Increased risk of intestinal cancer in Crohn's disease: a meta-analysis of population-based cohort studies

OBJECTIVES: The risk of intestinal malignancy in Crohn's disease (CD) remains uncertain since risk estimates vary worldwide. The global CD population is growing and there is a demand for better knowledge of prognosis of this disease. Hence, the aim of the present study was to conduct a meta-analysis of population-based data on intestinal cancer risk in CD. METHODS: The MEDLINE search engine and abstracts from international conferences were searched for the relevant literature by use of explicit search criteria. All papers fulfilling the strict inclusion criteria were scrutinized for data on population size, time of follow-up, and observed to expected cancer rates. STATA meta-analysis software was used to perform overall pooled risk estimates (standardized incidence ratio (SIR), observed/expected) and meta-regression analyses of the influence of specific variables on SIR. RESULTS: Six papers fulfilled the inclusion criteria and reported SIRs of colorectal cancer (CRC) in CD varying from 0.9 to 2.2. The pooled SIR for CRC was significantly increased (SIR, 1.9; 95% CI 1.4-2.5), as was the risk for colon cancer separately (SIR, 2.5; 95% CI 1.7-3.5). Regarding small bowel cancer, five studies reported SIRs ranging from 3.4 to 66.7, and the overall pooled estimate was 27.1 (95% CI 14.9-49.2). CONCLUSIONS: The present meta-analysis of intestinal cancer risk in CD, based on population-based studies only, revealed an overall increased risk of both CRC and small bowel cancer among patients with CD. However, some of the available data were several decades old, and future studies taking new treatment strategies into account are required.     

Adalimumab for Crohn's disease: Long-term sustained benefit in a population-based cohort of 438 patients

Background and aimsAdalimumab is an effective therapy for induction and maintenance of Crohn's disease. However, results in clinical trials don't necessarily reflect daily clinical practice. Therefore, we assessed real-life long-term clinical response to adalimumab in a large population-based cohort and identified clinical parameters affecting responseMethodsAll consecutive patients in North-Holland that started adalimumab between 2003 and 2011 were included, of which medical charts were reviewed. Response to induction therapy was assessed after 3 months. Sustained benefit of maintenance therapy was calculated from Kaplan–Meier survival tables depicting ongoing adalimumab treatment. Regression analyses were performed to identify factors predicting response to adalimumab therapy.ResultsIn total 438 Crohn's patients started adalimumab with 92.5% response to the induction phase. After 1 year 83.3% showed sustained benefit of maintenance treatment, followed by 74.0% after 2 years. Nevertheless, one third of patients were in steroid-free remission at the end of their follow-up. Response to induction was negatively affected by longer disease duration (OR 1.05; p < 0.01) and strictures (OR 3.73; p = 0.04). Increased CRP levels predicted higher rates of initial response (OR 0.31; p < 0.01). Concomitant thiopurines in the first 6 months of adalimumab treatment decreased the risk to fail maintenance therapy (HR 0.69, p = 0.05). Previous infliximab therapy did not affect response to adalimumab, however dose escalation was more often deemed necessary (p < 0.01).ConclusionAdalimumab was successful in the majority of patients, with 10% loss of response per subsequent year. Concomitant thiopurines might improve adalimumab maintenance treatment.     

The prevalence of gallstone disease in a defined cohort of patients with Crohn's disease

OBJECTIVE: Crohn's disease (CD) is associated with a high prevalence of gallstone disease but the relative risk has not been completely established. Ileal disease or resection have been considered as contributing factors to the increased risk. The aim of this study was to evaluate the prevalence of gallstone disease in a defined cohort of CD patients, to evaluate possible risk factors, and to evaluate the relative risk compared with the general population. METHODS: All inhabitants in Stockholm County born in 1933-1935 or 1953-1955, with CD diagnosed between 1955-1989 and not having had a previous cholecystectomy, were invited for an ultrasonography of the gallbladder. The prevalence of gallstone disease was related to disease extent, previous intestinal resections, age, and gender. The relative risk of developing gallstones was calculated using a recent study of gallstone disease in general, with similar age groups as controls. RESULTS: We found that 26.4% had gallstone disease (relative risk [RR] = 1.8; 95% confidence interval [CI], 1.2-2.7). The number of previous intestinal resections was the only significant risk factor. There was no significant difference in gallstone disease between gender (28.2% vs 24.1%) or age (34% vs 21.8%). CONCLUSIONS: Patients with Crohn's disease, regardless of gender and age, have almost a doubled risk of developing gallstone disease compared with the general population. Circumstances related to laparotomy may contribute to the increased risk. The lack of association between the disease extent and the site of previous intestinal resection, together with a previous finding of normal cholesterol saturation of the bile in patients with CD, indicate that these patients may develop pigment stones rather than cholesterol stones.     

Crohn's disease patient characteristics in a tertiary referral center: comparison with patients from a population-based cohort

OBJECTIVES: Data on the clinical presentation, effects of therapy and prognosis of patients with Crohn's disease are often based on patients from specialized referral centers. We assessed the extent of the selection based on the clinical and demographic characteristics. METHODS: All patients with Crohn's disease presenting to the University Hospital of Regensburg (Medical Department) were analyzed retrospectively with respect to demographic and disease specific characteristics. Only patients diagnosed <2 years before presentation were included in the main analysis. The original data from a population-based, prospectively assembled incidence cohort were available for comparison (EC-IBD, northern centers only, n=475). Age at diagnosis, disease location and behavior were categorized according to the Vienna classification. Differences were examined using chi-square tests. MAIN RESULTS: At the referral center, 394 patients were treated within a 5-year period. Of these, 116 patients fulfilled the inclusion criteria for the comparative analysis. Sixteen percent of the referral patients were diagnosed at age 40 or older, as compared with 32% in the population-based group (P<0.004). The distribution of disease location, sex, smoking behavior and positive family history was similar in both groups. Among the referral patients, more had fistulas (39% versus 20%, P<0.001). Also, more patients were receiving steroids (49% versus 27%) or other immunosuppressive therapy (12% versus 4%). The selection effects increase with duration of disease. CONCLUSIONS: Patients with late onset of disease, inflammatory only disease behavior and no need for immunosuppression are under-represented at a tertiary referral center.     

Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn's disease

BACKGROUND: The sensitivity of assays for antineutrophil cytoplasmic antibody (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA), and antipancreatic antibody (PAB) in different laboratories is unknown. Likewise, the sensitivity and diagnostic usefulness of these assays in patients with inflammatory bowel disease (IBD) in the community is unknown. METHODS: An incidence cohort of 290 patients with IBD were offered participation in the study. Blood was obtained from 162 patients (56%) (83 with ulcerative colitis, 79 with Crohn's disease) who agreed to participate. ANCA was determined in five laboratories. ASCA in two laboratories, and PAB in one laboratory. RESULTS: In ulcerative colitis, the sensitivity of ANCA determined in five laboratories varied widely, ranging from 0-63%. In Crohn's disease, the sensitivity of ASCA determined in two laboratories did not vary significantly, ranging from 39-44%; and the sensitivity of PAB determined in one laboratory was 15%. The optimal diagnostic usefulness was obtained from one laboratory where the positive predictive values of a positive ANCA assay combined with a negative ASCA assay for ulcerative colitis, and a negative ANCA combined with a positive ASCA for Crohn's disease, were 75% and 86%, respectively. CONCLUSIONS: In patients with IBD, the sensitivity of ANCA varied widely in different laboratories, whereas the prevalence of ASCA was similar. The positive predictive values of the ANCA assay combined with the ASCA assay for ulcerative colitis and Crohn's disease are high enough to be clinically useful.     

The risk of developing Crohn's disease after an appendectomy: a population-based cohort study in Sweden and Denmark

BACKGROUND: The relationship between appendectomy and Crohn's disease is controversial. A Swedish-Danish cohort study was conducted to assess the risk of developing Crohn's disease after an appendectomy. METHODS: 709 353 appendectomy patients in Sweden (since 1964) and Denmark (since 1977) were followed for first hospitalisations for Crohn's disease to 2004. Standardised incidence ratios (SIR) served as relative risks. RESULTS: Overall, 1655 Crohn's disease cases were observed during 11.1 million person-years of follow-up. Whereas appendectomy before the age of 10 years was not associated with the risk of Crohn's disease (SIR 1.00; 95% CI 0.80-1.25), the overall SIR of developing Crohn's disease was 1.52 (95% CI 1.45-1.59), being highest in the first 6 months (SIR 8.69; 95% CI 7.68-9.84). SIR diminished rapidly thereafter, with the risk of Crohn's disease reaching background levels after 5-10 years for Crohn's disease overall, as well as for Crohn's ileitis, ileocolonic Crohn's disease, Crohn's colitis and other/unspecified Crohn's disease. A long-term increased risk of Crohn's disease up to 20 years after the appendectomy was seen only in appendectomy patients without appendicitis or mesenteric lymphadenitis. CONCLUSION: The transient increased risk of Crohn's disease after an appendectomy is probably explained by diagnostic bias.     

Mortality and causes of death in Crohn's disease: follow-up of a population-based cohort in Copenhagen County,Denmark

BACKGROUND & AIMS: A population-based cohort comprising 374 patients with Crohn's disease diagnosed in Copenhagen County between 1962 and 1987 was observed until 1997 for mortality and causes of death. METHODS: Observed deaths were compared with expected deaths calculated by using individually computed person-years at risk and 1995 rates for Copenhagen County. Cumulative survival curves were calculated. RESULTS: A total of 84 deaths occurred vs. 67 expected (standardized mortality ratio [SMR], 1.3; 95% confidence interval [CI], 1.01-1.56): 45 women vs. 31.8 expected (SMR, 1.4; 95% CI, 1.03-1.89) and 39 men vs. 35.2 expected (SMR, 1.1; 95% CI, 0.79-1.51). An excess mortality was observed among women observed for 21-25 years after diagnosis. Among women aged <50 years at diagnosis, 25 deaths were observed vs. 7.3 expected (SMR, 3.42; 95% CI, 2.21-5.04). Fourteen (31%) of the observed deaths among women and 8 (21%) among men had a certain or possible connection to Crohn's disease. Among causes of death unrelated to Crohn's disease, an overrepresentation of gastrointestinal diseases, infections, and diseases of the urinary organs was observed. CONCLUSIONS: An increased mortality was observed late in the disease course that was most pronounced among women younger than 50 years at diagnosis and was attributed to death associated with severe Crohn's disease.     

Familial aggregation in Crohn's disease and ulcerative colitis in a Norwegian population-based cohort followed for ten years

Background and aimsTo explore the change in risk among 1st degree relatives of ulcerative colitis (UC) and Crohn's disease (CD) for development of concordant disease in an incidence cohort followed for ten years. Furthermore, we wanted to compare familial and sporadic cases regarding clinical characteristics and the course of the disease.MethodsThis population-based study included 421 patients with UC and 197 with CD enrolled from 1990 to 1994. Clinical characteristics and the number of 1st degree relatives of the patients were recorded continuously during ten years.ResultsAge at diagnosis in CD patients (OR = 0.95, 95% CI: 0.93–0.98) and cumulative relapse rate in UC patients (OR = 4.91, 95% CI = 1.16, 20.75) were significantly associated to familial clustering. Based on the calculated population prevalence of CD (262/100 000) and UC (505/100 000), the age-adjusted risk for development of concordant disease was 25.9 and 8.6 among siblings and parents of CD, respectively. In UC, the corresponding risks were 8.6 and 1.5. In the course of ten years the increase in risk was observed only among siblings (28%) and parents (97%) of UC, in contrast to no increase in CD. Moreover, the concordance for UC was high in three generations.ConclusionsOur study confirmed the importance of genetic influence on the development of CD. Within an observation period of ten years, the increased concordance and relapse rate in familial UC, might point to a larger genetic component in UC than previously suggested.     

Clinical course and costs of care for Crohn's disease: Markov model analysis of a population-based cohort.

BACKGROUND & AIMS: Crohn's disease results in substantial morbidity and high use of health services. The aim of this study was to describe the lifetime clinical course and costs of Crohn's disease in a 24-year population-based inception cohort of patients with Crohn's disease in Olmsted County, Minnesota. METHODS: Disease states were defined by medical and surgical treatment. A Markov model analysis calculated time in each disease state and present value of excess lifetime costs in comparison with an age- and sex-matched cohort. RESULTS: For a representative patient, projected lifetime costs were $39,906 per patient using median charges and $125,404 using mean charges. There were 29.1 years (63% of total) without medications. There were 12.7 years (27%) on aminosalicylate therapy, generating $11,467 (29%) in charges, and 3.2 years (7%) on corticosteroid or immunosuppressive therapy, generating $5147 (13%) in charges. Surgery generated $17,526 (44%) in charges. CONCLUSIONS: Most of the clinical course is spent in remission, either medical or surgical. Aminosalicylate therapy accounts for 29% of the costs of care. Surgery has the highest charges but the longest remissions. Treatment strategies that induce remission in mild disease and maintain remission with lower-cost maintenance therapy will have the largest effect on patient outcomes and costs.     

Osteopenia and osteoporosis in children.

The purpose of this paper is to review the normal physiologic processes of skeletal accretion, abnormalities that may occur in children with chronic illnesses, and therapeutic maneuvers that the clinician may be able to employ to prevent or partially correct abnormalities of skeletal growth. Skeletal maturation in children is dependent upon bone formation exceeding resorption, whereas in adults these two fundamental processes of homeostasis are closely balanced. Skeletal growth is effectively completed at the end of the period of adolescent growth acceleration with closure of the epiphyses. An important determinant of future fracture risk and osteoporosis is the peak bone mass achieved during this second decade of life. If the hereditarily determined peak bone mass is not established during that time, the patient will enter young adulthood with osteopenia, an increased fracture risk, and accelerated postmenopausal osteoporosis or involutional osteoporosis. Thus osteopenia and osteoporosis have their origins in childhood and adolescence.     

Incidence of Mycobacterium avium subspecies paratuberculosis in a population-based cohort of patients with Crohn's disease and control subjects

OBJECTIVE:  To define the incidence of Mycobacterium avium subspecies paratuberculosis (MAP) in patients with Crohn's disease (CD) and in control subjects.
METHODS:  Blood samples from 361 CD patients from a previously described population-based inflammatory bowel disease (IBD) cohort and 200 blood donor controls, of known NOD2 genotype, were screened by PCR for MAP-specific IS900 DNA. These results were correlated with NOD2 genotype.
RESULTS:  The PCR assay was capable of detecting 20 fg of purified MAP DNA, equivalent to roughly 100 MAP cells/mL of blood. MAP-specific IS900 DNA was detected in 33.8% of CD cases and 21.5% of controls (OR 1.86, 95% CI 1.247–2.785, P = 0.002). All study participants were genotyped for the NOD2 mutations 2104C>T (R702W), 2722G>C (G908R), and 3020insC (1007fs). Carriage of one or two NOD2 mutations was not associated with a significantly higher risk of CD (OR 0.75, 95% CI 0.465–1.207, P = 0.234). No significant association was seen in the CD cohort for carriage of one or two NOD2 mutations and MAP status (OR 0.883, 95% CI 0.494–1.579, P = 0.675).
CONCLUSIONS:  Screening peripheral blood using IS900 PCR indicated that MAP DNA could be detected in a significant proportion of CD cases from a large population-based cohort, and also, in control subjects. The over-representation of MAP DNA in CD suggests either a role or a probable role for MAP in the etiology of CD.     

Mortality in inflammatory bowel disease: a population-based cohort study

BACKGROUND & AIMS: There is no consensus regarding any increase in mortality with inflammatory bowel disease (IBD). In general, previous studies were not contemporary and were unable to correct for likely confounders. We have performed a large cohort study to examine contemporary IBD related mortality in the United Kingdom. METHODS: We selected subjects within the General Practice Research Database with a coded diagnosis of inflammatory bowel disease and up to 5 matched controls for each. We derived the date of recorded deaths and information on smoking and a variety of medical conditions. We calculated both the absolute risk of death and the relative risk as a hazard ratio corrected for available confounders by Cox regression. RESULTS: We included 16,550 IBD cases with 1047 deaths and 82,917 controls with 3758 deaths. The mortality rate was 17.1 per 1000 person-years overall for IBD cases and 12.3 for controls; this difference was greatest in the elderly. Conversion of these figures to hazard ratios by Cox regression gave hazard ratios of 1.54 (1.44-1.65) for all IBD, 1.44 (1.31-1.58) for ulcerative colitis (UC), and 1.73 (1.54-1.96) for Crohn's disease. The greatest hazard ratio for UC was among the 40-59-year age group (1.79 [1.42-2.27]) and for Crohn's disease among 20-39-year-olds (3.82 [2.17-6.75]). CONCLUSIONS: IBD is associated with an overall small increase in mortality rate greatest in relative terms in younger subjects but in absolute terms in the elderly.