Colitis, Ulcerative

Essentials of Diagnosis

• Bloody diarrhea

• Lower abdominal cramps and fecal urgency

• Anemia

• Low serum albumin

• Negative stool cultures

• Sigmoidoscopy is key to diagnosis

General Considerations

• Idiopathic inflammatory condition that involves the mucosal surface of the colon, resulting in diffuse friability and erosions with bleeding

• One-fourth of patients have disease confined to the rectosigmoid region (proctosigmoiditis); one-half have disease that extends to the splenic flexure (left-sided colitis); and one-fourth have disease that extends more proximally (extensive colitis)

• In patients with distal colitis, the disease progresses with time to more extensive involvement in 25%

• Most affected patients experience periods of symptomatic flare-ups and remissions

Demographics

• More common in nonsmokers and former smokers, severity may worsen in patients who stop smoking

• Appendectomy before age 20 reduces risk

Symptoms and Signs

• Bloody diarrhea

• Cramps, abdominal pain

• Fecal urgency, tenesmus

• Tenderness, evidence of peritoneal inflammation

• Bright red blood on digital rectal examination

• Extraintestinal symptoms

Mild disease

• Fewer than 4–6 bowel movements per day

• Rectal bleeding

• Stools may be formed or loose

• Left lower quadrant cramps, relieved by defecation

• No significant abdominal pain or tenderness

• Mild anemia and hypoalbuminemia

Moderate disease

• Diarrhea more severe with frequent bleeding

• Abdominal pain and tenderness (but not severe)

• Mild fever, anemia, and hypoalbuminemia

Severe disease

• > 6 bloody bowel movements per day

• Signs of hypovolemia and impaired nutrition

• Abdominal pain and tenderness

Fulminant disease

• Rapid progression (over 1–2 weeks) of symptoms and signs of severe toxicity

  • Hypovolemia

  • Hemorrhage requiring transfusion

  • Abdominal distention with tenderness

Toxic megacolon

• Occurs in < 2% of cases

• Colonic dilation of > 6 cm on radiographs

• Signs of toxicity

• Heightens risk of perforation

Extracolonic manifestations

• Occur in 50% of cases

• Oral ulcers

• Erythema nodosum, pyoderma gangrenosum

• Episcleritis or uveitis

• Spondylitis or sacroiliitis

• Thromboembolic events

• Oligoarticular or polyarticular nondeforming arthritis

• Sclerosing cholangitis

Differential Diagnosis

• Infectious colitis

  • Salmonella

  • Shigella

  • Campylobacter

  • Amebiasis

  • Clostridioides difficile

  • Enteroinvasive Escherichia coli

• Ischemic colitis

• Crohn disease

• Diverticular disease

• Colon cancer

• Antibiotic-associated diarrhea or pseudomembranous colitis

• Infectious proctitis: gonorrhea, chlamydia, herpes, syphilis

• Radiation colitis or proctitis

• Cytomegalovirus colitis in immunocompromised persons

Laboratory Tests

• Degree of abnormality of the hematocrit, serum albumin, and inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) reflects disease severity

• Stools for bacterial culture, ova, and parasites

• Detection of C difficile toxins TcdA and TcdB by rapid enzyme immunoassays (EIA) has 75–90% sensitivity with one stool specimen, > 90–95% sensitivity with two specimens

• Nucleic acid amplification tests (eg, polymerase chain reaction assays)

  • Preferred over EIA

  • Amplify the toxin TcdB gene

  • Have a 97% sensitivity

  • Able to detect the NAP1 hypervirulent C difficile strain

Imaging Studies

• Abdominal imaging with plain radiographs or CT is obtained in patients with severe colitis to look for significant colonic dilation

• Barium enema is of little usefulness and may precipitate toxic megacolon

Diagnostic Procedures

• Sigmoidoscopy establishes diagnosis

  • Mild to moderate disease is characterized by erythema, friability, and erosions

  • Moderate to severe disease with deep ulceration and spontaneous bleeding

• Colonoscopy should not be performed in patients with fulminant disease because of the risk of perforation

• However, after improvement, colonoscopy is recommended to determine extent of disease

• Early aggressive therapy with corticosteroids, immunomodulators, and/or biologic agents is warranted for patients with

  • Systemic signs of inflammation (anemia, low serum albumin, or elevated C-reactive protein or erythrocyte sedimentation rate levels)

  • Deep ulcerations with extensive disease on colonoscopy

Medications

Mild to moderate colitis

• Oral 5-aminosalicylic acid (5-ASA) (mesalamine or balsalazide) for induction of remission

  • Optimal dose is 2–3 g once daily in combination with mesalamine 1 g suppository or 4 g enema at bedtime

  • Most patients improve within 4–8 weeks

• Patients who do not improve within 4–8 weeks of 5-ASA therapy should have an oral corticosteroid added, eg, budesonide MMX (9 mg/day orally for 4–8 weeks) or prednisone

• Oral sulfasalazine (1.5–2 g twice daily) is uncommonly used due to its side effects but is sometimes prescribed in patients with significant arthritis

Distal colitis

• Mesalamine rectal suppositories 1000 mg per rectum once daily for proctitis or mesalamine rectal suspension, 4 g per rectum at bedtime for proctosigmoiditis, for 4–8 weeks; 75% of patients improve

• Hydrocortisone enema or foam (80–100 mg) or budesonide foam are prescribed for proctitis or proctosigmoiditis

• For patients with distal disease who do not improve with topical or oral mesalamine therapy, the following options may be considered:

  • Combination of topical mesalamine with an oral 5-ASA agent

  • Topical corticosteroid

  • Addition of oral corticosteroid (prednisone or budesonide MMX 9 mg/day) for 4–8 weeks to rectal and oral 5-ASA

Moderate to severe colitis

• Corticosteroids

  • Prednisone

    • Initial oral dose: 40–60 mg daily, depending on the severity of illness

    • Thereafter, tapering should proceed by 5–10 mg/week

    • After taper to 20 mg/day, slower tapering (2.5 mg/week) is sometimes required

    • Complete tapering without symptomatic flare-ups is possible in the majority of patients

    • Up to 30% of patients either do not respond to prednisone or have symptomatic flares during tapering that prevent its complete withdrawal

  • Oral mesalamine (2-4 g/day) is used as maintenance therapy for patients achieving remission

  • The addition of a thiopurine (azathioprine or mercaptopurine) is sometimes used to promote complete steroid withdrawal and maintain long-term remission

• Anti-TNF agent therapy

  • Infliximab

    • FDA approved in the United States for the treatment of patients with moderate to severe ulcerative colitis who have had an inadequate response to conventional therapies (oral corticosteroids, mercaptopurine or azathioprine, and mesalamine)

    • Induction regimen: 5 mg/kg administered at 0, 2, and 6 weeks

    • When initiating therapy, azathioprine, mercaptopurine, or methotrexate may be added for the first year to increase the likelihood of disease remission and reduce the development of antibodies that may result in secondary loss of response to anti-TNF therapies

    • If infliximab monotherapy is preferred, monitoring serum trough levels and anti-drug antibody titers should be obtained at least once in order to optimize drug dosing

    • Long-term maintenance regimen: infliximab 5–10 mg/kg intravenously every 4–8 weeks

  • Adalimumab and golimumab

    • FDA approved for the treatment of ulcerative colitis

    • However, both are likely inferior in efficacy to infliximab

    • Based on meta-analysis data and results of the VARSITY trial, neither can be recommended for treatment of ulcerative colitis

• Anti-integrin therapy

  • Vedolizumab is recommended for the treatment of moderate to severe ulcerative colitis in patients who have not responded to, lost response to, or been intolerant of other therapies

  • Vedolizumab induction (300 mg intravenously at 0, 2, and 6 weeks) led to clinical improvement in 47.1% of patients compared with 25.5% who were given placebo

  • Among patients who demonstrated initial clinical improvement, 41.8% of those given long-term maintenance treatment with vedolizumab (300 mg intravenously every 8 weeks) were in clinical remission at 1 year compared with 15.9% of those given placebo

  • Due to its efficacy and superior safety profile, vedolizumab may become the preferred first-line biologic agent for the treatment of moderate to severe ulcerative colitis

• Janus kinase inhibitor therapy

  • Tofacitinib 5 mg orally twice daily achieves remission

  • Tofacitinib is restricted to second line therapy in patients who not responded or have lost response to anti-TNF therapy due to increased risk of thrombosis and death in patients with rheumatoid arthritis

• Ustekinumab, a monoclonal antibody that binds the p40 subunit of IL-12 and IL-23

  • FDA approved for the treatment of moderate to severe ulcerative colitis

  • In phase III trials, 62% of patients who received intravenous ustekinumab (6 mg/kg) showed a clinical response of 62% compared to 31% of patients in placebo group

  • Among patients who started long-term maintenance treatment with ustekinumab 90 mg vs a placebo by subcutaneous injection every 8 weeks, clinical remission was significantly higher with ustekinumab (44%) vs placebo (24%)

  • Given its efficacy and excellent safety profile, ustekinumab may be viewed as another first-line biologic agent for the treatment of moderate to severe ulcerative colitis along with infliximab and vedolizumab

• Probiotics

  • Probiotics are sometimes considered as adjunctive therapy for mild-to-moderate disease

  • But in randomized, controlled trials, there was no significant benefit versus placebo in the treatment of mild to moderate ulcerative colitis

Severe and fulminant colitis

• Broad-spectrum antibiotics targeting anaerobes and gram-negative bacteria

• Intravenous corticosteroids or cyclosporine, as discussed above

• Infusion of infliximab, 5–10 mg/kg, has been shown to be effective in treating severe colitis in patients who did not improve within 4–7 days of intravenous corticosteroid therapy

• Higher doses of infliximab (three infusions of 5–10 mg/kg within 2–3 weeks) may result in lower colectomy rates than conventional doses (eg, 5 mg/kg at 0, 2, and 6 weeks)

Maintenance therapy

• Long-term oral maintenance therapy with sulfasalazine, 1–1.5 g twice daily, or mesalamine, 1.6–2.4 g once daily, has been shown to reduce relapse rates to < 35%

• For distal colitis: oral mesalamine, balsalazide, or sulfasalazine reduces the relapse rate from 80–90% to < 20% within 1 year

• Immunomodulators: 6-mercaptopurine 1.0–1.5 mg/kg orally daily or azathioprine 2.0–2.5 mg/kg orally daily is of benefit in 60% of patients with severe or refractory disease, allowing tapering of corticosteroids and maintenance of remission

• Infliximab 5 mg/kg intravenously every 8 weeks for moderate to severe disease; up to half of patients maintain clinical response at 1 year

Refractory disease

• Mercaptopurine or azathioprine

Surgery

• Total proctocolectomy with ileostomy (standard ileostomy, continent ileostomy, or ileoanal anastomosis) required in 25% of patients

• Indications for surgery include

  • Patients with severe disease (eg, severe hemorrhage) who do not improve at 7–10 days

  • Patients with fulminant disease who do not improve after 48–72 hours of corticosteroid, infliximab, or cyclosporine therapy

  • Perforation

  • Refractory disease requiring long-term corticosteroids to control symptoms

  • Dysplasia or carcinoma on surveillance colonoscopic biopsies

Therapeutic Procedures

Mild to moderate colitis

• Regular diet

• Limit intake of caffeine and gas-producing vegetables

Severe colitis

• Discontinue all oral intake

• Avoid opioid and anticholinergic agents

• Restore circulating volume with intravenous fluids and blood transfusion

• Correct electrolyte abnormalities

Fulminant colitis and toxic megacolon

• Nasogastric suction, roll patients from side to side on the abdomen

• Serial examinations and abdominal radiographs to look for worsening dilation

Complications

• Toxic megacolon

• Colon cancer

Prognosis

• Lifelong disease characterized by exacerbations and remissions

• In most patients, disease is readily controlled by medical therapy without need for surgery

• Majority never require hospitalization

• Surgery (total proctocolectomy) results in complete cure of the disease

Prevention

• Colon cancer occurs in ~0.5–1.0% per year of patients who have had colitis for > 10 years

• Colonoscopy with multiple random mucosal biopsies is recommended every 1–2 years in patients with extensive colitis, beginning 8–10 years after diagnosis

• Folic acid, 1 mg once daily orally, decreases risk of colon cancer

When to Refer

• When colonoscopy is indicated, both for evaluation of activity and extent of active disease and for surveillance for neoplasia in patients with quiescent disease for more than 8–10 years

• When hospitalization is required

• When surgical colectomy is indicated

When to Admit

• Patients with moderate to severe symptoms that do not respond to oral corticosteroids and require a trial of bowel rest and intravenous corticosteroids

• Patients with severe disease manifested by frequent bloody stools, anemia, weight loss, and fever

• Patients with fulminant disease manifested by rapid progression of symptoms, worsening abdominal pain, distention, high fever, tachycardia