De-escalating dose intensified anti-TNF therapy is possible in about two thirds of IBD patients, a small Australian study has shown. De-escalation was shown to be feasible and safe in patients who had achieved deep remission, and who underwent tight monitoring, according to Victorian researchers.
The findings, which showed patients were able to maintain reduced dosing 12 months after de-escalation without safety concerns, have bolstered cautious confidence in the strategy, which so far has been hampered by fears that de-escalation, even in the setting of deep remission, could trigger flares and loss of treatment response. And reassuringly patients who had recurrent inflammation and required re-intensification of doses responded successfully.
Gastroenterologists from the Alfred Hospital in Melbourne trialed de-escalation in 25 patients – 20 with Crohn’s disease and five with ulcerative colitis – in deep remission following dose-intensified infliximab (5 mg/kg 6 weekly) or adalimumab (40 mg weekly) for 7–27 months for secondary loss of response.
At 12 months 64% (16/25) were successfully maintained on the de-escalated dose.
At a median of 6 months, 36% (9/25) of patients experienced a disease flare requiring either re-escalation of anti-TNF therapy (6 patients) or enrolment into a clinical trial (3 patients). But remission was recaptured in all patients who required dose re-intensification, note investigators.
Though small, the study is one of only a handful demonstrating success of anti-TNF therapy de-escalation following dose intensification, said Dr Robert Bryant, Head of Inflammatory Bowel Disease at The Queen Elizabeth Hospital writing in a linked editorial.
Speaking to the limbic, gastroenterologist Associate Professor Miles Sparrow, director of the IBD Unit at The Alfred Hospital and lead investigator said patients had been in deep remission for at least six months prior to de-escalation being attempted.
“We feel at our clinic patients should be in deep remission – they have no symptoms and their tests of inflammation are normal – before de-escalation. The next question is how long should they be in deep remission before you de-escalate? The principle is the longer the better. In this study patients had been in deep remission for six months. It was in those patients that we said let’s try and de-escalate you and get you back to normal doses.”
While some patients did relapse, Professor Sparrow said re-escalation recaptured response, a finding that has allayed some concern that relapse with de-escalation could signal loss of response to escalated therapy.
“That’s a legitimate fear with biologic therapy – that patients can develop antibodies against a drug that neutralises it and stops it from working again but it’s been shown that only happens in a minority of patients where previously it was thought it happened in the majority of cases.”
Close monitoring essential
Writing in their editorial, Dr Bryant and colleagues said intensive monitoring within the 12 months post-withdrawal is imperative given that risk of relapse is the highest within the first year.
But monitoring for clinical symptoms alone is not enough, they warned, particularly since subclinical disease recurrence may occur as a ‘harbinger of a clinical flare’.
They added that the close monitoring and early detection of recurrent inflammation and appropriate action in the current study led to ‘100% success’ with dose re-intensification.
Meanwhile de-escalation in patients who have undergone multiple prior surgeries should be viewed with caution, given the risk of short bowel syndrome if further surgery is required due to relapse, they said.
Stressing that while the study is small and findings will need to be replicated in larger, ideally prospective trials, Professor Sparrow said clinicians should consider de-escalation in patients who have required escalating therapies rather than ‘setting and forgetting’.
“There is a mentality that when patients need escalation they need to stay on therapy indefinitely. We wanted to see if that was actually necessary or whether it was possible, once you get patients into remission, to de-escalate them back to usual therapy.”
The benefits of such a strategy are patient safety – keeping patients well on the lowest doses of medication – as well as cost, he points out.
“These are expensive drugs and a significant proportion of patients require escalated doses of biologic therapy above what is reimbursed by the PBS,” he said noting that this additional compassionate therapy is usually provided by industry. “We don’t want to be asking industry for unnecessary drugs – the available compassionate therapy should go to patients who need it. The worst case scenario is that patients don’t need this extra drug and yet they’re still getting it while other patients who might benefit from it aren’t getting it as a result.”
The study is published in Digestive Disease and Sciences.