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Summary: Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4+ T‐helper subset distribution and enhanced production of pro‐inflammatory cytokines such as interleukin 17A and interferon gamma. The role of monocytes (MCs) in ITP is less widely described, but innate immune cells have a role in shaping CD4+ T‐cell phenotypes. Glucocorticoids (GCs) are commonly used for first‐line ITP treatment and modulate a broad range of immune cells including T cells and MCs. Using multiparameter flow cytometry analysis, we demonstrate the expansion of intermediate MCs (CD14++CD16+) in untreated patients with newly diagnosed ITP, with these cells displaying a pro‐inflammatory phenotype, characterised by enhanced expression of CD64 and CD80. After 2 weeks of prednisolone treatment (1 mg/kg daily), the proportion of intermediate MCs reduced, with enhanced expression of the anti‐inflammatory markers CD206 and CD163. Healthy control MCs were distinctly different than MCs from patients with ITP before and after GC treatment. Furthermore, the GC‐induced phenotype was not observed in patients with chronic ITP receiving thrombopoietin receptor agonists. These data suggest a role of MCs in ITP pathogenesis and clinical response to GC therapy. [ABSTRACT FROM AUTHOR]

In humans, the three main circulating monocyte subsets are defined by their relative cell surface expression of CD14 and CD16. They are all challenging to study because their characteristics are strongly context specific, and this has led to a range of conflicting reports about their function, which is especially so for CD14++CD16+ (intermediate) monocytes. Ex vivo cultures are also often confounded by the concomitant use of immunosuppressive drugs. We therefore sought to characterize the phenotype and function of intermediate monocytes in the setting of acute inflammation prior to treatment in a cohort of 41 patients with acute alcoholic hepatitis (AH). Circulating intermediate monocytes were enriched in patients with AH and had an activated phenotype with enhanced expression of CCR2 and CD206 compared with healthy controls. Proinflammatory cytokine expression, including IL-1β and IL-23, was also higher than in healthy controls, but both classical (CD14++CD16-) and intermediate monocytes in AH were refractory to TLR stimulation. Compared with healthy controls, both AH monocyte subsets had greater phagocytic capacity, enhanced ability to drive memory T cell proliferation in coculture, and skewed CD4+ T cells to express an increased ratio of IL-17/IFN-γ. Furthermore, liver tissue from AH patients demonstrated an enrichment of monocytes including the intermediate subset compared with controls. These data demonstrate that intermediate monocytes are expanded, functionally activated, induce CD4+ T cell IL-17 expression, and are enriched in the liver of patients with AH. [ABSTRACT FROM AUTHOR]

Summary: Background: Treating severe alcoholic hepatitis involves the exposure of patients to corticosteroids for 7 days to assess "response". Aim: To assess the prognostic and therapeutic implications of baseline neutrophil‐to‐lymphocyte ratio (NLR) in patients with severe alcoholic hepatitis. Methods: Patients recruited to the STOPAH trial and an independent validation group were analysed retrospectively. Area under the receiver operating curve (AUC) analysis was performed. Kaplan‐Meier analysis was used to assess survival. Log‐rank test and odds ratio (OR) were used for comparative analysis. Results: Baseline NLR was available for 789 STOPAH patients. The AUC for NLR was modest for 90‐day outcome (0.660), but was associated with infection, acute kidney injury (AKI) and severity of alcoholic hepatitis. Ninety‐day survival was not affected by prednisolone treatment if NLR < 5 or > 8 but mortality was reduced with prednisolone treatment when the NLR was 5‐8 (21.0% cf. 34.5%; P = 0.012). Prednisolone treatment increased the chance of Lille response if the NLR was  ≥ 5 (56.5% cf. 41.1%: P = 0.01; OR 1.86) but increased the risk of day 7 infection (17.3% cf. 7.4%: P = 0.006; OR 2.60) and AKI (20.8% cf. 7.0%: P = 0.008; OR 3.46) if the NLR was > 8. Incorporation of NLR into a modified Glasgow alcoholic hepatitis score (mGAHS) improved the AUC to 0.783 and 0.739 for 28‐day and 90‐day outcome, respectively. Conclusion: The NLR is associated with AKI and infection in severe alcoholic hepatitis. The NLR identifies those most likely to benefit from corticosteroids at baseline (NLR 5‐8). The mGAHS has a good predictive value for 28‐ and 90‐day outcomes. Linked Content This article is linked to Abdallah and Singal paper. To view this article, visit https://doi.org/10.1111/apt.15399. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Dhanda et al papers. To view these articles, visit https://doi.org/10.1111/apt.17307 and https://doi.org/10.1111/apt.17335 [ABSTRACT FROM AUTHOR]

Human peripheral monocytes have been categorized into three subsets based on differential expression levels of CD14 and CD16. However, the factors that influence the distribution of monocyte subsets and the roles that each subset plays in autoimmunity are not well studied. In this study, we show that circulating monocytes from patients with autoimmune uveitis exhibit a skewed phenotype toward intermediate CD14++CD16+ cells, and that this is associated with glucocorticoid therapy. We further demonstrate that CD14++ CD16+ monocytes from patients and healthy control donors share a similar cell-surface marker and gene expression profile. Comparison of the effects of intermediate CD14++CD16+ monocytes with classical CD14++CD16- and nonclassical CD14+CD16++ monocytes revealed that the intermediate CD14++CD16+ subset had an attenuated capacity to promote both naive CD4+ T cell proliferation and polarization into a Th1 phenotype, and memory CD4+ T cell proliferation and IL-17 expression. Furthermore, CD14++CD16+ cells inhibit CD4+ T cell proliferation induced by other monocyte subsets and enhance CD4+ T regulatory cell IL-10 expression. These data demonstrate the impact of glucocorticoids on monocyte phenotype in the context of autoimmune disease and the differential effects of monocyte subsets on effector T cell responses. [ABSTRACT FROM AUTHOR]

Objective In 2010, the European Society of Gastrointestinal Endoscopy delivered guidelines on the prophylaxis of postendoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis (PEP). These included Grade A recommendations advising the use of prophylactic pancreatic stent (PPS) and non-steroidal anti-inflammatory drugs (NSAIDs) in high-risk cases. Our study aim was to capture the current practice of UK biliary endoscopists in the prevention of PEP. Design In summer 2012, an anonymous online 15-item survey was emailed to 373 UK consultant gastroenterologists, gastrointestinal surgeons and radiologists identified to perform ERCP. Results The response rate was 59.5%(222/373). Of the respondents, 52.5%considered ever using PPS for the prevention of PEP. PPS users always attempted insertion for the following procedural risk factors: pancreatic sphincterotomy (48.9%), suspected sphincter of Oddi dysfunction (46.5%), pancreatic duct instrumentation (35.9%), previous PEP (25.2%), precut sphincterotomy (8.5%) and pancreatic duct injection (7.8%). Prophylactic NSAID use was significantly associated with attempts at PPS placement (p<0.001). 64.1%of non-PPS users cited a lack of conviction in their benefit as the main reason for their decision. Self-reported pharmacological use rates for PEP prevention were: NSAIDs (34.6%), antibiotics (20.6%), rapid intravenous fluids (13.2%) and octreotide (1.6%). 6% routinely measured amylase post-ERCP. Conclusions Despite strong evidence-based guidelines for prevention of PEP, less than 53% of ERCP practitioners use pancreatic stenting or NSAIDs. This suggests a need for the development of British Society of Gastroenterology guidelines to increase awareness in the UK. Even among stent users, PPS are being underused for most high-risk cases. Prophylactic pharmacological measures were rarely used as was routine post-ERCP serum amylase measurement. [ABSTRACT FROM AUTHOR]

Resistance to the anti-inflammatory and immunosuppressive effects of steroids is an important clinical problem that complicates the treatment of approximately 30% of patients with conditions for which steroids are normally first-line therapy. Previous studies have shown that steroid-resistant (SR) patients have more severe disease and higher levels of inflammatory cytokine production than steroid-sensitive (SS) patients, but the molecular mechanisms for this remain poorly understood. Peripheral blood mononuclear cells from healthy volunteers were tested for steroid resistance by their in vitro response to the anti-proliferative effects of dexamethasone. The SR cohort had high baseline levels of NFκB DNA binding activity, equivalent to that in phytohemagglutinin (PHA)-stimulated SS cells. In SR cells, dexamethasone exposure, but not PHA, increased binding of the p65 NFκB subunit to the κB promoter element. Glucocorticoid receptor (GR) was not detected at either the κB promoter element or the glucocorticoid response element (GRE), suggesting that it does not translocate to the nucleus in these cells. Conversely, in SS cells, baseline p65 DNA binding activity was low and significantly increased by PHA, but not by dexamethasone. Unlike in SR cells, GR was detected at the κB element and at the GRE. These findings suggest that in SR patients, steroids may be harmful by increasing NFκB activity which would exacerbate disease by increasing transcription of inflammatory cytokines. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Israelsen et al papers. To view these articles, visit https://doi.org/10.1111/apt.16111 and https://doi.org/10.1111/apt.16150 [ABSTRACT FROM AUTHOR]

Background: Alcohol use is the third leading risk factor of death and disability in the UK and costs the NHS £3.5 billion per year. Despite the high prevalence and healthcare burden of Alcohol-related Liver Disease (ArLD), there has been minimal research addressing prevention, morbidity and mortality. Reasons for this include stigma and lack of interest from public, charitable and commercial funding bodies. The objectives of this project were to identify and develop interdisciplinary partnerships, to explore stigma in ArLD, to develop a representative Patient and Public Involvement and Engagement (PPIE) group, to build research capacity, and to develop interdisciplinary research proposals targeting key research priorities., Methods: ArLD networks were identified by members of the Project Steering Group. Health Care Professionals (HCPs) from different backgrounds were invited to join the ARMS-Hub. PPIE representatives were invited through charities and support groups. Research areas were identified, discussed, prioritised and ranked. Research questions were refined during an in-person symposium. A mentorship programme was created to encourage and facilitate networking and knowledge exchange for early career researchers., Results: We established the ARMS-Hub with 31 HCPs and 40 PPIE members. There were five stakeholder meetings, which included PPIE representation. Three virtual and three in-person PPIE meetings took place. Topics relevant to stigma in ARLD identified during the meetings were education and awareness, language, and access. Priorities identified were the disconnect between mental health and liver services, education around the wider harms of alcohol, and education of HCPs regarding stigma. We established a mentorship network that regularly meets to support development of new research ideas., Conclusions: Stigma is central to lack of research engagement from professionals and PPIE. The main priority identified relates to the disconnect between mental health and liver services. This collaborative study has allowed development of a research agenda to address this priority., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Dhanda A et al.)

Competing Interests: Competing interests: None declared.

Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4 + T-helper subset distribution and enhanced production of pro-inflammatory cytokines such as interleukin 17A and interferon gamma. The role of monocytes (MCs) in ITP is less widely described, but innate immune cells have a role in shaping CD4 + T-cell phenotypes. Glucocorticoids (GCs) are commonly used for first-line ITP treatment and modulate a broad range of immune cells including T cells and MCs. Using multiparameter flow cytometry analysis, we demonstrate the expansion of intermediate MCs (CD14 ++ CD16 + ) in untreated patients with newly diagnosed ITP, with these cells displaying a pro-inflammatory phenotype, characterised by enhanced expression of CD64 and CD80. After 2 weeks of prednisolone treatment (1 mg/kg daily), the proportion of intermediate MCs reduced, with enhanced expression of the anti-inflammatory markers CD206 and CD163. Healthy control MCs were distinctly different than MCs from patients with ITP before and after GC treatment. Furthermore, the GC-induced phenotype was not observed in patients with chronic ITP receiving thrombopoietin receptor agonists. These data suggest a role of MCs in ITP pathogenesis and clinical response to GC therapy., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons.)