Rapid and Sustained Improvement in Bone and Cartilage Turnover Markers With the Anti-Interleukin-6 Receptor Inhibitor Tocilizumab Plus Methotrexate in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate Results From a Substudy of the Multicenter Double-Blind, Placebo-Controlled Trial of Tocilizumab in Inadequate Responders to Methotrexate Alone
Rapid and Sustained Improvement in Bone and Cartilage Turnover Markers With the Anti-Interleukin-6 Receptor Inhibitor Tocilizumab Plus Methotrexate in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate Results From a Substudy of the Multicenter Double-Blind, Placebo-Controlled Trial of Tocilizumab in Inadequate Responders to Methotrexate Alone
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DOI：
10.1002/art.25053
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发表时间：
2010-01-01
影响因子：
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通讯作者：
Smolen, Josef S.
中科院分区：
文献类型：
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作者：
Garnero, Patrick;Thompson, Elizabeth;Smolen, Josef S.
Objective.在多中心、双盲、安慰剂对照OPTION（甲氨蝶呤应答不充分的托珠单抗治疗试验）研究中，研究托珠单抗（TCZ）加稳定剂量的甲氨蝶呤（MTX）对中重度类风湿关节炎（RA）和对MTX应答不充分的患者骨和软骨代谢生化标志物的影响。本研究纳入了OPTION研究入组的623例活动性RA患者中的416例。患者随机接受TCZ（4 mg/kg或8 mg/kg）或安慰剂静脉注射，每4周一次，MTX继续以稳定的研究前剂量（10-25 mg，持续20周，最终随访时间为第24周）。骨形成的血清生化标志物（骨钙素，I型胶原的N-末端前肽[PINP]），骨吸收（I型胶原的C-末端交联端肽[CTX-I]和基质金属蛋白酶[ICTP]产生的I型胶原的C-末端交联端肽），软骨代谢在基线和第4、16、17、18、19、1 24.结果TCZ在第4周诱导PIIANP、HELIX-II和MMP-3水平的显著剂量依赖性降低，并维持至第24周，这种效应与骨形成标志物水平的增加相关，与安慰剂相比，仅对PINP和仅在第4周显著（两种TCZ剂量均P < 0.01）。TCZ诱导骨降解标志物CTX-I和ICTP显著降低，提供了对骨转换有益作用的初步证据。与ACR 50无应答者相比，在第24周达到美国流变学会50%改善标准（达到ACR 50应答）或达到临床缓解（根据28个关节疾病活动性评分< 2.6确定）的TCZ治疗患者ICTP、HELIX-II和MMP-3水平降低更大。TCZ联合MTX可降低全身性骨吸收、软骨更新和蛋白水解酶MMP-3水平，这提供了证据，
Objective. To investigate the effects of tocilizumab (TCZ) added to a stable dosage of methotrexate (MTX) on biochemical markers of bone and cartilage metabolism in patients in the multicenter double-blind, placebo-controlled OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to MTX.Methods. Included in this study were 416 of the 623 patients with active RA enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or 8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable prestudy doses (10-25 mg for 20 weeks, with a final followup at week 24). Serum biochemical markers of bone formation (osteocalcin, N-terminal propeptide of type I collagen [PINP]), bone resorption (C-terminal crosslinking telopeptide of type I collagen [CTX-I] and C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N-terminal propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX-II]), and matrix metalloproteinase 3 (MMP-3) were measured at baseline and at weeks 4, 16, and 24.Results. TCZ induced marked dose-dependent reductions in PIIANP, HELIX-II, and MMP-3 levels at week 4 that were maintained until week 24, an effect associated with increased levels of bone formation markers that were significant as compared with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ induced significant decreases in the bone degradation markers CTX-I and ICTP, providing initial evidence of a beneficial effect on bone turnover. TCZ-treated patients who met the American College of Rheumatology 50% improvement criteria (achieved an ACR50 response) or achieved clinical remission (as determined by a Disease Activity Score in 28 joints < 2.6) at week 24 had greater reductions in ICTP, HELIX-II, and MMP-3 levels as compared with ACR50 nonresponders.Conclusion. TCZ combined with MTX reduces systemic bone resorption, cartilage turnover, and proteolytic enzyme MMP-3 levels, which provides evidence