RESUMO
BACKGROUND: Although a mainstay of treatment of moderate to severe Crohn's disease (CD), corticosteroids use presents significant challenges because of large interindividual variability in response. Corticosteroid-dependence is of particular concern in children, where high rates have been reported. We examined the burden of corticosteroid-resistance and dependence in a well-characterized cohort of pediatric CD patients and investigated potential predictors of response. METHODS: Children diagnosed with CD (<18 years), were recruited from two Canadian pediatric gastroenterology clinics. Immediate and long-term responses to corticosteroid therapy were retrospectively ascertained. Response rates (resistance and dependence) were estimated and potential predictors assessed using logistic regression analysis. RESULTS: Of the 645 CD patients, 364 (56.2%) received corticosteroids. The frequency of corticosteroid-resistance was (8.0%) (95% confidence interval [CI]: 5.0%-11%) and 40.9% (95% CI: 39.0%-46.0%) became dependent. In univariate analysis female gender (odds ratio [OR] = 2.49, 95% CI: 1.1-5.5, P = 0.025), disease severity (OR = 2.43, 95% CI: 1.10-5.38, P = 0.029), and complicated disease (OR = 2.75, 95% CI: 1.18-6.41, P = 0.019) were associated with resistance. In multivariate analysis lower age at diagnosis (OR = 1.34,95% CI: 1.03-3.01, P = 0.040), coexisting upper digestive tract involvement (OR = 1.35, 95% CI: 1.06-3.07, P = 0.031), and concomitant immunomodulator use (OR = 0.35, 95% CI: 0.16-0.75, P = 0.007) were significantly associated with steroid dependency. CONCLUSIONS: Our results demonstrate that steroid dependency is a frequent complication in children with CD. Children with an earlier age at diagnosis and coexisting upper digestive tract involvement could be potentially targeted for steroid-sparing therapy.
Assuntos
Anti-Inflamatórios/uso terapêutico , Prednisona/uso terapêutico , Canadá , Criança , Estudos de Coortes , Doença de Crohn/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Recent genome-wide studies have implicated the autophagy genes ATG16L1 and IRGM in the pathogenesis of Crohn's disease (CD). We investigated whether these genes were associated with CD in Canadian children. METHODS: A case-control study was carried out at 2 pediatric gastroenterology clinics in Canada. Confirmed cases of CD <20 years diagnosed using standard criteria were classified according to the Montreal Classification scheme. Single nucleotide polymorphisms (SNPs) rs2241880 (ATG16L1) and rs10065172 (IRGM) along with CARD15 SNPs, SNP8, SNP12, and SNP13 were genotyped. RESULTS: A total of 289 CD cases and 290 controls were studied. The mean age (+/-SD) of the cases was 12.1 (+/-3.5) years of age. Most cases were male (55.4%), had disease location L3 +/- L4 (56.7%), and an inflammatory phenotype B1 +/- p (87.2%) at diagnosis. rs2241880 (ATG16L1) was strongly associated with CD (allelic P = 1.24 x 10(-6)). Children with GG genotype had a more than 3-fold elevated risk for disease as compared to the wildtype AA homozygotes (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.93-4.94; P = 1.8 x 10(-6)). Association with SNP rs2241880 was specific for ileal disease (with or without colonic involvement) (case-based allelic P = 0.02; P-value versus controls = 9.5 x 10(-8)). The frequency of IRGM SNP rs10065172 was higher in cases but differences with controls were not statistically significant. No interactions between CARD15 and either ATG16L1 or IRGM were evident. CONCLUSIONS: We have confirmed associations between CD and ATG16L1 in a pediatric cohort of Canadian children. Associations with IRGM need to be further evaluated in larger studies.
Assuntos
Autofagia/genética , Proteínas de Transporte/genética , Doença de Crohn/epidemiologia , Doença de Crohn/genética , Proteínas de Ligação ao GTP/genética , Adolescente , Proteínas Relacionadas à Autofagia , Canadá/epidemiologia , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
BACKGROUND AND OBJECTIVES: Interleukin (IL)-23 is a key regulator of inflammation and influences the activities of T-helper 17 (Th-17) lymphocytes. Recent reports indicate that variants in the gene coding for its receptor (IL-23R) are strongly associated with Crohn's disease (CD). We investigated whether DNA variants in the IL-23R gene determine susceptibility for CD in Canadian children. DESIGN AND METHODS: A case-control and case-parent trio design was implemented at three pediatric centers across Canada. Cases of CD (
