Top-down treatment with infliximab plus an immunomodulator substantially improves outcomes for patients with newly diagnosed Crohn’s disease compared with accelerated step-up therapy, UK research finds.
Previous trials had supported earlier use of anti-tumour necrosis factor therapy, usually in combination with an immunomodulator, researchers wrote in The Lancet Gastroenterology and Hepatology.
However, the most common strategy in the UK and globally was an accelerated step-up approach, where treatment is escalated until the tendency to relapse is controlled, they said.
The multi-centre PROFILE trial enrolled 386 patients aged 16-80 years with newly diagnosed, active Crohn’s disease, who had raised C-reactive protein, calprotectin of 200 μg/g or more, plus active inflammation on ileo-colonoscopy.
Patients were stratified based on a blood-based biomarker previously found to correlate with the need for future treatment escalation and then randomised to either top-down therapy or the accelerated step-up approach.
Over 48 weeks off follow-up, the biomarker did not show any clinical utility.
However, 79% of patients achieved sustained steroid-free and surgery-free remission in the top-down group, compared with 15% in the conventional therapy group, a 64-percentage point difference, they reported.
‘Top-down treatment also showed greater efficacy in achieving endoscopic remission, improved quality of life, and reduced number of flares requiring treatment escalation,’ they wrote.
It was also safer than conventional therapy for Crohn’s disease, with fewer adverse and serious adverse events and no increased rate of infection.
A reduced need for urgent abdominal surgery was also found, with one person in the top-down group requiring surgery for complications, compared with 10 people in the step-up group, they added.
‘These findings are potentially transformative for the management of Crohn’s disease,’ the study authors concluded.
‘While PROFILE did not identify a clinically useful biomarker, it has provided clear evidence with regards to optimal treatment strategy from diagnosis.’
First author Dr Nuru Noor, of the Department of Medicine at the University of Cambridge, said the study findings redefined what should be considered as early treatment for Crohn’s disease.
‘Historically, treatment with an advanced therapy like infliximab within two years of diagnosis has been considered ‘early’ and an ‘accelerated step-up’ approach therefore “good enough”,’ he said.
‘As soon as a patient is diagnosed with Crohn’s disease, the clock is ticking – and has likely been ticking for some time – in terms of damage happening to the bowel, so there’s a need to start on an advanced therapy such as infliximab as soon as possible.’
Chief investigator Professor Miles Parkes, who is director of the NIHR Cambridge Biomedical Research Centre, said the study showed clinicians could prevent most adverse outcomes for Crohn’s disease, including need for urgent surgery, with a treatment strategy that was safe and becoming increasingly affordable.
‘If you take a holistic view of safety, including the need for hospitalisations and urgent surgery, then the safest thing from a patient point of view is to offer “top-down” therapy straight after diagnosis rather than having to wait and use “step-up” treatment,’ he said.
In February 2023, the Medicines and Healthcare products Regulatory Agency approved upadacitinib for use in patients with moderate to severely active Crohn’s disease who have had either an inadequate response, or were intolerant to, conventional therapy or a biological agent.
