Research Award: Searching For Biomarkers to Predict a Drug’s Side Effects 

By Vandana Suresh | Feb. 8, 2024

Ever since glucocorticoids were introduced in clinics to treat rheumatoid arthritis (RA) in the early 1950s, they have improved the lives of millions of people living with RA by reducing inflammation and restoring a sense of well-being. However, despite their therapeutic benefits, these drugs (also known as corticosteroids) are also known to cause serious side effects in some individuals, especially if used in larger dosages or long-term.

But are certain people more vulnerable than others to these side effects? To answer that question, the Arthritis Foundation has awarded a $150,000 RA Research Program award to Michael George, MD, MSCE, assistant professor in medicine at the University of Pennsylvania. With this funding, his team will analyze data collected by the Veterans’ Affairs Rheumatoid Arthritis Registry in search of genetic traits that can forecast adverse glucocorticoid effects.

“I think a lot of providers and patients have a love-hate relationship with glucocorticoids because, while these drugs are effective, they also cause unwanted side effects,” Dr. George says. “Our research can lead to a more targeted way to treat people with rheumatoid arthritis. We want to identify the people with RA who are at high risk [of adverse effects] versus those who are low risk and consequently benefit from being on these medications.”

Risks of Long-Term Use

The treatment options for rheumatoid arthritis have significantly expanded in recent decades. Medications now include nonsteroidal anti-inflammatory drugs (NSAIDs), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), glucocorticoids and, more recently, biologic DMARDs (biologics) and their biosimilars. As the standard of care, patients are frequently prescribed a short course of glucocorticoids, like prednisone, to reduce inflammation and pain. However, 30% to 40% of patients remain on glucocorticoids for many years. Such long-term usage can lead to serious and sometimes irreversible side effects, like cardiovascular disease and diabetes.

“Even though people might be planning to use glucocorticoids for a short time, many end up staying on them for a long time because when they try to come off, their symptoms come back, even when they’re on a biologic,” says Dr. George. “And then there are other people who may be afraid to be on a biologic and prefer to stay on glucocorticoids instead.”

Genetic Role

While most patients with RA taking glucocorticoids see immediate therapeutic benefits, their overall response to the medications can vary, with some patients experiencing more adverse reactions. Research now suggests that an individual’s genetic makeup may play an essential role in their response to glucocorticoids.

“Genetic predisposition has never been looked at in people with rheumatoid arthritis,” says Dr. George. “Certainly, there may be other things that predispose people to have side effects; for example, if the patient already has high blood sugar, glucocorticoids might make it worse. But the key part is building our understanding of the genetic markers to predict the potential side effects from the glucocorticoids.”

Recent high-profile work from a basic science laboratory showed that glucocorticoids have different effects on different cells of the body. In particular, the study revealed that children with certain genetic traits were much more likely to have high blood sugar when receiving glucocorticoids for their leukemia than those without those genetic traits. Specifically, this research identified 28 different genetic markers strongly associated with how fat and liver cells respond to glucocorticoids and the development of high blood glucose.

Dr. George’s team will explore whether the same genetic markers in fat and liver cells are associated with adverse symptoms in RA patients taking glucocorticoids. In addition, for their research, they will analyze prospective data from the Veterans’ Affairs Rheumatoid Arthritis Registry, which contains information about patient medication, disease activity and genetic data.

“This project wouldn’t be possible without the support from the Arthritis Foundation. We’re excited about what we’ll find and future studies that it can lead to,” says Dr. George. “Hopefully, in the near future, we will have the genetic predictors to help create the best treatment plan for RA patients.”