Nuclear actin aggregation is a hallmark of anti-synthetase syndrome-induced dysimmune myopathy.
OBJECTIVE
To analyze antisynthetase syndrome-associated myositis by modern myopathologic methods and to define its place in the spectrum of idiopathic inflammatory myopathies (IIMs).


METHODS
Skeletal muscle biopsies from antisynthetase syndrome-associated myositis and other IIMs from different institutions worldwide were analyzed by histopathology, quantitative PCR, and electron microscopy.


RESULTS
Myonuclear actin filament inclusions were identified as a unique morphologic hallmark of antisynthetase syndrome-associated myositis. Nuclear actin inclusions were never found in dermatomyositis, polymyositis, sporadic inclusion body myositis, autoimmune necrotizing myopathy associated with signal recognition particle or 3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies, or nonspecific myositis associated with other systemic diseases, harboring myositis-associated autoantibodies, and presenting myofiber necrosis. We show that molecules involved in actin filament formation and actin shuttling mechanisms are altered in antisynthetase syndrome, and may thus be involved in pathologic myonuclear actin aggregation. In addition, we have identified a typical topographic distribution of necrotic myofibers predominantly located at the periphery of muscle fascicles accompanied by inflammation and destruction of the perimysial connective tissue.


CONCLUSIONS
Antisynthetase syndrome-associated myositis is characterized by distinctive myonuclear actin filament inclusions, including rod formations and a typical necrotizing perimysial myositis. This supports the hypothesis that antisynthetase syndrome-associated myositis is unique and should not be grouped among dermatomyositis, polymyositis, sporadic inclusion body myositis, necrotizing autoimmune myositis, or nonspecific myositis.


METHODS
This study provides Class II evidence that for patients with IIMs, the presence of myonuclear actin filament inclusions accurately identifies patients with antisynthetase syndrome-associated myositis (sensitivity 81%, specificity 100%).
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany. werner.stenzel@charite.de.
Werner
W
Stenzel
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Corinna
C
Preuße
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Yves
Y
Allenbach
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Debora
D
Pehl
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Reimar
R
Junckerstorff
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Frank L
FL
Heppner
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Kay
K
Nolte
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Eleonora
E
Aronica
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Veronika
V
Kana
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Elisabeth
E
Rushing
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Udo
U
Schneider
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Kristl G
KG
Claeys
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Olivier
O
Benveniste
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Joachim
J
Weis
From the Departments of Neuropathology (W.S., C.P., D.P., F.L.H., H.H.G.) and Rheumatology (U.S.), Charité-Universitätsmedizin Berlin, Germany; the Département de Médecine Interne et Immunologie Clinique (Y.A., O.B.), Centre de Référence Maladies Neuro-Musculaires Paris Est, Assistance Public-Hôpitaux de Paris Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France; the Section of Neuropathology, Department of Anatomical Pathology (R.J.), Path West Laboratory Medicine, Royal Perth Hospital, Perth; School of Pathology and Laboratory Medicine (R.J.), University of Western Australia, Nedlands, Australia; the Institute of Neuropathology (K.N., K.G.C., J.W.) and the Department of Neurology (K.G.C.), RWTH Aachen, Germany; the Department of Pathology and Neuropathology (E.A.), AMC University, Amsterdam, the Netherlands; the Department of Neuropathology (V.K., E.R.), University of Zürich, Switzerland; and the Department of Neuropathology (H.H.G.), University Medicine, Johannes Gutenberg University, Mainz, Germany.
Hans H
HH
Goebel
D008841:Actin Cytoskeleton / Q000473:pathology; D000199:Actins / Q000378:metabolism*; D001706:Biopsy; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000473:pathology*; D018482:Muscle, Skeletal / Q000473:pathology* / Q000648:ultrastructure; D009220:Myositis / Q000150:complications / Q000175:diagnosis / Q000473:pathology*; D009336:Necrosis / Q000473:pathology; D012680:Sensitivity and Specificity
D000199:Actins