Biomarkers May Distinguish Active, Inactive Systemic Juvenile Idiopathic Arthritis

A unique set of biomarkers may help identify active systemic juvenile idiopathic arthritis (sJIA) from both inactive sJIA as well as healthy controls, according to a study published in Pediatric Rheumatology.¹

“There is no pathognomonic feature that distinguishes sJIA from other conditions, but few laboratory parameters may be supportive for diagnosis of sJIA, such as elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil and platelet counts,” investigators stated. “Manifestations of sJIA, including macrophage activation syndrome (MAS), neurological complications, limitation in functional outcome by arthritis, and long-term damage from chronic inflammation can be severe and have significant impacts on patients’ quality of life.”

Plasma samples were collected from 21 sJIA patients and 60 healthy controls matched for age and sex (ranging from 3 to 16 years) at Astrid Lindgren’s Children Hospital in Stockholm, Sweden. Inactive sJIA was defined as experiencing no clinical signs of disease activity, a Physician’s Global Assessment (PGA) of disease activity score of 0, and CRP and ESR levels within normal range. Immunoprofiling was conducted via a proteomic immunoassay. The biomarker panel consisted of 92 immune-related proteins. Canonical pathways and cellular functions were analyzed by Ingenuity Pathway Analysis (IPA) based on whether biomarkers were up- or down-regulated.

Of the 69 biomarkers included, Hierarchical Clustering Analysis (HCA) and Principal Component Analysis (PCA) could not completely separate the 3 groups during analysis. A cross-sectional analysis was conducted in an attempt to further separate the cohorts, with an emphasis on 10 proteins. The most notable biomarkers that aided in the classification were interleukin 6 (IL-6), IL-18, and S100 calcium-binding protein A12 (S100A12), which were increased in patients with active sJIA when compared with healthy controls. Other factors, such as CD6, CXCL1, CXCL11, CXCL5, CASP8, SIRT2, and KITLG were expressed differently in patients with either active or inactive sJIA when compared with controls. Interestingly, IL-18 was increased during inactive sJIA when compared with the control cohort. This may indicate that suppressive mechanisms are activated when patients are in a state of remission.

Nine patients with sJIA were further examined, with 11 proteins showing significantly different levels between inactive and active sJIA. IL-6, MMP1 and S100A12 had p-values lower than 0.0001, which confirmed results from the cross-sectional analysis.

High Mobility Group Box 1 (HMGB1), a damage-associated molecular pattern, levels were upregulated in patients with active sJIA in comparison with inactive sJIA. Of the 9 patients studied, 8 exhibited higher HMGB1 levels during active disease state.

Proteins in 3 groups (active sJIA vs controls, inactive sJIA vs controls, and active sJIA vs inactive sJIA) were analyzed using IPA. However, it could not predict significant pathway activation, due to a limited about of input factors.

The small sample of patients and differing medication schedules limited the study, as medications affect immune activity and inflammatory proteins. However, focusing on biomarkers and prognosis is more practical, as patients in real-world settings have a variety of symptoms and complex medical histories. Another limitation is that several proteins, including IL1β and S100A8/9, were not available and therefore not incorporated into the analysis.

“Further studies of the pathogenic features of the newly revealed biomarkers and their potential use as diagnostic tools and as new targets for therapy development are highly warranted,” investigators concluded.

Reference:

Qu H, Sundberg E, Aulin C, et al. Immunoprofiling of active and inactive systemic juvenile idiopathic arthritis reveals distinct biomarkers: a single-center study. Pediatr Rheumatol Online J. 2021;19(1):173. Published 2021 Dec 28. doi:10.1186/s12969-021-00660-9