Crohn's disease in Olmsted County, Minnesota, 1940–1993: Incidence, prevalence, and survival

Background & Aims: Many centers worldwide have reported an increased incidence of Crohn's disease, but population-based data in North America are sparse. We studied the incidence and prevalence of Crohn's disease in Olmsted County, Minnesota, and examined temporal trends in incidence and survival. Methods: Residents diagnosed with Crohn's disease between 1970 and 1993 were incidence cases, and residents with Crohn's disease who were alive on January 1, 1991, were prevalence cases. Cases from previous studies were reconfirmed. Rates were adjusted using 1990 U.S. Census figures for whites. Incidence trends were evaluated with a Poisson regression model. Survival from diagnosis was compared with that expected for U.S. north-central whites. Results: Between 1940 and 1993, 225 incidence cases were identified, for an adjusted incidence rate of 5.8 per 100,000 person-years. On January 1, 1991, there were 145 residents with Crohn's disease, an adjusted prevalence rate of 133 per 100,000, 46% higher than that seen in 1980. Incidence rates before 1964 were significantly lower than those of 1989–1993. Observed survival was less than expected (P = 0.007). Conclusions: The incidence of Crohn's disease has stabilized since the 1970s at a rate higher than that seen previously. Prevalence has increased by 46% since 1980. Overall survival is slightly decreased.GASTROENTEROLOGY 1998;114:1161-1168     

Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial

BACKGROUND & AIMS: No therapy has been shown to reliably prevent the evolution of postoperative recurrence of Crohn's disease. The aim of the current trial was to compare 6-mercaptopurine (6-MP) and mesalamine with placebo for the prevention of clinical, endoscopic, and radiographic recurrence of Crohn's disease after resection and ileocolic anastomosis. METHODS: Five centers randomized 131 patients to receive 6-MP (50 mg), mesalamine (3 g), or placebo daily in a double-blind, double-dummy trial. Patients had clinical assessments at 7 weeks and then every 3 months; colonoscopy at 6, 12, and 24 months; and small bowel series at 12 and 24 months. End points were clinical, endoscopic, and radiographic recurrence rates at 24 months. RESULTS: Clinical recurrence rates (intent to treat) by life-table analysis at 24 months were 50% (95% confidence interval [CI], 34%-68%), 58% (95% CI, 41%-75%), and 77% (95% CI, 61%-91%) in patients receiving 6-MP, mesalamine, and placebo, respectively. Endoscopic recurrence rates were 43% (95% CI, 28%-63%), 63% (95% CI, 47%-79%), and 64% (95% CI, 46%-81%), and radiographic recurrence rates were 33% (95% CI, 19%-54%), 46% (95% CI, 29%-66%), and 49% (95% CI, 30%-72%), respectively. 6-MP was more effective than placebo ( P < 0.05) at preventing clinical and endoscopic recurrence over 2 years. Patient withdrawals resulted in 69% of the study population evaluable for the clinical recurrence end point. CONCLUSIONS: 6-MP, 50 mg daily, was more effective than placebo at preventing postoperative recurrence of Crohn's disease and should be considered as a maintenance therapy after ileocolic resection.     

Long-term fracture risk in patients with Crohn's disease: a population-based study in Olmsted County,Minnesota

BACKGROUND & AIMS: Osteoporosis is common in patients with Crohn's disease, but less is known about their risk of actual fractures. METHODS: The medical records of all 238 Olmsted County, Minnesota, residents diagnosed with Crohn's disease between 1940 and 1993 were reviewed for evidence of subsequent fractures compared with a control group of county residents matched by age and sex. The risk ratio of fracture in patients relative to controls was estimated using the Cox proportional hazards regression model. The cumulative incidence of fracture following diagnosis was estimated using the Kaplan-Meier method. RESULTS: Sixty-three patients had 117 different fractures. The cumulative incidence of any fracture from the time of diagnosis onward was 36% at 20 years versus 32% in controls (P = 0.792). Compared with controls, the overall risk ratio for any fracture was 0.9 (95% confidence interval [CI], 0.6-1.4), whereas the relative risk for an osteoporotic fracture was 1.4 (95% CI, 0.7-2.7). The risk ratio for thoracolumbar vertebral fracture was 2.2 (95% CI, 0.9-5.5). Cox proportional hazards regression identified only age as a significant clinical predictor of fracture risk (hazard ratio per 10-year increase in age, 1.3; 95% CI, 1.1-1.5). Specifically, use of corticosteroids and surgical resection did not predict risk of fracture among these unselected patients with Crohn's disease from the community. CONCLUSIONS: In this population-based inception cohort of patients with Crohn's disease, the risk of fracture was not elevated relative to age- and sex-matched controls.     

Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989.

No reports of the incidence rates for primary systemic amyloidosis (AL) have come to our attention. Records of all residents of Olmstead County, Minnesota, with a diagnosis of amyloidosis were obtained from the Mayo Clinic and its affiliated hospitals, as well as other medical groups that might have seen local patients for the period January 1, 1950 to December 31, 1989. Twenty-one patients fulfilled the criteria for the diagnosis of AL. The median age was 73.5 years, and 62% were men. In all but one patient the diagnosis was made ante mortem. The clinical data of the 21 patients were similar to those referral patients with AL seen at Mayo Clinic. Immunohistochemical stains were positive for monoclonal light chains in the amyloid deposits in 15 of the 21 cases. In six cases, tissue was not available for immunohistochemical studies. Three of the six patients without immunohistochemical stains had a free monoclonal lambda light chain in the urine, and the other three had a monoclonal serum protein. Immunoelectrophoresis/immunofixation detected a monoclonal (M)-protein in the serum of 16 of 17 patients tested. A monoclonal light chain was found in the urine of 10 of 15 patients. The overall sex- and age-adjusted rate per million person-years was 6.1 from 1950 to 1969 and 10.5 from 1970 to 1989. The similarity of these rates suggests no significant increase over time.     

A randomized, double-blind, controlled withdrawal trial in Crohn's disease patients in long-term remission on azathioprine

BACKGROUND & AIMS: An open study reported that patients with Crohn's disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is discontinued. To confirm this observation, we performed a multicenter, double-blind, noninferiority withdrawal study. METHODS: Patients who were in clinical remission on azathioprine for > or = 42 months were randomized to continue azathioprine or to receive an equivalent placebo for 18 months. The primary end point was clinical relapse at 18 months. RESULTS: Forty patients were randomly assigned to receive azathioprine and 43 to receive placebo. Characteristics of patients at entry were similar in the 2 study groups. At 18 months, 3 patients had a relapse in the azathioprine group, and 9 had a relapse in the placebo group. Kaplan-Meier estimates of the relapse rate at 18 months were 8% +/- 4% and 21% +/- 6%, respectively. The hypothesis that placebo was inferior to azathioprine was not rejected (P = .195). Among the baseline variables, C-reactive protein level > 20 mg/L, time without steroids < 50 months, and hemoglobin level < 12 g/dL were found to be predictive of relapse in the multivariate analysis. CONCLUSIONS: This study shows that azathioprine withdrawal is not equivalent to continued therapy with azathioprine for maintenance of remission in patients with Crohn's disease who have been in remission on azathioprine for > or = 3.5 years. Thus, azathioprine maintenance therapy should be continued beyond 3.5 years.     

Epidemiologic aspects of Crohn's disease: a population based study in Olmsted County, Minnesota, 1943-1982.

The overall age and sex adjusted incidence of Crohn's disease among Olmsted County, Minnesota, residents was 4.0 per 100,000 person-year in the period 1943-1982. Ileitis, ileocolitis, and colitis each accounted for about one third of the 103 incidence cases. Incidence rates were greater in woman than men, were higher in the urban portions of the county, and rose over time. Overall, the natural history of Crohn's disease in the community may be milder than that reported for patients at referral centres, as over half of all patients had no complications and only a third required surgery for Crohn's disease. Only one developed adenocarcinoma of the colon (relative risk = 2.0, NS). Survival was relatively unimpaired for the cohort, but Crohn's disease may have played a role in half of the deaths. The prevalence of Crohn's disease was 90.5/100,000 population on 1 January 1980.     

Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo-controlled trial

BACKGROUND & AIMS: Crohn's disease almost inevitably recurs after ileocolonic resection, and effective prophylactic therapy has not been identified. We investigated the efficacy and safety of ornidazole, a nitroimidazole antibiotic, for the prevention of clinical recurrence of Crohn's disease after curative ileocolonic resection in a placebo-controlled double-blind clinical trial. METHODS: Eighty patients were randomized to ornidazole 1 g/day or placebo started within 1 week of resection and continued for 1 year. The primary end point was the proportion of patients with clinical recurrence at 1 year. Secondary end points were endoscopic recurrence at 3 months and 12 months after resection. RESULTS: Two patients in the ornidazole group withdrew consent and were not dosed. Ornidazole significantly reduced the clinical recurrence rate at 1 year from 15 of 40 (37.5%) patients in the placebo group to 3 of 38 (7.9%) patients in the ornidazole group (Fisher exact test, 8.03; P = .0046; odds ratio, 0.14; 95% confidence interval, 0.037-0.546). Ornidazole reduced endoscopic recurrence at 12 months from 26 of 33 (79%) in the placebo group to 15 of 28 (53.6%) in the ornidazole group (chi2 , 4.37; P = .037; odds ratio, 0.31; 95% confidence interval, 0.10-0.94). Endoscopic recurrence at 3 and 12 months predicted clinical recurrence. Significantly more patients in the ornidazole group dropped out from the study because of side effects (P = .041). CONCLUSIONS: Ornidazole 1 g/day is effective for the prevention of recurrence of Crohn's disease after ileocolonic resection.     

Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota, 1940-2000

BACKGROUND: We previously reported that the prevalence of Crohn's disease (CD) and ulcerative colitis (UC) in Olmsted County, Minnesota, had risen significantly between 1940 and 1993. We sought to update the incidence and prevalence of these conditions in our region through 2000. METHODS: The Rochester Epidemiology Project allows population-based studies of disease in county residents. CD and UC were defined by previously used criteria. County residents newly diagnosed between 1990 and 2000 were identified as incidence cases, and persons with these conditions alive and residing in the county on January 1, 2001, were identified as prevalence cases. All rates were adjusted to 2000 US Census figures for whites. RESULTS: In 1990-2000 the adjusted annual incidence rates for UC and CD were 8.8 cases per 100,000 (95% confidence interval [CI], 7.2-10.5) and 7.9 per 100,000 (95% CI, 6.3-9.5), respectively, not significantly different from rates observed in 1970-1979. On January 1, 2001, there were 220 residents with CD, for an adjusted prevalence of 174 per 100,000 (95% CI, 151-197), and 269 residents with UC, for an adjusted prevalence of 214 per 100,000 (95% CI, 188-240). CONCLUSION: Although incidence rates of CD and UC increased after 1940, they have remained stable over the past 30 years. Since 1991 the prevalence of UC decreased by 7%, and the prevalence of CD increased about 31%. Extrapolating these figures to US Census data, there were approximately 1.1 million people with inflammatory bowel disease in the US in 2000.     

Infliximab in fistulizing Crohn's disease

The treatment of fistulizing CD has evolved greatly in the last 15 years, largely caused by improvements in medical therapy. Tables 2 and 3 summarize all published controlled and uncontrolled trials of immunomodulator and biologic therapy for the treatment of Crohn's fistulae. The advent of immunomodulators and anti-TNF-alpha agents has transformed the treatment of Crohn's fistulae from almost exclusively surgical to placing a much larger emphasis on medical therapy, either as initial therapy alone, with surgery reserved for refractory cases, or in combination with surgery from the start. For this reason, surgeons and gastroenterologists must work in concert to provide the best care for each patient. Proper fistula management also relies heavily on accurate diagnosis, especially defining the anatomy of the fistula, ascertaining whether abscess formation is present, and determining the location and extent of intestinal inflammation.     

The risk of missed gastroesophageal cancer diagnoses in users and nonusers of antisecretory medication

BACKGROUND & AIMS: Some patients with early gastroesophageal cancer may appear to "heal" because of antisecretory medication, but the risk of a missed diagnosis is unknown. The aim of the study was to estimate the incidence of gastroesophageal cancer with or without pre-endoscopic treatment with antisecretory medication. METHODS: We extracted data on use of endoscopies, gastroesophageal cancer diagnoses, death, migration, and use of antisecretory medication (H(2) blockers and proton pump inhibitors) from 5 population-based registries covering 1974-2002. We included all citizens in Funen County (population, 470,000) who between 1993 and 2002 were investigated by endoscopy for the first time. The patients were followed up until death, emigration, or the end of the study period. RESULTS: Among 27,829 patients with a first endoscopy (mean age, 56 years; 48% male, 115,804 person-years of follow-up), 461 had gastroesophageal cancer diagnosed at the first endoscopy and 52 were diagnosed during a median follow-up of 2.7 years after the first endoscopy. The incidence during follow-up was similar to the background population (standardized incidence ratio, 1.24; 95% confidence interval, 0.81-1.91), increased with age, and was higher in male patients. The incidence of gastroesophageal cancer during follow-up was 46 per 100,000 person-years in users of antisecretory medication the last 180 days before the first endoscopy compared with 44 per 100,000 person-years in nonusers (age and sex standardized difference, 4 per 100,000 person-years; 95% confidence interval, -14 to 22). CONCLUSIONS: Very few cancers are missed at endoscopy. The risk seems similar in users and nonusers of antisecretory medication before endoscopy.     

Treatment of fistulizing Crohn's disease

The primary goals of the clinician in the treatment of fistulizing Crohn's disease (CD) include (1) defining the anatomy of the fistula, (2) draining any associated infectious material, (3) eradicating the fistulous tract through medical or surgical therapies, and (4) preventing recurrence of fistulas. Evaluation and therapeutic decisions require close collaboration between the gastroenterologist and surgeon. Appropriate evaluation should include identification of septic complications, delineation of the fistulous tract including the origin and terminus of the fistula, and determination of the extent of bowel involvement with active CD. Drainage of abscesses and control of septic complications through the placement of drains or setons is essential. Conservative therapy with avoidance of sphincter muscle-cutting procedures is the standard approach. The appropriate approach to asymptomatic patients is uncertain because there are little data to indicate if treatment alters the natural course of disease.     

Treatment of fistulizing Crohn's disease

The appropriate treatment of patients with fistulas in the setting of Crohn's disease requires a knowledge of the specific medical and surgical literature of fistulizing Crohn's. The patient with symptomatic fistulizing Crohn's disease may respond differently to specific medical therapy than a patient with symptomatic obstructing Crohn's disease. Certain medications that are useful for the treatment of patients with obstructive Crohn's disease may not be helpful in the treatment of fistulas in patients with fistulizing Crohn's disease (e.g., corticosteroids and mesalamine); in fact, some medications are believed to be detrimental (e.g., corticosteroids). Few studies have been performed to assess the efficacy of specific medications on fistulas directly. To date, there has been only one published prospective randomized controlled trial that was designed to assess the efficacy and safety of a specific medication on fistulas in patients with Crohn's disease; it showed clinical efficacy over placebo in a statistically significant manner. The judicious use of surgery remains an integral part of the management of certain presentations of fistulizing Crohn's disease, and the appropriate integration of surgical and medical therapy is of paramount importance in the management of these patients. This review provides an overview of pertinent medical and surgical literature as it pertains to management of patients with fistulizing Crohn's disease.     

Long-term natural history of Crohn's disease

Crohn's disease is a chronic inflammatory granulomatous process that usually involves different sites in the intestinal tract. Genetic and environmental factors are thought to play a role in its etiology and pathogenesis.The disorder has a heterogeneous clinical expression and data from tertiary care settings have documented its female predominance, occasional familial nature,and high rate of stricture formation and penetrating disease. It may appear from early childhood to late adulthood, although over 80% are currently diagnosed before age 40 years, usually with terminal ileal and colonic involvement. Several studies have now shown differences in phenotypic clinical expression depending on the initial age at diagnosis, with pediatric-onset disease being more severe and more extensive with more involvement of the upper gastrointestinal tract compared to adult-onset disease. In addition, longterm studies from these tertiary care settings have documented that the disorder may evolve with time into a more complex disease with stricture formation and penetrating disease complications (i.e. fistula and abscess). Although prolonged remission with no evidence of inflammatory disease may occur, discrete periods of symptomatic and active granulomatous inflammatory disease may re-appear over many decades. Long-term studies on the natural history have also suggested that discrete events (or agents) may precipitate this granulomatous inflammatory process.     

A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn's disease

BACKGROUND & AIMS: Placebo-controlled, randomized clinical trials (PC-RCTs) are commonly used to assess therapies for Crohn's disease (CD). Knowledge of the placebo rates of remission and response and understanding of design factors that influence these rates is important for designing future clinical trials evaluating pharmacotherapy of CD. The aims of this study were to estimate rates of remission and response in patients with active CD receiving placebo and to identify factors influencing these rates. METHODS: We performed a systematic review and meta-analysis of PC-RCTs evaluating therapies for active CD identified from MEDLINE from 1966 to 2001. RESULTS: The pooled estimates of the placebo rates of remission and response were 18% (95% confidence interval, 14%-24%; range, 0%-50%) and 19% (95% confidence interval, 13%-28%; range, 0%-46%), respectively, both with significant heterogeneity among studies (P < 0.01 for remission, P < 0.03 for response). In multivariate models, study duration, number of study visits, and entry Crohn's Disease Activity Index score were important predictors of the placebo remission rate, with study duration the most important. However, no single factor could account for all of the heterogeneity. Factors that influence the placebo response rates were similar to those affecting the placebo remission rates. The absolute benefit of active treatment beyond placebo was generally larger when outcome was measured by response than remission. CONCLUSIONS: Placebo remission and response rates in PC-RCTs for active CD are variable. Study duration, number of study visits, and disease severity at entry have a large influence on placebo remission rates.     

The Prevalence of Diabetic Cardiomyopathy: A Population-Based Study in Olmsted County,Minnesota

BackgroundDiabetic cardiomyopathy defined as either systolic or diastolic dysfunction in otherwise healthy diabetic persons is not clearly understood. The prevalence and outcomes of this disease in a community-based population have not been defined.Methods and ResultsCross-sectional survey of 2042 randomly selected residents of Olmsted County, Minnesota, aged 45 years or older between June 1997 and September 2000. All patients underwent Doppler echocardiographic assessment of systolic and diastolic function. Diabetic cardiomyopathy was defined in a person with diabetes and any systolic or at least moderate diastolic dysfunction without a history of coronary disease, hypertension, significant valvular disease, or congenital heart disease. The diagnosis of diabetic cardiomyopathy was made in 23 people, corresponding to a community population prevalence rate of 1.1%. Among diabetic patients, 16.9% met criteria for diabetic cardiomyopathy and 54.4% had diastolic dysfunction. Diabetes was associated with a 1.9-fold increase in risk of any left ventricular dysfunction, a 1.7-fold increase in risk of diastolic dysfunction, and a 2.2-fold increase in risk of systolic dysfunction. Among patients with diabetic cardiomyopathy, the cumulative probability of death was 18%, development of heart failure was 22%, and development of death or heart failure was 31% at 9 years.ConclusionDiabetic cardiomyopathy is relatively common in the community with a prevalence of 1.1%. The morbidity and mortality of patients with diabetic cardiomyopathy is high.