Topics in Inflammatory Bowel Disease
John F. Valentine, MD
University of Utah
Ogden Surgical-Medical Society May 15th, 2013
1
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
2
Changing Epidemiology of UC
Molodecky NA, et al. Gastro 2012 142(1):46-54
4
Changing Epidemiology of UC
Molodecky NA, et al. Gastro 2012 142(1):46-54
5
Changing Epidemiology of CD
Molodecky NA, et al. Gastro 2012 142(1):46-54
6
Changing Epidemiology of CD
Molodecky NA, et al. Gastro 2012 142(1):46-54
7
Age-Specific Incidence of IBD *
Crohn’s Disease
Ulcerative Colitis
10
10
8
8
6
6
4
4
2
2
0
0
0
20
40
60
Age (yrs)
80
0
20
40
60
80
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; 1999:23-29.
Kugathasan et al. J Pediatr 2003;143:525-31.
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%
4% 2%
2%
4% 2%
6%
6%
Caucasian
African Am
Hispanic
87%
Asian
86%
Other
Wisconsin New IBD Diagnosis
Wisconsin Pediatric Population
Kugathasan et al. J Pediatr 2003;143:525-31.
Ca
Afr
His
As
Oth
Current Etiologic Hypothesis for IBD
Microbial
Flora
Lack of Infections
(Hygiene Hypothesis)
Asthma
Bronchitis
Multiple sclerosis
Neuropathy
Myasthenia gravis
Chronic renal disease
Pericarditis
Psoriasis
Celiac disease
Hidradenitis suppurativa
Danese et al. World J Gastroenterol 2005;11:7227–36.
Bernstein et al. Gastroenterol 2005;129:827–836
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
Alterations in
colonic flora
Lack of immune education?
Lack of parasites?
Constructing the Diagnosis of IBD
• Careful process of putting together pieces of a
puzzle to accumulate enough evidence to
diagnose IBD
14
28%
25%
47%
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
17
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
18
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
19
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
20
Systemic Complications and
Malnutrition, growth failure
Colon Cancer
 Cumulative incidence*
 2% by 10 years
 8% by 20 years
 18% by 30 years
*Eaden et al. Gut 2001;48:526-535
Osteoporosis
Oral Lesions
22
Ocular Lesions
23
Cutaneous Lesions
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
25
Components of IBD Diagnosis
• Clinical picture
• Endoscopic information/pathologic specimens
• Radiographic evidence
• Chronic course of symptoms
– Important to fully evaluate cause of diarrhea
26
Useful Laboratory Tests
• Blood work
– CBC, TSH, ESR, CRP
• Serologic markers
– Anti-Saccharomyces cerevisiae Antibody (ASCA), Antineutrophil cytoplasmic antibody (pANCA), anti-OmpC, antiCBir1
• Fecal calprotectin and lactoferrin
– Elevated in inflammation, no increased in IBS
27
Serologic Blood Tests:
May be helpful
Not good enough by themselves
28
Prevalence of IBD-Specific
Antibody Markers
Marker
1Quinton
3Taregan
CD (%)
UC (%)
Non-IBD (%)
pANCA1
15
65
<5
ASCA1
60
5
<5
Omp C2
55
2
<5
CBir13
50
6
8
JF, et al. Gut. 1998;42:788-791. 2Cohavy O, et al. Infect Immun. 2000;68:1542-1548.
SR, et al. Gastroenterology. 2005;128:2020-2028.
Presence Anti-CBir1
Anti-CBir1 Antibody (O.D.)
3
50%
2
1
0
P vs CD:
% Positive
Level
8%
Normal
Controls
n=40
<0.001
<0.001
14%
Inflammatory
Controls
n=21
<0.02
<0.003
Targan SR, et al. Gastroenterology. 2005;128:2020-2028.
6%
UC
CD
n=50
n=100
<0.001
<0.001
n/a
n/a
ASCA in Celiac Sprue
Eur J Gastroenterol & Hep 2006;18:75-78
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.
32
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
34
Endoscopic Features of IBD
Ulcerative colitis
• Edema
• Erythema/Loss of vascularity
• Friability
• Erosions
• Mucopurulent exudate
• Spontaneous bleeding
• Ulceration
35
Endoscopic Features of IBD
Crohn’s Disease
• Patchy edema, erythema
– Discontinuous
• Apthous ulcerations
• Coalescing ulcerations
• Cobblestoning
• Longitudinal “bear claw”
ulcers
36
IBD Treatment Principles
Determine underlying cause/location
of disease
Tailor therapy to patient’s manifestations
Achieve and maintain remission
Monitor for toxicity/complications
37
First-line Treatment of IBD
Role 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
38
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
30-40% beyond sigmoid
Enema
Oral
40-50% rectosigmoid
Suppository
39
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
40
Serious Potential Adverse Effects From
Prolonged Corticosteroid Therapy
Adverse effect
Infection
Hypertension
Diabetes
Osteonecrosis
Osteoporosis
Myopathy
Cataracts
Glaucoma
Psychosis
Lichtenstein GR et al. ACG 2008;Abstract 14
Sandborn WJ. Can J Gastroenterol. 2000;14(suppl C):17C-22C
Use of corticosteroids
in IBD should always
have an effective exit
strategy.
41
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):251-4
2. 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
42
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
43
What are the main side-effects
of 6MP/Azathioprine?
44
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®)
45
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.
CDAI Score
250
Primary Failure
200
Secondary Failure
150
Remission
4 weeks
8 weeks
12 weeks
1 Year
46
Pt with initial response but loss of
effect (secondary failure)
Assess for Inflammation
Exclude infection
Inflammation
present
Assess Infliximab
level/anti-bodies to
Infliximab
No inflammation
Treat underlying
causes:
IBS, SBBO, stricture etc...
47
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
48
SONIC
Clinical Remission
Without Corticosteroids at Week 26
Primary Endpoint
Proportion of Patients (%)
100
p<0.001
80
p=0.006
p=0.022
57
60
44
40
30
20
0
51/170
AZA + placebo
75/169
IFX + placebo
96/169
IFX+ AZA
Colombel JF , et al. NEJM 2010; 362: 1882-1395.
49
49
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
50
Adverse Events Associated with
Anti-TNF Treatment
51
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.
Cord blood/
maternal
ratio
160%
153%
3.9%
IFX and ADA could be detected in the infants up to 6 months.
Mahadevan U, et al. Clin Gastroenterol Hepatol 2013;11:286-92.
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
53
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
54
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
55
Vaccination Recommendations
Initiate 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;10:1231-8
2. CDC MMWR February 1, 2013 / 62(01);9-19
56
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-intiiativesCrohn’s
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.
Path: “At least high grade dysplasia arising in a background of
inflammation.”
Resection: Well differentiated mucinous adenocarcinoma.
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 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 Diagnosis
Probability of Remaining
Cancer-Free
Thirty-Year Analysis of a Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis.
N=600
1.0
High-grade
dysplasia
N=19
0.9
Low-grade
dysplasia
N=36
0.8
0.7
0.6
0.5
0
1
2
3
4
5
6
7
8
9
10
Years
Rutter MD, et al. Gastroenterology. 2006;130:1030-1038.
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):501-23
2. Ullman T. et al. IBD 2010;5(4):630-8 62
IBD Medication Pearls
63
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;96:2929–2932
2. Kripalani S. et al. Arch In Med 2007;167(6):540-50
64
Impact of Non-adherence
Patients Who Do Not Adhere to Therapy Have a 5-fold Greater Risk of Flare
100
Adherent—89%
75
% of Patients
Remaining
in Remission
P=.001
Chance of
Maintaining
Remission
50
Nonadherent—39%
Chance of
Maintaining
Remission
25
0
0
12
24
36
Time (mo)
Adherent (n) = 40
Nonadherent (n) = 59
36
32
32
28
Adapted from Kane SV et al. Am J Med. 2003;114:39-43.
65
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;28:478-482
2. Kane S. et al. Am J Med 2003;114:39-43
3. Tang J. et al. Dig Dis Sci 2010;55(6):1696-1703
66
Infections and mortality in the TREAT registry –
15,000 patient years experience
Multivariate analysis
4.5
Mortality
4
Serious infections
Odds Ratio
3.5
3
2.5
2
*
IFX
1.5
AZA
6-MP
MTX
IFX
AZA
6-MP
MTX
Steroids
†
Steroids
1
0.5
0
*p=0.001; †p<0.0001
Lichtenstein et al. Clin Gastroenterol Hepatol. 2006;4:621-30
Medication Choice in Pregnancy
Yes
Medication
No
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 2007;13(11):1443-1445
2. Kwan LY et al. Expert Rev Clin immunol 2010;6(4):643-657
68
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
69
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
70