Mapping Anti-Mitochondrial Antibodies over Time in a Lupus Inception Cohort

Yann Becker¹, Éric Boilard¹, Emmanuelle Rollet-Labelle¹, Christian Lood², Anne-Sophie Julien³, Joannie Leclerc¹, Tania Lévesque¹, Murray Urowitz⁴, John Hanly⁵, Caroline Gordon⁶, Sang-Cheol Bae⁷, Juanita Romero-Diaz⁸, Jorge Sanchez-Guerrero⁹, Ann E Clarke¹⁰, Sasha Bernatsky¹¹, Daniel Wallace¹², David Isenberg¹³, Anisur Rahman¹⁴, Joan Merrill¹⁵, Dafna Gladman¹⁶, Ian N. Bruce¹⁷, Michelle Petri¹⁸, Ellen M. Ginzler¹⁹, Mary Anne Dooley²⁰, Rosalind Ramsey-Goldman²¹, Susan Manzi²², Andreas Jönsen²³, Graciela Alarcón²⁴, Ronald van Vollenhoven²⁵, Cynthia Aranow²⁶, Guillermo Ruiz-Irastorza²⁷, S. Sam Lim²⁸, Murat Inanc²⁹, Kenneth Kalunian³⁰, Soren Jacobsen³¹, Christine Peschken³², Diane Kamen³³, Anca Askanase³⁴, Jill Buyon³⁵ and Paul R Fortin³⁶, ¹Centre de Recherche ARThrite, CHU de Québec - Université Laval, Québec, QC, Canada, ²Division of Rheumatology, University of Washington, Seattle, WA, ³Université Laval, Québec, QC, Canada, ⁴University of Toronto, University Health Network, Schroeder Arthritis Institute, Toronto, ON, Canada, ⁵Division of Rheumatology, Queen Elizabeth II Health Sciences Center (Nova Scotia Rehabilitation Site) and Dalhousie University, Halifax, NS, Canada, ⁶Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom, ⁷Hanyang University Medical Center, Seoul, Republic of Korea, ⁸Instituto Nacional de Ciencias Medicas y Nutricion SZ, Ciudad de México, Mexico, ⁹Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON, Canada, ¹⁰University of Calgary, Division of Rheumatology, Cumming School of Medicine, Calgary, AB, Canada, ¹¹Research Institute of the McGill University Health Centre, Montréal, QC, Canada, ¹²Cedars-Sinai Medical Center, Los Angeles, CA, ¹³University College London, London, United Kingdom, ¹⁴Centre for Rheumatology, Department of Medicine, University College London, London, United Kingdom, ¹⁵Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁶Toronto Western Hospital, Schroeder Arthritis Institute, Toronto, ON, Canada, ¹⁷Centre for Epidemiology Versus Arthritis, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom, ¹⁸Johns Hopkins University School of Medicine, Division of Rheumatology, Baltimore, MD, ¹⁹SUNY Downstate Health Sciences University, Department of Medicine, Brooklyn, NY, ²⁰Raleigh Neurology Associates, Chapel Hill, NC, ²¹Northwestern University Feinberg School of Medicine, Chicago, USA, Chicago, IL, ²²Allegheny Health Network, Lupus Center of Excellence, Wexford, PA, ²³Department of Clinical Sciences, Lund, Section for Rheumatology, Lund University, Lund and Skåne University Hospital, Lund, Sweden, ²⁴The University of Alabama at Birmingham, Oakland, ²⁵Amsterdam University Medical Centers, Amsterdam, Netherlands, ²⁶Feinstein Institutes for Medical Research, Manhasset, NY, ²⁷Autoimmune Diseases Research Unit, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain, ²⁸Emory University, Atlanta, GA, ²⁹Division of Rheumatology, Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University, Istambul, Turkey, ³⁰University of California San Diego, La Jolla, CA, ³¹Rigshospitalet, Copenhagen, Denmark, ³²University of Manitoba, Winnipeg, MB, Canada, ³³Medical University of South Carolina, Charleston, SC, ³⁴Columbia University Medical Center, New York, NY, ³⁵NYU Grossman School of Medicine, New York, NY, ³⁶Centre ARThrite - CHU de Québec - Université Laval, Québec, QC, Canada

Meeting: ACR Convergence 2022

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

Session Information

Date: Saturday, November 12, 2022

Title: SLE – Diagnosis, Manifestations, and Outcomes Poster I: Diagnosis

Session Type: Poster Session A

Session Time: 1:00PM-3:00PM

Background/Purpose: Mitochondria can be both pro-inflammatory and antigenic. We hypothesize (1) that anti-mitochondrial antibodies (AMA) are present in lupus and (2) can predict outcomes. Our aim was to map three AMAs in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort and test their effects on clinical outcomes.

Methods: The SLICC inception cohort recruited SLE patients 15 months or less after their diagnosis (1997 ACR classification criteria) from 31 centers in 11 countries. We included all participants with up to 4 biospecimens available as well as healthy controls. We retrieved their sociodemographic and disease characteristic variables [disease activity (SLEDAI-2K), damage (SLICC damage index (SDI)) and medications]. Clinical outcomes of interest were death, arterial (AVE) and venous vascular events; nephritis, SDI, and neuropsychiatric SLE (NPSLE). Covariables included in all models: sex, race/ethnicity, age, time since diagnosis, body mass index (BMI), hypertension, hypercholesterolemia, use of prednisone, antimalarial and immuno-suppressors with the addition of history of past AVE for the AVE models. Antibodies against whole mitochondria (AwMA), mitochondrial DNA (AmtDNA), or RNA (AmtRNA) were assessed using in-house direct ELISAs and reported on a continuous scale. We used Spearman’s correlation to evaluate associations between AMAs; Wilcoxon-Mann-Whitney test for correlations between groups; and Cox regressions models using baseline value of each AMA individually as predictor variables adjusted for covariables and multiple imputations for the effects of AMAs on clinical outcomes.

Results: We tested 127 healthy controls and 3450 SLE biospecimens from 1114 SLICC participants and analyzed data from 9788 SLICC clinical visits. There were 89% females with baseline characteristics (mean+sd): age (35.4+13.4 years), SLE duration (0.46+0.35 years), and baseline SLEDAI-2K (5.3+5.3). Correlations between AMAs were low to moderate. Figure 1 shows that the levels of the three AMAs are higher in SLE patients than controls and while AwMA levels clearly increase over time, levels of AmtDNA remain constant and those of AmtRNA show a trend towards increasing over time. Correlations between AMAs and SLEDAI-2K were low (coefficients < 0.20). Multivariable analyses using individual baseline AMA levels as predictor variables adjusted for covariables and with multiple imputations for missing values showed that higher levels of AwMA were predictive of death (HR [95%CI] = 3.03 [1.34, 6.82], p=0.008); lower levels of AmtRNA of AVE (4.54 [1.52, 13.53], p=0.007); and higher levels of both AmtDNA (3.05 [2.05, 4.54], p< 0.0001) and AmtRNA (1.56 [1.12, 2.18], p< 0.008) of nephritis. We did not find associations with any of the three AMAs and venous thrombosis, SDI, or NP-SLE.

Conclusion: Lupus patients have more AMAs than healthy controls and their levels may vary over time. While higher baseline levels of AwMA predicted deaths and higher levels of AmtDNA and AmtRNA predicted nephritis, we found an inverse relationship with lower levels of AmtRNA predicting AVE. These results confirm that AMAs are associated with clinical outcomes in SLE.

Figure 1: Evolution of anti-mitochondrial antibodies (AMAs) over time.
The upper row reports on mean optical density values (OD 405nm) of AMAs targeting either whole organelles (AwMA), mitochondrial DNA (AmtDNA), or mitochondrial RNA (AmtRNA). Data are mean ± SD, horizontal blue lines display mean levels of corresponding AMA measured in healthy donors. The lower row shows the distributions of AwMA, AmtDNA and AmtRNA for healthy controls and SLE patients at each visit.

Disclosures: Y. Becker, None; É. Boilard, None; E. Rollet-Labelle, None; C. Lood, Eli Lilly, Gilead Sciences, Pfizer, Bristol-Myers Squibb(BMS), Redd Pharma, Horizon Diagnostic, Exagen Diagnostic; A. Julien, None; J. Leclerc, None; T. Lévesque, None; M. Urowitz, None; J. Hanly, None; C. Gordon, UCB, Amgen, Astra-Zeneca, AbbVie, Sanofi, MGP; S. Bae, None; J. Romero-Diaz, Biogen; J. Sanchez-Guerrero, None; A. Clarke, AstraZeneca, Bristol Myers Squibb (BMS), GlaxoSmithKline (GSK); S. Bernatsky, None; D. Wallace, None; D. Isenberg, Merck/MSD, astra zeneca, Eli Lilly, Servier, Amgen; A. Rahman, None; J. Merrill, UCB, GlaxoSmithKline, AbbVie, EMD Serono, Remegen, Celgene/Bristol Myers Squibb, AstraZeneca, Amgen, Janssen, Lilly, Genentech, Aurinia, Astellas, Alexion, Sanofi, Zenas, Proventio; D. Gladman, AbbVie, Amgen, Eli Lilly, Janssen, Gilead, Novartis, Pfizer, Bristol-Myers Squibb(BMS), Galapagos, UCB Pharma, Celgene; I. Bruce, AstraZeneca, Bristol-Myers Squibb(BMS), Eli Lilly, Aurinia, Janssen, GlaxoSmithKlein(GSK); M. Petri, Exagen, AstraZeneca, Alexion, Amgen, AnaptysBio, Argenx, Aurinia, Biogen, Caribou Biosciences, CVS Health, EMD Serono, Eli Lilly, Emergent Biosolutions, GlaxoSmithKline (GSK), IQVIA, Janssen, Kira Pharmaceuticals, MedShr, Sanofi, SinoMab, Thermofisher, BPR Scientific Advisory Committee; E. Ginzler, Aurinia Pharma; M. Dooley, None; R. Ramsey-Goldman, None; S. Manzi, AstraZeneca, GlaxoSmithKline (GSK), Exagen Diagnostics Inc, AbbVie, HGS, Cugene, Lilly, UCB Advisory Board, Lupus Foundation of America; A. Jönsen, None; G. Alarcón, None; R. van Vollenhoven, Bristol Myers Squibb (BMS), GlaxoSmithKline (GSK), UCB, Merck/MSD, Pfizer, Roche, AbbVie, AstraZeneca, Biogen, Galapagos, Janssen, Miltenyi, R-Pharma; C. Aranow, None; G. Ruiz-Irastorza, None; S. Lim, None; M. Inanc, None; K. Kalunian, AbbVie/Abbott, Amgen, AstraZeneca, Aurinia, Biogen, Bristol Myers Squibb (BMS), Eli Lilly, Equillium, Genentech, Gilead, Janssen, Roche, Lupus Research Alliance, Pfizer, Sanford Consortium, Viela, Nektar; S. Jacobsen, None; C. Peschken, None; D. Kamen, None; A. Askanase, AstraZeneca, GlaxoSmithKlein(GSK), Aurinia, Amgen, Pfizer, Idorsia, Eli Lilly, UCB, AbbVie/Abbott, Janssen, Bristol-Myers Squibb(BMS); J. Buyon, None; P. Fortin, AstraZeneca, GlaxoSmithKlein(GSK).

To cite this abstract in AMA style:

Becker Y, Boilard É, Rollet-Labelle E, Lood C, Julien A, Leclerc J, Lévesque T, Urowitz M, Hanly J, Gordon C, Bae S, Romero-Diaz J, Sanchez-Guerrero J, Clarke A, Bernatsky S, Wallace D, Isenberg D, Rahman A, Merrill J, Gladman D, Bruce I, Petri M, Ginzler E, Dooley M, Ramsey-Goldman R, Manzi S, Jönsen A, Alarcón G, van Vollenhoven R, Aranow C, Ruiz-Irastorza G, Lim S, Inanc M, Kalunian K, Jacobsen S, Peschken C, Kamen D, Askanase A, Buyon J, Fortin P. Mapping Anti-Mitochondrial Antibodies over Time in a Lupus Inception Cohort [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/mapping-anti-mitochondrial-antibodies-over-time-in-a-lupus-inception-cohort/. Accessed .

« Back to ACR Convergence 2022

ACR Meeting Abstracts - https://acrabstracts.org/abstract/mapping-anti-mitochondrial-antibodies-over-time-in-a-lupus-inception-cohort/