Mortality in acute severe ulcerative colitis was low, but higher in steroid non-responders. Patients treated with second-line medical therapies had no higher risk of in-hospital mortality than those undergoing surgery. Second-line 'rescue' medical therapy usage is increasing; however, ciclosporin response rates were relatively low.

Multicolor flow cytometry and cell sorting are powerful immunologic tools for the study of hepatic mϕ, yet there is no consensus on the optimal method to prepare liver homogenates for these analyses. Using a combination of mϕ and endothelial cell reporter mice, flow cytometry, and confocal imaging, we have shown that conventional flow‐cytometric strategies for identification of Kupffer cells (KCs) leads to inclusion of a significant proportion of CD31hi endothelial cells. These cells were present regardless of the method used to prepare cells for flow cytometry and represented endothelium tightly adhered to remnants of KC membrane. Antibodies to endothelial markers, such as CD31, were vital for their exclusion. This result brings into focus recently published microarray datasets that identify high expression of endothelial cell‐associated genes by KCs compared with other tissue‐resident mϕ. Our studies also revealed significant and specific loss of KCs among leukocytes with commonly used isolation methods that led to enrichment of proliferating and monocyte‐derived mϕ. Hence, we present an optimal method to generate high yields of liver myeloid cells without bias for cell type or contamination with endothelial cells.

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood. Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1α (hypoxia-inducible factor-1α)-mediated neutrophil adaptation, resulting in resolution of lung injury. Methods: Neutrophil activation of IL4Ra (IL-4 receptor α) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4. Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α–dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo , IL-4Ra–deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis. Conclusions: We describe an important interaction whereby IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury.

Background Intravenous (IV) steroids remain the first-line treatment for patients with acute ulcerative colitis (UC). However, 30% of patients do not respond to steroids, requiring second-line therapy and/or surgery. There are no existing indices that allow physicians to predict steroid nonresponse at admission. We aimed to determine if admission biochemical and endoscopic values could predict response to IV steroids. Methods All admissions for acute UC (ICD-10 K51) between November 1, 2011, and October 31, 2016 were identified. Case note review confirmed diagnosis; clinical, endoscopic, and laboratory data were collected. Steroid response was defined as discharge home with no further therapy for active UC. Nonresponse was defined as requirement for second-line therapy or surgery. Univariate and binary logistic regression analyses were employed to identify factors associated with steroid nonresponse. Results Two hundred and thirty-five acute UC admissions were identified, comprising both acute severe and acute nonsevere UC; 155 of the 235 patients (66.0%) responded to steroids. Admission C-reactive protein (CRP) (P = 0.009, odds ratio [OR] 1.006), albumin (P < 0.001, OR 0.894) and endoscopic severity (P < 0.001, OR 3.166) differed significantly between responders and nonresponders. A simple UC severity score (area under the curve [AUC] 0.754, P < 0.001) was derived from these variables; 78.1% (25 of 32) of patients with concurrent CRP ≥50 mg/L, albumin ≤30 g/L, and increased endoscopic severity (severe on physician’s global assessment) (maximum score = 3) did not respond to IV steroids (positive predictive value [PPV] 78.1%, negative predictive value [NPV] 87.1%). Conclusions More than three quarters of patients scoring 3 (albumin ≤30 g/L, CRP ≥50 mg/L, and increased endoscopic severity) did not respond to IV steroids. This combination of parameters (ACE) identifies on admission a high-risk population who may benefit from earlier second-line medical treatment or surgical intervention.

Patients identified as high risk using the Travis or the Ho scoring systems are more likely to be resistant to IV steroids and require surgery. Risk of surgery in both high-risk populations is lower than previously reported.

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Conclusion (1) A distinct subset of miRNAs is deregulated in the mucosa of actively inflamed sigmoid UC in patients who are on no treatment. (2) Introduction High dose steroids followed by colectomy if required remains the mainstay of treatment for active ulcerative colitis (UC). Recently we have seen the introduction of second-line medical therapies with the hope of avoiding the need for surgery when medical therapy fails. Using a cohort of 2981 and 3049 ulcerative colitis patients from the 2nd and 3rd rounds of the UK IBD audit we aim to assess whether the use of second-line medical therapies has an impact on the need for surgery and complication of surgery when needed. Methods We audited 3049 patients with ulcerative colitis. Median age was 42; there were 1421 females and 1628 males. ). There were significantly more patients proceeding to surgery following anti-TNFa therapy in 2010 10.82% (17/157) vs 3.7% (6/163) (p<0.008). Using the Travis criteria we also found that there were significantly less high risk surgical patients in 2010, 67.5% (106/157) compared to 83.4% (136/163) (p<0.002); this was also reflected in a significant reduction in the overall amount of high risk patients in the ASUC population. Post-operative complications are not statistically different between patients who did and did not receive rescue medical therapy 40.0% (26/65) vs 34.8% (32/92) (p<0.8). There was also no statistical difference in complications between rounds, 32.5% (53/163) in 2008 vs 36.9% (58/157) in 2010 (p<0.4). Conclusion The surgical rate has remained the same over the two audit periods; however there has been a significant reduction in the proportion of high risk patients undergoing operations. This could in part be related to the increased use of second line medical therapies between the two audit rounds, with significantly more patients receiving anti-TNFa prior to surgery. The use of second line medical therapies did not increase the risk of surgery.

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