A top-down approach of initiating treatment with infliximab plus immunomodulator upon diagnosis of Crohn’s disease (CD) reduces the risk of related abdominal surgery, as well as those of disease progression and hospitalization, as compared with the conventional step-up approach, according to long-term data from the PROFILE trial.
Over a median follow-up of 5 years, only six patients in the top-down arm required abdominal surgery, the primary outcome, as opposed to 28 in the step-up arm. This corresponded to a more than five times higher risk of needing abdominal surgery for patients managed with step-up care (adjusted hazard ratio [aHR], 5.23, 95 percent confidence interval [CI], 1.99–13.76), said Dr Nurulamin Noor from the University of Cambridge in England during his presentation at the annual DDW meeting. [Noor N, et al, DDW 2026]
Noor noted that the finding was consistent regardless of disease location (ileal, colonic, ileocolonic CD) and disease behaviour (B1 or B2 disease).
Patients who received top-down treatment were also less likely to progress to B2/B3 disease and undergo hospitalization due to CD (excluding abdominal surgeries), with the risk of both outcomes being two times higher for patients in the step-up arm (disease progression: aHR, 2.46, 95 percent CI, 1.25–4.86; hospital admissions: aHR, 2.01, 95 percent CI, 1.18–3.41).
Noor explained that even with accelerated step-up care, where more than 50 percent of patients in the step-up arm were already on anti-TNF, “the outcomes … were not as good as with top-down therapy from diagnosis.”
“In terms of safety, historically there’s been a reluctance among some clinicians to use a top-down approach due to potential concerns about overtreatment. Over 5 years of follow-up, we found no difference in safety outcomes between the two groups, either for serious infections or for malignancies,” he added.
Serious infections, such as cellulitis, pneumonia, urinary tract infection, and tuberculosis, occurred in 8 percent of patients in the top-down arm and 7 percent in the step-up arm. Malignancies, including basal cell carcinoma and haematological and solid organ malignancies, were documented in 2 percent and 3 percent of patients in the respective treatment arms.
“Our data suggest that the course of CD can be modified with early effective therapy,” Noor said.
As to how early anti-TNF therapy could modify the disease course, Noor pointed to the inflammatory biomarker data, wherein an early and sustained normalization of C-reactive protein (CRP) levels was observed in the top-down arm. On the other hand, the step-up arm had a slower decrease in CRP levels, with a consistently higher burden of inflammation over the 5-year follow-up, he noted, adding that a similar pattern was observed for longitudinal faecal calprotectin data.
“We’ve recently published that controlling inflammation early and from diagnosis is also a highly cost-effective strategy and actually saves money for healthcare services and payers,” he pointed out.
Asked whether the long-term data would apply to non-anti-TNF advanced therapies, Noor highlighted the need for further studies. “Whether those other non-anti-TNF therapies can modify the course of CD, we don’t know. That’s an important area for future research to address with long-term data.”
PROFILE included 386 symptomatic patients with newly diagnosed moderate or severe CD, elevated concentration of inflammatory markers, and at least moderate endoscopic activity. These patients were randomly assigned to receive top-down treatment or undergo conventional step-up care for 48 weeks, followed by treatment according to local standards of care.
A total of 358 patients (93 percent) completed the follow-up, including 182 in the top-down arm and 176 in the step-up arm. The median follow-up was 5 years.