Kirkham Bruce, Chaabo Khaldoun, Hall Christopher, Garrood Toby, Mant Timothy, Allen Elizabeth, Vincent Alexandra, Vasconcelos Joana C, Prevost Andrew T, Panayi Gabriel S, Corrigall Valerie M
Department of Rheumatology, Guys and St Thomas' NHS Foundation Trust Hospital.
Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London.
Rheumatology (Oxford). 2016 Nov;55(11):1993-2000. doi: 10.1093/rheumatology/kew287. Epub 2016 Aug 7.
Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum-resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers.
Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg. Patients received a single i.v. infusion over 1 h and were observed as inpatients overnight. A 12-week follow-up for clinical, rheumatological and laboratory assessments for safety, efficacy (DAS28-ESR) and biomarker analysis was performed.
No infusion reactions or serious adverse drug reactions were noted. Adverse events were evenly distributed between placebo and BiP groups with no BiP-related toxicities. Haematological, renal and metabolic parameters showed no drug-related toxicities. Remission was only achieved by patients in the 5 and 15 mg groups, and not patients who received placebo or 1 mg BiP. Good DAS28-ESR responses were achieved in all treatment groups. The BiP responding patients showed significantly lower serum concentrations of CRP, 2 weeks post-infusion compared with pre-infusion levels, and of VEGF and IL-8 from the placebo group.
BiP (⩽15 mg) is safe in patients with active RA. Some patients had clinical and biological improvements in RA activity. BiP merits further study.
ISRCTN registry, http://isrctn.com, ISRCTN22288225 and EudraCT, https://eudract.ema.europa.eu, 2011-005831-19.
结合免疫球蛋白蛋白（BiP）是一种驻留于人类内质网的应激蛋白。在临床前研究中，它因诱导调节性细胞而具有抗炎特性。这项针对接受过常规治疗但失败的活动性类风湿关节炎（RA）患者开展的BiP随机、安慰剂对照、剂量递增双盲I/IIA期试验，主要目的是评估安全性。通过DAS28-ESR和生物标志物变化来衡量潜在疗效。
24例接受过一种或多种改善病情抗风湿药（DMARDs）治疗但失败的活动性RA患者，依次被分为三组，每组8例，随机分配接受安慰剂（2例患者）或BiP（6例患者），剂量分别为1、5或15毫克。患者接受1小时的单次静脉输注，并作为住院患者过夜观察。进行为期12周的随访，对安全性、疗效（DAS28-ESR）和生物标志物分析进行临床、风湿病学和实验室评估。
未观察到输注反应或严重药物不良反应。不良事件在安慰剂组和BiP组中分布均匀，未出现与BiP相关的毒性反应。血液学、肾脏和代谢参数均未显示出与药物相关的毒性。仅5毫克组和15毫克组的患者实现了病情缓解，接受安慰剂或1毫克BiP的患者未实现缓解。所有治疗组的DAS28-ESR反应均良好。与输注前水平相比，BiP反应患者在输注后2周时血清CRP浓度显著降低，且与安慰剂组相比，VEGF和IL-8浓度也较低。
BiP（≤15毫克）对活动性RA患者安全。部分患者的RA活动度在临床和生物学方面有所改善。BiP值得进一步研究。
ISRCTN注册库，http://isrctn.com，ISRCTN22288225；以及欧盟临床试验注册库，https://eudract.ema.europa.eu，2011-005831-19。
