In a significant stride towards refining the management of Crohn’s disease, recent UK research has underscored the efficacy of adopting a top-down treatment strategy over the conventional accelerated step-up approach. Published in The Lancet Gastroenterology and Hepatology, the multi-centre PROFILE trial has delineated compelling evidence favoring the early initiation of infliximab, coupled with an immunomodulator, for patients newly diagnosed with Crohn’s disease.

Historically, the prevailing treatment paradigm for Crohn’s disease, both in the UK and globally, leaned towards an accelerated step-up approach, characterized by escalating treatment until disease relapse is effectively controlled. However, insights gleaned from previous trials advocating for the early integration of anti-tumour necrosis factor therapy had not fully permeated clinical practice.

The PROFILE trial enrolled 386 patients aged 16-80 with newly diagnosed, active Crohn’s disease, marked by raised C-reactive protein, calprotectin levels of 200 μg/g or higher, and evident inflammation on ileo-colonoscopy. Stratified based on a blood-based biomarker purportedly predictive of future treatment escalation, participants were randomized to receive either top-down therapy or the conventional step-up regimen.

Over a 48-week follow-up period, although the biomarker failed to demonstrate clinical utility, the efficacy outcomes between the two groups were starkly disparate. A remarkable 79% of patients subjected to the top-down approach attained sustained steroid-free and surgery-free remission, in stark contrast to a mere 15% in the conventional therapy cohort, delineating a substantial 64-percentage point difference. Furthermore, top-down therapy exhibited superior efficacy in achieving endoscopic remission, bolstering quality of life, and mitigating the frequency of flares necessitating treatment escalation.

Remarkably, the safety profile of top-down therapy surpassed that of conventional treatment modalities, manifesting in fewer adverse events and serious complications, alongside no discernible escalation in infection rates. Notably, the incidence of urgent abdominal surgery was markedly reduced in the top-down cohort, with only one individual necessitating surgical intervention compared to ten in the step-up group.

Dr. Nuru Noor, the lead author of the study, emphasized the paradigm shift engendered by these findings, redefining the conceptualization of early intervention in Crohn’s disease. He articulated the imperative of promptly initiating advanced therapies such as infliximab upon diagnosis to forestall disease progression and mitigate bowel damage.

Echoing these sentiments, Professor Miles Parkes, the chief investigator of the study, underscored the holistic safety profile of top-down therapy, contending that it obviates the need for hospitalizations and urgent surgical interventions, thereby offering patients a more favorable clinical trajectory.

The regulatory approval of upadacitinib in February 2023 further augments the therapeutic armamentarium available for patients with moderate to severely active Crohn’s disease, enriching the treatment landscape with additional options for those with inadequate responses to conventional therapy or biological agents.

In essence, the findings of the PROFILE trial herald a transformative milestone in the management of Crohn’s disease, advocating for the early adoption of top-down therapy as the cornerstone of therapeutic intervention. With its demonstrable efficacy, favorable safety profile, and potential to avert adverse outcomes, this approach epitomizes a paradigmatic shift towards optimizing patient outcomes and mitigating disease burden.