IBD and IBS: Not to be confusedprimarycareinternalmedicine2018.com/uploads/1/2/2/3/...IBD and IBS:...

Adam S. Cheifetz, MD Director, Center for Inflammatory Bowel Disease

Beth Israel Deaconess Medical Center Professor of Medicine

Harvard Medical School 2019

IBD and IBS: Not to be confused

August 2019

Conflict of Interest Disclosure

I disclose the following financial relationships with commercial entities that produce healthcare-related products or services relevant to the content I am planning, developing, or presenting:

Adam S. Cheifetz, MD

Consulting: Janssen, Abbvie, Takeda, Pfizer, Samsung, Arena, Bacainn, EMD Serono, Arsanis, Grifols, Prometheus Research support: Inform Dx

Talk Overview 1. Discuss how we can optimize the treatment of IBD through

personalization of care and earlier treatment with effective agents 2. Discuss the goals of care in IBD and how they are evolving 3. Briefly review the medical therapies available for IBD 4. Understand the preventive care that is warranted in the patient

with IBD 5. Brief review of Irritable Bowel Syndrome (IBS): epidemiology,

pathophysiology, clinical features, and natural history 6. Discuss treatment of IBS

Clinical pearls (for the non-GI) When to refer to Gastroenterology • Rectal bleeding / iron deficiency anemia • Night time symptoms • Unintentional weight loss • Strong family history of IBD or colon cancer

Patient with known IBD with GI symptoms • Never assume symptoms are a flare of IBD • Always rule out infection • Assess for triggers of IBD (nsaids, noncompliance,

infection, stress)

Optimizing and Personalizing the Treatment of IBD • Treat smarter (predict who will have aggressive disease) • Treat earlier (with effective therapy) • Treat deeper (mucosal healing) • Treat to target • Treat more effectively (proactive TDM)

Why talk about IBD?

• At least 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, but peak incidence is in late

adolescence and early adulthood • Chronic destructive diseases • Huge impact on QOL

Hanauer S, NEJM 1996;334(13):841-848 Rogers et al, Journal of Chronic Disease 1971;24:743

(Idiopathic) Inflammatory Bowel Disease

Left-sided Colitis Proctitis

Pancolitis

Upper GI 5%

Ileocolic 50%

Colon 20%

Small bowel 30%

Perianal 33%

Ulcerative Colitis Small intestine is NOT involved Mucosal disease Rectal involvement Continuous

Crohn’s Disease “Mouth to anus” Transmural Rectal sparing Skip lesions

Progression of Digestive Damage and Inflammatory Activity in a Theoretical CD Patient

Pariente et al. Inflamm Bowel Dis 2011;17(6):1415-22.

Crohn’s disease is progressive and destructive

Pre-clinical Clinical

Inflamm

atory Activity

(CD

AI, C

DEIS, C

RP)

Surgery

Stricture

Stricture

Fistula/abscess

Disease onset

Diagnosis Early disease

Dig

estiv

e D

amag

e From controlling disease activity

in terms of clinical symptoms and inflammatory markers

To preventing progression of structural bowel damage

Up to 80% of CD patients will require surgical intervention and there is a high rate of post-

operative recurrence

Munkholm P, et al. Gastroenterology. 1993;105:1716–1723.

Years

Prob

abili

ty (%

)

Mean ± 2 SD

0

20

40

60

80

100

0 2 5 8 11 14 17 20

Number of events 122 26 15 7 7 4 8 1 8 2 2 2 3 2 1

20

40

80

100

0

60

Years

% o

f Pat

ient

s

0 1 2 3 4 5 6 7 8

Survival without surgery

Survival without laboratory recurrence

Survival without symptoms

Survival without endoscopic lesions

Rutgeerts P, et al. Gastroenterology. 1990;99:956–963.

Personalized Medicine (CD)

Diagnosis

“High risk”

“Low risk”

Early biologic / combination

therapy

Budesonide

Risk stratification •Clinical factors

•Serology/genetics

•Endoscopy

Predict which biologic mechanism is most effective and safest

www.gastro.org/IBDcarepathway.

Optimizing the Treatment of IBD • Treat smarter (predict who will have aggressive disease) • Treat earlier (with effective therapy) • Treat deeper (mucosal healing) • Treat to target • Treat more effectively (proactive TDM)

Assessment of Disease Risk in Crohn’s Disease

• Assess current and prior disease burden • Differentiate between activity and severity

Low Risk

• Age at initial diagnosis > 30 years • Limited anatomic involvement • No perianal and/or severe rectal disease • Superficial ulcers • No prior surgical resection • No stricturing and/or penetrating

behavior

Moderate/High Risk

• Age at initial diagnosis < 30 years • Extensive anatomic involvement • Perianal and/or severe rectal disease • Deep ulcers • Prior surgical resection • Stricturing and/or penetrating behavior

Available at: www.gastro.org/IBDcarepathway. Accessed March 25, 2017.

AGA Clinical Pathway for Ulcerative Colitis Colectomy Risk

Low colectomy risk • Limited anatomic

extent • Mild endoscopic

disease

High colectomy risk

CMV, cytomegalovirus. Sandborn WJ. Gastroenterology. 2014;147:702-705.

• Extensive colitis • Deep ulcers • Age < 40 years • High CRP and ESR • Steroid-requiring disease • History of hospitalization • C. difficile infection • CMV infection

Early Treatment with Effective Therapy (Theory)

• Treat disease when inflammatory (before it can be destructive) • Better able to induce and maintain remission • Improve function and QOL • Early mucosal healing to prevent complications and improve long-term

outcomes

• However, • Significant number of patients may not require more potent treatments • Side effects of medications • Cost

Lichtenstein GR, et al. Inflamm Bowel Dis. 2004;10:S2–S10. Caprilli R, et al. Digestive Liver Dis. 2005;37:973–979.

The Importance of Early Intervention – Lessons from Pivotal Anti-TNF Studies – “Time is Gut”

Disease duration (years)

CD

pat

ient

s in

rem

issi

on (%

)

0 1 2 3 4 5 6 7 8 9 10

SUTD1 SONIC2 CHARM5 GETAID3 ACCENT 14 100

90

80

70

60

50

40

30

20

10

0

1D’Haens G, et al. Lancet 2008;371:660–67; 2Sandborn WJ, et al. Presented at ACG 2008; 3Lemann M, et al. Gastroenterology 2006;130:1054–1061; 4Hanauer S, et al. Lancet 2002;359:1541–49; 5Colombel JF, et al. Gastroenterology 2007;132:52–65;

Why is endoscopic healing important? • In clinical trials

o FDA mandated end point o More objective end point than clinical remission

• In clinical practice, mucosal healing can guide medical therapy o Assess disease activity o 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

Pineton de Chambrun G, et al. Nat Rev Gastroenterol Hepatol. 2010;7(1):15-29.

Treat to Target

What are the options for treating IBD? How do we chose the best medication for new onset IBD?

Medical Therapy of Ulcerative Colitis Therapy Induction of

Remission Maintenance of Remission

5-ASA +++ (mild to moderate)

+++ (mild to moderate)

Corticosteroids +++ -

6MP/AZA + ++

Anti-TNF +++ +++

Vedolizumab ++ +++

Tofacitinib +++ +++

Cyclosporine +++ -

Vedolizumab (Entyvio)

• Selective adhesion molecule inhibitor (SAM-i) • Monocolonal antibody to a4b7 integrin - intravenous • FDA approved summer 2014 • Effective for moderate to severe IBD

• UC > Crohn’s • Maintenance > Induction

• Appears safe (safer than anti-TNF) • 1 case of PML (progressive multifocal leukoencephalopathy) in

undiagnosed HIV patient with IBD

23 Sanborn and Feagan, NEJM 2013.

Tofacitinib • Janus Kinase (JAK) inhibitor • Oral small molecule • FDA approved 5/30/2018 • Effective for induction and maintenance of remission in moderate to severe UC for both TNF naïve

and TNF exposed • FDA Update 7/2019

• Inadequate response or are intolerant to anti-TNF • Limit 10mg BID dose beyond induction to those with loss of response

• Based on post-marketing study of RA patients over age 50 with at least 1 cardiovascular risk factor where: • “Overall incidence of PE to be 5-fold higher in the tofacitinib 10 mg twice daily arm of the study compared with the TNF

inhibitor arm, and approximately 3-fold higher than tofacitinib in other studies across the tofacitinib program. Additionally, all-cause mortality in the 10 mg twice daily arm was higher compared with the tofacitinib 5 mg twice daily and the TNF inhibitor groups.”

• Safety issues • Zoster, serious infection, lymphoma (?), non-melanoma skin cancers, lymphopenia, lipid

elevation, venous thrombosis

24 Sanborn and Feagan, NEJM 2017 EMA and FDA announcements 2019

Medical Therapy of Crohn’s Disease Therapy Induction of

Remission Maintenance of Remission

5-ASA +/- -

Antibiotics +/- -

Corticosteroids +++ -

6MP/AZA + ++

Methotrexate ++ ++

Anti-TNF +++ +++

Anti-integrins (SAM-i) ++ +++

Ustekinumab +++ +++

Biologic therapy

Immunomodulators

Corticosteroids 5-ASA

New Paradigm: Treating beyond symptoms

Biologic therapy

Immunomodulators

Corticosteroids

Step-up approach

Top-down (early aggressive) approach

Corticosteroid Therapy for CD

* 30 D after initiating corticosteroid therapy † 1 patient lost to follow-up

Immediate Outcome* (n=74)

1-Year Outcome (n=73†)

Steroid Dependent

28% (n=21)

Prolonged Response

32% (n=24)

Surgery 38%

(n=28)

Faubion W, et al. Gastroenterology. 2001;121:255-260.

Complete Remission

58% (n=43)

Partial Remission

26% (n=19)

No Response 16%

(n=12)

Steroids are bad • They are abused by doctors and patients alike • They do not alter the disease course • They have bad short term side-effects • They have very bad long-term side-effects

– Skin, bones, adrenal axis, cataracts

• Increase risk of mortality in patients with IBD

Anti-TNFs for Crohn’s Disease

Colombel JF, et al. Gastroenterology. 2007;132(1):52-65.

Infliximab (Remicade) Placebo (n=170)

5mg/kg (n=172)

10mg/kg (n=157)

Remission at 26 weeks, % 17 40a 47a,b Remission at 56 weeks, % 12 36a 41a,b

Adalimumab (Humira) Placebo (n=170)

Every other week

(n=172)

Weekly (n=157)

Remission at 26 weeks, % 17 40a 47a,b

Remission at 56 weeks, % 12 36a 41a,b

Sandborn WJ, et al. N Engl J Med. 2007;357(3):228-238.

Certolizumab pegol (Cimzia)

Placebo (n=101)

Certolizumab pegol (n=112)

P

Remission at 26 weeks,% 26 42 .01

Intravenous (IFX); Subcutaneous (ADA, CTP) Similar efficacy < 40% of responders in remission at 1 year Safety issues – immunogenicity, infection, melanoma, lymphoma, psoriaform reactions

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 • 1 case of PML (progressive multifocal leukoencephalopathy) in patient with

undiagnosed 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 • Risk of Progressive multifocal leukoencephalopathy (PML) • JC antibody test available for risk stratification

30 Sanborn and Feagan, NEJM 2013

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

• Appear lower when compared to anti-TNF • Prior to use (rule out latent hepatitis B or tuberculosis)

• Malignancy • Similar malignancy rates to general population

31 Sandborn et al, NEJM 2012 JAMA Dermatol. 2015;151(9):961-969. doi:10.1001/jamadermatol.2015.0718

Personalized Medicine (CD)

Diagnosis

“High risk”

“Low risk”

Early biologic / combination

therapy

Budesonide

Risk stratification •Clinical factors

•Serology/genetics

•Endoscopy

Predict which mechanism is most effective and safest

www.gastro.org/IBDcarepathway.

Comparative Effectiveness • SONIC (Combination of IFX/AZA > IFX > AZA in naïve CD) • CYSIF (cyclosporine = infliximab in severe steroid refractory UC) • One head to head trial of different biologics just completed

• Others are underway • Can’t compare results across trials • Anti-TNF, vedolizumab, ustekinumab, and tofacitinib seem to have reasonable

efficacy for indications tested • Systematic review and network meta-analyses

• Infliximab and vedolizumab appear most effective as first-line agents for UC • Infliximab and adalimumab appear most effective as first-line agents for CD

33 Singh et al, APT 2018 Singh et al, APT 2018

VARSITY: A Double-Blind, Double-Dummy, Randomised, Controlled Trial of Vedolizumab Versus Adalimumab in Patients With Active Ulcerative Colitis

Results:

Schreiber et al, European Crohn’s and Colitis Organization 2019, Abstract OP34

CI, confidence interval. *Mucosal healing: Mayo endoscopic subscore of ≤1 point. Data from full analysis set, which includes all randomised patients who received at least 1 dose of study drug.

Week 52

How to Chose the First Agent? Disease specific factors • Severity of disease

• EIM

• Perianal disease

• Associated conditions (psoriasis, RA)

Patient specific factors • Age

• Co-morbidities (CHF, renal disease, recent cancer); pregnancy

• Patient preference

Medication specific factors • Efficacy (clinical remission, endoscopic healing,

perianal, EIM)

• Safety

• Rapidity of onset

• Durability of remission

• Immunogenicity

• Availability and data on TDM

• How it is administered

• Time on market (devil you know)

• Cost?

Physician comfort

Insurers / Payers

Optimize whatever drug you chose • First agent works best • TNF-exposed patients do not respond as well as TNF-naïve

patients • High rate of secondary loss of response • Risk of developing anti-drug antibodies is not insignificant

• Highest with anti-TNF

• TDM (particularly proactive TDM) is underutilized • If you are not doing proactive TDM, combination therapy with

infliximab (and likely other anti-TNF) should be used

Therapeutic Drug Monitoring – Proactive Monitoring

• Commonly performed in other situations – Cyclosporine, tacrolimus in solid organ transplantation – Cyclosporine and tacrolimus use in UC – Vancomycin and gentamycin in sepsis

• Therapeutic window • High concentrations can result in increased toxicity

– Low concentrations result in lack of efficacy – Biologics – low concentrations result in immunogenicity

Monchaud C, et al. Clin Pharmacokinet. 2009;48(7):419-462. Van Assche G, et al. Gastroenterology. 2003;125(4):1025-1031. Ziring DA, et al. J Pediatr Gastroenterol Nutr. 2007;45(3):306-311. Zelenitsky S, et al. Int J Antimicrob Agents. 2013;41(3):255-260. Hansen M, et al. Acta Anaesthesiologica Scandinavica. 2001;45(6):734-740.

Patients who achieved a trough concentration > 5 ug/ml had a longer duration on infliximab

P = 0.6

P < 0.0001*

Vaughn B et al. Inflamm Bowel Dis 2014 Nov;20(11):1996-2003

Retrospective, observational study. 126 patients with IBD who responded to infliximab and received maintenance therapy and underwent either proactive TDM or standard of care (reactive TDM or empiric dose escalation

Less IBD-Related Surgery, Hospitalization, ATI, and Serious Infusion Reactions with Proactive TDM

Papamichael K, et al. Clin Gastroenterol Hepatol. 2017;15(10):1580-1588.

IBD-related surgery IBD-related hospitalization

ATI SIR

Farraye FA, Melmed G, Lichtenstein GR, Kane S. Am J Gastroenterol. 2017 Feb;112(2):241-258

• 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 guidelines

Farraye FA, et al. Am J Gastroenterol. 2017;112(2):241-258.

ACG Vaccination Guidelines 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):241-258.

Other ACG Recommendations for Adults with IBD

Colorectal 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. 2017 Laine L et al. Gastroenterology. 2015

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

http://cornerstoneshealth.org/checklist/

Irritable Bowel Syndrome (IBS)

Lacy B et al. Gastroenterology. 2016;150:1393-1407 Rome Organization. Rome IV Disorders and Criteria.

Rome IV Criteria for IBS

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

Associated with a change

in frequency of stool

Associated with a change

in form (appearance) of stool

Recurrent abdominal pain at least 1 day / week in the last 3 months

associated with 2 or more of the following:

Related to defecation

IBS Affects up to 1/5 of Population, But Only a Small Percentage Seek Care

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

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

Percentage of loose or watery stools Perc

enta

ge o

f har

d or

lum

py s

tool

s

0

100

25

50

75

25 50 75 100

IBS-C* IBS-M

IBS-D† IBS-U

* Bristol Stool Form Scale 1-2 † Bristol Stool Form Scale 6-7 IBS-M = IBS-mixed IBS-U = unclassified IBS

Adapted from: Lacy B et al. Gastroenterology. 2016;150:1393-1407

IBS Frequently Co-exists with Other Chronic Conditions

Ladabaum et al, Gastroenterology 2007; 132: W1172 Whitehead et al, Am J Gastroenterol 2007; 102: 2767–76

Vandvik et al, Aliment Pharmacol Ther 2004; 20: 1195–203

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

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

Conditions That Can Mimic 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

Alarm Features • Symptom onset > 50 years • Blood in stools/Fe def anemia • Weight loss (unintentional) • FH CRC/IBD • Nocturnal Symptoms

Lactose intolerance

Colorectal carcinoma

Celiac disease

Enteric infection

Inflammatory bowel

disease

Thyroid disease

Recommendations from the ACG for Diagnostic Testing in IBS

Test Recommendation CBC serum chemistries TSH, Stool for ova and parasites Abdominal imaging

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

tTG

IBS-D

Lactose breath testing If symptoms persist after dietary modification

Breath testing for SIBO Insufficient data to recommend Routine colonoscopy 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.

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

Poulis et al. Eur J Gastro Hepatol. 2002 Apr;14(4):409-12

Role of Fecal Markers of Intestinal Inflammation in Distinguishing IBS vs IBD

• 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%)

1. Sherwood RA. J Clin Pathol 2012;65(11):981-985 2. Waugh N, et al. Health Technol Assess. 2013;17(55):xv-xix,1-211

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

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

• IBS symptoms improve with moderate 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.

The FODMAP Diet Fermentable Oligo-, Di-, Mono-saccharides And Polyols 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.

A 4 wk RCT Comparing the Low FODMAP Diet vs. Modified NICE* Guidelines in US Adults with IBS-D

Eswaran et al. Am J Gastroenterol 2016; 111:1824–1832 *National Institute for Health and Care Excellence

Example from the NICE guideline for IBS: Reduce resistant starches • whole grains, sweetcorn, and muesli that contains bran • undercooked potato or maize/corn • oven chips, fried rice, pizza, garlic bread, pasta salad, cakes

Bloating/ distension

Abdominal pain/

discomfort

Altered bowel function

Bloating • Probiotics • Antibiotics

Diarrhea • Loperamide • Probiotics • Cholestyramine • Rifaximin • Eluxadoline

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

Abdominal pain/discomfort • Antispasmodics • Antidepressants • Linaclotide • Plecanitidine

Constipation • Psyllium • Lubiprostone • Linaclotide • Plecanitidine • Osmotic laxatives

Examples of Pharmacologic Treatments for IBS

Soluble Fiber (Psyllium) May be Effective in Some IBS Patients

• Fiber can exacerbate bloating, flatulence, distention, and 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<.05

4 2 3 0

5 6 7 8 9 10 11 12 Study Duration (weeks)

Psyllium, 10 g (n=85) Bran, 10 g (n=97) Placebo (rice flour), 10 g (n=93)

1

10

20

30

40

50 R

espo

nder

s * *

*

*

Proportion of patients with adequate relief of symptoms each week1

Probiotics • Probiotics improve global IBS symptoms,

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

• Recommendations regarding individual species, preparations, or strains cannot be made

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

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)

Polyethylene Glycol (PEG) improves bowel movements but does not improve abdominal symptoms in IBS-C

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

Spontaneous Complete Bowel Movements (SCBMs) Abdominal Discomfort/Pain

*P<.0001.

N=68 N=71

• Between 1 and 3 sachets of PEG 3350 + E (13.8 g per day) or matching placebo were given • Patients adjusted the dose based on stool consistency E=electrolytes.

Lubiprostone, a luminal Cl-C2 channels Activator (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, %

Linaclotide, a Guanylate Cyclase C Agonist

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 μg QD for IBS-C Adult men and women

Plecanitide, a Guanylate Cyclase C Agonist FDA Approved dose 3mg QD for IBS-C

Brenner et al, AJG 2018

2 phase 3 trials (n=1879) Percent overall responders 30% vs. 18% placebo 22% vs. 14% placebo Hit secondary endpoints

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

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

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

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

Phase III Trials (Target 1 and 2) Rifaximin for IBS-D

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

• 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

• 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

*P<0.02 vs placebo Assessment at 12 weeks GIS = Global Improvement Scale

Safety Profile of Alosetron

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

Alosetron, a 5-HT3 antagonist, Improves Global Symptoms in

Women with Severe IBS-D

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

Activation reduces pain, gastric propulsion

μ opioid receptor Inhibition restores

G-protein signaling; reduces

μ agonist-related desensitization

δ opioid receptor

Lembo A et al. NEJM 2016

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

Antidepressants Can Improve IBS Symptoms

• 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 without Improvement in IBS Symptoms1

Res

pond

ents

(%) RR = 0.67

(95% CI=0.58-0.77) NNT = 4

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.

IBS Key Points: • IBS is very common and can significantly impact QOL • IBS is a clinical diagnosis and treatment a requires close clinician-

patient 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

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