文章信息
- 黄琴, 谢宁, 罗纳川, 韩静霆, 徐文苑
- HUANG Qin, XIE Ning, LUO Nachuan, HAN Jingting, XU Wenyuan
- 粒细胞集落刺激因子和促红细胞生成素单药或联合用药治疗多发性硬化的临床效果分析
- An Evaluation of Individual and Combined Therapy Using Granulocyte-Colony Stimulating Factor and Erythropoietin in Multiple Sclerosis
- 中国医科大学学报, 2019, 48(10): 919-925
- Journal of China Medical University, 2019, 48(10): 919-925
-
文章历史
- 收稿日期:2018-07-12
- 网络出版时间:2019-09-27 14:55
2. 南昌大学第一临床医学院2017级临床医学专业, 南昌 330031
2. 2017 Clinical Medicine, First Clinical Medical College of Nanchang University, Nanchang 330031, China
多发性硬化(multiple sclerosis,MS)是以中枢神经系统白质炎性脱髓鞘病变为主要特点的自身免疫性疾病。MS通过致神经变性作用导致患者不可逆的神经损伤和残疾[1-2]。目前,MS急性期主要采用激素冲击、静脉注射免疫球蛋白和血浆置换治疗,但这些治疗方案复发率均较高。临床上亟需能够有效地降低MS致残率及复发率的治疗途径。
粒细胞集落刺激因子(granulocyte-colony stimulating factor,G-csf)是一种多效细胞生长因子,是先天性免疫反应的激活剂及适应性免疫反应的抑制因子[3],能动员内源性干细胞参与MS的治疗,且安全有效[4]。促红细胞生成素(erythropoietin,EPO)是一种主要由肝脏和肾脏分泌的糖蛋白,在促进骨髓红系祖细胞的增殖和分化中发挥着重要作用,EPO及其衍生物在MS的动物模型中具有巨大的治疗潜力[5-8]。本研究拟探讨G-csf和EPO单药或联合用药治疗MS的临床效果,旨在探索治疗MS的新途径。
1 材料与方法 1.1 研究对象选择南昌大学第一附属医院神经内科2010年5月至2014年5月诊治的60例MS患者,均符合McDonald诊断标准[9]。其中,男20例,女40例,年龄25~55岁,平均(39.1±5.7)岁;病程0.5~4.5年,平均(2.4±0.98)年;全面功能障碍评分(Expanded Disability Status Scale,EDSS)3.0~8.5分,平均(6.43±1.15)分;伴有眼球震颤7例,视力障碍22例,运动功能障碍51例,眼肌麻痹11例,感觉障碍48例,假性球麻痹7例,共济失调10例。所有患者均行MRI检查,均伴有脱髓鞘性改变,大脑半球受累44例,脑干13例,小脑10例,颈髓9例,胸髓18例,腰髓1例,伴视神经损伤8例,均伴有2个以上部位同时受损。本研究获得本院伦理委员会批准,所有入选研究对象均签署知情同意书。
纳入标准:符合McDonald诊断标准;年龄20~55岁。排除标准:合并严重的糖尿病、心脏病、高血压、消化性溃疡、股骨头坏死、肝肾功能不全、血液系统疾病或凝血功能障碍;妊娠、过敏体质者;患有传染病、免疫性疾病、遗传病、恶性肿瘤、脑血管意外;入院前或治疗期间发生严重感染;因各种原因不能应用甲基强的松龙、G-csf和(或)EPO者。
分组:将60例患者随机分为G-csf组、EPO组、G-csf+EPO联合组和对照组,每组15例。各组患者年龄、性别、病程、受累部位、临床症状、辅助检查及治疗前EDSS评分等各项指标均无统计学差异(P > 0.05)(表 1)。
Group | Age(year) | The EDSS score before treatment | Duration of disease(year) | Gender | |
Male | Female | ||||
G-csf group | 36.13±4.78 | 6.43±1.18 | 2.49±1.00 | 5 | 10 |
EPO group | 37.53±3.20 | 6.40±1.02 | 2.62±0.92 | 5 | 10 |
G-csf+EPO group | 36.20±4.18 | 6.53±1.08 | 2.29±0.91 | 5 | 10 |
Control group | 39.00±5.32 | 6.50±1.25 | 2.16±1.10 | 5 | 10 |
1.2 治疗方案及用药
(1)对照组:缓慢静脉滴注甲基强的松龙500 mg/d+0.9%氯化钠500 mL,1次/d,连续5 d,随后改为泼尼松口服,逐渐减量[80 mg/(次·d)×10 d,60 mg/(次·d)×5 d,40 mg/(次·d)×5 d,30 mg/(次·d)× 5 d,20 mg/(次·d)×5 d,10 mg/(次·d)×5 d],直至停药;给予0.9%氯化钠溶液200 mL静脉滴注,3次/周× 4周。(2)G-csf治疗组:在对照组治疗的基础上,给予重组人G-csf 5 μg/(kg·d)前臂三角肌皮下注射,连续应用7 d;给予0.9%氯化钠溶液200 mL静脉滴注,3次/周×4周。每日检查外周血白细胞计数1次。(3)EPO治疗组:在对照组治疗的基础上,静脉滴注1 500 U/kg重组人EPO+0.9%氯化钠溶液200 mL,3次/周×4周,用药当天查外周血常规1次。(4)EPO+G-csf联合组:综合以上3组治疗方法,用药当天查外周血常规1次。
1.3 随访分别于治疗前和治疗后1、7、14、28 d及3、6、12和24个月,对患者进行EDSS评分;于治疗前和治疗后14、28 d及3、6、12和24个月,行头颅MRI(T2WI及增强序列)检查(3.0T,德国柏林西门子公司)。
疗效判断标准:(1)影像学指标,观察头颅MRI(平扫+增强)病灶大小及数量,颅内增强病灶(contrast-enhancing lesions,CELs)数目在注射0.1 mmol/kg钆喷酸葡胺5 min后进行扫描收集;(2)EDSS评分,对患者的神经系统功能(大脑、脑干、小脑、感觉、大小便、视觉、锥体和其他)[10]进行系统的评价。
主要观察指标:(1)血常规(外周血白细胞、红细胞、血红蛋白水平),血液生化,肝功能,肾功能,凝血功能,D-二聚体;(2)血压;(3)药物不良反应,包括发热、皮疹、胃肠道反应、血栓性栓塞事件、肌肉、关节和骨骼疼痛等。
1.4 统计学分析采用SPSS 22.0统计软件进行统计学分析。数据用x±s表示,采用方差分析及t检验进行比较。P < 0.05为差异有统计学意义。
2 结果 2.1 EDSS评分及头颅MRI(T2WI)4组整体分析:EDSS评分及头颅MRI T2WI病灶数目在各组间比较、各测量时间点比较及分组和时间的交互作用均有统计学差异(P < 0.05)。各治疗组与对照组比较,差异有统计学意义(P < 0.05);二者各治疗组间比较,联合组均优于单药治疗组,两两比较差异有统计学意义(P < 0.05),二者在单药治疗组间无差异。组内时间点间精细比较:各治疗组各时间点EDSS评分与治疗前、随访期间时间点与随访前(治疗28 d)比较绝大多数差异有统计学意义(P < 0.007),对照组治疗期间(其中治疗14、28 d后)与治疗前比较差异有统计学意义,随访时间点中治疗后6、12、24个月与治疗前比较其增长值超治疗前,随访各时间点与随访前比较(治疗28 d后),差异有统计学意义(P < 0.007)。各治疗组治疗期间各时间点MRI T2WI与治疗前比较,差异均有统计学意义,随访期间时间点与随访前(治疗28 d后)比较,增长差异有统计学意义(P < 0.008),联合组差异无意义,对照组治疗期间,病灶数目无明显变化,随访期间病灶数目随时间增长逐渐增多,差异有统计学意义(P < 0.008)。见表 2~7。
Time | G-csf group | EPO group | G-csf+EPO group | Control group |
Before treatment | 6.43±1.18 | 6.40±1.02 | 6.53±1.08 | 6.50±1.25 |
7 days after treatment | 5.63±1.14 | 6.13±1.08 | 5.47±1.08 | 6.40±1.24 |
14 days after treatment | 5.27±1.08 | 5.77±1.10 | 4.90±0.97 | 6.23±1.10 |
28 days after treatment | 5.13±0.99 | 5.13±0.93 | 4.20±0.94 | 6.00±1.10 |
3 months after treatment | 5.43±1.07 | 5.30±0.90 | 4.20±0.94 | 6.27±1.10 |
6 months after treatment | 5.70±1.13 | 5.53±1.03 | 4.53±1.14 | 6.63±1.16 |
12 months after treatment | 5.97±1.17 | 5.77±1.07 | 4.63±1.09 | 6.97±0.99 |
24 months after treatment | 6.07±1.27 | 5.93±1.13 | 4.73±1.15 | 7.30±0.86 |
Overall analysis: two-factor repeated measurement analysis of variance(spherical test). Comparison between groups: F = 6.091, P = 0.001. Time point comparison: F = 137.864, P < 0.001, G-G adjustment coefficient: 0.461. Group × time point: F = 26.216, P < 0.001, G-G adjustment coefficient: 0.461. |
Time | Comparison between groups(F, P) | ①vs②(Lsd-t, P) | ①vs③(Lsd-t, P) | ①vs④(Lsd-t, P) | ②vs③(Lsd-t, P) | ②vs④(Lsd-t, P) | ③vs④(Lsd-t, P) |
A | 0.043, 0.988 | 0.08, 0.936 | 0.24, 0.810 | 0.16, 0.873 | 0.32, 0.749 | 0.24, 0.810 | 0.08, 0.936 |
B | 2.181, 0.100 | 1.21, 0.233 | 0.40, 0.689 | 1.85, 0.070 | 1.61, 0.114 | 0.64, 0.523 | 2.25, 0.028 |
C | 4.489, 0.007 | 1.29, 0.203 | 0.94, 0.349 | 2.49, 0.016 | 2.23, 0.030 | 1.20, 0.235 | 3.43, 0.001 |
D | 8.198, < 0.001 | < 0.01, 1.000 | 2.57, 0.013 | 2.39, 0.020 | 2.57, 0.013 | 2.39, 0.020 | 4.96, < 0.001 |
E | 10.684, < 0.001 | 0.36, 0.718 | 3.36, 0.001 | 2.27, 0.027 | 2.99, 0.004 | 2.63, 0.011 | 5.63, < 0.001 |
F | 8.931, < 0.001 | 0.41, 0.684 | 2.87, 0.006 | 2.29, 0.026 | 2.46, 0.017 | 2.70, 0.009 | 5.16, < 0.001 |
G | 11.718, < 0.001 | 0.51, 0.615 | 3.37, 0.001 | 2.53, 0.014 | 2.87, 0.006 | 3.04, 0.004 | 5.90, < 0.001 |
H | 13.365, < 0.001 | 0.33, 0.744 | 3.28, 0.002 | 3.04, 0.004 | 2.96, 0.005 | 3.37, 0.001 | 6.32, < 0.001 |
A, before treatment; B, 7 days after treatment; C, 14 days after treatment; D, 28 days after treatment; E, 3 months after treatment; F, 6 months after treatment; G, 12 months after treatment; H, 24 months after treatment. ①, G-csf group; ②, EPO group; ③, G-csf+EPO group; ④, control group. |
Item | ①(t, P) | ②(t, P) | ③(t, P) | ④(t, P) |
A vs B | 9.798, < 0.001 | 4.000, 0.001 | 16.000, < 0.001 | 1.871, 0.082 |
A vs C | 14.642, < 0.001 | 10.717, < 0.001 | 17.978, < 0.001 | 3.228, 0.006 |
A vs D | 13.667, < 0.001 | 19.000, < 0.001 | 17.270, < 0.001 | 5.916, < 0.001 |
E vs D | 4.583, < 0.001 | 2.646, 0.019 | 3.228, 0.006 | *** |
F vs D | 6.859, < 0.001 | 4.583, < 0.001 | 5.292, < 0.001 | 5.104, < 0.001 |
G vs D | 7.906, < 0.001 | 6.141, < 0.001 | 6.500, < 0.001 | 10.640, < 0.001 |
H vs D | 6.820, < 0.001 | 5.527, < 0.001 | 5.870, < 0.001 | 8.891, < 0.001 |
The significance level α’ of the time point comparison is 0.007. *** means that there is no change in the value before and after the comparison, there is no effective pairing, and t and P cannot be calculated. A, before treatment; B, 7 days after treatment; C, 14 days after treatment; D, 28 days after treatment; E, 3 months after treatment; F, 6 months after treatment; G, 12 months after treatment; H, 24 months after treatment. ①, G-csf group; ②, EPO group; ③, G-csf+EPO group; ④, control group. |
Time | G-csf group | EPO group | G-csf+EPO group | Control group |
Before treatment | 13.20±4.04 | 13.13±4.10 | 12.67±3.35 | 13.07±3.86 |
14 days after treatment | 11.40±3.79 | 11.93±3.53 | 10.40±3.02 | 13.07±3.86 |
28 days after treatment | 9.33±3.31 | 10.00±3.32 | 7.87±2.26 | 13.07±3.86 |
3 months after treatment | 10.27±3.47 | 10.80±3.51 | 7.87±2.26 | 14.27±3.83 |
6 months after treatment | 11.40±3.40 | 11.33±3.56 | 7.87±2.26 | 15.07±3.61 |
12 months after treatment | 12.33±3.42 | 11.93±3.47 | 7.93±2.25 | 15.67±3.83 |
24 months after treatment | 13.60±3.52 | 13.13±3.50 | 8.13±2.47 | 17.13±3.50 |
Overall analysis: two-factor repeated measurement analysis of variance(spherical test). Comparison between groups: F = 6.786, P = 0.001. Time point comparison: F = 137.864, P < 0.001, G-G adjustment coefficient: 0.410. Group × time point: F = 26.216, P < 0.001, G-G adjustment coefficient: 0.410. |
Time | Comparison between groups(F, P) | ① vs ②(Lsd-t, P) | ① vs ③(Lsd-t, P) | ① vs ④(Lsd-t, P) | ② vs ③(Lsd-t, P) | ② vs ④(Lsd-t, P) | ③ vs ④(Lsd-t, P) |
A | 0.058, 0.981 | 0.05, 0.962 | 0.38, 0.706 | 0.09, 0.925 | 0.33, 0.741 | 0.05, 0.962 | 0.28, 0.777 |
B | 1.454, 0.237 | 0.41, 0.684 | 0.77, 0.446 | 1.28, 0.206 | 1.18, 0.244 | 0.87, 0.388 | 2.05, 0.045 |
C | 6.849, 0.001 | 0.56, 0.575 | 1.24, 0.220 | 3.16, 0.003 | 1.80, 0.077 | 2.59, 0.012 | 4.39, < 0.001 |
D | 9.472, < 0.001 | 0.44, 0.662 | 1.98, 0.053 | 3.30, 0.002 | 2.42, 0.019 | 2.86, 0.006 | 5.28, < 0.001 |
E | 12.232, < 0.001 | 0.06, 0.955 | 2.97, 0.004 | 3.08, 0.003 | 2.92, 0.005 | 3.14, 0.003 | 6.06, < 0.001 |
F | 13.847, < 0.001 | 0.33, 0.741 | 3.66, 0.001 | 2.77, 0.008 | 3.32, 0.002 | 3.10, 0.003 | 6.42, < 0.001 |
G | 19.113, < 0.001 | 0.39, 0.698 | 4.56, < 0.001 | 2.95, 0.005 | 4.17, < 0.001 | 3.34, 0.002 | 7.51, < 0.001 |
A, before treatment; B, 14 days after treatment; C, 28 days after treatment; D, 3 months after treatment; E, 6 months after treatment; F, 12 months after treatment; G, 24 months after treatment. ①, G-csf group; ②, EPO group; ③, G-csf+EPO group; ④, control group. |
Item | ①(t, P) | ②(t, P) | ③(t, P) | ④(t, P) |
A vs B | 8.088, < 0.001 | 6.000, < 0.001 | 12.475, < 0.001 | *** |
A vs C | 12.614, < 0.001 | 11.447, < 0.001 | 12.220, < 0.001 | *** |
D vs C | 7.897, < 0.001 | 4.000, < 0.001 | *** | 8.290, < 0.001 |
E vs C | 10.020, < 0.001 | 6.325, < 0.001 | *** | 10.247, < 0.001 |
F vs C | 12.550, < 0.001 | 10.640, < 0.001 | 1.000, 0.334 | 8.107, < 0.001 |
G vs C | 13.514, < 0.001 | 18.963, < 0.001 | 2.256, 0.041 | 11.355, < 0.001 |
The significance level α’ of the time point comparison is 0.008. *** means that there is no change in the value before and after the comparison, there is no effective pairing, and t and P cannot be calculated. A, before treatment; B, 7 days after treatment; C, 28 days after treatment; D, 3 months after treatment; E, 6 months after treatment; F, 12 months after treatment; G, 24 months after treatment. ①, G-csf group; ②, EPO group; ③, G-csf+EPO group; ④, control group. |
2.2 头颅MRI增强病灶
经治疗后,对照组及3个治疗组影像学病灶均消失,随访期间(治疗后3、6、12、24月),各治疗组与对照组比较差异有统计学意义(P < 0.05),各治疗组间比较差异无统计学意义(P > 0.05)。提示G-csf或EPO单药或联合治疗可延缓MS的复发。见表 8~9。
Time | G-csf group | EPO group | G-csf+EPO group | Control group |
Before treatment | 2.00±0.926 | 2.07±0.884 | 2.13±0.915 | 2.27±1.223 |
14 days after treatment | 0 | 0 | 0 | 0 |
28 days after treatment | 0 | 0 | 0 | 0 |
3 months after treatment | 0.07±0.258 | 0.07±0.258 | 0 | 0.07±0.258 |
6 months after treatment | 0.20±0.561 | 0.13±0.352 | 0.07±0.258 | 0.73±0.704 |
12 months after treatment | 0.20±0.561 | 0.13±0.352 | 0 | 1.33±0.816 |
24 months after treatment | 0.27±0.594 | 0.27±0.594 | 0.13±0.352 | 1.07±0.884 |
Time | Comparison between groups(F, P) | ①vs②(Lsd-t, P) | ①vs③(Lsd-t, P) | ①vs④(Lsd-t, P) | ②vs③(Lsd-t, P) | ②vs④(Lsd-t, P) | ③vs④(Lsd-t, P) |
A | 0.196, 0.899 | 0.18, 0.855 | 0.37, 0.715 | 0.73, 0.467 | 0.18, 0.855 | 0.55, 0.585 | 0.37, 0.715 |
D | 0.333, 0.801 | 0, 1 | 0.82, 0.418 | 0, 1 | 0.82, 0.418 | 0, 1 | 0.82, 0.418 |
E | 5.578, 0.002 | 0.37, 0.716 | 0.73, 0.468 | 2.92, 0.005 | 0.37, 0.716 | 3.29, 0.002 | 3.65, 0.001 |
F | 20.658, < 0.001 | 0.35, 0.730 | 1.04, 0.302 | 5.90, < 0.001 | 0.69, 0.490 | 6.25, < 0.001 | 6.95, < 0.001 |
G | 6.793, 0.001 | 0, 1 | 0.58, 0.567 | 3.45, 0.001 | 0.58, 0.567 | 3.45, 0.001 | 4.03, < 0.001 |
A, before treatment; D, 3 months after treatment; E, 6 months after treatment; F, 12 months after treatment; G, 24 months after treatment. ①, G-csf group; ②, EPO group; ③, G-csf+EPO group; ④, control group. |
2.3 不良反应
用药后出现血压轻度增高5例,其中,联合治疗组2例,EPO组3例,停药后自行缓解。所有患者均无发热、皮疹、胃肠道反应、血栓性栓塞事件、骨质疏松、股骨头坏死、肌肉、关节和骨骼疼痛等不良反应。对于使用G-csf的患者,应注意监控外周血白细胞计数,如计数 > 25×109/L,则停药1~2 d观察;对于使用EPO的患者,需注意使血红蛋白≤220 g/L。
3 讨论MS是以中枢神经系统脱髓鞘病变为特点的自身免疫性疾病,目前尚缺乏有效的治疗措施。
本研究在糖皮质激素治疗的基础上加用G-csf及EPO治疗MS,对患者EDSS评分、MRI T2WI+增强序列病变数进行评估及随访,随访周期为24个月。结果显示,G-csf、EPO单药治疗或G-csf联合EPO治疗均能改善患者的EDSS评分,其中以联合治疗组效果最佳;4组治疗后T2WI序列高信号病变数目均减少,且联合治疗组明显优于单药治疗组;单药或联合治疗组MRI增强序列强化的病灶数目均较对照组减少(P < 0.05),但单药组及联合治疗组无统计学差异。但是,在随访期间,4组MRI增强序列显示均有不同数量的复发,以联合治疗组最少,但单药及联合治疗组间差异无统计学意义。
实验性变态反应性脑脊髓炎(experimental allergic encephalomyelitis,EAE)是T细胞介导的中枢神经系统炎性和脱髓鞘性自身免疫性疾病,广泛用于人类MS等脱髓鞘疾病的动物模型[11]。研究[12-14]表明,G-csf和EPO能抑制EAE中枢神经系统的炎症浸润和脱髓鞘病变,且对EAE具有保护作用,G-csf还能刺激内源性神经再生,动员骨髓干细胞入血并迁移入脑,促进神经功能修复,据此笔者推测二者在治疗MS等脱髓鞘疾病中可能有联合作用,故设计了本研究。本研究结果表明,二者联合治疗MS效果明显优于单药治疗。
NAJMI等[15]的随机双盲试验研究中,将EPO与甲泼尼龙(methylprednisolone,MPred)联合用于严重的运动性复发缓解型MS患者,观察到EPO+MPred组MRI T2WI病变数明显减少,治疗2个月后EPO+MPred组通过动态指数(ambulatory index,AI)和EDSS评分观察到最大行走距离明显改善,且这种改善一直持续到治疗后的第三个月。MORANSARD等[16]研究发现,EAE中适度升高的脑内EPO水平具有显著的神经保护作用,而无需调节免疫应答。本研究中,EPO组及联合治疗组在改善EDSS评分及MRI病灶数目方面都取得了较好的结果,再一次验证了EPO的神经保护作用。但其主要作用机制尚不明确,EPO的抗炎症和增强生存信号机制可能发挥了关键作用[5]。
PENG[12]研究发现G-csf通过诱导EAE模型的自身反应性T细胞凋亡,延缓疾病的进展,降低发病的频率及严重程度。其作用机制可能与其作为造血生长因子动员内源性干细胞进入中枢神经系统,促进神经功能恢复,及其抑制炎症及脱髓鞘变化有关,与本研究结果一致。本研究中,G-csf单药及联合EPO治疗组在24个月的随访期间均未出现MS复发。
MRI T1WI、T2WI,特别是增强像,对MS病灶,尤其是新发病灶的诊断意义很大。MRI T2WI病变代表MS的累积性病变,均为永久损伤。正常情况下,造影剂(钆喷酸葡胺)本身不能通过血脑屏障,而MS患者颅内出现增强病灶,提示血脑屏障渗漏[17-18],而血脑屏障渗漏则是MS的特点之一,代表疾病的新发或复发。本研究发现,与对照组相比,单药组及联合治疗组T2WI病灶明显减少,且在24个月的随访期间均并未出现病灶增加,表明EPO及G-csf的作用是长效性的。另外,ZHAO等[19]证实G-csf可以自由渗透血脑屏障,LI等[20]研究发现EPO也能穿过血脑屏障并降低血脑屏障的脱髓鞘和渗透性改变,因此,G-csf和EPO在保护血脑屏障方面具有一定的联合作用,与本研究结果一致。根据以往的研究,推测联合治疗组与单药治疗组在增强病灶方面应有差异,但本研究中并未得出相应的结果,可能与样本量不够大有关,这亦是本研究存在的不足之处。
EPO与G-csf用于治疗MS安全有效。本研究中,除少数患者用药后出现了血压及血细胞计数轻度升高外,无其他不良反应。MORANSARD等[16]也证实了颅内EPO水平只需适度升高即可产生较明显的神经保护效应。
综上所述,本研究将G-csf及EPO联合应用于MS患者的治疗,疗效确定且安全,开辟了一条治疗多发性硬化的新途径,但是二者的作用机制有待进一步研究。
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