クローン病患者の予後を改善する(Improving outcomes for Crohn’s patients)

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2024-02-22 ケンブリッジ大学

クローン病治療の大規模な臨床試験で、すべての患者に診断直後から早期の先進療法を提供することが、治療成績を飛躍的に向上させることが示された。遺伝子署名によるバイオマーカーを使って、患者の症状再発リスクを予測し、疾患の治療方法をテストした。この方法により、緊急の腹部手術を必要とする患者の数が10分の一に減少した。

<関連情報>

新たにクローン病と診断された患者に対するトップダウン治療戦略と早期ステップアップ治療戦略のバイオマーカーによる層別化比較(PROFILE):多施設共同非盲検無作為化比較試験 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

Nurulamin M Noor, PhD ;James C Lee, PhD ;Simon Bond, PhD;Francis Dowling, BSc;Biljana Brezina, MSc;Kamal V Patel, MRCP;et al.
The Lancet Gastroenterology and Hepatology  Published:February 22, 2024
DOI:https://doi.org/10.1016/S2468-1253(24)00034-7

クローン病患者の予後を改善する(Improving outcomes for Crohn’s patients)

Summary

Background
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.

医療・健康
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