Pulmonary hypertension in juvenile-onset systemic lupus erythematosus: a case series

OBJECTIVES: Systemic lupus erythematosus (SLE) is a rare multisystem autoimmune disorder with a variable clinical phenotype. Pulmonary hypertension (PHTN) is a recognised (and not uncommonly asymptomatic) complication of the condition with an associated poor prognosis in adults. It is relatively rare in juvenile-onset SLE (JSLE). METHODS: We present a retrospective descriptive case series of four female children aged 4 to 15 years at presentation of JSLE and aged 8 to 27 years at time of diagnosis of PHTN from the United Kingdom. All cases were identified through the UK JSLE Cohort Study. RESULTS: Of 665 children with JSLE in the UK cohort study to date (data from 2006–2020), four (0.6%) were identified as having PHTN. 3/4 of the PHTN cases presented with cardiovascular symptoms and / or signs at presentation. 3/4 were treated with Rituximab and had a good long-term outcome. Shared clinical features include high baseline disease activity scores. CONCLUSION: JSLE has a high associated cardiovascular morbidity and mortality and early identification of treatable complications such as PHTN is vital. We suggest that children with high baseline disease activity scores and those presenting with cardiovascular symptoms and signs are most likely to have concurrent PHTN. Routine echocardiography is an effective screening tool and should be used as part of a standard diagnostic work-up

Drug Development and Clinical Trials Translational Medicine Medicine for MRCP

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The Impact of Immunocompromise on Outcomes of COVID-19 in Children and Young People - A Systematic Review and Meta-Analysis

Background: Despite children and young people (CYP) having a low risk for severe Coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated. Methods: A comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31st October 2021 (to exclude vaccinated populations), was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalisation and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity. Findings: The systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP (n=793) and CYP in general population (n=102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%) and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared to CYP in general population. This shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies. Interpretation: This is the only up to date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalised cohorts alone and included 35% studies from low- and medium-income countries. Future research is required to characterise individual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes. Funding: There was no funding source specifically dedicated for this study. CC is supported by a National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospital (UCLH). The study was performed within the Centre for Adolescent Rheumatology Versus Arthritis at University College London (UCL), UCL Hospital and Great Ormond Street Hospital (GOSH) supported by grants from Versus Arthritis (21593 and 20164), Great Ormond Street Children’s Charity, and the NIHR-BRC at both GOSH and UCLH

CD8+ T Cell Phenotype and Function in Childhood and Adult-Onset Connective Tissue Disease

CD8+ T cells are cytotoxic lymphocytes that destroy pathogen infected and malignant cells through release of cytolytic molecules and proinflammatory cytokines. Although the role of CD8+ T cells in connective tissue diseases (CTDs) has not been explored as thoroughly as that of other immune cells, research focusing on this key component of the immune system has recently gained momentum. Aberrations in cytotoxic cell function may have implications in triggering autoimmunity and may promote tissue damage leading to exacerbation of disease. In this comprehensive review of current literature, we examine the role of CD8+ T cells in systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, polymyositis, and dermatomyositis with specific focus on comparing what is known about CD8+ T cell peripheral blood phenotypes, CD8+ T cell function, and CD8+ T cell organ-specific profiles in adult and juvenile forms of these disorders. Although, the precise role of CD8+ T cells in the initiation of autoimmunity and disease progression remains to be elucidated, increasing evidence indicates that CD8+ T cells are emerging as an attractive target for therapy in CTDs

Sex Differences in Lipid Metabolism: Implications for Systemic Lupus Erythematosus and Cardiovascular Disease Risk

It is known that healthy women during childbearing years have a lower risk of cardiovascular disease (CVD) and coronary heart disease compared to age matched men. Various traditional risk factors have been shown to confer differential CVD susceptibilities by sex. Atherosclerosis is a major cause of CVD and mortality and sex differences in CVD risk could be due to reduced atherogenic low and very low-density lipoproteins (LDL and VLDL) and increased atheroprotective high density lipoproteins (HDLs) in women. In contrast, patients with systemic lupus erythematosus (SLE), a chronic inflammatory disease that predominately affects women, have an increased atherosclerotic and CVD risk. This increased CVD risk is largely associated with dyslipidaemia, the imbalance of atherogenic and atheroprotective lipoproteins, a conventional CVD risk factor. In many women with SLE, dyslipidaemia is characterised by elevated LDL and reduced HDL, eradicating the sex-specific CVD protection observed in healthy women compared to men. This review will explore this paradox, reporting what is known regarding sex differences in lipid metabolism and CVD risk in the healthy population and transgender individuals undergoing cross-sex hormone therapy, and provide evidence for how these differences may be compromised in an autoimmune inflammatory disease setting. This could lead to better understanding of mechanistic changes in lipid metabolism driving the increased CVD risk by sex and in autoimmunity and highlight potential therapeutic targets to help reduce this risk

CD8+ T-Cells in Juvenile-Onset SLE: From Pathogenesis to Comorbidities

Diagnosis of systemic lupus erythematosus (SLE) in childhood [juvenile-onset (J) SLE], results in a more severe disease phenotype including major organ involvement, increased organ damage, cardiovascular disease risk and mortality compared to adult-onset SLE. Investigating early disease course in these younger JSLE patients could allow for timely intervention to improve long-term prognosis. However, precise mechanisms of pathogenesis are yet to be elucidated. Recently, CD8+ T-cells have emerged as a key pathogenic immune subset in JSLE, which are increased in patients compared to healthy individuals and associated with more active disease and organ involvement over time. CD8+ T-cell subsets have also been used to predict disease prognosis in adult-onset SLE, supporting the importance of studying this cell population in SLE across age. Recently, single-cell approaches have allowed for more detailed analysis of immune subsets in JSLE, where type-I IFN-signatures have been identified in CD8+ T-cells expressing high levels of granzyme K. In addition, JSLE patients with an increased cardiometabolic risk have increased CD8+ T-cells with elevated type-I IFN-signaling, activation and apoptotic pathways associated with atherosclerosis. Here we review the current evidence surrounding CD8+ T-cell dysregulation in JSLE and therapeutic strategies that could be used to reduce CD8+ T-cell inflammation to improve disease prognosis

Multi-Omic Biomarkers for Patient Stratification in Sjogren's Syndrome—A Review of the Literature

Sjögren's syndrome (SS) is a heterogeneous autoimmune rheumatic disease (ARD) characterised by dryness due to the chronic lymphocytic infiltration of the exocrine glands. Patients can also present other extra glandular manifestations, such as arthritis, anaemia and fatigue or various types of organ involvement. Due to its heterogenicity, along with the lack of effective treatments, the diagnosis and management of this disease is challenging. The objective of this review is to summarize recent multi-omic publications aiming to identify biomarkers in tears, saliva and peripheral blood from SS patients that could be relevant for their better stratification aiming at improved treatment selection and hopefully better outcomes. We highlight the relevance of pro-inflammatory cytokines and interferon (IFN) as biomarkers identified in higher concentrations in serum, saliva and tears. Transcriptomic studies confirmed the upregulation of IFN and interleukin signalling in patients with SS, whereas immunophenotyping studies have shown dysregulation in the immune cell population frequencies, specifically CD4+and C8+T activated cells, and their correlations with clinical parameters, such as disease activity scores. Lastly, we discussed emerging findings derived from different omic technologies which can provide integrated knowledge about SS pathogenesis and facilitate personalised medicine approaches leading to better patient outcomes in the future