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Novel Diagnostic Strategies in Inflammatory Bowel Disease Mark H. Flasar, M.D. Assistant Professor of Medicine Division of Gastroenterology and Hepatology The “Short” List Laboratory testing Serologic markers Genetic testing Metabolite monitoring Markers of disease activity (serum, stool)

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novel diagnostic strategies in inflammatory bowel disease

Novel Diagnostic Strategies in Inflammatory Bowel Disease

Mark H. Flasar, M.D.

Assistant Professor of Medicine

Division of Gastroenterology and Hepatology

the short list
The “Short” List
  • Laboratory testing
    • Serologic markers
    • Genetic testing
    • Metabolite monitoring
    • Markers of disease activity (serum, stool)
  • Radiography
    • Enterography (CT, MRI)
    • Pelvic imaging (MRI)
    • Ultrasound
  • Endoscopy
    • Chromoendoscopy
    • Advanced endoscopic imaging
    • Rectal EUS for fistulae
all that in 30 minutes
All That in 30 Minutes???

“THAT’S

UN-POSSIBLE!”

serology the two jakes
Serology: “The Two Jakes”
  • ASCA: The “Crohn’s Disease Ab”
    • + in ≈ 60% of CD1-3
    • IgA + IgG vs. cell wall of S. cerevisiae
  • pANCA: The “Ulcerative Colitis Ab”
    • + in ≈ 40-80% UC, 2-28% CD (“UC-like” CD)4
    • Newer assay more specific for UC
      • Loss of perinuclear stain after DNAse
other cd abs ompc and cbir1
Other CD Abs: OmpC and CBir1
  • Anti-OmpC*
    • IgA + in 55% of CD5
    • Vs. E. coli outer membrane porin C protein
  • Anti-Cbir1ŧ
    • IgA + in 50-55% CD6,7
    • 40% Ab- CD pts are + for anti-CBir17
  • Anti-I2
    • + in 54% CD8-9
    • Vs. bacterial DNA in LP monocytes
other abs pab and anti glycans
Other Abs: PAB and anti-Glycans
  • Anti-Glycan Abs11,12
    • Vs. bacterial/fungal cell wall carbohydrates
    • ALCA, ACCA, AMCA + in 18-38% CD
  • Anti pancreatic Ab (PAB)
    • + in 30% CD10
    • unknown relevance in CD
serology what is it good for
Serology: What is it Good For?
  • Diagnosis
    • IBD vs. Functional/Healthy
    • CD vs. UC
    • Pre-clinical marker
  • Predict disease course or complications in IBD
    • CD and UC phenotype
    • CD and UC progression/aggression
    • Risk of pouchitis after IPAA for UC
    • Following disease activity/treatment response
asca panca for ibd vs healthy

pANCA+

60% sensitive

94% specific for UC

Duerr R. H. et al. Gastroenterology 1991;100:1590

ASCA, pANCA for IBD vs. Healthy

13. Vermeire S, et al. Gastroenterology 2001;120:827

asca panca for ibd vs healthy9
ASCA, pANCA for IBD vs. Healthy

14. Peeters M, et al. Am J Gastroenterol 2001;96:730

utility of serodiagnostics in pediatric ibd use of a two step assay
Utility of Serodiagnostics in Pediatric IBD: Use of a Two-Step Assay

15. Dubinsky MC, et al. Am J Gastroenterol 2001;96:758

summary ibd vs functional healthy
Summary: IBD vs. Functional/healthy
  • pANCA and ASCA are specific for UC and CD respectively
    • Can HELP rule in disease (if high PTP)
  • The moderate sensitivity and low negative predictive value preclude them as a screening test
    • Unable to rule out disease
  • Potential application in pediatric disease to avoid invasive work up
    • Not in recent algorithm
serology what is it good for12
Serology: What is it Good For?
  • Diagnosis
    • IBD vs. Functional/Healthy
    • CD vs. UC
    • Pre-clinical marker
  • Predict disease course or complications in IBD
    • CD and UC phenotype
    • CD and UC progression/aggression
    • Risk of pouchitis after IPAA for UC
    • Following disease activity/treatment response
asca for cd vs uc
ASCA for CD vs. UC

16. Vermeire S, et al. Gastroenterology 2001;120:827

diagnosis cd vs uc
Diagnosis: CD vs. UC
  • 97 IC pts √ for ASCA/pANCA and followed17
  • 31/97 (32%) “Declared themselves”
  • 48% pts had all – Abs
    • 85% of these, dx remained IC
  • Adding anti-OmpC and anti-I2 in did not help18
diagnosis cd vs uc ic
Diagnosis: CD vs. UC (IC)
  • 238 UC pts for IPAA had preop serology19
    • anti-OmpC, anti CBir1, ASCA, pANCA
    • 16 (7%) developed CD after IPAA
      • MV analysis ASCA+ 3-fold risk CD
  • Glycan panelgASCA, ALSA, ACCA11
    • 1 Ab+: sens 77%, spec 90%, PPV 91%, NPV 77%
    • 2+ Abs+ increased specificity/PPV
      • At expense of sens/NPV.
summary cd vs uc ic
Summary: CD vs. UC (IC)
  • Most specific test is combining ASCA/ANCA20, 21
    • PPV ranges 77-96% in several studies22-24
  • IC is likely a distinct clinical entity
    • Serology as adjunct
    • Newer markers may help (CBir1)
      • 44% pANCA+ CD. vs 4% of pANCA+ UC pts25
serology what is it good for19
Serology: What is it Good For?
  • Diagnosis
    • IBD vs. Functional/Healthy
    • CD vs. UC
    • Pre-clinical marker
  • Predict disease course or complications in IBD
    • CD and UC phenotype
    • CD and UC progression/aggression
    • Risk of pouchitis after IPAA for UC
    • Following disease activity/treatment response
diagnosis pre clinical markers
Diagnosis: Pre-clinical markers
  • pANCA variably present in UC relatives26-29
  • ASCA+ in CD relatives 5x more than controls30,31
  • Study of 40 IBD patients’ banked sera32
    • 31% of CD pts were ASCA+ prior to dx
      • No ASCA+ controls
    • 25% UC pts were pANCA+
      • No pANCA+ controls
      • No UC pts were ASCA+
serology what is it good for21
Serology: What is it Good For?
  • Diagnosis
    • IBD vs. Functional/Healthy
    • CD vs. UC
    • Pre-clinical marker
  • Predict disease course or complications in IBD
    • CD and UC phenotype
    • CD and UC progression/aggression
    • Risk of pouchitis after IPAA for UC
    • Following disease activity/treatment response
relationship between marker antibodies and cd cohort
Relationship Between Marker Antibodies and CD Cohort
  • Analyzed immune response heterogeneity in 330 pts33
    • Found ASCA 56%, OmpC 55%, I2 50%, and pANCA 23%
    • Described 4 distinct immune response “phenotype” clusters
      • ASCA+, OmpC and I2 +, pANCA+, All negative
  • 15-20% had all neg Abs
antibody expression correlates with clinical characteristics
Antibody Expression Correlates with Clinical Characteristics

34. Vasiliauskas EA, et al. Gut 2000;47:487

cd progression phenotype
CD progression/phenotype
  • ASCA+  more aggressive, complicated disease
    • Higher levels  earlier disease onset35,36
    • In adult CD
      • FS, IP, SB resection, early surgery34,37-41,45
      • Higher long-term health care costs46
    • In peds CD
      • 3x odds relapse in children42
      • early onset, fistula/abscess recurrence, repeat surgery, SB dz43,44
  • ASCA+/pANCA-
    • SB involved more often than colon alone34
cd progression phenotype25
CD progression/phenotype
  • pANCA+ identifies34,35,47,48
    • “UC-like” subgroup, good therapy response , later onset
  • anti-OmpC
    • Levels assoc w/disease progression (non-FS/IPFSIP)39,49
    • Assoc w/FS, IP and SB surgery3, 34,38,47,49
    • Assoc w/FS, IP in pediatrics44
  • Anti-I2
    • assoc w/ FS and SB surgery34,47-8
  • Anti-CBir1
    • assoc w/FS, IP dz and SB surgery6,7
dose response of ab in cd
“Dose response” of + Ab in CD
  • Number and level of + Abs correlate w/severity
  • ↑ immune reactivity may = ↓ immune tolerance
  • ASCA+/anti-OmpC+anti-I2+ assoc w/↑ risk vs. all -Abs
    • FS, IP and surgery (3-8x)38
  • 196 pt prospective peds cohort had similar results44
    • ASCA+/anti-OmpC+/anti-I2+/anti-CBir1+
      • 11x risk IP or FS w/subsequent surgery if all 4+ vs. all 4-
      • Time to complication significantly less if ANY + Ab
dose response of ab in cd27
“Dose response” of + Ab in CD

39. Arnott ID, et al. Am J Gastroenterol 2004;99:2376

dose response of ab in cd28
“Dose response” of + Ab in CD
  • CD behavior from presence AND level of markers38
    • “Quartile sum” (dose-response) of I2, ASCA, OmpC
      • Higher quartileshigher FS, SB dz, SB surg, IP and lower UC-like
cd progression phenotype29
CD progression/phenotype
  • Aggressive pediatric CD predicted by Abs50
  • If Anti-CBir1+/anti-OmpC+/ASCA+:
    • 6x odds FS, 9x odds IP and 3x odds SB dz
    • Same pattern seen for higher Ab response levels
    • MV analysis
      • Anti-CBir1, anti-OmpC assoc w/IP
      • ASCA, anti-CBir1 assoc. w/FS
uc progression phenotype
UC progression/phenotype
  • pANCA+ higher probability of
    • severe L-sided dz
    • treatment-resistance
    • aggressive course with earlier surgery51
    • pouchitis after IPAA35,52
follow up treatment response
Follow-up/treatment response
  • no corr. pANCA+, titer and UC activity49
    • Titer same after colectomy32
  • ASCA stable/independent of CD activity32,35,48
    • ACCA, ALCA stable as well11
  • No corr. ASCA to anti-TNF response52
    • Trend to poorer response to ASCA-/pANCA+ pts
  • CD w/anti-OmpC+/I2+
    • better response to budesonide + Cipro/Flagyl
    • while abs – better to budesonide alone54
summary progression phenotype
Summary: progression/phenotype
  • Antibody profiles can predict CD behavior
    • Stratify to therapy regimens
  • Multiple antibodies associated with higher risks
  • pANCA+ associated with pouchitis after IPAA in UC
conclusion serology
Conclusion: Serology
  • Helpful if positive in correct population
    • Can help Rule IN disease if high PTP
    • Can help Rule OUT disease if low PTP
  • Diagnostic ADJUNCT
  • Possible alternative in certain populations
  • Future hope for UC vs. CD
  • Pre-clinical?
  • Associated with phenotype/complications
thiopurine adrs
Thiopurine ADRs
  • Dose dependent (usually 2/2 toxic metabolites)
    • Hemotoxicity
      • Leukopenia: 3.8-11.5%
      • Pancytopenia: 0.4-2%
      • Thrombocytopenia: 1.2%
    • Hepatotoxicity: 0.3-9.9%
      • 4.6% of 173 adult IBD patients69
    • Infections: 7.4-14.1%
    • Malaise, nausea: 11%
thiopurine adrs36
Thiopurine ADRs
  • Dose-independent (hypersensitivity)
    • Flu-like symptoms (including fever):2-6.5%
    • GI distress: 4.6%
    • Pancreatitis:1.2-4.9%
    • NRH, HVOD, AIN, pneumonitis: rare/case reports
    • Malignancy:?
      • Purported 4x lymphoma risk in IBD70
      • Benefits outweigh risks in decision analysis71
metabolite monitoring
Metabolite Monitoring
  • 6-TG corresponds with clinical efficacy while 6-MMP corresponds with hepatotoxicity72-3
    • Peds clinical efficacy related to 6-TGN > 235 pmol/8x10e8 RBC
    • Hepatotoxicity corr w/6-MMP> 5700 pmol/8x10e8 RBC (3x risk)
metabolite monitoring38
Metabolite Monitoring
  • Monitoring of 6-TG + 6-MMP levels may allow prediction of toxicity and guide dose titration
    • Mixed results from studies73,77-8
metabolite monitoring con
Metabolite Monitoring: CON
  • No diff in 6-TGN between responders and NR79-82
  • No diff in 6-TGN between remission and NR78, 81, 83-85
metabolite monitoring pro
Metabolite Monitoring: PRO
  • Correlation between 6-TG and remission72-3, 86-91
  • Higher 6-TGN levels assoc. with greater clinical response73, 90, 92-3
  • Meta-analysis showed higher 6-TG assoc w/sig higher levels remission94
    • 6-TGN >230-260 pmol/8x10e8 RBC more likely to be in remission (OR 3.27, 95% CI 1.71-6.27)
  • Cost-effective analysis suggested MM may decrease costs and improve outcomes vs. usual care95
metabolite monitoring41
Metabolite Monitoring
  • Controversy whether monitoring good for predicting toxicity
  • Recent retrospective study reports poor test characteristics of 6-MMP levels in predicting hepatotoxicity at 5,300 and 9,800 cutoffs69
summary metabolite monitoring
Summary: Metabolite Monitoring
  • Useful in pts not achieving expected results despite appropriate dose and time intervals
    • Very low 6-TG and 6-MMPnoncompliance
      • Very rarely poor absorption form short gut
    • 6-MMP:6-TG>10-11 suggests preferential shunting to 6-MMP
      • Suggests unfavorable metabolism, unlikely to be clinically effective89,96
    • Suboptimal 6-TG levels (<230-260 pmol/8x10e8 RBC and no shunting to 6-MMP), doses could be pushed to get optimal levels
  • Likely not useful for toxicity
ct enterography
CT Enterography
  • Allows visualization of lumen, mucosa, bowel wall and extraluminal pathology
    • Traditional oral contrast has similar attenuation to enhancing mucosa
    • Multidetector CT scanner
    • 1-2L of Low Houndsfield-unit oral contrast (<30 HU)
      • Water +/- methylcellulose, lactulose, PEG
      • barium/sorbitol (improves distension)
    • Traditional IV contrast
ct enterography44
CT Enterography
    • problematic in cases of suspected infection or perforation
      • Fluid collections/abscesses appear similar to bowel
  • Mucosal enhancement on CTE correlates with endoscopically and histologically active mucosal disease97-8
ct enterography45
CT Enterography

Abscess seen better after positive oral contrast

ct enterography46
CT Enterography

Normal

Terminal

Ileum

ct enterography47
CT Enterography

Active

Disease

ct enterography49
CT Enterography
  • Enteroclysis
    • 100% agreement with surgical findings of fistula and stricture99-100
  • SBFT
    • Reported 85-95% sensitivity/specificity for identification of stricture, fistula and mucosal abnormalities101
    • Incorrectly identified stricture number in 31% vs. operative findings102
ct enterography51
CT Enterography
  • CTE compared to operative findings in 36 CD patients103
  • CTE correctly identified
    • 100% strictures (83% accuracy)
    • 100% abscesses
    • 94% fistulae (86% accuracy for # fistulae)
    • 97% inflammatory mass
  • Overestimated or underestimated disease extent in 31%
    • Stricture, fistula, inflammatory mass, abscess counts
chromoendoscopy ce
Chromoendoscopy (CE)
  • Conventional Colonoscopy (CC) surveillance
    • 2-4 bx every 10cm in colon, q5cm in rectum
    • Known miss rates for even for visible exophytic lesions
      • Tandem endoscopy studies 15-24% adenomas <1 cm missed55-6
      • Similar results for colectomy specimens vs. preop colonoscopy57
chromoendoscopy ce53
Chromoendoscopy (CE)
  • Flat and depressed lesions have premalignant importance58
    • Can look like normal mucosa endoscopically (easy miss)
    • Depressed can become invasive early on
    • Only 20-50% intraepithelial neoplasia detected with CC59
  • Even miss rate for CRC
    • 4% CRC colectomy pts had “normal” colonoscopy in preop 6-36mo60
chromoendoscopy ce54
Chromoendoscopy (CE)
  • Chromo= dyes applied to mucosa during endoscopy
    • highlight and better characterize specific mucosal changes
    • Allows visualization of otherwise invisible mucosal changes
      • enhancing detection and accuracy
    • Absorptive, reactive, and contrast staining dyes
      • Indigo carmine: nonabsorbed; collects in mucosal depressions
      • Methylene blue: absorbed in normal cytoplasm; irregularities pale
      • Cresyl violet: taken up in crypts of Leibeukuhn; appears as dots/pits. Pit patterns have histologic correlates. Can be used with the above 2 stains
chromoendoscopy ce55
Chromoendoscopy (CE)
  • CC poorly detects flat/depressed lesions
    • Requires more meticulous training and examination
  • Chromo +/- mag.  detection of flat/raised neoplasia
    • In R colon and in pts w/multiple adenomas61
    • In non-IBD pts with hx adenomas62
    • In screening population adenomas randomized to CC vs. CE63
      • Better detection of adenomas with pan-CE (espec. diminutive lesions)
chromoendoscopy in ibd
Chromoendoscopy in IBD
  • HRCE better detection (esp. flat) in 85 UC patients64
  • 165 UC pts randomized to CC vs CE65
    • CE better an defining degree/extent inflammation
    • CE better at dysplasia detection than CC (32 v 10 lesions)
  • 100 UC surveillance pts got sequential CC and CE65
    • Pan-CE with target bx after standard CC bx protocol
      • CC: ALL 2,904 random bx neg; 2/43 target bxdysplasia
      • CE: 7/114 target bxdysplasia
chromoendoscopy in ibd57
Chromoendoscopy in IBD
  • 350 UC pts had HMCE matched to UC controls w/CC66
    • Target bx AND 4-quadrant randoms
  • HMCE
    • Detected sig. more lesions
    • Alone detected 79% of dysplasia
    • 0.16% random bx +
    • 8% targeted bx +
  • CC
    • 0.14% random bx +
    • 1.6% target bx +
chromoendoscopy in ibd58
Chromoendoscopy in IBD
  • Dye spraying adds about 10 minutes to colonoscopy67
  • Abandoning random bx will shorten procedure
  • Should be pretty even in terms of time after learning curve
  • Recent CCFA committee on IBD CRC/dysplasia surveillance endorses CE in “appropriately trained endoscopists”68
rectal eus
Rectal EUS
  • 20-30% CD develop perianal disease103
    • Diagnostics include MRI, fistolography (radiating, inaccurate vs surgery, painful, cannot delineate relation to perianal structures), CT (radiating, limited for fistula), EUA
  • EUS has emerging role
    • Accurate imaging of perianal region preoperatively
      • Road-mapping; theoretically reduce risk incontinence
    • Therapeutic (abscess drainage)
    • Safe
    • Can assess response to therapy
      • Superficial fistula closure may not herald deep tract closure
    • No radiation
rectal eus60
Rectal EUS
  • Can accurately delineate EAS, IAS, and pathologic defects
  • Identified 82% fistula c/w EUA in unblinded series
    • Better performance than fistulography105
  • EUS detected 82% fistula vs 24% by CT c/w EUA+fistulography
    • No difference in abscess detection106
  • Anal endosonography (AES) 100% sensitive vs. 55% for MRI in detecting perianal abscesses found at EUA
    • AES 89% sensitive vs. 48% for MRI in fistula detection107
rectal eus61
Rectal EUS
  • Prospective, blinded study of EUS, MRI, EUA vs. “consensus gold standard”
    • Accuracy EUS 91%, MRI 87%, EUA 91%
    • Combination of any 2 modalities increased accuracy to 100%108
  • To assess medical response:
    • IFX trial: AES at entry and 10 weeks in 30 perianal CD pts109
      • 54% had week 10 clinical closure; only 18% closed by AES
      • Those with week 10 closure on AES had sig. lower relapse rates
    • 21 perianal CD pts with baseline, serial EUS during surgical/medical rx110
      • 52% showed no persistent fistula activity; 64% of these able to stop rx
rectal eus62
Rectal EUS
  • Future:
    • Contrast-enhanced EUS: 3% Hydrogen peroxide
    • 3D-EUS
    • Both methods likely comparable111
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