Iitbl B lS dIrritable Bowel Syndrome: What’s the...

Brian E. Lacy, MD, PhD, FACG

I it bl B l S dIrritable Bowel Syndrome: What’s the Latest?American College of Gastroenterology

Las Vegas, January 2014B i E L Ph D M D FACGBrian E. Lacy, Ph.D., M.D., FACG

Professor of Medicine Geisel School of Medicine at Dartmouth

Chief, Section of Gastroenterology & HepatologyDartmouth-Hitchcock Medical Center

Lebanon, NH

Rome III Criteria for IBS

Recurrent abdominal pain or discomfort

Onset associated with a change in frequency of

Onset associated with a change inImprovement with

d f i

pat least 3 days/month in the last 3 months

associated with ≥ 2 of the following:

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

Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

a change in frequency ofstool

change inform of stooldefecation

ACG Board of Governors/ASGE Best Practices Course - Las Vegas, NV Copyright 2014 American College of Gastroenterology

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IBS: What’s the Latest?• IBS subtypes: patients aren’t stagnant• Distinguishing IBS-C from CCDistinguishing IBS C from CC• Utility of testing• Methane• Antibiotics• Probiotics• Celiac disease

Di• Diet• Osmotic agents• Secretagogues

In Clinical Practice Patients Move from Group to Group

IBS-C: IBS with constipation

CCIBS-C

IBS-M

p

CC: Chronic constipation

IBS-M: mixed or alternating symptoms of constipation and diarrhea)

Simren M, et al. Scand J Gastroenterol 2001;36(5):545–52Tillisch K, et al. Am J Gastroenterol 2005;100(4):896–904Mearin F, et al. Eur J Gastroenterol Hepatol 2003;15(2):165–72 Drossman DA, et al. Gastroenterology 2005;128(3):580–9Wong RK, et al. Am J Gastroenterol 2010;105:2228-2234


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Distinguishing IBS-C from CC

• No firm rationale to distinguish IBS-C from CC b th R ittby the Rome committee

• Treatments are often similar– Tegaserod (no longer available in N.A.)– Lubiprostone– Prucalopride (available in the EU)Prucalopride (available in the EU)– Linaclotide

Distinguishing IBS-C From CC

• Symptom-based criteria for CC and IBS overlap– Abdominal pain/discomfort and gas/bloating creates

a spectrum between CC and IBS

PAIN/DISCOMFORT & GAS/BLOATING- +

IBS-C

Brandt LJ, et al. Am J Gastroenterol 2005;100(suppl 1):S5 .

CC


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Histologic Findings in IBS Patients and Controls;Populations Not Matched for Age or Gender

Utility of Testing: Yield of Colonoscopy in IBS

Populations Not Matched for Age or Gender

LesionIBS Patients

n=466 (%)

Controlsn=451

(%)P Value

Adenomas 36 (7.7) 118 (26.1) <0.0001

Hyperplastic polyps 39 (8.4) 52 (11.5) NS

Colorectal adenocarcinoma 0 (0.0) 1 (0.2) NSCo o ecta ade oca c o a 0 (0 0) (0 ) S

IBD 2 (0.4) 0 (0.0) NS

Microscopic colitis 7 (1.5) N/A N/A

Microscopic colitis was more common in a subset of patients with IBS-D who were ≥45 years (2.3%).

IBD, inflammatory bowel disease; IBS-D, irritable bowel syndrome diarrhea-predominant; N/A, not applicable; NS, not significant.

Chey WD, et al. Am J Gastroenterol 2010;105:859-865.

Pretest Probability of Organic Disease1

Organic DiseaseIBS Patients

(%)Control/Population

(%)

Colitis/IBD 0.51-0.98 0.3-1.2

Colorectal cancer 0-0.51 0-6 (varies with age)

Lactose malabsorption 38 26

Thyroid dysfunction 4.2 5-9

1. American College of Gastroenterology Task Force on Irritable Bowel Syndrome, et al. Am J Gastroenteroll 2009;104(suppl 1):S1-S35. 2. Cash BD, et al. Gastroenterology 2011;141:1187-

1193.

y y

Celiac disease 3.6 0.7

Celiac disease: antibodies2 7.3 4.8

Celiac disease: confirmed2 0.41 0.44


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Methane & Constipation

• About 1/3rd of population produces CHCH4

• Predominant organism is Methanobrevibacter smithii

• Thought to be present in 60% of humans in left colon

• 107-1010 per g dry weight

Methane and Constipation

80 2 0P<0 05

Prevalence of CH4 in slow transitConstipation

AUC of methane on breath test

30

40

50

60

70

80

wit

h M

eth

ane

>3p

pm

100

150

200

250

than

e A

UC

(p

pm

)

P<0.05P<0.05

0

10

20

Control NormalTransit

SlowTransit

Per

cen

t

0

50

Control NormalTransit

SlowTransit

Met

Attaluri, et al. Am J Gastro, 2010Attaluri, et al. Am J Gastro, 2010..


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Methane Gas Infusion Slows Transit

80

20

40

60%

Ma

rke

r R

ec

ov

ery n=5, p<0.0001

69% mean slowing

0Room Air Methane

Pimentel, et al. Am J Physiol 2006.

69% mean slowing of transit

Rifaximin: Most Extensively Studied Antibiotic for IBS

G t di t d tibi ti• Gut-directed antibiotic• Not systemically absorbed• Doses studied for IBS: 400 mg BID to 550 mg TID • Generally well tolerated

Ad ff i l d h d h bd i l• Adverse effects include: headache, abdominal pain, and upper respiratory tract infection

Ford AC, et al. Clin Gastroenterol Hepatol 2009;7:1279-1286. Pimentel M, et al. N Engl J Med 2011;364:22-32.

*This agent is not currently FDA approved for IBS.


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Rifaximin Trials: Global Relief of IBS Without Constipation

• 2 Phase 3 randomized controlled trials; N=1260 40

45

controlled trials; N 1260 patients

• Rifaximin 550 mg TID x 2 weeks; patients followed additional 10 weeks

• 40.7% vs. 31.7% with adequate relief of global

15

20

25

30

35

40

RifaximinPlacebo

adequate relief of global symptoms (P<0.001)

0

5

10

T-I T-II CombT-I, TARGET 1 trial; T-II, TARGET 2 trial; Comb, Combination of both trials.*Rifaximin is not currently FDA-approved for IBS.

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

Probiotics


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Probiotics for IBS• Lactobacilli – anaerobic, gram (+) rods

– casei– plantarum – acidophilus– reuteri

• Bifidobacteria – anaerobic, gram (+) rods• VSL #3 (8 separate organisms: 3 Bifidobacteria, 1

Streptococcus, 4 Lactobacilli)• Enterococcus• Streptococcus salivarius• Saccharomyces

Moayyedi P, et al. Gut 2010:59:325-332. Epub 2008 Dec 17.

Probiotics: Mechanisms of Action

• Competitive inhibitionB i t ti• Barrier protection

• Immune effects• Anti-inflammatory effects• Production of various substances (enzymes,

SCFA, bacteriocidal agents), g )• Ability to alter local pH and physiology• Provides nutrition to colonocytes

Camilleri M. J Clin Gastroenterol 2006;40:264-269.


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Bifidobacteria Infantis 35624 for IBS Global Assessment of Relief

8070ee

k P=0.01187060504030

Answ

erin

g “Y

es” a

t We

4 (%

)

20

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

SGA: (Subjects’ Global Assessment) a yes/no response to the following question:

“Please consider how you felt in the past week in regard to your IBS, in particular your general well being, and symptoms of abdominal discomfort or pain, bloating or distension, and altered bowel habit. Compared with the way you felt before beginning the medication, have you had adequate relief of your IBS symptoms?”

PlaceboB Infantis1 x 106

B Infantis1 x 108

B Infantis1 x 1010

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Wheat & IBS

• Gluten-related disorders– Celiac disease– Dermatitis herpetiformis– Gluten ataxia– Non-celiac gluten sensitivity


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Gluten

• A storage protein in wheat, barley, rye• Genetically susceptible individuals (HLA-DQ2 and

HLA-DQ8) develop an immune response• Worldwide prevalence of celiac disease in IBS

patients = 4%1

• US prevalence of celiac disease in IBS patients = p p0.41%2

• KEY POINT: The vast majority of IBS patients don’t have celiac disease.

1Green Lancet 2003; 2Cash et al, Gastroenterology 2011

IBS & Diet• Low carbohydrate• Low fructose/fructanLow fructose/fructan• Low gluten• Low FODMAP

(Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyol)


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Low Carbohydrate Diet

• Prospective, randomized, controlled study17 d t IBS D ti t• 17 moderate-severe IBS-D patients

• 4-week very low carbohydrate diet (VLCD)– 51% fat; 45% protein; 4% carbohydrate

• Endpoint: adequate relief for > 2 weeks• 13 completed the study13 completed the study• All 13 met the responder definition• 10 experienced adequate relief for all 4 weeks

Austin et al, Clin Gastro & Hepatol 2009

Low Carbohydrate Diet

• Secondary Endpoints also improved– Decrease in stool frequency– Improvement in stool consistency– Decreased abdominal pain– Improvement in quality-of-life


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IBS & Low Fructose/Fructan Diet•26 IBS patients with fructose malabsorption (Rome II; + breath test; mean age = 38) •Prior response to low fructose/low fructan diet•Randomly re-challenged with offending foods•70% of those receiving fructose, 77% receiving fructans, and 79% receiving a mixture noted return/worsening of symptoms compared to glucose (14%; p < 0.002)

Sheperd et al, Clin Gastroenterol Hepatol 2008;6:765-771

IBS & Low Gluten

• R, DB, PC, re-challenge study• 34 IBS patients (Rome III); celiac excluded• Prior improvement in Sx on gluten-free diet• 16 gm of non-fermentable gluten/day vs. 16

grams of gluten• Primary endpoint: adequate symptom relief• Gluten-group had less improvement in Sx than

those on gluten-free (68% vs. 40%; p = .001)

Biesiekierski et al, Am J Gastro 2011


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IBS & Low Gluten Diet

Biesiekierski et al, Am J Gastro 2011

IBS and Gluten-free Diet

• 45 Pts with IBS-D (43 women); 4-weeks• Gluten-free diet (23) vs. Gluten-diet (22)• Genotype analysis performed• Stool frequency, intestinal transit and

intestinal permeability measured• Results: Gluten diet was associated with

increased SB permeability, especially in HLA-DQ2/8 positive patients

Vazquez-Roque et al, Gastroenterology 2013;144:903-911


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What Are FODMAPs?

Honey, apples, pears, peaches mangos fruit juice

Excess

Fermentable Oligo-, Di-, Monosaccharides And Polyols

Sorbitol

peaches, mangos, fruit juice, dried fruit

Apricots, peaches, artificial sweeteners artificially

Wheat (large amounts), rye (large amounts), onions, leeks, zucchini

Fructose

Fructans

Shepherd SJ, et al. J Am Diet Assoc. 2006;106:1631-1639. Shepherd SJ, et al. Clin Gastroenterol Hepatol 2008;6:765-771. Gibson PR, et al. J Gastroenterol Hepatol 2010;25:252-

258.

Lentils, cabbage, Brussels sprouts, asparagus, green beans, legumes

Raffinose

sweeteners, artificially sweetened gums

IBS & Low FODMAP Diet: Or, what is there left to eat?

• Lean proteins• Gluten-free breads, rolls, pasta• Rice, corn, oat products• Quinoa• Safe fruits and vegetables:

– Snow peas, bok choy, mandarin oranges


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IBS & Low FODMAP Diet: Some Problems Exist

• What is the cut-off for FODMAP content?• Resources differ on low FODMAP diets• Total meal FODMAPs should be counted, not

individual FODMAP

IBS: Prospective study to Evaluate Low FODMAP diet

• 82 consecutive IBS patients (NICE criteria)• Detailed symptom and dietary evaluation• 9 month evaluation – performed in UK• Individual symptoms and global IBS symptoms

measured• 39 in the standard diet group• 42 in the low FODMAP diet group

Staudacher et al, J Hum Nutr Diet, 2011


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90100

d %Standard Diet

** † †

Improvements in IBS Symptom Scores: Low FODMAP vs Control Diet

2030405060708090

Patie

nts W

ith Im

prov

edSy

mpt

om R

espo

nse,

% Low FODMAP Diet** † †

††

010

Staudacher HM, et al. J Hum Nutr Diet 2011;24:487-495.

*P≤0.001† P<0.05

IBS Symptom Improvement: Low FODMAP Diet vs. Standard Diet

• Bloating (82% vs. 49%)• Abdominal pain (85% vs. 61%)• Flatulence (87% vs. 50%)• Nausea (67% vs. 29%)• Diarrhea (83% vs. 62%; ns)( ; )• Composite symptom score (86% vs. 49%)


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Osmotic Agents: PEG for IBS-C

7

8

2

3

4

5

6

7

Pretreatment

• 27 adolescents: PEG improved number ofBMs (P<0.05) but not pain in IBS-C patients

1. Khoshoo V, et al. Aliment Pharmacol Ther 2006;23:191-196.

0

1

2

# BMs Pain Level

Posttreatment

BMs, bowel movements; PEG, polyethylene glycol.

Osmotic Agents: PEG for IBS-C

• Prospective, multi-center, R, DB, PCR III it i• Rome III criteria

• 139 patients (mean age = 41; 83% women)• 28 day study; 13.8 gm/ sachet;• 1-3 sachets/day vs. placebo• Primary endpoint: mean # of SBM/dayPrimary endpoint: mean # of SBM/day• Results: At week 4, 4.4 SBM/week vs. 3.1

SBM/week (PEG vs. placebo; p < .0001)


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PEG 3350 for IBS-C

Efficacy of Linaclotide in Patients With IBS-C

3Treatment Period* RW Period†

z

Mea

n Ch

ange

Fro

mBa

selin

e +/

-SEM

2

1

0BL 1 2 3 4 5 6 7 8 9 10 11 1212 13 14 15 16

z

N=800

Weeks

BL 1 2 3 4 5 6 7 8 9 10 11 12

Treatment PeriodPlaceboLinaclotide 290 µg

Rao S, et al. Am J Gastroenterol 2012;107:1714-1724.

*P<0.0001 for linaclotide patients vs placebo patients (ANCOVA).†P<0.001 for linaclotide/linaclotide patients vs linaclotide/placebo patients (ANCOVA).

ANCOVA, analysis of covariance; RW, randomized withdrawal.

12 13 14 15 16

RW Treatment SequencePlacebo/linaclotide 290 µgLinaclotide 290 µg/linaclotide 290 µgLinaclotide 290 µg/placebo

Weeks


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Linaclotide Phase 3 IBS-C Trial:Abdominal Pain Over 26 Weeks

-10

0 Linaclotide 290 µg PlaceboCh

ange

in W

orst

Ab

dom

inal

Pai

n, %

-60

-50

-40

-30

-20

10

Chey WD, et al. Am J Gastroenterol 2012;107:1702-1712.

ITT population, observed cases, LS-mean presented: P-values based on ANCOVA at each week. Bars represent 95% CI.

P=0.0007 for week 1P<0.0001 for weeks 2-26

-60

Trial Week

BL 2 4 6 8 10 12 14 16 18 20 22 24 26

N=804ITT, intention to treat; LS, least squares.

Summary

• IBS is a constantly evolving field• Rome IV 2015 – expect changes in the

definition• Our understanding of IBS physiology continues

to expand• Expect new treatment options within the next• Expect new treatment options within the next

few years


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Iitbl B lS dIrritable Bowel Syndrome: What’s the...

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