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Racial variability in immune responses only partially explains differential systemic sclerosis disease severity
  1. Kamini E Kuchinad1,
  2. Ji Soo Kim1,
  3. Adrianne Woods1,
  4. Gwen Leatherman1,
  5. Laura Gutierrez-Alamillo1,
  6. Maureen D Mayes2,
  7. Robyn Domsic3,
  8. Paula S Ramos4,
  9. Richard M Silver5,
  10. John Varga6,
  11. Lesley Ann Saketkoo7,8,
  12. Suzanne Kafaja9,
  13. Victoria K Shanmugan10,
  14. Jessica Gordon11,
  15. Lorinda Chung12,
  16. Elana J Bernstein13,
  17. Pravitt Gourh14,
  18. Francesco Boin15,
  19. Daniel L Kastner16,
  20. Scott L Zeger17,
  21. Livia Casciola-Rosen1,
  22. Fredrick M Wigley1,
  23. Ami A Shah1
  1. 1 Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  2. 2 Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center John P and Katherine G McGovern Medical School, Houston, Texas, USA
  3. 3 Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  4. 4 Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA
  5. 5 Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
  6. 6 Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
  7. 7 New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
  8. 8 Section of Pulmonary Medicine, University Medical Center - Comprehensive Pulmonary Hypertension Center and Interstitial Lung Disease Clinic Programs, Louisiana State University School of Medicine, New Orleans, Louisiana, USA
  9. 9 Internal Medicine/Division of Rheumatology, University of California Los Angeles, Los Angeles, California, USA
  10. 10 Office of Autoimmune Disease Research, National Institute of Health, Bethesda, Maryland, USA
  11. 11 Department of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, New York, USA
  12. 12 Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA
  13. 13 Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
  14. 14 NIAMS, National Institutes of Health, Bethesda, Maryland, USA
  15. 15 Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  16. 16 National Human Genome Research Institute Division of Intramural Research, Bethesda, Maryland, USA
  17. 17 Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA
  1. Correspondence to Dr Ami A Shah; Ami.Shah{at}jhmi.edu

Abstract

Objective To understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients.

Methods 803 black and 2178 white SSc patients had systematic testing for autoantibodies using Euroimmun (centromere (ACA), RNA-polymerase III (POLR3), Scl70, PM/Scl, NOR90, Th/To, Ku, U3RNP and Ro52) and commercial ELISA (U1RNP). In this observational study, logistic regression was performed to assess the association between self-identified race and outcomes, adjusting for autoantibodies. To estimate whether the effect of race was mediated by autoantibody status, race coefficients from multivariate models including and excluding autoantibodies were compared.

Results Anti-Scl70, anti-U1RNP, anti-U3RNP, anti-Th/To, anti-Ku and anti-NOR90 were more common in the black cohort than in the white cohort, which was enriched for ACA, anti-POLR3 and anti-PM/Scl. Black individuals had a higher prevalence of severe Raynaud’s, skin, lung, gastrointestinal and renal disease whereas white individuals had a higher prevalence of severe heart and muscle disease. Adjusting for autoantibodies decreased the effect of race on outcome for telangiectasias, forced vital capacity <70%, pulmonary hypertension and severe lung, heart, muscle and gastrointestinal disease by 11%–44% and increased the association between race and renal crisis and severe kidney disease by 37%–52%.

Conclusions This study is the largest systematic analysis of autoantibody responses in a geographically diverse population of black SSc patients. Black and white individuals with SSc have distinct autoantibody profiles. Autoantibodies explain only a fraction of the effect of race on clinical outcomes, suggesting other factors contribute to disparate outcomes between these groups.

  • Autoantibodies
  • Systemic Sclerosis
  • Epidemiology
  • Risk Factors

Data availability statement

Data are available on reasonable request. Data are available on reasonable request from the corresponding author and GRASP consortium.

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Data availability statement

Data are available on reasonable request. Data are available on reasonable request from the corresponding author and GRASP consortium.

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Footnotes

  • Handling editor Josef S Smolen

  • X @PSRamos_PhD, @DrBernstein

  • Contributors The following authors made substantial contributions to the conception or design of the work: KEK, JSK, FMW and AAS; to acquisition of data: KEK, JSK, AW, GL, LG-A, MDM, RD, PSR, RMS, JV, LAS, SK, VKS, JG, LC, EJB, PG, FB, DLK, LC-R, FMW and AAS; and to analysis and interpretation of data: KEK, JSK, SLZ, FMW and AAS. All authors played a role in drafting the article or revising it critically for important intellectual content, and all provided finalapproval of the version of the article to be published. AAS is the guarantor.

  • Funding This study was supported in part by NIH/NIAMS T32 AR048522-19, R01 AR073208, P30 AR072582, P30 AR070254, K24 AR080217, the Scleroderma Research Foundation, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Bechtle Precision Medicine Fund in Scleroderma, the Martha McCrory Professorship, the Sara and Alex Othon Fund and the Johns Hopkins inHealth initiative. EJB was supported by NIH/NIAMS K23-AR-075112, NIH/NHLBI R01-HL-164758, and Department of Defense W81XWH2210163.

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests RD received consulting fees from CSL Behring and Astra-Zeneca. LAS received grant funding from Horizon Pharmaceuticals, aTyr Pharmaceuticals and Kinevant Pharmaceuticals and honoraria from Janssen Pharmaceuticals. She served on the data safety monitoring board for Argenx Pharmaceuticals. LC received grant funding from Boehringer Ingelheim and consulting fees from Kyverna, Eicos Sciences, Genentech, IgM Biosciences, Lilly. She participated in an advisory capacity for Mitsubishi Tanabe and Janssen. FB received honoraria from Janssen. RMS received grant funding from Boehringer Ingelheim, Merck and Amgen; he is the CEO of FibroBiologics. JV received consulting fees from TeneoBio, and Conquest; he serves on the data safety monitoring board for Conquest. MDM received grant funding from Prometheus Biosciences, Mitsubishi Tanabe, Boehringer Ingelheiem, Eicos, Corbus and Horizon Pharmaceuticals. She received consulting fees from Cabaletta Pharmaceuticals; she served on the advisory board for Mitsubishi Tanabe and Eicos Sciences. AS has grant support from Kadmon, Arena Pharmaceuticals, Medpace and Eicos Sciences.

  • 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.