不同剂量司库奇尤单抗治疗中、重度强直性脊柱炎疗效与安全性的Meta分析

Therapeutic Efficacy and Safety of Different Doses of Secukinumab in the Treatment of Medium and Severe Ankylosing Spondylitis:A Meta-analysis

目的:系统评价不同剂量司库奇尤单抗治疗中、重度强直性脊柱炎(AS)的疗效与安全性,为临床治疗AS提供循证参考。方法:计算机检索Medline、PubMed、Cochrane图书馆、Embase、中文科技期刊数据库、中国期刊全文数据库、万方数据库以及ClinicalTrials.gov,检索时限为各数据库建库起至2020年3月。收集不同剂量(75、150、300 mg)司库奇尤单抗(试验组)对比安慰剂(对照组)治疗中、重度AS的随机对照试验(RCT)。对符合纳入标准的临床研究进行资料提取,并采用Cochrane风险偏倚评估工具5.1.0进行质量评价后,采用Rev Man 5.3统计软件对司库奇尤单抗治疗AS的疗效[在国际社会脊椎关节炎评估标准量表中改善了20%的患者所占比例(ASAS20);ASAS40;与AS相关的6个常规临床领域中,至少5个领域的评分改善≥20%、其余领域没有恶化的患者所占比例(ASAS5/6);从基线到16周时的Bath强直性脊柱炎疾病活动指数(BASDAI)缓解值;规定时间内在4个ASAS领域中国际社会脊椎关节炎评估标准量表得分≤2分的患者所占比例(ASAS PR)]与安全性[因不良反应撤出治疗发生率、严重不良反应发生率、一般不良反应(鼻咽炎、头痛、腹泻)发生率]进行Meta分析。结果:共纳入5项RCT,合计1624例患者。Meta分析结果显示,试验组患者ASAS20[总体:OR=2.62,95%C(I2.14,3.20),P<0.00001;75 mg:OR=2.63,95%C(I1.28,5.40),P=0.008;150 mg:OR=2.58,95%CI(2.01,3.32),P<0.00001;300 mg:OR=2.63,95%CI(1.37,5.06),P=0.004]、ASAS40[总体:OR=2.82,95%CI(2.13,3.74),P<0.00001;75 mg:OR=3.14,95%CI(1.86,5.31),P<0.0001;150 mg:OR=2.79,95%CI(1.85,4.20),P<0.00001;300 mg:OR=2.73,95%C(I1.33,5.58),P=0.006]、ASAS5/6[总体:OR=3.82,95%C(I2.61,5.59),P<0.00001;75 mg:OR=5.59,95%C(I3.29,9.49),P<0.00001;150 mg:OR=3.45,95%C(I2.08,5.70),P<0.00001;300 mg:OR=3.85,95%CI(1.75,8.47),P=0.0008]、ASAS PR[总体:OR=4.69,95%C(I3.07,7.16),P<0.00001;75 mg:OR=5.48,95%C(I2.50,11.99),P<0.0001;150 mg:OR=3.71,95%CI(2.19,6.29),P<0.00001;300 mg:OR=20.0,95%CI(2.58,155.14),P=0.004]均显著高于对照组,BASDAI缓解值[总体:WMD=-1.15,95%CI(-1.50,-0.79),P<0.00001;75 mg:WMD=-1.40,95%CI(-2.08,-0.72),P<0.0001;150 mg:WMD=-1.03,95%CI(-1.52,-0.54),P<0.0001;300 mg:WMD=-1.20,95%CI(-2.03,-0.37),P=0.005]显著大于对照组,差异均有统计学意义。试验组患者总体[OR=1.77,95%CI(1.22,2.57),P=0.003]以及150 mg剂量亚组[OR=1.84,95%CI(1.18,2.86),P=0.007]的鼻咽炎发生率显著高于对照组,其他安全性指标总体及各剂量下比较差异均无统计学意义(P>0.05)。结论:75、150、300 mg的司库奇尤单抗治疗中、重度AS的疗效和安全性均较好,但150 mg可能会增加鼻咽炎的发生率。

OBJECTIVE:To evaluate therapeutic efficacy and safety of different doses of Secukinumab in the treatment of medium and severe ankylosing spondylitis(AS),and to provide evidence-based reference for clinical treatment of AS.METHODS:Retrieved from Medline,PubMed,Cochrane Library,Embase,VIP,CJFD,Wanfang database and ClinicalTrials.gov,during the inception to March 2020,randomized controlled trials(RCTs)about different doses of secukinumab(75,150,300 mg)versus placebo in the treatment of medium and severe AS were collected.After data extraction of clinical studies met the inclusion criteria,quality evaluation with Cochrane risk bias evaluation tool 5.1.0,Rev Man5.3 statistical software was used for Meta-analysis of therapeutic efficacy[in the international society for the evaluation of spondyloarthritis scale,the proportion of 20%patients improved(ASAS20);ASAS40;among 6 routine clinical areas related to AS,the scores of at least 5 areas improved by at least 20%,and there was no patients receiving treatment due to deterioration in other areas(ASAS 5/6);remission value of Bath ankylosing spondylitis disease activity index(BASDAI)from baseline to 16 th week,the proportion of the patients with the international society for the evaluation of ankylosing spondyloarthritis(ASAS PR)score no higher than 2 in the 4 ASAS fields within the specified time]and safety[the incidence of withdrawal from treatment due to ADR,the incidence of serious ADR,the incidence of general ADR(nasopharyngitis,headache,diarrhea)].RESULTS:A total of 5 RCTs were included,involving 1624 patients.Meta-analysis showed that ASAS20[total:OR=2.62,95%CI(2.14,3.20),P<0.00001;75 mg:OR=2.63,95%CI(1.28,5.40),P=0.008;150 mg:OR=2.58,95%CI(2.01,3.32),P<0.00001;300 mg:OR=2.63,95%CI(1.37,5.06),P=0.004],ASAS40[total:OR=2.82,95%CI(2.13,3.74),P<0.00001;75 mg:OR=3.14,95%CI(1.86,5.31),P<0.0001;150 mg:OR=2.79,95%CI(1.85,4.20),P<0.00001;300 mg:OR=2.73,95%CI(1.33,5.58),P=0.006],ASAS5/6[total:OR=3.82,95%CI(2.61,5.59),P<0.00001;75 mg:OR=5.59,95%CI(3.29,9.49),P<0.00001;150 mg:OR=3.45,95%CI(2.08,5.70),P<0.00001;300 mg:OR=3.85,95%CI(1.75,8.47),P=0.0008],ASAS PR[total:OR=4.69,95%CI(3.07,7.16),P<0.00001;75 mg:OR=5.48,95%CI(2.50,11.99),P<0.0001;150 mg:OR=3.71,95%CI(2.19,6.29),P<0.00001;300 mg:OR=20.0,95%CI(2.58,155.14),P=0.004]in trial group was significantly higher than control group;BASDAI improvement[total:WMD=-1.15,95%CI(-1.50,-0.79),P<0.00001;75 mg:WMD=-1.40,95%CI(-2.08,-0.72),P<0.0001;150 mg:WMD=-1.03,95%CI(-1.52,-0.54),P<0.0001;300 mg:WMD=-1.20,95%CI(-2.03,-0.37),P=0.005]of trial group were significantly higher than those of control group,with statistical significance.The total incidence of nasopharyngitis in trial group[OR=1.77,95%CI(1.22,2.57),P=0.003]and 150 mg dose subgroup[OR=1.84,95%CI(1.18,2.86),P=0.007]was significantly higher than control group,without significant difference in other safety indexes among total and different dose subgroups(P>0.05).CONCLUSIONS:75 mg,150 mg and 300 mg of secukinumab are all effective and well tolerated for medium and severe AS patients,and 150 mg of secukinumab may increase the incidence of nasopharyngitis.