Kirino Yohei, Kawaguchi Yasushi, Tada Yoshifumi, Tsukamoto Hiroshi, Ota Toshiyuki, Iwamoto Masahiro, Takahashi Hiroki, Nagasawa Kohei, Takei Shuji, Horiuchi Takahiko, Ichida Hisae, Minota Seiji, Ueda Atsuhisa, Ohta Akihide, Ishigatsubo Yoshiaki
a Department of Stem Cell and Immune Regulation , Yokohama City University Graduate School of Medicine , Kanagawa , Japan.
b Institute of Rheumatology , Tokyo Women's Medical University , Tokyo , Japan.
Mod Rheumatol. 2018 Sep;28(5):858-864. doi: 10.1080/14397595.2017.1422231. Epub 2018 Jan 11.
Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD.
Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis.
Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis.
We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria.
血红素加氧酶（HO）-1是一种在单核细胞/巨噬细胞中高表达的血红素降解酶，其血清水平可能是成人斯蒂尔病（AOSD）的有前景的生物标志物。我们在此报告关于AOSD患者血清铁蛋白和HO-1水平的数据。
在高细胞因子血症研究组的协作下，我们共收集了145例AOSD患者的血清。三位独立专家根据临床信息判断患者是否为确诊的AOSD。这91例“确诊AOSD”患者进一步分为活动期、缓解期和复发组。纳入46例系统性血管炎、败血症等患者作为疾病对照。采用酶联免疫吸附测定法（ELISA）检测血清铁蛋白和HO-1水平。探讨临床症状、血清铁蛋白和HO-1之间的关联。进行多变量回归分析以确定与确诊AOSD诊断相关的独立变量。
与疾病对照相比，活动期和复发期AOSD患者的血清铁蛋白和HO-1水平显著更高，且经治疗后降低。虽然血清铁蛋白和HO-1水平之间存在显著相关性，但在某些情况下如缺铁性贫血存在差异。受试者工作特征分析确定了血清铁蛋白（>819 ng/ml；敏感性76.1%，特异性73.8%）和血清HO-1（>30.2 ng/ml；敏感性84.8%，特异性83.3%）的最佳水平，这些水平可将AOSD与对照区分开来。有趣的是，复发的AOSD患者中有88.9%超过血清HO-1>30.2 ng/ml的临界值，但只有50.0%超过血清铁蛋白>819 ng/ml（p = 0.013），这表明血清HO-1水平可能是AOSD疾病状态的一个便捷指标。多变量分析确定中性粒细胞增多、RF/ANA阴性、咽痛和血清HO-1升高为与AOSD诊断相关的独立变量。
我们证实血清铁蛋白和HO-1是AOSD的高度特异性和敏感性生物标志物。未来需要进行大样本量的前瞻性研究，以确定这些生物标志物是否可纳入山口标准。
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