Pitt Researchers Look to DNA to Better Understand Lupus

By: Sarah Katz

Researchers at the University of Pittsburgh and UPMC recently discovered that certain genes contribute to Lupus flare-ups and disease progression, a major step forward in developing targeted treatments for the disease.

Lupus is a chronic autoimmune disease that causes symptoms like fatigue, skin rash, joint pains and fever. Lupus can also affect major organs and cause kidney inflammation and damage. The illness moves through cycles of remission and flare ups. There is no cure for Lupus, and treatments are limited to immunosuppressants and managing the symptoms.

Dr. Amr Sawalha

“We have to identify the mechanisms that underlie the disease process and flares-ups in Lupus patients to know the best treatment options,” said Dr. Amr Sawalha, division director of rheumatology at UPMC Children’s Hospital of Pittsburgh and professor of pediatrics and medicine at the University of Pittsburgh.

To figure out exactly how Lupus works, Sawalha and his team looked at one of the most basic building blocks of life — DNA.

Every cell in your body has the same DNA. To become a distinct type of cell, like blood cells or muscle cells, DNA undergoes a process called methylation. Methylation is a chemical reaction that causes certain parts of your DNA to be silenced or turned off. Based on what’s left, the cells change into their final form. This process is constantly happening in your body as new cells grow.

In Lupus patients, the methylation process doesn’t work the way it should, causing some parts of the DNA to be turned off or on that shouldn’t be. This irregular methylation is what causes a variety of the symptoms associated with Lupus.

While many studies have looked at the methylation in Lupus patients at one point in time, no one has studied the process over time. Sawalha and his team’s research recently published in JCI Insight is the first study that followed a cohort of patients over four years, tracking which parts of the DNA were silenced over time and the resulting symptoms.

Through their analysis, the researchers were able to show that when one specific part of patients’ DNA is abnormally activated, they will develop nephritis, a condition that causes the kidneys to become inflamed and thus stop effectively filtering waste from blood.

In addition, Sawalha and his team looked at methylation patterns across different patient populations.

“Lupus is more common and more severe in African-American patients,” said Sawalha, who is also the director of the Lupus Center of Excellence  at the University of Pittsburgh School of Medicine. “To better understand why, we looked at the whole genome and methylation patterns of DNA in African-American and European-American patients and compared them head on.”

Sawalha and his team found that when patients have specific patterns of DNA methylation changes, they are more likely to develop severe cases of Lupus. This sequence was more prevalent in African-American patients.

With this level of granular understanding of Lupus, Sawalha hopes we can move away from simply treating the symptoms of Lupus to treating the illness according to how it manifests in each person.

“We want to personalize treatment for Lupus patients,” Sawalha said. “Since Lupus can present in many forms, it makes the most sense to tailor the treatment to exactly how the illness is presenting in each patient.”

While there is still work to be done to better understand Lupus, this research is a step toward this individualized medicine.

“We’re excited by this research, and the potential of developing new treatments,” Sawalha said. “Because what we have now is clearly not sufficient.”