Disease Assessment in Crohn’s Disease and Ulcerative...

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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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


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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)


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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.


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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


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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


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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


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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


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


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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


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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.


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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.


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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


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“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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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


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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


• Improvement of symptoms


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.


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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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