Guselkumab是一种选择性抑制白细胞介素(IL)-23的药物，作用目标是IL-23p19亚单位。在3b期COSMOS试验中，Guselkumab在治疗活动性银屑病性关节炎（PsA）且对肿瘤坏死因子抑制剂（TNFi）缺乏反应（无效或不能耐受）的参与者中表现出有效性。具有活动性PsA（≥ 3个肿胀关节，≥ 3个触痛关节）并对一种或两种TNFi（TNFi-IR）缺乏反应的成年人被随机分为2比1，接受Guselkumab于第0周、第4周，然后每8周（Q8W），或接受安慰剂➔Guselkumab Q8W于第24周，可能在第16周进行早期逃逸。评估了血清细胞因子水平，包括干扰素γ（IFNɣ），白细胞介素-10（IL-10）和肿瘤坏死因子α（TNFα）；T细胞辅助17（Th17）效应细胞因子白细胞介素-17A（IL-17A），白细胞介素-17F（IL-17F）和白细胞介素-22（IL-22）；以及急性期蛋白C反应物（CRP），IL-6和血清淀粉样蛋白（SAA），并与健康对照组进行比较；还评估了Guselkumab在第24周之前的药效动力学。评估了基线生物标志物水平与1）基线疾病活动水平（28关节疾病活动评分用CRP [DAS28-CRP]，银屑病面积和严重指数[PASI]以及被银屑病影响的身体表面积[BSA]的百分比）和2）在第24周的临床反应（包括美国风湿病学院标准[ACR20]反应≥20%的改善）之间的关联性。COSMOS TNFi-IR参与者的IL-6，IL-10，IL-17A，IL-17F，IL-22，TNFα和IFNɣ的基线血清水平明显高于匹配的健康对照组。基线IL-6，CRP和SAA水平与基线DAS28-CRP相关。IL-17A和IL-17F水平与基线PASI分数和银屑病BSA相关。基线肿胀或触痛关节计数与基线生物标志物水平无关。在第24周，Guselkumab治疗组中基线CRP，SAA，IL-17A，IL-17F和IL-22的水平与治疗安慰剂组有显著下降。Guselkumab治疗组第24周的IL-17F和IL-22水平与匹配的健康对照组无显著差异。在第24周，Guselkumab治疗组达到ACR20反应的参与者与非反应者相比，基线IL-22和IFNɣ水平较高。COSMOS活动性，TNFi-IR PsA参与者的结果表明，Guselkumab降低了与IL-23/IL-17途径相关的效应细胞因子水平，包括与基线关节炎和皮肤病活动相关的因子。ClinicalTrials.gov：NCT03796858。©2023. BioMed Central Ltd.,其中的一部分属于Springer Nature。

Guselkumab is a selective interleukin (IL)-23 inhibitor targeting the IL-23p19 subunit. In the phase 3b COSMOS trial, guselkumab demonstrated efficacy in treating participants with active psoriatic arthritis (PsA) and inadequate response (IR; lack of efficacy or intolerance) to tumor necrosis factor inhibitors (TNFi).Adults with active PsA (≥ 3 swollen joints,  ≥ 3 tender joints) and IR to one or two TNFi (TNFi-IR) were randomized 2:1 to guselkumab at Weeks 0, 4, then every 8 weeks (Q8W) or placebo➔guselkumab Q8W at Week 24 with possible early escape at Week 16. Levels of serum cytokines, including interferon ɣ (IFNɣ), IL-10, and tumor necrosis factor α (TNFα); T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22; and acute phase proteins C-reactive protein (CRP), IL-6, and serum amyloid A (SAA), were assessed and compared with matched healthy controls; guselkumab pharmacodynamics through Week 24 were also assessed. Associations between baseline biomarker levels and 1) baseline disease activity (28-joint disease activity score using CRP [DAS28-CRP], psoriasis area and severity index [PASI], and % body surface area [BSA] affected by psoriasis) and 2) clinical response (including  ≥ 20% improvement in American College of Rheumatology criteria [ACR20] response) at Week 24 were assessed.Baseline serum levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNɣ were significantly higher in COSMOS TNFi-IR participants than in matched healthy controls. Baseline IL-6, CRP, and SAA levels were associated with baseline DAS28-CRP. IL-17A and IL-17F levels were associated with baseline PASI score and psoriasis BSA. Baseline swollen or tender joint counts did not associate with baseline biomarker levels. At Week 24, significant decreases from baseline in CRP, SAA, IL-17A, IL-17F, and IL-22 levels were seen in guselkumab, but not placebo-, treated participants. IL-17F and IL-22 levels at Week 24 in guselkumab-treated participants did not significantly differ from those of matched healthy controls. Guselkumab-treated participants achieving ACR20 response at Week 24 exhibited higher baseline IL-22 and IFNɣ levels versus nonresponders.Results from COSMOS participants with active, TNFi-IR PsA suggest guselkumab reduces levels of effector cytokines associated with the IL-23/IL-17 pathway, including those associated with baseline arthritis and skin disease activity.ClinicalTrials.gov: NCT03796858.© 2023. BioMed Central Ltd., part of Springer Nature.