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

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

Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases With Time, Based on Systematic Review

https://www.ualberta.ca/~loewen/Medicine/GIM%20Residents%20Core%20Reading/IBD,%20CROHN'S%20AND%20U.C/accent%20i%20trial.pdf

Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial

Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and these have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis. Second, efforts directed towards the identification of environmental factors implicate commensal bacteria (or their products), rather than conventional pathogens, as drivers of dysregulated immunity and IBD. Third, murine models, which exhibit many of the features of ulcerative colitis and seem to be bacteria-driven, have helped unravel the pathogenesis/mucosal immunopathology of IBD.

Unravelling the pathogenesis of inflammatory bowel disease

Background Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor α, is an established treatment for Crohn's disease but not ulcerative colitis. Methods Two randomized, double-blind, placebo-controlled studies — the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively) — evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. Results In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0...

/pdf/infliximab-for-induction-and-maintenance-therapy-for-4v31zm5xxu.pdf

Infliximab for induction and maintenance therapy for ulcerative colitis.

Background and Methods. We assessed the familial occurrence of inflammatory bowel disease in Copenhagen County, where there has been a long-term interest in the epidemiology of such disorders. In 1987 we interviewed 662 patients in whom inflammatory bowel disease had been diagnosed before 1979, asking whether their first- and second-degree relatives had this disorder. Ninety-six percent of the patients (504 with ulcerative colitis and 133 with Crohn's disease) provided adequate information. Results. As compared with the general population, the first-degree relatives of the 637 patients with ulcerative colitis or Crohn's disease had a 10-fold increase in the risk of having the same disease as the patients, after standardization for age and sex. The risk of having the other of the two diseases was also increased, but less so, and the increase in the risk of having Crohn's disease was not significant in the relatives of patients with ulcerative colitis. The risk of ulcerative colitis in first-degree...

https://www.nejm.org/doi/pdf/10.1056/NEJM199101103240203

Familial Occurrence of Inflammatory Bowel Disease

Course of ulcerative colitis: Analysis of changes in disease activity over years

The outcome of the first steroid treatment course was prospectively studied in a regional cohort of 196 patients with Crohn's disease diagnosed 1979-1987. The immediate outcome after 30 days, and the prolonged outcome 30 days after treatment had stopped, are described. In all 109 patients treatment was analysed. Complete remission was obtained in 48%, partial remission in 32%, and no response in 20% within 30 days of treatment. Among primary responders (complete and partial remission), 55% remained in prolonged response after treatment had finished, while 45% relapsed or could not be withdrawn from treatment within one year. Localisation of disease, age, sex or clinical symptoms did not significantly correlate with outcome, which can be summarised as prolonged steroid response in 44%, steroid dependency in 36%, and steroid resistant in 20% of the patients.

https://gut.bmj.com/content/gutjnl/35/3/360.full.pdf

Frequency of glucocorticoid resistance and dependency in Crohn's disease.

Background: The study was a follow-up of an inception cohort of 373 patients with Crohn's disease.Methods: Annual assessments, life table analyses, and Markov chain analyses, estimating the probability for remission and relapse with time, and working capacity were carried out.Results: The clinical course of Crohn's disease differs markedly over time, from ever-relapsing cases to a quiescent course with remission for several years, interrupted by years with relapse. No predictive factors have been found for the subsequent course with regard to age, sex, extent of disease at diagnosis, and treatment in the year of diagnosis. The relapse rate within the year of diagnosis and the following 2 years, however, does correlate positively (p = 0.00001) with the relapse rate in the following 5 years. Furthermore, the relapse rate for 1 year during the disease course influences the relapse rate the following year, indicating a disease pattern over time with waves of at least 2 years' duration. A slight tendency towar...

Disease Activity Courses in a Regional Cohort of Crohn's Disease Patients

https://www.gastrojournal.org/article/0016-5085(92)91163-X/pdf

Ebbe Langholz

Papers

Familial Occurrence of Inflammatory Bowel Disease

Course of ulcerative colitis: Analysis of changes in disease activity over years

Frequency of glucocorticoid resistance and dependency in Crohn's disease.

Disease Activity Courses in a Regional Cohort of Crohn's Disease Patients

Colorectal cancer risk and mortality in patients with ulcerative colitis.