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Abstract：
Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc). Prognostic biomarkers are needed to identify SSc-ILD patients at risk for progressive pulmonary fibrosis. This study investigates autoantibodies measured in bronchoalveolar lavage (BAL) fluid and in serum in reference to the clinical disease course of SSc-ILD.
Fifteen patients with new onset SSc-ILD underwent bronchoscopy. Autoantibody levels were analyzed using addressable laser bead immunoassay from BAL fluid and the serum. In a separate longitudinal cohort of 43 patients with early SSc-ILD, autoantibodies in serum were measured at baseline and pulmonary function tests were performed at least 2 times over the course of at least 2 or more years. Linear mixed effect models were created to investigate the relationship between specific autoantibodies and progression of SSc-ILD. Finally, lung tissue from healthy controls and from subjects with SSc was analyzed for the presence of the Ro52 antigen using immunohistochemistry.
Among SSc-ILD patients who were positive for anti-Ro52 (N = 5), 3 (60%) had enrichment of anti-Ro52 in BAL fluid at a ratio exceeding 50x. In the longitudinal cohort, 10/43 patients (23%) were anti-Ro52 positive and 16/43 (37%) were anti-scl-70 positive. Presence of anti-Scl-70 was associated with a lower vital capacity (VC) at baseline (-12.6% predicted VC [%pVC]; 95%CI: -25.0, -0.29; p = 0.045), but was not significantly associated with loss of lung function over time (-1.07%pVC/year; 95%CI: -2.86, 0.71; p = 0.230). The presence of anti-Ro52 was significantly associated with the loss of lung function over time (-2.41%pVC/year; 95% CI: -4.28, -0.54; p = 0.013). Rate of loss of lung function increased linearly with increasing anti-Ro52 antibody levels (-0.03%pVC per arbitrary units/mL and year; 95%CI: -0.05, -0.02; p < 0.001). Immunohistochemical staining localized the Ro52 antigen to alveolar M2 macrophages in peripheral lung tissue both in subjects with and without SSc.
This study suggests that antibodies targeting Ro52 are enriched in the lungs of patients with new-onset SSc-ILD, linking Ro52 autoimmunity to the pulmonary pathology of SSc. Clinical and immunohistochemical data corroborates these findings and suggest that anti-Ro52 may serve as a potential biomarker of progressive SSc-ILD.
Fifteen patients with new onset SSc-ILD underwent bronchoscopy. Autoantibody levels were analyzed using addressable laser bead immunoassay from BAL fluid and the serum. In a separate longitudinal cohort of 43 patients with early SSc-ILD, autoantibodies in serum were measured at baseline and pulmonary function tests were performed at least 2 times over the course of at least 2 or more years. Linear mixed effect models were created to investigate the relationship between specific autoantibodies and progression of SSc-ILD. Finally, lung tissue from healthy controls and from subjects with SSc was analyzed for the presence of the Ro52 antigen using immunohistochemistry.
Among SSc-ILD patients who were positive for anti-Ro52 (N = 5), 3 (60%) had enrichment of anti-Ro52 in BAL fluid at a ratio exceeding 50x. In the longitudinal cohort, 10/43 patients (23%) were anti-Ro52 positive and 16/43 (37%) were anti-scl-70 positive. Presence of anti-Scl-70 was associated with a lower vital capacity (VC) at baseline (-12.6% predicted VC [%pVC]; 95%CI: -25.0, -0.29; p = 0.045), but was not significantly associated with loss of lung function over time (-1.07%pVC/year; 95%CI: -2.86, 0.71; p = 0.230). The presence of anti-Ro52 was significantly associated with the loss of lung function over time (-2.41%pVC/year; 95% CI: -4.28, -0.54; p = 0.013). Rate of loss of lung function increased linearly with increasing anti-Ro52 antibody levels (-0.03%pVC per arbitrary units/mL and year; 95%CI: -0.05, -0.02; p < 0.001). Immunohistochemical staining localized the Ro52 antigen to alveolar M2 macrophages in peripheral lung tissue both in subjects with and without SSc.
This study suggests that antibodies targeting Ro52 are enriched in the lungs of patients with new-onset SSc-ILD, linking Ro52 autoimmunity to the pulmonary pathology of SSc. Clinical and immunohistochemical data corroborates these findings and suggest that anti-Ro52 may serve as a potential biomarker of progressive SSc-ILD.
摘要：
背景：间质性肺病（ILD）是系统性硬化症（SSc）患者最常见的死亡原因。需要预后生物标志物来鉴定有进行性肺纤维化风险的SSc-ILD患者。这项研究针对SSc-ILD的临床病程，研究了支气管肺泡灌洗液（BAL）和血清中测得的自身抗体。
方法：15例新发SSc-ILD患者接受支气管镜检查。使用来自BAL液和血清的可寻址激光珠免疫测定法分析自身抗体水平。在43例早期SSc-ILD患者的单独纵向队列中，在基线时测量血清中的自身抗体,并在至少2年或更长时间内进行至少2次肺功能检查.建立线性混合效应模型以研究特异性自身抗体与SSc-ILD进展之间的关系。最后,使用免疫组织化学方法分析来自健康对照和SSc受试者的肺组织中Ro52抗原的存在。
结果：在抗Ro52阳性的SSc-ILD患者中（N=5），3(60%)在BAL流体中以超过50x的比例富集抗Ro52。在纵向队列中，10/43患者（23％）为抗Ro52阳性，16/43（37％）为抗scl-70阳性。抗Scl-70的存在与基线时肺活量（VC）较低有关（-12.6％预测VC[％pVC]；95CI：-25.0，-0.29；p=0.045），但随着时间的推移与肺功能丧失无显著相关性(-1.07%pVC/年;95CI:-2.86,0.71;p=0.230).随着时间的推移，抗Ro52的存在与肺功能的丧失显着相关（-2.41％pVC/年；95％CI：-4.28，-0.54；p=0.013）。肺功能丧失率随着抗Ro52抗体水平的增加而线性增加(每任意单位/mL和年-0.03%pVC;95CI:-0.05,-0.02;p<0.001)。在有和没有SSc的受试者中，免疫组织化学染色将Ro52抗原定位于周围肺组织中的肺泡M2巨噬细胞。
结论：这项研究表明，针对Ro52的抗体在新发SSc-ILD患者的肺部富集，将Ro52自身免疫与SSc的肺部病理学联系起来。临床和免疫组织化学数据证实了这些发现，并表明抗Ro52可以作为进行性SSc-ILD的潜在生物标志物。
方法：15例新发SSc-ILD患者接受支气管镜检查。使用来自BAL液和血清的可寻址激光珠免疫测定法分析自身抗体水平。在43例早期SSc-ILD患者的单独纵向队列中，在基线时测量血清中的自身抗体,并在至少2年或更长时间内进行至少2次肺功能检查.建立线性混合效应模型以研究特异性自身抗体与SSc-ILD进展之间的关系。最后,使用免疫组织化学方法分析来自健康对照和SSc受试者的肺组织中Ro52抗原的存在。
结果：在抗Ro52阳性的SSc-ILD患者中（N=5），3(60%)在BAL流体中以超过50x的比例富集抗Ro52。在纵向队列中，10/43患者（23％）为抗Ro52阳性，16/43（37％）为抗scl-70阳性。抗Scl-70的存在与基线时肺活量（VC）较低有关（-12.6％预测VC[％pVC]；95CI：-25.0，-0.29；p=0.045），但随着时间的推移与肺功能丧失无显著相关性(-1.07%pVC/年;95CI:-2.86,0.71;p=0.230).随着时间的推移，抗Ro52的存在与肺功能的丧失显着相关（-2.41％pVC/年；95％CI：-4.28，-0.54；p=0.013）。肺功能丧失率随着抗Ro52抗体水平的增加而线性增加(每任意单位/mL和年-0.03%pVC;95CI:-0.05,-0.02;p<0.001)。在有和没有SSc的受试者中，免疫组织化学染色将Ro52抗原定位于周围肺组织中的肺泡M2巨噬细胞。
结论：这项研究表明，针对Ro52的抗体在新发SSc-ILD患者的肺部富集，将Ro52自身免疫与SSc的肺部病理学联系起来。临床和免疫组织化学数据证实了这些发现，并表明抗Ro52可以作为进行性SSc-ILD的潜在生物标志物。
