Scandinavian Journal of Gastroenterology

ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20

The epidemiology of inflammatory bowel disease Johan Burisch & Pia Munkholm To cite this article: Johan Burisch & Pia Munkholm (2015) The epidemiology of inflammatory bowel disease, Scandinavian Journal of Gastroenterology, 50:8, 942-951, DOI: 10.3109/00365521.2015.1014407 To link to this article: http://dx.doi.org/10.3109/00365521.2015.1014407

Published online: 17 Feb 2015.

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Date: 30 November 2016, At: 03:07

Scandinavian Journal of Gastroenterology. 2015; 50: 942–951

REVIEW

The epidemiology of inflammatory bowel disease

JOHAN BURISCH1,2 & PIA MUNKHOLM2 1

Gastrounit, Medical Section, Hvidovre University Hospital, Hvidovre, Denmark, and 2Danish Centre for eHealth & Epidemiology, North Zealand University Hospital, Copenhagen, Denmark

Abstract Background and aims. The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are chronic relapsing disorders of unknown aetiology. The aim of this review is to present the latest epidemiology data on occurrence, disease course, risk for surgery, as well as mortality and cancer risks. Material and methods. Gold standard epidemiology data on the disease course and prognosis of patients with inflammatory bowel disease (IBD) are based on unselected population-based cohort studies. Results. The incidence of ulcerative colitis (UC) and Crohn’s disease (CD) has increased overall in Europe from 6.0 per 100,000 person-years in UC and 1.0 per 100,000 person-years in CD in 1962 to 9.8 per 100,000 person-years and 6.3 per 100,000 person-years in 2010, respectively. The highest incidence of IBD is found on the Faroe Islands. Overall, surgery rates have been declining over the last decades, partly due to aggressive medical therapy. Among IBD patients, mortality risk is increased by up to 50% in CD when compared to the background population, but this is not the case for UC. In CD, 25 – 50% deaths are disease-specific deaths, e.g. malnutrition, postoperative complications and intestinal cancer. In UC, disease-specific causes of deaths include colorectal cancer (CRC), and surgical and postoperative complications. The risk of CRC and small bowel cancer is increased two- to eightfold among IBD patients. Various subgroups carry increased risk of malignancy, e.g. those with persistent inflammation, long-standing disease, extensive disease, young age at diagnosis, family history of CRC and co-existing primary sclerosing cholangitis. The risk of extra-intestinal cancers, including lymphoproliferative disorders (LD) and intra- and extrahepatic cholangio carcinoma, is significantly higher among IBD patients. Conclusion. In recent years, self-management and patient empowerment, combined with evolving eHealth solutions, has utilized epidemiological knowledge on disease patterns and has been improving compliance and the timing of adjusting therapies, thus optimizing efficacy by individualizing medication in the community setting.

Key Words: Cancer, crohn’s disease, epidemiology, mortality, ulcerative colitis

Introduction The World Inflammatory Bowel Disease (IBD) Day is officially celebrated every May 19 since 2012, led by patient organizations representing 36 countries on four continents. Its purpose is to raise awareness of IBD. Crohn’s disease (CD) and ulcerative colitis (UC) affect morethanfivemillionpeopleworldwide,with1.4million in the US alone, and three million in Europe [1]. The incidence of IBD is increasing worldwide in both adult [2] and pediatric-onset IBD patients [3], especially in traditionally low-incident regions such as Asia, South America and southern and eastern Europe [4,5].

Epidemiological inception cohorts enable clinicians to observe the various patterns of disease courses of IBD patients – from aggressive to indolent types – during lifelong follow-up [6–8]. Prior to the introduction of biological therapy in IBD care, costs were mainly driven by surgery and hospitalizations [9] but recent studies indicate that this cost profile has changed and healthcare costs are now mainly driven by use of biological agents [10,11]. Worsening constraints on healthcare costs demand up-to-date and accurate information regarding the cost of IBD care for decision makers. Therefore, unselected population-based cohort studies are needed in order to describe the

Correspondence: Pia Munkholm, MDSc, Danish Centre for eHealth and Epidemiology, Nordsjællands Hospital, Frederikssundsvej 30, DK 3600 Frederikssund, Denmark. Tel: +4540858494. E-mail: [email protected]

(Received 27 December 2014; accepted 29 January 2015) ISSN 0036-5521 print/ISSN 1502-7708 online
2015 Informa Healthcare DOI: 10.3109/00365521.2015.1014407

The epidemiology of IBD healthcare costs in the general IBD population within the era of biologicals, as well as for clinicians seeking to optimize the management of treatment. The aim of this overview is to focus on current knowledge regarding the outcome of inception cohorts regarding mortality, cancer, surgery and disease course. Furthermore, it appraises the new eHealth tools that use a patient’s ability to describe their own disease pattern to make possible individualized medical treatment [12–14].

Occurrence of IBD Incidence and prevalence

Country

Center

IBD

Romania

Timis

4.1

Moldova

Chisinau

4.3

Russia

Moscow

5.1

Croatia

Zagreb

6.3 7.7

Lithuania

Kaunas

Greece

loanninia

8.5 9.2

Estonia

Southern Estonia

10.3

Italy

Northern Italy

10.9

Portugal

Val de Sousa

11.1

Cypyus

Nicosia

11.2

Czech Republic Prague

12.2

Ireland

Adelaide & Meath

13.2

Israel

Beer Sheva

13.2

Denmark

Amager

17.2

UK

Hull & East Yorkshire 18.1

UK

Brent & Harrow

Spain

Vigo

20.4

Denmark

Aarhus

21.2

Denmark

Herning

21.2

Denmark

Herlev

22.4

Hungary

Veszprem province

23.0

Greenland

Greenland

24.0

Denmark

Viborg

24.6

Finland

Pirkanmaa

26.2

Sweden

Orebro

26.5

Iceland

Iceland

28.7

Denmark

Funen

30.7

Sweden

Linköping

38.7

Faroe Islands

Faroe Islands

81.5

19.9

Highest incidence

Czech Republic South Bohemia

In Europe, incidence rates for UC range from 0.9 to 24.0 per 100,000 person-years and from 0.0 to 11.5 per 100,000 person-years for CD [15,20]. Prevalence of UC varies from 2.4 to 294 [21] cases per 100,000 persons, whereas the prevalence of CD ranges from 1.5 [22] to 213 [23] cases per 100,000 persons. For IBD, the highest prevalence rates are found in Northern Europe. Similarly, in North America incidence rates for CD range from 0 to 20.2 per 100,000 person-years and from 0 to 19.2 per 100,000 person-years for UC [2]. Prevalence ranges from 25.9 [24] to 318.5 [16] cases per 100,000 persons for CD and from 37.5 [25] to 248.6 [16] cases per 100,000 persons for UC. While these variations might be caused by differences in lifestyle and environmental factors, as well as disease awareness, part of the explanation could derive from methodological differences relating to the types of cohorts under observation, methods of data collection used and the organization of healthcare in the countries studied. In Europe, two unselected inception cohorts have investigated the occurrence of IBD using a high quality, unified epidemiological methodology in a multicentre setting. The European Collaborative Study on IBD (EC-IBD) found a North-South gradient in Europe between 1991 and 1993; the same study also suggested, however, that the difference in IBD incidence between Northern and Southern Europe was narrowing [20]. Recently, the

Lowest incidence

IBD occurs across the world but with considerable variations in both incidence and prevalence, both within and between geographic regions. The highest incidence rates of both CD and UC are found in Northern Europe [1,15] and North America [16,17], with IBD more common in industrialized than in non-industrialized countries. The incidence of IBD continues to increase worldwide [2] – especially in what were once low-incidence regions, such as Asia [18] and Eastern Europe [19] – suggesting that the occurrence of IBD may be influenced by environmental risk factors.

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Figure 1. Incidence rates (per 100,000) of cases aged 15 years or older for inflammatory bowel disease in selected areas in Europe in 2010 [15].

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Epidemiological Committee (EpiCom) study, consisting of 31 centres from 23 European countries, demonstrated a 2:1 West-East gradient in IBD incidence in Europe [15] (Figure 1). The combined incidence rate in all centres was 5.4 per 100,000 person-years for CD and 8.2 per 100,000 personyears for UC. As with the EC-IBD study, the incidence rates observed in the EpiCom study correlated with the gross national product of countries rather than with their geographical placement. The combined incidence rate of IBD observed on the Faroe Islands (81.5 per 100,000) is the highest rate in the world to be reported to this day [15,26]. Fewer data are available regarding IBD occurrence beyond Europe and North America, and the data that are available often consist of selected hospital-based cohorts that are not representative of the whole IBD population. However, the Asia-Pacific Crohn’s and Colitis Epidemiology (ACCESS) study used a methodology similar to that of the EpiCom study and found an annual overall incidence per 100,000 of 0.8 for UC and 0.5 for CD in eight Asian countries and incidence rates of 7.3 for UC and 14.0 for CD in Australia [4].

colorectum distal to the splenic flexure (left-sided colitis), and one-third with involvement proximal to the splenic flexure (extensive colitis) [15,19,28,36]. In CD, one-third of patients are diagnosed with disease located at the terminal ileum, one-third with isolated large bowel disease, and one-third with ileo-colonic disease. Approximately 5–10% present with CD located proximal tothe terminal ileum, whileperianaldisease (fistula, abscesses) occurs in 10–20% of patients at diagnosis. In terms of disease behavior, up to one-third of patients may present with complicated disease phenotype (stricturing or penetrating disease) at the time of diagnosis [15,19,37–39]. Disease course Disease activity

In most populations, patients with UC are diagnosed in their 30s and 40s and patients with CD in general 5–10 years earlier, between 20 and 30 years of age. However, the diagnosis of IBD can occur at any age from 0 to > 90 years [15,17,19,20,27,28]. Some studies have reported a smaller, second peak in incidence, typically in the sixth or seventh decade of life, especially among UC patients [28–30], but it remains uncertain whether these differences in age distribution are real or whether they are caused by, for instance, differences in the diagnostic tools available or by obesity in a young-age-debut phenotype of the diseases. CD occurs more frequently in women, particularly in high-incidence areas [29,31–33], yet in some low-incidence areas CD occurs more frequently in men. In contrast, no substantial gender-related difference exists in UC, although some populations have found a slight predominance of male patients [34].

The clinical course of both UC and CD is characterized by alternating periods of remission and relapse. The majority of patients present with moderateto-severe symptoms at diagnosis, but disease activity tend to decrease over time. In the European EpiCom cohort, 75% of patients were in remission while on medical and surgical treatment by the end of the first year following diagnosis [6,40]. The long-term disease course of IBD has been described in two landmark studies from Copenhagen, Denmark [41,42]. In CD, and excluding the first 2 years subsequent to diagnosis, a constant proportion of 55% of patients were in remission each year, while 15% had low disease activity and 30% moderate-to-high disease activity. The individual patients, however, alternated from year to year between these disease states [41]. Furthermore, 13% of patients experienced remission for several years, while 20% had continuous activity with relapse each year of follow-up, and 67% fluctuated between years of relapse and years in remission. Similarly in UC, approximately 50% of patients were in remission each year of follow-up [42], while the proportion of patients with active disease during each year decreased to 30%. A quarter of patients were in remission during all years of follow-up, while 18% had active disease every year, and 57% experienced intermittent activity.

Disease phenotype

Disease phenotype

Disease phenotype by disease extent for UC, as well as age, disease location and behavior for CD, are defined according to the Montreal classification [35]. In UC, the disease extent at the time of diagnosis is roughly similar across different populations, with some variations in the rates of proctitis. Approximately one-third of patients will present with disease limited tothe rectum (proctitis), one-third with involvement limited to the portion of the

The anatomical location of CD is relatively stable over time [39,43] in contrast to disease behavior, which in many patients will worsen. In the Olmsted County, Minnesota cohort, 19% of patients were diagnosed with complicated disease behavior and the cumulative risk of developing either stricturing or penetrating disease was approximately 33% after 5 years and 50% after 20 years of follow-up [39]. Ileal disease

Demographic features of IBD

945

The epidemiology of IBD location was significantly associated with changes in disease behavior. Perianal complications developed in 11% of patients during follow-up. In UC, extension of the colonic involvement can occur during the disease course. In a Danish population-based cohort, more than 50% of patients with proctitis or proctosigmoiditis at diagnosis experienced further proximal extension of disease during 25 years of follow-up. However, 75% of patients diagnosed with extensive colitis regressed during follow-up as well [44]. In the Norwegian IBSEN cohort, 28% of patients diagnosed with proctitis extended to left-sided colitis and 14% to extensive colitis during 10 years of follow-up [45].

Surgery Surgery rates for both CD and UC have been declining during the last three decades [29,46–48], possibly because of more aggressive medical therapy, a change in physicians’ attitudes towards surgery, or because of a reduction in doctor and/or patient delay from onset of symptoms to diagnosis. In a Danish cohort of CD patients diagnosed between 1962 and 1987, the cumulative probability of intestinal resection was 35%, 61% and 82% after 1, 10 and 20 years of follow-up [49], respectively. Half of these patients experienced re-operation during the disease course. However, more recent population-based cohorts have reported surgery rates of 10–14% after 1 year and 18 – 35% after 5 years of follow-up [19,29,40,47,50,51]. Terminal ileal location and stricturing or penetrating disease behavior carries the highest risk for surgery [40,50]. The change in treatment strategy, i.e. earlier and more frequent use of immunomodulators and biologicals (Figure 2), has been associated with

reductions in surgery rates for CD [46,52]; however, whether more aggressive medical therapy with immunomodulators, as well as the introduction of biological therapy, will reduce the long-term requirement for surgery remains to be seen. In UC, early reports on colectomy rates found that 9% of patients were colectomized in the year of diagnosis, while after 10 years the cumulative probability of colectomy was 24% [53]. In a more recent Danish cohort of patients diagnosed between 2003 and 2005 from the same geographical area, colectomy rates were 6% after 1 year and 10% after 5 years of follow-up [29,51] – that is, similar to the results of the IBSEN cohort [45] as well as the European EC-IBD [54] and EpiCom cohorts [40]. During the disease course of UC patients, rates of colectomy decrease, with the majority performed during the first 2 years of disease and in the majority of patients with pancolitis.

Mortality Patients with CD carry a slightly higher risk of dying than the general population. This has been shown in several inception cohorts from North America and Europe [55–58]; however, other cohorts have found no increased risk of mortality [59–61]. Most deaths, 25 – 50%, are caused by CD (malnutrition, postoperative complications, intestinal cancer) [55–57], while smoking, more prevalent in CD patients than in the general population, accounts for most other deaths (e.g. because of respiratory diseases and infections). A recent meta-analysis confirmed in 35 cohorts that the all-cause standardized mortality ratio (SMR) based on inception cohort studies alone was 1.34 (95% CI, 1.15–1.56) [62], and thus, the risk of dying among patients with CD was 34% higher

Ulcerative colitis 1.0

Surgery Biological therapy

0.9

Surgery 0.9

Immunomodulators Proportion of patient population

Proportion of patient population

Crohn’s disease 1.0

0.8 Glucocorticosteroids

0.7 0.6 0.5 0.4 5-ASA

0.3 0.2

Biological therapy

0.8 0.7

Immunomodulators 0.6 0.5 0.4

Glucocorticosteroids

0.3 0.2

5-ASA

0.1

0.1 No treatment

0.0 0

1

2

No treatment

0.0 3

4 5 6 7 8 Time since diagnosis (months)

9

10

11

12

0

1

2

3

4 5 6 7 8 Time since diagnosis (months)

9

10

11

12

Figure 2. Distribution of ulcerative colitis and Crohn’s disease patients within the highest treatment steps during the first year of disease in Western and Eastern Europe [6,11].

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J. Burisch & P. Munkholm

than in the age- and gender-matched general population. While the majority of these cohorts pre-date the introduction of biological therapy and widespread use of immunomodulating agents, a recent nationwide registry study from Denmark confirmed a 50% higher mortality among CD patients than among the general population, which did not change during the study period of 1982 to 2010 [63]. Contrary to CD, the overall mortality for patients with UC is not greater than that of the general population, and in some populations it is even better [56,59,60,64,65]. However, mortality is increased among newly diagnosed patients and in patients with extensive disease [64]. In the aforementioned metaanalysis, the all-cause SMR in inception cohort studies was confirmed to be 1.08 (95% CI, 0.97–1.21), similar to an older meta-analysis of only population-based inception cohorts [66]. In the latter, 17% of deaths were caused by UC itself (e.g., colorectal cancer (CRC) and surgical or postoperative complications), while the risk of dying from pulmonary cancer and other tobaccorelated diseases was reduced, as the smoking prevalence in UC is lower than in the general population.

1.9 (95% CI: 1.4–2.5) with a higher risk of CD colitis (RR 4.5 (95%, CI 1.3-14.9)). When compared with the general population CD markedly increases the risk of small bowel cancer (SBC) by between 15 and 66 times [82–84]; however in the most recent reports from Denmark the SBC risk was much lower than previously reported [84], but still significantly increased (SIR 8,4, 95% CI: 4.3–14.7). SBC is usually found in the inflammatory areas and as such substantiates the proposed sequence of carcinogenesis as inflammation-dysplasia-carcinoma [85,86]. Patients with primary sclerosing cholangitis (PSC) and associated IBD have an increased risk of CRC. A recent systematic review of data on incidence of de novo CRC after liver transplantation (LT) in patients with PSC revealed a pooled IR of 5.8 per 1000 person-years (95% CI = 3.8–7.8). Patients with PSC-IBD and an intact colon at the time of LT had a pooled IR of 13.5 per 1000 person-years (95% CI = 8.7–18.2), justifying aggressive colonoscopy surveillance for patients with PSC-IBD even after LT [87].

Cancer

Reported risk factors for CRC in UC include extensive disease [79,80,88,89], young age at diagnosis [79,80,88], a family history of CRC [90], co-existing PSC [91–93], persistent inflammation of the colon [69,70], and long-standing disease [88]. In CD colitis, the risk of CRC seems to be similar to that of UC if the extension and duration are comparable [94–96]. The gender-related risk of CRC in UC was reported to be higher in men than in women in earlier studies (by up to 60%) [97–100]. The frequent use of biologicals does not seem to carry an increased risk of cancer after 1 year and up until 3 years in median follow-up [101]. However, recent meta-analyses of the use of thiopurines have found increased risk of lymphoma [102] and malignant melanoma of the skin (SIR, 1.4; 95% CI, 1.0–1.9) [84], whereas the risk of developing non-melanoma skin cancer in patients with IBD on thiopurines is only modestly elevated [103]. In addition, smoking-related cancers were observed more frequently among those with IBD in a national Danish cohort (SIR, 1.5; 95% CI, 1.3–1.8) [84], and the frequency of smokers is significantly higher among CD patients at diagnosis and throughout life when compared with UC patients, as shown in a recent European inception cohort [15].

Patients with IBD carry an increased risk of CRC – with immunosuppression and inflammation being the two main drivers of carcinogenesis [67] – and patients with IBD with extensive long-standing colitis are at higher risk of CRC than individuals in the general population [68]. Prior studies have proposed an association between severity of histological inflammation and risk of CRC in IBD patients [69–72], and higher median elevation of CRP and ERS is associated with an increased risk of CRC in IBD [73]. In addition to gastrointestinal malignancy, IBD patients are also at increased risk of extra-intestinal malignancy [74], lymphoma [67,75] and non-melanomaskincancer [76–78]. Intestinal cancer In a recent meta-analysis of population-based studies of UC, the estimated standardized incidence ratio (SIR) for CRC was 2.4 (95% CI: 2.1–2.7) [79]. The risk of CRC, however, seems to be decreasing over time as shown in a Danish time-trend study where the risk ratio (RR) decreased from 1.34 during 1979–1988 to 0.57 during 1999–2009 [80]. A Swedish cohort study during the period 1954–1989 and followed-up until 2004 did not find any change of CRC occurrence in IBD [81]; however, mortality from CRC decreased 70% during the study period. As for CD, two meta-analyses [82,83] of population-based studies estimated a pooled SIR for CRC of

Risk factors

Extra-intestinal cancer Extra-intestinal cancers occur more frequently among IBD patients than in the general population. A metaanalysis of population-based cohorts demonstrated

The epidemiology of IBD

Homemonitoring

Relapse

Remission

Symptom score + fecal calprotectin Relapse confirmed via eHealth web-application

Lead time

Relapse

Conventional approach

947

Remission

Relapse confirmed by symptoms in the out-patient clinic Figure 3. Influence of eHealth monitoring of the disease course of patients with inflammatory bowel disease.

that CD patients are at elevated risk of developing extra-intestinal cancers compared to UC patients, whose risk is similar to the general population [74]. Patients with UC have significantly increased risk of liver-biliary cancer and leukemia, but a decreased risk of lung cancer [74]. CD patients are, moreover, at increased risk of developing cancer of the upper GI tract, lung or urinary bladder [74]. The risk of cholangiocarcinoma, intra- and extrahepatic, is significantly increased among IBD patients, (RR = 2.63, 95% CI = 1.47–4.72) [104]. Immunosuppressive therapy may, in a dose- and time-dependent manner, facilitate the genesis of de novo malignancies [67]. Lymphoproliferative disorders There are three specific forms of lymphoproliferative disorders (LD): Epstein-Barr virus-related posttransplant like LD, hepato-splenic T-cell lymphoma, and post-mononucleosis lymphoproliferation. The risk of the latter two forms of LD can be reduced when using monotherapy instead of combined immunosuppression in the long-term among young males [105]. The overall risk of lymphoma in patients with IBD appears to be similar or slightly greater than for the general population (SIR, 1.9; 95% CI, 1.5–2.3) [84], whereas the increased risk of lymphoma has been found among IBD patients taking thiopurines and is often associated with Epstein–Barr virus [74,75,105–107]. Fewer than 40 cases of hepatosplenic T-cell lymphoma have been reported in IBD to date. All 40 patients were treated with thiopurines, and 50% had additional treatment with ant-TNF, in median time of 6 years, > 90% are males younger than 35 years of age [108]. Pattern recognition of disease course and eHealth Transferring knowledge about disease course patterns gained from epidemiological studies of inception cohorts [6,41,42] has been made possible via eHealth. In recent years, eHealth has been introduced as an important “adjuvant” to medical therapy that can

improve compliance and adherence to medication among IBD patients [12], time to remission [12,109] and health-related quality of life (HRQoL) [12,13]. In a recent meta-analysis, six randomized controlled trials showed that distance management (including telemedicine and web-based intervention) significantly decreases the number of clinic visits and can improve quality of life in certain groups of patients [110]. Furthermore, eHealth disease management was validated in another meta-analysis of telemedicine in IBS and IBD. Generally speaking, improvement of HRQoL, adherence to therapies, knowledge about the disease, reduction of healthcare costs for IBD, and time to remission, were all shown [111]. One way of using eHealth is via web-based selfmonitoring. In this concept, treatment decisions are based on patients’ reported disease activity [112] (e.g. according to the Simple Clinical Colitis Activity Index, SCCAI or Harvey-Bradshaw index, HBI) validated in conjunction with faecal calprotectin home testing. The results can be shown using a traffic light system in the web-application, visible to the patients, IBD-nurse and the treating physician. Guidance and medication adjustment can be provided immediately and the patient is able to see their own disease course pattern, thus improving the short-term disease course [12,109] (Figure 3). Based on the evidence to date, eHealth internet-based technology is a promising tool that can be utilized to both promote and enhance gastrointestinal disease management. The long-term influence of eHealth on disease course and outcome awaits future studies. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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[28]

[29]

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