Monocyte STAT1 phosphorylation and treatment response of JAK inhibitors in chronic nonbacterial osteomyelitis
Abstract Background Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory disease of unknown cause, predominantly affecting teens and young adults. The early diagnosis and management are challenging due to the lack of reliable diagnostic markers and the occasional intractable cases des...
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BMC
2025-01-01
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| Series: | Pediatric Rheumatology Online Journal |
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| Online Access: | https://doi.org/10.1186/s12969-025-01059-6 |
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| author | Motoshi Sonoda Keishiro Kinoshita Nobutaka Harada Sungyeon Park Shunichi Adachi Yutaro Yada Katsuhide Eguchi Toshifumi Fujiwara Makiko Kido-Nakahara Noriko Kinjo Masataka Ishimura Shouichi Ohga |
| author_facet | Motoshi Sonoda Keishiro Kinoshita Nobutaka Harada Sungyeon Park Shunichi Adachi Yutaro Yada Katsuhide Eguchi Toshifumi Fujiwara Makiko Kido-Nakahara Noriko Kinjo Masataka Ishimura Shouichi Ohga |
| author_sort | Motoshi Sonoda |
| collection | DOAJ |
| description | Abstract Background Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory disease of unknown cause, predominantly affecting teens and young adults. The early diagnosis and management are challenging due to the lack of reliable diagnostic markers and the occasional intractable cases despite conventional anti-inflammatory treatments. Janus kinase (JAK) inhibitors have recently shown potential utility; however, reports on their use for pediatric patients with CNO remain limited, and no established biomarkers exist to monitor disease activity. We aimed to investigate the pathophysiology of CNO and explore the rapid testing methods for accurate diagnosis and also assessing the disease activity. Methods We assessed intracellular phosphorylation of signal transducer and activator of transcription 1 (pSTAT1) in peripheral blood monocytes or T cells following interferon-gamma (IFNγ) stimulation, using flow cytometry in 9 patients under 15 years old with CNO. The pSTAT1 expression levels were compared with those in patients with STAT1-gain of function (STAT1-GOF) mutations (n = 5), other autoinflammatory diseases (n = 7), and healthy controls. Clinical and immunological data were monitored in 4 patients with intractable CNO treated with adjunctive JAK inhibitors, focusing on scoring scales, imaging data, lymphocyte subsets, cytokine profiles, and pSTAT1 levels. Results Monocyte pSTAT1 expression after IFNγ stimulation was elevated at diagnosis or during active CNO, similar to levels observed in STAT1-GOF cases. The pSTAT1 levels in CNO patients were significantly higher than those in other autoinflammatory diseases (p = 0.024) or controls (p < 0.001). Notably, pSTAT1 levels in CNO monocytes fluctuated with disease activity, decreasing in 5 patients during clinical remission following conventional therapies (p = 0.016). In four intractable cases, pSTAT1 levels remained high despite conventional treatments but significantly decreased after initiating JAK inhibitors (p = 0.036). This reduction correlated with improved patient pain visual analog scale (p = 0.008), CNO clinical disease activity score (p = 0.029), and better bone and joint imaging, though cytokine levels remained unchanged. Conclusions The monocyte pSTAT1 levels after IFNγ stimulation reflect the activity of CNO, indicating the diagnostic utility as well as the monitoring effect of disease control. Adjunctive JAK inhibitors successfully controlled inflammation in treatment-resistant cases. Rapid pSTAT1 testing may help reduce osteo-articular complications, although the long-term adverse effects and resistance should be further investigated. |
| format | Article |
| id | doaj-art-8b127507a4e34d7caa94ce68cbeb6576 |
| institution | Kabale University |
| issn | 1546-0096 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Pediatric Rheumatology Online Journal |
| spelling | doaj-art-8b127507a4e34d7caa94ce68cbeb65762025-01-26T12:19:56ZengBMCPediatric Rheumatology Online Journal1546-00962025-01-0123111110.1186/s12969-025-01059-6Monocyte STAT1 phosphorylation and treatment response of JAK inhibitors in chronic nonbacterial osteomyelitisMotoshi Sonoda0Keishiro Kinoshita1Nobutaka Harada2Sungyeon Park3Shunichi Adachi4Yutaro Yada5Katsuhide Eguchi6Toshifumi Fujiwara7Makiko Kido-Nakahara8Noriko Kinjo9Masataka Ishimura10Shouichi Ohga11Department of Pediatrics, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Dermatology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Pediatrics, Graduate School of Medicine, University of the RyukyusDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Pediatrics, Graduate School of Medical Sciences, Kyushu UniversityAbstract Background Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory disease of unknown cause, predominantly affecting teens and young adults. The early diagnosis and management are challenging due to the lack of reliable diagnostic markers and the occasional intractable cases despite conventional anti-inflammatory treatments. Janus kinase (JAK) inhibitors have recently shown potential utility; however, reports on their use for pediatric patients with CNO remain limited, and no established biomarkers exist to monitor disease activity. We aimed to investigate the pathophysiology of CNO and explore the rapid testing methods for accurate diagnosis and also assessing the disease activity. Methods We assessed intracellular phosphorylation of signal transducer and activator of transcription 1 (pSTAT1) in peripheral blood monocytes or T cells following interferon-gamma (IFNγ) stimulation, using flow cytometry in 9 patients under 15 years old with CNO. The pSTAT1 expression levels were compared with those in patients with STAT1-gain of function (STAT1-GOF) mutations (n = 5), other autoinflammatory diseases (n = 7), and healthy controls. Clinical and immunological data were monitored in 4 patients with intractable CNO treated with adjunctive JAK inhibitors, focusing on scoring scales, imaging data, lymphocyte subsets, cytokine profiles, and pSTAT1 levels. Results Monocyte pSTAT1 expression after IFNγ stimulation was elevated at diagnosis or during active CNO, similar to levels observed in STAT1-GOF cases. The pSTAT1 levels in CNO patients were significantly higher than those in other autoinflammatory diseases (p = 0.024) or controls (p < 0.001). Notably, pSTAT1 levels in CNO monocytes fluctuated with disease activity, decreasing in 5 patients during clinical remission following conventional therapies (p = 0.016). In four intractable cases, pSTAT1 levels remained high despite conventional treatments but significantly decreased after initiating JAK inhibitors (p = 0.036). This reduction correlated with improved patient pain visual analog scale (p = 0.008), CNO clinical disease activity score (p = 0.029), and better bone and joint imaging, though cytokine levels remained unchanged. Conclusions The monocyte pSTAT1 levels after IFNγ stimulation reflect the activity of CNO, indicating the diagnostic utility as well as the monitoring effect of disease control. Adjunctive JAK inhibitors successfully controlled inflammation in treatment-resistant cases. Rapid pSTAT1 testing may help reduce osteo-articular complications, although the long-term adverse effects and resistance should be further investigated.https://doi.org/10.1186/s12969-025-01059-6AutoinflammationCNOSTAT1 phosphorylationJAK inhibitors |
| spellingShingle | Motoshi Sonoda Keishiro Kinoshita Nobutaka Harada Sungyeon Park Shunichi Adachi Yutaro Yada Katsuhide Eguchi Toshifumi Fujiwara Makiko Kido-Nakahara Noriko Kinjo Masataka Ishimura Shouichi Ohga Monocyte STAT1 phosphorylation and treatment response of JAK inhibitors in chronic nonbacterial osteomyelitis Pediatric Rheumatology Online Journal Autoinflammation CNO STAT1 phosphorylation JAK inhibitors |
| title | Monocyte STAT1 phosphorylation and treatment response of JAK inhibitors in chronic nonbacterial osteomyelitis |
| title_full | Monocyte STAT1 phosphorylation and treatment response of JAK inhibitors in chronic nonbacterial osteomyelitis |
| title_fullStr | Monocyte STAT1 phosphorylation and treatment response of JAK inhibitors in chronic nonbacterial osteomyelitis |
| title_full_unstemmed | Monocyte STAT1 phosphorylation and treatment response of JAK inhibitors in chronic nonbacterial osteomyelitis |
| title_short | Monocyte STAT1 phosphorylation and treatment response of JAK inhibitors in chronic nonbacterial osteomyelitis |
| title_sort | monocyte stat1 phosphorylation and treatment response of jak inhibitors in chronic nonbacterial osteomyelitis |
| topic | Autoinflammation CNO STAT1 phosphorylation JAK inhibitors |
| url | https://doi.org/10.1186/s12969-025-01059-6 |
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