Assessment of Clinical Response to Janus Kinase Inhibition in Patients With Familial Chilblain Lupus and TREX1 Mutation
Assessment of Clinical Response to Janus Kinase Inhibition in Patients With Familial Chilblain Lupus and TREX1 Mutation
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DOI：
10.1001/jamadermatol.2018.5077
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发表时间：
2019-03-01
期刊：
影响因子：
10.9
通讯作者：
Guenther, Claudia
中科院分区：
文献类型：
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作者：
Zimmermann, Nick;Wolf, Christine;Guenther, Claudia
家族性冻疮性狼疮是一种单基因常染色体显性遗传性皮肤红斑狼疮，在大多数情况下是由3个主要修复核酸酶1(TREX1)的突变引起的。家族性冻疮狼疮在儿童早期表现为冷诱导的疼痛红斑浸润性病变，导致肢解，并与全身受累有关，表现为皮肤和血液中I型干扰素(干扰素)信号升高。目的评价Janus激酶抑制剂巴利西尼治疗家族性寒战狼疮的临床疗效，评价寒战对患者成纤维细胞的影响。设计、背景和研究对象在本病例系列中，3例由TREX1基因突变引起的家族性寒战狼疮患者接受巴力替尼治疗3个月。每天给予巴利替尼4 mg，连续3个月。通过修订的皮肤狼疮面积和严重程度指数来评估皮肤狼疮皮损的疗效和措施，皮肤和关节受累的疼痛用视觉模拟量表评估，用聚合酶链式反应测定血液中的I型干扰素信号。结果3例患者(女性2例，男性1例；平均年龄51[24]岁)显示皮肤狼疮皮损明显改善，全身I型干扰素活性受到抑制。1名患者疼痛完全缓解，2名患者关节炎症相关疼痛部分减轻。没有严重不良反应的报道。患者成纤维细胞暴露于寒冷中，在体外诱导应激反应和加速衰老，同时诱导干扰素刺激的基因。结论和相关性这些发现证实了在3名患者中单基因形式的狼疮患者中Janus激酶抑制的治疗效果，并为在TREX1缺陷细胞中寒冷导致疾病恶化的过程提供了机械性的见解。这一发现可能与其他I型干扰素介导的疾病相关，并暗示Janus激酶抑制也是一种潜在的治疗多因素皮肤红斑狼疮的选择。
IMPORTANCE Familial chilblain lupus is a monogenic autosomal dominant form of cutaneous lupus erythematosus that in most cases is caused by mutations in the 3 prime repair exonuclease 1 (TREX1). Familial chilblain lupus presents in early childhood with cold-induced painful erythematous infiltrates leading to mutilation and is associated with systemic involvement illustrated by an elevated type I interferon (IFN) signature in the skin and blood. Effective treatment is currently not available.OBJECTIVES To evaluate the clinical response to the Janus kinase inhibitor baricitinib in familial chilblain lupus and assess the effect of cold on patient fibroblasts.DESIGN, SETTING, AND PARTICIPANTS In this case series, 3 patients with familial chilblain lupus due to TREX1 mutation underwent treatment with baricitinib for 3 months.INTERVENTIONS Doses of baricitinib, 4mg, were administered daily for 3 months.MAIN OUTCOMES AND MEASURES Reduction of cutaneous lupus lesions was measured by the revised cutaneous lupus area and severity index, pain due to skin and joint involvement was assessed by visual analog scale, type I IFN signature in blood was determined by polymerase chain reaction, and the in vitro response of fibroblasts to cold exposure was analyzed.RESULTS All 3 patients (2 women and 1 man; mean [SD] age, 51 [24] years) showed a significant improvement of cutaneous lupus lesions with suppression of systemic type I IFN activation. One patient had a complete remission regarding pain and, in 2 patients, pain associated with joint inflammation was partially reduced. No severe adverse reactions were reported. Exposure of patient fibroblasts to cold induced a stress response and enhanced senescence along with induction of IFN-stimulated gene in vitro.CONCLUSIONS AND RELEVANCE These findings demonstrate the therapeutic efficacy of Janus kinase inhibition in a monogenic form of lupus among 3 patients and provide mechanistic insight into the process of disease exacerbation by cold in TREX1-deficient cells. This finding may be relevant to other type I IFN-mediated disorders and implicates Janus kinase inhibition as a potential therapeutic option also for multifactorial cutaneous lupus erythematosus.