Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck, Innsbruck, Austria.
Division of Rheumatology and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Ann Rheum Dis. 2023 Feb;82(2):253-261. doi: 10.1136/ard-2022-222479. Epub 2022 Aug 16.
We investigated whether soluble immune checkpoints (sICPs) predict treatment resistance, relapse and infections in patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV).
Plasma sICP concentrations from available samples obtained during conduct of the RAVE trial were measured by immunoabsorbent assays from patients with either proteinase 3 (PR3) or myeloperoxidase (MPO)-ANCA vasculitis and were correlated with clinical outcomes, a set of biomarkers and available flow cytometry analyses focusing on T cell subsets. Log-rank test was used to evaluate survival benefits, and optimal cut-off values of the marker molecules were calculated using Yeldons J.
Analysis of 189 plasma samples at baseline revealed higher concentrations of sTim-3, sCD27, sLag-3, sPD-1 and sPD-L2 in patients with MPO-ANCA vasculitis (n=62) as compared with PR3-ANCA vasculitis (n=127). Among patients receiving rituximab induction therapy (n=95), the combination of lower soluble (s)Lag-3 (<90 pg/mL) and higher sCD27 (>3000 pg/mL) predicted therapy failure. Twenty-four out of 73 patients (32.9%) in the rituximab arm reaching remission at 6 months relapsed during follow-up. In this subgroup, high baseline values of sTim-3 (>1200 pg/mL), sCD27 (>1250 pg/mL) and sBTLA (>1000 pg/mL) were associated with both sustained remission and infectious complications. These findings could not be replicated in 94 patients randomised to receive cyclophosphamide/azathioprine.
Patients with AAV treated with rituximab achieved remission less frequently when concentrations of sLag-3 were low and concentrations of sCD27 were high. Higher concentrations of sTim-3, sCD27 and sBTLA at baseline predicted relapse in patients treated with rituximab. These results require confirmation but may contribute to a personalised treatment approach of AAV.
我们研究了可溶性免疫检查点（sICPs）是否可预测抗中性粒细胞胞质抗体（ANCA）相关性血管炎（AAV）患者的治疗抵抗、复发和感染。
通过免疫吸附测定法，从接受蛋白酶 3（PR3）或髓过氧化物酶（MPO）-ANCA 血管炎治疗的患者的可用样本中测量 RAVE 试验期间获得的血浆 sICP 浓度，并将其与临床结果、一组生物标志物和聚焦于 T 细胞亚群的可用流式细胞术分析相关联。对数秩检验用于评估生存获益，使用 Yeldons J 计算标记物的最佳截断值。
分析 189 份基线血浆样本显示，与 PR3-ANCA 血管炎（n=127）相比，MPO-ANCA 血管炎（n=62）患者的 sTim-3、sCD27、sLag-3、sPD-1 和 sPD-L2 浓度更高。在接受利妥昔单抗诱导治疗的患者（n=95）中，较低的可溶性（s）Lag-3（<90pg/mL）和较高的 sCD27（>3000pg/mL）联合预测治疗失败。在利妥昔单抗组中，73 例达到 6 个月缓解的患者中有 24 例（32.9%）在随访期间复发。在这个亚组中，基线时 sTim-3（>1200pg/mL）、sCD27（>1250pg/mL）和 sBTLA（>1000pg/mL）的高基线值与持续缓解和感染并发症相关。这些发现不能在随机接受环磷酰胺/硫唑嘌呤治疗的 94 例患者中复制。
接受利妥昔单抗治疗的 AAV 患者的缓解率较低，当 sLag-3 浓度较低且 sCD27 浓度较高时。基线时较高的 sTim-3、sCD27 和 sBTLA 浓度预测利妥昔单抗治疗患者的复发。这些结果需要进一步证实，但可能有助于制定 AAV 的个体化治疗方法。
