Week 12 Reduction in MM-SES-CD is Predictive of...

Week 12 Reduction in MM-SES-CD is Predictive of Delayed Response to Upadacitinib in Crohn’s disease

Abstract

BACKGROUND & AIMS: Delayed clinical response to biologics and small molecules has been observed in inflammatory bowel disease, but little is known about the characteristics and outcomes of delayed responders to upadacitinib in Crohn's disease (CD). We aimed to evaluate early endoscopic and biochemical markers to help identify patients with CD who exhibit delayed response to upadacitinib compared with nonresponders. METHODS: This was a post-hoc analysis of patient-level data from the U-EXCEED and U-EXCEL clinical trials. Patients with moderate-to-severe CD randomized to upadacitinib 45 mg once daily were assessed for clinical response at week 12. Those who did not achieve clinical response by week 12 were offered an additional 12 weeks of open-label upadacitinib at 30 mg daily, and those with week 24 clinical response were considered delayed responders. The primary outcome was week 24 clinical response, defined as a decrease ≥30% in the average daily frequency of very soft or liquid stools or in the abdominal pain score with neither worse than baseline. Logistic regression was used to assess the likelihood of achieving outcomes of interest. RESULTS: Among 665 patients randomized to upadacitinib, 194 (29.2%) were nonresponders at week 12. Of these, 122 had week 24 data available, with 64 (52.5%) achieving delayed response at week 24. Most delayed responders had achieved at least a 20% reduction in Modified Multiplier of the Simple Endoscopic Score for Crohn's Disease (MM-SES-CD) by week 12 (51/64; 79.7%). Patients who failed to achieve at least a 20% reduction in the MM-SES-CD at week 12 were unlikely to achieve a delayed clinical response (13/39 [33.3%] vs 51/83 [61.5%]; adjusted odds ratio, 0.22; 95% confidence interval, 0.09-0.53; P = .001). Similar findings were observed for achievement of MM-SES-CD <22.5 by week 12. Improvement in endoscopic burden defined using the SES-CD and reduction in inflammatory biomarkers including C-reactive protein or fecal calprotectin by week 12 were not predictive of week 24 delayed response to upadacitinib. CONCLUSIONS: Delayed clinical response to upadacitinib occurs in a substantial proportion of initial nonresponders. Failure to achieve week 12 reduction in MM-SES-CD is associated with a high likelihood of delayed nonresponse, supporting its utility in guiding treatment decisions.