Asia Pacific Working Party on Crohn’s Disease Vineet Ahuja Dept of Gastroenterology All India Institute of Medical Sciences New Delhi, India

Asia Pacific Working Party on Crohn’s Disease

Vineet AhujaDept of Gastroenterology

All India Institute of Medical SciencesNew Delhi, India

Statement 9

It is important to differentiate Crohn’s disease from Intestinal tuberculosis.

Behcet’s disease should be excluded in areas of high prevalence.

BD is a multisystem vasculitis with systemic involvement which features mucocutaneous, ocular, articular, vascular,intestinal, urogenital, and neurologic involvement

•Intestinal involvement is uncommon : 5-25% •High frequency of complications : intestinal perforation, fistula formation,and, occasionally, massive hemorrhage

Prevalence of Behcet’s disease is higher in middle and east Asia, including Japan, Korea, and China, especially in areas along the “Silk Road’’

Behcet’s Disease

Longitudinal ulcers with a cobblestoneappearance : CD

Round and oval ‘punched-out’ ulcers : BDMost common site : ileocaecal area

Development and Validation of Novel Diagnostic Criteria for Intestinal Behçet’s disease in Korean Patients With Ileocolonic Ulcers. Am J Gastroenterol 2009; 104:2492–2499;

Development and Validation of Novel Diagnostic Criteria for Intestinal Behçet’s disease in Korean Patients With Ileocolonic Ulcers. Am J Gastroenterol 2009; 104:2492–2499;

Differential diagnosis of intestinal Behcet’s disease and Crohn’s disease by colonoscopic findings.S. K. Lee*, B. K. Kim*, T. I. Kim,W. H. Kim Endoscopy 2009; 41: 9-16

Differential diagnosis of intestinal Behcet’s disease and Crohn’s disease by colonoscopic findingsS. K. Lee*, B. K. Kim*, T. I. Kim,W. H. Kim Endoscopy 2009; 41: 9-16

115–BD135 -CD

Disease ASCA positivity

Intestinal Behcet’s disease ( n=106)

44.3%

Behcet’s Disease (n=30) 3.3%

Healthy controls ( n=45) 8.8%

Anti-Saccharomyces cerevisiae Antibody in Intestinal Behcet’s Disease Patients: Relation to Clinical Course Chang Hwan Choi, Dis Colon Rectum 2006; 49: 1849–1859

CD BD

Non caseating epitheloid granuloma

Rare

Transmucosal inflammation No

Submucosal fibrosis No

Not seen Lymphocytic venulitis s/0 vasculitis

A case of Behçet’s disease accompanied by colitis with longitudinal ulcers and granuloma JGH (2002) 17, 105–108

Guideline Statements for Diagnosis of Intestinal Behcet’s Disease (Japan)Diagnosis of Intestinal Behcet’s disease can be made ifA. There is a typical oval-shaped large ulcer in the terminal ileum, ORB. There are ulcerations or inflammation in the small or large intestine,AND clinical findings meet the diagnostic criteria of Behcet’s disease

Diagnostic Criteria (International Study Group for Behçet’s Disease, 1990)Recurrent oral Uleration+ 2 of the following :Recurrent genital ulcerationEye lesions : uveitisSkin lesions : Erythema nodosumPositive Pathergy test

Cheon JH, Korean J Gastroenterol 2009;53:187-193

•Li X, Liu X, Zou Y, Ouyang C, Wu X, Zhou M, Chen L, Ye L, Lu F. Predictors of Clinical and Endoscopic Findings in Differentiating Crohn's Disease fromIntestinal Tuberculosis. Dig Dis Sci. 2010 May 14. [Epub ahead of print] •Makharia GK, Srivastava S, Das P, Goswami P, Singh U, Tripathi M, Deo V,Aggarwal A, Tiwari RP, Sreenivas V, Gupta SD. Clinical, endoscopic, andhistological differentiations between Crohn's disease and intestinaltuberculosis. Am J Gastroenterol. 2010 Mar;105(3):642-51. •Amarapurkar DN, Patel ND, Rane PS. Diagnosis of Crohn's disease in Indiawhere tuberculosis is widely prevalent. World J Gastroenterol. 2008 Feb7;14(5):741-6.•Differentiation of Crohn’s disease from intestinal tuberculosis in India in 2010.World J Gastroenterol 2011 January 28; 17(4): 433-443•Zhou ZY, Luo HS. Differential diagnosis between Crohn's disease andintestinal tuberculosis in China. Int J Clin Pract. 2006 Feb;60(2):212-4.•Kumarasinghe MP, Quek TP, Chau CY, Mustapha NR, Luman W, Ooi CJ. Endoscopicbiopsy features and diagnostic challenges of adult Crohn's disease at initialpresentation. Pathology. 2010 Feb;42(2):131-7. •Almadi MA, Ghosh S, Aljebreen AM. Differentiating intestinal tuberculosis fromCrohn's disease: a diagnostic challenge. Am J Gastroenterol. 2009Apr;104(4):1003-12.

Intestinal Tuberculosis

Statement 10

The colonoscopic features which suggest a diagnosis of CD include anorectal lesions, longitudinal ulcers, aphthous ulcers, cobblestone appearance. Features suggestive of ITB include transverse ulcers, involvement of fewer than four segments and a patulous ileocaecal valve

Analysis of Colonoscopic Findings in the DifferentialDiagnosis Between Intestinal Tuberculosis and Crohn’s Disease .Lee YJ et al Endoscopy 2006; 38 (6): 592–597

A score of + 1 was assigned to the four endoscopic parameters(anorectal lesions, longitudinal ulcers, aphthous ulcers, and cobblestoneappearance) that are characteristic of Crohn’s disease, and ascore of –1 was given to the other four parameters (involvement offewer than four segments, a patulous ileocecal valve, transverse ulcers,and scars or pseudopolyps) that are characteristic of intestinal tuberculosis.The mean value of the scores for the eight parameters was 1.61 inpatients with Crohn’s disease and –1.95 in patients with intestinal tuberculosis(P < 0.001).

ENDOSCOPY Amarapurkar et al Makharia et al Li et al Lee et al

CD (26) ITB(26) CD(53) ITB(53) CD(130)

ITB

(122) CD(44) TB (44)

Skip lesions 6 2 35 9

Erythema 14 5

Friability 14 0

Aphthous ulcers 9 5 29 7 53.8 44.3 36 9

Linear ulcers 15 6 16 4 54.7 8.2 18 1

Superfi cial ulcers 27 9

Nodularity 13 26 48.5 32.8

Cobblestoning 15 6 9 0 27.7 1.6 15 3

Stricture 8 5 9 8

Neoplasm-like appearance 0 2

Fistula 3 0

Pseudo polyps 9 5 12 23

Fewer than four segments 8 36

Anorectal lesions 37 4

Ileocecal lesions 39 40

Patulous ileocecal valve 4 16

Transverse ulcers 4.6 41 11 29

SITE OF INVOLVEMENT Amarapurkar et al Makharia et al Li et al

CD (26) ITB(26) CD(53) ITB(53) CD(130) ITB (122)

Stomach 0 2 3 1

Duodenum 1 2 3 2

Jejunum 1 2 9 0

Ileum 16 20 13 8 66.2 59.8

Ileocecal area 20 21 47 49 55.4 75.4

Ascending colon 18 21 34 23 46.2 62.3

Descending colon 10 5 32 7 33.8 24.6

Sigmoid colon 35 6 44.6 23

Rectum 8 5 33 10 38.5 16.4

Anal canal 2 1 8 2

Esophagus 0 1

Analysis of Colonoscopic Findings in the DifferentialDiagnosis Between Intestinal Tuberculosis and Crohn’s Disease .Lee YJ et al Endoscopy 2006; 38 (6): 592–597

Limitations of endoscopic findings

• Overlap not Exclusive findings• Small sample size• No single finding is diagnostic• Correct diagnosis in 90% of cases by scoring

system• No validation studies in different geographical

locations• Scoring system not useful if colon not involved

Statement 11

When granulomas are seen, features which favour ITB are necrosis (caseating), confluence, multiplicity, large size and submucosal location of granulomas and disproportionate degree of submucosal inflammation.

The granulomas seen in CD are usually scant and tiny ( microgranulomas).

Resected specimens: Distinguishing features of intestinal tuberculosis and Crohn’s disease

Macroscopic• TB(n=159) • transverse, circumferential ulcers• short strictures• serosal nodules• • CD(n=10)• longitudinal, serpiginous ulcers along the mesenteric attachment • cobble stone mucosa • fissuring ulcers• submucosal widening• long strictures • frequent presence of fistulae and anal lesions

Tandon and Prakash, Gut 1972; Tonghua et al, Chin Med J, 1981

Resected specimens: Distinguishing features of intestinal tuberculosis and Crohn’s disease

Microscopic• TB: • large, confluent, usually caseating granulomas surrounded by an

inflammatory cuff and fibrosis • pyloric gland metaplasia• fibrosis of the muscularis propria

• CD:• Discrete, small granulomas without a cuff of inflammatory cells or

peripheral fibrosis • transmural lymphoid follicles • lymphangiectasia• subserosal fibrosis

Tandon and Prakash, Gut 1972; Tonghua et al, Chin Med J, 1981

? Applicability to mucosal biopsies

• Changes below superficial submucosa cannot be evaluated • transmural lymphoid follicles, submucosal widening, serosal nodules,

fibrosis of the muscularis propria and even fissuring ulcers

• granulomas found exclusively in regional lymph nodes and not in the intestinal wall in 6 to 24% of resected specimens!

• Quantity of tissue limited: ? Sampling error

• Hoon et al 1950 - 44 cases; Anand SS 1956 - 50 cases; Tandon et al 1972 – 159 cases

TB versus Crohn’s on Mucosal Biopsies

• Only clinically confirmed cases with histological findings

• Total of 100 cases (50 of TB and 50 of Crohn’s)

• Granulomas: size, number, location• Other lesions• Segmental distribution of changes

Pulimood et al, Gut 1999; Pulimood et al, J Gastroenterol Hepatol, 2005


Tuberculosis:• Caseation• Confluence• Lymphoid cuff • Granulomas larger than 400 micrometer• 5 or more granulomas in biopsies from one segment• Granulomas located in the submucosa or granulation tissue:

often with palisaded histiocytes• Disproportionate submucosal inflammation

Pulimood et al, Gut 1999; Pulimood et al, J Gastroenterol Hepatol, 2005


Crohn’s disease:Granulomas• Small (<200 micrometer) • Discrete• Very few / single • Poorly organised • Commonly located in the mucosa

• “microgranulomas”: aggregates of histiocytes

• Crypt-centric inflammation: pericryptal granulomas and focally enhanced colitisPulimood et al, Gut 1999; Pulimood et al, J Gastroenterol Hepatol, 2005


Histological features that were not useful

• Aphthous ulcers• Chronic inflammation• Architectural alteration• Patchy inflammation• Skip lesions

Segmental Distribution of Lesions in Intestinal Tuberculosis and Crohn’s Disease

Granulomatous Inflammation

Tuberculosis(n=31 cases)

Crohn’s disease(n=33 cases)

Table 2 :Prevalence of selected histological parameters in patients with intestinal

tuberculosis (ITB) and Crohn’s disease(CD): A comparison of three studies.Pulimood et al.

(1999)

South India

Pulimood et al.

(2005)

South India

Kirsch et al. (2006),

Cape

Town, South Africa

Jin et al

(2010)

Korea

ITB

(n =20)

CD

(n = 20)

ITB

(n = 33)

CD (n =

31)

ITB (n =

18)

CD (n =

25)

TB ( n=52) CD ( n=26)

Caseous necrosis 40 0 36 0 22 0 26.9 0

Confluent granulomas 60 0 42 3 50 0 46.2 7.8

‡5 granulomas ⁄ biopsy site 40 0 45 0 44 24

‡10 granulomas ⁄ biopsy site - - - - 33 0

Large granulomas Diameter

>200 micron

90 5

Diameter >400

micron

51 0

Area > 0.05 mm2

67 8

75 19.2

Submucosal granulomas 45 5 39 6 44 12

Ulcers lined by bands of

Epithelioid histiocytes

45 5 61 0 61 8

Disproportionate

submucosal

Inflammation

65 5 - - 67 10

Architectural distortion distant

to granulomatous inflammation

- - 0 62 - -

Role of mucosal biopsies in the differentiation of intestinal tuberculosis from Crohn’s disease

• Certainly useful, but have their limitations

• Need to explore the use of complementary techniques like molecular studies to improve the diagnostic yield

• A trial of 8-12 weeks anti TB therapy is reasonable in patients where it is not possible to confidently differentiate ITB from CD

• In patients showing no or partial symptom response at 8-12 weeks, a repeat colonoscopy should be done.

• To differentiate ITB from CD, a colonoscopy is suggested to document mucosal healing at the completion of ATT.

Colonoscopy evaluation after short-term anti-tuberculosis treatment in nonspecific ulcers on the ileocecal areaPark et al, World J Gastroenterol 2008 ; 14(32):5051-5058

18 patients with nonspecificulcers on the ileocecal area7 patients of confirmed tuberculous colitis

The follow-up colonoscopy was performed after 2-3 months of ATT


If there were healing of active ulcers similar to tuberculous colitis on follow up colonoscopy findings, the patients were classified as“suspicious tuberculous colitis group”, If there were still active ulcers or extension of the lesion, classified as “suspicious IBD group”.

Mean duration for short-term follow up was 107.3 days



2-mo to 3-months trial of ATT andcolonoscopy follow-up are very useful for differential diagnosis of tuberculous colitis with other inflammatory bowel diseases

Response to trial of antitubercular therapy in patients with

ulceroconstrictive intestinal disease and an eventual diagnosis of Crohn’s disease

Khushboo Munot1 , Ashwin N Ananthakrishnan2, Vikas Singla1, Jaya Benjamin1, Saurabh Kedia1, Rajan Dhingra1, Govind Makharia1,

Vineet Ahuja1

1Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India, 2

Gastrointestinal Unit, Massachusetts General Hospital, Boston, USA

Objectives

Evaluating a) clinical response b) temporal profile of nonresponse/relapse c) mucosal response to anti-tubercular therapy in patients with

ulceroconstrictive intestinal disease and an eventual diagnosis of Crohn’s disease

Ulceroconstrictive Small or large intestine disease

ATT trial : 2 months of INH, rifampicin,pyrizinamide, ethambutol 4-7 months of INH, rifampicin

Patient follow up : 1 , 2 , 3 and 6 months Every 6 months thereafter

Final diagnosis of CD made : Loss of response following ATT with response to steroids

For comparison of symptom response: 25 confirmed cases of ITB

Outcome Measures

1. Global symptomatic response : on a visual analogue scale at 1,2, 3, 6 and > 6 months following ATT initiation

2. Individual symptom response of weight loss, abdominal pain, diarrhea, subacute intestinal obstruction (SAIO) and hematochezia

3. Colonoscopy changes at end of therapy were compared to baseline colonoscopy

50% response 75% response

100% responseVisual Analog Scale

Complete Response

Partial Response

No Response

Relapse

380 patients with Crohn’s disease

115 (30.26%) patients received a trial of anti tubercular therapy before being eventually diagnosed as Crohn’s disease

109 CD patients were included in the study

6 patientsLongitudinal records not available

Patient Flow chart

Duration of ATT (months) Mean ( range )<6 months6 months7-8 months9 months10-11 months12 months>12 months

8.22 (3-20)

9 (8.3%)34 (31.2%)13 (11.9%)29 (26.6%)6 (5.5%)11 (10.1%)7 (6.3%)

PCR in Colonic biopsy positive for Mycobacterium tuberculosis

12/59 ( 20.3%)

Therapy for Crohn’s disease started while the patient was on ATT

22 (20.2%)

Time Interval of diagnosis of CD after starting ATT trial (months) Mean ( range)

14.70 (3-48)

Overall response to ATT : Temporal Profile

N= 109 N=109 N=109 N =87 N =63

Figures denotepercentages

Time Period –Response CD (n=109)N(%) ITB(n=25)N(%) P valueAt 1 month(n=109)Complete response 1 (0.9) p<0.001Partial response 9 (8.3) 21 (84)No response 99 (90.8) 4 (16)At 2 months( n=109)Complete response 3 (2.8) 4 (16) p<0.001Partial response 14 (12.8) 20 (80)No response 90 (82.6) 1 (4)Worsened 2 (1.8)At 3 months(n=109)Complete response 5 (4.6) 17 (68) p<0.001Partial response 38 (34.9) 8 (32)No response 63 (57.8)Worsened/relapsed 3 (2.7)At 6 months(n=87)Complete response 15 (17.4) 23 (92) p<0.001Partial response 29 (33.7) 2 (8)No response 35 (39.6)Worsened/relapsed 8 (9.3)

Figures denote percentages

P<0.001

P<0.001

Abdominal pain

Weight Loss

Comparison of Individual symptom profile in patients with CD and ITB on ATT

Figures denote percentages P=0.013

P=0.001

Diarrhoea

SAIO P=0.065Hematochezia

Comparison of Individual symptom profile in patients with CD and ITB on ATT

Changes observed on colonoscopy before starting ATT and after ATT trial in patients with Crohn’s Disease

N=62Figures denotepercentages

Crohn’s Disease (n=62)

ITB (n=17)

Segment involved by disease before and after ATTTerminal IleumBaseline 30 (48.4%) 12 (85.7%)After therapy 29 (46.8%) 0Ileocaecal valve Baseline 14 (22.6%) 11 (78.6%)After therapy 18 (29%) 0Caecum and Ascending colon Baseline 39 (62.9%) 10 (66.7%)After therapy 37 (52.7%) 2 (13.3%)Transverse ColonBaseline 21 (33.9%) 3 (17.6%)After therapy 25 (40.4%) 2 (11.8%)

Crohn’s Disease (n=62)

ITB (n=17)

Segment involved by disease before and after ATTDescending colonBaseline 18 (29%) 5 (29.4%)After therapy 24 (38.7%) 3 (17.6%)Sigmoid ColonBaseline 20 (32.2%) 3 (17.6%)After therapy 26 (41.9%) 0RectumBaseline 16 (25.8%) 2 (11.8%)After therapy 20 (32.3%) 0Perianal Baseline 8 (12.9%) 0After therapy 10 (16.1%) 0

N=67 N=17

P<0.001Figures denote Percentages

Changes observed on colonoscopy before starting ATT and after ATT trial in patients with Crohn’s Disease

Conclusions

• 30% of CD patients in India require a therapeutic trial of ATT before confirmation of the diagnosis

• With 6 months of ATT , a global symptomatic response is seen in 50% of Crohn’s disease

• Colonoscopy did not show corresponding mucosal healing

• All ITB patients showed either complete or partial response by 3 months of therapy suggesting that persistence of symptoms or relapse after a 3-month ATT trial may indicate a diagnosis of CD

Diagnostic confusion between ITB and CD

Start ATT

Clinical Response : 2 months

Worsening Repeat colonoscopy and biopsyPossibility of CD


Worsening No improvement on colonoscopy Possibility of CD


Partial improvement

Improvement

Colonoscopy If no change in lesions : CD

Colonoscopy If healing of lesions : ITB

Statement 14

Statement 14 -Amended

Starting concomitant therapy for CD and ITB should be discouraged in patients that are indeterminate for ITB and CD except in patients presenting with severe disease requiring urgent response. [III-C]

[Dual therapy for inderterminate for ITB and CD presenting with severe disease requiring immediate response, concomitant CD and a complete ATT course can be considered.

In patients with mild to moderate disease indeterminate for ITB and CD who were initially treated with ATT alone and showed partial or no response at 8-12 weeks, the options include switch or add-on CD treatment.

For severe disease, surgery may be an option] - subtext

Timer Period –Response CD (n=109)N(%)

ITB(n=25)N(%)

P value

At 1 month(n=109)Complete response 1 (0.9) p<0.001Partial response 9 (8.3) 21 (84)No response 99 (90.8) 4 (16)At 2 months( n=109)Complete response 3 (2.8) 4 (16) p<0.001Partial response 14 (12.8) 20 (80)No response 90 (82.6) 1 (4)Worsened 2 (1.8)At 3 months(n=109)Complete response 5 (4.6) 17 (68) p<0.001Partial response 38 (34.9) 8 (32)No response 63 (57.8)Worsened/relapsed 3 (2.7)At 6 months(n=87)Complete response 15 (17.4) 23 (92) p<0.001Partial response 29 (33.7) 2 (8)No response 35 (39.6)Worsened/relapsed 8 (9.3)

Case Scenarios

• A patient has completed 5 months of ATT and then shows lack of response

• ? Drug resistant tuberculosis

Documents

Asia Pacific Working Party on Crohn’s Disease Vineet Ahuja Dept of Gastroenterology All India Institute of Medical Sciences New Delhi, India