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Gastroenterology Research and Practice
Volume 2016 (2016), Article ID 1619053, 9 pages
http://dx.doi.org/10.1155/2016/1619053
Review Article

The Changing Phenotype of Inflammatory Bowel Disease

Department of Medicine and the APC Microbiome Institute, University College Cork, National University of Ireland, Cork, Ireland

Received 8 September 2016; Revised 1 November 2016; Accepted 8 November 2016

Academic Editor: Bjørn Moum

Copyright © 2016 Carthage Moran et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

It is widely known that there have been improvements in patient care and an increased incidence of Inflammatory Bowel Disease (IBD) worldwide in recent decades. However, less well known are the phenotypic changes that have occurred; these are discussed in this review. Namely, we discuss the emergence of obesity in patients with IBD, elderly onset disease, mortality rates, colorectal cancer risk, the burden of medications and comorbidities, and the improvement in surgical treatment with a decrease in surgical rates in recent decades.

1. Introduction

The incidence of Inflammatory Bowel Diseases (IBD) is increasing worldwide [1]. There continues to be remarkable changes in the incidence of IBD amongst different ethnic groups in recent decades as they are exposed to increasingly industrialized environments [2]. Less well known are the phenotypic changes that have occurred in patients with IBD (see Table 1) [3].

Table 1: The changing phenotype of patients with IBD [3].

2. Disease Phenotype

Disease phenotype at diagnosis of IBD has changed in recent decades [3]. A Danish study, investigating consecutive population based cohorts, describes these changes: the proportion of Crohn’s disease (CD) amongst total IBD cohort increased and the prevalence of CD and ulcerative colitis (UC) patients who were smokers at diagnosis decreased with time. The median age at diagnosis was stable over five decades for CD patients but increased from 34 years to 38 years in patients with UC [4].

A Dutch population study of patients newly diagnosed in 2006 found that 61% of patients with CD had ileal involvement, 31% had stricturing or penetrating disease [5]. Mean age at diagnosis for CD patients was 36.7 years. In the Olmsted County cohort study (1970–2004), 64% of patients at diagnosis had ileal involvement and 18.6% complicated disease [6]. The phenotype at diagnosis in patients with UC is generally split equally between proctitis, left sided disease, and pancolitis [7, 8]. The proportion of patients presenting with pancolitis increased over the last five decades in Denmark [4].

The phenotype of disease amongst Asian patients with IBD has been described to differ from that of patients from North America and Western Europe [9]. Male predominance [10] increased ileocolonic disease has been described amongst Asian cohorts of patients with CD. However a prospective study failed to show significant difference in disease location between Australian and Asian cohorts [8] (see Table 2 for disease location at diagnosis amongst different geographical cohorts). A follow-up study of this cohort revealed that disease behavior for Asian patients with CD can be as severe as in the West [11].

Table 2: Disease location at diagnosis as per Montreal Classification.

IBD in patients with Primary Sclerosing Cholangitis (IBD-PSC) represents a distinct phenotype. There is a male predominance, with three-quarters of patients having coexisting UC and PSC [12]. In patients with UC there is an increased risk of pancolitis [12] and subsequent pouchitis (not related to the severity of liver disease) [13] and colorectal cancer [14], in addition to risks of cholangiocarcinoma, liver failure, and gallbladder cancer. In patients with coexisting CD and PSC, colonic disease is present in the vast majority of patients [12]. Prolonged duration of IBD is associated with an increased risk of cholangiocarcinoma in patients with IBD-PSC [15].

3. Obesity

Malnutrition has long been recognized as a complication of IBD. Previously attention was focused on patients who were underweight, but obesity is increasingly associated with IBD [16]. Obesity has reached epidemic proportions in western countries, becoming an equal if not greater contributor to burden of disease than smoking in the United States [17]. Regression in life expectancy in the 21st century is predicted if the rate of obesity goes unabated [18].

A Scottish study reported that the prevalence of obese and overweight patients in an IBD population was 18% and 38%, respectively [19]. In the overweight/obese cohort of UC patients there were higher levels of surgery, but the converse was true for the CD cohort. Interestingly in this study there were significantly more obese patients with CD than UC [19]. A third of patients with IBD in a cohort from Texas were obese [20]. Patients with CD enrolling in clinical trials had an increase in weight and disease activity in the last 20 years [21].

Mesenteric fat has long been shown to be an indicator of regional disease activity in CD. “Creeping fat” [22], or fat wrapping, has been used by surgeons to help identify the most diseased regions of bowel. However the role of obesity in development of IBD is unclear. Adipose tissue is not inert; it is well known to be actively involved in both systemic and intestinal inflammatory responses in patients with IBD [23]. A large prospective study found no association between obesity and development of incident IBD [24]. This study had a predominance of middle-aged subjects. IBD tends to present at an earlier age. Conversely, a recent case control study investigated a cohort of patients aged 50 to 70 years, finding obesity was more common in patients with CD than community controls [25]. A subsequent study found that obese women were at elevated risk of developing CD [26].

Early paediatric IBD cohorts have been described as being underweight and malnourished, with lower BMI than background population distribution [27]. However, more recent studies reveal that children with IBD are affected by current population trends towards weight gain; 20–30% and 10% of UC and CD incident cases were overweight or at risk of being overweight as per BMI [28]. These studies also showed that 7–9% and 22–24% of UC and CD incident cases had a low BMI [28].

A large, multicenter cohort study of children with IBD performed in the US, where childhood obesity is epidemic [29], found the overall prevalence of overweight or obesity in this IBD population to be 23%, with 30% and 20% of UC and CD populations overweight or obese [30]. Paediatric patients with CD who are overweight or obese have higher rates of IBD-related surgery, similar to findings in adult populations [31]. Higher use of corticosteroids was found in the overweight/obese UC (35% vs 27%) but not CD group.

The rise of obesity is especially concerning in patients with IBD as it is a known risk factor for colorectal cancer (CRC) [32] and can affect efficacy of medical treatment, including anti-TNF therapies [33, 34]. Obesity is associated with increased blood loss, operative time, and conversion to open surgery in patients with IBD undergoing laparoscopic surgery [35].

4. Elderly Onset IBD

The proportion of the world’s population that is elderly is increasing [36]. The prevalence of IBD is increasing worldwide [2], thus managing elderly patients with IBD is an increasing clinical encounter. There is a paucity of literature regarding elderly onset IBD in comparison to “early” onset IBD. This is compounded by the fact that in many clinical trials elderly patients are excluded from study enrollment.

Roughly 10% of patients present with first presentation of IBD aged greater than 65 years [37]. A recent population based cohort study in northern France described the natural history of elderly onset (>60 years) IBD. 5% and 12.5% of incident cases of CD and UC, respectively, were classified as elderly onset over study timeframe (1988–2006). The clinical history at diagnosis and course of disease was milder in elderly onset IBD than younger onset disease [38]. Half of the patients in this large cohort did not undergo surgery nor were exposed to medications other than 5-ASA [38]. Patients with elderly onset IBD had lower IBD-specific healthcare utilization than patients with earlier onset IBD [37]. In contrast, a survey of hospital discharges suggested geriatric IBD patients accounted for a quarter of all IBD-related hospitalizations [39], with higher mortality than younger patients. This study included all patients with IBD older than 65, not just patients with elderly onset IBD [39]. Elderly onset IBD is not associated with an increased risk of intestinal cancer; however there is an increased risk of developing lymphoproliferative (not associated with thiopurine exposure) and myeloproliferative disorders [40].

Elderly patients with acute severe UC (ASUC) had worse outcomes compared to younger patients in audits of IBD care in the United Kingdom. Patients aged greater than sixty years with ASUC had a roughly 4% mortality, compared to 0.1% if younger than sixty [41]. Patients aged greater than eighty with ASUC had mortality rates of 10% [41]. A retrospective Japanese study reported poor outcomes in elderly patients with UC undergoing emergency surgery, with a mortality rate of 27% at 30 days postoperatively for emergency surgery compared to 1% for elective surgery [42].

Colonic CD is more common than small bowel disease or ileocolonic disease in elderly onset disease [43, 44]. There is also a greater tendency for inflammatory, uncomplicated behavior [43] with a relatively low proportion of patients progressing to complicated disease (9%) [38, 45]. Elderly onset UC is characterized by left sided or extensive colitis at presentation, with disease extension rare [38].

In geriatric patients with IBD, longer disease duration is associated with Vitamin D, Vitamin B12, and iron deficiency [46]. Older patients have been shown to have an expedited time to referral, investigation, and diagnosis than younger patients [47]. Other diseases that can mimic symptoms of IBD include diverticulosis, NSAID colitis, microscopic colitis, and ischaemic colitis. Extensive biopsy sampling and vigilance are necessary in order to avoid an erroneous diagnosis purely based on histological mimicry of changes seen in segmental colitis associated with diverticular disease (SCAD), when diagnosing IBD in the presence of diverticulosis coli [48].

5. Comorbidities

As the phenotype of IBD changes, so do comorbidities. Studies suggest that fatty liver disease is more common than PSC in patients with IBD [49]. The prevalence of PSC in IBD cohorts is estimated to be less than 5% [49, 50], although a recent study revealed that 8% of patients with long-term IBD screened with magnetic cholangiography had probable PSC (these patients had subclinical PSC, that is, no symptoms and normal liver function tests) [51]. Nonalcoholic fatty liver disease in patients with IBD is common, with estimated prevalence of 8 to 23% [49, 52]. Patients with IBD develop nonalcoholic fatty liver disease (NAFLD) with less metabolic risk factors compared to patients without IBD [52]. The rate of NAFLD likely depends on environmental and genetic risk factors of study population, as a recent prospective Swedish study detected lower rates of NAFLD than American studies [53]. Disease specific risk factors for NAFLD in patients with IBD include small bowel surgery, use of steroids, and disease duration and activity [52, 54]. As the prevalence of NAFLD and subsequently nonalcoholic steatohepatitis induced cirrhosis, increases in patients with IBD, liver failure, and transplantation will complicate management of patients with IBD. Concomitant chronic liver disease doubles the inpatient mortality rate in patients with IBD [55].

It is well known that patients with IBD are at increased risk of developing venous thromboembolism (VTE) [56, 57]. Patients with IBD are at increased risk of developing VTE upon hospital discharge compared with other patients [58]. The inflammatory cascade that increases risk of VTE likely also places patients with IBD at increased risk of heart failure [59] and atrial fibrillation [60] during periods of disease activity. Flares of disease are also associated with increased risk of myocardial infarction, stroke [61], and cardiovascular death [62]. A recent meta-analysis concluded that patients with IBD are at increased risk of ischaemic heart disease, but not of cardiovascular mortality [57]. Further studies are needed to investigate the role of medications and lifestyle factors in patients with IBD to clarify the role their role in the development of cardiovascular disease.

Anxiety and depressive symptoms commonly affect patients with IBD [63] and are associated with body image dissatisfaction [64] and nonadherence to medication [65]. Evidence suggests that treating mood disorders can improve IBD disease activity [66, 67]. Concomitant treatment of mood disorders with antidepressants (multiple classes including tricyclic antidepressants and selective and nonselective serotonin reuptake inhibitors) reduced IBD relapse and steroid use in a retrospective case control study [67]. Tricyclic antidepressants can also improve ongoing GI symptoms in patients with adequate IBD therapy, as defined by their physician [68]. Symptom response was similar in a cohort of patients with IBD compared to group of patients with IBS [68].

6. Medication Burden

Patients with IBD are often prescribed multiple medications. Patients with IBD have greater use of antidepressants, sedatives, and analgesics (including narcotic analgesics) than matched controls [78]. Older patients with IBD are at increased risk of polypharmacy and potential adverse medication interactions [79]. An American study found that half of patients with CD met criteria for polypharmacy [80] and that this finding correlated with decreased quality of life and increased disease activity.

Narcotic use was identified in 13% of this cohort, and narcotic use was associated with increased use of other medications, including neuropsychiatric medications [81]. A Canadian population study showed that 5% of patients with IBD will become heavy opiate users within 10 years of IBD diagnosis [82]. An American study found that 70% of patients hospitalized with IBD as primary indication were given narcotics [83]. Factors associated with narcotic use include history of surgery, smoking, and outpatient narcotic use [83]. Healthcare models affect rates of narcotic use amongst patients with IBD, as demonstrated by the variance of narcotic use in different countries and an Australian study, which demonstrated that the introduction of nurse specialists reduced narcotic use amongst patients with IBD [84]. Our anecdotal evidence would be that narcotic use has decreased in recent decades. This is likely secondary to improved medical care and recognition of psychological issues.

7. Mortality

There is an increased mortality rate in patients with CD [85, 86] compared to the general population, with conflicting evidence as to relative mortality rates in patients with UC [86, 87]. A population based Canadian study found that there was an increased mortality rate in both CD and UC in the first year after diagnosis compared to the general population, but this only persisted beyond a year in CD and in those who underwent gastrointestinal surgery [88]. A meta-analysis of population based and inception cohorts demonstrated an elevated overall mortality for patients with both UC and CD, with standardized mortality ratios of 1.19 (95% confidence interval, 1.06–1.35) and 1.38 (95% confidence interval, 1.23–1.55) [86]. This meta-analysis revealed that summary mortality rate for CD remained constant over time but improved for UC [86].

A large Danish population study found that mortality in patients with UC decreased over three decades, secondary to decreased mortality from colorectal cancer, suicide, and gastrointestinal disorders [89]. Unfortunately patients with CD were still found to have 50% greater mortality compared to general population, and this did not change over study period of 1982 to 2010 [89]. A diagnosis of PSC was identified as a predictor of premature mortality in an Irish cohort of patients with IBD [90].

8. Reduced Risk of Colorectal Cancer?

The risk of CRC in patients with IBD is less than previously reported (meta-analysis of population based studies described a pooled standardized incidence ratio of 1.7 [73]) and is not increased in all patients [91]. The incidence of colorectal cancer (CRC) in patients with UC has decreased in the last few decades [92]. A nationwide Danish cohort found that patients diagnosed with UC in the 1980s were at increased risk of CRC compared to background population; however that excessive risk of CRC has declined and no longer exceeds that of the general population [74]. Extensive colonic disease, concomitant PSC, young age at diagnosis, and longer duration of disease are at increased risk of developing CRC in patients with IBD [73, 74].

Why the risk of CRC is declining in patients is not fully understood. There is conflicting evidence on the role of 5-ASA medications, thiopurines, and biologic medications as chemopreventive agents [93]. Endoscopic surveillance of patients with IBD is recommended, and colonoscopy in preceding three years is associated with reduced incidence of CRC [94]. These finding are in keeping with a German study that found colonoscopy within preceding 10 years was associated with a 77% reduced risk of CRC in the general population [95].

The decrease in gastrointestinal malignancies observed in recent decades has been accompanied by an increase in nongastrointestinal malignancies [96]. There is an increased risk of developing haematological malignancies [91]. Ongoing thiopurine exposure of greater than one year is associated with increased risk of lymphoma in patients with IBD. This elevated risk is not persistent after thiopurines are discontinued [97].

Patients with IBD on immunosuppressive therapy appear to be at increased risk of high grade cervical dysplasia or cancer [98] and melanomatous and nonmelanomatous skin cancer [99, 100].

9. Reduced Surgical Rates

The risk of IBD-related surgery has decreased in recent decades [101]; see Table 1 [3]. Advances in medications [71, 72] and specialization of management of patients with IBD [70], in addition to improved surgical techniques, have led to reduced rates of surgery. Further studies on the impact of biological agents on surgical rates are needed.

Surgical intervention remains integral to managing patients with complex IBD and can improve patients’ quality of life [102] and should not always be seen as a poor outcome, especially in those with localized disease [103].

10. Conclusion

Further studies are needed to investigate the relationship between ongoing chronic inflammation and systemic medications and the development of obesity and cardiovascular disease. Gastroenterologists need to be aware of emerging comorbidities in patients with IBD. Caution is needed in extrapolating results from existing randomized control trials, as most patients would be ineligible to participate in recent trials, whether due to their comorbidities, medication use, or disease phenotype [104].

The increased prevalence of obesity poses a challenge in the management of patients with IBD, not least due to the potential of further increased risk of CRC. Positive lifestyle habits such as exercise and smoking cessation, which may have disease modifying behavior [105], should be encouraged regularly. As the proportion of elderly patients with IBD increases, the potential for polypharmacy and adverse medication interactions also increases. Thus close liaison between gastroenterologists and patient’s general physicians needs to remain an integral in the care of patients with IBD.

Competing Interests

The authors have no conflict of interests to declare.

Acknowledgments

The authors are supported, in part, by Science Foundation Ireland in the form of a centre grant (Alimentary Pharmabiotic Centre: Grants SFI/12/RC/2273 and 12/RC/2273).

References

  1. N. A. Molodecky, I. S. Soon, D. M. Rabi et al., “Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review,” Gastroenterology, vol. 142, no. 1, pp. 46–54, 2012. View at Google Scholar
  2. J. Cosnes, C. Gower-Rousseau, P. Seksik, and A. Cortot, “Epidemiology and natural history of inflammatory bowel diseases,” Gastroenterology, vol. 140, no. 6, pp. 1785–1794, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. D. Sheehan, C. Moran, and F. Shanahan, “The microbiota in inflammatory bowel disease,” Journal of Gastroenterology, vol. 50, no. 5, pp. 495–507, 2015. View at Publisher · View at Google Scholar · View at Scopus
  4. T. Jess, L. Riis, I. Vind et al., “Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark,” Inflammatory Bowel Diseases, vol. 13, no. 4, pp. 481–489, 2007. View at Publisher · View at Google Scholar · View at Scopus
  5. V. J. A. A. Nuij, Z. Zelinkova, M. C. M. Rijk et al., “Phenotype of inflammatory bowel disease at diagnosis in the Netherlands: a population-based inception cohort study (the Delta Cohort),” Inflammatory Bowel Diseases, vol. 19, no. 10, pp. 2215–2222, 2013. View at Publisher · View at Google Scholar · View at Scopus
  6. K. T. Thia, W. J. Sandborn, W. S. Harmsen, A. R. Zinsmeister, and E. V. Loftus Jr., “Risk factors associated with progression to intestinal complications of Crohn's disease in a population-based cohort,” Gastroenterology, vol. 139, no. 4, pp. 1147–1155, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. B. Moum, M. H. Vatn, A. Ekbom et al., “Incidence of ulcerative colitis and indeterminate colitis in four counties of southeastern Norway, 1990–93: a prospective population-based study,” Scandinavian Journal of Gastroenterology, vol. 31, no. 4, pp. 362–366, 1996. View at Publisher · View at Google Scholar · View at Scopus
  8. S. C. Ng, W. Tang, J. Y. Ching et al., “Incidence and phenotype of inflammatory bowel disease based on results from the Asia-Pacific Crohn's and colitis epidemiology study,” Gastroenterology, vol. 145, no. 1, pp. 158–165.e2, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. S. J. Park, W. H. Kim, and J. H. Cheon, “Clinical characteristics and treatment of inflammatory bowel disease: a comparison of Eastern and Western perspectives,” World Journal of Gastroenterology, vol. 20, no. 33, pp. 11525–11537, 2014. View at Publisher · View at Google Scholar · View at Scopus
  10. K. Asakura, Y. Nishiwaki, N. Inoue, T. Hibi, M. Watanabe, and T. Takebayashi, “Prevalence of ulcerative colitis and Crohn's disease in Japan,” Journal of Gastroenterology, vol. 44, no. 7, pp. 659–665, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. S. C. Ng, Z. Zeng, O. Niewiadomski et al., “Early course of inflammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia,” Gastroenterology, vol. 150, no. 1, pp. 86–95, 2016. View at Publisher · View at Google Scholar
  12. K. Boonstra, K. J. van Erpecum, K. M. J. van Nieuwkerk et al., “Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 18, no. 12, pp. 2270–2276, 2012. View at Publisher · View at Google Scholar · View at Scopus
  13. C. Penna, R. Dozois, W. Tremaine et al., “Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis,” Gut, vol. 38, no. 2, pp. 234–239, 1996. View at Publisher · View at Google Scholar · View at Scopus
  14. H. H. Zheng and X. L. Jiang, “Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a meta-analysis of 16 observational studies,” European Journal of Gastroenterology & Hepatology, vol. 28, no. 4, pp. 383–390, 2016. View at Google Scholar
  15. A. F. Gulamhusein, J. E. Eaton, J. H. Tabibian, E. J. Atkinson, B. D. Juran, and K. N. Lazaridis, “Duration of inflammatory bowel disease is associated with increased risk of cholangiocarcinoma in patients with primary sclerosing cholangitis and IBD,” The American Journal of Gastroenterology, vol. 111, no. 5, pp. 705–711, 2016. View at Publisher · View at Google Scholar
  16. T. Nic Suibhne, T. C. Raftery, O. McMahon, C. Walsh, C. O'Morain, and M. O'Sullivan, “High prevalence of overweight and obesity in adults with Crohn's disease: associations with disease and lifestyle factors,” Journal of Crohn's and Colitis, vol. 7, no. 7, pp. e241–e248, 2013. View at Publisher · View at Google Scholar · View at Scopus
  17. H. Jia and E. I. Lubetkin, “Trends in quality-adjusted life-years lost contributed by smoking and obesity,” American Journal of Preventive Medicine, vol. 38, no. 2, pp. 138–144, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. V. B. Young, L. H. Raffals, S. M. Huse et al., “Multiphasic analysis of the temporal development of the distal gut microbiota in patients following ileal pouch anal anastomosis,” Microbiome, vol. 1, no. 1, article 9, 2013. View at Publisher · View at Google Scholar · View at Scopus
  19. H. Steed, S. Walsh, and N. Reynolds, “A brief report of the epidemiology of obesity in the inflammatory bowel disease population of Tayside, Scotland,” Obesity Facts, vol. 2, no. 6, pp. 370–372, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Flores, E. Burstein, D. J. Cipher, and L. A. Feagins, “Obesity in inflammatory bowel disease: a marker of less severe disease,” Digestive Diseases and Sciences, vol. 60, no. 8, pp. 2436–2445, 2015. View at Publisher · View at Google Scholar · View at Scopus
  21. G. W. Moran, M.-F. Dubeau, G. G. Kaplan, R. Panaccione, and S. Ghosh, “The increasing weight of Crohn's disease subjects in clinical trials: a hypothesis-generatings time-trend analysis,” Inflammatory Bowel Diseases, vol. 19, no. 13, pp. 2949–2956, 2013. View at Publisher · View at Google Scholar · View at Scopus
  22. C. Fink, I. Karagiannides, K. Bakirtzi, and C. Pothoulakis, “Adipose tissue and inflammatory bowel disease pathogenesis,” Inflammatory Bowel Diseases, vol. 18, no. 8, pp. 1550–1557, 2012. View at Publisher · View at Google Scholar · View at Scopus
  23. P. Gonçalves, F. Magro, and F. Martel, “Metabolic inflammation in inflammatory bowel disease: crosstalk between adipose tissue and bowel,” Inflammatory Bowel Diseases, vol. 21, no. 2, pp. 453–467, 2015. View at Publisher · View at Google Scholar · View at Scopus
  24. S. S. M. Chan, R. Luben, A. Olsen et al., “Body mass index and the risk for crohn's disease and ulcerative colitis: Data from a European Prospective Cohort Study (The IBD in EPIC Study),” American Journal of Gastroenterology, vol. 108, no. 4, pp. 575–582, 2013. View at Publisher · View at Google Scholar · View at Scopus
  25. M. A. Mendall, A. V. Gunasekera, B. J. John, and D. Kumar, “Is obesity a risk factor for Crohn's disease?” Digestive Diseases and Sciences, vol. 56, no. 3, pp. 837–844, 2011. View at Publisher · View at Google Scholar · View at Scopus
  26. H. Khalili, A. N. Ananthakrishnan, G. G. Konijeti et al., “Measures of obesity and risk of Crohn's disease and ulcerative colitis,” Inflammatory Bowel Diseases, vol. 21, no. 2, pp. 361–368, 2015. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Ferguson and D. M. Sedgwick, “Juvenile onset inflammatory bowel disease: height and body mass index in adult life,” British Medical Journal, vol. 308, no. 6939, pp. 1259–1263, 1994. View at Publisher · View at Google Scholar · View at Scopus
  28. S. Kugathasan, J. Nebel, J. A. Skelton et al., “Body mass index in children with newly diagnosed inflammatory bowel disease: observations from two multicenter North American inception cohorts,” The Journal of Pediatrics, vol. 151, no. 5, pp. 523–527, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. C. L. Ogden, M. D. Carroll, L. R. Curtin, M. M. Lamb, and K. M. Flegal, “Prevalence of high body mass index in US children and adolescents, 2007-2008,” The Journal of the American Medical Association, vol. 303, no. 3, pp. 242–249, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. M. D. Long, W. V. Crandall, I. H. Leibowitz et al., “Prevalence and epidemiology of overweight and obesity in children with inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 17, no. 10, pp. 2162–2168, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. A. Blain, S. Cattan, L. Beaugerie, F. Carbonnel, J. Gendre, and J. Cosnes, “Crohn's disease clinical course and severity in obese patients,” Clinical Nutrition, vol. 21, no. 1, pp. 51–57, 2002. View at Publisher · View at Google Scholar
  32. A. G. Renehan, M. Tyson, M. Egger, R. F. Heller, and M. Zwahlen, “Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies,” The Lancet, vol. 371, no. 9612, pp. 569–578, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. J. W. Harper, M. N. Sinanan, and T. L. Zisman, “Increased body mass index is associated with earlier time to loss of response to infliximab in patients with inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 19, no. 10, pp. 2118–2124, 2013. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Bhalme, A. Sharma, R. Keld, R. Willert, and S. Campbell, “Does weight-adjusted anti-tumour necrosis factor treatment favour obese patients with Crohn's disease?” European Journal of Gastroenterology and Hepatology, vol. 25, no. 5, pp. 543–549, 2013. View at Publisher · View at Google Scholar · View at Scopus
  35. M. K. Krane, M. E. Allaix, M. Zoccali et al., “Does morbid obesity change outcomes after laparoscopic surgery for inflammatory bowel disease? review of 626 consecutive cases,” Journal of the American College of Surgeons, vol. 216, no. 5, pp. 986–996, 2013. View at Publisher · View at Google Scholar · View at Scopus
  36. Population Division and DESA, United Nations: World Population Ageing 1950–2050, http://www.un.org/esa/population.
  37. G. C. Nguyen, L. Sheng, and E. I. Benchimol, “Health care utilization in elderly onset inflammatory bowel disease: A Population-Based Study,” Inflammatory Bowel Diseases, vol. 21, no. 4, pp. 777–782, 2015. View at Publisher · View at Google Scholar · View at Scopus
  38. C. Charpentier, J. Salleron, G. Savoye et al., “Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study,” Gut, vol. 63, no. 3, pp. 423–432, 2014. View at Publisher · View at Google Scholar · View at Scopus
  39. A. N. Ananthakrishnan, E. L. McGinley, and D. G. Binion, “Inflammatory bowel disease in the elderly is associated with worse outcomes: a national study of hospitalizations,” Inflammatory Bowel Diseases, vol. 15, no. 2, pp. 182–189, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. H. Cheddani, L. Dauchet, M. Fumery et al., “Cancer in elderly onset inflammatory bowel disease: a population-based study,” The American Journal of Gastroenterology, vol. 111, no. 10, pp. 1428–1436, 2016. View at Publisher · View at Google Scholar
  41. R. W. Lynch, D. Lowe, A. Protheroe, R. Driscoll, J. M. Rhodes, and I. D. R. Arnott, “Outcomes of rescue therapy in acute severe ulcerative colitis: data from the United Kingdom inflammatory bowel disease audit,” Alimentary Pharmacology and Therapeutics, vol. 38, no. 8, pp. 935–945, 2013. View at Publisher · View at Google Scholar · View at Scopus
  42. H. Ikeuchi, M. Uchino, H. Matsuoka et al., “Prognosis following emergency surgery for ulcerative colitis in elderly patients,” Surgery Today, vol. 44, no. 1, pp. 39–43, 2014. View at Publisher · View at Google Scholar · View at Scopus
  43. A. N. Ananthakrishnan, H. Y. Shi, W. Tang et al., “Systematic review and meta-analysis: phenotype and clinical outcomes of older-onset inflammatory bowel disease,” Journal of Crohn's and Colitis, vol. 10, no. 10, pp. 1224–1236, 2016. View at Publisher · View at Google Scholar
  44. J. K. Hou, L. A. Feagins, and A. K. Waljee, “Characteristics and behavior of elderly-onset inflammatory bowel disease: a multi-center US study,” Inflammatory Bowel Diseases, vol. 22, no. 9, pp. 2200–2205, 2016. View at Publisher · View at Google Scholar
  45. H. J. Freeman, “Crohn's disease initially diagnosed after age 60 years,” Age and Ageing, vol. 36, no. 5, pp. 587–589, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. M. Juneja, L. Baidoo, M. B. Schwartz et al., “Geriatric inflammatory bowel disease: phenotypic presentation, treatment patterns, nutritional status, outcomes, and comorbidity,” Digestive Diseases and Sciences, vol. 57, no. 9, pp. 2408–2415, 2012. View at Publisher · View at Google Scholar · View at Scopus
  47. M. J. Wagtmans, H. W. Verspaget, C. B. Lamers, and R. A. van Hogezand, “Crohn's disease in the elderly: a comparison with young adults,” Journal of Clinical Gastroenterology, vol. 27, no. 2, pp. 129–133, 1998. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Hadithi, M. Cazemier, G. A. Meijer et al., “Retrospective analysis of old-age colitis in the Dutch inflammatory bowel disease population,” World Journal of Gastroenterology, vol. 14, no. 20, pp. 3183–3187, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. E. Gizard, A. C. Ford, J.-P. Bronowicki, and L. Peyrin-Biroulet, “Systematic review: the epidemiology of the hepatobiliary manifestations in patients with inflammatory bowel disease,” Alimentary Pharmacology and Therapeutics, vol. 40, no. 1, pp. 3–15, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. C. N. Bernstein, J. F. Blanchard, P. Rawsthorne, and N. Yu, “The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study,” American Journal of Gastroenterology, vol. 96, no. 4, pp. 1116–1122, 2001. View at Publisher · View at Google Scholar · View at Scopus
  51. A. K. Lunder, J. R. Hov, A. Borthne et al., “Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with long-term inflammatory bowel disease,” Gastroenterology, vol. 151, no. 4, pp. 660–669.e4, 2016. View at Publisher · View at Google Scholar
  52. A. Sourianarayanane, G. Garg, T. H. Smith, M. I. Butt, A. J. McCullough, and B. Shen, “Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease,” Journal of Crohn's and Colitis, vol. 7, no. 8, pp. e279–e285, 2013. View at Publisher · View at Google Scholar · View at Scopus
  53. A. Rönnblom, T. Holmström, H. Tanghöj, F. Rorsman, and D. Sjöberg, “Appearance of hepatobiliary diseases in a population-based cohort with inflammatory bowel diseases (Inflammatory Bowel Disease Cohort of the Uppsala Region),” Journal of Gastroenterology and Hepatology, vol. 30, no. 8, pp. 1288–1292, 2015. View at Publisher · View at Google Scholar · View at Scopus
  54. T. Bessissow, N. H. Le, K. Rollet, W. Afif, A. Bitton, and G. Sebastiani, “Incidence and predictors of nonalcoholic fatty liver disease by serum biomarkers in patients with inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 22, no. 8, pp. 1937–1944, 2016. View at Publisher · View at Google Scholar
  55. D. L. Nguyen, M. L. Bechtold, and M. M. Jamal, “National trends and inpatient outcomes of inflammatory bowel disease patients with concomitant chronic liver disease,” Scandinavian Journal of Gastroenterology, vol. 49, no. 9, pp. 1091–1095, 2014. View at Publisher · View at Google Scholar · View at Scopus
  56. H. Yuhara, C. Steinmaus, D. Corley et al., “Meta-analysis: the risk of venous thromboembolism in patients with inflammatory bowel disease,” Alimentary Pharmacology and Therapeutics, vol. 37, no. 10, pp. 953–962, 2013. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Fumery, C. Xiaocang, L. Dauchet, C. Gower-Rousseau, L. Peyrin-Biroulet, and J.-F. Colombel, “Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: A Meta-Analysis of Observational Studies,” Journal of Crohn's and Colitis, vol. 8, no. 6, pp. 469–479, 2014. View at Publisher · View at Google Scholar · View at Scopus
  58. E. A. Scoville, G. G. Konijeti, D. D. Nguyen, J. Sauk, V. Yajnik, and A. N. Ananthakrishnan, “Venous thromboembolism in patients with inflammatory bowel diseases: a case-control study of risk factors,” Inflammatory Bowel Diseases, vol. 20, no. 4, pp. 631–636, 2014. View at Publisher · View at Google Scholar · View at Scopus
  59. S. L. Kristensen, O. Ahlehoff, J. Lindhardsen et al., “Inflammatory bowel disease is associated with an increased risk of hospitalization for heart failure: a danish nationwide cohort study,” Circulation: Heart Failure, vol. 7, no. 5, pp. 717–722, 2014. View at Publisher · View at Google Scholar · View at Scopus
  60. S. L. Kristensen, J. Lindhardsen, O. Ahlehoff et al., “Increased risk of atrial fibrillation and stroke during active stages of inflammatory bowel disease: a nationwide study,” Europace, vol. 16, no. 4, pp. 477–484, 2014. View at Publisher · View at Google Scholar · View at Scopus
  61. W.-S. Huang, C.-H. Tseng, P.-C. Chen et al., “Inflammatory bowel diseases increase future ischemic stroke risk: a Taiwanese population-based retrospective cohort study,” European Journal of Internal Medicine, vol. 25, no. 6, pp. 561–565, 2014. View at Publisher · View at Google Scholar · View at Scopus
  62. S. L. Kristensen, O. Ahlehoff, J. Lindhardsen et al., “Disease activity in inflammatory bowel disease is associated with increased risk of myocardial infarction, stroke and cardiovascular death—a Danish nationwide cohort study,” PLoS ONE, vol. 8, no. 2, Article ID e56944, 2013. View at Publisher · View at Google Scholar · View at Scopus
  63. J. R. Goodhand, M. Wahed, J. E. Mawdsley, A. D. Farmer, Q. Aziz, and D. S. Rampton, “Mood disorders in inflammatory bowel disease: relation to diagnosis, disease activity, perceived stress, and other factors,” Inflammatory Bowel Diseases, vol. 18, no. 12, pp. 2301–2309, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. E. McDermott, G. Mullen, J. Moloney et al., “Body image dissatisfaction: clinical features, and psychosocial disability in inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 21, no. 2, pp. 353–360, 2015. View at Publisher · View at Google Scholar · View at Scopus
  65. C. P. Selinger, J. Eaden, D. Brian Jones et al., “Modifiable factors associated with nonadherence to maintenance medication for inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 19, no. 10, pp. 2199–2206, 2013. View at Publisher · View at Google Scholar · View at Scopus
  66. E. Szigethy, S. I. Bujoreanu, A. O. Youk et al., “Randomized efficacy trial of two psychotherapies for depression in youth with inflammatory bowel disease,” Journal of the American Academy of Child and Adolescent Psychiatry, vol. 53, no. 7, pp. 726–735, 2014. View at Publisher · View at Google Scholar · View at Scopus
  67. J. R. Goodhand, F. I. S. Greig, Y. Koodun et al., “Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective case-matched observational study,” Inflammatory Bowel Diseases, vol. 18, no. 7, pp. 1232–1239, 2012. View at Publisher · View at Google Scholar · View at Scopus
  68. H. N. Iskandar, B. Cassell, N. Kanuri et al., “Tricyclic antidepressants for management of residual symptoms in inflammatory bowel disease,” Journal of Clinical Gastroenterology, vol. 48, no. 5, pp. 423–429, 2014. View at Publisher · View at Google Scholar · View at Scopus
  69. C. Rungoe, E. Langholz, M. Andersson et al., “Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979–2011,” Gut, vol. 63, no. 10, pp. 1607–1616, 2014. View at Publisher · View at Google Scholar · View at Scopus
  70. G. C. Nguyen, Z. Nugent, S. Shaw, and C. N. Bernstein, “Outcomes of patients with Crohn's disease improved from 1988 to 2008 and were associated with increased specialist care,” Gastroenterology, vol. 141, no. 1, pp. 90–97, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. A. V. Ramadas, S. Gunesh, G. A. O. Thomas, G. T. Williams, and A. B. Hawthorne, “Natural history of Crohn's disease in a population-based cohort from Cardiff (1986–2003): a study of changes in medical treatment and surgical resection rates,” Gut, vol. 59, no. 9, pp. 1200–1206, 2010. View at Publisher · View at Google Scholar · View at Scopus
  72. P. L. Lakatos, P. A. Golovics, G. David et al., “Has there been a change in the natural history of Crohn's disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977–2009,” American Journal of Gastroenterology, vol. 107, no. 4, pp. 579–588, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. M. W. M. D. Lutgens, M. G. H. van Oijen, G. J. M. G. van der Heijden, F. P. Vleggaar, P. D. Siersema, and B. Oldenburg, “Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies,” Inflammatory Bowel Diseases, vol. 19, no. 4, pp. 789–799, 2013. View at Publisher · View at Google Scholar · View at Scopus
  74. T. Jess, J. Simonsen, K. T. Jorgensen, B. V. Pedersen, N. M. Nielsen, and M. Frisch, “Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years,” Gastroenterology, vol. 143, no. 2, pp. 375–381, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. L. Lakatos, L. S. Kiss, G. David et al., “Incidence, disease phenotype at diagnosis, and early disease course in inflammatory bowel diseases in Western Hungary, 2002–2006,” Inflammatory Bowel Diseases, vol. 17, no. 12, pp. 2558–2565, 2011. View at Publisher · View at Google Scholar · View at Scopus
  76. D. Sjöberg, T. Holmström, M. Larsson et al., “Incidence and natural history of ulcerative colitis in the Uppsala Region of Sweden 2005–2009—results from the IBD Cohort of the Uppsala Region (ICURE),” Journal of Crohn's and Colitis, vol. 7, no. 9, pp. e351–e357, 2013. View at Publisher · View at Google Scholar · View at Scopus
  77. D. Sjöberg, T. Holmström, M. Larsson et al., “Incidence and clinical course of Crohn's disease during the first year—results from the IBD Cohort of the Uppsala Region (ICURE) of Sweden 2005–2009,” Journal of Crohn's and Colitis, vol. 8, no. 3, pp. 215–222, 2014. View at Publisher · View at Google Scholar · View at Scopus
  78. J. P. Buckley, M. D. Kappelman, J. K. Allen, S. A. Van Meter, and S. F. Cook, “The burden of comedication among patients with inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 19, no. 13, pp. 2725–2736, 2013. View at Publisher · View at Google Scholar · View at Scopus
  79. A. Parian and C. Y. Ha, “Older age and steroid use are associated with increasing polypharmacy and potential medication interactions among patients with inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 21, no. 6, pp. 1392–1400, 2015. View at Publisher · View at Google Scholar · View at Scopus
  80. R. K. Cross, K. T. Wilson, and D. G. Binion, “Polypharmacy and Crohn's disease,” Alimentary Pharmacology and Therapeutics, vol. 21, no. 10, pp. 1211–1216, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. R. K. Cross, K. T. Wilson, and D. G. Binion, “Narcotic use in patients with Crohn's disease,” American Journal of Gastroenterology, vol. 100, no. 10, pp. 2225–2229, 2005. View at Publisher · View at Google Scholar · View at Scopus
  82. L. E. Targownik, Z. Nugent, H. Singh, S. Bugden, and C. N. Bernstein, “The prevalence and predictors of opioid use in inflammatory bowel disease: a population-based analysis,” The American Journal of Gastroenterology, vol. 109, no. 10, pp. 1613–1620, 2014. View at Publisher · View at Google Scholar · View at Scopus
  83. M. D. Long, E. L. Barnes, H. H. Herfarth, and D. A. Drossman, “Narcotic use for inflammatory bowel disease and risk factors during hospitalization,” Inflammatory Bowel Diseases, vol. 18, no. 5, pp. 869–876, 2012. View at Publisher · View at Google Scholar · View at Scopus
  84. A. A. Mikocka-Walus, D. Turnbull, G. Holtmann, and J. M. Andrews, “An integrated model of care for inflammatory bowel disease sufferers in Australia: development and the effects of its implementation,” Inflammatory Bowel Diseases, vol. 18, no. 8, pp. 1573–1581, 2012. View at Publisher · View at Google Scholar · View at Scopus
  85. D. Duricova, N. Pedersen, M. Elkjaer, M. Gamborg, P. Munkholm, and T. Jess, “Overall and cause-specific mortality in Crohn's disease: a meta-analysis of population-based studies,” Inflammatory Bowel Diseases, vol. 16, no. 2, pp. 347–353, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. M. Bewtra, L. M. Kaiser, T. Tenhave, and J. D. Lewis, “Crohn's disease and ulcerative colitis are associated with elevated standardized mortality ratios: a meta-analysis,” Inflammatory Bowel Diseases, vol. 19, no. 3, pp. 599–613, 2013. View at Publisher · View at Google Scholar · View at Scopus
  87. T. Jess, M. Gamborg, P. Munkholm, and T. I. A. Sørensen, “Overall and cause-specific mortality in ulcerative colitis: meta-analysis of population-based inception cohort studies,” The American Journal of Gastroenterology, vol. 102, no. 3, pp. 609–617, 2007. View at Publisher · View at Google Scholar · View at Scopus
  88. C. N. Bernstein, Z. Nugent, L. E. Targownik, H. Singh, and L. M. Lix, “Predictors and risks for death in a population-based study of persons with IBD in Manitoba,” Gut, vol. 64, no. 9, pp. 1403–1411, 2015. View at Publisher · View at Google Scholar · View at Scopus
  89. T. Jess, M. Frisch, and J. Simonsen, “Trends in overall and cause-specific mortality among patients with inflammatory bowel disease from 1982 to 2010,” Clinical Gastroenterology and Hepatology, vol. 11, no. 1, pp. 43–48, 2013. View at Publisher · View at Google Scholar · View at Scopus
  90. A. O'toole, P. Walsh, D. Keegan et al., “Mortality in inflammatory bowel disease patients under 65 years of age,” Scandinavian Journal of Gastroenterology, vol. 49, no. 7, pp. 814–819, 2014. View at Publisher · View at Google Scholar · View at Scopus
  91. L. H. Wang, Y. J. Yang, W. C. Cheng, W. Wang, S. Lin, and C. Shieh, “Higher risk for hematological malignancies in inflammatory bowel disease: a nationwide population-based study in Taiwan,” The American Journal of Gastroenterology, vol. 111, no. 9, pp. 1313–1319, 2016. View at Publisher · View at Google Scholar
  92. C. Castaño-Milla, M. Chaparro, and J. P. Gisbert, “Systematic review with meta-analysis: the declining risk of colorectal cancer in ulcerative colitis,” Alimentary Pharmacology and Therapeutics, vol. 39, no. 7, pp. 645–659, 2014. View at Publisher · View at Google Scholar · View at Scopus
  93. L. Beaugerie and S. H. Itzkowitz, “Cancers complicating inflammatory bowel disease,” New England Journal of Medicine, vol. 372, no. 15, pp. 1441–1452, 2015. View at Publisher · View at Google Scholar · View at Scopus
  94. A. N. Ananthakrishnan, A. Cagan, T. Cai et al., “Colonoscopy is associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases,” Clinical Gastroenterology and Hepatology, vol. 13, no. 2, pp. 322.e1–329.e1, 2015. View at Publisher · View at Google Scholar · View at Scopus
  95. H. Brenner, J. Chang-Claude, C. M. Seiler, A. Rickert, and M. Hoffmeister, “Protection from colorectal cancer after colonoscopy: a population-based, case-control study,” Annals of Internal Medicine, vol. 154, no. 1, pp. 22–30, 2011. View at Publisher · View at Google Scholar · View at Scopus
  96. M. D. Kappelman, D. K. Farkas, M. D. Long et al., “Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation,” Clinical Gastroenterology and Hepatology, vol. 12, no. 2, pp. 265.e1–273.e1, 2014. View at Publisher · View at Google Scholar · View at Scopus
  97. D. S. Kotlyar, J. D. Lewis, L. Beaugerie et al., “Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-analysis,” Clinical Gastroenterology and Hepatology, vol. 13, no. 5, pp. 847–858.e4, 2015. View at Publisher · View at Google Scholar · View at Scopus
  98. J. R. Allegretti, E. L. Barnes, and A. Cameron, “Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis,” Inflammatory Bowel Diseases, vol. 21, no. 5, pp. 1089–1097, 2015. View at Publisher · View at Google Scholar · View at Scopus
  99. U. Kopylov, M. Vutcovici, A. Kezouh, E. Seidman, A. Bitton, and W. Afif, “Risk of lymphoma, colorectal and skin cancer in patients with IBD treated with immunomodulators and biologics: A Quebec Claims Database Study,” Inflammatory Bowel Diseases, vol. 21, no. 8, pp. 1847–1853, 2015. View at Publisher · View at Google Scholar · View at Scopus
  100. M. D. Long, C. F. Martin, C. A. Pipkin, H. H. Herfarth, R. S. Sandler, and M. D. Kappelman, “Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease,” Gastroenterology, vol. 143, no. 2, pp. 390.e1–399.e1, 2012. View at Publisher · View at Google Scholar · View at Scopus
  101. A. D. Frolkis, J. Dykeman, M. E. Negrón et al., “Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies,” Gastroenterology, vol. 145, no. 5, pp. 996–1006, 2013. View at Publisher · View at Google Scholar · View at Scopus
  102. E. K. Wright, M. A. Kamm, P. De Cruz et al., “Effect of intestinal resection on quality of life in Crohn's disease,” Journal of Crohn's and Colitis, vol. 9, no. 6, pp. 452–462, 2015. View at Google Scholar
  103. G. Cullen, A. O'Toole, D. Keegan, K. Sheahan, J. M. Hyland, and D. P. O'Donoghue, “Long-term clinical results of ileocecal resection for Crohn's disease,” Inflammatory Bowel Diseases, vol. 13, no. 11, pp. 1369–1373, 2007. View at Publisher · View at Google Scholar · View at Scopus
  104. C. Ha, T. A. Ullman, C. A. Siegel, and A. Kornbluth, “Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population,” Clinical Gastroenterology and Hepatology, vol. 10, no. 9, pp. 1002–1007, 2012. View at Publisher · View at Google Scholar · View at Scopus
  105. G. E. Reese, T. Nanidis, C. Borysiewicz, T. Yamamoto, T. Orchard, and P. P. Tekkis, “The effect of smoking after surgery for Crohn's disease: a meta-analysis of observational studies,” International Journal of Colorectal Disease, vol. 23, no. 12, pp. 1213–1221, 2008. View at Publisher · View at Google Scholar · View at Scopus