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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)

Radiography

– Enterography (CT, MRI)

– Pelvic imaging (MRI)

– Ultrasound

Endoscopy

– Chromoendoscopy

– Advanced endoscopic imaging

– Rectal EUS for fistulae

All That in 30 Minutes???

“THAT’S UN-POSSIBLE!”

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

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

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?

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

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

0

10

20

30

40

50

60

70

% o

f P

atie

nts

60% sensitive 94% specific for UC

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

pANCA+

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

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

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


Diagnosis

– IBD vs. Functional/Healthy

– CD vs. UC– Pre-clinical marker






ASCA for 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

Sensitivity Specificity PPV NPV

ASCA+/ANCA- CD 67% 78% 80% 64%

ASCA-/ANCA+ UC 78% 67% 64% 80%

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 panelgASCA, 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)

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

Prevalence effects on PPV, NPV

Serology Panel: Effects of Prevalence

59% Prevalence 15% Prevalence

IBD 93% Sens PPV 96% 75%

95% Spec NPV 90% 99%

CD 88% Sens CD PPV 96% 74%

98% Spec CD NPV 93% 100%

UC 93% Sens UC PPV 89% 73%

97% Spec UC NPV 98% 99%


Diagnosis


– CD vs. UC

– Pre-clinical marker Predict disease course or complications in IBD





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+


Diagnosis


– CD vs. UC

– Pre-clinical marker






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

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

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


pANCA+ identifies34,35,47,48

– “UC-like” subgroup, good therapy response , later onset anti-OmpC

– Levels assoc w/disease progression (non-FS/IPFSIP)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

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


Number of + Abs (ASCA, OmpC, I2)

0 1 2 3

SB Disease 44% 51% 56% 82%

Progression 24% 52% 73% 87%

FS 29% 55% 54% 71%

SB Surgery 32% 57% 52% 89%

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


CD behavior from presence AND level of markers38

– “Quartile sum” (dose-response) of I2, ASCA, OmpC

» Higher quartileshigher FS, SB dz, SB surg, IP and lower UC-like


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

pANCA+ higher probability of

– severe L-sided dz

– treatment-resistance

– aggressive course with earlier surgery51

– pouchitis after IPAA35,52

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

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

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

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 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

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)


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

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

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


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

Useful in pts not achieving expected results despite appropriate dose and time intervals

– Very low 6-TG and 6-MMPnoncompliance

» 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

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 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 Enterography

Abscess seen better after positive oral contrast

CT Enterography

NormalTerminalIleum

CT Enterography

Active

Disease

CT Enterography

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

Performance of Various Imaging Modalities vs.Ileoscopy in CD Patients

Sensitivity Specificity

Bodily KD, et al. Radiology 2006;238:505

CTE 70% 97%

Wold PB, et al. Radiology 2003;229:275

CTE 78% 83%

CT enteroclysis 75% 100%

SBFT 62% 90%

Diagnostic Yield of Various Imaging Modalities in CD Patients

Yield

Hara AK, et al. Radiology 2006;238:128

WCE 71%

Ileoscopy 65%

CTE 53%

SBFT 24%

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)

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


– 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


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


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

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 bxdysplasia

» CE: 7/114 target bxdysplasia


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 +


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

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 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 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 EUS

Future:

– Contrast-enhanced EUS: 3% Hydrogen peroxide

– 3D-EUS

– Both methods likely comparable111

References

1. Quintin JF, et al. Gut 1998;42:788

2. Bossuyt X, et al. Clin Chem 2006;52:171


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

5. Landers CJ, et al. Gastroenterology 2002;123:689

6. Lodes MJ, et al. J Clin Invest 2004;113:1296

7. Targan SR, et al. Gastroenterology 2005;128:2020

8. Bossuyt X, et al. Clin Chem 2006;52:171

9. Sutton CL, et al. Gastroenterology 2000;119:23

10. Lawrance IC, et al. Inflamm Bowel Dis 2005;11:890-897

11. Ferrante M, et al. Am J Gastroenterol 2006;A:129

12. Dotan I, et al. Gastroenterology 2006;131:366-378


14. Peeters M, et al. Am J Gastroenterol 2001;96:73015. Dubinsky MC, et al. Am J Gastroenterol 2001;96:75816. Vermeire S, et al. Gastroenterology 2001;120:82717. Joossens S, et al. Gastroenterology 2002;122:1242 18. Joossens S, et al. Gut 2006;55:166719. Melmed GY, et al. Gastroenterology 2007;132:A511

20. Papp M, et al. World J Gastroenterol 2007;13:2028

21. Targan S, AGA Inst. Postgraduate Course, 2006

22. Koutroubakis IE, et al. Am J Gastroenterol 2001;96:449

23. Vidrich A, et al. J Clin Immunol 1995;15:293

24. Linskens RK, et al. Eur J Gastroenterol Hepatol 2002;14:1013-18

25. Targan SR, et al. Gastroenterology 2005;128:2020

26. Seibold F, et al. Gastroenterology 1994;107:532

27. Shanahan F, et al. Gastroenterology 1992;103:456

28. Lee JC, et al. Gastroenterology 1995;108:428

29. Folwaczny C, et al. Scand J Gastroenterol 1998;33:523

30. Seibold F, et al. Scand J Gastroenterol 2001;36:196

31. Sendid B, et al. Am J Gastroenterol 1998;93:1306

32. Israeli E, et al. Gut 2005;54:1232

33. Landers CJ, et al. Gastroenterology 2002;123:689

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

35. Vasiliauskas, et al. Gastroenterology 1996;110:1810

36. Nakamura RM, et al. Clin Chem Acta 2003;335:19

References

37. Sandborn WJ, et al. Mayo Clin Proc 1996;71:431

38. Mow WS, et al. Gastroenterology 2004;126:414

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

40. Walker L, et al. Clin Exp Immunol 2004;135:490

41. Forcione D, et al. Gut 2004;53:1117

42. Desir B, et al. Clin Gastroenterol Hepatol 2004;2:139

43. Amre DK, et al. Am J Gastroenterol 2006;101:645

44. Dubinsky, et al. Am J Gastro 2006;101:360

45. Riis L, et al. Inflam Bowel Dis 2007;31:24

46. Odes S, et al. Inflamm Bowel Dis

47. Klebl FH, et al. Inflamm Bowel Dis 2003;9:302

48. Vermiere S, et al. Inflamm Bowel Dis 2001;7:8

49. Papp M, et al. World J Gastroenterol 2007;13:2028

50. Dubinsky MC, et al. Gastroenterology 2007;132:A17

51. Sandborn WJ, et al. Am J Gastroenterol 1995;90:740

52. Fleshner PR, et al. Gut 2001;49:671

52. Esters N, et al. Am J Gastroenterol 2002;97:1458

53. Yacyshyn BR, et al. Clin Exp Immunol 2005;141:141

54. Mow WS, et al. Dig Dis Sci 2004;49:1280

55. Rex DK, et al. Gastroenterology 1997;112:24

56. Hixson LJ, et al. J Natl Cancer Inst 1990;82:1769

57. Postic G, et al. Am J Gastroenterol 2002;97:3182

58. Thorlacius H, et al. Inflamm Bowel Dis 2007;13:911

59. Ransohoff DF, et al. Dis Colon Rectum 1985;28:383

60. Bressler B, et al. Gastroenterology 2004;127:452

61. Brooker JC, et al. Gastrointest Endosc 2002;56:333

62. Trecca A, et al. Chir Ital 2004;56:31

63. Hurlstone DP, et al. Gut 2004;53:248

64. Jaramillo E, et al. Gastrointest Endosc 1996;44:15

65. Kiesslich R, et al. Gastroenterology 2003;124:880

65. Rutter MD, et al. 2004;53:256

References

66. Hurlstone DP, et al. Endoscopy 2005;37:1213

67. Kiesslich, et al 2003/Hurlstone DP, et al. Endoscopy 2006;38:1213

68. Itzkowitz SH, et al. Inflamm Bowel Dis 2005;11:314

69. Shaye OA, et al. Am J Gastroenterol 2007;102:2488

70. Kandiel A, et al. Gut 2005;54:1121

71. Lewis JD, et al. Gastronterology 2000;118:1018

72. Cuffari C, et al. Gut 1996;39:401

73. Dubinsky MC, et al. Gastroenterology 2000;118:705

74. Schaefler, et al. Pharmacogenetics 2004;14:407

75. Schwab M, et al. Pharmacogenetics 2002;12:429

76. Colombel JF, et al. Gastroenterology 2000;118:1025

77. Seidman EG, et al. Gastroenterology 2004;126:A209

78. Lowry PW, et al. Gut 2001;49:665

79. Paerregaard A, et al. Scand J Gastroenterol 2002;37:371

80. Wusk B, et al. Eur J Gastroenterol Hepatol 2004;16:1407

81. Gupta P, et al. J Pediatr Gastroenterol Nutr 2001;33:450

82. Belaiche J, et al. Scand J Gastroenterol 2001;36:71

83. Reuther LO, et al. Scand J Gastroenterol 2003;38:972

84. Goldenberg BA, et al. Am J Gastroenterol 2004;99:1744

85. Hindorf U, et al. Aliment Pharmacol Ther 2006;24:331

86. Cuffari C, et al. Aliment Pharmacol Ther 2000;14:1009

87. Cuffari C, et al. Gut 2001;48:642

88. Wright S, et al. Gut 2004;53:1123

89. Hindorf U, et al. Scand J Gastroenterol 2004;39:1105

90. Cuffari C, et al. Clin Gastroenterol Hepatol 2004;2:410

91. Roblin X, et al. Aliment Pharmacol Ther 2005;21:829

92. Mardini HE, et al. J Clin Gastroenterol 2003;36:390

93. Achkar JP, et al. Inflamm Bowel Dis 2004;126:339

94. Osterman MT, et al. Gastroenterology 2006;130:1047

95. Dubinsky MC, et al. Am J Gastro 2005;100:2239

96. Dubinsky MC, et al. Gastroenterology 2002;122:904

97. Colombel JF, et al. Gut 2006;55:1561 98. Bodily KD, et al. Radiology 2006;238:505

References

99. Ott DJ, et al. Radiology 1985;155:31

100. Maglinte DD, et al. Radiology 1992;184:54

101. MacKalski BA, et al. Gut 2006;55:733

102. Otterson MF, et al. Surgery 2004;136:854

103. Vogel J, et al. Dis Colon Rectum 2007

104. Schwartz DA, et al. Gastroenterology 2000;118:A337

105. Tio TL, et al. Gastrointest Endosc 1990;36:331

106. Schrater-Sehn AU, et al. Endoscopy 1993;25:582

107. Orsoni P, et al. Br J Surg 1999;86:360

108. Schwarz DA, Gastroenterology 2001;121:1064

109. Ardizzone S, et al. Inflamm Bowel Dis 2004;10:91

110. Schwartz DA, et al. Inflamm Bowel Dis 2005;11:727

111. Buchanan GN, et al. Dis Colon Rectum 2005;48:141

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