The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.
The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.
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JAK抑制剂tofacitinib抑制类风湿关节炎中的滑膜JAK1-STAT信号传导。
DOI：
10.1136/annrheumdis-2014-206028
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发表时间：
2015-06
影响因子：
27.4
通讯作者：
Firestein GS
中科院分区：
文献类型：
--
作者：
Boyle DL;Soma K;Hodge J;Kavanaugh A;Mandel D;Mease P;Shurmur R;Singhal AK;Wei N;Rosengren S;Kaplan I;Krishnaswami S;Luo Z;Bradley J;Firestein GS
托法替尼是一种口服Janus激酶（JAK）抑制剂，用于治疗类风湿性关节炎（RA）。受托法替尼影响的途径和对原位基因表达的影响尚不清楚。因此，研究了托法替尼对滑膜病理学的影响。一项在甲氨蝶呤应答不足的RA患者中进行的随机、双盲、II期连续滑膜活检研究（A3921073; NCT 00976599）。接受甲氨蝶呤背景治疗的患者接受托法替布10 mg每日2次或安慰剂治疗28天。 在第-7天和第28天进行滑膜活检，并通过免疫测定或定量PCR进行分析。在A3921073第28天和长期扩展研究（A3921024; NCT 00413699）第3个月，通过疾病活动评分和欧洲抗风湿联盟（EULAR）应答确定临床应答。第28天，托法替尼暴露导致EULAR中度至良好缓解（11/14例患者），而安慰剂无效（1/14例患者）。托法替尼治疗显著降低了基质金属蛋白酶（MMP）-1和MMP-3（p<0.05）以及趋化因子CCL 2、CXCL 10和CXCL 13（p<0.05）的滑膜mRNA表达。未观察到滑液炎症评分或T细胞、B细胞或巨噬细胞的存在的总体变化。滑膜信号转导和转录激活因子1（STAT 1）和STAT 3磷酸化的变化与4个月的临床反应密切相关（p<0.002）。与安慰剂相比，托法替尼在第28天显著降低血浆CXCL 10（p<0.005）。托法替尼降低类风湿滑膜中金属蛋白酶和干扰素调节的基因表达，临床改善与STAT 1和STAT 3磷酸化的降低相关。JAK 1介导的干扰素和白细胞介素-6信号可能在滑膜反应中起关键作用。NCT 00976599。
Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. NCT00976599.
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滑膜组织对利妥昔单抗的反应：作用机理和反应生物标志物的鉴定。
影响因子：
27.4
作者：
Thurlings, R. M.;Vos, K.;Wijbrandts, C. A.;Zwinderman, A. H.;Gerlag, D. M.;Tak, P. P.
通讯作者：
Tak, P. P.
影响因子：
27.4
作者：
Buch MH;Boyle DL;Rosengren S;Saleem B;Reece RJ;Rhodes LA;Radjenovic A;English A;Tang H;Vratsanos G;O'Connor P;Firestein GS;Emery P
通讯作者：
Emery P
影响因子：
158.5
作者：
van Vollenhoven, Ronald F.;Fleischmann, Roy;Wilkinson, Bethanie
通讯作者：
Wilkinson, Bethanie
影响因子：
27.4
作者：
Simelyte, E;Boyle, DL;Firestein, GS
通讯作者：
Firestein, GS
DOI：
10.4049/jimmunol.1200310
发表时间：
2012-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Pattison MJ;Mackenzie KF;Arthur JS
通讯作者：
Arthur JS