Although the precise cause of systemic lupus erythematosus (SLE) is not known, it is clear that the disease develops in a genetically predisposed individual after exposure to environmental triggers. A number of genes associated with an increased risk of lupus have been identified, many in just the last several years. Yet, despite a known genetic component conferring risk of disease, the concordance in identical twins is less than 50%, suggesting that there are significant environmental or other nongenetic factors at work.
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Explore This IssueJune 2010
In order to further understand the interplay between genetic and environmental factors that may be involved in the initiation of disease, our research team at the Feinstein Institute for Medical Research in Manhasset, N.Y., in collaboration with many others nationwide, has initiated a study to longitudinally follow individuals at increased risk of developing SLE—the unaffected sisters of women with SLE. The goals of this study are twofold: to increase our understanding of how lupus develops and to begin devising personalized prevention and therapy strategies.
Risk Knowns and Unknowns
The risk of developing SLE is approximately 0.1% in the population (0.2% in females). In first-degree relatives, the risk is 4% to 8%.1 Despite the fact that SLE occurs nine times more frequently in females than males, few studies have evaluated the risk of developing disease separately in female and male first-degree relatives. One study suggests that the risk that sisters of lupus patients have of developing SLE may be as high as 10%.2 Studies also suggest that disease generally develops in the initially unaffected sister within seven years, with a range of two to 16 years, of the diagnosis of SLE in the proband (affected sister).3 In an early study, Christian and colleagues observed a 7% incidence of SLE in first-degree relatives of lupus patients over a 10-year prospective study.4
Like many other autoimmune diseases, SLE begins with a period when there may be circulating autoantibodies without any overt evidence of disease; nevertheless, some individuals with these antibodies never develop disease. Harley and colleagues retrospectively examined serum samples from 130 individuals in the military who subsequently developed SLE.5 Antinuclear antibodies (ANAs) were seen prior to the diagnosis of SLE in 78% of patients. In general, although there was significant variability, symptoms did not develop until a mean of nine years after the initial detection of autoantibodies. Onset of symptoms occurred within a year of the appearance of some autoantibodies (e.g., anti-Sm or anti-RNP) and most individuals had three autoantibodies by the time symptoms developed. The accumulation of autospecificities correlated with the development of clinical disease.
There is a general awareness that type 1 interferon (IFN) contributes to disease pathogenesis, at least in a subset of lupus patients.6 Genes that lie within the interferon pathway are risk factors for SLE.7 Approximately 50% of patients display a gene expression profile in peripheral blood mononuclear cells characterized by upregulation of several IFN-inducible genes (interferon signature). Recently, Crow and colleagues have shown that approximately 50% of SLE patients have high levels of serum type 1 IFN, and 20% of their unaffected first-degree relatives also display this phenotype.8 Because high serum levels of type 1 IFN cluster in families, it may be a marker of an at-risk family. There is currently no way to estimate the individual risk to family members with any precision.
The SisSLE Study
The underlying hypothesis of our research, known as the Sisters of Women with Systemic Lupus Erythematosus (SisSLE) study, is that an algorithm based on genetics, serology, serum cytokines, Epstein-Barr virus exposure, vitamin D level, chemokines, and peripheral blood gene expression profile can be developed to assess an individual’s risk of developing lupus. By longitudinally following individuals at increased risk of developing SLE, it should also be possible to discern distinct patterns of disease progression; these patterns will reflect different pathways of immune dysregulation and will suggest different therapeutic targets in different cohorts of patients. Thus, this study should increase our understanding of the development of lupus and should begin the process of developing customized prevention and therapy. The study is currently enrolling female lupus patients and their unaffected sisters; the sisters will be followed for up to seven years and monitored for the development of clinical and serologic disease. Individuals will be enrolled throughout the United States and rheumatologists throughout the country are invited to help recruit their patients into this important study. [Editor’s note: “Sisters Volunteer for Study to Find Answers” on p. 25 interviews two sisters who enrolled in SisSLE to hear why this trial is important to them.]
This study will collect DNA from the unaffected sisters and the sister with SLE. Specimens of serum and cells from sisters of patients with SLE will also be collected annually to establish the prevalence and incidence of lupus related phenotypes (i.e., autoantibodies and altered gene expression) in the absence of clinical lupus, in these relatives. Potential environmental triggers, such as vitamin D levels, will also be analyzed. The sisters will be questioned biannually about the development of symptoms that might indicate the evolution into clinical disease. While the overwhelming majority of the sisters will not develop SLE, some of these sisters will progress. The experimental approach is based on the assumption that the unaffected sisters of individuals with an onset of SLE before age 35 years are likely to be enriched for lupus genetic risk alleles, and therefore these individuals will be most informative for longitudinal follow-up in order to accomplish the goals of the study. This study is a unique opportunity to investigate the genes, gene expression, and the serologic progression in unaffected sisters of SLE patients and identify those factors that predict for or protect against the development of clinical SLE.
Physicians following female patients meeting ACR classification criteria for SLE when they were age 35 years or younger and who have at least one sister or half-sister who is currently age 35 years or younger are invited to refer their SLE patient for this study. Nurse coordinators at the Feinstein Institute for Medical Research will handle all subsequent logistics, including obtaining informed consent of the patient with SLE and her sisters, conducting phone interviews, and arranging for blood collection and shipment back to the Feinstein Institute. This is an important study to which all rheumatologists may contribute. The results will increase our understanding of how lupus develops and will ultimately lead to the development of strategies for personalized prevention and therapy. For more information on the trial or on enrolling patients, visit www.SisSLE.org or call 1-877-698-9467.
Dr. Aranow is an associate investigator; Dr. Mackay is an assistant investigator; Dr. Gregersen is chief of the Center for Genomics and Human Genetics; and Dr. Diamond is chief of the Center for Autoimmune and Musculoskeletal Diseases. The authors all work at the Feinstein Institute for Medical Research.
- Michel M, Johanet C, Meyer O, et al. Familial lupus erythematosus. Clinical and immunologic features of 125 multiplex families. Medicine (Baltimore). 2001;80:153-158.
- Giles I, Isenberg D. Lupus in the family—analysis of a cohort followed from 1978 to 1999. Lupus. 2001;10:38-44.
- Priori R, Medda E, Conti F, et al. Familial autoimmunity as a risk factor for systemic lupus erythematosus and vice versa: A case-control study. Lupus. 2003;12:735-740.
- Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore). 1971;50:85-95.
- Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003; 349:1526-1533.
- Baechler EC, Gregersen PK, Behrens TW. The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol. 2004;16:801-807.
- Graham RR, Kyogoku C, Sigurdsson S, et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci U S A. 2007;104:6758-6763.
- Niewold TB, Hua J, Lehman TJ, Harley JB, Crow MK. High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun. 2007;8:492-502.