Overview of the medical management of severe or refractory Crohn disease in adults
- Richard J Farrell, MD
Richard J Farrell, MD
- Gastroenterology Consultant, Connolly Hospital
- Associate Clinical Professor, Royal College of Surgeons in Ireland
- Mark A Peppercorn, MD
Mark A Peppercorn, MD
- Professor of Medicine
- Harvard Medical School
Crohn disease is an inflammatory condition of unknown etiology that can affect any portion of the gastrointestinal tract from the mouth to the perianal area. Its transmural inflammatory nature coupled with the variability of organ distribution gives rise to a spectrum of clinical presentations, each of which has to be considered separately in deciding upon the proper therapeutic approach. (See "Clinical manifestations, diagnosis and prognosis of Crohn disease in adults".)
Clinical trials of Crohn disease often use formal grading systems to describe disease severity. Two commonly used systems are the Crohn's Disease Activity Index (CDAI) (calculator 1) and the Harvey-Bradshaw Index (HBI) (calculator 2) , which is a simplified derivative of the CDAI. The HBI has been shown to correlate with the CDAI . A drop in the CDAI of 100 points corresponds to a 3-point drop in the HBI. A CDAI of <150 (clinical remission) corresponds to an HBI of <4.
The following working definitions may be more practical for clinical practice :
●Asymptomatic remission (CDAI <150) – Patients who are asymptomatic either spontaneously or after medical or surgical intervention. Patients requiring steroids to remain asymptomatic are not considered to be in remission but are referred to as being "steroid-dependent."
●Mild to moderate Crohn disease (CDAI 150-220) – Ambulatory patients able to tolerate an oral diet without dehydration, toxicity, abdominal tenderness, mass, obstruction, or >10 percent weight loss.
- Harvey RF, Bradshaw JM. A simple index of Crohn's-disease activity. Lancet 1980; 1:514.
- Vermeire S, Schreiber S, Sandborn WJ, et al. Correlation between the Crohn's disease activity and Harvey-Bradshaw indices in assessing Crohn's disease severity. Clin Gastroenterol Hepatol 2010; 8:357.
- Lichtenstein GR, Hanauer SB, Sandborn WJ, Practice Parameters Committee of American College of Gastroenterology. Management of Crohn's disease in adults. Am J Gastroenterol 2009; 104:465.
- Te HS, Schiano TD, Kuan SF, et al. Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease. Am J Gastroenterol 2000; 95:3150.
- Peyrin-Biroulet L, Deltenre P, de Suray N, et al. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol 2008; 6:644.
- Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol 2011; 106:644.
- Kestens C, van Oijen MG, Mulder CL, et al. Adalimumab and infliximab are equally effective for Crohn's disease in patients not previously treated with anti-tumor necrosis factor-α agents. Clin Gastroenterol Hepatol 2013; 11:826.
- Osterman MT, Haynes K, Delzell E, et al. Comparative effectiveness of infliximab and adalimumab for Crohn's disease. Clin Gastroenterol Hepatol 2014; 12:811.
- Stidham RW, Lee TC, Higgins PD, et al. Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease. Aliment Pharmacol Ther 2014; 39:1349.
- Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 2006; 130:323.
- Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Gut 2007; 56:1232.
- Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007; 132:52.
- Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N Engl J Med 2007; 357:239.
- Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology 2005; 129:807.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761024lbl.pdf (Accessed on September 28, 2016).
- Chingcuanco F, Segal JB, Kim SC, Alexander GC. Bioequivalence of Biosimilar Tumor Necrosis Factor-α Inhibitors Compared With Their Reference Biologics: A Systematic Review. Ann Intern Med 2016; 165:565.
- Costa J, Magro F, Caldeira D, et al. Infliximab reduces hospitalizations and surgery interventions in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2013; 19:2098.
- Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010; 362:1383.
- 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.
- Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012; 142:63.
- Torres J, Boyapati RK, Kennedy NA, et al. Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease. Gastroenterology 2015; 149:1716.
- http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm398065.htm (Accessed on May 21, 2014).
- Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol 2008; 6:1370.
- Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2013; 369:711.
- Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med 2012; 367:1519.
- http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/761044Orig1s000ltr.pdf (Accessed on September 26, 2016).
- Benson JM, Peritt D, Scallon BJ, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs 2011; 3:535.
- 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.
- Malchow H, Ewe K, Brandes JW, et al. European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment. Gastroenterology 1984; 86:249.
- Steinhart AH, Ewe K, Griffiths AM, et al. Corticosteroids for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2003; :CD000301.
- Akobeng AK, Thomas AG. Enteral nutrition for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2007; :CD005984.
- Ostro MJ, Greenberg GR, Jeejeebhoy KN. Total parenteral nutrition and complete bowel rest in the management of Crohn's disease. JPEN J Parenter Enteral Nutr 1985; 9:280.
- Kappelman MD, Horvath-Puho E, Sandler RS, et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 2011; 60:937.
- Miehsler W, Reinisch W, Valic E, et al. Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism? Gut 2004; 53:542.
- Nguyen GC, Sam J. Rising prevalence of venous thromboembolism and its impact on mortality among hospitalized inflammatory bowel disease patients. Am J Gastroenterol 2008; 103:2272.
- Carter MJ, Lobo AJ, Travis SP, IBD Section, British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004; 53 Suppl 5:V1.
- Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:381S.
- Korelitz BI, Present DH. Favorable effect of 6-mercaptopurine on fistulae of Crohn's disease. Dig Dis Sci 1985; 30:58.
- Agrawal A, Durrani S, Leiper K, et al. Effect of systemic corticosteroid therapy on risk for intra-abdominal or pelvic abscess in non-operated Crohn's disease. Clin Gastroenterol Hepatol 2005; 3:1215.
- Garcia JC, Persky SE, Bonis PA, Topazian M. Abscesses in Crohn's disease: outcome of medical versus surgical treatment. J Clin Gastroenterol 2001; 32:409.
- Gervais DA, Hahn PF, O'Neill MJ, Mueller PR. Percutaneous abscess drainage in Crohn disease: technical success and short- and long-term outcomes during 14 years. Radiology 2002; 222:645.
- Cullen G, Vaughn B, Ahmed A, et al. Abdominal phlegmons in Crohn's disease: outcomes following antitumor necrosis factor therapy. Inflamm Bowel Dis 2012; 18:691.
- Rieder F, Zimmermann EM, Remzi FH, Sandborn WJ. Crohn's disease complicated by strictures: a systematic review. Gut 2013; 62:1072.
- SEVERE DISEASE
- REFRACTORY DISEASE
- Azathioprine and 6-mercaptopurine
- Biologic therapies
- - Anti-TNF therapies
- Adalimumab and certolizumab pegol
- Safety of anti-TNF therapies
- Switching or de-escalating biologic or immunomodulator therapies
- Failure of anti-TNF therapy
- - Anti-integrin antibodies
- - Anti-IL-12/23 antibody
- Continued disease resistance
- VENOUS THROMBOEMBOLISM
- MEDICAL MANAGEMENT OF CROHN DISEASE COMPLICATIONS
- Localized peritonitis
- Small bowel obstruction
- POSTOPERATIVE RECURRENCE
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS