Sonoda Motoshi, Kinoshita Keishiro, Harada Nobutaka, Park Sungyeon, Adachi Shunichi, Yada Yutaro, Eguchi Katsuhide, Fujiwara Toshifumi, Kido-Nakahara Makiko, Kinjo Noriko, Ishimura Masataka, Ohga Shouichi
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Pediatr Rheumatol Online J. 2025 Jan 23;23(1):6. doi: 10.1186/s12969-025-01059-6.
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.
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.
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.
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.
慢性非细菌性骨髓炎（CNO）是一种病因不明的罕见自身炎症性疾病，主要影响青少年和青年。由于缺乏可靠的诊断标志物，且尽管采用传统抗炎治疗仍有部分病例难以治疗，早期诊断和管理具有挑战性。Janus激酶（JAK）抑制剂最近显示出潜在的应用价值；然而，关于其在儿童CNO患者中的应用报道仍然有限，并且尚无已确立的生物标志物来监测疾病活动。我们旨在研究CNO的病理生理学，探索准确诊断和评估疾病活动的快速检测方法。
我们使用流式细胞术评估了9例15岁以下CNO患儿外周血单核细胞或T细胞在干扰素-γ（IFNγ）刺激后信号转导子和转录激活子1（pSTAT1）的细胞内磷酸化情况。将pSTAT1表达水平与功能获得性STAT1（STAT1-GOF）突变患者（n = 5）、其他自身炎症性疾病患者（n = 7）及健康对照者进行比较。对4例接受JAK抑制剂辅助治疗的难治性CNO患者的临床和免疫学数据进行监测，重点关注评分量表、影像学数据、淋巴细胞亚群、细胞因子谱和pSTAT1水平。
IFNγ刺激后单核细胞pSTAT1表达在诊断时或CNO活动期升高，与STAT1-GOF病例中观察到的水平相似。CNO患者的pSTAT1水平显著高于其他自身炎症性疾病患者（p = 0.024）或对照组（p < 0.001）。值得注意的是，CNO单核细胞中的pSTAT1水平随疾病活动而波动，5例患者在传统治疗后的临床缓解期下降（p = 0.016）。在4例难治性病例中，尽管进行了传统治疗，pSTAT1水平仍居高不下，但在开始使用JAK抑制剂后显著下降（p = 0.036）。这种下降与患者疼痛视觉模拟量表改善（p = 0.008）、CNO临床疾病活动评分改善（p = 0.029）以及更好的骨关节影像学表现相关，尽管细胞因子水平未变。
IFNγ刺激后单核细胞pSTAT1水平反映了CNO的活动情况，表明其具有诊断效用以及疾病控制监测作用。JAK抑制剂辅助治疗成功控制了难治性病例的炎症。快速pSTAT1检测可能有助于减少骨关节炎并发症，尽管其长期不良反应和耐药性仍需进一步研究。
