Editorial: Real-World Evidence of Upadacitinib—An Effective Induction Therapy for Crohn's Disease? Authors' Reply

Abstract

We thank Drs. Belinchon and Plevris for their editorial [1] on our article, which provides real-world data on the effectiveness and safety of upadacitinib induction therapy in Crohn's disease (CD) [2]. We fully agree with their valuable comments.

The editorial rightly highlighted a few limitations of our study, including its retrospective design, short duration of follow-up and safety analysis constraints—all of which we have acknowledged. A longer follow-up of this cohort is ongoing, with the following objectives: (1) to confirm the effectiveness of upadacitinib as maintenance therapy in CD, (2) to assess the rate of mucosal healing achieved with this drug in real life, and (3) to provide longer term safety data. Encouragingly, reassuring safety data from the phase-3 U-ACTIVATE long-term extension trial were presented at the 2025 ECCO Congress; in over 1000 patient-years, there were two major adverse cardiovascular events (MACE), four venous thromboembolic events (VTE) and seven malignancies (excluding non-melanoma skin cancer) [3]. However, as patients in real-world practice may differ substantially from patients included in this study, further safety analyses regarding rare serious adverse events like VTE, MACE or malignancies are required. Studies based on medical-administrative databases could be a solution to address this problem. However, these studies are limited by lack of information regarding several factors that can influence the safety profile of a drug in inflammatory bowel diseases (IBDs), such as phenotype, disease activity and severity. ICARE-II, a prospective longitudinal observational multicentre cohort study promoted by GETAID in France, aims to evaluate the real-life safety of Janus kinase inhibitors (JAKi) as well as anti-IL23p19 and S1p modulators in IBD by including more than 6000 patients followed for a minimum of 4 years.

However, the 54% steroid-free clinical remission rate at Week 12 is promising, especially considering the highly refractory nature of this cohort. These results align with previous works on smaller cohorts [4, 5]. However, like other therapies, upadacitinib appears to face the same ‘therapeutic ceiling’, with response rates plateauing around 30%–60% [6]. The identification of predictors may be one way of breaking through this ceiling. In this regard, the identified phenotypic predictors, likely surrogates of disease severity, are insufficient. Further research into the mechanisms of resistance to JAKi therapy in CD is crucial to advancing beyond this limitation.