PREDICT-UC, infliximab pharmacokinetics, and the pursuit of personalised rescue therapy in acute severe ulcerative colitis

Ulcerative colitis (UC) is a chronic, immune-mediated inflammatory disease affecting the rectum and colon to a variable extent and severity (1). At the extreme end of severity sits acute severe ulcerative colitis (ASUC) which can be life threatening and requires urgent inpatient management. Patients typically experience ≥6 bloody stools per day with signs of systemic toxicity. It is managed initially with intravenous corticosteroids, but if refractory disease, patients currently have just two approved options of medial rescue therapy—ciclosporin or infliximab (IFX) (2,3). If these medical options fail to induce a satisfactory clinical response (often after day 10 of admission or day 7 of IFX), then colectomy is recommended. Since the introduction of IFX in the late 1990s, colectomy rates for ASUC have dropped from 29% between 1992 and 1993, to 15% between 2015 and 2019 (4). Despite these improvements, there remains room for treatment optimisation.

Therapeutic drug monitoring (TDM) for IFX, by measuring anti-drug antibodies and drug levels, is now well established in the management of inflammatory bowel disease (IBD). Proactive TDM prevents underdosing, whilst reactive TDM distinguishes pharmacokinetic (PK) failure from mechanistic failure, thus informing whether dose optimisation or class switching is required. This can extend treatment durability and prevent avoidable relapse (5).

In moderate-severe UC, higher serum IFX trough levels are associated with more favourable clinical outcomes (6). Conversely, greater baseline disease activity is associated with lower IFX levels, with patients with ASUC at particular risk (7,8). These observations can be explained by a variety of mechanisms that result in increased IFX clearance in states of higher inflammatory burden such as ASUC (Figure 1) (9).

Figure 1 Mechanisms of accelerated infliximab clearance in ASUC. Increased intestinal epithelial damage results in loss of IFX and albumin in the faeces. High levels of TNFα in the severely inflamed colon bind and neutralise available colonic IFX, becoming a “TNFα sink”. Intestinal damage also reduces neonatal Fc receptor-mediated IFX recycling, leading to increased lysosomal IFX proteolysis and degradation. Increased immune cell activity also increases phagocytosis and IFX proteolysis. Created in BioRender. Povlsen S. [2026] https://BioRender.com/ca62z1u. ASUC, acute severe ulcerative colitis; IFX, infliximab; TNFα, tumor necrosis factor alpha.

While the approved IFX induction dosing strategy of 5 mg/kg at weeks 0, 2 and 6 has been used successfully to rescue many patients with ASUC, concern that increased drug clearance in ASUC may lead to underexposure has prompted the use of alternative induction strategies. However, there has been a lack of clarity from observational studies to date as to which strategy is more efficacious, or which patient-related factors can identify the most appropriate strategy.

PREDICT-UC is the first prospective open label randomised trial comparing the safety and efficacy of standard (5 mg/kg week 0, 2, 6), accelerated (5 mg/kg week 0, 1, 3), and intensified (10 mg/kg week 0, 1) IFX induction dosing strategies in corticosteroid-refractory ASUC. This multi-centre trial conducted across 13 Australian tertiary hospitals enrolled 138 patients with 1:1:1 randomisation. The trial did not meet its primary endpoint: an initial 10 mg/kg dose was not superior to 5 mg/kg in achieving clinical response by day 7 (65% vs. 61%, P=0.62). There were also no significant differences in time to clinical response, change in Lichtiger score, early colectomy rates, or serious adverse events. Furthermore, there were no significant differences in clinical response by day 14 or clinical remission, endoscopic remission, steroid-free remission or colectomy rates by month 3 between standard, accelerated or intensified induction regimens.

On initial reading this may suggest the choice of induction strategy is irrelevant for patients with corticosteroid-refractory ASUC. However, the choice of induction strategies in this trial was designed so that each arm had 15–20 mg/kg IFX dosed over the first 90 days until maintenance dosing began. This left patients in accelerated and intensified arms with long periods without IFX dosing prior to maintenance dosing, compared to patients receiving standard induction. In clinical practice, intensified induction strategies may instead dose 30–40 mg/kg over this period with more even dosing intervals (10). A more nuanced picture emerges when the PREDICT-UC results are considered alongside its IFX PK analyses, recently reported by Suen et al. [2026] in a prospective observational study published in Gastroenterology (11).

Comparison of IFX exposure across induction arms may help explain why PREDICT-UC did not meet its clinical endpoints, as similar 90-day IFX area under the curve (µg*day/mL) were found across all induction strategies. In fact, day 90 IFX trough levels were highest in the standard and lowest in the intensified induction strategy groups. This is contrary to theoretical aim of intensified induction strategies to increase IFX exposure, thereby counteracting the increased IFX clearance in states of high inflammatory burden.

Modelling methodologies (multivariable Poisson and Cox regressions) were used to delve further into the data to identify independent predictors of clinical outcomes, with IFX clearance between day 1–7 (early clearance) emerging as the strongest predictor (Table 1).

A significant contributor to IFX clearance appears to be faecal loss, evidenced by the positive correlation between faecal IFX levels, C-reactive protein (CRP) and endoscopic severity as assessed by Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score, and its association with day 7 IFX non-response. When patients were equally divided into ‘high’ and ‘low’ clearance groups using a threshold ≥0.62 L/d, this identified patients less likely to respond to IFX by day 7, more likely to fail IFX by day 14, and more likely to require colectomy by 3 months. Among patients with high early clearance, an initial 10 mg/kg dose was more likely result in day 7 IFX response compared to 5 mg/kg. Similarly, patients with high clearance were more likely to require colectomy if they were allocated to the accelerated or standard induction arms compared to the intensified arm, and more likely to demonstrate non-response by day 14 if they were allocated to standard, compared to intensified or accelerated arms. In contrast, there was no difference in patients with low clearance. Furthermore, patients with high early clearance who did not respond to the initial IFX dose had higher day 14 response rates if they received a second 10 mg/kg dose compared to 5 mg/kg.

It must be noted that the authors also found early IFX clearance to be higher overall in patients receiving an initial 10 mg/kg versus 5 mg/kg dose. This makes it challenging to unravel the relationship between IFX dose, clearance and clinical outcome. Whether high clearance in this study truly identifies a more pharmacokinetically at-risk population more likely to respond to 10 mg/kg dosing, or whether dose choice itself artificially separates these groups remains unanswered.

Two markers of potential prognostic clinical utility were identified using data derived from PREDICT-UC, although these have not yet been externally validated. Lower day 3 serum IFX levels were predictive of IFX failure by day 14 and colectomy by 3 months (Table 1). Specifically, a patient who achieves a day 3 serum IFX concentration of >57.9 µg/mL has a 97% chance of avoiding colectomy by 3 months. Conversely, a level ≤57.9 µg/mL carries a 24% 3-month colectomy risk. Similarly, a day 3 threshold of ≤53.6 µg/mL has a day 14 IFX failure positive predictive value (PPV) of 42%, and negative predictive value (NPV) of 81%.

Next, the prognostic capabilities of the identified thresholds for IFX clearance and day 3 levels will need to be externally validated. Robust prognostic measures such as these will help clinicians have well informed discussions with patients, their families, and surgical colleagues in describing risk, potential outcomes, and treatment options. However, barriers to their adoption include long testing turnaround times and a lack of widely available web or app-based PK assessment tools for this indication.

Whether the PREDICT-UC PK data supports a drive to ‘personalised’ IFX induction strategies remains up for debate. TITRATE, a recent PK dashboard-driven trial for personalised IFX dosing in ASUC, failed to reach statistical significance in its primary endpoint (12). Suen and colleagues suggest this may be due to their lower serum IFX threshold (target >28 µg/mL in the first 28 days) than the day 3 IFX thresholds identified in this study (11). A recently published model uses baseline CRP and weight, IFX induction dosing schedule and at least one IFX level measured during the induction period to estimate 3-month colectomy risk, showing overall 85% classification accuracy (13). External validation and adjusting the model to specifically inform precision dosing are logical next steps.

Given the apparent safety of intensified induction strategies, it is equally important to question why one would not give intensified IFX induction to any patient with corticosteroid refractory ASUC. With increasingly widespread adoption of intensified IFX induction strategies, real-world data may in time help answer whether this approach does in fact reduce 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-2026-0081/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0081/coif). S.P. has support for travel and attending meetings from Lilly. R.H. has received honoraria from Takeda. H.A.O. has received support for attending meetings from Dr Falk. K.P. has received grants from AbbVie; payment or honoraria from AbbVie, J&J, Dr Falk, Takeda, Alfasigma, Pfizer and Celltrion; and support for travel and attending meetings from AbbVie, J&J, Lilly, Tillets, Takeda and Ferring. S.H. has received consulting fees from Pfizer, Banook Group, Lilly and Dr Falk; payment or honoraria from Lilly, AbbVie, J&J and Takeda; and support for travel and attending meetings from Alfasigma, AbbVie, Ferring, Pharmacosmos and J&J. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet 2023;402:571-84. [Crossref] [PubMed]
2. Moran GW, Gordon M, Sinopolou V, et al. British Society of Gastroenterology guidelines on inflammatory bowel disease in adults: 2025. Gut 2025;74:s1-s101. [Crossref] [PubMed]
3. Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG Clinical Guideline Update: Ulcerative Colitis in Adults. Am J Gastroenterol 2025;120:1187-224. [Crossref] [PubMed]
4. Adams A, Gupta V, Mohsen W, et al. Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response. Gut 2023;72:433-42. [Crossref] [PubMed]
5. Cheifetz AS, Abreu MT, Afif W, et al. A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease. Am J Gastroenterol 2021;116:2014-25. [Crossref] [PubMed]
6. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology 2014;147:1296-1307.e5. [Crossref] [PubMed]
7. 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. [Crossref] [PubMed]
8. Ungar B, Mazor Y, Weisshof R, et al. Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis. Aliment Pharmacol Ther 2016;43:1293-9. [Crossref] [PubMed]
9. Povlsen S, Patel K, Roblin X, et al. Therapeutic Drug Monitoring in Special Circumstances in Inflammatory Bowel Disease. J Clin Med 2025;14:7956. [Crossref] [PubMed]
10. Bartlett R, Mohamedrashed M, Yogakanthi S, et al. Trends in Length of Stay, Steroid Use and Colectomy Rates in Patients Admitted with Acute Severe Ulcerative Colitis: The Impact of Accelerated and Intensified Infliximab Dosing. Dig Dis Sci 2026;71:2347-54. [Crossref] [PubMed]
11. 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]
12. Gecse K, Van Oostrom J, Rietdijk S, et al. DOP056 TDM-Based Dose-Intensification of Infliximab is not Superior to Standard Dosing in Patients with Acute Severe Ulcerative Colitis: Results from the TITRATE Study. J Crohns Colitis 2025;19:i194-5.
13. Niyigena E, Hoffert Y, Afif W, et al. Personalized infliximab rescue therapy to maximize colectomy-free survival in patients with acute severe ulcerative colitis. J Crohns Colitis 2026;20:jjag029. [Crossref] [PubMed]