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Crohn’s disease is an idiopathic, chronic, inflammatory disease of the gastrointestinal tract that primarily affects the small intestine and colon. Crohn’s disease is associated with significant morbidity, the need for treatment with sulfasalazine, mesalamine, corticosteroids and other immunomodulating agents, surgical resection of the intestine and a slightly increased mortality.1 Knowledge of the natural history of Crohn’s disease (e.g. the likelihood of surgical intervention or the likelihood of experiencing a flare of Crohn’s disease in a given year) guides physicians when counselling Crohn’s disease patients and offering advice regarding treatment options. More importantly, Crohn’s disease is an idiopathic disorder, which may be caused by a combination of environmental and genetic factors. Better understanding of the epidemiology of Crohn’s disease (e.g. differences in prevalence of Crohn’s disease based on gender or geographical region) may identify areas for further research.
Multiple studies have reported the incidence, prevalence, gender distribution and age of onset of Crohn’s disease in well-defined, population-based cohorts of patients in North America and Western Europe.2 However, these trials have reported a wide variation in the prevalence and incidence of Crohn’s disease. Some of these differences between studies may be due to different study methodologies, while some differences in trial results may be due to true differences in the genetic or environmental factors present in certain populations. Multiple studies have also reported wide variations in the natural history of Crohn’s disease. Many of these studies utilized referral centre populations, which may create a ‘referral centre’ bias (i.e. patients referred to quaternary medical centres may have the most severe disease activity levels and be more likely to undergo surgery and use multiple medications). Therefore, studies of the natural history of Crohn’s disease should be performed in well-defined, population-based patient cohorts.3–9 The use of systematic reviews may facilitate the identification of appropriately designed studies and a comprehensive evaluation of divergent results, while delineating topics that require further research.
Systematic reviews utilize comprehensive literature searches, with pre-specified inclusion criteria for the selection of studies, and duplicate extraction of data by independent investigators. These techniques minimize bias in the identification of appropriately designed studies and in the extraction of study data. This systematic review quantifies the prevalence and incidence of Crohn’s disease in North America and describes the gender distribution and the age at diagnosis among Crohn’s disease patients. In order to better define the natural history of Crohn’s disease, this systematic review also addresses: (i) the percentage of Crohn’s disease patients with inactive or quiescent, mildly active, moderately active or severely active Crohn’s disease in a given year; (ii) the percentage of Crohn’s disease patients experiencing a flare of active Crohn’s disease in a given year; (iii) the percentage of Crohn’s disease patients treated with conventional steroids in a given year; (iv) the percentage of Crohn’s disease patients treated with 5-aminosalicylate products in a given year; and (v) the percentage of Crohn’s disease patients treated with surgery.
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This systematic review of the incidence and prevalence of Crohn’s disease in North America identified several important pieces of demographic information. Firstly, the current prevalence of Crohn’s disease in North America is 144–198 cases per 100 000 persons. Secondly, the incidence rate of Crohn’s disease currently ranges between 3 and 14 new cases per 100 000 person-years. Thirdly, there is a very slight female predominance. Fourthly, the peak period for the onset of Crohn’s disease is in the second and third decades of life.
If the incidence rates of Crohn’s disease identified by this systematic review are extrapolated to the North American population as a whole, between 9000 and 44 000 new cases of Crohn’s disease should be diagnosed in North America annually. If recent prevalence data (144–198 cases per 100 000 persons) are extrapolated to the entire North American population, the current prevalence of Crohn’s disease may be between 400 000 and 600 000 cases. These estimates have several limitations. Because they assume a uniform prevalence both geographically and across ethnic groups, they may overestimate the prevalence. However, these figures may be an underestimate of the true prevalence, as the only longitudinal prevalence data available suggest that the prevalence of Crohn’s disease is increasing, and the data available are already 6–9 years old. Regardless of the exact number, these data indicate that the burden of Crohn’s disease in North America is significant.
The majority of patients with Crohn’s disease are diagnosed in the second or third decade of life. There was a variation in the overall age distribution of cases, however, with half of the studies suggesting a bimodal distribution and half suggesting a unimodal distribution. The age distributions are likewise mixed in European studies. Perhaps this may be explained by misclassification or by varying diagnostic criteria; alternatively, the condition may be expressed heterogeneously under different environmental conditions.
Systematic reviews may be most helpful because they identify new areas for research. The data in this systematic review suggest that people in northern latitudes and Caucasians are more likely to develop Crohn’s disease. The slight female predominance of Crohn’s disease was a fairly consistent finding, but its cause and significance remain unclear. In several of these cohorts, a dramatic increase in incidence among females in the third decade of life explained much of the overall increase in incidence that occurred in the 1960s.14, 22 Such occurrences have led to speculation about the role of female hormones in general, and oral contraceptives and hormone replacement therapy in particular, in the pathogenesis of Crohn’s disease. Although cigarette smoking, a well-described risk factor for Crohn’s disease, was not formally studied in these cohorts, it also became more prevalent among women in the 1960s, coincident with the rise in incidence and prevalence. Future research focused on these issues may better delineate the environmental, hormonal and genetic factors which predispose patients to Crohn’s disease.
This systematic review also identified several important pieces of information about the natural history of Crohn’s disease. At any given point in time following the first year of the disease, roughly 10% of Crohn’s disease patients have high activity, 25% have low activity and 65% are in remission. However, a static view of disease activity is misleading, as disease activity often fluctuates. Approximately 13% of Crohn’s disease patients have chronically active disease, 73% have a chronic intermittent course, while only 10% remain in remission over many years. This pattern of disease activity highlights the need for effective drug therapy, both for the control of active disease and for the maintenance of disease remission.
Approximately 43% of Crohn’s disease patients required conventional corticosteroids at some point in their disease history, and roughly 10% required corticosteroids in any given year. About 30% of patients required sulfasalazine or 5-aminosalicylate products in any given year. Up to 57% of all patients required at least one surgical resection.
The above natural history data were extracted from several studies of a single population-based cohort in North America,7–9 which may raise concern about the generalizability of these data. However, the natural history of Crohn’s disease in Olmsted County is surprisingly similar to that in Copenhagen County, Denmark,3–6 which to our knowledge is the best-characterized inception cohort of Crohn’s disease in either Europe or North America. A study of disease activity performed in Copenhagen County reported that, in the first year after diagnosis, 80% of patients had high disease activity, 15% had low activity and 5% were in remission. After the first year, 30% had high activity, 15% had low activity and 55% were in remission during any given year (Figure 2).6 The same study reported the clinical course over a continuous 5-year period (years 3–7); 25% of patients had active disease every year, 22% were in remission and 53% changed between years with remission and years with relapse (Figure 3).6 Considering the first 7 years, 20% of patients had active disease every year, 13% had a relapse-free course and 67% fluctuated between years with relapse and years in remission. In Copenhagen County, 56% of patients with Crohn’s disease received treatment with conventional corticosteroids at some point in their disease history.5 During the first 3 years following the diagnosis of Crohn’s disease, 58% of patients did not receive corticosteroid therapy, 19% received corticosteroids for 1 year and 22% received corticosteroids for two or more years.6 During the first 3 years following the diagnosis of Crohn’s disease, 20% of patients did not receive therapy with 5-aminosalicylate products, 16% received 5-aminosalicylate products for 1 year and 64% received 5-aminosalicylate products for two or more years.6 An early study from Copenhagen County reported that 42% of patients with Crohn’s disease had one operation within 10 years of diagnosis and an additional 13% had two or more operations within 10 years.3 A subsequent study from Copenhagen County reported that the cumulative probability of operation 15 years after the diagnosis of Crohn’s disease was 70%.4
Figure 2. Disease activity distribution in the total patient group in each year from diagnosis and 25 years ahead. (From year 14 to year 25, the mean values are given, as no significant change upwards or downwards occurred.) Number of patients (Pt) in parentheses (Reprinted with permission from Munkholm et al.6).
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Figure 3. Graphical presentation of the prevalence figures of 5-year activity courses for 171 patients, 3–7 years after diagnosis (Reprinted with permission from Munkholm et al.6).
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The differences in the prevalence of use of medical and surgical therapy in these two cohorts may reflect differences in disease activity, but more likely reflect differences in medical practice between the two locales. The relatively high prevalence of conventional corticosteroid use highlights the burden of disease activity and again points to the need for more effective and less toxic drugs to control disease activity.
Overall, this review of the data has identified several areas that deserve attention in future research. The information about natural history is based on fairly limited data. Despite all that has been written about Crohn’s disease, we found only two population-based cohorts in which medication usage, disease activity and surgical history were described in detail.3–9 The natural history data discussed above come from Olmsted County, MN, USA and Copenhagen County, Denmark, limiting the generalizability of these data. The development of wider population-based networks of Crohn’s disease patients would be ideal to develop more generalizable natural history data. The available data also do not provide enough information to determine whether age, gender, ethnicity, disease location or other possible prognostic factors may help to predict which patients are likely to be in remission for many years. Finally, future prevalence and incidence data must focus on environmental, hormonal and genetic factors which may predispose patients to Crohn’s disease. All of these issues could be adequately addressed with the development of a nationwide longitudinal database of Crohn’s disease patients.