PROFILE 4-year follow-up shows that early effective “top-down” therapy is associated with reduced long-term Crohn’s disease complications

Background
PROFILE demonstrated better outcomes over 48 weeks for patients with Crohn’s disease (CD) receiving “top-down” (TD) therapy from diagnosis compared to an accelerated “step-up” (SU) strategy. 10 abdominal surgeries were required in SU vs 1 in the TD arm. We aimed to address whether early effective treatment can modify the longer-term course of CD with follow-up of PROFILE participants.

Methods
PROFILE was an RCT of adults with newly-diagnosed active CD. Patients were randomised to receive TD (infliximab + immunomodulator) or SU (conventional) treatment until week 48. After this they were managed according to local standards of care. Medical records for PROFILE participants were reviewed and objective outcomes data extracted – including need for abdominal surgery, hospital admission and progression to B2/B3 disease – for up to 5 years after the week 48 end-of-trial visit. Data were analysed based on the original PROFILE randomisation and modified intention-to-treat population. Odds ratios and 95% confidence intervals were computed to quantify the strength of association between initial treatment strategy and outcome. Time-to-event analysis was conducted using the Kaplan-Meier method and Cox proportional hazards model.

Results
Of the 386 patients in the PROFILE primary trial, 357 (92%; 180 TD, 177 SU) had follow-up data available. Median follow-up was 1352 days (∼4.5 years from diagnosis). During PROFILE 100% of TD and 41% of SU patients received anti-TNF therapy. By the end of the follow-up, 100% of TD and 78% of SU had received any advanced therapy. Focusing on outcomes, and regardless of treatments received, CD-related abdominal surgeries were more frequent in SU compared to TD patients (OR = 5.00; 95% CI = 2.02-12.43; Figure 1A). During post-PROFILE follow-up, 17 surgeries were required in SU vs 5 in TD. In aggregate, from diagnosis, there were 27 surgeries in 25 patients initially treated by SU, with an earlier time to surgery, vs 6 surgeries in 6 TD patients (Figure 1B). 25/27 abdominal surgeries in the SU group were for CD complications (12 stricturing [B2], 13 penetrating [B3]) vs 5/6 in TD (3 B2, 2 B3). Progression to B2 / B3 disease was more frequent in SU compared to TD (33 vs 13; OR = 2.61; 95% CI = 1.33-5.12). Incidence of CD-related hospital admissions (excluding surgeries) was higher in SU vs TD (44 vs 15; OR = 3.75; 95% CI = 2.00–7.02).

Conclusion
Over 4 years follow-up, “top-down” treatment was associated with reduced disease progression (2x), reduced hospitalisation (3x), and reduced need for abdominal surgery (5x). Early and effective control of inflammation is associated with a modified course of Crohn’s disease and should be considered the standard-of-care treatment strategy from diagnosis.