Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 TARGET study.
Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 TARGET study.
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DOI：
10.1136/rmdopen-2017-000607
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发表时间：
2018
期刊：
影响因子：
6.2
通讯作者：
Boyapati A
中科院分区：
文献类型：
--
作者：
Gabay C;Msihid J;Zilberstein M;Paccard C;Lin Y;Graham NMH;Boyapati A
白细胞介素-6（IL-6）协调炎性血管翳的形成，导致类风湿性关节炎（RA）的关节损伤。Sar是一种阻断IL-6 R α的人单克隆抗体。在TARGET（NCT 01709578）中，一项在对肿瘤坏死因子抑制剂应答不足或不耐受的中重度RA成人中进行的III期研究，与安慰剂+csDMARD相比，皮下注射sar 200 mg或150 mg每2周一次（q2 w）+常规合成疾病缓解抗风湿药物（csDMARD）显著降低了疾病活动性。与滑膜炎症相关的生物标志物的循环水平（基质金属蛋白酶3（MMP-3）、I型胶原MMP裂解片段（C1 M）、III型胶原MMP裂解片段（C3 M））、髓样（可溶性细胞间粘附分子1（sICAM-1）、IL-8和钙卫蛋白）和淋巴激活在来自TARGET子研究的患者中评价了骨重建（趋化因子、CXC基序、配体13（CXCL 13）、CXCL 10、B细胞活化因子）和骨重建（核因子-κ受体活化剂B配体（RANKL）、骨保护素和骨钙素）。与安慰剂相比，Sar在第24周显著降低了C1 M、C3 M、CXCL 13、MMP-3和总RANKL水平;一些标志物在第2周被显著抑制，并正常化至健康对照的水平。sICAM-1水平可预测第12周sar 200 mg q2 w组中C反应蛋白和临床疾病活动指数低疾病活动（LDA）反应的疾病活动评分。观察到一种趋势，即基线时sICAM-1水平较低的患者与sICAM-1水平较高的患者相比，有更好的反应。Sar + csDMARD降低了滑膜炎症和骨吸收的循环生物标志物; sICAM-1可预测Sar达到LDA。NCT 01709578;后结果。
Interleukin-6 (IL-6) orchestrates formation of an inflammatory pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a human monoclonal antibody blocking the IL-6Rα. In TARGET (NCT01709578), a phase 3 study in adults with moderate-to-severe RA and inadequate response or intolerance to tumour necrosis factor inhibitors, subcutaneous sarilumab 200 mg or 150 mg every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) significantly reduced disease activity versus placebo plus csDMARDs. Circulating levels of biomarkers associated with synovial inflammation (matrix metalloproteinase 3 (MMP-3), collagen type I MMP-cleaved fragment (C1M), collagen type III MMP-cleaved fragment (C3M)), myeloid (soluble intercellular adhesion molecule 1 (sICAM-1), IL-8 and calprotectin) and lymphoid activation (chemokine, CXC motif, ligand 13 (CXCL13), CXCL10, B cell-activating factor) and bone remodelling (receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin and osteocalcin) were evaluated in patients from a TARGET substudy. Sarilumab significantly decreased C1M, C3M, CXCL13, MMP-3 and total RANKL levels at week 24 versus placebo; some markers were significantly suppressed at week 2 and normalised to levels in healthy controls. Levels of sICAM-1 were predictive of disease activity score by C-reactive protein and clinical disease activity index low disease activity (LDA) response in the sarilumab 200 mg q2w group at week 12. A trend was observed in which patients with lower sICAM-1 levels at baseline had better response compared with patients with higher sICAM-1. Sarilumab plus csDMARDs decreased circulating biomarkers of synovial inflammation and bone resorption; sICAM-1 was predictive of achieving LDA with sarilumab. NCT01709578; Post-results.
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影响因子：
2.4
作者：
Chastek, Benjamin;Becker, Laura K.;Curtis, Jeffrey R.
通讯作者：
Curtis, Jeffrey R.
影响因子：
4.9
作者：
Koczan D;Drynda S;Hecker M;Drynda A;Guthke R;Kekow J;Thiesen HJ
通讯作者：
Thiesen HJ
影响因子：
3.4
作者：
Yasunori, Kageyama;Masaaki, Takahashi;Akira, Nagano
通讯作者：
Akira, Nagano
影响因子：
27.4
作者：
Huizinga TW;Fleischmann RM;Jasson M;Radin AR;van Adelsberg J;Fiore S;Huang X;Yancopoulos GD;Stahl N;Genovese MC
通讯作者：
Genovese MC
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y