Menarche in Pediatric Patients with Crohn’s Disease

Background and Aims

The timing of menarche in Crohn’s disease (CD) is poorly described. Our objectives were to study age at menarche onset in CD, and factors associated with this.

Methods

We compared the age at menarche of 34 CD patients with that for 545 controls, using data in the National Health and Nutrition Examination Survey (NHANES).

Results

Mean chronological age (CA) of CD patients (15.6 years) did not differ from that of the NHANES cohort (15.7 years; P = 0.91). The median CA at menarche (13.9 years) in CD was older than in the NHANES sample (12.0 years) (P < 0.00005). In CD patients, the cumulative incidence of menarche was 10 % at CA 12 years, 51 % at CA 14 years, and 100 % at CA 16 years. Sixty-eight percent reached menarche by bone age (BA) 13.5 years and 100 % by BA greater than 14.0 years. Menarche occurred earliest in South Asians, followed by East Asians, and then Caucasians (P = 0.02).

Conclusions

CA at menarche is delayed in CD compared with the NHANES cohort. BA at menarche in CD is similar to BA at menarche reported for healthy children. CA at menarche in CD differs by race. If menarche has not occurred by BA greater than 14.0 years, endocrinology referral should be considered.     

Efficacy of Adalimumab in Korean Patients with Crohn’s Disease

Background/Aims

Adalimumab is effective for both remission induction and the maintenance of Crohn’s disease (CD) in Western countries. We evaluated the efficacy of adalim-umab in the conventional step-up treatment approach for CD in Korea.

Methods

We retrospectively reviewed 62 patients with CD who were treated with adalimumab. Their Crohn’s disease activity index (CDAI) was measured at weeks 4, 8, and 52. Clinical remission was defined as a CDAI score <150. Induction and maintenance outcomes were analyzed.

Results

Forty-one patients (66.1%) achieved a reduction of 70 CDAI points at week 8. Among them, 28 (45.2%) achieved clinical remission at week 8, 20 (32.3%) maintained remission at week 52. The absence of prior anti-tumor necrosis factor (TNF) therapy and Montreal classification L1 at baseline predicted clinical remission at week 8 in the multivariate logistic regression analysis. In the Cox proportional hazards model, the hazard ratio for the secondary loss of response during maintenance therapy after clinical remission induction was significantly higher in patients who showed initial mild CDAI severity or Montreal classification A3.

Conclusions

In our study, anti-TNF therapy-naive and Montreal classification L1 were associated with adalimumab efficacy as induction therapy in CD. Further studies are warranted to determine the prognostic factors for the long-term response after adalimumab therapy.     

The Risk of Cancer in Patients with Crohn’s Disease

Purpose The risk of cancer in patients with Crohn’s disease is not well defined. Using meta-analytical techniques, the present study was designed to quantify the risk of intestinal, extraintestinal, and hemopoietic malignancies in such patients. Methods A literature search identified 34 studies of 60,122 patients with Crohn’s disease. The incidence and relative risk of cancer were calculated for patients with Crohn’s disease and compared with the baseline population of patients without Crohn’s disease. Overall pooled estimates, with 95 percent confidence intervals, were obtained, using a random-effects model. Results The relative risk of small bowel, colorectal, extraintestinal cancer, and lymphoma compared with the baseline population was 28.4 (95 percent confidence interval, 14.46–55.66), 2.4 (95 percent confidence interval, 1.56–4.36), 1.27 (95 percent confidence interval, 1.1–1.47), and 1.42 (95 percent confidence interval, 1.16–1.73), respectively. On subgroup analysis, patients with Crohn’s disease had an increased risk of colon cancer (relative risk, 2.59; 95 percent confidence interval, 1.54–4.36) but not of rectal cancer (relative risk, 1.46; 95 percent confidence interval, 0.8–2.55). There was significant association between the anatomic location of the diseased bowel and the risk of cancer in that segment. The risk of small bowel cancer and colorectal cancer was found to be higher in North America and the United Kingdom than in Scandinavian countries with no evidence of temporal changes in the cancer incidence. Conclusions The present meta-analysis demonstrated an increased risk of small bowel, colon, extraintestinal cancers, and lymphoma in patients with Crohn’s disease. Patients with extensive colonic disease that has been present from a young age should be candidates for endoscopic surveillance; however, further data are required to evaluate the risk of neoplasia over time. Presented at the meeting of the European Society of Coloproctology, Lisbon, Portugal, September 13 to 16, 2006.     

CARD15/NOD2 in a Tunisian Population with Crohn’s Disease

Crohns disease (CD) is a heterogeneous disorder. A genetic linkage to chromosome 16 (IBD1) has been previously observed and replicated in unrelated populations. Recently, in this region, NOD2/CARD15 has been identified as a susceptibility gene. The aim of this report is to determine whether this gene is implicated in CD in a Tunisian population. One hundred thirty patients with CD and 90 healthy individuals were genotyped for the three common NOD2 variants (C2104T in exon 4, G2722C in exon 8, and 3020insC in exon 11). Furthermore, the 11 exons of the NOD2 gene were sequenced in 20 patients with CD. Results showed that the frequency of the CARD15 variants in the Tunisian population is significantly lower than that observed in the European and American population. Direct sequencing of CARD15 did not permit us to identify a characteristic mutation in our population. No association was confirmed between CD and the NOD2 gene in our Tunisian population. Furthermore, the NOD2/CARD15 gene has a variable association with CD in different populations. These results indicate the genetic variation of CD in different ethnic groups.     

Racial Differences in Disease Activity and Quality of Life in Patients with Crohn’s Disease

Background

The existing literature on racial differences in Crohn’s disease (CD) activity and quality of life (QOL) is limited and extrapolated from surrogate measures.

Aim

The aim of our study was to compare objective markers of disease activity and QOL over time by race.

Study

A clinical data repository of inflammatory bowel disease (IBD) patients at University of Maryland, Baltimore IBD Program, was used. CD patients from 2004 to 2009 were included if they had greater than or equal to two clinic visits with disease activity and QOL scores during the study period. Differences in disease activity and QOL were compared by race over time.

Results

A total of 296 patients with CD met inclusion criteria; of these, 19 % (56/296) were African Americans (AA) and 81 % (240/296) were Caucasian. Baseline disease activity and QOL scores did not differ by race (p > 0.05). Caucasians had a steady decline in disease activity and increase in QOL. AA experienced a similar pattern of change in disease activity and QOL scores over time; however, the declines were not statistically significant between groups. At each time point post-baseline, disease activity and QOL scores were similar between races.

Conclusion

We found that Caucasian and AA patients with CD had similar disease activity and QOL scores at initial presentation and over time. Thus, AA do not represent a more severe subgroup of CD patients to treat. These findings have important implications for clinicians that care for patients with CD.     

Outcome of Patients with Nonstenotic, Nonfistulizing Crohn’s Disease

The nonstenotic, nonfistulizing (or inflammatory) pattern of Crohn's disease appears to be unstable in time and may evolve toward either the stenotic or the fistulizing pattern. We aimed to assess the course of the inflammatory disease and its relation to certain clinical characteristics. After a mean follow-up of 93 months, we evaluated 73 patients with an inflammatory pattern. The behavior trend and its relation to disease location, initial treatment, and need for corticosteroids, immunosuppressors, and surgical resection were analyzed. In 64% of the patients the inflammatory pattern did not change, while in 14 and 22% it evolved toward a stenotic and a fistulizing pattern, respectively. This change was mainly determined by the appearance of perianal disease (75%). The mean time to behavior evolution was 67 months. Most patients required corticosteroids (92%). Need for immunosuppressors (48%) and surgical resection (30%) was significantly greater (P < 0.05) among patients with a change in pattern than in those with persistent inflammatory disease. The inflammatory pattern of CD remains stable in about half of patients. The course of this pattern is not indolent, however, since the needs for immunosuppression and surgical resection during follow-up are considerable.     

Deficit of Gammadelta T Lymphocytes in the Peripheral Blood of Patients with Crohn’s Disease

Background  

Gammadelta T lymphocytes are an important component of innate immunity. Previous studies have shown their role in the development of Crohn’s-like colitis in mice.     

Long-Term Outcomes of Adalimumab Treatment in 254 Patients with Crohn’s Disease: A Hospital-Based Cohort Study from Korea

Digestive Diseases and Sciences - Large-scale studies regarding the long-term outcomes of adalimumab (ADA) treatment in Asian patients with Crohn’s disease (CD) are still scarce. We...     

Outcome Predictors for Thiopurine Maintenance Therapy in Patients with Crohn’s Disease

Background  

Little is known about the factors that predict clinical relapse in Crohn’s disease patients receiving thiopurine therapy to maintain remission. The objective of this study was, therefore, to investigate these factors.     

Long-Term Quality of Life in Patients with Crohn’s Disease and Perianal Fistulas: Influence of Fecal Diversion

Purpose Symptomatic perianal fistulas impair quality of life in patients with Crohn’s disease. Fecal diversion improves symptoms but may impair quality of life. This study was designed to compare long-term quality of life in patients with Crohn’s disease with symptomatic perianal fistulas who were treated with or without fecal diversion. Methods From 1996 to 2002, perianal fistulas were treated in 116 patients with Crohn’s disease. A questionnaire, including four quality of life instruments, was mailed to each patient (Short-Form General Health Survey, Gastrointestinal Quality of Life Index, Cleveland Global Quality of Life Score, Short Inflammatory Bowel Disease Questionnaire). Results Questionnaires were returned by 77 of 116 patients (66 percent). Thirty-four of these patients had undergone fecal diversion, whereas 43 had not. Median follow-up was 49 (range, 18–97) months in diverted and 44 (range, 14–98) months in undiverted patients (not significant). In the diverted group, 44 percent complained of Crohn’s disease-related symptoms, which was less compared with 79 percent in undiverted patients (P < 0.05). Diverted patients achieved 68 ± 1 percent of the maximum possible score on the Gastrointestinal Quality of Life Index compared with 60 ± 2 percent in undiverted patients (mean ± standard error of the mean; P < 0.001); diverted patients scored better on the subscale “gastrointestinal symptoms” of the Gastrointestinal Quality of Life Index (81 ± 1 percent vs. 67 ± 2 percent; P < 0.001). There was no difference in the Short Inflammatory Bowel Disease Questionnaire between diverted and undiverted patients except for the subscale “bowel function” (91 ± 2 percent vs. 76 ± 2 percent; P < 0.0001). No difference in quality of life was detected by the Short-Form General Health Survey and Cleveland Global Quality of Life Score. Conclusions In the investigated population of patients with Crohn’s disease, quality of life seems to be similar or potentially superior in diverted patients suffering from perianal fistulas compared with undiverted patients. A diverting stoma, therefore, may improve quality of life in patients with severe perianal Crohn’s disease. Presented at the meeting of the American Gastroenterological Association, Digestive Diseases Week, Los Angeles, California, May 20 to 25, 2006, and published in abstract form Gastroenterology 2006;130(Suppl 2):A620.     

No Benefit of Continuing 5-Aminosalicylates in Patients with Crohn’s Disease Treated with Anti-metabolite Therapy

Digestive Diseases and Sciences - 5-aminosalicylates (5-ASA) are frequently used in the management of Crohn’s disease (CD). We used a de-identified administrative claims database to compare...     

The Relation Between NOD2/CARD15 Mutations and the Prevalence and Phenotypic Heterogeneity of Crohn’s Disease: Lessons from the Israeli Arab Crohn’s Disease Cohort

The prevalence of Crohn’s disease depends on geographic location and racial background. Arg702Trp, Gly908Arg, and Leu1007fsinsC mutations in the NOD2/CARD15 gene are associated with Crohn’s disease in Caucasians. The mutation rate among Israeli Jewish patients is 27%–41%. The prevalence of Crohn’s disease is much lower in the Israeli Arab compared to the Israeli Jewish population. We studied the NOD2/CARD15 mutation rate and disease phenotype (according to the Vienna classification) among the Israeli Arabs and compared them with those in an Israeli Jewish cohort. We recruited 66 Israeli Arab patients and 122 ethnically matched controls. Five patients (8.2%) and three controls (2.3%) carried one NOD2/CARD15 mutation. The phenotypic characteristics of the Arab and Jewish patients were very similar. We conclude that NOD2/CARD15 mutations do not contribute to Crohn’s susceptibility in the Israeli Arab population and suggest that NOD2/CARD15 mutations have an important effect on Crohn’s prevalence within a specific population but not on the phenotype. R. Safadi, MD, and R. Eliakim, MD, share senior authorship     

The Fate of the Ileal Pouch in Patients Developing Crohn’s Disease

PURPOSE Recent studies have suggested that a subset of patients with Crohns colitis may have a favorable outcome after ileal pouch-anal anastomosis and have advocated elective ileal pouch-anal anastomosis in selected patients with Crohns disease. We have not offered ileal pouch-anal anastomosis to patients with known Crohns disease, but because of the overlap in clinical presentation of ulcerative colitis and indeterminate colitis, some patients receiving an ileal pouch-anal anastomosis are subsequently found to have Crohns disease. We review our experience with these patients to identify potential preoperative predictors of ultimate pouch failure.METHODS Patients with a final diagnosis of Crohns disease were identified from an ileal pouch-anal anastomosis registry. These patients are followed prospectively. Preoperative and postoperative clinical and pathologic characteristics were evaluated as predictors of outcome. Median (range) values are listed.RESULTS Thirty-two (18 females) patients (4.1 percent) with a final diagnosis of Crohns disease were identified from a registry of 790 ileal pouch-anal anastomosis patients (1980–2002). Patients underwent ileal pouch-anal anastomosis in two stages (11 patients) or three stages (21 patients). The preoperative diagnosis was ulcerative colitis in 24 patients and indeterminate colitis in 8 patients. Median follow-up was 153 (range, 13–231) months. The median time from ileal pouch-anal anastomosis to diagnosis of Crohns disease was 19 (range, 0–188) months. Complications occurred in 93 percent, including perineal abscess/fistula (63 percent), pouchitis (50 percent), and anal stricture (38 percent). Pouch failure (excision or current diversion) occurred in nine patients (29 percent) at a median of 66 (range, 6–187) months. Two of these 9 patients had preoperative anal disease (not significant). Comparing patients with failed pouches (n = 9) to patients with functioning pouches (n = 23), post-ileal pouch-anal anastomosis perineal abscess (67 vs. 26 percent, P = 0.05) and pouch fistula (89 vs. 30 percent, P = 0.01) were more commonly associated with pouch failure. Preoperative clinical, endoscopic, and pathologic features were not predictive of pouch failure or patient outcome. For those with a functional pouch, 50 percent have been or are currently on medication to treat active Crohns disease. This group had six bowel movements in 24 (range, 3–10) hours, with leakage in 60 percent and pad usage in 45 percent.CONCLUSIONS Patients who undergo ileal pouch-anal anastomosis and are subsequently found to have Crohns disease experience significant morbidity. Preoperative characteristics, including the presence of anal disease, were not predictive of subsequent pouch failure. We choose not to recommend the routine application of ileal pouch-anal anastomosis in any subset of patients with known Crohns disease.Reprints are not available.     

p53 Mutations are Associated with Dysplasia and Progression of Dysplasia in Patients with Crohn’s Disease

Background: Mutations in the tumor suppressor gene p53 are associated with neoplasia in ulcerative colitis, but little is understood of their significance in Crohn’s disease (CD). Purpose: To explore p53 expression as a marker of neoplasia in CD patients. Methods: This is a retrospective review of CD patients who underwent p53 IHC staining in our center between 1995 and 2003. The p53 status was correlated to the presence and grade of neoplasia at the time of staining and in subsequent follow-up. Results: Fourteen CD patients had p53 assessment: eight were p53 positive and six were p53 negative. Seven of eight p53+ had dysplasia (six LGD, one HGD); one of six p53−had dysplasia (LGD) (P = 0.03). Four p53+ patients with follow-up had persistent dysplasia and two had progression to a higher grade. Three p53− patients with follow-up remained free of dysplasia. Conclusions: This limited study shows that p53 over expression in CD patients is associated with dysplasia that may progress to a higher grade of neoplasia over time.     

Assessment of Variables Associated with Smoking Cessation in Crohn’s Disease

Background

Patients with Crohn’s disease (CD) who smoke have a more complicated disease course.

Aims

Our primary objective was to assess smoking related variables that were associated with smoking cessation versus continued smoking in patients with CD.

Methods

A multi-center study identified CD patients who were seen at the University of Chicago and University of Calgary IBD clinics. Patients were categorized into three subgroups: lifetime non-smokers, current smokers, or ex-smokers. Participants completed questionnaires assessing their cigarette smoking behavior. Current smokers were prospectively followed for 6?months to assess smoking status and attempts to quit. Logistic regression analysis was performed to identify factors associated with smoking cessation.

Results

Three hundred patients were enrolled with 148 identifying themselves as lifetime non-smokers, 70 as current smokers, and 82 as ex-smokers. Patients who reported their first cigarette within 5?min of waking were more likely to be current smokers (OR?=?21; 95% CI 3.94–107.3) as compared to patients who waited greater than 60?min. Current smokers were more likely to have one or more household members who smoked compared to ex-smokers (P?Conclusions Patients who report a short time to first cigarette in the morning may have more difficulty in smoking cessation. Current smokers were more likely to have another smoker in the household compared to ex-smokers. Current smokers had low levels of motivation to quit smoking and consequently with no intervention, very few quit 6?months after the baseline assessment.     

An Evaluation of Vaginal Symptoms in Women with Crohn’s Disease

There are limited data available that address the prevalence of vaginal complaints in women with Crohn’s disease. This study assessed the frequency of vaginal involvement and types of vaginal symptoms in women with Crohn’s disease managed at a university inflammatory bowel disease program. The charts of 50 women with Crohn’s disease seen consecutively during a three-month period were reviewed for the presence of vaginal involvement. The intestinal distribution of Crohn’s disease [colonic, small bowel (SB), colonic/SB] was determined, and the presence of vaginal symptoms and types of complaints were assessed. Eleven of the 50 women (22%) described vaginal symptoms. Vaginal complaints included ten patients with labial swelling and one patient with passage of stool through the vagina. Nine of the 11 women with vaginal complaints also had concurrent intestinal symptoms and perineal manifestations (P < 0.001). This study suggests that vaginal involvement in Crohn’s disease may be a more frequent phenomenon than previously reported.     

Subclinical Intestinal Inflammation in Siblings of Children with Crohn’s Disease

Background  

Intestinal permeability and altered inflammatory responses, along with genetic and environmental factors, likely contribute to the pathogenesis of Crohn’s disease.     

Differences in Yeast Intolerance Between Patients with Crohn’s Disease and Ulcerative Colitis

Purpose Alimentary factors, especially those modifying the intestinal flora, may influence the course of inflammatory bowel disease. It is known that T and B cells of patients with Crohn’s disease can be stimulated with the yeast antigen, mannan. We evaluated the impact of eating habits with special respect to food containing yeast on the course of inflammatory bowel disease. Methods Questionnaires were sent to 180 German-speaking patients of the Inflammatory Bowel Disease Outpatient Clinic at the University Hospital Bern, Switzerland. The following information was obtained by the questionnaires: (1) course of disease, (2) eating habits, (3) environmental data, and (4) inflammatory bowel disease questionnaire. The survey was anonymous. Results A total of 145 patients (80.5 percent 95 with Crohn’s disease, and 50 with ulcerative colitis) responded. Food items containing yeast were better tolerated by patients with ulcerative colitis than by patients with Crohn’s disease. A significant difference between the two groups was observed concerning food containing raw yeast (dough, P = 0.04; and pastry, P = 0.001). Conclusions Food items containing raw yeast led to more frequent problems for patients with Crohn’s disease than for patients with ulcerative colitis. This observation supports our previous data, which showed the stimulatory effect of the yeast antigen, mannan, on B and T cells of patients with Crohn’s disease but not of controls. Poster presentation at Digestive Disease Week (DDW), organized by the American Gastrointestinal Association, Chicago, Illinois, May 14 to 19, 2005.     

Prevalence of Celiac Disease Among Patients with Behcet’s Disease in Iran

Background Behcet's disease and Celiac disease, both common in Iran, share many immunopathogenic and clinical features. Based on the possible association between these two diseases, this study is designed to determine the frequency of non-diagnosed celiac disease in patients with Behcet’s disease. Methods The sera of 288 consecutive patients with Behcet’s disease were screened with anti-endomysial antibody and anti-tissue transglutaminase antibody for celiac disease. Those with a positive test underwent upper gastrointestinal endoscopy and duodenal biopsies to confirm the diagnosis of celiac disease. The patients with celiac disease were put on a gluten free diet to evaluate its efficacy on the improvement of their lesions. Results Fourteen patients had positive anti-tissue transglutaminase antibody test (two with positive anti-endomysial antibody as well). Duodenal biopsies showed findings compatible with Marsh 3 in one and Marsh 1 in three other patients. All the diagnosed patients with celiac disease responded to the gluten free diet. Conclusion Our findings didn’t support any association between celiac disease and Behcet’s disease in Iranian patients compared to the general population of Iran.     

Identification of Disease-Associated DNA Methylation in B Cells from Crohn’s Disease and Ulcerative Colitis Patients

Background

Changes in the methylation status of inflammatory bowel disease (IBD)-associated genes could significantly alter levels of gene expression, thereby contributing to disease onset and progression. We previously identified seven disease-associated DNA methylation loci from intestinal tissues of IBD patients using the Illumina GoldenGate BeadArray assay.

Aims

In this study, we extended this approach to identify IBD-associated changes in DNA methylation in B cells from 18 IBD patients [9 Crohn??s disease (CD) and 9 ulcerative colitis (UC)]. B cell DNA methylation markers are particularly favorable for diagnosis due to the convenient access to peripheral blood.

Methods

We examined DNA methylation profiles of B cell lines using the Illumina GoldenGate BeadArray assay. Disease-associated CpGs/genes with changes in DNA methylation were identified by comparison of methylation profiles between B cell lines from IBD patients and their siblings without IBD. BeadArray data were validated using a bisulfite polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) method. To verify that observed changes in DNA methylation were not due to virus transformation, we compared specific CpG DNA methylation levels of GADD45A and POMC between B cell lines and matching peripheral blood B lymphocytes from five individuals.

Results

Using this approach with strict statistical analysis, we identified 11 IBD-associated CpG sites, 14 CD-specific CpG sites, and 24 UC-specific CpG sites with methylation changes in B cells.

Conclusions

IBD- and subtype-specific changes in DNA methylation were identified in B cells from IBD patients. Many of these genes have important immune and inflammatory response functions including several loci within the interleukin (IL)-12/IL-23 pathway.