With Systemic Lupus Erythematosus, Finding a Cause Is No Simple Task

Existing evidence suggests genetics, environmental factors, and exposure to specific chemicals—such as those in cigarettes—can all increase a person’s risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can be hard to identify due to the wide range of organs it affects. In a new review article, investigators noted that the causes of the disease, like its symptoms, can also be wide-ranging and hard to pin down.

Corresponding author Sasha Bernatsky, MD, PhD, of McGill University, said while genetic factors can play an important role in the pathogenesis of an individual’s lupus, genetics are only part of the equation. Writing in the journal Rheumatic Disease Clinics of North America, she and colleagues said genetic risk factors account for only about one-third of heritability in people with a family history of SLE.

The rest of the equation, the investigators said, appears to come down to a complex mix of environmental triggers and exposures, as well as personal factors such as whether the patient has a history of smoking.

One theory, Bernatsky and colleagues said, is that there is a 2-phase sequence that leads to the development of autoimmune diseases like SLE.

“There is a ‘first hit’ genetic or environmental exposure that induces an initial break of tolerance, leading to initiation of autoantibody production,” they wrote. “When a ‘second hit’ environmental exposure occurs, the initially limited autoimmune response becomes more florid, with inflammation developing in target organs, and the onset of clinical disease.”

One of the potential triggers is viral infection. Several viruses, including Epstein-Barr Virus, cytomegalovirus, and human T-cell lymphotropic virus have been tied to SLE risk, though the authors said the studies underpinning those associations have limitations. If infection does play a role in SLE, Bernatsky and colleague said it may not play an immediate one. It is possible, they said, that an infection early in life can convey a susceptibility to SLE later in life. And although there is reason to believe viral infections may be tied with SLE risk, the authors said the same is not true of vaccination. Epidemiologic studies do not support a link to vaccines, they said.

“[T]he body of evidence linking vaccines to SLE risk is weak, and therefore withholding vaccines to minimize SLE risk is not recommended,” they wrote.

Another active area of investigation is whether a person’s diet might predispose them to SLE. The authors noted that SLE has been linked with diets that are high in carbohydrates and low in monosaturated fatty acids, saturated fats, and trans fatty acids. Low levels of vitamin D have also been linked with SLE risk, they said, though efforts to examine whether vitamin D supplementation might delay SLE onset did not produce a meaningful effect.

Exposure to pollutants and chemicals are another potential risk factor, according to Bernatsky and colleagues. Smoking, organic pollutants, and occupational exposure to crystalline silica have all been associated with an increased risk of SLE, they said.

From a scientific standpoint, the investigators said it can be difficult to pinpoint causes for SLE. They noted that most studies evaluate just a single exposure, even though it is likely that SLE is the result of multiple factors.

“Given the heterogeneity of SLE and the modest associations between individual exposures and SLE risk, its onset is likely affected by a multitude and interaction of exposures, which needs to be further studied to allow for better interventions to address the risk of SLE, particularly among vulnerable populations,” they wrote.

From a clinical standpoint, the authors closed by noting that it can be difficult to give patients a satisfying answer when patients want to know what “caused” their lupus. However, they said the lack of a clear answer could provide a pathway to a broader discussion.

“Discussion of these factors with our patients represents an opportunity to highlight global strategies to optimize health, including avoidance of tobacco exposure,” they wrote.


Liu JL, Woo JMP, Parks CG, Costenbader KH, Jacobsen S, Bernatsky S. Systemic lupus erythematosus risk: the role of environmental factors. Rheum Dis Clin N Am. Published online October 1, 2022. doi:10.1016/j.rdc.2022.06.005

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