Anti-RNApol3-Associated myocarditis: an emerging disease linking autoimmunity and infection

Quentric et al. Annals of Intensive Care (2025) 15:38 https://doi.org/10.1186/s13613-025-01443-1 Annals of Intensive Care Open Access RESEARCH Anti-RNApol3-Associated myocarditis: an emerging disease linking autoimmunity and infection Paul Quentric1,2, Jean-Luc Charuel3, Quentin Moyon2,4, Guillaume Hékimian4, Karim Dorgham1, François Lifermann5, Mathieu Kerneis6,7, Alexis Mathian1,2, Karim Aacha6, Isabelle Melki8, Juliette Chommeloux4, Matthieu Petit4, Melchior Gautier4, Pierre Bay9, Philippe Rouvier10, Etienne Charpentier11, Omaira da Mata-Jardin1, Lucie Lefevre4, Christophe Parizot3, Ouriel Saura4, David Levy4, Sofia Ortuno4, Matthieu Schmidt4,7, Charles-Edouard Luyt4,7, Guy Gorochov1,3, Zahir Amoura1,4, Alain Combes4,7 and Marc Pineton de Chambrun1,2,4,7* Abstract Background Fulminant myocarditis (FM) is a severe condition primarily triggered by viruses. Anti-RNA polymerase III autoantibodies (RNApol3) which are typically found in patients with severe systemic sclerosis, have been reported in patients with influenza-related FM. Our objective is to provide additional insight into RNApol3-associated FM. Methods We retrospectively included all patients admitted to our institution between January 2013 and June 2023 with acute myocarditis and positive serum RNApol3. We compared their characteristics, etiologies, and outcomes with those of a cohort of RNApol3 negative acute myocarditis. Results Twenty-nine RNApol3-positive patients, comprising 83% females with a mean age of 39 ± 12 years, were included in this study. Each patient was admitted to the intensive care unit at least once and 11 (38%) relapsed. Triggers included influenza virus in 55% and SARS-CoV-2 virus in 48% of cases. The lowest left ventricular ejection fraction was 10 [5-10] % and the highest troponin value was 82 [22–360] times the ULN. Patients required dobutamine (94%), veno-arterial extracorporeal membrane oxygenation (85%) and pericardiocentesis (38%). At the last follow-up, 76% of patients were still alive, while 7% had undergone cardiac transplantation, and 3% required a left ventricular assist device. Compared to RNApol3-negative cases, RNApol3-positive myocarditis was associated with female gender, fulminant evolution, tamponade, a higher likelihood of being caused by a proven viral infection, and a higher rate of relapse. Conclusion RNApol3-associated myocarditis is an emerging disease linking autoimmunity and infection and a unique cause of acquired, pathogen-specific, organ-specific immunodeficiency. RNApol3 should be screened in all cases of FM, especially in young women infected by RNA viruses. The risk of FM in RNApol3-positive systemic sclerosis needs further investigation. *Correspondence: Marc Pineton de Chambrun Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Quentric et al. Annals of Intensive Care (2025) 15:38 Page 2 of 13 Keywords Fulminant myocarditis, Anti-RNA-polymerase III autoantibodies, Extracorporeal membrane oxygenation, Autoimmunity, Viral infection, Systemic sclerosis Graphical abstract Introduction Fulminant myocarditis is a complex, multifaceted, and often severe disease characterized by inflammation of the myocardium, induced by viruses, bacteria, toxins, or immune-mediated conditions [1]. The etiological investigation is challenging due to the numerous diseases known to cause myocarditis [2]. Viruses are considered the leading cause, yet the pathophysiology of virusinduced myocardial lesions remains elusive. In 2020, Pineton de Chambrun and colleagues first described, in 11 patients, the unusual association of mainly influenzae virus-induced fulminant myocarditis with persistent autoantibodies targeting RNA-polymerase III (RNApol3) [3]. More recently, these rare autoantibodies have been reported in patients with severe COVID-19-related fulminant myocarditis [4]. Anti-RNApol3 autoantibodies are typically found in patients with systemic sclerosis associated with severe organ involvement, yet none of the patients in these two studies had such a condition. Systemic sclerosis is an orphan disease characterized by autoimmunity, fibrosis of the skin and internal organs and vasculopathy. It has the highest mortality among all rheumatic diseases [5]. Systemic sclerosis cardiac involvement is frequent and very heterogeneous: chronic inflammatory myocarditis, myocardial fibrosis [6, 7], congestive heat failure, arrythmia, impaired ventricular relaxation [8] and also pulmonary hypertension [9]. The laboratory diagnosis of systemic sclerosis (SSc) relies on the detection of antinuclear antibodies, primarily characterized by four mutually exclusive specificities: anti-topoisomerase I (Scl-70), anti-centromere, antinucleolar, or anti-RNApol3 autoantibodies. The latter are highly specific for SSc, found in approximately 5–20% of patients, and were initially proposed as markers of severe disease. RNApol3 is a protein that transcribes DNA to synthesize 5 S ribosomal RNA, tRNA, and other small RNAs. Transfer RNA is a small RNA that connects messenger RNA to the growing amino acid chain during protein synthesis. An increasing body of literature suggests that RNApol3 can transcribe viral or cellular DNA sequences into immunostimulatory RIG-I ligands. These ligands bind to RIG-I-like receptors, which are key sensors of viral infections. This interaction mediates the transcriptional induction of type I interferons and other genes that collectively orchestrate an antiviral host response [10]. The role of anti-RNApol3 autoantibodies in the pathophysiology of viral fulminant myocarditis remains to be elucidated. Given the limited data on this new disease, we aim to further describe the spectrum and outcomes of anti-RNApol3-associated myocarditis. Materials and methods Patient selection We retrospectively included all patients admitted to our institution between January 2013 and June 2023 with myocarditis and positive serum anti-RNApol3 autoantibodies (patients were sourced from our immunology department’s database). We used the clinically suspected myocarditis classification criteria and the ESC 2015 (...truncated)