activity and biomarker measures: ulcerative colitis...• icc screen, wk 6, wk 10 site vs. central:...

Activity and Biomarker

Measures: Ulcerative

Colitis

Mark T. Osterman, MD MSCE

Assistant Professor of Medicine

University of Pennsylvania

Outline

• Activity Measures

–Clinical activity

–Endoscopic activity

–Histological activity

• Biomarker Measures

–Serum biomarkers

–Stool biomarkers

Index Variables Score Remis

Truelove-Witts Freq, bleed, T, HR, Hgb, ESR N/A N/A

Powell-Tuck Well-being, pain, freq, consist, T,

bleed, anorexia, N/V, tender, EIM

0-20 0

Rachmilewitz Freq, bleed, PGA, pain, T, EIM, lab 0-29 <4

Seo Bleed, freq, ESR, Hgb, alb 50-250 N/A

PGA Sx relief (Likert) 1-6 1

Lichtiger Freq, noct, bleed, incont, pain,

well-being, tender, α-diarrheal

0-21 <3

Invest Glob Eval Sx score (Likert) 0-4 0

SCCAI Freq, noct, urge, bleed, well-

being, EIM

0-19 N/A

UC Clin Score Freq, bleed, PFA, PGA 0-12 <1

Pt-Def Remis In remission: yes/no Yes/no Yes

Purely Clinical Indices

Patient-Defined Remission • Survey

–56 outpatients

–Are you in remission: yes / no

• 7-point Likert score

–Has your condition improved /

worsened since last visit

• Remission defined as absence of rectal

bleeding and modified Baron Score 0-2:

sens 86% / spec 76%

Higgins PD et al, Gut 2005

SCCAI Bowel frequency (day): 1-3

4-6

7-9

>9

0

1

2

3

Bowel frequency (night): 0

1-3

4-6

0

1

2

Urgency: None

Hurry

Immediately

Incontinence

0

1

2

3

Bleeding: None

Trace

Occasionally frank

Usually frank

0

1

2

3

Well-being: Very well

Slightly below par

Poor

Very poor

Terrible

0

1

2

3

4

EIM: Uveitis

Pyoderma gangrenosum

Erythema nodosum

Arthropathy

1

1

1

1

Remission

• <2 correlates with PDR

Response

• >2-pt decrease correlates

with patient-defined

significant improvement

Relapse

• >5 highly predictive per

Seo Index

Walmsley RS et al, Gut 1998

Jowett SL et al, Scand J Gastroenterol 2003

Higgins PD et al, Gut 2005

Partial Mayo Score Stool frequency: Normal

1-2 / day above normal

3-4 / day above normal

>5 / day above normal

0

1

2

3

Bleeding: None

Streaks of blood in <50% of BMs

Obvious blood in >50% of BMs

Blood alone

0

1

2

3

PGA: Normal (no symptoms)

Mild disease

Moderate disease

Severe disease

0

1

2

3

Schroeder KW et al, N Engl J Med 1987

Rutgeerts P et al, N Engl J Med 2005

Lewis JD et al, Gastroenterology 2008

Remission

• <2 with no individual subscore >1

Response

• Decrease of >3 pts and >30% from baseline

+ Rectal bleeding decrease >1 pt or absolute subscore 0-1

Partial Mayo Score

Lewis JD et al, Inflamm Bowel Dis 2008

Remission Response

6-pt PMS

Remission

• <1

Response

• Decrease of >2 pts from baseline

How Many Days of Data • Issues: Sx recall, day-to-day variability of Sx

• Recall: 6-pt PMS (n=28, 61% inactive)

– Questionnaires: baseline (all), 1 of next 7 d

– No difference in ΔPMS from baseline for 1-2

vs. 3-5 vs. 6-8 d groups

• Variability: 6-pt PMS (n=31, 68% inactive)

– 7d electronic diary, only 58% completed all

– Mean max ΔPMS higher with active

– ρ = 0.82, 0.86, 0.91 for avg of all 7d vs. last 1,

avg of last 2, avg of last 3 d

Henao MP et al, Inflamm Bowel Dis 2015

The Problem with Clinical Indices “It is evident that placebos have a high degree of

therapeutic effectiveness…being produced in 35.2 +

2.2% of cases.” ̶ Henry Knowles Beecher, 1955

Beecher HK, JAMA 1955

Hrobjartsson A et al, N Engl J Med 2001

Barsky AJ et al, JAMA 2002

PBO Type Pts Trials Pooled Estimate

Binary 3099 21 RR 0.97 (0.88-1.07)

Continuous 2363 24 SMD -0.20 (-0.37 to -0.04)

Nocebo phenomenon

• Reporting of AEs to PBO

• 25% freely report AEs to PBO but 71% report AEs

when actively asked about them

Placebo Response in UC Pooled remission rate 13% (range 0-40%)

Su C et al, Gastroenterology 2007

Predictors OR (95% CI)

Study location (Europe vs. N. America) 2.9 (1.5-5.4)

F/u time (per 1 wk) 2.0 (1.2-3.1)

# F/u visits (per 1 visit) 2.2 (1.3-3.7)

Disease duration (per 1 yr) 1.4 (1.1-1.7)

Baseline UCDAI (per 1-pt) 0.1 (0.04-0.49)

Strict outcome (DAI 0 vs. <3) Rate 5% vs. 17%

Rectal bleeding subscore (per 1-pt) 0.04 (<0.001-0.25)

Endoscopic mucosal healing 0.4 (0.2-0.7)

Pooled response rate 28% (range 0-67%)

Other Predictors OR (95% CI)

Publication yr (per 1 yr) 1.04 (1.002-1.1)

↓ UCDAI >3 vs. >2 Rate 30% vs. 52%

No bleeding

Bleeding on light touch

Spontaneous bleeding

0

1

2

Endoscopic Indices Powell-Tuck

Baron Score Normal

Hypovascular, granular, hyperemia



0

1

2

3

Modified Baron Score

Normal

Hypovascular, granular, hyperemia



Clear ulceration, denuded mucosa

0

1

2

3

4

Vascular pattern: Normal

Patchy obliteration

Obliteration

0

1

2

Bleeding: None

Mucosal

Luminal mild

Luminal moderate / severe

0

1

2

3

Erosions / ulcers: None

Erosions

Superficial ulcer

Deep ulcer

0

1

2

3

Normal

Mild: erythema, hypovascular, mild friability

Moderate: marked erythema, avascular, friability, erosions

Severe: spontaneous bleeding, ulceration

0

1

2

3

Endoscopic Indices Mayo Endoscopic Score: 0-3

UC Endoscopic Index of Severity (UCEIS): 0-8

Schroeder KW et al, N Engl J Med 1987

Travis SP et al, Gut 2012

Mayo Endoscopic Score

Vascular pattern: Normal

Partially visible

Complete loss

0

1

2

Granularity: None

Fine

Coarse

0

1

2

Ulceration: None

Erosions / pinpoint ulceration

Numerous shallow ulcers w/ mucopus

Deep excavated ulcerations

Diffusely ulceration w/ >30% involvement

0

1

2

3

4

Bleeding / friability: Normal

Friable, bleeding to touch


0

1

2

Endoscopic Indices UC Colonoscopic Index of Severity (UCCIS): 0-162

Score = 3.1 x (vascular pattern sum) + 3.6 x (granularity sum) +

3.5 x (ulceration sum) + 2.5 x (bleeding/friability sum)

Thia KT et al, Inflamm Bowel Dis 2011

Samuel S et al, Clin Gastroenterol Hepatol 2013

Flex Sig vs. Colonoscopy

Endoscopy Status # Discordant r

Active (n=239)

Mayo >2

Mayo >1

UCEIS

9

1

N/A

0.84

0.96

0.92

Mucosal Healing (n=139)

Mayo <1

Mayo = 0

7

1

0.85

0.95

Colombel J-F et al, Gastroenterology 2016

• Analysis of 239 / 331 videos from

EUCALYPTUS (Etrolizumab phase 2 RCT)

• Only 4.5-7.5% had worse disease proximally

The Problem With Endoscopy Descriptor Intrarater κ

(2 pairs per rater)

Interrater κ

(21 per rater)

Vascular pattern 0.51 0.34

Erythema 0.37 0.25

Mucosal surface 0.37 0.26

Edema 0.33 0.23

Mucopus 0.38 0.32

Bleeding 0.51 0.29

Incidental friability 0.37 0.30

Contact friability 0.33 0.23

Erosions / ulcers 0.56 0.36

Erosion / ulcer extent 0.51 0.32

Travis SP et al, Gut 2012

Central Reading of Endoscopy

• Analysis of high-dose mesalamine tab (800 mg) RCT

• Significance not reached (UCDAI endo = 0) with site

read vs. central read due to PBO rate 21% vs. 14%

• 7 central readers evaluated

• ICC screen, wk 6, wk 10 site vs. central: 0.11, 0.31, 0.44

• Site reader scores generally higher than central reader

• Central: unbiased, expert, no interobserver variability

Feagan BG et al, Gastroenterology 2013

Central UCDAI Mod Baron UCEIS VAS

Intra ICC 0.89 0.88 0.89 0.91

Inter ICC 0.79 0.78 0.83 0.78

Stricter Outcome Measures

• Corticosteroid-free remission

• Rectal bleeding

– ACT / GEMINI 1: response rectal bleeding

decrease >1 pt or absolute subscore 0-1

– Tofacitinib: rectal bleeding subscore = 0

• Endoscopic mucosal healing / remission

– Even stricter but yet to be incorporated as

primary outcome

• ?Histological healing

Why Histology as Outcome

• Logical as UC is mucosal disease

• Histological healing is true mucosal

healing

• Up to 24-90% of endoscopically normal

may have microscopic inflammation

• May be better predictor of relapse, CS

use, hospitalization than endoscopy

Osterman MT, J Clin Gastroenterol 2013

Bryant RV et al, Gut 2016

Riley SA et al, Gut 1991

Zenlea T et al, Am J Gastroenterol 2016

Semiquant:

0 = none

1 = mild

2 = mod

3 = severe

Crypt abscesses 0-3

PMNs in lamina propria 0-3

Surface epithelial integrity 0-3

Mucin depletion 0-3

Round cells in lamina propria 0-3

Crypt architecture irregularity 0-3

PMNs in epithelium: None

<25% crypts

25-75% crypts

>75% crypts

0

1

2

3

PMNs in lamina propria: Mild increase

Mod increase

Marked increase

4

5

6

Erosion or ulceration 7

Riley SA et al, Gut 1991

Feagan BG et al, N Engl J Med 2005

Riley Index

Modified Riley Score

Geboes Index

Geboes K et al, Gut 2000

0.0

0.1

0.2

0.3

Architectural changes: None

Mild

Mild or mod diffuse or multifocal

Severe diffuse or multifocal

1.0

1.1

1.2

1.3

Chronic inflammatory infiltrate: No increase

Mild or equivocal increase

Moderate increase

Marked increase

2.0 (2A for Eos, 2B for PMNs)

2.1

2.2

2.3

Lamina propria Eos and PMNs: No increase

Mild or equivocal increase

Moderate increase

Marked increase

3.0

3.1

3.2

3.3

Epithelial PMNs: None

<5% crypts involved

<50% crypts involved

>50% crypts involved

4.0

4.1

4.2

4.3

Crypt destruction: None

Probable – local excess of PMNs in part of crypt

Probable – marked attenuation

Unequivocal crypt destruction

5.0

5.1

5.2

5.3

5.4

Erosion or ulceration: No erosion, ulceration, granulation tissue

Recovering epithelium + adjacent inflammation

Probable erosion – focally stripped

Unequivocal erosion

Ulcer or granulation tissue

Proposed histologic healing

Predictive of clinical relapse

Bressenot A et al, Gut 2015

Index / Components Intrarater κ Interrater α

Riley

PMNs in lamina propria

Crypt abscesses

Mucin depletion

Surface epithelial integrity

Round cells in lamina propria

Crypt architecture irregularity

0.75-0.89

0.67-1.00

0.40-0.57

0.73-0.93

0.40-0.73

0.53-0.71

0.85

0.67

0.73

0.75

0.67

0.64

Geboes

Architectural changes

Chronic inflammatory infiltrate

Lamina propria Eos

Lamina propria PMNs

Epithelial PMNs

Crypt destruction

Erosion or ulceration

0.58-0.70

0.47-0.73

0.46-0.56

0.66-0.93

0.68-0.70

0.75-0.84

0.85-0.92

0.65

0.73

0.40

0.82

0.74

0.63

0.82

The Problem With Histology

Basal Plasmacytosis

• Dense infiltration of plasma cells in

lower third of mucosa

• Predictive of relapse in quiescent UC

– Modified Baron 0-1: HR 4.5 (1.7-11.9)

– Mayo = 0: OR 5.13 (1.32-19.99)

Goldman H, Pathology of GI Tract 1998

Bitton A et al, Gastroenterology 2001

Bessissow T et al, Am J Gastroenterol 2012

MARQUEE Study: CCFA CRA

• Prevalence of endoscopic (Mayo, UCEIS, UCCIS)

and histological disease (Riley, basal plasmacy)

in clinically quiescent UC

• Correlate endoscopic and histological scores

• Determine risk of relapse by endoscopic and

histological score to see which most predictive

• Basis for possible RCT of therapy escalation to

biologic for patients in clinical remission on

optimized 5-ASA but with active mucosal

disease

Serum Biomarkers • 451 pediatric patients

– PUCAI: sens / spec for cutoffs CRP 71-86% / 77-91%,

ESR 67-81% / 69-79%

– Beattie endo: r CRP 0.55, ESR 0.41

– 36% of mod-severe had CRP < 5 mg/L but useful as

f/u indicator if elevated when active

• 722 endoscopies in 552 patients

– Mayo: r CRP 0.50, ESR 0.40

– Modified Baron: r CRP 0.52, ESR 0.43

• Limited data on predicting clinical relapse

• CRP short ½-life 19h, ESR affected by Hct

• CRP: mesenteric adipocytes (CD, severe UC) Turner D et al, J Crohns Colitis 2011

Yoon JY et al, Dig Dis Sci 2014

Sands BE Gastroenterology 2015

Stool Biomarkers

• Lactoferrin

– Iron-binding protein in PMN granules and

serum, secreted by mucosal membranes

• Calprotectin

– Calcium- and zinc-binding protein

– 60% of cytosolic proteins in PMNs

• Fecal immunochemical test (FIT)

– Quantification of hemoglobin concentration

Kane SV et al, Am J Gastroenterol 2003

Roseth AG et al, Scand J Gastroenterol 1992

Levi Z et al, Ann Intern Med 2007

Stool vs. Serum: Endo Activity

Marker / Disease Pooled

Sens (%)

Pooled

Spec (%)

CRP: IBD Range 5-10 mg/dL

49 (34-64) 92 (72-98)

Fecal Calprotectin Range 6-280 µg/g

IBD

UC

88 (84-90)

88 (84-92)

73 (66-79)

79 (68-87)

Fecal Lactoferrin: IBD Range 0.07-7.25 µg/mL

82 (73-88) 79 (62-89)

Mosli MH et al, Am J Gastroenterol 2015

Meta-analysis: 19 studies, 2499 patients

FC Level: Endo Activity

FC cutoff

(µg/g)

Pooled

Sens (%)

Pooled

Spec (%)

50 92 (90-94) 60 (52-67)

100 84 (80-88) 66 (59-73)

250 80 (76-84) 82 (77-86)

Lin J-F et al, Inflamm Bowel Dis 2014

Meta-analysis: 8 studies, 744 patients

FC Level: Outcomes in RCT FC cutoff (mg/kg) Sens (%) Spec (%) Sum (%)

Clinical Remission

50

100

150

200

250

43

54

68

70

71

91

83

79

73

71

134

137

147

143

142

Endoscopic Remission

50

100

150

200

250

52

67

79

82

82

88

81

75

70

67

140

147

153

151

149

Mucosal Healing

50

100

150

200

250

29

44

54

57

58

92

89

85

79

71

121

133

139

136

134

Sandborn WJ et al, Gastroenterology 2016

FC: Predicting Relapse Study Details N FC Cutoff

(µg/g)

Sens

(%)

Spec

(%)

Mao Meta-analysis

5 studies, 12 mo

318 120-164 77 71

Yamamoto 5-ASA maint

12 mo

80 170 76 76

De Vos IFX maint

↑ as early as 3 mo

87 300

2 in 1 mo

58

62

93

100

Molander IFX induction

12 mo

26

60

139 72

all

80

All

De Vos IFX ind, FC wk 2

Wk 10 endo remis

53 <50

80% ↓

54 67

FC: Histological Inflammation Study Details N Findings

Guardiola Prospective

Clin and endo remis

PMS, Mayo endo

Histo: epithelial PMN

59 Active: FC 278 (136-

696) vs. 68 (30-172)

FC 155: sens 78,

spec 71

Theede Active and inactive

PMS, Mayo / UCEIS

Histo: mod Harpaz

120 FC by histo 0-3: 237,

1398, 1080, 1530

FC 171: sens 75,

spec 90

Zittan Active and inactive

Mayo, UC/colonic CD

Histo: Geboes / basal

plasmacytosis

27 FC 100: r Geboes

0.77, basal plas 0.80

FC 100: sens 100,

spec 77

The Problem With FC • Correlates with disease activity / extent

– Severely active short vs. mildly active long segment

• Associated with lifestyle / diet

– Higher with higher age, obesity, physical inactivity

– Lower with fiber and vegetable consumption

• Much variability during bowel prep

– Can go from very high to very low so best to get

sample before or 2-5 days after

• ?Varies with amount of blood / mucus in BMs

• Affected by assay

– 2 ELISA, 1 enz fluoroassay, 2 quant immunochrom:

r 0.65, 0.65, 0.69, 0.70, 0.75, 0.77, 0.82, 0.85, 0.91, 0.93 Kolho K-L et al, J Pediatr Gastroenterol Nutr 2012

Labaere D et al, United Eur Gastroenterol J 2014

Kawashima K et al, BMC Gastroenterology 2016

Poullis A et al, Cancer Epidemiol Biomarkers Prev 2004

FC: Intra-Individual Variability Study Details Within-BM Within-day Btwn-day

Lasson 18 pt, 287 sample

Q-BM x 2d

2 sample / ea BM

Mild-mod UC

ICC 0.79

(0.48-0.90)

Med CV 0.52

↑ with ↑ time

btwn BM,

looser BMs

1st on d1 vs.

1st on d2:

med CV 0.41

Calafat 18 pt, 56 sample

1st, 1-3 more BM

in 1d

Severe UC

Med CV 0.40

FC highest

in 1st, 2nd BM

Kristensten 50 pt, 150 sample

BM AM, PM, AM

2 sample / 1 BM

Mixed IBD activity

Mean CV

0.03

UC: κ 0.69

CD: κ 0.84

UC: κ 0.68

CD: κ 0.84

Du 45 pt, 312 sample

3 sample / 1st, 1-2

more BM in 1d

50% inactive IBD

Clin sig

var 8-25%

Lowest:

1st, FC 250

Clin sig var

13-26%

Lowest: FC

250

DEAR

Red circles denote primary outcome

compared in the RCT

Randomized

Randomized

Measure FC

FC<50 mcg/g FC>=50 mcg/g

Week 6

Baseline

Measure FC

Week 12

Week 48

Remission

F/U to 48 weeks

NOT taking mesalamine

Measure FC Measure FC

Randomized

Measure FC

Taking 2.4g

MMX-M

Measure FC

<50 mcg/g >=50 mcg/g <50 mcg/g >=50 mcg/g

Measure FC

Taking mesalamine*

Switch to 2.4g

MMX-M

<50 mcg/g >=50 mcg/g <50 mcg/g >=50 mcg/g

Measure FC Measure FC Measure FC Measure FC Measure FC Measure FC

Group 1

Group 3 Group 4 Group 2

* 3gm/day or less of mesalamine other than MMX

mesalamine (MMX-M)

<50 mcg/g

2b

>=50 mcg/g

2a

2.4g

MMX-M

2aSD

4.8g

MMX-M

2aID

2.4g MMX-M

3SD

4.8g

MMX-M

4.8g

MMX-M

2.4g

MMX-M

4.8g

MMX-M

No MMX-

M

2.4g

MMX-M

4.8g

MMX-M

4.8g MMX-M

3ID

No MMX-M

4SD

2.4g MMX-M

4ID

Osterman MT et al, Clin Gastroenterol Hepatol 2014

n=58 n=61

ITT

PP

Osterman MT et al, Clin Gastroenterol Hepatol 2014

Stool Trek: The Next Generation

Vinding KK et al, Inflamm Bowel Dis 2016

• Dip 3-5X in BM, shake, settle 10 min, 2 drops supernat at S

• Lat flow device (LFD): nitrocellulose memb, gold-labeled

α-FC (T) and control (C) Abs, incubate 10 min, take pic

• Ratio of T:C lines staining intensity determines FC

• Dots: green (FC <200), yellow (200-600), red (>600)

Fecal Immunochemical Test (FIT)

Nakarai A, Am J Gastroenterol 2013

Takashima S et al, Am J Gastroenterol 2015

Nakarai A et al, World J Gastroenterol 2016

Outcome N / Endo Sens (%) Spec (%)

Endo (Hgb <100 ng/mL)

Mayo 0

Mayo 0-1

Mayo 2-3

152 / 310

92

60

87

71

87

60

MH: FIT (100) vs. FC (250)

Mayo 0

Mayo 0-1

92 / 105

95 vs. 82

81 vs. 70

62 vs. 62

68 vs. 66

Clinical relapse (n=194)

• FIT Hgb <100: HR 0.17 (0.10-0.28)

• Clinical remission >1y and neg FIT: HR 0.11 (0.04-0.23)

activity and biomarker measures: ulcerative colitis...• icc screen, wk 6, wk 10 site vs. central:...

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