Autoantibody profiling to identify individuals at risk for systemic lupus erythematosus
Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can have devastating clinical repercussions including irreversible damage to vital organs. Although SLE is uncommon, estimated to affect 1/2500 persons in the USA, the incidence of disease is significantly higher in young minority women and may represent the most common serious medical disorder in this segment of the population [1], [2]. Until recently, the onset of clinical symptoms was viewed as an unfortunate consequence of the wrong (“right”) combination of susceptibility alleles in a permissive environment with little or no warning, thus preempting the benefits of early diagnosis or treatment. However, recent advances in genetics, immunology and environmental epidemiology suggest that early or even pre-clinical identification of individuals at risk may be feasible. For example, new data document that a progressive increase in the number of autoantibodies precedes the onset the actual diagnosis of lupus [3], [4].
The most important diagnostic test for SLE remains the presence of antinuclear antibodies (ANAs), because a negative result virtually rules out the possibility of lupus. However, ANA testing is relatively non-specific, and ‘false-positive ANA’ is a frequent cause of unnecessary medical evaluations that can cause significant anxiety. Although it is likely that pre-clinical SLE patients show ANA positivity, identification of the subset at greatest risk for clinical illness is not currently possible.
The first goal of the present study was to characterize autoantibodies related to lupus in a rheumatology registry that includes subjects with a full spectrum of the disease ranging from SLE and its incomplete forms to first degree relatives of these patients. These results were then used to provide a context for interpreting and identifying the size and characteristics of the potential population at risk for autoimmunity in general and lupus in particular within a general, unselected cohort of over 3000 individuals living in an urban area, with significant proportions of African-Americans and Hispanics who are at high risk of developing SLE. This is one of the largest reported samples of unselected subjects screened with new multiplex immunoassays. The findings confirm the relatively high prevalence of autoreactivity in the healthy population. Further analyses of the clinically normal subjects who have autoantibodies will be a necessary step in the identification and characterization of preclinical autoimmunity. It has been suggested that such an approach could contribute to the long term goals of predicting and preventing autoimmune disease [5].
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Patients
Rheumatology clinic patients were recruited at UT Southwestern Medical Center at Dallas and included subjects from clinics at Parkland Hospital, a large publicly-funded facility, and from the Aston Ambulatory Care Center. Studies were carried out on a total of 176 subjects who were divided into three categories related to lupus: (1) patients with systemic lupus erythematosus (SLE) who satisfied four or more of the American College of Rheumatology classification criteria [6], [7]; (2) patients
Significance of ANA positivity by ELISA
The positive predictive value of the ANA tested using the SLE and normal control groups in the DRADR was 85.7%, and the negative predictive value was 62%, consistent with the high prevalence of SLE in the study group.
A receiver operating characteristics curve (ROC) calculated using the ANA values obtained in the SLE and normal subgroups had an area under the curve of 0.8786, consistent other reports [11] (Fig. 1A). When the ANA values were used to divide the DRADR patients into quartiles, a
Discussion
SLE pathogenesis in susceptible individuals most likely involves a progression from a non-reactive, non-autoimmune state to benign autoimmune status whereby levels of autoantibodies are increased, followed by a pathologic transition that gives rise to increasing levels of a variety of autoantibodies with damage to kidneys, joints, heart, brain and skin. SLE has been associated with more autoantibodies, over 100, than any other autoimmune disorder [15]. As routine autoantibody levels are not
Acknowledgements
Special thanks to S. Narasimhulu and L. Davis for assistance with DRADR collection and analysis and to M. Basit, T. Eversole and G. Stanek for help with DHS collection and analysis. Dallas Heart Study is part of the Reynolds Cardiovascular Clinical Research Center at UT Southwestern, which is supported by the Donald W. Reynolds Foundation. AEW is supported in part by a grant from the Lupus Foundation. NJO is the recipient of support from the McGee Foundation.
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