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.

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. FUNDING: Wellcome and PredictImmune Ltd.

Mindfulness-based therapy for inflammatory bowel disease patients with functional abdominal symptoms or high perceived stress levels.

BACKGROUND AND AIMS: Psychological interventions are used in patients with inflammatory bowel disease (IBD) but there is uncertainty about who the optimal target population is. Multi-convergent therapy (MCT) is a form of psychotherapy that combines mindfulness meditation with aspects of cognitive behavioural therapy and has been used in the management of irritable bowel syndrome (IBS). This study aimed to assess the feasibility and efficacy of MCT in the management of IBD patients with either functional abdominal symptoms or high perceived stress levels. METHODS: Sixty-six IBD patients in clinical remission with either IBS-type symptoms or high perceived stress levels were randomly allocated to a 16-week MCT course or waiting list control group. Patients were followed-up for one year with the Inflammatory Bowel Disease Questionnaire (IBDQ) as the primary outcome measurement. RESULTS: A higher mean IBDQ score was observed in the active group compared to controls at the 4-month assessment (167 vs. 156, p=0.081), but this was not statistically significant nor did it reached the predefined clinically significant difference of 20. In patients with IBS-type symptoms at baseline there was a significantly higher mean IBDQ score in the active group compared to controls (161 vs. 145, p=0.021). There was no difference between groups in relapse rate based on faecal calprotectin measurement. CONCLUSIONS: IBS-type symptoms in patients with IBD represent a potential therapeutic target to improve quality of life. This study suggests that MCT may be useful in the management of these symptoms but larger studies are required to confirm this. CLINICAL TRIAL REGISTRATION NUMBER: NCT01426568.

Upper gastrointestinal cancer in its early stages is predominantly asymptomatic.

BACKGROUND: Current guidelines for urgent endoscopic investigation of dyspepsia are based on alarm features and age criteria. However, there is concern that this type of guideline may delay the diagnosis of upper gastrointestinal (GI) cancer. OBJECTIVE: To evaluate the timescale of symptoms in upper GI cancer, determining whether patients experience dyspepsia before developing alarm features, and hence whether the current guidelines may delay diagnosis. METHOD: A prospective study of patients diagnosed with upper GI cancer between May 2004 and January 2007. A structured interview was performed directly after endoscopic diagnosis regarding the nature and duration of symptoms. RESULTS: Alarm features were present in 56 of the 60 patients interviewed. Only eight patients reported dyspepsia before developing their alarm feature; three of these had complained of dyspepsia for >10 years, one reported dyspepsia preceding the alarm feature by 18 months and in four patients dyspepsia preceded the alarm feature by ≤8 weeks. Preceding dyspepsia did not cause significant delay in referral for endoscopy (p=0.670), or affect tumour stage at diagnosis (p=0.436) or length of survival (p=0.325). CONCLUSION: It is rare for patients with upper GI cancer to experience significant dyspepsia before the onset of their alarm symptoms, therefore limiting the prospect of an earlier diagnosis. Early upper GI cancer is largely asymptomatic, and guidelines should limit the availability of open-access gastroscopy in simple dyspepsia. Increased awareness of the need to urgently investigate patients with concurrent anaemia or weight loss is required.