“Women had a much higher rate of transition to lupus compared with their male family members,” said Dr. James. The study also examined how those who transitioned were related to the original lupus patient. “We thought this would be all sisters, but what we found was that there were transitions in all kinds of family members, including cousins, nieces and a few nephews of lupus patients too.”
Each person who transitioned to lupus had at least a positive ANA test and most also had either a clinical symptom or another autoantibody. Analysis of the transitioned patients’ baseline results on the Connective Tissue Disease Screening Questionnaire showed that individuals with higher scores were more likely to transition to lupus.
When they looked at soluble mediators, “we found altered cytokines … in first-degree blood relatives of lupus patients who transitioned. First-degree relatives who transitioned had higher levels of BLyS even at baseline compared with those who did not transition and with family members who were ANA negative and unaffected,” said Dr. James.
The researchers also found increased levels of TNF receptor 1, MCP-3 and stem cell factor in relatives who transitioned to SLE, but surprisingly low levels of regulatory cytokines, such as IL-10 and TGF-b.
Environmental Exposures
Epstein-Barr virus has interested lupus researchers as one early trigger of autoimmunity. In a 2019 paper, Dr. James and her colleagues recontacted 436 family members of SLE patients who did not have the disease at baseline to see if they had transitioned to classified disease within a 6.3-year follow-up period.12
Analyzing blood samples, researchers measured patients’ antibodies against Epstein-Barr viral capsid antigen and early antigen. They found transitioning patients had higher levels of anti-early antigen antibodies and serological evidence of Epstein-Barr virus reactivation. Their recent research also identified environmental factors that may increase family members’ transition risk, including vitamin D deficiency, especially if individuals also have risk alleles for a single-nucleotide polymorphism in the CYP24A1 allele, and sleeping less than seven hours per night.13,14
Possible Protective Factors
Of women in the U.S., up to 30% will have a positive ANA test at some point, but few develop systemic autoimmune disease, Dr. James said. How are they able to escape the development of autoimmune disease?
Using the Oklahoma Immune Cohort of 789 individuals, she and her colleagues found 57 individuals who were ANA positive and had anti-dsDNA, anti-chromatin, anti-Ro, anti-La, anti-Sm and other lupus-associated autoantibodies. “We also looked at the racial composition of those individuals who were autoantibody-positive,” she said. “African Americans were on the lower end of positivity, with only 4.0% having one of these autoantibody specificities. Native Americans had the highest rate of autoantibodies and European Americans were in the middle. When we looked at multivariable logistic regression, only female sex was a significant, independent predictor.”15