Adverse cardiovascular events in rheumatoid arthritis patients treated with JAK inhibitors: An analysis of postmarketing spontaneous safety reports.

OBJECTIVES: The ORAL Surveillance trial, a postmarketing safety clinical trial, found an increased risk of adverse cardiovascular events and venous thromboembolism (VTE) in patients treated with Janus Kinase (JAK) inhibitors compared to tumor necrosis factor (TNF) inhibitors. However, additional studies yielded mixed results and data on other JAK inhibitors are limited. METHODS: A retrospective, pharmacovigilance study using the FDA adverse event reporting system (FAERS) to assess reporting of adverse cardiovascular events following treatment with JAK inhibitors in rheumatoid arthritis (RA) patients between January 2015 and June 2023. To identify disproportionately increased reporting, an adjusted reporting odds ratio (adj.ROR) was calculated with a multivariable logistic regression model. RESULTS: We identified safety reports of 75,407 RA patients treated with JAK inhibitors (tofacitinib, n = 52,181; upadacitinib, n = 21,006; baricitinib, n = 2,220) and 303,278 patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs; TNF inhibitors, rituximab, and tocilizumab). The mean age was 61.2(±12) and 59.0(±13), respectively; 82 % and 81 % were women. Compared to bDMARDs, JAK inhibitors were associated with an increased reporting of VTE [n = 1,393, adj.ROR=2.11 (1.97-2.25)], stroke [n = 973, adj.ROR=1.25 (1.16-1.34)], ischemic heart disease [IHD, n = 999, adj.ROR=1.23 (1.13-1.33)], peripheral edema [n = 2699, adj.ROR=1.22 (1.17-1.28)], and tachyarrhythmias [n = 370, adj.ROR=1.15 (1.00-1.33)]. Most of the events occurred in the first year after treatment initiation. When different JAK inhibitors were compared, VTE, stroke, and IHD were more frequently reported with upadacitinib and baricitinib than tofacitinib. When stratified by age category, all safety signals were statistically significant in patients aged≤65 years. CONCLUSION: In this global postmarketing study, JAK inhibitors are associated with increased reporting of VTE, stroke, IHD, and tachyarrhythmias. These adverse events were reported following all JAK inhibitors that were studied, suggesting a class effect.

Exploring the Link Between Ankylosing Spondylitis and Inflammatory Bowel Disease: A Retrospective Cohort Study.

BACKGROUND: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are chronic conditions with overlapping pathogenic mechanisms. The genetic predisposition and inflammatory pathways common to both diseases suggest a syndemic relationship. While some evidence points to a connection between the two conditions, other reports do not support this link. OBJECTIVES: To investigate the association between AS and the subsequent incidence of IBD. To identify potential risk factors and effect modifiers that contribute to this relationship. METHODS: Utilizing the Chronic Disease Registry of Clalit Health Services, we conducted a retrospective cohort study of individuals diagnosed with AS between January 2002 and December 2018. We compared these patients with age- and sex-matched controls, excluding those with a prior diagnosis of IBD. Statistical analyses included chi-square and t-tests for demographic comparisons, and Cox proportional hazards models for evaluating the risk of IBD development, with adjustments for various co-morbidities and demographic factors. RESULTS: The study included 5825 AS patients and 28,356 controls. AS patients demonstrated a significantly higher incidence of IBD with hazard ratios of 6.09 for Crohn's disease and 2.31 for ulcerative colitis, after multivariate adjustment. The overall incidence of IBD in the AS cohort was significantly higher compared to controls. CONCLUSIONS: AS patients exhibit a markedly increased risk of developing IBD. These findings advocate for heightened clinical vigilance for IBD symptoms in AS patients and suggest the need for a multidisciplinary approach to patient care. Further research into the shared pathogenic pathways is needed to develop personalized treatment strategies and improve patient management.

Ecogastroenterology: cultivating sustainable clinical excellence in an environmentally conscious landscape.

Gastrointestinal practices, especially endoscopy, have a substantial environmental impact, marked by notable greenhouse gas emissions and waste generation. As the world struggles with climate change, there emerges a pressing need to re-evaluate and reform the environmental footprint within gastrointestinal medicine. The challenge lies in finding a harmonious balance between ensuring clinical effectiveness and upholding environmental responsibility. This task involves recognising that the most significant reduction in the carbon footprint of endoscopy is achieved by avoiding unnecessary procedures; addressing the use of single-use endoscopes and accessories; and extending beyond the procedural suites to include clinics, virtual care, and conferences, among other aspects of gastrointestinal practice. The emerging digital realm in health care is crucial, given the potential environmental advantages of virtual gastroenterological care. Through an in-depth analysis, this review presents a path towards sustainable gastrointestinal practices, emphasising integrated strategies that prioritise both patient care and environmental stewardship.

Deep Learning and Gastric Cancer: Systematic Review of AI-Assisted Endoscopy.

BACKGROUND: Gastric cancer (GC), a significant health burden worldwide, is typically diagnosed in the advanced stages due to its non-specific symptoms and complex morphological features. Deep learning (DL) has shown potential for improving and standardizing early GC detection. This systematic review aims to evaluate the current status of DL in pre-malignant, early-stage, and gastric neoplasia analysis. METHODS: A comprehensive literature search was conducted in PubMed/MEDLINE for original studies implementing DL algorithms for gastric neoplasia detection using endoscopic images. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The focus was on studies providing quantitative diagnostic performance measures and those comparing AI performance with human endoscopists. RESULTS: Our review encompasses 42 studies that utilize a variety of DL techniques. The findings demonstrate the utility of DL in GC classification, detection, tumor invasion depth assessment, cancer margin delineation, lesion segmentation, and detection of early-stage and pre-malignant lesions. Notably, DL models frequently matched or outperformed human endoscopists in diagnostic accuracy. However, heterogeneity in DL algorithms, imaging techniques, and study designs precluded a definitive conclusion about the best algorithmic approach. CONCLUSIONS: The promise of artificial intelligence in improving and standardizing gastric neoplasia detection, diagnosis, and segmentation is significant. This review is limited by predominantly single-center studies and undisclosed datasets used in AI training, impacting generalizability and demographic representation. Further, retrospective algorithm training may not reflect actual clinical performance, and a lack of model details hinders replication efforts. More research is needed to substantiate these findings, including larger-scale multi-center studies, prospective clinical trials, and comprehensive technical reporting of DL algorithms and datasets, particularly regarding the heterogeneity in DL algorithms and study designs.

A comparative systematic review and meta-analysis on the diagnostic accuracy of non-invasive tests for Helicobacter pylori detection in elderly patients.

Background: Helicobacter pylori (H. pylori) infection, a type I carcinogen, affects approximately 50% of the global population, correlating with various gastric pathologies. Notably, diagnostic sensitivities of non-invasive methods, such as the stool antigen test (HpSA), Serology, and Urea Breath Test (UBT), have been suggested to be less effective in older age groups. This study systematically reviews and meta-analyzes the diagnostic accuracy of these tests within the elderly population. Methods: A comprehensive literature search was performed across multiple databases, including PubMed, Medline, and Web of Science, up to July 2023. Data were pooled and analyzed using random-effects models. Sensitivity, specificity, and Diagnostic Odds Ratios (DOR) were computed for the tests. Heterogeneity and risk of bias were assessed. Results: Eight studies involving diverse geographic locations and totaling between 46 and 1,441 participants per study were included. The pooled sensitivity and specificity for HpSA were 72.5 and 94.7%, for Serology 83.7 and 73.3%, and for UBT 96.4 and 88.3%, respectively. DOR for UBT, HpSA, and Serology were 94.5, 47.9, and 14.2, respectively. High levels of heterogeneity were observed across the studies. Conclusion: UBT and HpSA proved effective for diagnosing H. pylori in those over 60, while serology showed lower specificity. Despite methodological variations in available studies, these non-invasive tests offer reliable alternatives, especially for older patients who recently undergone endoscopy or without an indication for it, warranting consideration by healthcare practitioners.

Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review.

Celiac disease (CD) presents a complex interplay of both innate and adaptive immune responses that drive a variety of pathological manifestations. Recent studies highlight the role of immune-mediated pathogenesis, pinpointing the involvement of antibodies against tissue transglutaminases (TG2, TG3, TG6), specific HLA molecules (DQ2/8), and the regulatory role of interleukin-15, among other cellular and molecular pathways. These aspects illuminate the systemic nature of CD, reflecting its wide-reaching impact that extends beyond gastrointestinal symptoms to affect other physiological systems and giving rise to a range of pathological landscapes, including refractory CD (RCD) and, in severe cases, enteropathy-associated T cell lymphoma. The existing primary therapeutic strategy, a gluten-free diet (GFD), poses significant challenges, such as low adherence rates, necessitating alternative treatments. Emerging therapies target various stages of the disease pathology, from preventing immunogenic gluten peptide absorption to enhancing intestinal epithelial integrity and modulating the immune response, heralding potential breakthroughs in CD management. As the understanding of CD deepens, novel therapeutic avenues are emerging, paving the way for more effective and sophisticated treatment strategies with the aim of enhancing the quality of life of CD patients. This review aims to delineate the immunopathology of CD and exploring its implications on other systems, its complications and the development of novel treatments.

Gastric Perforation After Microwave Ablation to Adjacent Hepatocellular Lesion.

Locoregional treatment modalities for hepatocellular carcinoma are generally effective and safe and benefit the subset of patients who are not eligible for surgery or have marginal hepatic function. This case report discusses a 77-year-old patient with cirrhosis who underwent microwave lesion ablation for 3 hepatocellular carcinoma nodules. On the 12th day after ablation, the patient was diagnosed with a perforation of the anterior wall of the stomach near one of the target ablation sites on the left side of the liver. The patient underwent surgical therapy with clinical improvement. This report highlights the potential risks associated with microwave ablation for hepatocellular carcinoma.

The association between ankylosing spondylitis and psychiatric disorders: Insights from a population based cross-sectional database.

BACKGROUND: Ankylosing spondylitis (AS) is an inflammatory rheumatic disease involving the axial skeleton ultimately resulting in physical disability and psychological sequalae. The current study aims to evaluate the link between AS and psychiatric disorders, and to investigate the impact of different disease modifying drugs on such link. METHODS: A large retrospective, population-based, cross-sectional study utilizing the Clalit-Health-Service (CHS) database was conducted on 5825 AS patients and 25,984 age- and sex-matched control individuals. The prevalence of psychiatric morbidity was compared between AS patients and age- and gender-matched controls. Predictors for psychiatric disorders in AS patients were also investigated. RESULTS: The prevalence of psychiatric morbidity was higher in AS patients compared to controls (13.8 % vs. 9.8 %, p < 0.001). Similarly, major depression was positively associated with AS (OR 1.60, 95 % CI 1.43-1.79, p < 0.001), however, schizophrenia was negatively associated with AS (OR 0.60, 95 % CI 0.42-0.89, p < 0.011). Conventional DMARDs (cDMARDs) and anti-TNF used for management of AS were not shown to be predictors for psychiatric illnesses in AS patients. CONCLUSIONS: Patients with AS are at a higher risk of developing psychiatric disorders, with increased risk of depression and lower risk of schizophrenia. cDMARDs and TNF-inhibitors are not predictors of psychiatric disorders in AS patients.

Artificial neural networks can be effectively used to model changes of intracranial pressure (ICP) during spinal surgery using different noninvasive ICP surrogate estimators.

BACKGROUND: Artificial intelligence (AI) techniques play a major role in anesthesiology, even though their importance is often overlooked. In the extant literature, AI approaches, such as artificial neural networks (ANNs), have been underutilized, being used mainly to model patient's consciousness state, to predict the precise number of anesthetic gases, the level of analgesia, or the need of anesthesiological blocks, among others. In the field of neurosurgery, ANNs have been effectively applied to the diagnosis and prognosis of cerebral tumors, seizures, low back pain, and also to the monitoring of intracranial pressure (ICP). METHODS: A multilayer perceptron (MLP), which is a feedforward ANN, with hyperbolic tangent as activation function in the input/hidden layers, softmax as activation function in the output layer, and cross-entropy as error function, was used to model the impact of prone versus supine position and the use of positive end expiratory pressure (PEEP) on ICP in a sample of 30 patients undergoing spinal surgery. Different noninvasive surrogate estimations of ICP have been used and compared: namely, mean optic nerve sheath diameter (ONSD), noninvasive estimated cerebral perfusion pressure (NCPP), Pulsatility Index (PI), ICP derived from PI (ICP-PI), and flow velocity diastolic formula (FVDICP). RESULTS: ONSD proved to be a more robust surrogate estimation of ICP, with a predictive power of 75%, whilst the power of NCPP, ICP-PI, PI, and FVDICP were 60.5%, 54.8%, 53.1%, and 47.7%, respectively. CONCLUSIONS: Our MLP analysis confirmed our findings previously obtained with regression, correlation, multivariate receiving operator curve (multi-ROC) analyses. ANNs can be successfully used to predict the effects of prone versus supine position and PEEP on ICP in patients undergoing spinal surgery using different noninvasive surrogate estimators of ICP.

Are Chronic Pain Syndromes the Reason for Statin-associated Muscle Symptoms?

BACKGROUND: Statin-induced myalgia is defined as muscle pain without elevation of serum creatine phosphokinase levels and is a well-known complaint among statin users. Chronic pain syndromes affect a high percentage of the population. These pain syndromes may confound the reports of statin-induced myalgia. OBJECTIVES: To compare the occurrence of chronic pain among patients on statin therapy who developed myalgia with those who did not. METHODS: This study included 112 statin-treated patients, who were followed at the lipid center at Sheba Medical Center. Fifty-six patients had a diagnosis of statin-associated muscle symptoms (SAMS) and 56 did not. Verified questionnaires were used to assess the diagnoses of fibromyalgia, pain intensity, functional impairment, anxiety, and depression in the study population. RESULTS: Patients with statin myalgia were more likely to fulfil the diagnostic criteria for fibromyalgia than patients without statin myalgia (11 [19.6%] vs. 0, respectively). Patients in the SAMS group exhibited higher levels of anxiety and depression compared with the control group. Female sex, higher scores on the Brief Pain Inventory pain intensity scale, and a Hamilton rating scale level indicative of an anxiety disorder were found to be significant predictors for fibromyalgia in patients presenting with statin myalgia. CONCLUSIONS: A significant percentage of patients diagnosed with statin myalgia fulfilled the diagnostic criteria for fibromyalgia depression or anxiety disorder. Detection of these patients and treatment of their primary pain disorders or psychiatric illnesses has the potential to prevent unnecessary cessation of effective statin therapy.

The Putative Adverse Effects of Bisphenol A on Autoimmune Diseases.

Bisphenol A (BPA) is a monomer that is widely used in the manufacturing of polycarbonate plastics (including storage plastics and baby bottles) and is considered to be one of the most widely used synthetic compounds in the manufacturing industry. Exposure to BPA mainly occurs after oral ingestion and results from leaks into food and water from plastic containers. According to epidemiological data, exposure is widespread and estimated to occur in 90% of individuals. BPA exhibits pleiotropic and estrogen-like effects; thus, it is considered an endocrine-disrupting chemical. A growing body of evidence highlights the role of BPA in modulating immune responses and signaling pathways, which results in a proinflammatory response by enhancing the differential polarization of immune cells and cytokine production profile to one that is consistent with proinflammation. Indeed, epidemiological studies have uncovered associations between several autoimmune diseases and BPA exposure. Data from animal models provided consistent evidence, which highlighted the role of BPA in the pathogenesis, exacerbation, and perpetuation of various autoimmune phenomena including neuroinflammation in the context of multiple sclerosis, colitis in inflammatory bowel disease, nephritis in systemic lupus erythematosus, and insulitis in type 1 diabetes mellitus. Owing to the widespread use of BPA and its effects on immune system dysregulation, a call for careful assessment of patients' risks and public health measures are needed to limit exposure and subsequent deleterious effects. The purpose of this study is to explore the autoimmune triggering mechanisms and present the current literature supporting the role of BPA in the pathogenesis of autoimmune diseases.

The risk of depression and anxiety in patients with familial mediterranean fever - a cross-sectional study.

BACKGROUND: Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease associated with various systemic comorbidities. Recent research regarding the association with depression and anxiety has yielded conflicting results. The current study aims were to examine whether such an association exists using big data analysis methodology. METHODS: This study was conducted as a cross-sectional analysis based on the Clalit Health Services database. We compared the proportions of depression and anxiety in patients diagnosed with FMF and age- and sex- matched controls. We used the Chi-square test and T-test for univariate analysis. Multivariate logistic regression was then applied to control for possible confounding variables. RESULTS: The study included 7,670 patients with FMF and 7,670 matched controls. The prevalence of both depression and anxiety was found to be higher in the FMF group as compared to controls (6.22% and 4.58%, respectively, p<0.001, and 4.93% and 3.14%, respectively, p<0.001). These proportions remained significant after adjusting for important confounders, such as smoking and socioeconomic status. LIMITATIONS: Temporal association does not indicate a causal relationship, the validity of the diagnoses relies on clinical records and is not based on formal classifications or diagnostic criteria, information regarding disease duration and other parameters were not accessible. CONCLUSIONS: Our data imply that FMF is independently associated with both depression and anxiety. These findings highlight the importance of raising awareness for these comorbidities.

SARS-CoV-2 Infection Induces Psoriatic Arthritis Flares and Enthesis Resident Plasmacytoid Dendritic Cell Type-1 Interferon Inhibition by JAK Antagonism Offer Novel Spondyloarthritis Pathogenesis Insights.

Objective: Bacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares. Methods: Normal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated. Results: CD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection). Conclusion: Entheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.

Why Inhibition of IL-23 Lacked Efficacy in Ankylosing Spondylitis.

The term spondyloarthritis pertains to both axial and peripheral arthritis including ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which is strongly linked to psoriasis and also the arthritis associated with inflammatory bowel disease. The argument supporting the role for IL-23 across the spectrum of SpA comes from 4 sources. First, genome wide associated studies (GWAS) have shown that all the aforementioned disorders exhibit IL-23R pathway SNPs, whereas HLA-B27 is not linked to all of these diseases-hence the IL-23 pathway represents the common genetic denominator. Secondly, experimental animal models have demonstrated a pivotal role for the IL-23/IL-17 axis in SpA related arthropathy that initially manifests as enthesitis, but also synovitis and axial inflammation and also associated aortic root and cutaneous inflammation. Thirdly, the emergent immunology of the human enthesis also supports the presence of IL-23 producing myeloid cells, not just at the enthesis but in other SpA associated sites including skin and gut. Finally, drugs that target the IL-23 pathway show excellent efficacy for skin disease, efficacy for IBD and also in peripheral arthropathy associated with SpA. The apparent failure of IL-23 blockade in the AS which is effectively a spinal polyenthesitis but evidence for efficacy of IL-23 inhibition for peripheral enthesitis in PsA and preliminary suggestions for benefit in axial PsA, raises many questions. Key amongst these is whether spinal inflammation may exhibit entheseal IL-17A production independent of IL-23 but peripheral enthesitis is largely dependent on IL-23 driven IL-17 production. Furthermore, IL-23 blocking strategies in animal models may prevent experimental SpA evolution but not prevent established disease, perhaps pointing towards a role for IL-23 in innate immune disease initiation whereas persistent disease is dependent on memory T-cell responses that drive IL-17A production independently of IL-23, but this needs further study. Furthermore, IL-12/23 posology in inflammatory bowel disease is substantially higher than that used in AS trials which merits consideration. Therefore, the IL-23 pathway is centrally involved in the SpA concept but the nuances and intricacies in axial inflammation that suggest non-response to IL-23 antagonism await formal definition. The absence of comparative immunology between the different skeletal sites renders explanations purely hypothetical at this juncture.

Regulation of entheseal IL-23 expression by IL-4 and IL-13 as an explanation for arthropathy development under dupilumab therapy.

OBJECTIVES: Dupilumab blocks the IL-4 receptor (IL-4R) and thus signalling of the 'Th2' cytokines IL-4 and IL-13. It has a license to treat atopic eczema and was recently linked to emergent enthesitis and psoriasis. We investigated the cellular and functional basis for how IL-4/IL-13 regulates the IL-23-IL-17 axis in entheseal stromal, myeloid and lymphocyte cells. METHODS: Immunohistochemistry was performed on healthy enthesis samples from patients undergoing elective spinal surgery to investigate entheseal tissue IL-4R expression and cytokine expression by intracellular flow cytometry for IL-4 and IL-13. Digested human enthesis samples were stimulated with lipopolysaccharide (LPS) for IL-23 induction, either alone or with IL-4 or IL-13. Enthesis fibroblasts were stimulated with TNF and IL-17 with and without IL-4 or IL-13 to assess the effect on CCL20 secretion. Synovial fluid samples from PsA patients were also analysed by ELISA for levels of IL-4 and IL-13. RESULTS: The IL-4/IL-13 receptor was present in both the peri-entheseal bone and enthesis soft tissue, and entheseal-derived T cells produced basal levels of IL-4, but not IL-13. Both IL-4 and IL-13 attenuated LPS-induced entheseal IL-23 production. IL-4 also downregulated secretion of TNF/IL-17A-induced CCL20 from entheseal fibroblasts. Both IL-13 and IL-4 were also detectable in the synovial fluid of PsA patients. We also noted a seronegative inflammatory oligoarthritis whilst under dupilumab therapy. CONCLUSION: Our findings suggest a previously unknown protective role for IL-4/IL-13 in entheseal induction of the IL-23-IL-17 axis. These findings point towards a novel explanation for IL-13 pathway single nucleotide polymorphisms in PsA and also a molecular explanation for why anti-IL-4/IL-13 therapy may induce musculoskeletal entheseal pathology as recently reported.

Normal human enthesis harbours conventional CD4+ and CD8+ T cells with regulatory features and inducible IL-17A and TNF expression.

BACKGROUND: The human enthesis conventional T cells are poorly characterised. OBJECTIVES: To study the biology of the conventional T cells in human enthesis. METHODS: CD4+ and CD8+ T cells were investigated in 25 enthesis samples using immunofluorescence, cytometrically, bulk RNAseq and quantitative real-time PCR following anti-CD3/CD28 bead stimulation to determine interleukin (IL)-17A and tumour necrosis factor (TNF) levels. T-cell receptor (TCR) repertoires were characterised and a search for putative T-cell reactivity was carried out using TCR3 database. The impact of pharmacological antagonism with retinoic acid receptor-related orphan nuclear receptor gamma t inhibitor (RORγti), methotrexate and phosphodiesterase type 4 inhibitor (PDE4i) was investigated. RESULTS: Immunofluorescence and cytometry suggested entheseal resident CD4+ and CD8+ T cells with a resident memory phenotype (CD69+/CD45RA-) and tissue residency gene transcripts (higher NR4A1/AhR and lower KLF2/T-bet transcripts). Both CD4+ and CD8+ T cells showed increased expression of immunomodulatory genes including IL-10 and TGF-ß compared with peripheral blood T cells with entheseal CD8+ T cells having higher CD103, CD49a and lower SIPR1 transcript that matched CD4+ T cells. Following stimulation, CD4+ T cells produced more TNF than CD8+ T cells and IL-17A was produced exclusively by CD4+ T cells. RNAseq suggested both Cytomegalovirus and influenza A virus entheseal resident T-cell clonotype reactivity. TNF and IL-17A production from CD4+ T cells was effectively inhibited by PDE4i, while RORγti only reduced IL-17A secretion. CONCLUSIONS: Healthy human entheseal CD4+ and CD8+ T cells exhibit regulatory characteristics and are predicted to exhibit antiviral reactivity with CD8+ T cells expressing higher levels of transcripts suggestive of tissue residency. Inducible IL-17A and TNF production can be robustly inhibited in vitro.

The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease.

Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.

Interleukin-23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy.

The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL-23R or the interleukin-23 (IL-23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin-17 (IL-17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL-23R-expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL-23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL-23R-expressing myeloid cells and various innate and adaptive T cells that produce IL-17 family cytokines have also been described in the human enthesis. Blockade of IL-23 pathway with either anti-p40 or anti-p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL-23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

The novel cytokine Metrnl/IL-41 is elevated in Psoriatic Arthritis synovium and inducible from both entheseal and synovial fibroblasts.

Meteorin-like(IL-41), is a novel cytokine that is thought to be immunoregulatory and is highly expressed in psoriatic skin. We investigated IL-41 protein expression in synovial tissue in RA(Rheumatoid Arthritis), PsA(Psoriatic Arthritis) and OA(Osteoarthritis) patients and evaluated IL-41 production from healthy enthesis samples, as the enthesis represent the primary inflammatory site in PsA. IL-41 was measured in synovial fluid from PsA, RA and OA patients. Synovial biopsies were stained for IL-41 by immunohistochemistry. IL-41 was highly expressed in the synovial fluid and synovial tissue of PsA patients (median = 7722 pg/ml) when compared to OA patients (median = 5044 pg/ml). We found that entheseal stromal cells were the dominant producer of IL-41 from the enthesis. Moreover, stromal derived IL-41, could be further induced by IL-17A/F and TNF. In conclusion, IL-41 is expressed in PsA synovium and is present and inducible at the enthesis. Its functional effect in psoriatic inflammation remains to be fully elucidated.

HPV vaccines and lupus: current approaches towards preventing adverse immune cross-reactivity.

INTRODUCTION: If not properly treated, human papillomavirus (HPV) infection may evolve from a common sexually transmitted disease to genital warts and cervical cancer. Various prophylactic HPV vaccines (HPVv), approved to reduce the incidence of the infection, have been found to be effective and safe; however, accounts of post-vaccination autoimmune phenomena, including systemic lupus erythematosus (SLE), have been reported in genetically susceptible individuals. AREAS COVERED: Infectious agents play a role in breaking the immunologic tolerance to self-antigens, resulting in autoimmune events. There is molecular evidence supporting the involvement of HPV in SLE, with a high prevalence of L1 HPV peptide homology to proteins being associated with SLE. Therefore, approaches in vaccine preparations aiming to prevent adverse immune cross-reactivity are sought. Performing a broad search of the literature, we review the association between SLE, HPV, and HPVv, with a focus on the mechanisms of molecular mimicry and cross-reactivity, and the approaches currently being elaborated towards preventing such phenomena. EXPERT COMMENTARY: The advantages of using low-similarity peptide antigens may be two-fold, abolishing the risk of cross-reactivity and eliminating the vaccine adjuvantation procedure. Vaccines based on pathogen unique sequences would provide effective vaccine preparation while curbing the risk for the human host.