Ruxolitinib treatment of a patient with steroid-dependent severe autoimmunity due to STAT1 gain-of-function mutation
Ruxolitinib treatment of a patient with steroid-dependent severe autoimmunity due to STAT1 gain-of-function mutation
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DOI：
10.1007/s12185-020-02860-7
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发表时间：
2020-03-16
影响因子：
2.1
通讯作者：
Kure, Shigeo
中科院分区：
文献类型：
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作者：
Moriya, Kunihiko;Suzuki, Tasuku;Kure, Shigeo
信号换能器和转录1功能获得激活因子（STAT1 GOF）突变是慢性皮肤粘膜念珠菌病（CMC）最常见的原因。我们报道了口服ruxolitinib（一种Janus激酶（JAK）家族酪氨酸激酶抑制剂）对一名因STAT1 GOF T385M突变而患有类固醇依赖性严重自身免疫的3岁男性的临床和免疫状态的影响。患者对感染的易感性通过抗菌素预防和免疫球蛋白替代治疗得到改善，但他继续表现出严重的自身免疫致残症状。超过三分之一的STAT1 GOF突变患者表现出自身免疫表现，据报道该患者的突变导致CMC伴有自身免疫。应用流式细胞术分析鲁索利替尼治疗前后白细胞介素(IL)-17A和ifn - γ水平及免疫表型。治疗4个月后，外周血IL-17A水平未升高，ifn - γ水平下降。在ifn - γ刺激患者细胞后，STAT1磷酸化水平显著降低。在临床上，巨细胞病毒发生了再激活，但得到了控制。没有发现其他不良反应。我们报道了ruxolitinib对CMC和类固醇依赖性自身免疫的JAK1/2抑制的潜力。然而，长期服用是必要的，因为停止治疗后效果不能持续。
Signal transducer and activator of transcription 1 gain-of-function (STAT1 GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC). We report the effect of oral ruxolitinib, an inhibitor of Janus kinase (JAK) family tyrosine kinases, on the clinical and immune status of a 3-year-old male with steroid-dependent severe autoimmunity due to a STAT1 GOF T385M mutation. The patient's susceptibility to infection improved with antimicrobial prophylaxis and immunoglobulin replacement therapy, but he continued to exhibit severely disabling symptoms of autoimmunity. More than one-third of patients with STAT1 GOF mutations present with autoimmune manifestations, and this patient's mutation was reported to cause CMC with autoimmunity. We analyzed the interleukin (IL)-17A and IFN-gamma levels and immunophenotype by flow cytometry before and during treatment with ruxolitinib. The peripheral IL-17A level did not increase, but the IFN-gamma level decreased after 4 months of therapy. The STAT1 phosphorylation level decreased significantly upon stimulation of patient cells with IFN-gamma. Clinically, cytomegalovirus reactivation occurred, but was controlled. No other adverse effect was noted. We report the potential of JAK1/2 inhibition with ruxolitinib for both CMC and steroid-dependent autoimmunity. However, long-term administration is necessary, as the effect is not sustained after treatment is discontinued.