Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis,entero-enteral fistulas,and frequent need for surgical intervention with high risk of re-stenosis

Objective. The identification of CARD15 as a susceptibility gene for Crohn's disease (CD) offers new possibilities for patient classification and risk assessment. The purpose of this study was to carry out a CARD15 sequence analysis in a large single-center IBD cohort and to investigate the impact of different genotypes on disease phenotypes. Material and methods. A total of 445 unrelated patients with IBD (68.1% CD, 28.5% ulcerative colitis (UC), 3.4% indeterminate colitis (IC)) were included in the study. Clinical data were recorded by detailed questionnaire and analysis of the charts. CARD15 variants (R702W, G908R, 1007fs (frameshift)) were identified by DNA sequence analysis. Results. CARD15 variants were found in 142 inflammatory bowel disease (IBD) patients (31.9%) including 120 CD patients (39.6%). In CD, the presence of two CARD15 variants was associated with ileal disease (p=0.008 versus wild-type (wt); OR 4.04; 95% CI 1.36–11.96) and a fibrostenotic phenotype (p=0.002 versus wt; OR 5.47; 95% CI 1.61–18.58). Subgroup analysis of 19 patients (4.3%) homozygous for the CARD15 variant 1007fs (3020ins C) revealed an association with onset of CD at an early age (p=0.014 versus wt), ileal involvement (p=0.001), and intestinal stenoses in all patients (p=0.001) frequently requiring surgery (73.7%; p=0.093). Of these patients 78.6% developed re-stenoses after surgical resection; 52.6% of the homozygotes were diagnosed as having entero-enteral fistulas. Conclusions. Patients homozygous for the 1007fs mutation had an early disease onset with long-segment ileal stenoses and entero-enteral fistulas. They frequently needed surgical intervention and had a high risk of re-stenosis. Genotyping therefore appears to be an important diagnostic tool in identifying severely affected patients requiring individualized treatment strategies at an early stage of the disease.     

Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis

OBJECTIVE: The identification of CARD15 as a susceptibility gene for Crohn's disease (CD) offers new possibilities for patient classification and risk assessment. The purpose of this study was to carry out a CARD15 sequence analysis in a large single-center IBD cohort and to investigate the impact of different genotypes on disease phenotypes. MATERIAL AND METHODS: A total of 445 unrelated patients with IBD (68.1% CD, 28.5% ulcerative colitis (UC), 3.4% indeterminate colitis (IC)) were included in the study. Clinical data were recorded by detailed questionnaire and analysis of the charts. CARD15 variants (R702W, G908R, 1007fs (frameshift)) were identified by DNA sequence analysis. RESULTS: CARD15 variants were found in 142 inflammatory bowel disease (IBD) patients (31.9%) including 120 CD patients (39.6%). In CD, the presence of two CARD15 variants was associated with ileal disease (p=0.008 versus wild-type (wt); OR 4.04; 95% CI 1.36-11.96) and a fibrostenotic phenotype (p=0.002 versus wt; OR 5.47; 95% CI 1.61-18.58). Subgroup analysis of 19 patients (4.3%) homozygous for the CARD15 variant 1007fs (3020ins C) revealed an association with onset of CD at an early age (p=0.014 versus wt), ileal involvement (p=0.001), and intestinal stenoses in all patients (p=0.001) frequently requiring surgery (73.7%; p=0.093). Of these patients 78.6% developed re-stenoses after surgical resection; 52.6% of the homozygotes were diagnosed as having entero-enteral fistulas. CONCLUSIONS: Patients homozygous for the 1007fs mutation had an early disease onset with long-segment ileal stenoses and entero-enteral fistulas. They frequently needed surgical intervention and had a high risk of re-stenosis. Genotyping therefore appears to be an important diagnostic tool in identifying severely affected patients requiring individualized treatment strategies at an early stage of the disease.     

CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn's disease.

BACKGROUND & AIMS: The risk for Crohn's disease (CD) is determined in part by genetic factors. Three recently described mutations in the CARD15(NOD2) gene have been associated with adult-onset CD. We investigated the effect of CARD15 mutations on disease manifestation, disease progression, and the risk for early surgery in childhood-onset CD. METHODS: Genotyping for 3 CARD15 mutations: R702W, G908R, and 3020insC, was performed in 186 children with CD from a prospective cohort. A transmission-disequilibrium test was used to test for association with CD. Genotype with disease location and behavior was tested with logistic regression analysis. The effect of mutations on surgical outcome was evaluated using a Cox proportional hazard analysis. RESULTS: The mean age at CD diagnosis was 12.4 years. The frequency of allelic mutations observed was 6.6% for R702W, 6% for G908R, and 13.1% for 3020insC. Of Caucasian CD children, 42% had at least one CARD15 mutation. None of the non-Caucasian children with CD had any CARD15 mutation. A significant association was detected for 3020insC (P = .0045). Ileal location (odds ratio, 4.3; P = .003) and stricturing disease (odds ratio, 6.6; P = .0001) was more frequent and the risk for surgery was higher (hazard ratio, 5.8; P < .0001) and surgery occurred earlier (hazard ratio, 2.24) in those children with 3020insC mutation compared with those without 3020insC. CONCLUSIONS: In children with pediatric-onset CD, early development of stricturing behavior leading to surgical resection is influenced by ileal location and 3020insC variant of the CARD15 mutation. Genetic testing may identify children with CD who are at risk for early surgery.     

Impact of the increasing use of immunosuppressants in Crohn's disease on the need for intestinal surgery

BACKGROUND/AIM: Immunosuppressants are now used much earlier in the course of Crohn's disease; however their effect on the natural history of the disease, especially on the need for surgery, is not known. The aim of this study was to assess the evolution of the need for surgery in Crohn's disease during the last 25 years. PATIENTS AND METHODS: The medical charts of 2573 patients were reviewed retrospectively. The use of immunosuppressants (azathioprine or methotrexate), the need for intestinal resection, and the occurrence of intestinal complications were assessed using Kaplan-Meier analysis in five consecutive cohorts of patients defined by the date of diagnosis of Crohn's disease (1978-82; 1983-87; 1988-92; 1993-97; 1998-2002). RESULTS: In 565 patients seen in the authors' unit within the first three months after diagnosis, characteristics of Crohn's disease at diagnosis did not differ from one cohort to another. The five year cumulative probability to receive immunosuppressants increased from 0 in the 1978-82 cohort to 0.13, 0.25, 0.25, and 0.56 in the 1983-87, 1988-92, 1993-97, and 1998-2002 cohorts, respectively (p<0.001). Concomitantly, the cumulative risk of intestinal resection remained unchanged (from 0.35 to 0.34 at five years; p=0.81). The cumulative risk of developing a stricturing or a penetrating intestinal complication remained also unchanged. Similar results were obtained in the 2008 patients seen during the same period who were referred to us more than three months after diagnosis. CONCLUSION: Although immunosuppressants have been used more frequently over the last 25 years, there was no significant decrease of the need for surgery, or of intestinal complications of Crohn's disease.     

Anti-TNF antibodies in the treatment of inflammatory intestinal stenoses in Crohn's disease

Stenoses are a frequent complication in patients with Crohn's disease and represent a major diagnostic and therapeutic challenge. The proper assessment of the nature of a stenosis as inflammatory or fibrotic is critical for appropriate treatment, since symptomatic fibrotic stenoses require surgical resection. Standard diagnostic procedures to assess the nature of a stenosis include endoscopy, conventional contrast radiography and magnetic resonance tomography. Recent data suggest, that the positron-emission-tomography possesses a high sensitivity and specificity to confirm inflammatory activity in the bowel. The recombinant monoclonal anti-TNF-antibody Infliximab (Remicade) has been approved for the treatment of steroid refractory and steroid dependent Crohn's disease in Germany since 9/2000 and the efficacy of Infliximab is well documented. However, few data exist about the treatment of inflammatory stenoses with Infliximab. We performed a retrospective analysis of our experience with Infliximab in patients with Crohn's disease with special reference to patients with inflammatory stenoses. Among a total of 21 patients treated with Infliximab 11 patients had an inflammatory stenosis. 9 of these patients responded well to Inflimab and became completely asymptomatic for a considerable period of time. Infliximab was tolerated well except for one patient who developed an intrabdominal abscess. The notable clinical response of patients with inflammatory stenoses to Infliximab suggests that treatment with Infliximab might be helpful to postpone or avoid surgical intervention. This finding should be further investigated in a prospective randomized study.     

The value of ileoscopy with biopsy in the diagnosis of intestinal Crohn's disease

Studies to determine the diagnostic value of ileoscopy and biopsy are not available. In an attempt to clarify the role of this technique in the diagnosis of intestinal Crohn's disease, 110 patients with a radiological diagnosis of inflammatory disease of the terminal ileum were examined in a prospective study. Suspicion of Crohn's disease was rejected in 28 patients. In 18 patients the terminal ileum was normal, while 10 patients had lymphoid nodular hyperplasia. Endoscopic lesions with a predictive value of 0.96 were found in 25 of 48 patients with the final diagnosis of Crohn's disease. Diagnostic granulomas were only found in 4 patients, but lesions consistent with Crohn's disease were present in the pathology sections of 17 patients. It was concluded that ileoscopy with biopsy is a valuable tool in the diagnosis of inflammatory ileal disease and can provide useful information about the nature and extent of the inflammation.     

NOD2/CARD15 gene polymorphisms in Crohn's disease: a genotype- phenotype analysis

OBJECTIVES: Three recently identified NOD2/CARD15 mutations have been described associated with an increased susceptibility Crohn's disease (CD). Our aim was to examine the potential association of these NOD2 mutations with CD and different subsets of CD phenotypes in our population. METHODS: Two hundred and five well-defined CD patients from north-western France and 95 ethnically matched healthy controls were genotyped for mutations R702W, G908R and Leu1007insC by DNA sequencing. Allele and genotype frequencies of NOD2 variants were examined in the whole series of CD and in different subgroups of CD phenotypes defined by the clinical characteristics of the Vienna classification (age at diagnosis, location and behaviour) or by histological features (granuloma). RESULTS: Carriers of at least one NOD2/CARD15 variant were significantly more frequent in CD than in controls (38.0% versus 20.0%, P < 0.002), and the R702W allele was the most significant contributor to this NOD2 association with CD. Homozygotes and compound heterozygotes combined had a higher risk of CD (odds ratio = 12.0, P < 0.0026) than simple heterozygotes for any variant (odds ratio = 2.2, P < 0.013) compared with subjects with no variant. Univariate analysis revealed that carriage of at least one NOD2 mutation was significantly associated with ileal involvement (P < 0.03), and stricturing evolution (P < 0.0015). Granuloma was associated with an excess of the R702W allele (16.1% versus 8.0%, Pc < 0.035), and was correlated with a young age at diagnosis, whatever the NOD2/CARD15 genotype. Multivariate analysis demonstrated that carriage of NOD2/CARD15 mutants, especially R702W, was primarily and independently associated both with stricturing evolution of CD and the presence of granuloma. CONCLUSIONS: In our population, all NOD2/CARD15 mutant genotypes, especially compound heterozygosity, were found to increase the risk of CD, but R702W was the sole allele showing a significant association with CD. In addition, we confirm the positive and independent association of the R702W mutation with stricturing behaviour and describe a second one with the presence of granuloma.     

Wireless capsule endoscopy versus ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn's disease: a prospective study

BACKGROUND AND AIMS: Following ileocolonic resection for Crohn's disease (CD), early endoscopic recurrence predicts recurrence of symptoms. The aim of the study was to compare ileocolonoscopy and wireless capsule endoscopy (WCE) for the detection of postoperative recurrence in CD. METHODS: WCE and ileocolonoscopy were performed within six months following surgery in 32 prospectively enrolled patients. Two independent observers interpreted the results of WCE. Recurrence in the neoterminal ileum was defined by a Rutgeerts score>or=1. When observers at WCE did not concur, WCE results were considered as either true negative or true positive and sensitivity and specificity were calculated according to both assumptions. RESULTS: Recurrence occurred in 21 patients (68%) and was detected by ileocolonoscopy in 19 patients. Sensitivity was 90% and specificity 100%. Sensitivity of WCE was 62% and 76% and specificity was 100% and 90%, respectively, depending on assumptions. There was a correlation between the severity of the lesions measured by both methods (p<0.05). Lesions located outside the scope of conventional endoscopy were detected by WCE in two thirds of patients with excellent interobserver agreement (kappa>0.9) for all lesions with the exception of ulceration (kappa=0.7). CONCLUSIONS: The sensitivity of WCE in detecting recurrence in the neoterminal ileum was inferior to that of ileocolonoscopy. In contrast, WCE detected lesions outside the scope of ileocolonoscopy in more than two thirds of patients. Additional follow up studies are needed to assess the clinical relevance of such lesions. At the present time, it seems that WCE cannot systematically replace ileocolonoscopy in the regular management of patients after surgery.     

Association of NOD2/CARD15 variants with Crohn's disease in a Greek population

OBJECTIVE: Single nucleotide polymorphisms in the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease (CD), but whether this susceptibility extends to all ethnic groups and geographic areas remains unknown. The aim of the present study was to evaluate the NOD2/CARD15 mutations in Greek patients with CD. METHODS: Individuals were genotyped for three NOD2/CARD15 mutations: R702W, G908R and L1007fsinsC. Blood samples were obtained from 120 patients with CD, 85 patients with ulcerative colitis, and 100 unrelated healthy controls. RESULTS: Mutations in NOD2/CARD15 were observed with significantly greater frequency in CD patients (98/120, 81.7%) than in ulcerative colitis patients (40/85, 47%) (P < 0.0001) or in healthy individuals (21/100, 21%) (P < 0.0001). For CD patients, compared with controls, the odds were increased for carriage of the R702W (odds ratio, 12.25) and less for the G908R (odds ratio, 5.2) and L1007fsinsC (odds ratio, 3.9) mutations. The age of onset of CD was lower in Greek mutation carriers as compared with non-carriers of Greek origin (28.2 +/- 14.6 years versus 34 +/- 12.3 years, respectively; P = 0.036). Additionally, the frequency of NOD2/CARD15 mutations was increased in ileitis or ileocolitis compared with non-ileal disease. CONCLUSIONS: The NOD2/CARD15 mutations are risk factors for CD in Greece, they appear to predict an earlier age of onset and are associated particularly with ileitis or ileocolitis.     

Small intestinal adenocarcinoma in Crohn's disease: a case-control study

BACKGROUND: Small bowel adenocarcinoma is an uncommon complication of Crohn's disease. We sought to describe the clinical features, outcomes, and risk factors of small bowel adenocarcinoma in Crohn's disease. METHODS: A centralized diagnostic index identified all patients with Crohn's disease with small bowel adenocarcinoma evaluated at our institution between 1976 and 2000, and the medical records were abstracted. Two controls with Crohn's disease were selected for each case, matched by gender and age. RESULTS: Nine cases (four males) were identified. The patients presented with abdominal pain (89%), obstruction (89%), and weight loss (78%). Cancer was located in the ileum in 8 patients (89%) and the jejunum in 1 patient (11%). All cases but 1 had either lymph node involvement or metastasis. All cases had surgery, with 1 receiving adjuvant chemotherapy. No significant risk factors were found. The mortality rates at 1 and 2 years were 42% and 61%. CONCLUSIONS: Small bowel adenocarcinoma is a rare complication of Crohn's disease that typically involves the ileum. Affected patients have symptomatic, advanced malignancies upon diagnosis. No significant risk factors were identified.     

Diverse effects of the CARD15 and IBD5 loci on clinical phenotype in 630 patients with Crohn's disease

OBJECTIVES: Genetic variants at the CARD15 and IBD5 loci are strongly associated with Crohn's disease (CD), but evidence of the effect of these variants on the clinical expression of CD is conflicting and has often been hampered by small sample sizes. We studied 630 well-characterized patients to clarify the genotype/phenotype relationship in CD. METHODS: Patients and healthy controls were genotyped for three common mutations in CARD15 and a marker of the IBD5 risk haplotype. Allele frequencies were compared between phenotypic subgroups using chi2 or Fisher's exact tests. Genotype/phenotype analysis was carried out using multinomial logistic regression modelling allowing for adjustment for correlated or confounding factors. RESULTS: The mean age at diagnosis was significantly lower in carriers of the CARD15 or IBD5 risk alleles. After correction for age and smoking, CARD15 mutations were strongly associated with both ileal disease (P=8.8 x 10(-6)) and stenotic disease (P=0.003), but the association with stenotic disease appeared to be due to a confounding effect with ileal disease. CARD15 mutations were also associated with the presence of granulomas (P=5.7 x 10(-5)), which remained significant after adjustment for age at diagnosis and disease location (P=0.0047). The IBD5 risk haplotype frequency was significantly elevated in cases with perianal disease (P=0.028) and axial spondyloarthropathy (P=0.012). CONCLUSION: Genetic variants at the CARD15 and IBD5 loci have diverse effects on clinical expression in CD. CARD15 mutations are significantly correlated with the presence of granulomas.     

Oral contraceptive use and the clinical course of Crohn's disease: a prospective cohort study.

BACKGROUND: Women with Crohn's disease are usually advised not to take oral contraceptives, but, unlike smoking, there is no clear association between current oral contraceptive use and more severe disease. AIM: To assess the effect of oral contraceptive use on the clinical course of Crohn's disease. PATIENTS: 331 women, aged 16-50 years, with Crohn's disease and Crohn's disease activity index <200, were enrolled consecutively during a one year period. Patients were classified at inclusion as oral contraceptive users or non-users and smokers or non-smokers. METHODS: A prospective 12-18 month cohort study was used. The main outcome measures were flare up rate and time to flare up. RESULTS: In total, 134 women used oral contraceptives, in most cases low oestrogen formulations. During the study period, 61 oral contraceptive users (46%) developed a flare up, compared with 85 non-users (43%). The hazard ratio for oral contraceptive use was 1.11 (95% confidence interval 0.80 to 1.55). Variables associated with flare up were smoking status, recently active disease, baseline Crohn's disease activity index, and presence of anoperineal lesions. The same results were obtained when the analysis was restricted to patients eligible for a relapse prevention trial. CONCLUSION: Unlike smoking, oral contraceptives have no effect on Crohn's disease activity.     

Predicting the need for surgery in Crohn's disease with contrast harmonic ultrasound

OBJECTIVE: Harmonic flash echo imaging (H-FEI), an intermittent scanning method using injection of Levovist, enables the evaluation of microperfusion of the gastrointestinal wall. The aim of this study was prospectively to investigate the relationship between bowel blood flow and the likelihood of the need for surgery in 70 patients with active Crohn's disease (CD), using conventional ultrasonography (US) and H-FEI. MATERIAL AND METHODS: For H-FEI, Levovist injection was followed by scanning of the bowel segment of interest with intermittent harmonic imaging for 2 min (interval, 4 s; transmission pulse at 2.3 MHz; reception at 4.6 MHz). We calculated the mean echo-intensity for the bowel wall showing strongest opacity in the FEI series for each patient. Maximum bowel-wall thickness, wall stratification, maximum echo-intensity obtained by H-FEI, CD activity index, and C-reactive protein concentration were compared between patients treated successfully with medication after H-FEI (group M) and those who proved to need surgery (group S). RESULTS: No significant differences in clinical variables were evident between groups M (n=45) and S (n=25). The subsequent need for surgery was significantly indicated by multivariate analysis, showing loss of stratification in the bowel wall (odds ratio (OR)=5.98, 95% confidence interval (CI)=1.4-25.1, p=0.015) and high echo-intensity according to H-FEI (OR=1.02, CI=1.005-1.034, p=0.007). CONCLUSION: In active CD, patients with bowel segments showing a loss of stratification and rich perfusion by H-FEI are likely to need surgical treatment.     

Remicade does not abolish the need for surgery in fistulizing Crohn's disease

PURPOSE: Tumor necrosis factor antagonist therapy in the form of infliximab has been shown to promote significant healing in fistulizing Crohn's disease and therefore is often considered as a possible alternative to surgery. Our aim was to evaluate the role of infliximab in supplanting surgery for fistulizing Crohn's disease. METHODS: We performed a retrospective chart review of all adult patients who received infliximab for fistulizing Crohn's disease at one institution between September 1998 and October 2000. RESULTS: Twenty-six patients (14 male; mean age, 38 years; range, 19-80 years) received a mean of three (range, one to six) doses of infliximab (5 mg/kg) with the intent to cure fistulizing Crohn's disease. Nine patients (35 percent) had perianal, 6 (23 percent) enterocutaneous, 3 (12 percent) rectovaginal, 4 (15 percent) peristomal, and 4 (15 percent) intra-abdominal fistulas. Nineteen (73 percent) of the patients had had prior surgery for Crohn' s disease. Six patients (23 percent) had a complete response to infliximab with fistula closure, 12 (46 percent) had a partial response, and 8 (31 percent) had no response to infliximab. Fourteen (54 percent) patients still required surgery for their fistulizing Crohn's disease after infliximab therapy (10 bowel resections, 4 perianal procedures), whereas half (6/12) of the patients treated with infliximab who still had open fistulas after treatment declined surgical intervention. Five of six patients with fistula closure on infliximab had perianal or rectovaginal fistulas. None of the patients with either enterocutaneous or peristomal fistulas were healed with infliximab. CONCLUSIONS: Although it was associated with a 61 percent complete or partial response rate, infliximab therapy did not supplant the need for surgical intervention in the majority of our patients with fistulizing Crohn's disease. Seventy-three percent of the patients either required surgery or still had open fistulas after infliximab therapy. Infliximab was much more effective in treating perianal disease than abdominal enterocutaneous disease.