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Clinical Features and Treatment Outcomes of Chronic Nonbacterial Osteomyelitis in Children: A Multicenter Study in China
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摘要:
目的 分析我国儿童慢性无菌性骨髓炎(chronic nonbacterial osteomyelitis, CNO)的临床特点及治疗效果，为CNO临床诊疗提供参考和借鉴。 方法 收集2014年3月至2022年8月就诊于国内5家医学中心(复旦大学附属儿科医院、中国医学科学院北京协和医院、南京医科大学附属儿童医院、重庆医科大学附属儿童医院和吉林大学第一医院)且符合纳入与排除标准的CNO患儿临床资料，并根据治疗方案分为单纯非甾体抗炎药(nonsteroidal anti-inflammatory drugs，NSAID)组、传统抗风湿病药物(disease modifying anti-rheumatic drugs，DMARD)组、肿瘤坏死因子拮抗剂(tumor necrosis factor inhibitor，TNF-i)组、双膦酸盐组、双膦酸盐+TNF-i组，比较各组临床特征并采用改良医师总体评估评分进行疗效评价。 结果 共纳入58例CNO患儿，男女比例约为1.15(31例比27例)；平均发病年龄为(8.5±3.4)岁，平均确诊年龄为(9.8±3.2)岁；中位随访时间为10.9(5.0，30.1)个月；近3年共确诊46例(79.3%)；发热31例(53.4%)、骨痛和/或关节痛54例(93.1%)、红细胞沉降率升高51例(87.9%)、C反应蛋白升高45例(77.6%)；常见骨受累部位为下肢骨，其中股骨42例、胫骨41例，3例就诊时即存在椎骨压缩性骨折；33例骨活检结果为亚急性或慢性骨髓炎；各治疗组缓解率无统计学差异(P=0.562)，双膦酸盐+TNF-i组11个月缓解率为60.0%，NSAID组和DMARD组11个月缓解率分别为55.6%和33.3%；NSAID组和TNF-i组12个月缓解率分别为66.7%和52.4%；共40例随访时间≥6个月，随访终点治疗缓解率为81.3%。 结论 我国多中心CNO患儿临床表现缺乏特异性，以骨痛和/或关节痛为主要临床特点，可伴有发热、外周血白细胞基本正常、C反应蛋白和/或红细胞沉降率升高，各治疗组疗效相似，目前NSAID抗炎治疗为临床首选治疗方案。 Abstract:Objective To investigate the clinical features and treatment outcomes of chronic non-bacterial osteomyelitis (CNO) from five tertiary pediatric rheumatology services in China and provide possible treatment options for clinicians. Methods In this multicenter, retrospective study, pediatric patients diagnosed with CNO in Children's Hospital of Fudan University, Peking Union Medical College Hospital, Children's Hospital of Nanjing Medical University, Children's Hospital of Chongqing Medical University and the First Hospital of Jilin University from March 2014 to August 2022 were included. According to the treatment plan, the patients were divided into nonsteroidal anti-inflammatory drugs (NSAID) group, traditional disease modifying anti-rheumatic drugs (DMARD) group, tumor necrosis factor inhibitor (TNF-i) group, bisphosphonate group, and bisphosphonate+TNF-i group, and physician global assessment score was used to evaluate the efficacy. Results Retrospective data analysis showed that the disease was more common in boy sthan girls(31 vs. 27), and the average age at onset of symptoms was 8.5±3.4 years, the mean age of diagnosis was 9.8±3.2 years, and the Median follow-up was 10.9(5.0, 30.1) months. A total of 46 cases (79.3%) were diagnosed in the last 3 years. Bone pain and / or arthralgia was the predominant symptom in 54(93.1%) patients followed by fever in 31(53.4%) patients. Raised inflammatory markers (ESR and CRP) were present in 87.9% and 77.6% of the patients. The most frequently affected bones were lower limb bones, including 42 cases of femur and 41 cases of tibia; 3 patients had compression fractures of the vertebrae at the time of diagnosis. Bone biopsy was conducted in 33 cases, and subacute or chronic osteomyelitis manifested with inflammatory cells infiltration were detected. The remission rate was not statistically different between treatment groups (P=0.562), with the remission rate at 11 months in the bisphosphonate+TNF-i group being 60.0%, 55.6% and 33.3% in the NSAID and DMARD groups respectively; 66.7% and 52.4% in the NSAID and TNF-i groups respectively at 12 months. A total of 40 patients were followed up for ≥6 months, with the remission rate of 81.3%. Conclusions Our multicenter study describes the features and outcomes of CNO patients in China. The characteristics of CNO children from multiple centers in China were lack of specificity. Bone pain and/or arthralgia were the main clinical symptoms, accompanied by fever, normal white blood cells, and raised inflammatory markers (CRP and/or ESR). Although anti-inflammatory treatment regimens were different, the efficacy of the treatment groups was similar. Anti-inflammatory therapy is currently the first choice. -
Key words:
- children /
- chronic nonbacterial osteomyelitis /
- clinical features /
- treatment outcomes
作者贡献：刘海梅、张天誉、马乐、张志勇和徐萌负责收集、整理临床资料及患者随访；刘海梅负责论文设计、数据统计及撰写；张涛负责数据整理、统计、分析；徐虹、唐雪梅和杨思睿负责论文设计；俞海国、宋红梅和孙利负责论文设计、实施及论文修订。利益冲突：所有作者均声明不存在利益冲突 -
表 1 58例慢性无菌性骨髓炎患儿一般资料
指标 数值 平均发病年龄(x±s，岁) 8.5±3.4 平均确诊年龄(x±s，岁) 9.8±3.2 男性患儿(%) 53.4 中位诊断延迟时间[M(P25，P75)，月] 5.2(1.6，30.3) 中位随访时间[M(P25，P75)，月] 10.9(5.0，30.1) 中位骨受累病灶数[M(P25，P75)，个] 6(4，8) ≥2个骨受累病灶[n(%)] 55(94.8) 临床症状[n(%)] 骨痛和/或关节痛 54(93.1) 发热 31(53.4) 跛行 18(31.0) 局部肿胀 18(31.0) 结节性红斑 4(6.9) 掌跖脓疱疮 4(6.9) 痤疮 2(3.4) 关节炎 9 (15.5) 骨受累部位[n(%)] 颅骨 2(3.4) 下颌骨 3(5.2) 锁骨 5(8.6) 胸骨 2(3.4) 肋骨 2(3.4) 椎骨 6(10.3) 骨盆和/或骶骨 19(32.8) 肱骨 14(24.1) 尺骨 12(20.7) 桡骨 17(29.3) 手(掌骨等) 1(1.7) 股骨 42(72.4) 胫骨 41(70.7) 腓骨 25(43.1) 髌骨 2(3.4) 足(跗骨等) 23(39.7) 实验室检查 WBC＜10×109/L[n(%)] 52(89.7) 平均WBC(x±s，×109/L) 7.2±2.4 Hb＜110 g/L[n(%)] 12(20.7) 平均Hb(x±s，g/L) 116±13.0 CRP＞8 mg/L[n(%)] 45(77.6) 平均CRP(x±s，mg/L) 31.8±36.7 ESR＞20 mm/h[n(%)] 51(87.9) 平均ESR(x±s，mm/h) 58±34 阳性家族史[n(%)] 0(0) 骨活检[n(%)] 33(56.9) WBC：白细胞；Hb：血红蛋白；CRP：C反应蛋白；ESR：红细胞沉降率 
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表 2 不同治疗组慢性无菌性骨髓炎患儿一般资料
指标 NSAID组(n=12) DMARD组(n=8) TNF-i组(n=9*) 双膦酸盐组(n=14*) 双膦酸盐+TNF-i组(n=10) 男性患儿[n(%)] 8(66.7) 3(37.5) 9(100) 6(42.9) 4(40.0) 平均发病年龄(岁) 8.7 6.8 4.2 9.5 9.7 平均确诊年龄(岁) 9.0 6.9 6.1 9.6 9.8 延迟诊断时间(月) 3.4 1.5 23.1 1.5 1.4 随访时间(月) 44.9 36.4 36.6 20.2 14.2 发热[n(%)] 6(50.0) 5(62.5) 3(33.3) 8(57.1) 6(60.0) 骨痛和/或关节痛[n(%)] 10(83.3) 6(75.0) 7(77.8) 14(100) 10(100) WBC(×109/L) 6.8 6.7 7.2 7.7 8.1 Hb(g/L) 121 111 113 113 119 CRP(mg/L) 24.7 50 24.7 17.7 55.4 CRP升高[n(%)] 6(50.0) 8(100) 7(77.8) 9(64.3) 7(70.0) ESR(mm/h) 40 81 70 57 60 ESR升高[n(%)] 11(91.7) 8(100) 8(88.9) 13(92.9) 9(90.0) PGA评分≥2分[n(%)] 9(75.0) 8(100) 8(88.9) 13(92.9) 9(90.0) WBC、Hb、CRP、ESR：同表 1；PGA：医师总体评估；NSAID: 非甾体抗炎药；DMARD: 抗风湿病药物；TNF-i：肿瘤坏死因子拮抗剂；*随访至少3个月的CNO患儿为49例，因治疗6个月临床判定无效，NSAID组中2例转入双膦酸盐组，1例转入TNF-i组，DMARD组1例转入TNF-i组
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