Anakinra for neutrophilic pustular skin disease

从2013年1月1日至2019年10月31日，纳入17岁经组织病理学证实的脓疱性银屑病(PP)患者，涉及5%的体表面积或掌底受累。阿纳金拉(100 mg/d)开始治疗，剂量每4周递增一次，共12周，至300 mg/d，随后停止治疗并进行第16周评估。主要终点是12周时总体表面积(TBSAI)的变化。次要终点包括银屑病关节炎疾病活动指数(DAPSA)、皮肤病生活质量指数(DLQI)和不良事件(AEs)的变化。这项研究得到了NIH机构审查委员会的批准(13-C-0071/13-AR-0071)。获得知情同意。 18名参与者参加了测试。女性15例，IQR中位数为47.8岁(43.3岁，55.0岁)。在14名可评估的参与者中，有7人在Anakinra治疗12周后根据总胆红素指数下降50%确定为临床反应(中位数-0.9IQR(-1.80.0)，p=0.033)。停药4周后，TBSAI维持疗效(中位数0.3，智商比(0.0，1.8)，p=0.074)。基线活检显示IL-36的强烈染色持续到第12周，而在第12周，无论反应如何，7/8的患者髓过氧化物酶(MPO)染色减弱。 DAPSA(中位数-9.7，IQR(-16.4，-4.7)，p=0.0005)和DLQI(中位数-7.0，IQR(-9.0，-5.0，p=0.0001)改善。在调整心血管危险因子188后，Anakinra与血管炎症减轻相关(β=0.18p&lt；0.001)。在16/18名患者中发现了以前与PP相关的基因变异。 大多数不良反应为1-2级，包括注射部位反应、头痛、恶心、感染、瘙痒和疼痛。 我们证明，阿纳金拉每天300毫克是一些PP患者的安全有效的治疗方法。目的和自我报告的措施在阿纳金纳治疗后有所改善，阿纳金拉在所有剂量水平下耐受性良好。除一名应答者外，所有应答者在DLQI评分中均表现出5分的改善(2到5分的变化暗示着临床上重要的差异)。此外，我们系统地描述了脓疱型银屑病的关节和血管炎症的负担和治疗反应。我们的结果，包括局限性和全身性PP患者，与杏树研究形成对比，在杏树研究中，掌底脓疱病患者每天服用阿纳金纳100 mg，连续8周没有临床疗效。这种差异可能是由于使用的剂量较低和/或治疗持续时间较短，并强调了对脓疱性牛皮癣可能需要更高剂量的阿纳金纳。本研究受制于样本量小和不受控制的开放标签设计。需要更大规模的研究来证实阿纳金拉对PP的疗效，并探索遗传因素。 这篇题为《阿纳金拉治疗难治性脓疱性牛皮癣：第二阶段，开放标签，剂量递增试验》的手稿被接受发表在《美国皮肤病杂志》上。2022年7月27日，正在出版中。

Individuals >17 years old with histopathologically-confirmed Pustular Psoriasis (PP) involving 5% body surface area or palmoplantar involvement were enrolled from January 1, 2013 to October 31, 2019. Anakinra (100mg daily) was initiated with dose escalation every 4 weeks for 12 weeks up to 300mg daily, followed by treatment withdrawal and week 16 assessment. Primary endpoint was change in total body surface area involvement (TBSAI) at week 12. Secondary endpoints included changes in Disease Activity Index for Psoriatic Arthritis (DAPSA), Dermatology Life Quality Index (DLQI), and Adverse Events (AEs). This study was approved by the NIH Institutional Review Boards (13-C-0071/13-AR-0071). Informed consent was obtained. Eighteen participants were enrolled. Fifteen were female and median interquartile range (IQR) age was 47.8 years (43.3, 55.0). Seven of 14 evaluable participants achieved clinical response as determined by 50% reduction in TBSAI after 12 weeks of anakinra (median -0.9, IQR (- 1.8, 0.0), p=0.033). Response was maintained 4 weeks after withdrawal of anakinra therapy by TBSAI (median 0.3, IQR (0.0, 1.8), p=0.074). Baseline biopsies showed intense staining of IL-36 which persisted at week 12, whereas intense myeloperoxidase (MPO) staining decreased in 7/8 patients at week 12, regardless of response. DAPSA (median -9.7, IQR (-16.4, -4.7), p=0.0005) and DLQI (median, -7.0, IQR (-9.0, -5.0), p=0.0001) improved at week 12. All systemic inflammatory markers were reduced at week 12 and increased 4 weeks after drug discontinuation. Anakinra was associated with vascular inflammation reduction after cardiovascular risk factor 188 adjustment (beta=0.18, p<0.001). Genetic variants previously associated with PP were identified in 16/18 patients. Most adverse events were grade 1-2, including injection site reactions, headaches, nausea, infection, pruritus, and pain. We demonstrate that anakinra up to 300mg daily is a safe and effective treatment for some patients with PP. Objective and self-reported measures improved following anakinra therapy, and anakinra was well-tolerated at all dose levels. All but one responder demonstrated >5-point improvement in DLQI score (2 to 5-point change suggests a clinically-important difference). Additionally, we systematically describe the burden and therapeutic response of joint and vascular inflammation in pustular psoriasis. Our results, which include localized and generalized PP patients, contrast with the APRICOT study, in which palmoplantar pustulosis participants treated with anakinra 100mg daily for 8 weeks did not achieve clinical response. This difference may be attributable to lower doses used and/or shorter treatment duration, and underscores the potential requirement for higher doses of anakinra for pustular psoriasis. This study is limited by its small sample size and uncontrolled open-label design. Larger studies are needed to confirm anakinra efficacy in PP and to explore genetic contributions. This manuscript, entitled 'Anakinra for Refractory Pustular Psoriasis: A Phase II, Open Label, Dose-Escalation Trial' was accepted for publication to the J Am Acad Dermatol. July 27, 2022 and is in press.