University College Dublin, Dublin, Ireland.
University of Toronto, Toronto, Ontario, Canada.
Arthritis Rheumatol. 2024 Sep;76(9):1397-1407. doi: 10.1002/art.42921. Epub 2024 Jul 1.
Our objective was to evaluate the association of serum biomarkers with baseline psoriatic arthritis (PsA) disease activity, pharmacodynamic effects of deucravacitinib on biomarker levels, and the relationship between biomarkers and clinical responses to deucravacitinib.
The phase 2 trial (ClinicalTrials.gov identifier: NCT03881059) randomly assigned 203 patients with PsA 1:1:1 to placebo, deucravacitinib at 6 mg once daily (QD), or deucravacitinib at 12 mg QD. Serum biomarkers associated with the interleukin 23 (IL-23) pathway (IL-17A, β-defensin [BD-2], and IL-19), type I interferon pathway, inflammation, and collagen matrix turnover were measured by immunoassay. Clinical responses (≥75% improvement from baseline in the Psoriasis Area and Severity Index [PASI75] and ≥20% improvement from baseline in American College of Rheumatology criteria [ACR20] responses) were measured at week 16. Hematologic variables were also assessed.
IL-17A, BD-2, and IL-19 had a modest association with PASI scores (r = 0.4, r = 0.56, and r = 0.5, respectively) at baseline. In deucravacitinib groups, IL-17A, BD-2, IL-19, C-X-C motif ligand 9 (CXCL9), CXCL10, C-reactive protein, matrix metalloproteinase 3, and collagen type 4 degradation marker levels were significantly reduced at week 16 versus baseline (P < 0.01); higher levels of IL-23 pathway-associated biomarkers predicted higher PASI75 and ACR20 response rates in deucravacitinib-treated patients. Significantly higher PASI75 response rates were seen in patients with high baseline IL-17A (odds ratio 15.76) and BD-2 levels (odds ratio 15.41) versus low baseline IL-17A and BD-2 levels. Changes in hematologic variables that are characteristic of JAK inhibition were not observed with deucravacitinib.
Deucravacitinib significantly impacted biomarkers associated with Tyk2 signaling pathways of key inflammatory cytokines, including IL-23 and type I interferon, and those related to collagen matrix turnover. These biomarkers may predict treatment responses to deucravacitinib.
我们的目的是评估血清生物标志物与基线银屑病关节炎（PsA）疾病活动的关系、度鲁特韦对生物标志物水平的药效学影响，以及生物标志物与度鲁特韦临床应答之间的关系。
这项 2 期临床试验（ClinicalTrials.gov 标识符：NCT03881059）按 1:1:1 的比例将 203 例 PsA 患者随机分为安慰剂组、度鲁特韦 6mg 每日 1 次（QD）组和度鲁特韦 12mg QD 组。通过免疫测定法测量与白细胞介素 23（IL-23）通路（IL-17A、β-防御素[BD-2]和 IL-19）、I 型干扰素通路、炎症和胶原基质转换相关的血清生物标志物。在第 16 周测量临床应答（基于银屑病面积和严重程度指数[PASI75]从基线改善≥75%和基于美国风湿病学会标准[ACR20]应答从基线改善≥20%）。还评估了血液学变量。
IL-17A、BD-2 和 IL-19 在基线时与 PASI 评分具有中等相关性（r = 0.4、r = 0.56 和 r = 0.5，分别）。在度鲁特韦组中，IL-17A、BD-2、IL-19、C-X-C 基序配体 9（CXCL9）、CXCL10、C 反应蛋白、基质金属蛋白酶 3 和胶原类型 4 降解标志物水平在第 16 周与基线相比显著降低（P < 0.01）；在接受度鲁特韦治疗的患者中，较高水平的 IL-23 通路相关生物标志物预示着更高的 PASI75 和 ACR20 应答率。与低基线 IL-17A 和 BD-2 水平相比，基线 IL-17A（优势比 15.76）和 BD-2 水平（优势比 15.41）较高的患者出现更高的 PASI75 应答率。未观察到度鲁特韦引起与 JAK 抑制相关的血液学变量的变化。
度鲁特韦显著影响与关键炎症细胞因子（包括 IL-23 和 I 型干扰素）和与胶原基质转换相关的 Tyk2 信号通路相关的生物标志物。这些生物标志物可能预测度鲁特韦的治疗反应。
