OMAHA, NE — New findings concerning the risk of interstitial lung disease in rheumatoid arthritis (RA) and how body composition and metabolic dysregulation are tied to RA and inflammation were among the highlights of research presented at the 20th Annual Fall Meeting of the VA Rheumatoid Arthritis (VARA) Registry held in September.
Interstitial lung disease (ILD) is a complication of RA that can have devastating consequences and thus has been a focus of VERA, said Ted Mikuls, MD, MSPH, principal investigator for the multicenter VARA Registry since its inception in 2003.1
“[RA-ILD research] aims to identify the genetic and non-genetic risk factors for RA-ILD development, harness these risk factors and peripheral biomarkers to improve RA-ILD identification, and then advance RA-ILD management through better disease prognostication and treatment selection,” said Bryant England, MD, PhD, assistant professor of medicine at the University of Nebraska Medical Center (UNMC) and staff physician with the VA Nebraska-Western Iowa Health Care System. England discussed new research, including a study which found a significant inverse association between serum IL-33 concentration and the risk of developing incident RA-ILD, but no associations with prevalent ILD. The findings suggest a serum alarmin IL-33 assessment could potentially contribute to clinical risk stratification in patients with RA.
“Such research has been possible largely due to VA funding, the VARA Repository and its linkages to other databases, as well as tools created by the team that allow accurate RA-ILD classification and phenotyping,” he said.
Metabolic disturbances, too, are common in RA, and include changes in cholesterol and higher risks of cardiometabolic conditions, said Josh Baker MD, MSCE, associate professor of medicine (rheumatology) at the Hospital of the University of Pennsylvania and the VA Medical Center Baker has been interested in adipokines (circulating proteins that control metabolism) as a way of better understanding the metabolic disturbances that occur in RA, he said. In a recent study using VARA data, he found that patients with very high adiponectin levels have greater systemic inflammation and an altered relationship between adiponectin and diabetes risk.
“The VARA registry has provided the data to support several studies aimed at better understanding these changes and their prognostic value in the disease,” he said.
“These studies are among more than 130 studies and reports published using the VARA Registry since its establishment to serve as a resource for VA research”, said Mikuls, a professor of medicine in the Division of Rheumatology at the University of Nebraska Medical Center in Omaha, where he has a dual appointment with the Omaha VAMC.
What VARA Is—and Does
Although RA affects as many as 1 in 20 veterans, it was rarely studied in veterans prior to VARA.
“At the time, back in the early 2000s, there was very little information out there about rheumatoid arthritis in veteran populations,” Mikuls told U.S. Medicine. “In a lot of ways, it is a unique and special population. I think the added benefit that made it possible was the VA was really a pioneer in electronic health records in the late 1990s, and that made it possible to study patients from multiple different VA medical centers and be looking at the same outcomes and the same processes.”
As the name sounds, the VARA registry is a cohort of U.S. veterans, all of whom have been diagnosed with rheumatoid arthritis, Mikuls said. The registry contains longitudinal measures of disease activity and valuable links to administrative data, enabling researchers to examine outcomes like comorbid conditions and interstitial lung disease.
Additionally, the registry is linked to a biobank and includes external datasets, such as the National Death Index for coding cause-specific mortality and Medicare data to track care received by veterans outside the VA health system.
In a little more than two decades, VARA has grown to 17 enrolling sites with more than 3,600 participating veterans and has provided a “unique and amazing opportunity to study RA outcomes, particularly in this high-risk population of U.S. veterans,” Mikuls said. VARA has served as an important resource for both VA and non-VA researchers across the country, serving as a focus for a wide scope of clinical and translational research.
In addition to RA-ILD and metabolic dysregulation in RA, research topics at the fall meeting included:
- Frailty and osteoporosis in RA
- Health disparities in RA-related cardiovascular disease
- RA mortality with immune checkpoint inhibitors
- Genetic susceptibility in RA and associations with disease severity
- Serum urate as a predictor of RA outcomes
- RA-related risk of serious infection
Directions for Future Research
While much of VARA’s meetings are devoted to research findings, the group also takes the opportunity at their meetings to look at directions for future research, Mikuls said. One they are considering is a greater focus on the effects of airborne hazards. At this year’s meeting, Michael Falvo PhD, co-director of the Airborne Hazards and Burn Pits Center of Excellence (AHBPCE) at the NJ War Related Illness and Injury Study Center, spoke with the group about leveraging exposure data in the VA.
“We have done some work on burn pits, and that is kind of where our interest lies,” Mikuls said. “A couple of years ago, Bryant England published a paper showing associations between burn-pit exposure in our veterans with RA with autoantibody status, and I we think there is potentially a relationship with RA and the development of extrarticular manifestations of disease and outcomes. So that is something we would like to explore more and having Dr. Falvo perhaps lays the early groundwork for us to do that work.
Work Goes Beyond Veterans
Although the findings are specifically about veterans, Mikuls said they have the potential to help people with RA both in and outside of the VA.
Further, VARA provides something other databases don’t—a predominantly male cohort with a disease that predominantly affects women.
“We have over 400 women in the registry, which is not a small number, even though men comprise the majority of the VA cohort. This affords us the opportunity to look at [outcomes in men] specifically. This group is a little out there in terms of other disease cohorts,” he pointed out.
Mikuls stressed that the consortium’s research would not be possible without the participating veterans. “We are completely reliant on and dedicated to the veterans who are participating. It is really amazing because they are not only willing but eager to participate in the work, and that is a service model they follow that got them into the military and led them to the VARA registry,” he said. “That work doesn’t go anywhere without veteran participants.”
- VARA. (2024, September 9-10). 20th Annual Fall VARA Meeting. UNMC Truhlsen Center, Omaha, NE. https://hjf.cventevents.com/event/VARA2024/summary
