Initial dose of infliximab 5 mg/kg ‘should be adequate’ in most cases of acute severe UC
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Key takeaways:
- There was no difference in clinical response at day 7 in infliximab 10 mg/kg vs. 5 mg/kg rescue dosing.
- Intensified, accelerated and standard dosing achieved similar remission and colectomy rates at month 3.
No significant differences were reported in clinical response at day 7 between 5 mg/kg and 10 kg/kg doses of infliximab in acute severe ulcerative colitis, nor were there differences in intensified, accelerated or standard dosing at month 3.
“We undertook PREDICT UC to better understand the optimal dosing approach for infliximab in acute severe ulcerative colitis, because [it] is a life-threatening medical emergency that occurs in up to 25% of patients with UC and is associated with a mortality of up to 1%,” Peter De Cruz, PhD, study author and director of the inflammatory bowel disease service at Austin Health in Melbourne, Australia, told Healio. “We know that approximately 30% of patients fail first-line therapy with corticosteroids and approximately 20% fail second-line rescue therapy with either infliximab or cyclosporine, resulting in the need for emergency colectomy.”
He continued: “Even though, in clinical practice, higher-dose or more frequent-dose infliximab regimens are often used, until now there has been no evidence to indicate whether such practice makes any difference to outcomes.”
Intensified vs. accelerated vs. standard dosing
In an open-label, multicenter trial, De Cruz and colleagues compared intensified infliximab dosing vs. standard dosing in 138 patients (54% men) with corticosteroid-refractory, acute severe UC between July 2016 and September 2021.
Patients were randomly assigned to an initial rescue dose of infliximab 10 mg/kg (n = 46) or 5 mg/kg (n = 92), with evaluation for response at day 7. Patients in the 10 mg/kg group, designated the intensified induction strategy (IIS) group, received a second infliximab dose at day 7 or earlier, depending on the time of nonresponse.
Between days 3 and 7, patients in the 5 mg/kg group were randomly assigned again to a standard induction strategy (SIS) or accelerated induction strategy (AIS). The SIS group (n = 44) received infliximab 5 mg/kg at weeks 0, 2 and 6 with an extra 5 mg/kg dose between days 3 and 7 if not responsive, while the AIS group (n = 48) received infliximab 5 mg/kg at weeks 0, 1, and 3, with the dose increasing to 10 mg/kg for non-responders between days 3 and 7.
The primary outcome was clinical response by day 7, defined as a reduction in Lichtiger score to less than 10 with a decrease of at least 3 points from baseline, improvement in rectal bleeding and reduced stool frequency ( 4 per day). After the second randomization, exploratory outcomes included clinical response at day 14 and colectomy-free survival at day 30 and 3 months.
No ‘significant difference’ in clinical response
According to results published in The Lancet Gastroenterology & Hepatology, there was no significant difference in the proportion of patients in the 10 mg/kg and 5 mg/kg groups who achieved the primary outcome by day 7 (65% vs. 61%; RR = 1.06; 95% CI, 0.94-1.2, adjusted for thiopurine history). There also were no significant differences between groups in time to response or change in Lichtiger score.
In addition, from baseline to day 7, 4% of patients in the 10 mg/kg group and 0% in the 5 mg/kg group underwent colectomy. Three serious adverse events were reported in three patients in each group.
After the second randomization, 74% of patients in the IIS group, 73% in AIS and 68% in SIS achieved clinical response at day 14, with no significant differences in clinical remission (50% vs. 52% vs. 48%), steroid-free remission (41% vs. 42% vs. 41) or endoscopic remission (46% vs. 46% vs. 48%) at month 3. The researchers also reported no significant differences in patients undergoing colectomy at month 3 (7% vs. 19% vs. 12%).
“We did not find any significant difference between the intensified, accelerated and standard dosing infliximab regimens in PREDICT UC,” De Cruz told Healio. “We hypothesize that the lack of significant difference may relate to infliximab overall being a highly potent induction agent, irrespective of the dose given.”
He added, “Intensified and accelerated arms achieved remission earlier than the standard arm but lost this advantage at month 3, most likely because the gap between the last infliximab induction dose to 3 months was too large. This suggests to us that there may be a window of opportunity for us to consolidate outcomes by giving more infliximab prior to month 3.”
Additional results showed infectious adverse events potentially linked to treatment occurred among 4%, 17% and 18% of patients between day 8 and month 3, with no reports of death.
“Based on the lack of difference in the primary outcome of clinical response at day 7 between a first dose of 5 mg/kg and 10 mg/kg, an initial dose of 5 mg/kg should be adequate for most patients,” De Cruz told Healio. “However, in sicker patients — those with albumin less than 25 or CRP of at least 50 — a 10 mg/kg dose is likely to be beneficial.”
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