Y-ECCO Literature Review: Saiumaeswar Yogakanthi
Early infliximab levels and clearance predict outcomes after infliximab rescue in acute severe ulcerative colitis: Results from PREDICT-UC
Li Wai Suen CFD, Choy MC, Con D, et al.
Gastroenterology 2025 July 21. doi: 10.1053/j.gastro.2025.07.020
Introduction
Acute Severe Ulcerative Colitis (ASUC) represents a potentially life-threatening complication/presentation of Ulcerative Colitis, and rescue therapy in steroid-refractory disease is a key tenet of management [1]. Infliximab is an effective and widely used agent in this setting, although whether additional benefit may be gained from intensified dosing has remained a subject of debate for many years [2]. The primary results of PREDICT-UC were published in 2024. This was a multi-centre, open-label, randomised control trial conducted across 13 hospitals in Australia that compared intensified and standard infliximab rescue therapy in patients with steroid-refractory ASUC [3]. While the clinical trial overall did not observe a difference in its primary endpoint of clinical response to infliximab by day 7 when comparing initial infliximab doses of 5 mg/kg and 10 mg/kg, numerically lower response rates in the setting of low albumin (<25 g/L) and a higher C-reactive protein (≥50 mg/L) were seen in those who received an initial 5 mg/kg dose. Based on these subgroup findings, many have raised the question of whether a subset of patients with a higher inflammatory burden and/or drug clearance may benefit from a higher initial dose. In this study, Li Wai Suen and colleagues present additional analysis from the PREDICT-UC cohort, examining whether serum and faecal infliximab levels and infliximab clearance are associated with clinical outcomes.
Methods
A total of 138 patients were enrolled in PREDICT-UC, with 46 receiving an initial infliximab dose of 10 mg/kg and 92 receiving an initial dose of 5 mg/kg. Samples from 135 patients in this cohort were used in the analysis. Specimens were collected at days 1, 3, 5, 7, 14, 30 and 42 and at month 3 after the first infliximab dose. Serum infliximab levels were quantified using an enzyme-linked immunosorbent assay, with antibody testing also performed in patients with low levels (defined as <2 µg/ml). Faecal analyses were performed using the same assays on stool supernatant created through homogenisation of the stool. Estimation of infliximab clearance and exposure was performed using a two-compartment pharmacokinetic model with first-order elimination using previously established values along with the available serum infliximab levels.
Key findings
Serum infliximab levels
Day 3 serum infliximab level was found to have several clinical associations: lower day 3 serum levels were observed in those who had infliximab failure at day 14 and those who underwent colectomy by 3 months. Furthermore, in those who received an initial 5 mg/kg infliximab dose, lower serum levels were noted in non-responders at day 7, though this pattern was not seen in those who received a 10 mg/kg initial dose.
Faecal infliximab levels
Faecal infliximab levels were found to be higher at both day 1 and day 3 in patients who received an initial 10 mg/kg dose compared to those who received an initial 5 mg/kg, and positive correlations were seen with C-reactive protein and endoscopic severity as assessed by the UCEIS score. Lower day 3 faecal infliximab levels were associated with day 7 response; on sub-group analysis, this finding was retained in the 5 mg/kg group but not in the 10 mg/kg group. A long-term predictive ability was also seen, with a low faecal infliximab level at day 1 predicting Mayo endoscopic remission and combined clinical and endoscopic remission at 3 months.
Infliximab clearance
Infliximab clearance was highest during the first 3 days post administration, with a gradual decrease over time to day 30. Early clearance was higher overall in those receiving an initial dose of 10 mg/kg (vs 5 mg/kg). Day 3 clearance was higher in patients who did not respond to infliximab by day 14 than in those who demonstrated a response. Day 7 clearance was higher in those who demonstrated an initial non-response by day 7, those with non-response by day 14 and those who required a colectomy. Most pertinently, patients with a high early clearance were more likely to demonstrate response to an initial 10 mg/kg infliximab dose than to an initial 5 mg/kg dose after accounting for thiopurine exposure; in contrast, no difference in response was observed in those with low early clearance. Among patients with high early clearance who did not respond to the initial infliximab dose, day 14 response rate was higher in patients who received a second 10 mg/kg dose compared to 5 mg/kg. In contrast, no difference was seen in those with low early clearance.
Discussion
This study provides important insights into the use of infliximab in the setting of ASUC. First, the study illustrates the potential utility of early therapeutic drug monitoring, with day 3 serum infliximab levels being shown to be associated with short-term clinical response and avoidance of colectomy. Second, faecal loss of infliximab appears to be associated with clinical outcomes and correlated with disease severity. Third and perhaps most significantly, infliximab clearance appears to be a potential predictor of which patients are likely to benefit from intensified dosing, with this factor also outperforming C-reactive protein in short-term risk stratification. These findings suggest that pharmacokinetic assessment may help identify those patients who will benefit from intensified dosing, while permitting the avoidance of unnecessary drug exposure in others. In the era of emerging novel rescue therapies such as JAK inhibitors and increased utilisation of sequential rescue therapy, identification of pharmacokinetic vs pharmacodynamic infliximab failure is particularly relevant to ensure minimisation of ineffective immunosuppression, and here the study’s findings offer a potential avenue to accelerate decision-making regarding dose optimisation vs switching to another mechanism [4, 5].
The strengths of this study include its use of a large, multi-centre cohort, extensive collection of serum and faecal samples, and robust statistical modelling. Recruitment for any prospective study assessing ASUC is challenging, as is reflected in the five-year recruitment period required for the overall study; in this context, generation of the dataset itself is noteworthy. Nonetheless, the study does have limitations. In particular, as acknowledged by the authors, multiple hypothesis tests were performed without formal adjustments, thereby increasing the possibility of a type I statistical error and a false association. Indeed, the TITRATE study, which previously evaluated personalised infliximab dosing using a Bayesian pharmacokinetic algorithm in ASUC, did not meet its primary composite endpoint at day 42 and was stopped early based on futility [6]. Notably, the target infliximab concentrations in TITRATE were lower than the thresholds identified in the current analysis of PREDICT-UC. Taken together, these findings highlight the importance of a future interventional trial based on the study’s findings to determine whether a pharmacokinetic based strategy is associated with improved outcomes.
Conclusion
This prospective study using data and samples from the PREDICT-UC trial offers novel insights into infliximab use in ASUC, highlighting the potential utility of early serum levels for the prediction of clinical outcomes and the potential value of pharmacokinetic modelling to guide intensified and accelerated dosing. These findings, if validated, suggest that a personalised approach to infliximab therapy in ASUC will be possible in the future.
References
- Riviere P, Li Wai Suen C, Chaparro M, De Cruz P, Spinelli A, Laharie D. Acute severe ulcerative colitis management: unanswered questions and latest insights. Lancet Gastroenterol Hepatol 2024;9:251–62.
- Gisbert JP, Garcia MJ, Chaparro M. Rescue therapies for steroid-refractory acute severe ulcerative colitis: a review. J Crohns Colitis 2023;17:972–94.
- 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.
- Singh A, Goyal MK, Midha V, et al. Tofacitinib in acute severe ulcerative colitis (TACOS): a randomized controlled trial. Am J Gastroenterol 2024;119:1365–72.
- Garcia MJ, Riestra S, Amiot A, et al. Effectiveness and safety of a third-line rescue treatment for acute severe ulcerative colitis refractory to infliximab or ciclosporin (REASUC study). Aliment Pharmacol Ther 2024;59:1248–59.
- 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(Suppl 1):i194–i5.
Profile
Saiumaeswar Yogakanthi is a gastroenterologist from Melbourne, Australia, currently undertaking a fellowship in Inflammatory Bowel Disease at Cambridge University Hospitals in the United Kingdom. His research interests include therapeutic drug monitoring and predictive biomarkers.