Ebbe Langholz

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

The outcome of the first steroid treatment course was prospectively studied in a regional cohort of 196 patients with Crohns 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partial remission), 55% remained in prolonged response after treatment had finished, while 45% relapsed or could not be withdrawn from treatment within one year.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.

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.

Colorectal cancer risk and mortality in patients with ulcerative colitis

A regional inception cohort of 1161 ulcerative colitis (UC) patients was followed up from diagnosis to the end of 1987. The follow-up rate for death and occurrence of cancer was 99.9% (median observation time, 11.7 years; range, 0-26 years). One hundred forty-one deaths were observed, 26 caused by UC or complications thereof. No significant excess mortality was found after the first year, but in the year of diagnosis the relative risk of death was 2.4 (P < 0.001). The cumulative colectomy rate 25 years after diagnosis was 32.4%. The initial extent of disease significantly influenced the colectomy probability, being 35% in total colitis, 19% in substantial colitis, and 9% in distal colitis within the first 5 years after diagnosis. Six patients developed colorectal cancer within the observation period. Compared with the expected number of 6.6, the relative risk for patients with UC was 0.9. The calculated cumulative cancer incidence was 3.1% after 25 years (95% confidence limits, 0.0-6.8). The calculated lifetime risk (0-74 years) for development of colorectal cancer was 3.5% for UC patients compared with 3.7% for the Danish population. It is concluded that with an active approach to medical and surgical treatment, as practiced here, patients whose colons are left intact bear no significantly increased risk of colorectal malignancy.

Intestinal cancer risk and mortality in patients with Crohn's disease

BACKGROUND It is important to know about mortality, risk of intestinal cancer, and surgical intervention as well as possible predictive factors for patients with Crohns disease. These prognostic parameters were estimated by regular follow-up of a complete, regional incidence cohort of 373 patients. METHODS Annual assessments of clinical conditions were the basis for statistical evaluation with life table analysis, calculations of relative risk, and lifetime cancer risk. RESULTS Survival curves for the total group of patients with Crohns disease and the background population did not differ. However, a subgroup of patients aged 20-29 years at diagnosis (P = 0.04) and a subgroup of patients with extensive small bowel disease (P = 0.03) showed slightly increased mortality within the first 5 years. Cancer in small and/or large bowel occurred in 3 patients vs. an expected 1.8(P = NS). Small bowel cancer was found in 2 patients vs. the 0.04 expected (P = 0.001). Lifetime risk of intestinal cancer was 4.1% compared with 3.8% for the Danish population in general (P = NS). Probability of surgical resection within 15 years after diagnosis was 70%. The initial extent of disease significantly influenced the probability for resection, which was 78% in ileocecal enteritis and 44% in all other localizations within 5 years after diagnosis. CONCLUSIONS The overall mortality and life-time risk of cancer in patients with Crohns disease was not found increased, although the risk of rare small bowel cancer was significantly increased.

Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: A population‐based study from Copenhagen, Denmark

Background: It remains uncertain whether the increasing incidence of inflammatory bowel disease (IBD) during the last decades has been accompanied by an alteration in the presentation, course, and prognosis of the disease. To answer this question, 3 consecutive population‐based IBD cohorts from Copenhagen, Denmark (1962–2005), were assessed and evaluated. Methods: Phenotype, initial disease course, use of medications, cumulative surgery rate, standardized incidence ratio of colorectal cancer (CRC), and standardized mortality ratio (SMR) were compared in the 3 cohorts, which had a total of 641 patients with Crohns disease (CD) and 1575 patients with ulcerative colitis (UC). Results: From 1962 to 2005, the proportion of IBD patients suffering from CD increased (P < 0.001), time from onset of symptoms to diagnosis of CD decreased (P = 0.001), and median age at diagnosis of UC increased (P < 0.01). The prevalence of upper gastrointestinal involvement and pure colonic CD varied significantly between cohorts. UC patients diagnosed in the 1990s had a higher prevalence of proctitis, received more medications, and had a milder initial disease course than did previous patients. The surgery rate decreased significantly in CD but not in UC. The risk of CRC in IBD was close to expected over the entire period, whereas the mortality of patients with CD increased (overall SMR, 1.31; 95% CI, 1.07–1.60). Conclusions: Despite variations in the presentation and initial course of IBD during the last 5 decades, its long‐term prognosis remained fairly stable. Treatment of IBD changed recently, and future studies should address the effect of these changes on long‐term prognosis.

Incidence and Prevalence of Crohn's Disease in the County of Copenhagen, 1962-87: A Sixfold Increase in Incidence

The incidence of Crohns disease increased sixfold from 1962 to 1987 in the county of Copenhagen. The mean annual incidence for 1979-87 was 4.1 per 10(5) inhabitants. The increase was found equally in both sexes, with an approximately 40% higher incidence in women. The maximal incidence was found in the 15- to 24-year age group, being 12.8 per 10(5) per year for women and 6.0 per 10(5) per year for men, as mean of the period 1979-87. The prevalence at the end of the study was 54 per 10(5) inhabitants, 46 per 10(5) in men and 63 per 10(5) in women. The clinical appearance of the disease at the time of diagnosis was remarkably similar during the study period with regard to both the localization of disease and the clinical symptoms and signs. A slightly higher percentage of the patients, however, were in high disease activity at diagnosis in the later years of the study.

Incidence and Prevalence of Ulcerative Colitis in Copenhagen County from 1962 to 1987

The incidence of ulcerative colitis was estimated during the period 1962 to 1987 in the county of Copenhagen. Within this area of approximately 550,000 inhabitants, 1161 patients were diagnosed. The mean annual incidence for the period was 8.1 per 10(5) inhabitants. There were significant increases in incidence in the early 1970s and in the early 1980s, both of which were followed by significant decreases. A bimodal age distribution was found in men, with incidence peaks in young adult life and late in life. In women a peak incidence was found in the young adult age group. The interval from onset of symptoms to diagnosis in terms of years remained unchanged over the period, with a median of 1 year (range, 0-37 years). The extent of disease at diagnosis was total colon in 18% of the patients, a substantial part of the colon in 36%, and distal colon in 44%--with no changes during the study period. The distribution of different localizations did not differ among age groups except for a tendency towards more extensive disease in young patients, below 20 years of age. The disease activity in the 1st year was fulminant in 9.1% of the cases, moderate to high in 70.7%, and low in 20.2%, with a tendency towards higher activity in patients diagnosed late in the study period. The prevalence of ulcerative colitis increased steadily during the study period, reaching a value at the end of the study (31 December 1987) of 161 per 10(5) inhabitants.

Long-term risk of cancer in ulcerative colitis: A population-based cohort study from Copenhagen County

BACKGROUND & AIMS Ulcerative colitis (UC) is associated with an increased risk for colorectal cancer (CRC) and possibly also increased risk for cancers outside the intestinal tract. We followed-up a population-based cohort of 1160 patients with UC diagnosed in Copenhagen County between 1962 and 1987 for up to 36 years to analyze the overall and site-specific cancer risk. METHODS Observed vs. expected cancers were presented as standardized morbidity ratio (SMR) with 95% exact confidence intervals (CI) calculated by using individual person-years at risk and sex- and age-specific incidence rates for the Danish background population in 1995. RESULTS The cohort was followed-up for a median of 19 years, or 22,290 person-years. A total of 124 malignancies were observed compared with 139.85 expected (SMR, .89; 95% CI, .74-1.07). The observed number of CRCs was almost exactly equal to expected: 13 cases vs. 12.42 (SMR, 1.05; 95% CI, .56-1.79). The cumulative probability of CRC was .4% by 10 years, 1.1% by 20 years, and 2.1% by 30 years of disease. Among men, melanoma was increased (SMR, 3.45; 95% CI, 1.38-7.10); otherwise, no increased risk for cancer could be detected. No hepatobiliary cancers and no increased risk for lymphoma or leukemia were found. CONCLUSIONS Neither the overall cancer risk, nor the CRC risk, were increased in this population-based cohort after a median of 19 years of follow-up evaluation. An active surgical approach in medical treatment failures and long-term use of 5-aminosalicylic acid (5-ASA) as relapse prevention may explain this remarkable result.

Inflammatory Bowel Diseases with Onset in Childhood: Clinical Features, Morbidity, and Mortality in a Regional Cohort

BACKGROUND AND METHODS In a geographically derived incidence cohort diagnosed from 1962 to 1987 we identified all patients with onset of inflammatory bowel diseases (IBD) before the age of 15 years, to describe the clinical course and to compare the course and prognosis with those of adult-onset IBD. RESULTS The mean incidence of IBD among children below 15 years was 2.2/10(5), 2.0 for ulcerative colitis (UC) and 0.2 for Crohns disease (CD). At diagnosis children with UC had more extensive disease than adults (P < 0.05). Abdominal pain was also more frequent. The cumulative colectomy probability was 6% after 1 year and 29% after 20 years, not different from that of adults. More females underwent colectomy. With regard to disease activity, apart from the year of diagnosis 60-70% of UC patients were in remission in each of the first 10 years of disease; for CD about 50% were in remission. One patient with UC developed carcinoma of the sigmoid colon. Time between onset of UC and development of carcinoma was 12 years. For CD no differences in clinical appearance at diagnosis and course between children and adults were found in relationship to surgery. No deaths occurred among CD patients. Three CD patients were severely growth-retarded already at diagnosis. CONCLUSION The incidence of IBD is low in childhood. At diagnosis children with UC have more widespread disease than adults. Childhood-onset CD does not differ in clinical presentation, disease course, or prognosis from adult-onset CD. However, growth retardation is a problem among male CD patients.

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.