IBD and IBS: Not to be confused

Transcription

1 IBD and IBS: Not to be confused Adam S. Cheifetz, MD Director, Center for Inflammatory Bowel Disease Beth Israel Deaconess Medical Center Associate Professor of Medicine Harvard Medical School 2018

2 Conflict of Interest Disclosure Adam S. Cheifetz I disclose the following financial relationships with commercial entities that produce health care-related products or services relevant to the content I am planning, developing, or presenting: Company Relationship Content Area Janssen Abbvie Takeda Pfizer Arena AlphaSigma Samsung Miraca Ferring AMAG Consulting Consulting Consulting Consulting Consulting Consulting Consulting Consulting / Research Consulting Consulting June 2018 IBD IBD IBD IBD IBD IBD IBD IBD GI / preps Iron deficiency

3 Talk Overview 1. Brief review of Inflammatory Bowel Disease (IBD): epidemiology, pathophysiology, clinical features, and natural history 2. Review the goals of care and medical therapies available for IBD and their associated risks 3. Discuss the preventive care that is warranted in the patient with IBD 4. Brief review of Irritable Bowel Syndrome (IBS): epidemiology, pathophysiology, clinical features, and natural history 5. Discuss treatment of IBS

4 (Idiopathic) Inflammatory Bowel Disease Crohn s Disease and Ulcerative Colitis Indeterminate Colitis (IBD-u) From the Johns Hopkins Digestive Disease Library Other Colitides Microscopic colitis Collagenous Lymphocytic Diversion colitis Diverticular colitis Pouchitis

5 Epidemiology of IBD Approximately 1.6 million cases estimated in US Divided equally between UC and Crohn s disease Approximately 10,000 new cases diagnosed annually Onset at any age Peak incidence is in late adolescence and early adulthood Similar prevalence in males and females Hanauer S, NEJM 1996;334(13): Rogers et al, Journal of Chronic Disease 1971;24:743

6 Pathogenesis of IBD Genetic Susceptibility Altered Immune System Environmental Triggers

7 Smoking in IBD Crohn s disease Increased risk in current smokers Less responsive to treatment More likely to develop recurrence Ulcerative Colitis Smoking can protect against UC Ex-smokers and non-smokers are more likely to develop UC

8 Nonselective NSAIDs Induce Clinical Relapse in IBD RCT of 209 IBD patients in clinical remission 20% 25% relapse with nonspecific NSAIDS Within 7 days 1/3 required steroids to induce remission Cox-2 specific NSAIDS and low dose ASA appear to be safe in the short term Takeuchi, et al, Clin Gastro Hep 2006 Sandborn, et al, Gastro 2006

9 Disease Characteristics Ulcerative Colitis Small intestine is NOT involved Mucosal disease Rectal involvement Continuous Proctitis Left-sided Colitis Upper GI 5% Crohn s Disease Mouth to anus Transmural Rectal sparing Skip lesions Small bowel 30% Ileocolic 50% Colon 20% Pancolitis Perianal 33%

10 Cumulative Probability (%) Progression of Crohn's Disease Inflammatory Penetrating Stricturing Patients at risk: Months N= Cosnes J, et al. Inflam Bowel Dis. 2002;8:

11 Up to 80% of CD Patients will Require Surgical Intervention and There Is a High Rate of Postoperative Recurrence Probability (%) Mean ± 2 SD Number Years of events % of Patients Years Survival without surgery Survival without laboratory recurrence Survival without symptoms Survival without endoscopic lesions Munkholm P, et al. Gastroenterology. 1993;105: Rutgeerts P, et al. Gastroenterology. 1990;99:

12 Clinical pearls When to refer (red flags) Rectal bleeding / iron deficiency Night time symptoms Weight loss Family history of organic disease (colon ca, ibd) Patient with known IBD with GI symptoms Never assume symptoms are a flare of IBD Always rule out infection Assess for triggers of IBD

13 IBD Management Goals Induce Remission Prevent Hospitalizations Endoscopic Remission Establish Diagnosis Avoid Complications Maintain Remission Prevent Surgery

14 Pineton de Chambrun G, et al. Nat Rev Gastroenterol Hepatol. 2010;7(1): Why Is Mucosal Healing Important? In clinical trials o o FDA mandated end point More objective end point than clinical remission In clinical practice, mucosal healing can guide medical therapy o o Assess disease activity Growing evidence that mucosal healing is an important goal, because it appears to be associated with improved long-term outcomes Decreased likelihood of a flare Decreased progression to disease complications Decreased need for surgery and hospitalization

15 Treat to Target

16 Medical Therapy of Ulcerative colitis Therapy 5-ASA Induction of Remission +++ (mild to moderate) Maintenance of Remission +++ (mild to moderate) Corticosteroids MP/AZA + ++ Anti-TNF Vedolizumab Tofacitinib Cyclosporine +++ -

17 Vedolizumab (Entyvio) Selective adhesion molecule inhibitor (SAM-i) Monocolonal antibody to a4b7 integrin - intravenous FDA approved summer 2014 for moderate to severe UC and CD Effective UC > Crohn s Maintenance > Induction Appears safe (as safe as anti-tnf, maybe safer) 1 case of PML (progressive multifocal leukoencephalopathy) reported June 2018 in patient with HIV Sanborn and Feagan, NEJM

18 Janus Kinase (JAK) inhibitor Oral small molecule Tofacitinib (Xeljanz) FDA approved summer 5/30/2018 Effective for induction and maintenance of remission in moderate to severe UC TNF naive TNF exposed Safety issues Zoster, serious infection, lymphoma (?), skin cancers (nonmelanoma), lymphopenia, lipid elevation Sanborn and Feagan, NEJM

19 Therapy Medical Therapy of Crohn s Disease Induction of Remission Maintenance of Remission 5-ASA +/- - Antibiotics +/- - Corticosteroids MP/AZA Methotrexate Anti-TNF Anti-integrins (SAM-i) Ustekinumab (anti-il12/23)

20 Medical Therapy of Crohn s Disease Therapy Induction of Remission Maintenance of Remission Mesalamine (5-ASA) +/- - Safe and well tolerated Effective in UC, little to no data for CD Rare paradoxical response Rare interstitial nephritis Monitor renal function yearly

21 Medical Therapy of Crohn s Disease Therapy Induction of Remission Maintenance of Remission 5-ASA +/- - Antibiotics +/- - Corticosteroids Ineffective for maintaining remission Side effects (increased serious infection and mortality) Budesonide is safer than prednisone, but only effective for ileal and right colonic disease

22 Medical Therapy of Crohn s Disease Therapy Induction of Remission Maintenance of Remission 5-ASA +/- - Antibiotics +/- - Corticosteroids MP/AZA Takes up to 3 months to work Side effects: Pancreatitis, allergy, bone marrow suppression, hepatotoxicity, infection, abnormal PAP smears Increased risk of lymphoma (~4-5 fold over baseline) Non-melanoma skin cancer Requires frequent labs (CBC, LFTs)

23 Medical Therapy of Crohn s Disease Therapy Induction of Remission Maintenance of Remission 5-ASA +/- - Antibiotics +/- - Corticosteroids MP/AZA Methotrexate % response rate Contraindicated in pregnancy Infection Monitor CBC and LFTs Bone marrow suppression Hepatitis

24 Medical Therapy of Crohn s Disease Therapy Induction of Remission Maintenance of Remission 5-ASA +/- - Antibiotics +/- - Corticosteroids MP/AZA Methotrexate Anti-TNF

25 Anti-TNFs for Crohn s Disease Monoclonal antibodies to tumor necrosis factor Intravenous (IFX); Subcutaneous (ADA, CTP) Similar efficacy < 40% of responders in remission at 1 year Safety issues infection, lymphoma, skin cancers, skin reactions immunogenicity Infliximab (Remicade) Placebo (n=170) 5mg/kg (n=172) 10mg/kg (n=157) Remission at 26 weeks, % a 47 a,b Remission at 56 weeks, % a 41 a,b Adalimumab (Humira) Placebo (n=170) Every other week (n=172) Colombel JF, et al. Gastroenterology. 2007;132(1): Sandborn WJ, et al. N Engl J Med. 2007;357(3): Weekly (n=157) Remission at 26 weeks, % a 47 a,b Remission at 56 weeks, % a 41 a,b Certolizumab pegol (Cimzia) Placebo (n=101) Certolizumab pegol (n=112) Remission at 26 weeks,% P

26 Biosimilars US Approved for IBD infliximab-dyyb (Inflectra) adalimumab-atto (Amjevita) infliximab-abda (Renflexis) adalimumab-adbm (Cyltezo) infliximab-qbtx (Ixifi) infliximab (Remicade) adalimumab (Humira) infliximab (Remicade) adalimumab (Humira) infliximab (Remicade)

27 Medical Therapy of Crohn s Disease Therapy Induction of Remission Maintenance of Remission 5-ASA +/- - Antibiotics +/- - Corticosteroids MP/AZA Methotrexate Anti-TNF Anti-integrins

28 Selective adhesion molecule inhibitors (SAM-i) Vedolizumab (Entyvio) Monocolonal antibody to a4b7 integrin FDA approved summer 2014 for moderate to severe UC and CD Appears safe (as safe as anti-tnf, likely safer) 1 case of PML (progressive multifocal leukoencephalopathy) reported June 2018 in patient with HIV Natalizumab (Tysabri): Monoclonal Ab sgainst α4 integrin Effective and FDA approved for induction and maintenance of remission in moderate-severe Crohn s who have failed anti-tnf Monotherapy only; TOUCH program Risk of Progressive multifocal leuko- encephalopathy (PML) JC antibody test available for risk stratification Sanborn and Feagan, NEJM

29 Therapy Medical Therapy of Crohn s Disease Induction of Remission Maintenance of Remission 5-ASA +/- - Antibiotics +/- - Corticosteroids MP/AZA Methotrexate Anti-TNF Anti-integrins Ustekinumab (anti-il12/23)

30 Ustekinumab (Stelara) Monocolonal antibody to IL-12/23 (p40) FDA approved October 2016 for moderate to severe CD FDA approved 2009 for moderate to severe psoriasis Appears safe (most of data in psoriasis) Infection Probably lower when compared to anti-tnf Prior to use (rule out latent hepatitis B or tuberculosis) Malignancy Similar malignancy rates to general population Have been some reports of accelerated non-melanomatous skin cancers Confounded by patient population (psoriasis, UV therapy) Sandborn et al, NEJM 2012 JAMA Dermatol. 2015;151(9): doi: /jamadermatol

31 Ulcerative Colitis Failure of medical therapy Complications Perforation Hemorrhage Toxic megacolon Cancer / Dysplasia Symptomatic stricture Curative Permanent ileostomy IPAA (ileal pouch anal anastomosis) Surgical Indications Crohn s Disease Failure of medical therapy Complications Perforation Abscess Strictures Fistulae Malignancy / Dysplasia Hemorrhage Toxic megacolon

32 What Biologic Do We Chose First? Potential Considerations for Choosing Biologic? Rapid induction of remission Durability of remission (dose optimization +/- TDM) Favorable safety profile Patient preference for mode of administration Insurance / Payor Time on the market Immunogenicity (need for combination therapy) Mucosal healing Ref. in notes Impact on EIMs Fistula response

33 Optimizing Treatment of IBD - Predicting severity of Crohn s disease - Earlier use of effective therapy - More objective treatment goals (treating to target) - Mucosal healing - Biochemical marker normalization - Therapeutic drug concentration monitoring (TDM) - Proactive vs. Reactive - Minimizing risks of disease and medications

34 Farraye FA, Melmed G, Lichtenstein GR, Kane S. Am J Gastroenterol Feb;112(2):

35 ACG Vaccination Guidelines for Adults with IBD Annual influenza vaccination with non-live trivalent inactivated vaccine Pneumococcal vaccination with both Prevnar 13 and Pneumovax 23 if on immunosuppressive therapy If over age 50, consider vaccination against herpes zoster Before initiating immunosuppressive therapy, assess for prior exposure to varicella and vaccinate if naive, when possible Age-appropriate vaccinations before initiating immunosuppressive therapy, when possible Vaccination against diphtheria, pertussis, and tetanus; hepatitis A; hepatitis B; and human papilloma virus, per CDC Farraye guidelines FA, et al. Am J Gastroenterol. 2017;112(2):

36 Other ACG Recommendations for Adults with IBD Annual cervical cancer screening for women who are on immunosuppressive therapy Melanoma screening, independent of the use of biologic therapy Screening for non-melanoma skin cancer if any history of azathioprine or 6-mercaptopurine Screening for depression and anxiety Osteoporosis screening for patients with conventional risk factors Counseling on smoking cessation, if needed, for patients with CD Farraye FA, et al. Am J Gastroenterol. 2017;112(2):

37 Live Vaccines and Patients with IBD Generally contraindicated in patients using high-dose steroids (prednisone 20 mg/d or equivalent) or anti-tnf agents Clinicians should weigh the risk of natural infection vs. the risk associated with vaccination Common live virus vaccines: Inhaled influenza (FluMist) Measles, mumps, rubella Varicella Herpes zoster (Zostavax) Oral typhoid Yellow fever (for travel to endemic areas) CDC. MMWR Recomm Rep. 2011;60(2):1-64.

38 Inactivated Varicella-Zoster Vaccine (Shingrix) May be given to immunosuppressed patients 2 doses IM (0 months and then 2-6 months later) Very effective RPCT of HZ/su (n = 15400) in non-immunocompromised adults 50 Overall vaccine efficacy was 97.2% (95% [CI], 93.7%-99.0%), compared to placebo; mean follow-up of 3.2 years Solicited reports of injection-site and systemic reactions within 7 days of vaccination were more frequent in the vaccine group SAE, potential IMID or deaths similar to placebo Lal H, Cunningham A, Godeaux O, et al. N Engl J Med. 2015;372: Lal H, Cunningham A, Godeaux O, et al. N Engl J Med. 2015;372:

39 Bone Health Patients with IBD are at increased risk of osteopenia ( 50%), osteoporosis ( 15%) and osteoporotic fracture Indications for bone density screening in IBD: History of fracture Corticosteroids (longer than 3 months exposure or repeated use) Postmenopausal women Males older than 50 years Hypogonadism Additional risk factors for bone loss: Chronic inflammation, smoking, malnutrition Targownik LE, et al. Maturitas. 2013;76(4): Bernstein CN, et al. Gastroenterology. 2003;124(3):

40 Cancer Prevention Cervical cancer Yearly Pap if immunosuppressed Skin cancer Yearly dermatology exam (ALL patients); Sun-exposure precautions Colon cancer Risk is 2-3 times higher than general population; occurs at younger age Risk is same for UC and CD Certain factors increase risk of colon cancer Extent of disease (1/3), duration of disease (8-10 years), PSC, inflammation Surveillance colonoscopies for patients with 1/3 colon involved Every 1-3 years after 8-10 years of disease Farraye FA et al. Am J Gastroenterol Laine L et al. Gastroenterology. 2015

41 Therapy related monitoring Mesalamines Yearly renal function (also CBC, LFTs with sulfasalazine) Thiopurines CBC, LFTs (every 3 months; more frequent at initiation) Methotrexate CBC, LFTs (every 3 months; more frequent at initiation); periodic renal function Anti-TNF and ustekinumab TB and HBV prior to initiation; yearly assessment of risk factors Periodic CBC, LFTs Natalizumab JC virus prior to initiation and following on therapy; TOUCH program CBC, LFTs Vedolizumab CBC, LFTs Tofacitinib CBC, LFTs, lipids

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44 Irritable Bowel Syndrome (IBS)

45 Rome IV Criteria for IBS Recurrent abdominal pain at least 1 day / week in the last 3 months associated with 2 or more of the following: 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. 2016;150: Rome Organization. Rome IV Disorders and Criteria.

46 Adapted from Drossman and Thompson, Ann Intern Med 1992; 116(pt 1): 1009 Sandler, Gastroenterology 1990; 99: 409 IBS Affects up to 1/5 of Population, But Only a Small Percentage Seek Care Psychological disturbance Pain Specialists Primary care ~25% Consulters ~75% Nonconsulters ~70% ~30% Female Male

47 IBS Irritable Bowel Syndrome More common in women (2x) Common in young adults (20s-40s) Chronic, relapsing symptoms Long-term follow-up suggests ~ 20% worsened ~ 50% remained unchanged ~ 30% improved Can have significant impact on QOL 1. El-Serag HB, et al. Aliment Pharmacol Ther. 2004;19: Engsboro AL, et al. Aliment Pharmacol Ther. 2012;35:

48 Percentage of hard or lumpy stools 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 Percentage of loose or watery stools Adapted from: Lacy B et al. Gastroenterology. 2016;150:

49 IBS Frequently Co-exists with Other Chronic Conditions Ladabaum et al, Gastroenterology 2007; 132: W1172 Whitehead et al, Am J Gastroenterol 2007; 102: Vandvik et al, Aliment Pharmacol Ther 2004; 20:

50 Chang L. Gastroenterology. 2011;140: Chey WD, et al. JAMA. 2015;313: Pathophysiology of IBS Enhanced stress response Altered pain perception Altered brain-gut interaction Altered motility Visceral hypersensitivity Dysbiosis Increased intestinal permeability Increased gut mucosal immune activation

51 Celiac disease Conditions That Can Mimic IBS Lactose intolerance Thyroid disease Enteric infection Inflammatory bowel disease Colorectal carcinoma Alarm Features Organic disease in the absence of alarm features is uncommon Symptom onset > 50 years Blood in stools/fe def anemia Weight loss (unintentional) FH CRC/IBD Nocturnal Symptoms ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35

52 Recommendations from the ACG for Diagnostic Testing in IBS Test CBC serum chemistries TSH, Stool for ova and parasites Abdominal imaging Recommendation Not recommended in patients with typical IBS symptoms and no alarm features ttg Lactose breath testing Breath testing for SIBO Routine colonoscopy IBS-D If symptoms persist after dietary modification Insufficient data to recommend Not recommended in patients <50 years old with typical IBS symptoms and no alarm features ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.

53 Poulis et al. Eur J Gastro Hepatol Apr;14(4): Role of C-Reactive Protein and ESR in Distinguishing IBS vs. IBD Non-specific markers of inflammation CRP is preferred over ESR due to its: shorter half-life unlike ESR, CRP is not affected by conditions such as anemia, thalassemia and age CRP in differentiating IBS from active IBD Sensitivity of 100% and a specificity of 67% (cut-off of 2.3 mg/l) Helpful if positive, but 30% of patients don t mount CRP

54 Role of Fecal Markers of Intestinal Inflammation in Distinguishing IBS vs IBD 1. Sherwood RA. J Clin Pathol 2012;65(11): Waugh N, et al. Health Technol Assess. 2013;17(55):xv-xix,1-211 Calprotectin and Lactoferrin In addition to IBD elevated levels can be seen in diverticulitis, infection, ischemia and cancer Distinguishing IBS vs IBD Lactoferrin: 8 studies 1 Sensitivity (78 91%): Specificity (63 100%) Calprotectin: 7 studies 2 > 50 µg/g: sensitivity (99%) specificity (74%) > 100 µg/g: sensitivity (94%) specificity (82%)

55 Treatment of IBS Good patient-doctor relationship Education and reassurance Mild-moderate Dietary modification and lifestyle changes > pharmacologic therapies Severe or failed diet/lifestyle Pharmacologic therapies

56 1. Moayyedi P, et al. Clin Transl Gastroenterol. 2015;6:e Somers SC, Lembo A. Gastroenterol Clin North Am. 2003;32: ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S Johannesson E, et al. Am J Gastroenterol. 2011;106: 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

57 The FODMAP Diet Fermentable Oligo-, Di-, Mono-saccharides And Polyols Eliminate foods containing FODMAPs 1-3 Excess Fructose Lactose Fructans Galactans Polyols fruit apple, mango, pear, cherries, watermelon sweeteners sugar, high-fructose corn syrup other honey, asparagus 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. 2013;108: Shepherd SJ, Gibson PR. J Am Diet Assoc. 2006;106:

58 Examples of Pharmacologic Treatments for IBS Bloating Probiotics Antibiotics Bloating/ distension Diarrhea Loperamide Probiotics Cholestyramine Rifaximin Eluxadoline Altered bowel function Abdominal pain/ discomfort 1. Brandt LJ et al, for the ACG Task Force on IBS. Am J Gastroenterol. 2009;104(Suppl 1): 2. S1-S Chey WS, et al. Gut and Liver. 2011; Abdominal pain/discomfort Antispasmodics Antidepressants Linaclotide Plecanitidine Constipation Psyllium Lubiprostone Linaclotide Plecanitidine Osmotic laxatives

59 Soluble Fiber (Psyllium) May be Effective in Some IBS Patients Responders Proportion of patients with adequate relief of symptoms each week 1 1 * * *P<.05 Psyllium, 10 g (n=85) Bran, 10 g (n=97) Placebo (rice flour), 10 g (n=93) 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. 2009:339:B3154-B ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. * *

60 Probiotics Probiotics improve global IBS symptoms, abdominal pain, bloating, and flatulence scores NNT of 7 (95 % CI ) Subanalysis showed only combination probiotics, Lactobacillus plantarum DSM 9843 and E. coli DSM17252, to be effective Recommendations regarding individual species, preparations, or strains cannot be made Ford AC, et al. Am J Gastroenterol. 2014;109:

61 Pharmacologic Treatment of IBS-C First line (after psyllium) Osmotic laxatives (PEG) Second line Lubiprostone (Amitiza); Cl channel activator FDA approved 8 μg BID in women with IBS-C Linaclotide (Linzess); Guanylate cyclase agonist FDA approved dose 290 μg QD for IBS-C Adult men and women 5% withdrawal rate secondary to diarrhea Plecanitidine (Trulance); Guanylate cyclase agonist FDA approved 2018 at 3mg QD Diarrhea most common AE (1.5% withdrawal rate)

62 Polyethylene Glycol (PEG) improves bowel movements but does not improve abdominal symptoms in IBS-C Spontaneous Complete Bowel Movements (SCBMs) Abdominal Discomfort/Pain N=68 N=71 *P< Between 1 and 3 sachets of PEG E (13.8 g per day) or matching placebo were given Patients adjusted the dose based on stool consistency E=electrolytes. Chapman RW, et al. Am J Gastroenterol. 2013;108(9):

63 Lubiprostone, a luminal Cl-C 2 channels Activator (and possibly CFTR) Combined Overall Responders, % P = 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 Drossman DA et al. Aliment Pharmacol Ther. 2009;29:

64 Linaclotide, a Guanylate Cyclase C Agonist FDA Approved dose 290 μg QD for IBS-C Adult men and women Abdominal Pain Responder FDA Responder CSBM +1 Responder 30% abdominal pain reduction + increase 1 CSBM from baseline; in the same week for 50% of weeks (i.e, 6 out of 12 weeks) % FDA Responders Chey WD et al. AJG % Placebo N= %* Lin 290 µg N=401

65 Plecanitide, a Guanylate Cyclase C Agonist FDA Approved dose 3mg QD for IBS-C 2 phase 3 trials (n=1879) Percent overall responders 30% vs. 18% placebo 22% vs. 14% placebo Hit secondary endpoints Brenner et al, AJG 2018

66 Ford et al., AJG, 2014 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

67 Pharmacologic Treatment of IBS-D First line Anti-diarrheal agents (loperamide) Bile acid sequestrants (cholestryramine) Second line Rifaximin (Xifaxan) - bloating Third line Alosetron (Lotronex) ; females 5HT-3 receptor antagonist Restricted due to ischemic colitis (1:1000) and severe constipation Eluxadoline (Viberzi) Mu-opiod receptor agonist and delta-opioid antagonist Pancreatitis (>3 drinks a day; s/p cholecystectomy) Now contraindicated in patients s/p cholecystectomy

68 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 Brandt LJ et al. Am J Gastroenterol 2002; 97 suppl:s7

69 Phase III Trials (Target 1 and 2) Rifaximin for IBS-D Rifaximin limited systemic absorption (<0.4%) 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 550 mg or placebo, TID x 2 weeks Pimintel M, Lembo A et al; TARGET Study Group. N Engl J Med. 2011;364:22-32.

70 Safety Profile of Alosetron Alosetron, a 5-HT3 antagonist, Improves Global Symptoms in Women with Severe IBS-D Black-box warning: serious GI effects Ischemic colitis 2 per 1000 pts over 3 months 3 per 1000 pts over 6 months Constipation Alosetron (1 mg bid) = 29% Placebo = 6% Alosetron [package insert]. GlaxoSmithKline; 2006 Krause R et al. Am J Gastroenterol 2007; 102:1709 *P<0.02 vs placebo Assessment at 12 weeks GIS = Global Improvement Scale

71 Eluxadoline for IBS-D Mixed mu (μ) opioid receptor agonist / delta (δ) opioid receptor antagonist Low systemic absorption 25% response vs. 16% placebo response (phase 3) FDA approved 75 and 100 mg BID for IBS-D Pancreatitis (0.3%) Contraindicated if alcohol intake is > 3 drinks per day or s/p cholecystectomy 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. NEJM 2016

72 Ford et al., AJG, 2014 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 shortterm 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

73 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, et al. Am J Gastroenterol. 2014; Patients without Improvement in IBS Symptoms 1 Respondents (%) RR = 0.67 (95% CI= ) NNT = 4

74 Psychological Therapy for IBS Therapy Trials N RR (95% CI) Ford AC, et al. Am J Gastroenterol Sep;109: NNT (95% CI) Cognitive behavioral therapy (CBT) ( ) 3 (2-6) Relaxation training or therapy ( ) Hypnotherapy ( ) 4 (3-8) Multi-component psychological therapy ( ) 4 (3-7) Self-administered, minimal-contact CBT ( ) CBT via Internet ( ) Dynamic psychotherapy ( ) 3.5 (2-25) Stress management ( ) Multi-component therapy via telephone ( ) Mindfulness meditation training ( ) Total ( ) CI=confidence interval; NNT=number needed to treat; RR=risk ratio; = not provided.

75 Key Points: IBS IBS is very common and can significantly impact QOL IBS is a clinical diagnosis and treatment a requires close clinicianpatient relationship Treatment is based on symptoms Would start with diet, exercise and lifestyle before pharmacologic therapies in most Next best steps: Assess for alarm features (red flags) GI consult should be considered when using some of the newer agents

76 IBD Key Points: Differentiate between UC and Crohn s Rapid advances in medications Goals of care and treatment paradigms are changing endoscopic healing; treat to target; early aggressive therapy Next best steps: Vaccinate patients Screen and treat for osteopenia / osteoporosis Cancer surveillance is important Colon cancer, skin cancer, and cervical cancer (on IMM) Monitor for complications of IBD medicines GI consult should be considered to treat patients with IBD