1. Antibiotics and Risk of New Onset Inflammatory Bowel Disease: A Meta-Analysis Ryan Ungaro 1, Charles Bernstein 2, Richard Gearry 3, Anders Hviid 4, Kaija-Leena Kolho 5, Matthew Kronman 6, Souradet Shaw 2, Herbert Van Kruiningen 7, Jean-Frédéric Colombel 1, Ashish Atreja 1 2013 CCFA Advances in Inflammatory Bowel Diseases Conference 1. Ichan School of Medicine at Mount Sinai, New York, NY 2. University of Manitoba, Winnipeg, Canada 3. University of Otago, Christchurch, New Zealand 6. Seattle Children’s Hospital, Seattle, Washington 7. University of Connecticut, Storrs, Connecticut 4. Statens Serum Institut, Coopenhagen, Denmark 5. University of Helsinki, Helsinki, Finland

2. Disclosures Nothing to Disclose

3. Background ●Medications emerging as risk factor for IBD ●Antibiotics may increase risk of CD and UC 1 ●However some studies have found no association 2,3 ●Few studies have reported risk associated with specific antibiotic classes 1. De Vroey et al. Am J Gastroenterol. 2010;105(12) 2. Castiglione F et al. J Crohns Colitis. 2012;6(3) 3. Van Kruiningen et al. Inflamm Bowel Dis. 2005;11(4)

4. Study Aims 1. To examine antibiotic use as a risk factor for new onset IBD, CD and UC 2. To evaluate if effect of antibiotics different in children versus adults 3. To determine IBD risk with specific antibiotic classes

5. Methodology ●Meta-analysis of Observational Studies in Epidemiology (MOOSE) 1 ●Search strategy ○Medline, Embase and Cochrane databases ○Search keywords: ■Inflammatory bowel disease, Crohn’s disease, ulcerative colitis, antibiotics, penicillin, cephalosporin, tetracycline, fluoroquinolone, macrolide, sulfonamide, metronidazole 1. Stroup DF, et al. JAMA 2000;283.

6. Methodology ●Inclusion criteria ○Cohort or case-control ○Data on exposure to antibiotics prior to new diagnosis of IBD (CD, UC, or both) ●Data collection ○Two reviewers extracted data ○Authors contacted if data not available in published manuscript (7 studies) ●Data analysis ○Random-effects model to determine overall pooled estimates and 95% confidence intervals (CI) ○The Newcastle-Ottawa Scale (NOS) to assess study quality 1 1. Wells et al. Accessed at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

7. Search Results 4508 Citations Retrieved 2558 from Pubmed 1798 from Embase 149 from Cochrane 3 from Backward Snowballing 1234 Review Articles Excluded 3274 Original Articles 3259 Articles Excluded by Title and Abstract Review 16 Original Articles 5 Studies Excluded After Full Text Review ●3 used surrogate for antibiotic use ●1 without controls ●1 insufficient data available 11 Articles Included ●8 Case-Control ●3 Cohort

8. * provided extra data 1. Wells et al. Accessed at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Case-Control Studies StudyYearCountryCases, nControls, n Population Age, years Quality Score (NOS) 1 Card et al2004UK587 CD146041.64 (mean)8 Van Kruiningen et al* 2005Belgium74 CD14024 (mean)7 Gearry et al*2010New Zealand638 CD, 653 UC 60020 or older (no average given) 8 Han et al2010New Zealand315 CD53645.6 (mean)5 Shaw et al*2010Canada27 CD, 9 UC3608.4 (mean)7 Shaw et al*2011Canada1025 CD, 1218 UC 22,34643.4 (mean)6 Castiglione et al2012Italy468 CD, 527 UC 56236 (median, CD) 37 (median, UC) 3 Virta et al*2012Finland233 CD, 362 UC 23809.7 (mean, CD) 8.5 (mean, UC) 8 Pediatric studies highlighted

9. Cohort Studies StudyYearCountryCases, nCohort Size, n Population Age, years Quality Score (NOS) 1 Margolis et al 2010UKCD 71, UC 99, 37 IBDU 94,48722.1 (mean)9 Hviid et al*2011Denmark50 CD, 67 UC 577,6273.4 (mean)8 Kronman et al* 2012UK449 CD, 272 UC, 27 IBDU 1,072,42617 or younger (no average given) 9 * provided extra data 1. Wells et al. Accessed at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. IBDU = IBD, type unclassified Pediatric studies highlighted

10. Included Studies ●11 total studies with 7,208 patients diagnosed with IBD ○3,937 patients with CD ○3,207 patients with UC ○64 patients with IBDU ●Majority studies (9 of 11) explicitly excluded some time period prior to new diagnosis of IBD ○Range from 3.9 months to 4 years ○Limit confounding by diagnostic delay IBDU = IBD, type unclassified

11. Antibiotic exposure associated with increased overall risk of new onset IBD I 2 = 82.35, p = 0.00 (CD) (UC)

12. Antibiotic exposure and risk of new onset IBD in adults and children I 2 = 48.78, p = 0.099 I 2 = 90.07, p = 0.00 Adults Children OR 1.431 (95% CI 1.116-1.834) OR 1.894 (95% CI 1.237-2.989) (CD) (UC)

13. Antibiotic exposure associated with increased risk of new onset CD I 2 = 84.87, p = 0.00

14. Antibiotic exposure and risk of new onset CD in adults and children I 2 = 89.97, p = 0.00 I 2 = 0.00, p = 0.63 Adults OR 1.565 (95% CI 1.177-2.081) Children OR 2.747 (95% CI 1.723-4.379)

15. Antibiotic exposure NOT associated with increased risk of new onset UC I 2 = 47.41, p = 0.07

16. Antibiotic exposure and risk of new onset UC in adults and children I 2 = 72.71, p = 0.012 I 2 = 0.00, p = 0.87 Adults OR 1.058 (95% CI 0.851-1.316) Children OR 1.112 (95% CI 0.773-1.602)

17. Most classes of antibiotics are associated with increased risk of new onset IBD Antibiotic ClassNumber of Studies Providing Data Pooled OR (95% CI)P valueHeterogeneity I 2 (p value) Metronidazole35.010 (1.646 - 15.245)0.005I 2 = 91.018 (0.000) Quinolones31.789 (1.027 - 3.118)0.040I 2 = 85.901 (0.001) Broad-spectrum penicillins 31.313 (1.143 - 1.509)0.000I 2 = 70.824 (0.032) Tetracyclines41.301 (1.173 - 1.443)0.000I 2 = 0.000 (0.794) Cephalosporins41.268 (1.143 - 1.407)0.000I 2 = 6.703 (0.360) Macrolides41.231 (1.112 - 1.363)0.000I 2 = 20.012 (0.290) Sulfonamides41.174 (1.058 - 1.302)0.003I 2 = 0.000 (0.396) Penicillin31.117 (0.761 - 1.639)0.572I 2 = 74.191 (0.021)

18. Limitations ●Data compiled from retrospective studies ○Questionnaire studies subject to recall bias ●Range in the quality of studies (based on QOS scale) ●Significant heterogeneity in certain analyses ●Different antibiotic exposure exclusion time periods

19. Summary ●Antibiotic exposure increases odds of new diagnosis IBD ●Antibiotic use increases risk new onset CD but not UC ●CD risk greatest in children ●Most antibiotic classes associated with IBD ○Penicillin not associated ○Metronidazole and quinolones most strongly associated

20. Discussion 2. Perez-Cobas et al. Gut. 2013; 62(11). 1. Manichanh C et al.Nat Rev Gastroenterol Hepatol. 2012;;9(10). 3. Gradel KO et al. Gastroenterology. 2009;137. Antibiotics may increase IBD risk by altering microbiome Alternatively, association may be surrogate marker for increased risk infections in CD

21. Thank You ●Ashish Atreja ●Jean-Frederic Colombel ●Charles Bernstein ●Richard Gearry ●Anders Hviid ●Kaija-Leena Kolho ●Matthew Kronman ●Souradet Shaw ●Herbert Van Kruiningen ●Crohn’s and Colitis Foundation of America