Is Accelerated Infliximab Induction Beneficial for Severe Ulcerative Colitis?

Standard induction therapy with infliximab has only modest efficacy for acute severe ulcerative colitis (UC). In 2015, Dutch researchers reported that infliximab nonresponders have greater fecal losses of the drug than responders do, which kindled interest in accelerated induction protocols that might optimize infliximab levels in serum and tissue.

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One approach to acceleration is to give infliximab at shorter intervals than the standard 5 mg/kg at weeks zero, two and six. The other is to give higher doses.

Based on both a retrospective study and a meta-analysis, Ashwin N. Ananthakrishnan, MD, MPH, a gastroenterologist at Massachusetts General Hospital, and colleagues found no association between accelerated infliximab induction and lower rates of colectomy, compared with standard induction therapy. Nevertheless, they believe prospective studies of accelerated protocols are warranted. Their findings are published in Clinical Gastroenterology and Hepatology.

A Multicenter Retrospective Cohort

The study cohort included 213 patients who were hospitalized with steroid-refractory acute severe UC and received infliximab rescue therapy at one of three centers between 2005 and 2017. The average patient age was 31 and 60% were men.

The researchers divided the patients into two groups according to infliximab administration schedule: standard (n=132) or accelerated (upfront dosing at 10 mg/kg or infusions at shorter intervals than standard, n=81). At two centers, the choice of schedule was based on symptoms or endoscopic severity; at the other, it was based on the ratio of C-reactive protein (CRP) to albumin.

Effect of Schedule on Risk of Colectomy

The proportion of patients who required in-hospital colectomy was similar in the accelerated (9%) and standard groups (8%). Neither were there any between-group differences in the longer-term risk of colectomy (at three, six, 12 and 24 months).

Multivariable analysis confirmed the lack of difference between accelerated and standard infliximab induction with respect to in-hospital and longer-term colectomy rates. Low-serum albumin was the only variable that was consistently an independent predictor of colectomy and it remained significant until almost two years after hospitalization.

Analysis of the Accelerated Group Detects Some Benefit

In a preplanned subgroup analysis, Dr. Ananthakrishnan and his colleagues divided the accelerated group into two subgroups: those who received an upfront 10 mg/kg infusion as their first dose and those who received a "chaser" regimen: an initial dose of 5 mg/kg followed by 5 or 10 mg/kg before week two.

On multivariable analysis, compared with patients who received chaser doses, those who had infliximab 10 mg/kg upfront had a numerically lower risk of colectomy while hospitalized and at three months. The colectomy rate was significantly lower at 12 months and 24 months in the upfront 10 mg/kg groups.

Systematic Review and Meta-Analysis

In a systematic review, the researchers identified seven eligible studies (three full-text papers, four meeting abstracts) of infliximab induction therapy for patients with acute severe UC (accelerated, n=181; standard schedule, n=436). There was no significant difference between groups at three months, 12 months or two years.

Potential Explanations

The authors advance four potential explanations for the lack of benefit of accelerated infliximab in their study:

• Confounding by disease severity cannot be excluded since the practice at each center was to accelerate induction for patients believed to have more severe disease
• There might truly be no benefit of an accelerated regimen; the apparent need for it may be a marker of severe disease that would require colectomy regardless of the type of medical intervention
• Because patients who received 10 mg/kg upfront had lower rates of colectomy than those who received chaser doses, an early, aggressive approach may be necessary, perhaps even with doses higher than 10 mg/kg in some cases
• Specific subgroups of patients, such as those identified using CRP/albumin ratio or absolute CRP values, may be most likely to benefit from accelerated infliximab induction

Randomized trials are warranted, the authors conclude, to compare rescue treatment strategies for patients with acute severe UC.

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