Predicting Rheumatoid Arthritis Severity and Treatment

By Vandana Suresh | May 30, 2025

One of the biggest challenges of chronic diseases is predicting and managing the severity of the disease and its symptoms and what treatments will be effective. In addition, the risk for refractory disease, where treatments fail to work for a patient, is much higher for those with chronic diseases, like rheumatoid arthritis (RA), than for people with conditions that aren’t chronic. These challenges can impact important aspects of an individual’s life, including work, finances, relationships and overall well-being.

Recognizing the need to identify which individuals will have refractory RA, the Arthritis Foundation has awarded an RA Research Program grant to Thomas Riley, MD, a post-doctoral fellow at PennMedicine. With the funding, Dr. Riley will investigate the genetic risks for disease severity and treatment response in RA patients in the Veteran’s Affairs Rheumatoid Arthritis Registry (VARA).

“A key problem in RA is knowing who’s going to respond to therapy, whether it’s the first-line therapy like methotrexate or next-line therapy with TNF inhibitors and biologics, and who might benefit from trying something different,” said Dr. Riley. “With the Arthritis Foundation grant, we want to use genetics to predict who will have higher disease activity and who might respond to therapies like methotrexate.” 

About 30% to 50% of people with RA do not respond to first-line therapies. These individuals are then put on biologics, starting with TNF inhibitors. If patients fail to achieve low disease activity or remission after trying at least two or more biologics, then they are considered to have refractory RA. This uncontrolled disease poses a huge economic burden from increased health care costs, work disability and potential impact on overall quality of life. Identifying those likely to experience refractory disease would better inform disease management strategies.

Past research, particularly genome-wide association studies (GWAS), has shown that there is considerable genetic variation in people with RA, and this diversity is a key contributor to the risk for RA. Using genetic data collected in GWAS, Dr. Riley plans to assess whether the overall genetic risk for developing RA can identify those individuals who will have greater disease severity and are less likely to respond to treatments. The VARA registry will play a crucial role.

“We’re lucky to have the VARA registry because it is rich with patient clinical and phenotypic data,” said Dr. Riley. “I’m interested in using the genetic data to help define a phenotype, high genetic risk that could help us understand the differences in how people with RA respond to treatments.”

He plans to look at specific markers associated with a high risk for RA and perform a technique called polygenic scoring, where an individual’s genetic predisposition to RA is scored by combining the effects of many genetic risks and variants. He will then compare this score of an individual patient with their disease activity and treatment response to uncover possible links.

“I’m so grateful to receive the award from the Arthritis Foundation for their support of this research,” said Dr. Riley. “But I also greatly value the Foundation’s support for junior investigators like me who can get the training and experience needed to pursue larger grants to further their research."