Letter to the Editor: Missing mechanistic data and small inflammatory bowel disease cohorts: Key barriers in ustekinumab switching

Abstract

This comment discusses the real-world study by Kritzinger et al, published in the recent issue of the World Journal of Gastroenterology, which reports preserved short-term clinical efficacy, stable biomarkers, and high treatment persistence after a mandatory non-medical switch from originator ustekinumab to a biosimilar in inflammatory bowel disease. While acknowledging the novelty and clinical relevance of these findings, the letter highlights two key limitations that constrain their applicability to challenging bedside scenarios. First, outcomes are largely based on symptom scores and routine biomarkers, with limited systematic assessment of endoscopic or radiologic targets, making alignment with current treat-to-target strategies uncertain. Second, the cohort predominantly comprises long-standing, clinically stable ustekinumab responders, limiting extrapolation to high-risk patients with active or only partial disease control at the time of switching. Additionally, the comment addresses the economic drivers of biosimilar policies, potential nocebo effects in mandatory switching scenarios, and the importance of shared decision-making for vulnerable patients.

Key Words: Inflammatory bowel disease; Ustekinumab; Biosimilar switching; Therapeutic drug monitoring; Treat-to-target strategy; Nocebo effect; Shared decision-making

Core Tip: Kritzinger et al report high treatment persistence and stable clinical outcomes after non-medical switching from originator ustekinumab to its biosimilar in inflammatory bowel disease. While reassuring, the findings derive from a cohort of long-term, stable responders and lack systematic evaluation of objective endpoints such as endoscopic healing. These limitations restrict generalizability to higher-risk patients – those with active or partially controlled disease – at the time of switch. Future studies must incorporate treat-to-target endpoints and focus on vulnerable subgroups to guide individualized biosimilar conversion strategies in real-world practice.

TO THE EDITOR

The study by Kritzinger et al[1], published in the recent issue of the World Journal of Gastroenterology, report high treatment persistence and stable clinical outcomes after non-medical switching from originator ustekinumab to its biosimilar in inflammatory bowel disease (IBD). While reassuring, the findings derive from a cohort of long-term, stable responders and lack systematic evaluation of objective endpoints such as endoscopic healing. These limitations restrict generalizability to higher-risk patients – those with active or partially controlled disease – at the time of switch. Future studies must incorporate treat-to-target endpoints and focus on vulnerable subgroups to guide individualized biosimilar conversion strategies in real-world practice.

BIOSIMILAR SWITCHING THERAPY FOR IBD

The observational study by Kritzinger et al[1] was read with great interest, as it reports preserved clinical efficacy, stable biomarkers, and high treatment persistence (95% at 24 weeks) following a mandatory non-medical switch from originator ustekinumab to its biosimilar in 81 patients with IBD. The authors must be lauded for their provision of the initial real-world data on ustekinumab biosimilar switching, a contribution that is especially timely in light of recent policy mandates in Canadian provinces such as Quebec[2]. The findings of the present study are consistent with extensive experience from anti-tumor necrosis factor (anti-TNF) biosimilar transitions[3-5], offering initial reassurance for clinicians and patients.

Nevertheless, while the present study addresses a significant evidence gap, it is submitted that its clinical applicability to complex, routine practice scenarios – particularly among high-risk patients – is constrained by two interrelated limitations that merit critical discussion. Furthermore, important contextual factors including economic drivers, psychological impacts, and decision-making processes require consideration when implementing biosimilar switching policies.

Firstly, the primary reliance on symptom-based scores and routine serological/fecal biomarkers as efficacy endpoints gives rise to concerns about alignment with contemporary “treat-to-target” paradigms in IBD management. The term “clinical remission” was defined using the Harvey-Bradshaw Index for Crohn’s disease and the partial Mayo score for ulcerative colitis, supplemented by C-reactive protein and fecal calprotectin. Despite their practicality, these measures serve as imperfect surrogates for mucosal healing, which is now the gold-standard objective endpoint endorsed by international guidelines[6,7]. Importantly, multiple studies have demonstrated significant discordance between symptom-based remission and objective mucosal healing in IBD patients on ustekinumab therapy[8]. For instance, in the UNIFI trial cohort, approximately 30%-40% of patients reporting clinical remission still exhibited endoscopic activity despite ustekinumab treatment[9]. The study observes that endoscopic data were collected “where available”, suggesting that this may be an ancillary, non-systematic assessment rather than a protocol-driven outcome. Absent standardized endoscopic or cross-sectional imaging evaluations before and after the switch, it remains uncertain whether clinical and biochemical stability truly reflects sustained objective disease control at the tissue level. It is important to note that subclinical inflammation may persist despite the absence of symptoms, which can lead to long-term complications such as stricturing, fistulising, or colectomy. Given that ustekinumab is often prescribed for moderate-to-severe or refractory IBD, the omission of objective healing metrics limits the study’s ability to inform modern therapeutic goals.

Secondly, the study cohort is highly selected and does not represent the full spectrum of IBD patients who may undergo non-medical switching in real-world settings. It is noteworthy that 87% of patients were in clinical remission at baseline, and the median duration of ustekinumab therapy prior to switch was 58 months. Furthermore, 82.7% of patients had previously experienced biologic exposure, yet the majority demonstrated stability, suggesting a favourable disease trajectory. This low-risk profile stands in stark contrast to the clinical reality faced by many gastroenterologists, who routinely treat patients with active disease, partial response, recent dose intensification, or incomplete mucosal healing. It is of note that all four patients who discontinued the biosimilar had undergone prior dose optimisation and had failed ≥ 1 previous biologic, suggesting heightened vulnerability in this subgroup. However, the analysis does not include a significant number of high-risk patients. The extrapolation of results from deep remitters to unstable patients has the potential to engender unwarranted confidence in biosimilar switching, with the concomitant possibility of compromised outcomes.

These limitations have direct policy implications. In systems that mandate universal non-medical switches, decisions are applied uniformly, irrespective of individual disease activity. A patient with elevated C-reactive protein, ongoing symptoms, and unhealed mucosa who is barely maintaining ustekinumab response may face significant risk upon conversion, but the current data offer no guidance for this scenario. This concern is amplified by the economic drivers behind biosimilar adoption. Cost considerations frequently motivate policy-level switching mandates, with biosimilars typically priced 15%-30% lower than originator products. While these savings benefit healthcare systems, they may not directly translate to improved patient outcomes if switching protocols fail to account for individual risk factors.

The psychological dimension of mandatory switching cannot be overlooked. Nocebo effects – where negative expectations lead to worse outcomes – have been well-documented in biosimilar transitions, particularly when patients feel their preferences were disregarded. Studies show that up to 25% of discontinuations after mandatory switches may be attributable to nocebo effects rather than true pharmacological failure. This phenomenon underscores the critical importance of shared decision-making and comprehensive patient education before implementing any biosimilar switch. For high-risk patients, transparent communication about the rationale for switching, realistic expectations, and close monitoring plans can mitigate psychological distress and improve adherence[10].

Furthermore, while Mukherjee et al[11] concentrated on anti-TNF agents, their findings illustrate the broader principle that the utility of therapeutic drug monitoring (TDM) for ustekinumab remains undefined, as no validated therapeutic range exists in IBD. Recent data suggest that ustekinumab trough levels above 1.4 μg/mL may correlate with mucosal healing in Crohn’s disease, while levels below 0.6 μg/mL are associated with increased risk of clinical relapse. These emerging thresholds highlight the importance of incorporating TDM into switching protocols, particularly for high-risk patients. Without standardized TDM protocols for ustekinumab, interpreting “stable” biomarkers becomes challenging, especially when tissue-level confirmation is absent.

Regarding biosimilar switching guidelines, China currently lacks specific national standards for ustekinumab biosimilar conversion, unlike European countries that have established frameworks through the European Medicines Agency. Chinese clinical practice largely follows international consensus while considering local healthcare economics and regulatory requirements. Generally, biosimilar switching is considered appropriate for patients with sustained clinical and endoscopic remission for at least 6-12 months, stable biomarker profiles, and no history of immunogenicity to biologic therapies. Conversely, switching is not recommended for patients with recent disease flares, incomplete response requiring dose optimization, primary non-response to biologics, or those with psychological concerns about biosimilar efficacy[12]. High-risk patients – particularly those with complicated disease behavior, prior multiple biologic failures, or inadequate social support systems – warrant individualized assessment before any non-medical switch.

The data on biosimilar switching failure rates remain limited but crucial for informed decision-making. For anti-TNF agents, pooled analyses suggest discontinuation rates of 10%-15% after non-medical switching, with higher rates observed in patients with active disease at the time of switch[4,5]. While the 5% discontinuation rate reported by Kritzinger et al[1] is reassuring, this number likely underestimates the true failure rate in more complex patient populations. The most common risks associated with ustekinumab biosimilar switching include loss of response, immunogenicity development, and potential nocebo effects in mandatory switching scenarios.

Additionally, while the 24-week follow-up is reasonable for initial safety, longer-term data are needed to assess immunogenicity, which can develop insidiously. Unlike anti-TNF agents, TDM for ustekinumab remains non-standardized, complicating the differentiation between pharmacokinetic failure and true loss of efficacy.

CONCLUSION

Kritzinger et al[1] provide valuable preliminary evidence supporting ustekinumab biosimilar switching in a stable, low-risk population. However, to truly inform individualized clinical decisions and equitable health policy, future studies should: (1) Routinely incorporate objective healing endpoints as primary or key secondary outcomes; (2) Conduct prospective, powered analyses of high-risk subgroups – such as those with active disease, prior anti-TNF failure, or need for dose escalation – at the time of switch; (3) Assess the economic impact and cost-effectiveness of selective vs universal switching strategies; (4) Evaluate strategies to mitigate nocebo effects through patient-centered communication and shared decision-making frameworks; and (5) Extend follow-up duration to evaluate long-term immunogenicity and durability of response. Incorporating these elements will ensure that biosimilar adoption enhances – not jeopardizes – the quality of care for all IBD patients, regardless of their baseline risk profile.

ACKNOWLEDGEMENTS

We sincerely thank Kritzinger for his inspiration and encouragement.