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1

Provided by Integrity Continuing Education, Inc.Supported by an educational grant from Salix Pharmaceuticals, Inc., a division of Valeant Pharmaceuticals North America LLC.

Optimizing Outcomes of Patients with IBS-D through Early Diagnosis and Appropriate

Treatment Selection

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Faculty Affiliation

Rockford Yapp, MD, MPH, AGAFFounder and PresidentDigestive Health ServicesDowners Grove, IllinoisClinical AssociateNorthwestern UniversityDivision of HepatologyChicago, Illinois

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Faculty Disclosures

Speakers’ Bureaus: AbbVie, Allergan, Gilead Sciences, Salix Pharmaceuticals, Inc.

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4

Learning Objectives

Describe an approach to the diagnosis of irritable bowel syndrome with diarrhea (IBS-D) based upon clinical evaluation for defined signs and symptoms and appropriate use of testing strategies

Identify strategies for evaluating the impact of IBS-D on patient quality of life (QOL)

Summarize current clinical data on the efficacy and safety of newer treatments for IBS-D

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Overview of IBS

Most frequently diagnosed functional GI disorder in primary and secondary care practices

Affects ~15% - 20% of global populations

Characterized by abdominal discomfort or pain accompanied by altered bowel function in the absence of structural or biochemical abnormalities

Subtypes include IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed IBS (IBS-M) and un-subtyped IBS depending on the predominant stool pattern

Associated with high medical costs, frequent doctor visits, missed workdays, and an overall detrimental impact on HRQOL

GI, gastrointestinal; HRQOL, health-related quality of life. Lacy BE. Int J Gen Med. 2016;9:7-17.

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Patient-identified Factors that Contribute to Disease Burden

61.5

53.5

50.2

49.6

45.4

42.2

39.2

39

27.3

10.8

0 10 20 30 40 50 60 70

Social limitations

Cannot leave home

Work/school limitations

Limitations in thinking

Trouble sleeping

Nausea

Limitations in home activities

Poor quality of life

Incontinence

Other troubles

Respondents (%)

IBS Patients: Their illness experience and unmet needs, International Foundation for Functional Gastrointestinal Disorders (IFFGD); 2009.

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Healthcare Provider Understanding of the Burden of IBS

AGA. IBS in America. Available at: http://www.multivu.com/players/English/7634451-aga-ibs-in-america-survey/docs/survey-findings-pdf-635473172.pdf

5

17

29

31

18Extremely well

Very well

Somewhat well

Not very well

Not at all

How well do you think your health-care professional understands how bothersome your symptoms are?

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Pathogenesis of IBS

Psychological stress, abuse

(sexual, physical),

smoking, diet

EXTRINSIC FACTORS

Adapted from: Gazouli M, et al. Nat Rev Gastroenterol Hepatol. 2016;13(2):77-87.

Psychological stress, abuse

(sexual, physical), smoking, diet

Infection, dysbiosis

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Genes

Gut microbiota

Pathogenesis of IBS

EXTRINSIC FACTORS

INTRINSIC FACTORS

CNV, copy-number variation; miRNA, micro ribonucleic acid; SNP, single nucleotide polymorphism. Adapted from: Gazouli M, et al. Nat Rev Gastroenterol Hepatol. 2016;13(2):77-87.

Psychological stress, abuse

(sexual, physical), smoking, diet

Infection, dysbiosis

4

10

Emotional regulation

Visceral sensation/ pain modulation

Brain-gut axis

Spinal afferents

GI transit secretion

HPA

Genes

Gut microbiota

Pathogenesis of IBS

PERIPHERAL INTERMEDIATE PHENOTYPE

EXTRINSIC FACTORS

INTRINSIC FACTORS

CENTRAL NEUROBIOLOGICAL/BEHAVIORAL INTERMEDIATE PHENOTYPE

HPA, hypothalamo-pituitary-adrenocortical [system].Adapted from: Gazouli M, et al. Nat Rev Gastroenterol Hepatol. 2016;13(2):77-87.

Psychological stress, abuse

(sexual, physical), smoking, diet

Infection, dysbiosis

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Emotional regulation

Visceral sensation/ pain modulation

Brain-gut axis

Spinal afferents

GI transit secretion

HPA

Genes

Gut microbiota

Pathogenesis of IBS

Psychological stress, abuse

(sexual, physical), smoking, diet

Infection, dysbiosis

Chronic fatigue,

depression, anxiety

Migraine, fibromyalgia

Chronic abdominal

pain or discomfort and altered bowel

habits: IBS

PERIPHERAL INTERMEDIATE PHENOTYPE

EXTRINSIC FACTORS

INTRINSIC FACTORS

CENTRAL NEUROBIOLOGICAL/BEHAVIORAL INTERMEDIATE PHENOTYPE

CLINICAL PHENOTYPE

Adapted from: Gazouli M, et al. Nat Rev Gastroenterol Hepatol. 2016;13(2):77-87.

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Comorbidities Associated with IBS

GERD, gastroesophageal reflux disease.Lackner JM, et al. Clin Gastroenterol Hepatol. 2013;11(9):1147-1157.

91% of patients with IBS reported ≥1 comorbidity

Average number reported was 5 (1 mental, 4 physical)

Anxiety, depression, back pain, agoraphobia, tension headache, insomnia were associated with greater illness and symptom burden

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Many Patients with Severe IBS-D Remain Undiagnosed

†Score = 6 or 7; range: 1=very mild to 7=very severe; ‡score = 6 or 7, range: 1=not at all disruptive to 7=extremely disruptive; *P<.05 vs. undiagnosed group.

Sayuk GS, et al. Am J Gastroenterol. 2017;112(6):892-899.

3652 49

61

2624 29 2941

20

0

20

40

60

80

100

Discomfort/Pain Diarrhea Loose/Mushy Stools Urgency Bloating

% o

f Ind

ivid

uals

W

ith S

ever

e IB

S-D

† Diagnosed (n=1094)

Undiagnosed (n=830)

32

61

44

64

1927

4027

46

18

0

20

40

60

80

100

Discomfort/Pain Diarrhea Loose/Mushy Stools Urgency Bloating

Diagnosed (n=1094)Undiagnosed (n=830)

** *

*

*

% o

f Ind

ivid

uals

Ex

peri

enci

ng E

xtre

mel

y D

isru

ptiv

e Sy

mpt

oms‡

*

*

*

*

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Screening and Diagnosis

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Case Study #1: 40-year-old Female

Clinical presentation:– Recurrent abdominal pain and periods of loose stools (symptoms

present since patient’s early 20s)– Increase in frequency and severity of attacks over the past

8 months– Stools are frequently watery (occasionally with mucus, but

without blood) – Bowel movements 4 to 7 times per day and not awakening her– Abdominal pain

• Associated with bloating and gas

• Exacerbated by eating

• Relieved with defecation

– Weight loss of 9 lbs over the past 3 to 4 months

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Case Study #1: Physical Exam

Vital signs– HR: 97 bpm– RR: 18 breaths/min– BP: 126/82 mmHg

CV and pulmonary exam:– Normal

Abdominal exam:– Abdomen is flat– Bowel sounds are normal– Tympany in the upper-left quadrant– No organomegaly– Mild generalized tenderness

BP, blood pressure; bpm, beats per minute; CV, cardiovascular; HR, heart rate; mmHg, millimeter of mercury; RR, respiratory rate.

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Case Study Discussion

Individual symptoms have limited accuracy Alarm features are crucial for guidance Role of testing Recommended diagnostic tests

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Diagnosis of IBS

Rome IV Criteria

1. Symptom onset ≥6 months prior to diagnosis2. Recurrent abdominal pain, on average, ≥1 day/week in the last

3 months with ≥2 of the following:• Related to defecation• Associated with a change in stool frequency• Associated with a change in stool form (appearance)

Lacy BE, et al. Gastroenterology. 2016;150(6):1393-1407.e1395.

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Rome III vs Rome IV

“Pain” is now required to meet major criterion – Not assumed to begin with stool changes (only that the symptoms

are associated)– Related to defecation rather than necessarily relieved after defecation

Threshold for pain during symptomatic periods raised from 3/month to 1/week

Subtyping is dependent on patient report of stool type* frequency (not numerical percentages)

*Based on the standard Bristol Stool Scale

ROME Foundation Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders. J Gastrointestinal Liver Dis. 2006;15(3):307-312; Lacy BE, et al. Gastroenterology. 2016;150(6):1393-1407.e1395; Available at: https://ibsimpact. wordpress.com/2016/06/09/new-rome-iv-diagnostic-criteria-for-irritable-bowel-syndrome-ibs-unveiled-may-2016/

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Type Description Image

1 Separate hard lumps, like nuts

2 Sausage-shaped but lumpy

3 Like a sausage or snake but with cracks on its surface

4 Like a sausage or snake, smooth and soft

5 Soft blobs with clear-cut edges

6 Fluffy pieces with ragged edges, a mushy stool

7 Watery, no solid pieces

Bristol Stool Form Scale

Available at: http://bowelcontrol.nih.gov/Bristol_Stool_Form_Scale_508.pdf

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ACG Guideline Recommendations for Diagnostic Testing

Routine diagnostic testing* NOT recommended for patients with typical symptoms and no alarm features

Serologic screening for celiac sprue Recommended for patients with IBS-D and IBS-M

Lactose breath testing Recommended if lactose maldigestion persists despite dietary modification

Breath testing for SIBO Insufficient data to recommend

Routine colonic imaging NOT recommended for patients < 50 years of age with typical IBS symptoms and no alarm features

Colonoscopic imaging Recommended for IBS patients with alarm features and those > 50 years of age

Random biopsies Consider to rule out microscopic colitisif colonoscopy is performed

*CBC, serum chemistries, thyroid function studies, stool for ova and parasites, abdominal imaging.ACG, American College of Gastroenterology; CBC, complete blood cell count; SIBO, small intestine bacterial overgrowth.Brandt LJ, et al. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.

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Biomarkers for the Diagnosis of IBS-D

#For availability: high = widely available; moderate = available only in specialized clinics; low = only available in referrallabs/center; *application in IBS-C as well; ¥IBS (pain)

Camilleri M, et al. Expert Rev Gastroenterol Hepatol. 2017;11(4):303-316.

Type BiomarkerDiagnostic

Utility Availability# Cost-effectiveness

SerumInflammatory (interleukins, cytokines) Low Moderate Moderate

Enteroendocrine (serotonin, chromogranin) Low Moderate Moderate

Fecal

Fecal bile acids High Low High

Soluble mediators (proteases, chromogranin, calprotectin)

Low Moderate Low

Microbiome* Moderate Moderate Low

GI Tract

Colonic transit* High Moderate Moderate

Visceral hypersensitivity* Low Low Low

Permeability Moderate Low Moderate

Mucosal biomarkers (mast cells, B & T cells, enteroendocrine ; miRNAs*)

Low Low Low

Neurological & psychological

Brain imaging¥ Moderate Low Low

Psychological markers* Moderate High Low

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Comparative Positivity Rates for Anti-CdtB and Anti-vinculin across IBS Subtypes

CdtB, cytolethal distending toxin B. Rezaie A, et al. Dig Dis Sci. 2017;62(6):1480-1485.

43.3

32.4

58.1

20

36

44

13.316.7

26.7

9.36.7

16.3

0

10

20

30

40

50

60

70

Anti-CdtB+ Anti-vinculin+ Anti-CdtB+ or Anti-vinculin+

IBS-D IBS-M IBS-C Healthy Control

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Typical Features of IBS

Loose/frequent stools Constipation Bloating Abdominal cramping, discomfort, or pain Symptoms:

– Brought on by food intake/specific food sensitivities– Dynamic over time (change in pain location, change in

stool pattern)

Brandt LJ, et al. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.

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Red Flags for Organic Conditions

Fever Unexplained weight loss Rectal bleeding or melena Nocturnal diarrhea Unexplained iron-deficiency anemia Symptom onset after 50 years of age Severe or progressively worsening symptoms Family history of organic GI diseases (eg, colon cancer,

celiac disease, or IBD)

Brandt LJ, et al. Am J Gastroenterol. 2009;104 (suppl) 1:S1-35.

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Management of IBS-D

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Goals of Treatment

Improve individual symptoms

Ameliorate global symptoms

Prevent complications

Reduce impact on the individual and

society

Lacy BE, et al. Therap Adv Gastroenterol. 2009;2(4):221-238.

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Case Study #2: 27-year-old Male

Medical history– 3-year history of abdominal pain and diarrhea– Intermittent episodes of lower abdominal cramping and

bloating associated with 4 to 5 loose bowel movements occurring ~3 days per week

– Abdominal pain occurs shortly after meals or with increased stress, diminishes following a bowel movement

Social history– Currently in his final year of graduate school– Eating habits are unpredictable due to erratic academic

schedule

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Case Study #2 (cont’d)

Treatment history– Increased fiber intake exacerbates symptoms– Loperamide

• Effective for reducing fecal urgency and diarrhea• Does not relieve pain and bloating

– Dicyclomine hydrochloride (prescribed by PCP) • Moderate reduction in the frequency of cramping • Occasional diarrhea • Drowsiness• Confusion

PCP, primary care provider.

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Case Study Discussion

Inadequate symptom control/response to conventional therapies is common

Consideration of adverse effects Newer pharmacologic management strategies Psychological interventions

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31

Pharmacologic Treatment Options

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Conventional Pharmacotherapies for the Treatment of IBS-D

Class (Agents) Evidence Efficacy Common AEs

Antidiarrheals

(diphenoxylate hydrochloride/ atropine sulfateand loperamide)

Very low• Beneficial for diarrhea,

but not global symptoms or pain

• Constipation

Antispasmodics

(eg, hyoscyamine sulfate and dicyclomine hydrochloride)

Low

• Some agents offer benefits for global symptoms and pain

• Dry eyes/mouth

• Sedation

• Constipation

AE, adverse effects.Chey WD, et al. JAMA. 2015;313(9):949-958.1

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Newer Agents for the Treatment of IBS-D

Class (Agent) Putative Mechanism of Action

Alosetron • Inhibits GI motility via antagonism of 5-HT3 receptors of the enteric nervous system and possibly within the central nervous system

Eluxadoline• Inhibits gastric emptying, increases sphincter tone, and induces stationary

motor patterns via interactions with opioid receptors (agonism at μ- and Κ-receptors and antagonism at δ-receptors)

Rifaximin

• Is a broad antibiotic against GI aerobic and anaerobic Gram-positive and Gram-negative bacteria (may allow resetting of the microbiota)

• Alters the inflammatory environment and bacterial end-products in patients with various GI disorders

Cremonini F, et al. J Neurogastroenterol & Motil. 2003;15(1):79-86.Pimentel M. Aliment Pharmacol Ther. 2016;43 Suppl 1:37-49.Holzer P. Regul Pept. 2009;155(1-3):11-17.

12

34

0

10

20

30

40

50

PBO 0.5 mg QD 1 mg QD 1 mg BID

Mea

n (S

E) L

ost W

orkp

lace

Pr

oduc

tivi

ty (h

)

Baseline Week 12

Impact of Alosetron Treatment in Women with Severe IBS-D

*P<.05; **P<.01; ***P<.001

BID, twice daily; PBO, placebo; QD, once daily. Cremonini F, et al. Aliment Pharmacol Ther. 2012;36(5):437-448.

Alosetron treatment resulted in improvements in HRQOL, restriction of daily activities, and treatment satisfaction over PBO in women with severe IBS-D.

Workplace Productivity Social/Leisure Activity

0

7

14

21

28

PBO 0.5 mg QD 1 mg QD 1 mg BID

Mea

n (S

E) N

umbe

r of D

ays

Baseline Week 12

–7.2 h–11.0 h

–11.1 h–21.1 h* ***

** **

–4.6 days–6.7 days

–5.6 days–7.0 days

Alosetron Alosetron

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Adverse Effects of Alosetron

*In 43/44 patients, these events were associated with other medical conditions.

Krause R, et al. Am J Gastroenterol. 2007;102(8):1709-1719.

Placebo (N=176)

Alosetron

0.5 mg QD(N=175)

1 mg QD(N=172)

1 mg BID(N=176)

Most common AEs (%)Constipation 5 9 16 19Abdominal pain 3 5 6 7Nausea 6 5 3 6Sinusitis 6 3 3 6Headaches 2 5 5 2AEs for symptoms of potential ischemic colitis* (%)Any event 4 9 6 7Bloody diarrhea or rectal bleeding 2 4 3 3Worsening of abdominal pain <1 2 3 3Bloody diarrhea or rectal bleeding and worsening of abdominal pain 1 2 0 <1

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Alosetron: Black Box Warnings

Infrequent but serious GI adverse reactions (eg, ischemic colitis, serious complications of constipation) reported; some have resulted in hospitalization and, rarely, blood transfusion, surgery, or death

Prescribing physicians must be enrolled in Prescribing Program for Lotronex

Indicated only for women with severe IBS-D that have not responded adequately to conventional therapy

Discontinue immediately in patients who develop constipation or symptoms of ischemic colitis; do not resume in those who develop ischemic colitis

Lotronex® [package insert]. San Diego, CA: Prometheus Laboratories Inc.; 2014.

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Eluxadoline Treatment Results in Sustained Reduction of IBS-D Symptoms over 6 Months

Eluxadoline treatment resulted in more patients reporting a ≥30% reduction in abdominal pain score and a stool-consistency score <5 on ≥50% of the days†.

†Represents composite primary efficacy end point*P<.0; ** P<.001Lembo AJ, et al. N Engl J Med. 2016;374(3):242-253.

19.0 20.2 19.523.430.4

26.729.332.7

31.0

0

20

40

60

80

100

IBS-3001 Trial IBS-3002 Trial Pooled Data

Patie

nts

(%)

Placebo Eluxadoline, 75 mg Eluxadoline, 100 mg

N=427 N=426 N=427 N=381 N=382 N=382 N=808 N=806 N=809

****

*****

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Early Response Predicts Sustained Response to Eluxadoline in Patients with IBS-D

Chey WD, et al. Aliment Pharmacol Ther. 2017;45(10):1319-1328.

12.5

77.2

66.3 68.3

49.5

22.8

81.573.9 72.8

63.0

24.6

77.870.7 71.7

57.1

0

20

40

60

80

100

Weeks 1-4Responders

Weeks 1-12Responders

Weeks 1-26Responders

Weeks 9-12Responders

Weeks 21-24Responders

Resp

onde

rs (%

)

Placebo BID Eluxadoline 75 mg BID Eluxadoline 100 mg BID

n=80

9

n=80

8

n=80

6

n=10

1

n=18

4

n=19

8

n=10

1

n=18

4

n=19

8

n=10

1

n=18

4

n=19

8

n=10

1

n=18

4

n=19

8

Weeks 1-4 Responders

Over two-thirds of patients who responded over the first month retained a positive response over 6 months of treatment with eluxadoline.

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Adverse Effects of Treatment with Eluxadoline

SAEs, serious adverse events.

Lembo AJ, et al. N Engl J Med. 2016;374(3):242-253.Cash BD, et al. The American Journal of Gastroenterology. 2017;112(2):365-374.

11.9

19.5

42.4

49.5

18.2

25.8

49.3

56.1

19.5

25.0

44.3

50.9

0

10

20

30

40

50

60

<1 <2 <12 <26

Patie

nts

repo

rtin

g A

Es (%

)

Study Interval (weeks)

0.1 0.2

1.3

2.1

0.6

0.9

2.5

3.0

0.70.9

2.0

3.4

0

1

2

3

4

<1 <2 <12 <26

Patie

nts

repo

rtin

g SA

Es (%

)

Study Interval (weeks)

Placebo BID (n=975)Eluxadoline 75 mg BID (n=807)Eluxadoline 100 mg BID (n=1032)

a b

AEs SAEs

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Rifaximin Treatment Is Associated in Sustained Reduction of IBS Symptoms Over 12 Weeks

Pimentel M, et al. N Engl J Med. 2011;364(1):22-32.

TARGET 1 and 2 Trials

Two weeks of treatment with rifaximin resulted in a greater percentage of patients achieving adequate relief of global IBS symptoms.

Patie

nts

with

Ade

quat

e Re

lief (

%)

0 2 4 6 8 10 12Week

60

50

40

30

20

10

0

14-DayDouble-

blind treatment

phase

10-week follow-up(no study medication)

P=.001

Rifaximin

Placebo

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Repeat Treatment with Rifaximin Is Safe and Effective in Patients with IBS-D

*Statistically significant difference vs placebo.

TID, three times daily.Lembo A, et al. Gastroenterology. 2016;151(6):1113-1121.

2-weektreatment

Treatment-freeobservation

2-week treatment

Treatment-free observation

0.0

-0.5

-1.0

-1.5

-2.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Weeks

Mea

n Ch

ange

Fro

m B

asel

ine

in A

bdom

inal

Pai

n Sc

ores

* * ** * * *

*

* * **

Rifaximin 550 mg TID

Placebo

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Safety and Tolerability of Rifaximin

Lembo A, et al. Gastroenterology. 2016;151(6):1113-1121.

Open-Label Population

Double-Blind Population

AE, n (%) Rifaximin, 550 mg TID(n=2579)

Rifaximin 550 mg TID (n=328)

Placebo (n=308)

Any AE 822 (31.9) 140 (42.7) 140 (45.5)

Drug-related AE 85 (3.3) 6 (1.8) 8 (2.6)

Serious AE 28 (1.1) 4 (1.2) 4 (1.3)

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Most Common Adverse Effects Observed with Rifaximin Treatment

Lembo A, et al. Gastroenterology. 2016;151(6):1113-1121.

Open-Label Population Double-Blind Population

AE, n (%)Rifaximin, 550 mg TID

(n=2579)Rifaximin 550 mg

TID (n=328)Placebo (n=308)

Most common AEsNausea 52 (2.0) 12 (3.7) 7 (2.3)Upper respiratory tract infection 41 (1.6) 12 (3.7) 8 (2.6)Urinary tract infection 35 (1.4) 11 (3.4) 15 (4.9)Nasopharyngitis 36 (1.4) 10 (3.0) 9 (2.9)Alanine aminotransferase increased 24 (0.9) 9 (2.7) 4 (1.3)Blood creatinine phosphokinase increased 31 (1.2) 9 (2.7) 3 (1.0)Bronchitis 15 (0.6) 9 (2.7) 5 (1.6)Aspartate aminotransferase increased 24 (0.9) 7 (2.1) 4 (1.3)Diarrhea 20 (0.8) 7 (2.1) 3 (1.0)Influenza 33 (1.3) 7 (2.1) 2 (0.6)Sinusitis 34 (1.3) 7 (2.1) 7 (2.3)Headache 42 (1.6) 4 (1.2) 9 (2.9)Arthralgia 17 (0.7) 3 (0.9) 8 (2.6)

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Nonpharmacological Management of IBS-D

45

Study or SubgroupRisk Ratio

M-H, Random, 95% CIRisk Ratio

M-H, Random, 95% CISoltoft, 1976 1.20 (0.70, 2.04)

Manning, 1977 0.86 (0.42, 1.74)

Kruis, 1986 1.04 (0.78, 1.37)

Lucey, 1987 0.75 (0.20, 2.75)

Rees, 2005 0.86 (0.39, 1.91)

Bijkerk, 2009 0.84 (0.71, 1.00)

Subtotal (95% CI) 0.90 (0.79, 1.03)

Total events

Heterogeneity: r2 = 0.00; 2 = 2.76, d.f. = 5 (P=.74); I2 = 0%

Test for overall effect: Z = 1.47 (P=.14)

Ritchie, 1979 0.60 (0.37, 0.97)

Longstreth, 1981 1.15 (0.69, 1.92)

Arthurs, 1983 0.75 (0.39, 1.43)

Nigam, 1984 0.63 (0.45, 0.88)

Prior, 1987 0.89 (0.75, 1.05)

Jalihal, 1990 0.55 (0.11, 2.59)

Bijkerk, 2009 0.88 (0.74, 1.04)

Subtotal (95% CI) 0.83 (0.73, 0.94)

Total events

Heterogeneity: r2 = 0.01; 2 = 7.32, d.f. = 6 (P=.29); I2 = 18%

Test for overall effect: Z = 2.80 (P=.005)

Soluble Fiber Supplementation Improves Global Symptoms of IBS

Note: Details regarding study weight calculations available in the original publication.

M-H, Mantel-Haenszel.Moayyedi P, et al. Am J Gastroenterol. 2014;109(9):1367-1374.

Bran

Ispaghula

16

46

Benefit of a Gluten-Free Diet in Patients with IBS-D

ANOVA, analysis of variance; GFD, gluten-free diet; HLA, human leukocyte antigen.Aziz I, et al. Clinical Gastroenterology and Hepatology. 2016;14(5):696-703.e691.

A dietitian-led GFD provided sustained benefit to patients with IBS-D. The symptoms that improved differed in magnitude according to HLA-DQ status.

P < 0.01 (ANOVA)500

400

300

200

100

0

IBS-

Sym

ptom

Sev

erity

Sco

re

Week 0 Week 2 Week 4 Week 6Time-Period on GFD

47

A Diet Low in FODMAPs Reduces IBS Symptoms

FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; VAS, visual analog scale. Halmos EP, et al. Gastroenterology. 2014;146(1):67-75.e65.

VAS

(0-1

00 m

m)

-7 7 14 21Day

60

40

20

-7 7 14 21Day

Healthy Controls IBS

BaselineTypical Australian dietLow FODMAP

60

40

20

48

Treatment with Bifidobacterium infantis Capsule Reduces Symptoms of IBS

*P<.03 vs placebo.

Whorwell PJ, et al. Am J Gastroenterol. 2006;101(7):1581-1590.

-0.29-0.33

-0.29

-0.45-0.39

-0.36

-0.6

-0.4

-0.2

0

Abdominalpain/discomfort

Bloatingdistension Urgency

Incompleteevacuation Straining Overall

Mea

n D

iffer

ence

vs

Plac

ebo

(%)

***

17

49

Low FODMAP diet vs Lactobacillus rhamnosusGG in IBS

A significant reduction in the IBS-SSS was observed in the low FODMAP and L. rhamnosus GG groups compared to the normal Danish/Western diet group at week 6 (P < 0.01)

IBS-SSS, Irritable Bowel Syndrome - Severity Scoring System.Pedersen N, et al. World J Gastroenterol;2014;20(43):16215-16226.

P>.01500

400

300

200

100

0

IBS-

SSS

Tota

l Sco

re

0 6Time (week)

+o

x

+o

x

Low FODMAP

L. rhamnosus GG

Normal Danish/ Western diet

50

Impact of Psychological Intervention on IBS Symptoms

Study Effect size (Hedges’ g) and 95% CIBlanchard 1992a

Blanchard 1992b

Blanchard 1993

Blanchard 2007a

Craske 2011

Drossman 2003

Galovski 1998

Greene 1994

Heymann-Monnikes 2000

Hunt 2009

Jarrett 2009

Kaptchuck 2008

Keefer 2001

Kennedy 2006

Lackner 2008

Lahmann 2010

Lindfors2012a

Lindfors2012b

Ljotsson 2010

Ljotsson 2011a

Ljotsson 2011b

Mahvi-Shirazi 2012

Moss-Morris 2010

Neff 1987

Payne 1995

Ringstrom 2010

Roberts 2006

Robinson 2006

Sanders 2007

Shinozaki 2010

Tkachuk 2003

Van Der Veek 2007

Van Dulmen 1996

Vollmer 1998

Zernicke 2012

Red shading indicates P<.05

Interventions examined in this meta-analysis included a range of therapies:– Cognitive– Cognitive behavioral– Relaxation– Psychodynamic– Mindfulness– Gut-directed hypnosis

CI, confidence interval. Henrich JF, et al. J Psychosom Res. 2015;78(3):205-222.

-2.00 -1.00 0.00 1.00 2.00Favors Control Favors Treatment

51

Long-term Management

18

52

Improving Physician-Patient Communication: Encouraging Patients to Speak Up

EarlyTalk to healthcare providers about recurring abdominal pain and bowel symptoms rather than suffering in silence or taking advice from non-healthcare professionals.

CompletelyInstead of just saying “I have constipation” or “I have diarrhea,” tell healthcare providers about the full extent of symptoms, how they impact life, and what approaches have been tried to manage them.

OftenInform healthcare providers if symptoms return despite treatment efforts so they can assess alternatives.

IBS in America: Survey Highlights Physical, Social and Emotional Impact. Available at: http://partner.gastro.org/ibs-in-america-survey-highlights-physical-social-and-emotional-impact

53

Patient Misconceptions Regarding the Natural History of IBS

Halpert A, et al. Am J Gastroenterol. 2007;102(9):1972-1982.Halpert A, et al. Dig Dis Sci. 2010;55(2):375-383.

72.7% 70.7% 67.3%

57.7%

0

20

40

60

80

100

DevelopColitis

DevelopMalnutrition

RequireSurgery

DevelopCancer

Patie

nts

Eith

er in

Agr

eem

ent

or U

nsur

e (%

)

54

Additional IBS Resources

International Foundation for Functional Gastrointestinal Disorders – http://www.iffgd.org/

Institute for Functional Medicine– https://www.functionalmedicine.org/

Irritable Bowel Syndrome Association– http://www.ibsgroup.org/ibsassociation.org/

IBS Page– http://ibspage.com/

19

55

Summary

IBS-D is a highly prevalent functional bowel disorder that imposes a tremendous burden due to its pervasive negative impact on the physical, social, and economic well-being of affected individuals

Diagnosis is based upon a thorough clinical history and physical examination, in conjunction with application of the Rome IV criteria

Treatment options include several pharmacologic and nonpharmacologic strategies, which have shown efficacy at reducing IBS-D symptoms and improving QOL

Long-term management should be individualized and include education and support to foster patient understanding of the disease, ensure treatment adherence, and guide therapeutic expectations

56

Questions & Answers

57

Thank You!

20

58

Back-up Slide Library

59

Many Patients with IBS-D Remain Undiagnosed

Sayuk GS, et al. Am J Gastroenterol. 2017;112(6):892-899.

43.1% of survey participants with a history of GI symptoms who met diagnostic criteria for IBS (N=1,094) did not have a medical diagnosis.

Diagnosed IBS

Undiagnosed IBS

60

QOL Is Significantly Worse for Patients with IBS vs the General US Population

Gralnek IM, et al. Gastroenterology. 2000;119(3):654-660.

0

20

40

60

80

100

120

PF RL-P BP GH EW-B RL-E E/P SF

SF-3

6 sc

ale

scor

e (m

ean

+ SD

) US population IBS

BP, bodily pain; E/F, energy/fatigue; EW-B, emotional well-being; GH general health; PF, physical functioning; QOL, quality of life; RL-E, role limitations-emotional; RL-P, role limitations-physical; SF, social functioning; SF-36, 36-Item Short Form Health Survey.

21

61

The Impact of IBS on QOL Relative to Other Chronic Conditions

Gralnek IM, et al. Gastroenterology. 2000;119(3):654-660.

0

20

40

60

80

100

120

PF RL-P BP GH EW-B RL-E E/P SF

SF-3

6 sc

ale

scor

e (m

ean

+ SD

)

US population GERD DM IBS

DM, diabetes mellitus.

62

The Impact of IBS on Employment

12.8%

17.3%

69.9%

Patients with IBS jobless due to health

Patients with IBS jobless not due to health

Patients with IBS currently working

IBS Patients: Their illness experience and unmet needs, International Foundation for Functional Gastrointestinal Disorders (IFFGD); 2009.

Further evaluation revealed that 30% of patients with severe IBS symptoms reported being jobless vs only 5% of those with mild symptoms.

63

Reduction in Productivity Attributed to GI Symptoms of IBS

Dean BB, et al. Am J Manag Care. 2005;11(1, Suppl):S17-S26.

IBS was associated with a 21% reduction in work productivity, equivalent to working less than 4 days in a 5-day work week.

1.7

20.1 21.1

26.9

0.4

5.9 6.18.1

0

5

10

15

20

25

30

Absenteeism Presenteeism Total ReducedWork Productivity

ActivityImpairment

Mea

n Re

duct

ion

(%)

Employees with IBS (n=720) Employees without IBS (n=1056)

22

64

Economic Costs Associated with IBS in the US

Reviewed in: Lembo AJ. Pract Gastroenterol. 2007;31(suppl):3-9.

Annual CostCategory Previous Estimates

Direct $1.6 to $10.5 billion

Indirect As high as $20 billion*

Total $30 billion

*Based on costs associated with patients seeking medical attention.

65

Subtyping IBS by Predominant Stool Pattern

Longstreth GF, et al. Gastroenterology. 2006;130(5):1480-1491.

IBS-C

IBS-U

IBS-M

IBS-D

% Loose or Watery Stools

% H

ard

or L

umpy

Sto

ols

0

25

5

0

75

1

00

25 50 75 100

66

Bloating vs Distention

Bloating describes the sensation of increased abdominal pressure and distention describes a change in abdominal girth

Pathophysiological mechanisms are likely different, but overlapping Distention may be alleviated by relieving constipation, but the treatment

of bloating may require approaches involving sensory modulation

Available at: http://www.iffgd.org/site/manage-your-health/symptoms-causes/bloating-distension Agrawal A, et al. Aliment Pharmacol Ther. 2008;27(1):2-10.

23

67

Potential Biomarkers for IBS-D: anti-CdtB and anti-vinculin

Pimentel M, et al. PLoS One. 2015;10(5):e0126438.

0 1 2 3 4Antibody Titers

Healthy control

IBS

Crohn’s disease

Ulcerative colitis

Celiac disease

0 1 2 3 4Antibody Titers

Healthy control

IBS

Crohn’s disease

Ulcerative colitis

Celiac disease

Anti-CdtB Anti-vinculin

68

Accuracy of Patient-reported GI Symptom Measures

0 10 20 30 40 50 60 70

Number of stools

Days with fluffy stools

Days abdominal pain

Days with sausage stools

Days with urgency

Worst urgency

Worst abdominal pain

Average abdominal pain

Days with hard, lumpy stools

Average urgency

Days with watery stools

*Diary data was collected close to the time of patients’ experiences and was minimally vulnerable to distortion from forgetting and recall bias.

Lackner JM, et al. Neurogastroenterol Motil. 2014;26(12):1802-1811.

Percentage of patients whose recall deviated ≥2 units from electronic diary data*

69

Post-infectious IBS (PI-IBS) Travelers’ diarrhea (TD) is associated with an increased risk

for IBS

Symptoms of PI-IBS may take months to resolve, despite a negative workup

Juckett G, et al. Am Fam Physician. 2011 Nov 15;84(10):1119-26.Schwille-Kiuntke J, et al. Aliment Pharmacol Ther. 2015 Jun;41(11):1029-37

TD Exposed TD-free Control Risk Ratio Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI Year M-H, Random, 95% CI

Okhuysen 6 60 0 37 2.1% 8.10 (0.47, 139.69) 2004

Stermer 16 118 7 287 21.1% 5.56 (2.35, 13.16) 2006

Trivedi 16 93 1 27 4.3% 4.65 (0.65, 33.45) 2011

Pitzurra 26 852 12 1624 32.6% 4.13 (2.09, 8.14) 2011

Nair 20 348 12 469 30.7% 2.25 (1.11, 4.53) 2014

Lalani 3 126 7 389 9.2% 1.32 (0.35, 5.04) 2014

Total (95% CI) 1597 2833 100.0% 3.35 (2.22, 5.05)

Total events 87 39

Heterogeneity: Tau2 = 0.02; Chi2 = 5.28; df = 5 (P = 0.38); I2 = 5%

Test for overall effect: Z = 5.76 (P < 0.00001)0.01 0.1 1 10 100

TD-free Control TD Exposed

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70

Early Response Predicts Sustained Response to Eluxadoline in Patients with IBS-D

By Day 7, the 75- and 100-mg eluxadoline groups had greater response rates (60% for both) vs placebo (50%), an effect which persisted through Month 6.

Chey WD, et al. Aliment Pharmacol Ther. 2017;45(10):1319-1328.

100

90

80

70

60

50

40

30

20

10

00 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 126 119 133 140 147 154 161 168 175 182

Days

Res

po

nd

ers

(%)

Placebo BIDEluxadoline 75 mg BIDEluxadoline 100 mg BID

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Adverse Effects of Treatment with Eluxadoline

Most commonly observed:

Pancreatitis developed in 5 (2 in the 75 mg group and 3 in the 100 mg group) of the 1666 patients in the safety population (0.3%)

AEPlacebo

(%)

75 mg Eluxadoline

(%)

100 mg Eluxadoline

(%)

Constipation 2.5 7.4 8.6

Vomiting 1.4 8.1 7.5

Abdominal pain 4.1 5.8 7.2

Lembo AJ, et al. N Engl J Med. 2016;374(3):242-253.

72

Safety and Tolerability of Rifaximin

URTI, upper respiratory tract infection; UTI, urinary tract infection.

Schoenfeld P, et al. Aliment Pharmacol Ther. 2014;39(10):1161-1168.

1617

9 9

6 7

43

4 4

1

0

5

10

15

20

25

Patie

nts

Expe

rienc

ing

AE

%

GI-associated AEs

Infection-associated AEs

25

73

Implementation of a Low-FODMAP Diet for IBS

TeachPatients

Assistance from a trained dietician is ideal

Alternatively, vettedbooks, web-based resources, and mobile apps may be employed

GaugeResponse

2 to 4 week period Bloating and

abdominal pain are most likely to respond

Diarrhea is more likely to improve than constipation

ReintroduceFoods

Foods with individual FODMAPs should be reintroduced in a stepwise manner for responders

The full low-FODMAP diet is not intended to last a lifetime. The low-FODMAP diet is not intended for people without GI symptoms.

74

Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols (FODMAPs)

Galacto-oligosaccharides

Human milk

Pulses*

Legumes

Some grains, nuts, & seeds

Disaccharides & Monosaccharides

Lactose

– Milk

– Commercial breads, cakes, & slimming products

Fructose

‒ Fruit

‒ Fruit products

‒ High-fructose sweetened foods

Fructans

Wheat

Onions

Polyols

Fruits

Vegetables

Sugar-free

gum

*Pulses are part of the legume family, but the term “pulse” refers only to the dried seed (eg, chickpeas, lentils, and beans)Note: Additional recommendations for implementing a low FODMAP diet are available at: http://www.ibsdiets.org/fodmap-diet/

Staudacher HM, et al. Nat Rev Gastroenterol Hepatol. 2014;11(4):256-266.

75

Gluten-Free Diet in Patients with IBS-D

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Pre Post Pre Post Pre Post

Gluten-free diet (n=23)

Gluten-containing diet (n=22)

Frequency(BM/Day)

Form(BSFS)

Ease ofPassage (1-7)

P=.04

BM, bowel movement; BSFS, Bristol Stool Form Scale.

Vazquez-Roque MI, et al. Gastroenterology. 2013;144(5):903-911.e903.

26

76

Fear of Symptoms Impacts QOL in Patients with IBS: IBSOS Study

Lackner JM, et al. Am J Gastroenterol. 2014;109(11):1815-1823.

IBSOS, irritable bowel syndrome outcome study.

IBS quality of life

Fear of GI symptoms

DemographicsEducation

Clinical Variables

IBS severitytrait anxietydistress

24%

14%

10%

77

IBS-D Is Associated with Lower Disease-Specific QOL vs IBS-C

Singh P, et al. World J Gastroenterol. 2015;21(26):8103-8109.

IBS-QOL SubscaleIBS-C

(n = 54)IBS-D

(n = 56)IBS-M

(n = 121) P valueInterference with activity 82.3 59.6 61.6 < .001

Social reaction 80 59.6 61.6 .0082

Food avoidance 61.1 45 47.2 .0203

Relationships 84.7 75.4 73.3 .0304

Dysphoria 69.2 57.1 58 .06

Health worry 64.3 60.9 57.3 .28

Sexual 73.9 74.6 68.8 0.5

Body image 69.2 66 64.9 .631

Total 74.5 61.6 63 .0105

78

Potential Pathophysiological Mechanisms Underlying Bloating and Distention

Agrawal A, et al. Aliment Pharmacol Ther. 2008;27(1):2-10.

Mechanism Evidence to Date

Gas excess Occasional cause of bloating, unlikely to be responsible in the majorityof patients

Gas handling Patients demonstrate normal gas volumes, but abnormal intestinal gas handling

Sensory dysfunction Visceral hyposensitivity is linked to distention, whereas hypersensitivityis linked to bloating but not necessarily distention

Motor dysfunctionImpact of motility patterns or transit time is uncertain; bloating is seen with IBS-D and IBS-C, which are associated with rapid and slow transit, respectively

Abnormal anterior wall muscular activity

Suggested muscle weakness, and impaired viscerosomatic reflexes and abdominal-wall dystony with bloating in IBS

Carbohydrate intolerance and altered gut flora

Small bowel bacterial overgrowth is not consistently observed in IBS, but may account for symptoms in some patients

27

79

Celiac Disease and Gluten Sensitivity in Patients with IBS

Celiac disease (CD) is an autoimmune GI condition with symptoms similar to IBS

CD, diagnosed by positive serology and biopsy, is more prevalent among IBS vs non-IBS populations (although conflicting data exists)

The frequency of abnormal IgA-class AGAs in suspected IBS cases raises the possibility that gluten may cause symptoms in sensitive individuals, even in the absence of developed CD

Diagnostic Parameter Pooled OR (95% CI)

Positive IgA-class AGAs 3.40 (1.62-7.13)

Positive EMAs or tTGA 2.94 (1.36-6.35)

Biopsy-proved celiac disease 4.34 (1.78-10.6)

AGA, anti-gliadin antibody; EMA, endomysial antibody; IgA, immunoglobulin A; OR, odds ratio; tTGA, tissue transglutaminase. Cash BD, et al. Gastroenterology. 2011;141(4):1187-1193.Verdu EF, et al. Am J Gastroenterol. 2009;104(6):1587-1594.Ford AC, et al. Arch Intern Med. 2009;169(7):651-658.

80

General Approach to Treatment with Probiotics

Quality and consistency may be questionable

– Shelf-life limitations

– Lack of government-sanctioned quality-control standards

Clinical trial data in IBS-D are limited, contradictory, strain-dependent and are derive from small patient samples

– VSL#3® double-blind, placebo-controlled study; 8-week treatment (n=25)

– Results: no improvement of small-bowel or colonic transit; no effect on bowel dysfunction, abdominal pain, flatulence, or urgency

Potential benefits must be weighed against economic costs

Lacy BE. Int J Gen Med. 2016;9:7-17.

81

Emerging Food-based Approaches to IBS Management

Functional Foods Medical Foods

• Health benefits beyond basic nutrition (eg, disease prevention and/or treatment)

• Includes the following:

− Conventional foods with bioactive components

− Foods enriched or fortified with bioactive food compounds

− Synthesized food ingredients that provide or are precursors to compounds with health benefits

• FDA category for specific dietary management of a disease or condition

• Given under physician supervision, but do not require a prescription

• Must comply with the following:

− FDA-labeling requirements

− Ingredients are known and comply with FDA regulations

− Specially formulated and processed (not naturally occurring)

Reviewed in: Chey WD. Am J Gastroenterol. 2016.

28

82

Biofeedback in the Treatment of IBS

Treatment Method Findings

Electronic stethoscope to provide auditory feedback to modify colonic motility

Symptom improvement in 5/5 patients; results not subsequently replicated

Rectosigmoid area balloon probe used to provide visual feedback on bowel motility

14/21 patients learned the technique; noclinical correlations were shown

Forehead EMG biofeedback and thermal biofeedback as nonspecific relaxation training techniques to counteract the effects of stress in patients with IBS

Symptoms improved in ~50% of 40 patients with refractory IBS in 3 months; no control group or long-term follow-up

Combined progressive muscle relaxation, thermal biofeedback, cognitive therapy, and education

No improvement over an attention-placebo condition

Reviewed in: Chiarioni G, et al. Nat Clin Pract Gastroenterol Hepatol. 2008;5(7):371-382.

EMG, electromyography.

83

Psychological Interventions for the Treatment of IBS

Types of psychological intervention– Cognitive therapy – Cognitive behavioral therapy– Relaxation– Psychodynamic – Mindfulness – Gut-directed hypnosis

Systematic review and meta-analysis suggests significant improvement of symptoms and psychological well-being

Henrich JF, et al. J Psychosom Res. 2015;78(3):205-222.