AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease

Crohn’s disease (CD) is a chronic inflammatory bowel disease with substantial morbidity when not adequately controlled.1Feuerstein J.D. Cheifetz A.S. Crohn disease: epidemiology, diagnosis, and management.Mayo Clin Proc. 2017; 92: 1088-1103Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Historically, approximately 20% of patients with CD were hospitalized every year, and the risk of surgery within 1 year of diagnosis was 24%, 36% by 5 years, and 47% by 10 years.2Frolkis A.D. Dykeman J. Negrón M.E. et al.Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies.Gastroenterology. 2013; 145: 996-1006Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar In recent years, outcomes have improved, likely because of earlier diagnosis, increasing use of biologics, escalation or alteration of therapy based on disease severity, and endoscopic management of colorectal cancer. CD includes multiple different phenotypes. The Montreal Classification categorizes CD as stricturing, penetrating, inflammatory (nonstricturing and nonpenetrating), and perianal disease.3Burr N.E. Lord R. Hull M.A. et al.Decreasing risk of first and subsequent surgeries in patients with Crohn's disease in England from 1994 through 2013.Clin Gastroenterol Hepatol. 2019; 17: 2042-2049.e4Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 4Jeuring S.F. Van Den Heuvel T.R. Liu L.Y. et al.Improvements in the long-term outcome of Crohn’s disease over the past two decades and the relation to changes in medical management: results from the population-based IBDSL cohort.Am J Gastroenterol. 2017; 112: 325-336Crossref PubMed Scopus (72) Google Scholar, 5Burisch J. Kiudelis G. Kupcinskas L. et al.Natural disease course of Crohn’s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.Gut. 2019; 68: 423-433Crossref PubMed Scopus (83) Google Scholar Each of these phenotypes can present with a range in severity from mild to severe disease.6Torres J. Mehandru S. Colombel J.-F. et al.Crohn's disease.Lancet. 2017; 389: 1741-1755Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar This guideline addresses the medical management of moderate to severe luminal and fistulizing CD. The International Organization for the Study of Inflammatory Bowel Diseases characterizes severe disease as having a high risk for adverse disease-related complications, including surgery, hospitalization, and disability, based on a combination of structural damage, inflammatory burden, and impact of quality of life. Contributors to severe disease include large or deep mucosal lesions on endoscopy or imaging, presence of fistula and/or perianal abscess, presence of strictures, prior intestinal resections, particularly of segments >40 cm, presence of a stoma, extensive disease (ileal involvement >40 cm, or pancolitis), anemia, elevated C-reactive protein, and low albumin. With respect to symptoms, patients with severe disease may have at least 10 loose stools per day, daily abdominal pain, presence of anorectal symptoms (eg, anorectal pain, bowel urgency, incontinence, discharge, and tenesmus), systemic corticosteroid use within the prior year, lack of symptomatic improvement despite prior exposure to biologics and/or immunosuppressive agents, or significant impact of the disease on activities of daily living.7Siegel C.A. Whitman C.B. Spiegel B.M. et al.Development of an index to define overall disease severity in IBD.Gut. 2018; 67: 244-254Crossref PubMed Scopus (68) Google Scholar Moderate to severe disease can also be defined using the Crohn’s Disease Activity Index. This standardized disease assessment score categorizes severity of disease as: remission <150, mild to moderate as 150–220, moderate to severe as 220–450 and severe >450.8Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's Disease Activity Index: National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2863) Google Scholar For this guideline, moderate to severe disease was considered a Crohn’s Disease Activity Index score of 220 or higher. There are a number of different drug classes available for the management of moderate to severe CD, including tumor necrosis factor (TNF)–α antagonists (ie, infliximab, adalimumab, certolizumab pegol), anti-integrin agents (natalizumab, vedolizumab), interleukin 12/23 antagonist (ustekinumab), immunomodulators (thiopurines, methotrexate), and corticosteroids (prednisone, budesonide).1Feuerstein J.D. Cheifetz A.S. Crohn disease: epidemiology, diagnosis, and management.Mayo Clin Proc. 2017; 92: 1088-1103Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar In general, most drugs, with the exception of corticosteroids, that are initiated for induction of remission are continued as maintenance therapy. Unless otherwise specified, we do not present separate recommendations for induction and maintenance of remission. The drugs are listed, in general, in order of US Food and Drug Administration approval. This guideline does not address surgical management of moderate to severe CD. Therapeutic drug monitoring to guide the use of biologic therapy has been addressed in a separate American Gastroenterological Association (AGA) guideline and is not included in this guideline.9Feuerstein J.D. Nguyen G.C. Kupfer S.S. et al.American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease.Gastroenterology. 2017; 153: 827-834Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar This document presents the official recommendations of the AGA on the medical management of moderate to severe luminal and fistulizing CD in adults. This guideline addresses the outpatient medical management of moderate to severe luminal and fistulizing CD, although we anticipate that most of the recommendations would apply to inpatients as well. The guideline was developed by the AGA Institute’s Clinical Guidelines Committee and approved by the AGA Governing Board. It is accompanied by a technical review that provides a detailed synthesis of the evidence from which these recommendations were formulated.10Singh S. AGA technical review on the medical management of moderate to severe luminal and fistulizing Crohn’s disease.Gastroenterology. 2021; 160: 2512-2556Abstract Full Text Full Text PDF Scopus (5) Google Scholar Development of this guideline and the accompanying technical review was fully funded by the AGA Institute without additional outside funding. Members of the Guideline Panel and Technical Review Panel were selected by the AGA Governing Board and Chair of the Clinical Guidelines Committee with careful consideration of conflict of interest. The Guideline Panel included the chair (J.P.T.) adult gastroenterologists with IBD expertise (E.H., E.S., H.S.), Technical Review GRADE methodology chairs (J.F., S.S.) and GRADE experts (S.S., Y.F.Y.). This guideline and its accompanying technical review10Singh S. AGA technical review on the medical management of moderate to severe luminal and fistulizing Crohn’s disease.Gastroenterology. 2021; 160: 2512-2556Abstract Full Text Full Text PDF Scopus (5) Google Scholar were developed using a process outlined previously. The AGA process for developing clinical practice guidelines follows the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and adheres to best practices in guideline development, as outlined by the National Academy of Medicine (formerly Institute of Medicine).11Institute of MedicineClinical Practice Guidlines We Can Trust. National Academies Press, 2011Google Scholar