• Persistent symptoms despite medical therapy
• Steroid dependent disease
• Dysplasia/malignancy

Discuss the types of surgery in UC?
Types of surgery: Since UC only affects large bowel, a proctocolectomy is curative. Further ileal pouch surgery allows patients to live without ileostomy. Surgical options are:

• Proctocolectomy with ileostomy
• Total colectomy with ileorectal anastomosis
• Colectomy, mucosal proctectomy, and ileal pouch-anal canal anastomosis (IPAA)
• Colectomy and stapled ileal pouch distal rectal anastomosis (IPDRA)

Discuss the various surgeries for UC?

• Total colectomy with ileostomy is the procedure of choice in emergency situations. Subsequent proctectomy with ileal pouch-anal anastomosis can be done electively. IPAA has high complication rates when performed on patients with acute/toxic colitis.
• Further, ileostomy may also be needed if IPAA is not technically possible or has failed. Most patients’ small bowel will extend the necessary length, and a variety of techniques are employed to make the ileum reach the anal canal. In the unusual event that the small bowel does not reach, a permanent ileostomy may be needed.
• Ileorectal/IPDRA anastomosis is technically easier surgery than IPAA. Further it leaves the rectal mucosa behind. This may cause persistence of symptoms and future risk of malignancy. The ileorectal anastomosis has the advantage of better continence, especially at night. This operation may be considered in:
  • Pts with minimal rectal involvement and not suitable for IPAA but refuse ileostomy or where stoma is relatively contraindicated (e.g. ascites)
  • Some advocate the operation in women of child bearing age because of the risk of infertility with IPAA
  • It may also be a good choice for patients in whom Crohn’s disease cannot be excluded. IPAA is usually avoided in patients with Crohn’s disease because of poorer functional outcomes and a higher failure rate.

Discuss the complications of pouch surgery?

• Early complications-   The most common complications include small bowel obstruction (17–20%), wound infections (5.8%), and bleeding (3.8%). Other complications- anastomotic leak, portal vein thrombosis
• Late complications
  • Anastomotic stricture.
  • Fistula and abscess
  • Pouchitis- chronic pouchitis occurs in 10%.
  • Irritable pouch syndrome
  • Reduced fertility
  • Anorectal dysfunction (anismus).
  • Pouch failure- (defined as removal of the pouch or the need for an ileostomy) – 7-13% at 10 years. Commonest cause is fistula
• Post pouch- Mean no of stools at 5 years-Day-(6 + 2), night (2+1). Major nocturnal incontinence is 22% over 10 years

Discuss pouch surgery and pregnancy?
Pregnancy and delivery are safe in patients with IPAA.  Whether vaginal or Caesarean delivery is better remains controversial. The type of delivery should be influenced by obstetric consideration but also the potential risk of sphincter injury. Some have favoured Caesarean sections

Discuss the types of pouch?
The J, S and W reservoirs are the most common types of pouches used. Selection of pouch design depends on a variety of factors, including age, patient size and individual anatomy.

• UC complicated by PSC is associated with an increased risk of CRC.
• Alteration in the composition of colonic bile acids has been implicated. This may also account of the disproportionately higher incidence of right sided colon cancers in PSC.
• The prevalence of UC in PSC patients approaches 90%. Thus all patients with PSC should have a flexible sigmoidoscopy. Colonic biopsies should be done even if the mucosa looks macroscopically normal.

Discuss surveillance?

Annual colonoscopy is recommended by British Society of Gastroenterology. The annual surveillance should be done regardless of the duration of colitis. Surveillance should continue after liver transplantation too.

If the biopsies reveal indefinite dysplasia, repeat colonoscopy should be done every 6-12 months. Colectomy should be recommended for high grade dysplasia. Colectomy should also be considered in low grade dysplasia. An alternative is repeat colonoscopy in 3-6 months to confirm the diagnosis. If there are multiple sites of low grade dysplasia or multiple inflammatory polyps that preclude adequate surveillance, colectomy should definitely be recommended.

Discuss chemoprevention?

Ursodeoxycholic acid (UDCA) may be chemoprotective against the development of colon cancer

Pouchitis is the inflammation of the ileal pouch reservoir. It is the most common long-term complication in patients with IPAA which significantly affects patients’ quality of life. It is estimated that approximately 50% of patients who have undergone IPAA surgery for UC will develop at least one episode of pouchitis.

Discuss the pathogenesis?

Pouchitis almost exclusively occurs in patients with underlying UC and is rarely seen in patients with FAP. Although the etiology and pathogenesis of pouchitis are not entirely clear, bulk of evidence points towards an abnormal mucosal immune response (innate and adaptive) to altered microflora in the pouch leading to acute and/or chronic inflammation.

Discuss the diagnosis of pouchitis?

• Clinical features- increased stool frequency, urgency, tenesmus, abdominal pain, hematochezia, fever, and extraintestinal manifestations of inflammatory bowel disease.
• Endoscopy- erythematous, friable mucosa, and haemorrhages, erosions and/or ulcerations.
• Histology- Both acute and chronic inflammatory changes are seen
• The diagnosis is based on the combination of clinical, endoscopic and histologic features.
• Natural history- 50% of the affected patients will have recurrent episodes of pouchitis requiring repeated treatment.

Discuss the treatment for pouchitis?

• Acute episodes of pouchitis respond well to a single course of antibiotics. The first-line therapy includes a 7 day course of oral metronidazole (1-2 gm per day) or ciprofloxacin (1gm/d).
• Some develops chronic, relapsing symptoms, which may require long-term or continuous therapy. Low dose ciprofloxacin may be used. The probiotic VSL#3 (3 to 6 g/day) may also be an acceptable alternative.
• A Cochrane review concluded that oral probiotic therapy with VSL-3 over a 36 week period appears to be an effective therapy for reducing the risk of disease recurrence among patients with non-active pouchitis.
• Antibiotic-refractory pouchitis which is often difficult to treat is a common cause of pouch failure.

Discuss severe UC?

• Severe UC is a potentially life threatening condition.
• 65% of patients treated with corticosteroids will be symptom free by the end of five days, 15% will have significant improvement, and 25% will not improve. Those who fail to improve may be treated with intravenous ciclosporin or undergo colectomy.
• The mortality in severe UC is currently < 1% in specialist centres.
• Thus only one patient in a hospital need to die from delayed decision making or complications of ciclosporin to negate the benefit of medical therapy. Ultimately it is about saving lives, not colon.

Define severe acute UC?

Severe acute UC is usually defined by the original classification put forward by Truelove and Witts. They defined severe UC as presence of six or more bowel motions per day associated with one or more of the following:

• temperature >37.8
• Large amounts of rectal bleeding
• Heart rate >90/minute
• Haemoglobin of <10.5 g/dl
• ESR >30 mm/h

Can you predict the need for surgery in severe acute UC?

• A delay in referral for colectomy is associated with increased mortality. It is thus clearly important to identify those who are likely to need colectomy at an early stage, so that surgery is not inappropriately delayed.
• The simplest approach is objective re-evaluation on the third day of intensive treatment. A stool frequency of more than 8/day or CRP of > 45mg/L at 3 days predicts the need for colectomy on that admission in 85% of cases.
• It must be understood that the CRP and stool frequency criteria are simply a guide and neither immutable nor always reproduced.  However, at the very least, patients meeting these criteria may be considered for surgical referral and/or treatment with ciclosporin.

Discuss ciclosporin vs. infliximab in severe acute colitis?

• Response rates in controlled trials with infliximab in corticosteroid-refractory UC patients are inferior to those reported with intravenous ciclosporin therapy, although the two drugs have not been compared directly.
• It is worth noting that most intravenous cyclosporine trials report 60 to 85 percent response rates in corticosteroid-resistant UC.
• Currently, infliximab can be considered in patients with acute steroid-refractory disease who are reluctant to undergo colectomy and in whom ciclosporin is contraindicated

Discuss the evidence for ciclosporin use in severe acute UC?

• There have been four controlled studies of intravenous ciclosporin in patients with severe ulcerative colitis.
• These trials showed that intravenous ciclosporin (with continued IV steroids) is effective in inducing remission in more than 80% of patients with severe ulcerative colitis.
• An initial dose of 2mg/kg/day intravenous ciclosporin is as effective as 4mg/kg/day and is thus preferred from the standpoint of safety.
• However, the long-term outcome of patients who have had their colon salvaged with ciclosporin is less promising. A series from Oxford reported that only 58% needed colectomy after 7 years follow up. Bojic reported that by failing corticosteroids the patient’s likelihood of requiring a colectomy in the next 10 years is 80%, regardless of the treatment.

Discuss the role of immunomodulators in decision making?

• The rate of colectomy was significantly higher in patients already taking azathioprine when ciclosporin was started compared with those who started azathioprine concurrently with ciclosporin.
• Ciclosporin is thus, at best, a bridge to maintenance therapy, and its use should be carefully considered if maintenance therapy with azathioprine or mercaptopurine is not an option, either because of intolerance to or relapse in spite of thiopurine therapy.

Who to treat with ciclosporin?

• Rescue therapy with ciclosporin could be considered on the third day of intensive treatment if predictive factors are poor (>8 bloody stools, or 3-8 bloody stools and CRP>45).
• Ciclosporin is suitable for patients with persistent severe colitis after 7 days of intravenous steroids who do not need immediate colectomy.
• Use of ciclosporin should be carefully considered in the following cases:
• Long standing chronic active colitis
• Pancolitis for >10 years
• Thiopurine resistance or intolerance
• Do not use ciclosporin in presence of moderate to severe renal impairment (creatinine > 130 micromol/litre or 20-30% reduction in eGFR), previous or current malignancy (except treated basal or squamous cell carcinoma) and current infection.

How to treat?

• 2 mg/kg/day as a 24 hr continuous IV infusion (continue up to 7 days depending on the response).
• Prerequisites before using ciclosporin:

1. Check the renal function, LFTs, magnesium and cholesterol.
2. Magnesium and cholesterol are best checked on admission in case intravenous ciclosporin is given.

• The risk of seizures is increased in patients with a low cholesterol (<3.0 mmol/l) or magnesium (<0.50 mmol/l). Oral therapy is an alternative in these circumstances. Microemulsion ciclosporin does not contain the chromophore present in intravenous ciclosporin that has been associated with neurotoxicity causing seizures in patients with hypocholesterolaemia or hypomagnesaemia.
• CMV colitis can mimic UC and is thought to be responsible for treatment failure in up to 10% of patients labelled as steroid refractory. Treatment of CMV may obviate colectomy. So consider doing a flexible sigmoidoscopy before starting ciclosporin.
• Monitoring
• Check ciclosporin levels on day 2 and then every 3 days (aim 100-200 ng/ml).
• Monitor U&E, LFT, Mg and Cholesterol on alternate days.
• Reduce the ciclosporin dose by 25% if any of these occur:

1. serum creatinine rises by more than 30% from baseline
2. SBP is > 150mm Hg or DBP exceeds 90 mm Hg despite antihypertensive treatment. Hypertension is treated with a calcium channel blocker such as nifedepine, because it may offer protection against ciclosporin induced nephrotoxicity. However the use of calcium channel blockers can lead to a rise in serum ciclosporin levels, so careful drug level monitoring is essential.
3. Serum liver enzymes double

When to convert to oral ciclosporin?

• Once response occurs convert to oral ciclosporin in 2 divided doses. An oral dose of 5mg/kg/day is equivalent to 2mg/kg/day intravenous dose since the oral bioavailability of neoral is 30-40%. However the blood levels need to be monitored and the dose titrated accordingly.
• Convert to oral steroids at the same time and taper dose by 5mg every week.
• Consider starting (or optimizing to maximum dose if already on thiopurines) azathioprine or mercaptopurine before discharge.
• The patient may be discharged home after 1-2 days of observation on oral ciclosporin.
• Measure ciclosporin levels at week 1 and week 2 and then monthly.
• Use PCP prophylaxis with triple immunosuppression (Co-trimoxazole 960mg 1 tab administered three times per week).

When do you consider stopping ciclosporin?

Discontinue ciclosporin after 3-6 months by reducing the dose by 50% for 2 weeks, followed by complete ciclosporin withdrawal.

What is the bottom line for ciclosporin?

By careful selection of patients at high risk of colectomy, (avoiding those in poor general condition), and use of low-dose i.v or oral ciclosporin at an early stage, ciclosporin is a safe and effective salvage therapy in acute colitis. With the introduction of thiopurines on discharge from hospital and continuing ciclosporin for 3-6 months, long term results could be maximized, with about 40-50% long term success.

Discuss measurement of ciclosporin levels?

The levels could be done at anytime during the 24 hr infusion. Trough levels are needed once the patient is on oral ciclosporin.

Ref

1. Stenner JMC, White P, Gould SR. Audit of the management of severe ulcerative colitis in a DGH. Gut 2001; 48:A87.
2. Travis SPL, Farrant JM et al. Predicting outcome in severe ulcerative colitis. Gut 1996; 38:905-10.
3. Ho GT, Mowat C, Goddard C. Predicting outcome and risk assessment in severe ulcerative colitis. Gastroenterology 2003; 124:A2.
4. Lichtiger S, Present, DH, Kornbluth, A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994; 330:1841-5
5. D’Haens G, Lemmens L, Hiele M, et al. Intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis. Gastroenterology 2001; 120:1323-9.
6. Svanoni F, Bonassi U, Bagnolo F, et al. Effectiveness of cyclosporine A (CsA) in the treatment of active refractory ulcerative colitis (UC). Gastroenterology 1998; 114:A1096.
7. Van Assche G, D’Haens, G, Noman, M, et al. Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology 2003; 125:1025-31.
8. Campbell S, Travis S, Jewell D. Ciclosporin use in acute ulcerative colitis: a long term experience. Eur J Gastroenterol Hepatol 2005; 17:79-84.
9. Bojic D, Al-Ali M, Jewell DP et al. Pattern and outcome of severe ulcerative colitis 2005, 15 year data. Gut 2005:54(suppl. VII):A155.
10. Cohen RD, Brodsky AL, Hanauer SB. A comparison of the quality of life in patients with severe ulcerative colitis after total colectomy versus medical treatment with intravenous cyclosporin. Inflamm Bowel Dis 1999; 5:1-10.
11. Carter MJ, Lobo AJ, Travis SP .Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004 Sep; 53 Suppl 5:V1-16.
12. Cottone M, Pietrosi G, Martorana G et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. Am J Gastroenterol 2001; 96:773.
13. Morales JM, Andres A et al. Calcium antagonist therapy prevent chronic cyclosporin nephrotoxicity after renal transplantation. Transplant Proc 1992;24:89-91
14. Actis GC, Volpes R, Rizzetto M. Oral microemulsion cyclosporin to reduce steroids rapidly in chronic active ulcerative colitis. Eur J Gastroenterol Hepatol 1999; 11: 905–8.

• The incidence of UC is approximately 10–20 per 100 000 per year with a reported prevalence of 100–200 per 100 000.
• UC has a slight excess of mortality in the first two years after diagnosis, but little subsequent difference from the normal population. However, a severe attack of UC is still a potentially life threatening illness.
• Distal colitis- confined to the rectum (proctitis) or rectum & sigmoid
• Left sided colitis-up to the splenic flexure
• Extensive colitis-up to the hepatic flexure
• Pancolitis -affecting the whole colon.
• For UC the extent is defined as the proximal margin of macroscopic disease, because this is most clearly related to the risk of complications, including dilatation and cancer. The implications of limited macroscopic disease with extensive microscopic inflammation remain unclear.
• The clinical course of UC is marked by exacerbation and remission. About 50% of patients with UC have a relapse in any year. About 20–30% of patients with pancolitis come to colectomy.
• After the first year approximately 90% of patients are fully capable of work (defined by <1 month off work per year), although UC causes significant employment problems for a minority.
• UC- 6% rectal sparing and 7% will have backwash ileilitis. In PSC-UC group 52% rectal sparing and 51% will have backwash ileilitis

Discuss the management of UC?

Left sided or extensive UC:

• Mesalazine 2–4 g daily is an effective first line therapy for mild to moderately active disease.  Mesalazine is more than twice as effective as placebo (OR 0.39; CI 0.29 to 0.52), but not significantly better than sulphasalazine 2-4gm/day (OR 0.87; CI 0.63 to 1.20).
• Olsalazine (1.5–3 g daily) may be used with left sided disease as it has a higher incidence of diarrhoea.
• Sulphasalazine has a higher incidence of side effects compared with newer 5-ASA drugs. However, it can usefully be used in patients with arthritis.
• These agents often require 3-6 weeks to exert their maximal effect.
• Prednisolone (40 mg daily) may be needed where mesalazine has been unsuccessful or a prompt response is needed. The dose can be tapered gradually, usually by 5 mg per week.  More rapid reduction is associated with early relapse.
• Topical agents (either steroids or mesalazine) may be added for troublesome rectal symptoms.

Distal colitis or proctitis

• Topical mesalazine 1 g daily (500mg BD or 1 gm OD -in appropriate form for extent of disease) combined with oral mesalazine are effective first line therapy. Combination therapy is more effective than topical or systemic therapy alone.
• Choice of topical formulation is determined by the proximal extent of the inflammation (suppositories for disease to the rectosigmoid junction, foam or liquid enemas for more proximal disease).
• Liquid enemas are difficult to retain, requiring patients remain in a horizontal position for at least 30 minutes. Foam enemas may be more comfortable and easier to retain.
• Topical mesalazine is more effective and hence preferred over topical steroids.
• Systemic steroids may be needed if the patient failed to respond to combination therapy.
• Proximal constipation should be treated with stool bulking agents or laxatives. It is important to treat constipation to ensure delivery of mesalazine to the inflamed colon.

Severe UC

Severe acute ulcerative colitis (UC) is usually defined by the original classification put forward by Truelove and Witts. They defined severe UC as presence of six or more bowel motions per day associated with one or more of the following:

• temperature >37.8
• Large amounts of rectal bleeding
• Heart rate >90/minute
• Haemoglobin of <10.5 g/dl
• ESR >30 mm/h

Management of severe UC

• Daily examination to evaluate abdominal tenderness and rebound tenderness. Regular monitoring of vital signs. A stool chart to record number and character of bowel movements, including the presence or absence of blood and liquid versus solid stool.
• Measurement of FBC, ESR, or CRP, serum electrolytes, serum albumin, and liver function tests every 24–48 hours.
• Daily AXR if colonic dilatation (transverse colon diameter >5.5 cm) is detected at presentation. If not dilated, there should be a low threshold for further radiological assessment if there is clinical deterioration.
• Subcutaneous low molecular weight heparin to reduce the risk of thromboembolism.
• Nutritional support if the patient is malnourished. Fluid and electrolyte replacement as needed.
• Intravenous corticosteroids (hydrocortisone 400 mg/day or methylprednisolone 60 mg/day).
• Withdraw anticholinergic, antidiarrhoeal agents, NSAID and opioid drugs, which risk precipitating colonic dilatation. Where non-specific pain relief is needed, an opioid that has less effect on motility such as tramadol may help.
• Continue of aminosalicylates once oral intake resumes, although these have not been studied in severe disease. Topical therapy (corticosteroids or mesalazine) if tolerated and retained, although there have been limited studies in acute severe disease.
• Objective re-evaluation on the third day of intensive treatment. A stool frequency of >8/day or CRP>45 mg/l at 3 days appears to predict the need for surgery in 85% of cases. Surgical review and input from specialist colorectal nurse or stoma therapist is appropriate at this stage. There is no benefit from intravenous steroids beyond 7–10 days.
• Consideration of colectomy or intravenous ciclosporin 2 mg/kg/day if there is no improvement during the first 3 days. See the guidelines for Ciclosporin use in UC.

Discuss Toxic megacolon?

• Toxic megacolon is a severe complication of IBD that is characterized by non obstructive colonic dilatation (total or segmental) plus systemic toxicity.
• Clinical features
  • Signs and symptoms of colitis poorly responsive to therapy are often present prior to the development of toxic colon. Diarrhoea may improve with the onset of toxic colon.
  • Physical examination reveals a toxic patient with abdominal distension and tenderness, with or without signs of peritonitis. It is important to remember that steroids may mask the signs.
• Investigations
  • AXR- the transverse or right colon is usually the most dilated. A maximum colonic diameter of more than 6 cm is consistent with the diagnosis of megacolon.
  • CT scan may be needed if complication of megacolon (e.g. perforation) is suspected.
  • Limited endoscopy without bowel preparation and minimal air insufflation may be done with extreme caution in suspected IBD patients presenting for the first time.
• Treatment
  • Management should be jointly with the surgical team. Medical treatment is successful in almost half the patients with toxic megacolon
  • NPO
  • NG tube to decompress the GIT
  • Broad spectrum antibiotics to reduce septic complications. A third generation cephalosporin with metronidazole can be used
  • Stop all anti motility drugs (Imodium, codeine etc)
  • Stress ulcer and DVT prophylaxis
  • IV steroids
  • Close monitoring
  • Failure to improve within 48 to 72 hours, or any signs of deterioration will require immediate colectomy.

Discuss maintenance therapy in UC?

• Lifelong maintenance therapy is recommended for all patients.  Discontinuation of medication may be considered for those with distal disease in prolonged remission.
• Benefits of maintenance treatment;
  • Maintenance therapy with all 5-ASA drugs may reduce the risk of colorectal cancer by up to 75% (OR 0.25, CI 0.13 to 0.48).
  • Reduces the risk of relapse. If you take ASA 1 in 4 chance of relapse at 1 year. If placebo- 3 in 4 chance of relapse at 1 year. Number needed to treat (NNT) is 6 to prevent one relapse of the disease.
• Drugs used for maintenance:
  • Oral mesalazine 1–2 g daily or balsalazide 2.5 g daily should be considered as first line therapy. Topical mesalazine may be used in patients with distal disease with/without oral mesalazine.
  • Azathioprine 1.5–2.5 mg/kg/day or mercaptopurine 0.75–1.5 mg/kg/day is effective at maintaining remission in UC. Immunomodulators are used in patients who frequently relapse despite adequate dose of mesalazine.
  • No published evidence exists to support the use of methotrexate to induce or maintain remission in UC.

Discuss refractory UC?

Some patients remain symptomatic despite intensive medical treatment. Options are:

• Surgery
• Infliximab

Discuss infliximab in UC?

• The role of anti-TNF therapy in active UC, steroid-dependent UC, refractory pouchitis, and in maintenance of disease remission is unclear. It must be remembered that ulcerative colitis can be cured by colectomy. The role of infliximab in preventing colectomy is uncertain.
• The efficacy of infliximab in inducing remission in UC is not brilliant. ACT 1 trial showed that approximately four patients would need to be treated to achieve one response. A similar magnitude of benefit was observed in ACT 2.
• Response rates with infliximab in corticosteroid-refractory UC patients are inferior to those reported with intravenous ciclosporin, although the two drugs have not been compared in a head to head trial. Infliximab can be considered in patients with acute steroid-refractory disease who are reluctant to undergo colectomy and in whom Ciclosporin is contraindicated.
• Dosing- The recommended dosing regimen (based on ACT trials) for induction of remission is three IV infusions of infliximab (5mg/kg) at zero, two and six weeks. For severe steroid refractory UC, the initial dose of infliximab is an IV infusion (5mg/kg) at week 0. For responding patients the dose can be repeated at week 2 and 6.
• Maintenance dosing- No RCT has yet attempted to determine the optimal dosing of infliximab for maintaining remission in UC. The ACT 1 and ACT 2 trials used maintenance dosing of 5mg/kg on scheduled basis every 8 weeks to maintain remission following completion of an induction regime for 30 and 52 weeks respectively. While outcomes at 30 and 52 weeks continued to favour active therapy, further studies are needed to establish the therapeutic gain of long term maintenance therapy beyond one year.

Discuss acute severe colitis?

See the section on use of ciclosporin