Risk Stratification Efforts
There are now two ongoing joint efforts by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) to define these populations and “bring some consensus to the field,” Mankia said.
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The first aims to create a unanimous risk stratification tool for future RA prevention studies. The proposed system, devised for individuals with new joint symptoms who are at a risk for RA, was presented at the EULAR 2024 annual meeting and will be further discussed at the upcoming ACR 2024 annual meeting in Washington, DC.
The system uses a point system based on six criteria — three lab tests and three criteria commonly assessed in clinical practice:
- Morning stiffness
- Patient-reported joint swelling
- Difficulty making a fist
- Increased C-reactive protein
- RF positivity
- ACPA positivity
These criteria were picked so that the risk stratification tool can be used without imaging; however, the inclusion of MRI can further refine the score.
The ACR-EULAR task force that created the tool has emphasized that this criterion is specifically designed for research purposes and should not be used in clinical practice. Using this stratification tool should allow future clinical studies to group patients by similar risk, Deane said.
“Not that all studies have to look at exactly the same people, but each study should have similar risk stratification,” he said.
The second ACR-EULAR joint effort is taking a population-based approach to risk stratification, Deane said, to better predict RA risk in individuals without common symptoms like joint pain.
The aim is to create something analogous to the Framingham Risk Score in predicting cardiovascular disease, in which simple variables like total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, and smoking status can be used to calculate an individual’s 10-year risk for CVD, Deane explained.
The second approach could also identify patients earlier in the progression to RA, which may be easier to treat than later stages of disease.
Understanding RA Origins
However, treating an earlier stage of disease might require a different approach. Up to this point, medical interventions for RA prevention used drugs approved to treat RA, but inventions during the pre-RA stage — before any joint symptoms appear — might require targeting different immunologic pathways.
“The general concept is if there is a pre-RA stage when joints are not involved, that means all the immunologic abnormalities are probably happening somewhere else in the body,” he said. “The big question is: Where is that, and how exactly is that happening?”
One theory is that RA begins to develop in mucosal sites, such as the intestines or lungs, before it involves synovial joints.
“In the absence of resolution, these localized immune processes transition into a systemic process that targets the joints, either by direct effects of microbiota, molecular mimicry, and/or immune amplification,” wrote Deane and coauthors in a recent review article in Annals of the Rheumatic Diseases. “This, in turn, leads to inappropriate engagement of a range of effector mechanisms in both synovium and periarticular sites.”
Following this logic, the progression of the at-risk stage of RA could be considered a continuum along which there are multiple possible points for intervention. It’s also probable that the disease can develop through multiple pathways, Deane said.
“If you look at all the people who get rheumatoid arthritis, there’s probably no way those could have the same exact pathways,” he said. “There’s probably going to be different endotypes and understanding that is going to help us prevent disease in a better way.”