Guidelines: Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease

Amy Karon

June 16, 2021

For adult outpatients with moderate to severe Crohn's disease, new guidelines from the American Gastroenterological Association strongly recommend induction and maintenance therapy with anti–tumor necrosis factor–alpha agents or ustekinumab over no treatment.

"Although [related] evidence supporting infliximab and adalimumab was moderate certainty, the evidence for certolizumab pegol was low certainty," wrote Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center in Boston and his associates, on behalf of the AGA Clinical Guidelines Committee in Gastroenterology. Vedolizumab received a conditional recommendation based on less robust evidence for induction in this setting.

Outcomes in Crohn's disease 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," Feuerstein and his associates wrote.

This update reflects these changes, strongly recommending biologic monotherapy over thiopurine monotherapy for induction. It also suggests "early induction with a biologic, with or without an immunomodulator, rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids." For the latter assessment, the guidelines noted that some studies were open label (which increases risk of bias) and that upfront combination therapy with a biologic and an immunomodulator could sometimes lead to overtreatment. Nonetheless, studies shown associations between the step-up approach and "a potential risk of harm from disease progression related to inadequate disease therapy."

The guidelines also recommend that patients who have never received biologic drugs receive induction therapy with infliximab, adalimumab, or ustekinumab, rather than certolizumab pegol. This strong recommendation reflects the findings of a network meta-analysis conducted by the AGA in which certolizumab pegol was least effective, with no evidence for clear differences in efficacy among infliximab, adalimumab, and ustekinumab. A network meta-analysis is a type of study that enables experts to compare therapies indirectly when head-to-head trials are lacking.

For patients who are naive to both biologics and immunomodulators, the guidelines suggest combination treatment with infliximab or adalimumab plus a thiopurine rather than monotherapy with either biologic. Because of a lack of randomized controlled trials, no recommendation is made regarding combination therapy with ustekinumab or vedolizumab.

For patients who have received but never responded to anti-TNF-alpha therapy (so-called primary nonresponders), ustekinumab is strongly recommended, and vedolizumab is conditionally recommended. For patients who initially responded to infliximab and then lost their response (secondary nonresponders), adalimumab and ustekinumab are strongly recommended, while vedolizumab receives another conditional recommendation.

For patients with moderate to severe luminal disease, induction and maintenance with infliximab, adalimumab, certolizumab pegol, vedolizumab, or ustekinumab are recommended over no treatment. Thiopurine monotherapy is suggested over no treatment for maintenance of remission, but not for induction. For methotrexate, subcutaneous or intramuscular monotherapy is suggested over no treatment. The sole available trial on oral methotrexate (12.5 mg/week) was negative, and "it is not clear if a higher dose would have been more effective," according to the guidelines. They strongly recommend against using 5-aminosalicytes or sulfasalazine because of lack of efficacy for maintaining remission and suggest not using natalizumab because of the risk of progressive multifocal leukoencephalopathy (PML). Corticosteroids are considered preferable to no treatment for induction but not for maintenance.

For patients with fistulizing disease, infliximab has "the most robust evidence" and receives a strong recommendation for induction and maintenance, while adalimumab, ustekinumab, and vedolizumab receive conditional recommendations. "In contrast, evidence suggests certolizumab pegol may not be effective for induction of fistula remission," the guidelines state. For patients with perianal disease with an active fistula but no abscess, combining biologics with antibiotics is strongly recommended over biologic monotherapy.

The guidelines define moderate to severe Crohn's disease as a Crohn's Disease Activity Index (CDAI) score of 220 or higher, the typical cutoff used in clinical trials. The recommendations apply to outpatient management, but in most cases would also apply to inpatients.

An expert commentary accompanying the guidelines praises their "rigorous methods" based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Edith Y. Ho, MD, of Stanford (Calif.) University and her associates also laud the "innovative methods" that were used to compare treatments and assess data quality. In addition to the network meta-analysis, the guidelines set an a priori minimal clinically important difference (MCID) score of 10% for risk of treatment failure versus placebo. This led to more clinically relevant guidance, such as the conditional recommendation for vedolizumab in luminal disease since this drug did not meet the MCID threshold. Finally, the commentators emphasized that the guidelines are meant to facilitate, not dictate, treatment decisions: "Choice of therapies and treatment strategies will continue to rely on clinical judgment as well, and will continue to be informed by patient-specific values and preferences."

The AGA Institute was the sole source of funding. Four coauthors disclosed ties to Celgene, Takeda, Pendopharm, Merck Canada, Guardant Health, Ferring, and AbbVie. Feurstein and the other guidelines coauthors reported having no conflicts of interest. Some authors on the editorial disclosed relationships with AbbVie, Pfizer, and Janssen, but the remaining had no conflicts to disclose.

This article originally appeared on , part of the Medscape Professional Network.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.