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.

Venous Thromboembolism Following Discharge from Hospital in Patients Admitted for Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Patients admitted to hospital with inflammatory bowel disease[IBD] are at increased risk of venous thromboembolism[VTE]. This study aims to identify IBD patients at increased VTE risk on hospital discharge and to develop a risk scoring system to recognise them. METHODS: Hospital episode statistics data were used to identify all patients admitted with IBD as an emergency or electively for surgery. All patients with VTE within 90 days of hospital discharge were identified. A multilevel logistic regression model was used to identify patient- and admission-level factors associated with VTE. A scoring system to identify patients at higher risk for VTE was constructed. RESULTS: A total of 201 779 admissions in 101 966 patients were included. The rate of VTE within 90 days was 17.2 per 1000 patient-years at risk and was highest in patients admitted as an emergency who underwent surgery[36.9]. VTE was associated with: female sex (odds ratio 0.65 [95% confidence interval 0.53-0.80], p <0.001); increasing age [49-60 years] (4.67 [3.36-6.49], p <0.001); increasing length of hospital stay [>10 days] (3.80 [2.80-5.15], p <0.001); more than two hospital admissions in previous 3 months (2.23 [1.60-3.10], p <0.001); ulcerative colitis (1.48 [1.21-1.82], p <0.001); and emergency admission including surgery (1.59 [1.12-2.27], p = 0.010); or emergency admission not including surgery (1.59 [1.08-2.35], p = 0.019) compared with elective surgery. A score >12 in the VTE scoring system gave a positive predictive value [PPV] of VTE of 1%. The area under the curve [AUC] was 0.714 [95% CI 0.70-0.73]. CONCLUSION: IBD patients admitted to hospital with a prolonged length of stay, increasing age, male sex, or as an emergency were at increased risk of VTE following discharge. Higher-risk patients were identifiable by a VTE risk scoring system.

Postoperative complications and mortality following colectomy for ulcerative colitis.

BACKGROUND & AIMS: Complications after colectomy for ulcerative colitis (UC) have not been well characterized in large, population-based studies. We characterized postoperative in-hospital complications, stratified them by severity, and assessed independent clinical predictors, including use of immunosuppressants. METHODS: We performed population-based surveillance using administrative databases to identify all adults (≥18 y) who had an International Classification of Diseases-9th/10th revisions code for UC and a colectomy from 1996 to 2009. All medical charts were reviewed. The primary outcome was severe postoperative complications, including in-hospital mortality. Logistic regression was used to assess predictors of complications after colectomy and then restricted to patients undergoing emergent or elective surgeries. RESULTS: Of the 666 UC patients who underwent a colectomy, a postoperative complication occurred in 27.0% and the mortality rate was 1.5%. Independent predictors of postoperative complications were age (for patients >64 vs 18-34 y: odds ratio [OR], 1.95; 95% confidence interval [CI], 1.07-3.54), comorbidities (>2 vs none: OR, 1.89; 95% CI, 1.06-3.37), and admission status (emergent vs elective colectomy: OR, 1.62; 95% CI, 1.14-2.30). Significant risk factors for an emergent colectomy included time from admission to colectomy (>14 vs 3-14 d: OR, 3.32; 95% CI, 1.62-6.80) and a preoperative complication (≥1 vs 0: OR, 3.04; 95% CI, 1.33-6.91). A prescription of immunosuppressants before colectomies did not increase the risk for postoperative complications. CONCLUSIONS: Postoperative complications frequently occur after colectomy for UC, predominantly among elderly patients with multiple comorbidities. Patients who were admitted to the hospital under emergency conditions and did not respond to medical treatment had worse outcomes when surgery was performed 14 or more days after admission.

Optimizing the safety of biologic therapy for IBD.

The introduction of biologic therapy for the treatment of IBD has substantially changed its management. The safety concerns associated with biologic therapies include the increased risk of infection, autoimmunity, development of lymphoma and demyelinating disease, and the risk of worsening heart failure. There are several strategies for minimizing the risks associated with biologic therapies. Pretreatment strategies include taking a proper history from the patient, physical examination of the patient, screening for latent tuberculosis and ruling out sepsis. Vaccination of patients against vaccine preventable diseases is also recommended. During treatment, patients should be closely monitored and any symptoms that develop should be dealt with early. Education of physicians and patients is also important to allow the early detection of any adverse events.

Mesalazine in inflammatory bowel disease: a trendy topic once again?

5-aminosalicylic acid (5-ASA) preparations (eg, mesalazine, mesalamine) are well-established preparations used in the management of inflammatory bowel disease. These drugs are most useful for the treatment of mild to moderate flares of ulcerative colitis and, especially, for maintenance of remission. Although most gastroenterologists are very familiar with these drugs, the interest in these drugs has undergone a resurgence, with new preparations offering convenience and high dosage, while preserving their customary safety. New dosage regimens are likely to become standard practice in the near future. There is also considerable interest in chemoprevention of colorectal cancer in the context of inflammatory bowel disease, and the role of long-term maintenance therapy with 5-ASAs in achieving such chemoprevention. A mechanism of action for such chemoprevention has been provided by the agonism of the peroxisome proliferator-activated receptor-gamma by 5-ASA, which unifies its efficacy as an anti-inflammatory and chemopreventive agent. In the future, even more effective agents based on 5-ASA are expected, based on more powerful agonism of peroxisome proliferator-activated receptor-gamma; 5-ASA preparations have become 'trendy' again.