THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Special anniversary session highlights Foundation-funded research insights

The Rheumatology Research Foundation is the largest private funding source of rheumatology research and training in the United States. Since its establishment in 1985, the Foundation has granted more than 2,600 individual awards, committing more than $131 million directly to research and training.

The Foundation celebrates its 30th anniversary this year, and on Tuesday afternoon will play host to a special session commemorating the anniversary and featuring presentations covering some of the cutting-edge research financed by the Foundation, providing insight into the pathogenesis, diagnosis, and treatment of rheumatoid arthritis.

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Mara L. Becker, MD, MSCE

A Signature for Response to Methotrexate in Juvenile Idiopathic Arthritis
Mara L. Becker, MD, MSCE, will discuss the results of a study looking at the effect cellular interactions between folate and methotrexate (MTX) may have on early drug response in juvenile idiopathic arthritis (JIA). Dr. Becker is Associate Professor of Pediatrics at the University of Missouri-Kansas City School of Medicine and Division Director, Rheumatology, at Children’s Mercy Hospital in Kansas City, Mo.

“As in adults, there are few predictors of response to methotrexate in children, and since the drug is slow-acting, it leaves children vulnerable to potential side effects or delay in effective treatment without a guarantee of response,” Dr. Becker said. “If we can identify who will be an optimal or poor responder to MTX, we may be able to choose the most appropriate drug at the onset of therapy.”

In a prospective study, Dr. Becker and her colleagues measured the baseline folate status of patients before MTX was initiated, with follow-up measurements at 3 and 6 months on therapy, noting how MTX is accumulated and how folate status changes at a cellular level over time.

“The polyglutamated form of MTX has gotten a lot of attention as a biomarker of response to MTX,” she said. “However, we’re particularly interested in the folate pathway upon which it acts, because the folate pathway is a dynamic system, and we cannot consider one without the other.”

Because the function of the folate pathway is dependent upon many enzymes that are subject to genetic variability, the researchers are also investigating the role that genetic variation may play in folate and MTX homeostasis and drug response. The vast variability in response to MTX, Dr. Becker noted, provides the opportunity to identify extreme responders to the drug.

“There are definitely differences in cellular folate and MTX concentrations in responders and non-responders, and although MTX is traditionally considered a folate antagonist, depleted cellular folate is not necessarily associated with better clinical response,” she said. “I expect that an individual’s ability to respond to MTX is related to a number of factors, and we will need to continue a translational investigative approach to best characterize the variability in drug response and predict optimal outcomes in JIA.”

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Lindsey A. Criswell, MD, MPH, DSc

DNA Methylation Profiling in Rheumatoid Arthritis
Lindsey A. Criswell, MD, MPH, DSc, Professor and Chief of the Division of Rheumatology at the University of California, San Francisco, will present information on a study exploring variation in DNA methylation patterns among RA patients and how that might provide insight into how certain environmental factors impact risk and severity of RA.

“DNA methylation is one form of epigenetic change to the DNA, in which methyl groups get added to or taken off of certain places along the DNA, and that can have a profound impact on whether genes get expressed or the level of expression,” Dr. Criswell said. “The important piece is that factors in the environment, including various medications, drugs, infections, nutrition, and other exposures, can affect methylation status, so it’s a really powerful way to try to extend our understanding of genes and disease and identify the environmental contributions.”

In beginning their study, Dr. Criswell looked at research conducted at the University of California, San Diego, in which researchers identified differences in methylation patterns in joint tissue of RA patients versus osteoarthritis and healthy controls.

In their study, Dr. Criswell and her colleagues enrolled approximately 100 subjects, two-thirds of whom were RA patients, the remaining third being healthy individuals without RA or other autoimmune diseases. They took fresh blood samples from each subject and sorted them into four different cell subtypes. In each of those subtypes, the investigators characterized the methylation pattern across the entire genome and then looked for methylation patterns that distinguish rheumatoid arthritis patients from healthy individuals.

“Interestingly, one of the four blood types that we were studying — naïve CD4 T cells — demonstrated the same methylation pattern that the UC San Diego researchers saw in the joint tissue,” Dr. Criswell said. “This suggests that there may be a way to detect this methylome signature in patients in a relatively straightforward fashion.”

Then, just considering the RA patients, they looked for DNA methylation patterns that distinguish patients who have more, vs. less, active disease, as well as patients who had accumulated more, vs. less, damage because of their disease.

Building on their ongoing work with a new pilot grant from the Foundation, Dr. Criswell and her colleagues are initiating a study to specifically investigate how medications commonly used for rheumatoid arthritis affect the methylation pattern and, hence, gene expression. They hope to identify DNA methylation profiles that help identify which patients are most likely to respond to specific medications.

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V. Michael Holers, MD

Pathogenic Humoral Autoimmunity in the Transition to Clinically Apparent Rheumatoid Arthritis
The origins of rheumatoid arthritis-related autoimmunity and how the process evolves early in the disease is the focus of research that will be presented by V. Michael Holers, MD, Head of the Division of Rheumatology at the University of Colorado School of Medicine.

“Initially, about 15 years ago, we began to evaluate the question of whether there were biomarkers or changes in the blood that one could see prior to the onset of clinically apparent arthritis,” Dr. Holers said. “That question followed research that was ongoing in other autoimmune diseases — type 1 diabetes in particular —where it was quite clear that there were blood biomarkers, specifically autoantibodies specific for this disease, that were present in the blood prior to the development of the clinical syndrome.”

Dr. Holers and colleagues hypothesized that a similar process might be going on with RA and, in their initial studies, they were able to identify RA autoantibodies that appeared on average approximately 3-5 years prior to the development of arthritis, at which time the individuals appeared to be completely asymptomatic.

“We knew that these individuals had signs of systemic inflammation in blood biomarkers and that they had autoantibodies that had characteristics of pathogenic antibodies, not just false positive tests, but real disease-associated antibodies,” he said. “So we went looking and we found that a substantial number of these individuals had asymptomatic inflammation in the lung. We then went on to see that, in some instances, they were making autoantibodies in the lung when we couldn’t even find the antibodies in the blood yet.”

They are now looking at the antibodies in the blood and trying to determine what characteristics of those antibodies might change over time as an individual progresses from an asymptomatic state to having rheumatoid arthritis.

“We have been able to identify the development of new types of antibodies, as well as changes in the physical characteristics of those antibodies, that allowed them to better engage immune effector systems,” Dr. Holers said.

Further, they identified complement activation fragments, the presence of which indicates antibodies actually working and inducing inflammation, he said.

“I think we need to continue to work very hard to understand how the antibodies change over time and what causes them to be more pathogenic,” Dr. Holers said. “If we can understand that process, we can work to develop strategies to stop that from occurring.”