The IL-18/IFNγ axis in systemic JIA and MAS-new answers, more questions.
The IL-18/IFNγ axis in systemic JIA and MAS-new answers, more questions.
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系统性 JIA 和 MAS 中的 IL-18/IFNγ 轴-新答案，更多问题。
DOI：
10.1093/rheumatology/keab342
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Schulert,GrantS
中科院分区：
文献类型：
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作者：
Schulert,GrantS
系统性JIA(SJIA)是儿童关节炎的一个独特的亚型，以突出的关节外特征、显著的天然免疫效应器的激活以及IL-1和IL-6驱动的炎症[1]而闻名。这些发现已经转化为高效的细胞因子靶向治疗，目前被广泛认为是治疗新发SJIA的首选药物。然而，相当少数的患者(在随机临床试验[2，3]中可能有20-30%)对初始治疗无效，迫切需要识别生物标记物来指导治疗方法。在SJIA细胞因子环境中特别值得注意的是IL-18，这是一种IL-1家族细胞因子，与其他风湿性和炎症性疾病相比循环水平显著升高[4]。SJIA在儿童关节疾病中也是独一无二的，因为它与巨噬细胞激活综合征(MAS)密切相关，MAS是一种典型的细胞因子风暴综合征，过度激活的淋巴细胞和分化良好的巨噬细胞会导致吞血、高铁血症、细胞减少、凝血障碍和器官功能障碍。虽然SJIA和MAS之间的生物学基础还不完全清楚，但越来越多的证据支持IFNc的核心作用，与没有MAS的SJIA相比，IFNc在MAS中被高度激活[5]。与临床上相似的家族性噬血细胞性淋巴组织细胞增多症不同，溶细胞活性的遗传缺陷会导致持续的淋巴细胞激活，而MAS可能是由过量的IL-18产生激活淋巴细胞和NK细胞IFNc产生所致。在本期《风湿学》杂志上，Hinze及其同事的最新工作[6]为SJIA的IL-18/IFNc轴、其与MAS的关系以及与治疗反应的关系提供了新的见解。这项研究调查了Canakinumab的OpenLabel扩展试验，Canakinumab是一种抗IL-1b的单抗，针对SJIA和活跃的全身特征的患者[7]。总体而言，根据ACR儿科50标准(ACR50)水平，60%的患者有反应。Hinze等人。使用多重细胞因子图谱显示SJIA患者基线时大多数炎症生物标志物，包括IL-1b、IL-6、IL-18、CXCL9、CXCL10和S100A12均升高。尽管最近有MAS的患者被排除在这项试验之外，但IFNc诱导的趋化因子CXCL9水平最高的是在试验期间出现MAS的患者，特别是在开始治疗的60天内。有趣的是，对至少ACR30的Canakinumab有反应的患者有显著更高的IL-18和IFNc基线水平，以及更低的CXCL9水平。这些水平通过特异性ELISA得到证实，虽然IL-18和CXCL9可以在不同平台之间高度相关，但IFNc没有显示显著的相关性。考虑到IL-18、IFNc和CXCL9之间的生物学关系，作者发现，在预测Canakinumab应答时，IL-18：CXCL9的基线比率比单一生物标志物表现得更好，受试者-操作曲线下的面积为0.74-0.81，取决于临床应答水平。综上所述，这项工作表明，IL-18/IFNc轴的不同调节可能有助于预测IL-1阻断的临床反应。细胞因子导向治疗已迅速成为SJIA的标准治疗方法，但对特定药物的治疗反应各不相同。因此，越来越多的人对基于生物学的生物标志物来预测治疗反应或无反应感兴趣。新发病的SJIA以明显的外周中性粒细胞增多而显著，在临床有效治疗期间迅速恢复正常。最近的一项研究发现，循环中…的升高
Systemic JIA (SJIA) is a distinctive subtype of childhood arthritis notable for prominent extra-articular features, prominent activation of innate immune effectors, and evidence of IL-1 and IL-6 driven inflammation [1]. These discoveries have been translated into highly effective cytokine-targeted therapy now broadly considered firstline for new-onset SJIA. However, a substantial minority of patients (perhaps 20–30% in randomized clinical trials [2, 3]) fail to respond to initial therapy, and there is a critical need to identify biomarkers to guide treatment approach. Particularly notable in the SJIA cytokine environment is IL-18, an IL-1 family cytokine with markedly elevated circulating levels compared with other rheumatic and inflammatory diseases [4]. SJIA is also unique among childhood arthropathies for the strong association with macrophage activation syndrome (MAS), a prototypical cytokine storm syndrome where excessively activated lymphocytes and well-differentiated macrophages lead to haemophagocytosis, hyperferritinaemia, cytopenias, coagulopathy, and organ dysfunction. While the biologic basis for the association between SJIA and MAS is incompletely understood, increasing evidence supports a central role for IFNc, which has been shown to be highly activated in MAS compared with active SJIA without MAS [5]. In contrast to the clinically similar familial haemophagocytic lymphohistiocytosis, where genetic defects in cytolytic activity leads to persistent lymphocyte activation, MAS may be driven by this excessive IL-18 production activating lymphocyte and NK cell IFNc production. In this issue of Rheumatology, recent work by Hinze and colleagues [6] provides new insights into the IL-18/IFNc axis in SJIA, its association with MAS, and relationship to treatment response. This present study examined patients in the openlabel extension trial of canakinumab, an anti-IL-1b monoclonal antibody, for patients with SJIA and active systemic features [7]. Overall,> 60% of patients showed response, based on the ACR Pediatric 50 criteria (ACR50) level. Hinze et al. used multiplex cytokine profiling to show that SJIA patients at baseline showed elevations in most inflammatory biomarkers, including IL-1b, IL-6, IL-18, CXCL9, CXCL10, and S100A12. Although patients with recent MAS were excluded from this trial, the highest levels of the IFNc-induced chemokine CXCL9 were seen in patients who developed MAS during the trial, and especially within 60days of treatment initiation. Interestingly, patients who responded to canakinumab with at least an ACR30 had significantly higher baseline levels of IL-18 and IFNc, and lower levels of CXCL9. These levels were confirmed using specific ELISA, and while IL-18 and CXCL9 could be validated with high correlation between platforms, IFNc showed no significant correlation. Given the biological relationship between IL-18, IFNc, and CXCL9, the authors found that the baseline ratio of IL-18: CXCL9 performed better than a single biomarker alone at predicting canakinumab response, with area under the receiver-operating curve of 0.74–0.81 depending on level of clinical response. Together, this work suggests that differential regulation of IL-18/IFNc axis may help predict clinical response to IL-1 blockade. Cytokine-directed therapy has rapidly become standard of care in SJIA, but treatment responses to specific medications are variable. As such, there is increasing interest in biologically based biomarkers to predict treatment response or non-response. New-onset SJIA is notable for a marked peripheral neutrophilia, which rapidly normalizes during clinically effective treatment. One recent study found that elevated circulating …