Editorial: Upadacitinib in Perianal Crohn's Disease. Authors' Reply

We thank Goyal and Bishu for their editorial discussion on our article on the 1‐year effectiveness of upadacitinib in patients with highly refractory perianal Crohn's disease (pCD) [1, 2]. We agree with their observations on this complex disease manifestation.

Our study was conducted in a refractory cohort, which likely contributed to the modest therapeutic effect observed and the need for reinduction strategies. Nevertheless, the clinical remission rate supports the potential of upadacitinib in anti‐TNF–refractory pCD. High‐quality evidence remains the top research priority in pCD [3], as few randomized controlled trials have been conducted, limiting evidence‐based therapeutic decision‐making [4]. A major methodological challenge is the definition of outcomes. Recently, the TOpClass expert group proposed a radiological definition of healing in pCD based on the absence of T2‐weighted and post‐contrast T1‐weighted hyperintensity and the presence of a completely fibrotic fistula tract. However, these outcomes require further validation.

Three advanced therapies have been evaluated in RCT: infliximab, ustekinumab, and guselkumab. Infliximab has long been considered the cornerstone of treatment for pCD. More recently, the USTAP study demonstrated in a small RCT including 32 participants, 70% of whom had prior exposure to anti‐TNF, a combined remission rate of 62% with ustekinumab at week 12, compared with 25% in the placebo group. This year, the highly anticipated results of the FUZION RCT including 286 patients with active pCD, with approximately two‐thirds of whom had previous biologic exposure, showed at week 24 that guselkumab achieved combined fistula remission rates of 28% with 100 mg every 8 weeks and 27% with 200 mg every 4 weeks, compared with 10% in the placebo group [5]. These encouraging results suggest that guselkumab may emerge as the most valuable treatment option for patients with pCD after failure of infliximab.

Consequently, in our opinion, and based on the data available to date, upadacitinib should be considered a third‐line treatment option. This positioning within the therapeutic armamentarium is supported by our findings in a highly refractory pCD population, characterized by a median of four prior biologic failures, as well as by the absence of any negative impact of the number of prior biologic failures on the rate of clinical remission at 1 year [1].

Beyond positioning upadacitinib within the current treatment algorithm, its role in future combination strategies deserves attention. In luminal CD, the DUET‐CD RCT demonstrated a benefit of combining golimumab and guselkumab in patients with two or more failures of prior advanced therapies [6]. Likewise, a monocentric retrospective cohort study has paved the way for combination therapy in pCD, with an encouraging clinical remission rate of 49% after a median follow‐up of 27 months in anti‐TNF–refractory pCD patients [7]. Consequently, upadacitinib thus represents a rational candidate for investigation within combination therapy strategies in pCD, particularly in patients with multiple prior biologic failures.

Author Contributions

Nicolas Richard: writing – original draft. Mathurin Fumery: writing – review and editing.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Linked Article

This article is linked to Richard et al. papers. To view these article, visit https://doi.org/10.1111/apt.70759 and https://doi.org/10.1111/apt.70682.

Richard N. and Fumery M., “Editorial: Upadacitinib in Perianal Crohn's Disease. Authors' Reply,” Alimentary Pharmacology & Therapeutics 64, no. 4 (2026): 546–547, 10.1111/apt.70817.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.