OP05PROFILE 4-year follow-up shows that early effective “top-down” therapy is associated with reduced long-term Crohn’s disease complications

Abstract 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. Conflict of interest: Noor, Nurulamin: Grants: NMN reports grants from Celltrion, Dr Falk, Pfizer, Pharmacosmos, Tillotts. Personal Fees: NMN reports personal fees from AbbVie, BMS, Celltrion, Ferring, J&J, Lilly, Pfizer, Pharmacosmos, Takeda. Advisory board fees: NMN reports advisory board fees from AbbVie, BMS, Pfizer, Takeda. Zheng, Haiyan: HZ discloses research grants from National Institute for Health and Care Research and AstraZeneca. Sharip, Mohmmed Tauseef: Consultancy fees from Teva and Dr Falk Pharma. Lee, James: Grant: GSK Personal Fees: Abbie, C4X Discovery, PredictImmune, Falk Robertson, David: DSR discloses payment or honoraria from American Statistical Association grants from LifeArc, National Institute for Health and Care Research, Wellcome and advisory board membership of Birmingham Clinical Trials Unit, and PlaqueTec. Parkes, Miles: Grant: Gilead, Pfizer, AstraZeneca, Galapagos, Lilly, Takeda