Clinical Features and Outcomes of Paediatric Patients With Isolated Colonic Crohn Disease

Objectives: Adult studies suggest that patients with isolated colonic Crohn disease (L2 CD) exhibit unique characteristics differentiating them from patients with ileo-caecal (L1) CD and ulcerative colitis (UC). We aimed to characterize clinical features and outcomes of paediatric patients with L2. Methods: Retrospective data was collected through the Porto Inflammatory Bowel Disease group of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) on Paediatric patients with L2, L1 or UC at different time-points. Outcome measures included time to first flare, hospital admissions, initiation of anti-tumor necrosis factor-alpha (TNF alpha) drug, stricture and surgery. Results: Three hundred patients were included: 102 L1, 94 L2 and 104 UC. Rates of hematochezia at presentation were 14.7%, 44.7% and 95.2%, while rates of fever were 12.7%, 26.6% and 2.9%, for patients with L1, L2 and UC, respectively (P < 0.001 for all comparisons). Skip lesions were identified in 65% of patients with L2, and granulomas in 36%, similar to L1 patients. Rates of anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic (pANCA) positivity significantly differed between the three groups: 25.4% and 16.7% for patients with L2, compared with 55.2% and 2.3%, and 1.8% and 52.9% for patients with L1 and UC, respectively. Response rates to exclusive enteral nutrition were comparable between L1 and L2 (78.3-82.4%), as was the response to oral steroids (70.4-76.5%) in the three groups. While times to first flare and admission were similar between groups, patients with L1 were commenced on anti-TNF alpha earlier. Moreover, stricturing phenotype and need for colectomy were very rare in patients with L2. Conclusions: Significant differences are observed in the clinical presentation and outcomes of Paediatric patients with L2, compared to patients with L1 and UC.Peer reviewe

Infliximab in young paediatric IBD patients : it is all about the dosing

Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients = 10 years). Median age was 8.3 years (IQR 6.9-8.9) in YP compared with 14.3 years (IQR 12.8-15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 mu g/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0-12.9) vs. OP; 5.5 mg/kg (IQR 5.0-9.3);p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI - 1.2 to - 1.01);p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP;p = 0.56). Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years. What is Known

Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.R35 GM118173 - NIGMS NIH HHS; U01 TR002625 - NCATS NIH HHS; P30 CA008748 - NCI NIH HHS; FC010144 - Cancer Research UK; FC010144 - Medical Research Council; FC010144 - Wellcome TrustPublished versio

Infantile and very early onset-inflammatory bowel disease: a multicenter study

Objective: In this study, we described disease characteristics and assessed long-term outcomes, in patients diagnosed with very-early-onset inflammatory bowel disease (VEOIBD) (diagnosed before 6 years of age), and infantile-IBD (before 2 years). Methods: Cases from 21 centers worldwide diagnosed with VEOIBD (2008-2018), with minimum two years of follow-up, were retrospectively reviewed. Results: The total cohort included 243 patients (52% males, median follow-up of 5.8[IQR 3.2- 8.4] years, including 69[28%] with infantile-IBD. IBD subtypes included Crohn’s disease (CD), ulcerative colitis (UC) or IBD-unclassified (IBDU) in 30%, 59% and 11%, respectively. Among patients with CD - 94% had colonic involvement, and among patients with UC/IBDU – 75% had pancolitis. Compared to non-infantile VEOIBD, patients with infantile-IBD presented with higher rates of IBDU, lower hemoglobin and albumin levels and higher C-reactive protein, and had lower response rates to first induction therapy and to corticosteroids therapy (p&lt;0.05 for all). Colectomy and diversion surgeries were performed in 11% and 4%, respectively, with no significant differences between age groups. Corticosteroid-free remission rates were 74% and 78% after 3 and 5 years, respectively, and 86% at end of follow-up. Genetic testing was performed in 96 (40%) patients. Among tested population 15 (16%) were identified with monogenic disease. This group demonstrated lower response rates to induction therapies, higher rates of surgical intervention and higher rates of major infections (p&lt;0.05 for all). Conclusion: Patients with VEOIBD, including infantile-IBD, exhibit low rate of disease complications and surgical interventions at the long-term. Patients with monogenic-IBD are at risk of more severe disease course

The Role of Innate Immune IL-10 Receptor Signaling in Controlling Intestinal Immune Responses

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine. Patients with deleterious mutations in either IL10 or its receptor (IL10R) develop severe inflammatory bowel disease (IBD) within the first months of life; similarly, Il10rb-/- mice develop spontaneous colitis. The precise mechanisms of IL-10R-dependent control of immune tolerance and intestinal mucosal homeostasis are not well defined. Here I demonstrate that IL-10R signaling in innate immune cells is critical for regulating mucosal homeostasis and prevention of colitis. Loss of IL-10R-dependent signaling caused wild-type CD4+ T cells to become colitogenic in a murine colitis transfer model. Moreover, My data indicate that IL-10R-dependent signals modulated the differentiation and function of bone-marrow-derived macrophages and intestinal macrophages into either pro-inflammatory macrophages or functionally competent anti-inflammatory macrophages in mice. Similarly, monocyte-derived macrophages from very early onset IBD patients harboring loss of function mutations in IL10RA and IL10RB genes also exhibited impaired differentiation and function of pro- and anti-inflammatory macrophages. These results define a unique and non-redundant role for IL-10R signaling in innate immune cell control of intestinal mucosal homeostasis in mice and humans

Successful antibiotic eradication of Streptococcus pneumoniae infection of a ventriculoatrial shunt

SummaryA case of Streptococcus pneumoniae meningitis in a possibly immune-compromised child with a ventriculoatrial shunt is described. The infection was successfully eradicated by treatment with intravenous ceftriaxone and rifampicin, without removal of the shunt