Low copy numbers of complement and deficiency are risk factors for myositis, its subgroups and autoantibodies

Danlei Zhou, Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
Emily H. King, Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
Simon Rothwell, National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, UK.
Olga Krystufkova, Institute of Rheumatology and Department of Rheumatology, Charles University, Prague, Czech Republic.
Antonella Notarnicola, Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, University Hospital Karolinska, Stockholm, Sweden.
Samantha Coss, Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
Rabheh Abdul-Aziz, Division of Rheumatology, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Katherine E. Miller, Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
Amanda Dang, Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
G Richard Yu, Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
Joanne Drew, Division of Rheumatology, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Emeli Lundström, Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, University Hospital Karolinska, Stockholm, Sweden.
Lauren M. Pachman, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Gulnara Mamyrova, Division of Rheumatology, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Rodolfo V. Curiel, Division of Rheumatology, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Boel De Paepe, Department of Neurology, Ghent University Hospital, Ghent, Belgium.
Jan L. De Bleecker, Department of Neurology, Ghent University Hospital, Ghent, Belgium.
Antony Payton, Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
William Ollier, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, UK.
Terrance P. O'Hanlon, Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Bethesda, MD, USA.
Ira N. Targoff, Veteran's Affairs Medical Center, University of Oklahoma Health Sciences Center, and Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Willy A. Flegel, Department of Transfusion Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Vidya Sivaraman, Division of Rheumatology, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Edward Oberle, Division of Rheumatology, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Shoghik Akoghlanian, Division of Rheumatology, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Kyla Driest, Division of Rheumatology, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Charles H. Spencer, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Yee Ling Wu, Division of Rheumatology, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Haikady N. Nagaraja, Division of Biostatistics, The Ohio State University, Columbus, Ohio, USA.
Stacy P. Ardoin, Division of Rheumatology, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Hector Chinoy, National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, UK.
Lisa G. Rider, Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Bethesda, MD, USA.

Document Type

Journal Article

Publication Date

9-28-2022

Journal

Annals of the rheumatic diseases

DOI

10.1136/ard-2022-222935

Keywords

autoantibodies; dermatomyositis; polymyositis

Abstract

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total , and and in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various GCN groups. Low GCNs of (=2+3) and deficiency (=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10 for , and 2.82 (2.48-3.21), p=7.0×10 for deficiency. Contingency and regression analyses showed that among patients with deficiency, the presence of became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: deficiency is relevant in dermatomyositis, is important in IBM and both deficiency and contribute interactively to risk of polymyositis.

Department

Medicine

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