{"doi":"10.1101/2023.11.03.23297727","title":"MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with the COVID-19 Pandemic (MIP-C)","abstract":"Abstract Background Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5 + -DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 senses single-stranded RNA and is a key pattern recognition receptor for the SARS-CoV-2 virus. Methods This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018-December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5 + -DM outbreak. Results Sixty new anti-MDA5+, but not other MSAs surged between 2020-2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. Few (8/60) had a prior history of COVID-19, whereas 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. Conclusions A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.","journal":"medRxiv","year":2023,"id":413652,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9624,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":807708,"name":"Saptarshi Sinha","orcid":"0000-0002-4100-5727","position":1,"is_corresponding":false},{"id":1194912,"name":"Paula David","orcid":"0000-0003-0075-5895","position":2,"is_corresponding":false},{"id":800005,"name":"Gabriele De Marco","orcid":"0000-0003-2406-161X","position":3,"is_corresponding":false},{"id":356455,"name":"Sahar Taheri","orcid":"0000-0001-6716-7356","position":4,"is_corresponding":false},{"id":1177507,"name":"Ella McLaren","orcid":null,"position":5,"is_corresponding":false},{"id":243499,"name":"Sheetal Maisuria","orcid":null,"position":6,"is_corresponding":false},{"id":1147457,"name":"Gururaj Arumugakani","orcid":"0000-0002-3561-2424","position":7,"is_corresponding":false},{"id":1195202,"name":"Zoe Ash","orcid":null,"position":8,"is_corresponding":false},{"id":1195203,"name":"Catrin Buckley","orcid":null,"position":9,"is_corresponding":false},{"id":1195204,"name":"Lauren Coles","orcid":null,"position":10,"is_corresponding":false},{"id":1195205,"name":"C. 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