Topics in Inflammatory Bowel Disease

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Topics in Inflammatory Bowel Disease
John F. Valentine, MD University 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
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Age-Specific Incidence of IBD
Ulcerative Colitis
Crohns Disease
10
10
Incidence / 100,000
0
0
0
80
0
80
Age (yrs)
Age (yrs)
Per 100,000 population Reprinted from Lashner
BA. In Stein SH and Rood RP, eds. Inflammatory
Bowel Disease A Guide for Patients and Their
Families. Lippincott-Raven Publishers 199923-29.
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Kugathasan et al. J Pediatr 2003143525-31.
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Epidemiology of IBD
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
0.5
2
2
2
4
4
6
6
87
86
Wisconsin New IBD Diagnosis
Wisconsin Pediatric Population
Kugathasan et al. J Pediatr 2003143525-31.
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Current Etiologic Hypothesis for IBD
Microbial Flora
Lack of Infections (Hygiene Hypothesis)
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Asthma Bronchitis Multiple sclerosis Neuropathy
Myasthenia gravis Chronic renal
disease Pericarditis Psoriasis Celiac
disease Hidradenitis suppurativa
Danese et al. World J Gastroenterol
200511722736. Bernstein et al. Gastroenterol
2005129827836
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Environmental Triggers of IBD

• Antibiotics
• Diet
• Low fiber
• Refined sugars
• NSAID use
• Stress
• Infections
• Improved hygiene?
• Low Vitamin D
• Smoking
• Protective against UC
• Risk factor for CD

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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

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25
47
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IBD Symptomatology

• Crohns Disease

• Ulcerative Colitis

• 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

• 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

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Systemic Complications and
Malnutrition, growth failure
Osteoporosis
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Oral Lesions
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Ocular Lesions
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Cutaneous Lesions
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Physical Findings in IBD

• Crohns 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
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Prevalence of IBD-Specific Antibody Markers
Marker CD () UC () Non-IBD () pANCA1 15 65 lt5 A
SCA1 60 5 lt5 Omp C2 55 2 lt5 CBir13 50 6 8
1Quinton JF, et al. Gut. 199842788-791.
2Cohavy O, et al. Infect Immun.
2000681542-1548. 3Taregan SR, et al.
Gastroenterology. 20051282020-2028.
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Presence Anti-CBir1
3
2
Anti-CBir1 Antibody (O.D.)
1
0
Normal Controls
Inflammatory Controls
UC
CD
n40 n21 n50 n100
P vs CD
Positive lt0.001 lt0.02 lt0.001 n/a
Level lt0.001
lt0.003 lt0.001 n/a
Targan SR, et al. Gastroenterology.
20051282020-2028.
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ASCA in Celiac Sprue
Eur J Gastroenterol Hep 20061875-78
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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 200857 205210.
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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 IBDCrohns 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

Tailor therapy to patients manifestations
Achieve and maintain remission
Monitor for toxicity/complications
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First-line Treatment of IBDRole of 5-ASA

• Topical Therapy

• Oral Therapy

• Rectal administration
• Mesalamine enema 4gm/60ml
• Mesalamine 1mg/suppository
• Preferred therapy for proctitis
• Synergy obtained by combining with 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 Crohns disease

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Site of Delivery Based on 5-ASA Formulation

• Topical therapys 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 CDRole
of Steroids

• Budesonide (Enterocort EC)
• FIRST-line therapy for ileo-colonic Crohns
  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
Adverse effect

• Infection
• Hypertension
• Diabetes
• Osteonecrosis
• Osteoporosis
• Myopathy
• Cataracts
• Glaucoma
• Psychosis

Use of corticosteroids in IBD should always have
an effective exit strategy.
Lichtenstein GR et al. ACG 2008Abstract
14 Sandborn WJ. Can J Gastroenterol.
200014(suppl C)17C-22C
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Managing Steroid Risk

• Crohns patients consider baseline DEXA
• Ca absorption may impaired by inflammation1,2
• Supplement with Ca/Vit D while taking steroids
• Stable Crohns 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 197671(2)251-4
2. Kumari M, et al. Mol Nutr Food Res
   201054(8)1085-91
3. Siffledeen JS, et al. Clin Gastro Hep
   20053(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)-a
• 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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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.

250
Primary Failure
CDAI Score
200
Secondary Failure
150
Remission
4 weeks
8 weeks
12 weeks
1 Year
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Pt with initial response but loss of effect
(secondary failure)
Assess for Inflammation Exclude infection
Inflammation present
No inflammation
Treat underlying causes IBS, SBBO, stricture
etc...
Assess Infliximab level/anti-bodies to Infliximab
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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

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Clinical Remission Without Corticosteroids at
Week 26
SONIC
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Primary Endpoint
100
plt0.001
80
p0.006
p0.022
57
60
Proportion of Patients ()
44
40
30
20
51/170
75/169
96/169
0
AZA placebo
IFX placebo
IFX AZA
Colombel JF , et al. NEJM 2010 362 1882-1395.
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Combination or MonotherapyPros 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
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Placental transfer of anti-TNF agents in IBD
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

• 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.

Cord blood/ maternal ratio
160
153
3.9
Mahadevan U, et al. Clin Gastroenterol Hepatol
201311286-92.
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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
   2006130(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 gt 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
200410677-692
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Vaccination Recommendations
Initiate before IMM Currently on IMM Close contacts ok?
Live attenuated vaccines Live attenuated vaccines Live attenuated vaccines 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 Inactivated vaccines Inactivated vaccines 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 gt5 years Yes
HepA/B Standard doses 2x dose if titers neg. Yes
Menigococcal If at risk If at risk Yes

• Wasan S. et al. AJG 2010101231-8
• 2. CDC MMWR February 1, 2013 / 62(01)9-19

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AGA IBD QI Measures 2012 PQRS
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-intiiativesCrohns

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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.
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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, 1992 2
Itzkowitz Harpaz, Gastroenterology, 2004 3
Itzkowitz Present. Inflamm Bowel Dis
200511314321
4 AGA Technical Review on the Diagnosis and
Management of Colorectal Neoplasia in IBD.
Gastroenterol 2010138746774
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Time to Cancer After Dysplasia Diagnosis
Thirty-Year Analysis of a Colonoscopic
Surveillance Program for Neoplasia in Ulcerative
Colitis.
N600
1.0
High-gradedysplasia N19
0.9
Low-gradedysplasia N36
0.8
Probability of RemainingCancer-Free
0.7
0.6
0.5
0
2
4
6
8
10
1
3
5
7
9
Years
Rutter MD, et al. Gastroenterology.
20061301030-1038.
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Colorectal Cancer Risk Reduction

• Initial screening colonoscopy after 8 years of UC
  or Crohns 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 2010105(3)501-23
2. Ullman T. et al. IBD 20105(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 (gt4)
• Higher frequency of dosing
• Male gender
• Single status
• Counseling and dose minimization increase
  adherence2

1. Kane S. et al. AJG 20019629292932
2. Kripalani S. et al. Arch In Med
   2007167(6)540-50

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Impact of Non-adherence
Patients Who Do Not Adhere to Therapy Have a
5-fold Greater Risk of Flare
100
Adherent89
Chance of Maintaining Remission
75
P.001
of PatientsRemaining in Remission
50
Nonadherent39
Chance of Maintaining Remission
25
0
0
12
24
36
Time (mo)
40
36
32
Adherent (n)
Nonadherent (n)
59
32
28
Adapted from Kane SV et al. Am J Med.
200311439-43.
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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 201028478-482
2. Kane S. et al. Am J Med 200311439-43
3. Tang J. et al. Dig Dis Sci 201055(6)1696-1703

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Infections and mortality in the TREAT registry
15,000 patient years experience
Multivariate analysis
Serious infections
Mortality

IFX

AZA 6-MP MTX
AZA 6-MP MTX
IFX
Steroids
Steroids
p0.001 plt0.0001
Lichtenstein et al. Clin Gastroenterol Hepatol.
20064621-30
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Medication Choice in Pregnancy
Yes Yes No 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

1. Wolf JL, Inflamm Bowel Dis 200713(11)1443-1445
   
2. Kwan LY et al. Expert Rev Clin immunol
   20106(4)643-657

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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
• Crohns and Colitis Foundation of America
• Encourage adherence to effective therapies for
  IBD patients.
• Once daily dosing with mesalamine
• Patient education regarding benefits