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
2009 Nominee Unpaid Taxes
Outcome
Tim Geithner $34,000 Confirmed
Tom Daschle $128,000 Withdrew
Dollar amounts matter
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 quo2. Check 6-TGN, 6 MMP levels
• Adjust 6-mercaptopurine dose3. Add an anti-TNFα
Case: Management Options
1. Status quo2. Check 6-TGN, 6 MMP levels
• Adjust 6-mercaptopurine dose3. Add an anti-TNFα
Alternative Title: Mucosal Healing May be Like a Fedora
Mucosal Healing
Fedora
FDAMarketers
Popular with HipstersMovie Stars
No Easy to Spot Yes
No Really Important
No
Mucosal Healing May be Like a Fedora
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
• ACT-1 & ACT-2• 484 IFX• 244 Placebo
• Mayo score: 0,1,2,3• 8 wk
• Conclusion: Mucosal healing at 8wk correlates with improved clinical outcome
Colombel JF Gastroenterology 2011;141:1194-1201
IFX Wk30
PLA Wk30
IFX Wk54
PLA WK54
0
10
20
30
40
50
60
70
80
0123
% Symptomatic Remission
P< 0.0001
Mayo Score
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
Colectomy by 5 years
0
1
2
3
4
5
6
7
8
9
10
MH +
MH -
%
Frøslie E, et al Gastroenterology 2007; 133:412-22
P=0.02
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
Remission No Complaints Mucosal Healing0
10
20
30
40
50
60
MH +MH -
Frøslie E, et al Gastroenterology 2007; 133:412-22
NS NS NS
%
IBSEN
354 pt
at 5 yr
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
• 82 adult UC pts
• Endoscopy• Normal, or erythema
• Acute histologic activity• Acute inflam cells• Crypt abscesses• Mucin depletion
• Relapse rate at 12 moAcu
te In
flam
Crypt
Abs
cess
Muc
in Dep
letion
0102030405060708090
Yes
No
P<0.005
P<0.02 P<0.02
Relapse Rate at 12 Months
%
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
May
o 0
May
o ≥
10
102030405060708090
100
Geboes < 3.1
Geboes ≥ 3.1
%
Rosenberg L et al Clin Gastro Hep 2013; 11:991-6
Abnormal Histology is Like a Positive CrP
• Mesalazine trials
• 380 pt with active UC
• Clinical Activity Index
• Endoscopy Score
• Outcome:• Higher remission rate if
no histologic inflammation before treatment
Clinical Re-mission
0
10
20
30
40
50
60
70
80
90
100
Endoscopy + Histology +
Endoscopy + Histology -
Wolff S et al. Inflam Bowel Dis 2013;19:2611-15
%
Pre-treatment:
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
• Padova, Italy
• 19 UC pt, 19 Controls
• Remission
Clinical
Mayo Endos Score
• I.V. Fluorescein
• Confocal probe• Fluorescence• Crypt Diameter
0 2 4 6 8 100
102030405060708090
100
Low
Medium
High
12 months
Clinical Remission
%
Buda A et al ScienceDirect 4 Sept 2013
Inflammatory
Activity
Endoscopic mucosal healing without histologic healing may not protect from cancer
Ulcerative Colitis: Mucosal inflammation is a risk factor for Colorectal Neoplasia
Any neoplaisa Advanced neoplasia0
0.5
1
1.5
2
2.5
3
3.5
4• Mt Sinai, NYC
• 408 pt
• Endoscopic surveillance with biopsies
• Histologic inflammation graded
Mean Histology Inflammation Score
HR=2.8(95% CI = 1.2-6.2
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 Anti-TNFα Era
Population-based Cohorts 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 quo2. 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
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