Behçet’s disease ?Diagnostic criteria

Intestinal BD ?Colonoscopic findingsDifferential diagnosisSerologic markers

Won Ho Kim, M.D.Yonsei University, Seoul

Diagnostic Challenges in Asia; Intestinal Behçet’s Disease

Behçet’s Disease- Historical Background -

Behçet’s DiseaseHippocrates, at 5th BC

Hulusi Behçet, at 1937

Intestinal Behçet’s DiseaseBechgaard, at 1940

chronic recurrent multi-systemicinflammatory disorder

Diagnostic Criteria for Behçet’s Disease

Major criteria

Arthritis

GI lesions

Vascular lesions

CNS lesions

Epididymitis

Minor criteria

Behçet’s Disease Research Committee of Japan

(1987)

Typical ocular symptom + 1 major or 2 minor

CriteriaType

2 major features1 major + 2 minor

Suspected type

2 major + 2 minor

3 major featuresIncomplete type

4 major featuresComplete type

International Study Groupfor Behçet’s Disease (ISGBD)

Read by physician at 24-48 hPositive Pathergy test

Erythema nodosum, Pseudofolliculitis, or papulopustular lesionsAcneiform nodules in postadolescent patients

Skin lesions

Uveitis, or cells in vitreous on slit lamp Retinal vasculitis

Eye lesionsAphthous ulceration or scarringRecurrent genital ulceration

plus 2 of

Minor, major aphthous, or herpetiformulceration, recurred at least 3 times in one 12 month period

Recurrent oral ulceration

(1990)

GI Involvement in Behçet’s Disease

Perforation

Fistula

Abscess

Bleeding

Complications

General Aspects of Intestinal BD

Frequency3-25% of BDWide geographic differences

East Asia > Mediterranean

Age/Sex ratio3rd decade for BD 4th decade for intestinal BDM > F in intestinal BD

Symptoms: variableAbdominal pain (most common)DiarrheaBleeding

Burdens of Intestinal BD- Compared with UC and CD -

Probability of AZA/6-MP use

Choi CH, et al. presented at the Falk Sym. 2002

Cumulative operation rate

Choi IJ, et al. Kor J Gastroenterol 2000;36:504-14

80

60

40

20

012 24 36 48 60 72 84 96

BD (n=66)

CD (n=140)p=0.20

Months

Ope

ratio

n ra

te (%

)

80

60

40

20

0

Prob

abili

ty (%

)

12 24 36 48 60 72 84 96Months

BD (n=133)

CD (n=72)

UC (n=197)

Diagnosis of Intestinal BD

Diagnosis of BD Diagnostic criteria

Presence of intestinal lesion and differentiation from other disease

Endoscopic and radiologicalHistopathologicLaboratory markersClinical course

Application of Diagnostic Criteria for BD in Intestinal BD

Is the presence of systemic symptoms mandatory for diagnosis of intestinal BD ?Japanese criteria

Too complexMore feasible for diagnosis in cases with step-wise manifestation of symptoms

ISGBD criteriaMore unified, simple diagnosisOral ulcer / Pathergy test ?

Lee CR, et al. Inflamm Bowel Dis 2001;7:243-9

Symptoms in Intestinal BD - Typical BD vs. Atypical BD -

Lee CR, et al. Inflamm Bowel Dis 2001;7:243-9

Colonoscopic Characteristics

Satisfaction for Diagnostic Criteria

At the end point of follow-up

24 (19.0%)28 (22.2%)suspicious

At diagnosis of intestinal BD

59 (46.8%)67 (53.2%)

17 (13.5%)

62 (49.2%)23 (18.3%)

102 (81.0%)24 (19.0%)

62 (49.2%)

33 (26.2%)3 ( 2.4%)

not-satisfiedsatisfied

ISGBD criterianot-satisfied

incompletecomplete

Japanese criteria

Severance hospital (n = 126 )Mean F/U period after Dx of intestinal BD: 63.9 months

Onset and Prevalence of Systemic Onset and Prevalence of Systemic Manifestation in Intestinal BDManifestation in Intestinal BD

3 (2.4%)0 (0.0%)10.61 ± 5.41CNS Lesions

0 (0.0%)0 (0.0%)-Epididymitis

70 (55.6%)27 (21.4%)0.67 ± 5.29Genital ulcers

8.95 ± 9.00

3.95 ± 7.62

3.32 ± 5.76

0.98 ± 6.80

-5.38 ± 8.40

Onset(yr)

7 (5.6%)

65 (51.6%)

37 (29.4%)

77 (61.1%)

122 (96.8 %)

At the end point of follow-up

1 (0.8%)

24 (19.0%)

14 (11.1%)

38 (30.2%)

97 (77.0 %)

At diagnosis of intestinal BD

Vascular lesions

Arthritis

Eye lesions

Skin lesions

Oral ulcers

Criteria of BD

Pathergy test (n=115):12 (9.6%)

Colonoscopic Findings in Intestinal BD

Single / Few

Large / Deep

Round / Oval

Discrete / Elevated margin

Lee CR, et al. Inflamm Bowel Dis 2001;7:243-9

Pathologic Findings in Intestinal BD

Non-specific inflammationVasculitis

Lymphocytic infiltration

No granuloma

Differential Diagnosis- Colonoscopic Findings -

Colonic ulceration may be induced by broad spectrums of disease.

Similarity with Crohn’s diseaseGI symptomsExtra-intestinal symptoms

: oral ulcer, skin lesions, arthritis …Clinical course of diseasePresence of intestinal ulceration

0.06514 (20)10 (10)Stricture<0.00123 (33)4 ( 4 )Inflammatory polyp0.00110 (10)1 ( 1 )Perianal lesion

12 (17)7 ( 7 )Aphthous

13 (19)23 (23)Nodular<0.00139 (56)21 21)Aphthous lesion

21 (30)61 (61)Deep / Undermining<0.001Border

34 (49)81 (81)Discrete36 (51)19 (19)Ill-defined

<0.05Erythema of ulcer margin19 (27)43 (43)Normal 51 (73)57 (57)Erythematous

<0.05Ulcer margin44 (63)40 (40)Flat13 (19)37 (37)Smoothly elevated

pCD (%) n=70BD (%) n=100

49 (70)39 (39)Shallow<0.001Depth

21 (30)24 (24)Irregular / Geographic34 (49)1 ( 1 )Longitudinal3 ( 4 )68 (68)Round / Oval

<0.001Shape59 (84)15 (15)>57 (10)17 (17)2~54 ( 6 )68 (68)1

<0.001Number

Intestinal BD vs. CD in Colonoscopic Finding

Kim TI, et al. Journal of Gastroenterol Hepatol 2001;16;30(A)

p < 0.001

CD(n=70)

5 16 35 14

BD(n=100)

68 25 2 5

Focalsingle

Focalmultiple Segmental Diffuse

Distribution of Lesions

Kim TI, et al. Journal of Gastroenterol Hepatol 2001;16;30(A)

Ulcer shape

Round/Oval Longitudinal

Distribution of lesion

Focal singleFocal multiple

SegmentalDiffuse

Intestinal Behçet’s disease Crohn’s disease

Classification And Regression Tree (CART)

Irregular/Geographic

Hit ratio:0.9189

Diagnosis of Intestinal BD- Serologic marker -

Pathogenesis of BDAberrant immune activityTriggering environmentGenetic predisposition

Suggested auto-antibody in BDAntibody to retinal antigensAntibody to heat shock protein (HSP)Antibodies to α-tropomyosinAntibody to endothelial cell antigen (AECA)

Immunologic factor

Genetic factor Environmental factor

Behçet’s Disease

ASCA (Anti-Saccharomyces Cervisiae Antibody)

10-15%UC (reported ranges from other’s study)

40-70%CD (reported ranges from other’s study)

4 (8.8%)Healthy controls (n=45)

1 (3.3%)BD (n=30)

47 (44.3%)

ASCA (+)

Intestinal BD (n=106)

Figure 1. Staining of the cell wall of Saccharomycescerevisiae caused by antibodies to Saccharomycescerevisiae -positive serum (immunofluorescence, x400).

Choi CH, et al. Gatroenterology 2004;126:203(A)

ASCA and Clinical Course in Intestinal BD

(%)100

100806040200

80

60

40

20

ASCA(-)

ASCA(+) p = 0.006

Cumulative probability of the 1st operation

MonthsChoi CH, et al. Gatroenterology 2004;126:203(A)

No differences inClinical findingsTreatment with AZA/6MPProbability of 2nd op. Relapse rates

Anti α-enolase Ab

37.5%BD (n=40)

40 %UC (n=100)

31 %CD (n=100)

0%Healthy controls (n=23)

63%Intestinal BD (n=100)

AAEA (+)

Shin SJ, et al. Journal of Gastroenterol Hepatol 2005;20:143(A)

Glycolytic enzymePlasminogen receptor on the surface of endothelumModulation of fibrinolysis

α-enolase

Association with various autoimmune diseases :RA, SLE, MCTD, IBD, sytemic sclerosis

Anti α-enolase antibody

Summaries and Conclusions

Behçet’s disease is…Intestinal Behçet’s disease is…

Dx of intestinal Behçet’s disease Characteristic colonoscopic findingsApplication of diagnostic criteria Antibody assay

Clinical activity index