Clinical, Biochemical, and Genetic Features of 41 Han Chinese Families With Primary Hypertrophic Osteoarthropathy, and Their Therapeutic Response to Etoricoxib: Results From a Six-Month Prospective Clinical Intervention
Clinical, Biochemical, and Genetic Features of 41 Han Chinese Families With Primary Hypertrophic Osteoarthropathy, and Their Therapeutic Response to Etoricoxib: Results From a Six-Month Prospective Clinical Intervention
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41 个中国汉族原发性肥厚性骨关节病家族的临床、生化和遗传特征及其对依托考昔的治疗反应：六个月前瞻性临床干预的结果
DOI：
10.1002/jbmr.3157
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发表时间：
2017-08-01
影响因子：
6.2
通讯作者：
Zhang, Zhen-Lin
中科院分区：
文献类型：
--
作者：
Li, Shan-Shan;He, Jin-We;Zhang, Zhen-Lin
原发性肥厚性骨关节病（PHO）是一种罕见的遗传性疾病，由前列腺素代谢途径的遗传缺陷引起；前列腺素E-2 （PGE(2)）分解代谢紊乱导致PGE(2)水平升高可能是其发病机制。本文对43例汉族PHO患者进行了研究，其中41例接受了治疗。在7例患者中发现了导致肥厚性骨关节病的HPGD基因突变，原发性常染色体隐性1 (PHOAR1; OMIM 259100)，在36例患者中发现了导致肥厚性骨关节病的SLCO2A1基因突变，原发性常染色体隐性2 （PHOAR2; OMIM 614441）。PHO的临床表型各不相同，从轻度孤立的手指棍棒症到严重的厚皮病和致残性关节肿胀，甚至在家庭中也是如此。PHOAR2的循环PGE(2)代谢特征与PHOAR1不同。不同亚组之间厚皮病的发生频率和严重程度也有所不同。百分比的PHOAR2患者出现胃肠道出血，但在PHOAR1亚组中未观察到这种症状。尽管尿PGE(2)或PGE- m与性激素没有明显的关联，但临床证据强调性激素在前列腺素转运蛋白调控PHOAR2发病中的重要作用。选择性环氧化酶-2抑制剂依托妥昔布治疗被证明是有益和安全的。在6个月的干预期间，我们检测到它在降低大多数入组患者尿PGE(2)水平方面的显著疗效；临床表型评估，包括厚皮病，手指杵状和关节肿胀，得到改善。我们没有发现依托昔布对骨膜病有积极作用的明显证据；然而，尿PGE(2)和血清骨转换标志物之间的显著联系表明PGE(2)降低在骨膜病治疗中的潜在作用。这是基因诊断为PHO的受试者中最大的队列报道。我们首次系统研究了PHOAR1和PHOAR2在生化和临床方面的差异，并前瞻性地显示了依托昔布对PHO患者的积极疗效和安全性。(C) 2017年美国骨与矿物研究学会。
Primary hypertrophic osteoarthropathy (PHO) is a rare inherited disease caused by genetic defects in the prostaglandin metabolism pathway; disturbed prostaglandin E-2 (PGE(2)) catabolism resulting in increased PGE(2) level is suggested in the pathogenesis. Fortythree Han Chinese patients with PHO were studied and 41 of them were treated. Mutations in the HPGD gene, causing hypertrophic osteoarthropathy, primary, autosomal recessive 1 (PHOAR1; OMIM 259100), were identified in seven patients, and mutations in the SLCO2A1 gene, causing hypertrophic osteoarthropathy, primary, autosomal recessive 2 (PHOAR2; OMIM 614441), were identified in 36 patients. Clinical phenotypes of PHO varied, ranging from mild isolated finger clubbing to severe pachydermia and disabling joint swelling, even within families. Circulating PGE(2) metabolism features of PHOAR2 were different from those of PHOAR1. Different frequency and severity of pachydermia between the subgroups were also indicated. A percentage of PHOAR2 patients suffered from gastrointestinal hemorrhage, but this symptom was not observed in the PHOAR1 subgroup. Clinical evidence highlighted the essential role of sex hormones in prostaglandin transporter regulation with respect to PHOAR2 onset, although no significant associations of urinary PGE(2) or PGE-M with sex hormones were identified. Treatment with etoricoxib, a selective cyclooxygenase-2 inhibitor, was proved to be beneficial and safe. We detected its notable efficacy in decreasing urinary PGE(2) levels in the majority of the enrolled patients during 6 months of intervention; clinical phenotypes assessed, including pachydermia, finger clubbing, and joint swelling, were improved. We found no visible evidence of a positive effect of etoricoxib on periostosis; however, significant links between urinary PGE(2) and serum bone turnover markers indicated a potential role of decreased PGE(2) in periostosis management. This is the largest reported cohort of subjects genetically diagnosed with PHO. For the first time, we systematically investigated the biochemical and clinical differences between PHOAR1 and PHOAR2, and prospectively showed the positive efficacy and safety of etoricoxib for PHO patients. (C) 2017 American Society for Bone and Mineral Research.