Editorial: Redefining Safety in Post‐Liver Transplant IBD—Why Therapeutic Effectiveness Is the Ultimate Shield

The management of inflammatory bowel disease (IBD) in patients who have undergone liver transplantation (LTx) presents a distinct clinical challenge, balancing intestinal inflammation against complications from augmented immunosuppression. In their recent dual-center retrospective study of 36 patients with IBD and LTx (89% with primary sclerosing cholangitis (PSC)), Chin and colleagues provide a valuable contribution to this data-scarce area, concluding that "gut-specific" and "systemic" biologics have similar safety profiles in post-LTx IBD patients, based on comparable rates of infectious events 1. An important finding by the authors is the five-fold increased risk of severe infections associated with corticosteroid co-therapy. Corticosteroid use in IBD has been consistently associated with adverse events including the risk of infections. A large, real-world study of > 2000 patients with IBD demonstrated a significantly higher rate of hospitalisations due to infection (odds ratio 2.89; 95% CI 1.82–4.61) in excess corticosteroid users 2. Similarly, baseline corticosteroid use is significantly associated with serious infections in upadacitinib treated patients with ulcerative colitis 3. This is due to the inherent properties of corticosteroids but also likely reflective of poor disease control which increases the risk of adverse events. From the PYRAMID registry, patients with Crohn's disease who responded to adalimumab were 34% less likely to develop serious infections compared to non-responders to adalimumab, further highlighting the role of underlying disease control in mitigating infection risk 4. This principle is magnified in PSC. We argue that in this high-stakes population, safety must be redefined: the safest therapy is the one that most effectively achieves sustained control of mucosal inflammation (Table 1). The risk in PSC-IBD extends beyond infections to include the high risk of colorectal neoplasia which is directly linked to mucosal inflammation 5-7. For these patients, achieving sustained mucosal healing is not merely a therapeutic goal but an urgent chemopreventive strategy that reframes the safety discussion entirely. The often infrequent risks associated with an effective therapy are far outweighed by the tangible risk of malignancy from uncontrolled disease, making it a serious misstep to choose a biologic based on a perceived marginal safety benefit at the expense of superior effectiveness 8. The study's inherent limitations temper its conclusions. Its retrospective nature, short follow-up, and small patient numbers prevent definitive attribution of causality and subgroup analysis of different LTx immunosuppressive regimens. Furthermore, the primary outcome is confounded by cholangitis—a complication of the underlying PSC which dilutes comparisons of mechanistic safety of IBD therapies. While we commend the authors, these limitations make it clear we must look beyond infection rates. The conversation must shift from broad classifications to comparative effectiveness. It remains unclear if therapeutic hierarchies in IBD hold true for the distinct PSC-IBD phenotype. While reviews confirm advanced therapies are effective for the associated luminal inflammation, conflicting data on optimal agents highlight that PSC-IBD must be recognised as its own entity 9. Without robust trials for this population, clinicians must extrapolate from comparative effectiveness evidence in conventional IBD. Generating real-world evidence for this cohort is essential to move beyond this necessity. Mohammed Nabil Quraishi: writing – original draft. Badr Al-Bawardy: writing – review and editing. M.N.Q. has received speaker fees from Johnson and Johnson, Takeda, Abbvie, and Lilly and consultancy fees from Johnson and Johnson and Lilly. B.A.-B. has received speaker fees from AbbVie, Takeda, Bristol-Myers Squibb, Eli Lilly, Hikma, Janssen Pharmaceuticals, and consultancy fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, Pfizer, and Janssen. This article is linked to Chin et al papers. To view these articles, visit https://doi.org/10.1111/apt.70283 and https://doi.org/10.1111/apt.70341. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.