title: Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study.
abstract: In an effort to find naturally occurring substances that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experienced muscle pain and weakness during treatment. In a smaller proportion of patients, the myopathy progressed to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients that develop an immune-mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies but, until today, a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls has not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria.
authors: Department of Immunology, Immunochemistry & Autoimmunity Laboratory, Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière University Hospital Paris, France.
authors: Lucile
authors: L
authors: Musset
authors: Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Internal Medicine and Clinical Immunology, Hospital University Department: Inflammation, Immunopathology and Biotherapy (DHU i2B), Paris, France; Sorbonne Universités, University Pierre et Marie-Curie-Paris 6, Inserm U974, Paris, France.
authors: Yves
authors: Y
authors: Allenbach
authors: Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Internal Medicine and Clinical Immunology, Hospital University Department: Inflammation, Immunopathology and Biotherapy (DHU i2B), Paris, France; Sorbonne Universités, University Pierre et Marie-Curie-Paris 6, Inserm U974, Paris, France.
authors: Olivier
authors: O
authors: Benveniste
authors: Rouen University Hospital, Department of Immunology, Rouen, France; Inserm U905, Rouen, France; Normandie Univ, IRIB, Rouen, France.
authors: Olivier
authors: O
authors: Boyer
authors: Department of Laboratory Medicine, University Hospitals Leuven, Belgium; Department of Microbiology and Immunology, Catholic University of Leuven, Belgium.
authors: Xavier
authors: X
authors: Bossuyt
authors: Department of Research, Inova Diagnostics, San Diego, CA, USA.
authors: Chelsea
authors: C
authors: Bentow
authors: Department of Research, Inova Diagnostics, San Diego, CA, USA.
authors: Joe
authors: J
authors: Phillips
authors: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors: Andrew
authors: A
authors: Mammen
authors: KU Leuven - University of Leuven, Department of Neurosciences, VIB - Vesalius Research Center, Experimental Neurology - Laboratory of Neurobiology, Leuven, Belgium; University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
authors: Philip
authors: P
authors: Van Damme
authors: Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Belgium; Rheumatology, University Hospitals Leuven, Belgium.
authors: René
authors: R
authors: Westhovens
authors: Division of Rheumatology, Department of Medicine, University of Padova, Padova, Italy.
authors: Anna
authors: A
authors: Ghirardello
authors: Division of Rheumatology, Department of Medicine, University of Padova, Padova, Italy.
authors: Andrea
authors: A
authors: Doria
authors: Department of Medicine, University of Calgary, Calgary, Canada.
authors: May Y
authors: MY
authors: Choi
authors: Department of Medicine, University of Calgary, Calgary, Canada.
authors: Marvin J
authors: MJ
authors: Fritzler
authors: Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Canada.
authors: Heinrike
authors: H
authors: Schmeling
authors: Division of Connective Tissue Disease & Autoimmunity, Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Yoshinao
authors: Y
authors: Muro
authors: Department of Immunology and Rheumatology, Hospital General de Occidente and University of Guadalajara, Zapopan, Jalisco, México.
authors: Ignacio
authors: I
authors: García-De La Torre
authors: Internal Medicine Department, Hospital Civil "Dr. Juan I. Menchaca", Guadalajara, Jalisco, México.
authors: Miguel A
authors: MA
authors: Ortiz-Villalvazo
authors: Laboratory of Clinical Pathology, San Antonio Hospital, Tolmezzo, Italy.
authors: Nicola
authors: N
authors: Bizzaro
authors: Laboratory of Immunology and Allergology, S. Giovanni di Dio Hospital, Florence, Italy.
authors: Maria
authors: M
authors: Infantino
authors: Laboratory of Autoimmune Disease Diagnostics, P.O. Spirito Santo, Pescara, Italy.
authors: Tiziana
authors: T
authors: Imbastaro
authors: Department of Rheumatology, China-Japan Friendship Hospital, Beijing, China.
authors: Qinglin
authors: Q
authors: Peng
authors: Department of Rheumatology, China-Japan Friendship Hospital, Beijing, China.
authors: Guochun
authors: G
authors: Wang
authors: Institute of Rheumatology and Department of Rheumatology, Charles University, Prague, Czech Republic.
authors: Jiří
authors: J
authors: Vencovský
authors: Institute of Rheumatology and Department of Rheumatology, Charles University, Prague, Czech Republic.
authors: Martin
authors: M
authors: Klein
authors: Institute of Rheumatology and Department of Rheumatology, Charles University, Prague, Czech Republic.
authors: Olga
authors: O
authors: Krystufkova
authors: Rheumatology and Clinical Immunology, Spedali Civili of Brescia, University of Brescia, Italy; University of Pavia, Italy.
authors: Franco
authors: F
authors: Franceschini
authors: Rheumatology and Clinical Immunology, Spedali Civili of Brescia, University of Brescia, Italy; University of Pavia, Italy.
authors: Micaela
authors: M
authors: Fredi
authors: Department of Immuno-hematology, Henri Mondor University Hospital, Créteil, France.
authors: Sophie
authors: S
authors: Hue
authors: Department of Immuno-hematology, Henri Mondor University Hospital, Créteil, France.
authors: Thibaut
authors: T
authors: Belmondo
authors: Division of Immunology, 3rd Department of Internal Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors: Katalin
authors: K
authors: Danko
authors: Department of Research, Inova Diagnostics, San Diego, CA, USA. Electronic address: mmahler@inovadx.com.
authors: Michael
authors: M
authors: Mahler
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000276:immunology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D015337:Multicenter Studies as Topic; D009135:Muscular Diseases / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced / Q000276:immunology; D012372:ROC Curve
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: Autoantibodies; Autoimmune myositis; HMGCR; Immune-mediated necrotizing myopathy; Statins