Causes of IBD: The Role of Genetics and Microbes and the Epidemiology of IBD

Transcription

1 Causes of IBD: The Role of Genetics and Microbes and the Epidemiology of IBD James D. Lewis, MD, MSCE Professor of Medicine and Epidemiology Perelman School of Medicine at the University of Pennsylvania

2 Agenda Define epidemiology terms Discuss the incidence and prevalence of inflammatory bowel disease (IBD), including Crohn s disease (CD) and ulcerative colitis (UC) Discuss the pathogenesis of IBD, including environmental, immune, genetic, and microbial factors Review relevant epidemiologic studies on risk factors for IBD development and progression Review the hygiene hypothesis Provide an overview of disability and costs of care in IBD

3 Audience Response Question Which of the following does NOT play a key role in the pathogenesis of IBD? A. Genetic susceptibility B. Gut microbes C. Immune response D. Mycobacterium paratuberculosis 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0% 0% 0% 0% 10

4 Audience Response Question Current cigarette smoking is a risk factor for developing: 100% A. Both Crohn s disease and ulcerative colitis B. Crohn s disease but not ulcerative colitis C. Ulcerative colitis but not Crohn s disease D. Neither Crohn s disease nor ulcerative colitis 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0% 0% 0% 0% 10

5 What Is IBD? IBD is characterized by: Chronic inflammation of the GI tract Most often has a progressive or remitting and relapsing course The two major forms of IBD are CD and UC IBD is not IBS (irritable bowel syndrome) Abbreviations: CD, Crohn s disease; IBD, inflammatory bowel diseases; IBS, irritable bowel syndrome; GI, gastrointestinal; UC, ulcerative colitis. CDC. Accessed April 13, Kornbluth A, et al. Am J Gastroenterol. 2010;105(3): Lichtenstein GR, et al. Am J Gastroenterol. 2009;104(2):

6 What Is Epidemiology? The study of occurrence of illness Provides estimates of frequency Incidence = new cases per year Prevalence = frequency of all cases For chronic condition with near-normal life expectancy, prevalence = incidence x remaining life expectancy Can assess for potential risk factors Can study natural history of disease

7 Incidence of IBD Has Significantly Increased Over Time in the United States Crohn s disease ulcerative colitis P <.0001 between 1940 and 2000 for both diseases Loftus CG, et al. Inflamm Bowel Dis. 2007;13(3):

8 Prevalence of IBD Has Increased in the United States Abbreviations: VA, Veterans Affairs health system; IC, indeterminate colitis. Hou JK, et al. Inflamm Bowel Dis. 2013;19(5):

9 Prevalence of IBD in North America Studies come from: Manitoba health claims database Olmsted County, Minnesota: Rochester Epidemiology Project MarketScan insurance claims database Crohn s & Colitis Foundation study of 9 HMOs Kaiser Permanente Northern California Prevalence ranges from 400 to 500 cases per 100,000 persons, or 0.4% to 0.5% Stated another way, between 1 in 200 and 1 in 250 people in North America have IBD Back of envelope calculation based on 325 million people in United States in 2017: 1.3 to 1.6 million Americans Abbreviations: CDC, Centers for Disease Control and Prevention; HMO, health maintenance organization. Bernstein CN, et al. Am J Gastroenterol. 2006;101(7): Herrinton LJ, et al. Inflamm Bowel Dis. 2007;13(4): Kappelman MD, et al. Clin Gastroenterol Hepatol. 2007;5(12): Samuel S, et al. Inflamm Bowel Dis. 2013;19(9):

10 Pathogenesis of IBD Immune response Microbes IBD Genetic susceptibility Environmental triggers

11 Role of Genetics in IBD Immune response Microbes Genetic susceptibility IBD Environmental triggers

12 Genetic Susceptibility Concordance in Twins CD UC (%) (%) Monozygotic Dizygotic Ornholm M, et al. Scand J Gastroenterol. 2000;35(10): Tysk C, et al. Gut. 1988;29(7):

13 Selected Genetic Associations With CD and UC Gene Gene Location Associated With: CD UC NOD2 16q12 Yes No ATG16L1 2q37 Yes No IRGM 5q33 Yes? IL23R 1p31 Yes Yes IL12B 5q33 Yes Yes STAT3 17q21 Yes Yes MHC 6p21 Yes Yes IL10 1q32? Yes IFNG 12q15 No Yes Adapted from Abraham C, Cho JH. N Engl J Med. 2009;361(21):

14 Role of Microbes in IBD Immune response Microbes Genetic susceptibility IBD Environmental triggers

15 Individualized Microbial Landscape 90% of cells in our body are bacterial Most of these reside in the gut We are born germ-free The microbes that live in our gut come from the environment Infant diet, hygiene, medications, breast-fed vs formula-fed Genetic influence Identical twins have similar bacterial communities

16 Bacteria Have Important Role in the GI Ecosystem Extract calories and nutrients from indigestible complex carbohydrates Synthesize vitamins and short-chain fatty acids Protect against injury to the cells lining the colon Instruct our immune system Regulate fat storage Stimulate intestinal angiogenesis Eckburg PB, et al. Science. 2005;308(5728):

17 Varied Habitat for Bacteria in Gut Very low concentrations in stomach, duodenum Increasing concentrations moving downstream Highest in colon Increased complexity of microflora moving downstream Stomach: Duodenum: 10 2 Jejunum: 10 2 Proximal ileum: 10 3 Distal ileum: Colon: Sartor RB. Gastroenterology. 2008;134(2): Illustration: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

18 Clinical Arguments for Role of Bacteria in IBD Creating an alternate route for eliminating feces (ostomy bag) reduces severity of CD and pouchitis 1 Therapeutic benefit of antibiotics 1 Antibodies against microorganisms in patients with IBD 1 Efficacy of probiotics in pouchitis and UC 1 Mice raised completely free of bacteria do not develop colitis; mice colonized with normal intestinal resident bacteria do develop colitis Sartor RB. Gastroenterology. 2008;134(2): Barnes SL, et al. J Immunol. 2007;179(10): Liu B, et al. Gastroenterology. 2006;130(4 suppl 2):A Qian BF, et al. Gastroenterology. 2006;130(4 suppl 2):A-355.

19 Fecal Microbiota and IBD Reduction in numbers and diversity of fecal microbiota (Firmicutes) seen in IBD Decreased fecal concentrations of Faecalibacterium prausnitzii associated with increased postoperative recurrence of CD Secreted products of F prausnitzii exhibit immunomodulatory properties Adherent-invasive E coli detected in some IBD Darfeuille-Michaud A, et al. Gastroenterology. 2004;127(2): Frank DN, et al. Proc Natl Acad Sci U S A. 2007;104(34): Sokol H, et al. Proc Natl Acad Sci U S A. 2008;105(43): Sokol H, et al. Inflamm Bowel Dis. 2009;15(8):

20 Diet and Microbiome and IBD? Large differences in microbiome between regions and between rural/urban High-fat diets increase Proteobacteria and Firmicutes, and decrease Bacteroidetes Kashyap PC, et al. J Allergy Clin Immunol. 2013;132(1): e5. Wu GD, et al. Anaerobe. 2013;24:

21 Role of Environment in IBD Immune response Microbes IBD Genetic susceptibility Environmental triggers

22 Relationship Between Environmental Factors and Development of CD and UC Risk elevated OC use GI infections High carbs/fats Urban/pollution Antibiotics Smoking Stress Linoleic acid Vitamin D High fiber H pylori Helminths Smoking CD UC Both CD and UC Abbreviations: carbs, carbohydrates; GI, gastrointestinal; H pylori, Helicobacter pylori; OC, oral contraceptive. Ponder A, Long MD. Clin Epidemiol. 2013;5: Lowered risk

23 Cigarette Smoking and IBD: Updated Meta-Analysis UC 13 studies, >11,000 patients for UC Current smoking is protective of development of UC: OR, 0.58 (95% CI, ) Quitting smoking is associated with UC: OR, 1.79 (95% CI, ) CD 9 studies, >10,000 patients for CD Current smoking is associated with CD: OR, 1.76 (95% CI, ) Former smoking is weakly associated with CD: OR, 1.30 (95% CI, ) Abbreviations: OR, odds ratio; CI, confidence interval. Mahid SS, et al. Mayo Clin Proc. 2006;81(11):

24 Summary of Nurses Health Study Findings Risk factors Ex-smoking, UC Smoking, CD Hormone replacement, UC Oral contraceptives, CD NSAID use 15 days/month for UC and CD Vitamin D deficiency, CD > UC Depressive symptoms, CD Trans-saturated fats, UC Protective factors Long-chain n-3 polyunsaturated fatty acids, UC Dietary fiber intake, CD Fruits > vegetables > cereal/grains/legumes Abbreviation: NSAID = nonsteroidal anti-inflammatory drugs. Ananthakrishnan AN, et al. Ann Intern Med. 2012;156(5): Ananthakrishnan AN, et al. Gastroenterol. 2012;142(3): Ananthakrishnan AN, et al. Gastroenterol. 2013;145(5): Ananthakrishnan AN, et al. Gut. 2014;63(5): Ananthakrishnan AN, et al. Clin Gastroenterol Hepatol. 2013;11(1): Higuchi LM, et al. Am J Gastroenterol. 2012;107(9): Khalili H, et al. Gastroenterol. 2012;143(5): Khalili H, et al. Gut. 2013;62(8):

25 Hygiene Hypothesis Incidence of immune-mediated diseases rising in developed countries Due to modern hygiene, lack of exposure to bacteria? IBD incidence, prevalence highest in Western nations Conflicting data in IBD Manitoba case-control: early childhood exposure to pets, being from larger families were protective Montreal case-control: owning a pet was a risk factor; less crowding, owning personal towel were protective Amre DK, et al. Am J Gastroenterol. 2006;101(5): Bernstein CN, et al. Am J Gastroenterol. 2006;101(5): Molodecky NA, et al. Gastroenterology. 2012;142(1):46-54.e42.

26 H pylori Infection Is Protective Against IBD Risk: Meta-Analysis 23 articles Pooled risk of IBD in H pylori infected individuals: RR, 0.64 (95% CI, ) RR, 0.60 in CD; RR, 0.75 in UC Significant heterogeneity Subgroups analyses by methods of diagnosis, region, and age could not explain Abbreviations: CI, confidence interval; H pylori, Helicobacter pylori; RR, relative risk. Luther J, et al. Inflamm Bowel Dis. 2010;16(6):

27 Helminth Exposure May Be Protective Against Risk of IBD Can have profound effects on mucosal immune system 1 South African case-control study of childhood exposure to helminths 1 OR of CD, 0.2 (95% CI, ) OR of UC, 0.2 (95% CI, ) In 2 small trials, therapy with Trichuris suis ova (TSO, eggs of the pig whipworm) was associated with disease response in CD and UC 2,3 Two 12-week randomized, double-blind, placebo-controlled phase 2 trials of TSO in active CD TRUST-1: Did not meet primary endpoint 4 TRUST-2: Was stopped early because of lack of efficacy 5 Abbreviations: OR, odds ratio; CI, confidence interval. 1. Chu KM, et al. Inflamm Bowel Dis. 2013;19(3): Summers RW, et al. Gut. 2005;54(1): Summers RW, et al. Gastroenterology. 2005;128(4): Schölmerich J, et al. J Crohns Colitis. 2017;11(4): ClinicalTrials.gov identifier NCT

28 Antibiotic Use May Increase Risk of IBD Case-control study of pediatric-onset IBD in Manitoba 58% of cases had antibiotics prescribed in first year of life vs 39% of controls OR, 2.9 (95% CI, ) Case-control study of adult-onset IBD in Manitoba 12% of cases had at least 3 antibiotic courses at 2 to 5 years before diagnosis vs 7% of controls OR, 1.5 (95% CI, ) Abbreviations: CI, confidence interval; OR, odds ratio. Shaw SY, et al. Am J Gastroenterol. 2010;105(12): Shaw SY, et al. Am J Gastroenterol. 2011;106(12):

29 Gastroenteritis and Risk of IBD US military database: Infectious gastroenteritis increased risk of IBD by 40% Previous diagnosis of irritable bowel syndrome along with gastroenteritis increased risk of IBD 5-fold Large General Practice Research Database study in UK: 2- to 3-fold increased risk of IBD among those with gastroenteritis Garcia-Rodriguez LA, et al. Gastroenterology. 2006;130(6): Porter CK, et al. Gastroenterology. 2008;135(3):

30 The Return of Diet as a Risk Factor? Difficult to study May exert effect indirectly via microflora Increased sugar intake Increased fat intake Increased protein intake Future studies may need to focus on dietary patterns rather than individual foods Chapman-Kiddell CA, et al. Inflamm Bowel Dis. 2010;16(1):

31 Psychological Stress and IBD Recent systematic review of 18 prospective studies examining stress as a risk factor for disease exacerbations 13 studies showed a significant association Coping behaviors appear to modulate effect of stress Cámara RJ, et al. Digestion. 2009;80(2):

32 IBD Disability Index Validated instrument used for clinical trials and to establish extent of disability in patients with IBD 1 Asks about: 2 Overall health Sleep and energy, affect, body image, pain Ability to: regulate defecation, look after one s health, engage in interpersonal activities, work or attend school Body mass index and weight loss Blood in stool Arthritis and arthralgia Effect of medication, food, family support, health care Access to/benefit from social security systems and health care Complements Crohn s Disease Activity Index 1. Colombel JF. Gastroenterol Hepatol (NY). 2013;9(5): Peyrin-Biroulet L, et al. Gut. 2012;61(2):

33 Morbidity and Mortality Are Increased With IBD Disease affects ability to work IBD patients have higher rate of absenteeism Permanent work disability predicted by severe disease Increased risk of cancer over time SIR, 3.0 (95% CI, ) with pediatric-onset IBD Quality of life impaired even with inactive IBD (n = 226) Functional GI disorders in 65%, with concomitant anxiety or depression in 34% each IBS and anxiety decrease quality of life (P.03) Mortality elevated UC: SMR, 1.19 (95% CI, ) CD: SMR, 1.38 (95% CI, ) Bewtra M, et al. Inflamm Bowel Dis. 2013;19(3): Fedorak RN, et al. Can J Gastroenterol. 2010;24(11): Kim ES, et al. J Clin Gastroenterol. 2013;47(4):e38-e44. Peneau A, et al. Am J Gastroenterol. 2013;108(10): Siebert U, et al. Inflamm Bowel Dis. 2013;19(4): Abbreviations: CI, confidence interval; SIR, standardized incidence ratio; SMR, standardized mortality ratio.

34 Economic Impact of IBD in the United States Measure (annual) CD UC Prevalence 359, ,000 Health care usage Ambulatory care visits 1.1 million 716,000 Hospitalizations 187, ,000 Prescriptions 1.8 million 2.1 million Mortality Cost breakdown US health insurer $2.04 billion $0.53 billion Patient out-of-pocket $0.26 billion $0.07 billion Gunnarsson C, et al. Dig Dis Sci. 2012;57(12): NIDDK.

35 Costs of Care for IBD Direct costs of IBD are high Hospital, emergency care, physician visits, prescriptions, and OTC medications Annual per-capita health insurer and patient out-of-pocket costs, P <.001 vs no IBD Total IBD direct costs in US for 2004 = $1.84 billion CD: $8,265 per patient annually UC: $5,066 per patient annually Indirect costs are substantial Include lost productivity due to work absenteeism, caregiver loss of productivity, lost earnings from early mortality Total indirect costs in US for 2004 = $328 million Abbreviation: OTC, over-the-counter. Everhart JE. USDHHS 2008, NIH Publication No Gunnarsson C, et al. Dig Dis Sci. 2012;57(12): Kappelman MD, et al. Gastroenterology. 2008;135(6): Longobardi T, et al. Am J Gastroenterol. 2003;98(5): Sandler RS, et al. Gastroenterology. 2002;122(5):

36 Disease Severity Increases Costs for IBD Disease extent, complications increase costs Comparison of surgical and medical therapy Health care costs for chronic UC in 2 years after surgery vs medical therapy not significantly different Main cost drivers after surgery were Brooke ileostomy and pouchitis; cost driver after medication was disease extent Census data on patients with IBD (1999) 32% out of work because of symptoms in past year: OR, 2.14 (95% CI, ) $3.6 billion in lost productivity due to symptomatic IBD $5228 per symptomatic patient with IBD annually Abbreviation: CI, confidence interval. Holubar SD, et al. Dis Colon Rectum. 2012;55(12): Longobardi T, et al. Am J Gastroenterol. 2003;98(5):

37 Summary IBD is characterized by chronic inflammation of the GI tract that usually has a progressive or remitting/relapsing course The incidence and prevalence of IBD in the US are increasing The understanding of IBD pathogenesis is evolving rapidly Studies of migrant populations suggest environmental factors The hygiene hypothesis is promising Changes in fecal microbiome? IBD is associated with high morbidity/mortality and costs