Rome III Criteria for IBS. Irritable Bowel Syndrome: What s the Latest? IBS: What s the Latest? Distinguishing IBS-C from CC

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1 Rome III Criteria for IBS Irritable Bowel Syndrome: What s the Latest? Tim Burke, DO Pacific Digestive Associates Clackamas, OR Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 of the following: Improvement with defecation Onset associated with a change in frequency of stool Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis Onset associated with change in form of stool Longstreth GF, et al. Gastroenterology2006; 130: IBS: What s the Latest? IBS subtypes: patients aren t stagnant Distinguishing IBS-C from CC Utility of testing Methane Antibiotics Probiotics Celiac disease Diet Osmotic agents Secretagogues In Clinical Practice Patients Move from Group to Group IBS-C IBS-M CC Simren M, et al. Scand J Gastroenterol 2001; 36(5): Tillisch K, et al. Am J Gastroenterol 2005; 100(4): Simren M, et al. Eur J Gastroenterol Hepatol 2003; 15(2): Simren M, et al. Gastroenterology2005; 128(3):580-9 Simren M, et al. Am J Gastroenterol 2010; 105: IBS-C: IBS with constipation CC: Chronic Constipation IBS-M: mixed or alternating symptoms of constipation and diarrhea Distinguishing IBS-C from CC No firm rationale to distinguish IBS-C from CC by the Rome committee Treatments are often similar Tegaserod (no longer available in N.A.) Lubiprostone Prucalopride (available in the EU) Linaclotide Distinguishing IBS-C from CC Symptom-based criteria for CC and IBS overlap Abdominal pain/discomfort and gas/bloating creates a spectrum between CC and IBS - PAIN/DISCOMFORT & GAS/BLOATING + CC IBS-C Brandt LJ, et al. Am J Gastroenterol 2005; 100(suppl 1): S5 1

2 Utility of Testing: Yield of Colonoscopy in IBS Lesion Histologic Findings in IBS Patients and Controls; Populations Not Matched for Age and Gender IBS Patients n=466 Controls n=451 PValue Adenomas 36 (7.7) 118 (26.1) < Hyperplastic Polyps 39 (8.4) 52 (11.5) NS Colorectal adenocarcinoma 0 (0.0) 1 (0.2) NS IBD 2 (0.4) 0 (0.0) NS Microscopic colitis 7 (1.5) N/A N/A Pretest Probability of Organic Disease 1 Organic Disease IBS Patients Control/Population Colitis/IBD Colorectal cancer (varies with age) Lactose malabsorption Thyroid dysfunction Celiac Disease Celiac disease: antibodies Celiac disease: confirmed Microscopic colitis was more common in a subset of patients with IBS-D who were 45 years (2.3%). IBD, inflammatory bowel disease; IBS-D, irritable bowel syndrome diarrhea-predominant; N/A, not applicable; NS, not significant. Chey WD, et al. Am J Gastroenterol 2010; 105: American College of Gastroenterology Task Force on Irritable Bowel Syndrome, et al. Am J Gastroenterol 2009; 104(suppl 1): S1-S Cash BD, et al. Gastroenterology2011; 141: Methane & Constipation Methane and Constipation About 1/3 rd of the population produces CH 4 Prevalence of CH 4 in slow transit Constipation AUC of methane on breath test Predominant organism is Methanobrevibacter smithii Thought to be present in 60% of humans in left colon per g dry weight Attaluri, et al. Am J Gastro, 2010;105, Methane Gas Infusion Slows Transit 69% mean slowing of transit Rifaximin: Most Extensively Studied Antibiotic for IBS Gut-directed antibiotic Not systemically absorbed Doses studied for IBS: 400 mg BID to 550 mg TID Generally well tolerated Adverse effects include: headache, abdominal pain, and upper respiratory tract infection Pimentel, et al. AJPGI. 290;1089,2006. *This agent is not currently FDA approved for IBS Ford AC, et al. Clin Gastroenterol Hepatol 2009;7: Pimentel M, et al. N Engl J Med 2011; 364:

3 RifaximinTrials: Global Relief of IBS Without Constipation 2 Phase 3 randomized controlled trials; n=1260 patients Rifaximin 550 mg TID x 2 weeks; patients followed additional 10 weeks Probiotics What about Probiotics? Could some methane-producing bacteria respond to probiotics? 40.7% vs. 31.7% with adequate relief of global symptoms (p<0.001) T-I, TARGET 1 trial; T-II, TARGET 2 trial; Comb, Combination of both trials. *Rifaximin is not currently FDA-pproved for IBS Pimentel M, et al. N Engl J Med 2011;364:22-32 Probiotics for IBS Lactobacilli anaerobic, gram (+) rods casei plantarum acidophilus reuteri Bifidobacteria anaerobic, gram (+) rods VSL #3 (8 separate organisms: 3 Bifidobacteria, 1 Stretococcus, 4 Lactobacilli) Enterococcus Streptococcus salivarius Saccharomyces Probiotics: Mechanisms of Action Competitive inhibition Barrier protection Immune effects Anti-inflammatory effects Production of various substances (enzymes, SCFA, bacteriocidal agents) Ability to alter local ph and physiology Provides nutrition to colonocytes Moayyedi P, et al. GUT 2010:59: Epub 2008 Dec 17 Camilleri. J Clin Gastroenterol2006;40,264. BifidobacteriaInfantis35624 for IBS Global Assessment of Relief B Infantis B Infantis B Infantis Placebo 1x x10 8 1x10 6 SGA: (Subjects Global Assessment) a yes/no response to the following question: Please consider how your felt in the past week in regard to your IBS, in particular your general well being, and symptoms of abdominal discomfort or pain, bloating or distention, and altered bowel habit. Compared with the way you felt before beginning the medication, have you had adequate relief of your IBS symptoms? Whorwell PJ, et al. Am J Gastroenterol 2006;101: Wheat & IBS Gluten-related disorders Celiac disease Dermatitis herpetiformis Gluten Ataxia Non-celiac gluten sensitivity 3

4 Gluten A storage protein in wheat, barley, and rye Genetically susceptible individuals (HLA-DQ2 and HLA-DQ8) develop an immune response Worldwide prevalence of celiac disease in IBS patients = 4% 1 US prevalence of celiac disease in IBS patients = 0.41% 2 KEY POINT: The vast majority of IBS patients do not have celiac disease Low carbohydrate Low fructose/fructan IBS & Diet Low gluten Low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccarides, and Polyol) 1 Green. Lancet 362; 383:2003; 2 Cash et al. Gastroenterology141;1187:2011 Low Carbohydrate Diet Prospective, randomized, controlled study 17 moderate-severe IBS-D patients 4-week very low carbohydrate diet (VLCD) 51% fat; 45% protein; 4% carbohydrate Endpoint: adequate relief for > 2weeks 13 completed the study All 13 met the responder definition 10 experienced adequate relief for all 4 weeks Low Carbohydrate Diet Secondary Endpoints also improved Decrease in stool frequency Improvement in stool consistency Decreased abdominal pain Improvement in quality-of-life Austin et al, Clin Gastro & Hepatol7;706:2009 IBS & Low Fructose/Fructan Diet 26 IBS patients with fructose malabsorption (Rome II; + breath test; mean age = 38) Prior response to low fructose/low fructan diet Randomly re-challenged with offending foods 70% of those receiving fructose, 77% receiving fructans, and 79% receiving a mixture noted return/worsening of symptoms compared to glucose (14%; p < 0.002) Sheperdet al, Clin GastroenterolHepatol2008; 6: IBS & Low Gluten R, DB, PC, re-challenge study 34 IBS patients (Rome III); celiac excluded Prior improvement in Sx on gluten-free diet 16 gm of non-fermentable gluten/day vs. 16 grams of gluten Primary endpoint: adequate symptom relief Gluten-group had less improvement in Sx than those on gluten-free (68% vs. 40%; p =.001) Biesiekierski et al, Am J Gastro 2011;106:508. 4

5 IBS & Low Gluten Diet IBS and Gluten-free Diet 45 Pts with ISB-D (43 women); 4-weeks Gluten-free diet (23) vs. Gluten-diet (22) Genotype analysis performed Stool frequency, intestinal transit and intestinal permeability measured Results: Gluten diet was associated with increased SB permeability, especially in HLA- DQ2/8 positive patients Biesiekierski et al, Am J Gastro, 2011; 106:508. Vazquez-Roque et al, Gastroenterology2013; 144: What Are FODMAPs? Fermentable Oligo-, Di-, Monosaccharides And Polyols Excess Fructose Fructans Sorbitol Raffinose Honey, apples, pears, peaches, mangos, fruit juice, dried fruit Wheat(large amounts), rye (large amounts), onions, leeks, zucchini Apricots, peaches, artificial sweeteners, artificially sweetened gums Lentils, cabbage, brussel sprouts, asparagus, green beans, legumes IBS & Low FODMAP Diet: Or, what is there left to eat? Lean proteins Gluten-free breads, rolls, pasta Rice, corn, oat products Quinoa Safe fruits and vegetables: Snow peas, bok choy, mangarin oranges Shepherd SJ, et al. J Am Diet Assoc.2006;106: Shepherd SJ, et al. Clin GastroenterolHepatol2008;6: Gibson PR, et al. J GastroenterolHepatol 2010;25: IBS & Low FODMAP Diet: Some Problems Exist What is the cut-off for FODMAP content? Resources differ on low FODMAP diets Total meal FODMAPs should be counted, not individual FODMAPs IBS: Prospective study to Evaluate Low FODMAP diet 82 consecutive IBS patients (NICE criteria) Detailed symptom and dietary evaluation 9 month evaluation performed in UK Individual symptoms and global IBS symptoms measured 39 in the standard diet group 42 in the low FODMAP diet group Staudacheret al, J Hum Nutr Diet, 2011, 24,

6 Improvements in IBS Symptom Scores: Low FODMAP vs. Control Diet * *p p < 0.05 IBS Symptom Improvement: Low FODMAP Diet vs. Standard Diet Bloating (82% vs. 49%) Abdominal pain (85% vs. 61%) Flatulence (87% vs. 50%) Nausea (67% vs. 29%) Diarrhea (83% vs. 62%; ns) Composite symptom score (86% vs. 49%) Staudacher HM, et al. J Hum Nutr Diet 2011;24: Osmotic Agents: PEG for IBS-C SMs, bowel movements; PEG, polyethylene glycol KhoshooV, et al. Aliment PharmacolTher2006;23: adolescents: PEG improved number of BMs (p < 0.05) but not pain in IBS-C patients Osmotic Agents: PEG for IBS-C Prospective, multi-center, R, DB, PC Rome III criteria 139 patients (mean age = 41; 83% women) 28 day study; 13.8 gm/sachet; 1-3 sachets/day vs. placebo Primary endpoint: mean # of SBM/day Results: At week 4, 4.4 SBM/week vs. 3.1 SBM/week (PEG vs. placebo; p <.0001) Chapman. Am J Gastroenterol 2013;108,1508 PEG 3350 for IBS-C Efficacy of Linaclotidein Patients with IBS-C Treatment Period* RW Period n = 800 Treatment Period RW Treatment Sequence ANCOVA, analysis of convariance; RW, randomized withdrawl Rao S, et al. Am J Gastroenterol2012;107: *p < for linaclotide patients vs. placebo patients (ANCOVA) p < for linaclotide/linaclotide patients vs. linaclotide/placebo patients (ANCOVA) 6

7 Linaclotide Phase 3 IBS-C Trial: Adbominal Pain Over 26 Weeks p = for week 1 P < for weeks 2-26 Summary IBS is a constantly evolving field Rome IV 2015 expect changes in the definition Our understanding of IBS physiology continues to expand Expect new treatment options within the next few years ITT population, observed cases, LS-mean presented: p-values basted on ANCOVA at each week. Bars represent 95% CI ITT, intention to treat; LS, least squares n = 804 CheyWD, et al. Am J Gastroenterol2012;107:

What s the Latest? Rome III Criteria for IBS

What s the Latest? Rome III Criteria for IBS Irritable Bowel lsyndrome: What s the Latest? American College of Gastroenterology Las Vegas, January 2014 Bi Brian E. Lacy, Ph.D., PhD M.D., MD FACG Professor of Medicine Geisel School of Medicine at