Janus 激酶抑制治疗持久性多形红斑及其发病机制中干扰素 γ 和白细胞介素 15 的作用。
Treatment of Persistent Erythema Multiforme With Janus Kinase Inhibition and the Role of Interferon Gamma and Interleukin 15 in Its Pathogenesis.
机构信息
Department of Dermatology, Yale School of Medicine, Yale University, New Haven, Connecticut.
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York.
出版信息
JAMA Dermatol. 2021 Dec 1;157(12):1477-1482. doi: 10.1001/jamadermatol.2021.4084.
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.
重要性
持久性多形红斑（PEM）的发病机制尚未完全阐明，除了糖皮质激素外，目前尚无有效的治疗方法。
目的
报告使用 Janus 激酶（JAK）抑制剂治疗 PEM 的结果，并阐明多形红斑（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研究，纳入了 2015 年至 2021 年在 2 家主要三级转诊中心皮肤科诊所接受托法替尼和/或 upadacitinib 治疗的 4 例 PEM 患者。4 例 PEM 患者对多种治疗方法均无效，接受了治疗。其中 1 例患者在治疗前和治疗期间进行了皮肤活检，用于 RNA 测序和蛋白质组分析。通过对 12 例 EM 患者（本研究中 3 例接受托法替尼治疗和 9 例历史样本）活检标本中细胞因子表达的 RNA 原位杂交分析，验证了分子发现。
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。
主要结果和措施
评估 4 例接受 JAK 抑制剂治疗的患者的 PEM 活动变化。中位（范围）随访时间为 20.5 个月（10.0-36.0 个月）。
结果
研究人群中 4 名女性患者的平均（SD）年龄为 46.2（13.7）岁，平均（SD）疾病持续时间为 21.75（11.30）年。所有 4 名患者的临床症状均明显改善。在 1 例患者中，托法替尼治疗后出现显著改善，RNA 测序结果显示干扰素γ（IFN-γ）和白细胞介素 15（IL-15）为细胞因子，在疾病早期皮肤中具有高表达，随后托法替尼治疗后被抑制。在 12 例 EM 活检标本中检测到的 IFNG-和 IL15 阳性细胞显示，与正常皮肤相比，IFNG（8.72 个细胞/mm；95%CI，2.60-14.84）和 IL15（14.13 个细胞/mm；95%CI，0.14-28.11）的表达显著上调（P = .008 和 P = .045）。
结论和相关性
本病例系列研究结果表明，JAK 抑制剂可能对治疗 PEM 有效，IFN-γ 和 IL-15 可能是疾病的重要细胞因子介质。
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