Management of ulcerative colitis in Taiwan: consensus guideline of the Taiwan Society of Inflammatory Bowel Disease

1. Epidemiology

Analyses of data from the population-based Taiwan National Health Insurance Research Database (NHIRD) show steadily increasing incidence and prevalence of UC in Taiwan from 1998 to 2010.456 In 2010, the incidence rate of UC in Taiwan was 1.351 (95% CI, 1.140–1.562) per 100,000 males and 0.858 (95% CI, 0.691–1.024) per 100,000 females, approximately double the incidence rate observed in 2000, which was 0.690 (95% CI, 0.537–0.843) per 100,000 males and 0.386 (95% CI, 0.269–0.503) per 100,000 females.6 Consequently, the prevalence rate of UC in Taiwan has increased more than 5-fold from 1.436 (95% CI, 1.225–1.671) per 100,000 males and 0.891 (95% CI, 0.724–1.084) per 100,000 females in 2000 to 7.610 (95% CI, 7.119–8.125) per 100,000 males and 4.77 (95% CI, 4.388–5.178) per 100,000 females in 2010. In another National health insurance research database (NHIRD)-based study, the incidence and prevalence of UC per 100,000 persons increased from 0.61 and 0.62, respectively, in 1998 to 0.94 and 7.62, respectively, in 2008.4

Worldwide, the incidence and prevalence of IBD are highest in Europe and North America and the rates have been stable over recent decades in these regions.23 In Asia, however, IBD has become increasingly prevalent, though still less so than in Western countries.14 The UC incidence rates in North American and Europe have been reported to be between 6–15.6 and 10–20.3 per 100,000 persons, respectively.15 In Asia-Pacific, a recent population-based study involving 9 countries revealed higher incidence of UC in highly urbanized areas, including Guangzhou, China; Hong Kong; and Macau, with crude annual incidence per 100,000 persons of 2.2, 1.7, and, 1.0, respectively.14 The increasing incidence of UC in Asian countries, including Taiwan, could be attributed to “Westernization” of lifestyle, though increased disease awareness and diagnosis are also possible explanations.1617

According to nationwide studies, the male to female ratio for UC is 1.4 to 1.6 in Taiwan.4567 A population-based analysis of UC incidence in cities in China, Hong Kong, Indonesia, Macau, Malaysia, Singapore, Sri Lanka, and Thailand also showed more male than female patients in UC (male, 57.9%).14 In contrast, reported incidence of UC was more similar between genders in Japan (male, 53.4%) and Korea (male, 49.9%).1819 Epidemiological studies conducted in countries with predominantly Caucasian populations have shown either balanced incidence between genders or higher incidence in males.11202122

Extraintestinal manifestations of UC primarily involve the musculoskeletal, cutaneous, hepatobiliary, and ocular systems.23 A recent analysis of IBD clinical presentation using data extracted from NHIRD found that 11.2% of UC cases in Taiwan from 1998 to 2011 exhibited gastrointestinal complications and extraintestinal manifestations.24 During the 14-year study period, the prevalence of extraintestinal manifestations increased from 2.8% to 26.6%. The increase was mostly attributed to a steady rise in the prevalence of peripheral arthritis, the most common of the manifestations, from 1% in 1998 to 15.4% in 2011. A hospital-based study conducted at the National Taiwan University Hospital using data from 1988 to 2008 revealed that 4.5% of UC patients had extraintestinal manifestations, with primary sclerosing cholangitis, reported in 1.5% of patients, being the most common manifestation in this study.25 In contrast, the reported prevalence of extraintestinal manifestations is substantially higher in Western countries, ranging from 21% to 40%.2627 Less awareness of extraintestinal manifestations in Taiwan and/or real differences due to ethnicity may account for the discrepancy in rates.

2. Diagnosis

No single gold standard for the diagnosis of UC exists. Medical history, clinical evaluation, and typical endoscopic and histological findings must all be taken into consideration for diagnosis. Exclusion of infectious etiology is of exceptional importance, as symptoms of infectious colitis, including those of bacterial, viral, and amebic causes, overlap with those observed with UC.282930313233

Since there is no single diagnostic marker for UC, diagnosis is heavily suspected from the presence of characteristic clinical symptoms. In order to rule out other causes, patients should also be questioned regarding medication use, recent travel, food intolerances, and contact with infectious illnesses. Possible manifestations affecting the eyes, mouth, joints, or skin should be assessed.9

Severity of clinical parameters, including stool frequency, stool consistency, bloody mucoid stool, rectal bleeding, and rectal urgency, should be considered when classifying a patient's disease activity. Appropriate classification of disease extent and severity determines intensity of treatment.34 In clinical trials, clinical disease activity and severity of UC have been commonly scored using Truelove and Witts criteria and the Mayo score.3536 To meet criteria for NHI reimbursement of biologic agents, assessment of disease severity during follow-up using the Mayo score is recommended.

Continuous and confluent inflammation involving the rectum with or without proximal continuous extension into the colon is the typical endoscopic finding in treatment-naive UC patients. There is usually a clear demarcation between inflamed and normal mucosa. Erythema, vascular congestion of the mucosa, loss of visible vascular pattern, granularity, friability, erosions, and superficial ulcerations are endoscopic features of disease activity that is mild to moderate.912 Severe UC is characterized by spontaneous hemorrhage and mucosal ulcerations, and the presence of deep ulcerations has been associated with poor prognosis.3738

Atypical endoscopic features such as an isolated cecal patch of inflammation, a discontinuous pattern of inflammation, and rectal sparing may mimic CD. Therefore, endoscopic characteristics of UC are essential but not specific for a definitive diagnosis. Pathology findings and clinical presentation are also essential for diagnosis, especially in patients with atypical endoscopic features. In addition to guiding diagnosis, colonoscopy is also useful for determining the extent and severity of lesions. However, colonoscopy should be avoided in patients with acute severe colitis to prevent disease aggravation, procedural delays, and increased risk of perforation.939

Plain abdominal radiography is a reliable tool for estimating the extent of active UC and identifying abnormalities such as colonic dilatation, perforation, and obstruction.40 Colonic segmental dilatation exceeding 5 cm in diameter with an irregular mucosal edge outlined by gas on a plain abdominal radiograph correlates strongly with ulceration.41 When radiographic findings are unclear or if no abnormalities are found on radiography when they are highly suspected, the patient should undergo more accurate imaging with CT.42

The committee recommends the use of a checklist for use during histological assessment to support thorough evaluation and accurate diagnosis (Fig. 1). Change to the mucosal architecture includes glandular distortion (crypt branching or shortening, widening of the crypts, and irregular mucosal surface) and abnormalities in epithelial cells (Paneth cell metaplasia, depletion in goblet cells, and mucin depletion). 434445 Pathogenesis of crypt architecture and epithelial cell abnormalities is related to regeneration and repair following previous damage.946 Histological examination should also include evaluation of the presence of dysplasia and or malignant changes.

Fig. 1

Recommended checklist for use during histological assessment of UC. Use of this checklist during histological assessment to support thorough evaluation of mucosal architecture and inflammatory infiltrates and exclusion of differential diagnoses is recommended. TB, tuberculosis; CMV, cytomegalovirus.

Features of inflammatory status include presence of basal plasmacytosis and neutrophilic or eosinophilic infiltration Basal plasmacytosis, also referred to as subcryptal plasma cells, is the presence of plasma cells between the base of the crypts and the muscularis mucosae.43 Neutrophils present in the intestinal crypt are a feature of cryptitis.47 An increase in eosinophils in the lamina propria has been observed in UC; however, as eosinophil are a general sign of inflammation, they are also present in other forms of colitis.48 Conversely, the presence of well-formed epithelioid granulomas in the lamina propria support a diagnosis of CD over UC.49 To assess histological disease activity, the committee recommends the use of the Nancy index at initial diagnosis of UC (reasons for recommending the Nancy index are described below in Section 5.3). It is also suggested that previous biopsy slides be reviewed and assessed upon diagnosis of UC.

A number of histopathological features distinguish UC from CD. Mucin preservation in association with active disease, epithelioid granulomas in the lamina propria, isolated ileal erosions, and pyloric gland metaplasia are features suggestive of CD.495051 Nevertheless, microscopic distinction between UC and CD can be difficult, often resulting in an intermediate diagnosis of “IBD unclassified.” Pathology testing also helps to exclude infectious colitis, such as pseudomembranous, tuberculosis (TB), or cytomegalovirus (CMV) colitis, or malignancy, such as lymphoma or colorectal cancer (CRC).

Endoscopic findings of UC differ according to the severity of disease and history of treatments. In treatment-naive UC patients, endoscopic characteristics are usually typical (as described above in Statement 2.4). In treated cases of UC, endoscopically and histologically discontinuous disease marked by rectal sparing and/or patchy inflammation may develop.525354 In long-standing disease, inflamed mucosa may revert to endoscopically normal mucosa, and the occurrence does not seem to be related to the use of any specific therapy, including rectal therapy.5253 In these patients, rectal sparing and patchiness are not necessarily markers of CD, and the diagnosis should not be changed.5354

3. Specific Considerations

HBV infection is endemic in Asia with East Asia having the highest prevalence among all Asian regions—over 8% of East Asian males aged over 35 years are positive for HBsAg.55 Acute HBV reactivation due to immunosuppressive therapy in patients with IBD can be life-threatening; therefore, to minimize the risk of this complication, HBV screening should be performed prior to the initiation of immunomodulating/immunosuppressive agents for UC.5657

In studies assessing outcome of HBV infection in patients with IBD, 25% to 36% of patients who were HBsAg-positive experienced liver dysfunction.5859 In HBV-infected patients, most cases of HBV reactivation have been observed in those treated with 2 or more immunomodulators for a long period of time, were positive for HBV DNA, and/or had not received prophylactic antiviral treatment.57

Prophylactic antiviral treatment with nucleotide/nucleoside analogues is recommended in patients with detectable HBV DNA. Antiviral prophylaxis should be initiated 2 weeks before start of immunomodulators and continued for 6 to 12 months after their withdrawal.57 Entecavir and tenofovir are preferred in patients with IBD due to their rapid onset of action, high antiviral potency, and low incidence of resistance.57

Vaccination against HBV is suggested in all patients who are naive to HBV. However, a lower response rate to HBV vaccination has been observed in patients with IBD.6061 A study comparing standard-dose protocol and an accelerated double-dose protocol for HBV vaccination in patients with IBD found a significantly higher seroconversion rate in patients vaccinated with double dose (75%) versus standard dose (41%).61 Serological response should be assessed 1 to 2 months after completion of vaccination and regularly thereafter, with a recommended HBsAb level of >100 IU/L.57

Taiwan is a TB-endemic country with a TB prevalence of 97 per 100,000 persons.62 Patients with IBD are at higher risk of TB infection than the general population due to the use of immunomodulators including biologic treatments.57 Furthermore, diagnosis of TB can be more difficult in patients on anti-tumor necrosis factor (anti-TNF) therapy as their disease is more commonly atypical, extrapulmonary, and disserminated.57 In Taiwan, 4.2% of all reported TB cases in 2010 were extrapulmonary, 5.8% of which occurred in the gastrointestinal tract.62 Careful evaluation of clinical presentation and endoscopic, radiographic, and histological findings is needed to differentiate intestinal TB from CD. All UC patients should be screened for latent TB prior to biologic therapy with a combination of physical examination, chest radiography, and TST or IGRA. It should be noted that results of TST can be affected by prior BCG vaccination, whereas IGRA (QuantiFERON-TB GOLD) is not affected.63

In patients with latent TB, chemoprophylaxis is highly effective in decreasing the risk of TB reactivation. Treatment of latent TB should follow the current guideline recommendations set forth by the Taiwan Centers for Disease Control.64 Biologic therapy should not be initiated until at least 4 weeks of TB treatment has been administered. Consultation with an infectious disease or chest specialist for multidisciplinary care is mandatory.

For patients with IBD receiving biologic treatment, signs and symptoms of active TB disease should be monitored regularly. Chest radiography, and IGRA if available, should be performed every 6 to 12 months.62 Travel and TB contact history should be monitored while the patient is receiving immunosuppressive treatment. An infectious disease specialist should be consulted when necessary.

4. Treatment

In the management of patients with UC, it is crucial to promptly identify those with severe disease requiring hospital admission to avoid delays in monitoring and treatment. Clinical disease severity can be assessed using the Mayo scoring system, which classifies severity according to frequency of bowel movements, rectal bleeding, endoscopic findings, and physician's global assessment.36 Those with mild or moderately active disease can be managed on an outpatient basis, with choice of treatment based on location of disease (proctitis, left-sided colitis, or pancolitis). Treatment is aimed at inducing and maintaining remission, preventing complications, and improving quality of life, and should be individualized according to distribution and pattern of disease, previous response to treatment, and balance between treatment effectiveness and toxicity. The treatment algorithm recommended by the committee is presented in Fig. 2.

Fig. 2

Recommended algorithm for the treatment of UC. Treatment algorithm for patients with mild-to-moderate or severe UC developed through consensus of an expert panel established by the Taiwan Society of Inflammatory Bowel Disease. Recommendations were formulated after consideration of available evidence and expert opinion as well as the medical environment specific to Taiwan. ^aOral budesonide-MMX (9 mg/day) could be an alternative; ^bFor patients with acute severe UC, infliximab is better. 5-ASA, 5-aminosalicylic acid (mesalamine); Tx, treatment; AZA, azathioprine; 6-MP, 6-mercaptopurine; IV, intravenous; CMV, cytomegalovirus; MMX, Multi-Matrix System; TFDA, Taiwan Food and Drug Administration.

Topical mesalamine is the first line therapy for proctitis and left-sided colitis as results from meta-analyses have shown that rectal mesalamine is more effective than either rectal steroids or oral mesalamine.656667 The combination of oral and topical mesalamine may be more effective in patients with distal UC.68 The second-generation corticosteroid budesonide in the MMX formulation can be considered as an alternative to topical mesalamine. Despite the high efficacy of systemic corticosteroids, their use is associated with significant safety concerns that affect almost all organ systems.6970 Budesonide-MMX is a novel oral formulation of budesonide that provides targeted and extended release of drug to the entire colon, including the left colon, while minimizing systemic absorption.7172 In the CORE I study which included patients with active, mild-to-moderate UC, rates of combined clinical and endoscopic remission at week 8 were 17.9% with budesonide-MMX 9 mg and 12.1% with mesalamine 2.4 g, compared with 7.4% with placebo (P =0.014 and P =0.22).73 Rates of remission were 17.4% with budesonide-MMX 9 mg and 12.6% with controlled ilealrelease budesonide 9 mg, compared with 4.5% with placebo (P =0.005 and P =0.048) at week 8 in the phase III colonic release (CORE) I study.74 Use of systemic corticosteroids is appropriate in patients not responding to initial treatment.10 In UC patients with refractory disease, azathioprine, mercaptopurine, tacrolimus, or biologic agents may be required.

In a randomized trial of 127 patients, combination therapy with oral mesalamine 4 g/day and a 1 g mesalamine enema was superior to oral therapy alone for inducing remission in patients with extensive mild-to-moderate UC.75 Budesonide-MMX can be considered as an alternative to topical mesalamine. Several randomized trials have shown noninferiority of once daily dosing of mesalamine to divided doses in achieving remission.767778 Further treatment of patients with mild-to-moderate pancolitis unresponsive to mesalamine is the same as that for patients with mild-to-moderate proctitis or left-sided colitis unresponsive to mesalamine.

Patients with acute severe UC must be admitted for intensive treatment as the condition could be life threatening. A Mayo score ≥11 or any sign of systemic toxicity, such as tachycardia, fever, and elevated ESR or CRP indicates severe UC. Intravenous corticosteroids effectively induce remission in severe UC and is the mainstay of treatment.7980 Methylprednisolone (maximum 1 mg/kg/day or 60 mg/day) or hydrocortisone 100 mg 4 times daily is appropriate; higher doses have not been shown to improve outcomes.1080 Infectious causes, including CMV and Clostridium difficile, should be ruled out.

Patients with severe UC that is refractory to intravenous steroids (as assessed between the 3rd and 5th day after initiation of therapy) should be treated with cyclosporine or biologic agents as 2nd-line therapy. A randomized trial has shown comparable colectomy rates between patients with steroid-refractory severe UC treated with cyclosporine or infliximab.81 Patient-specific factors and the risk of adverse events should be considered in the selection of second-line therapy.

Colectomy is indicated if the patient fails to respond to second-line therapy within 4 to 7 days. Colectomy may also be appropriate upon admission or after failure of intravenous corticosteroids. Decision-making regarding the timing of colectomy for severe UC can be aided by clinical (stool frequency and temperature), and biochemical markers (CRP, ESR, albumin, and pH) as well as radiological and endoscopic findings (colonic dilatation, presence of ileus, and depth of ulceration).108283848586 When indicated, colectomy should be performed timely as delayed surgery in patients with acute severe UC who do not respond to medical therapy is associated with poorer postoperative outcomes.87

Remission in UC is generally defined as 1 or 2 stools a day without rectal bleeding, fever, or tachycardia and mucosal healing on endoscopic assessment with complete discontinuation of corticosteroids.1035 In a Cochrane Review published in 2016, use of oral mesalamine was significantly associated with lower risk of relapse compared with placebo (RR, 0.69; 95% CI, 0.62–0.77).88 Higher dose of oral mesalamine was not associated with a higher incidence of adverse effects and may be beneficial in maintaining remission in patients with extensive UC or frequent relapses. In addition, meta-analysis results found once daily administration of oral mesalamine to be as effective as conventional dosing (2 or 3 times daily) for maintenance of remission. Topical therapy with suppositories is most effective for proctitis as it delivers the active compound directly to the site of inflammation.89 For left-sided colitis, topical therapy with enemas, foams, or gel can be considered due to their ability to spread proximally. 90 The combination of oral mesalamine and intermittent rectal mesalamine is associated with higher remission rates and should be considered for second-line maintenance therapy.10

While steroids are standard treatment for remission induction in UC, first-generation steroids, such as prednisone, are not advised for use as maintenance treatment due to adverse events associated with long-term use, including increased risk of serious infections, bone disease, the development of cushingoid features, and increased risk of mortality.91 In a study evaluating the efficacy of budesonide-MMX for the maintenance of remission, the probability of relapse in patients receiving budesonide-MMX 6 mg was 40.9% compared to 59.7% in those receiving placebo, though the rate of maintained remission at month 12 was not significantly different between groups.71 Further studies are needed to evaluate the benefit of budesonide-MMX in maintenance of UC remission.

Azathioprine is recommended for maintenance of remission in patients with steroid-dependent UC. In a Cochrane Review of trials evaluating the efficacy of thiopurines for maintenance of remission in UC, azathioprine was shown to be superior to placebo (OR for failure to retain remission, 0.41; 95% CI, 0.24–0.70).92 In addition, a randomized trial including patients with active steroid-dependent UC found that those treated with azathioprine for 6 months were significantly more likely to achieve steroid-free remission than those treated with mesalamine (OR, 4.78; 95% CI, 1.57–14.5).93 Furthermore, maintenance with azathioprine is recommended for patients receiving cyclosporine or tacrolimus for induction of remission. Use of thiopurines has been associated with reduced risk of colectomy after remission induction with cyclosporine.9495

The currently available anti-TNF therapies (infliximab, adalimumab, and golimumab) appear to have similar efficacy and safety profiles.969798 Choice of agent depends on availability, route of administration, patient preference, and cost. Infliximab, however, is presently the only anti-TNF agent with evidence specifically in support of its efficacy in steroid-refractory acute severe UC.99100 A biologic of a different mechanistic class is vedolizumab, an anti-α4β7-integrin agent which inhibits lymphocyte recruitment to the inflamed gut. Vedolizumab has been shown to be efficacious in inducing and maintaining clinical remission in patients with UC.101 Reassessment of disease activity, exclusion of complications, and consideration of surgery should be carried out for loss of response to anti-TNF therapy. An increase in dose or dosing frequency should be attempted prior to switching to another biologic agent, as switching reduces future therapeutic options.10

Major safety concerns with biologic therapy include infection and malignancy.56 Use of anti-TNF agents increases the risk of opportunistic infections, such as reactivation of TB.102 The risk is further increased with long-term use of anti-TNF agents in combination with other immunosuppressive therapies. 103 Hepatosplenic T-cell lymphoma, a rare and usually fatal cancer, has been reported in young patients who were treated with combination infliximab and a thiopurine for IBD.104105 Though the role of anti-TNF agents in the pathogenesis of hepatosplenic T-cell lymphoma has not been established, the long term use of combined anti-TNF therapy and a thiopurine should be avoided in young, particularly male, patients.

5. Monitoring

6. Surgery

Delay in surgical treatment in indicated UC patients is associated with high morbidity and mortality.12136 Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) is one of the elective surgical procedures for UC. A staged procedure (colectomy first) is usually recommended in acute severe UC when patients do not respond to medical therapy. Ileorectal anastomosis can be considered as an alternative to IPAA in special cases, such as for preservation of sexual function and fertility, as studies have shown that open IPAA is associated with sexual dysfunction and reduced female fecundity.137138139140 While ileorectal anastomosis does not disturb sphincter function nor impair fertility, the retained rectum remains at risk for dysplasia and carcinoma and long-term surveillance is advised.141

When performing restorative proctocolectomy, a 2- or 3-stage procedure with a temporary covering loop ileostomy is recommended. Compared with a one-stage procedure, a 2-stage procedure may reduce the risk of anastomotic leakage, peritonitis, and pelvic sepsis.142 Patients who are urgent cases, debilitated by colitis, taking high doses of steroids, have serious associated disease, or have indeterminate colitis should not undergo a 1-stage procedure.142

The most common complication of IPAA is pouchitis, a nonspecific inflammation of the ileal reservoir, which occurs in up to 50% of patients 10 years after IPAA.137143 Symptoms of pouchitis include increased stool frequency and liquidity, abdominal cramping, urgency, tenesmus, and pelvic discomfort.144145 Other etiologies, including irritable pouch syndrome, cuffitis, CD of the pouch, and postoperative complications such as anastomotic leak or stricture, may mimic pouchitis; therefore, endoscopic and histological findings should be considered in diagnosis.143146 Patients who develop typical signs and symptoms of acute pouchitis after IPAA should be treated with antibiotics, such as a 2-week course of metronidazole 20 mg/kg/day or ciprofloxacin 1 g/day. Chronic pouchitis, persistent symptoms that do not respond to conventional therapy, is a leading cause of pouch failure and should be treated with combination antibiotic therapy or oral budesonide.143146

7. Cancer Surveillance

Between 2000 and 2010, 5 cases of CRC were observed among 2,098 patients with UC in Taiwan, corresponding to a prevalence rate of 0.24% and an incidence rate of 60.19 per 100,000 persons.6 The incidence rate of CRC in UC patients is markedly higher than that in the overall population in Taiwan, which was 34.75 per 100,000 persons between 2000 and 2006.147 Histological inflammation is an established risk factor for the development of CRC and the risk of developing CRC dramatically increases with longstanding UC. In a meta-analysis including 19 studies, cumulative risk of CRC in UC was 1.6% at 10 years, 8.3% at 20 years, and 18.4% at 30 years.148 In a case-control study of UC patients, family history of sporadic CRC was an independent risk factor for CRC; those with CRC were twice as likely to have a family history of sporadic CRC than those without CRC.149 Patients with both primary sclerosing cholangitis and UC have been shown to be at higher risk of CRC than UC patients without primary sclerosing cholangitis, with an adjusted RR of 3.15.150

As earlier detection of CRC improves prognosis, surveillance colonoscopies should be performed at defined intervals to identify dysplastic change in colonic mucosa, which is associated with an increased risk of CRC.143151 Frequency of endoscopic surveillance, varying from 1 to 4 years, should be tailored to the individual patient's risk factor profile.143 Annual surveillance colonoscopy with biopsies should be performed regularly after 8 to 10 years of first manifestation. UC patients with IPAA may not require regular surveillance as the risk for CRC in such patients is low. Surveillance colonoscopies should be performed in remission to avoid misinterpretation of inflammatory activity. Chromoendoscopy with targeted biopsies is the preferred procedure as it has been shown to yield higher detection rates of intraepithelial neoplasias in UC than white-light endoscopy with random biopsies.152

In addition to CRC, patients with UC may be at increased risk of other cancers. Although analysis of data from 1998 to 2013 collected from NHIRD showed no increase in overall cancer risk in patients with UC in Taiwan, compared with control patients, a significant standardized incidence ratio (SIR) was found in UC patients for hematological malignancies (SIR, 2.51), non-Hodgkin's lymphoma (SIR, 3.0), and urinary tract cancers (SIR, 2.05).7 In a population-based study conducted in Europe, UC was associated with an increased risk of gastrointestinal cancers, specifically cancer of the liver (SIR, 1.6) and gallbladder (SIR, 2.5), as well as a slightly increased risk of extraintestinal cancers (SIR, 1.1).153 Risk of cholangiocarcinoma in patients with IBD is significantly higher in patients with UC, and primary sclerosing cholangitis has been found to be a major risk factor for cholangiocarcinoma. 154155 In addition, a diagnosis of dysplasia or cancer of the colon or rectum prior to IPAA has been shown to be a risk factor for pouch dysplasia or adenocarcinoma in patients with UC.156