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Topics in Inflammatory Bowel Disease

John F. Valentine, MDUniversity of Utah

Ogden Surgical-Medical Society May 15th, 2013

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This presentation promotes no commercial vendor and is not supported financially by any commercial vendor.

• Dr. Valentine receives research support from: NIH, Janssen Biotech, Inc. (formerly Centocor Biotech, Inc), Abbott, Takeda, Celgene Cellular Therapeutics, Pfizer, Genentech

• Dr. Valentine has been a consultant for: Genentech

• Speakers Bureau: None

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Changing Epidemiology of UC

Molodecky NA, et al. Gastro 2012 142(1):46-54

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Changing Epidemiology of UC

Molodecky NA, et al. Gastro 2012 142(1):46-54

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Changing Epidemiology of CD

Molodecky NA, et al. Gastro 2012 142(1):46-54

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Changing Epidemiology of CD

Molodecky NA, et al. Gastro 2012 142(1):46-54

Ulcerative Colitis Crohn’s Disease

Inci

den

ce

/ 1

0 0,0

00

Age-Specific Incidence of IBD *

*Per 100,000 populationReprinted from Lashner BA. In: Stein SH and Rood RP, eds. Inflammatory Bowel Disease: A Guide for Patients and Their Families. Lippincott-Raven Publishers; 1999:23-29.

10

0

2

4

6

8

0 20 40 60 80

10

0

2

4

6

8

0 20 40 60 80

Age (yrs) Age (yrs)

Kugathasan et al. J Pediatr 2003;143:525-31.

Wisconsin study: incidence for CD 4.56 (95% CI, 3.77-5.35) incidence for UC 2.14 (95% CI, 1.6-2.68) Mean age at diagnosis 12.5 y Only 11% had a family Hx of IBD

Epidemiology of IBD

Caucasian

African Am

Hispanic

Asian

Other

Caucasian

African Am

Hispanic

Asian

Other

Wisconsin New IBD Diagnosis Wisconsin Pediatric Population

87%

6%4% 2% 0.5%

6%4% 2% 2%

86%

Kugathasan et al. J Pediatr 2003;143:525-31.

Current Etiologic Hypothesis for IBD

Microbial Flora

Lack of Infections(Hygiene Hypothesis)

Danese et al. World J Gastroenterol 2005;11:7227–36.Bernstein et al. Gastroenterol 2005;129:827–836

AsthmaBronchitisMultiple sclerosisNeuropathyMyasthenia gravisChronic renal diseasePericarditisPsoriasis

Celiac diseaseHidradenitis suppurativa

Environmental Triggers of IBDAntibiotics

Diet Low fiber Refined sugars

NSAID use

Stress

Infections

Improved hygiene?

Low Vitamin D

Smoking Protective against UC Risk factor for CD

Alterations in colonic flora

Lack of immune education? Lack of parasites?

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Constructing the Diagnosis of IBD

• Careful process of putting together pieces of a puzzle to accumulate enough evidence to diagnose IBD

28% 25% 47%

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IBD Symptomatology

Crohns Disease• Altered bowel movements

– Increased stool frequency– Decreased stool

consistency

• Abdominal pain– RLQ exacerbated by eating– May be associated with

bloating

• Bleeding not common– Large volume bleed rarely

Ulcerative Colitis• Altered bowel movements

– Increased stool frequency– Decreased stool consistency– Proctitis: possible

constipation

• Abdominal pain– LLQ cramps before BM,

relieved by defecation– Tenesmus

• Blood in stool

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Historical Points Suggestive of IBD

• Specific questions may differentiate purulent exudate from mucus– Presence of blood with pus suggests IBD

• Presence of blood in stool favors UC over CD– More pronounced bleeding, UC more likely

• Careful scrutiny for systemic sx, extraintestinal sx important

• Specifically ask about prior history of peri-anal abscess, fistulas, fissures

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Historical Points Suggestive of IBD

• Alternating diarrhea and constipation more strongly suggest IBS vs IBD

• Nocturnal diarrhea more common in IBD

• Functional symptoms remaining after bout of enteric infection may confuse the clinical picture– Lingering abdominal pain, loose/urgent stools

should prompt objective evaluation by endo/path

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IBD or IBS – How to use the ROS• Anemia, abnormal LFTs, elevated WBC, CRP• Extra-intestinal manifestations

– Arthropathy-both axial and peripheral– Skin rashes

• E. nodosum• Pyoderma gangrenosum

– Eye symptoms• Uveitis• Conjunctivits/episcleritis

– Oral ulcerations• Ano-rectal complaints

Systemic Complications and

OsteoporosisMalnutrition, growth failureColon Cancer

Cumulative incidence* 2% by 10 years 8% by 20 years 18% by 30 years

*Eaden et al. Gut 2001;48:526-535

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Oral Lesions

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Ocular Lesions

Cutaneous Lesions

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Physical Findings in IBD• Crohn’s Disease

– Oral lesions– Ocular lesions– Skeletal manifestations– Skin lesions

• Erythema nodosum– Abdominal exam

• Mass / tendreness– Perianal disease

• Skin tags• Anal fissure• Perianal fistula• Rectovaginal fistula• Anal stenosis

• Ulcerative colitis– Oral lesions– Ocular lesions– Skeletal manifestations– Skin lesions

• Pyoderma– Abdominal exam

• Tenderness

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Components of IBD Diagnosis

• Clinical picture

• Endoscopic information/pathologic specimens

• Radiographic evidence

• Chronic course of symptoms– Important to fully evaluate cause of diarrhea

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Useful Laboratory Tests

• Blood work– CBC, TSH, ESR, CRP

• Serologic markers– Anti-Saccharomyces cerevisiae Antibody (ASCA), Anti-

neutrophil cytoplasmic antibody (pANCA), anti-OmpC, anti-CBir1

• Fecal calprotectin and lactoferrin– Elevated in inflammation, no increased in IBS

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Serologic Blood Tests:May be helpful

Not good enough by themselves

Prevalence of IBD-Specific Antibody Markers

1Quinton JF, et al. Gut. 1998;42:788-791. 2Cohavy O, et al. Infect Immun. 2000;68:1542-1548. 3Taregan SR, et al. Gastroenterology. 2005;128:2020-2028.

Marker CD (%) UC (%) Non-IBD (%)

pANCA1 15 65 <5

ASCA1 60 5 <5

Omp C2 55 2 <5

CBir13 50 6 8

n=40 n=21 n=50 n=100

8% 14% 6%

50%50%

0

1

2

3

Anti-

CBir1

Anti

body

(O.D

.)

Normal Controls

Inflammatory Controls UC CD

P vs CD:

% Positive <0.001 <0.02 <0.001 n/a Level <0.001 <0.003 <0.001 n/a

Targan SR, et al. Gastroenterology. 2005;128:2020-2028.

Presence Anti-CBir1

ASCA in Celiac SprueASCA in Celiac Sprue

Eur J Gastroenterol & Hep 2006;18:75-78

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C. diff in IBD has worse outcomes Nationwide population based retrospective study

based on hospital discharge diagnosis (2003)

Primary outcome: in-hospital mortality

CDI-IBD 2,804, CDI 44,400, IBD 77, 366

Compared to non-IBD CDI, CDI-IBD had:

2x greater mortality

6x more likely to undergo surgery

3x longer length of stay

2x more likely to require blood transfusion

Ananthakrishnan et al . Gut 2008;57: 205–210.

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Indications for Endoscopy in IBD

• Obtain an accurate diagnosis

• Assess disease activity or possible extension

• Dilate strictures in fibro-stenotic disease

• Detect cancer precursors in long-standing colonic disease

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Endoscopic Features of IBDUlcerative colitis

• Edema

• Erythema/Loss of vascularity

• Friability

• Erosions

• Mucopurulent exudate

• Spontaneous bleeding

• Ulceration

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Endoscopic Features of IBDCrohn’s Disease

• Patchy edema, erythema– Discontinuous

• Apthous ulcerations

• Coalescing ulcerations

• Cobblestoning

• Longitudinal “bear claw” ulcers

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IBD Treatment Principles

Determine underlying cause/location of disease

Monitor for toxicity/complications

Tailor therapy to patient’s manifestations

Achieve and maintain remission

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First-line Treatment of IBDRole of 5-ASA

Topical Therapy• Rectal administration

– Mesalamine enema 4gm/60ml

– Mesalamine 1mg/suppository

• Preferred therapy for proctitis

• Synergy obtained by combining with oral therapy

Oral Therapy• Standard formulation

– Asacol– Pentasa– Dipentum– Sulfasalazine– Colazal

• Delayed release formulations– Apriso– Lialda

• Efficacy of 5-ASA use supported by significant body of evidence in UC, not in Crohn’s disease

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Site of Delivery Based on 5-ASA Formulation

• Topical therapy’s ability to reduce inflammation directly linked to ability to reach site of inflammation

20% pancolitis

Oral

30-40% beyond sigmoid

Enema

40-50% rectosigmoid

Suppository

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Second-line Treatment of UC, First Line CD:Role of Steroids

• Budesonide (Enterocort EC®)– FIRST-line therapy for ileo-colonic Crohn’s disease– 9mg daily for 8 weeks– No true maintenance benefit– Fewer side effects than prednisone

• Prednisone– 40-60mg daily for 1-2 weeks or until response– Taper over 5 mg a week until 20 mg a day then 2.5-5 mg a

week taper– Consider initiating steroid-sparing therapy

(immunomodulators and/or anti-TNF therapy) if severe disease or two flares in a year

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Serious Potential Adverse Effects From Prolonged Corticosteroid Therapy

Infection

Hypertension

Diabetes

Osteonecrosis

Osteoporosis

Myopathy

Cataracts

Glaucoma

Psychosis

Adverse effect

Lichtenstein GR et al. ACG 2008;Abstract 14Sandborn WJ. Can J Gastroenterol. 2000;14(suppl C):17C-22C

Use of corticosteroids in IBD should always have an effective exit

strategy.

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Managing Steroid Risk• Crohn’s patients – consider baseline DEXA

– Ca++ absorption may impaired by inflammation1,2

• Supplement with Ca/Vit D while taking steroids– Stable Crohn’s only needs standard therapy2,3

• Check Vit D levels, replace as necessary

• Assess BMD q 1-2 years for steroid exposed

1. Krawitt EL, et al. Gastro 1976;71(2):251-42. Kumari M, et al. Mol Nutr Food Res 2010;54(8):1085-91 3. Siffledeen JS, et al. Clin Gastro Hep 2005:3(2):122-32

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Second Line Therapy CD/UC: Immunomodulators

AZA (Azathioprine), 6-MP (Mercaptopurine), MTX (Methotrexate)

• Commonly used when patients initiate prednisone– Steroid sparing agent for long-term management

• Long-term risks– Bone marrow suppression (Aza/6mp Interaction with

allopurinol)– Infection– Lymphoma– Hepatotoxicity

• Need routine testing for safety

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What are the main side-effects of 6MP/Azathioprine?

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Second Line Therapy CD/UC: Anti-TNF Therapy

• Monoclonal antibody against Tumor Necrosis Factor (TNF)-α

• Transformative therapy for induction and maintenance of remission

• Three currently forms approved for marketing:– Infliximab (Remicade®)– Adalimumab (Humira®)– Certolizumab pegol (Cimzia®)

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CD

AI

Sco

re

150Remission

Secondary Failure

Primary Failure

4 weeks 8 weeks 12 weeks 1 Year

250

200

Defining Primary and Secondary Failure• Primary Failure: an IBD pt that never responded to the biologic.

• Secondary Failure: an IBD pt who initially responds to the biologic but loses response over time.

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Pt with initial response but loss of effect (secondary failure)

Assess for InflammationExclude infection

Inflammation present

Assess Infliximab level/anti-bodies to

Infliximab

Treat underlying causes:

IBS, SBBO, stricture etc...

No inflammation

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Preparation for Anti-TNF Therapy

• Quantiferon Gold or TB skin test (ppd)

• Chest X-ray

• Hepatitis B- HepBsAg, HepBsAb, HepBcoreAb

• Thiopurine methyl-transferase (TPMT) testing if considering AZA in combination– Homozygous recessive 1/300: excess BM

suppression

Clinical Remission Without Corticosteroids at Week 26

SONIC 49

Primary Endpoint

30

44

57

0

20

40

60

80

100

Pro

po

rtio

n o

f P

atie

nts

(%

)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.006 p=0.022

51/170 75/169 96/169

Colombel JF , et al. NEJM 2010; 362: 1882-1395. 49

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Combination or Monotherapy:Pros and Cons

Reasons For Reasons Against

Improved remission rates Safety / Lymphoma

Improved mucosal healing Cost?

Reduced antigenicity Compliance?

Reduced steroid requirement

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Adverse Events Associated with Anti-TNF Treatment

31 pregnant women with IBD receiving infliximab (n = 11), adalimumab (n = 10), or certolizumab (n = 10). Serum concentrations of the drugs were measured at birth in the mother, infant / cord blood

Mahadevan U, et al. Clin Gastroenterol Hepatol 2013;11:286-92.

Concentrations of IFX and ADA, but not CZP, were higher in infants at birth and their cords than in their mothers.

IFX and ADA could be detected in the infants up to 6 months.

Placental transfer of anti-TNF agents in IBD

Cord blood/maternal

ratio

160% 153%

3.9%

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Enhancing Safety of IBD Treatment

• Although some IBD treatments increase risk of complications, some risks can be mitigated

• Close monitoring for infections, rapid treatment

• Regular monitoring of lab studies (CBC, CMP)

• Thiopurine metabolites (6-TGN and 6-MMP)

• Preventative measures

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Preventative Measures for IBD Patients on Immunotherapy

• Annual PAP smear

• Skin cancer screening– No tanning bed– Minimize sun exposure

• Consider PCP prophylaxis with triple therapy– TMP/SMX three times weekly– Dapsone if sulfa allergic

1. Lichtenstein GR et al. Gastroenterology 2006;130(3):935-9

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Immunization of IBD Patients• Consider immunizations early

– Before steroids, AZA, anti-TNF– Unable to use live vaccinations– Other vaccines have reduced titers

• Definition of immunosuppressed state– Steroid treatment 20mg/d > 2 weeks, or within 3

months of stopping– Active AZA/6-MP, MTX, Anti-TNF agents or within

3 months of stopping– Significant protein/calorie malnutrition

1. Sands BE, et al. Inflamm Bowel Dis 2004;10:677-692

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Vaccination RecommendationsInitiate before IMM Currently on IMM Close contacts

ok?

Live attenuated vaccines

MMR Yes: 6 weeks Contraindicated Yes

Zoster Yes: 2-4 weeks Contraindicated* Yes-cover rash

Varicella Yes: 2-4 weeks Contraindicated Yes-cover rash

Inactivated vaccines

Tetanus Yes if none within 10y No change Yes

HPV Yes- 0, 2, 6 months No change Yes

Influenza Yes, if none annually Avoid FluMist Yes, No if FluMist

Pneumococcal Yes, if none prior Booster if >5 years Yes

HepA/B Standard doses 2x dose if titers neg. Yes

Menigococcal If at risk If at risk Yes

1. Wasan S. et al. AJG 2010;10:1231-82. CDC MMWR February 1, 2013 / 62(01);9-19

1. Document disease activity and severity

2. Recommend steroid-sparing therapy after 60 days

3. Assess bone health if steroid-exposed

4. Recommend influenza vaccine

5. Recommend pneumococcal vaccine

6. Document recommendation for cessation of smoking

7. Assess for HBV status pre-anti-TNF

8. Assess for latent TB pre-anti-TNF

www.gastro.org/practice/quality-intiiativesCrohn’s

AGA IBD QI Measures 2012 PQRS

32 yo woman with pan UC x 13 years treated with mesalamines only except for 4 short coursed of steroids for flares. She was referred to the IBD Clinic further evaluation of UC and biopsies of a sigmoid colon mass with low grade dysplasia.

Resection: Well differentiated mucinous adenocarcinoma.

Path: “At least high grade dysplasia arising in a background of inflammation.”

How Many Biopsies are Enough?

How Many Biopsies are Enough?

• Less than 1% total colonic surface area sampled!• To exclude highest grade of dysplasia with1

– 95% confidence – need 64 biopsies– 90% confidence – need 33 biopsies

• Minimum of 32-40 biopsies recommended2,3,4

• 4 biopsies every 10 cm• Patients must understand the limitations of

surveillance and accept the possibility that dysplasia or cancer can still arise

1 Rubin et al., Gastroenterology, 19922 Itzkowitz & Harpaz, Gastroenterology, 20043 Itzkowitz & Present. Inflamm Bowel Dis 2005;11:314–321

4 AGA Technical Review on the Diagnosis and Management of Colorectal Neoplasia in IBD. Gastroenterol 2010;138:746–774

Time to Cancer After Dysplasia DiagnosisTime to Cancer After Dysplasia Diagnosis

Rutter MD, et al. Gastroenterology. 2006;130:1030-1038.

0

Pro

bab

ility

of R

em

ain

ing

Ca

nce

r-F

ree

0.5

0.8

0.9

1.0

2 4 6 8 10

Years

High-gradedysplasiaN=19

0.6

0.7

1 3 5 7 9

Low-gradedysplasiaN=36

N=600Thirty-Year Analysis of a Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis.

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Colorectal Cancer Risk Reduction• Initial screening colonoscopy after 8 years of UC

or Crohn’s colitis1

– Four biopsies every 10cm

• Repeat colonoscopy every 2-3 years, presence of dysplasia suggests need for colectomy

• Annual colonoscopy at diagnosis for colonic IBD plus primary sclerosing cholangitis

• Additional risk factors:– Early age of onset, – Family history of CRC– Severe microscopic inflammation

1. Kornbluth A. et al. AJG 2010;105(3):501-232. Ullman T. et al. IBD 2010;5(4):630-8

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IBD Medication Pearls

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Medication Adherence

• IBD patients exhibit poor compliance with medication regimens1

• Risk factors identified include1

– Multiple medications (>4)– Higher frequency of dosing– Male gender– Single status

• Counseling and dose minimization increase adherence2

1. Kane S. et al. AJG 2001;96:2929–29322. Kripalani S. et al. Arch In Med 2007;167(6):540-50

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Impact of Non-adherence

Adapted from Kane SV et al. Am J Med. 2003;114:39-43.

0

25

50

75

100

40 36 32Adherent (n) =Nonadherent (n) =59 32 28

Adherent—89%

Nonadherent—39%

0 12 24Time (mo)

36

% of PatientsRemaining in Remission

Chance of Maintaining Remission

Chance ofMaintaini

ng Remission

Patients Who Do Not Adhere to Therapy Have a 5-fold Greater Risk of Flare

P=.001

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Medication Adherence

• Once daily 5-ASA may increase adherence1

• Benefits of adherence2

– Reduction in flares– Avoid steroids

• TREAT registry double risk of death with steroids• Multiple courses, low dose not effective regimen

• Chronic 5-ASA confers chemopreventative effect3

• Reduce risk of CRC/dysplasia with 5-ASA use in UC

1. Kane S. Dig Dis 2010;28:478-4822. Kane S. et al. Am J Med 2003;114:39-433. Tang J. et al. Dig Dis Sci 2010;55(6):1696-1703

Infections and mortality in the TREAT registry – 15,000 patient years experience

Infections and mortality in the TREAT registry – 15,000 patient years experience

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Od

ds

Rat

io

*p=0.001; †p<0.0001

IFX AZA6-MPMTX

Steroids

IFXAZA6-MPMTX

Steroids

*

Serious infectionsMortality

Multivariate analysis

†

Lichtenstein et al. Clin Gastroenterol Hepatol. 2006;4:621-30

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Medication Choice in Pregnancy

1. Wolf JL, Inflamm Bowel Dis 2007;13(11):1443-14452. Kwan LY et al. Expert Rev Clin immunol 2010;6(4):643-657

Yes No

Medication FDA class Medication FDA class

5-ASA B Steroids (1st trimester) C

AZA/6-MP D Ciprofloxacin C

Anti-TNF B MTX X

Cyclosporine C

Asacol is class C in pregnancy all other mesalamine derivatives are class B

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Summary IBD• Understanding the diagnosis is important for

effective management.

• Beware of disease mimickers and look for infections

• Remission should be achieved successfully before a transition to maintenance

• Steroids: effective short-term but use should be minimized by steroid-sparing agents

• 5-ASA therapy should be dosed and delivered to the area of disease

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Summary IBD

• Colonoscopic surveillance at 8 years of disease and annually in IBD + PSC

• Appropriate vaccinations• Patient education is important:

Crohn’s and Colitis Foundation of America

• Encourage adherence to effective therapies for IBD patients.– Once daily dosing with mesalamine– Patient education regarding benefits