Scientists at the Johns Hopkins School of Medicine say they have uncovered insights as to why lupus symptoms and severity present differently in individuals. The researchers believe this discovery will lead to further understanding of the biological mechanisms behind lupus, and may lead to shifts in how clinicians treat patients.
Their new study is published in Cell Reports Medicine in an article titled, “Uncoupling interferons and the interferon signature explains clinical and transcriptional subsets in SLE.”
“Systemic lupus erythematosus (SLE) displays a hallmark interferon (IFN) signature. Yet, clinical trials targeting type I IFN (IFN-I) have shown variable efficacy, and blocking IFN-II failed to treat SLE,” the researchers wrote. “Here, we show that IFN type levels in SLE vary significantly across clinical and transcriptional endotypes.”
Interferons normally help to fight infection or disease, but are overactive in lupus, causing widespread inflammation and damage.
“For years, we have accumulated knowledge that interferons play a role in lupus,” said corresponding author and rheumatologist Felipe Andrade, MD, PhD, associate professor of medicine at the Johns Hopkins School of Medicine. He says this research began with questions about why certain lupus treatments were ineffective for some patients. “We have seen instances where the patient surprisingly didn’t improve—we wondered if certain interferon groups were involved.”
Some lupus treatments are designed to suppress a specific group of interferons, known as interferon I. The researchers believed that two other interferon groups, interferon II and interferon III, may be to blame for these poor treatment responses.
To investigate, the researchers observed at how different combinations of interferon I, II, or III, and their overactivity, may present in people with lupus. They took 341 samples from 191 participants to determine the activity of the three interferon groups, and used human cell lines engineered to react to the presence of each specific interferon group to analyze the samples. Through this process, the researchers determined that the majority of participants fell into four categories: those only with increased interferon I; those with a combination of increased interferons I, II, and III; those with a combination of increased interferons II and III; or those with normal interferon levels.
The researchers were able to use these findings to also make several associations between these interferon combinations and lupus symptoms. In those with elevated interferon I, lupus was mainly associated with symptoms affecting the skin, such as rashes or sores. Participants with elevated levels of interferon I, II, and III exhibited the most severe presentations of lupus, often with significant damage to organ systems, such as the kidneys. However, not every symptom found in lupus was associated with elevated interferons.
The formation of blood clots and low platelet counts, which also affect clotting, did not have an association with increased levels of interferon groups I, II, or III. Researchers say this indicates that both interferon-dependent and other biological mechanisms are involved in this complex disease. The study also found that genetic testing of genes associated with these interferon groups, or the interferon signature, did not always indicate elevated interferon levels. The researchers plan to investigate this in future studies.
“Evaluating a patient’s elevated interferon combinations allows for a better understanding of how they may react to treatments, and would allow clinicians to group them into clinical subtypes of lupus,” said rheumatologist Eduardo Gómez-Bañuelos, MD, PhD, assistant professor of medicine at the Johns Hopkins University School of Medicine and the study’s first and additional corresponding author..
