Anakinra for neutrophilic pustular skin disease

从2013年1月1日至2019年10月31日，招募了17岁以上的个体，其组织病理学证实的脓疱性银屑病（PP）累及5%体表面积或掌跖受累。阿那白滞素（每日100 mg）开始给药，剂量递增，每4周一次，持续12周，直至每日300 mg，然后停药，第16周进行评估。主要终点是第12周时全身表面积受累（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（AE）的变化。本研究已获得NIH机构审查委员会的批准（13-C-0071/13-AR-0071）。获得知情同意书。 18名参与者被招募。15例为女性，中位四分位距（IQR）年龄为47.8岁（43.3，55.0）。14名可评价参与者中有7名获得临床应答，通过阿那白滞素12周后TBSAI降低50%确定（中位数-0.9，IQR（-1.8，0.0），p=0.033）。在阿那白滞素停药后4周，TBSAI（中位数0.3，IQR（0.0，1.8），p=0.074）维持应答。基线活检显示IL-36的强染色在第12周持续存在，而在第12周时，7/8例患者的强髓过氧化物酶（MPO）染色降低，无论反应如何。 第12周时，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。所有全身炎症标志物在第12周降低，停药后4周升高。在调整心血管危险因素188后，阿那白滞素与血管炎症减少相关（β =0.18，p<0.001）。在16/18例患者中发现了先前与PP相关的遗传变异。 大多数不良事件为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，阿那白滞素高达300毫克，每天是一个安全和有效的治疗一些患者的PP。阿那白滞素治疗后，客观和自我报告的测量得到改善，阿那白滞素在所有剂量水平下均耐受良好。除一名应答者外，所有应答者均表现出DLQI评分改善>5分（2至5分的变化表明具有临床重要性的差异）。此外，我们系统地描述了脓疱型银屑病关节和血管炎症的负担和治疗反应。我们的研究结果包括局限性和全身性PP患者，与APRICOT研究形成对比，在APRICOT研究中，掌跖脓疱病参与者接受阿那白滞素100 mg每日治疗8周未达到临床反应。这种差异可能归因于使用的剂量较低和/或治疗持续时间较短，并强调了脓疱性银屑病可能需要更高剂量的阿那白滞素。本研究受样本量小和非对照开放标签设计的限制。需要更大规模的研究来证实阿那白滞素在PP中的疗效，并探索遗传贡献。 这篇题为“阿那白滞素治疗难治性脓疱性银屑病：一项II期、开放标签、剂量递增试验”的手稿被接受发表在《美国皮肤病学学会杂志》上。2022年7月27日，正在印刷中。

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.