Globalisation of inflammatory bowel disease: perspectives from the evolution of inflammatory bowel disease in the UK and China

Review

Globalisation of inflammatory bowel disease: perspectives from the evolution of inflammatory bowel disease in the UK and China Gilaad G Kaplan, Siew C Ng

The UK and China provide unique historical perspectives on the evolution of the incidence of inflammatory bowel disease, which might provide insight into its pathogenesis. Historical records from the UK document the emergence of ulcerative colitis during the mid-1800s, which was later followed by the recognition of Crohn’s disease in 1932. During the second half of the 20th century, the incidence of inflammatory bowel disease rose dramatically in high-income countries. Globalisation at the turn of the 21st century led to rapid economic development of newly industrialised countries such as China. In China, the modernisation of society was accompanied by the recognition of a sharp rise in the incidence of inflammatory bowel disease. The prevalence of inflammatory bowel disease is expected to continue to rise in high-income countries and is also likely to accelerate in the developing world. An understanding of the shared and different environmental determinants underpinning the pathogenesis of inflammatory bowel disease in western and eastern countries is essential to implement interventions that will blunt the rising global burden of inflammatory bowel disease.

Introduction Inflammatory bowel disease—including Crohn’s disease and ulcerative colitis—describes chronic inflammatory conditions of the gastrointestinal tract that are believed to arise in genetically susceptible individuals exposed to environmental exposures, resulting in an abnormal immune response to the intestinal microbiome.1 More than 200 susceptibility loci have been associated with development of Crohn’s disease or ulcerative colitis.2 Many of these genes are involved with the interplay between the gastrointestinal immune systems and the intestinal microbiome.3 Numerous environmental exposures influence the development of inflammatory bowel disease, with evidence suggesting that factors such as smoking and diet might confer a risk through manipulation of the intestinal microbiome.4,5 Historically, inflammatory bowel disease was described as a disease of white people of European descent who were raised in highly affluent western countries such as the UK, North America, and Australia.6 In the last decade, these notions have been shattered as numerous epidemiological studies have shown that diagnosis of inflammatory bowel disease is not limited by socioeconomic status, race and ethnicity, or geographical borders. This realisation indicates that the disease is not genetically imprinted, but manifests through environmental pressures driven by the westernisation of society—defined as the alteration of society towards increased urbanisation, more hygienic environments, industrialisation, and diets lower in dietary fibre and higher in meat. The major drivers of westernisation need to be understood to develop interventional strategies that can mitigate the development of inflammatory bowel disease and reduce its burden among afflicted individuals.6 The UK represents a prime example of the westernisation of society, additionally offering the www.thelancet.com/gastrohep Vol 1 December 2016

possibility of correlating societal changes to the emergence and rise of inflammatory bowel disease in high-income countries. Since the early descriptions of ulcerative colitis in the 1800s, a rich history of case descriptions, hospital records, and modern epidemiological studies have been recorded in the UK.7 This 200-year body of work provides clues to the origin of inflammatory bowel disease. Unfortunately, the environmental drivers of inflammatory bowel disease remain a mystery because the disease has largely been studied in nations where the westernisation of society was established generations ago. The rise of inflammatory bowel disease in newly industrialised countries such as China offers an unprecedented opportunity to essentially travel back in time and study the origin of a disease using 21st-century knowledge and techniques.8–10 The purpose of this Review is to contrast the evolution of inflammatory bowel disease in the UK and China to understand the common patterns driving its incidence and to prepare for its global rise.

Lancet Gastroenterol Hepatol 2016; 1: 307–16 Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, AB, Canada (G G Kaplan MD); and Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China (Prof S C Ng PhD) Correspondence to: Gilaad Kaplan, Teaching Research and Wellness Center, 3280 Hospital Drive NW, 6D56 Calgary, AB T2N 4Z6, Canada [email protected]

200-year history of inflammatory bowel disease in the UK Inflammatory bowel disease is considered a relatively new disease. In 1859, Sir Samuel Wilks of England recognised a gastrointestinal disease distinct from infectious gastroenteritis, which was subsequently named ulcerative colitis in 1875.11 By contrast, Crohn, Ginzburg, and Oppenheimer12 first described regional ileitis—now known as Crohn’s disease—in 1932. The UK’s health system includes a robust historical record of medical conditions through time that can paint a picture of the evolution of inflammatory bowel disease over the past 200 years.8,13,14 Tracking its evolution across time is essential to understand the environmentally driven root causes of inflammatory bowel disease embedded in post-industrialised changes to society (figure 1). 307

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1828 Abercrombie’s book describes early cases of inflammatory bowel disease in the UK

1977 Crohn’s disease incidence in Cardiff climbs to 1·7 per 100 000

1909 Allchin’s address on ulcerative colitis to the Royal Society of Medicine in London

2002 Prevalence of Crohn’s disease is 130 per 100 000 and prevalence of ulcerative colitis is 243 per 100 000 in the UK

1932 Crohn, Ginzburg, and Oppenheimer’s paper on regional ileitis in the USA

2005 Crohn’s disease incidence in Cardiff is 6·6 per 100 000 UK

2010 Estimated 266 394 inflammatory bowel disease cases in China

1956 First case of ulcerative colitis reported in China 2000 Up to 2000 patients with Crohn’s disease and up to 10 000 patients with ulcerative colitis in China

China

2016 Six regions in China display inflammatory bowel disease incidence from 0·5 to 3·4 per 100 000 Ulcerative colitis to Crohn’s disease ratio reduced from 8·9 to 1·0 in China

Figure 1: Historical development of inflammatory bowel disease in the UK and China

The industrial revolution was born in the UK during the 18th century, leading to remarkable social, environmental, dietary, occupational, and cultural changes.15 By the early 1800s, several landmark medical cases were reported which, when viewed through a retrospective prism, include some of the earliest descriptions of diseases that today are referred to as inflammatory bowel disease.13,16–18 Take, for example, John Abercrombie’s 1828 book, Pathological and Practical Researches on Diseases of the Stomach, the Intestinal Canal, the Liver and Other Viscera of the Abdomen, which includes comprehensive case descriptions of digestive diseases in the UK.19 Among the 97 cases of digestive diseases described in Abercrombie’s book, several cases might have been inflammatory bowel disease. One such case is a 13-year-old girl from Edinburgh who is considered one of the earliest case descriptions of paediatric-onset Crohn’s disease.13,18,19 Additionally, many contemporary physicians have retrospectively argued that cases in the 1800s recorded as chronic infectious gastroenteritis or dysentery, abdominal tuberculosis, chronic appendicitis, and bowel cancer were actually ulcerative colitis or Crohn’s disease.13,16–18,20,21 Collectively, medical records from the early-to-mid-1800s imply that inflammatory bowel disease had already emerged in the UK. On Jan 26, 1909, Sir William Allchin addressed the Royal Society of Medicine in London, UK. In his address he stated “ulcerative colitis is a provisional title therefore, 308

and its future retention or rejection will be largely determined by a clearing up of certain points in connexion with the natural history of the disease”.22 The address described hundreds of cases of ulcerative colitis admitted to five London hospitals, with Allchin estimating that each hospital admitted two to three cases of ulcerative colitis per year.22 At the turn of the 20th century, increased reporting of ulcerative colitis was driven by multiple factors: expanded awareness, advances in medical technology (eg, advent of rigid sigmoidoscopy), and organised data records from hospitals. By systematically tabulating diagnoses, hospitals provided insight into the rising incidence of ulcerative colitis during the early 1900s in the UK, ultimately confirming the retention of ulcerative colitis as an everlasting title.7 Cardiff is one of few regions to have continuously documented the changing incidence of a disease from its origin (ie, recognition of Crohn’s disease in 1932) to the burden it imparts in the 21st century. The original publication from Mayberry, Rhodes, and Hughes23 in 1979 documented the rising incidence of Crohn’s disease from 1934 to 1977. This historic seven-decade study documented a slow yet steady rise in the incidence of Crohn’s disease from approximately 1·7 per 100 000 per year (1934–77) to 6·6 per 100 000 per year (1996–2005).23–26 Since 2000, UK studies have reported a rise in the incidence of Crohn’s disease (from 2·4 to 8·9 per 100 000 per year) and ulcerative colitis (from 9·7 to 16·9 per 100 000 per year).8 Prevalence in 2002 was estimated at 130 per 100 000 for www.thelancet.com/gastrohep Vol 1 December 2016

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Crohn’s disease and 243 per 100 000 for ulcerative colitis.27 Today, 2·5–3 million residents of Europe are estimated to be afflicted with inflammatory bowel disease28—a remarkable evolution for diseases that were merely a handful of sporadic cases in the early 1800s.

100-year history of inflammatory bowel disease in China China is home to 20% of the world’s population. In 2015, approximately 1·4 billion people lived in China. Inflammatory bowel disease was previously thought to be rare in China, but is now rapidly increasing. Incidence and prevalence of inflammatory bowel disease in China is mimicking the rapid evolution of inflammatory bowel disease in the developed world as a result of a rapid society transition culminating in a westernised environment (figure 1).29 In China, the first case of ulcerative colitis was reported in 1956 by the Peking Union Medical College Hospital.30,31 Since then, the incidence of ulcerative colitis has risen substantially.9,32,33 The diagnostic criteria of ulcerative colitis in China—similar to that of the Lennard-Jones criteria—was published in 1978, and subsequently revised at the 1993 National Conference of Chronic Non-Infective Diarrhoea Disease in Taiyuan, China.34 Traditional Chinese medicine has been widely used to treat inflammatory bowel disease in China. Because many patients with chronic diarrhoea seek traditional Chinese medicine, inflammatory bowel disease in China was probably underestimated, especially before 1978 when the disease was not well recognised in China. In 2002, in one of the first large-scale analyses,31 10 218 cases of ulcerative colitis were identified from 1560 Chinese papers published between 1981 and 2000. Among these, 2506 cases were diagnosed between 1981 and 1990, and 7512 between 1991 and 2000—tripling from one decade to the next. A review of the Chinese literature revealed that approximately 150 000 cases of inflammatory bowel disease (97% were ulcerative colitis) have been reported in the past 15 years.35,36 Ouyang and colleagues37 searched the Chinese Scientific and Technological Periodical Contents and the Chinese Biological and Medical databases for inflammatory bowel disease cases from 1991 to 2010 and found that the number of cases increased from 76 530 to 266 394, corresponding to a 2·5-fold increase. Similarly, reports of Crohn’s disease are becoming more common in several provinces and cities in mainland China, although a lag phase exists when compared with ulcerative colitis.38,39 From 1950 to 2002, 1526 cases of Crohn’s disease were reported by more than 50 hospitals from 22 provinces and cities in mainland China, with a male predominance and a mean age at diagnosis of 37 years.40 By 2000, reports suggested there were up to 2000 patients with Crohn’s disease in China.38 Since then, the estimated number of patients with Crohn’s disease in mainland China has ranged from www.thelancet.com/gastrohep Vol 1 December 2016

18 000 to 48 000.40 Accurate population-based prevalence and incidence data of Crohn’s disease is difficult to provide, because the absence of specific clinical manifestations of Crohn’s disease and the difficulty in differentiating the disease from intestinal tuberculosis means patients have often been misdiagnosed. A conservative estimate of the prevalence of ulcerative colitis in China is 11·6 per 100 000, and 1·4 per 100 000 for Crohn’s disease.41 In 2013, the first population-based incidence studies of inflammatory bowel disease were reported from two areas in China.9,33 The first study was done in 2010 in central Wuhan, where gastroenterologists in 17 hospitals identified new cases of inflammatory bowel disease; the study covered the health-care service of central Wuhan with an at-risk population of 6 million. The study found 131 new cases of inflammatory bowel disease: 97 ulcerative colitis cases and 34 Crohn’s disease cases. That same year, a second population-based study from Guangdong Province in southern China reported that the incidence of Crohn’s disease and ulcerative colitis were 0·5 and 1·5 per 100 000 people in Wuhan and 1·1 and 2·1 per 100 000 people in Guangzhou, respectively.9 A year later, reports from Daqing, northern China, showed a lower age-adjusted incidence for Crohn’s disease (0·1 per 100 000 people per year) and ulcerative colitis (1·6 per 100 000 people per year).9,32,33 The incidence of inflammatory bowel disease appeared to be higher in southern China compared with northern China (3·9 vs 2·0 per 100 000 people per year).9,33 This difference might relate to increased urbanisation and economic standing in certain areas of southern China, such as Guangzhou. In a multinational population-based study42 conducted between 2011 and 2013 across Asia, involving nine regions of China (Hong Kong, Macau, Guangzhou, Wuhan, Chengdu, Xian, Daqing, Kunming, and Xiangshan), the incidence of ulcerative colitis varied from 0·07 to 4·90 per 100 000 people per year and the incidence of Crohn’s disease varied from 0·07 to 3·86 per 100 000 people per year. The highest incidence of inflammatory bowel disease occurred within urbanised regions of Asia such as Guangzhou, Hong Kong, and Macau, whereas incidence remained very low in regions with more rural inhabitants and less industrialisation.42 Within China, the incidence of inflammatory bowel disease is considerably higher in urban areas compared with in rural areas.42 This variation might be explained by differences in climate, lifestyle, diet, and living conditions between different parts of China. Furthermore, economic differences between urban and rural areas, as well as access to health care and technology including endoscopy, might be more limited in rural parts of China. Hong Kong, one of the most affluent cities in China, has undergone rapid socioeconomic changes since 1990—a transformation which is underway in mainland China. In the first national inflammatory bowel disease registry in Hong Kong, over 2500 patients with 309

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inflammatory bowel disease were identified from 1981 to 2014. Age-adjusted incidence per 100 000 individuals increased by 30-fold from 0·1 in 1985 to 3·1 in 2014, whereas the incidence ratio of ulcerative colitis to Crohn’s disease reduced from 8·9 to 1·0 over 30 years.43 Hong Kong has been largely urban since the 19th and early 20th centuries, remaining a British colony until 1997. By contrast, China is well on its way to becoming a predominantly urban nation by 2035.44 China’s urban population is estimated to balloon by 200 million within a decade. With mainland China reaching increased affluence in urbanisation, diet, and medical access, it might yet follow the path of Hong Kong with rising inflammatory bowel disease incidence. The resulting pressure on China’s health-care system and on its people could be substantial.

Lessons learned from history The historical perspective on the rise of inflammatory bowel disease in the UK and China highlights common patterns that give clues into the pathogenesis of the disease. Inflammatory bowel disease emerges in parallel with industrialisation and economic societal advancement. In the UK, ulcerative colitis emerged at the turn of the 19th century and was soon joined by Crohn’s disease in the early 20th century. The epidemiological study tracing the incidence of Crohn’s disease from 1934 to 1977 in Cardiff highlighted that the steepest rise in incidence began after World War 2.23 During these times, British society further transitioned from an agricultural-based economy to an industrial-based economy, which was followed by urbanisation of cities with rapid population growth and increased density.15 The rapid growth of urban centres necessitated a shift in diet to feed the population, gravitating towards increased propensity for refined sugars and animal fat and reduced consumption of plantbased foods and fibre.6,15 Similar patterns have also been observed in China—just later in time. Until about 150 years ago, most Chinese individuals had little or no contact with western people and were not influenced by western dietary habits or lifestyle, instead leading lifestyles characterised by low-calorie, carbohydrate-rich diets with minimal animal fat and regular physical activity. Since economic reform in 1978, China has undergone a rapid and exponential rise in both national and personal incomes.45 This rise has been accompanied by a substantial change in lifestyle, associated with an increase in consumption of sugar-rich carbonated beverages, animal and dairy products, and processed meals, along with a concurrent decrease in intake of dietary fibre. According to the Chinese National Nutrition Survey,46 from 1992 to 2006, China saw the proportion of energy intake from animal foods rise from 9% to 14% and the proportion from fat rise from 22% to 30%. The proportion of mainland Chinese living in urban areas also doubled from 1982 to 2012, reaching 50%. During this period, the number of inflammatory bowel disease cases 310

rose by approximately 2·5-fold, with a 15·7-fold increase in the number of patients with Crohn’s disease.37 Rapid economic transformation has created a fertile ground for an epidemic of inflammatory bowel disease in newly industrialised countries undergoing westernisation of their societies. The risk of developing the disease is increased for individuals exposed to a westernised environment early in life. In western countries, the incidence of paediatric-onset inflammatory bowel disease continues to rise,47 whereas adult-onset inflammatory bowel disease has stabilised and, in some cases, begun to decline.48,49 By contrast, environmental exposures that have specific age effects might explain the differential patterns in incidence across age groups. For example, the prevalence of smoking in western countries has steadily dropped over the past generation. Adolescents in the 1990s and 2000s who did not start smoking—often owing to public health initiatives— would have been less likely to subsequently develop Crohn’s disease in adulthood. Also, first-generation offspring of immigrants from southeast Asia, a low-prevalence region, to the UK were at increased risk of being diagnosed with inflammatory bowel disease50—a finding corroborated by a Canadian study.51 As the disease is most commonly diagnosed in adolescence and early adulthood, the rapidly rising incidence seen in China today might reflect the influence of economic reforms introduced in 1978 that would have primarily affected children born since the 1980s. In part, the correlation between the rapid rise in the incidence and economic advancement of nations is also explained by expansion of awareness, recognition, detection, and disease surveillance.6 Nonetheless, within this scenario, chronic inflammatory diseases like inflammatory bowel disease emerge and flourish. Although the presence of inflammatory bowel disease shares many common traits in its eastern and western manifestations, several important differences exist that could shed light onto the environmental determinants of the disease.

Contrasting environmental risk factors Crohn’s disease and ulcerative colitis are polyphenotypic diseases. Genetic research has shown that inflammatory bowel disease is associated with 200 susceptible loci.2,3 However, one of the most commonly identified Crohn’s disease loci in white individuals which regulates autophagy—ATG16L1—is not genetically linked to Asians with Crohn’s disease.52 By contrast, NOD2 is associated with Crohn’s disease in both white individuals living in the UK and Asians residing in China, but different single nucleotide polymorphisms exist among patients carrying NOD2 variants in the west (1007fs, Arg702Trp, Glu908Arg) versus the east (Pro268Ser).52 The first and largest trans-ancestry association study of inflammatory bowel disease found that although the majority of inflammatory bowel disease risk loci showed consistent direction and magnitude in both western and www.thelancet.com/gastrohep Vol 1 December 2016

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eastern populations, cross-population variance can be explained by differences in effect size (TNFSF15 and ATG16L1) and in allele frequency (NOD2) for some of these loci.2 Overall, genetic susceptibility loci suggest that the pathogenesis of inflammatory bowel disease is driven by the interplay of an abnormal immune response to intestinal microbes. However, the molecular mechanisms underpinning the pathogenesis of inflammatory bowel disease might differ between Asia and western countries (figures 2, 3). Unsurprisingly, the environmental determinants of inflammatory bowel disease in the east do not entirely mirror those in the west (figures 2, 3). Some environmental modifiers of the disease seem to be universal in that studies consistently demonstrate an association in regions across the world. For example, breastfeeding has long been considered protective for Crohn’s disease and ulcerative colitis, as well as other chronic immune-mediated diseases like asthma, in western countries.53 Likewise, the ACCESS54 cohort demonstrated that individuals who were breastfed for less than a year had an approximately tenfold higher risk of developing Crohn’s disease or ulcerative colitis than individuals who were breastfed for a year or longer. In China, growth of the formula-milk market since the 1980s—paralleling the rapid development of China’s economy—has led to a substantial drop in breastfeeding. In 2014, less than 16% of urban Chinese women (30% in rural China) exclusively breastfed their infants,55 despite WHO’s recommendation of exclusive breastfeeding for 6 months. In both urban and rural regions, the rates continue to decline. The shift away from breastfeeding in a post-industrialised society appears to be a consistent risk factor for the development of inflammatory bowel disease, regardless of geography and ethnicity. In rural China, such as the Yunnan Province, where a similar, high proportion of patients with inflammatory bowel disease and matched controls breastfed their infants, a lower disease incidence has been reported.56 Diet has long been considered an important environmental determinate of inflammatory bowel disease, particularly as understanding of the effect of diet on the microbiome expands.57,58 Despite this knowledge, study of diet as a modifier of the risk of inflammatory bowel disease has proven challenging and led to inconsistent conclusions in the west.59 However, cohort studies have provided reliable data by capturing dietary information using validated questionnaires prior to the diagnosis of the disease. For example, high fibre consumption has been shown to be associated with a reduced risk of development of inflammatory bowel disease in western countries.60 In China, the consumption of fried or salty foods and frozen meals has been associated with a risk of ulcerative colitis, whereas fruit consumption was protective.56 In studies from China, tea was a novel protective factor for inflammatory bowel disease development,54 and studies www.thelancet.com/gastrohep Vol 1 December 2016

Crohn’s disease UK

China

Risk factors (+) Antibiotics <15 years of age Smoking Intestinal infections Appendectomy Genes (+) ATG16L1 (+) NOD2 (1007fs, Arg702Trp, Glu908Arg)* (+) IL-23*

Protective (–) Breastfeeding Genes (+) TNFSF8–TNFSF15† (+) IRGM (+) PTGER4

Protective (–) Antibiotics <15 years of age Pet dog in childhood Tea consumption Physical activity Null difference (/) Smoking Appendectomy Genes (/) ATG16L1 (+) NOD2 (Pro268Ser) (+) CXCL5

Figure 2: Examples of dissimilar and shared genetic and environmental determinants of Crohn’s disease between the UK and China fs=frameshift. *Monomorphic in Chinese and east Asian people. †Larger effect size in Chinese and east Asian people.

Ulcerative colitis UK Protective (–) Appendectomy Null difference (/) Flush toilet in childhood Daily coffee consumption Risk factors (+) Antibiotics <15 years of age Smoking Intestinal infections Genes (+) IL23A

Protective (–) Breastfeeding Former smoker Genes (+) HLA-DQA1* (+) HLA-DQB1* (+) FCGR2A (+) RNF186 (+) OTUD3

Protective (–) China Antibiotics <15 years of age Tea consumption Fruit consumption Physical activity In-house water tap in childhood Flush toilet in childhood Null difference (/) Appendectomy Intestinal infections Risk factors (+) Fried, salty, or frozen food Heavy sugar intake Genes (+) PTGER3 (+) TNF308 (+) CTLA4

Figure 3: Examples of dissimilar and shared genetic and environmental determinants of ulcerative colitis between the UK and China *Larger effect size in Chinese and east Asian people.

have confirmed that dietary polyphenols, such as green tea polyphenols, possess both protective and therapeutic effects in mucosal inflammation. Additive compounds, including dietary emulsifiers used in modern diets, might have contributed to the increased incidence of inflammatory bowel disease. Dietary emulsifiers (carboxymethylcellulose and polysorbate-80) at 0·1% concentrations were sufficient to induce low-grade inflammation in mice through disruption of the composition of their intestinal microbiota, thereby predisposing these animals to the development of colitis and metabolic syndrome.61 The growth of the emulsifier 311

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industry in Asia has primarily been driven by increased processed-food production and innovations in dairy, bakery, oil, and meat products. Whether the chronic and broad use of emulsifiers in food products also predisposes humans with increased susceptibility to the onset of metabolic or inflammatory diseases remains unclear. Further studies are required to investigate the exact levels of exposures to these compounds in humans, along with the mechanisms and the effects of the compounds on obesity, intestinal inflammation, and the microbiota. According to WHO, physicians, especially those in primary health care, are prescribing antibiotics to half of all outpatients. Antibiotic use early in life or just prior to diagnosis has been shown in several western studies to be associated with the development of Crohn’s disease.62 The putative mechanism is thought to be via disturbances of the gut microflora. By contrast, an Asian cohort study and a study of Middle Eastern migrants residing in Australia showed that antibiotic use before the age of 15 years was associated with a reduced risk of development of Crohn’s disease.63 Future confirmatory studies from Asia specifically looking at the types and duration of antibiotics are necessary to determine whether antibiotic use in childhood has differential effects between eastern and western populations.54 The so-called hygiene hypothesis postulates that individuals raised in a sanitary environment are more likely to develop inflammatory bowel disease. Countries with high levels of hygiene and income are associated with increased risk of developing the disease.64 This correlation is observed in western countries after the 1950s where the first wave of rapid modernisation and increasing affluence after World War 2 corresponded to the rising incidence of inflammatory bowel disease. Several factors which act as proxy markers related to hygiene—including childhood rural dwelling, farm-animal access, large family size, bedroom sharing, urbanisation, and pet ownership—have been associated with a decreased development of both Crohn’s disease and ulcerative colitis.65–67 In China and parts of Asia, the incidence of tuberculosis and Helicobacter pylori is declining, corresponding to an increased incidence of inflammatory bowel disease.68 What remains unknown is whether the hygiene hypothesis is applicable worldwide. The presence of confounding factors makes isolation of hygiene as the sole responsible risk factor in the development of inflammatory bowel disease difficult. Socioeconomic affluence, geography, and diet—which are associated with hygiene status—might be independent risk factors themselves in the development of the disease. Smoking appears to be the most interesting paradox between western and eastern countries. In western countries, the association between smoking and inflammatory bowel disease is paradoxical: compared with never smokers, current smokers are more likely to be diagnosed with Crohn’s disease, whereas former 312

smokers are more likely to be diagnosed with ulcerative colitis.69 By contrast, studies54,56,70 show that former smokers in China are more likely to be diagnosed with ulcerative colitis, but current smokers are not more likely to be diagnosed with Crohn’s disease. That a consistent relationship exists for smoking in ulcerative colitis in both western and eastern countries but does not exist for smoking and Crohn’s disease is a puzzling mystery. Comparative epidemiological studies evaluating environmental determinants of inflammatory bowel disease across different populations—ranging from highly developed western countries to newly industrialised countries of Asia to developing nations in Africa—offer the potential to comprehensively explain the different mechanisms that drive evolution of inflammatory bowel disease in society. Understanding of these environmental modifiers of inflammatory bowel disease is required to address the global rise in its incidence and prevalence.

Future global evolution of inflammatory bowel disease The prevalence of inflammatory bowel disease continues to steadily rise in western countries.8 The young age of onset and low mortality of the disease, in conjunction with natural population growth, causes compounding prevalence over time.6 Predictive modelling estimates the prevalence of inflammatory bowel disease in Canada will rise by 2·8% per year from 2015 to 2025, which corresponds to a predicted prevalence of 0·9% of the population living with the disease in 2025.71 Gastroenterology clinics in western countries will need to adapt personnel, resources, and infrastructure to accommodate management of an expected high volume of patients. In parallel to the rising prevalence of inflammatory bowel disease in western countries, biological agents are becoming the mainstay therapy for many patients with Crohn’s disease and ulcerative colitis.72–75 Biological drugs are being increasingly prescribed, and early into the diagnosis.76 Moreover, newly approved biological agents like vedolizumab and promising agents like ustekinumab and tofacitinib will redefine the treatment paradigms of inflammatory bowel disease. However, the trade-off has been the exponential escalation of drug costs. In the future, these costs will be offset in part by the adoption of biosimilars. However, the combination of compounding inflammatory bowel disease prevalence with increased reliance on biological drugs will stress health-care systems already struggling with increasing health-care costs.6 Furthermore, over the next decade the average age of patients with inflammatory bowel disease living in western countries will continue to rise. As the population of patients with the disease ages, this population will accumulate comorbidities.77 Approximately 10–20% of patients with inflammatory bowel disease have extra-intestinal manifestations of the disease such as arthritis, primary sclerosing cholangitis, iritis, or www.thelancet.com/gastrohep Vol 1 December 2016

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ankylosing spondylitis.78,79 An ageing population with inflammatory bowel disease will also be diagnosed with other comorbidities of ageing such as diabetes and cancer.80,81 In addition, chronic immunosuppression with immunomodulators and biological agents increases the risk of infections and cancers such as lymphoma and non-melanoma skin cancers.82,83 Consequently, ambulatory care of patients with inflammatory bowel disease living in western countries will become increasingly complex, time-consuming, resource-intensive, and costly over the next decade (panel). In newly industrialised countries such as China, primary care remains a relatively new concept to the public and health-care community, as most practice still involves hospital-based acute and episodic care. In a survey84 of 23 major hospitals in China, the number of hospitalised cases of ulcerative colitis steadily increased over a 14-year period. A similar survey24 of patients with Crohn’s disease hospitalised in 15 major Chinese hospitals showed a rise in hospitalisation from eight per 100 000 in 1990 to 22 per 100 000 in 2002. In northwest China, inflammatory bowel disease hospitalisation rates doubled in 12 years, from 2·0% in 2002 to 4·1% in 2014.85 A particular concern of the inflammatory bowel disease epidemic in China is the substantial proportion of young people affected by the disease. Given the increased risk of complications and disease progression in young patients, the potential health-care burden and economic implications associated with inflammatory bowel disease can be alarming. Biological drugs are now the main form of treatment for patients with inflammatory bowel disease with poor prognostic features and rapidly progressive disease. Although biological agents are cost-effective for inflammatory bowel disease,86 the budgetary effects of treatment are substantial. In China, patients who can pay will have increased access to biological therapy. Consequently, the expense of biological agents will lead to disparity of care within China based on socioeconomic status. Life expectancy in China has also increased from 68 years to 73 years of age over the past 30 years.87 The burden of ageing as well as rising rates of inflammatory bowel disease in the young will inevitably strain China’s healthcare system, as well as affect societal productivity and quality of life, especially in rural populations experiencing rapid urbanisation. This cost to society will be a wake-up call if rapid socioeconomic development is not balanced by preventive and control measures. As access to delivery of care and specialised care improves, so will awareness and diagnosis of inflammatory bowel disease. How China tackles this public health challenge in the next decade will provide important lessons for other newly industrialised countries faced with a similar burden (panel). Moreover, the lessons learned from China are highly relevant for most newly industrialised countries and developing countries that will soon transition to increased economic growth. Although data from newly www.thelancet.com/gastrohep Vol 1 December 2016

Panel: Factors driving the epidemic of inflammatory bowel disease and proposed strategies for a solution Host factors Challenges • Genetic predisposition • Rising rates of young-onset disease • Compounding prevalence over time Strategies • Targeted approach to identify high-risk individuals for early intervention • Preventive measures targeting the microbiome and enviromental factors to reduce the risk of development of disease • Innovations in health-care delivery for a high volume of patients with inflammatory bowel disease Demographic factors Challenges • Ageing population with inflammatory bowel disease-associated comorbidities • Rising disease burden and health-care expenditures • Development of disease complications (eg, malignancies, infections) • Escalating biological drug costs • Increased ambulatory and in-patient care • Shrinking workforce and reduced societal productivity Strategies • Reinforce prevention and practice of evidence-based medicine with community and primary care support • Personalised medicine geared towards optimisation of type and dosage of biological drugs • National surveillance of social, psychological, and behavioural risk factors; health-care needs; and access to care • Establishment of national inflammatory bowel disease registries to monitor trends for service planning • Maintain access to, and equity of, health care—including medications and endoscopies— to both urban and rural areas Societal factors Challenges • Rapid urbanisation in newly industrialised countries • Economic and social disparity between residents • Population migration from rural to urban areas • Changes in food technology with shift in diet from plant-based foods and fibre to refined sugars and animal fat and emulsifiers • High population density and overcrowding in urban cities • Increased formula feeding and reduced breastfeeding • Widespread and liberal antibiotic prescription • Increased psychosocial stress • Insufficient awareness and health information Strategies • Intersectoral policies to protect the environment and ensure sustainability of economic development • Food and environmental policies to ensure healthy diet and safety of drugs (including traditional Chinese medicine) • Community empowerment through early health education to improve diagnosis and disease awareness • Control and policy for tobacco, formula milk, and antibiotics • Investment in basic and clinical research focused on prevention of inflammatory bowel disease

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Search strategy and selection criteria We searched MEDLINE and Embase from their origin up to March 31, 2016 for the following keywords: “inflammatory bowel disease”, “Crohn’s disease”, “ulcerative colitis”, “China”, “United Kingdom” without language restrictions. We focused on original articles, reviews, and meta-analyses. We included literature and other data sources that we judged to be important and timely contributions to this topic. We also identified articles through searches of our own files. We generated the final reference list on the basis of originality and relevance to the broad scope of this Review.

industrialised countries outside of Asia are sparse, available information points to common patterns. For example, in São Paulo, Brazil, the incidence of ulcerative colitis between 1996 and 2005 rose from 4·5 to 6·8 per 100 000 per year. Although the incidence of Crohn’s disease was lower than was the incidence of ulcerative colitis, it doubled between 1996–2000 and 2001–05, from 1·5 to 3·5 per 100 000 per year.88 A nationwide study89 in Turkey (2000–03) reported the incidence of Crohn’s disease as 2·2 per 100 000 per year and of ulcerative colitis as 4·4 per 100 000 per year. A study90 from Constantine, Algeria (2003–08) reported the incidence of Crohn’s disease as 5·8 per 100 000 per year and of ulcerative colitis as 3·3 per 100 000 per year. Moreover, data from the ACCESS42 cohort show the incidence in Hyderabad, India (2012–13) of Crohn’s disease is 2·9 per 100 000 per year and of ulcerative colitis is 5·4 per 100 000 per year. Collectively, these data suggest that the epidemiological patterns observed in China are likely evolving in newly industrialised countries worldwide.

Conclusion Over the past 200 years, inflammatory bowel disease has become entrenched in modern society. Although incidence might be beginning to level off, the prevalence of disease continues to rise exponentially. Higher volumes of ageing patients mean western clinics will be challenged with rising burden and cost over the next generation. With increased urbanisation and economic advancement, newly industrialised countries such as China are experiencing a rapid rise in the incidence of inflammatory bowel disease. The next decade will reveal whether the prevalence in these countries will approximate that of western countries. Nonetheless, the sheer size of countries like China means that the absolute number of patients with inflammatory bowel disease is expected to be considerable. Emergence of new chronic diseases that are complicated and costly will necessitate restructuring of health-care delivery and infrastructure. Various factors—host, demographic, and societal—will challenge the global inflammatory bowel disease community, but strategies could be implemented to counter them (panel). The moment has arrived for a focused effort in funding 314

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