Incidence and associated factors of cetuximab-induced hypersensitivity infusion reactions in 1392 cancer patients treated in four French areas: a possible association with Lyme disease?

BACKGROUND: Previous studies have observed an increased incidence of Cetuximab-induced hypersensitivity infusion reactions (CI-IRs) in the southeastern states of the USA. Tick's bites were suspected of generating cross-reactions between cetuximab and alpha-gal. This study aims was to describe the incidence and associated risk factors of CI-IRs, in the French areas chosen according to their Lyme disease incidence. PATIENTS AND METHODS: A retrospective chart review was conducted on patients that received cetuximab infusion from January 2010 to June 2019 in 4 French areas with different Lyme disease incidence rates. RESULTS: Of 1392 patients, 117 (8.4%) experienced a CI-IR, including 68 severe (grade 3 or 4) reactions (4.9%). This CI-IR incidence was significantly higher in the Lyme disease high-risk area than in the other areas (13.2% versus 7.1%, 8.1% and 6.4%; P = 0.016). Sex (P = 0.53), premedication (P = 0.91), primary cancer location (P = 0.46) and chemotherapy regimen type (P = 0.78) had no impact on CI-IR incidence in the overall population. In the head and neck squamous cell carcinoma (HNSCC) patient subgroup, CI-IRs were significantly more frequent in the high-risk area (16.4% versus 6.7%, 7.1% and 7.0%; P = 0.0015). CONCLUSION: This study suggests that patients treated in the French area with the highest incidence of Lyme disease are at a higher risk of CI-IRs.

The RAGE signaling pathway is involved in intestinal inflammation and represents a promising therapeutic target for Inflammatory Bowel Diseases.

Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions of the intestinal tract. IBD are believed to result from an inappropriate immune response against the intestinal flora in genetically predisposed patients. The precise etiology of these diseases is not fully understood, therefore treatments rely on the dampening of symptoms, essentially inflammation, rather than on the cure of the disease. Despite the availability of biologics, such as anti-TNF antibodies, some patients remain in therapeutic failure and new treatments are thus needed. The multiligand receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in inflammatory reactions and immune system activation. Here, we investigated the role of RAGE in intestinal inflammation and its potential as a therapeutic target in IBD. We showed that RAGE was upregulated in inflamed tissues from IBD patients compared to controls. Rage-/- mice were less susceptible to intestinal and colonic inflammation development than WT mice. WT mice treated with the RAGE-specific inhibitor FPS-ZM1 experienced less severe enteritis and colitis. We demonstrated that RAGE could induce intestinal inflammation by promoting oxidative stress and endothelial activation which were diminished by FPS-ZM1 treatment. Our results revealed the RAGE signaling pathway as a promising therapeutic target for IBD patients.

Post-operative complications in elderly onset inflammatory bowel disease: a population-based study.

BACKGROUND: IBD diagnosed after the age of 60 is increasing. Data on post-operative complications in elderly onset IBD are scarce. AIM: To describe the incidence of and factors associated with post-operative complications in elderly onset IBD, diagnosed after the age of 60. METHODS: Using EPIMAD Cohort (1988-2006), among 841 incident IBD patients, 139 (17%) underwent intestinal surgery, including 100 Crohn's disease (CD) and 39 ulcerative colitis (UC). RESULTS: After a median post-operative follow-up of 6 years (2-10), 50 (36%) patients experienced at least 1 complication with a total of 69. During the first 30 post-operative days, the mortality rate was 4%. Thirty-two early complications (<30 days) were observed in 23 patients (17%), with 15 infectious, without significant difference between CD and UC. More than half early post-operative complications (n = 19, 59%) were severe (>grade 2) without significant difference between CD and UC (P = 0.28). Thirty-seven long-term adverse effects of surgical therapy (≥30 days) were observed in 33 patients (24%). Multivariate analysis found (1) acute severe colitis (OR = 7.84 [2.15-28.52]) and emergency surgery (OR = 4.46 [1.75-11.36]) were associated with early post-operative complications, and (2) Female gender (HR = 2.10 [1.01-4.37]) and delay before surgery >3 months (HR = 2.09 [1.01-4.31]) with long-term adverse effects of surgical therapy. CONCLUSIONS: One-third of elderly IBD patients experienced at least 1 post-operative complication. Half of the early complications were severe, and infectious. Emergency surgery was the key driver for post-operative complication.

Independent Validation of a Self-Report Version of the IBD Disability Index (IBDDI) in a Population-Based Cohort of IBD Patients.

Introduction: A new clinician-administered inflammatory bowel disease (IBD) Disability Index (IBDDI) was recently developed and validated among a population in France. We aimed to validate the IBDDI in a North American setting and adapt for use as a self-report tool. Methods: Persons 18-65 years old from the population-based University of Manitoba IBD Research Registry were mailed a self-administered survey. This survey included the IBDDI and several scales that should correlate with a disability measure- the World Health Organization (WHO) Disability Assessment Scale (WHODAS) 2.0, Work and Social Adjustment Scale (WSAS), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the K6-Kessler Emotional Distress Scale. We used Pearson correlation coefficients to assess construct validity, Cronbach's alpha to assess internal consistency, and Factor analysis to assess which of the IBDDI items likely belonged to a single IBD-related disability factor. Results: In response to the survey request,1143 (46% of those contacted) participated (61% female, mean age 51, 52% with Crohn's disease). On an index scale from 0-100, 14% had a score ≥50 (extreme disability, 18% of those with Crohn's disease; 10% of those with ulcerative colitis). There were strong correlations between IBDDI and WSAS (0.76), WHODAS (0.76), K6 (0.73), and an inverse correlation with IBDQ (-0.86). The Cronbach's alpha was high (0.88). All but 2 items (number of liquid stools in the past week and arthritis/arthralgia) of the 14 identified for IBDDI loaded highly onto a single factor (factor loading > 0.40). Conclusions: The findings support the validity of this new self-report version of the IBDDI as a sound measure of disability in IBD.

Systematic review and meta-analysis: assessment of factors affecting disability in inflammatory bowel disease and the reliability of the inflammatory bowel disease disability index.

BACKGROUND: The Inflammatory Bowel Disease Disability Index (IBD-DI) has recently been developed for patients with Crohn's disease (CD) and ulcerative colitis (UC). AIM: To assess the severity of disability and associated factors using the IBD-DI, and review the validity of the IBD-DI as a tool. METHOD: Systematic review of cross-sectional studies. Patients included had UC or CD and were classified as active, in remission, or needing surgery, biological and/or steroid treatment. We included studies assessing disability using the IBD-DI and that were captured by electronic and manual searches (January 2017). The possibility of bias was evaluated with the Newcastle-Ottawa Scale. RESULTS: Nine studies were included with 3167 patients. Comparatively, patients with active disease had higher disability rates than those in remission (SMD [CI95] = 1.49[1.11, 1.88], I2  = 94%, P<.01), while patients on biological treatment had lower disability rates than those receiving corticosteroid treatment (SMD [CI95] = -0.22[-0.36, -0.08], I2  = 0%, P<.01). Disease activity and unemployment were found to be associated factors. The IBD-DI scored "good" for internal consistency, "fair" to "excellent" for intra-rater reliability and "excellent" for inter-rater reliability. Construct validity was "moderately strong" to "very strong" and structural validity was found to be mainly unidimensional. The IBD-DI had excellent responsiveness, while its interpretability was only useful on a group level. CONCLUSIONS: This systematic review and meta-analysis found a significant association between disease activity, treatment received and disability; although significant heterogeneity was found. The IBD-DI is reliable and valid, but further studies are needed to measure its interpretability.

Incidence and Phenotype at Diagnosis of Very-early-onset Compared with Later-onset Paediatric Inflammatory Bowel Disease: A Population-based Study [1988-2011].

BACKGROUND AND AIMS: Very-early-onset inflammatory bowel disease [VEO-IBD] is a form of IBD that is distinct from that of children with an older onset. We compared changes over time in the incidence and phenotype at diagnosis between two groups according to age at IBD diagnosis: VEO-IBD diagnosed before the age of 6 years, and early-onset IBD [EO-IBD] diagnosed between 6 and 16 years of age. METHODS: Data were obtained from a cohort enrolled in a prospective French population-based registry from 1988 to 2011. RESULTS: Among the 1412 paediatric cases [< 17 years], 42 [3%] were VEO-IBD. In the VEO-IBD group, the incidence remained stable over the study period. In contrast, the incidence of EO-IBD increased from 4.4/105 in 1988-1990 to 9.5/105 in 2009-2011 [+116%; p < 10-4]. Crohn's disease [CD] was the most common IBD, regardless of age, but ulcerative colitis [UC] and unclassified IBD were more common in VEO-IBD cases [40% vs 26%; p = 0.04]. VEO-IBD diagnosis was most often performed in hospital [69% vs 43%; p < 10-3]. Rectal bleeding and mucous stools were more common in patients with VEO-IBD, whereas weight loss and abdominal pain were more frequent in those with EO-IBD. Regarding CD, isolated colonic disease was more common in the VEO-IBD group [39% vs 14%; p = 0.003]. CONCLUSIONS: In this large population-based cohort, the incidence of VEO-IBD was low and stable from 1988 to 2011, with a specific clinical presentation. These results suggest a probable genetic origin for VEO-IBD, whereas the increase in EO-IBD might be linked to environmental factors.

Ulcerative proctitis is a frequent location of paediatric-onset UC and not a minor disease: a population-based study.

OBJECTIVE: Natural history of paediatric-onset ulcerative proctitis (UP) is poorly described. Our aim was to describe the phenotype and disease course of incident UP in a population-based study of paediatric-onset UC. PATIENTS AND METHODS: All patients with UC diagnosed <17 years from 1988 to 2004, and followed during >2 years have been extracted from a population-based registry. UC location was defined according to the Paris classification. Cumulative risks for use of immunosuppressants (IS), anti-tumour necrosis factor alpha (TNF-α) therapy, colonic extension and colectomy were described using Kaplan-Meier method. Risk factors for colonic extension were assessed using Cox proportional hazards models. RESULTS: 158 patients with paediatric-onset UC (91 females) with a median age at diagnosis of 14.5 years (Q1: 11.4-Q3: 16.1) have been identified and followed during a median of 11.4 years (8.2-15.8). Among them, 25% had UP (E1) at diagnosis and 49% of them presented a colonic extension at maximal follow-up. In these children, the cumulative risk for colonic extension was 10% at 1 year, 45% at 5 years and 52% at 10 years. No parameter at diagnosis was associated with colonic extension in the UP (E1 group). IS use was significantly lower in patients with UP than in those with E2, E3 or E4 location (p=0.049). For the UP cohort, the cumulative risk for colectomy was 3% at 1 year, 10% at 5 years, 13% at 10 years and 13% at 15 years. Risks for colonic extension, treatment with anti-TNF-α and colectomy did not differ between the E1 group and the E2-E3-E4 group. CONCLUSIONS: UP is frequent in paediatric-onset UC and should not be considered as a minor disease. Compared with more extensive UC locations, risks for colonic extension, anti-TNF-α therapy and colectomy were similar in UP, whereas the risk for use of IM was lower.

Periodontal manifestations of inflammatory bowel disease: emerging epidemiologic and biologic evidence.

Inflammatory bowel disease and periodontitis are both described as a disproportionate mucosal inflammatory response to a microbial environment in susceptible patients. Moreover, these two conditions share major environmental and lifestyle-related risk factors. Despite this intriguing pathogenic parallel, large-scale studies and basic research have only recently considered periodontal outcomes as relevant data. There are mounting and consistent arguments, from recent epidemiologic studies and animal models, that these two conditions might be related. This article is a comprehensive and critical up-to-date review of the current evidence and future prospects in understanding the biologic and epidemiologic relationships between periodontal status and inflammatory bowel disease.

Bacteriome and Mycobiome Interactions Underscore Microbial Dysbiosis in Familial Crohn's Disease.

UNLABELLED: Crohn's disease (CD) results from a complex interplay between host genetic factors and endogenous microbial communities. In the current study, we used Ion Torrent sequencing to characterize the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in patients with CD and their nondiseased first-degree relatives (NCDR) in 9 familial clusters living in northern France-Belgium and in healthy individuals from 4 families living in the same area (non-CD unrelated [NCDU]). Principal component, diversity, and abundance analyses were conducted, and CD-associated inter- and intrakingdom microbial correlations were determined. Significant microbial interactions were identified and validated using single- and mixed-species biofilms. CD and NCDR groups clustered together in the mycobiome but not in the bacteriome. Microbiotas of familial (CD and NCDR) samples were distinct from those of nonfamilial (NCDU) samples. The abundance of Serratia marcescens and Escherichia coli was elevated in CD patients, while that of beneficial bacteria was decreased. The abundance of the fungus Candida tropicalis was significantly higher in CD than in NCDR (P = 0.003) samples and positively correlated with levels of anti-Saccharomyces cerevisiae antibodies (ASCA). The abundance of C. tropicalis was positively correlated with S. marcescens and E. coli, suggesting that these organisms interact in the gut. The mass and thickness of triple-species (C. tropicalis plus S. marcescens plus E. coli) biofilm were significantly greater than those of single- and double-species biofilms. C. tropicalis biofilms comprised blastospores, while double- and triple-species biofilms were enriched in hyphae. S. marcescens used fimbriae to coaggregate or attach with C. tropicalis/E. coli, while E. coli was closely apposed with C. tropicalis Specific interkingdom microbial interactions may be key determinants in CD. IMPORTANCE: Here, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal (Candida tropicalis) and bacterial (Serratia marcescens and Escherichia coli) species that are associated with CD dysbiosis. Additionally, we found that the level of anti-Saccharomyces cerevisiae antibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis We also identified positive interkingdom correlations between C. tropicalis, E. coli, and S. marcescens in CD patients and validated these correlations using in vitro biofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays.

Review article: the natural history of paediatric-onset ulcerative colitis in population-based studies.

BACKGROUND: A better knowledge of the natural history of disabling chronic diseases is essential to improve patient management, evaluate the impact of treatment strategies and provide predictors for disabling disease and comprehensive information for patients. AIM: To summarise our current knowledge issued from population-based studies of the natural history of ulcerative colitis (UC) in children. METHODS: We searched MEDLINE (source PubMed) and international conference abstracts, and included all population-based studies that evaluated long-term outcome of paediatric-onset (<17 years at diagnosis) UC. RESULTS: A total of 26 population-based studies were considered in this review from the total of 61 articles or abstracts screened. Most patients presented disease extension and about two-thirds of patients had pancolitis at the end of follow-up. One-half of patients experienced extra-intestinal manifestations and primary sclerosing cholangitis was observed in 5-10% of patients. Overall, patients did not appear to have any significant growth retardation or delayed puberty. About two-thirds of patients required corticosteroid therapy and up to 25% were steroid dependent. An increased use of thiopurines was observed and the most recent data indicate that up to one-half of patients were exposed to thiopurines and 10-30% were exposed to anti-tumour necrosis factor. One-half of patients required hospitalisations and 20% of patients required colectomy after a follow-up of 10 years. CONCLUSIONS: Paediatric-onset UC is characterised by a high rate of disease extension. About 20% of patients had been operated at 10-year follow-up. New population-based studies are needed to evaluate the impact of new treatment strategies comprising immunosuppressants and biologics.

Systematic review: fertility in non-surgically treated inflammatory bowel disease.

BACKGROUND: Inflammatory bowel diseases (IBD) typically affect young patients during the reproductive years, and reproductive issues are of key concern to them. AIM: To evaluate the impact of IBD on fertility in both women and men with IBD who had no history of surgical treatment for IBD. METHODS: We searched MEDLINE, Cochrane Library, EMBASE and international conference abstracts and included all controlled observational studies that evaluated fertility in Crohn's disease (CD) and/or ulcerative colitis (UC) in women and/or men. RESULTS: Eleven studies matching our criteria were included. In women with CD, there was a 17-44% reduction in fertility as compared with controls. Reduction in fertility was linked to voluntary childlessness, while there was no evidence of physiological causes of infertility. Most studies did not find any reduction in fertility in women with UC as compared with controls. In men with CD, there was an 18-50% reduction in fertility as compared with controls with no difference in reproductive capacity. There was no evidence of reduced fertility in men with UC. CONCLUSIONS: The infertility observed in both women and men with CD is due to voluntary childlessness as opposed to involuntary infertility. This voluntary childlessness is often based on incorrect beliefs about the impact of the disease on fertility and pregnancy outcomes. Our results reinforce the need to increase awareness among male and female patients that IBD does not itself lead to reduced fertility.

The changing pattern of Crohn's disease incidence in northern France: a continuing increase in the 10- to 19-year-old age bracket (1988-2007).

BACKGROUND: Crohn's disease incidence rates have stabilised in industrialised countries since the 1980s. Conversely, a continuing increase in childhood-onset Crohn's disease incidence has been reported. AIM: To confirm trends in inflammatory bowel disease (IBD) incidence in northern France over an extended time period (1988-2007) with a focus on childhood-onset Crohn's disease. METHODS: The IBD patients recorded in the EPIMAD registry between 1988 and 2007 were included. Standardised incidence rates were calculated for Crohn's disease and ulcerative colitis in the entire population, and separately according to age. Evolution of phenotypes at diagnosis was also studied. RESULTS: A total of 12 084 incident IBD cases (7428 Crohn's disease and 4656 ulcerative colitis) were recorded. Crohn's disease incidence rates increased from 5.2 cases/100 000 persons in 1988-1990 to 6.7 in 2006-2007 (+29%), stabilising after a peak at 7.1 in 1997-1999. Crohn's disease incidence rates in the 10-19-year age category increased by 71%, from 6.5 (1988-1990) to 11.1 (2006-2007). The frequency of initial ileo-colonic localisation increased from 52.9% in 1988-1990 to 68.6% in 2006-2007 (P<0.0001). Ulcerative colitis incidence rates decreased during the same period. CONCLUSIONS: From 1988 to 2007, Crohn's disease incidence increased by 29% in northern France and by 71% in the 10-19-year-old age group. Consequently, studies on Crohn's disease risk factors should focus on the population under 20 years of age.

[Inflammatory bowel disease: genetic or environmental diseases?]. / Maladies inflammatoires chroniques de l'intestin: maladies génétiques ou de l'environnement?

Pathophysiology of inflammatory bowel diseases depends on the interaction between genetic susceptibility and environmental factors leading to a deregulated immune intestinal response resulting in bowel lesions. Epidemiologic variations of inflammatory bowel diseases with time (incidence, prevalence) and space suggest a role for risk environmental factors, but so far only smoking habits and appendectomy have been identified as influencing the risk of occurrence and the course of the diseases. Studies of monozygotic and dizygotic twins and the existence of familial aggregation are strong evidence for an important, but not exclusive, role for genetic susceptibility. Since the discovery of NOD2/CARD15 mutations, numerous genes have been associated with inflammatory bowel diseases, some of them involved in the regulation of innate immunity and cellular clearance of infectious agents (autophagy). Thus, new hypothesis include a key role of mucosal human microbiota which could be partly influenced by environmental factors generated by modern life. The improvement of life hygiene, the change of food composition and habits, the industrial pollution in developed countries, may influence, directly or by the way of modifying intestinal human microbiota, inflammatory bowel diseases risk occurrence.

Environmental risk factors in paediatric inflammatory bowel diseases: a population based case control study.

BACKGROUND: Environmental exposures in early life have been implicated in the aetiology of inflammatory bowel disease. OBJECTIVE: To examine environmental risk factors prior to the development of inflammatory bowel disease in a paediatric population based case control study. METHODS: A total of 222 incident cases of Crohn's disease and 60 incident cases of ulcerative colitis occurring before 17 years of age between January 1988 and December 1997 were matched with one control subject by sex, age, and geographical location. We recorded 140 study variables in a questionnaire that covered familial history of inflammatory bowel disease, events during the perinatal period, infant and child diet, vaccinations and childhood diseases, household amenities, and the family's socioeconomic status. RESULTS: In a multivariate model, familial history of inflammatory bowel disease (odds ratio (OR) 4.3 (95% confidence interval 2.3-8)), breast feeding (OR 2.1 (1.3-3.4)), bacille Calmette-Guerin vaccination (OR 3.6 (1.1-11.9)), and history of eczema (OR 2.1 (1-4.5)) were significant risk factors for Crohn's disease whereas regular drinking of tap water was a protective factor (OR 0.56 (0.3-1)). Familial history of inflammatory bowel disease (OR 12.5 (2.2-71.4)), disease during pregnancy (OR 8.9 (1.5-52)), and bedroom sharing (OR 7.1 (1.9-27.4)) were risk factors for ulcerative colitis whereas appendicectomy was a protective factor (OR 0.06 (0.01-0.36)). CONCLUSIONS: While family history and appendicectomy are known risk factors, changes in risk based on domestic promiscuity, certain vaccinations, and dietary factors may provide new aetiological clues.

Opposite evolution in incidence of Crohn's disease and ulcerative colitis in Northern France (1988-1999).

BACKGROUND: Northern France was characterised by a high incidence of Crohn's disease (CD) and a low incidence of ulcerative colitis (UC) according to the first inquiry undertaken in the late 1980s. AIMS: To assess the trends in the incidence of inflammatory bowel disease (IBD) over a 12 year period (1988-1999) in the same area of Northern France. PATIENTS: Patients living in Northern France (Nord, Pas-de-Calais, Somme, and Seine Maritime--total of 5,790,526 inhabitants) between 1988 and 1999 were included in the study. Case ascertainment was established according to methodology previously described. METHODS: Trends in incidence were studied using a Poisson regression model in four three year periods (1988-90, 1991-93, 1994-96, and 1997-99) adjusted for age at diagnosis and sex. Incidence rates were standardised for age with the European standard population. RESULTS: During 1988-99, 7066 cases of IBD were recorded (56.8% CD, 37.7% UC, and 5.5% indeterminate colitis). Mean annual incidence rate of CD increased from 5.2/100,000 inhabitants in 1988-90 to 6.4 in 1997-99 (adjusted p for trend <0.001). In contrast, the incidence of UC decreased from 4.2 to 3.5 (adjusted p for trend <0.001). The ileocolonic subtype of CD increased by 25% even though median age at diagnosis and frequency of digestive investigations were not different. CONCLUSIONS: Contrary to what has been reported in other countries in Northern Europe, the incidence of CD increased by 23% in 12 years in Northern France while that of UC decreased by 17% during the same period. This indicates that some factors which influence IBD frequency (in both directions) are still at work in this area of Europe, and that further studies aimed at identifying these should be performed. The rising incidence of CD could enhance the burden of this disease on the public health system in France.

CARD4/NOD1 is not involved in inflammatory bowel disease.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD. PATIENTS AND METHODS: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test. RESULTS: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence. CONCLUSION: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

Inflammatory bowel disease in spouses and their offspring.

BACKGROUND & AIMS: The rarity of inflammatory bowel disease (IBD) in both husband and wife is often given as an argument against an infectious origin. We registered conjugal instances of IBD in Northern France and in Belgium between 1989 and 2000. METHODS: Couples were assigned to group A if both partners had symptoms of IBD before cohabitation, to group B if one spouse had IBD before cohabitation and the other experienced first symptoms afterwards, and to group C if both partners got the disease after cohabitation. Risk of IBD was assessed in their offspring. RESULTS: Thirty conjugal instances were registered. Seventeen were concordant for Crohn's disease and 3 for ulcerative colitis; 10 were mixed. Two belonged to group A, 6 to group B, and 22 to group C. In group C, IBD occurred in the first affected spouse an average of 9 years after cohabitation and in the second spouse an average of 8.5 years later. Group C conjugal forms were more frequent than expected by chance (P < 0.02). Fifty-four children were born to 25 couples; among them 9, of whom 4 were siblings, developed Crohn's disease at a median age of 15 years. CONCLUSIONS: The frequency of conjugal forms of IBD suggests an etiologic role for environmental factors. Offspring of 2 affected parents have a high risk of developing IBD.