The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus kinase 1–dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase–PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3⁺/CD8⁺ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus kinase 1 for signal transduction.

IL-23 / T辅助17型细胞轴是牛皮癣的靶标。TYK2 / Janus激酶1抑制剂PF-06700841将在表达这些信号分子的细胞（包括T细胞和角质形成细胞）中直接抑制TYK2依赖性IL-12和IL-23信号以及Janus激酶1依赖性信号。这项临床研究试图确定PF-06700841改善银屑病临床表现的炎症基因和细胞途径。中度至重度银屑病患者（n = 30）被随机分配为每日一次30 mg（n = 14）或100 mg（n = 7）PF-06700841或安慰剂（n = 9），持续28天。在基线，第2周和第4周从非病变和病变皮肤进行活检。使用微阵列分析和逆转录酶-PCR评估了牛皮癣转录组和角质形成细胞中IL-17诱导的基因的变化。早在2周时就观察到IL-17A，IL-17F和IL-12B mRNA的降低，并且在4周后病变基因表达正常化了约70％。免疫组化显示角质形成细胞活化，表皮厚度，KRT16和Ki-67表达以及免疫细胞浸润CD3的标志物明显减少治疗2周后⁺ / CD8 ⁺（T细胞）和CD11c（树突状细胞），与组织学评分改善相对应。PF-06700841通过抑制需要TYK2和Janus激酶1进行信号转导的促炎细胞因子来改善慢性斑块状牛皮癣的临床症状。