1. No category

Con: Asymptomatic Ulcerative Colitis
Patients on an Immunomodulator
with Persistent Moderate Mucosal
Inflammation Should Not Add A
Biologic or Switch to a Biologic
William Tremaine, MD
Disclosure
• Companies have licensed the Mayo Score for
UC and I have received $12,000 personal
compensation from Mayo Clinic’s royalty
sharing policy.
Regarding Disclosures:
Editorial Comments
Dollar amounts matter
2009 Nominee
Outcome
Tim Geithner
Unpaid
Taxes
$34,000
Tom Daschle
$128,000
Withdrew
Confirmed
Case History
• 32 year-old
• UC for 16 years
• Steroid responsive
• Maintenance
• mesalamine 1.2g/d
• mercaptopurine 1.5 mg/kg
• Asymptomatic
• Surveillance colonoscopy
• Moderate activity
• Some normal areas
Case Continued
• Colon biopsies
• Patchy minimally active chronic colitis, some
areas of inactive colitis, some normal
biopsies. No dysplasia
• CrP = 9.0
normal < 8.0
Case: Management Options
1. Status quo
2. Check 6-TGN, 6 MMP levels
• Adjust 6-mercaptopurine dose
3. Add an anti-TNFα
Case: Management Options
1. Status quo
2. Check 6-TGN, 6 MMP levels
• Adjust 6-mercaptopurine dose
3. Add an anti-TNFα
Alternative Title: Mucosal Healing
May be Like a Fedora
Mucosal Healing May be Like a Fedora
Mucosal
Healing
Fedora
FDA
Marketers
Popular with
Hipsters
Movie Stars
No
Easy to Spot
Yes
No
Really
Important
No
Don’t Make Clinical Decisions Based on
Mucosal Healing Because:
• The definition of mucosal healing is fuzzy
• Treatment based on mucosal healing can be
unnecessary and harmful
• In the long run, mucosal healing isn’t worth
much
• Histologic remission is what’s important
• Ultimately, population-based studies not
treatment trials will prove what is important
What is Mucosal Healing in UC?
• Mayo UC Score of 0 or 1
Mayo Score: Ulcerative Colitis
Stool Frequency
0-3
Rectal Bleeding
0-3
Endoscopy
0-3
Physician’s Global Assessment
0-3
Schroeder KW Tremaine WJ NEJM 1987
Mayo Score: Endoscopy Score
• Normal mucosa
0
• Mild erythema, mild friability
1
• Marked erythema, friability erosions 2
• Spontaneous bleedings, ulcers
3
Schroeder KW Tremaine WJ NEJM 1987
Mayo Score: Dec 2, 2013
Don’t Make Clinical Decisions Based on
Mucosal Healing Because:
• The definition of mucosal healing is fuzzy
• Treatment based on mucosal healing can be
unnecessary and harmful
• In the long run, mucosal healing isn’t worth
much
• Histologic remission is what’s important
• Ultimately, population-based studies not
treatment trials will prove what is important
A Mayo Score of 1 is not as good
as a Mayo Score of 0
Fuzzy Math
0
Mucosal Healing with Infliximab
(IFX): Long-term outcome in UC
80
• ACT-1 & ACT-2
• 484 IFX
• 244 Placebo
• Mayo score: 0,1,2,3
• 8 wk
70
% Symptomatic Remission
P< 0.0001
60
50
Mayo Score
0
1
2
3
40
30
• Conclusion: Mucosal healing 20
at 8wk correlates with
10
improved clinical outcome
0
IFX
PLA
IFX
PLA
Wk30 Wk30 Wk54 WK54
Colombel JF Gastroenterology 2011;141:1194-1201
Don’t Make Clinical Decisions Based on
Mucosal Healing Because:
• The definition of mucosal healing is fuzzy
• Treatment based on mucosal healing can be
unnecessary and harmful
• In the long run, mucosal healing isn’t worth
much
• Histologic remission is what’s important
• Ultimately, population-based studies not
treatment trials will prove what is important
Overtreatment Based on Mucosal
Healing: Number Needed to Harm
• 2 Multicenter German studies
• Mesalazine vs Placebo for UC
• 1027 patients
• Remission
• Symptomatic
• Endoscopic
• Histologic
• Post hoc analysis
Wolff S et al. Inflam Bowel Dis 2013;19:2611-15
Overtreatment Based on Mucosal
Healing: Number Needed to Harm
• Endoscopic mucosal disease activity
• False positive 13.7%
• NNH = 1 / 0.137 = 7.3
• For asymptomatic UC patients without mucosal
healing, additional treatment isn’t needed in
about one out of 7 patients.
Wolff S et al. Inflam Bowel Dis 2013;19:2611-15
Don’t Make Clinical Decisions Based on
Mucosal Healing Because:
• The definition of mucosal healing is fuzzy
• Treatment based on mucosal healing can be
unnecessary and harmful
• In the long run, mucosal healing isn’t worth
much
• Histologic remission is what’s important
• Ultimately, population-based studies not
treatment trials will prove what is important
1 Yr Mucosal Healing: 5 YR Follow-up
• IBSEN
• 354 UC pt
%
• Colonoscopy
• 1 yr & 5 yr after diagnosis
• Results
• Predictors of healing at 1
year
• > 12 yr education
• Extensive disease
10
9
8
7
6
5
4
3
2
1
0
P=0.02
MH +
MH -
Colectomy by 5
years
Frøslie E, et al Gastroenterology 2007; 133:412-22
Colectomy in UC: Reasons
• Medically refractory disease
• Fear of cancer
• Adverse effects from medical therapy
• Physician recommendation
• Unable to afford medical therapy
Colectomy in UC: Reasons
• Medically refractory disease
• Fear of cancer
• Adverse effects from medical therapy
• Physician recommendation
• Unable to afford medications
?
1 Yr Mucosal Healing: 5 YR Follow-up
60
NS
NS
NS
%
50
IBSEN
354 pt
40
30
MH +
MH -
20
10
0
Remission
No Complaints Mucosal Healing at 5 yr
Frøslie E, et al Gastroenterology 2007; 133:412-22
Don’t Make Clinical Decisions Based on
Mucosal Healing Because:
• The definition of mucosal healing is fuzzy
• Treatment based on mucosal healing can be
unnecessary and harmful
• In the long run, mucosal healing isn’t worth
much
• Histologic remission is what’s important
• Ultimately, population-based studies not
treatment trials will prove what is important
Histologic Remission is Better Than
Endoscopic Remission
Relapse Rate at 12 Months
• 82 adult UC pts
90
%
• Endoscopy
• Normal, or erythema
80
• Acute histologic activity
• Acute inflam cells
• Crypt abscesses
• Mucin depletion
50
• Relapse rate at 12 mo
P<0.005
70
60
P<0.02
P<0.02
40
30
20
Yes
10
No
0
Acute
Inflam
Crypt
Mucin
Abscess Depletion
Riley SA et al Gut 1991; 32:174-178
Mayo Score vs Histology
• Beth Israel, Boston
• 103 pt, UC surveillance
• 708 colonic segments
• Mayo Score
• Biopsies
• Geboes Score
• >3.1 Moderate inflam
% 100
90
80
70
60
50
40
30
20
10
0
Geboes < 3.1
Geboes ≥ 3.1
Mayo Mayo
0
≥1
Rosenberg L et al Clin Gastro Hep 2013; 11:991-6
Abnormal Histology is Like a Positive CrP
• Mesalazine trials
100
%
90
• 380 pt with active UC
80
• Clinical Activity Index
70
Pre-treatment:
• Endoscopy Score
60
Endoscopy +
Histology +
• Outcome:
• Higher remission rate if
no histologic
inflammation before
treatment
Wolff S et al. Inflam Bowel Dis
2013;19:2611-15
50
40
Endoscopy +
Histology -
30
20
10
0
Clinical Remission
Histology is a better measure of remission
than white light endoscopy
But hi-tech endoscopy may be just as good
as histology
Laser Endomicroscopy for Prediction of
Relapse in UC
Clinical Remission
• Padova, Italy
•
•
•
•
100
19 UC pt, 19 Controls
90
80
Remission
% 70
60
Clinical
50
Mayo Endos Score 40
30
I.V. Fluorescein
20
10
Confocal probe
0
• Fluorescence
• Crypt Diameter
Inflammatory
Activity
Low
Medium
High
0
2
4
6
8 10 12 months
Buda A et al ScienceDirect 4 Sept 2013
Endoscopic mucosal healing without
histologic healing may not protect from
cancer
Ulcerative Colitis: Mucosal inflammation
is a risk factor for Colorectal Neoplasia
Mean Histology Inflammation Score
• Mt Sinai, NYC
• 408 pt
• Endoscopic surveillance
with biopsies
• Histologic inflammation
graded
HR=2.8
(95% CI = 1.2-6.2
4
3.5
3
2.5
2
1.5
1
0.5
0
Any
neoplaisa
Advanced
neoplasia
Bansal R Gastroenterology 2007; 133: 1099-1105
Don’t Make Clinical Decisions Based on
Mucosal Healing Because:
• The definition of mucosal healing is fuzzy
• Treatment based on mucosal healing can be
unnecessary and harmful
• In the long run, mucosal healing isn’t worth
much
• Histologic remission is what’s important
• Ultimately, population-based studies not
treatment trials will prove what is important
Babies Born on 3 Consecutive Nights
Wednesday
Thursday
Friday
Are these sequences equally likely?
Babies Born on 3 Consecutive Nights
Wednesday
Thursday
Friday
The Law of Small Numbers
Kahneman D Thinking Fast and Slow 2011: 115
M
M
M
M
M
M
Litmus Test for a Disease Modifying Agent
Does mucosal healing
change the natural
history of ulcerative
colitis?
Colectomy Rates in Ulcerative Colitis
Pre-Biologic Era
Population-based Cohorts
Anti-TNFα Era
Clinical trials + Referral
Center Studies +
Population-based Cohorts
29%
10-36%
Filippi J et al Current Drug Targets 2011; 12:1440-7
Case: Management Options
1. Status quo
2. Add an anti-TNFα
Shared Decision
Making
Conclusions
• Mucosal healing is an imperfect endpoint
convenient for clinical trials and marketing
• Histologic healing may be more important
• Population-based studies, not treatment trials,
will ultimately determine best management
endpoints