Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Arthritis Rheumatol. 2019 Nov;71(11):1943-1954. doi: 10.1002/art.41073. Epub 2019 Oct 1.
Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA-LD).
Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed.
Eighteen patients with SJIA-LD were identified. Radiographic findings included diffuse ground-glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA-LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin-18 (IL-18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA-LD lacked genetic, serologic, or functional evidence of granulocyte-macrophage colony-stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA-LD rarely demonstrated proteinaceous material and had less lipid-laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA-LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA-LD contained elevated levels of IL-18 and the interferon-γ-induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA-LD identified up-regulated type II interferon and T cell activation networks. This signature was also present in SJIA-LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA-LD.
Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.
全身性幼年特发性关节炎（JIA）与一种新近被认识但定义和特征尚不明确的肺部疾病（LD）相关。本研究旨在描述与全身性 JIA 相关的新型炎症性 LD（命名为 SJIA-LD）的临床特征、危险因素以及组织病理学和免疫学特征。
自 2010 年以来，我们从辛辛那提儿童医院医疗中心的全身性 JIA 患者的病历中提取了临床数据。进行了流行病学、细胞、生化、基因组和转录谱分析。
共确定了 18 例 SJIA-LD 患者。影像学表现包括弥漫性磨玻璃影、胸膜下网状影、小叶间隔增厚和淋巴结肿大。病理学表现包括斑片状但广泛的淋巴浆细胞浸润以及混合性肺泡蛋白沉积症（PAP）和内源性类脂性肺炎的特征。与无 LD 的全身性 JIA 患者相比，SJIA-LD 患者的全身性 JIA 诊断年龄更小（优势比[OR]6.5，P=0.007），更常发生巨噬细胞活化综合征（MAS）（OR 14.5，P＜0.001），生物治疗的不良反应发生率更高（OR 13.6，P＜0.001），血清白细胞介素 18（IL-18）水平更高（中位数 27612pg/ml 与 5413pg/ml；P=0.047）。SJIA-LD 患者缺乏粒细胞-巨噬细胞集落刺激因子途径功能障碍的遗传、血清学或功能证据，这是家族性或自身免疫性 PAP 的特征。此外，SJIA-LD 患者的支气管肺泡灌洗液（BAL）中很少有蛋白样物质，载脂巨噬细胞也少于原发性 PAP 患者（SJIA-LD 患者为 10.5%，原发性 PAP 患者为 66.1%；P＜0.001）。SJIA-LD 患者的 BAL 液中含有高水平的 IL-18 和干扰素-γ诱导的趋化因子 CXCL9 和 CXCL10。SJIA-LD 患者肺组织的转录组分析确定了上调的 II 型干扰素和 T 细胞激活网络。在缺乏大量组织病理学发现的 SJIA-LD 人类肺组织切片中也发现了这种特征，这表明这种激活特征可能先于并驱动 SJIA-LD 的肺病理学。
儿童全身性 JIA 中越来越多地发现肺部疾病，特别是与 MAS 相关。该实体具有独特的临床和免疫学特征，代表一种尚未明确的炎症性 LD。
