Editorial: Upadacitinib—A Promising Induction Agent for Paediatric Crohn's Disease?

Upadacitinib is an oral selective Janus kinase 1 (JAK 1) inhibitor, and its efficacy in inducing clinical and endoscopic remission has been demonstrated in randomised controlled trials in adult populations, both in Ulcerative colitis (UC) and Crohn's Disease (CD) [1-3]. Upadacitinib is currently used ‘off-label’ or without regulatory approval in children with refractory inflammatory bowel disease (IBD), exposing these patients to a medication without established safety, efficacy and dosing data.

To address this, Cohen et al. [4] conducted a retrospective multicentre cohort study, involving 30 international centres, to evaluate the effectiveness and safety of Upadacitinib as an induction therapy in 100 young patients with active CD. All of these patients had prior biologic exposure. At the end of the 8-week follow-up period, clinical response, clinical remission and corticosteroid/exclusive enteral nutrition-free clinical remission were achieved in 75%, 56% and 52% of patients, respectively. End of induction biomarkers including C-reactive protein normalised in 68% of patients, while faecal calprotectin normalised (< 150 μg/g) in 58% of patients. Drug durability was outlined, with 89% remaining on the medication over the induction period. Adverse events were reported in 24 patients, with 50% of them experiencing acne. Almost all patients (86%) received a dose of 45 mg/day over induction, the accepted dosing regimen in adult patients [1-3]. Importantly, early evidence of clinical response (at week 4) was a positive predictor for corticosteroid-free remission (CFR) at week 8 (odds ratio = 26 [95% confidence interval 5–139], p < 0.001). This rapid response may be a key attribute for paediatric patients as a steroid-sparing strategy.

A key limitation of the study is that this is an adolescent cohort, with a median (IQR) age of 15.8 (14.3–17.2) years. Younger children are often excluded from clinical trials in paediatrics; therefore, paediatric gastroenterologists depend on real-world evidence studies to generate efficacy data. The authors do make efforts to outline weight-based (mg/kg) and body surface area-based (mg/m²) dosing, but true pharmacokinetic (PK) and pharmacodynamic (PD) studies are needed to guide rational dosing regimens, especially in younger children. A further caveat is that steroid dosing/weaning plans were not standardised across the cohort, potentially influencing the reported outcomes at week 8. Lack of endoscopic outcome measures are recognised as a limitation by the authors. Whilst adverse events were relatively rare in this study, long-term prospective safety registries are required to identify incidence rates of rare and severe adverse events in children treated with Upadacitinib.

In conclusion, this real-world evidence study provides key insights into the clinical effectiveness of Upadacitinib for the induction of remission in paediatric CD. The authors deserve commendation for establishing this extensive international collaboration, which has been instrumental in gathering critical evidence that should support the approval of this novel therapy for adolescent patients. Further open-label PK/PD studies are required to expedite approval for younger patients, ensuring careful optimisation of dosing strategies.

Vincenzo Stranges declares no conflicts of interest. Eileen Crowley has received an educational grant and speaker fees from AbbVie, Pfizer, and consulting fees from Abbvie, Pfizer, Sanofi and Alimentiv Inc.

This article is linked to Cohen et al paper. To view this article, visit https://doi.org/10.1111/apt.70016.