特应性皮炎患者更换 JAK 抑制剂:日常临床实践中的未解之谜。

Styliani Mastraftsi, Michail Bakakis, Aikaterini Tsiogka, Ileana Afroditi Kleidona, Stamatios Gregoriou
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引用次数: 0

摘要

特应性皮炎(AD)患者换药的数据很少(1-3)。我们报告了一例严重特应性皮炎患者的病例,该患者对达帕替尼反应不足,但在换用阿罗西替尼后出现了完全反应。一名23岁的男性重症AD患者参加了Measure Up双盲、安慰剂对照3期随机临床试验。基线时,湿疹面积严重性指数(EASI)为50.6,研究者总体评估(IGA)为4,受影响体表面积(BSA)为80%,最严重瘙痒-数字评分量表(WP-NRS)为10/10(图1)。第 124 周时,患者停止了试验,当时的 EASI 为 9.2,IGA 为 3,BSA 为 20%,WP-NRS 为 5/10。停药一个月后,在期待解除绑定的同时,患者再次出现 AD 病情加重,EASI 为 45.6,IGA 为 4,BSA 为 80%,WP-NRS 为 10/10。当时,希腊还不能同时使用杜必鲁单抗和曲妥珠单抗,而达达替尼因患者满意度不高(部分原因是在之前的达达替尼治疗期间复发了眼部单纯疱疹感染)而未被使用。患者接受了阿罗西替尼治疗,每天 200 毫克。开始治疗一个月后,患者的病情得到了完全控制(EASI 0.0,IGA 0,BSA 0%,WP-NRS 0/10)(图 2)。连续治疗 12 个月后,患者的病情得到了控制,且未出现任何不良反应。解除盲法后,确认患者在参与临床试验期间每天服用了 15 毫克的达帕西替尼。在治疗重症AD患者时,如果反应不充分,何时换药以及换用哪种药物是一个尚未明确界定的问题。JADE EXTEND 研究的数据表明,使用杜必鲁单抗疗效不佳的患者可以从换用两种剂量的阿罗西替尼中获益(1)。然而,在这项研究中,一些患者在接受了 200 毫克阿罗西替尼治疗后仍未取得疗效。此外,JADE EXTEND 研究的亚人群分析评估了患者导向湿疹测量(POEM)≤2 和皮肤科生活质量指数(DLQI)≤1 等难以达到的患者导向结果,进一步强调了换药可能对大量患者有益,但其中一些患者的需求仍未得到满足(4)。文献中缺乏有关AD患者切换Janus激酶(JAK)抑制剂的数据。在关键研究中,巴利昔尼和达帕替尼在16周时进行了评估,而阿罗西替尼在12周时进行了评估,因此早期疾病控制的目标治疗可能有所不同。就本病例而言,由于阿罗西替尼和达达替尼均为选择性 JAK1 抑制剂,因此无法明确界定所获得的不同临床反应。因此,所针对的炎症通路和预期的免疫功能调节可能是相似的。我们可以认为,阿罗西替尼的高剂量与奥达替尼的低剂量相比,可能是反应改善的原因。然而,我们无法评估临床结果是否与每天服用30毫克全剂量的奥帕他替尼具有可比性,也无法评估每天服用100毫克半剂量的阿罗西替尼是否也会导致同一患者的反应不充分。多年来,在同一类治疗药物之间进行转换也一直是银屑病治疗中争议颇多的问题;然而,最近的数据表明,在白细胞介素(IL)-17A 拮抗剂之间进行转换可能对某些患者有益,尽管其潜在的作用机制仍在研究之中(5,6)。在应答不足的情况下,治疗方法的调整可包括:增加剂量、在 JAK 抑制剂的基础上增加甲氨蝶呤等传统治疗方法、改用单克隆类药物或改用另一种 JAK 抑制剂,同时考虑到已发表的对新型药物疗效的荟萃分析。因此,在目前的 AD 治疗中,确定从治疗到靶点、转换或增加治疗的逐步算法的需求尚未得到满足。不同国家的报销政策不同,再加上缺乏比较研究,可能会使在现有治疗指南中增加此类建议变得更加复杂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Switching between JAK Inhibitors in Patients with Atopic Dermatitis: Unanswered Questions in Daily Clinical Practice.

Data on switching between agents in patients with atopic dermatitis (AD) are scarce (1-3). We report the case of a patient with severe AD and inadequate response to upadacitinib who showed a complete response after switching to abrocitinib. A 23-year-old male patient with severe AD was enrolled in the Measure Up double-blind, placebo-controlled, phase 3 randomized clinical trial. At baseline, the Eczema Area Severity Index (EASI) was 50.6, the Investigator's Global Assessment (IGA) was 4, the affected Body Surface Area (BSA) was 80%, and the Worst Pruritus-Numeric Rating Scale (WP-NRS) was 10/10 (Figure 1). At week 124, the patient discontinued participation in the trial, while EASI was 9.2, IGA 3, BSA 20%, and WP-NRS 5/10 at the time. After one month off treatment, and while expecting unblinding, the patient again presented with exacerbation of AD, since EASI was 45.6, IGA 4, BSA 80%, and WP-NRS 10/10. At that point of time, access to both dupilumab and tralokinumab was not available in Greece, while upadacitinib was avoided due to inadequate patient satisfaction, partly due to recurrent ocular herpes simplex infections during the previous upadacitinib treatment. The patient was prescribed abrocitinib 200 mg daily. One month after initiation of therapy, the patient achieved complete control of the disease (EASI 0.0, IGA 0, BSA 0%, and WP-NRS 0/10) (Figure 2). This has been maintained with no reported adverse events after 12 months of continuous treatment. After unblinding, the patient was confirmed to have received 15 mg of upadacitinib daily during his participation in the clinical trial. When to switch agents in the treatment of patients with severe AD if the response is not adequate, and what agent to switch to, is an issue that is not clearly defined. Data available from the JADE EXTEND study concluded that patients failing to achieve efficacy outcomes with dupilumab can benefit from switching to both doses of abrocitinib (1). However, a number of patients in this study did not achieve efficacy outcomes even after treatment with 200 mg of abrocitinib. Furthermore, sub-population analysis of the JADE EXTEND study, evaluating difficult-to-achieve patient-oriented outcomes such as Patient Oriented Eczema Measure (POEM) ≤2 and Dermatology Life Quality Index (DLQI) ≤1, further emphasized that switching might be beneficial for a significant number of patients, but unmet need was still evident for some of them (4). The literature lacks data on switching between Janus kinase (JAK) inhibitors in AD. Treat-to-target might be different for early control of the disease, as baricitinib and upadacitinib were assessed at 16 weeks, while abrocitinib was assessed at 12 weeks in the pivotal studies. Regarding the present case, the different clinical response obtained cannot be clearly defined since abrocitinib and upadacitinib are both selective JAK1 inhibitors. Consequently, the targeted inflammatory pathways and the expected regulation of immune functionality could be similar. We may assume that the high dose of abrocitinib vs. the low dose of upadacitinib could have accounted for the improved response. However, it is impossible to assess whether clinical outcomes would have been comparable with the administration of the full dose of upadacitinib 30 mg daily or whether usage of a half-dose of abrocitinib 100 mg daily would have also resulted in inadequate response in the same patient. Switching within the same class of treatment agents has also been a heavily-debated issue for psoriasis for many years; however, recent data suggest that switching between interleukin (IL)-17A antagonists may be of benefit to some patients, although the underlying mechanism of action is still under investigation (5,6). Treatment modification in inadequate response could include: up-dosing, adding classical treatments like methotrexate to the JAK inhibitor, switching to monoclonals, or switching to another JAK inhibitor, taking into account published metanalyses of the efficacy of novel agents. Consequently, there is an unmet need to determine an algorithmic step-by-step approach of treat-to-target and switching or adding treatment in the current landscape of AD therapy. Different policies of reimbursement in different countries, along with a lack of comparative studies, may complicate adding such recommendations to existing treatment guidelines.

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