Peter P. De Cruz

Description:Autoimmune enteropathy (AIE) is a rare condition, which can be debilitating. We report a steroid-refractory case of AIE which responded to upadacitinib.

Description:Disrupted intestinal homeostasis and barrier function contribute to the development of diseases such as inflammatory bowel disease. BECLIN-1, a core component of two class III phosphatidylinositol 3 kinase complexes, has a dual role in autophagy and endocytic trafficking. Emerging evidence suggests that its endocytic trafficking function is essential for intestinal integrity. To investigate the fatal gastrointestinal phenotype observed in BECLIN-1 knockout mice, we used organoids derived from these animals to show that BECLIN-1 deletion disrupts the localization of CADHERIN1/ECADHERIN to adherens junctions and OCCLUDIN to tight junctions. Impaired cargo trafficking to the lysosome was also observed. Filamentous actin cytoskeleton also became disorganized though there were no changes in its spatial interaction with CATENIN BETA1/BETA-CATENIN nor in BETA-CATENIN localization. The trafficking defects were all less pronounced or absent in organoids lacking an autophagy-only regulator, ATG7, emphasizing BECLIN-1's trafficking role in maintaining gut homeostasis and barrier function. These findings advance our understanding of epithelial dysfunction and the mechanisms underlying intestinal diseases.

Description:Objective: The role of infliximab therapeutic drug monitoring (TDM) in acute severe ulcerative colitis (ASUC) management is unknown. We aimed to identify whether infliximab TDM is associated with ASUC outcomes. Methods: Serum and stool samples were collected from patients enrolled in the PREDICT-UC randomised controlled trial (NCT02770040), which compared intensified and standard infliximab rescue in steroid-refractory ASUC. Infliximab levels measured after trial conclusion and clearance derived using pharmacokinetic modelling were correlated with outcomes. Results: Infliximab levels were measured in 681 serum and 198 faecal samples from 135 patients. Lower day 3 serum infliximab levels predicted infliximab failure on day 14 (AUROC=0.63, P=0.043) and colectomy by 3 months (AUROC=0.77, P=0.0027); a threshold of ≤57.9 ug/mL had 83% sensitivity, 67% specificity, 24% PPV and 97% NPV for colectomy. Patients with high clearance between day 1-7 (≥0.62L/day) were more likely to respond to an initial 10 mg/kg vs 5 mg/kg infliximab dose (RR 1.50, 95%CI 1.01-2.23), and had a higher risk of colectomy if they received an initial 5 mg/kg vs 10 mg/kg dose (HR 4.81, 95%CI 1.09-21.37). In patients with high clearance who did not respond to the first infliximab dose, day 14 response rate was higher with a second 10 mg/kg vs 5 mg/kg dose (38% vs 11%; RR 3.43, 95%CI 1.05-11.19). Day 3 faecal infliximab levels correlated with endoscopic severity and was associated with day 7 non-response (P=0.016). Conclusions: Early infliximab levels and clearance calculation can predict outcomes in ASUC. This is the first study to demonstrate that high infliximab clearance may be overcome by intensified infliximab dosing.

Description:Objective: 'Gut-specific' biologics are associated with fewer infectious complications than 'systemic' biologics in inflammatory bowel disease (IBD) which represents an important consideration in transplant recipients. This study evaluated the safety of combining transplant immunosuppression with 'gut-specific' versus 'systemic' biologics to manage IBD following liver transplantation (LTx). Methods: A retrospective dual-centre study of IBD patients exposed to biologics following LTx between 2001 and 2023 was undertaken. Primary outcome was the incidence rate of infectious events per patient-year of biologic exposure. Infectious events were stratified by 'gut-specific' (vedolizumab) and 'systemic' (anti-TNF/ustekinumab) biologic exposure with severe events defined by hospitalisation. Secondary outcomes included the impact of non-biologic immunosuppression on the incidence of infectious and non-infectious complications. Results: Thirty-six IBD patients were exposed to 59 (median 12 [IQR 6-27] months) biologic episodes following LTx. Patients were collectively exposed to 44.5 and 44.4 patient-years of 'gut-specific' (vedolizumab = 27 [45.7%]) and 'systemic' (anti-TNF = 22 [37.2%]; ustekinumab = 10 [16.9%]) biologics, respectively. Twenty-seven (45.7%) biologic episodes were associated with 41 infectious events, a median of 8 months (IQR 4.5-13.5) following biologic initiation. Rates of infectious events were not significantly different between 'gut-specific' and 'systemic' biologic exposures (0.43 vs. 0.50 per patient-year, incidence rate ratio [IRR] 1.09 [95% CI 0.58-2.02, p = 0.79]). Corticosteroid exposure at biologic initiation was the only non-biologic immunosuppressant associated with severe infectious events (IRR 5.40 [95% CI 1.66-17.63, p < 0.01]). Conclusions: Incidence of infectious events observed between IBD/LTx patients exposed to 'gut-specific' and 'systemic' biologics were similar. Biologic choice should not be influenced by concerns regarding their co-prescription with transplant immunosuppression. Corticosteroid co-therapy at biologic initiation may be associated with more severe infectious events.

Description:Tofacitinib has described efficacy in ulcerative colitis but not Crohn's disease (CD). However, patients with stricturing CD were excluded from initial randomized controlled trials. We report a case of stricturing colonic CD, which responded to tofacitinib therapy.