9/17/2020 Disclosures: Brooks D. Cash, MD, FACG Consultant/Speakers’ Bureau: Salix, Allergan, Takeda, Ironwood, Alfasigma, Arena DSMB: Vibrant Brian E. Lacy, MD, PhD, FACG No conflicts of interest. 1 Current and Emerging Concepts in Irritable Bowel Syndrome Brooks D. Cash, M.D., FACP, FACG, FASGE, AGAF Dan and Lillie Sterling Professor of Medicine McGovern Medical School Chief, Gastroenterology, Hepatology, and Nutrition University of Texas Health Science Center Houston, TX 2 American College of Gastroenterology 1 9/17/2020 Disclosures • Consultant/Speakers’ Bureau: Salix, Allergan, Takeda, Ironwood, Alfasigma, Arena • DSMB: Vibrant 3 Objectives 1.Discuss the pathophysiology and diagnostic criteria for IBS 2.Explore the data for lifestyle and over the counter therapies for IBS symptoms 3.Review the mechanisms of action, efficacy, and safety profiles of FDA approved IBS therapies 4.Examine emerging therapies for IBS 4 American College of Gastroenterology 2 9/17/2020 Rome IV Criteria for IBS Recurrent abdominal pain at least 1 day/week (on average) in the last 3 months associated with ≥ 2 of the following Related to defecation Associated with Associated with a change a change in stool form in stool frequency Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis Lacy BE, et al. Gastroenterology. 2016 McGovern Medical School 5 Multifactorial Pathophysiology of IBS Inflammation, Psychosocial Immune Factors Dysregulation Genetic Predisposition Microbiome Visceral Malabsorption Hypersensitivity Issues IBS Abnormal Symptom Diet Motility Complex Chey WD, et al. JAMA. 2015;313:949‐958. Drossman DA. Gastroenterology. 2016;150:1262‐1279. Holtmann G, et al. Dig Dis. 2017:35:5‐13. Radovanovic‐Dinic B, et al. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2018;162:1‐9. McGovern Medical School 6 American College of Gastroenterology 3 9/17/2020 Principles of IBS Management • Exclude organic GI disease • Make a positive diagnosis • Establish a rapport; educate and reassure • Categorize IBS subtype based on prevalent stool form (BSFS) • First line: lifestyle and dietary modifications and OTC therapies targeting abnormal stool form/most bothersome symptoms • Escalate to FDA approved/validated therapies • Non‐FDA/off‐label/psychological therapies McGovern Medical School 7 Diagnostic Testing for Suspected IBS and No Alarm Features* All IBS Subtypes1 CBC Age‐appropriate CRC screening IBS‐D1,2 IBS‐M1 IBS‐C1 • CRP or fecal calprotectin • CRP or fecal calprotectin If severe or medically refractory, • IgA TtG ± quantitative IgA • IgA TtG ± quantitative IgA refer to specialist for physiologic • When colonoscopy performed, • Stool diary/App testing obtain random biopsies • Consider abdominal plain film to assess for fecal loading • Serum 7‐C4 or fecal bile acids where available *Alarm Features include age ≥50 years old, blood in stools, nocturnal symptoms, unintentional C4, 7α‐hydroxy‐4‐cholesten‐3‐one; CRC, colorectal cancer weight loss, change in symptoms, recent antibiotic use, and family history of organic GI disease screening; CRP, C‐reactive protein; Ttg, tissue transglutaninase 1. Chey WD et al. JAMA. 2015;313(9):949‐958. 2. Pimentel M et al. PLoS ONE. 2015;10(5):e0126438. McGovern Medical School 8 American College of Gastroenterology 4 9/17/2020 Lifestyle Modifications (all have some evidence of benefit) • Dietary • Low FODMAP • Gluten restriction • Keto/Mediterranean • Low fat • Activity • Exercise • Sleep hygiene • Minimize/eliminate ETOH • Best evidence for IBS‐D, likely due to decrease in metabolic byproducts McGovern Medical School 9 Dietary Considerations in IBS • FODMAPS are an important trigger of meal‐related symptoms in IBS1 • Low FODMAP diet found to improve overall symptom scores compared with typical diet in IBS patients2 • Gluten‐free diet found to be beneficial in some patients with IBS‐D3,4 –Wheat contains fructans and other proteins that may also cause symptoms in IBS patients5 –Most patients who associate their symptoms with wheat will have wheat sensitivity, not celiac disease6 • Food antigens found to cause changes in the intestinal mucosa of IBS patients that are associated with patient responses to exclusion diets7 1. Shepherd SJ et al. Am J Gastroenterol. 2013;108:707‐717. 2. Halmos EP et al. Gastroenterology. 2014;146:67‐75.3. Biesiekierski JR et al. Gastroenterology. 2011;106:508‐514. 4. Vazquez‐ Roque MI et al. Gastroenterology. 2013;144:903‐911.e3. 5. Chey WD, et al. JAMA. 2015;313(9):949‐958. 6. Leonard MM et al. JAMA. 2017;318(7):647‐656. 7. Fritscher ‐Ravens A et al. Gastroenterology. 2014;147:1012‐1020. McGovern Medical School 10 American College of Gastroenterology 5 9/17/2020 Low FODMAP versus mNICE Diet for IBS‐D: Adequate Relief & FDA Endpoint 84 patients with IBS‐D randomized to LFD or mNICE x 4 weeks and completed study ‐ median age was 43 years (range 19‐68); 65 were women Adequate Relief FDA Composite Responder 80 80 P = 0.31 P = 0.13 60 52 60 41 40 40 Percent 27 Percent Responders 20 Responders 20 13 0 0 LFD mNICE LFD mNICE n=45 n=39 n=45 n=39 >30% reduction in pain and decrease in BSFS >1 compared to baseline Eswaran SL et al. Am J Gastroenterol. 2016;111(12):1824‐1832. McGovern Medical School 11 IBS Pharmacologic Options by Symptom1,2 Abdominal Pain/discomfort Bloating Antispasmodics* Rifaximin Antidepressants* Lubiprostone Lubiprostone Linaclotide Linaclotide Plecanatide Plecanatide Abdominal Probiotics* Alosetron pain/ Bloating/ Rifaximin discomfort distension Eluxadoline Constipation Diarrhea Tegaserod Fiber* Loperamide* MOM/PEG solution* Diphenoxylate‐ Lubiprostone Altered bowel atropine* Linaclotide function Cholestyramine* Plecanatide Alosetron Tegaserod Rifaximin Tenapanor Eluxadoline Prucalopride* *Not currently FDA‐approved for IBS 1. Brandt LJ, et al. Am J Gastroenterol. 2002;97(11 suppl):S7‐S26. 2. Drossman DA et al. Gastroenterology. 2002;123:2108‐2131. McGovern Medical School 12 American College of Gastroenterology 6 9/17/2020 OTC Options • Antidiarrheals: Imodium, clays/binders • Anti‐spasmodics • Peppermint oil • Probiotics McGovern Medical School 13 Conventional Nonspecific Agents for IBS‐D Recommendations from an American College of Gastroenterology monograph There is insufficient 2 Recommendation evidence to Clinical trials Strong recommend loperamide for 42 Quality of evidence use in IBS Patients treated Very Low There is insufficient Recommendation evidence to 23 Weak Clinical trials recommend antispasmodics 2,154 Quality of evidence available in US* Patients treated Low *Recommendation revised to reflect evidence for products available in US Ford AC et al. Am J Gastroenterol. 2014;109(Suppl 1):S2‐S26. McGovern Medical School 14 14 American College of Gastroenterology 7 9/17/2020 Peppermint Oil • Active ingredients: L‐menthol, rosmarinic acid, limonene1 • Primary effect: Ca+2 channel smooth muscle relaxation • Possible mediation via TRPM8, k‐opioid agonist, antibacterial, anti‐inflammatory, carminative2 • Dose unclear; typically 90‐180 mg up to TID • 7 RCT, 634 patients • NNT = 4 • AEs similar to placebo: GERD, dyspepsia reported Cash BD et al. Dig Dis Sci. 2016;61:560‐571. Henstrom M et al. Gut. 2017;66(9):1725‐1727. McGovern Medical School 15 •. Probiotics • 53 RCT, 5545 patients; 50% trials at low risk for bias • Significant heterogeneity • Evidence of publication bias • Probiotics superior to placebo • NNT=7 • Combination probiotics: RR = 0.79 (0.68‐0.91) • IBS dose/brand: unknown • Symptoms most likely to improve pain, bloating, flatulence • Low rate of AEs Ford AC et al. Am J Gastroenterol. 2018;113(Suppl 2):1‐18. McGovern Medical School 16 American College of Gastroenterology 8 9/17/2020 FDA Approved Therapies for IBS‐D • Rifaximin • Eluxadoline • Alosetron McGovern Medical School 17 Rifaximin for IBS‐D TARGET 1 & TARGET 2 Trials Adequate Relief Adequate Relief • Poorly absorbed antibiotic; of Global IBS Symptoms of Bloating inhibits protein synthesis 80 80 • Dosing 550 mg TID x 2 weeks P < 0.001 • 7 RCT; 2654 patients 60 P = .01 P = .03 60 PAdequate = .005 ReliefP of=.02 P < .001 IBS‐Related Bloating % • NNT= 8 40.8 40.6 40.7 39.5 41 40.2 • AEs similar to placebo 40 40 31.2 32.2 31.7 31.9 • 2/3 responders need 28.7 30.3 Patients, repeat treatment 20 20 • No value in re‐treating non‐ responders 0 0 n=309 n=314 n=315 n=320 n=624 n=634 n=309 n=314 n=315 n=320 n=624 n=634 TARGET 1TARGET 2 Combined TARGET 1 TARGET 2 Combined Pimentel M et al. N Engl J Med. 2011;364(1):22‐32. Rifaximin Placebo McGovern Medical School 18 American College of Gastroenterology 9 9/17/2020 Rifaximin for IBS‐D TARGET 3 Trial Retreatment Efficacy 80 First Second Repeat Treatment Repeat Treatment Responder defined as Data for last observation carried forward • Responding to IBS‐related abdominal pain 60 and stool consistency for ≥2 of 4 weeks P = .02 P = .04 Recurrence defined as % • Loss of response for ≥3 of 4 weeks 40 33 36.9 29.3 25 Urgency and bloating improved 20 significantly with both repeat treatments Patients, Abdominal pain and stool consistency 0 improved significantly n=328 n=308 n=295 n=283 with first retreatment Rifaximin Placebo Lembo A et al. Gastroenterology. 2016;151(6):1113‐1121. McGovern Medical School 19 Eluxadoline for IBS‐D Composite Responder Rates IBS‐3001 & IBS‐3002 Trials • Mixed opioid receptor modulator • μ/κ‐opioid receptor agonist; δ‐ opioid antagonist 1,2 • Dosing: 100 mg BID • 3 RCT, 3235 patients • NNT= 13 • AEs: Constipation, abdominal pain, SO spasm, pancreatitis Placebo BID Eluxadoline 75 mg BID Eluxadoline 100 mg BI • Contraindicated if no GB or h/o Composite responder defined as pancreatitis, heavy ETOH users • 30% reduction in worst abdominal pain score AND improvement in stool consistency of <5 on the Bristol Stool Scale • Daily improvement in BOTH symptoms on at least 50% of days in the trial Fujita W et al. Biochemical Pharmacology. 2014;92(3):448‐4565.; Wade PR et al.