Patients with newly diagnosed Crohn’s disease who were randomly assigned to start anti-tumor necrosis factor (anti-TNF) therapy at diagnosis were less likely to need Crohn’s disease-related abdominal surgery than those assigned to conventional step-up care, according to long-term follow-up of the PROFILE trial published online Sept. 10 in The Lancet Gastroenterology & Hepatology.
Over a median of about five years, 26 of 193 patients (13%) originally assigned to step-up care needed surgery, compared with six of 193 (3%) assigned to top-down treatment. Top-down treatment was also associated with lower rates of progression to stricturing or penetrating disease and of Crohn’s disease-related hospitalization.
“One of the most notable things we saw in the PROFILE trial was the large benefit seen at the end of one year from using early anti-TNF biologic therapy in a ‘top-down’ approach compared to our more conventional ‘step-up’ approach to care,” Nurulamin M. Noor, MD, PhD, of the University of Cambridge School of Clinical Medicine and Cambridge University Hospitals NHS Foundation Trust in Cambridge, England, a joint first author and the study’s corresponding author, told GI & Hepatology News. “After the end of one year, all patients reverted back to their local standards of care. Despite the fact that almost 90% of patients in the ‘step-up’ arm started on maintenance treatment for their Crohn’s disease over the next five years, we saw substantially better outcomes in patients who had initially been treated with early treatment from diagnosis.”
In the original trial, 79% of top-down patients were in sustained steroid-free and surgery-free remission throughout the 48-week treatment period, compared with 15% of step-up patients, according to the paper.
The multicenter, open-label PROFILE trial randomly assigned 386 patients ages 16 to 80 with newly diagnosed active Crohn’s disease at 40 hospitals in the United Kingdom — 193 to each group. The top-down group received infliximab plus an immunomodulator (azathioprine, low-dose mercaptopurine with allopurinol, or methotrexate) from diagnosis. The step-up group received corticosteroids first, escalating to an immunomodulator and then infliximab for persistent disease activity or flares. Treatment followed protocol for 48 weeks, after which patients returned to usual care at their local hospitals.
For the extended follow-up, investigators retrospectively reviewed medical records through January 2026; 358 patients (93%) had records available after week 48. The primary outcome was Crohn’s disease-related abdominal surgery and time to first surgery. Secondary outcomes included progression from inflammatory to stricturing or penetrating disease and Crohn’s disease-related hospital admissions. Median follow-up was about five years from randomization.
For the primary outcome, time to first surgery was significantly shorter with step-up treatment, with an adjusted hazard ratio of 5.23. The absolute risk reduction for surgery with top-down treatment was 10 percentage points, corresponding to a number needed to treat of nine.
Benefits were also observed for secondary outcomes: disease progression to stricturing or penetrating Crohn’s disease occurred in 17% of patients assigned to step-up therapy compared with 7% of those assigned to top-down treatment. Crohn’s disease-related hospitalizations, excluding admissions for surgery, occurred in 21% and 11% of patients, respectively. Time to both outcomes was also shorter with step-up care, with adjusted hazard ratios of 2.46 for progression and 2.01 for hospitalization.
Serious infections occurred in 6% of step-up patients and 7% of top-down patients, and malignancies in 3% and 2%, respectively. One death occurred in the top-down group, from acute myeloid leukemia, which a hematology specialist review judged most likely age-related and unconnected to Crohn’s disease or its treatment, according to the paper. The authors noted that the follow-up was not powered to detect differences in long-term safety outcomes.
Among the 91 step-up patients (47%) who started anti-TNF therapy within a year of randomization — a group the authors called accelerated step-up — the need for surgery was still higher than in the top-down group, according to the paper.
“Given that all patients reverted back to standard of care at the end of one year, I think many people expected that the outcomes between the early ‘top-down’ treatment and conventional ‘step-up’ treatment groups would converge over time,” Noor said. Instead, the gap in surgery rates opened within the first year after diagnosis and continued to widen through follow-up, according to the paper. “The risk of worse clinical outcomes continued to increase in patients originally managed with ‘step-up’ care,” Noor said, “highlighting that early inflammatory disease control in the first year after diagnosis still appears to be paying dividends for patients several years later.”
Most significant adverse outcomes occurred within two years of diagnosis, the authors reported — the window historically used to define early intervention. “Our data suggest that, for many patients, this might already be too late,” they wrote.
In terms of limitations, the study acknowledged that follow-up after 48 weeks was retrospective and that subsequent treatment decisions were made according to local practice, introducing potential confounding. The authors wrote that potential biases in the retrospective data “limit strong assertions about causality.” They also noted that absolute event rates were low, that safety reporting during extended follow-up was not standardized, and that the step-up comparator might no longer be viewed as ideal, although it remains widely used in practice. Patients with mild Crohn’s disease were also excluded, limiting generalizability to that particular population.
The authors wrote that step-up approaches rest on “the assumption that it is safe to wait and see whose disease declares itself as needing treatment escalation,” and concluded that early top-down treatment “should be considered the standard-of-care strategy” for patients newly diagnosed with moderate or severely active Crohn’s disease. The PROFILE investigators argue that effective treatment from diagnosis may do more than suppress inflammation — it may help prevent irreversible disease progression.
“When a patient is diagnosed with moderate or severe Crohn’s disease, historically there was always a concern about whether they would need treatment or not, and whether they might be overtreated with early use of advanced therapies,” Noor said. “[In this study] we have shown that moderate or severe Crohn’s disease is not a benign condition. Without treatment, it inevitably progresses for many patients. PROFILE, and other recent studies, provide really helpful data for clinicians and patients to show that the clock is ticking at the point of diagnosis, and that the safest and most effective treatment strategy for patients is to control inflammation as effectively as possible, as soon as possible.”
Wellcome and Celltrion funded the study. Noor and several coauthors reported financial relationships with companies including AbbVie, Bristol Myers Squibb, Celltrion, Pfizer, and Takeda.