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An Autoimmune Myositis-Overlap Syndrome Associated With Autoantibodies to Nuclear Pore Complexes: Description and Long-Term Follow-up of the Anti-Nup Syndrome

Senécal, Jean-Luc MD, FRCPC, FACP; Isabelle, Catherine MD, MSc, FRCPC; Fritzler, Marvin J. MD, PhD; Targoff, Ira N. MD; Goldstein, Rose MD, CM, FRCPC; Gagné, Michel MD, CSPQ; Raynauld, Jean-Pierre MD, FRCPC; Joyal, France MD, MSc, FRCPC; Troyanov, Yves MD, FRCPC; Dabauvalle, Marie-Christine PhD

doi: 10.1097/MD.0000000000000223

Autoimmune myositis encompasses various myositis-overlap syndromes, each being identified by the presence of serum marker autoantibodies. We describe a novel myositis-overlap syndrome in 4 patients characterized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes. The clinical phenotype was characterized by prominent myositis in association with erosive, anti-CCP, and rheumatoid factor-positive arthritis, trigeminal neuralgia, mild interstitial lung disease, Raynaud phenomenon, and weight loss. The myositis was typically chronic, relapsing, and refractory to corticosteroids alone, but remitted with the addition of a second immunomodulating drug. There was no clinical or laboratory evidence for liver disease. The prognosis was good with 100% long-term survival (mean follow-up 19.5 yr).

By indirect immunofluorescence on HEp-2 cells, sera from all 4 patients displayed a high titer of antinuclear autoantibodies (ANA) with a distinct punctate peripheral (rim) fluorescent pattern of the nuclear envelope characteristic of nuclear pore complexes. Reactivity with nuclear pore complexes was confirmed by immunoelectron microscopy. In a cohort of 100 French Canadian patients with autoimmune myositis, the nuclear pore complex fluorescent ANA pattern was restricted to these 4 patients (4%). It was not observed in sera from 393 adult patients with systemic sclerosis (n = 112), mixed connective tissue disease (n = 35), systemic lupus (n = 94), rheumatoid arthritis (n = 45), or other rheumatic diseases (n = 107), nor was it observed in 62 normal adults.

Autoantibodies to nuclear pore complexes were predominantly of IgG isotype. No other IgG autoantibody markers for defined connective tissue diseases or overlap syndromes were present, indicating a selective and highly focused immune response. In 3 patients, anti-nuclear pore complex autoantibody titers varied in parallel with myositis activity, suggesting a pathogenic link to pathophysiology. The nuclear pore complex proteins, that is, nucleoporins (nup), recognized by these sera were heterogeneous and included Nup358/RanBP2 (n = 2 patients), Nup90 (n = 1), Nup62 (n = 1), and gp210 (n = 1). Taken together the data suggest that nup autoantigens themselves drive the anti-nup autoimmune response. Immunogenetically, the 4 patients shared the DQA1*0501 allele associated with an increased risk for autoimmune myositis.

In conclusion, we report an apparent novel subset of autoimmune myositis in our population of French Canadian patients with connective tissue diseases. This syndrome is recognized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes that react with nups, consistent with an “anti-nup syndrome.”

From the Department of Medicine, Divisions of Rheumatology (JLS, CI, JPR, YT) and Internal Medicine (FJ), and Laboratory for Research in Autoimmunity, Research Center of the Centre Hospitalier de l’Université de Montréal, University of Montreal Faculty of Medicine, Montreal, Quebec, Canada; Mitogen Advanced Diagnostics Laboratory (MJF), Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; Veterans Affairs Medical Center (INT), University of Oklahoma Health Sciences Center, and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States; McGill University (RG), Montreal, Quebec, Canada; Polyclinique Saint-Eustache (MG), Saint-Eustache, Quebec, Canada; Biocenter (MCD), Division of Electron Microscopy, University of Würzburg, Am Hubland, Würzburg, Germany.

Correspondence: Jean-Luc Senécal, MD, Division of Rheumatology, Centre Hospitalier de l’Université de Montréal, 1560 Sherbrooke Street East (M-4243), Montreal, Quebec, Canada, H2L 4M1 (e-mail:

Abbreviations: ACR = American College of Rheumatology, AIM = autoimmune myositis, ALBIA = addressable laser bead immunoassay, ANAs = autoantibodies to nuclear antigens, CENP-B = centromere protein B, CK = creatine kinase, CHUM = Centre Hospitalier de l’Université de Montréal, DLCO = carbon monoxide lung diffusing capacity, ELISA = enzyme-linked immunosorbent assay, ENMC = European Neuromuscular Centre, LC-1 = liver cytosolic-1 antigen, LIA = line immunoassay, LKM-1 = liver-kidney-microsome-1, MCTD = mixed connective tissue disease, MDA-5 = melanoma differentiation-associated protein 5, MTX = methotrexate, NPCs = nuclear pore complexes, NUPs = nucleoporins, OM = overlap myositis, PBC = primary biliary cirrhosis, PML = promyelocytic leukemia cell antigen, SLA/LP = soluble liver antigen/liver pancreas antigen, SLE = systemic lupus erythematosus, RNP = ribonucleoprotein, SRP = signal recognition particle, SumoAE = small ubiquitin-like modifier activating enzyme, TRIM21 = tripartite motif.

Financial support and conflicts of interest: This study was supported in part by operating grants MT-14636, MOP-62687, and MOP-81252 from the Canadian Institutes of Health Research (to JLS), by Department of Veterans Affairs Medical Research Funds (to INT), and by donations from Sclérodermie Québec and Mrs Gisèle Sarrazin-Locas in support of The Laboratory for Research in Autoimmunity. JLS holds the University of Montreal Scleroderma Research Chair. MJF holds the Arthritis Society Research Chair at the University of Calgary. Authors JLS, CI, MCD, RG, and FJ have no conflicts of interest to disclose. The authors listed below have received financial support (personal or institutional) from the listed institutions or pharmaceutical companies, unrelated to the present work. MJF: EUROIMMUN, ImmunoConcepts, INOVA Diagnostics; INT: Oklahoma Medical Research Foundation Clinical Immunology Laboratory, UpToDate; YT: Abbvie, Amgen, BMS, Janssen, Roche, UCB, Warner-Chilcott; MG: Novartis; JPR: Arthrolab, Amgen, BMS, Cellgene, Janssen, Lilly, Roche, Pfizer.

© 2014 by Lippincott Williams & Wilkins, Inc.