Dörner Thomas, Tanaka Yoshiya, Dow Ernst R, Koch Alisa E, Silk Maria, Ross Terres Jorge A, Sims Jonathan T, Sun Zhe, de la Torre Inmaculada, Petri Michelle
Department of Medicine and Department of Rheumatology and Clinical Immunology, Charite Universitatsmedizin Berlin and Deutsches Rheumaforschungszentrum (DRFZ), Berlin, Germany
First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Ann Rheum Dis. 2022 Aug 11;81(9):1267-1272. doi: 10.1136/annrheumdis-2022-222335.
To elucidate the mechanism of action of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, and describe immunological pathways related to disease activity in adults with systemic lupus erythematosus (SLE) receiving standard background therapy in a phase II trial.
Patients with SLE were treated with baricitinib 2 mg or 4 mg in a phase II randomised, placebo-controlled study. Sera from 239 patients (baricitinib 2 mg: n=88; baricitinib 4 mg: n=82; placebo: n=69) and 49 healthy controls (HCs) were collected at baseline and week 12 and analysed using a proximity extension assay (Target 96 Inflammation Panel (Olink)). Interferon (IFN) scores were determined using an mRNA panel. Analytes were compared in patients with SLE versus HCs and in changes from baseline at week 12 between baricitinib 2 mg, 4 mg and placebo groups using a restricted maximum likelihood-based mixed models for repeated measures. Spearman correlations were computed for analytes and clinical measurements.
At baseline, SLE sera had strong cytokine dysregulation relative to HC sera. C-C motif chemokine ligand (CCL) 19, C-X-C motif chemokine ligand (CXCL) 10, tumour necrosis factor alpha (TNF-α), TNF receptor superfamily member (TNFRSF)9/CD137, PD-L1, IL-6 and IL-12β were significantly reduced in patients treated with baricitinib 4 mg versus placebo at week 12. Inflammatory biomarkers indicated correlations/associations with type I IFN (CCL19, CXCL10, TNF-α and PD-L1), anti-double stranded DNA (dsDNA) (TNF-α, CXCL10) and Systemic Lupus Erythematosus Disease Activity Index-2000, tender and swollen joint count and worst joint pain (CCL19, IL-6 and TNFRSF9/CD137).
These results suggest that baricitinib 4 mg downregulated key cytokines that are upregulated in patients with SLE and may play a role in a multitargeted mechanism beyond the IFN signature although clinical relevance remains to be further delineated.
NCT02708095.
在一项II期试验中，阐明巴瑞替尼（一种Janus激酶（JAK）1/2抑制剂）的作用机制，并描述接受标准背景治疗的系统性红斑狼疮（SLE）成年患者中与疾病活动相关的免疫途径。
在一项II期随机、安慰剂对照研究中，SLE患者接受2毫克或4毫克巴瑞替尼治疗。在基线和第12周收集了239例患者（巴瑞替尼2毫克组：n = 88；巴瑞替尼4毫克组：n = 82；安慰剂组：n = 69）和49名健康对照者（HCs）的血清，并使用邻位延伸分析（Target 96炎症检测板（Olink））进行分析。使用mRNA检测板确定干扰素（IFN）评分。使用基于限制最大似然的重复测量混合模型，比较SLE患者与HCs之间以及巴瑞替尼2毫克、4毫克和安慰剂组在第12周时相对于基线的变化中的分析物。计算分析物与临床测量值之间的Spearman相关性。
在基线时，与HC血清相比，SLE血清存在明显的细胞因子失调。在第12周时，与安慰剂相比，接受4毫克巴瑞替尼治疗的患者中，C-C基序趋化因子配体（CCL）19、C-X-C基序趋化因子配体（CXCL）10、肿瘤坏死因子α（TNF-α）、肿瘤坏死因子受体超家族成员（TNFRSF）9/CD137、程序性死亡配体1（PD-L1）、白细胞介素6（IL-6）和白细胞介素12β显著降低。炎症生物标志物表明与I型干扰素（CCL19、CXCL10、TNF-α和PD-L1）、抗双链DNA（dsDNA）（TNF-α、CXCL10）以及系统性红斑狼疮疾病活动指数-2000、压痛和肿胀关节计数以及最严重关节疼痛（CCL19、IL-6和TNFRSF9/CD137）存在相关性。
这些结果表明，4毫克巴瑞替尼下调了SLE患者中上调的关键细胞因子，并且可能在超越IFN特征的多靶点机制中发挥作用，尽管其临床相关性仍有待进一步阐明。
NCT02708095。
