Refractory Crohn Disease

Educational Objectives

The goals of this program is to improve the diagnosis and management of refractory Crohn disease. After hearing and assimilating this program, the clinician will be better able to:

1. Diagnose refractory Crohn disease.
2. Implement evidence-based management strategies for refractory Crohn disease.

Summary

Refractory Crohn disease (CD): patients with refractory CD often have prolonged therapeutic history of medications with eventual secondary loss of response despite dose escalation or primary nonresponse despite dose escalation with a stricturing phenotype, requiring ileocecectomy and ulcerations; symptoms — include abdominal pain in the right lower quadrant, 4 to 5 loose nonbloody bowel movements a day with increasing perianal drainage, and pain; potentially aggressive phenotypes include the stricturing phenotype and perianal disease

Treatment: colonoscopy is recommended to ascertain active disease indicated by inflammation as opposed to other causes, eg, inflammatory bowel disease, bile salt diarrhea; optimization of current therapy is crucial prior to switching therapies; a meta-analysis by Nguyen et al (2022) found that routine therapeutic drug monitoring was not effective in CD; reactive therapeutic drug monitoring is helpful for assessment of antibodies; guidelines from the American Gastroenterology Association outline goals for infliximab, adalimumab, and certolizumab; goals for vedolizumab and ustekinumab are not well established; if neutralizing antibody titer is high, a change in regimen is recommended; tumor necrosis factor (TNF) receptor-associated factor (TRAF) is difficult to manage; the decision to increase the dose empirically or wait for TRAF results is controversial

Immunomodulators: the addition of immunomodulators to standard therapy is controversial; for TNF, the immunomodulatory agent is started alongside biologic agent; useful in patients with no history of primary nonresponse (eg, thiopurine, methotrexate); benefit with TNF inhibitors is limited; evidence is against switching between thiopurine and methotrexate

Infliximab: has good evidence but is not recommended in patients with high antibody titer with secondary loss of response; can be tried even in patients with partial response or intolerance; 30% to 40% of such patients may be recaptured

Risankizumab: a 600-mg intravenous dose and a subsequent subcutaneous formulation has been recently approved by the US Food and Drug Administration; prior biologic failure indicates lower response remission; a selective p19 interleukin 23 (IL-23) antibody; an option for patients who do not respond to ustekinumab

Combination biologic therapy: recommended for patients with partial response to a previous agent; dual biologic therapy is safe; Sands et al (2007) demonstrated efficacy of natalizumab plus infliximab in CD with no increase in risk for infection; helpful in inducing remission in refractory patients and those with ongoing extraintestinal manifestations; the majority of observational studies suggest no serious adverse effects with combination therapy; the ideal candidate is an individual with partial response

Mesenchymal stem cell therapy: recommended for patients with refractory perianal disease; combined surgical drainage and anti-TNF medication are useful for closure of perianal fistulas; refractory perianal disease affects 20% to 25% of CD patients; locally injected allogeneic adipose-derived stromal stem cells are beneficial in such patients; large quantities are easy to collect through abdominal liposuction or other means, and provides long lasting benefit; approved by the European Medicine Agency; multiple trials are underway in the United States; the ADMIRE-CD trial (Garcia-Olmo et al; 2022) evaluated combined response, combined remission at 14 wk; imaging showed no large collections and good outcomes

Future therapies: upadacitinib (Janus kinase inhibitor) has completed most of its studies; sphingosine 1-phosphate modulating agents have been tried (ozanimod, etrasimod); guselkumab is an IL-23 inhibitor; another potential target is mucosal addressin cell adhesion molecule-1 (MAdCAM-1) inhibition, which has shown benefit for these agents in early-phase studies

Microbiome: the role of the microbiome is being evaluated (eg, adherent-invasive Escherichia coli)

Combination therapy: DUET-CD trial is evaluating the use of combination agents (anti-TNF with IL-23 inhibitor) for CD; the ABBV-154 study is evaluating the use of adalimumab conjugated to a glucocorticoid receptor modulator that targets the TNF cells that are expressing TNF through the transmembrane TNF, then delivers the steroid to specific cells; it can be administered initially as an intravenous agent, followed by subcutaneous route

Pediatric CD: clinicians must recognize very early-onset irritable bowel syndrome (IBD) in infants and children <6 yr of age; this subset constitutes 10% to 15% of pediatric IBD patients and tend to have more complex disease with poor response to treatment; Kelsen et al (2020) demonstrated high failure rates of infliximab in patients with very early-onset IBD; 15% to 20% of these patients had a monogenetic defect in IL-10, immune dysregulation, polyendocrinopathy and enteropathy, X-linked syndrome, common variable immunodeficiency, and chronic granulomatous disease (CGD); genetic analysis is crucial for management; infliximab is avoided in patients with CGD

Readings

Garcia-Olmo D, Gilaberte I, Binek M, et al. Follow-up study to evaluate the long-term safety and efficacy of darvadstrocel (mesenchymal stem cell treatment) in patients with perianal fistulizing Crohn's disease: ADMIRE-CD Phase 3 randomized controlled trial. Dis Colon Rectum. 2022;65(5):713-720. doi:10.1097/DCR.0000000000002325; Nguyen NH, Solitano V, Vuyyuru SK, et al. Proactive therapeutic drug monitoring versus conventional management for inflammatory bowel diseases: A systematic review and meta-analysis. Gastroenterology. 2022;163(4):937-949.e2. doi:10.1053/j.gastro.2022.06.052; Reider S, Binder L, Fürst S, et al. Hematopoietic stem cell transplantation in refractory Crohn's disease: Should it be considered?. Cells. 2022;11(21):3463. Published 2022 Nov 2. doi:10.3390/cells11213463; Tanida S, Ozeki K, Mizoshita T, et al. Managing refractory Crohn's disease: challenges and solutions. Clin Exp Gastroenterol. 2015;8:131-140. Published 2015 Apr 10. doi:10.2147/CEG.S61868.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Keyashian was recorded at 2023 Updates in Gastroenterology & Hepatology, held April 13-15, 2023, in Redwood City, CA, and presented by Stanford University School of Medicine. For information about upcoming CME activities from this presenter, please visit med.stanford.edu/cme. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.50 CE contact hours.

Lecture ID:

GE372302

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.