*Ulcerative Colitis

Chapter: Ulcerative Colitis
McMaster Section Editor(s): Paul Moayyedi
Section Editor(s) in Interna Szczeklika: Witold Bartnik†, Małgorzata Szczepanek, Władysław Januszewicz
McMaster Author(s): John K. Marshall
Author(s) in Interna Szczeklika: Witold Bartnik†
† Deceased.
Additional Information

Definition, Etiology, Pathogenesis Top

Ulcerative colitis (UC) is a diffuse inflammatory condition involving the rectum and extending proximally to a varying degree. UC and Crohn disease are the two major forms of inflammatory bowel diseases (IBD). The etiology of IBD remains uncertain, but centers on an overactive intestinal immune response in individuals with a genetic predisposition.

Clinical Features and Natural History Top

1. Signs and symptoms: The most common presenting symptoms are increased stool frequency, rectal bleeding, and urgency. In patients with limited proctitis, stool frequency may be normal and constipation may even occur. In such cases, rectal bleeding may be the only symptom. Fatigue and weight loss are frequent. Severe flares may be associated with symptoms of dehydration, tachycardia, abdominal tenderness, and fever. Signs and symptoms of specific intestinal and extraintestinal manifestations of IBD are described below.

2. Clinical classification: The inflammatory lesions may be confined to the rectum (proctitis) or extend proximally and contiguously through the colon. In some cases of pancolitis, “backwash” ileitis can also occur. Patients with distal disease can have localized periappendiceal inflammation, referred to as a cecal patch. The following classification of disease extent can have practical implications for the choice of treatment modality (topical vs systemic):

1) Proctitis, with inflammation limited to the rectum.

2) Left-sided colitis, with inflammation above the rectum but distal to the splenic flexure.

3) Extensive colitis, with inflammation proximal to the splenic flexure.

3. Natural history: UC is a chronic condition with periods of active disease (“flares”) and periods of remission. Most flares are unexplained, but some are associated with specific triggers, such as stress, changes in diet, nonsteroidal anti-inflammatory drugs, enteric infections, and antibiotic therapy.

4. Classification of disease activity: A variety of scoring systems have been developed to grade the activity of UC. The most commonly used of these is the Mayo score (Table 1), which combines symptoms with endoscopic findings and a physician’s global assessment. The score ranges from 0 to 12 points, with higher scores indicating more severe disease.

Diagnosis Top

Diagnostic Tests

1. Laboratory tests: No abnormalities are specific for UC. In patients with active disease, the following may be observed:

1) Features of inflammation: Elevated C-reactive protein [CRP], thrombocytosis, leukocytosis.

2) Anemia, hypoalbuminemia, and electrolyte disturbances (in severe disease).

3) Elevated fecal calprotectin levels.

4) Negative testing for infectious gastroenteritis. Patients with active disease should also be tested specifically for Clostridium difficile infection.

2. Imaging studies:

1) Plain abdominal radiographs may reveal thumbprinting, signifying mucosal edema. Colonic dilation in patients with active disease (transverse colon >6 cm in diameter in the median plane: Figure 1) is a concerning finding suggestive of toxic megacolon.

2) Barium enema (Figure 2) in early disease shows mucosal granularity and shallow mucosal ulceration. Chronic inflammation can lead to inflammatory polyps, loss of haustration, and shortening of the colon (lead-pipe appearance). Barium enema is now performed rarely and should be avoided in severe disease.

3) Cross-sectional imaging with ultrasonography, CT, or magnetic resonance imaging (MRI) can show mural thickening with stratification, loss of haustration, and widening of the presacral space. CT is not sensitive for mild mucosal disease. In severe disease, CT is useful to exclude perforation and abscess.

3. Endoscopy with proctosigmoidoscopy (Figure 3) can be performed without prior preparation on the first presentation (cathartics such as phosphate enemas may change the endoscopic appearance). Biopsy is important to confirm the diagnosis. In active disease, the mucosa is erythematous, granular, edematous, opaque, and friable; contact bleeding is observed, and vascular pattern is absent. In severe forms, ulcers, pseudopolyps, and large amounts of purulent exudate and blood are seen in the intestinal lumen. In persistent disease, the distal colon is narrowed. In periods of remission, the appearance of the mucosa may be normal. Full colonoscopy is not needed for diagnosis and may be contraindicated in more active disease. However, colonoscopy is useful to define disease extent, differentiate UC from Crohn disease, and survey for cancer.

4. Histologic features depend on the phase of the disease. In active disease, increased numbers of granulocytes, lymphocytes, and plasma cells are present in the lamina propria, along with crypt abscesses and reduced numbers of goblet cells. In remission, distorted glandular architecture, thinning of muscularis mucosa, and Paneth cell metaplasia are observed. Examination for features of CMV infection is important in patients with severe disease activity.

Diagnostic Criteria

Diagnosis is based primarily on the endoscopic and histologic findings.

Differential Diagnosis

Differential diagnosis includes bacterial (eg, Salmonella, Shigella, Campylobacter, Yersinia, gonococci) or parasitic (eg, amebiasis) infection, pseudomembranous colitis, Crohn disease (Table 2), colorectal cancer, ischemic colitis, and radiation proctitis.

Treatment Top

1. Classes of medications:

1) Oral 5-aminosalicylic acid (5-ASA) compounds, administered as pure 5-ASA (mesalazine) or its derivatives: sulfasalazine, olsalazine, and balsalazide. Mesalazine can also be administered rectally as suppositories or enemas.

2) Oral glucocorticoids include prednisone, prednisolone, and budesonideIV glucocorticoids include hydrocortisone and methylprednisolone.

3) Immunosuppressants include thiopurines (azathioprine and 6-mercaptopurine) and cyclosporine (INN ciclosporin).

4) Biologic agents include tumor necrosis factor (TNF)-alpha antagonists (adalimumab, golimumab, infliximab) and the alpha4beta7 leukocyte integrin antagonist vedolizumab.

5) Janus kinase (JAK) inhibitors, among which tofacitinib is now approved for the treatment of UC.

2. Both 5-ASA and glucocorticoids (hydrocortisone, budesonide) can be administered rectally as suppositories or enemas, as monotherapy in patients with distal disease, or as adjuncts to systemic therapies in patients with more extensive disease.

Treatment of an Acute Flare (Induction of Remission)

Mild to Moderate Disease Activity

1. Outpatient management is typical. In general, there is no restriction of lifestyle and diet. Strategies to maintain and follow bone health should be discussed (prevention and treatment of bone mineral loss: see Osteoporosis). Vaccinations should be updated, recognizing that live vaccines cannot be administered to patients receiving immunosuppressant or biologic therapy (see Immunoprophylaxis of Infectious Diseases in Adults).

2. Selection of drugs:

1) Proctitis5-ASA suppositories (or enemas) at least 1 g/d as monotherapy or in combination with oral 5-ASA or rectal glucocorticoid.

2) Left-sided colitis5-ASA enemasEvidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Marshall JK, Thabane M, Steinhart AH, Newman JR, Anand A, Irvine EJ. Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD004115. doi: 10.1002/14651858.CD004115.pub2. Review. PubMed PMID: 20091560. combined with oral 5-ASA >2 g/d; oral 5-ASA monotherapy and rectal 5-ASA or steroid monotherapy can be considered, but are less effective.

3) Extensive colitis: Oral 5-ASA >2 g/d as monotherapy or preferably in combination with rectal 5-ASA.

4) Consider oral systemic glucocorticoids if 5-ASA therapy is optimized and fails. Oral budesonide formulations with colonic delivery can also be used in mild to moderate disease in patients who do not respond to 5-ASA or do not tolerate 5-ASA.

Severe Disease

1. Hospitalization is usually required. Carry out tests for C difficile and CMV as well as plain abdominal radiographs to identify possible complications that require urgent surgical assessment (toxic megacolon or perforation). Prophylaxis against venous thromboembolism (VTE) should be administered (see Primary Prevention of Venous Thromboembolism).Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of studies. Support for this recommendation is inferred from benefit of intervention in unselected nonsurgical hospitalized patients. Kahn SR, Lim W, Dunn AS, et al; American College of Chest Physicians. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e195S-226S. doi: 10.1378/chest.11-2296. PubMed PMID: 22315261; PubMed Central PMCID: PMC3278052.

2. Intensive medical management:

1) Administer IV hydration. Blood transfusion may be necessary. Oral or enteral feeding is preferred, but patients unable to tolerate enteric feeds or those who require surgery should be considered for parenteral nutrition.

2) Initiate IV glucocorticoids with hydrocortisone 300 mg/d or methylprednisolone 60 mg/d (in the case of glucocorticoid intolerance use infliximab or IV cyclosporine [INN ciclosporin]). Evaluate the response to glucocorticoids (stool frequency, CRP, plain abdominal radiograph) after 3 days. If effective, continue the glucocorticoid for additional 4 to 7 days before switching to oral therapy and taper down the dose. Otherwise consider surgery or second-line therapy.

3) Second-line therapy is IV infliximab 5 mg/kg or IV cyclosporine 2 mg/kg/d. If there is no improvement within 5 to 7 days (or earlier in case of deterioration), consider surgery (colectomy).

4) Do not use antibiotics unless there is evidence of bacterial infection.

3. Manage specific complications (see Complications, below).

Relapses and Refractory Disease

1. For patients who relapse despite treatment with 5-ASA, consider 5-ASA dose optimization, concomitant oral/rectal 5-ASA, oral glucocorticoids, and biologic therapy.

2. For patients with glucocorticoid-refractory disease, consider biologic therapyEvidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011 Apr;106(4):644-59, quiz 660. doi: 10.1038/ajg.2011.73. Epub 2011 Mar 15. Review. PubMed PMID: 21407183. Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD005112. Review. PubMed PMID: 16856078. Lv R, Qiao W, Wu Z, Wang Y, Dai S, Liu Q, Zheng X. Tumor necrosis factor alpha blocking agents as treatment for ulcerative colitis intolerant or refractory to conventional medical therapy: a meta-analysis. PLoS One. 2014 Jan 27;9(1):e86692. doi: 10.1371/journal.pone.0086692. eCollection 2014. PubMed PMID: 24475168; PubMed Central PMCID: PMC3903567. (alone or in combination with an immunosuppressant) or a JAK inhibitor.

3. For patients with glucocorticoid-dependent disease, consider a thiopurine immunosuppressant, biologic therapy, or a JAK inhibitor.

4. Always consider surgery.

Maintenance of Remission

Long-term maintenance therapy to prevent relapse should be considered in all patients with UC after successful induction. The choice of drugs depends on the extent, frequency, and severity of the disease, the effectiveness of previous maintenance therapy, and the drug used during the previous exacerbation.

1. For patients responding to oral or rectal 5-ASA or to glucocorticoids, the treatment of choice is oral or rectal 5-ASA. Once-daily dosing of oral 5-ASA ≥2 g/d is acceptable.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to concerns about the single-blind design of some trials, and concern that the compliance in clinical trials may not reflect the compliance in community settings. Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012 Oct 17;10:CD000544. doi: 10.1002/14651858.CD000544.pub3. Review. PubMed PMID: 23076890. Feagan BG, MacDonald JK. Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis. Inflamm Bowel Dis. 2012 Sep;18(9):1785-94. doi: 10.1002/ibd.23024. Epub 2012 May 29. Review. PubMed PMID: 22644954. Ford AC, Khan KJ, Sandborn WJ, Kane SV, Moayyedi P. Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis. Am J Gastroenterol. 2011 Dec;106(12):2070-7; quiz 2078. doi: 10.1038/ajg.2011.296. Epub 2011 Sep 6. Review. PubMed PMID: 21894226. Rectal 5-ASA can be administered daily or titrated to a reduced dose frequency (eg, 3 d/wk). Use rectal treatments in patients with proctitis, oral or rectal treatments in patients with left-sided colitis, and oral treatments in other patients. Apart from maintaining remission, a potential benefit of 5-ASA maintenance therapy is chemoprevention of colorectal cancer. A second-line treatment is a long-term combination of oral and rectal 5-ASA.

2. For patients who require repeated courses of glucocorticoids, consider a thiopurine or a biologic agent, either alone or in combination with a thiopurine.

3. For patients in whom remission was induced with an anti-TNF agent, continue that agent alone or in combination with azathioprine.

4. For patients in whom remission was induced with a JAK inhibitor, continue that agent as maintenance therapy.

Surgical Treatment

1. Indications for surgical treatment include persistent UC symptoms despite optimal medical treatment. In severe UC not responding to intensive glucocorticoid treatment within 3 to 5 days or within 5 to 7 days of rescue therapy with infliximab or cyclosporine [INN ciclosporin], surgical treatment is urgent. Other indications include cancer or dysplasia, colonic stricture, or (rarely) refractory extraintestinal manifestations.

2. Types of surgery:

1) Total resection of the rectum and colon (proctocolectomy) with the formation of a permanent end ileostomy.

2) Restorative proctocolectomy with the formation of an ileal pouch and an ileal pouch–anal anastomosis (IPAA). This is the most common surgery, but it may require up to 3 stages for completion.

Follow-Up Top

1. Objective measures of disease activity (complete blood count [CBC], CRP, fecal calprotectin) every 3 to 12 months.

2. Monitoring for hepatobiliary complications (clinical assessment, liver biochemistry) every 12 months.

3. Cancer surveillance (colonoscopy recommended after 6-10 years from the time of diagnosis in various clinical practice guidelines and repeated at intervals depending on previous findings and disease duration: Figure 4). Surveillance colonoscopy is best performed when the patient is in remission; 4 biopsies should be collected from every 10 cm of the intestine along its entire length, plus additional samples from suspicious sites (strictures, raised lesions other than postinflammatory polyps). Chromoendoscopy (Figure 5) with targeted biopsy is an emerging alternative.

Complications Top

Intestinal Complications

1. Toxic megacolon (toxic dilation) is a potentially fatal complication occurring in ~3% of patients during a severe (often the first) flare. Clinical manifestations include abdominal pain and distention, high-grade fever, tachycardia, and abdominal signs of peritoneal inflammation. Diagnosis is based on the clinical features and plain abdominal radiographs (Figure 1). Intense supportive care (nasogastric decompression, broad-spectrum antibiotics, hydration) and urgent surgical assessment are required due to a high risk of perforation.

2. Patients with long-standing UC face an increased risk of colorectal cancer, although the magnitude of the increased risk is controversial and lower than previously thought. Predisposing factors include disease duration, disease extent, inflammatory polyps, persistent histologic inflammation, family history of colorectal cancer, and primary sclerosing cholangitis. Cancer surveillance is indicated (see Follow-Up, above).

Extraintestinal Complications

Many patients develop inflammatory processes in other organs and systems. Some occur mainly during active disease and do not require specific treatment (eg, peripheral arthritis, iritis, and erythema nodosum). Others (eg, axial arthritis and most hepatobiliary complications) develop independently of colitis activity.

1. Skeletal and articular complications: Arthritis (peripheral or axial; see Arthritis in the Course of Inflammatory Bowel Disease), osteopenia, and osteoporosis.

2. Hepatobiliary complications: Primary sclerosing cholangitis and autoimmune hepatitis.

3. Cutaneous complications: Erythema nodosum, pyoderma gangrenosum.

4. Ocular complications: Iritis, episcleritis.

Tables and FiguresTop

Table 1. The Mayo Clinic score for grading the activity of ulcerative colitis

Assessment

Points

Stool frequency

Patient reporting a normal number of daily stools

0

1-2 more stools than normal

1

3-4 more stools than normal

2

≥5 more stools than normal

3

Rectal bleeding

None

0

Blood streaks seen with stool less than half of the time

1

Blood with most stools

2

Pure blood passed

3

Endoscopic findings

Normal or inactive colitis

0

Mild friability, erythema, decreased vascularity

1

Friability, marked erythema, absent vascular pattern, erosions

2

Ulcerations and spontaneous bleeding

3

Physician’s global assessment

Normal

0

Mild colitis

1

Moderate colitis

2

Severe colitis

3

Higher scores are correlated with more severe ulcerative colitis.

Source: Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987 Dec 24;317(26):1625-9. PubMed PMID: 3317057.

Table 2. Differential diagnosis of ulcerative colitis and Crohn disease

Symptoms

Ulcerative colitis

Crohn disease

Bleeding

Common

Rare

Abdominal pain

Not severe

Common and can be severe

Palpable abdominal mass

Very rare

Fairly common

Fistulas

Very rare

Common

Involvement of the rectum

95%

50%

Perianal lesions

5%-18%

50%-80%

Pseudopolyps

13%-15%

Rare

Toxic megacolon

3%-4%

Rare

Intestinal perforation

2%-3%

Rare

Intestinal stricture

Rare

Common

Figure 1. Toxic megacolon seen on a plain abdominal radiograph. The transverse colon is 11 cm in diameter in the midline (arrow).

Figure 2. Barium enema in ulcerative colitis with involvement of the entire left sided colon. Strictures and loss of haustration in the sigmoid colon, descending colon, and part of the transverse colon. Numerous filling defects consistent with pseudopolyps.

Figure 3. Endoscopic findings in moderate ulcerative colitis. Absent vascular pattern and loss of haustration. The mucosa is friable and bleeds on contact with the endoscope.

Figure 4. Cancer surveillance in patients with ulcerative colitis. Based on the 2012 European Crohn’s and Colitis Organisation guidelines (see Additional Information for details).

Figure 5. A focus of low-grade dysplasia (arrows) revealed by indigo carmine staining.

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