Jéru Isabelle, Hentgen Véronique, Normand Sylvain, Duquesnoy Philippe, Cochet Emmanuelle, Delwail Adriana, Grateau Gilles, Marlin Sandrine, Amselem Serge, Lecron Jean-Claude
Université Pierre et Marie Curie-Paris 6, UMR S933, Paris, France.
Arthritis Rheum. 2011 Jul;63(7):2142-8. doi: 10.1002/art.30378.
A new class of autoinflammatory syndromes called NLRP12-associated disorders (NLRP12AD) has been associated with mutations in NLRP12. Conflicting data on the putative role of NLRP12 in interleukin-1β (IL-1β) signaling have been found in in vitro analyses. This prospective study was undertaken to assess the secretion of IL-1β and 3 IL-1β-induced cytokines (IL-1 receptor antagonist [IL-1Ra], IL-6, and tumor necrosis factor α [TNFα]) in patients' peripheral blood mononuclear cells (PBMCs) cultured ex vivo and to evaluate the patients' response to IL-1Ra (anakinra), a major drug used in the treatment of autoinflammatory disorders.
Patients' disease manifestations and cytokine measurements were recorded before anakinra treatment was started, during 14 months of therapy, and after discontinuation of anakinra treatment.
Spontaneous secretion of IL-1β by patients' PBMCs was found to be dramatically increased (80-175 fold) compared to healthy controls. Consistent with these findings, anakinra initially led to a marked clinical improvement and to a rapid near-normalization of IL-1β secretion. However, a progressive clinical relapse occurred secondarily, associated with an increase in TNFα secretion, persistent elevated levels of IL-1Ra and IL-6, and a reactivation of IL-1β secretion. Anakinra was discontinued after 14 months of therapy.
Our findings provide in vivo evidence of the crucial role of IL-1β in the pathophysiology of NLRP12AD. This is the first time anakinra has been used to treat this disorder. This study provides new insights into the mechanisms underlying resistance to anti-IL-1 therapy observed in a few patients with autoinflammatory syndromes. Our data also point to the potential of ex vivo cytokine measurements as predictors of response to treatment.
一类名为NLRP12相关疾病（NLRP12AD）的新型自身炎症综合征与NLRP12基因突变有关。在体外分析中发现了关于NLRP12在白细胞介素-1β（IL-1β）信号传导中假定作用的相互矛盾的数据。本前瞻性研究旨在评估体外培养的患者外周血单核细胞（PBMC）中IL-1β和3种IL-1β诱导的细胞因子（IL-1受体拮抗剂[IL-1Ra]、IL-6和肿瘤坏死因子α[TNFα]）的分泌情况，并评估患者对IL-1Ra（阿那白滞素）的反应，IL-1Ra是治疗自身炎症性疾病的主要药物。
在开始阿那白滞素治疗前、治疗14个月期间以及停止阿那白滞素治疗后，记录患者的疾病表现和细胞因子测量结果。
发现患者PBMC自发分泌的IL-1β与健康对照相比显著增加（80 - 175倍）。与这些发现一致，阿那白滞素最初导致明显的临床改善以及IL-1β分泌迅速接近正常水平。然而，随后出现了进行性临床复发，伴有TNFα分泌增加、IL-1Ra和IL-6水平持续升高以及IL-1β分泌重新激活。治疗14个月后停用阿那白滞素。
我们的研究结果提供了体内证据，证明IL-1β在NLRP12AD病理生理学中的关键作用。这是首次使用阿那白滞素治疗这种疾病。本研究为一些自身炎症综合征患者中观察到的抗IL-1治疗耐药机制提供了新的见解。我们的数据还指出了体外细胞因子测量作为治疗反应预测指标的潜力。
