con: asymptomatic ulcerative colitis patients on an immunomodulator with persistent moderate mucosal...

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

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

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

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.


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

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 -


%

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

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

con: asymptomatic ulcerative colitis patients on an immunomodulator with persistent moderate mucosal...

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