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  • Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in patients with dermatomyositis with anti-TIF1γ autoantibodies

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Myositis
Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in patients with dermatomyositis with anti-TIF1γ autoantibodies
  1. Yuji Hosono1,
  2. Brandon Sie2,
  3. Iago Pinal-Fernandez1,3,
  4. Katherine Pak1,
  5. Christopher A Mecoli4,
  6. Maria Casal-Dominguez1,3,
  7. Blake M Warner5,
  8. Mariana J Kaplan6,
  9. Jemima Albayda4,
  10. Sonye Danoff7,
  11. Thomas E Lloyd3,
  12. Julie J Paik4,
  13. Eleni Tiniakou4,
  14. Rohit Aggarwal8,
  15. Chester V Oddis8,
  16. Siamak Moghadam-Kia8,
  17. Carmelo Carmona-Rivera6,
  18. Jose César Milisenda9,
  19. Josep Maria Grau-Junyent9,
  20. Albert Selva-O'Callaghan10,
  21. Lisa Christopher-Stine3,4,
  22. H Benjamin Larman2,
  23. Andrew Lee Mammen1,3,4
  1. 1 Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
  2. 2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3 Department of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  4. 4 Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  5. 5 National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
  6. 6 Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
  7. 7 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  8. 8 Department of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  9. 9 Department of Internal Medicine, Hospital Clinic de Barcelona, Barcelona, Spain
  10. 10 Internal Medicine, Vall d'Hebron University Hospital, Barcelona, Spain
  1. Correspondence to Dr Andrew Lee Mammen, Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA; andrew.mammen{at}nih.gov; Dr H Benjamin Larman, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; hlarman1{at}jhmi.edu

Abstract

Objectives In dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with an increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies.

Methods Phage ImmunoPrecipitation Sequencing using sera from 43 patients with DM suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins patients with myositis (255 with DM, 28 with antisynthetase syndrome, 40 with immune-mediated necrotising myopathy, 29 with inclusion body myositis and 19 with polymyositis), 80 rheumatological disease controls (25 with Sjogren’s syndrome, 25 with systemic lupus erythematosus and 30 with rheumatoid arthritis (RA)) and 200 healthy comparators were screened for anti-SP4 autoantibodies by ELISA. A validation cohort of 46 anti-TIF1γ-positive patient sera from the University of Pittsburgh was also screened for anti-Sp4 autoantibodies.

Results Anti-Sp4 autoantibodies were present in 27 (10.5%) patients with DM and 1 (3.3%) patient with RA but not in other clinical groups. In patients with DM, 96.3% of anti-Sp4 autoantibodies were detected in those with anti-TIF1γ autoantibodies. Among 26 TIF1γ-positive patients with anti-Sp4 autoantibodies, none (0%) had cancer. In contrast, among 35 TIF1γ-positive patients without anti-Sp4 autoantibodies, 5 (14%, p=0.04) had cancer. In the validation cohort, among 15 TIF1γ-positive patients with anti-Sp4 autoantibodies, 2 (13.3%) had cancer. By comparison, among 31 TIF1γ-positive patients without anti-Sp4 autoantibodies, 21 (67.7%, p<0.001) had cancer.

Conclusions Anti-Sp4 autoantibodies appear to identify a subgroup of anti-TIF1γ-positive DM patients with lower cancer risk.

  • Dermatomyositis
  • Autoantibodies
  • Autoimmune Diseases

Data availability statement

Data are available upon reasonable request. All data relevant to the study are either included in the article or will be shared upon request.

https://doi.org/10.1136/ard-2022-222441

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    Data availability statement

    Data are available upon reasonable request. All data relevant to the study are either included in the article or will be shared upon request.

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    Footnotes

    • HBL and ALM are joint senior authors.

    • YH, BS, IP-F and KP are joint first authors.

    • Handling editor Josef S Smolen

    • Twitter @docrota, @H Benjamin Larman @larmanlab

    • HBL and ALM contributed equally.

    • Contributors ALM is responsible for the overall content as guarantor and accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish. ALM, HBL, YH, IP-F, BS, and KP contributed to the conception and/or design of the work. All authors contributed to the acquisition, analysis, or interpretation of data for the work. ALM, IP-F, HBL, and BS worked on the initial draft of the manuscript. All authors had the opportunity to revise the work critically for important intellectual content. All authors gave final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

    • Funding This work was supported, in part, by the Intramural Research Program of the National Institutes of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (AR041203). The Johns Hopkins Rheumatic Diseases Research Core Center, where some of the autoantibodies were assayed, is supported by NIH P30-AR070254. This work was also supported by the Hyuai and Siuling Zhang Discovery Fund and Dr Peter Buck.

    • Competing interests YJ, IP-F, KP, MC-D, MJK, JA, TEL, ET, CVO, SM-K, CC-R, JCM, JMG-J, AS-O'C and ALM report no competing interests. CAM has received support from NIH grant 1K23AR075898 and the Jerome L. Greene Foundation; reconsulting fees from Guidepoint Consultations and Boehringer Ingelheim; and payment for expert testimony from the Department of Justice–Vaccine Injury Compensation Program. BMW received support from NIH grant Z01-DE000704. SD received support grants or contract from BMS, Boehringer-Ingelheim and Genentech/Roche; royalties or licences from UpToDate; consulting fees from Boehringer-Ingelheim; payment for presentations from France Foundation; support for travel from Boehringer-Ingelheim; participates in an advisory board for Galecto and Galapagos; and is a senior medical advisor for the Pulmonary Fibrosis Foundation and the American Thoracic Society. JJP received support from NIH grant K23AR073927; grants or contracts from Pfizer, Kezer and Corbus; royalties from UpToDate; and consulting fees from Pfizer, Kezar, EMD Serono, Proivant and Guidepoint Consultation. RA received grants or contracts from Mallinckrodt, Q32, Pfizer, EMD-Serono and Bristol Myers-Squibb; and consulting fees from Mallinckrodt, EMD Serono, Octapharma, Kezar, CSL Behring, Pfizer, Bristol Myers-Squibb, Astrazeneca, Alexion, Boehringer-Ingelheim, Argenx, Corbus, Roivant, Jannsen, Merck, Kyverna, Galapagos, Actigraph, Abbvie, Scipher, Horizon Therapeutics, Teva and Beigene. LC-S received grants or contracts from Pfizer, Corbus and Kezar; royalties from Inova Diagnostics; consulting fees from Janssen, Boehringer-Ingelheim, Mallinckrodt, EMD-Serono, Argenx, Allogene and Horizon Therapeutics; expert testimony for Bendin Sumrall and Ladner LLC, Feldman, Kleidman Coffey, & Sappe LLP Downs Ward Bender Hauptmann & Herzog, P.A., and Sulloway and Hollis; and patents from Inova Diagnostics and RDL. HBL received support from NIH grant R01GM136724; is a founder of ImmuneID, Portal Bioscience and Alchemab; and is an advisor to TScan Therapeutics.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.