Ulcerative Colitis

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon that follows a course of relapse and remission. In a small number of cases, ulcerative colitis is associated with extra-intestinal features. Disease extent can be divided into:

• Distal disease (left-sided colitis): colitis confined to the rectum (proctitis) or rectum and sigmoid colon (proctosigmoiditis).
• More extensive disease includes: left-sided colitis (up to the splenic flexure, 40% of patients), extensive colitis (up to the hepatic flexure), and pancolitis (affecting the whole colon, 20% of patients).

It is sometimes difficult to distinguish between ulcerative colitis and isolated colonic Crohn's disease, and such patients can be described as having indeterminate colitis.¹

• Ulcerative colitis affects about 1 in 1000 people in the Western world.¹
• Peak incidence is between the ages of 10 and 40 years. May affect people of any age and 15% of people are over the age of 60 at diagnosis.²

• The aetiology is unknown. The consensus is it is a response to environmental triggers (infection, drugs, or other agents) in genetically susceptible individuals. The genetic component is not as strong in ulcerative colitis as it is in Crohn's disease. However 10-20% of patients with ulcerative colitis have at least one family member with inflammatory bowel disease (ulcerative colitis or Crohn's disease).¹
• There are marked differences between ethnic groups with some (such as Ashkenazi Jews) having a particularly high incidence.
• Non-steroidal anti-inflammatory drugs may cause an episode of acute active disease in some patients with inflammatory bowel disease.

Symptoms

• The cardinal symptom is bloody diarrhoea.
• Associated symptoms include colicky abdominal pain, urgency, or tenesmus (a feeling of incomplete defecation with an inability or difficulty to empty the bowel at defecation).
• Disease limited to the rectum (proctitis) may present with constipation and rectal bleeding.
• May be symptoms of systemic upset, including malaise, fever, weight loss, and symptoms of extraintestinal (joint, cutaneous, and eye) manifestations.
• The presentation may mimic gastrointestinal infection and the history should include recent foreign travel in considering the possibility of an infective cause.
• Recent medication history is also important in considering other possible causes of the presenting gastrointestinal upset.

Signs

• Depending on disease severity, may be clearly unwell, pale, febrile and dehydrated. May have a tachycardia and hypotension.
• Abdominal examination may reveal tenderness, distension or palpable masses.
• If abdominal tenderness is associated with abdominal distension, then acute admission to hospital is required as the patient could have toxic megacolon, which is potentially fatal. Other warning signs of potentially severe disease include tachycardia, fever and anaemia.

Approximately 4% of patients will have extraintestinal disease which may include:

• Related to the activity of colitis:
  • Erythema nodosum
  • Aphthous ulcers
  • Episcleritis
  • Acute arthropathy affecting the large joints (e.g. wrists, hips, knees)
• Usually related to activity of colitis:
  • Pyoderma gangrenosum
  • Anterior uveitis
• Not related to activity of colitis:
  • Sacroiliitis
  • Ankylosing spondylitis
  • Primary sclerosing cholangitis

• The main differential is Crohn's disease which has very similar clinical features. The diagnosis is usually made from the biopsy result following a sigmoidoscopy or colonoscopy.
• Infective colitis.
• Mild colitis may mimic irritable bowel syndrome.

The diagnosis should be made on the basis of clinical suspicion supported by appropriate macroscopic findings on sigmoidoscopy or colonoscopy, typical histological findings on biopsy, and negative stool examinations for infectious agents.³

• Initial investigations include:
  • Full blood count, renal function and electrolytes, liver function tests, ESR and CRP.
  • Stool culture, including ova, cysts and parasites and also Clostridium difficile toxin.
• Abdominal radiography: essential in the initial assessment of patients with suspected severe inflammatory bowel disease, to exclude toxic dilatation and perforation. May also help to assess disease extent in UC or identify proximal constipation.
• Sigmoidoscopy and rectal biopsy: for all patients presenting with diarrhoea, rigid sigmoidoscopy should be performed unless there are immediate plans to perform flexible sigmoidoscopy.
• Colonoscopy:
  • Usually preferable to flexible sigmoidoscopy, because the extent of disease can be assessed, but in moderate to severe disease there is a higher risk of bowel perforation and flexible sigmoidoscopy is safer.
  • The extent of the disease is defined as the proximal margin of macroscopic inflammation, because this is most clearly related to the risk of complications, including dilatation and cancer.
  • It is advisable that patients with UC should have a colonoscopy after 8-10 years to re-evaluate disease extent.

Disease severity in ulcerative colitis¹

Management depends on disease activity and extent:

• Mild:
  • Fewer than four stools daily, with or without blood
  • No systemic disturbance
  • Normal ESR and CRP
• Moderate:
  • Four to six stools a day with minimal systemic disturbance
• Severe:
  • More than six stools a day containing blood and evidence of systemic disturbance (fever, tachycardia, anaemia, or hypoalbuminaemia)

Disease activity can be evaluated using a simple clinical activity index, such as the Simple Clinical Colitis Index, which has been shown to correlate with more complicated severity assessment tools.⁴

• Patients with severe colitis should be admitted to hospital for assessment and treatment.
• Patients with moderate disease, who fail to respond to steroids within two weeks, should be admitted to hospital.
• Patients who respond partially to treatment should be seen urgently in the outpatient department and treated for refractory colitis.

• Topical management is appropriate for some patients with active disease. This is usually the case for those with proctitis and often the case if the disease extends into the sigmoid.
• For those with more extensive disease, oral or parenteral therapy are the mainstays of treatment, although some of these patients may get additional benefit from topical therapy.
• Leukophoresis (extracorporeal removal of leukocytes from the blood) may be beneficial in carefully selected patients with ulcerative colitis, but the evidence on efficacy is not yet adequate to support a role in treatment.⁵
• Beware antimotility drugs (e.g. codeine, loperamide), and antispasmodic drugs, which may precipitate paralytic ileus and megacolon in active ulcerative colitis.

Drug treatments³

• Aminosalicylates:
  • Mesalazine - 5-aminosalicylic acid (5-ASA) - is as effective as sulfasalazine at inducing remission.⁶ Oral mesalazine is less effective than oral corticosteroids and so should be used as sole treatment only in mild attacks. Topical mesalazine is probably slightly more effective than topical corticosteroids.
  • Oral mesalazine is mostly used to maintain remission (it reduces the relapse rate by about two thirds compared with placebo).⁷ Mesalazine also seems to help reduce the risk of colorectal cancer.¹
  • The newer 5-ASA preparations are inferior to sulfasalazine in maintenance therapy but have fewer adverse effects.⁸ Sulfasalazine has a higher incidence of side effects compared with newer 5-ASA drugs but selected patients, e.g. those with a reactive arthropathy, may benefit.
  • Olsalazine has a higher incidence of diarrhoea in pancolitis and is best for patients with left-sided disease, or intolerance of other 5-ASAs.
• Corticosteroids:
  • Corticosteroids are used to induce remission in relapses of ulcerative colitis. They have no role in maintenance therapy.
  • Corticosteroids may be applied topically (suppositories, liquid or foam enemas), orally or intravenously.
• Thiopurines:
  • Azathioprine and its active metabolite 6-mercaptopurine may be used when:¹
    • Patients are intolerant to corticosteroids
    • Patients need two or more corticosteroid courses in a calendar year
    • Disease relapses when the dose of prednisolone is less than 15 mg a day
    • If disease relapses within six weeks of stopping steroids
  • Azathioprine seems to be effective for at least five years, and increasing the duration of treatment will keep patients in remission for longer.¹
  • A recent meta-analysis suggested that patients with inflammatory bowel disease who take azathioprine have a slightly increased risk of lymphoma, particularly B cell lymphoma associated with Epstein Barr virus infection.¹
• Ciclosporin:
  • Is an effective salvage therapy for patients with severe refractory colitis and has a rapid onset of action.
  • It reduces the colectomy rate by 50% in the short-term, but its use is controversial because of toxicity (drug-associated mortality is about 3%) and the long-term failure rate.¹
• Infliximab:
  • Infliximab is effective in inducing clinical remission in patients with moderate to severe ulcerative colitis, whose disease is refractory to conventional treatment using corticosteroids and/or immunosuppressive agents.⁹
  • Infliximab is recommended as an option for the treatment of acute exacerbations of severely active ulcerative colitis only in patients in whom ciclosporin is contraindicated or clinically inappropriate.¹⁰
  • Infliximab is not recommended for the treatment of subacute manifestations of moderately to severely active ulcerative colitis.¹¹
• Stool bulking agents:
  • In left-sided disease, distal transit is rapid but proximal transit is slowed, which can result in proximal constipation.
  • Relief of proximal constipation by stool bulking agents or laxatives may help induce remission in proctitis.¹

Active ulcerative colitis

• Suppositories for disease to the rectosigmoid junction, and foam or liquid enemas for more proximal left-sided disease.
• In mild to moderate disease, topical mesalazine combined with oral mesalazine, olsalazine, or balsalazide daily, are effective first line therapy. Topical mesalazine alone or oral mesalazine alone are effective, but less effective than combination therapy. Topical corticosteroids are less effective than topical mesalazine, and should be reserved as second line therapy for patients who are intolerant of topical mesalazine.
• Proximal constipation with distal active colitis should be treated with stool bulking agents or laxatives. Antidiarrhoeal agents should be avoided as they do not reduce stool frequency in colitis and increase the risk of toxic megacolon.
• Oral corticosteroids are indicated in mild disease that fails to respond to topical treatment and mesalazine, in moderate disease (e.g. patients with bloody diarrhoea), or when a prompt response is required. Patients should be treated with oral prednisolone 40 mg daily (or equivalent), with topical agents used as adjunctive therapy. Prednisolone should be reduced gradually according to severity and patient response, generally over a period of 8 weeks.
• Patients with chronic active steroid-dependent disease should be treated with azathioprine or mercaptopurine.
• Ciclosporin may be effective for severe, steroid refractory colitis.

Severe ulcerative colitis

• Patients who have failed to respond to maximal oral treatment with a combination of mesalazine and/or steroids with or without topical therapy, or those who present with severe disease, should be admitted for intensive intravenous therapy.
• Monitoring of pulse rate, stool frequency, C-reactive protein, and plain abdominal radiograph help identify those who need colectomy.
• Acute onset UC is sometimes difficult to distinguish from infective colitis, but treatment with corticosteroids should not be delayed until stool microbiology results are available.
• Subcutaneous heparin to reduce the risk of thromboembolism.
• Nutritional support (by enteral or parenteral route) if the patient is malnourished.
• Intravenous corticosteroids (hydrocortisone 400 mg/day or methylprednisolone 60 mg/day). There is no benefit from intravenous steroids beyond 7-10 days.
• Withdrawal of anticholinergic drugs, antidiarrhoeal agents, NSAID and opioid drugs, as continuing them risks colonic dilatation.
• Continuation 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.
• Intravenous antibiotics only if infection is considered, or immediately before surgery.
• Objective re-evaluation on the third day of intensive treatment. A stool frequency of more than 8 per day or CRP greater than 45 mg/l at 3 days predicts the need for surgery in 85% of cases. Consideration of colectomy or intravenous ciclosporin if there is no improvement during the first 3 days.
• Following induction of remission, oral ciclosporin for 3-6 months is appropriate.

Maintenance of remission

• Lifelong maintenance therapy is generally recommended for all patients, especially those with left-sided or extensive disease, and those with distal disease who relapse more than once a year.
• Stopping medication may be appropriate for patients with distal disease who have been in remission for 2 years, but there is evidence that maintenance therapy reduces the risk of colorectal cancer.

Surgical

• The procedure of choice in acute fulminant ulcerative colitis is a subtotal colectomy leaving a long rectal stump.
• Indications for colectomy:¹
  • Toxic megacolon; surgery should be performed within 24 hours unless the condition resolves.
  • Severe ulcerative colitis that fails to respond to corticosteroid therapy within seven to 10 days.
  • Chronic persisting colitis in a non-acute setting on the grounds of poor therapeutic response and poor quality of life.
  • High-grade dysplasia or cancer.
• Smoking cessation significantly reduces post-operative relapse.

• Colorectal cancer: for those with extensive colitis opting for surveillance, colonoscopies (with biopsies) should be conducted every 3 years in the second decade, every 2 years in the third decade, and annually in the fourth decade of disease.^12,13 The risk of colorectal cancer increases with younger age at onset, longer duration of disease, and increased extent of colonic involvement.¹
• Patients with primary sclerosing cholangitis appear to be at higher risk of cancer, and they should have more frequent (perhaps annual) colonoscopy.
• Pouchitis: up to 45% of patients who undergo ileal pouch surgery for UC suffer from pouchitis. Metronidazole or ciprofloxacin for 2 weeks is the first line therapy. Mesalazine or corticosteroids may be used in acute pouchitis if antibiotics are ineffective. Long-term, low dose metronidazole or ciprofloxacin are potentially effective for chronic pouchitis.
• Management of extraintestinal manifestations: those that are associated with active intestinal disease largely respond to therapy aimed at controlling disease activity, whereas those that occur whether disease is inactive or quiescent, run a course independent of therapy for intestinal disease.
• Osteoporosis: is common, although the absolute fracture risk, contribution of steroids and role of prophylaxis remain a subject for debate.

• With modern medical and surgical management, the disease now has a slight excess of mortality in the first two years after diagnosis, but little subsequent difference from the normal population.¹⁴
• However, a severe attack of UC is still a potentially life-threatening illness.
• About 50% of patients with UC have a relapse in any year. An appreciable minority has frequently relapsing or chronic, continuous disease and, overall, 20-30% of patients with pancolitis require colectomy.
• After the first year approximately 90% of patients are fully capable of work, although UC causes significant employment problems for a minority.