title: Dermatomyositis With or Without Anti-Melanoma Differentiation-Associated Gene 5 Antibodies: Common Interferon Signature but Distinct NOS2 Expression.
abstract: The anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is specifically associated with dermatomyositis (DM). Nevertheless, anti-MDA5(+)-patients experience characteristic symptoms distinct from classic DM, including severe signs of extramuscular involvement; however, the clinical signs of myopathy are mild or even absent. The morphological and immunological features are not yet described in adulthood. Data concerning the pathophysiology of anti-MDA5 DM are sparse; however, the importance of the interferon (IFN) type I pathway involved in DM has been shown. Our aim was to define morphological alterations of the skeletal muscle and the intrinsic immune response of anti-MDA5-positive DM patients. Immunohistological and RT-PCR analysis of muscle biopsy specimens from anti-MDA5 and classic DM were compared. Those with anti-MDA5 DM did not present the classic features of perifascicular fiber atrophy and major histocompatibility complex class I expression. They did not show significant signs of capillary loss; tubuloreticular formations were observed less frequently. Inflammation was focal, clustering around single vessels but significantly less intense. Expression of IFN-stimulated genes was up-regulated in anti-MDA5 DM; however, the IFN score was significantly lower. Characteristic features were observed in anti-MDA5 DM and not in classic DM patients. Only anti-MDA5 DM showed numerous nitric oxide synthase 2-positive muscle fibers with sarcoplasmic colocalization of markers of regeneration and cell stress. Anti-MDA5-positive patients demonstrate a morphological pattern distinct from classic DM.
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany; Department of Internal Medicine and Clinical Immunology and Inflammation, Immunopathology, and Biotherapy, Pierre et Marie Curie University, Paris, France; U974, INSERM, Sorbonne Universities, University Pierre et Marie-Curie, Paris, France. Electronic address: yves.allenbach@aphp.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Allenbach
authors.affiliation: Department of Internal Medicine and Clinical Immunology and Inflammation, Immunopathology, and Biotherapy, Pierre et Marie Curie University, Paris, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Leroux
authors.affiliation: Neuromuscular Diseases Unit, Neurology, Hospital de la Santa Creu I Sant Pau, Universita Autonoma de Barcelona and Institute de Recerca Sant Pau, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Suárez-Calvet
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Preusse
authors.affiliation: Neuromuscular Diseases Unit, Neurology, Hospital de la Santa Creu I Sant Pau, Universita Autonoma de Barcelona and Institute de Recerca Sant Pau, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Gallardo
authors.affiliation: Department of Internal Medicine and Clinical Immunology and Inflammation, Immunopathology, and Biotherapy, Pierre et Marie Curie University, Paris, France; U974, INSERM, Sorbonne Universities, University Pierre et Marie-Curie, Paris, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Hervier
authors.affiliation: Department of Internal Medicine and Clinical Immunology and Inflammation, Immunopathology, and Biotherapy, Pierre et Marie Curie University, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Rigolet
authors.affiliation: Department of Internal Medicine 2, Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Universities, Pierre et Marie Curie University, Paris, France.
authors.forename: Miguel
authors.initials: M
authors.lastname: Hie
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Debora
authors.initials: D
authors.lastname: Pehl
authors.affiliation: Department of Internal Medicine, Assistance Publique-Hôpitaux de Paris, Mondor Hospital, Creteil, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Limal
authors.affiliation: Department of Pathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hufnagl
authors.affiliation: Department of Pathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Zerbe
authors.affiliation: Department of Physiology, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Meyer
authors.affiliation: Department of Pathology, Mondor Hospital, Creteil, France.
authors.forename: Jessie
authors.initials: J
authors.lastname: Aouizerate
authors.affiliation: Department of Pneumology Avicennes University Hospital, Assistance Publique-Hôpitaux de Paris, Bobigny, France.
authors.forename: Yurdagul
authors.initials: Y
authors.lastname: Uzunhan
authors.affiliation: Department of Neuropathology, Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Maisonobe
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Hans-Hilmar
authors.initials: HH
authors.lastname: Goebel
authors.affiliation: Department of Internal Medicine and Clinical Immunology and Inflammation, Immunopathology, and Biotherapy, Pierre et Marie Curie University, Paris, France; U974, INSERM, Sorbonne Universities, University Pierre et Marie-Curie, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Benveniste
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
mesh_terms: D000328:Adult; D015415:Biomarkers; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D003882:Dermatomyositis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D012038:Regeneration; D012189:Retrospective Studies; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D007372:Interferons; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1