Post on 07-Feb-2018
Stephen B. Hanauer, MD, FACG
DiseaseAssessment in Crohn’s Disease
and Ulcerative ColitisStephen B. Hanauer, MD, FACG
Professor of MedicineNorthwestern University Feinberg School of Medicine
Learning Objective
• Describe the clinical evaluation of IBD, including blood and stool biomarkers, endoscopic and radiographic imaging
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
AGA Clinical Pathways for IBD (combined)
Assess inflammatory status
Assess symptoms/signs• Diarrhea• Bleeding• Urgency/Tenesmus• Abdominal pain• Localized tenderness• Weight loss• Joint pain• Cutaneous signs
Perform clinical lab testing• CBC• CRP• CMP• Fecal calprotectin• ESR
Select imaging modalities (if indicated)
Perform endoscopy
Identify symptoms without inflammatory
markers
Identify symptoms with inflammatory
markers*
Perform CTE or MRE
Consider whether treatment decisions to be based on inflammatory markers vs confirming with colonoscopy. This may depend on whether there was historically good correlation between the biomarker selected and colonoscpy in the specific patient.CMP, complete metabolic panel; CTE, computed tomography enterography; ESR, erythrocyte sedimentation rate; MRE, magnetic resonance enterography.
Sandbrn WJ. Gastroenterology 2014;147:702-5 Dassopoulos T, et al. Gastroenterology. 2015;149:238-45.
Challenges to Current Clinical Endpoints in IBD
• Symptoms may be non-specific• Do not correlate to endoscopic findings of “healing” in clinical trials• Do not delineate extent of disease• Patients live with active disease!
• Symptoms may lag behind the development of active inflammation• Endoscopy has not been routinely included in goals• Endoscopy is invasive and expensive
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
Mucosal Healing as a Surrogate for Longer Term Outcomes
Associated with:
• Better quality of life
• Fewer hospitalizations
• Fewer surgeries
• Longer time to clinical relapse
• Reduction in dysplasia/cancer (UC)
Sands, B. ACG-FDA Workshop 2012
Risk of Colectomy in Severe UC Patients with Severe Ulcerations
• 85 consecutive patients with active UC
• Severe endoscopic lesions (SELs):
• Deep ulcers
• Well-like ulcers
• Large mucosal erosions
• Extensive loss of mucosal layer with or without residual mucosal areas
Carbonnel F, et al. Dig Dis Sci. 1994;39:1550-1557.
93%
26%
No SEL
SEL
Colectomy 43/46 pts
Colectomy 9/39 pts
OR= 41 (95% CI 10.5-164)
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
Rubin DT et al. Presented at: DDW 2011. Chicago, IL; May 2011. Abstract Su1182.
Many Asymptomatic UC Patients Have ActiveInflammation at Colonoscopy
N=82 patients, 120 colonoscopies.Analysis represents mean values, per patient.
Grade of Endoscopic
Inflammation
80
60
40
20
00 1 2 3
68%
17% 12
% 2%
Endoscopic Inflammation
Grade of HistologicInflammation
100
60
40
20
00 1 2 3
11%
78%
7% 4%
Histologic Inflammation
80
89%
31%
Pat
ien
ts (
%)
Pat
ien
ts (
%)
70.862.5
27.3
18.2
0
20
40
60
80
100
Pat
ient
s (%
)
SES 0 SES 1–8
Remission off steroids Remission off steroids and anti-TNF
Mucosal Healing After Therapy Predicts Improved Outcomes in Crohn’s Disease
SES=Simple Endoscopic Score.Baert F et al. Gastroenterology. 2010;138:463-468.
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
14.1 14
38.4
0
20
40
60
80
100
6 8
313143
62
0
20
40
60
80
100
Pat
ient
s (%
)
No severe endoscopic lesions Severe endoscopic lesions
Pat
ient
s un
derg
oing
M
AS
(%
)
Complete Partial NoneDegree of mucosal healing
1 3 8Year of follow-up
Mucosal Healing Reduces Risk for Colectomy in Crohn’s Disease
Risk of Colectomy According to Severe Endoscopic Lesions1
MAS=major abdominal surgery; SEL=severe endoscopic lesions (extensive and deep ulcerations on index colonoscopy)1. Allez M et al. Am J Gastroenterol. 2002;97:947-953.2. Schnitzler F et al. Inflamm Bowel Dis. 2009;15:1295-1301.
Degree of Mucosal Healing andRisk of Major Abdominal Surgery2
Histological healing, the ultimate therapeutic goal in UC?
Histological remission and healing UC
Reduced risk of surgery/ hospitalization
Reduced risk of relapse
More likely symptom-free
57.9% of patients with no significant
histological inflammation
were symptom-free, versus 16.7%
of patients with inflammation
(Isaacs 2010)
Higher relapse rate in patients with presence versus absence of acute
inflammatory cell infiltrate (52% versus 25%, P=0.02) and with presence versus
absence of crypt abscesses (78% versus 27%, P<0.005)
Histologic remission associated with lower rate of
hospitalization (OR 0.27; 95% CI, 0.07-0.95; P=0.048)
For every unit increase in
cumulative mean histologic
inflammation score, there was a 3-fold increase in
advanced neoplasia
(Gupta et al 2007) Long-term clinical, endoscopic, and
histologic remissionMore favorable disease
coursePeyrin-Biroulet L, Bressenot A, Kampman W, et al. Clin Gastroenterol
Hepatol. 2014;12:929-934.
Reduced risk of colorectal cancer
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
Histological Normalization in UC Is Associated with Lower Clinical Relapse Rates
Christensen B, et al. Presented at DDW; May 17, 2015. Abstract 592.
25% patients had CR in median 1.3 yearsCR-free Survival: 91% at 1 year, 68% at 3 years 53% at 5 years
Complete Histological Remission
Histological Quiescence
Histological Inflammation
Defining Histological Remission
• No standardized definition• “Healing” vs. “Remission”• Multiple histological scoring systems
• Residual inflammation with architectural distortionNormalization• Absence of neutrophils is key
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
Limitations of Histological Assessments
• Lack of Validation or Standardization• Histological Reporting• Scoring• Definition of Remission
• Sampling Error & Transmural Assessments• Invasive/Expensive Procedures (scope and pathologic interpretation)
• Need for surrogate (e.g. super low calprotectin?)
• Will immunological and/or microbiological remission be required?
Is A Treat-to-Target Approach Feasible in IBD?
SymptomsQoL
LabsCRP
Calprotectin?
Mucosal healingHospitalizations
Surgery
Biologic(Deep remission)
Histologic remissionDisease modification
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
Working Definitions of Deep Remission
Deep remission implies resolution of inflammatory symptoms and objective signs of inflammation
No bowel damage or disability
Existing bowel damage or disability
• Resolution of symptoms
• Resolution of objective measures of inflammation (endoscopy, imaging, biomarkers)
• Improvement of symptoms
• Resolution of objective measures of inflammation (endoscopy, imaging, biomarkers)
Colombel JF et al. Dig Dis. 2012;30 Suppl 3:107-111.
Potential Role of Serologic and Genetic Testing
• Diagnosing Disease• Predicting Development of Disease• Predicting Course of Disease
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
ECCO Consensus on CD: Definitions and diagnosis
• Genetic factors and serological markers of immune reactivity, considered alone or in combination, have been so far unhelpful in predicting the future course of CD at diagnosis.
• No evidence-based recommendation can be made to implement the routine clinical use of molecular markers (genetic, serologic) for the classification of UC patients
Journal of Crohn's and Colitis (2010) 4, 7–27 Journal of Crohn’s and Colitis (2012) 6,965-90
Ideal Biomarkers
• Easy to measure• Noninvasive• Reproducible• Inexpensive
• Responsive to change• High PPV and NPV
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
Overview of Biomarkers in IBDBiomarker Description Clinical Considerations
Calprotecin1,2 Granulocyte cytosolic proteinStable in feces for days
• Elevated in NSAID enteropathy, cancer, celiac disease, microscopic colitis
• Sensitivity and specificity vary greatly based on cutoff value Lactoferrin1,2 Neutrophil granule protein
Stable in feces
C-reactive protein (CRP)1
Acute-phase proteinProduced in liver under influence of IL-6/TNF-α/IL-1βShort half-life (~19 hours)
• May be more elevated in CD than in UC• Elevated in other conditions (eg, infections,
obesity, CAD)• May be low in ileal disease or those with low
BMI, even in active disease• Minimal or no CRP response in 10%–40%• May be influenced by genetic polymorphisms
Erythrocyte sedimentation rate (ESR)1
Rate RBCs settle in 1 hour• Influenced by anemia, gender, pregnancy• Peaks less rapidly than CRP• Resolves more slowly than CRP
CAD=coronary artery disease; CRP=C-reactive protein; IL=interleukin; RBC=red blood cell1. Montalto M et al. Eur Rev Med Pharmacol Sci. 2013;17:1569-1582.2. Vermeire S et al Gut.2006;55:426-431.
Biomarkers Correlate Well With Endoscopic But Not Clinical Activity Indices
+ indicates significant correlation coefficients (P<.05); NS, nonsignicant correlations.When stratified by extent, correlation coefficients were highest for colonic disease
IL-6 Calprotectin Lactoferrin CDAI SES-CD
hsCRP + + + NS +
IL-6 + + NS +
Calprotectin + + +
Lactoferrin + +
CDAI NS
CDAI=Crohn’s disease activity index; CRP=C-reactive protein; IL=interleukin; SES-CD=Simple Endoscopic Score-Crohn’s Disease.Jones JL et al. Clin Gastroenterol Hepatol. 2008;6:1218-1224.
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
Fecal Calprotectin Correlates With Disease Activity
• UC patients in remission on infliximab 5 mg/kg q8w (n=113)
• Fecal calprotectin measured monthly for 1 year• Deep remission = normal endoscopy at baseline and week 52 +
Mayo score <3• 27% were in deep remission• Fecal calprotectin levels highly correlate with disease
activity• Fecal calprotectin <50 mg/kg at all time points in patients in
deep remission• Median fecal calprotectin 477 mg/kg in patients with a flare• Two consecutive levels >300 mg/kg predicted a flare
De Vos M et al. ECCO 2012. Abstract no. OP 07.
A normal FC after induction therapy predicts sustained
clinical remission*
Fecal Calprotectin Predicts Outcome After Induction Therapy With TNF Antagonists
• Patients• 60 IBD patients
(CD, n=34; UC, n=26)
• Treated with TNF antagonists
• Documented FC level at baseline and after induction therapy
• Results• FC normalized (≤100 mcg/g) in 31
patients (52%)
• At ~12 months, 84% of patients with normal FC after induction were in clinical remission vs 38% of those with elevated post-induction FC
*Remission defined as a Harvey-Bradshaw Index <4.Molander P et al. Inflamm Bowel Dis. 2012;18:2011-2017.
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
Calprotectin best at discriminating inactive vs active CD
Endoscopic activity Inactive (0–3) Mild (4–10) Moderate (11–19) High (≥20)
No. of patients 26 40 27 47
CDAIP value
79±86 (13–281) 85±70 (14–297) 116±47 (44–323) 218±75 (86–417)
Calprotectin (µg/g)P value
104±138 (10–725) 231±244 (12–1009) 395–256 (68–912) 718±320 (93–1327)
CRP (mg/L)P value
12±19 (3–94) 8±10 (3–53) 23±31 (3–172) 40±28 (5–121)
Leukocytes (g/L)P value
7.7±3.1 (4–17.9) 7.6±2.8 (3.7–13.6) 8.8±3.1 (1.4–15.8) 11.1±3.5 (2.9±18.6)
0.739 0.201 <0.001
<0.001 0.008 <0.001
0.349 0.013 0.019
0.903 0.117 0.004
Schoepfer A et al. Am J Gastroenterol 2010;105:162–169.
Numbers are presented as mean ± SD and range
RR=relative risk.Tibble JA et al. Gastroenterology. 2000;119:15-22.
43 CD
37 UC
In remission for 1-4 months
25 (58%) relapsed over period of 12 months
19 (51%) relapsed over period of 12 months
RR 10.6 (CD)
RR 13.4 (UC)
High Fecal Calprotectin is Associated with Risk of Relapse in IBD
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
“Routine Monitoring”
• Anemia• Metabolic Profile• CRP• Vitamin D• Vitamin B12• Fecal Calprotectin
Causes of Anemia in Inflammatory Bowel Disease (IBD)
Iron deficiencyAnemia of chronic disease
Vitamin B12 deficiencyFolate deficiencyDrug-induced (sulfasalazine, thiopurines)
HemolysisMyelodysplastic syndromeAplasia (often drug-induced)Innate hemoglobinopathies or disorders of erythropoiesis
Co
mm
on
1O
ccas
ion
al1
Rar
e1
Iron deficiency
1. Gasche C, et al. Inflamm Bowel Dis. 2007;13:1545-1553. 2. Kulnigg S, Gasche C. Aliment Pharmacol Ther. 2006;24:1507-1523
Most common form of anemia in IBD1,2
Commonly caused by intestinal blood loss, malnutrition, and impaired iron uptake1,2
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Stephen B. Hanauer, MD, FACG
ULN
High CDAI-High CRP
High CDAI-Low CRP
Low CDAI-High CRP
Low CDAI-Low CRP
Baseline CDAI
150 200 250 300 350 400 450 500
Lo
g C
RP
mg
/L
0.01
0.1
1
10
100
Relationship between CDAI and CRP
Modigliani R, et al. Gastroenterology. 1990;98(4):811-818.
Close monitoring of CRP and fecal calprotectin predicts clinical relapse after infliximab withdrawal
De Suray N et al. Presented at DDW; May 21, 2012. Abstract 864.
IFX, infliximab
CRP evolution
Time before relapse or end of follow-up (months)
CRP
(mea
n, 9
5% C
I/µg
/g)
-14 -6 0
30
0
10
2025
5
15
-12 -10 -8 -4 -2
p<0.001
Non-relapsers
Relapsers
Calprotectin evolution
Calp
ro(m
ean,
95%
CI/
µg/g
)
-14Time before relapse or end of follow-up (months)
-6 0
1200
0
400
8001000
200
600
-12 -10 -8 -4 -2
p=0.001
Non-relapsers
Relapsers
Sub-analysis of the STORI study (in patients with CD in remission)
● In relapsers:– Higher median CRP and calprotectin during follow-up – Sudden and pronounced increase in CRP and calprotectin during 4 months prior to relapse
● CRP of 6.1 mg/L and calprotectin of 305 µg/g best for prediction of relapse
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
Working Definitions of Deep Remission
Deep remission implies resolution of inflammatory symptoms and objective signs of inflammation
No bowel damage or disability
Existing bowel damage or disability
• Resolution of symptoms
• Resolution of objective measures of inflammation (endoscopy, imaging, biomarkers)
• Improvement of symptoms
• Resolution of objective measures of inflammation (endoscopy, imaging, biomarkers)
Colombel JF et al. Dig Dis. 2012;30 Suppl 3:107-111.
UC: Stratify According to Colectomy Risk
Identify Patient at High Risk for Colectomy
• Extensive colitis
• Deep ulcers
• Age <40
• High CRP and ESR
• Steroid-requiring disease
• History of hospitalization
• C. difficile infection
• CMV infection
Identify Patient at Low Risk for Colectomy
• Limited anatomic extent
• Mild endoscopic disease
Dassopoulos T, et al. Gastroenterology. 2015;149:238-45.
ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology
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Stephen B. Hanauer, MD, FACG
AGA Clinical Pathway for Crohn’s Disease: Characterizing Risk
Sandborn WJ. Gastroenterology. 2014;147:702-705.
>30 years Age at diagnosis <30 years
Limited Anatomic involvement Extensive
No Perianal and/or severe rectal disease Yes
Superficial Ulcers Deep
No Prior surgical resection Yes
No Stricturing and/orpenetrating behavior Yes
Low Risk High Risk
Summary
• Current “Clinical Pathways” include assessment of laboratory, endoscopic and imaging assessments at diagnosis
• Clinical End-Points (Targets) include resolution of:• Clinical• Laboratory• Endoscopy
• Ongoing monitoring is critical to insure long-term outcomes• Histologic and “deeper biologic” targets are likely to be clarified in
future
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