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Monocyte STAT1 phosphorylation and treatment response of JAK inhibitors in chronic nonbacterial osteomyelitis
Motoshi Sonoda1, Keishiro Kinoshita2, Nobutaka Harada2
1Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan. sonoda.motoshi.541@m.kyushu-u.ac.jp.
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.
Insights
Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) levels in monocytes indicate chronic nonbacterial osteomyelitis (CNO) activity. This finding supports pSTAT1 testing for diagnosis and monitoring, with Janus kinase (JAK) inhibitors showing promise for treatment-resistant cases.
Area of Science:
- Immunology
- Rheumatology
- Pediatrics
Background:
- Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory disease affecting adolescents and young adults.
- Diagnosis and management are challenging due to a lack of reliable biomarkers and treatment resistance.
- Janus kinase (JAK) inhibitors show potential, but data in pediatric CNO and monitoring biomarkers are limited.
Purpose of the Study:
- Investigate CNO pathophysiology and explore rapid diagnostic testing methods.
- Assess disease activity using novel biomarkers.
- Evaluate JAK inhibitors in treatment-resistant pediatric CNO.
Main Methods:
- Assessed intracellular signal transducer and activator of transcription 1 (pSTAT1) phosphorylation in monocytes/T cells after interferon-gamma (IFNγ) stimulation via flow cytometry in 9 pediatric CNO patients.
- Compared pSTAT1 levels with STAT1-gain of function (STAT1-GOF) mutations, other autoinflammatory diseases, and healthy controls.
- Monitored clinical and immunological data, including pSTAT1 levels, in 4 intractable CNO cases treated with JAK inhibitors.
Main Results:
- Monocyte pSTAT1 expression was elevated at diagnosis/active CNO, similar to STAT1-GOF cases and significantly higher than controls or other autoinflammatory diseases.
- pSTAT1 levels correlated with CNO disease activity, decreasing during remission and remaining high in intractable cases.
- JAK inhibitor treatment in 4 patients reduced pSTAT1 levels, correlating with improved pain scores, clinical disease activity, and imaging.
Conclusions:
- Monocyte pSTAT1 levels after IFNγ stimulation reflect CNO activity, supporting its use for diagnosis and monitoring.
- Adjunctive JAK inhibitors effectively controlled inflammation in treatment-resistant pediatric CNO.
- Rapid pSTAT1 testing may reduce osteo-articular complications, warranting further investigation into long-term effects and resistance.
