Role of Histology to Measure
Clinical Benefit and Appropriate
Timing of Assessment
Benjamin Lebwohl MD, MS
Herbert Irving Assistant Professor of Medicine and Epidemiology
Celiac Disease Center
Columbia University
1
Disclosure
• Site Principal Investigator:
– Alvine Pharmaceuticals
2
Reasons to Care About Histology
• Initial histology: confirms the celiac disease
diagnosis
• Follow-up histology: narrows the cause(s) of
persistent symptoms
• Prognostic implications
3
Challenges Relating to Histology
• Invasive
• Need for uniform/expert interpretation
• Uncertainties re: grading multiple specimens
– Most abnormal specimen?
– Average of specimens?
Kinetics of gluten-induced damage
≠
Kinetics of healing
4
Appropriate Methods for Assessing Histology
• Adequate number of specimens (≥4)
• One bite per pass to maximize chances of
well-orientated specimens
• Centralized interpretation
• Quantification of villous height : crypt depth
ratio
5
Gluten
Gluten-Free Diet
Green and Cellier. N Engl J Med 2007;357:1731-1743.
6
Marsh Classification
3A: Partial
3B: Subtotal
3C: Total
7
Villous Height:Crypt Depth Ratio
Ludvigsson JF, et al. Gut 2014; 63:1210-28.
8
Histology Can Separate Causes of
Persistent Symptoms
Leffler et al. Clin Gastroenterol Hepatol. 2007;5:445-50.
9
Persistent Villous Atrophy and Clinical Outcomes
Outcome
Hazard Ratio
(95% CI)
Interpretation
Mortality
1.01 (0.86-1.19)
No increased risk
Ischemic Heart Disease
0.97 (0.73-1.30)
No increased risk
Low Birth Weight
(Clin Gastroenterol Hepatol 2015; in press)
0.98 (0.41-2.39)
No increased risk
Lymphoproliferative Malignancy
2.26 (1.18-4.34)
Increased risk
Hip Fracture
1.67 (1.05-2.66)
Increased risk
(Aliment Pharmacol Ther 2013;37:332-9.)
(PLOS One 2015;10:e0117529.)
(Ann Intern Med 2013;159:169-75.)
(J Clin Endocrinol Metab 2014;99:609-16.)
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Prognostic Signifiance of Failing to Heal
• Lymphoma, fractures
• Improvement vs. healing?
• Persistent intraepithelial lymphocytosis?
11
Kinetics of Gluten-Induced Damage
Author (year)
Number of pts
Gluten amount Duration
Change?
Ciclitira (1985)
10
1.2-2.4mg/day
6 weeks
No
Catassi (2007)
13
10mg/day
90 days
No
Catassi (2007)
13
50mg/day
90 days
Villous
shortening
Leffler (2013)
10
3,000 mg/day
14 days
Villous
shortening
Leffler (2013)
10
7,500 mg/day
14 days
Villous
shortening
Leffler et al. Gut 2013 62:996-1004.
Dennis and Leffler (Ed): Real Life With Celiac Disease. AGA Press 2010.
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Two Week Gluten Challenge
Leffler, et al. Gut 2013;62:996-1004.
13
ALV003: 6-Week 2g Gluten Challenge
Gastroenterology. 2014;146:1649-58.
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Rate of Healing ≠ Rate of Damage
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Variable Rates of Mucosal Healing
Author
Setting
Sample size Follow-up time Persistent
Villous Atrophy
Collin
Finland, 2004
65
8 years
6-12 months
4%
67%
Lee
New York, 2003
39
8.5 years
79%
Lanzini
Italy, 2009
465
16 months
27%
Ciacci
Italy, 2002
390
6.9 years
24%
Selby
Australia,1999
89
8.3 years
43%
Hutchinson
UK, 2010
284
1.6 years
20%
241
2 years
5 years
66%
34%
Rubio-Tapia Minnesota, 2010
Adapted from Alberto Rubio-Tapia
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What is Healing?
• Resolution of villous atrophy (Marsh 3)
• Outcome = VH:CD ≥ 3
– Follow-up histology = Marsh 0 or Marsh 1
• Persistent villous atrophy
– Follow-up histology = Marsh 3
17
Follow-up Biopsy and
Persistent Villous Atrophy
Follow-up biopsy
Lebwohl, et al. Aliment Pharmacol Ther. 2013;37:332-9.
18
Within 6 Months-5 Year Window Period
Within window
Within Window
Lebwohl, et al. Aliment Pharmacol Ther. 2013;37:332-9.
19
Predictors of Persistent Villous Atrophy
Variable
Proportion
with
persistent VA
Gender
Male
Female
45%
42%
Initial histology
Partial VA
Subtotal/total VA
30%
42%
Educational Attainment
<2 years of high school
2 year of high school
3 years of high school
College
52%
45%
43%
35%
p value
0.03
<0.0001
<0.0001
Aliment Pharmacol Ther. 2014;39:488-95.
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Age and Persistent Villous Atrophy
Aliment Pharmacol Ther. 2014;39:488-95.
21
Healing Depends On…
• Adherence to gluten-free diet
• Age
• Other host or environmental factors?
22
Conclusions (1)
• Histology is central to the diagnosis of celiac
disease and has been linked to outcomes
– Lymphoproliferative malignancy
– Fracture
• Villous damage is predictable and
reproducible, and can be assessed during a 14
day gluten challenge
23
Conclusions (2)
• Histology can be used for inclusion criteria
– Confirm initial diagnosis
– Persistent villous atrophy as cause of persistent
symptoms
• Mucosal healing is not universal, nor is the
timing uniform and predictable
• Histologic improvement cannot be counted on to
measure clinical benefit
24
Conclusions (3)
• Histology can be used as a secondary
qualitative endpoint
– Lack of worsening over 2-6 weeks can be used as a
reproducible endpoint
– Stable or non-worsened histology
25