Update on Irritable Bowel Syndrome

Anthony Lembo, M.D. Beth Israel Deaconess Medical Center

Harvard Medical School Boston, MA

Highlights

• FDA approval for 2 new IBS-D treatments – Rifaximin and eluxadoline

• Diagnostic test for IBS (IBSchek) • Controlled trials with the FODMAP diet • Delayed release peppermint oil

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 terms – mucous colitis – colonic spasm – neurogenic mucous colitis – irritable colon

W. Cumming, London Medical Gazette, 1849;NS9;969-973.

– unstable colon – nervous colon – spastic colon – nervous colitis – spastic colitis

Longstreth GF et al. Gastroenterology. 2006;130(5):1480-1491. Rome Organization. Rome III Disorders and Criteria. Available at: http://www.romecriteria.org/criteria/. Accessed February 29, 2013.

Rome III Criteria for IBS

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

Onset associated with a change

in frequency of stool

Onset associated with a change

in form of stool

Recurrent abdominal pain or discomfort at least 3 days / month in the last 3 months associated with 2 or more of the following:

Improvement with

defecation

Additional IBS “testing,” including routine laboratory tests and colonoscopy, unnecessary unless alarm features present

7

http://www.romecriteria.org/criteria/

Epidemiology • IBS is the most commonly diagnosed gastrointestinal disorder1

1. Chey WD, et al. JAMA. 2015;313:949-958. 2. Lovell RM, et al. Clin Gastroenterol Hepatol. 2012;10:712-721.

Prevalence of IBS in various countries2

5

Natural History of IBS • Chronic, relapsing disease1 • Data from a systematic review of patients in long-term

follow-up1 – 2%-18% worsened – 30%-50% remained unchanged – 12%-38% improved

• Patients migrate between classifications – The majority of patients change

subtypes over time2 – Most common migrations are

to and from IBS-M3 • Patients seldom migrate directly

between IBS-C and IBS-D

1. El-Serag HB, et al. Aliment Pharmacol Ther. 2004;19:861-870. 2. Engsboro AL, et al. Aliment Pharmacol Ther. 2012;35:350-359. 3. Garrigues V, et al. Aliment Pharmacol Ther. 2007;25:323-332.

IBS-C

IBS-D IBS-M

6

Impact of IBS on quality of life compared with other medical conditions

30

40

50

60

70

80

90

Mea

n SF

-36

scor

e

National norm

Diabetes type II

IBS

Clinical depression

Adapted from Wells et al., Alimentary Pharmacology Therapies, 1997; 11: 1019-1030.

IBS Pyramid Specialists

Primary care ~25% Consulters

~75% Nonconsulters

~70% Female

~30% Male

Pain

Psychological disturbance

Adapted from Drossman and Thompson, Ann Intern Med 1992; 116(pt 1): 1009 Sandler, Gastroenterology 1990; 99: 409

Economic burden of IBS

Healthcare costs Productivity costs

Billions of dollars 0 20 40 60 80 100 120

Arthritis

Hypertensive disease IBS

Stroke

Diabetes

Asthma

Migraine

Disordered CNS-ENS interactions in IBS

Psychological/ cognitive

Gut luminal/ mucosal

IBS Symptoms Heightened

Sensorimotor Activity

Adapted from Clouse RE. J Funct Syndrome 2001; 1:61-68

Brain-Gut Axis

Pathophysiology of IBS Environmental Contributors

to IBS Symptoms

• Early life stressors (abuse, psychosocial stressors)1,2

• Food intolerance2 • Antibiotics2 • Enteric infection2

Host Factors as Contributors to IBS Symptoms

• Enhanced stress response1 • Altered pain perception1,2 • Altered brain-gut interaction2 • Dysbiosis2 • Increased intestinal

permeability1,2 • Increased gut mucosal

immune activation2 • Visceral hypersensitivity2

1. Chang L. Gastroenterology. 2011;140:761-765. 2. Chey WD, et al. JAMA. 2015;313:949-958.

11

Role of Immune Activation in Post-Infectious IBS

0

50

100

150

200

Discomf Inflamm Psych

IBS + IBS - Control

*

* *

Gwee, Gut, 1999;44:400.

Control

3 wks post infectious

Spiller, Gut, 2000; 47(6): 807.

Increased Enterochromaffin Cells

Visceral Hypersensitivity chronic lymphocytes at f/u psychological disturbance at baseline

http://gut.bmjjournals.com/cgi/content/full/47/6/804/F1

Key Organic Diseases in Differential Diagnosis of IBS

ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35.

Organic disease in the absence of alarm features is uncommon

Lactose intolerance

Colorectal carcinoma

Celiac disease

Enteric infection

Inflammatory bowel disease

Thyroid dysfunction

13

Positive Diagnostic Strategy Was Non-inferior to Strategy of Exclusion

• 302 primary care patients (18-50 years of age) who fulfilled ROME III criteria for IBS with no alarm features

• A positive diagnostic strategy was non-inferior to using a strategy of exclusion with regard to HRQoL and was associated with lower direct costs

*Full blood count, C-reactive protein, plasma-calcium, -bilirubin, -ALT, -alkaline phosphatase, -albumin, serum-TSH, serum-tissue transglutaminase, lactase gene test.

†Full blood count, C-reactive protein.

Strategy of Exclusion Positive Strategy

Blood analysis Stool samples for parasite Sigmoidoscopy with biopsies

Begtrup LM, et al. Clin Gastroenterol Hepatol. 2013;11:956-962.

* †

ALT=alanine aminotransferase; HRQoL=health-related quality of life; TSH=thyroid-stimulating hormone.

American College of Gastroenterology Recommendations for

Diagnostic Testing in IBS Test Recommendation Complete blood count Serum chemistries Thyroid function studies Stool for ova and parasites Abdominal imaging

Not recommended in patients with typical IBS symptoms and no alarm features

Serologic screening for celiac sprue

Pursue in IBS-D and IBS-M

Lactose breath testing Consider if symptoms persist after dietary modification

Breath testing for SIBO Insufficient data to recommend Routine colonoscopy Not recommended in patients

Alarm Features for Organic Disorders

• Symptom onset after age 50 years • Blood in stools • Nocturnal symptoms • Anemia • Weight loss (unintentional) • Change in symptoms • Family history of organic gastrointestinal disease

Patients with alarm features

should undergo further investigation

ACG Task force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. 16

T17

0

10

20

30

40

50

60

0 2 4 6 8 10 12 14 16

Week

% with relief

*P

Treatments for IBS

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

Barrett, JS. Nutr Clin Pract 2013, 28:300 Gibson, PR &SJ Shepherd J Gastroenterol Hepatol 2010; 25(2):2

Dietary and Lifestyle Considerations

• Only a few well-controlled RCTs of elimination diets in IBS have been conducted1

• Up to ⅔ of IBS patients associate symptom onset or worsening with eating a meal2,3

• Maintaining a brief diary of dietary intake and symptoms may help determine if a correlation exists between food and IBS symptoms2 – Fatty/greasy food – Poorly absorbed carbohydrates – Gas-producing foods – Soluble fiber

• One small study demonstrated improved IBS symptoms with physical activity4

1. Moayyedi P, et al. Clin Transl Gastroenterol. 2015;6:e107. 2. Somers SC, Lembo A. Gastroenterol Clin North Am. 2003;32:507-529. 3. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. 4. Johannesson E, et al. Am J Gastroenterol. 2011;106:915-922.

FODMAPs=fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; RCT=randomized, controlled trial.

20

The FODMAP Diet Eliminate foods containing FODMAPs1-3

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;108:707-717. 2. Shepherd SJ, Gibson PR. J Am Diet Assoc. 2006;106:1631-1639. 3. Barrett JS, Gibson PR. Ther Adv Gastroenterol. 2012;5:261-268.

21

-7 0 7 14 21 -7 0 7 14 21

Low-FODMAP vs Typical Australian Diet

Halmos EP, et al. Gastroenterology. 2014;146:67-75.

Mean overall GI symptoms improved with low-FODMAP diet in IBS patients (≤0.5 g of FODMAPs per meal)

VAS

(0-1

00 m

m)

IBS Healthy Controls

Day Day

Baseline Typical Australian diet Low-FODMAP diet

60

40

20

60

40

20

P

Both Low-FODMAP and Traditional IBS Diets Reduced IBS Symptom Severity

Böhn L, et al. Gastroenterology. 2015. doi: 10.1053/j.gastro.2015.07.054.

P=.002 Low FODMAPs

P

Psychological Therapy for IBS

Ford AC, et al. Am J Gastroenterol. 2014 Sep;109:1350-1365.

Therapy Trials N RR

(95% CI) NNT

(95% CI) Cognitive behavioral therapy (CBT) 9 610 0.60 (0.44-0.83) 3 (2-6)

Relaxation training or therapy 6 255 0.77 (0.57-1.04) –

Hypnotherapy 5 278 0.74 (0.63-0.87) 4 (3-8)

Multi-component psychological therapy 5 335 0.72 (0.62-0.83) 4 (3-7)

Self-administered, minimal-contact CBT 3 144 0.53 (0.17-1.66) –

CBT via Internet 2 140 0.75 (0.48-1.17) –

Dynamic psychotherapy 2 273 0.60 (0.39-0.93) 3.5 (2-25)

Stress management 2 98 0.63 (0.19-2.08) –

Multi-component therapy via telephone 1 126 0.78 (0.64-0.93) –

Mindfulness meditation training 1 75 0.57 (0.32-1.01) –

Total 36 2334 0.68 (0.61-0.76)

CI=confidence interval; NNT=number needed to treat; RR=risk ratio; – = not provided.

24

Similar & significant differences for: Abdominal pain, bloating, tiredness & satisfaction with stool consistency

Gluten Free Diet for Functional Disorders?

Bloating/ distension

Abdominal pain/

discomfort

Altered bowel function

Bloating • Probiotics • Antibiotics

Diarrhea • Loperamide • Probiotics • Rifaximin • Eluxadoline

1. Brandt LJ et al, for the ACG Task Force on IBS. Am J Gastroenterol. 2009;104(Suppl 1):S1-S35. 2. Chey WS, et al. Gut and Liver. 2011;253-266.

Abdominal pain/discomfort • Antispasmodics • Antidepressants • Linaclotide

Constipation • Ispaghula/psyllium • Lubiprostone • Linaclotide • Osmotic laxatives • Tegaserod

Pharmacologic Treatments for IBS

50

Probiotics

• 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

• Probiotics improve global symptoms, bloating, and flatulence. Recommendations regarding individual species, preparations, or strains cannot be made

Ford AC, et al. Am J Gastroenterol. 2014;109:1547-1561. 27

Efficacy of Psyllium in IBS

• Bulking agents can exacerbate bloating, flatulence, abdominal distention, and abdominal discomfort.2,3 Dose should be titrated gradually2

1. Bijkerk CJ, et al. BMJ. 2009:339:B3154-B3160. 2. ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. 3. Eswaran S, et al. Am J Gastroenterol. 2013;108:718-727.

*P

Polyethylene Glycol (PEG) for IBS-C

Chapman RW, et al. Am J Gastroenterol. 2013;108(9):1508-1515.

Spontaneous Complete Bowel Movements

(SCBMs) Abdominal

Discomfort/Pain

*P

Antidepressants • Effective at reducing IBS symptoms and

abdominal pain1

• Adverse effect profiles may guide use in IBS subtypes2 – 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

1. Ford AC, et al. Am J Gastroenterol. 2014;1350-1365. 2. Chey WD, et al. JAMA. 2015;313:949-958.

RR=relative risk; SSRI=selective serotonin-reuptake inhibitor; TCA=tricyclic antidepressant.

Patients Reporting Unimproved IBS

Symptoms1

0%

10%

20%

30%

40%

50%

60%

70%

Placebo Antidepressants R

espo

nden

ts (%

)

RR = 0.67 (95% CI=0.58-0.77)

NNT = 4

30

Antidepressants – Tips for improving Effectiveness

• Inform patients of expected AE (e.g. sedation, agitation, anticholinergic)

• Start low (10-25 mg/d) and advance slowly, especially in the elderly and those with somatization disorder

• Try to reach a daily dose of 50 mg • Switch to an alternative TCA or SSRI if intolerance

or SE occur • Use adverse-effect profiles to help select agents

Clouse, Gastroenterology, 1999

Osmotic Laxative Polyethylene glycol (PEG) Improves Bowel Function But Not Pain in IBS-C

Chapman et al. Am J Gastroenterol 2013; 108:1508–1515

T33

Cl- Cl-

Na+

K+ K+

K+ 2Cl

Tight junction

H2O Na+

H2O Na

+

Ion Transport

Na+

CFTR channel Enterocytes Cl C2 channel

T168

Increasing Fluid in the GI Tract via Chloride Channels

Lubiprostone

• Activates luminal Cl-C2 channels (and possibly CFTR)

• 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

Drossman DA et al. Aliment Pharmacol Ther. 2009;29:329-341.

P = .001

Com

bine

d

Ove

rall

Resp

onde

rs, %

Chart1

Lubiprostone 8 µg BID n=780

Placebon=387

Column1

17.9

10.1

Sheet1

Column1

Lubiprostone 8 µg BID n=78017.9

Placebon=38710.1

To resize chart data range, drag lower right corner of range.

Linaclotide

13.9%

≥30% abdominal pain reduction + increase ≥1 CSBM from baseline; in the same week for 50% of weeks (i.e, 6 out of 12 weeks)

% F

DA

Res

pond

ers

33.7%*

Placebo N=403

Lin 290 µg N=401

FDA Responder

CSBM +1 Responder

Abdominal Pain

Responder

Chey WD et al. AJG 2013.

FDA Approved dose 290 ug QD for IBS-C Adult men and women

Chart1

APC+1APC+1

Placebo

266 ug

13.9

33.7

Sheet1

Placebo266 ug

APC+113.933.7

To resize chart data range, drag lower right corner of range.

T36

Alosetron Improves Global Symptoms in Women with Severe IBS-D

Krause R et al. Am J Gastroenterol 2007; 102:1709

% GIS Responders

*P

T37

Safety Profile of Alosetron

•Black-box warning: serious GI effects •Ischemic colitis

• 2 per 1000 patients over 3 months • 3 per 1000 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; 2006

T38

Antispasmodics for IBS

• May be effective for post-prandial pain; unlikely to be effective for chronic pain

• Cause smooth-muscle relaxation by either • Direct effect (eg, mebeverine, pinaverium) • Anticholinergic or antimuscarinic properties

(eg, dicyclomine, hyoscamine) • Calcium channel blockade (peppermint oil)

• Heterogeneous trials, small sample sizes, • Side effects: dry mouth, constipation, urinary retention

and visual disturbances

T39

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 2002; 97 suppl:S7

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, 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

Ford et al., AJG, 2014

Rifaximin • Broad spectrum antimicrobial agent

• Minimally absorbed (

• 2 identical phase 3, double-blind, placebo-controlled trials (Target 1 and 2) • Randomized to rifaximin 550 mg or placebo, TID x 2 weeks

Rifaximin for IBS with Diarrhea

1. Pimintel M, Lembo A et al; TARGET Study Group. N Engl J Med. 2011;364:22-32.

∆ = 7.6

∆ = 9.0

∆ = 8.1

ReTreatment with Rifaximin in IBS-D IBS-related Abdominal Pain and Stool Consistency (Worst Case Analysis)

Perc

enta

ge o

f Res

pond

ers

First and Second Repeat Treatment Phases Rifaximin Placebo

44 Responder: Patient responding to IBS-related Abdominal Pain (>30%

improvement) nd Stool consistency (>50% decrease in # BMs with type 6 or 7) from Consistency for ≥ 2 of the 4 weeks

Chart1

1st Repeat Tx(Primary Endpoint)1st Repeat Tx(Primary Endpoint)

2nd Repeat Tx2nd Repeat Tx

Both 1st and 2nd Repeat TxBoth 1st and 2nd Repeat Tx

p = 0.0232

p = 0.0023

p = 0.0263

Rifaximin

Placebo

32.6

25

35.3

27.2

23.1

14.1

Primary ITT

PlaceboRifaximin

1st Repeat Tx(Primary Endpoint)25.032.6

2nd Repeat Tx27.235.3

Both 1st and 2nd Repeat Tx14.123.1

combined

PlaceboRifaximinRifaximinPlacebo

RFIB30073141Pooled Data4132

RFIB30083241

Primary ITT

p = 0.0125

p = 0.0263

∆ = 10

∆ = 9

p = 0.0008

∆ = 9

Rifaximin

Placebo

Percent of Responders

Primary Robust Pool

p = 0.0125

∆ = 10

p = 0.0263

∆ = 9

Rifaximin

Placebo

Percent Responders

Key Sec ITT

p = 0.0008

∆ = 9

Rifaximin

Placebo

Percent Responders

Key Sec Robust Pool

RifaximinPlacebo

PP (LOCF)4131

ITT (Observed Cases)4132

ITT (Multiple Imputation)4233

Key Sec Robust Pool

p = 0.0003

p = 0.0008

p = 0.0010

∆ = 10

∆ = 9

∆ = 9

Rifaximin

Placebo

Percent Responders

Monthly SGA IBS Sym-ITT

RifaximinPlacebo

RFIB30074029

RFIB30084132

Combined Data4030

RifaximinPlacebo

RifaximinPlaceboPooled Data4030

RFIB30074029

RFIB30084132

Monthly SGA IBS Sym-ITT

p = 0.0045

p = 0.0167

∆ = 11

∆ = 9

∆ = 10

p = 0.0002

Rifaximin

Placebo

Monthly SGA IBS Sym-PP

p = 0.0045

∆ = 11

p = 0.0167

∆ = 9

Rifaximin

Placebo

Percent Responders

Monthly SGA Bloating-ITT

∆ = 10

p = 0.0002

Rifaximin

Placebo

Percent Responders

Monthly SGA Bloating-PP

RifaximinPlacebo

PP (LOCF)4130p

Eluxadoline for IBS-D • 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

• Phase IIb 100 and 200 mg BID doses showed efficacy

Activation reduces pain, gastric propulsion

μ opioid receptor

Inhibition restores G-protein signaling;

reduces μ agonist-related desensitization

δ opioid receptor

45

Eluxadoline, a mixed mu (μ) opioid receptor agonist / delta (δ) opioid receptor antagonist for IBS-D

*p30% improvement) and Stool consistency (BSS score

Low-dose TCAs Contemporary Antidepressants Psychotherapy Behavioral interventions

Alosetron Eluxadoline Rifaximin Linaclotide Loperamide Lubiprostone Antispasmodics Fiber Antispasmodics Laxatives Reassurance Reassurance

severe

moderate

mild

Diarrhea predominant Constipation predominant alternating

Summary Treatment Options in IBS

Update on Irritable Bowel SyndromeHighlightsEarly description �of symptoms defining IBSRome III Criteria for IBSEpidemiology Natural History of IBSImpact of IBS on quality of life �compared with other medical conditionsSlide Number 8Economic burden of IBSDisordered CNS-ENS interactions in IBSPathophysiology of IBS Role of Immune Activation in Post-Infectious IBSKey Organic Diseases in �Differential Diagnosis of IBSPositive Diagnostic Strategy Was �Non-inferior to Strategy of Exclusion American College of Gastroenterology Recommendations for �Diagnostic Testing in IBSAlarm Features for Organic DisordersSlide Number 17Treatments for IBSDiets in IBSDietary and Lifestyle Considerations The FODMAP DietLow-FODMAP vs Typical Australian DietBoth Low-FODMAP and Traditional IBS Diets Reduced IBS Symptom SeverityPsychological Therapy for IBSSlide Number 25Pharmacologic Treatments for IBS�Probiotics Efficacy of Psyllium in IBSPolyethylene Glycol (PEG) for IBS-CAntidepressants Antidepressants – Tips for improving EffectivenessOsmotic Laxative Polyethylene glycol (PEG) Improves Bowel Function But Not Pain in IBS-CSlide Number 33LubiprostoneLinaclotideSlide Number 36Slide Number 37Slide Number 38Slide Number 39ACG Task Force Recommendations for IBS-DACG Task Force Recommendations for IBS-CRifaximinRifaximin for IBS with DiarrheaReTreatment with Rifaximin in IBS-D�IBS-related Abdominal Pain and Stool Consistency (Worst Case Analysis)Eluxadoline for IBS-DEluxadoline, a mixed mu (μ) opioid receptor agonist / delta (δ) opioid receptor antagonist for IBS-DSummary Treatment Options in IBS