Treatment Options After Upadacitinib Failure in Crohn's Disease

Primary Recommendation: IL-23 Inhibitors

The British Society of Gastroenterology recommends risankizumab for patients with moderate-to-severe Crohn's disease who have had inadequate response to previous biologic therapies, including JAK inhibitors (moderate certainty evidence) 1
In biologic-exposed patients, risankizumab is favored over ustekinumab, adalimumab, and vedolizumab, with no demonstrated superiority between risankizumab and upadacitinib 2
The AGA strongly recommends ustekinumab for induction and maintenance of remission in moderate-to-severe Crohn's disease after failure of anti-TNF therapy (strong recommendation, moderate certainty evidence) 3, 1
Ustekinumab achieves clinical remission with a relative risk of 1.76 (95% CI: 1.40-2.22) versus placebo 1
Endoscopic improvement occurs in 47.7% of patients receiving ustekinumab compared with 29.9% receiving placebo 1

If the patient is anti-TNF naïve, infliximab or adalimumab should be considered before IL-23 inhibitors 3
The AGA recommends infliximab, adalimumab, or ustekinumab over certolizumab pegol for induction of remission in biologic-naïve patients (strong recommendation, moderate certainty evidence) 3
However, if anti-TNF therapy was previously failed, switching to another anti-TNF is generally less effective than switching to a different mechanism of action 1
The AGA recommends vedolizumab for patients who fail to achieve complete remission with corticosteroids, thiopurines, methotrexate, or anti-TNF therapy (strong recommendation, moderate-quality evidence) 4
Vedolizumab response should be evaluated between 10-14 weeks to determine need for therapy modification 4, 1
In biologic-exposed patients, vedolizumab ranks lower than risankizumab and upadacitinib in comparative efficacy 2

Screen for tuberculosis, viral hepatitis, and update immunizations before initiating any new biologic or JAK inhibitor 2
Monitor for herpes zoster infection, which occurs more frequently with JAK inhibitors (4.0-7.2% on maintenance therapy) 2
The FDA and European Medicines Agency caution about cardiovascular risk, venous thromboembolism, and malignancy with JAK inhibitors in higher-risk patients 2
Avoid live vaccines during treatment with IL-23 inhibitors 1

Do not switch to another JAK inhibitor (tofacitinib or filgotinib) after upadacitinib failure — switch to a different mechanism of action instead 1
Do not delay switching therapy in steroid-dependent patients — steroid-dependent pattern already constitutes treatment failure requiring escalation 1
Do not use corticosteroids for maintenance of remission (strong recommendation against) 4, 1