Ole Haagen Nielsen

Familial Occurrence of Inflammatory Bowel Disease

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 Crohns disease) provided adequate information. RESULTS As compared with the general population, the first-degree relatives of the 637 patients with ulcerative colitis or Crohns 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 Crohns disease was not significant in the relatives of patients with ulcerative colitis. The risk of ulcerative colitis in first-degree relatives of patients with ulcerative colitis appeared to be virtually independent of the generation to which the first-degree relative belonged and of the sex of the patient and the relative. The risk of ulcerative colitis in first-degree relatives tended to be higher if the disease had been diagnosed in the patient before the age of 50, but the risk seemed to be independent of the current age of the relatives. The prevalence of the same disease as that of the patient (either ulcerative colitis or Crohns disease) among second-degree relatives was increased; the prevalence of the other disease was not increased. CONCLUSIONS The 10-fold increase in the familial risk of ulcerative colitis and Crohns disease strongly suggests that these disorders have a genetic cause.

Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1β generation

Inflammation is part of the non‐specific immune response that occurs in reaction to any type of bodily injury. In some disorders, the inflammatory process − which under normal conditions is self‐limiting − becomes continuous and chronic inflammatory diseases might develop subsequently. Pattern recognition molecules (PRMs) represent a diverse collection of molecules responsible for sensing danger signals, and together with other immune components they are involved in the first line of defence. NALP3 and NOD2, which belong to a cytosolic subgroup of PRMs, dubbed Nod‐like‐receptors (NLRs), have been associated recently with inflammatory diseases, specifically Crohns disease and Blau syndrome (NOD2) and familial cold autoinflammatory syndrome, Muckle–Wells syndrome and chronic infantile neurological cutaneous and articular syndrome (NALP3). The exact effects of the defective proteins are not fully understood, but activation of nuclear factor (NF)‐κB, transcription, production and secretion of interleukin (IL)‐1β and activation of the inflammasome are some of the processes that might hold clues, and the present review will provide a thorough update in this area.

Upregulation of Interleukin-12 and -17 in Active Inflammatory Bowel Disease

Background: Cytokines are essential mediators of the intestinal inflammation during active episodes of inflammatory bowel disease (IBD). Interleukin (IL)-12 and IL-17 are potent immunoregulatory cytokines whose roles in the pathogenesis of IBD are unknown. The aim of this study was to evaluate the colonic expression of IL-12 and IL-17 genes in IBD. Methods: Fifty-one patients (22 with ulcerative colitis (UC), 17 with Crohn disease (CD), and 12 controls) who underwent colonoscopy were included. IBD disease activity was determined using a clinical grading scale. The degree of inflammation, as well as the content of CD4+ T cells (synthesizing IL-17) and CD68+ macrophages (synthesizing IL-12) in colonic biopsies, was determined. The amounts of IL-12 and IL-17 mRNA were assessed by RT-PCR, using GAPDH as an internal standard. Results: In colonic specimens, IL-17 mRNA expression was increased in moderately and severely active UC (P = 0.03) and in all degrees of activity in CD (P < 0.04). Levels of IL-12 mRNA were upregulated in both active UC and active CD compared to controls (P < 0.02). In cases of remission, IL-12 mRNA expression was similar to that found in control samples. Compared to controls, histological examination showed significant differences in signs of chronic and acute inflammation in UC (P < 0.01) and CD (P < 0.02), revealing a high correlation between clinical disease activity and histological scoring (r 2  = 0.92, P < 0.005). Whereas CD4+ T cells were observed in lymphocyte aggregates located profound in the lamina propria, CD68+ macrophages were primarily found just underneath the surface epithelium. The density of CD4+ and CD68+ cells correlated significantly with the amounts of IL-17 and IL-12 mRNA, respectively (P < 0.05). Conclusion: The expression of both IL-12 and IL-17 mRNA is induced in active UC and CD and may thus be involved in sustaining the intestinal inflammation in IBD. Inhibition of IL-12 or IL-17 might be future therapeutic targets in IBD.

Clinical Evidence Supporting the Radical Scavenger Mechanism of 5-Aminosalicylic Acid

5-Aminosalicylic acid, the therapeutically active metabolite of sulfasalazine, was exposed to oxygen-derived free radicals produced by the Fenton reaction in vitro, and several metabolites were detected and characterized by high performance liquid chromatography and ultraviolet spectrophotometry. The majority of these metabolites were present in methanolic extracts of feces samples from sulfasalazine-treated patients with inflammatory bowel disease but not in rheumatoid arthritis patients with normal bowel function. The presence of these metabolites, which have not been demonstrated in vivo before, provides evidence of an interaction between 5-aminosalicylic acid and oxygen-derived free radicals in sulfasalazine-treated patients with inflammatory bowel disease. Since the concentration of lipid peroxides, which is dependent on the release of oxygen-derived free radicals, was significantly increased in pretreatment rectal biopsies of the patients, and further was normalized concomitantly with a significant improvement in disease activity over the 5-wk treatment period, an important role of the radical scavenger mechanism of 5-aminosalicylic acid in sulfasalazine therapy of chronic inflammatory bowel disease is strongly suggested.

Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn's disease

BACKGROUND AND AIMS New lesions of Crohns disease occur early after ileal or ileocolonic resection and ileocolonic anastomosis. We performed a double blind controlled trial to evaluate the safety and tolerance of recombinant human interleukin 10 (IL-10; Tenovil) in subjects operated on for Crohns disease. We also assessed the effect of Tenovil in preventing endoscopic recurrence 12 weeks after surgery. METHODS Patients with Crohns disease who underwent curative ileal or ileocolonic resection and primary anastomosis were randomised within two weeks after surgery to receive subcutaneous Tenovil 4 μg/kg once daily (QD) (n=22) or 8 μg/kg twice weekly (TIW) (n=21), or placebo (QD or TIW) (n=22). An ileocolonoscopy was performed after 12 weeks of treatment. RESULTS Compliance was excellent. The most frequently observed adverse events were mild and moderate in severity and equally distributed across treatment groups. Thirty seven patients in the pooled Tenovil group and 21 patients in the pooled placebo group were evaluable by endoscopy. At 12 weeks, 11 of 21 patients (52%) in the placebo group had recurrent lesions compared with 17 of 37 patients (46%) in the Tenovil group (ns). The incidence of severe endoscopic recurrence was similar in both groups (9%). CONCLUSION Tenovil treatment for 12 consecutive weeks in patients with Crohns disease after intestinal resection was safe and well tolerated. No evidence of prevention of endoscopic recurrence of Crohns disease by Tenovil was observed.

Pregnancy in Ulcerative Colitis

The course of pregnancy in 97 women with ulcerative colitis was studied over a 12-year period. During this period they had 173 pregnancies and delivered 136 children. There were two gemellary deliveries. Nine women had a spontaneous and 16 an induced abortion, of which 4 were performed on therapeutic indication. For a woman with ulcerative colitis the risk of an exacerbation of the bowel disease was 32% per year in her fertile years, whereas it was 34% per year during pregnancy. This difference is not statistically significant. As compared with women with an inactive bowel disease, women in whom the disease was active at the start of pregnancy had a small but significantly greater risk of spontaneous abortion and premature delivery. The frequency of malformations, prematurity, and neonatal hyperbilirubinaemia was not higher in the children of ulcerative colitis mothers than in those of healthy mothers. Treatment with sulphasalazine, salazosulphadimidine, and corticosteroids had no influence on the course and outcome of pregnancy. Birth length and weight of the children of mothers with ulcerative colitis equalled those for children of healthy mothers. In conclusion, pregnancy does not necessitate any change in the usual medical treatment of ulcerative colitis. Women with ulcerative colitis should be advised preferably to conceive at a time when their bowel disease is inactive. Generally, ulcerative colitis constitutes no indication for induced abortion.

Changes in Extent of Ulcerative Colitis A Study on the Course and Prognostic Factors

Background: The prognosis of patients with ulcerative colitis (UC) has previously been described with regard to mortality, cancer occurrence, and need for colectomy on the basis of an annual follow-up of a regional cohort of UC patients in Copenhagen County diagnosed in 1962–87. The objective of this study was to examine the prognosis with regard to spread of disease and to evaluate possible prognostic factors with regard to spread of disease and colectomy by multivariate regression analysis. Methods: An inception cohort of 1161 patients with UC was examined by actuarial analysis and by multivariate regression analysis of a subgroup of 467 patients diagnosed in 1979–87. Results: The probability for further progression of proctosigmoiditis, evaluated by sigmoidoscopy and radiology, was 53% after 25 years. The probability for regression was 76.8% for substantial colitis and 75.7% for pancolitis after 25 years. Multivariate regression analysis showed that the occurrence of the symptoms abdominal pain and dia...

Established and emerging biological activity markers of inflammatory bowel disease

Assessment of disease activity in inflammatory bowel disease (IBD), i.e., ulcerative colitis (UC) and Crohns disease (CD), is done using clinical parameters and various biological disease markers. Ideally, a disease marker must: be able to identify individuals at risk of a given disorder, be disease specific, mirror the disease activity and, finally, be easily applicable for routine clinical purposes. However, no such disease markers have yet been identified for IBD. In this article, classical disease markers including erythrocyte sedimentation rate, acute phase proteins (especially orosomucoid and CRP), leukocyte and platelet counts, albumin, neopterin, and beta2-microglobulin will be reviewed together with emerging disease markers such as antibodies of the ANCA/ASCA type, cytokines (e.g., IL-1, IL-2Ralpha, IL-6, IL-8, TNF-alpha, and TNF-alpha receptors) and with various adhesion molecules. It is concluded that none of the pertinent laboratory surrogate markers of disease activity in IBD are specific or sensitive enough to replace basic clinical observation such as the number of daily bowel movements, general well-being, and other parameters in parallel. Further studies are highly warranted to identify and assess the clinical importance and applicability of new laboratory markers for the diagnosis or the disease activity of IBD.

Extraintestinal manifestations of inflammatory bowel disease: Epidemiology, diagnosis, and management

Abstract Extraintestinal manifestations occur rather frequently in inflammatory bowel disease (IBD), e.g. ulcerative colitis (UC) and Crohns disease (CD). The present paper provides an overview of the epidemiology, clinical characteristics, diagnostic process, and management of rheumatic, metabolic, dermatologic (mucocutaneous), ophthalmologic, hepatobiliary, hematologic, throm-boembolic, urinary tract, pulmonary, and pancreatic extraintestinal manifestations related to IBD. Articles were identified through search of the PubMed and Embase databases, the Cochrane Library, and the web sites of the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) (cut-off date October 2009). The search terms ‘Crohns disease’, ‘inflammatory bowel disease’, or ‘ulcerative colitis’ were combined with the terms ‘adalimumab’, ‘anemia’, ‘arthritis’, ‘bronchiectasis’, ‘bronchitis’, ‘cutaneous manifestations’, ‘erythema nodosum’, ‘extraintestinal manifestations’, ‘hyperhomocysteinemia’, ‘infliximab’, ‘iridocyclitis’, ‘lung disease’, ‘ocular manifestations’, ‘osteomalacia’, ‘pancreatitis’, ‘primary sclerosing cholangitis’, ‘renal stones’, ‘sulfasalazine’, ‘thromboembolism’, and ‘treatment’. The search was performed on English-language reviews, practical guidelines, letters, and editorials. Articles were selected based on their relevance, and additional papers were retrieved from their reference lists. Since some of the diseases discussed are uncommon, valid evidence of treatment was difficult to obtain, and epidemiologic data on the rarer forms of extraintestinal manifestations are scarce. However, updates on the pathophysiology and treatment regimens are given for each of these disorders. This paper offers a current review of original research papers and randomized clinical trials, if any, within the field and makes an attempt to point out practical guidelines for the diagnosis and treatment of various extraintestinal manifestations related to IBD.

Tumor Necrosis Factor Inhibitors for Inflammatory Bowel Disease

A 35-year-old man presents with an exacerbation of Crohn’s ileocolitis. He received a diagnosis of Crohn’s disease 8 years ago and has been treated on three previous occa sions with prednisone. Because of a recurrent need for glucocorticoids, treatment with azathioprine (150 mg per day) was started 1 year ago. He now reports abdominal pain in the right lower quadrant, which developed 1 week ago, with an increase in stool frequency to eight to nine stools per day. Laboratory tests show a hemoglobin concentration of 10.7 g per deciliter and a C-reactive protein level of 21 mg per liter. Magnetic resonance enterography shows inflammation localized to the distal ileum and colon. The patient is referred to a gastroenterologist. An ileocolonoscopy reveals patchy erythema and ulcerations near the hepatic flexure as well as similar lesions in the terminal ileum. Biopsy specimens obtained during colonoscopy show acute and chronic granulomatous inflammation, and the gastroenterologist recommends treatment with a tumor necrosis factor (TNF) inhibitor. T h e C l i nic a l Probl e m Inflammatory bowel disease, an umbrella term for a range of diseases of which ulcerative colitis and Crohn’s disease are the two prevailing entities, is a common chronic gastrointestinal disorder. Extrapolation from available data suggests that in the United States and Canada, more than 780,000 persons have ulcerative colitis and 630,000 have Crohn’s disease, and the global incidence of both disorders is increasing. 1 Inflammatory bowel disease has serious effects in terms of morbidity and qual ity of life. 2 In the era before biologic therapy was available, the rate of hospitaliza tion owing to medical complications, the need for surgery, or both was 194 admis sions per 1000 patient-years in a population-based cohort of patients with Crohn’s disease. 3 In the first 10 years after a diagnosis of Crohn’s disease, the cumulative rate of surgery is 40 to 55%. 3 In a recent large, population-based epidemiologic study of ulcerative colitis, the rate of colectomy 20 years after diagnosis was 14.8%. 4 Furthermore, extraintestinal manifestations (rheumatologic, dermatologic, oph thalmologic, hematologic [including thromboembolic], and hepatic complications) may at any time affect a third of all patients with inflammatory bowel disease. 5 According to meta-analyses of studies in unselected population-based cohorts, the risk of colorectal cancer is modestly increased among patients with both ulcerative colitis and Crohn’s disease, 6 and the latter disorder also carries a markedly in creased relative risk of small-bowel cancer among those with ileal inflammation, 7 although the absolute risk is low. However, these data are primarily from studies conducted at a time when there were fewer treatment options than there are today.