Role of Histology to Measure Clinical Benefit and Appropriate Timing of Assessment

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1 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

2 Disclosure Site Principal Investigator: Alvine Pharmaceuticals 2

3 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

4 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

5 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

6 Gluten Gluten-Free Diet Green and Cellier. N Engl J Med 2007;357:

7 Marsh Classification 3A: Partial 3B: Subtotal 3C: Total 7

8 Villous Height:Crypt Depth Ratio Ludvigsson JF, et al. Gut 2014; 63:

9 Histology Can Separate Causes of Persistent Symptoms Leffler et al. Clin Gastroenterol Hepatol. 2007;5:

10 Persistent Villous Atrophy and Clinical Outcomes Outcome Hazard Ratio (95% CI) Interpretation Mortality (Aliment Pharmacol Ther 2013;37:332-9.) 1.01 ( ) No increased risk Ischemic Heart Disease (PLOS One 2015;10:e ) Low Birth Weight (Clin Gastroenterol Hepatol 2015; in press) Lymphoproliferative Malignancy (Ann Intern Med 2013;159: ) Hip Fracture (J Clin Endocrinol Metab 2014;99: ) 0.97 ( ) No increased risk 0.98 ( ) No increased risk 2.26 ( ) Increased risk 1.67 ( ) Increased risk 10

11 Prognostic Signifiance of Failing to Heal Lymphoma, fractures Improvement vs. healing? Persistent intraepithelial lymphocytosis? 11

12 Kinetics of Gluten-Induced Damage Author (year) Number of pts Gluten amount Duration Change? Ciclitira (1985) mg/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 : Dennis and Leffler (Ed): Real Life With Celiac Disease. AGA Press

13 Two Week Gluten Challenge Leffler, et al. Gut 2013;62:

14 ALV003: 6-Week 2g Gluten Challenge Gastroenterology. 2014;146:

15 Rate of Healing Rate of Damage 15

16 Variable Rates of Mucosal Healing Author Setting Sample size Follow-up time Persistent Villous Atrophy Collin Finland, years 6-12 months 4% 67% Lee New York, years 79% Lanzini Italy, months 27% Ciacci Italy, years 24% Selby Australia, years 43% Hutchinson UK, years 20% Rubio-Tapia Minnesota, years 5 years 66% 34% Adapted from Alberto Rubio-Tapia 16

17 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

18 Follow-up Biopsy and Persistent Villous Atrophy Follow-up biopsy Lebwohl, et al. Aliment Pharmacol Ther. 2013;37:

19 Within 6 Months-5 Year Window Period Within window Within Window Lebwohl, et al. Aliment Pharmacol Ther. 2013;37:

20 Predictors of Persistent Villous Atrophy Variable Gender Male Female Initial histology Partial VA Subtotal/total VA Educational Attainment <2 years of high school 2 year of high school 3 years of high school College Proportion with persistent VA 45% 42% 30% 42% 52% 45% 43% 35% p value 0.03 < < Aliment Pharmacol Ther. 2014;39:

21 Age and Persistent Villous Atrophy Aliment Pharmacol Ther. 2014;39:

22 Healing Depends On Adherence to gluten-free diet Age Other host or environmental factors? 22

23 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

24 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

25 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