Early infliximab levels and clearance predict outcomes in acute severe ulcerative colitis

Acute severe ulcerative colitis (ASUC) is the most aggressive and potentially fatal form of ulcerative colitis (UC), affecting approximately 20% of patients at disease onset and frequently necessitating hospitalization (1). Because of the high risk of complications, the European Crohn’s and Colitis Organisation (ECCO) recommends urgent hospitalization for ASUC in a specialized unit and prompt initiation of intravenous (IV) therapy (2). IV corticosteroids are still the primary treatment for ASUC (3), but 30–40% of patients do not respond and require rescue medical therapy or surgery (4).

Infliximab and cyclosporine have long been the main rescue therapies for steroid-refractory ASUC and have demonstrated comparable short- and long-term efficacy (5,6). More recently, the PREDICT-UC randomized trial evaluated different infliximab induction strategies—standard, intensified, and accelerated—and found similar rates of clinical response by day 14, as well as comparable remission and colectomy rates at 3 months (7). Standard induction consisted of infliximab 5 mg/kg administered at weeks 0, 2, and 6. Accelerated induction involved earlier repeat dosing, including additional dosing between days 3–7 and at week 3, whereas intensified induction used an initial infliximab dose of 10 mg/kg with additional dose escalation in patients with inadequate early response.

Consistent with these findings, a recent network meta-analysis reported that standard infliximab therapy was associated with lower colectomy rates than cyclosporine at 3 months, while by 12 months, standard, intensified, and accelerated infliximab strategies were all associated with lower colectomy rates than cyclosporine, without significant differences between infliximab regimens (8).

Therapeutic drug monitoring (TDM) is emerging as a promising strategy for optimizing biologic therapy in UC. In patients with moderate-to-severe UC, higher trough infliximab concentrations have been linked to better remission rates (9). However, the role of early infliximab pharmacokinetics in ASUC remains unclear.

The association between early infliximab exposure and clinical outcomes in patients with steroid-refractory ASUC was investigated in a recent post hoc analysis of the PREDICT-UC trial (10). The study demonstrated that lower serum infliximab levels on day 3 (≤57.9 µg/mL) predicted treatment failure by day 14 and colectomy within 3 months. In addition, increased infliximab clearance by day 7 was associated with early non-response, subsequent treatment failure, and a higher risk of colectomy.

Higher fecal infliximab concentrations on day 3 were also associated with greater endoscopic disease severity and predicted non-response at day 7. Importantly, the study suggests that increased infliximab clearance, previously associated with poor outcomes, may be overcome by intensified infliximab dosing strategies.

These findings are supported by observational data showing that infliximab clearance is a major determinant of outcomes in ASUC (11-13). Small retrospective studies in adults have reported associations between high infliximab clearance and week-14 clinical non-response (11) and an increased risk of colectomy at 6 months (13). Higher infliximab clearance has also been linked to an increased risk of colectomy in pediatric populations, as reported in similar studies (12).

Several mechanisms may contribute to increased infliximab clearance in ASUC. Hypoalbuminemia and faster drug clearance can result from severe intestinal inflammation, which can also cause intestinal protein loss and disruption of the mucosal barrier (14). Furthermore, patients with higher infliximab clearance have worse clinical outcomes and higher rates of infliximab antibodies, according to observational studies (15).

Increased drug clearance has also been linked to worse clinical and endoscopic outcomes in ambulatory patients with moderate-to-severe UC, according to clinical trials (16). Additionally, in hospitalized patients with ASUC receiving standard induction dosing, increased infliximab clearance during induction has been linked to subtherapeutic drug exposure and adverse long-term outcomes (11).

From a clinical perspective, findings from the PREDICT-UC trial suggest that early TDM, particularly measuring serum infliximab around day 3 and assessing early infliximab clearance within the first week, may help identify patients at higher risk of treatment failure (10). While serum infliximab concentrations may be more readily applicable in clinical practice, estimating infliximab clearance currently requires pharmacokinetic modeling, which is not widely available in routine settings. Furthermore, findings from the PREDICT-UC trial support the potential role of early on-treatment infliximab clearance assessment within the first week after treatment initiation.

In addition, the utility of TDM in ASUC depends on obtaining infliximab measurements within a clinically meaningful timeframe to support urgent treatment decisions. The study also discussed the potential role of point-of-care infliximab assays, although further validation in the ASUC setting is still required. Furthermore, although intensified infliximab dosing may help overcome high drug clearance in selected patients, prospective studies are still needed to determine whether pharmacokinetic-guided dosing strategies improve clinical outcomes and reduce colectomy risk.

Overall, these findings highlight the potential importance of early infliximab pharmacokinetics in predicting treatment outcomes in patients with ASUC. Measurement of early infliximab levels and drug clearance may help identify individuals at higher risk of treatment failure and allow earlier therapeutic optimization. Prospective studies are needed to determine whether pharmacokinetic-guided infliximab dosing can translate into improved clinical outcomes and lower colectomy rates.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0037/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0037/coif). The authors have no conflicts of interest to declare.

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References

1. Gisbert JP, Chaparro M. Acute severe ulcerative colitis: State of the art treatment. Best Pract Res Clin Gastroenterol 2018;32-33:59-69. [Crossref] [PubMed]
2. Spinelli A, Bonovas S, Burisch J, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Surgical Treatment. J Crohns Colitis 2022;16:179-89. [Crossref] [PubMed]
3. Calméjane L, Laharie D, Kirchgesner J, et al. Review article: Updated management of acute severe ulcerative colitis: From steroids to novel medical strategies. United European Gastroenterol J 2023;11:722-32. [Crossref] [PubMed]
4. Hindryckx P, Jairath V, D'Haens G. Acute severe ulcerative colitis: from pathophysiology to clinical management. Nat Rev Gastroenterol Hepatol 2016;13:654-64. [Crossref] [PubMed]
5. Laharie D, Bourreille A, Branche J, et al. Long-term outcome of patients with steroid-refractory acute severe UC treated with ciclosporin or infliximab. Gut 2018;67:237-43. [Crossref] [PubMed]
6. Williams JG, Alam MF, Alrubaiy L, et al. Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial. Lancet Gastroenterol Hepatol 2016;1:15-24. [Crossref] [PubMed]
7. Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024;9:981-96. [Crossref] [PubMed]
8. Hayek MA, Beshr MS, Nounou MV, et al. Comparative efficacy of immunomodulators, biologics, and advanced therapies for steroid-refractory acute severe ulcerative colitis: A network meta-analysis and time-to-event analysis. Dig Liver Dis 2025;57:2304-20. [Crossref] [PubMed]
9. Papamichael K, Rakowsky S, Rivera C, et al. Infliximab trough concentrations during maintenance therapy are associated with endoscopic and histologic healing in ulcerative colitis. Aliment Pharmacol Ther 2018;47:478-84. [Crossref] [PubMed]
10. Li Wai Suen CFD, Choy MC, Con D, et al. Early Infliximab Levels and Clearance Predict Outcomes After Infliximab Rescue in Acute Severe Ulcerative Colitis: Results From PREDICT-UC. Gastroenterology 2026;170:118-31. [Crossref] [PubMed]
11. Kevans D, Murthy S, Mould DR, et al. Accelerated Clearance of Infliximab is Associated With Treatment Failure in Patients With Corticosteroid-Refractory Acute Ulcerative Colitis. J Crohns Colitis 2018;12:662-9. [Crossref] [PubMed]
12. Whaley KG, Xiong Y, Karns R, et al. Multicenter Cohort Study of Infliximab Pharmacokinetics and Therapy Response in Pediatric Acute Severe Ulcerative Colitis. Clin Gastroenterol Hepatol 2023;21:1338-47. [Crossref] [PubMed]
13. Battat R, Hemperly A, Truong S, et al. Baseline Clearance of Infliximab Is Associated With Requirement for Colectomy in Patients With Acute Severe Ulcerative Colitis. Clin Gastroenterol Hepatol 2021;19:511-518.e6. [Crossref] [PubMed]
14. Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol 2009;65:1211-28. [Crossref] [PubMed]
15. Brandse JF, Mathôt RA, van der Kleij D, et al. Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis. Clin Gastroenterol Hepatol 2016;14:251-8.e1-2.
16. Vande Casteele N, Jeyarajah J, Jairath V, et al. Infliximab Exposure-Response Relationship and Thresholds Associated With Endoscopic Healing in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol 2019;17:1814-1821.e1. [Crossref] [PubMed]