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Inflammatory Bowel Disease in Iran Inflammatory bowel disease IBD Including Ulcerative Colitis (UC) and Crohn’s Disease (CD), is a chronic and recurrent disease triggered by genetic, environmental, and immunologic factors. UC can be histologicaly distinguished from CD by the localized inflammation in the superficial layer of the colonic mucosa. Inflammatory bowel disease IBD Considerable variation in the epidemiology of IBD has been observed around the world, with a wide range of both within and between geographic regions. IBD is reported more common in developed countries than developing countries according to previous articles. With the highest incidence and prevalence rates in North America and Europe. Evolution in Epidemiology of IBD As developing nations have become more industrialized, the incidence of IBD has increased. Several studies have reported that the incidence of IBD has increased markedly over the latter part of the 20th century. Evolution in Epidemiology of IBD Studies have shown that individuals emigrating from low prevalent regions (eg, Asia) to higher prevalent countries eg, England, are at increased risk for developing IBD, particularly among first-generation children. The emergence of IBD in traditionally low prevalent regions (eg, in Hispanic and Asia) suggests that the development of IBD may be influenced by environmental risk factors. Geographic Patterns In the developing world, defining incidence and prevalence is considerably more difficult because many countries lack health care systems administrative databases. Also, care is centralized in hospitals; thus, hospitalization records may more accurately reflect prevalence of disease as compared with hospitalization records from the developed world. Geographic Patterns Where outpatient management of IBD is more common. To properly interpret the incidence or prevalence data and evaluate time trends, a systematic review of all population- based studies is needed. Time trend in IBD Since The etiology and pathogenesis of IBD is not fully understood. Insight into the worldwide epidemiology of IBD is important : To identify Geographic patterns and time trends To highlight the burden of IBD globally, To determinant Possible environmental role in IBD Epidemiology of IBD in Iran The objectives of our study were to conduct a time trends patterns of IBD in Iran. To evaluate the change in incidence . Compare with systematic review of the worldwide incidence and prevalence of UC and CD , Prevalence Rate for UC and CD in Europe ,the UC estimates ranged from 4.9 to 505 per 100,000, in Asia and the Middle East, 4.9 to 168.3 per 100,000 in North America, 37.5 to 248.6 per 100,000 The CD estimates ranged from 0.6 to 322 per 100,000 in Europe, 0.88 to 67.9 per 100,000 in Asia and the Middle East, and 16.7 to 318.5 per 100,000 in North America Epidemiology of IBD in Iran 1985- Ulcerative colitis in Iran: a review of 112 cases, by Mir-Madjlessi et al. 1973-1982 They reported the extreme rarity of Crohn's disease in Iran. 2005- Inflammatory bowel disease in Iran: A review of 457 cases, by Aaghazadeh , Zali, et al. Including 401 UC, 47 CD and 9 IC 2008- Epidemiology of Inflammatory Bowel Disease in Iran: A review of 803 cases by Derakhshan et al. Gastroenterology and Hepatology from bed to bench. 2008;1(1):19-24 1992-2007 Including 671 UC, 109 CD and 23 IC Epidemiology of IBD in Iran 2009- Epidemiologic Characteristics of 500 Patients with IBD in Iran Studied from 2004 through 2007, by Vahedi et al. Arch Iranian Med . 2012- Epidemiology of Pediatric Inflammatory Bowel Diseases in Southern Iran, by Dehghani et al. 2001-2007 36 IBD including 26 UC and 9 CD 2013- Epidemiological and Clinical Characteristics of Inflammatory Bowel Disease in Patients from Northwestern Iran, by Masnadi Shirazi et al. Middle East Journal of Digestive Diseases, Vol.5, No.2, April 2013 2005-2007 200 IBD patients including 183 UC and 17 CD IBD Registry and epidemiological research in RCGLD IBD Registry in Taleghani Hospital, Shahid Beheshti University, Tehran, Iran Private clinic IBD Registry and epidemiological research in RCGLD (cont.) During 10 years, between 1992 and 2012 we recorded patient’s data in a questionnaire Demographic information Medical, familial and habitual history Diagnosis identification Signs and symptoms at onset and visit date Extra-intestinal manifestations Complications Colonoscopy reports IBD Registry and epidemiological research in RCGLD (cont.) The interview was performed face to face by trained practitioners. General information was retrieved from medical records of patients by gastroenterologists. The patients were followed up by telephone who required proper information. Gastroenterologists confirmed IBD in patients based on clinical, radiological, endoscopic and pathological criteria. IBD Registry and epidemiological research in RCGLD (cont.) The data base were updated through referring IBD patients for determining any other changes such as; Hospitalization Drug use Colonoscopy Pathology Laboratory tests New disease Results of IBD registry studies in RCGLD From 1992 to 2012, 2257 patients with IBD were confirmed in this study. The result of the data registry system concluded 1914 343 with UC (84.8 %) with CD (15.2 %) Prevalence of IBD The prevalence of UC was 5 times higher than CD. Similar to the fourfold higher incidence of ulcerative colitis than Crohn's disease in Japanese, Korean, and Chinese cohorts According to recent studies, both diseases have been reported with an increase in number in eastern countries. Male to female graph in IBD (%) Mean age at onset Mean age at diagnosis Characteristics of IBD CD was diagnosed at a younger age than UC and IC. The peak age of onset in this study appears to be in the 2nd and 3rd decades of life in UC and CD patients, consistence with findings in the West and Asia for IBD. Results of IBD registry studies in RCGLD Never smoked 93.5% patients with UC 90.2% with CD Current smokers 6.5% patients with UC 10.8% with CD Appendectomy 4.4% UC patients, 14.2% CD patients was carried out in Level of Education and IBD Results of IBD registry studies in RCGLD UC presented with diarrhea (75.3%) hematochesia bloody (73%) diarrhea (64.8%) abdominal pain (57.4%) weakness (56.8%) tenesmus (55.8%) UC presentation Results of IBD registry studies in RCGLD CD patients complained of abdominal diarrhea (62.3%) weakness weight pain (72.6%) (52.1%) loss (55.8%) CD presentation Results of IBD registry studies in RCGLD Extension of disease was evaluated with colonoscopy procedure in UC patients as follows: 10.9% proctitis 14.3% proctosigmoiditis 13.8% left side colitis 5.9% pancolitis Colonoscopy was performed in CD patients in which 71.8% were categorized as having ileocolitis and terminal ileum was affected in 21.8% of patients. Extension of disease in UC Results of IBD registry studies in RCGLD Major complications of UC were severe bleeding (3.4%) dysplasia (1.1%) pouchitis (0.2%) intestinal perforation (0.5%) toxic mega colon (0.4%) stenosis (0.9%) Results of IBD registry studies in RCGLD Extraintestinal manifestations were reported in 59.9% of UC patients 64.2% of CD Musculoskeletal (26.8%) and skin (18.2%) disorders were the most common affected sites in IBD patients. Sclerosing cholangitis was diagnosed in 8.1% of IBD patients Results of IBD registry studies in RCGLD The mean lag time between age of onset and age of diagnosis was 8 months in UC 20 months in CD In CD patients 25.6% had documented fistula. Colectomy rate was 2.8% UC patients and 15.8% CD patients . Colorectal cancer was determined in 1% of IBD patients (UC and CD patients). Previous study on appendectomy and tonsillectomy in Iranian IBD patients 2006- Appendectomy, tonsillectomy, and risk of inflammatory bowel disease: a case control study in Iran. Int J Colorectal Dis (2006) 21: 155–159. 382 UC and 46 CD were studied. 382 controls for UC and 184 controls for CD were enrolled. Appendectomy is protective in UC, but a risk factor in CD among Iranian population. Tonsillectomy was not associated with either UC or CD disease. UC, but not CD, is a disease of non- smokers. The inverse association between ulcerative colitis and OCP or NSAID in the Iranian population is noted. Results of IBD registry studies in RCGLD Familial history of IBD was presented in 14.2% UC patients, of whom 57.9% had a positive family history in first-degree and 42.1% in seconddegree relatives. IBD was affected 15.8% cases of CD patients, identifying 57.1% in first- and 42.9% in second-degree relatives. IBD Genetics research in RCGLD 2007- The frequency of C3435T MDR1 gene polymorphism in Iranian patients with ulcerative colitis. Int J Colorectal Dis. 2007 Sep; 22(9):999-1003. 300 UC and 300 controls C3435T polymorphism of the MDR1 gene has an association with UC in Iranian population as in western countries. 2008- Frequency of three common mutations of CARD15/NOD2 gene in Iranian IBD patients. Indian journal of Gastroenterology, 2008, Vol. 27, No 1: 9-11. 100 UC, 40 CD and 100 controls R702W mutation of CARD15/NOD2 gene was more frequent in CD patients than controls IBD Genetics research in RCGLD (cont.) Association of vitamin D receptor gene polymorphisms in Iranian patients with inflammatory bowel disease. J Gastroenterol. Hepatol. 2008 Dec;23(12):1816-22. 150 A UC, 80 CD and 150 controls probable association of the Fok I polymorphism in VDR receptor gene and Crohn's susceptibility in Iranian population was observed. IBD Genetics research in RCGLD (cont.) 2011- NOD2 exonic variations in Iranian Crohn's disease patients. Int J Colorectal Dis (2011) 26:775–781. 90 CD and 120 controls 21 sequence variations were identified among all exonic regions of the NOD2 gene, of which eight had an allele frequency of more than 5%. Eight new mutations (one in exon 2 and seven in exon 4) were observed. IBD Genetics research in RCGLD (cont.) The three main variants (R702W, G908R, and 1007fs) showed allele frequencies of 13.3%, 2.2%, and 1.7%, respectively. Three new variations (P371T, A794P, and Q908H) and R702W mutation were significantly more frequent in Crohn's disease patients compared to controls. Eight novel mutations were identified in the NOD2 exons, but the pathophysiological importance of these variants remains unclear. Iranian patients with their different genetic reservoirs may demonstrate some novel characteristics for disease susceptibility. Genetic Factors Among the 100 IBD genes and loci defined, only nucleotide binding oligomerization domain protein 2 (NOD2) (5% penetrance or 20-fold risk in mutation homozygotes, has a meaningful contribution to CD risk alone. All remaining genes and loci contribute modestly to IBD risks, However, the exact relationship between genetic susceptibility and the role of the environment in the pathogenesis of IBD still largely remains a mystery Time Trends of IBD types In Iran Changing Environment The clinical picture of a patient with IBD results from a complex interaction of genetic, environmental, developmental and disease course factors, such as the patient’s age, nutritional status and presence of co-morbidities. Genetic Factors Genetic susceptibility plays a key role in IBD development. 8- to 10-fold greater risk of IBD among relatives of ulcerative colitis ,and Crohn’s disease. To be involved in the ethiology of IBD, Are associated with immune functions, Mucosal transport functions, or bacterial recognition. Environmental Factors Given the patho-physiologic complexity inherent in IBD, it is unlikely that genetics alone will provide sufficient information for time trend in IBD. Rates of appendectomies have decreased in developed countries, whereas the incidence of UC has remained constant. Health Care Improvement The rising incidence of IBD during the 20th century may be explained by environmental exposures that result from increasing urbanization; For example, IBD occurs more commonly in urban versus rural regions. Environmental Risk Factors Individuals raised in urban areas are exposed to considerably different environmental risk factors than those living outside these regions., microbial exposures, sanitation, occupations, Diet, lifestyle behaviors, medications, and pollution exposures, which have all been implicated as potential environmental risk factors for IBD. Access to Medical Services however, this increase could be due to. Increased awareness of IBD by physicians and the public, Advancements in diagnostic methods for IBD Such as access to medical services, Access to colonoscopies, Withy greater differentiation of CD from UC. Environmental Factors Smoking cannot explain worldwide increases in CD; as the incidence of CD is low in several populations of heavy smokers (Asia, Africa) and high in some populations of mild smokers. Dysbiosis, Microbiota etc., However, these parameters cannot account for all variations in IBD incidence and prevalence; Where Do we Stand Now? The Global Prevalence The incidence of IBD is increasing or stable in virtually every region of the world. Since 1980, 56% of CD and 29% of UC studies have shown a statistically significant increasing incidence. Because mortality in IBD is low, and the disease is most often diagnosed in the Young, These findings suggest that the global prevalence of IBD will continue to increase substantially. Treatment Target IBD are Evolving Increasing use of immunomodulators, such as thiopurines, the introduction of infliximab in 1998 From Clinical Remission to Mucosal healing Deep Remission. Has changed the course of disease in many patients. Future Direction To advance our understanding of the key determinants of IBD in the developed and developing world, future population-based studies should focus on Reporting incidence and/or prevalence of IBD stratified by gene-environment-phenotype interactions. Conclusions (1) As we move forward into the next two to three decades of IBD, we will face a series of challenges. We must: 1. Identify disease targets and patients who will benefit the most by certain classes of drugs. 2. Design treatment strategies that will decrease loss of response to therapy. Conclusions (2) 3. Identify individual risk factors for aggressive disease and treat those patients accordingly to change the natural history of disease. 4. Develop strategies that will minimize neoplastic and infectious risks of our targeted drug therapies. Future Direction of IBD