What evidence is there to support intensive induction therapy of infliximab for acute, severe ulcerative colitis? Is there data to support a 5mg/kg dose or 10 mg/kg dose approach? Is there data to support administration of early doses (e.g. second dose before day 14)? Is there data to support adjusting dose for serum albumin level?

Comment by InpharmD Researcher

Data suggests that infliximab as rescue therapy in the hospital setting for acute severe ulcerative colitis (ASUC) is beneficial for patients refractory to IV glucocorticoids, and may potentially prevent colectomy and improve long-term outcomes. However, the optimal infliximab dosing regimen for ASUC remains debated. Although the standard infliximab dose is 5 mg/kg, some evidence suggests this dose may not adequately target inflammation in patients with severe disease. Intensive induction regimens (10 mg/kg) have been proposed to enhance treatment outcomes in patients with ASUC; however, dose escalations have not yet shown clear superiority over standard dosing, including in the PREDICT-UC trial (see Table 1). Additionally, data evaluating accelerated induction regimens (administration of the second dose before day 14) have similarly found no benefit on clinical outcomes compared to standard induction regimens. In general, available evidence evaluating the benefit of intensified and accelerated infliximab dosing strategies in patients with ASUC is conflicting and limited to observational data. While a low serum albumin, frequently identified in ASUC, has been associated with low serum infliximab levels and non-response to infliximab, evidence to support dose adjusting infliximab based on the serum albumin level is currently lacking. In one study (Govani et al), the protocol utilized CRP-to-albumin ratio to guide initial infliximab dosing, with 10 mg/kg used if the ratio exceeded 1.

Background

According to the 2020 American Gastroenterological Association (AGA) guidelines, infliximab or cyclosporine are recommended in hospitalized adult patients with acute severe ulcerative colitis (ASUC) refractory to intravenous (IV) corticosteroids (conditional recommendation, low quality evidence). The panel suggests using either infliximab or cyclosporine in hospitalized adult patients with ASUC refractory to a 3 to 5 day trial of IV corticosteroids. However, no recommendations were made on the routine use of intensive versus standard infliximab dosing in hospitalized adult patients with ASUC, refractory to IV corticosteroids, being treated with infliximab (no recommendation, knowledge gap). [1]

A recent 2024 review discusses the latest insight for management of ASUC, including the role of infliximab. For patients admitted to the hospital who are steroid-refractory, infliximab is considered one of the options for rescue therapy along with calcineurin inhibitors. Infliximab and cyclosporine appear to be equally effective rescue therapies for ASUC when IV corticosteroids have failed; head-to-head trials have found no differences in outcomes between the two. Both infliximab and cyclosporine also appear to have similarly safe profiles based on trial data, though cyclosporine requires closer monitoring. The optimal infliximab dosing regimen for ASUC is debated, but high dose or accelerated induction schedules have not clearly shown superior outcomes to standard dosing due to scarce evidence. The standard dose for infliximab is 5 mg/kg on days 0, 14, and 42. The rationale for dose escalation is to bypass unfavorable pharmacokinetic profile, and one study found that ASUC patients demonstrated lower infliximab trough concentrations on day 14 compared to patients with only moderate ulcerative colitis (UC). Greater excretion of infliximab might also occur in ASUC patients. Yet, the impact on treatment remains largely inconclusive. The PREDICT UC study (NCT02770040) compared a dose-intensified induction of infliximab (10 mg/kg at weeks 0 and 1) versus the accelerated regimen (5 mg/kg at weeks 0, 1, and 3), with a standard induction group as a control (see Table 1). [2]

While Infliximab and cyclosporine currently have similar safety and efficacy profiles, certain criteria may help guide treatment decisions between the two agents. Cyclosporine may be preferred for patients without comorbidities like renal impairment. It is also used as a bridge to thiopurines in thiopurine-naive patients. Infliximab is preferred for patients with extra-intestinal manifestations due to its efficacy in controlling inflammation, while cyclosporine is not recommended for conditions like ankylosing spondylitis and psoriasis. Additionally, infliximab is chosen more often by clinicians due to cyclosporine’s requirement for closer monitoring via IV infusion and concentration monitoring. However, cyclosporine is cheaper. Early data suggested cyclosporine carried a higher risk of opportunistic infections, but subsequent studies found similar mortality rates between cyclosporine and infliximab. While data remains insufficient, a few preliminary studies reported certain factors that may predict the failure of rescue therapy with infliximab or cyclosporine (see Table 5). [2]

A 2023 review discussed observational data demonstrating a correlation between the higher serum concentrations of infliximab and improved treatment outcomes and the importance of optimal dosing strategies and specific therapeutic drug monitoring of infliximab in the ASUC setting. Given the increased clearance of infliximab and the high inflammatory burden in ASUC patients, investigations on accelerated or intensified dosing strategies as well as target drug concentration thresholds are warranted in this patient population. However, available evidence evaluating the benefit of intensified and accelerated infliximab dosing strategy in this population is conflicting and limited to observational data (see Table 2). Several retrospective studies indicated a potential benefit in the choice of intensive infliximab induction or accelerated dosing in ASUC. In one 2015 retrospective study, a significantly lower rate of early colectomy was present in patients who received an accelerated dosing strategy compared to the standard regimen (7% vs 40%, respectively; p= 0.042). Of note, this study included an uneven, small sample size and was subject to selection biases owing to the observational nature. On the other hand, a 2020 meta-analysis of five observational studies revealed no significant difference in short-term colectomy risk in ASUC patients treated with intensified dosing versus the standard dosing strategy. Overall, given the observational nature of studies, an optimal use of intensified dosing strategy remains inconclusive. Future randomized controlled trials (RCTs) are warranted to compare the clearance-based dosing to standard dosing as well as specific threshold target concentrations for infliximab dosing. [3], [4]

A 2023 review of the literature on salvage therapy options available for the management of patients with ASUC aimed to provide the optimal therapeutic approach for this high-risk population. Available data indicated infliximab was associated with a significant difference in avoiding in-hospital colectomy compared with placebo (29% vs. 67%, respectively; p= 0.017). While the standard induction and maintenance dosing of infliximab generally follows the 5 mg/kg infusion at weeks 0, 2, and 6 and then Q8W thereafter, pharmacokinetic studies on infliximab evaluated the dose intensification in the setting of ASUC. However, data supporting high-dose infliximab are controversial in this patient population. A 2019 meta-analysis of 41 cohorts (N= 2,158 patients) demonstrated no significant difference in efficacy outcomes of patients who received standard dosing (5 mg/kg) compared to high-dose or accelerated dosing (odds ratio [OR] 0.70; 95% confidence interval [CI] 0.39 to 1.27; p= 0.24), despite being used in patients with a significantly higher mean C-reactive protein (CRP) and lower albumin levels. [5], [6]

Available data suggest infliximab as well as calcineurin inhibitors are the mainstay in the management of patients refractory to corticosteroid therapy. However, the overall inflammatory burden such as severe hypoalbuminemia (<3.5 g/dL), increased inflammation indices (CRP ≥25 mg/L), and endoscopic severity according to the Mayo Endoscopic Score may lead to detecting relatively high concentrations of infliximab in stool and increased infliximab clearance. Other underlying co-morbidities (e.g., renal disease, uncontrolled hypertension, hypocholesterolemia), especially in the geriatric population, may also be used as a guide to individualize the treatment approach. While conclusions on the use of an intensified dosing strategy cannot be made owing to limited available data, studies with potential stratification of patients based on infliximab failure may provide insight into the optimization of salvage therapy in ASUC population. [5], [6]

Likewise, another review article from 2020 discussed rescue therapy with infliximab in patients with ASUC refractory to corticosteroids, specifically accelerated infliximab dosing in this patient population. Evidence from limited studies demonstrated an enhanced infliximab clearance in ASUC patients, suggesting an intensified infliximab dosing regimen may benefit the patients in improved clinical outcomes. It is also noted that a low serum albumin, frequently identified in ASUC, has been associated with low serum infliximab levels and non-response to infliximab, both in adult, and pediatric patients. However, evidence to support dose adjusting infliximab based on the serum albumin level appears to be lacking. One 2016 retrospective study revealed a significantly lower level of infliximab (7.15 ± 5.3 mcg/mL) associated with ASUC patients two weeks following the infliximab induction initiation compared to patients with moderately severe UC (14.4 ± 11.2 mcg/mL; p= 0.007). Despite this pharmacokinetic data, several reviews did not reveal a significant difference in short-term or long-term colectomy rates associated with intensified dosing regimens, including more frequent doses of 5 mg/kg or inclusion of a 10 mg/kg loading dose. Moreover, pooled analysis from a 2019 meta-analysis (N= 10 studies; 705 patients) did not find a significant difference in beneficial outcomes between accelerated induction regimens and standard induction dosing. Overall, given the limitations of the included studies, investigations in high-quality RCTs are warranted to optimize the infliximab regimens based on individual risk stratifications. [7], [8], [9]

A 2021 network meta-analysis aimed to identify the optimal rescue therapy for patients with acute glucocorticosteroid-refractory UC to prevent colectomy and improve long-term outcomes. A total of seven RCTs involving 534 patients were included. The findings revealed that both infliximab and cyclosporine significantly reduced the risk of colectomy at ≤1 month compared to placebo (relative risk [RR] with infliximab vs. cyclosporine 0.37; 95% CI 0.21 to 0.65). When assessing colectomy between >1 month and <1 year, both agents ranked equally in terms of colectomy risk (p= 0.75). Infliximab and cyclosporine were not more effective than placebo in reducing the risk of colectomy at ≥1 year; however, both drugs were significantly more efficacious than placebo in achieving response (infliximab failure to respond: RR 0.48; 95% CI 0.30 to 0.77; p= 0.67). Results also suggested that neither agent demonstrated superiority in inducing remission compared to placebo, nor were they more likely to cause serious adverse events than placebo. Based on these findings, it was concluded that both infliximab and cyclosporine are superior to placebo in terms of therapy response and avoiding colectomy within the first year, with no significant differences in efficacy or safety between the two agents. [10]

A 2017 literature review discusses the relationship between infliximab pharmacokinetics, dosing strategies, and disease behavior in patients with ASUC. A total of 76 studies assessing the pharmacokinetics and dose intensification strategies of infliximab in ASUC were included, which highlighted that increased clearance of infliximab was observed in patients with ASUC, influenced by the overall burden and leakage of the drug into the colonic lumen. Multiple studies have linked the severity of UC with infliximab treatment failure, indicating that the conventional dose of 5 mg/kg may not adequately target inflammation in severe UC. One prospective cohort study suggested that high baseline serum CRP (>50 mg/L) and low serum albumin (<35 g/L), along with extensive colitis, were independently associated with lower infliximab concentrations during the first 6 weeks of therapy. [11,12,8]

Due to these findings, infliximab dose optimization in patients with ASUC has been proposed to enhance treatment outcomes. Post-hoc analyses of the ACT 1 and 2 trials suggested potential efficacy improvement with infliximab dose increases. In these trials involving 728 patients with moderate-to-severe UC, only the 10 mg/kg dose was suggested to reduce colectomy need over 54 weeks. Additionally, a retrospective analysis of 50 corticosteroid-refractory ASUC patients demonstrated significantly lower early colectomy rates following the adoption of an intensified infliximab dosing regimen (three 5 mg/kg doses within a median period of 24 days). Overall, the authors emphasize the potential of infliximab dose optimization in patients with ASUC, as suggested by findings from uncontrolled studies; however, further robust data is necessary to validate these findings. [11,13,4]

A 2024 multicenter, retrospective cohort study conducted across seven tertiary hospitals in China examined the comparative effectiveness of accelerated versus standard infliximab (IFX) induction regimens in patients with steroid-refractory ASUC. Investigators enrolled 76 patients who met modified Truelove and Witts’ criteria and received at least two IFX doses following a minimum of 3 days of intravenous corticosteroids. Patients receiving 5 mg/kg IFX at Days 0 and ≥14 were categorized under the standard regimen (n= 29), while the accelerated group (n= 47) included those who received two doses within 13 days and/or an intensified dose of ≥7.5 mg/kg. Outcomes were adjusted for potential bias using propensity score analysis and institution-based stratification. Clinical endpoints included 30- and 90-day colectomy rates, clinical remission rates at Day 14 (Mayo ≤2 with subscores ≤1), response rates, length of hospitalization, and adverse event frequency. The 90-day colectomy rate was significantly higher in the accelerated group prior to adjustment (17.8% vs 0%, p= 0.019), while Day 14 clinical remission was lower (27.7% vs 65.5%, p= 0.001). However, after adjustment for propensity scores and institutional variations, no statistically significant differences were observed in colectomy risk (hazard ratio [HR] 0.13; 95% CI 0.01 to 2.91; p= 0.20) or clinical remission odds (OR 1.73; 95% CI 0.38 to 7.84; p= 0.48). Dose-response analysis using restricted cubic splines revealed a decreased colectomy hazard with cumulative IFX doses up to ~8 mg/kg administered within 5 days, while dosing beyond 5 days showed no incremental benefit. Multivariate logistic regression identified CRP >10 mg/L at IFX initiation (OR 5.00; 95% CI 1.27 to 24.34) as an independent predictor of non-remission at Day 14. A supporting meta-analysis incorporating 12 studies and 814 patients further demonstrated no significant difference in 3-month colectomy outcomes between accelerated and standard induction (OR 1.23; 95% CI 0.64 to 2.37; p= 0.54), reinforcing the findings seen in this study. [14]

Finally, a 2020 retrospective cohort analysis examined the effects of an accelerated IFX induction strategy for hospitalized adults with ASUC at a tertiary care center between 2013 and 2017. The investigation included 66 IFX-naïve patients who failed intravenous corticosteroids but were free of enteric infections and did not receive cyclosporine during admission. Patients were stratified into two groups: those who received a standard single-dose IFX induction (5 or 10 mg/kg on day 0 with conventional subsequent doses) and those treated under an accelerated protocol, receiving a second dose within 3 days based on incomplete CRP response. The protocol utilized CRP-to-albumin ratio to guide initial IFX dosing, with 10 mg/kg used if the ratio exceeded 1. CRP response assessed on days 3 and 6 informed subsequent IFX administration or surgical referral. Data from the 66 eligible patients demonstrated no statistically significant difference in 90-day colectomy rates between the accelerated and single-dose groups (30.3% vs 24.2%, p= 0.58), nor in one during index hospitalization (27.3% vs 21.2%, p= 0.57). Importantly, 69.7% of patients receiving a second IFX dose following partial biochemical response avoided colectomy within 90 days. Postoperative outcomes, including complication rates, blood loss, surgical time, and 30-day readmissions, did not significantly differ across groups. Multivariable analysis identified elevated CRP at IFX initiation (OR 1.25; p<0.01) and low albumin nadir (OR 0.20; p= 0.02) as significant predictors of colectomy. These findings support the feasibility of accelerated IFX induction as a rescue strategy in steroid-refractory ASUC without apparent increase in postoperative morbidity, though the authors recommended further prospective, multicenter investigations due to modest sample size and single-center design. [15]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

Are there any recommendations available to guide when it is appropriate to use infliximab as rescue therapy in the hospital setting for acute severe ulcerative colitis? What are the differences between 5 mg/kg and 10 mg/kg dosing?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-5 for your response.

Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial
Design	Open-label, multicenter, randomized controlled trial N= 138
Objective	To compare intensified and standard dose infliximab rescue strategies and explore maintenance therapies following infliximab induction in steroid-refractory acute severe ulcerative colitis (ASUC)
Study Groups	10 mg/kg (n=46) 5 mg/kg (n=92) IIS (n= 46) AIS (n= 48) SIS (n= 44)
Inclusion Criteria	Patients aged 18 years or older with ASUC confirmed by Truelove and Witts’ criteria, endoscopic severity corresponding to a Mayo Endoscopic Subscore of at least 2
Exclusion Criteria	Immediate colectomy indication, Crohn’s disease, confirmed enteric infection, haemodynamic instability, clinically significant cytomegalovirus infection, current malignancy, colitis-associated dysplasia, serious comorbidities precluding infliximab, history of infliximab hypersensitivity, recent biologicals or calcineurin inhibitors, pregnancy or breastfeeding
Methods	Patients were randomly assigned (1:2) to receive a first rescue intensified infliximab dose of 10 mg/kg or a standard dose of 5 mg/kg. Patients who received the initial 10 mg/kg dose of infliximab continued on as the intensified strategy group (IIS). Patients in the IIS group received a second infliximab dose of 10 mg/kg at day 7 if they clinically responded to the first dose, or at time of non-response between days 3 and 7 after the first dose. The 5 mg/kg group was re-randomized to standard induction strategy (SIS) or accelerated induction strategy (AIS). Patients in the SIS group received three doses of 5 mg/kg infliximab at week 0, week 2, and week 6 if they responded to the first dose (total 15 mg/kg over 6 weeks). Alternatively, they were given four doses with an additional 5 mg/kg dose at the time of non-response (between days 3-7 from the first dose) if they did not respond to the first dose (total 20 mg/kg over 6 weeks). Patients in the AIS group received three doses of 5 mg/kg infliximab at week 0, week 1, and week 3 if they responded to the first dose (total 15 mg/kg over 3 weeks). Alternatively, the AIS group received three doses with the second dose being 10 mg/kg given at the time of non-response (between days 3-7) for those who did not respond to the first dose, with the week 3 dose remaining at 5 mg/kg (total 20 mg/kg over 3 weeks). Clinical response was assessed by day 7, with maintenance therapy options explored from months 3 to 12.
Duration	July 20, 2016, to September 24, 2021
Outcome Measures	Primary: Clinical response by day 7 (reduction in Lichtiger score to <10 with a decrease of ≥3 points from baseline) Secondary: Time to clinical response, change in Lichtiger score, colectomy rate, adverse events, clinical remission, endoscopic remission, steroid-free remission, combined clinical and endoscopic remission
Baseline Characteristics	Characteristic	10 mg/kg (n= 46)	5 mg/kg (n= 92)	IIS (n= 46)	AIS (n= 48)	SIS (n= 44)
	Median age, years	33	32	33	34	32
	Male	57%	53%	57%	54%	52%
	Median disease duration at screening, years	4.1	2.7	4.1	2.0	4.3
	New diagnosis of ulcerative colitis at screening	33%	27%	33%	25%	30%
	Median duration of flare before hospital admission, weeks	6	3	6	3	3
	Previous ASUC diagnosis	30%	33%	30%	39%	26%
	Median duration of intravenous steroids before infliximab, days	4	4	4	4	4
	Median Lichtiger score	13	13	13	13	13
	Median admission CRP, mg/L	44.0	50.3	44.0	51.9	50.3
	Median admission albumin, g/L	31.4	32.1	31.4	32.5	31.7
Results	Outcome	10 mg/kg (n= 46)	5 mg/kg (n= 92)	RR (95% CI)	p-value
	Clinical response by day 7	30 (65%)	56 (61%)	1.06 (0.94 to 1.20)	0.32
	Colectomy by day 7	2 (4%)	0	-	NS
	Outcome	IIS (n= 46)	AIS (n= 48)	SIS (n= 44)	p-value
	Clinical response by day 14	34 (74%)	35 (73%)	30 (68%)	0.81
	There were no differences between the 10 mg/kg and 5 mg/kg groups for time to clinical response or change in Lichtiger score An exploratory analysis found high albumin and low C-reactive protein (CRP) to albumin ratio to be associated with improved rates of clinical response by day 7. In patients with a baseline albumin of less than 25 g/L, a day 7 response occurred in nine (64%) of 14 patients in the 10 mg/kg group versus 14 (45%) of 31 in the 5 mg/kg group (RR 1.43, 95% CI 0.86–2.39, p= 0.17). In patients with a baseline albumin of 25 g/L or higher, the respective response rates were 18 (62%) of 29 versus 38 (67%) of 57 (RR 0.97, 95% CI 0.85–1.10, p=0.59). Patients in the AIS and IIS groups combined had higher odds of being in CRP remission than those in the SIS group between weeks 2 and 6 (odds ratio 5.24; 95% CI 1.01–27.14, p=0.049). There were no differences between the IIS, AIS, and SIS groups for time to clinical response, change in Lichtiger score, colectomy rate, adverse events, clinical remission, endoscopic remission, steroid-free remission, and combined clinical and endoscopic remission. CI, confidence interval; NS, not significant; RR, risk ratio
Adverse Events	At day 7, 11 adverse events occurred in 9 (20%) patients in the 10 mg/kg group, and 22 adverse events occurred in 16 (17%) patients in the 5 mg/kg group. Three serious adverse events occurred in three patients in both the 10 mg/kg group and the 5 mg/kg group. Between day 8 and month 3, nine adverse events occurred in 7 (15%) of 46 patients in the IIS group, 36 adverse events occurred in 20 (42%) of 48 patients in the AIS group, and 17 adverse events occurred in 13 (30%) of 44 patients in the SIS group. Four serious adverse events were reported in 4 (9%) patients in the IIS group, 19 were reported in 10 (21%) patients in the AIS group, and eight were reported in 7 (16%) patients in the SIS group (p=0.27). Clostridioides difficile infection was more frequent in the AIS group (seven patients [15%]) versus the SIS group (one [2%]) or IIS group (none; p=0.0050).
Study Author Conclusions	Infliximab is a safe and effective rescue therapy in ASUC. In steroid-refractory ASUC, a first dose of 10 mg/kg infliximab was not superior to 5 mg/kg infliximab in achieving clinical response by day 7. Intensified, accelerated, and standard induction regimens did not result in a significant difference in clinical response by day 14 or in remission or colectomy rates by month 3.
Critique	The study is robust due to its multicenter, randomized controlled design, providing generalizable results. However, the open-label design and potential selection bias due to missing data not missing at random are limitations. The study's power was reduced by secondary randomizations. The maintenance phase was observational, which may affect the interpretation of long-term outcomes.

References:

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(11):981-996. doi:10.1016/S2468-1253(24)00200-0

Summary of Observational Studies on Infliximab Intensive Dosing Strategy for the Management of Acute Severe Ulcerative Colitis
Citation/Design	Population	Intensive Dosing Strategy	Primary Outcome	Results
Gibson (2015) Retrospective Cohort	Hospitalized patients receiving infliximab (IFX) for steroid-refractory ASUC N= 50 Standard dosing (n= 35) Accelerated dosing (n= 15)	Three induction doses of IFX 5 mg/kg in median 24 days	Colectomy during IFX induction	Significantly decreased rates of early colectomy in the accelerated arm (7% vs. 40%)
Shah (2018) Retrospective Cohort	Hospitalized, IFX-naïve, acute UC patients receiving induction IFX N= 146 Standard dose (n= 120) High dose (n= 26)	10 mg/kg induction dose of IFX	30-day colectomy	No significant difference in 30-day colectomy rates between high dose and standard dose groups in the unmatched cohort (15.4% vs. 17.5%) and matched cohort (9.5% vs. 9.5%)
Chao (2019) Retrospective Cohort	Hospitalized ASUC patients receiving IFX N= 72 Standard dose (n= 37) High dose (n= 35)	10 mg/kg induction dosing of IFX	Three-month colectomy	No significant difference in three-month colectomy rates between high dose and standard dose groups (14.3% vs. 5.4%)
Nalagatla (2019) Retrospective Cohort and Meta-analysis of 7 Retrospective Studies (3 full text, 4 abstract)	Hospitalized patients receiving IFX for steroid-refractory ASUC Retrospective Cohort: N= 213 total (n= 132 standard dosing; n= 81 accelerated dosing) Meta-analysis: N= 617 total (n= 436 standard dosing; n= 181 accelerated dosing)	10 mg/kg induction dosing of IFX or 5 mg/kg dosing at intervals shorter than weeks 0, 2, and 6	Retrospective Cohort: in-hospital colectomy Meta-analysis: in-hospital colectomy or one-month colectomy	No significant difference in in-hospital colectomy between accelerated dosing and standard dosing groups (9% vs. 8%) No significant difference in early colectomy between accelerated dosing and standard dosing in the meta-analysis (odds ratio 0.76, 95% confidence interval [CI] 0.36 to 1.61)
Govani (2020) Retrospective Cohort	Hospitalized ASUC patients receiving IFX N= 66 Standard dose (n= 33) Accelerated dosing dose (n= 33)	Two doses of IFX prior to day 14	90-day colectomy	No significant difference in 90-day colectomy rates between accelerated dosing and standard dosing groups (30.3% vs. 24.2%)
Feuerstein (2020) Meta-analysis of 5 Observational Studies	Hospitalized patients receiving IFX for steroid-refractory ASUC Total subjects not given	Shortened interval between IFX dosing (<2 weeks, dose stacking) or 10 mg/kg induction dosing	Short-term risk of colectomy	No significant difference in short-term risk of colectomy between intensive and standard dosing groups (relative risk 1.61, 95% CI 0.74 to 3.52)

References:

Adapted from:
Gordon BL, Battat R. Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis. J Clin Med. 2023;12(10):3378. Published 2023 May 10. doi:10.3390/jcm12103378

Dose-Intensified Infliximab Rescue Therapy for Severe Ulcerative Colitis Does Not Reduce Short-term Colectomy Rates or Increase Postoperative Complications
Design	Retrospective cohort study N= 145
Objective	To compare the colectomy and postoperative complication rates in hospitalized patients with severe ulcerative colitis receiving standard infliximab induction therapy (3 doses of 5mg/kg at weeks 0, 2, and 6) and dose-intensified regimens including a higher weight-based dosing or more rapid interval
Study Groups	5 mg/kg (n= 24) 10 mg/kg single-dose (n= 57) 10 mg/kg multiple-dose (n= 43)
Inclusion Criteria	Adult patients receiving inpatient infliximab related to an acute exacerbation of ulcerative colitis
Exclusion Criteria	Patients receiving outpatient infliximab before admission to isolate the impact of rescue therapy as opposed to regimen modification on disease course and treatment outcomes
Methods	Patient demographics, disease characteristics, infliximab regimens, colectomy rates, and perioperative outcomes were collected via medical record review. Infliximab regimens were categorized as standard (5 mg/kg at weeks 0, 2, and 6) or dose-escalated (10 mg/kg first dose) which was further divided into single or multiple inpatient doses. Other dosing regimens such as more rapid and slower intervals of dosing were a part of the study but excluded for this table to focus on comparisons between standard and escalated dose.
Duration	Data collection: January 1, 2008 to February 29, 2020
Outcome Measures	Primary: Colectomy rate within 3 months of rescue infliximab therapy Secondary: Perioperative outcomes
Baseline Characteristics		5 mg/kg (n= 24)	10 mg/kg single-dose (n= 57)	10 mg/kg multiple-dose (n= 43)
	Age, years	41	44	36
	Female	42%	40%	56%
	Race Asian Black Latino White Other Unknown	0 0 0 96% 0 4%	5% 12% 4% 74% 2% 4%	2% 5% 0 88% 0 5%
	Hemoglobin, g/dL	11.6	11.4	11.7
	Albumin, g/dL	2.9	3.4	3.1
	C-reactive protein mg/L	31	50	84
	Endoscopic Mayo score 2 3	26% 74%	27% 73%	17% 83%
	Disease duration, years	2.2	0.8	2.5
	Flare duration < 2 weeks 2-4 weeks > 4 weeks Unknown	9% 26% 65% 0	18% 23% 53% 7%	12% 23% 53% 12%
	Duration of oral steroids, > 4 weeks	36%	18%	23%
	Inpatient steroid use	96%	98%	98%
Results	Endpoint	5 mg/kg (n= 24)	10 mg/kg single-dose (n= 57)	10 mg/kg multiple-dose (n= 43)	p-Value
	90-day colectomy Days to colectomy (interquartile range [IQR])	3 (21%) 24 (14 to 50)	9 (16%) 21 (8 to 28)	10 (24%) 10 (8 to 14)	0.37
	Initial operation Total abdominal colectomy Total proctolectomy Ileo-anal pouch formation	2 (67%) 1 (33%) 0	7 (78%) 1 (11%) 1 (11%)	9 (90%) 1 (10%) 0	0.62
	Postoperative length of stay, days (IQR)	5 (4 to 11)	14 (6 to 23)	3.5 (3 to 6)	04
	Postoperative complication Minor Major Infectious	2 (67%) 0 1 (33%)	7 (78%) 2 (22%) 6 (66%)	1 (10%) 1 (10%) 1 (10%)	0.01 0.56 0.04
	30-day readmission	0	4 (44%)	1 (11%)	0.11
Adverse Events	N/A
Study Author Conclusions	No significant difference was found in colectomy rates between patients receiving standard or dose-intensified regimens. However, dose-intensified regimens, including multiple inpatient doses given to patients with more severe disease, were not associated with a greater risk of perioperative complications.
InpharmD Researcher Critique	The sample size was too small to definitively detect differences between standard and intensified infliximab dosing for acute severe ulcerative colitis. As an observational study, treatment assignments may have been affected by confounding factors.

References:

Kosaraju RS, Wong DJ, Roth EM, et al. Dose-Intensified Infliximab Rescue Therapy for Severe Ulcerative Colitis Does Not Reduce Short-term Colectomy Rates or Increase Postoperative Complications. Dis Colon Rectum. 2022;65(10):1232-1240. doi:10.1097/DCR.0000000000002176

Infliximab as rescue therapy in hospitalised patients with steroid-refractory acute ulcerative colitis: a long-term follow-up of 211 Swedish patients
Design	Multicenter, retrospective, observational study N= 211
Objective	To assess the long-term efficacy of infliximab (IFX) as rescue therapy in the treatment of ulcerative colitis (UC)
Study Groups	Study population (N= 211)
Inclusion Criteria	Age >17 years; hospitalization due to a moderate-to-severe attack of left-sided or extensive UC; disease course during hospital stay not responding to at least 3 days treatment with intravenous (IV) corticosteroids and IV rescue therapy given with IFX
Exclusion Criteria	Patients with chronic, steroid-dependent UC; earlier treatment with cyclosporin or IFX; concomitant enteric infection; ulcerative proctitis; Crohn's disease; inflammatory bowel disease unclassified
Methods	Patients hospitalized from September 1999 to February 2010 and treated with IFX 5 mg/kg for UC were identified through hospital discharge records. Diagnosis of UC was determined based on clinical, endoscopic, and histopathological criteria, with disease severity classified as moderate or severe using modified Truelove-Witts' criteria. Following hospitalization, all patients received at least three days of IV corticosteroid treatment. A steroid-refractory course and the need for rescue therapy were determined based on the 'fulminant colitis index' or the 'Seo index,' as well as clinical criteria. Rescue therapy consisted of one to three IFX 5 mg/kg infusions administered at weeks 0, 2, and 6, as determined by each physician. The number of IFX infusions was not predetermined and fluctuated over time. During the first part of the study period, a single infusion was typically administered. Later on, the three-dose regimen was gradually adopted. Subsequent maintenance treatment was defined as the administration of aminosalicylates, immunomodulators, or anti-TNFs for ≥3 months. Steroid-free clinical remission was characterized by the absence of rectal bleeding and ≤3 daily bowel movements without the need for corticosteroid therapy. Throughout the follow-up period, adverse events, incidences of malignancy, and deaths were recorded.
Duration	Between September 1999 and February 2010
Outcome Measures	Primary: Colectomy-free survival at 3 and 12 months after rescue treatment Secondary: Assessment of colectomy-free survival in relation to the number of IFX infusions as rescue therapy and subsequent maintenance therapy
Baseline Characteristics		Study population (N= 211)
	Age, years (IQR)*	35 (26-45)
	Female	83 (39.3%)
	Duration since diagnosis, years (IQR)	2 (0-7)
	Extent of UC Left-sided Extensive	26 (12%) 185 (88%)
	Type of UC First attack Relapse	74 (35%) 137 (65%)
	Severity of UC at hospitalization Moderate Severe	47 (22%) 164 (78%)
	Duration of UC flare, weeks (IQR)	4 (2-8)
	Duration of steroid treatment, weeks (IQR)	1 (0-3)
	Maintenance treatment prior to admission None 5-ASA Immunomodulators	107 (51%) 85 (40%) 19 (9%)
	Hemoglobin, g/L (IQR)	117 (101-129)
	CRP, mg/L (IQR)	75 (29-130)
	Albumin, g/L (IQR)	27 (23-30)
	Abbreviations: 5-ASA= 5-aminosalicylic acid; IQR= interquartile range; UC= ulcerative colitis * Age at rescue therapy
Results	Endpoint	Study population	HR (95% CI)	p-value
	The number of IFX infusions given 1 2 3	124/211 (58.8%) 21/211 (10%) 66/211 (31.3%)	-	-
	Short-term outcome 0-3 months^a Colectomy-free survival at 3 months Steroid-free clinical remission Active disease	149/211 (71%) 105/211 (50%) 44/211 (21%)	0.71 (0.64 to 0.77)*	-
	Long-term outcome 3-12 months^b Colectomy-free survival at 12 months Steroid-free clinical remission Active disease	133/209 (64%) 112/209 (54%) 21/209 (10%)	0.64 (0.57 to 0.70)**	-
	Colectomy at 3 months^c Induction with 2-3 infusions Induction with 1 infusion	7/86 6/77	1.03 (0.34 to 3.05)	0.96
	Abbreviations: CI= confidence interval; HR= hazard ratio * Probability of colectomy-free survival at 3 months ** Probability of colectomy-free survival after 12 months ^aOne patient died due to infection without having surgery. ^bTwo patients were lost to follow-up. ^cFindings are in relation to the number of IFX infusions as rescue therapy (n= 163); 48 patients had a colectomy during the first 14 days and did not receive a second dose of IFX in week 2. At 12 months, the frequency of colectomy was compared among patients (n= 149) who avoided colectomy at 3 months. Five patients (3%) didn't receive maintenance therapy due to side effects. Twenty-six (18%) were on aminosalicylates, 81 (54%) on immunomodulators, and 37 (25%) on anti-TNF therapy (36 on IFX, 1 on adalimumab), with 21 of them having combination therapy with thiopurines.
Adverse Events	Common Adverse Events: N/A
	Serious Adverse Events: Pneumonia (4/211), septicemia (2/211), cytomegalovirus infection (1/211), gluteal abscess (1/211) and thyroid cancer (1/211)
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	Infliximab is an effective rescue treatment, both short- and long-term, in a steroid-refractory attack of UC. Most IFX failures underwent surgery during the first 14 days, which calls for studies on how to optimise induction treatment with IFX. Serious complications, including mortality, were rare.
InpharmD Researcher Critique	While this study provides insights into the effectiveness of infliximab as a rescue treatment for steroid-refractory UC attacks, limitations such as the retrospective design, the absence of uniform criteria for defining steroid-refractory disease, as well as the variability in induction and maintenance therapies underscore the need for further research to validate these findings.

References:

Sjöberg M, Magnuson A, Björk J, et al. Infliximab as rescue therapy in hospitalised patients with steroid-refractory acute ulcerative colitis: a long-term follow-up of 211 Swedish patients. Aliment Pharmacol Ther. 2013;38(4):377-387. doi:10.1111/apt.12387

Factors predicting failure of rescue therapy in acute severe ulcerative colitis
	Timepoint	Drug	Study type
Clinical Age ≥ 50 years Fever and tachycardia	-- At day of initiation	Cyclosporine; infliximab Cyclosporine	Randomized controlled trial Retrospective
Biochemical or laboratory CRP ≥ 30 mg/L Albumin ≤ 25 mg/L CRP > 45 mg/L increased CRP to albumin ratio increased CRP to albumin ratio	At admission to hospital At day of initiation At day of initiation At day of initiation Day 3 after first infliximab infusion	Infliximab Infliximab Cyclosporine Infliximab Infliximab	Retrospective Retrospective Retrospective Retrospective Retrospective
Endoscopic Severe endoscopic lesions	At admission to hospital	Cyclosporine	Retrospective

References:

Adapted from:
Rivière 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(3):251-262. doi:10.1016/S2468-1253(23)00313-8