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Early and aggressive immunosuppressive therapy with tumor necrosis factor (TNF) inhibitors significantly outperformed conventional therapy for patients with newly diagnosed Crohn's disease and should become the standard for most patients, said clinical trial researchers.

Among the 386 patients randomized in the so-called PROFILE trial, sustained steroid- and surgery-free remission at 48 weeks was significantly more common in the group assigned to "top down" therapy (immunosuppression with anti-TNF plus an immunomodulator), as compared with those assigned to an accelerated "step-up" approach with conventional treatment and steroids (79% vs 15%, P<0.0001).

There were fewer adverse events, including disease flares, in the top-down group (168 vs 315), as well as fewer serious adverse events (15 vs 42) and fewer complications requiring surgery (one vs 10). There was no significant difference in serious infections (three vs eight), reported researchers led by Nurulamin Noor, PhD, of the Cambridge University Hospitals NHS Foundation Trust in England, in .

"PROFILE provides definitive evidence for the benefit of top-down over accelerated step-up treatment, at least for patients meeting the trial inclusion criteria of active symptoms, raised [C-reactive protein] or calprotectin of 200 μg/g or more, plus active inflammation on ileo-colonoscopy," Noor's team wrote.

"Given that this definition encompasses the majority of patients newly presenting with Crohn's disease," they continued, "the case appears clear-cut for implementation of top-down treatment as the standard of care for most patients as soon as possible after diagnosis."

The rate of endoscopic remission at 48 weeks was also significantly higher in the top-down versus step-up groups (67% vs 44%, P<0.0001), the study found. Endoscopic remission correlates with better long-term outcomes, including reduced need for surgery, the researchers noted. Abdominal surgery was necessary in one patient in the top-down group, for gallstone ileus.

In the step-up group, however, nine patients required intestinal resection for stricturing or fistulating complications. "This further underlines the importance of initiating highly effective treatment to control inflammation as soon as possible after diagnosis," the study authors said.

Jordan Axelrad, MD, a spokesperson for the agreed with the researchers' conclusions.

"Early, effective, 'top down' intervention in Crohn's disease with advanced therapies, specifically, biologic agents as optimized monotherapies or in combination with immunomodulators, has demonstrated in multiple studies to lead to better long-term outcomes, including reduced rates of complications such as strictures, fistulas, and surgeries, as well as improved quality of life," said Axelrad, of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City, who was not involved in the study.

Furthermore, Axelrad said, "step-up" use of conventional therapies may pose significant risks to patients with Crohn's disease, particularly high-risk patients with a more severe disease prognosis. "Patients managed under this approach are likely to experience complications of Crohn's disease as the impetus to eventually advance therapy lines to more effective agents, rather than starting with early effective therapies to avoid disease progression," he explained.

PROFILE was an open-label, multicenter, randomized trial conducted from 2017 to 2022. Participants were adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or fecal calprotectin or both, and endoscopic evidence of active inflammation). The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers.

The trial also evaluated a potential biomarker, which had been developed to predict a CD8 T-cell transcriptional signature previously correlated with need for treatment escalation in inflammatory bowel disease. Participants had blood drawn to test for this biomarker, and outcomes were stratified by biomarker subgroups, but no biomarker-treatment interaction was found.

"Failure to demonstrate clinical utility underlines why randomized trials are critical to test potential biomarkers and why they should be a mandatory step before clinical implementation," Noor and colleagues said.

A chief limitation of the study was its open-label design, the researchers noted. The willingness to diagnose a disease flare could have been biased according to treatment group. In addition, approximately one-third of patients had their end-of-trial ileo-colonoscopy scored by unblinded local investigators, which could have led to confirmation bias.

"Finally, although the high rates of endoscopic remission seen with top-down treatment suggest that the benefits of this strategy in reducing the need for surgery should be durable and potentially cost-effective well beyond 1 year, the relevant long-term follow-up data and health economic analyses are not yet available," Noor and colleagues noted.

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