Inflammatory Bowel Disease

General Principles

  • Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon and rectum, characterized by mucosal inflammation and typically presenting with bloody diarrhea. Rectal involvement is almost universal.
  • Crohn disease (CD) is characterized by transmural inflammation of the gut wall and can affect any part of the tubular GI tract.

Diagnosis

Clinical Presentation

  • Both disorders can present with diarrhea, weight loss, and abdominal pain. UC typically presents with bloody diarrhea. CD can also present with fistula formation, strictures, abscesses, or bowel obstruction.
  • Extracolonic manifestations of inflammatory bowel disease (IBD) include arthritis, primary sclerosing cholangitis, and ocular and skin lesions.

Diagnostic Testing

  • Endoscopy remains the preferred method for diagnosis, especially for UC, where contiguous inflammation is seen starting at the rectum and extending varying distances into the colon. Endoscopy may demonstrate colonic involvement in CD (erosions or ulcers with a patchy distribution and skip lesions); ileoscopy during colonoscopy may demonstrate terminal ileal involvement. Histopathology demonstrates chronic mucosal inflammation with crypt abscesses and cryptitis in UC and may demonstrate multinucleated giant cells and noncaseating granulomas in CD.
  • Cross-sectional imaging studies (CT and MRI scans) have value in the evaluation of CD, especially when luminal narrowing (stricture) or extraluminal complications (abscess, fistula) are suspected. Although MRI and CT enterography both adequately assess disease activity and bowel involvement in CD, MRI may be superior to CT.1,2 Contrast radiography (small bowel follow-through series, barium enema) may also be useful, particularly in CD.
  • Serologic markers play a limited role as adjuncts for diagnosis. Anti-Saccharomyces cerevisiae antibodies are typically seen in CD, and perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) are seen in UC. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) represent correlates for disease activity.
  • C. difficile colitis is more frequent in IBD patients compared with non-IBD populations; therefore, stool studies are warranted to look for this organism with disease flares.3 CMV superinfection can occur in patients on immunosuppressive agents and can be diagnosed by histopathology during endoscopy.4

Treatment

Medications

Treatment is based on the severity of disease, location, and associated complications.5 Management aims are to resolve the acute presentation and reduce future recurrences. Both UC and CD can be categorized into three categories of severity for management purposes:

  • Mild to moderate disease: Patients have little to no weight loss and good functional capacity and are able to maintain adequate oral intake. UC patients have less than four bowel movements daily with no rectal bleeding or anemia, normal vital signs, and normal ESR, whereas CD patients have little or no abdominal pain. Treatment typically begins with aminosalicylates but can include antibiotics and glucocorticoids.
    • 5-Aminosalicylates (5-ASA): Various formulations are available, each targeting different parts of the tubular gut, and are useful for both inducing and maintaining remission in mild to moderate disease. Infrequent hypersensitivity reactions include pneumonitis, pancreatitis, hepatitis, and nephritis. Sulfasalazine reaches the colon intact, where it is metabolized to 5-ASA and a sulfapyridine moiety. Benefit is seen in UC or CD limited to the colon, either as initial therapy (0.5 g PO bid, increased as tolerated to 0.5–1.5 g PO qid) or to maintain remission (1 g PO bid–qid). The sulfapyridine moiety is responsible for side effects of headache, nausea, vomiting, and abdominal pain, which are treated with dose reduction. Skin rash, fever, agranulocytosis, hepatotoxicity, and paradoxical exacerbation of colitis are rare hypersensitivity reactions. Reversible reduction in sperm counts can be seen in males. Folic acid supplementation is recommended because sulfasalazine can impair folate absorption.
    • Mesalamine: Newer 5-ASA preparations lack the sulfa moiety of sulfasalazine and are associated with fewer side effects but can be expensive.
      • Asacol is an oral formulation of 5-ASA released at a pH of 7 in the distal ileum. It is useful in UC and ileocecal/colonic CD at doses of 800–1600 mg PO tid.
      • Pentasa has a time- and pH-dependent release mechanism that allows drug availability throughout the small bowel and colon. It is useful in diffuse small bowel involvement with CD but can also be used in UC in doses of 0.5–1.0 g PO qid.
      • Apriso also has a pH-dependent release mechanism and distributes mesalamine throughout the colon when administered in doses of 1.5 g PO once daily.
      • Balsalazide (Colazal) is cleaved by colonic bacteria to mesalamine and an inert molecule. Therefore, it is only useful for colonic disease, at doses of 2.25 g PO tid for active disease and 1.5 g PO bid for maintenance.
      • Multimatrix delivery system mesalamine (Lialda) uses a novel delivery system that allows sustained 5-ASA release throughout the colon while decreasing frequency of administration. It is useful in colonic disease at doses of 1.2–2.4 g PO qday–bid.
    • Olsalazine (Dipentum) is a 5-ASA dimer cleaved by colonic bacteria and is useful in colonic disease. Significant diarrhea limits its use.
    • Antibiotics are commonly used clinically in mild to moderate CD as well as perianal disease, but not in UC where the role of bacteria has not been established. Their role should be limited to colonic or ileocolonic CD, perianal disease, fistulas, and abscesses. Typical antibiotics used are metronidazole (250–500 mg PO tid) and ciprofloxacin (500 mg PO bid), usually concurrently, for 2–6 weeks
      • Budesonide (Entocort; 6–9 mg PO qday) is a synthetic corticosteroid with first-pass liver metabolism that limits systemic toxicity while retaining local efficacy from high affinity to the glucocorticoid receptor, similar to oral corticosteroids. It is effective and safe for short-term use in mild to moderate ileocolonic CD and can replace mesalamine in inducing remission.5
      • Topical therapy is useful in IBD limited to distal left colon. Topical mesalamine agents are superior to topical steroids or oral aminosalicylates for mild to moderate distal UC or ulcerative proctitis.6 Sitz baths, analgesics, hydrocortisone creams, and local heat may provide symptomatic benefit in perianal CD in conjunction with systemic therapy.
  • Moderate to severe disease refers to CD patients who fail to respond to treatment for mild to moderate disease or those with significant weight loss, anemia, fever, abdominal pain or tenderness, and intermittent nausea and vomiting without bowel obstruction, or UC patients with more than six bloody bowel movements daily, fever, mild anemia, and elevated ESR.7 Predictive factors for moderate- to high-risk disease include age <30 years at initial diagnosis, extensive anatomic involvement, perianal and/or severe rectal disease, deep ulcers, prior surgical resection, and stricturing or penetrating behavior.5 The goal of therapy is to induce remission rapidly with corticosteroids and to maintain remission with immunosuppressive agents and/or biologic agents as appropriate. Treatment is typically continued until the patient fails to respond to a particular agent or the agent is no longer tolerated.
    • Glucocorticoids are effective in inducing remission in moderate to severe disease, especially with flares of disease activity.8
      • Prednisone is started orally (typically 40–60 mg PO daily) and continued until symptom improvement. The dose can then be tapered on a weekly basis because glucocorticoids are not recommended for maintenance therapy, and steroid-sparing alternatives should be sought for patients who appear dependent on these medications.
      • Oral or parenteral glucocorticoids should not be prescribed before ruling out an infectious process and should not be initiated for the first time over the telephone.
    • Immunosuppressive agents
      • 6-Mercaptopurine (1.0–1.5 mg/kg/d PO), a purine analog, and azathioprine (1.5–2.5 mg/kg/d PO), its S-imidazole precursor, cause preferential suppression of T-cell activation and antigen recognition and are useful in maintaining a glucocorticoid-induced remission in both UC and CD. Both azathioprine and 6-mercaptopurine are effective for inducing remission in active CD.9 Response may be delayed for up to 1–2 months, with optimal response occurring about 4 months after treatment initiation. Side effects include reversible bone marrow suppression, pancreatitis, and allergic reactions.
        • Determination of thiopurine methyltransferase (TPMT) enzyme activity prior to initiation of therapy will identify genetic polymorphisms that may predispose to toxicity with the use of these agents.10
        • Routine blood cell counts should be performed, initially every 1–2 weeks, to monitor for acute or delayed bone marrow suppression. On stable doses, testing can be performed every 3 months
        • 6-Thioguanine (6-TG) metabolite levels assess adequacy of dosing, whereas high 6-methyl mercaptopurine (6-MMP) levels may predict hepatotoxicity. Addition of allopurinol to the regimen preferentially pushes metabolism toward the active metabolite (6-TG) rather than the toxic metabolite (6-MMP).11
      • Methotrexate (15–25 mg IM or PO weekly) is effective as a steroid-sparing agent in CD but not UC. Side effects include hepatic fibrosis, bone marrow suppression, alopecia, pneumonitis, allergic reactions, and teratogenicity. In CD patients in remission, methotrexate is not as effective as azathioprine or infliximab for mucosal healing, and methotrexate added to infliximab is no more effective than infliximab monotherapy.12,13
        • Baseline CXR and monitoring of CBC and liver function tests should be performed routinely.
        • Patients with abnormal transaminases may require a liver biopsy to assess for hepatic fibrosis prior to treatment, and subsequent biopsies are performed for significant elevations thereafter.
    • Anti–tumor necrosis factor-α (anti–TNF-α) monoclonal antibodies modify immune system function and are beneficial in moderate to severe CD refractory to other approaches, including immunosuppressives, and indicated both for induction and maintenance of remission. Benefit has also been demonstrated in moderate to severe UC.14 Infliximab (Remicade; 5 mg/kg IV infusions at weeks 0, 2, and 6, followed by maintenance infusions every 8 weeks), adalimumab (Humira; 160 mg SC at week 0, then 80 mg SC at week 2, followed by 40 mg SC every 2 weeks), certolizumab pegol (Cimzia; 400 mg SC at weeks 0, 2, and 4, followed by maintenance doses every 4 weeks), and golilimumab (Simponi, 200 mg SC at week 0, then 100 mg SC at week 2 and every 4 weeks thereafter) are the available anti–TNF-α agents. Combination therapy with infliximab and azathioprine is more effective than monotherapy with either agent in UC.15 In addition to its role as an option for first-line therapy, adalimumab is also safe and effective for CD patients who have failed infliximab therapy.16 However, because elective switching from IV infliximab to SC adalimumab is associated with loss of tolerance and efficacy, adherence to the first anti–TNF-α agent is encouraged.17 Therapeutic drug monitoring can help optimize anti-TNF therapy, especially when symptoms persist.18 In moderate to severe CD, infliximab plus azathioprine or infliximab monotherapy is more likely to attain steroid-free clinical remission than azathioprine monotherapy.19
      • Anti–TNF-α therapy has been associated with reactivation of latent TB; hence, placement of a purified protein derivative skin test and CXR are essential prior to initiation of therapy.6 Hepatitis B status should also be assessed and vaccination provided prior to therapy. Opportunistic infections as well as infectious complications can develop, and congestive heart failure may worsen during therapy.
      • Acute and delayed hypersensitivity reactions, or antibodies to infliximab and anti–double-stranded DNA antibodies, can develop with infliximab infusions. Local injection site reactions have been reported with adalimumab and certolizumab pegol therapy.
    • Vedolizumab (Entyvio; 300-mg infusions at weeks 0 and 2, followed by infusions every 4–8 weeks), an α4β7 integrin antibody, has emerged as an alternative option for induction and maintenance of remission in both CD and UC.20
    • Natalizumab (Tysabri; 300-mg infusions at weeks 0, 4, and 8, followed by monthly infusions thereafter) is a humanized monoclonal antibody to α-4 integrin, used for moderate to severe CD refractory to all other approaches including anti–TNF-α antibodies. This agent may induce reactivation of human JC polyomavirus, causing progressive multifocal leukoencephalopathy, and is now rarely used.
    • Ustekinumab (Stelara; weight-dependent dosing of 260–520-mg infusion at week 1, followed by 90-mg subcutaneous maintenance injections every 8 weeks), a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, has shown promising results in moderate to severely active Crohn’s disease.21
    • Tofacitinib (Xeljanz; 5 mg or 10 mg oral twice a day, dosing to be determined) is an oral Janus kinase inhibitor that has shown promise in clinical trials in moderately to severely active ulcerative colitis in induction and maintenance therapy.22
  • Severe or fulminant disease describes patients typically hospitalized because of the severity of their symptoms. Fulminant CD patients have persistent symptoms despite conventional glucocorticoids or anti–TNF-α therapy or have high fevers, persistent vomiting, intestinal obstruction, intra-abdominal abscess, peritoneal signs, or cachexia.7 Fulminant colitis (both CD and UC) can present with profuse bloody bowel movements, significant anemia, systemic signs of toxicity (fever, sepsis, electrolyte disturbances, dehydration), and elevated laboratory markers of inflammation. Toxic megacolon occurs in 1%–2% of UC patients, wherein the colon becomes atonic and modestly dilated, with significant systemic toxicity.
    • Supportive therapy consists of NPO status with NG suction if there is evidence of small bowel ileus. Dehydration and electrolyte disturbances are treated vigorously, and blood is transfused for severe anemia. Anticholinergic and opioid medication should be discontinued in toxic megacolon.
    • Initial investigation includes cross-sectional imaging to evaluate for intra-abdominal abscess. Blood cultures and stool studies to exclude C. difficile colitis are performed. Cautious flexible sigmoidoscopy may be done to determine severity of colonic inflammation and for biopsies to exclude CMV colitis.
    • Once infection is excluded, intensive medical therapy with IV corticosteroids (methylprednisolone 1 mg/kg body weight or equivalent to 40–60 mg of prednisone) and broad-spectrum antimicrobials should be initiated.
    • If response is not seen, cyclosporine infusion (2–4 mg/kg/d, to achieve blood levels of 200–400 ng/mL) and tacrolimus infusion represent options in fulminant UC colitis.
    • Nutritional support is administered as appropriate after 5–7 days; TPN is often indicated if enteral nutrition is not tolerated.
    • Clinical deterioration/lack of improvement despite 7–10 days of intensive medical management, evidence of bowel perforation, and peritoneal signs are indications for urgent total colectomy.

Surgical Management

  • Surgery is generally reserved for fistulas, obstruction, abscess, perforation, or bleeding; medically refractory disease; and neoplastic transformation.8 Stricturoplasty is an option for focal tight strictures; biopsies should be obtained to rule out cancer at stricture sites.
  • In CD, recurrence close to the resected margins is common after bowel resection. Efforts should be made to avoid multiple resections in CD because of the risk of short bowel syndrome. Immunosuppressive agents should be discontinued before surgery and reinstituted if necessary during the postoperative period.
  • In UC, total colectomy is curative and may be preferred over long-term immunosuppressive or biologic therapy.

Lifestyle/Risk Modification

  • A low-roughage diet often is useful in mild to moderate IBD or in patients with strictures.
  • Patients with Crohn ileitis or ileocolonic resection may need vitamin B12 supplementation. Specific oral replacement of calcium, magnesium, folate, iron, vitamins A and D, and other micronutrients may be necessary in patients with small bowel CD.
  • TPN can be administered in patients with food intolerance for greater than 4 or 5 days. Bowel rest has not been shown to reduce time to remission but can be used for nutritional maintenance and symptom relief while waiting for the effects of medical treatment or as a bridge to surgery.

Special Considerations

  • In patients with both UC and Crohn colitis lasting longer than 8–10 years, annual or biennial colonoscopic surveillance for neoplasia should be performed, ideally using chromoendoscopy. Optimal biopsy technique continues to be studied and includes either four-quadrant mucosal biopsies every 5–10 cm using white light endoscopy or targeted biopsies using chromoendoscopy. Consistent histopathologic evidence of any grade of dysplasia is an indication for total colectomy. Narrow-band imaging during colonoscopy may represent an alternative to chromoendoscopy for targeted biopsies in IBD.23,24
  • Smoking cessation is generally warranted for all patients with IBD. There is epidemiologic evidence of a protective effect on a limited number of patients with UC. However, nicotine has been shown to increase metabolism of many medications routinely used to treat IBD, decreasing their efficacy.
  • Venous thromboembolism: Patients with IBD are at increased risk for both first and recurrent venous thromboembolism.25
  • Family planning is important in women with active disease as there is an increased association of premature delivery, low birth weight, and congenital abnormalities.26
  • Symptom control is important as adjunct to therapy but must be used cautiously.
    • Antidiarrheal agents may be useful as an adjunctive therapy in selected patients with mild exacerbations or postresection diarrhea. They are contraindicated in severe exacerbations and toxic megacolon.
    • Narcotics should be used sparingly for pain control because the chronicity of symptoms can lead to potential for dependence.

References

  1. Ordás I, Rimola J, Rodríguez S, et al. Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn’s disease. Gastroenterology. 2014;146:374-382.  [PMID:24177375]
  2. Fiorino G, Bonifacio C, Peyrin-Biroulet L, et al. Prospective comparison of computed tomography enterography and magnetic resonance enterography for assessment of disease activity and complications in ileocolonic Crohn’s disease. Inflamm Bowel Dis. 2011;17:1073-1080.  [PMID:21484958]
  3. Rodemann JF, Dubberke ER, Reske KA, et al. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5:339-344.  [PMID:17368233]
  4. Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Am J Gastroenterol. 2006;101:2857-2865.  [PMID:17026558]
  5. Terdiman JP, Gruss CB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology. 2013;145:1459-1463.  [PMID:24267474]
  6. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105:501-523.  [PMID:20068560]
  7. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104:465-483.  [PMID:19174807]
  8. Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011;60:571-607.  [PMID:21464096]
  9. Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2010;16:CD000545.
  10. Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:935-939.  [PMID:16530531]
  11. Ansari A, Patel N, Sanderson J, et al. Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2010;31:640-647.  [PMID:20015102]
  12. Laharie D, Reffet A, Belleannée G, et al. Mucosal healing with methotrexate in Crohn’s disease: a prospective comparative study with azathioprine and infliximab. Aliment Pharmacol Ther. 2011;33:714-721.  [PMID:21235604]
  13. Feagan BG, McDonald JW, Panaccione R, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease. Gastroenterology. 2014;146:681-688.  [PMID:24269926]
  14. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60:780-787.  [PMID:21209123]
  15. Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146:392-400.  [PMID:24512909]
  16. Lichtiger S, Binion DG, Wolf DC, et al. The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn’s disease who failed prior infliximab therapy. Aliment Pharmacol Ther. 2010;32:1228-1239.  [PMID:20955442]
  17. Van Assche G, Vermeire S, Ballet V, et al. Switch to adalimumab in patients with Crohn’s disease controlled by maintenance infliximab: prospective randomised SWITCH trial. Gut. 2012;61:229-234.  [PMID:21948942]
  18. Mitrev N, Vande Casteele N, Seow CH, et al. Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases. Aliment Pharmacol Ther. 2017;46:1037-1053.  [PMID:29027257]
  19. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383-1395.  [PMID:20393175]
  20. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699-710.  [PMID:23964932]
  21. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946-1960.  [PMID:27959607]
  22. Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376:1723-1736.  [PMID:28467869]
  23. Pellisé M, López-Cerón M, Rodríguez de Miguel C, et al. Narrow-band imaging as an alternative to chromoendoscopy for the detection of dysplasia in long-standing inflammatory bowel disease: a prospective, randomized, crossover study. Gastrointest Endosc. 2011;74:840-848.  [PMID:21802681]
  24. Moussata D, Allez M, Cazals-Hatem D, et al. Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy? Gut. 2018;67:616-624.  [PMID:28115492]
  25. Novacek G, Weltermann A, Sobala A, et al. Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism. Gastroenterology. 2010;139:779-787.  [PMID:20546736]
  26. Nguyen GC, Seow CH, Maxwell C, et al. The Toronto consensus statements for the management of inflammatory bowel disease in pregnancy. Gastroenterology. 2016;150:734-757.  [PMID:26688268]

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