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1.
Gastroenterology ; 167(2): 315-332, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38490347

RESUMO

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. METHODS: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. RESULTS: Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. CONCLUSIONS: We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.


Assuntos
Colangite Esclerosante , Colite Ulcerativa , Doença de Crohn , Humanos , Feminino , Masculino , Adulto , Colangite Esclerosante/imunologia , Colangite Esclerosante/genética , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/complicações , Pessoa de Meia-Idade , Colite Ulcerativa/imunologia , Colite Ulcerativa/genética , Colite Ulcerativa/diagnóstico , Doença de Crohn/imunologia , Doença de Crohn/genética , Doença de Crohn/diagnóstico , Adolescente , Fatores de Risco , Criança , Espondilite Anquilosante/genética , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/complicações , Predisposição Genética para Doença , Adulto Jovem , Fatores Sexuais , Dermatopatias/etiologia , Dermatopatias/imunologia , Dermatopatias/genética , Oftalmopatias/etiologia , Oftalmopatias/imunologia , Oftalmopatias/diagnóstico , Oftalmopatias/genética , Oftalmopatias/epidemiologia , Fenótipo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/diagnóstico , Modelos Logísticos , Idoso
2.
Dig Dis Sci ; 69(1): 235-245, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38015321

RESUMO

BACKGROUND: The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohn's disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR). METHODS: We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeert's score ≥ i2 within 15 months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics. RESULTS: The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) [0.13-0.53]). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI [0.32-1.36]). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results. CONCLUSION: In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.


Assuntos
Doença de Crohn , Humanos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/prevenção & controle , Doença de Crohn/cirurgia , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Estudos Retrospectivos , Estudos Prospectivos , Fator de Necrose Tumoral alfa , Necrose
3.
Gut ; 72(11): 2068-2080, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37080587

RESUMO

OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.


Assuntos
Fator B do Complemento , Doença de Crohn , Humanos , Fator B do Complemento/genética , Doença de Crohn/complicações , Qualidade de Vida , Seguimentos , Fagocitose
4.
Lancet ; 393(10182): 1708-1720, 2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-30935734

RESUMO

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 Tratamento
5.
Lancet ; 389(10080): 1710-1718, 2017 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-28259484

RESUMO

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.


Assuntos
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 & inibidores
6.
Am J Gastroenterol ; 113(10): 1524-1529, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30267029

RESUMO

OBJECTIVES: Environmental factors play an important role in the pathogenesis of Crohn's Disease (CD). In particular, by virtue of the instability of the microbiome and development of immunologic tolerance, early life factors may exert the strongest influence on disease risk and phenotype. METHODS: We used data from 1119 CD subjects recruited from RISK inception cohort to examine the impact of early life environment on disease progression. Our primary exposures of interest were breastfeeding in infancy and exposure to maternal, active, or passive smoke. Our primary outcomes were development of complicated (stricturing or penetrating) disease, and need for CD-related hospitalization, and surgery. Multivariable logistic regression models were used to define independent associations, adjusting for relevant covariates. RESULTS: Our study cohort included 1119 patients with CD among whom 15% had stricturing (B2) or penetrating disease (B3) by 3 years. 331 patients (35%) and 95 patients (10.6%) required CD-related hospitalizations and surgery respectively. 74.5% were breastfed in infancy and 31% were exposed to smoking among whom 7% were exposed to maternal smoke. On multivariable analysis, a history of breastfeeding was inversely associated with complicated (B2/B3 disease) 0.65, CI 95% 0.44-96; P = 0.03) in pediatric CD. Maternal smoking during pregnancy was associated with increased risk of hospitalization during the 3-year follow-up period (OR 1.75, CI 95% 1.05-2.89; P = 0.03). CONCLUSIONS: Early life environmental factors influence the eventual phenotypes and disease course in CD.


Assuntos
Aleitamento Materno/estatística & dados numéricos , Doença de Crohn/diagnóstico , Exposição Ambiental/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Adolescente , Criança , Colo/patologia , Constrição Patológica/epidemiologia , Constrição Patológica/etiologia , Doença de Crohn/complicações , Doença de Crohn/etiologia , Doença de Crohn/terapia , Progressão da Doença , Exposição Ambiental/estatística & dados numéricos , Feminino , Seguimentos , Hospitalização/estatística & dados numéricos , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , América do Norte/epidemiologia , Fenótipo , Gravidez , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fumar/epidemiologia , Fatores de Tempo , Poluição por Fumaça de Tabaco/estatística & dados numéricos
8.
Gastroenterology ; 146(2): 383-91, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24162032

RESUMO

BACKGROUND & AIMS: Standard therapy for children newly diagnosed with Crohn's disease (CD) includes early administration of immunomodulators after initial treatment with corticosteroids. We compared the effectiveness of early (≤3 mo after diagnosis) treatment with an anti-tumor necrosis factor (TNF)α with that of an immunomodulator in attaining clinical remission and facilitating growth of pediatric patients. METHODS: We analyzed data from the RISK study, an observational research program that enrolled patients younger than age 17 diagnosed with inflammatory (nonpenetrating, nonstricturing) CD from 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early immunomodulator, or no early immunotherapy. We evaluated relationships among therapies, corticosteroid and surgery-free remission (pediatric CD activity index scores, ≤10), and growth at 1 year for 204 children. Treatment after 3 months was a covariate. RESULTS: Early treatment with anti-TNFα was superior to early treatment with an immunomodulator (85.3% vs 60.3% in remission; relative risk, 1.41; 95% confidence interval [CI], 1.14-1.75; P = .0017), whereas early immunomodulator therapy was no different than no early immunotherapy (60.3% vs 54.4% in remission; relative risk, 1.11; 95% CI, 0.83-1.48; P = .49) in achieving remission at 1 year. Accounting for therapy after 3 months, early treatment with anti-TNFα remained superior to early treatment with an immunomodulator (relative risk, 1.51; 95% CI, 1.20-1.89; P = .0004), whereas early immunomodulator therapy was no different than no early immunotherapy (relative risk, 1.00; 95% CI, 0.75-1.34; P = .99). The mean height z-score increased compared with baseline only in the early anti-TNFα group. CONCLUSIONS: In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Quimioterapia de Indução/métodos , Adalimumab , Adolescente , Azatioprina/uso terapêutico , Criança , Desenvolvimento Infantil , Esquema de Medicação , Feminino , Seguimentos , Humanos , Infliximab , Masculino , Análise por Pareamento , Mercaptopurina/uso terapêutico , Metotrexato/uso terapêutico , Pontuação de Propensão , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
9.
World J Gastrointest Surg ; 16(3): 740-750, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38577075

RESUMO

BACKGROUND: Evidence suggests inflammatory mesenteric fat is involved in post-operative recurrence (POR) of Crohn's disease (CD). However, its prognostic value is uncertain, in part, due to difficulties studying it non-invasively. AIM: To evaluate the prognostic value of pre-operative radiographic mesenteric parameters for early endoscopic POR (ePOR). METHODS: We conducted a retrospective cohort study of CD subjects ≥ 12 years who underwent ileocecal or small bowel resection between 1/1/2007 to 12/31/2021 with computerized tomography abdomen/pelvis ≤ 6 months pre-operatively and underwent ileocolonoscopy ≤ 15 months post-operatively. Visceral adipose tissue (VAT) volume (cm3), ratio of VAT:subcutaneous adipose tissue (SAT) volume, VAT radiodensity, and ratio of VAT:SAT radiodensity were generated semiautomatically. Mesenteric lymphadenopathy (LAD, largest lymph node > 10 mm) and severe vasa recta (VR) engorgement (diameter of the VR supplying diseased bowel ≥ 2 × VR supplying healthy bowel) were derived manually. The primary outcome was early ePOR (Rutgeert's score ≥ i2 on first endoscopy ≤ 15 months post-operatively) and the secondary outcome was ePOR severity (Rutgeert's score i0-4). Regression analyses were performed adjusting for demographic and disease-related characteristics to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). RESULTS: Of the 139 subjects included, 45% of subjects developed early ePOR (n = 63). VAT radiodensity (aOR 0.59, 95%CI: 0.38-0.90) and VAT:SAT radiodensity (aOR 8.54, 95%CI: 1.48-49.28) were associated with early ePOR, whereas, VAT volume (aOR 1.23, 95%CI: 0.78-1.95), VAT:SAT volume (aOR 0.80, 95%CI: 0.53-1.20), severe VR engorgement (aOR 1.53, 95%CI: 0.64-3.66), and mesenteric LAD (aOR 1.59, 95%CI: 0.67-3.79) were not. Similar results were observed for severity of ePOR. CONCLUSION: VAT radiodensity is potentially a novel non-invasive prognostic imaging marker to help risk stratify CD patients for POR.

10.
J Clin Gastroenterol ; 47(5): 437-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23426446

RESUMO

Probiotic strains of Lactobacillus are currently used in a variety of clinical practices with limited evidence to support their use. Lactobacillus species are a normal part of gastrointestinal flora, and bacteremia with probiotic strains of Lactobacillus is very uncommon. We describe a case of Lactobacillus bacteremia in a 17-year-old boy with ulcerative colitis managed with systemic corticosteroids and infliximab, who presented with fever to 102°F, flushing, and chills 1 week after starting Lactobacillus rhamnosus GG probiotics. Initial blood culture on day 2 of his fever was positive for Lactobacillus, however, subsequent blood cultures on day 3 and 5 were negative. He was treated empirically with antibiotics for 5 days and defervesced by day 8 of his illness. 16 S rRNA sequence analysis identified the organism from the patient's blood culture and probiotic capsule as L. rhamnosus with a 99.78% match for both the strains. This case report highlights the potential risk of Lactobacillus bacteremia in immunosuppressed patients with severe active ulcerative colitis.


Assuntos
Bacteriemia/microbiologia , Colite Ulcerativa/terapia , Lacticaseibacillus rhamnosus , Probióticos/efeitos adversos , Probióticos/uso terapêutico , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Hospedeiro Imunocomprometido , Lacticaseibacillus rhamnosus/classificação , Lacticaseibacillus rhamnosus/genética , Lacticaseibacillus rhamnosus/isolamento & purificação , Lacticaseibacillus rhamnosus/patogenicidade , Masculino , RNA Ribossômico 16S/genética , Fatores de Risco , Análise de Sequência de DNA
11.
Am J Manag Care ; 29(12 Suppl): S227-S235, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37844322

RESUMO

OBJECTIVES: Evaluate the clinical utility of a precision-guided dosing test for infliximab (IFX) and its impact on treatment decision-making for inflammatory bowel disease (IBD). STUDY DESIGN: Prospective, multisite, clinical experience program. METHODS: Health care providers were given access to PredictrPK IFX, a precision-guided dosing test, for their patients with IBD on maintenance IFX therapy. Blood samples were drawn 20 to 56 days post infusion. A Bayesian data assimilation tool used clinical and serologic data to generate individual pharmacokinetic profiles and forecast trough IFX. Results were reported to providers to aid in-therapy management decisions and the decision-making process was assessed through questionnaires. Relationships between forecasted IFX concentration, disease activity, and therapy management decisions were analyzed by logistic regression. RESULTS: PredictrPK IFX was used for 275 patients with IBD by 37 providers. In 58% of cases, providers modified treatment plans based on the results, including dose modifications (41%; of these, one-third decreased dose) and discontinuation (8%) of IFX. Of the 42% where treatment was not modified, 97.5% had IFX levels of 5 µg/mL or greater. Patients with IFX concentrations less than 5 µg/mL were 3 and 7.3 times more likely to have active disease or discontinue IFX, respectively. There was unanimous agreement among providers who completed a postprogram survey that PredictrPK IFX was beneficial in guiding treatment decisions and added more value to their practice than routine therapeutic drug monitoring. CONCLUSIONS: PredictrPK IFX enables earlier and more precise dose optimization of IFX in patients with IBD, exerting a substantial impact on treatment decisions that may result in improved health outcomes and overall cost savings.


Assuntos
Fármacos Gastrointestinais , Doenças Inflamatórias Intestinais , Humanos , Infliximab/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Estudos Prospectivos , Teorema de Bayes , Doenças Inflamatórias Intestinais/tratamento farmacológico , Monitoramento de Medicamentos/métodos
12.
J Pediatr Gastroenterol Nutr ; 55(5): 534-40, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22684351

RESUMO

OBJECTIVES: Few clinical predictors are associated with definitive proctocolectomy in children with ulcerative colitis (UC). The purpose of the present study was to identify clinical predictors associated with surgery in children with UC using a disease-specific database. METHODS: Children diagnosed with UC at age <18 years were identified using the Pediatric Inflammatory Bowel Disease Consortium (PediIBDC) database. Demographic and clinical variables from January 1999 to November 2003 were extracted alongside incidence and surgical staging. RESULTS: Review of the PediIBDC database identified 406 children with UC. Approximately half were girls (51%) with an average age at diagnosis of 10.6 ±â€Š4.4 years in both boys and girls. Average follow-up was 6.8 (±4.0) years. Of the 57 (14%) who underwent surgery, median time to surgery was 3.8 (interquartile range 4.9) years after initial diagnosis. Children presenting with weight loss (hazard ratio [HR] 2.55, 99% confidence interval [CI] 1.21-5.35) or serum albumin <3.5 g/dL (HR 6.05, 99% CI 2.15-17.04) at time of diagnosis and children with a first-degree relative with UC (HR 1.81, 99% CI 1.25-2.61) required earlier surgical intervention. Furthermore, children treated with cyclosporine (HR 6.11, 99% CI 3.90-9.57) or tacrolimus (HR 3.66, 99% CI 1.60-8.39) also required earlier surgical management. Other symptoms, laboratory tests, and medical therapies were not predictive for need of surgery. CONCLUSION: Children with UC presenting with hypoalbuminemia, weight loss, a family history of UC, and those treated with calcineurin inhibitors frequently require restorative proctocolectomy for definitive treatment. Early identification and recognition of these factors should be used to shape treatment goals and initiate multidisciplinary care at the time of diagnosis.


Assuntos
Colite Ulcerativa/cirurgia , Hipoalbuminemia/complicações , Imunossupressores/uso terapêutico , Proctocolectomia Restauradora , Albumina Sérica/metabolismo , Redução de Peso , Inibidores de Calcineurina , Criança , Colite Ulcerativa/sangue , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Ciclosporina/uso terapêutico , Família , Feminino , Predisposição Genética para Doença , Humanos , Hipoalbuminemia/sangue , Incidência , Masculino , Medição de Risco , Tacrolimo/uso terapêutico , Fatores de Tempo
13.
J Adolesc Young Adult Oncol ; 10(5): 614-617, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-32960134

RESUMO

Biologic therapies have revolutionized the treatment of immune-mediated diseases. They are generally well tolerated; however, there are reports of malignancies associated with the use of these drugs. This case is of an adolescent with refractory Crohn's disease treated with ustekinumab, who subsequently developed Ewing's sarcoma. Patients treated with ustekinumab have reportedly developed B cell lymphoma, epithelioid sarcoma, as well as cancer of the lung, esophagus, ovary, testis, kidney, and thyroid. However, this is the first documented case of a patient treated with ustekinumab to develop Ewing sarcoma.


Assuntos
Doença de Crohn , Sarcoma de Ewing , Sarcoma , Adolescente , Doença de Crohn/tratamento farmacológico , Feminino , Humanos , Masculino , Sarcoma de Ewing/tratamento farmacológico , Ustekinumab/uso terapêutico
14.
J Crohns Colitis ; 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770196

RESUMO

BACKGROUND AND AIMS: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. METHODS: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. RESULTS: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). CONCLUSION: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.

15.
Gastroenterology ; 135(3): 744-55, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18639553

RESUMO

BACKGROUND & AIMS: 2-Deoxy-2-[(18)F]fluoro-d-glucose (FDG) uptake by positron emission tomography (PET), a measure of glucose transporter activity, has been used to detect mucosal inflammation. However, there is limited understanding of the biologic basis of mucosal FDG uptake. METHODS: A contrast-based computed tomographic isocontour method was developed to identify intestinal anatomic regions, and FDG uptake was integrated over these regions to achieve reproducible quantification during longitudinal assessment of individual mice. Intestinal FDG uptake was compared with histologic scores and with glucose transporter 1 levels in mucosal immune cells by flow cytometry. RESULTS: Intestinal FDG uptake quantitatively correlated with disease activity in mild (C3H/HeJ.IL-10(-/-)) and severe (129.Galphai2(-/-), CD4(+) CD45RB(high), and Galphai2(-/-) CD3(+) transfer) murine colitis models at all time points examined (P < .05) and was sufficiently sensitive to detect preclinical inflammation. FDG uptake was correlated by flow cytometric detection of glucose transporter 1 levels in mucosal CD4(+) T lymphocyte but not other intestinal immune cell types. CD4(+) T-cell transfer in vivo confirmed that mucosal FDG uptake was associated with the activated but not quiescent state. When intestinal inflammation was increased by treatment with piroxicam and decreased with anti-TL1A treatment, FDG uptake was correspondingly altered. CONCLUSIONS: This study clarifies the cellular basis of FDG signal in intestinal inflammation and introduces computed tomographic isocontour analysis of FDG-PET imaging for standardized quantitation of immune colitis.


Assuntos
Colite/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Linfócitos T CD4-Positivos/metabolismo , Colite/imunologia , Colite/metabolismo , Colite/patologia , Feminino , Transportador de Glucose Tipo 1/metabolismo , Inflamação , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestinos/diagnóstico por imagem , Ativação Linfocitária , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos , Camundongos Knockout , Piroxicam/farmacologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/farmacologia
16.
Inflamm Bowel Dis ; 25(1): 27-32, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931102

RESUMO

The Crohn's & Colitis Foundation has facilitated transformational research in pediatric inflammatory bowel disease (IBD), through the RISK and PROTECT studies, that has laid the groundwork for a comprehensive understanding of molecular mechanisms of disease and predictors of therapeutic response in children. Despite these advances, children have lacked timely and informed access to the latest therapeutic advancements in IBD. The Crohn's & Colitis Foundation convened a Pediatric Resource Organization for Kids with Inflammatory Intestinal Diseases (PRO-KIIDS) Clinical Innovations Meeting at the inaugural Crohn's and Colitis Congress in January 2018 to devise how to advance the care of children with IBD. The working group selected 2 priorities: (1) accelerating therapies to children with IBD and (2) stimulating investigator-initiated research while fostering sustainable collaboration; and proposed 2 actions: (a) the convening of a task force to specifically address how to accelerate pharmacotherapies to children with IBD and (b) the funding of a multicenter clinical and translational research study that incorporates the building of critical research infrastructure.10.1093/ibd/izy205_video1izy205.video15799266615001.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Guias de Prática Clínica como Assunto/normas , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Criança , Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Gerenciamento Clínico , Humanos , Prognóstico
17.
Inflamm Bowel Dis ; 25(7): 1208-1217, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-30601983

RESUMO

BACKGROUND: Variation in care is common in medical practice. Reducing variation in care is shown to improve quality and increase favorable outcomes in chronic diseases. We sought to identify factors associated with variation in care in children with newly diagnosed Crohn's disease (CD). METHODS: Prospectively collected data from a 28-site multicenter inception CD cohort were analyzed for variations in diagnostic modalities, treatment, and follow-up monitoring practices, along with complicated disease outcomes over 3 years in 1046 children. Generalized linear mixed effects models were used to investigate the intercenter variations in each outcome variable. RESULTS: The mean age at diagnosis was 12 years, and 25.9% were nonwhite. The number of participants ranged from 5 to 112 per site. No variation existed in the initial diagnostic approach. When medication exposure was analyzed, steroid exposure varied from 28.6% to 96.9% (P < 0.01) within 90 days, but variation was not significant over a 3-year period (P = 0.13). Early anti-tumor necrosis factor (anti-TNF) exposure (within 90 days) varied from 2.1% to 65.7% (P < 0.01), but variation was not significant over a 3-year period (P > 0.99). Use of immunomodulators (IMs) varied among centers both within 90 days (P < 0.01) and during 3 years of follow-up (P < 0.01). A significant variation was seen at the geographic level with follow-up small bowel imaging and colonoscopy surveillance after initial therapy. CONCLUSIONS: Intercenter variation in care was seen with the initial use of steroids and anti-TNF, but there was no difference in total 3-year exposure to these drugs. Variation in the initiation and long-term use of IMs was significant among sites, but further research with objective measures is needed to explain this variation of care. Small bowel imaging or repeat colonoscopy in CD patients was not uniformly performed across sites. As our data show the widespread existence of variation in care and disease monitoring at geographic levels among pediatric CD patients, future implementation of various practice strategies may help reduce the variation in care.


Assuntos
Doença de Crohn/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Assistência ao Paciente/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Índice de Gravidade de Doença , Anticorpos Monoclonais/uso terapêutico , Criança , Doença de Crohn/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Fatores de Risco
18.
Mucosal Immunol ; 12(2): 491-502, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30542108

RESUMO

Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer's patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.


Assuntos
Fatores Etários , Envelhecimento/fisiologia , Doença de Crohn/imunologia , Disbiose/imunologia , Íleo/imunologia , Nódulos Linfáticos Agregados/imunologia , alfa-Defensinas/metabolismo , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Doença de Crohn/epidemiologia , Disbiose/epidemiologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Puberdade , Risco , Células Th1/imunologia , alfa-Defensinas/genética
19.
Inflamm Bowel Dis ; 29(2): 328-331, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36508344

RESUMO

Active cytomegalovirus (CMV) infection complicates management of inflammatory bowel disease, but the relationship of resolved CMV infection to Crohn's disease (CD) behavior or localization is unknown. This article reports a striking risk (9-fold) of Crohn's disease localization to the colon with prior CMV infection. It also reports imputed mucosal cellular composition, HLA class 1, and KIR gene variants that delimit prior observations regarding HLA and KIR associations with Crohn's disease risk and behavior.


Assuntos
Doença de Crohn , Infecções por Citomegalovirus , Infecções por Herpesviridae , Doenças Inflamatórias Intestinais , Humanos , Doença de Crohn/complicações , Infecções por Citomegalovirus/complicações
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