Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis
Abstract Background Systemic juvenile idiopathic arthritis (sJIA) is the most severe subtype of JIA, with a combination of diverse clinical manifestations and a variable clinical course. A comprehensive understanding of molecular signatures at the systems level and the discovery of molecular subtype...
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BMC
2025-02-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-025-03498-8 |
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| author | In-Woon Baek Jung Woo Rhim Kyung-Su Park Ki-Jo Kim |
| author_facet | In-Woon Baek Jung Woo Rhim Kyung-Su Park Ki-Jo Kim |
| author_sort | In-Woon Baek |
| collection | DOAJ |
| description | Abstract Background Systemic juvenile idiopathic arthritis (sJIA) is the most severe subtype of JIA, with a combination of diverse clinical manifestations and a variable clinical course. A comprehensive understanding of molecular signatures at the systems level and the discovery of molecular subtypes are the initial steps toward personalized medicine in sJIA. Methods A blood transcriptomic dataset was collected from patients with systemic JIA (sJIA) (n = 168), polyarticular JIA (n = 254), oligoarticular JIA (n = 96), enthesitis-related arthritis (n = 40), and healthy controls (n = 220). Gene expression profiles were filtered for differentially expressed genes and unsupervised clustering, gene set enrichment, and network-based centrality analyses. The molecular signatures of three novel sJIA subgroups (designated as C1, C2, and C3) were investigated, focusing on their distinct features and treatment responses. Results Neutrophil degranulation and the IL-1 signaling pathway were the shared key processes for the three subgroups. Proinflammatory signals, including TNF, IL-6, TLR, and G-CSF signaling pathways, were identified with variation across the subgroups. C1 was the most inflammatory subset with a high-risk profile for macrophage activation syndrome. The C2 subset had the most activated IL-1 and IL-18 signaling pathways. C2 and C3 have higher levels of interferon-stimulated signatures. In a canakinumab-treated dataset, treatment response was correlated with IL1B expression and NF-κB signaling pathway, and neutrophil activation-associated processes were effectively suppressed in a good responder group. GSK3B and p38 MAPK inhibitors showed a significant counteracting effect on the perturbed gene expression of sJIA. Conclusions Neutrophil activation was the key feature in active sJIA. The three molecular subtype scheme enables the formulation of precision medicine strategies in sJIA. |
| format | Article |
| id | doaj-art-24a78e39c3044744a553b28b1e39767e |
| institution | Kabale University |
| issn | 1478-6362 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj-art-24a78e39c3044744a553b28b1e39767e2025-02-09T12:48:44ZengBMCArthritis Research & Therapy1478-63622025-02-0127111410.1186/s13075-025-03498-8Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritisIn-Woon Baek0Jung Woo Rhim1Kyung-Su Park2Ki-Jo Kim3Division of Rheumatology, Department of Internal Medicine, College of Medicine, Ewha Womans UniversityDepartment of Pediatrics, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of KoreaDivision of Rheumatology, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of KoreaDivision of Rheumatology, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of KoreaAbstract Background Systemic juvenile idiopathic arthritis (sJIA) is the most severe subtype of JIA, with a combination of diverse clinical manifestations and a variable clinical course. A comprehensive understanding of molecular signatures at the systems level and the discovery of molecular subtypes are the initial steps toward personalized medicine in sJIA. Methods A blood transcriptomic dataset was collected from patients with systemic JIA (sJIA) (n = 168), polyarticular JIA (n = 254), oligoarticular JIA (n = 96), enthesitis-related arthritis (n = 40), and healthy controls (n = 220). Gene expression profiles were filtered for differentially expressed genes and unsupervised clustering, gene set enrichment, and network-based centrality analyses. The molecular signatures of three novel sJIA subgroups (designated as C1, C2, and C3) were investigated, focusing on their distinct features and treatment responses. Results Neutrophil degranulation and the IL-1 signaling pathway were the shared key processes for the three subgroups. Proinflammatory signals, including TNF, IL-6, TLR, and G-CSF signaling pathways, were identified with variation across the subgroups. C1 was the most inflammatory subset with a high-risk profile for macrophage activation syndrome. The C2 subset had the most activated IL-1 and IL-18 signaling pathways. C2 and C3 have higher levels of interferon-stimulated signatures. In a canakinumab-treated dataset, treatment response was correlated with IL1B expression and NF-κB signaling pathway, and neutrophil activation-associated processes were effectively suppressed in a good responder group. GSK3B and p38 MAPK inhibitors showed a significant counteracting effect on the perturbed gene expression of sJIA. Conclusions Neutrophil activation was the key feature in active sJIA. The three molecular subtype scheme enables the formulation of precision medicine strategies in sJIA.https://doi.org/10.1186/s13075-025-03498-8Systemic juvenile idiopathic arthritisMolecular subtypeNeutrophilInterleukin-1 |
| spellingShingle | In-Woon Baek Jung Woo Rhim Kyung-Su Park Ki-Jo Kim Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis Arthritis Research & Therapy Systemic juvenile idiopathic arthritis Molecular subtype Neutrophil Interleukin-1 |
| title | Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis |
| title_full | Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis |
| title_fullStr | Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis |
| title_full_unstemmed | Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis |
| title_short | Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis |
| title_sort | blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis |
| topic | Systemic juvenile idiopathic arthritis Molecular subtype Neutrophil Interleukin-1 |
| url | https://doi.org/10.1186/s13075-025-03498-8 |
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