diagnostics and disease monitoring in ibd: state of the...

David T. Rubin, MD 2011 1

Diagnostics and disease monitoring in IBD:

State of the art 2011

D id T R bi MDDavid T. Rubin, MDAssociate Professor of Medicine

Co-Director, Inflammatory Bowel Disease CenterUniversity of Chicago Medical Center

The First Goal of Management in IBD: Obtain a Clear and Accurate Diagnosis

A clear diagnosis should provide information that:– Explains the patient’s current symptoms and problemsy– Is accurate now and withstands the test of time– Provides prognostic information– Makes a distinction in the management decisions such

that therapy chosen now impacts both short- and long-term outcomes.

– May have implications for the care of others (ie family y p ( ymembers).

In 2011, should include disease extent and current severity and some element of longitudinal prognosis.


What is Disease Monitoring in IBD?

Assessment of the status of disease activity over time.

Performed in order to control disease and prevent Performed in order to control disease and prevent symptomatic relapses or disability.

Monitoring requires:– Understanding of the disease process– Acceptable methods of assessment– Interventions that are effective and tolerable (by the patient and by

the MD))

Examples:– Clinical follow-up– Routine laboratory testing for drug efficacy or safety– Measures of mucosal integrity or immune activity

Clinical Features of UC and CD

Ulcerative ColitisUlcerative Colitis– Continuous inflammation– Colon only

Crohn’s DiseaseCrohn’s Disease– Patchy inflammation– Mouth to anus involvementy

– Superficial inflammation– Variable extent– Risk of cancer– Extraintestinal

manifestations

– Full-thickness inflammation– Fistulas and strictures– Risk of cancer– Extraintestinal

manifestations

Greatest Least

Frequency of Involvement


Montreal ClassificationCrohn’s disease

Location (L)

L1 Terminal ileum

L2 Colon

L3 Ileocolon

L4 Upper GI

Behavior (B)

B1 Non-stricturing, non-penetrating

B2 Stricturing

B3 Penetrating

(p) modifier Perianal

Montreal Classificationulcerative colitis

Classification by Extent

Ulcerative proctitis (E1)

Left-sided ulcerative colitis (E2)

Extensive ulcerative colitis (E3)


The Challenges to Diagnosis in IBD

Lack of knowledge about the disease and its various manifestations (primary care?)

Lag time of pre-symptomatic disease before presentation

Inaccurate classification system– Overlap of phenotypes between UC and Crohn’s

disease– Variations of existing disease presentations

The Spectrum of Utility in IBD

Predicting Behavior Rx Response

Need for

Surgery & Outcome

Monitoring

activity, response


Diagnosis in IBD

Primary Dx of IBD Rule out imposters

Clarification of IBD Dx Ileocolonoscopy with

biopsy Obvious GI symptoms/signs and classic presentation

Extra-intestinal symptoms/signs and findings

biopsy Distinction between IBS

and active inflammation Reliable expert pathology Evaluation of small bowel

– WCE– CTE/MRE

E d h i Re-evaluation over time Exam under anesthesia, exploratory lap

Use of other clues– family history– serologies– Non-GI specialists

Historical Features that Help to Confirm a Diagnosis of IBD

Appendectomy protects Early Appendectomy Early Appendectomy Protects Against UCProtects Against UCpp y p

against UC

Ex-smokers may develop UC

Smokers have CD

Family history usually concordant

Andersson RE, et al. N Engl J Med. 2001;344:808–814.


What about these phenotypes? Is this IBD?

Oral facial granulomatous disease

Isolated perianal disease Isolated perianal disease

Hydradenitis supporativa

Isolated pyoderma gangrenosum

Peri-appendiceal red patch?

Gastric inflammation in kids with UC?

Rectal sparing in “UC”?

“Incidental ileitis”

Wireless capsule findings?

Serologic markers?

• Infectious colitis (i l di Cl t idi

• Diversion colitis

E d i i

Most Common “Imposters” in the Differential Diagnosis of IBD

(including Clostridium difficile)

• Ischemic colitis

• Drug-induced (NSAID) enterocolitis

• Solitary rectal ulcer

• Endometriosis

• Malignancy

• Functional (IBS)

• Diverticular disease

syndrome

• Radiation enterocolitis

Adapted from Forcione DG, Sands BE. In: Sartor RB, Sandborn WJ. Kirsner’s Inflammatory Bowel Diseases. 6th ed. New York: Saunders; 2004:359-379.


Imaging in IBD

Macroscopic vs Microscopic

Diagnosisl ti f t l b– explanation of symptoms or lab

abnormalities– clarification of disease extent and severity

Cancer screening and surveillance

Prognosis, adjunctive to additional testing

Choice of therapy (class or delivery system)

Prevention of disease expression or complications?complications?

Small Intestinal Crohn’s Disease as Seenby Wireless Capsule Endoscopy


Promise and Problems of CE in IBD

PROMISE Exquisite imaging of small bowel

mucosa

PROBLEMS Observer-dependent interpretation

training required Less invasive diagnostics (?)

Emerging information about significance of findings, etc

Recent FDA indication for monitoring of CD

– training required– inter/intra observer variability

Uncertain significance of many findings- what’s “normal”?– Short-term– Long-term– Need blinded comparator

studies

Heterogeneous data quality of Heterogeneous data quality of studies

Capsule retention

Are All Small Bowel Lesions CD?


Diagnostic Yield of Wireless Capsule Endoscopy in Suspected or Known Crohn’s

Study N Indication Diagnostic Yield

Costamagna 3 Suspected CD or recurrence

67% CD

Scapa 13 Suspected CD 46% CD

Eliakim 20 Suspected CD 60% CD

Fireman 17 Suspected CD 71% CD

Liangpunsakul 3 Abdominal pain, Fe anemia

100% CD

Adapted from Loftus EV. Clin Gastroenterol Hepatol. 2004;2:14-16 with permission from American Gastroenterological Association.

Fe anemia

Herrerias 21 Suspected CD 43% CD

Mow 50 Known or suspected CD 60% CD

Suspected CD subgroupStudy IY (random) [95% CI] IY (random) [95% CI]

Costamagna 2002 0.00 [-0.85, 0.85]

Dubcenco 2004 0.38 [-0.04, 0.79]

Eliakim 2004 0.54 [0.35, 0.74]

Toth 2004 0.17 [-0.02, 0.37]

Chong 2005 0.00 [-0.11, 0.11]

Hara 2005 0.25 [-0.16, 0.66]

Total (95% CI)0.24 [-0.03, 0.51]

Total yield (fixed): 43% (CE), 13% (bariumradiography)

T t f h t it P < 0 001 I² 85 6%Test for heterogeneity: P < 0.001, I² = 85.6%

Test for overall effect: P = 0.09

-1 -0.5 0 0.5 1

Yield higher in barium radiography Yield higher in capsule endoscopy

Study IY (random) [95% CI] IY (random) [95% CI]

Costamagna 2002 0.50 [-0.21, 1.21]

Buchman 2004 0.03 [-0.20, 0.27]

Dubcenco 2004 0.70 [0.49, 0.90]

Established CD subgroup

Triester, Leighton, et al. AJG 2006.

22

Marmo 2004 0.45 [0.23, 0.67]

Toth 2004 0.61 [0.35, 0.87]

Chong 2005 0.62 [0.38, 0.86]

Hara 2005 0.67 [0.34, 0.99]

Total (95% CI)0.51 [0.31, 0.70]

Total yield (fixed): 78% (CE), 32% (barium radiography)

Test for heterogeneity: P = 0.001, I² = 72.9%

Test for overall effect: P < 0.001

-1 -0.5 0 0.5 1

Yield higher in barium radiography Yield higher in capsule endoscopy


How Often do Lesions Occur in Normal Volunteers?

Findings from a study of COX-2 selective NSAIDs and SB injury in normal volunteersNSAIDs, and SB injury in normal volunteers– 14% on no NSAIDS had “mucosal breaks” at

baseline

CE studies in osteoarthritis patients without GI symptoms and on no NSAIDSsymptoms and on no NSAIDS

– 17% on acetaminophen and no NSAIDS, had SB lesions at baseline

Goldstein et al. CGH 2005 Graham, et al CGH 2005

The Problem of Strictures


Capsule Retention

Capsule Retention Rate in CD Depends on Clinical Scenario

Author Patients Capsule CD?

(n) retention (%)(n) retention (%)

Herrerias 21 0 Suspected

Fireman 17 0 Suspected

Eliakim 20 0 Suspected

Sant’Anna 20 5 Susp (hi prob)

M 50 4 KMow 50 4 Known

Buchman 30 6 Known

Cheifetz 38 13 Known

Cheifetz 64 10 Suspected strictures


Small bowel radiographs:radiographs:

is it time to retire?

CT Enterography

Combines high-resolution CT scanning with some of the concepts of barium radiography

Ingestion of large volume of a negative contrast agent (either PO or via NJT) to distend loops– Water or diluted PEG

Intravenous contrast, scan after 70 seconds (venous phase)

Thin slices on helical CT

Signs of inflammation Signs of inflammation


Segmental Distribution of Small Bowel Mural Thickening

Small Bowel Mural Thickening (1-2 cm)


Homogeneous Mural Enhancementof Small Bowel

Perienteric Fat Stranding


Fistulas

Tracts

Usually enhancing (unless perianal)

+/- fluid/air/ fluid/air

Effective Doses of Radiation

CXR: 0.1 mSv

Round trip airflight NYC-London 0 1 mSv

CXR: 0.1 mSv

Round trip airflight NYC-London 0 1 mSv Round trip airflight, NYC-London, 0.1 mSv

Mammogram: 0.7 mSv

SBFT: 2-6 mSv

Average annual background radiation, 2.4 mSv

Standard CTE (single phase): 8-12 mSv

Radiation orker e pos re ann al limit 20 mSV

Round trip airflight, NYC-London, 0.1 mSv

Mammogram: 0.7 mSv

SBFT: 2-6 mSv

Average annual background radiation, 2.4 mSv

Standard CTE (single phase): 8-12 mSv

Radiation orker e pos re ann al limit 20 mSV Radiation worker exposure annual limit: 20 mSV

Bleed protocol CTE (triple phase): 30-40 mSv

International Space Station, annual: 170 mSv

Radiation worker exposure annual limit: 20 mSV

Bleed protocol CTE (triple phase): 30-40 mSv

International Space Station, annual: 170 mSv


MR Enterography

Ileal Inflammation

A. Enteroclysis

B. MRI Enterography

Schreyer AG, et al. Clin Gastroenterol Hepatol. 2004;2:491.


Accuracy of MRE versus Ileocolonoscopy (IC)

• 22 pediatric subjects underwent MRE and IC for newly diagnosed Crohn’s disease• 98 subjects with established Crohn’s disease

d t MRE d IC

• 4/10 false negative MRE’s were due to radiologic interpretation errors

Sensitivity(95% CI)

Specificity(95% CI)

TI/Anastomosis 72% (53% - 86%) 85% (74 – 92%)

Colorectum 59% (42% - 74%) 90% (80% - 96%)

underwent MRE and IC

• MRE has modest sensitivity for terminal ileal Crohn’s disease, utility in the colon is lower

• Radiologists interpretingMRE should be well-trained

Veereman et al. DDW 2011; abstract no. Su 1921Bruining et al. DDW 2011; abstract no. Su1189

• MRE had good sensitivity for ileal lesions, but sensitivity for colonic lesions was limited

Ability of MRI to Evaluate Therapeutic Response in Crohn’s Disease

• Magnetic resonance enterography (MRE) to evaluate response to Crohn’s therapy

• MR enteroclysis to evaluate effects of infliximab on transmural Crohn’s

• MR enteroclysis score of severity in ilealp py

• 27 subjects received adalimumab or corticosteroids for induction of remission

• Novel index (MaRIA) quantified severity of MR findings

• MaRIA correlated with CDEIS (r=0.70 at week 12)

• MaRIA score <40 predicted endoscopic remission (sensitivity 0.82, specificity

MR enteroclysis score of severity in ileal Crohn’s disease (MICD) calculated

• Primary endpoint: proportion of subjects with >2 points and >50% decrease in MICD at 26 weeks

• 15 subjects in final analyses

• 32% met primary endpoint

• Results were not compared with endoscopic or histological findings

0.85)

• MRE can accurately evaluate response to Crohn’s therapy

endoscopic or histological findings

• MR enteroclysis can monitor effects of infliximab in Crohn’s disease

• What should be done for patients who have evidence of active disease on MRI but are in clinical remission?

Van Assche et al. DDW 2011; abstract no. 344Ordás et al. DDW 2011; abstract no. 343


US to predict Crohn’s Disease Course

No US recurrenceNo endoscopic recurrence

Clinical recurrence-free survival by US recurrence Clinical recurrence-free survival by endoscopic recurrence

US recurrence Endoscopic recurrence

Daperno et al. DDW 2011; abstract no. Su1187.

• Small bowel US (SB-US) to predict repeat resection after ileocolectomy among 107 Crohn’s patients

• Median follow-up 3.3 years

• >i2 recurrence in 86%

• SB-US predicted need for surgery as well as IC

• SB-US could be an alternative to IC to assess course after ileocolonic resection for Crohn’s

Microbial Marker Antibodies in Crohn’s Disease (n = 303)

AntiAnti--AntiAnti--

All NegativeAll Negative

20.1%20.1%ASCAASCA

24.8%

11.2%11.2% OmpCOmpC

5.6%5.6%

I2I2

10.6%10.6%

12.9%12.9% 4.6%4.6%

79.9% of Patients

ASCAASCA

10.2%10.2%

Reprinted from Mow WS, et al. Gastroenterology. 2004;126:414-424. with permission from American Gastroenterological Association.


Serology as Initial Test?

• No prospectively supported datap p y pp

• Diagnostic algorithms not published

• ↓ prevalence: ↑ false positives

• ↑ in autoimmune disorders– ASCA: celiac, Behcet's, PBC, hepatitis

ANCA i hili & ll liti– ANCA: eosinophilic & collagenous colitis

– OMP-C & I2: infection, diverticulitis

• Cost

Austin et al. Clin Gastr Hep 2007;5:545–547Damoiseaux et al. J Clin Immunol 2002; 2(5):281-8

Serologies in IBD: What is State of the Art in 2011?

Diagnosis vs. Prognosis

The accurate integration of serology testing is a The accurate integration of serology testing is a function of the pre-test probability of IBD– i.e. If pre-test probability is low, positive serologies are

likely to be false positives– i.e. If pre-test probability is high, negative serologies

are likely to be false negatives

Serologies therefore are of diagnostic value in patients with intermediate likelihood of IBD


5-year clinical course after diagnosis

Age at onset40 40 0 0004

Predictors of Disabling Disease:

– <40 years vs ≥40 years; p=0.0004

Location of disease– small bowel + colon vs small bowel only; p=0.002

Smoking status– smoker vs ex- or non-smoker; p=0.09

Perianal lesion at diagnosis– yes vs no; p=0.01

Required steroids for first flare– yes vs no; p=0.0001

Beaugerie et al, Gastroenterology 2006; 130: 650

Serum Immune Responses Predict Rapid Disease Progression in Children with CD

n=70

p=0.03

n=97

Serologic markers: ASCA, anti-OmpC, anti-I2, anti-CBir1

Dubinsky M et al. Am J Gastroenterol 101:2006.


The Risk of Chronic Pouchitis is Significantly Increased With Pre-Op High Level pANCA

100f

25

50

75

100

ativ

e In

cid

ence

of

ic P

ou

chit

is (

%)

High level

M di l l

P = 0.03

0

25

0 6 12 24 36 48 60

Months After IPAA

Cu

mu

laC

hro

ni

Low levelMedium level

pANCA-neg

Fleshner, P et al. Gut 2001

Should we be treating to achieve mucosal healing?

YES!!Th i fl d d i j d

WAIT- NOT YET!W ’t t th i t• The inflamed and injured

bowel is the hallmark of active disease

• A healed bowel is the sign of disease control or resolution

M f th i

• We can’t get there in most patients with existing therapies.

• How is this defined???– Partial?– Complete?– Histology?• Many of our therapies can

achieve it.

• Existing strategies are not effective at longer term management control.

– Histology? – Endoscopy?– Radiographic??

• Cost

• Convenience


10 000

20 000 * * p< 0.0001*

Fecal Calprotectin Levels in IBD Patients with Active Disease and “Mucosal Healing”

100

1000lp

rote

ctin

mg/

LLo

g sc

ale

��

10

1

Ca

Crohn’s diseaseactive / remission

Ulcerative colitisactive / remission

Roseth Scand J Gastro 2004

Mucosal healing

IBD Diagnosis and Management: The Near Future

First Visit:

IBD Panel

Phenotype: Location, EIM, Behavior

Serology Genetics Proteomics

IBD Subtype

Disease Prognosis

Patient-specific treatment plan

Targeted-specific therapyDisease Monitoring for Efficacy and Safety

diagnostics and disease monitoring in ibd: state of the...

Documents