5-Year Data Support Top-Down Therapy in Crohn’s Disease

A “top-down” approach of early aggressive therapy for Crohn’s disease continued to achieve better outcomes versus a conventional accelerated “step-up” approach, long-term follow-up data from the PROFILE trial showed.

At 5-year follow-up, six Crohn’s disease-related abdominal surgeries occurred among patients who received a top-down approach of immunosuppression with the TNF inhibitor infliximab (Remicade) plus an immunomodulator compared with 28 surgeries in the step-up group (adjusted HR 5.23, 95% CI 1.99-13.76), reported Nurulamin Noor, PhD, of the University of Cambridge in England, at the annual Digestive Disease Week meeting.

Progression to B2/B3 disease was more frequent with step-up treatment (a sequential strategy where treatment intensity is gradually increased until the tendency to flare is controlled) versus top-down treatment (aHR 2.46, 95% CI 1.25-4.86), and the incidence of Crohn’s disease-related hospital admissions (excluding surgeries) was also higher (56 vs 34, respectively, aHR 2.01, 95% CI 1.18-3.41).

“We think this is probably the most robust evidence to date that it is possible to modify the course of Crohn’s disease,” Noor told MedPage Today. “The key thing is to initiate early effective therapy as soon as possible after diagnosis. This is something we’ve suspected for quite a while, but the 5-year follow-up data from PROFILE helps support this.”

“I think knowing this not only leads to short-term benefit, but [also] long-term benefit and long-term gains, [and] is really helpful for discussions between patients and clinicians,” he added.

In previous results published in 2024, Noor and colleagues showed that sustained steroid- and surgery-free remission at 48 weeks was significantly more common in the group assigned to top-down therapy compared with the step-up approach (79% vs 15%, P<0.0001), thus meeting the trial's primary outcome.

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 PROFILE trial was conducted at 40 sites in the U.K. from 2017 to 2022. It randomized 386 adults with newly diagnosed active Crohn’s disease to receive top-down treatment or conventional step-up treatment until week 48, after which they were managed according to local standards of care.

Of those 386 patients, follow-up data were available for 358 — 182 in the top-down group and 176 in the step-up group. Median follow-up was 1,352 days from diagnosis.

As for safety, “one of the concerns, historically, is that we have effective therapies, but if we use them too early, are we going to expose people to an unnecessary risk of side effects and toxicity,” Noor noted.

At week 48, there had been fewer adverse events, including disease flares, in the top-down group versus the step-up group (168 vs 315), as well as fewer serious adverse events (15 vs 42) and fewer complications requiring surgery (1 vs 10). For the long-term analysis, Noor and colleagues looked at the incidence of serious infections and malignancies and found no differences between the two approaches.

About 8% of patients in the top-down group developed serious infections versus 7% in the step-up group, while malignancies were reported in 2% and 3%, respectively.

The safety of the top-down approach “is a really important point,” Noor observed. “I think our data suggest that not only is it more effective to treat with the most effective medications as soon as possible, it’s actually safer for patients.”

Noor noted that his group also conducted a cost-effectiveness analysis using PROFILE data that showed the extra costs associated with an aggressive top-down approach are “more than offset by the fact you reduce hospital admissions, you reduce surgeries, you reduce visits to GPs, you reduce phone calls from patients to IBD [inflammatory bowel disease] helplines and IBD nurses. Not only is using effective therapies earlier … safer for patients, it is cheaper for healthcare services and payers to use this top-down approach.”