STOCKHOLM — Early use of combination biologic therapy, from the point of diagnosis, may fundamentally alter the long-term course of Crohn’s disease (CD), reducing surgery, hospitalization, and disease progression for years after treatment decisions are made, according to new 5-year follow-up data from the PROFILE randomized trial.

These findings provide some of the strongest long-term evidence to date that a “top-down” treatment strategy, in which anti-TNF therapy plus an immunomodulator are given immediately after diagnosis, can achieve true disease modification rather than simply short-term symptom control.

“This study shows that the course of Crohn’s disease can be modified with early effective therapy, and that effective control of inflammation should be considered the standard of care,” said Nurulamin Noor, MD, University of Cambridge, Cambridge, England, who presented the results here at the European Crohn’s and Colitis Organisation Congress (ECCO) 2026.

Trial Design and Long-Term Follow-Up

PROFILE was a multicenter, randomized controlled trial enrolling adults with newly diagnosed, moderate to severe CD. Patients were recruited at a median of just 2 weeks after diagnosis and randomly assigned to either top-down therapy, which consisted of infliximab combined with an immunomodulator from diagnosis, or “step-up” therapy, which involved conventional escalation of treatment with biologics introduced later if required. 

The primary outcome of the current follow-up study was abdominal surgeries, and the secondary outcomes were time to first surgery, disease progression to stricturing (B2) or penetrating (B3) disease, disease-related hospitalization, and safety outcomes, including serious infections.

Participants in both arms followed respective protocols for 48 weeks, after which patients returned to standard care but were followed for up to 5 years to assess long-term outcomes. Of the original 386 participants, 357 (92%) had long-term follow-up data available, with a median follow-up of approximately 5 years from diagnosis.

Fewer Surgeries, Less Disease Progression

The most striking difference between the two treatment strategies was the need for CD-related abdominal surgery. Over the full follow-up period, patients originally assigned to step-up therapy were over four times more likely to have CD-related abdominal surgeries (risk ratio [RR], 4.33; 95% CI, 1.82-10.29). There were 28 surgeries among 25 patients in the step-up group and six surgeries among six patients in the top-down group. 

The divergence between the two groups emerged within the first year and “continued to diverge throughout the 5-year follow-up widening over time,” said Noor, despite both groups receiving standard care after the trial period ended.

Disease progression to B2 or B3 CD also showed superior results in participants in the top-down group compared with the step-up group, with an RR for B2/B3 in the step-up vs top-down group of 2.50 (95% CI, 1.33-4.54).

Regarding time to disease progression, Noor said that “the data looks similar to the abdominal surgery findings, with separation between the two groups at 1 year, and the lines continue to diverge throughout the 5-year follow-up.”

He added that hospital admissions due to CD were 1.6 times higher in the step-up group than the top-down group (RR, 1.64; 95% CI, 1.13-2.40).

Biomarker data offered insight into why early intervention modified the disease course, said Noor.

Patients receiving top-down therapy achieved earlier and sustained normalization of inflammatory markers, including C-reactive protein and fecal calprotectin. In contrast, patients in the step-up arm showed slower improvement and a persistently higher inflammatory burden over time, even though many ultimately received biologic therapy, he noted.

By the end of the 5-year follow-up, 78% of step-up patients had received advanced therapies compared with 100% of the top-down group, and 41% of step-up patients received anti-TNF therapy compared with 100% of the top-down group.

Is Accelerated Step-Up ‘Good Enough’?

A key question addressed by the investigators was whether faster escalation in step-up patients, including initiating anti-TNF therapy within the first year, could achieve outcomes comparable to top-down treatment.

The results suggest that this is not the case, said Noor. “Even among patients who received biologics within the first year as part of an accelerated step-up approach, outcomes did not match those seen with immediate combination therapy from diagnosis.”

“We also looked at patients starting anti-TNF within 6 months, and those outcomes were still inferior,” he added.

Noor noted that concerns about overtreatment and long-term safety have historically limited enthusiasm for top-down strategies. However, after 5 years of follow-up, no differences were observed between the groups in rates of serious infections (7% vs 8% in the step-up vs top-down groups) or malignancies (3% vs 2%, respectively), he reported.

Implications for Clinical Practice

Session co-moderator Axel Dignass, MD, head of the Department of Medicine and professor of medicine and gastroenterology at the Agaplesion Markus Hospital, Goethe University, Frankfurt, Germany, remarked on the prolonged subclinical phase of CD, reinforcing the top-down approach. “At the time we make a diagnosis, the patient hasn’t suddenly just developed Crohn’s disease; that disease has been developing for many months, if not years, and this is why it’s so critical to intervene early with an effective therapy as soon as possible after diagnosis,” he explained.

“Around 15% of patients who enrolled into PROFILE already [had] B2 stricturing disease,” he added.

Overall, the PROFILE data challenge the traditional paradigm of reserving biologic therapy for later stages of disease and support a shift toward early, proactive treatment aimed at preventing irreversible bowel damage.

Noor reported receiving grants from Celltrion, Dr Falk, Pfizer, and other companies; personal fees from multiple sources, including AbbVie, BMS, and J&J; and advisory board fees from AbbVie, BMS, and Pfizer. Dignass reported receiving personal fees from multiple companies, including AbbVie, Alfasigma, Gilead, and Lilly.