Letter: Upadacitinib in Perianal Crohn's Disease: Does Clinical Closure Reflect True Remission? Authors' Reply

We thank Saward and Heerasing for their interest in 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 comments on the limitations of clinical evaluation of pCD.

In our article, as most retrospective real‐world studies in pCD, we focused on clinically meaningful outcomes, namely the absence of fistula drainage and healing of ulcerations. Although these outcomes are highly relevant to routine clinical practice, they are not validated and may be subject to limited intra‐ and inter‐observer reliability. In contrast, scores such as Perianal Disease Activity Index (PDAI) were developed using rigorous methodological standards; however, their use and feasibility in routine practice remain insufficiently studied [3]. Interestingly, real‐world studies suggest that the PDAI continues to be infrequently used, more than 30 years after its original description [4]. Moreover, the characterisation of fistula drainage and of the degree of induration within the PDAI retains a degree of subjectivity, which may contribute to the limited reproducibility reported for this score [3]. More broadly, these limitations are likely inherent to the clinical evaluation of pCD rather than to any specific scoring system. To overcome these limitations, there has been increasing interest in incorporating radiological assessment into both clinical trials and routine practice [3, 5]. Magnetic resonance imaging offers the advantage of evaluating the entire fistula tract, whereas clinical examination is largely restricted to the assessment of external openings and has demonstrated prognostic value for long‐term outcomes [6]. Despite these advantages, only a minority of patients in our cohort underwent radiological assessment [1]. This likely reflects the reality that, in highly refractory patients, clinicians currently have limited therapeutic options capable of consistently achieving radiological healing.

In our view, the frequency of re‐induction observed in our cohort and the challenge of maintaining long‐term disease control represent the two faces of Janus. The limited ability of upadacitinib to induce deep radiological remission in most patients may contribute to subsequent loss of response and the need for dose escalation over time. The complex and multifactorial pathogenesis of pCD may partly explain these incomplete or unsustained responses [7], as JAK inhibitors are unlikely to target all pathogenic pathways involved. A better understanding of these mechanisms of treatment escape could pave the way for tailored combination strategies in pCD [8].

In conclusion, the limitations of our study mirror the current challenges in the clinical management of pCD, where objective and reproducible outcome measures still need to be better integrated into routine practice. The definition of therapeutic targets should be balanced against the efficacy realistically achievable with currently available treatments. In the absence of validated biomarkers or clinical features that allow a truly personalised therapeutic strategy, clinicians should individualise treatment goals according to disease severity and treatment history, including the number of previous advanced therapy failures and the TOpClass classification system [9].

Author Contributions

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

Funding

The authors have nothing to report.

Conflicts of Interest

The authors' declarations of personal and financial interests are unchanged from those in the original article [1].

Linked Articles

This article is linked to Richard et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70815 and https://doi.org/10.1111/apt.70682.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.