Treatment of Persistent Erythema Multiforme With Janus Kinase Inhibition and the Role of Interferon Gamma and Interleukin 15 in Its Pathogenesis.
Treatment of Persistent Erythema Multiforme With Janus Kinase Inhibition and the Role of Interferon Gamma and Interleukin 15 in Its Pathogenesis.
复制标题
抑制 Janus 激酶治疗持续性多形红斑以及干扰素 γ 和白细胞介素 15 在其发病机制中的作用。
DOI：
10.1001/jamadermatol.2021.4084
复制
发表时间：
2021
期刊：
影响因子：
10.9
通讯作者：
William E. Damsky
中科院分区：
文献类型：
--
作者：
M. Murphy;Diana Gruenstein;Alice Wang;Danielle Peterson;J. Levitt;B. King;William E. Damsky
重要性
持续性多形性红斑（PEM）是知之甚少，缺乏有效的治疗以外的糖皮质激素。
目的
报告用Janus激酶（JAK）抑制剂治疗PEM后的结局，并阐明多形性红斑（EM）的细胞因子驱动因素。
设计、设置和参与者
这是一项回顾性病例系列，包括2015年至2021年在2家主要三级转诊中心的皮肤科诊所接受托法替尼和/或upadacitinib治疗的4例PEM患者。治疗了4例对多种治疗方法无效的PEM患者。在1例患者中，在治疗前和治疗期间获得皮肤活检标本用于RNA测序和蛋白质组学分析。通过RNA原位杂交分析共12例EM患者（本研究中3例接受托法替尼治疗，9例历史样本）活检标本中细胞因子表达，验证了分子结果。
干预措施
接受托法替尼5 - 10 mg每日2次或upadacitinib 15 mg每日1次治疗。
主要成果和措施
在用JAK抑制剂治疗的所有4名患者中评估PEM活性的变化。中位（范围）随访时间为20.5个月（10.0-36.0个月）。
结果
4例女性患者的研究人群的平均（SD）年龄为46.2（13.7）岁，平均（SD）病程为21.75（11.30）年。在所有4例患者中观察到显著的临床改善。在1例接受托法替尼治疗后出现显著改善的患者中，RNA测序鉴定出干扰素γ（IFN-γ）和白细胞介素15（IL-15）为细胞因子，其活性在基线时皮损皮肤中高度上调，随后在托法替尼治疗后受到抑制。12例患者的额外EM活检标本中IFNG和IL 15阳性细胞的测量显示，与正常皮肤相比，IFNG（8.72个细胞/mm; 95% CI，2.60-14.84）和IL 15（14.13个细胞/mm; 95% CI，0.14-28.11）显著上调（分别为P = 0.008和P = 0.045）。
结论和相关性
该病例系列研究的结果表明，JAK抑制可能有效治疗PEM，IFN-γ和IL-15可能是该疾病的重要细胞因子介质。
Importance
Persistent erythema multiforme (PEM) is poorly understood and lacks effective therapies other than glucocorticoids.
Objective
To report outcomes following treatment of PEM with Janus kinase (JAK) inhibition and to elucidate cytokine drivers of erythema multiforme (EM).
Design, Setting, and Participants
This was a retrospective case series of 4 patients with PEM treated with tofacitinib and/or upadacitinib in 2015 to 2021 at the dermatology clinics of 2 major tertiary referral centers. Four consecutive patients with PEM refractory to multiple treatment approaches were treated. In 1 patient, skin biopsy specimens were obtained for RNA sequencing and proteomic analysis before and during treatment. Molecular findings were validated through RNA in situ hybridization analysis of cytokine expression in biopsy specimens from a total of 12 patients with EM (3 treated with tofacitinib in this study and 9 historic samples).
Interventions
Treatment with tofacitinib, 5 to 10 mg, twice daily or upadacitinib, 15 mg, once daily.
Main Outcomes and Measures
Change in PEM activity was assessed in all 4 patients treated with a JAK inhibitor. Median (range) follow-up was 20.5 months (10.0-36.0 mo).
Results
The study population of 4 female patients had a mean (SD) age of 46.2 (13.7) years and a mean (SD) disease duration of 21.75 (11.30) years. Marked clinical improvement was noted in all 4 patients. In 1 patient with a robust improvement following treatment with tofacitinib, RNA sequencing identified interferon gamma (IFN-γ) and interleukin 15 (IL-15) as cytokines with activity both highly upregulated at baseline in lesional skin and subsequently suppressed following tofacitinib treatment. Measurement of IFNG- and IL15-positive cells in additional EM biopsy specimens of 12 patients showed significant upregulation of IFNG (8.72 cells per mm; 95% CI, 2.60-14.84) and IL15 (14.13 cells per mm; 95% CI, 0.14-28.11) compared with normal skin (P = .008 and P = .045, respectively).
Conclusions and Relevance
The results of this case series study suggest that JAK inhibition may be effective in treating PEM and that IFN-γ and IL-15 may be important cytokine mediators of the disease.