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

Abstract

To mitigate the progressive nature of Crohn's disease (CD), early introduction of advanced therapies is key [1]. However, despite therapeutic advances, we continue to encounter a ‘therapeutic ceiling’ for all therapies [2]. Ongoing development of new treatments is essential to allow patients the best chance of achieving normalisation of mucosal inflammation and, ultimately, quality of life.

Upadacitinib is an oral, selective Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe CD. The Phase 3 trials, U-EXCEL and U-EXCEED, demonstrated post-induction (Week 12) clinical remission (CDAI < 150) rates of 49.5% and 38.9%, respectively. Adverse events included acne, anaemia and infections such as Herpes zoster [3]. However, questions around generalisability remain. Many patients in real-world practice would not qualify for enrolment in these trials, while response rates to the drugs differ between those meeting versus not meeting inclusion criteria [4]. Therefore, large real-world cohorts are needed to assess generalisability for clinical practice.

Richard et al. conducted a retrospective, multicentre study in 29 French GETAID centres to assess the effectiveness and safety of upadacitinib induction therapy in CD. The primary outcome was steroid-free clinical remission (SFCR) at Week 12, defined by a Harvey Bradshaw Index (HBI) < 5 [5]. More than 200 patients with moderate to severe disease were included. The cohort was highly refractory, with 95% having failed two or more biologics. SFCR was achieved in 54.3% of patients at Week 12. Body mass index ≤ 18.5 kg/m² and HBI > 7 were predictors of lower rates of SFCR at Week 12. Regarding safety, 7.6% experienced serious adverse events, the most common being CD exacerbations. There was one case of EBV-associated lymphoma.

This valuable nationwide study suggests that, even in a very refractory cohort of patients with CD, upadacitinib can achieve high remission rates as early as Week 12. Interestingly, no association was found between SFCR and the number of prior biologics. These results are similar to those seen by others, supporting the notion that upadacitinib works quickly and is also a good option for patients with prior biologic failure. A relevant aspect is also the identification of two phenotypic predictors associated with lower SFCR, although these are probably related to a more severe disease phenotype. Reassuringly, no cases of Herpes zoster, thromboembolic events, or major adverse cardiovascular events were reported.

Nevertheless, this study has several limitations, mainly its retrospective nature and short follow-up. The lack of endoscopic data also makes it difficult to gauge the true benefit of the drug in this refractory population, especially considering the disconnect between symptoms and mucosal inflammation in CD. Furthermore, the study is underpowered for performing a true safety analysis. Of note, the case of EBV-associated lymphoma, although unlikely to be related to the drug, highlights the importance of careful patient monitoring for unknown long-term complications.

Despite these encouraging data, the concept of ‘therapeutic ceiling’ remains. Ongoing works to establish novel therapeutics, the role of combination therapies and the identification of biomarker predictors of drug response are key to overcoming this [2].