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Top-Down vs Accelerated Step-Up Treatment Strategies for Patients With Newly Diagnosed Crohn's Disease
TAKE-HOME MESSAGE
- This randomised biomarker-stratified trial involving 386 patients with newly diagnosed Crohn's disease compared the outcomes of the "top-down" approach (early combined immunosuppression with infliximab plus an immunomodulator) with those of an accelerated conventional "step-up" approach. At the end of 48 weeks, the top-down group had significantly higher rates of steroid- and surgery-free remission (79% vs 15%; P < .0001) and endoscopic remission (67% vs 44%; P < .0001) than the accelerated step-up group. The top-down group also had fewer adverse events.
- A more aggressive top-down approach may be more effective for achieving and maintaining remission in patients with newly diagnosed Crohn's disease.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies.
METHODS
PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228).
FINDINGS
Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight).
INTERPRETATION
Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease.
FUNDING
Wellcome and PredictImmune Ltd.
Additional Info
Disclosure statements are available on the authors' profiles:
A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial
Lancet Gastroenterol Hepatol 2024 Feb 21;[EPub Ahead of Print], NM Noor, JC Lee, S Bond, F Dowling, B Brezina, KV Patel, T Ahmad, PJ Banim, JW Berrill, R Cooney, J De La Revilla Negro, S de Silva, S Din, D Durai, JN Gordon, PM Irving, M Johnson, AJ Kent, KB Kok, GW Moran, C Mowat, P Patel, CS Probert, T Raine, R Saich, A Seward, D Sharpstone, MA Smith, S Subramanian, SS Upponi, A Wiles, HRT Williams, GR van den Brink, S Vermeire, V Jairath, GR D'Haens, EF McKinney, PA Lyons, JO Lindsay, NA Kennedy, KGC Smith, M ParkesFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
It has long been established that biologics, particularly when started early in the disease course, are highly effective.1 Despite this observation, dating to more than 15 years ago, the adoption of biologics early in the course of Crohn’s disease remains the exception rather than the rule.
The PROFILE study sought to validate a predictive blood-based biomarker, which was proposed to identify patients at high risk for disease progression, and, therefore, who would benefit most from top-down therapy with a TNF inhibitor. Although the study failed to demonstrate the predictive value of the biomarker, the results otherwise highlight some important elements in the management of patients with moderate to severe Crohn’s disease. First, the use of steroids alone without a form of maintenance therapy will lead, in most cases, to worse disease outcomes. The data published in this study showed rates of sustained steroid-free and surgery-free remission at 48 weeks of a remarkably high 79% in the top-down group, in stark contrast to just 15% in the accelerated step-up group. Second, isolated ileal Crohn’s disease remains a phenotype that is more complex to treat and associated with lower rates of remission. A more intensive approach should be considered when managing this phenotype. Third, nearly one-third of patients who did not escalate to a TNF inhibitor achieved endoscopic remission at week 48. This may represent a subset of patients with milder presentation and disease course.
The main takeaway from the PROFILE trial is that top-down management soon after diagnosis of moderate to severe Crohn’s disease is effective and is strongly associated with better disease outcomes. Despite these important findings, clinicians should be aware that although this strategy will be more effective for the majority of newly diagnosed patients, top-down therapy should be implemented in an individualized manner. Some patients will have mild presentations and would be excellent candidates for therapies other than TNF inhibitors, whether alone or in combination with immunomodulators. Current studies, including the PROFILE trial, have yet to identify valid biomarkers that accurately predict disease course or response to therapy in Crohn’s disease. The choice of therapy should always involve careful consideration of symptoms, endoscopic and radiologic findings, as well as the past medical history and comorbidities, which may warrant caution when using certain biologics, immunomodulators, or small molecules.
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