If the fable of the tortoise and the hare has taught us anything, it’s that going faster does not always mean a better outcome.
Less (infliximab) is (equal to) more (with respect to acute severe ulcerative colitis outcomes).
Corticosteroids are the recommended treatment for acute severe ulcerative colitis, a potentially life-threatening complication that affects up to one in four patients with the condition. Non-randomised studies suggesting infliximab is effective at reducing colectomy risk after 12 months of treatment, but the optimal dosing infliximab dosing strategy in these patients is unknown.
Now, a new Australian study, published in The Lancet Gastroenterology & Hepatology, reports an initial dose of 10mg/kg is no better in achieving a clinical response by day 7 than a 5mg/kg dose.
“Approximately 30% of patients fail first line therapy with corticosteroids and 20% fail second line rescue therapy with either infliximab or cyclosporin resulting in the need for emergency colectomy,” said Associate Professor Peter De Cruz, senior author and director of the inflammatory bowel disease service at the Austin Hospital in Melbourne.
“Although higher dose or more frequent dose infliximab regimens have entered clinical practice, until now there has been no evidence to indicate whether such practice makes a difference to outcomes.”
As part of the open-label randomised controlled trial, researchers recruited 138 patients with corticosteroid-refractory acute severe ulcerative colitis from 13 tertiary hospitals across the country.
The patients, who were diagnosed with acute severe ulcerative colitis according to Truelove and Witts’ criteria, were initially randomised to receive either a standard initial rescue dose (5mg/kg) or an intensified initial dose (10mg/kg) in a 2:1 fashion.
There was no difference in the proportion of patients who achieved a clinical response by day seven (a reduction in Lichtiger score to under 10 as well as a decrease of at least three points from baseline, improvements in rectal bleeding and a reduction in stool frequency) between the 5mg/kg (61%) and 10mg/kg (65%) doses.
No differences were observed between doses in other clinical outcomes, such as rates of colectomy, time to clinical response or change in Lichtiger score. There were also no differences in the proportion of patients experiencing adverse events (17% in the 5mg/kg group, 20% in the 10mg/kg group).
After the first week of treatment, patients who initially received 5mg/kg were again randomised based on whether they displayed a clinical response to the infliximab treatment after one week.
Patients who responded to the 5mg/kg treatment received two additional doses at this concentration over the next six weeks (called a standard induction strategy; SIS), while patients who did not respond to the smaller dose were put on an accelerated induction strategy (AIS) approach and received salvages dose of the 10mg/kg treatment on two occasions in the following three weeks.
All patients who initially received the 10mg/kg dose received a second dose at this concentration a week after the initial dose, regardless of whether they improved after the first week (an intensified induction strategy [ISS]).
The proportion of patients achieving a clinical response at the three-month mark did not differ between the three treatment groups – 74% in the IIS group, 73% in the AIS group, and 68% in the SIS group – nor were there differences in any of the secondary outcomes.
Professor De Cruz told Gut Republic he was initially surprised to see there were no significant differences between the dosing approaches in both the short- and long-term but felt there were still learnings to take from the current study.
“We observed that the 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 that there is a window of opportunity for us to consolidate outcomes by giving more infliximab prior to month three,” he said.
The researchers also felt the lack of difference between the dosing regimens could be explained by infliximab’s effectiveness in treating ulcerative colitis.
“We theorise that the absence of difference in our primary outcome is due to infliximab being a highly potent therapy in acute severe ulcerative colitis, and thus identifying small potential differences in efficacy among subgroups with greater disease severity might require an unfeasibly large sample size,” they wrote.
Serious adverse events (e.g., pulmonary embolism, gastrointestinal haemorrhage or certain kinds of infection) were most common in patients in the AIS group (21%) compared to the SIS (16%) and IIS (9%) groups, but this difference was not statistically significant.
The authors of an accompanying commentary felt whether or not the current findings meant the era of intensified or accelerated infliximab treatment approaches depended on whether the increased dosages resulted in increased drug concentrations in the body.
“[Infliximab’s] effectiveness is strongly influenced by its pharmacokinetics. Theoretically, three mechanisms can lead to reduced infliximab concentrations and lower response rates: high concentrations of circulating and tissue TNF, mononuclear cells causing proteolysis of infliximab-TNF complexes and a leaky gut causing faecal infliximab drug loss,” they wrote.
“[Therefore], the altered pharmacokinetics of infliximab might lead to subtherapeutic drug concentrations despite increased drug dosing… [but] pharmacokinetics cannot be the sole explanation for inadequate outcomes.”
