4 th Annual Digestive Disease IBS: New Management Approaches Disclosures Consultant Alkermes, Allergan, Forest, Ironwood, Prometheus, Salix Anthony Lembo, M.D. Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA Highlights Recent FDA approved treatments for IBS IBS-D: Rifaximin and Eluxadoline (215) IBS-C: Plecanatide (217) Rome IV Criteria for IBS (216) Controlled trials with the FODMAP diet Early description of symptoms defining IBS 1849 W Cumming The bowels are at one time constipated, at another lax, in the same person. How the disease has two such different symptoms I do not profess to explain.... Historical mucous colitis colonic spasm neurogenic mucous colitis irritable colon Defining IBS Manning Criteria Rome I Rome II unstable colon nervous colon nervous colitis spastic colitis W. Cumming, London Medical Gazette, 1849;NS9;969-973. Rome IV Criteria for IBS IBS Symptoms are Common Recurrent abdominal pain at least 1 day /week in the last 3 months associated with 2 or more of the following: Prevalence of IBS 1,2 Related to defecation Associated with a change in frequency of stool Associated with a change in form (appearance) of stool Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis Lacy B et al. Gastroenterology. 216;15:1393-147 Rome Organization. Rome IV Disorders and Criteria. 7 1. Chey WD, 6 et al. JAMA. 215;313:949-958. 2. Lovell RM, et al. Clin Gastroenterol Hepatol. 212;1:712-721.
IBS Patients Frequently Change Stool Subtype Percentage of hard or lumpy stools 1 75 5 25 IBS-C IBS-U IBS-M IBS-D Bristol Stool Form Scale 1-2 Bristol Stool Form Scale 6-7 IBS-M = IBS-mixed IBS-U = unclassified IBS 25 5 75 1 Percentage of loose or watery stools IBSC: IBS with constipation; IBS-A, Alternating IBS; IBS-D: IBS with diarrhea Proportions of patients in each subgroup stable over time but: 75% will experience a change in subgroup over time more likely to transition to IBS-C than to IBS-D transitions from IBS-C to IBS-D in less than a third of patients over a year Adapted from: Lacy B et al. Gastroenterology. 216;15:1393-147. 1. Tillisch K et al. Am J Gastroenterol. 25;1(4): 896 94. 2. Drossman DA. Gastroenterology. 25;128(7):1771-1772. IBS is More Common in Women IBS is Particularly Common in Young Adults 3 % with Rome II IBS 16 12 8 Men Women % Rome II IBS 2 1 USA W. Europe Japan 4 Andrews 25 Thompson 22 Sperber 25 Gwee 24 Talley 21 China 1 2 3 4 5 6 7 8 Age (years) E9 E1 IBS Frequently Co-exists with Other Chronic Conditions Natural History of IBS Chronic, relapsing symptoms Long-term follow-up suggests that ~ 2% worsened ~ 5% remained unchanged ~ 3% improved Ladabaum et al, Gastroenterology 27; 132: W1172 Whitehead et al, Am J Gastroenterol 27; 12: 2767 76 Vandvik et al, Aliment Pharmacol Ther 24; 2: 1195 23 1. El-Serag HB, et al. Aliment Pharmacol Ther. 24;19:861-87. 2. Engsboro 12AL, et al. Aliment Pharmacol Ther. 212;35:35-359. 3. Garrigues V, et al. Aliment Pharmacol Ther. 27;25:323-332.
IBS Patients have Lower HR-QOL IBS Pyramid Mean SF-36 score 9 8 7 6 5 4 3 National norm Diabetes type II IBS Clinical depression Psychological disturbance Pain Specialists Primary care ~25% Consulters ~75% Nonconsulters ~7% Female ~3% Male Adapted from Wells et al., Alimentary Pharmacology Therapies, 1997; 11: 119-13. Adapted from Drossman and Thompson, Ann Intern Med 1992; 116(pt 1): 19 Sandler, Gastroenterology 199; 99: 49 Economic burden of IBS What Causes IBS? Evolution of Pathophysiologic Hypotheses Asthma Migraine IBS Hypertensive disease Stroke Arthritis Diabetes 2 4 6 8 1 12 Billions of dollars Healthcare costs Productivity costs Abnormal Motility Visceral Hypersensitivity Brain-Gut Interaction Biochemical Receptors Microbiome GI Infections 195 217 Adapted from AGA IBS Teaching Series Genes Early learning Family influences What Causes IBS? External stressor Adverse life events Chronic psychological stress Gastrointestinal infection Alterations in gut microbiota Changes in diet Psychological disturbance Susceptible individual Physiological disturbance Pathophysiology of IBS Alterations in IBS Enhanced stress response Altered pain perception Altered brain-gut interaction Dysbiosis Increased intestinal permeability Increased gut mucosal immune activation Altered motility Visceral hypersensitivity Courtesy of Robin Spiller, MD IBS symptoms 1. Chang L. 18Gastroenterology. 211;14:761-765. 2. Chey WD, et al. JAMA. 215;313:949-958.
Conditions That Can Mimick IBS Positive Diagnostic Strategy vs Strategy of Exclusion in the Primary Care Setting 32 IBS (Rome III) patients (<5 years) + no alarm features Celiac disease Organic disease in the absence of alarm features is uncommon Alarm Features Symptom onset > 5 years Blood in stools/fe def anemia Weight loss (unintentional) Lactose intolerance Thyroid dysfunction Enteric infection Inflammatory bowel disease Colorectal carcinoma Blood analysis Stool samples for parasite Sigmoidoscopy with biopsies Strategy of Exclusion Positive Strategy A positive diagnostic strategy was non-inferior to using a strategy of exclusion with regard to HRQoL and was associated with lower direct costs CBC, CRP, Ca, bilirubin, ALT, Aφ, alb, TSH, ttg, lactase gene test CBC. CRP FH CRC/IBD Nocturnal Symptoms ACG Task Force on IBS. Am J Gastroenterol. 29;14(suppl 1):S1-S35 Begtrup LM, et al. Clin Gastroenterol Hepatol. 213;11:956-962. Recommendations from the ACG for Diagnostic Testing in IBS Test CBC serum chemistries TSH, Stool for ova and parasites Abdominal imaging ttg Lactose breath testing Breath testing for SIBO Routine colonoscopy Recommendation Not recommended in patients with typical IBS symptoms and no alarm features IBS-D If symptoms persist after dietary modification Insufficient data to recommend Not recommended in patients <5 years old with typical IBS symptoms and no alarm features % with relief 6 5 4 3 2 1 Treatment period Drug arm Therapeutic gain Placebo arm Natural history of disease + Placebo Effect Follow-up period P<.5 2 4 6 8 1 12 14 16. ACG Task Force on IBS. Am J Gastroenterol. 29;14(suppl 1):S1-S35. Week T22 Treatments for IBS Dietary and Lifestyle Considerations Only a few well-controlled RCTs of elimination diets in IBS have been conducted 1 Up to ⅔ of IBS patients associate symptom onset or worsening with eating a meal 2,3 Maintaining a brief diary of dietary intake and symptoms may help determine if a correlation exists between food and IBS symptoms 2 Fatty/greasy food Poorly absorbed carbohydrates Gas-producing foods Soluble fiber IBS symptoms Improve with moderate physical activity 4 FODMAPs=fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; RCT=randomized, controlled trial. 1. Moayyedi P, et al. Clin Transl Gastroenterol. 215;6:e17. 2. Somers SC, Lembo A. Gastroenterol Clin North Am. 23;32:57-529. 3. ACG Task 24Force on IBS. Am J Gastroenterol. 29;14(suppl 1):S1-S35. 4. Johannesson E, et al. Am J Gastroenterol. 211;16:915-922.
Diets in IBS Pros: Non-pharmacological therapy Symptom relief, at least short term Cons: No standard diet Difficult and expensive to follow Nutrition consult often necessary Long term impact on health is unclear Difficult to control for placebo effect in a dietary trial The FODMAP Diet Eliminate foods containing FODMAPs 1-3 Excess Fructose fruit apple, mango, pear, cherries, watermelon sweeteners sugar, high-fructose corn syrup other honey, asparagus Lactose Fructans Galactans Polyols milk milk from cows, goats, or sheep; custard, ice cream, yogurt cheeses soft unripened cheeses (eg, cottage cheese, ricotta) vegetables onion, leek, garlic, shallots, artichokes, asparagus, peas, beetroot, chicory cereals wheat, barley, rye legumes baked beans, chickpeas, kidney beans, lentils fruit apple, pear, apricot, cherries, peaches, nectarines, plums, watermelon vegetables cauliflower, mushrooms sweeteners sorbitol, mannitol, xylitol, chewing gum 1. Shepherd SJ, et al. Am J Gastroenterol. 213;18:77-717. 2. Shepherd SJ, Gibson PR. J Am Diet Assoc. 26;16:1631-1639. 3. Barrett JS, Gibson PR. Ther Adv Gastroenterol. 212;5:261-268. 26 Low-FODMAP vs Typical Australian Diet Mean overall GI symptoms improved with low-fodmap diet in IBS patients (.5 g of FODMAPs per meal) Traditional IBS Diet Improves IBS Symptoms Similar to low FODMAP Diet VAS (-1 mm) 6 4 2 IBS -7 7 14 21-7 7 14 21 Day Day Halmos EP, et al. Gastroenterology. 214;146:67-75. P<.1 Baseline Typical Australian diet Low-FODMAP diet 6 4 2 Healthy Controls IBS Severity Score 45 4 35 3 25 2 15 1 5 Böhn L, et al. Gastroenterology. 215. Day Day 14 Day 29 Low-FODMAP diet (n=33) Traditional IBS diet (n=34) P=.2 P<.1 Low FODMAPs Both diets Traditional IBS Diet Regular meal pattern; avoidance of large meals; reduced fat, insoluble fibers, caffeine, gas-producing foods (e.g., beans, cabbage, and onions), Greater emphasis on how and when to eat rather than the type of foods A Randomized Controlled Trial Comparing the Low FODMAP Diet vs. Modified NICE Guidelines in US Adults with IBS-D low FODMAP or mnice diet for 4 weeks. National Institute for Health and Care Excellence Eswaran et al. Am J Gastroenterol 216; 111:1824 1832 Psychological Therapy for IBS Therapy Trials N RR (95% CI) NNT (95% CI) Cognitive behavioral therapy (CBT) 9 61.6 (.44-.83) 3 (2-6) Relaxation training or therapy 6 255.77 (.57-1.4) Hypnotherapy 5 278.74 (.63-.87) 4 (3-8) Multi-component psychological therapy 5 335.72 (.62-.83) 4 (3-7) Self-administered, minimal-contact CBT 3 144.53 (.17-1.66) CBT via Internet 2 14.75 (.48-1.17) Dynamic psychotherapy 2 273.6 (.39-.93) 3.5 (2-25) Stress management 2 98.63 (.19-2.8) Multi-component therapy via telephone 1 126.78 (.64-.93) Mindfulness meditation training 1 75.57 (.32-1.1) Total 36 2334.68 (.61-.76) CI=confidence interval; NNT=number needed to treat; 3 Ford AC, et al. Am J Gastroenterol. 214 Sep;19:135-1365. RR=risk ratio; = not provided.
Bloating Probiotics Antibiotics Examples of Pharmacologic Treatments for IBS Bloating/ distension Diarrhea Loperamide Probiotics Cholestyramine Rifaximin Eluxadoline Altered bowel function Abdominal pain/ discomfort Abdominal pain/discomfort Antispasmodics Antidepressants Linaclotide Constipation Ispaghula/psyllium Lubiprostone Linaclotide Osmotic laxatives Probiotics Probiotics improve global symptoms, bloating, and flatulence. Recommendations regarding individual species, preparations, or strains cannot be made Associated with benefits in global IBS, abdominal pain, bloating, and flatulence scores NNT of 7 (95 % CI 4 12.5) Subanalysis showed only combination probiotics, Lactobacillus plantarum DSM 9843 and E. coli DSM17252, to be effective 1. Brandt LJ et al, for the ACG Task Force on IBS. Am J Gastroenterol. 29;14(Suppl 1):S1-S35. 2. Chey WS, et al. Gut and Liver. 211;253-266. 5 Ford AC, et al. Am J Gastroenterol. 214;19:1547-1561. Soluble Fiber (Psyllium) May be Effective in Some IBS Patients Proportion of patients with adequate relief of symptoms each week 1 5 4 P<.5 Polyethylene Glycol (PEG) does not Improve Abdominal Symptoms in IBS-C Spontaneous Complete Bowel Movements (SCBMs) Abdominal Discomfort/Pain N=68 N=71 Responders 3 2 Psyllium, 1 g (n=85) 1 Bran, 1 g (n=97) Placebo (rice flour), 1 g (n=93) 1 2 3 4 5 6 7 8 9 1 11 12 Study Duration (weeks) Fiber can exacerbate bloating, flatulence, distention, and discomfort. 2,3 Dose should be titrated gradually 2 1. Bijkerk CJ, et al. BMJ. 29:339:B3154-B316. 2. ACG Task Force on IBS. Am J Gastroenterol. 29;14(suppl 1):S1-S35. 3. Eswaran S, et al. Am J Gastroenterol. 213;18:718-727. 33 P<.1. Between 1 and 3 sachets of PEG 335 + E (13.8 g per day) or matching placebo were administered Patients adjusted the dose based on stool consistency Chapman RW, et al. Am J Gastroenterol. 213;18(9):158-1515. E=electrolytes. 34 Antidepressants Can Improve IBS Symptoms Effective at reducing IBS symptoms and abdominal pain 1 Adverse effect profiles may guide use in IBS subtypes 2 TCAs may cause constipation and may therefore not be well suited for patients with IBS-C SSRIs may cause diarrhea and are therefore not well suited for patients with IBS-D RR=relative risk; SSRI=selective serotonin-reuptake inhibitor; TCA=tricyclic antidepressant. 1. Ford AC, 35 et al. Am J Gastroenterol. 214;135-1365. 2. Chey WD, et al. JAMA. 215;313:949-958. Patients without Improvement in IBS Symptoms 1 Respondents (%) 7% 6% 5% 4% 3% 2% 1% % Placebo RR =.67 (95% CI=.58-.77) NNT = 4 Antidepressants Antidepressants Tips for improving Effectiveness Inform patients of expected AE (e.g. sedation, agitation, anticholinergic) Start low (1-25 mg/d) and advance slowly, especially in the elderly and those with somatization disorder Try to reach a daily dose of 5 mg Switch to an alternative TCA or SSRI if intolerance or SE occur Use adverse-effect profiles to help select agents Clouse, Gastroenterology, 1999
Increasing Fluid in the GI Tract via Chloride Channels Lubiprostone, a luminal Cl-C 2 channels Activator (and possibly CFTR) Enterocytes H 2 O Na + H 2 O Na + CFTR Na + Cl Cl - - Cl C2 channel channel Ion Transport K + Na + K + 2Cl K + Tight junction T37 T16 8 Combined Overall Responders, % P =.1 Drossman DA et al. Aliment Pharmacol Ther. 29;29:329 341. 2 12-wk Phase III Trials Overall responder = monthly responder 2-3 mths Monthly responder = at least moderate relief 2-4 wk or significant relief >2-4 wk FDA approved 8 ug BID in women with IBS-C Linaclotide, a Guanylate Cyclase-C agonist, for IBS-C FDA Composite Endpoint (primary endpoint) in Linaclotide Pivotal Trials 1,2 Plecanatide: A Guanylate Cyclase C Agonist FDA approved for treatment of chronic constipation 3 mg orally once a day Preliminary results from IBS-C Phase III Trials: plecanatide 3 mg (22%-3% vs 14%-18% placebo) Diarrhea occurred in 3-5% of patients receiving plecanatide 3 mg compared to 1% of placebotreated patients FDA-Defined Endpoint Each week, 3% decrease in worst abdominal pain + increase 1 CSBM from baseline for 6 of 12 weeks. CSBM, complete spontaneous bowel movement. 1. Chey W, et al. Am J Gastroenterol. 212;17:1714-1724. 2. Rao S, et al. Am J Gastroenterol. 212;17:1714-1724. ACG Task Force Recommendations for IBS-C Recommendation Quality Comments Diets Weak Very low Likely to relate to only some pts Fiber Weak Moderate Psyllium may be more effective than insoluble fiber Probiotics Weak Very low Likely only some pts will respond Polyethylene glycol Weak Very Low No evidence that PEG improves overall symptoms and pain in IBS Lubiprostone Strong Moderate Cost Linaclotide Strong High Cost Plecanatide was not included in the ACG Task Force Ford et al., AJG, 214 Loperamide for IBS with Diarrhea Only antidiarrheal studied in IBS Three RCTs of low-intermediate quality Decreased stool frequency and improved stool consistency but not abdominal pain or global IBS symptoms Most appropriate for patients with diarrhea-predominant symptoms Brandt LJ et al. Am J Gastroenterol 22; 97 suppl:s7 T42
Alosetron, a 5-HT3 antagonist, Improves Global Symptoms in Women with Severe IBS-D Safety Profile of Alosetron 6 5 4 % GIS 3 Responders 2 1 Placebo.5mg qd 1mg qd 1mg bid N=176 N=177 N=175 N=177 P<.2 vs placebo Assessment at 12 weeks Krause R et al. Am J Gastroenterol 27; 12:179 GIS = Global Improvement Scale T43 Black-box warning: serious GI effects Ischemic colitis 2 per 1 patients over 3 months 3 per 1 patients over 6 months Constipation Alosetron (1 mg bid), 29% Placebo, 6% No clinically relevant drug-drug interactions Pregnancy category B Alosetron [package insert]. GlaxoSmithKline; 26 T44 Phase III Trials (Target 1 and 2) Rifaximin for IBS-D TARGET 3: Safety and Efficacy of Rifaximin Retreatment Rifaximin limited systemic absorption (<.4%) In vitro activity against G+ and G- aerobic and anaerobic bacteria Phase III trials showed efficacy in improving global IBS-D symptoms and bloating 2 identical phase 3, double-blind, placebo-controlled trials (Target 1 and 2) Randomized to rifaximin 55 mg or placebo, TID x 2 weeks F/U, follow-up; EOS, end of study; PBO, placebo; RFX, rifaximin. Pimintel M, Lembo A et al; TARGET Study Group. N Engl J Med. 211;364:22-32. Lembo A, et al. Gastroenterology 217 TARGET 3: Efficacy of Retreatment Eluxadoline for IBS-D 48 Efficacy of First and Second Retreatments LOCF Analysis Urgency and bloating improved significantly with both repeat treatments Abdominal pain and stool consistency improved significantly with first retreatment Mixed mu (μ) opioid receptor agonist / delta (δ) opioid receptor antagonist Low systemic absorption and bioavailability Low potential for drug drug interactions Animal studies suggest eluxadoline should improve the diarrheal symptoms of IBS-D with limited constipation and durable analgesia FDA approved 75 and 1 mg BID for IBS-D LOCF, last observation carried forward. Responder defined as subjects responding to IBS-related Abdominal Pain and Stool Consistency for 2 of 4 weeks. Recurrence defined as a loss of response for 3 of 4 weeks. μ opioid receptor Activation reduces pain, gastric propulsion δ opioid receptor Inhibition restores G-protein signaling; reduces μ agonist-related desensitization Lembo A, et al. Gastroenterology 217
Eluxadoline Improves IBS-D Symptoms: Phase III Trials Responders (%) 35 3 25 2 15 1 5 16.7 9.5 1.3 26.2 27. 19.5 7.2 11.5 26.7 31. N=88 N=86 N=89 N=88 N=86 N=89 PBO p<.1 75 mg ELX 1 mg ELX Weeks 1 12 Weeks 1 26 Responder: Patient responding to Abdominal Pain (>3% improvement) and Stool consistency (BSS score <5or in absence of BM, if accompanied by 3% improvement in WAP compared to average baseline pain) for 5% of the weeks Pancreatitis developed in 5 (2 in 75-mg grp + 3 in 1-mg grp) of the 1666 pts in the safety population (.3%). Contraindicated if alcohol intake is > 3 drinks per day and in patients without a gallbladder Lembo A et al. NEJM 216 ACG Task Force Recommendations for IBS-D Recommendation Quality Comments Diets Weak Very low Likely to relate to only some pts Prebiotics Insufficient Evidence Probiotics Weak Very low Likely only some pts will respond Rifaximin Weak Moderate Cost Antispasmodics Weak Low Likely to be effective only short-term Loperamide Strong Very low Improves bowel function with limited effects on pain Antidepressants Weak High Associate with AE with a NNH of 9 Alosetron Weak Moderate Ischemic colitis, restricted to women Ford et al., AJG, 214 Summary Treatment Options in IBS severe moderate mild Low-dose TCAs Contemporary Antidepressants Psychotherapy Behavioral interventions Alosetron Eluxadoline Rifaximin Linaclotide Loperamide Lubiprostone Antispasmodics Fiber Antispasmodics Laxatives Diet Diet Diarrhea predominant Constipation predominant