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Ulcerative Colitis Treatment & Management

  • Author: Marc D Basson, MD, PhD, MBA, FACS; Chief Editor: BS Anand, MD  more...
 
Updated: Nov 18, 2015
 

Approach Considerations

The treatment of ulcerative colitis relies on initial medical management with corticosteroids and anti-inflammatory agents, such as sulfasalazine, in conjunction with symptomatic treatment with antidiarrheal agents and rehydration. Surgery is contemplated when medical treatment fails or when a surgical emergency (eg, perforation of the colon) occurs. Surgical options include total colectomy (panproctocolectomy) and ileostomy, total colectomy, and ileoanal pouch reconstruction or ileorectal anastomosis. In an emergency situation, subtotal colectomy with end-ileostomy is recommended.[4, 5, 6]

Chronic ulcerative colitis is associated with an increase in the risk of carcinoma, and colonic carcinoma may easily be missed in the setting of ulcerative colitis. Patients with ulcerative colitis must be made aware of the significant risk of colon cancer, and surgical intervention in nonacute cases should be encouraged after 10 years of disease or when symptoms are refractory or steroid dependent. Indications for surgery in ulcerative colitis vary and are discussed in detail in Surgical Treatment.

As yet, no evidence suggests that regular endoscopic screening of patients with ulcerative colitis improves survival. However, the current standard of practice by many gastroenterologists is to continue screening these patients at regular intervals, owing to the risk of cancer development and possible legal implications if it is not detected.

Consultations

Consultations include a gastroenterologist, as well as a surgeon for severe or fulminant colitis.

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Treatment of Mild Disease

In mild disease confined to the rectum, topical mesalazine (Asacol) given by suppository is the preferred therapy. Enemas and foams are less effective because their concentration in the rectum rapidly diminishes. Left-sided colonic disease is best treated with a combination of mesalazine suppository and an oral aminosalicylate. Combined oral and topical therapy is better than either route alone. Of the oral amino salicylates, sulfasalazine has the longest history. Sulfasalazine is 5-aminosalicylate (5-ASA) coupled to a sulfapyridine. It is poorly absorbed in the proximal bowel, and the bacteria in the colon uncouple the 5-ASA from the sulfa moiety, allowing 5-ASA to exert its anti-inflammatory effect on the colonic mucosa by inhibiting prostaglandin synthesis.

Mesalazine, another 5-ASA-containing molecule, is better tolerated orally than sulfasalazine and has become the preferred medication. A meta-analysis previously suggested that doses of at least 2 g per day are more effective in inducing remission and preventing relapse, but that exceeding 2.5 g per day might not have any additional benefit.[48]  However, more recent studies have shown that higher doses are beneficial in patients not responding to lower doses (eg, 2.4 g vs 4.8 g).[49]  [50, 51]

After remission, long-term maintenance therapy is encouraged, but compliance rates are low. One systematic review analyzed the outcomes of once-daily dosing of mesalazine compared to a conventional dosing schedule (minimum of b.i.d). It was concluded that once-daily dosing is as effective as divided dosing for relapse prevention, and such daily dosing may increase compliance, although this has not been formally evaluated.[52, 53]

Systemic steroids are indicated when disease fails to quickly respond to aminosalicylates.

In January 2013, the US Food and Drug Administration (FDA) approved an extended-release oral formulation of budesonide for the treatment of active mild-to-moderate ulcerative colitis in adults patients.[54] Because budesonide is a potent corticosteroid that exerts only minimal systemic activity, this formulation provides the benefit of a powerful anti-inflammatory drug delivered locally while avoiding many of the systemic side effects associated with systemic steroids.

In a pooled analysis of efficacy and safety outcomes from two phase 3 studies of budesonide MMX 9 mg and 6 mg and placebo in 672 patients with mild-to-moderate ulcerative colitis, Sandborn and colleagues found that budesonide MMX 9 mg was safe, efficacious, and well tolerated for inducing remission of mild-to-moderate disease.[55] The budesonide MMX 9 mg resulted in significantly greater combined clinical and colonoscopic remission rates compared with placebo, whereas the budesonide MMX 6 mg did not. Symptom resolution and colonoscopic improvement rates were also significantly greater with budesonide MMX 9 mg compared with placebo.[55]

Budesonide rectal foam was approved in October 2014 and is indicated for the induction of remission in adults with active mild-to-moderate distal ulcerative colitis extending up to 40 cm from the anal verge. Approval was based on 2 randomized, placebo-controlled trials (n=546) that showed that more participants who received the budesonide rectal foam achieved remission and a rectal bleeding score of 0 at 6 weeks of therapy than placebo.[56]

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Treatment of Acute, Severe Disease

Acute, severe ulcerative colitis (ie, >6 bloody bowel movements/d, with one of the following: fever >38°C, hemoglobin level < 10.5 g/dL, heart rate >90 bpm, erythrocyte sedimentation rate >30 mm/h, or C-reactive protein level >30) requires hospitalization and treatment with intravenous high-dose corticosteroids (hydrocortisone 400 mg/d or methylprednisolone 60 mg/d). A meta-analysis supports the use of glucocorticosteroids in inducing remission in acute severe ulcerative colitis.[57]

Alternative induction medications have been evaluated. Cyclosporine,tacrolimus, infliximab, adalimumab, and golimumab are often effective in bringing steroid-resistant disease under control. Infliximab has shown to be superior to placebo in inducing remission of moderate-to-severe ulcerative colitis.[58] These agents have not been compared in a randomized, controlled fashion, and therefore, one drug cannot be recommended over the others. They have all been associated with overwhelming sepsis. Cyclosporine and tacrolimus are both nephrotoxic and should not be used for long-term therapy. Infliximab requires the coadministration of an antimetabolite to limit the development of human anti-mouse antibody (HAMA).

In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, colectomy incidence was found to be 10% for the infliximab group, as compared to 17% for the placebo group through 54 weeks, and additional benefits of infliximab included fewer colitis-related hospitalizations and surgeries/procedures. In these 2 randomized, double-blind, placebo-controlled trials, the benefit of infliximab induction and maintenance therapy in moderate to severe ulcerative colitis was demonstrated in 728 patients.[59]

Adalimumab was approved by the FDA in September 2012 for ulcerative colitis unresponsive to immunosuppressants. Approval was based on 2 phase 3 clinical studies. Both studies enrolled patients who had moderate-to-severe active ulcerative colitis despite concurrent or prior treatment with immunosuppressants (ie, corticosteroids, azathioprine, 6-mercaptopurine). Clinical remission was achieved in each study by week 8 and maintained in the long-term maintenance study at week 52.[60, 61]

Golimumab was approved for induction and maintenance of ulcerative colitis in May 2013. In the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT) trial, a significantly higher proportion of patients receiving induction treatment with subcutaneous administrations of golimumab 200 mg at week 0 and 100 mg at week 2, or golimumab 400 mg at week 0 and 200 mg at week 2, met the primary endpoint of clinical response at week 6 compared with the placebo (51.8%, 55%, and 29.7% of patients achieving clinical response, respectively [P < .0001]).[62]

Some evidence suggests that in carefully selected patients who fail both steroids and either cyclosporine or infliximab, a crossover to the other of these second-line treatments may avoid colectomy in the short term (within 2 mo).[63]

The long-term outcome in such patients is less clear, and further followup studies are required both to assess the frequency with which such rescued patients progress to colectomy and to compare overall outcomes in the longer term in such patients after crossover of second-line therapy compared with transition to colectomy after the first failure of second-line therapy.

Vedolizumab is a recombinant humanized monoclonal antibody that binds to α4β7 integrin. Integrins are proteins involved in regulating cellular movement including migration of leukocytes to the gut. Vedolizumab is indicated for moderate to severe ulcerative colitis in patients who have had an inadequate response with, lost response to, or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids. Approval was based on a large phase 3 clinical trial conducted to simultaneously evaluate vedolizumab for both UC and Crohn disease, and included several clinical studies involving 2,700 patients in nearly 40 countries.

In patients with UC who had a response to vedolizumab induction, 41.8% continued to be in clinical remission at 52 weeks compared with 15.9% of patient taking placebo (P< 0.001).[64]

For induction, other treatments have been proposed—but are not standard therapy—and include the following:

  • Antibiotics have been used as an adjunct to steroid therapy but have not altered outcomes. However, a systemic review and meta-analysis by Khan et al suggests that antibiotic therapy may induce remission in active ulcerative colitis. [65]
  • Helminth ova have not been shown to be superior to placebo.
  • Heparin may promote epithelial repair but is not effective given current delivery systems.
  • Leukocytapheresis has some promise and is quite popular in Japan, where it has been used to induce remission [66] and prevent postoperative septic complications. [67] Confirmatory studies in adults [68] and pediatric patients [69] are very promising. However, it remains a resource-intensive treatment.
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Indications for Surgery

Historically, surgery has been viewed as definitive therapy for ulcerative colitis. Indications for surgery in ulcerative colitis are varied. Failure of medical management is the most common indication for surgery.

Indications for urgent surgery in patients with ulcerative colitis include (1) toxic megacolon refractory to medical management, (2) fulminant attack refractory to medical management, and (3) uncontrolled colonic bleeding. Indications for elective surgery in ulcerative colitis include (1) long-term steroid dependence, (2) dysplasia or adenocarcinoma found on screening biopsy, (3) and disease present for 7-10 years.

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Maintenance Therapy

Once remission has been achieved, maintenance therapy is recommended for all patients to prevent relapse. Oral aminosalicylates are indicated for disease that responded to ASA or steroids. Patients who do not continue with maintenance therapy experience high rates of relapse. Some patients are unable to maintain remission or are intolerant of 5-ASA. Azathioprine and 6-mercaptopurine are alternatives with proven effectiveness. For patients who were induced with infliximab, maintenance therapy should continue with infliximab or azathioprine.

If golimumab was used for induction with a good response, monthly maintenance therapy should continue with golimumab. In the PURSUIT maintenance trial, patients responding to golimumab induction were randomized to receive golimumab or placebo for maintenance. Golimumab 100 mg SC q4wk maintained a clinical response through week 54 in 51% of patients compared with 31% of patient taking placebo (P < .001).[70]

Corticosteroids may be used for induction of remission of active ulcerative colitis and continued for up to 8 weeks. A novel formulation of slow-release budesonide (Uceris) was approved by the FDA in January 2013. Approval was based on results from the CORE 1 study that showed endoscopic improvement at 8 weeks, increased remission rates, and clinical improvement with budesonide 9 mg once daily.[71]

Probiotics also appear to be effective at maintaining remission. Escherichia coli strain Nissle 1917 has been compared with mesalazine and proved to be similarly effective.[72] Bio-Three, a commercially available probiotic supplement (Enterococcus T-110, C butyricum TO-A, B mesentericus TO-A) produced remission in 45% of patients tested with mild-to-moderate ulcerative colitis.[73] Trials of fish oil to produce or maintain remission have shown no benefit over placebo.

No specific diet restrictions are required for patients with ulcerative colitis. However, many patients with ulcerative colitis can have concurrent lactose intolerance. No specific diet can maintain remission.

Elemental nutrition and parenteral nutrition have no primary therapeutic role in ulcerative colitis, although parenteral nutrition is often used in patients who are severely ill as effective nutritional support.

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Complications

Several complications have been reported after ileal pouch–anal anastomosis procedures. The anastomotic leak rate is 7-9%.[74] If anastomotic leak occurs, fecal diversion, percutaneous drain placement, or repeat surgery with removal or revision of the reservoir is required. Pelvic abscess, which frequently accompanies an anastomotic leak, occurs in about 5% of cases (reports vary from 0-25%). Among patients with a pelvic abscess, 26% require excision of the pouch. Only 5.9% of patients without an abscess have pouch failure that requires removal.

If the abscess is managed with diversion and drainage, the pouch may be spared. However, these patients have higher rates of long-term incontinence and pain compared with those without abscesses.[75] In patients who require pouch excision due to abscess, a gracilis muscle interposition flap has been used to maintain the anal canal and allow future attempts at pouch procedures.[76] Pouch-vesicle, pouch-vaginal, pouch-anal, and enterocutaneous fistulas occur with a frequency of about 1% each.

Outcomes of pouch procedures are classified as good to excellent in as many as 90% of patients. Stool frequency is less than 5 per day in as many as 74%. Difficulty with evacuation occurs in 20%. About 77% of patients require no dietary restrictions; the remaining patients have a lower stool frequency with a low-fat diet.[77] Complete incontinence is reported in only 2%. Bulk-forming agents are required in as many as 30%.

Sexual dysfunction, manifest by retrograde ejaculation or impotence, occurs in 3% of males. Although Meagher et al reported sexual dysfunction in only 6% of females,[78] Ogilvie et al reported that 47% of females have low Female Sexual Function Index (FSFI) scores, indicating sexual dysfunction.[79] Additionally, Cornish et al described a 25% incidence of sexual dysfunction manifested by dyspareunia or psychological aversion to intercourse for fear of stool leakage.[80] The report also documented an increase in infertility from 8% preoperatively to 26% postoperatively.

Pouchitis

Pouchitis is defined as a clinical syndrome in which the patient has increased stool frequency, malaise, fever, or incontinence. This syndrome usually responds to antibiotic therapy. The most frequently used antibiotics are ciprofloxacin or metronidazole. The incidence is reported to be 40-60%. Risk increases with time; 18% have pouchitis at 1 year, and 48% have pouchitis at 10 years.[78] Pouch dilatation and pouch-anal anastomotic stricture may lead to fecal stasis and predispose the patient to pouchitis. Patients without a pouch rarely develop pouchitis and have comparable stool frequency with time. Clostridium difficile and Clostridium perfringens have been disproportionately found in patients with ulcerative colitis after ileal pouch–anal anastomosis. Treatment of these infections has led to decreases in inflammation.[81, 82]

Toxic megacolon

Toxic megacolon occurs in less than 2% of cases and can be induced by hypokalemia, opiates, anticholinergics, and barium enemas. Patients are acutely ill. Conservative treatment can be tried for 24-48 hours with IV fluids, IV steroids, antibiotics, and IV cyclosporine. Patients may eventually require a total colectomy.

Carcinoma

Carcinoma is a known complication of ulcerative colitis in the small group of patients who have had the disease for approximately 10 years. The cancer tends to be multicentric, atypical in its appearance, and rapidly metastasizing. The risk of colorectal cancer increases by 0.5-1% per year. Regular surveillance is needed.

Although the incidence of colon adenocarcinoma is greatly reduced with total proctocolectomy and ileal pouch–anal anastomosis, it is not zero. The residual colonic mucosa is at risk for dysplasia and neoplastic transformation.[83]

Because of the increased risk of colorectal cancer, guidelines from the American College of Gastroenterology recommend that after 8-10 years of colitis, patients with ulcerative colitis should undergo annual or biannual surveillance colonoscopy with multiple biopsies at regular intervals. The finding of high-grade dysplasia in flat mucosa, confirmed on review by an expert pathologist, is an indication for colectomy; the finding of low-grade dysplasia in flat mucosa may also be an indication for colectomy to prevent progression to a higher grade of neoplasia.[84]

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Long-Term Monitoring

In a study that aimed to identify a panel of markers associated with the long-term outcome of infliximab therapy for patients with refractory ulcerative colitis (median follow-up, 5 y), Arias et al confirmed that short-term clinical response and mucosal healing—as well as baseline levels of C-reactive protein (CRP) of 5 mg/L or less and albumin of 35 g/L or greater—were independent predictors of colectomy-free survival.[85]  Moreover, infliximab levels over 2.5 μg/mL at week 14 of treatment predicted both relapse- and colectomy-free survival. A combined risk panel that included clinical response, mucosal healing, and levels of pANCA, CRP, and albumin identified patients at risk for disease relapse or colectomy.[85]

In patients with chronic pouch inflammation, villous hypertrophy and dysplasia may occur. Although dysplasia has never been found within the pouch of a pediatric patient, chronic inflammatory changes have been found, leading to the supposition that dysplasia may develop. Yearly screening endoscopy has been recommended for the first 5 years after the procedure. In children who have chronic inflammatory changes in the pouch reservoir, annual screening endoscopy should be performed. If no inflammation is present, screening endoscopy may be performed every 2 years.[86]

Patients with extensive colitis or left-sided colitis with negative findings on screening colonoscopy should begin surveillance colonoscopy in 1-2 years. For patients with ulcerative colitis and primary sclerosing cholangitis, screening and subsequent surveillance colonoscopy should begin on an annual basis at the time of onset of primary sclerosing cholangitis.

Patients with proctosigmoiditis have no increased risk for colorectal cancer compared with the general population. However, these patients should be managed according to the current guidelines on colorectal cancer screening. If high-grade dysplasia or cancer is found, colectomy is performed. The management of low-grade dysplasia is controversial[87] ; however, most experts would recommend colectomy.

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Contributor Information and Disclosures
Author

Marc D Basson, MD, PhD, MBA, FACS Associate Dean for Medicine, Professor of Surgery and Basic Science, University of North Dakota School of Medicine and Health Sciences

Marc D Basson, MD, PhD, MBA, FACS is a member of the following medical societies: Alpha Omega Alpha, American College of Surgeons, American Gastroenterological Association, Phi Beta Kappa, Sigma Xi

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

Michael A Grosso, MD Consulting Staff, Department of Cardiothoracic Surgery, St Francis Hospital

Michael A Grosso, MD is a member of the following medical societies: American College of Surgeons, Society of Thoracic Surgeons, and Society of University Surgeons

Disclosure: Nothing to disclose.

Alex Jacocks, MD Program Director, Professor, Department of Surgery, University of Oklahoma School of Medicine

Disclosure: Nothing to disclose.

Tri H Le, MD Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Penn State Milton S Hershey Medical Center

Tri H Le, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, American Society of Gastrointestinal Endoscopy, and Crohns and Colitis Foundation of America

Disclosure: Nothing to disclose.

Luis M Lovato, MD Associate Clinical Professor, University of California, Los Angeles, David Geffen School of Medicine; Director of Critical Care, Department of Emergency Medicine, Olive View-UCLA Medical Center

Luis M Lovato, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Anil Minocha, MD, FACP, FACG, AGAF, CPNSS Professor of Medicine, Director of Digestive Diseases, Medical Director of Nutrition Support, Medical Director of Gastrointestinal Endoscopy, Internal Medicine Department, University of Mississippi Medical Center; Clinical Professor, University of Mississippi School of Pharmacy

Anil Minocha, MD, FACP, FACG, AGAF, CPNSS is a member of the following medical societies: American Academy of Clinical Toxicology, American Association for the Study of Liver Diseases, American College of Forensic Examiners, American College of Gastroenterology, American College of Physicians, American Federation for Clinical Research, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Noel Williams, MD Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada

Noel Williams, MD is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

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Increased postrectal space is a known feature of ulcerative colitis.
Plain abdominal radiograph from a patient with known ulcerative colitis who presented with an acute exacerbation of his symptoms. The image shows thumbprinting in the region of the splenic flexure of the colon.
Double-contrast barium enema study shows pseudopolyposis of the descending colon.
Single-contrast enema study in a patient with known ulcerative colitis in remission shows a benign stricture of the sigmoid colon.
Plain abdominal radiograph in a 26-year-old with a 10-year history of ulcerative colitis shows a long stricture/spasm of the ascending colon/cecum. Note the pseudopolyposis in the descending colon.
Single-contrast enema study in a patient with total colitis shows mucosal ulcers with a variety of shapes, including collar-button ulcers (yellow arrow), in which undermining of the ulcers occurs, and double-tracking ulcers (red arrow), in which the ulcers are longitudinally orientated.
Double-contrast barium enema study shows total colitis. Note the granular mucosa in the cecum/ascending colon and multiple strictures in the transverse and descending colon in a patient with a more than a 20-year history of ulcerative colitis.
Single-contrast barium enema study shows burnt-out ulcerative colitis.
Intravenous urogram in the same patient as in Image 11 shows features of ankylosing spondylitis.
Lateral radiograph of the lumbar spine in the same patient as in Images 10-11 shows a bamboo spine.
Single-contrast barium enema study in a patient with Shigella colitis.
Postevacuation image obtained after a single-contrast barium enema study shows extensive mucosal ulceration resulting from Shigella colitis.
Double-contrast barium enema studies show granular mucosa associated with Campylobacter colitis.
Ulcerative colitis as visualized with a colonoscope.
Inflamed colonic mucosa demonstrating pseudopolyps.
Table 1. Distinguishing Ulcerative Colitis from Crohn Disease
Ulcerative Colitis Crohn Disease
Only colon involved Panintestinal
Continuous inflammation extending proximally from rectum Skip-lesions with intervening normal mucosa
Inflammation in mucosa and submucosa only Transmural inflammation
No granulomas Noncaseating granulomas
Perinuclear ANCA (pANCA) positive ASCA positive
Bleeding (common) Bleeding (uncommon)
Fistulae (rare) Fistulae (common)
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