Race, gender factor heavily in ‘many levels’ of lupus phenotypes
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Understanding the intersections of race, gender and molecular factors is critical to understanding lupus disease phenotypes, according to a presenter at the 2020 Congress of Clinical Rheumatology-East.
“I had to ask myself, what do we really know about how a phenotype affects how we treat a patient?” Joan T. Merrill, MD, Oklahoma Medical Research Foundation professor of medicine at the University of Oklahoma Health Sciences Center and adjunct professor in the School of Pharmacy, University of Oklahoma Health Sciences Center, said in her presentation.
In order to answer that question, Merrill said it is important to understand that a phenotype is defined as “some sort of observable characteristic” of patients, but that phenotype can keep changing because individuals are constantly evolving and interacting with their environment.
“Phenotype can be thought of on many levels,” she said.
Given that some nine out of 10 lupus patients are female, it is important for experts to dig deep as to why, according to Merrill. “There is a lot about being female, on a sophisticated level, that is related to lupus,” she said. “The phenotype of being female may be important in lupus.”
One reason for this pertains to B cells. “Those B cells that are associated with the pathogenesis of lupus are triggered more in females than males,” she said.
Hormones also can have “profound effects” how these B cells are regulated, according to Merrill. “I also want to add neutrophils to this,” she said. “We know that [neutrophils] are playing a role in interferon-alfa stimulated disease pathogenesis.”
While “plenty of men” with lupus also show up in Merrill’s practice, she believes that the cascade of symptoms that lead to lupus may be more amenable in the female phenotype. However, men often have more severe disease. “If you are a man and you tip over those dominoes, then you may have a really bad pathology of lupus,” she said.
The next issue to consider is race.
African American individuals are more likely to develop lupus, while those of Asian descent do not carry this predisposition and the risk is elevated only slightly in Native American populations, according to Merrill. “If you are multiracial, you are more likely to get lupus,” she said. “Perhaps this is because different genes with different risk factors are coming in, but we do not know for certain.”
Turning to disease severity, Merrill suggested that understanding serious complications like lupus nephritis is as important to understanding basic lupus phenotypes alone. “Incidence is not the same as severity,” she said.
That said, Merrill pointed out that race seems to play a role in lupus nephritis incidence rates. She highlighted data showing that lupus nephritis occurs in just 5.6 out of 100,000 individuals of Northern European descent, compared with 21.4 per 100,000 for those from India, 99.2 for those of African descent and 110.3 for those of Chinese descent.
Digging deeper into the cellular phenotypes of lupus, Merrill described a “circular process” of how plasmacytoid dendritic cells and type 1 interferon (IFN) signaling “pivot” around the B cell. Myeloid cells are involved and BLyS is produced. “They are all making cytokines,” she said. “It is hard to measure, but it is there, and it is causing trouble. Once you get the inflammation, you get CPG peptides. Once this starts, you can’t stop it.”
noted.
The issue with this complicated process is that it is different in every patient. “There are myriad potential differences in the structure of proteins, possibly changed by genes,” she said. “Genes complicate the picture.”
As for how molecular phenotypes of lupus nephritis pertain to therapeutic choices, Merrill said, unfortunately, there is simply not sufficient information as yet. That said, she said if a therapy does not appear to be working, clinicians should not wait to change course. “Time is kidney,” she said. “You do not want to let people sitting around spilling protein for a long time.”
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Merrill JT. Phenotypes in SLE-Can They Predict Disease Characteristics, Outcomes and Treatment Needs? Presented at: Congress of Clinical Rheumatology-East annual symposium; September 10-13, 2020 (virtual meeting).
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