University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Curr Opin Rheumatol. 2012 May;24(3):335-41. doi: 10.1097/BOR.0b013e32835190ef.
Since the introduction of biologic therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small molecule immune modulators would be developed that would have a risk : benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compounds over the past year.
Additional information has become available in the past year on five oral compounds including kinase inhibitors (tofacitinib, fostamatinib, VX-509), an S1P lyase inhibitor (LX 3305) and a chemokine receptor-1 antagonist (CCX354-C). Efficacy has been shown in phase III with tofacitinib and in phase II with fostamatinib and VX-509; safety was the primary endpoint of the trials of CCX354-C and LX3305. Regarding side effects, liver test elevation and neutropenia occurred with tofacitinib, VX-509 and fostamatinib; lipid elevation with tofacitinib and VX-509; creatinine elevation and anemia with tofacitinib, and hypertension and diarrhea with fostamatinib.
Compounds that inhibit tyrosine kinase pathways involved in cellular signalling have been shown to be effective in the treatment of RA with a reasonable risk : benefit ratio. It is too early to tell about inhibitors of other pathways.
自生物制剂被引入类风湿关节炎（RA）的治疗模式以来，人们一直希望开发出具有与生物制剂相似的风险获益比、对患者更方便且价格更低廉的口服小分子免疫调节剂。本文综述了过去一年中这些化合物在开发方面取得的进展。
过去一年，有 5 种口服化合物的更多信息可供参考，包括激酶抑制剂（托法替尼、 fostamatinib、VX-509）、S1P 裂解酶抑制剂（LX 3305）和趋化因子受体-1 拮抗剂（CCX354-C）。托法替尼在 III 期研究中显示出疗效，而 fostamatinib 和 VX-509 在 II 期研究中显示出疗效；CCX354-C 和 LX3305 的试验主要终点是安全性。关于副作用，托法替尼、VX-509 和 fostamatinib 会引起肝试验升高和中性粒细胞减少；托法替尼和 VX-509 会引起血脂升高；托法替尼会引起肌酐升高和贫血，而 fostamatinib 会引起高血压和腹泻。
抑制细胞信号转导中涉及的酪氨酸激酶途径的化合物已被证明在治疗 RA 方面有效，且具有合理的风险获益比。其他途径抑制剂的情况尚不清楚。
