Background/Purpose: Systemic Juvenile Idiopathic Arthritis (SJIA) is a severe inflammatory disorder that affects the joints as well as other organ systems, with complications including Macrophage Activation Syndrome (MAS) and Lung Disease (LD). Identification of biomarkers and cytokines remains crucial for prognosis and for defining therapeutic targets for SJIA with and without MAS and LD. In this study, we investigated plasma cytokine profiles in a large, multicenter cohort of refractory SJIA cases.

Methods: 22 SJIA patients were enrolled from 5 centers along with 6 healthy sibling controls. 11 had MAS at the onset of SJIA diagnosis, 8 had been diagnosed with LD, 4 have 1-year follow-up, 1 has 2-year follow-up. Based on clinical history, the samples were subdivided into groups as SJIA with/without MAS or LD. Plasma cytokine profiling of 37 cytokines, chemokines and immune-related signaling proteins were measured using the Target 48 Olink cytokine panel. Interferon transcriptional scores were determined using a custom Nanostring panel.

Results: Plasma levels of several cytokines—including IL-2, IL-1β, HGF, IL-7, IL-18, IFN-γ, CXCL8, CSF3, CCL7 and IL-17A—were significantly elevated in SJIA patients compared with sibling controls. Hierarchical clustering of the cytokine profiles showed that healthy controls clustered with a subset of patients samples, but were segregated from patients with SJIA and elevated IL-18. K-means clustering of patients revealed 3 distinct groups (Figure). SJIA with MAS (n=11) at onset showed an upregulation in IL-15 and Vascular Endothelial Growth Factor-A (VEGF-A) compared to the SJIA without MAS group (n=11). While CCL2 and CCL11 showed similar levels in SJIA patients without lung disease (no LD group, n=14) and sibling controls (SC group, n=6), these chemokines were significantly elevated in SJIA patients with lung disease (LD group, n=8). Of the 13 SJIA patients who underwent Interferon transcriptional score test, only one was newly diagnosed and treatment-naive, while the remaining patients had previously been diagnosed with SJIA and had already received treatment. Interferon transcriptional scores were normal in most patients, but were elevated at 3 patient visits and in one control. One patient had an elevated type I IFN score (120.5, normal range < 57) with various scratched bug bites and dry skin on shins and salves at time of sample collection. Another patient with a highly elevated type I IFN score (563.2) had a history of acute illnesses at the time of sample collection (cough and congestion). Another patient, triggered by disease flare and had MAS at the time of sample collection exhibited an elevated type I IFN score of 238.5.

Conclusion: This represents a multisite, longitudinal cohort of refractory SJIA patients. Our analysis reveals a distinct biomarker signature for SJIA complications, suggesting differential immunopathogenic mechanisms. Interestingly, most patients did not have an elevated interferon score at visit 1 for the study cohort. Further work will examine how inflammatory signatures change during treatment of refractory SJIA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cytokine-profiling-in-refractory-systemic-juvenile-idiopathic-arthritis-reveals-distinct-signatures-for-macrophage-activation-syndrome-and-lung-disease/