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Abstract Number: 1932

Identifying Clusters of Longitudinal Autoantibody Profiles Associated with Systemic Lupus Erythematosus Disease Outcomes

May Choi1, Irene Chen2, Ann Clarke3, Marvin Fritzler3, Katherine Buhler3, Murray Urowitz4, John Hanly5, Caroline Gordon6, Yvan St.Pierre7, Sang-Cheol Bae8, Juanita Romero-Diaz9, Francisco Sanchez-Guerrero10, Sasha Bernatsky11, Daniel Wallace12, David Isenberg13, Anisur Rahman14, Joan Merrill15, Paul R Fortin16, Dafna Gladman17, Ian N. Bruce18, Michelle Petri19, Ellen Ginzler20, Mary Anne Dooley21, Rosalind Ramsey-Goldman22, Susan Manzi23, Andreas Jnsen24, Graciela Alarcn25, Ronald van Vollenhoven26, Cynthia Aranow27, Meggan Mackay27, Guillermo Ruiz-Irastorza28, S Sam Lim29, Murat Inanc30, Kenneth Kalunian31, Sren Jacobsen32, Christine Peschken33, Diane Kamen34, Anca Askanase35, David Sontag2 and Karen Costenbader36, 1Brigham and Women's Hospital | University of Calgary, Calgary, AB, Canada, 2Massachusetts Institute of Technology, Cambridge, MA, 3University of Calgary, Calgary, AB, Canada, 4Center for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University of Toronto, Lupus Clinic, Toronto, ON, Canada, 5Dalhousie University, Halifax, NS, Canada, 6Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom, 7Research Institute of the McGill University Health Centre, Montréal, QC, Canada, 8Hanyang University Medical Center, Seoul, Republic of Korea, 9Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de México, Federal District, Mexico, 10University Health Network/Sinai Health system, Toronto, ON, Canada, 11McGill University, Montréal, QC, Canada, 12Cedars-Sinai, Los Angeles, CA, 13Centre for Rheumatology, University College London, London, United Kingdom, 14University College London, London, United Kingdom, 15Oklahoma Medical Research Foundation, Oklahoma City, OK, 16CHU de Quebec - Universite Laval, Québec City, QC, Canada, 17Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Toronto, ON, Canada, 18University of Manchester, Manchester, United Kingdom, 19Johns Hopkins University School of Medicine, Baltimore, MD, 20SUNY Downstate Health Sciences University, Brooklyn, NY, 21Raleigh Neurology Associates, Chapel Hill, NC, 22Northwestern University, Chicago, IL, 23Allegheny Health Network, Wexford, PA, 24Lund University, Lund, Sweden, 25University of Alabama at Birmingham, Birmingham, AL, 26Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Center, Amsterdam Rheumatology Center, Amsterdam, Netherlands, 27Feinstein Institutes for Medical Research, Manhasset, NY, 28Hospital Universitario Cruces, University of the Basque Country, Bizkaia, Spain, 29Department of Medicine, Division of Rheumatology, Emory University School of Medicine, Atlanta, GA, 30Istanbul University Faculty of Medicine, Istanbul, Turkey, 31UC San Diego, La Jolla, CA, 32Copenhagen Lupus and Vasculitis Clinic, Centre for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 33University of Manitoba, Winnipeg, MB, Canada, 34Medical University of South Carolina, Charleston, SC, 35Columbia University Medical Center, New York, NY, 36Brigham and Women's Hospital, Belmont, MA

Meeting: ACR Convergence 2021

Keywords: Autoantibody(ies), autoantigens, Biomarkers, Systemic lupus erythematosus (SLE)

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Session Information

Date: Tuesday, November 9, 2021

Title: Abstracts: SLE – Diagnosis, Manifestations, & Outcomes II: Predictors & Longitudinal Outcomes (1931–1934)

Session Type: Abstract Session

Session Time: 3:45PM-4:00PM

Background/Purpose: Prior studies of SLE clusters based on autoantibodies have utilized cross-sectional data from single centers. We applied clustering techniques to longitudinal and comprehensive autoantibody data from a large multinational, multi-ethnic inception cohort of well characterized SLE patients to identify clusters associated with disease outcomes.

Methods: We used demographic, clinical, and serological data at enrolment and follow-up visits years 3 and 5 from 805 patients who fulfilled the 1997 Updated ACR SLE Classification Criteria and were enrolled within 15 months of diagnosis. For each visit, ANA (HEp-2 indirect immunofluorescence assay), dsDNA, Sm, U1-RNP, SSA/Ro60, SSB/La, Ro52/TRIM21, histones, ribosomal P, Jo-1, centromere B, PCNA, antiphospholipid antibodies (IgG and IgM for anticardiolipin, anti–β2GP1, and aPS/PT, lupus anticoagulant (LAC), and IgG anti-β2GP1 D1), and anti-dense-fine speckled 70 were performed at a single lab (except LAC). K-means clustering algorithm on principal component analysis (10 dimensions) transformed longitudinal ANA and autoantibody profiles was used. We compared cluster demographic and clinical outcomes, including longitudinal disease activity (total and adjusted mean SLEDAI-2K [AMS]), SLICC/ACR damage index and organ-specific domains, SLE therapies and survival, using one-way ANOVA test and a Benjamini-Hochberg correction with false discovery rate alpha = 0.05. Results were visualized using t-distributed stochastic neighbor embedding (t-SNE).

Results: Four unique patient clusters were identified (Table 1, Figure 1). Cluster 1 (n=137), characterized by high frequency of anti-Sm and anti-RNP antibodies over time, was the youngest group at disease onset with a high proportion of subjects of Asian and African ancestry. At year 5, they had the highest disease activity (total SLEDAI-2K 4.3 [4.5] and AMS 4.3 [3.1]), were more likely to have active hematologic and mucocutaneous involvement, and to be on/exposed to immunosuppressants/biologics. Cluster 2 (n=377), the largest cluster, had low frequency of anti-dsDNA, were oldest at disease onset, and at year 5, had the lowest disease activity (total SLEDAI-2K 2.3 [3.3] and AMS 2.9 [2.5]), and were less likely to have nephritis and be on/exposed to immunosuppressants/biologics. Cluster 3 (n=79) had the highest frequency of antiphospholipid antibodies over time (Figure 2), were more likely to be of European ancestry, have an elevated body mass index, be former smokers, and by year 5, to have nephritis, neuropsychiatric involvement, including strokes and seizures (SLICC/ACR damage index). Cluster 4 (n=212) was characterized by anti-SSA/Ro60, SSB/La, Ro52/TRIM21, and histone antibodies, and active immunologic involvement (low complements) at year 5. Overall, survival of the 805 subjects was 94% at 5 years, and none of the clusters predicted survival.

Conclusion: Four SLE patient clusters associated with disease activity, organ involvement, and treatment were identified in this analysis of longitudinal ANA and autoantibody profiles in relation to SLE outcomes, suggesting these SLE subsets might be identifiable based on extended autoantibody profiles early in the disease and carry prognostic information.

Figure 1. Four autoantibody cluster groups identified among 805 SLE patients followed from enrolment through years 3 and 5. Latent space visualized using a t-distributed stochastic neighbor embedding (t-SNE) with colors based on cluster labels.

Figure 2. Antiphospholipid antibodies of the four cluster groups over time (E=enrolment, Y3=year 3, Y5=year 5). Group 3 had the highest frequency of antiphospholipid antibodies, including lupus anticoagulant, IgG and IgM anticardiolipin, IgG and IgM anti–β2-glycoprotein_1 (β2GP1), IgG anti-β2GP1 Domain 1 (D1), IgG and IgM antiphosphatidylserine/prothrombin (aPS/PT), over time compared to the other three clusters. Other connective tissue disease autoantibodies not shown. Line indicates the mean, shading indicates the standard deviation.


Disclosures: M. Choi, MitogenDx, 1, 2; I. Chen, None; A. Clarke, AstraZeneca, 2, GSK, 6, BMS, 2, Exagen Diagnostics, 2; M. Fritzler, Inova Diagnostics Inc., 2, 6, Werfen International, 2, Alexion Canada, 6, Mitogen Diagnostics Corp., 3, 8, 9, 10; K. Buhler, None; M. Urowitz, GlaxoSmithKline, 2, 5, 6, UCB, 2, Lilly, 6, AstraZeneca, 2; J. Hanly, None; C. Gordon, Centre for Disease Control, 2, 6, Astra-Zeneca, 2, 6, MGP, 2, 6, Sanofi, 2, 6, UCB, 2, UCB, 5, 6; Y. St.Pierre, None; S. Bae, None; J. Romero-Diaz, None; F. Sanchez-Guerrero, None; S. Bernatsky, None; D. Wallace, GlaxoSmithKline, 2, 6, Eli Lilly and Company, 2, 6, AstraZeneca, 2, 6, Aurunia, 2, 6, EMD Serono, 2; D. Isenberg, None; A. Rahman, Lilly, 6; J. Merrill, GlaxoSmithKline, 2, 5, UCB, 2, AbbVie, 2, EMD Serono, 2, Remegen, 2, Celgene/Bristol Myers Squibb, 2, AstraZeneca, 2, 5, Daiichi Sankyo, 2, Servier, 2, Immupharma, 2, Amgen, 2, Janssen, 2, Lilly, 2, Genentech, 2, Resolve, 2, Alpine, 2, Aurinia, 2, Astellas, 2, Alexion, 2, Provention, 2; P. Fortin, Lilly, 1, AbbVie, 1, AstraZeneca, 1; D. Gladman, AbbVie, 2, 5, Amgen, 2, 5, Eli Lilly, 2, 5, Galapagos, 2, 5, Gilead, 2, 5, Janssen, 2, 5, Novartis, 2, 5, Pfizer, 2, 5, UCB, 2, 5, Celgene, 2, 5, Bristol Myers Squibb, 2, 5; I. Bruce, None; M. Petri, Alexion, 1, Amgen, 1, Astrazeneca, 1, 5, Aurinia, 5, 6, Eli Lilly, 5, Emergent Biosolutions, 1, Exagen, 5, Gilead Biosciences, 2, GSK, 1, 5, IQVIA, 1, Idorsia Pharmaceuticals, 2, Janssen, 1, 5, Merck EMD Serono, 1, Momenta Pharmaceuticals, 2, PPD Development, 1, Sanofi, 2, Thermofisher, 5, UCB Pharmaceuticals, 2; E. Ginzler, None; M. Dooley, None; R. Ramsey-Goldman, None; S. Manzi, Astra Zenecs, 2, 5, Cugene, 2, Eli Lilly, 2, Exagen, 2, 5, 10, UCB, 2, GSK, 2; A. Jnsen, None; G. Alarcn, None; R. van Vollenhoven, Bristol Myers Squibb, 2, 5, Eli Lilly, 5, UCB, 2, 5, 6, Pfizer, 2, 6, 12, Support for educational programs; institutional grants, Roche, 12, Support for educational programs; institutional grants, Janssen, 2, 6, AbbVie, 2, 6, AstraZeneca, 2, Biotest, 2, GlaxoSmithKline, 2, 6, Biogen, 2, Galapagos, 2, 6, Gilead, 2, Sanofi, 2, Servier, 2, Vielabio, 2; C. Aranow, GlaxoSmithKline, 2, 5; M. Mackay, None; G. Ruiz-Irastorza, None; S. Lim, Bristol Myers Squibb, 5, GlaxoSmithKline, 2, ACR, 4, AstraZeneca, 5, Pfizer, 2, UCB, 2; M. Inanc, None; K. Kalunian, Amgen, 2, AbbVie, 2, AstraZeneca, 2, Biogen, 2, Bristol Myers Squibb, 2, Eli Lilly, 2, Equillium, 2, Genentech/Roche, 2, Gilead, 2, Janssen, 2, Lupus Research, 5, Pfizer, 5, Sanford Consortium, 5, Vielabio, 2, Aurinia, 2, Alliance, 2, Nektar, 2; S. Jacobsen, None; C. Peschken, AstraZeneca, 2, GlaxoSmithKline, 2, Eli Lilly, 2; D. Kamen, None; A. Askanase, GSK, 2, 5, AstraZeneca, 1, 5, Amgen, 1, Aurinia, 2, Abbvie, 1, Pfizer, 5, Eli Lilly, 5, Idorsia, 5; D. Sontag, CurAI, 2, GNS Healthcare, 2, ASAPP, 3; K. Costenbader, Neutrolis, 11, Merck, Exagen, Gilead, 5, Astra Zeneca, Neutrolis, 2.

To cite this abstract in AMA style:

Choi M, Chen I, Clarke A, Fritzler M, Buhler K, Urowitz M, Hanly J, Gordon C, St.Pierre Y, Bae S, Romero-Diaz J, Sanchez-Guerrero F, Bernatsky S, Wallace D, Isenberg D, Rahman A, Merrill J, Fortin P, Gladman D, Bruce I, Petri M, Ginzler E, Dooley M, Ramsey-Goldman R, Manzi S, Jnsen A, Alarcn G, van Vollenhoven R, Aranow C, Mackay M, Ruiz-Irastorza G, Lim S, Inanc M, Kalunian K, Jacobsen S, Peschken C, Kamen D, Askanase A, Sontag D, Costenbader K. Identifying Clusters of Longitudinal Autoantibody Profiles Associated with Systemic Lupus Erythematosus Disease Outcomes [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/identifying-clusters-of-longitudinal-autoantibody-profiles-associated-with-systemic-lupus-erythematosus-disease-outcomes/. Accessed .
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