Introduction

Acute Severe Ulcerative Colitis (ASUC) is a serious, potentially life-threatening condition. Hospital admission and prompt medical therapy with intravenous steroids is crucial, but rescue medical therapy with infliximab is frequently needed. Despite its frequency and relevance, there is no clear evidence about the optimal infliximab (IFX) dosing and timing in this context.

Aims & Methods

In a prospective multicentre, international cohort study, consecutive patients hospitalized for ASUC between 2/2019-1/2020 were included. The primary outcome was surgery during the first 90 days after admission (failure of medical treatment). For this analysis we identified and analyzed all patients receiving IFX as rescue therapy during the index admission. We used descriptive statistics along with non-parametric tests to determine patient characteristics and outcomes between IFX usage patterns.

Results

A total of 823 patients from 123 centers in 32 countries in five continents were included (median age 39 years [IQR, 28-54], 56% male, 64% non-smokers). IFX was started in 159 patients (19%) after a median of 6 days (IQR, 4-8) after starting steroids, with 27% after >7 days. The initial IFX dose was mostly 5 mg/kg (74%), followed by 10 mg/kg (23%). The overall response was considered adequate in 74%, this was numerically superior among those receiving 10 mg/kg (83% vs 74%, p=0.5). In 41 patients a second dose of IFX (26%) was administered during the admission. After a first dose of IFX 5 mg/kg or 10 mg/kg, most patients received a subsequent infusion with the same dosing (92% and 79%, respectively). Colectomy was performed in 35 patients (22%), without statistically significant differences between those with an initial dose of 5 or 10 mg/kg (23% vs 19%, p=0.6).

Conclusion

IFX is a relevant rescue therapy, required in around one in five patients with ASUC. Most patients receive 5 mg/kg, and this is usually followed by the same dosage. Still a proportion of patients receive higher doses with 10 mg/kg, but colectomy risk remains similar between both groups.

Introduction

The therapeutic landscape for ulcerative colitis (UC) is rapidly evolving, with an increasing number of biologic agents available.

Aims & Methods

This systematic review and meta-analysis synthesised randomised controlled trials (RCTs) data on biologic therapies for achieving key endoscopic and histologic endpoints in moderate to severe UC. A systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science and grey literature was conducted through November 2024. Separate meta-analyses were performed for induction and maintenance. A random-effects model was used to estimate relative risks (RR), with 95% confidence intervals (CI) and confidence in estimates was evaluated with the GRADE approach (Grading of Recommendation Assessment, Development and Evaluation).

Results

We included 40 RCTs (13 therapies , 14,369 patients). Thirty-two trials provided data in induction phase and twenty-eight in maintenance phase. During induction phase, all biologic therapies except for mirikizumab and filgotinib 100 mg demonstrated superiority over placebo (RR 2.02, 95% CI:1.76–2.31, I²=72%) for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 5.53, 95% CI: 3.78-8.09). In biologic-naive patients and in patients with no previous biologic failure status upadacitinib 30mg had the highest efficacy (RR 4.07, 95% CI:2.69-6.16). In biologic-exposed patients or those with previous biologic failure, upadacitinib 30mg also showed the greatest benefit (RR 10.52, 95% CI:4.55-24.34). For induction of mucosal healing, all interventions were superior to placebo (RR 2.95, 95% CI:2.11–4.13,I²=61%), except for filgotinib 100 mg. Risankizumab showed the highest efficacy (RR 10.25, 95% CI:2.49-42.11). In maintenance phase, all therapies showed superiority over placebo for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 4.18, 95% CI: 2.79–6.27). In biologic-naïve patients or those without prior biologic failure, all interventions—except filgotinib 100 mg and vedolizumab—were significantly superior to placebo, with etrasimod showing the highest efficacy (RR 3.12, 95% CI: 1.79–5.43). Among biologic-exposed patients or those with prior biologic failure, upadacitinib, mirikizumab, ustekinumab, etrasimod, tofacitinib, and risankizumab 180 mg were significantly superior to placebo. Upadacitinib showed the highest efficacy (RR 7.58, 95% CI: 3.42–16.8). For mucosal healing all therapies were superior to placebo, except for risankizumab. Upadacitinib showed the highest efficacy (RR 4.01 ,95% CI: 1.81–8.87). In biologic-naïve patients or those without prior biologic failure, only etrasimod, mirikizumab, upadacitinib 30 mg and subcutaneous infliximab were significantly superior to placebo, with upadacitinib showing the highest efficacy (RR 3.02, 95% CI: 1.18–7.71). Among biologic-exposed patients or those with prior biologic failure, only etrasimod, mirikizumab, and upadacitinib were significantly superior to placebo, with etrasimod demonstrating the highest efficacy (RR 9.45, 95% CI: 1.31–68.36).

Conclusion

Biologic and small-molecule therapies demonstrated substantial efficacy in achieving key endoscopic and histologic endpoints in moderate to severe UC. Upadacitinib consistently showed the highest efficacy across both induction and maintenance phases. Stratified analyses revealed enhanced response rates in biologic-naïve patients, supporting early initiation of advanced therapies. Our findings highlight the importance of individualised treatment strategies and the urgent need for standardised endpoint definitions to enhance comparability across future trials.

Introduction

The PROFILE trial in patients with newly-diagnosed Crohn’s disease demonstrated that “top-down” therapy, with combination infliximab and immunomodulator from diagnosis, provided superior efficacy and a better safety profile over a one-year follow-up period compared to a conventional “accelerated step-up” management approach.

Aims & Methods

The current study aimed to evaluate cost-effectiveness by assessing the healthcare cost and health outcomes associated with starting anti-TNF medication (intravenous infliximab, subcutaneous infliximab, subcutaneous adalimumab) as soon as possible after diagnosis. A de novo Markov model was developed to model the cost-effectiveness of using a “top-down” compared to “accelerated step-up” strategy in adults newly-diagnosed with active Crohn’s disease (HBI score >7, elevated CRP and/or faecal calprotectin >200ug/g and endoscopic evidence of disease activity with simple endoscopic score of Crohn’s disease activity of >6 [>4 if ileal-only disease]). Parameters were informed by individual patient data from PROFILE and data from the published literature. Use of intravenous infliximab, or subcutaneous infliximab, or subcutaneous adalimumab from diagnosis were modelled with biosimilar costs based on average real-world UK contract drug costs ascertained from 18 PROFILE trial sites in 2024. Key model outcomes included healthcare costs (drug acquisition, drug administration, disease management, hospitalisation, surgery) and health outcomes (quality-adjusted life years gained [QALYs]) measured over a 5-year time horizon.

Results

The base case cost-effectiveness analysis indicated that a “top-down” strategy dominated over an “accelerated step-up” approach. Initiating intravenous infliximab from diagnosis yielded greater clinical benefits, with an incremental gain of 0.17 QALYs per patient over a 5-year period, and was less costly, saving £1,681 per patient over the same time frame. Similar clinical benefits were obtained when modelling use of SC infliximab and adalimumab. The greatest cost savings were with adalimumab, totalling £10,059 per patient over 5 years. Sensitivity analyses further supported the robustness of the results for “top-down” therapy, showing it to be the most cost-effective option in 98.7% of model simulations.

Conclusion

This health economic analysis demonstrates that early effective “top-down” treatment with anti-TNF therapy from diagnosis results in lower healthcare resource use compared to an “accelerated step-up” strategy. The economic benefits align with improved clinical outcomes, as early, effective treatment better controls inflammation. Patients experience longer periods in remission, fewer disease-related flares, and enhanced quality of life. These findings were demonstrated for intravenous infliximab, subcutaneous infliximab and subcutaneous adalimumab. In newly-diagnosed patients with active Crohn’s disease, “top-down” treatment with anti-TNF therapy is more efficacious, safer and cost-effective than “accelerated step-up” based treatment strategies.

References

Noor NM, Lee JC, Bond S et al. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial. Lancet Gastroenterol Hepatol. 2024 May;9(5):415-427.

Disclosure

NMN declares educational/travel grants and/or speaker fees from AbbVie, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Galapagos, J&J, Lilly, Pfizer, Pharmacosmos, Takeda and Tillotts Pharma AG.

Introduction

An increasing number of patients in clinical practice are transitioning from intravenous (IV) to subcutaneous (SC) dosing of infliximab. In this simulation study, we evaluated hypothetical dosing scenarios for both (normal to obese) adults and children switching from steady-state IV to SC infliximab, as well as those initiating SC infliximab therapy.

Aims & Methods

By combining two previous published infliximab models (1,2) we were able to simulate both IV and SC dosing in adults and children. Various dosing regimens were simulated using a large virtual population. In each scenario, the distribution of trough concentrations and area under the plasma concentration time curve (AUC) was calculated.

Results

Peak levels were higher after IV dosing compared to SC dosing, while trough levels were higher after SC dosing leading to more stable infliximab levels over time. Overall exposure remained largely similar when switching from a standard IV to SC dosing regimen. Patients with a high body mass index and those on high-frequency IV dosing regimens of infliximab demonstrated reduced exposure when transitioned to the fixed SC dose. Paediatric patients exhibited higher exposure on the fixed SC dose. Simulation of SC induction schemes demonstrated early achievement of steady state plasma levels.

Conclusion

Infliximab exposure (AUC) remains largely similar when transitioning from standard IV to SC dosing. Current dosing regimens may not be optimal for morbidly obese patients, paediatric patients and patients on high-frequency infliximab regimens. These findings provide a foundation for future clinical research to refine SC infliximab dosing in these populations.

References

1) Hanzel J, Bukkems LH, Gecse KB, D’Haens GR, Mathôt RAA. Population pharmacokinetics of subcutaneous infliximab CT-P13 in Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2021;54:1309–19.
2) Fasanmade AA, Adedokun OJ, Blank M, Zhou H, Davis HM. Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn’s Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials. Clin Ther. 2011;33:946–64.

Disclosure

RW has no conflicts of interest. RK is an employee and stockholder of Insight RX, a company developing clinical decision software. LD has served as a speaker for AbbVie, Celltrion, Janssen-Cilag and Takeda and has developed continuing education materials for Ferring, all outside the submitted work.