas de Resultados Relatados pelo Paciente , Adolescente , Adulto , Produtos Biológicos/uso terapêutico , Compreensão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Remissão Espontânea , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Perfil de Impacto da Doença , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. METHODS: We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. FINDINGS: Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. INTERPRETATION: Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. FUNDING: Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.
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Doença de Crohn/complicações , Adalimumab/uso terapêutico , Adolescente , Anti-Inflamatórios não Esteroides/uso terapêutico , Criança , Estudos de Coortes , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/microbiologia , Progressão da Doença , Feminino , Microbioma Gastrointestinal , Humanos , Infliximab/uso terapêutico , Obstrução Intestinal/etiologia , Masculino , Prognóstico , Pontuação de Propensão , Estudos Prospectivos , Medição de Risco/métodos , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
BACKGROUND & AIMS: There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes. METHODS: We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center. RESULTS: We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P = .001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132-25.12). CONCLUSIONS: In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.
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Colite Ulcerativa/genética , Doença de Crohn/genética , Imunidade nas Mucosas/genética , Interleucinas/genética , Mucosa Intestinal/imunologia , Adolescente , Área Sob a Curva , Estudos de Casos e Controles , Criança , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Colo/patologia , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Feminino , Expressão Gênica , Humanos , Interleucina-13/genética , Subunidade alfa2 de Receptor de Interleucina-13/genética , Interleucina-17/genética , Interleucina-23/genética , Interleucina-5/genética , Mucosa Intestinal/metabolismo , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , RNA Mensageiro/análise , Curva ROC , Reto , Transcriptoma , Regulação para CimaRESUMO
BACKGROUND & AIMS: Up to 30% of patients with Crohn's disease (CD) require surgery within the first 5 years from diagnosis. We investigated the recent risk of bowel surgery in an inception cohort of pediatric patients with CD and whether early use of biologics (tumor necrosis factor antagonists) alters later disease course. METHODS: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group registry on 1442 children (age, ≤16 y) diagnosed with CD from January 2002 through December 2014. Data were collected at diagnosis, 30 days following diagnosis, and then quarterly and during hospitalizations for up to 12 years. Our primary aim was to determine the 10-year risk for surgery in children with CD. Our secondary aim was to determine whether early use of biologics (<3 mo of diagnosis) affected risk of disease progression. RESULTS: The 10-year risk of first bowel surgery was 26%. The 5-year risk of bowel surgery did not change from 2002 through 2014, and remained between 13% and 14%. Most surgeries occurred within 3 years from diagnosis. The only predictor of surgery was disease behavior at diagnosis. CD with inflammatory behavior had the lowest risk of surgery compared to stricturing disease, penetrating disease, or both. We associated slowing of disease progression to stricturing or penetrating disease (but not surgery) with early use of biologics, but this effect only became evident after 5 years of disease. Our results indicate that biologics slow disease progression over time (hazard ratio, 0.85; 95% CI, 0.76-0.95). CONCLUSIONS: In an analysis of data from a registry of pediatric patients with CD, we found that among those with significant and progressing disease at or shortly after presentation, early surgery is difficult to prevent, even with early use of biologics. Early use of biologics (<3 mo of diagnosis) can delay later disease progression to stricturing and/or penetrating disease, but this affect could become evident only years after initial management decisions are made.