1. IRRITABLE BOWEL SYNDROME Arnold Wald, M.D., AGA-F University of Wisconsin School of Medicine & Public Health, Madison, WI

2. 1. A 35 y.o. teacher develops a diarrheal illness while on a trip to Mexico. Ciprofloxacin and loperamide are taken for 3 days but postprandial crampy abdominal pain, intermittent loose stools and bloating persist for 2 months. There is no weight loss, blood in the stools, arthritis, rash or fever but the patient complains of fatigue. Physical examination is normal, stool is hemoccult negative and CBC and stool studies are normal. Which of the following statements about this condition is correct? a)It is more likely to occur if the teacher is female and anxious b)It is more likely to occur if the initial cause of the diarrhea was ST-producing E. coli 0157:H7 c)It is less likely to occur if the patient received antibiotics for the initial diarrheal illness d)The diagnosis is best made with colonoscopy and biopsy of a normal appearing mucosa

3. POST-INFECTIOUS IBS 20% of IBS pts describe acute infectious prodrome Occurs in 5-25% after bacterial enteritis Diarrhea predominant No difference among pathogens (bacterial and viral) Greater likelihood in females, long duration of diarrhea, and with use of antibiotics Occurs in subjects with anxiety, depression

4. 2. A 33 year old woman presents with a 3 year history of intermittent abdominal cramps, excessive bloating, intermittent diarrhea and no weight loss. Her physical examination is normal as is a CBC and C-reactive protein. Which of the following is correct? a) She has an increased risk of celiac disease and should be tested with serology. b) She has a 20% chance of having small intestinal bacterial overgrowth and should be tested with breath analysis. c)She is likely to have no increase in either small intestine or colonic gas volume. d)She is likely to have increased colonic methane gas production.

5. DIAGNOSTIC APPROACH TO PATIENT WITH IBS SYMPTOMS (NO “ALARM SIGNS”) CBC Hemoccult Routine colon cancer screening at ages > 50 yrs. (ACG Functional GI Disorders Task Force, 2002)

6. Prevalence of Abnormal Serum Tests for Celiac Disease IBS (n=492)Healthy Control (n=458) AGA IgA 1.6% 1.8% EMA 0.6% 0.4% tTG IgA 1.2% 0.4% DQ2 33% 39% DQ8 16% 18% Cash BD, et al. Gastroenterol 2011, 141: 1187-93

7. PROMETHEUS ® IBS Diagnostic-NOT READY FOR CLINICAL USE!! Performance of Validation Cohort at 50% Disease Prevalence (n=516) Sensitivity50% Specificity88% Positive predictive value (PPV)81% Negative predictive value (NPV)64% Accuracy70% The selected validation cohort included 50% from patients with IBS, 36% from patients with non-IBS disorders (IBD, celiac disease, or functional GI disorders), and 14% healthy controls

8. Small Intestinal Bacterial Overgrowth and IBS Hypothesis is based upon poor methodology and erroneous conclusions. Original studies not reproduced by others using either similar and/or better methods. (Walters, Posserud) Use of antibiotics to suppress colon bacteria effective in some patients with IBS.

9. 3.Which of the following treatments for IBS exhibits the greatest benefit over placebo in randomized controlled trials? a)Lubiprostone b)Rifaximin c)A good physician-patient relationship d)Hypnosis

10. 6 0 Global Improvement 70 0 Adequate Relief Percentage 12 0 Quality of Life Mean Change Waiting List (n=87) Limited (n=88) Augmented (n=87) Adapted from Kaptchuk, et al BMJ 2008 Patient-practitioner relationship is the most important component of the placebo effect in IBS

12. Lubiprostone for IBS-C: Overall response rate at week 12 7/2/201512TKGR-IBSC Adapted from Drossman et al, APT 2009; 29: 329 ***p=0.001 vs placebo Placebo (n=387) Lubiprostone 8 µg bid (n=780) *** 10.1 17.9*** 0 25% Pooled data from 2 Phase III studies

13. Rifaximin: Global Improvement Measure Outcomes Response rates (%)WeightTherapeutic Gain NNT RifaximinPlacebo Sharara 27.091.4%18%5.6 Pimentel 32.591.6%23.5%4.3 Lembo 52.344.225.2%8.1%12.3 Target 1 40.831.234.9%9.6%10.4 Target 2 40.632.236.8%8.4%11.9 Overall 43.334.2100%9.1%11.0

14. Gut-directed hypnotherapy effective in improving IBS symptoms 6 RCTs; patients refractory to standard management –reduces anxiety and improves symptom control in majority of patients with refractory IBS Cochrane review of 4 randomized clinical studies (n=147) –hypnotherapy improved abdominal pain and overall IBS symptoms –results should be interpreted with caution due to poor methodological quality and small sample sizes Hypnotherapy Hypnotherapy 7/2/201514TKGR-IBSC Cochrane Database of Systematic Reviews 2007

15. 4. A 44 y.o. woman with diarrhea predominant IBS is started on nortriptyline 10 mg daily but she complains of fatigue, disorientation and palpitations which persist after 10 days. Her IBS symptoms are unchanged. The most appropriate course of action is: a)Continue the drug for another 2 weeks as she will gradually adapt to side effects b) Discontinue the drug; start linaclotide 145 mcg daily c) Discontinue the drug; refer her for cognitive behavioral therapy d) Discontinue the drug; prescribe desipramine 10 mg daily

16. Psychotropic agents in IBS Antidepressants in small doses improve functional pain independently of psychotropic properties Known side effects can be useful in IBS SSRIs better than placebo for global improvement TCAs better than placebo for abdominal pain and symptom scores

17. Desipramine improves IBS symptoms 17 Modified from Drossman et al, Gastroenterology 2003; 125: 19–31 n=431 ** **p=0.006 vs placebo Composite symptom scale improvement 100 0 47% 60% 49% 73% Placebo Desipramine Intention-to-treat analysis Per-protocol analysis

18. Linaclotide for IBS-C Linaclotide for IBS-C 7/2/2015 Rao, et al. Am J Gastro 2012 NNT = 7.9 *p < 0.0001 Placebo (n=335) Linaclotide 290 µg (n=312) *** 21% 33.6%* 0% 60% FDA endpoint 30% Percent response FDA endpoint: > 30% reduction in abdominal pain AND increase > 1 CSBM for > 6 of 12 weeks

19. 5.A 30 y.o. normal weight woman presents because of intermittent diarrhea, bloating, flatulence and abdominal discomfort of many years duration. Her physical examination is normal, as is a CBC and sedimentation rate. She has tried simethicone, Gas X and Beano ® with no improvement. She does not smoke, consume milk products or drink carbonated beverages. Which of the following would be the most cost effective approach? a)Rifaxamin b) FODMAP restricted diet c)Citalopram d)Mediterranean diet

20. FODMAPs (Fermentable oligo-, di- and monosaccharides and polyols) Fructans (onions, wheat, artichokes) Galactans (legumes, cabbage, Brussel sprouts) Lactose Sorbitol Xylitol Mannitol Sucralose (Splenda)

21. 20 4040 6060 8080 % improved Bloating P<0.002 Abd Pain P<0.02 Flatulence P<0.001 Composite Score P<0.001 Std (n=35) FODMAP (n=39) Low FODMAP Diet is more effective than standard diet in IBS Staudacher HM, et al., J Hum Nutr Diet 2011 Oct; 24 (5): 487-95. 49 82 61 85 50 81 49 86

22. Low FODMAP Diet Reduces Symptoms of IBS From Halmos et al, Gastro 2014

23. Rifaximin: Bloating AuthorWeightOR95% CI P value Pimentel2.5%3.811.39,10.450.0095 Lembo26%1.300.87,1.950.1975 Target 133.9%1.641.18,2.290.0035 Target 237.5%1.381.07,2.050.0140 Overall100%1.551.27,1.89<0.001 Favors Placebo Favors Rifaximin

24. TREATMENT OF BLOATING AND IBS: Diet or Antibiotic? * www.drugstore.com, January 2014 RifaximinFODMAP Diet Mechanism of action Decreases colonic bacteria by killing bugs Decreases colonic bacteria by reducing dietary CHO Cost $910/42 tablets*Cost of Food Additional benefit Does not promote weight loss Might promote weight loss

25. References 1.ACG IBS Task Force, An evidence-based position statement on the management of IBS. Am J Gastroenterol 2009;104:S1-35. 2.Ford AC, Vandvik PO. Irritable bowel syndrome. Clin Evid(online) 2012 Jan 6 pii0410