Nut, Corn, and Popcorn Consumption and the Incidence of

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.)
10
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.
12
Two Week Gluten Challenge
Leffler, et al. Gut 2013;62:996-1004.
13
ALV003: 6-Week 2g Gluten Challenge
Gastroenterology. 2014;146:1649-58.
14
Rate of Healing ≠ Rate of Damage
15
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
16
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.
20
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