Susan Boackle Childress, M.D., Medical and Scientific Consulting Denver, CO, United States
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Ani Oganesyan1, Rachel Sharp2, Philip O’Neill3, Cynthia Aranow4, Laurent Arnaud5, Anca Askanase6, Sang-Cheol Bae7, Sasha Bernatsky8, Ian Bruce9, Jill Buyon10, Winn Chatham11, Ann Clarke12, Nathalie Costedoat-Chalumeau13, Mary Anne Dooley14, Paul R. Fortin15, Ellen Ginzler16, Dafna Gladman17, Caroline Gordon18, John G. Hanly19, Murat Inanç20, David Isenberg21, Soren Jacobsen22, Andreas Jonsen23, Kenneth Kalunian24, Diane L. Kamen25, S. Sam Lim26, Anselm Mak27, Eric Morand28, Christine Peschken29, Michelle Petri30, Bernando A. Pons-Estel31, Anisur Rahman32, Rosalind Ramsey-Goldman33, John Reynolds34, Juanita Romero-Diaz35, Guillermo Ruiz-Irastorza36, Jorge Sanchez-Guerrero37, Kristjan Steinsson38, Murray Urowitz39, Ronald van Vollenhoven40, Evelyne Vinet41, Alexandre Voskuyl42, Daniel Wallace43, Susan Manzi44, Kenneth L. Jones45 and Susan A. Boackle46, 1University of Colorado Anschutz Medical Campus, Aurora, CO, 2University of North Carolina at Chapel Hill, Chapel Hill, NC, 3University of Oklahoma Health Sciences Center, Oklahoma City, OK, 4Feinstein Institutes for Medical Research, Manhasset, NY, 5University Hospitals of Strasbourg, Strasbourg, France, 6Columbia University Medical Center, New York, NY, 7Hanyang University Hospital for Rheumatic Diseases and Hanyang University Institute for Rheumatology Research, Department of Rheumatology, Seoul, South Korea, 8Research Institute of the McGill University Health Centre, Montreal, QC, Canada, 9University of Manchester, Manchester, United Kingdom, 10NYU Grossman School of Medicine, New York, NY, 11University of Alabama at Birmingham, Birmingham, AL, 12University of Calgary, Division of Rheumatology, Cumming School of Medicine, Calgary, AB, Canada, 13Inserm DR Paris 5, Paris, France, 14Raleigh Neurology Associates, Chapel Hill, NC, 15Centre ARThrite - CHU de Québec - Université Laval, Quebec City, QC, Canada, 16SUNY Downstate Health Sciences University, Brooklyn, NY, 17Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Department of Medicine, University of Toronto, Toronto, ON, Canada, 18Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom, 19Dalhousie University, Halifax, NS, Canada, 20Istanbul University, Istanbul, Turkey, 21University College London, London, United Kingdom, 22Rigshospitalet, Copenhagen, Denmark, 23Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden, 24University of California San Diego, La Jolla, CA, 25Medical University of South Carolina, Charleston, SC, 26Emory University, Atlanta, GA, 27Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, 28Monash University, Centre for Inflammatory Diseases, Melbourne, Australia, 29University of Manitoba, Winnipeg, MB, Canada, 30Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Timonium, MD, 31Study Group of the Argentine Society of Rheumatology for Systemic Lupus Erythematosus, Buenos Aires, Argentina, 32Centre for Rheumatology, Division of Medicine, University College London, London, United Kingdom, 33Northwestern University, Chicago, IL, 34University of Birmingham, Birmingham, United Kingdom, 35Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico, 36Hospital Universitario Cruces, Barakaldo, Spain, 37University Health Network, Toronto, ON, Canada, 38Landspitali University Hospital, Reykjavik, Iceland, 39Schroeder Arthritis Institute, Krembil Research Institute; University of Toronto Lupus Clinic; Division of Rheumatology, Toronto, ON, Canada, 40Amsterdam University Medical Centers, Amsterdam, Netherlands, 41McGill University Health Centre, Montréal, QC, Canada, 42Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands, 43Cedars-Sinai Medical Center, Los Angeles, CA, 44Lupus Center of Excellence, Autoimmunity Institute, Allegheny Health Network, Pittsburgh, PA, 45Bioinformatics Solutions, Sheridan, WY, 46None, Denver, CO
Background/Purpose: Systemic lupus erythematosus is a heterogenous autoimmune disease characterized by inflammatory damage to multiple organ systems. We have shown that the single-nucleotide polymorphism (SNP) rs1876453 is associated with decreased risk of lupus, with a preferential effect on anti-double stranded (ds) DNA antibodies. Since anti-dsDNA antibodies develop prior to clinically apparent disease and are associated with more severe disease, we hypothesized that the minor A allele at rs1876453 would delay disease onset and improve clinical outcomes. We demonstrated a delay in lupus onset associated with the SNP using a large lupus association study [Large Lupus Association Study 2 (LLAS2)], and herein we explore the effects of the SNP on clinical outcomes using a longitudinal inception cohort.
Methods: Subjects genotyped using the Illumina platform from a longitudinal inception cohort [Systemic Lupus International Collaborating Clinics (SLICC), n=977] were studied. Age of onset was determined, and damage, disease activity, steroid exposure, and survival were assessed.
Results: As with the subjects in the LLAS2 cohort, the median age of diagnosis for subjects with the protective A allele at rs1876453 was significantly greater in the SLICC cohort [median (IQR), 33 (20) for GG, 36 (20) for AG, and 50 (31.5) for AA, p = 0.0167]. Subjects with the protective allele had similar scores for damage at 5 years, but their likelihood of developing damage by then was greater (41.6% for AG/AA vs 31.8% for GG at Year 5, p = 0.0270). This was not due to more severe disease, since they had lower disease activity [median SLEDAI (IQR) 2.5 (3.6) for GA/AA, 3.3 (3.8) for GG; p = 0.0163] and comparable steroid exposure. Although this was likely due in part to their older age at disease onset, there was a trend towards early damage even in patients younger than age 50 (p = 0.0762). Despite their older median age, their mortality rates were lower (p = 0.0414).
Conclusion: The minor allele at rs1876453 is associated with delayed onset, reduced overall disease activity, and lower mortality despite the increased probability of early damage. This increased risk of early damage may result from older age at disease onset or from a specific pathogenic mechanism in subjects with the protective SNP who develop lupus and will require further study.
A. Oganesyan: None; R. Sharp: None; P. O’Neill: None; C. Aranow: AstraZeneca, 2, Bristol-Myers Squibb(BMS), 2, GlaxoSmithKlein(GSK), 2, 5, kezar Inc, 2; L. Arnaud: AbbVie, 6, Alexion, 6, Alpine, 2, 6, Amgen, 6, AstraZeneca, 1, 2, 6, Biogen, 6, Boehringer Ingelheim, 6, Bristol-Myers Squibb(BMS), 2, 6, Eli Lilly, 6, GlaxoSmithKlein(GSK), 1, 2, 6, Grifols, 6, Janssen, 6, Kezar Life Sciences, 2, 6, LFB, 6, Medac, 6, Novartis, 2, 6, Pfizer, 6, Roche-Chugaï, 6, UCB, 6; A. Askanase: AbbVie, 2, Amgen, 2, AstraZeneca, 2, Aurinia, 2, Bristol-Myers Squibb, 2, Celgene, 2, Eli Lilly, 2, Genentech, 2, GSK, 2, Idorsia, 2, Janssen, 2, Mallinckrodt, 2, Pfizer, 2, UCB Pharma, 2; S. Bae: None; S. Bernatsky: None; I. Bruce: AstraZeneca, 1, 2, 5, 6, Aurinia, 2, GSK, 1, 2, 5, 6, Janssen, 5, 6, Lilly, 1, UCB, 6; J. Buyon: Bristol-Myers Squibb(BMS), 2, GlaxoSmithKlein(GSK), 2, Related Sciences, 1; W. Chatham: None; A. Clarke: AstraZeneca, 2, Bristol-Myers Squibb(BMS), 2, GlaxoSmithKlein(GSK), 2, 5, Otsuka, 2, Roche, 2; N. Costedoat-Chalumeau: None; M. Dooley: None; P. Fortin: AbbVie, 1, AstraZeneca, 1, 6, GlaxoSmithKlein(GSK), 1, 6, Roche-Genentech, 1; E. Ginzler: None; D. Gladman: AbbVie, 2, 5, Amgen, 2, 5, Bristol Myers Squibb, 2, Celgene, 2, 5, Eli Lilly, 2, 5, Galapagos, 2, Gilead Sciences, 2, Janssen, 2, 5, Novartis, 2, 5, Pfizer Inc, 2, 5, UCB, 2, 5; C. Gordon: AbbVie, 2, Alumis, 2, Amgen, 2, AstraZeneca, 2, Sanofi, 2, UCB Pharma, 2; J. Hanly: None; M. Inanç: Boehringer-Ingelheim, 6, Pfizer, 6, UCB, 6; D. Isenberg: None; S. Jacobsen: None; A. Jonsen: None; K. Kalunian: AbbVie/Abbott, 2, Amgen, 5, AstraZeneca, 2, Aurinia, 2, Bristol-Myers Squibb(BMS), 2, Eli Lilly, 2, EquilliumBio, 2, Genentech, 2, Gilead, 2, Janssen, 2, KezarBio, 1, Merck/MSD, 2, Novartis, 2, Pfizer, 2, Remegene, 2, Roche, 2, UCB, 5; D. Kamen: None; S. Lim: None; A. Mak: None; E. Morand: AbbVie, 2, 5, Amgen, 5, AstraZeneca, 2, 5, 6, Biogen, 2, 5, Bristol Myers Squibb, 2, 5, Eli Lilly, 2, 5, EMD Serono, 2, 5, Galapagos, 2, Genentech, 2, 5, GlaxoSmithKline, 2, 5, IgM, 2, Janssen, 2, 5, Novartis, 2, Servier, 2, Takeda, 2, UCB, 5; C. Peschken: AstraZeneca, 2, 5, GSK, 2, 5, Roche, 1, 2; M. Petri: Alexion, 1, Amgen, 1, AnaptysBio, 1, Annexon Bio, 1, Argenx, 1, Arhros-Focus Med/Ed, 6, AstraZeneca, 1, 5, Aurinia, 1, 5, 6, Axdev, 1, Biogen, 1, Boxer Capital, 2, Cabaletto Bio, 2, Caribou Biosciences, 2, CVS Health, 1, Eli Lilly, 1, 5, Emergent Biosolutions, 1, Exagen, 5, Exo Therapeutics, 2, Gilead Biosciences, 2, GlaxoSmithKlein(GSK), 1, 5, 6, Horizon Therapeutics, 2, Idorsia Pharmaceuticals, 2, IQVIA, 1, Janssen, 1, 5, Kira Pharmaceuticals, 2, MedShr, 6, Merck/EMD Serono, 1, Momenta Pharmaceuticals, 2, Nexstone Immunology, 2, Nimbus Lakshmi, 2, Proviant, 2, Sanofi, 2, Sinomab Biosciences, 2, Thermofisher, 5, UCB, 2; B. Pons-Estel: None; A. Rahman: None; R. Ramsey-Goldman: Ampel Solutions, 2, Calabetta, 2, Exagen, 2, Immunocor, 6; J. Reynolds: None; J. Romero-Diaz: None; G. Ruiz-Irastorza: None; J. Sanchez-Guerrero: None; K. Steinsson: None; M. Urowitz: None; R. van Vollenhoven: AbbVie, 2, 6, AstraZeneca, 2, 5, 6, Biogen, 6, Bristol-Myers Squibb(BMS), 2, 5, 6, Galapagos, 2, 5, 6, GlaxoSmithKline, 6, Janssen, 2, 6, MSD/Merck Sharp and Dohme, 5, Novartis, 5, Pfizer, 2, 5, 6, RemeGen, 2, Roche, 5, Sanofi, 5, UCB, 2, 5, 6; E. Vinet: None; A. Voskuyl: None; D. Wallace: None; S. Manzi: AbbVie, 5, Allegheny Singer Research Institute, 10, AstraZeneca, 2, 5, Exagen Diagnostics, Inc, 2, 9, 10, GSK, 2, 5, Lilly, 2, Lupus Foundation of America, 4, Novartis, 2, UCB Advisory Board, 2, Univiersity of Pittsburgh, 10; K. Jones: None; S. Boackle: None.
