Circulating Cell-Free DNA in Inflammatory Bowel Disease: Liquid Biopsies with Mechanistic and Translational Implications.

This review examines the role of circulating cell-free DNA (cfDNA) as potential drivers of inflammation and their potential application as mechanistic biomarkers in Inflammatory Bowel Diseases (IBD). These DNA fragments contain significant information about their origins, the underlying host pathology leading to their release, and possess properties that can fuel the inflammatory process. Recent advances in sequencing and analytical approaches have made the translation of cfDNA into clinical practice a promising prospect. We focus on the functional relevance of cfDNA in the inflammatory process and discuss its potential for future assessments of IBD activity and identification of therapeutic options.

Carvedilol versus endoscopic band ligation for secondary prophylaxis of variceal bleeding-long-term follow-up of a randomised control trial.

BACKGROUND AND AIMS: Carvedilol reduces rates of variceal bleeding and rebleeding by lowering portal pressure. However, an associated pleiotropic survival benefit has been proposed. We aimed to assess long-term survival in a cohort of patients previously randomised to receive either carvedilol or endoscopic band ligation (EBL) following oesophageal variceal bleeding (OVB). METHODS: The index study randomised 64 cirrhotic patients with OVB between 2006 and 2011 to receive either carvedilol or EBL. Follow-up was undertaken to April 2020 by review of electronic patient records. The primary outcome was survival. Other outcomes including variceal rebleeding and liver decompensation events were compared. RESULTS: 26 out of 33 participants received carvedilol in the follow-up period and 28 out of 31 attended regular EBL sessions. The median number of follow-up days for all patients recruited was 1459 (SE = 281.74). On the intention to treat analysis, there was a trend towards improved survival in the carvedilol group (p = 0.09). On per-protocol analysis, carvedilol use was associated with improved long-term survival (p = 0.005, HR 3.083, 95% CI 1.397-6.809), fewer liver-related deaths (0% vs 22.57%, p = 0.013, OR ∞, 95%CI 1.565-∞) and fewer admissions with decompensated liver disease (12% vs 64.29%, p = 0.0002, OR 13.2, 95% CI 3.026-47.23) compared to the EBL group. There was no statistically significant difference in variceal rebleeding rates. CONCLUSION: Following OVB in cirrhotic patients, carvedilol use is associated with survival benefit, fewer liver-related deaths and fewer hospital admissions with decompensated liver disease. Further studies are needed to validate this finding.

Carvedilol is associated with improved survival in patients with cirrhosis: a long-term follow-up study.

BACKGROUND: Primary prophylaxis of variceal haemorrhage with non-selective beta blockers (NSBB) or variceal band ligation (VBL) is now standard of care in patients with cirrhosis with portal hypertension. NSBB, and particularly carvedilol, may be associated with improved survival. AIM: To assess mortality in a cohort of patients previously randomised to either carvedilol or VBL. METHODS: We retrospectively analysed 152 patients recruited to a multi-centre randomised controlled trial between 7 April 2000 and 24 June 2006 designed to assess the efficacy of VBL versus carvedilol in preventing first variceal bleed. We used electronic records to undertake long-term follow-up (up to 20 years) with the primary outcome of all-cause mortality and secondary end points of liver-related mortality and decompensation events (ascites, encephalopathy, variceal bleeding). RESULTS: We included 152 patients in analysis with baseline characteristics well matched between the carvedilol (n = 77) and VBL (n = 75) groups. In the intention-to-treat analysis, carvedilol offered a significant survival advantage with median survival of 7.8 years compared to 4.2 years in the VBL group (P = 0.03). This survival benefit was maintained in per-protocol analysis when patients who crossed between treatment arms were excluded (P = 0.02). Transplant-free survival, liver-related mortality and decompensation events were similar in both groups. CONCLUSION: These data suggest that carvedilol offers a significant survival benefit for patients with cirrhosis and portal hypertension. The difference in all-cause and liver-related mortality suggests that this survival benefit may not be entirely liver-related. Prospective, studies are required to confirm these important findings.

Real-world effectiveness and safety of ustekinumab for the treatment of Crohn's disease: the Scottish ustekinumab cohort.

BACKGROUND AND AIM: Ustekinumab is a monoclonal antibody that targets interleukin-12/23. In Scotland, it was approved for the treatment of moderate to severe Crohn's disease in 2017. The objective of this study was to establish the real-world effectiveness and safety of ustekinumab in the treatment of Crohn's disease. METHODS: We conducted a retrospective study of patients receiving ustekinumab across eight Scottish National Health Service health boards between 2017 and 2019. Inclusion criteria included a diagnosis of Crohn's disease with symptoms attributed to active disease plus objective signs of inflammation at baseline (C-reactive protein ≥ 5 mg/L or fecal calprotectin ≥ 250 µg/g or inflammation on endoscopy/magnetic resonance imaging) and completion of induction plus at least one clinical follow-up at 8 weeks. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, deep remission, and perianal fistula response. Rates of serious adverse events were described quantitatively. RESULTS: Our cohort consisted of 216 patients (female sex, 37.9%; median age, 39.0 years, interquartile range [IQR] 28.8-51.8 years; disease duration, 9.9 years, IQR 6.0-16.5 years; prior biologic, 98.6%) with a median follow-up of 35.0 weeks (IQR 17.4-52.0 weeks). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission plus mucosal healing) were 32.0%, 32.7%, and 19.3%, respectively. In patients with active perianal disease (n = 37), the 12-month cumulative perianal response rate was 53.1%. The serious adverse event rate was 13.6 per 100 patient-years of follow-up. CONCLUSION: Ustekinumab is a safe and effective treatment for the treatment of complex Crohn's disease.

Case of steroid-resistant Crohn's-associated bronchiolitis in the setting of quiescent gastrointestinal disease treated with infliximab.

A fit, 36-year-old man with a history of Crohn's disease previously treated with azathioprine, presented acutely with progressive shortness of breath on exertion and pleuritic chest pain. At the time of presentation, his Crohn's disease was quiescent, supported by a normal faecal calprotectin. The initial chest CT suggested the presence of a diffuse inflammatory disorder and he was subsequently started on high dose oral steroids. Despite 4 months of steroid therapy, there was minimal improvement. Following discussion at the inflammatory bowel disease multidisciplinary team meeting, a decision was made to commence infliximab. Subsequently, he made a dramatic clinical and physiological recovery. His forced expiratory volume in 1 s improved from 2.22 L/min (50% predicted) to 3.65 L/min (93% predicted) and he returned to baseline levels of exercise.