Transcript IBD 101 Education Day – April 20th 2013

Archana Verma , MD
Iowa Digestive Disease Center
*
What is Inflammatory Bowel Disease ?
It is a chronic inflammatory condition of the intestine
characterized by remission and relapses caused by dysregulated
mucosal immune response to antigens of the normal commensal
microbiota that reside within the intestine of a genetically
susceptible host.
Major subtypes are :
 Crohn’s disease
 Ulcerative colitis.
 Indeterminate ( 5% of cases)
Factors leading to IBD
IBD
How common is IBD ?
 There are 1 million people with IBD in the US, equally split
between UC and Crohn’s disease.
 The prevalence is 175 -200 per 100,000 people.
 The incidence/ new cases per year is 3-14 per 100,000 people
 About 1/3rd patients develop IBD in their teens and twenties ,
and there is again a bump in the sixties and seventies
 Women are slightly more prone to IBD
Some famous people with IBD
Mike Mcready
David Garrard
President Eisenhower
Ben Morrison
Shannon Doherty
Mary Ann Mobley
Factors Leading to IBD – Genetic
Genetic Susceptibility to IBD
 More than 173 genes have been
identified using the GWAS –
 The first gene identified was the
NOD2/CARD15 gene
o 3 independent mutations are
associated with it
o One increases risk of Crohn’s by
3 fold , 2 would result in a 1040 fold increase
 Genes in autophagy / self
preservation ( ATG 16 L1) and IRGAM
and TH 17 pathway ( IL 23 R) also
cause IBD
 We have candidates
but no causal gene
 No role of genetic
testing in diagnosis
What does genetic susceptibility really mean ?
 3-7 % chance of a child developing
IBD one parent has it
 Increases to 1 in 3 if both parents
have it
 10-25% that if you have IBD a first
degree relative also has it
 Genetic risk is more in Crohn’s than
in UC
 If your child has
IBD, there is high
degree of
concordance of
disease type,
behavior and
location
 Genetic
anticipation
Factors Leading to IBD - Microbiota
IBD occurs most commonly in areas of maximum bacterial
flora
In animal studies , sterile gut do not develop IBD
Decrease in Faecalbacterium prausnitzii in ileum increases
risk of surgery
 Initial presentation of IBD may be precipitated by
intestinal bacterial infection like E.coli or Campylobacter
infection
Role of Intestinal Flora
 Bacteriodes decrease adherence and pathogen invasion
 Lactobacilli secrete SCFA which promote mucin secretion / IgA
 Help development of microvilli circulation
 Control release of cytokines
 Long term antibiotics disrupt flora and precipitate IBD
 Probiotics like Saccharomyces boulardii may reduce risk of
relapse
 Probiotics like lactobacillus may be helpful in UC
 Early studies of usefulness of fecal transplant in UC
Pathophysiology of IBD
Factors Leading to IBD - Immunology
Immunology of IBD
Immunology – Therapeutic Implications
Target
Mechanism
Therapeutic
Antigen
Eliminate pathogenic
bacterial stain
Antibiotic ( Rifaximin)/ Probiotic(VSL-3 )
and worms ( Trichuris suis)
T-cell / APC
Interaction
Manipulate T-Cell
Activation
Anti-CD3 ( visilizumab), CTA4lg(abatacept), azathioprine/6-MP
Cytokines/
Membrane
Receptors
Decrease proinflammatory / Increase
anti-inflammatory
cytokines
Anti- TNF ( infliximab, adalimumab,
certoluzimab pegol, golimumab), Anti-IL
12 ( ustekinamab ) , Anti – Il 23, Anti-IFN
γ, Anti-IL 6R ( Tocilizumab) , IL-10 (LLactis )
Immunology – Therapeutic Implications
Target
Mechanism
Therapeutic
Cellular
recruitment
Block T-cell or
endothelial cell
addressins
Anti-α4β7 ( Natalizumab,
Vedolizumab,CCX28-8), Anti MADCAM1,
PF-000547659, Abaticept
Inflammatory
mediators
Block Inflammatory
Signalling
Protease inhibitors, mesalamines, JAK-3
inhibitors ( Tofacitinib)
Barrier Function Increase Epithelial
and Repair
barriers and restitution
Epidermal growth factors , Stem cell
therapy
* No single symptom, physical finding
or test result can diagnose IBD
* The diagnosis is based on findings
obtained from history, physical
examination , laboratory ,
endoscopic , histologic and
radiologic studies
*
A doctor who cannot take a good history
and a patient who cannot give one are in
danger of giving and receiving bad
treatment. ~Author Unknown
Signs and symptoms of IBD
Crohn’s Disease
Ulcerative Colitis
 Insidious onset
 Acute onset
 Abdominal pain and diarrhea – usually
non - bloody
 Overt rectal bleeding and urgency
 Fever, weight loss
 Abdominal pain and diarrhea
 Perianal disease with rectal abcess and  Fever with abdominal distension
fistula
suggests severe disease
 Obstructive symptoms
 Extraintestinal manifestations
 Extraintestinal manifestations
r
i
t
i
s
.
j
p
g
Extraintestinal Manifestations
Organs
Manifestation
Eyes
Episcleritis , Uveitis , Iritis
Oral
Aphthous Ulcer
Dermatological
Erythema nodosum , pyoderma
gangrenosum, Sweet syndrome
Hepatobiliary
Primary sclerosing cholangitis,
Cholnagiocarcinoma , Gallstones
Musculoskeletal
Enterpathic arthropathy, Sacrolitis,
Ankylosing spondylitis,
Osteopenia/osteoporosis
Hematologic
Thromboembolic disease
Colonoscopy is the mainstay in IBD diagnosis
Crohn’s Disease
Ulcerative Colitis
Effect from mouth to anus – ileum
involved
Limited to colon
Patchy involvement with skip lesions
Confluent inflammation from the anal
verge extending proximally
Deep serpeginous ulcers
Diffuse superficial ulcerations
Transmural inflammation
Mucosal inflammation
Extent of disease
Crohn’s Disease
Frequency
Ulcerative Colitis
Frequency
 Ileocolonic
35 %
 Proctitis
5-10%
 Small bowel
only
28%
 Distal
44%
 Colon only
32%
 Left sided
36%
 Gastroduodenal
1-4%
 Pancolitis
18%
 Perianal
18%
Testing for IBD
Laboratory
Testing
Inflammation
CBC/CRP/CMP
Fecal lactoferrin
Stool Calprotectin
Malabsorption
B-12
Iron studies
Fat soluble vitamins
Rule out infection
C.Diff
Cultures
O/P
CMV
Imaging
Stage Disease
SBFT
CT/MR enterography
Capsule endoscopy
Rule out complication
CT scan
MRI pelvis
EUS
Respond intelligently even to
unintelligent treatment – Lao Tzu
*
Goals of IBD Therapy
Goal
Clinical Parameters
Outcomes
Response
Improved Symptoms
Improved quality of life
Remission
No symptoms
Normal labs
Decreased
hospitalization
Deep remission
Normal endoscopy
Mucosal healing
Avoidance of surgery
Minimal / no disability
Sustained
Minimize adverse effects of therapy
Step-up versus Top-Down Therapy
Step up
AZA / MTX
Steroids
Budesonide
5 ASA /Antibiotics
Increasing drug side effects
Anti - TNF
Increasing efficacy
Anti - TNF
AZA/MTX
Combination
Steroids
Top Down
Maintenance of Clinical remission in Crohn’s
at week 54 ACCENT II
FDA AdComm 030403
31
Mucosal healing in UC
 Rutters showed patients with UC
with endoscopic healing/
histological remission had lower
risk of CRC and approached risk of
general population.
 Inception cohort- moderate to
severe UC
o Decreased rates of
hospitalization 25% vs. 49%
o Less use of immunosuppressive
5% vs. 26%
o Lower rates of colectomy 3% vs.
18%
 Colombel showed ACTII post hoc
analysis showed week 8 mucosal
healing associated with decrease
risk of colectomy and need for
corticosteroids at week 30 and 54
 Decreases risk of
colon cancer
 Decreases need of
corticosteroids
 Decreases risk of
colectomy
Step-up versus Top-Down Therapy
Step up
AZA / MTX
Steroids
Budesonide
5 ASA /Antibiotics
Increasing drug side effects
Anti - TNF
Increasing efficacy
Anti - TNF
AZA/MTX
Combination
Steroids
Top Down
Common IBD Drugs– adverse effects
Drug
Side effect
Pregnancy
Category
5 ASA
Interstitial nephritis
B ( except
sulfasalazine
causes
reversible
sterility in men)
Antibiotic
Ciprofloxacin
Flagyl
Tendonitis
Peripheral neuropathy
C
B
Steroids
Moon facies, buffalo hump , acne, sleep disturbance and mood
disorders, osteoporosis, aseptic necrosis, myopathy, diabetes,
weight gain, adrenal suppression, hypokalemia , opportunistic
infections, cataract, glaucoma, growth retardation
/C
Thiopurines
Hepatitis, Bone marrow suppression, Pancreatitis,
Increased risk of lymphoma, infections and non-melanoma skin
cancer
C
Common IBD Drugs– adverse effects
Drug
Side effect
Pregnancy
Category
Methotrexate
Mucositis , nausea, pancytopenia, pneumonitis, hepatitis and
hepatic fibrosis
X
Cyclosporine
Nephrotoxicity, opportunistic infections, seizures if cholesterol <
100 or hypomagnesaemia
C
Natalizumab
PML - Risk
 0 % if JC virus negative,
 If JC virus positive and drug for < 2 years and no prior
immunosuppressant risk is 1 in 2000
 If JC virus positive and no prior immunosuppressant duration
of therapy > 2 years, risk 1 in 250
 If JC virus positive and duration of therapy > 2 years and
patient has been immunosuppressed , risk is in 1 in a 100
C
Anti-TNF therapy – adverse effects
 Allergic reaction early : 3.8% -16.5% , delayed
reaction:1-7 %
 Infections serious :3-9.9%, all : up to 25 % , twice as
likely to develop especially on steroids with HR 1.98 and
opioids 1.57
 Hepatosplenic lymphoma – only 36 cases in IBD patients,
90% in people < 35
 Combination risk of Concomtant thiopurine and anti TNF
1:22,000 for all ages
 Risk increases if age is < 35
 Risk of thiopurine monotherapy 1:7,204
 Risk of combination 1:3,534
 Non-Hodgkins lymphoma 6.1 cases per 10,000 vs
baseline of 1.9 cases
 Increased risk of non melenoma skin cancer (
Adalumimab 4.83)
 Pregnancy category B
Benefits
outweigh risks
for the right
patient
Therapy for IBD – Pros and Cons
Conventional stepup and accelerated
step-up
Early Top-Down
Risks
Lower Efficacy
Higher risk of infection / mortality with
repeated courses of steroids
High surgical risk
High risk of disease progression
Risks
Higher Cost, but cost effective
Side effect of drugs
Benefits
Benefits
Lower cost
Higher efficacy
Lower disease related complication
Higher rates of mucosal healing
Decreased rates of surgery / hospitalization
Improvement in growth/bone formation
Who should use top-down therapy
Crohn’s Disease
Ulcerative Colitis
 Diagnosis made before age 40
 Severe initial presentation
 Ileal disease
 Need for corticosteroids at
presentation
 Need for corticosteroids early
 Deep ulcerations on endoscopy
 Perianal disease
 Smoker
 Elevated CRP with low albumin and
persistent stooling in spite of 3 days
of IV steroids
High-risk patients => benefits of top-down therapy outweigh risks
Can I be tapered off combination therapy ?
 If in remission and tapered of inflixamab, risk of relapse is 44%
 Risk factors for relapse are
o
o
o
o
o
o
o
Male gender
Absence of previous surgery
Use of steroids within 6-12 months of infliximab withdrawal
WBC >6000
Fecal calprotectin > 300 mg
CDEIS > 0
Infliximab trough level > 2 mg / l
 If less than 2 of these factors exists, risk < 15% and may consider tapering
The doctor of the future will give no
medicine but will interest his patients
in the care of the human frame, in diet
and in the cause and prevention of
disease. ~Thomas Edison
*
Cancer Risk and IBD
Risk factors
 Extent of disease
 Duration of disease
 Family history of colon cancer
 Primary sclerosing cholangitis
Screening is recommended
after 8 years , after every
1-2 years
 Increased activity of disease
 Backwash ileitis
 Younger age of diagnosis
 Risk increases after 8-10 years of pancolitis by 2% at 10 years
8% at 20 years and 18% at 30 years
 In left side of colitis risk increases after 15 years
Preventive Guidelines for patients with IBD
Item
Comment
Bone density
 DEXA scan at diagnosis and repeat every 2 years
 Yearly DEXA scan if on corticosteroids or osteopenia with
active disease
 Check Vitamin D once a year
 Calcium supplementation
Cancer screening
 Yearly complete dermatological examination. Always use
sunscreen.
 Cervical cancer screening with 6 monthly PAP smear and
HPV testing if on AZA
 Breast cancer screening with yearly mammograms after
40/50
 CRC surveillance discussed earlier
Mal absorption
 Especially true in Crohn’s patients
 Check Vitamin B12, Fe studies and folate once a year
 Check fat soluble vitamins- Vitamin A and D once a year
Vaccination Guidelines for patients with IBD
Item
Comment
General
 Vaccinate as for general population
 Except live vaccines in immunosuppressed
At diagnosis
 Varicella vaccine if no history of chicken pox and
negative serologies
 Hepatitis B vaccine if negative serology
 Pneumococcal vaccine
 Inactivated influenza vaccine
 Human papilloma vaccine
Annually
 Influenza vaccine
Booster
 Pneumococcal vaccine in 5 years
Discretionary
 Travel vaccines – Hepatitis A
 Meningococcal vaccine
Family Members
 Usual vaccination except Rotavirus and live influenza
Pregnancy and IBD
PIANO registry
 1115 women entered who are on immunosupressants or biological agents
 896 women have delivered
 No increased risk of congenital anomalies
 Increased risk of spontaneous abortions – odds ratio is 2.56
 Increased risk of pre-term labor – odds ratio is 1.83
 After adjustment for pre-term birth, there was no increased risk of infection in
children at 4 , 9 and 12 months
“This is not the end, it is not even the
beginning of the end. But it is perhaps the
end of the beginning.” – Winston Churchill
*
Advances in medical therapy
Drug
Trial
Outcomes
Vedoluzimab
In moderate to severe UC who have
failed anti TNF, steroids and
immunosupressives
At 6 weeks
CR increased by 21.7%
Clinical remission by 11.5%
Mucosal healing by 40.9 %
Vedoluzimab
In responders every 8 week infusion of
300 mg
Durable mucosal healing in
42.6%
Vedoluzimab
Moderate to severe Crohn’s disease
failed anti-TNF, immunomodulator
and steroids
At 10 weeks higher
clinical remission, 0.6 %
versus 12.1 %, decrease
in CDAI 39.2% versus
22.3%
Adalimumab
Ultra-2 Trial
In moderate to severe UC
Remission of 18.5% by 8th
week
40.8% at 52 weeks
Trials through the Iowa IBD center
Study
Patient Population
Drug
CONTRIBUTE
UC
Age 18-75
Mild to moderate UC flare UCDAI>4 and <10 and
Mayo score >1 despite being on oral 5ASA/
mesalamine
Oral Budesonide MMX 9mg
(Uceris)
Pfizer
A7281009 UC
study
Moderate to severe UC
Mayo endoscopy score >/= 2
Failed/ intolerant to at least 1 conventional
therapy: immunosuppressant ,Mesalamine,
steroids/ anti TNF
PF-00547659
A fully human IgG2 anti
human MadCAM
monoclonal antibody
Pfizer
A7281006
Crohn’s
Age 18-75
Active moderate to severe Crohn's disease( CDAI
220-450) despite stable doses of mesalamine and
immunosuppressant's
Ulcerations on endoscopy
PF-00547659
A fully human IgG2 anti
human MadCAM
monoclonal antibody
UNITI 2
Crohn’s
Age >18
Crohn's disease for 3 months with CRP>3 and fecal
calprotectin >250
Ulcerations on colonoscopy
Intolerant or failed steroids/immunosuppressive
No previous antiTNF exposure
A fully human IgG1K
monoclonal Ab to IL12/23
p40 which binds to
IL12/23
The doctor is often more to be feared
than the disease. ~French Proverb
*