title: An autoimmune myositis-overlap syndrome associated with autoantibodies to nuclear pore complexes: description and long-term follow-up of the anti-Nup syndrome.
abstract: 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."
authors.affiliation: 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.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Senécal
authors.forename: Catherine
authors.initials: C
authors.lastname: Isabelle
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Fritzler
authors.forename: Ira N
authors.initials: IN
authors.lastname: Targoff
authors.forename: Rose
authors.initials: R
authors.lastname: Goldstein
authors.forename: Michel
authors.initials: M
authors.lastname: Gagné
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Raynauld
authors.forename: France
authors.initials: F
authors.lastname: Joyal
authors.forename: Yves
authors.initials: Y
authors.lastname: Troyanov
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Dabauvalle
mesh_terms: D000328:Adult; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009220:Myositis / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology*; D022022:Nuclear Pore / Q000276:immunology*; D011379:Prognosis; D013577:Syndrome
chemical_list: D000974:Antibodies, Antinuclear; D007166:Immunosuppressive Agents