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  • Journal article
    Austin K, Janagan S, Wells M, Crawshaw H, McAdoo S, Robson JCet al., 2022,

    ANCA associated vasculitis subtypes: response [response to letter]

    , Journal of Inflammation Research, Vol: 15, Pages: 5687-5688, ISSN: 1178-7031
  • Journal article
    Abhishek A, Boyton RJ, Peckham N, McKnight Á, Coates LC, Bluett J, Barber V, Cureton L, Francis A, Appelbe D, Eldridge L, Julier P, Valdes AM, Brooks T, Rombach I, Altmann DM, Nguyen-Van-Tam JS, Williams HC, Cook JA, VROOM study investigatorset al., 2022,

    Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial

    , The Lancet Respiratory Medicine, Vol: 10, Pages: 840-850, ISSN: 2213-2600

    BACKGROUND: Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. METHODS: We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. FINDINGS: Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the co

  • Conference paper
    Maughan R, Porter A, Dahanayake C, Ianonne C, Alapat R, Pericleous C, Youngstein T, Mason Jet al., 2022,

    Evaluating the Safety and Factors Associated with Treatment Cessation in Takayasu Arteritis

    , Publisher: WILEY, Pages: 4568-4569, ISSN: 2326-5191
  • Conference paper
    Chilcott J, Mcbeath K, Cole G, Gopalan D, Chaidos A, Ros-Soto J, Atta M, Barton C, Youngstein T, Plymen Cet al., 2022,

    Development of a new cardiac amyloid multidisciplinary team in a tertiary London centre

    , Publisher: WILEY, Pages: 104-105, ISSN: 1388-9842
  • Journal article
    Wilson-Morkeh H, Frise C, Youngstein T, 2022,

    Haemophagocytic lymphohistiocytosis in pregnancy

    , Obstetric Medicine, Vol: 15, Pages: 79-90, ISSN: 1753-4968

    Haemophagocytic lymphohistiocytosis is a life-threatening systemic inflammatory syndrome defined by persistent fever, cytopenia and multi-organ dysfunction. Primary haemophagocytic lymphohistiocytosis classically presents in childhood as a result of genetically abnormal perforin or inflammasome function, leading to the aberrant release of pro-inflammatory cytokines causing a hyperinflammatory state. Secondary haemophagocytic lymphohistiocytosis is an acquired phenomenon occurring at any age as a result of immune dysregulation to a specific trigger such as infection, haematological malignancy or autoimmune disease. Secondary haemophagocytic lymphohistiocytosis occurring in the pregnant woman represents a diagnostic challenge and carries a significant mortality. This has led to its first inclusion in the fourth Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the United Kingdom annual maternal report in 2017. This article presents an overview of haemophagocytic lymphohistiocytosis, reviews the literature on haemophagocytic lymphohistiocytosis in pregnancy, suggests diagnostic pathways and explores the safety and efficacy of existing and potential treatment strategies for haemophagocytic lymphohistiocytosis occurring during pregnancy.

  • Journal article
    Rosas IO, Brau N, Waters M, Go RC, Malhotra A, Hunter BD, Bhagani S, Skiest D, Savic S, Douglas IS, Garcia-Diaz J, Aziz MS, Cooper N, Youngstein T, Del Sorbo L, De La Zerda DJ, Ustianowski A, Gracian AC, Blyth KG, Carratala J, Francois B, Benfield T, Haslem D, Bonfanti P, van der Leest CH, Rohatgi N, Wiese L, Luyt CE, Bauer RN, Cai F, Lee IT, Matharu B, Metcalf L, Wildum S, Graham E, Tsai L, Bao Met al., 2022,

    Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

  • Journal article
    Uhlin F, Szpirt W, Kronbichler A, Bruchfeld A, Soveri I, Rostaing L, Daugas E, Lionet A, Kamar N, Rafat C, Myslivecek M, Tesar V, Fernstrom A, Kjellman C, Elfving C, McAdoo S, Molne J, Bajema I, Sonesson E, Segelmark Met al., 2022,

    Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study

    , JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 33, Pages: 829-838, ISSN: 1046-6673
  • Journal article
    Castaneda AB, Petty LE, Scholz M, Jansen R, Weiss S, Zhang X, Schramm K, Beutner F, Kirsten H, Schminke U, Hwang S-J, Marzi C, Dhana K, Seldenrijk A, Krohn K, Homuth G, Wolf P, Peters MJ, Dörr M, Peters A, van Meurs JBJ, Uitterlinden AG, Kavousi M, Levy D, Herder C, van Grootheest G, Waldenberger M, Meisinger C, Rathmann W, Thiery J, Polak J, Koenig W, Seissler J, Bis JC, Franceshini N, Giambartolomei C, Cohorts for Heart and Aging Research in Genomic Epidemiology CHARGE Subclinical Working Group, Hofman A, Franco OH, Penninx BWJH, Prokisch H, Völzke H, Loeffler M, O'Donnell CJ, Below JE, Dehghan A, de Vries PSet al., 2022,

    Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues.

    , Hum Mol Genet, Vol: 31, Pages: 1171-1182

    Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.

  • Journal article
    Stacey D, Chen L, Stanczyk P, Howson J, Mason A, Burgess S, MacDonald S, Langdown J, McKinney H, Downes K, Farahi N, Peters J, Basu S, Pankow JS, Tang W, Pankratz N, Sabater-Lleal M, De Vries PS, Smith NL, CHARGE Hemostasis Working Group, Gelinas AD, Schneider DJ, Janjie N, Samani NJ, Ye S, Summers C, Chilvers E, Danesh J, Paul Det al., 2022,

    Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

    , Nature Communications, Vol: 13, ISSN: 2041-1723

    Many individual genetic risk loci have been associated with multiple common human diseases. However, themolecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal themolecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) riskbut higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variantat the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitroexperimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C throughendothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CADthrough anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides aframework to reveal the mechanisms underlying similar cross-phenotype associations.

  • Journal article
    Prendecki M, McAdoo SP, Turner-Stokes T, Garcia-Diaz A, Orriss I, Woollard KJ, Behmoaras J, Cook HT, Unwin R, Pusey CD, Aitman TJ, Tam FWKet al., 2022,

    Glomerulonephritis and autoimmune vasculitis are independent of P2RX7 but may depend on alternative inflammasome pathways.

    , Journal of Pathology, Vol: 257, ISSN: 0022-3417

    P2RX7, an ionotropic receptor for extracellular ATP, is expressed on immune cells, including macrophages, monocytes and dendritic cells and is up-regulated on non-immune cells following injury. P2RX7 plays a role in many biological processes, including production of pro-inflammatory cytokines such as IL-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knock-out (KO) inbred rat strain and taking advantage of the human-resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A-438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its 'off-target' properties. We identify a novel ATP/P2RX7/K+ efflux-independent and caspase-1/8-dependent pathway for production of IL-1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off-target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an 'alternative inflammasome' pathway to produce IL-1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. This article is protected by copyright. All rights reserved.

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