Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, , Solna, Stockholm, Sweden.
Ann Rheum Dis. 2014 May;73(5):913-20. doi: 10.1136/annrheumdis-2012-202857. Epub 2013 Apr 26.
To perform a mechanistic study on the effect of interleukin (IL)-1 blockade by anakinra in patients with refractory myositis and to explore possible predictive biomarkers.
Fifteen patients with refractory myositis were treated with anakinra for 12 months. Clinical response was assessed by the six-item core set measures of disease activity International Myositis Assessment and Clinical Studies (IMACS) and functional index (FI). Repeated muscle biopsies were investigated for cellular infiltrates, IL-1α, IL-1β, IL-1Ra and major histocompatibility complex-class I by immunohistochemistry. Serum levels of IL-1Ra and granulocyte colony-stimulating factor (G-CSF) were measured by ELISA. T cell phenotype and functional assays were investigated by multicolour flow cytometry.
Seven patients had clinical response according to IMACS, four of them also showed improved FI. Responders had higher baseline extramuscular score compared with non-responders. In muscle biopsies, baseline CD163 macrophages and IL-1α expression were inversely correlated with muscle performance after 6 months treatment; all responders had IL-1Ra expression in the post-treatment biopsies but only 3/8 non-responders. In serum, IL-1Ra levels were increased and G-CSF was decreased after 6 months treatment, but their levels and changes were not related to clinical response. For T cells, an inverse correlation between baseline frequency of CD4 activated/memory T cells and decreased creatine kinase levels was observed. Five of six patients demonstrated less IL-17A and more IFN-γ secreting CD4 T cells after 6 months treatment. Moreover, anakinra reduced IL-17A secretion in vitro.
Patients with myositis may respond to anakinra. Extramuscular score, muscle CD163 macrophages and IL-1α expression, blood CD4 activated/memory T cells might associate with anakinra treatment response. Blocking the IL-1 receptor disfavoured Th17 cell differentiation both in vivo and in vitro.
对依那西普治疗难治性肌炎患者的作用进行机制研究，并探讨可能的预测生物标志物。
15 例难治性肌炎患者接受依那西普治疗 12 个月。采用国际肌炎评估与临床研究（IMACS）六项目核心组活动指标和功能指数（FI）评估临床反应。通过免疫组织化学法检测细胞浸润、IL-1α、IL-1β、IL-1Ra 和主要组织相容性复合体 I 类。通过 ELISA 法测量血清 IL-1Ra 和粒细胞集落刺激因子（G-CSF）水平。通过多色流式细胞术研究 T 细胞表型和功能。
根据 IMACS，7 例患者有临床反应，其中 4 例 FI 也得到改善。与无反应者相比，反应者基线时的肌肉外评分更高。在肌肉活检中，基线 CD163 巨噬细胞和 IL-1α 表达与 6 个月治疗后的肌肉功能呈负相关；所有反应者在治疗后活检中均有 IL-1Ra 表达，但只有 8 例非反应者中的 3 例。在血清中，IL-1Ra 水平在 6 个月治疗后升高，G-CSF 降低，但它们的水平和变化与临床反应无关。对于 T 细胞，基线时 CD4 激活/记忆 T 细胞的频率与肌酸激酶水平降低呈负相关。6 个月治疗后，5 例患者的 IL-17A 减少，IFN-γ 分泌的 CD4 T 细胞增多。此外，依那西普减少了体外的 IL-17A 分泌。
肌炎患者可能对依那西普有反应。肌肉外评分、肌肉 CD163 巨噬细胞和 IL-1α 表达、血液 CD4 激活/记忆 T 细胞可能与依那西普治疗反应有关。阻断 IL-1 受体在体内和体外均不利于 Th17 细胞分化。
