Mayo Clinic College of Medicine and Science, Rochester, Minnesota, San Raffaele University, Milan, Italy, and Santa Chiara Hospital, Trento, Italy.
University of Michigan Medical School, Ann Arbor.
Arthritis Rheumatol. 2018 Jul;70(7):1114-1121. doi: 10.1002/art.40471. Epub 2018 May 7.
To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3-ANCA] versus myeloperoxidase ANCA [MPO-ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA]).
A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest.
Levels of 9 circulating cytokines (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-15, IL-18, CXCL8/IL-8, CCL-17/thymus and activation-regulated chemokine [TARC], IL-18 binding protein [IL-18 BP], soluble IL-2 receptor α [sIL-2Rα], and nerve growth factor β [NGFβ]) were significantly higher in PR3-AAV than MPO-AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase-associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM-1]) were higher in MPO-AAV than in PR3-AAV, 6 cytokines (IL-6, GM-CSF, IL-15, IL-18, sIL-2Rα, and NGFβ) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3-AAV and MPO-AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL-15, IL-8, IL-18 BP, NGF-β, sICAM-1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis.
Distinct cytokine profiles were identified for PR3-AAV versus MPO-AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes.
评估抗中性粒细胞胞质抗体相关性血管炎（AAV）患者的循环细胞因子谱，根据抗中性粒细胞胞质抗体（ANCA）特异性（蛋白酶 3 ANCA [PR3-ANCA]与髓过氧化物酶 ANCA [MPO-ANCA]）或临床诊断（肉芽肿性多血管炎 [GPA]与显微镜下多血管炎 [MPA]）进行分类。
在 Rituximab 治疗 AAV 试验中，对 186 例活动期 AAV 患者纳入时进行了 29 种细胞因子的检测。在每个分类系统内，比较组间细胞因子浓度。采用多元分析，调整年龄、性别和肾功能不全，以每个生物标志物为因变量，以 ANCA 特异性和临床诊断为感兴趣的解释变量。
PR3-AAV 患者的 9 种循环细胞因子（白细胞介素-6 [IL-6]、粒细胞-巨噬细胞集落刺激因子 [GM-CSF]、白细胞介素-15 [IL-15]、白细胞介素-18 [IL-18]、CXCL8/IL-8、CCL-17/胸腺和激活调节趋化因子 [TARC]、白细胞介素-18 结合蛋白 [IL-18 BP]、可溶性白细胞介素-2 受体 α [sIL-2Rα]和神经生长因子 β [NGFβ]）水平明显高于 MPO-AAV，4 种细胞因子（sIL6R、可溶性肿瘤坏死因子受体 II [sTNFRII]、中性粒细胞明胶酶相关脂质运载蛋白 [NGAL]和可溶性细胞间黏附分子 1 [sICAM-1]）在 MPO-AAV 中高于 PR3-AAV，6 种细胞因子（IL-6、GM-CSF、IL-15、IL-18、sIL-2Rα和 NGFβ）在 GPA 中高于 MPA，3 种细胞因子（骨桥蛋白、sTNFRII 和 NGAL）在 MPA 中高于 GPA（均 P<0.05）。对于几乎所有细胞因子，PR3-AAV 与 MPO-AAV 之间的差异大于 GPA 与 MPA 之间的差异。多变量分析显示，当按 ANCA 特异性分组时，8 种细胞因子（IL-15、IL-8、IL-18 BP、NGF-β、sICAM-1、TARC、骨桥蛋白和肾损伤分子 1 [P<0.05]）比按临床诊断分组时能更好地区分 AAV 患者（较低的 P 值和较大的效应量）。
确定了 PR3-AAV 与 MPO-AAV 以及 GPA 与 MPA 之间的不同细胞因子谱。这些循环免疫介质的差异与 ANCA 特异性的相关性强于与临床诊断的相关性，表明 AAV 亚型的异质性不仅限于临床表型。
