Natural history of Crohn’s disease in patients who underwent intentional restorative proctocolectomy with ileal pouch-anal anastomosis

Natural history of Crohn’s disease in patients who underwentintentional restorative proctocolectomy with ileal pouch-analanastomosisB. SHEN*, S . PATEL� & L. LIAN* ,�

*Digestive Disease Institute, the

Cleveland Clinic Foundation,

Cleveland, OH, USA; �Department of

Colorectal Surgery, The Sixth

Affiliated Hospital of Sun Yat-Sen

University, Guangzhou, China

Correspondence to:

Dr B. Shen, The Digestive Disease

Institute—A31, The Cleveland Clinic

Foundation, 9500 Euclid Avenue,

Cleveland, OH 44195, USA.

E-mail: [email protected]

Publication data

Submitted 15 October 2009

First decision 5 November 2009

Resubmitted 21 December 2009

Accepted 22 December 2009

Epub Accepted Article 25 December

2009

SUMMARY

BackgroundCrohn’s disease is generally considered a relative contraindication forrestorative proctocolectomy with ileal pouch anastomosis (IPAA). Thenatural history of IPAA in these patients has not well been defined.

AimTo evaluate the natural history of IPAA in patients with a well-definedpreoperative Crohn’s disease.

MethodsAll patients from the Pouchitis Clinic who had a preoperative diagnosisof Crohn’s disease were screened and 11 patients met the inclusion cri-teria. The control group (with a 1:4 ratio) consisted of IPAA patientswith a preoperative diagnosis of UC.

ResultsDuring the follow-up period of 5.0 years, 7 of 11 (63.6%) with a pre-operative diagnosis of Crohn’s disease developed Crohn’s disease of thepouch. Crohn’s disease of the pouch developed 0.2–15 years after ileos-tomy closure. The remaining four patients with a preoperative diagnosisof Crohn’s disease did not demonstrate signs of Crohn’s disease in 2, 11,11 and 24 years after pouch surgery, respectively.

ConclusionsPost-operative development of Crohn’s disease of the pouch was com-mon in patients with a preoperative diagnosis of Crohn’s disease whounderwent IPAA. Long-term medical therapy was often required. Largemulti-centre studies are warranted to delineate further the natural his-tory of the disease, before Crohn’s disease is considered an indicationfor IPAA.

Aliment Pharmacol Ther 31, 745–753

Alimentary Pharmacology & Therapeutics

ª 2010 Blackwell Publishing Ltd 745

doi:10.1111/j.1365-2036.2009.04227.x

INTRODUCTION

Crohn’s disease (CD) of the pouch can develop any

time during the course of restorative proctocolecomy

with IPAA.1 It may even occur before ileostomy clo-

sure. Although there are no data on the actual annual

incidence of CD of the pouch, the disease entity has

increasingly been recognized, with reported cumula-

tive frequency ranging from 2.7% to 13%.2–10 This

discrepancy in the prevalence may reflect differences

in the sample size, clinical practice settings, diagnostic

criteria used and intensity of follow-up among the

studies.

Crohn’s disease of the pouch occurs in the follow-

ing settings: (i) an ileal pouch is intentionally

constructed in ‘motivated’ patients with a known

preoperative diagnosis of CD; (ii) an ileal pouch was

inadvertently constructed in patients with a preopera-

tive diagnosis of ulcerative colitis (UC) or indetermi-

nate colitis (IC) who were later found to have CD in

colectomy or rectal stump specimens; and (iii)

De novo CD of the pouch can occur weeks (early-

onset) to years (late-onset) after proctocolectomy or

IPAA for UC and a histopathological reassessment of

the proctocolectomy specimens may not show features

suggestive of Crohn’s colitis, such as granulomas and

transmural inflammation.4

Although CD or Crohn’s colitis is generally consid-

ered a relative contraindication for IPAA, the proce-

dure has been intentionally performed in a selected

group of patients with no obvious small intestinal or

perianal diseases.11–13 However, there were arguments

that Crohn’s colitis in some of original reported cases

might not be true Crohn’s disease, as rectal sparing in

non-index colonoscopy might have been a sign of

treated UC. On the other hand, we found that CD of

the pouch may or may not develop after IPAA in this

group of patients in our clinical practice, which may

be one of the reasons that the IPAA procedure has

been advocated in a highly selected patient population

with CD by some clinical investigators. There was dis-

crepancy in reported pouch outcomes in patients with

a preoperative diagnosis of CD or Crohn’s colitis.

While some studies suggested that patients with a pre-

operative diagnosis of CD had a higher pouch failure

rate,14, 15 others found that patients with a late-onset,

de novo CD of the pouch had a poorer prognosis than

those with a preoperative diagnosis of CD.12 A meta-

analysis was performed to evaluate 10 studies pub-

lished between 1980 and 2005 comparing outcomes

of patients undergoing IPAA for CD, UC and IC with a

total of 3103 patients. Patients with a preoperative or

post-operative diagnosis of CD developed more anas-

tomotic strictures than non-CD diagnoses with an

odds ratio of 2.12 and patients with CD (32%) experi-

enced pouch failure more frequently than patients

with UC (4.8%) or IC (5%). However, patients with iso-

lated Crohn’s colitis were not significantly at

increased risk for immediate post-operative complica-

tions.16 The discrepancy in pouch outcome among the

published studies can again be attributed to multiple

factors, such as inclusion criteria and exclusion crite-

ria, diagnostic criteria used for Crohn’s colitis and

institutional expertise. For example, it was not clear

that whether some of the patients truly had Crohn’s

colitis or just UC with patchy disease distribution due

to treatment. It was reported that ‘true’ Crohn’s colitis

with granulomas had a higher pouch failure rate after

IPAA.17

The natural history of the ileal pouch in patients

with a definitive preoperative diagnosis of CD has not

been well delineated. Since the establishment of our

subspecialty Pouchitis Clinic in 2002, we have diag-

nosed and managed a large number of patients with a

variety of ileal pouch disorders. CD of the pouch is

one of the most common long-term adverse sequalae

of IPAA. The aim of the study was to evaluate the nat-

ural history of IPAA in patients with a definite diag-

nosis of CD of the pouch, as compared with patients

who had a preoperative diagnosis of UC.

PATIENTS AND METHODS

Patients

The historical cohort included all patients who were

registered into the Institutional Review Board-approved

Pouchitis Registry from 2002 to 2008 and informed

consent was obtained from all patients. This Pouchitis

Registry, in which the pouch of approximately 50% of

patients was originally constructed outside institutions,

is different from our large 3500-case Pouch Registry

where all pouches were created at the Cleveland

Clinic.12 All patients in this study were recruited from

our subspecialty Pouchitis Clinic where the Pouchitis

Registry resides. The study group included IPAA

patients with a preoperative diagnosis of CD and the

control group consisted of IPAA patients with a preop-

erative diagnosis of UC. Age-matched IPAA patients

with a pre- and intra-operative diagnosis of UC were

746 B . SHEN et al.


ª 2010 Blackwell Publishing Ltd

randomly selected from the Pouchitis Database with

the case-to-control ratio of 1:4.

Inclusion and exclusion criteria

All patients from the Pouchitis Clinic who had a pre-

operative diagnosis of CD were screened. Twenty-three

patients carried a preoperative diagnosis of CD.

Among them, the diagnosis of CD in 12 patients was

based on ‘patchy disease distribution’ and ⁄ or ‘rectal

sparing’ in non-index colonoscopy. After careful

review of charts, particularly index colonoscopy and

biopsy reports, these patients had had diffuse colitis

with proctitis. Therefore, they actually had had UC

rather than Crohn’s colitis and therefore were excluded

from the study. The remaining 11 patients had true CD

as evidenced by characteristic clinical, endoscopic and

histological features (Table 1). We also excluded

patients with IPAA for IC or familial adenomatous

polyposis.

Diagnostic criteria

Pre- and intra-operative diagnosis of CD was based

on the following criteria: (i) endoscopic and histologi-

cal rectal sparing on index colonoscopy; (ii) the pres-

ence of non-caseating, non-foreign-body-associated

granulomas on colon biopsy and ⁄ or colectomy speci-

mens; (iii) transmural inflammation in the area out-

side deep ulceration in colectomy specimens in

patients with non-fulminant colitis; (iv) upper small

bowel involvement of chronic active inflammation

with or without granulomas; (v) perianal diseases with

abscesses, fistula-in-ano, and rectovaginal fistula, in

the absence of cryptoglandular abscess ⁄ fistulae; and

(vi) ulcerated fibrostenotic strictures at the colon,

ileocaecal valve, or small bowel. Anal fissures,

haemorrhoids and skin tags were not considered as a

criteria for CD.

Crohn’s disease of the pouch was diagnosed if there

were non-surgery related perianal fistulae, granulomas

on histology or inflammation and ulcerations in the

afferent limb or small bowel on endoscopy in the

absence of non-steroidal anti-inflammatory drug

use.18 Chronic antibiotic-refractory pouchitis was

defined as a condition where a patient fails to respond

to a 4-week course of a single antibiotic (metronida-

zole or ciprofloxacin), requiring prolonged therapy of

‡4 weeks consisting of ‡2 antibiotics, oral or topical

5-aminosalicylate, corticosteroid therapy or oral

immunomodulator therapy.

Demographic and clinical variables

We assessed multiple demographic and pre- and post-

clinical variables. The variables included age, gender,

tobacco use, family history of IBD, duration of IBD,

duration of pouch, indications for IPAA, preoperative

biological therapy, stage of pouch surgery, redo pouch,

pouch type, number of follow-up visits to the Pouchi-

tis Clinic, current use of biological therapy, current

use of immunomodulators and extraintestinal manifes-

tations (including the presence of arthralgia or arthrop-

athy, pyoderma gangrenosum, erythema nodosum,

Table 1. Preoperative diagnostic criteria for Crohn’s disease (n = 11)

Patients

Rectal sparingon indexcolonoscopy

Granuloma onbiopsy orcolectomy

Perianaldisease

Colonicstricture

Perianalfistula

Transmuralinflammationon colectomy

Upper GIdisease

1 No No No Yes Yes No No2 No No No No Yes No No3 No No No No Yes No No4 Yes Yes No No No Yes No5 No Yes No No No No No6 Yes Yes No No No No No7 Yes Yes No No No No No8 No Yes Yes Yes No No No9 Yes Yes No No No Yes No

10 Yes No No No Yes No Yes11 Yes Yes No No No No No

I LEAL POUCH-ANAL ANASTOMOSIS FOR CROHN’S D ISEASE 747



IBD-related ocular lesions, thromboembolic events and

primary sclerosing cholangitis). Pancolitis was defined

by the presence of endoscopic, macroscopic or micro-

scopic disease extending proximal to the splenic

flexure. Concurrent autoimmune disorders included

autoimmune thyroid diseases, rheumatoid arthritis,

pernicious anaemia, coeliac disease, systemic lupus

erythematosus, chronic asthma, type I diabetes, rheu-

matoid arthritis, psoriasis, autoimmune haemolytic

anaemia, vitiligo, idiopathic thrombocytopenic purpura

and multiple sclerosis.

Outcome measurement

We compared pouch failure, CD of the pouch, pouch-

associated hospitalization and post-operative long-term

medication use between the study and control groups.

Statistical analysis

Descriptive statistics were computed for all variables.

These included means, medians with interquartile

range for continuous factors and frequencies for cate-

gorical variables. Student’s t-tests, Wilcoxon rank sum

tests and Fisher’s Exact tests for categorical and non-

categorical variables. P values <0.05 were considered

statistically significant. SAS version 9.1 software (The

SAS Institute, Cary, NC, USA) was used to carry out

all analyses. A 1:4 case-control ratio was chosen to

increase the power of the study.

RESULTS

Demographic and clinical variables

Of 23 patients labelled CD before surgery, 11 truly did

have CD. The main cause for the false positivity for

CD was the ‘patchy’ disease and rectal sparing in

non-index colonoscopy. Therefore, 12 patients who

had been labelled as Crohn’s colitis were actually UC

and they had had diffuse colitis including rectal

involvement on index colonoscopy. Their later ‘patchy’

disease and rectal sparing might have resulted from

oral or topical medical therapy (Table 2).

Preoperative diagnosis of Crohn’s disease

A majority of the patients in the study groups

met multiple diagnostic criteria for CD before or dur-

ing colectomy. After carefully reviewing medical

records, particularly endoscopic and histological

report, six patients (54.5%) were found to have rectal

sparing on index colonoscopy. Seven patients (63.6%)

had noncaseating, non-foreign-body-associated granu-

lomas on colon biopsy or colectomy specimens. Simple

perianal fistulae were present in four patients (36.4%)

(Table 1).

Post-operative diagnosis of Crohn’s disease ofthe pouch

The mean duration of the pouch was 8.9 � 6.7 years.

During the follow-up period, 7 of 11 (63.6%) with a

preoperative diagnosis of CD eventually developed CD

of the pouch. The mean interval from pouch construc-

tion to diagnosis of CD of the pouch was 5.0 � 4.9

years, with a range from 0.2 to 15 years after ileo-

stomy closure. The remaining four patients with a

preoperative diagnosis of CD did not demonstrate any

signs of CD 2, 11, 11 and 24 years after pouch surgery

respectively. It appears that there were no consistent

patterns or phenotypes between preoperative CD and

post-operative CD of the pouch. For example, patient

2 and patient 3 had perianal fistulae before colectomy

and developed CD of the pouch with strictures and

ileitis without fistulae (Table 3).

Pouch outcomes

With a median of 7 (interquatile range 4–11) years of

follow-up, seven patients (63.6%) in the study group

developed CD of the pouch and four patients (35.4%)

showed no endoscopic, radiographic, and histological

evidence of CD. Therefore, a preoperative diagnosis of

CD did not necessarily lead to the development of CD

of the pouch. In contrast, in the control group, seven

patients (15.9%) developed CD of the pouch. It appears

that the pouch failure rate was similar between the

study and control groups.

Of the seven patients with CD in the study group,

two patients were treated with adalimumab, two

patients were treated with mercaptopurine, 10 patients

were on long-term antibiotics (metronidazole, tini-

dazole, ciprofloxacin or rifaximin). All three patients

with strictures were treated with endoscopic balloon

dilations (Table 4).

We also evaluated the 12 patients with a precolecto-

my diagnosis of ‘CD’ who were but later diagnosed

with UC after clinicopathological data were reviewed

again. The mean age of this group was 48.9 � 10.6

748 B . SHEN et al.



years, with four being women (33.3%). All of them

(100%) had extensive colitis. Three patients did have

use infliximab before colectomy. The mean duration

from UC diagnosis to pouch construction was

13.2 � 9.1 years. With a mean duration of 8.8 � 4.7

years, one patient (8.3%) developed inflammatory CD,

one (8.3%) had fistulizing CD and two patients (16.7%)

developed pouch failure from surgical complications

(chronic anastomotic sinus and leak).

DISCUSSION

Natural course of IPAA in patients with a known pre-

operative diagnosis of CD has not been well defined.

Table 2. Comparison of demographic and clinical data

Variables

PreoperativeCrohn’s disease

(n = 11)

Preoperativeulcerative colitis

(n = 44) P value

Mean current age, years, � standard deviation 45.2 � 18.5 47.5 � 15 0.58Male gender 9 (81.8%) 22 (50%) 0.09Mean duration of pouch, years, � standard deviation 8.8 � 6.6 8.6 � 6.1 0.93Caucasian race 11 (100%) 42 (95.4%) 1Smoking 0.06

Never 7 (63.6%) 40 (91%)Ex-smoker 2 (18.2%) 2 (4.5%)Active 2 (18.2%) 2 (4.5%)

Chronic NSAID use 2 (18.2%) 6 (13.6%) 0.65Family history of IBD 2 (18.2%) 7 (15.9%) 0.61Duration of UC from diagnosis to IPAA,median years (interquartile range)

3 (0–11) 5 (1–16.8) 0.32

Indication for colectomy 1Refractory disease 9 (81.8%) 36 (81.8%)Dysplasia 2 (18.2%) 8 (18.2%)

Preoperative extensive colitis 11 (100%) 42 (95.5%) 1Toxic megacolon 1 (9.1%) 1 (2.3%) 0.36Preoperative biological therapy 2 (18.2%) 2 (4.5%) 0.171st visit to pouchitis clinic to date,median yrs (interquartile range)

5 (3–5) 4 (2–4) 0.15

Duration of pouch construction to last visit,median years (interquartile range)

7 (4–11) 7 (4–10.8) 0.96

J pouch configuration 10 (90.9%) 43 (97.7%) 0.36Stage of pouch surgery 0.4

2 7 (63.6%) 35 (79.5%)3 3 (27.3%) 6 (13.6%)4 1 (9.1%) 3 (6.8%)

Primary sclerosing cholangitis 1 (9.1%) 1 (2.3%) 0.36Final diagnoses 0.08

Normal pouch 0 2 (4.5%)Irritable pouch syndrome 1 (9.1%) 8 (18.2%)Active pouchitis 3 (27.3%) 8 (18.2%)Refractory pouchitis 0 7 (15.9%)Crohn’s disease of the pouch 7 (63.6%) 7 (15.9%)Cuffitis 0 7 (15.9%)Surgical complication 0 4 (9.1%)Primary anismus 0 1 (2.3%)

Extraintestinal manifestations 0.07Joints 4 (36.4%) 14 (31.8%)Eyes 0 1 (2.3%)Thromboembolic events 2 (18.2%) 0

Mean number of visits of pouchitis clinic, 2.2 � 1.3 2.3 � 1.3 0.79




In patients with a true preoperative diagnosis of CD,

the majority (63.6%) eventually developed CD of the

pouch. It appears that CD of the pouch can develop

anytime after pouch construction, ranging from 0.2 to

15 years after ileostomy closure. On the other hand, a

preoperative diagnosis of CD did not necessarily trans-

late into the development of post-operative CD of the

pouch. In addition, a preoperative diagnosis of CD did

not necessarily indicate more pouch failure or pouch-

associated hospitalization than the patients with a

Table 4. Comparison of pouchoutcome

Variables

PreoperativeCrohn’sdisease(n = 11)

Preoperativeulcerativecolitis(n = 44) P value

Pouch failure 1 (9.1%) 4 (9.1%) 1Reason for pouch failure

Surgical complications 0 1 (2.3%)Chronic pouchitis 0 2 (4.5%)Crohn’s disease of the pouch 1 (9.1%) 1 (2.3%)

Chronic antibiotic use 10 (90.9%) 22 (50%) 0.017Chronic immunomodulator usefor pouch disorder

2 (18.2%) 3 (6.8%) 0.26

Post-operative biologics use forpouch disorders

2 (18.2%) 3 (6.8%) 0.26

Crohn’s disease of the pouch 7 (63.6%) 7 (15.9%) 0.003Phenotypes Crohn’s diseaseof the pouch

1

Inflammatory disease 1 (9.1%) 3 (6.8%)Fibrostenotic 2 (18.2%) 1 (2.3%)Fistulizing 4 (36.4%) 3 (6.8%)

Pouch-associated hospitalization 0.51For medical therapy 2 (18.2%) 4 (9.1%)For non-resection surgery 0 1 (2.3%)For pouch excision or permanentdiversion

1 (9.1%) 2 (4.5%)

Table 3. Post-operative development of Crohn’s disease of the pouch (n = 11)

Duration ofpouch, years

Interval frompouch to CDdiagnosis, years Most recent diagnosis

Diagnostic criteria for Crohn’s pouch

Perianalfistula

Ileitis +strictures Granulomas

1 24 NA Antibiotic-dependent pouchitis NA NA NA2 17 15 CD No Yes No3 4 0.2 CD No Yes No4 11 NA Irritable Pouch Syndrome NA NA NA5 8 4 CD Yes No No6 7 6 CD Yes No No7 2 2 CD No No Yes8 7 6 CD Yes No No9 5 2 CD Yes Yes Yes

10 11 NA Antibiotic-responsive pouchitis NA NA NA11 2 NA Irritable pouch syndrome NA NA NAMean � s.d. 8.9 � 6.7 5.0 � 4.9 (n = 7) – – – –

750 B . SHEN et al.



preoperative diagnosis of UC. However, in the former

group of patients, chronic antibiotic use was almost a

norm. In addition, numerically more patients in the

study group were using immumomodulators and ⁄ or

biologics than in the control group.

While restorative proctocolectomy with IPAA has

been routinely performed in patients with IC or

inflammatory bowel disease-unclassified (IBDU),19 it is

debatable whether patients with CD can have IPAA

procedure. In a study of 25 patients with a pre-

(n = 9) and post- (n = 16) operative diagnosis of CD,

with a mean follow-up of 38 months, 16 patients have

a functioning pouch, seven had pouch excision, one

had pouch diversion and one died. Only one of the

nine patients in whom there was a preoperative diag-

nosis of CD had a functioning pouch, with complica-

tions uniformly occurring within months of ileostomy

closure. In contrast, 15 of the 16 patients with a post-

operative diagnosis CD of the pouch maintained their

pouch. It was therefore suggested that patients with a

preoperative diagnosis of CD should be contraindicated

for having IPAA.14 This notion was further supported

by a study from Mt Sinai Hospital, Toronto. Of 1270

patients with IPAA (1135 UC, 36 CD, and, 21 IC),

pouch complications were significantly more common

in patients with a preoperative diagnosis of CD (64%)

or IC (43%) than patients with a preoperative diagnosis

of UC (22%). Pouch failure rates were 56% for CD,

10% for IC and 6% for UC.15 Furthermore, a descrip-

tive study of 52 patients with CD or IC from a total of

1652 patients from St Mark’s Hospital, London also

showed that patients with a preoperative diagnosis of

IC or IC favouring UC had a pouch failure rate of

11.5% vs. 57.5% for patients with CD or IC favouring

CD.20 Treatment of CD of the pouch can be challeng-

ing. There were scant data on treatment of this disease

entity of the pouch. Biological agents, such as inflix-

imab21 and adalimumab,22 have been used.

Ileal pouch anastomosis, on the other hand, has

been advocated for a highly selected group of patients

by some clinical investigators based on their ‘compa-

rable’ outcome. In a study of 41 pouch patients from

France with a pre- (n = 26) or post- (n = 15) operative

diagnosis of CD and a mean pouch follow-up of

47 months, two had persistent anal ulcers with pou-

chitis and granulomas on pouch biopsy and were trea-

ted medically; two experienced extrasphincteric

abscesses and seven presented pouch-perineal fistulas.

In the 20 patients followed up for more than 10 years,

7 (35%) experienced CD-related complications, which

required pouch excision in two (10%). The authors

suggested that these acceptable long-term results may

justify considering IPAA in selected patients with

Crohn’s colitis.23 A retrospective analysis examined

the long-term outcomes in 12 patients with IPAA who

had a preoperative diagnosis of CD as compared with

100 patients with a preoperative diagnosis of UC, with

a mean follow-up of 76 months (range 12–192).

Demographic and clinical data, post-operative compli-

cations, functional results, anxiety and quality of life

in the two groups were similar.10 A preoperative peri-

anal diseases, including fissure-in-ano, perianal

abscesses, fistula-in-ano, rectovaginal fistula and sig-

nificant haemorrhoids ⁄ skin tags were shown to be

associated with an increased risk for post-operative

anastomotic leaks and perianal complications, but not

occurrence of CD of the pouch or pouch failure.24

The prognosis of CD in patients with IPAA was

determined by multiple factors. A majority of our

patients who were able to maintain the pouch were on

long-term medical therapy. A recent case-control

study of 204 patients with CD of the pouch identified

from our 2834-case Pouch Registry showed that CD

diagnosis was made before IPAA in 20 (10%), from

post-operative histopathology (incidental) in 97(47%)

or made in a delayed fashion at median 36 months

after IPAA in 87 (43%). Multivariate analysis showed

that patients with CD of the pouch with a delayed

diagnosis had a higher risk for pouch failure than

those with a preoperative and perioperative diagnosis

of CD with a hazard ratio of 2.6 [95% confidence

interval (CI) 1.1–6.5]. In other words, for CD patients

with IPAA, when the diagnosis is established preopera-

tively or immediately following surgery, pouch loss

rates were low.12 These results are consistent with

findings in the current study. Of note, the patients in

the current study were identified from our 950-case

Pouchitis Database, which was different from the

3500-case Pouch Registry.

It was not clear whether the IPAA procedure inten-

tionally performed in patients with a preoperative

diagnosis of CD would necessarily lead to the develop-

ment of CD of the pouch. In addition, the exact mech-

anisms of CD of the pouch are not known. We

speculate that faecal stasis and anastomosis, combined

with component of surgically induced ischaemic injury

in genetically susceptible patients, may create a ‘CD-

friendly’ environment and the ‘thermostat’ of balance

between bacteria and mucosal immunity after

IPAA procedure might be reset to gear towards the




development of new sets of IBD, including pouchitis

and CD of the pouch. Multiple clinical studies have

shown that CD of the pouch can develop in patients

with a preoperative diagnosis of UC. Our anecdotal

experience suggested that CD patients who failed to

respond to biological therapy may have a favourable

response to the agents after IPAA and development of

CD of the pouch. On the other hand, not all patients

with a preoperative diagnosis of CD would develop CD

of the pouch after IPAA, as shown in this study.

Risk factors for CD of the pouch have been studied.

In addition to a preoperative diagnosis of CD,12 other

reported risk factors for the development of CD of the

pouch include sero-positive anti-Saccharomyces cere-

visiae-IgA,25 a family history of CD,25, 26 being active

smoker,27 a long duration of pouch, and a preopera-

tive diagnosis of IC.27, 28 Different phenotypes of CD

of the pouch were shown to be associated with differ-

ent risk factors.29 For example, the presence of IC,

younger age, and female gender were associated with

an increased risk for fistulizing CD of the pouch.29

The findings for the current study have several clini-

cal implications. As the natural history of Crohn’s coli-

tis and CD of the pouch is poorly defined, the findings

in the current study may help shed some light. Not all

patients with Crohn’s colitis would necessarily develop

CD of the pouch after restorative proctocolectomy. On

the other hand, not all patients with a clear-cut diag-

nosis of UC before surgery would be immune to the

development of CD of the pouch. Our recent study

(submitted to Digestive Disease Week 2010) showed

that UC patients with the absence of granulomas on

colon biopsy and colectomy specimens can develop

CD of the pouch as evidenced by the presence of non-

caseating granulomas. It is important to assess the dis-

ease distribution of colitis on index colonoscopy, as

patchy disease or rectal sparing can occur in patients

with UC who were medically treated.30, 31 IPAA can be

performed in a selected patient population with a pre-

operative diagnosis of Crohn’s colitis. However,

patients should be made aware that he or she would

have a high chance to develop CD of the pouch and to

maintain the pouch, long-term medical therapy with

or without endoscopy therapy is often required. In

addition, CD of the pouch in these patients often has

compromised health-related quality of life.32 Risks and

benefits of IPAA for these patients should carefully be

balanced.33

There are limitations to this historical cohort study.

There might have been referral bias as all patients

were evaluated and managed at our tertiary subspe-

cialty Pouchitis Clinic. The sample size was small, as it

was not a common practice to construct an ileal pouch

in patients with a known diagnosis of CD.

In conclusion, post-operative development of CD of

the pouch was common in patients with a preoperative

diagnosis of CD who underwent IPAA, but it does not

appear to be necessarily the natural consequence of all

patients. While a majority of the patients with pre- or

post- operative diagnosis of CD were able to keep their

pouches, long-term medical therapy was typically

required. Patients should be fully counselled for poten-

tial development of diseased pouch conditions. Large

multi-centre studies are warranted to delineate further

the natural history of the disease, before CD is consid-

ered an indication for IPAA.

ACKNOWLEDGEMENT

Declaration of personal interests: The authors would

like to thank Eli and Edyth Broad Foundation for the

support. Declaration of funding interests: None.

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Natural history of Crohn’s disease in patients who underwent intentional restorative proctocolectomy with ileal pouch-anal anastomosis