Article Text

Download PDFPDF

103 Exploratory segregation of patients upon their levels of anti- mitochondrial antibodies (AMAs) reveals associations between AMAs and disease manifestations
  1. Yann LC Becker1,2,
  2. Éric Boilard1,2,
  3. Emmanuelle Rollet-Labelle1,2,
  4. Christian Lood3,
  5. Anne-Sophie Julien2,
  6. Joannie Leclerc1,
  7. Tania Lévesque1,
  8. Murray Urowitz4,
  9. John Hanly5,
  10. Caroline Gordon6,
  11. Sang-Cheol Bae7,
  12. Juanita Romero-Diaz8,
  13. Jorge Sanchez-Guerrero9,
  14. Ann E Clarke10,
  15. Sasha Bernatsky11,
  16. Daniel Wallace12,
  17. David Isenberg13,
  18. Anisur Rahman14,
  19. Joan Merrill15,
  20. Dafna Gladman16,
  21. Ian N Bruce17,
  22. Michelle Petri18,
  23. Ellen Ginzler19,
  24. Mary Anne Dooley20,
  25. Rosalind Ramsey-Goldman21,
  26. Susan Manzi22,
  27. Andreas Jönsen23,
  28. Graciela Alarcon24,
  29. Ronald van Vollenhoven25,
  30. Cynthia Aranow26,
  31. Guillermo Ruiz-Irastorza27,
  32. Sam Lim28,
  33. Murat Inanc29,
  34. Kenneth Kalunian30,
  35. Soren Jacobsen31,
  36. Christine Peschken32,
  37. Diane Kamen33,
  38. Anca Askanase34,
  39. Jill Buyon35 and
  40. Paul R Fortin1,3
  1. 1Centre de Recherche ARThrite, CHU de Québec – Université Laval, Québec City, Québec, Canada
  2. 2Université Laval, Québec City, Québec, Canada
  3. 3Division of Rheumatology, University of Washington, Seattle, USA
  4. 4University of Toronto, University Health Network, Schroeder Arthritis Institute, Toronto, Ontario, Canada
  5. 5Division of Rheumatology, Queen Elizabeth II Health Sciences Center (Nova Scotia Rehabilitation Site) and Dalhousie University, Halifax, Nova Scotia, Canada
  6. 6Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
  7. 7Hanyang University Medical Center, Seoul, North Korea
  8. 8Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico City, Mexico
  9. 9Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, Ontario, Canada
  10. 10University of Calgary, Division of Rheumatology, Cumming School of Medicine, Calgary, Alberta, Canada
  11. 11Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
  12. 12Cedars Sinai Medical Center, Los Angeles, CA, USA
  13. 13University College London, London, UK
  14. 14Centre for Rheumatology, Department of Medicine, University College London, London, UK
  15. 15Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  16. 16Toronto Western Hospital, Schroeder Arthritis Institute, Toronto, Ontario, Canada
  17. 17Centre for Epidemiology Versus Arthritis, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, Manchester, UK
  18. 18Johns Hopkins University School of Medicine, Division of Rheumatology
  19. 19SUNY Downstate Health Sciences University, Department of Medicine, Brooklyn, NY, USA
  20. 20Raleigh Neurology Associates, Raleigh, NC, USA
  21. 21Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  22. 22Allegheny Health Network, Lupus Center of Excellence, PA, USA
  23. 23Department of Clinical Sciences, Lund, Section for Rheumatology, Lund University, Lund and Skåne University Hospital, Lund, Sweden
  24. 24The University of Alabama at Birmingham, Birmingham, AL, USA
  25. 25Amsterdam University Medical Centers, Amsterdam, Netherlands
  26. 26Feinstein Institutes for Medical Research, NY, USA
  27. 27Autoimmune Diseases Research Unit, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, UPV/EHU, Barakaldo, País Vasco, Spain
  28. 28Emory University, Atlanta, GA, USA
  29. 29Division of Rheumatology, Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
  30. 30University of California San Diego, San Diego, CA, USA
  31. 31Rigshospitalet, Copenhagen, Denmark
  32. 32University of Manitoba, Winnipeg, Manitoba, Canada
  33. 33Medical University of South Carolina, Charleston, SC, USA
  34. 34Columbia University Medical Center, NY, USA
  35. 35NYU Grossman School of Medicine, NY, USA


Background Mitochondria are intracellular organelles derived from the endosymbiosis between an α-proteobacterium and a primitive eukaryotic cell. Mitochondria thus display pro-inflammatory and antigenic properties, when released into the extracellular milieu.

Several cross-sectional studies reported increased levels of anti-mitochondrial antibodies (AMAs) in patients with systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). These autoantibodies also displayed correlations with the SLE disease activity index 2000 (SLEDAI-2K) and associations with various clinical manifestations (e.g. lupus nephritis, thromboses, carotid plaque). In the present study, we aim to detect AMAs against either whole organelles (AwMA), mitochondrial DNA (mtDNA) or RNA (mtRNA) through time in samples from patients included in the SLICC cohort.

Methods Clinically relevant variables (e.g., sociodemographic variables, disease-specific outcomes including death and arterial vascular events (AVE)) were documented and biosamples were harvested upon patient enrolment in the SLICC cohort, as well as at each follow-up visit. AMA levels were measured by in-house direct ELISAs whereas SLE autoantibodies were detected by clinical laboratories. Healthy individuals, defined as having no known illnesses and infectious symptoms at the time of the blood draw, were recruited. 90% confidence intervals were calculated for both limits of the 95% nonparametric two-sided reference intervals for values measured in healthy donors. AMA values were segregated into 3 categories: Normal values were determined as within the inner limits of the range while values outside this range were characterized as abnormal, either lower or higher than the reference interval. (figure 1). Marginal Cox models with AMAs in 3 categories were adjusted for covariables and are presented as [hazard ratio (95% CI)]. Interactions with sex were tested in models with the AMAs as continuous variables.

Results Sera from healthy individuals (n=126) or SLE patients included in the SLICC cohort, from their inclusion, up to 7 years of follow-up (n=1114 patients at baseline, 3577 samples in total). AwMA displayed lower correlations with antibodies to mitochondrial nucleic acids (versus AmtDNA: rs=0.37, and vs AmtRNA: rs=0.38), while antibodies to mitochondrial DNA or RNA shown higher correlations (rs=0.59). During our preliminary analyses on the distribution of the variables, We made intriguing observations regarding patients with AMA levels that were either lower or higher than those of healthy individuals. This information led us to categorize SLE patients as described in the methods and in figure 1. For each of the three antibodies assessed, SLE patients displayed more abnormal AMA levels at baseline than controls. The percentage of patients with higher levels of AwMA and AmtRNA increased at subsequent follow-up visits, while a slight decrease was observed for AmtDNA (figure 2). SLE patients with higher levels of AwMA showed higher risks of death [2.12 (1.18-3.83)]. It is of interest that an inverse relationship was found between AmtRNA and AVEs, with a small subset of patients with low levels of AmtRNA (n = 4), this autoantibody was associated with increased risks of this manifestation [4.46 (1.71-11.66)]. Additionally, patients with higher levels of AmtDNA and AmtRNA displayed increased risks of lupus nephritis [respectively: 3.05(2.05-4.54), and 1.56(1.12-2.18)]. Interestingly, there was an interaction with sex for AmtRNA levels effect on AVEs [males: 0.32 (0.11-0.99). Females: 1.56 (1.11-2.19)], and AmtDNA association with nephritis was only significant in female patients [4.00 (2.51-6.36)] (table 1).

Conclusion These results show that AMAs display different associations with disease manifestations in various clusters of patients. These results prompt for further analyses by machine-learning in order to delineate clusters of clinical interests by adding AMAs in the routine serological assessment of SLE autoantibodies.

Acknowledgements We acknowledge the contribution of the study participants, individual center support staff as well as investigators of the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort project who for the past 20 years have made this study possible.

LAY ABSTRACT The mitochondrion is a part of the cell that controls various biological mechanisms (e.g., energy supply, whether the cell should live or die, control, or produce various cellular components). They are derived, through evolution, from a microbe. Mitochondria may sometimes be jettisoned out of their host cell and subsequently elicit immune reactions – including the production of antibodies. Previous studies indicated that patients with autoimmune conditions such as systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS) have antibodies against mitochondria in their blood stream. Presence of these antibodies was associated with increased disease activity and clinical manifestations of these diseases (e.g. kidney disease, arterial vessel disease). In this study, we studied blood samples harvested by an international group dedicated to the study of SLE [i.e., the SLE International Collaborating Clinics (SLICC) cohort] and observed that patients may be clustered into groups, upon their levels of antibodies and/or sex, allowing to have a better appreciation of their risks of death, vascular events, and kidney disease. These results might lead to improved diagnosis and/or prognosis in SLE and thus, in improved care and quality of life for the people living with lupus.

Abstract 103 Figure 1

Segregation of the patients in categories. For each of the AMA assessed, values were divided into 3 categories. 95% nonparametric two-sided reference intervals were calculated, using values measured in healthy donors, to define a reference interval. In patients with SLE, values were considered as normal if they were included within the inner limits of the reference interval. Values outside this interval were characterized as abnormal (i.e. higher or lower levels).

Abstract 103 Figure 2

Evolution of the positivity to the three anti-mitochondrial antibodies assessed. Autoantibodies (i.e., IgG) to whole organelles (AwMA), mtDNA (AmtDNA) or mtRNA (AmtRNA) were assessed in sera from healthy individuals (n=126) or patients included in the SLICC cohort (n=1114 patients at baseline, 3577 samples in total). Through time, the frequency of patients with higher levels of AwMA appears to increase, while a decrease of the positivity to AmtDNA was detected.

Abstract 103 Table 1

Associations between AMAs and clinical manifestations of the disease.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: .

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.