Ongoing research in patients with oligoarticular juvenile idiopathic arthritis (JIA) so far suggests that a set of biomarkers in synovial fluid may help to predict which patients may be more likely to stay with persistent oligoarticular disease rather than progress to polyarticular disease, according to new research presented at the Childhood Arthritis and Rheumatology Research Alliance (CARRA) 2022 Annual Meeting. Identifying biomarkers in synovial fluid or possibly serum could aid families and physicians in being more proactive in treatment protocols, said AnneMarie C. Brescia, MD, of Nemours Children’s Hospital in Wilmington, Delaware.
“JIA carries the risk of permanent joint damage and disability, which can result when joint involvement evolves from oligoarticular into a polyarticular course, termed extended oligoarticular disease,” Brescia told attendees. “Since disease progression increases the risk for disability, early prediction of this course is essential.”
This group — those whose oligoarticular disease will begin recruiting joints and ultimately become extended oligoarticular JIA — is “very important because they have been shown to have worse health-related quality of life and greater risk of needing a joint replacement than even polyarticular [JIA],” Brescia said. “So, our lab has really focused on trying to predict who will fall in this group.”
Melissa Oliver, MD, an assistant professor of clinical pediatrics in the Division of Pediatric Rheumatology at the Indiana University School of Medicine in Indianapolis, was not involved in the study but agreed that having highly sensitive and specific biomarkers could be particularly helpful in clinical care.
“Biomarkers can help guide treatment decisions and help physicians and their patients share the decision-making about next choices and when to change,” Oliver told Medscape Medical News. “If a provider and parent know that their child has these markers in their serum or synovial fluid that may predict extension of their disease, then they may be more aggressive upfront with therapy.”
The study aimed to determine whether differential levels of synovial fluid proteins could be used to predict whether JIA would evolve into an extended course before it became clinically evident. Although early aggressive treatment is common with rheumatoid arthritis and can lead to remission, JIA treatment paradigms tend to be more reactive, Brescia said.
“It would be better to switch to proactive, that if we’re able to predict that this patient may have a more difficult course with extension to polyarticular, we could be prepared, we could inform the parents, and it would just help us have a more proactive approach,” she said.
The researchers used antibody arrays to detect the following inflammatory mediators in blinded samples: CD14, interleukin (IL)-1-alpha, IL-3, IL-5, IL-6, vascular endothelial growth factor (VEGF), and angiogenin. They analyzed 37 samples with persistent disease and 32 samples from disease that had not yet extended but would become extended in that patient. The samples came from patients who were taking no medicines or only NSAIDs. The researchers assessed the sensitivity and specificity of each biomarker. Sensitivity referred the biomarker’s ability to correctly indicate that the sample would extend, and specificity referred to the biomarker’s accuracy in determining that the disease in the sample would remain persistent.
Combining samples from cohorts at Nemours Children’s Health (14 persistent and 7 extended-to-be) and Cincinnati Children’s Hospital (23 persistent and 25 extended-to-be) yielded the following results:
|VEGF (Cincinnati only)||48%||43%|
|angiogenin (Cincinnati only)||44%||52%|
The findings revealed that the selected biomarkers were more accurate at predicting whose disease would remain persistent than predicting those that would extend, Brescia said. CD14 was the most specific biomarker, and IL-6 was the most sensitive biomarker in both groups.
When the researchers translated the findings from ELISA to the Luminex platform, positive results in synovial fluid for all these biomarkers were also positive in serum samples. Although the differences between persistent and extended-to-be samples did not reach statistical significance using Luminex, the pattern was the same for each biomarker.
“Luminex is more sensitive than ELISA. We believe that conducting an LDA [linear discriminant analysis] using these Luminex measurements will allow us to determine new cutoffs or new protein levels that are appropriate for Luminex to predict who will extend,” Brescia said. “It’s also our goal to develop a serum panel because…being able to detect these markers in serum would expand the applicability of these markers to more patients.”
Brescia then described the group’s work in defining clinically relevant subpopulations of patients based on fibroblast-like synoviocytes (FLS) cells in the synovial intimal lining that produce inflammatory cytokines.
“Our compelling, single-cell, RNA sequencing preliminary data revealing multiple subpopulations within the total FLS population supports our hypothesis that distinct FLS subpopulations correlate with clinical outcome,” Brescia told attendees. They looked at the percentage of chondrocyte-like, fibroblast-like, and smooth muscle-like subpopulations in samples from patients with oligoarticular JIA, extended-to-be JIA, and polyarticular JIA. Chondrocytes occurred in the largest proportion, and polyarticular JIA FLS had the largest percentage of chondrocytes, compared with the other two subpopulation groups.
“This is a work in progress,” Brescia said, “so hopefully you’ll hear about it next year.” In response to an attendee’s question, Brescia said she believes identifying reliable biomarkers will eventually lead to refining treatment paradigms.
“I think it will at least change the guidance we can provide parents about making next choices and how quickly to accelerate to those next choices,” Brescia said. For example, if a child’s serum or synovial fluid has markers that show a very high likelihood of extension, the parent may decide to proceed to the next level medication sooner. “I do think it will push both parents and doctors to be a little more proactive instead of reactive when the poor patient comes back with 13 joints involved when they had just been an oligo for years.”
Oliver noted the promise of CD14 and IL-6 in potentially predicting which patients’ disease will stay persistent but cautioned that it’s still early in evaluating these biomarkers, especially with the limited patient samples in this study.
“I think these results are promising, and it’s great that there are groups out there working on this,” Oliver said. “Once we have a reliable, highly sensitive and specific biomarker, that will definitely help providers, parents, and patients be more informed.”
The research was supported by the Open Net Foundation, the Arthritis Foundation, Delaware Community Foundation, the Delaware Clinical and Translational Research (DE-CTR) ACCEL Program, the Nancy Taylor Foundation for Chronic Diseases, and CARRA. Brescia and Oliver have disclosed no relevant financial relationships.
CARRA 2022: Childhood Arthritis and Rheumatology Research Alliance Annual Scientific Meeting. Presented May 3, 2022.
Tara Haelle is a Dallas-based science journalist. Follow her @tarahaelle.
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