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Purpose: Factors influencing response to medications in Crohn's disease (CD) patients are not fully understood. We aimed to evaluate the relationships between NOD2/CARD15 mutations, disease phenotype and age of CD diagnosis and response to medical treatment with systemic steroids, azathioprine (AZA) or 6-mercaptopurine (6-MP), and infliximab., Methods: A retrospective medical records analysis was made of patients previously tested for the CD-associated NOD2/CARD15 mutations. Harvey- Bradshaw score was used to assess remission or response to therapy., Results: CD-associated NOD2/CARD15 mutations were not related to the rate of steroids dependency or clinical response to AZA/6-MP and infliximab. Steroid dependency was associated with colonic involvement. Thirty-three of 127 (26%) patients with colonic disease were steroid dependent, compared with 7/72 (9.7%) patients with isolated small bowel disease (ISBD), (p = 0.009). ISBD was mildly associated with a better remission/response to AZA/6-MP treatment. Disease behavior and age of diagnosis were not related to response to therapy., Conclusions: Response to treatment with systemic steroids, AZA/6-MP and infliximab are not related to NOD2/CARD15 mutations, age of diagnosis and disease behavior. Patients with colonic disease have higher rates of steroid dependency.

Aims: Pediatric onset of Crohn disease (CD) is characterized by male sex predominance while adult-onset disease demonstrates female sex predominance. It has been postulated that this phenomenon may be genetically determined or due to an effect of estrogen on age of onset. Interleukin (IL)-6 modulates the TH17 pathway, and the IL-6 promoter is modulated by estrogen, possibly linking genetically determined inflammation and the presence of estrogen. The aim of our study was to investigate whether differences in IL-6 promoter genotype could explain male sex in earlier disease onset., Patients and Methods: We genotyped 333 patients with CD and 100 controls, 162 pediatric-onset patients (age of onset 18 years and younger) for the IL-6-174 polymorphic site. Genotype, sex, and age of onset were compared., Results: Males with IL-6-174GG genotype (the wild-type allele) had an increased risk for a younger age of onset compared to males with IL-6-174GC or CC genotype (G --> C genotype), hazard ratio (HR) 1.49, P = 0.02, 95% confidence interval (CI) 1.07-2.09. Females with GG genotype were not found to have an increased risk for a younger age of onset compared with females with G --> C genotype, HR 1.01, P = 0.96, 95% CI 0.72-1.41., Conclusions: Males with IL-6-174GG genotype are prone to develop CD at a younger age than males with the IL-6-174G --> C genotype. Our study suggests that age of onset may be modified by the IL-6-174GG genotype and this modification is sex dependent. This may be due to increased transcription of IL-6, an effect that may be repressed by estrogen in females.

Background: Disease behavior in Crohn's disease (CD) may be modified by disease location and genotype. Disease behavior may change over time, and thus analysis requires follow-up. To date, there have been few pediatric studies that have evaluated the association between disease behavior and genotype with prolonged follow-up. The aim of our study was to evaluate the effect of genotype, phenotype, and ethnicity on disease behavior in pediatric CD., Methods: Evaluation of 128 pediatric CD was followed by analysis of 232 pediatric and adult-onset CD patients. Inclusion required at least 2 years of follow-up. Phenotype, ethnicity, and disease duration were recorded. Patients were genotyped for polymorphisms in the NOD2/CARD15 gene., Results: Colonic involvement was more frequent in younger patients. Pediatric disease at end of follow-up was classified as inflammatory (78%), penetrating (7%), and stricturing (17%). Duration of follow-up (mean 4.9 pediatric and 6.4 years mixed) was associated with more stricturing and penetrating disease. There was no association between mean age of onset and NOD2/CARD15, or either of these with disease behavior. These observations were replicated in the mixed cohort. Sephardic Jewish origin was inversely correlated with inflammatory behavior (P = 0.006), independent of NOD2/CARD15 genotype., Conclusions: Duration of disease and ethnicity, irrespective of NOD2/CARD15 genotype and age of onset, were the only predictors for penetrating or stricturing disease.

Crohn's disease (CD) is caused by a combination of environmental and genetic factors. It is not clear at present whether age of onset (AOO) is a random event or dictated by genotype or environmental factors. Mutations in the NOD2/caspase recruitment domains 15 (CARD15) and in the Toll-like receptor 4 (TLR4) gene have been associated with increased susceptibility for CD. We sought to determine whether single or multiple mutations in these genes are linked to earlier susceptibility for CD. A cohort of 189 patients with CD (82 pediatric onset, 107 adult onset) were genotyped for three disease-associated single-nucleotide polymorphisms (SNPs), one haplotype association (JW1-SNP5), and one background polymorphism (P268S) of the NOD2/CARD15 gene and for two SNPs of TLR4. Analysis of heterozygosity, homozygosity, alleles, and haplotypes of cohort on age or pediatric onset was performed. AOO ranged from 8 mo to 68 y. The presence of the three NOD2/CARD15 and two TLR4 mutations, the NOD2/CARD15 JW haplotype, compound heterozygosity, and homozygosity were not associated with AOO. Presence of P268S in the absence of known NOD2/CARD15 mutations was correlated with increasing age and adult onset of CD, whereas pediatric-onset disease was associated with male gender and the wild-type NOD2/CARD15 haplotype. Mutations in NOD2/CARD15 and TLR4 are not significantly associated with AOO in our population. Mutations that are not in linkage disequilibrium with the background mutation P268S of the NOD2/CARD15 gene probably play a more significant role in pediatric-onset disease.

Background: Approximately one-fourth of new Crohn's disease diagnoses are made in individuals under the age of 20 years, in whom proximal Crohn's disease tends to be more common., Objectives: To describe the role of wireless capsule endoscopy in diagnosing isolated small intestinal Crohn's disease in two adolescents., Methods: Wireless capsule endoscopy was performed in two adolescents with severe protein-losing enteropathy and negative standard diagnostic workup., Results: Wireless capsule endoscopy successfully diagnosed Crohn's disease with uncharacteristic presentations and negative radiographic and endoscopic findings in both patients., Conclusions: The non-invasiveness and ease in performance of capsule endoscopy on an ambulatory basis make this diagnostic modality especially advantageous for children.

Objectives: Studies suggest that pediatric onset of Crohn's disease (CD) may demonstrate more frequent upper intestinal and colonic location and in male gender, in comparison to adults. Variability in age of onset (AOO) and location of disease have not been adequately explained to date. NOD2/CARD15 is highly expressed in the ileum, while TNF-alpha expression is distributed throughout the gastrointestinal tract. We hypothesized that polymorphisms that affect TNF-alpha function may influence variability of disease location and AOO of CD., Methods: We evaluated two CD cohorts based on AOO (pediatric and adult onset) and 100 ethnically matched healthy controls. Patients were evaluated for AOO, disease location, and genotyped for the presence of polymorphisms in NOD2/CARD15 and in the TNF-alpha promoter region., Results: Early AOO was associated with male gender, upper intestinal involvement, and a polymorphism in the binding site for NF-kappaB (TNF-863A polymorphism). NOD2 mutations and TNF-863A polymorphism had equivalent but opposite effects on disease location, with a strong combined effect (p= 0.004 corrected for multiple testing). NOD2/CARD15 was associated with ileal involvement, while presence of TNF-863A was inversely associated with ileal disease (OR = 0.42, p= 0.008) and positively associated with isolated colitis (OR = 2.16, p= 0.008, OR = 2.12, p= 0.03 corrected) and familial disease (p= 0.004)., Conclusions: Pediatric onset of CD in our population was associated with a frequent polymorphism in the binding site for NF-kappaB in TNF-alpha promoter but not to defined NOD2/CARD15 disease-associated mutations. This polymorphism is associated with colitis and familial disease. NOD2/CARD15 mutations and the TNF-863C/A polymorphism have equivalent but opposite effects on disease location. These findings may help explain differences in CD phenotype.

Background: It has long been believed that breastfeeding provides protection against ulcerative colitis and Crohn disease. Studies designated to test this hypothesis were conducted without reaching conclusive results., Objective: The aim of this meta-analysis was to examine the role of breastfeeding in preventing inflammatory bowel disease and to summarize the evidence gathered about this subject., Design: A meta-analysis was performed on 17 relevant articles that were found by using MEDLINE, EMBASE, the Internet, and articles' references. The publications were fully reviewed and divided, on the basis of their quality, into 3 groups., Results: Studies showed heterogeneous results. The pooled odds ratios of all the 17 reviewed studies, calculated according to the random-effects model, were 0.67 (95% CI: 0.52, 0.86) for Crohn disease and 0.77 (0.61, 0.96) for ulcerative colitis. However, only 4 studies for Crohn disease and 4 for ulcerative colitis were eventually included in the highest quality group. In this group, the pooled odds ratio was 0.45 (0.26, 0.79) for Crohn disease and 0.56 (0.38, 0.81) for ulcerative colitis., Conclusions: The results of this meta-analysis support the hypothesis that breastfeeding is associated with lower risks of Crohn disease and ulcerative colitis. However, because only a few studies were graded to be of high quality, we suggest that further research, conducted with good methodology and large sample sizes, should be carried out to strengthen the validity of these observations.

Objectives: The etiology and mechanism leading to granuloma formation in patients with Crohn's disease (CD) are presently unknown. The first susceptibility gene to be identified as a risk factor for CD is the NOD2/CARD15 gene on Chromosome 16. Mutations in NOD2 could affect the intracellular response to bacterial products and may eventually lead to granuloma formation. The association between NOD2 and granulomas has not been previously explored. We evaluated a possible association between NOD2 mutations and granuloma formation, and compared the prevalence of granulomas in both pediatric and adult cohorts., Methods: Patients were consecutively recruited through pediatric gastroenterology and adult gastroenterology programs. Patients were eligible if CD was confirmed, and they had undergone full colonoscopy with biopsy and/or surgical resection. Patients underwent genotyping for NOD2 disease-associated mutations., Results: A total of 230 patients were enrolled into the study, of whom 169 patients met all inclusion/exclusion criteria (Group 1, 77 patients [age range 1-16 years]; Group 2, 92 patients [age range 17-68 years]). Surgical resection was performed more often in adults (P < 0.005), and gastroscopy was performed more frequently in children (P < 0.001). Granulomas were found in 34% of the patients studied. The prevalence of granulomas did not differ by age, age group, or gender. A disease-associated NOD2 mutation was found in 37.8% of patients. Granulomas were found in 39% of patients with NOD2 mutations compared with 31% of those without NOD 2 mutations (difference was not significant). In addition, no difference was noted for the specific mutations., Conclusions: We did not find any correlation between NOD2 mutations and granuloma formation. The cause of granulomas in CD remains elusive.

Cigarette smoking worsens Crohn's disease (CD) but ameliorates ulcerative colitis (UC). In Israel, where there is no epidemiological association of smoking with CD, we examined the effects of current smoking on the course of CD and UC. Patients at nine public hospitals completed a questionnaire detailing their smoking history, disease course and treatments; subjects altering their smoking habit after the onset of disease were excluded. Sixty-four smokers and 144 nonsmokers had CD, and 34 smokers and 158 nonsmokers had UC. No differences were found between CD smokers and nonsmokers for hospitalizations, operations, and requirement for corticosteroid and immunosuppressive treatment. By contrast, UC smokers had less extensive disease than nonsmokers (P < 0.02) and fewer hospitalizations (P = 0.01) and operations (P = 0.025). Our results agree with a minority of studies showing no adverse effect of smoking on the course of CD, and confirm the protective effect of smoking in UC.

The question whether there is a transmissible pathogenetic agent as a cause for Crohn's disease, remains unanswered. Measles virus has been the subject of many intensive studies, in the attempt to find a role for it in the pathogenesis of inflammatory bowel disease. Whether an early infection with measles virus may predispose to Crohn's disease in later life is still not clear. We conducted a large scale multicentre study, in order to obtain sufficient data to answer this question. To do so, we compared inflammatory bowel disease patients, with Crohn's disease or ulcerative colitis, with two matched control groups: clinical controls, and community controls. A total of 531 patients, 271 with ulcerative colitis and 260 with Crohn's disease were interviewed, as well as 903 matched controls. Blood from 104 inflammatory bowel disease patients and 50 controls was tested for antibodies to measles virus. We did not find any differences related to measles vaccination, either in Crohn's disease or in ulcerative colitis. Exposure to measles in childhood was more frequent in Crohn's disease patients than in their controls, the difference being statistically significant (p < 0.05) in relation to community controls. The presence of IgG antibodies to measles virus was higher in patients with Crohn's disease than in patients with ulcerative colitis or controls (p = 0.084). Another observation of interest was the finding that Crohn's disease patients who had measles in childhood, more frequently had large bowel disease than those who had not had measles. These data lead us to postulate that there may be a role for measles infection in Crohn's disease, even if, at present, this role remains unclear.

TNF alpha is a pro-inflammatory cytokine in Crohn's disease and it's neutralization is beneficial in patients with active disease. Remicade is a chimeric monoclonal anti-TNF antibody. Remicade is used in our center since December 1998 in 13 patients who were treated for active disease or fistula. We followed the patients and treatment results in order to estimate the efficacy and safety of this preparation. Response to treatment was measured by the Crohn's Disease Activity Index (CDAI) in patients treated due to active disease, or by the presence of discharge from external fistulae. Five out of seven patients with fistulae had less or no discharge after completing a course of 3 infusions. Four out of 6 patients treated due to active disease improved significantly after a single infusion. Five out of the six needed additional injections due to symptom recurrence. Intervals between infusions were 2 weeks--for fistulae patients to 32 weeks for patients with active disease. Adverse events for the 13 patients were usually mild except for 4 patients that suffered from anaphylactic shock, disseminated eruption (2) and eosinophilic pneumonitis. In summary, treatment of patients with active Crohn's disease or fistulae with monoclonal anti-TNF antibodies is an effective and relatively safe option after established treatment has failed. Analyzing the results of on going clinical trials and of the patients treated off-protocol will enable to establish new treatment strategies for patients with active Crohn's disease and fistulae.

Objective: Appendectomy was shown to be protective in patients with ulcerative colitis (UC). There are fewer data in Crohn's disease (CD). Other operations were less studied. The aim of this study was to investigate the prevalence of appendectomy, cholecystectomy, and tonsillectomy, including their timing, in patients with inflammatory bowel disease in comparison to controls., Methods: Two hundred seventy-one patients with UC and 260 with CD, 475 clinic controls, and 428 community controls were interviewed., Results: Appendectomy was found in 5.5% patients with UC, in 11% of clinic controls (p < 0.05), and 7.7% of community controls (p = not significant). The differences were more significant for appendectomy before onset of disease. Appendectomy was performed in 19.2% of patients with CD, in 10.9% of clinic controls, and in 10.1% of community controls (p < 0.01). However, there were no significant differences when only appendectomy before onset of disease was considered. Cholecystectomy was found in 1.5% of patients with UC, in 6.1% of clinic controls (p < 0.01), and in 4.5% of community controls (p = not significant). The difference remained significant when confined to operations performed before disease onset. No such difference was found in patients with CD. No significant difference was found in the prevalence of tonsillectomy between patients and controls., Conclusions: Appendectomy is protective in UC; it is more frequent, but not a risk factor in CD. The role of cholecystectomy should be investigated further.

Objective: The association between smoking and inflammatory bowel disease (IBD) is well established, but data in Jewish patients in Israel were discrepant. The aim of this study was to examine the smoking habits of Jewish IBD patients in Israel in a large scale, multicenter study., Methods: Patients with established IBD aged 18-70 yr were interviewed in relation to smoking and other habits. Two controls (one clinic and one neighborhood control matched by age, sex, community group, and education) were sought for each subject., Results: A total of 534 patients (273 ulcerative colitis [UC], and 261 Crohn's disease [CD]), along with 478 clinic controls and 430 neighborhood controls, were interviewed. There was no significant difference in the smoking habits between CD patients and their controls. Of patients with CD, 24.5% were current smokers, as compared to 19.9% of clinic controls and 25.2% of neighborhood controls (NS). The odds ratio for CD in current smokers was 1.30 (95% confidence interval 0.85-1.99) versus clinic controls, and 0.96 (0.63-1.46) versus neighborhood controls. There were also no significant differences in the proportion of ex-smokers between the groups. Only 12.9% of UC patients were current smokers versus 21.9. % Clinic controls, and 26.4% community controls (p<0.005). The proportions of ex-smokers were higher in UC patients 29.7% versus 25.9%, and 19.5% in their respective controls (p<0.001 vs. community controls). No significant differences were found in the proportions of never-smokers between IBD patients and controls. All the above trends were similar in four different parts of the country. The proportion of current smokers in UC decreased with the extent of disease (19.7% in proctitis, 13.6% in left-sided, and 4.5% in total colitis) (p<0.05). Patients with UC were more likely to be light smokers(1-10 cigarettes/day), whereas patients with CD were more likely to be moderate smokers (11-20 cigarettes/day) in comparison to their controls., Conclusions: The lack of association between smoking and CD has now been established in Jewish patients in Israel. The association was found in UC. The stronger genetic tendency in CD may contribute to this discrepancy.

The incidence of Crohn's disease has risen dramatically over the past few years. The peak age of onset is in late adolescence, but it rarely occurs in the first few years of life. We describe a 5-year-old boy with recurrent bouts of fever, aphthous stomatitis, and anemia which did not respond to routine antibiotic therapy. It was only after a few months, when the characteristic symptoms of inflammatory bowel disease (IBD): abdominal pain and diarrhea appeared, that the diagnosis of Crohn's disease was made. This case illustrates the difficulty in diagnosing IBD in young children. The presenting symptoms of IBD in children are often nonspecific and extra-intestinal. There is usually a low index of suspicion by the physician as to the possibility of IBD in a young child.