Network meta-analysis on efficacy and safety of different biological agents in treatment of rheumatoid arthritis

doi:10.12307/2024.587

Abstract

Abstract: OBJECTIVE: There are many kinds of biological agents for the treatment of rheumatoid arthritis in clinic, but the differences in therapeutic efficacy and safety are still unclear. The purpose of this study is to compare the differences in effectiveness and safety of different biological agents for the treatment of rheumatoid arthritis.
METHODS: CNKI, VIP, WanFang, China Biomedical Literature System, PubMed, Cochrane Library, Web of Science, and Embase databases were searched to collect the randomized controlled trials on biological agents for rheumatoid arthritis that meet the requirements from inception to October 1, 2022. The literature was selected by EndNote software, and the quality of the included literature was evaluated by RevMan 5.3 software. The software Stata 14.2 was used for direct meta-analysis and network meta-analysis of ACR20 (American College of Rheumatology 20% response), ACR50 (American College of Rheumatology 50% response), ACR70 (American College of Rheumatology 70% response), erythrocyte sedimentation rate, and adverse reactions.
RESULTS: Totally 39 articles were included, including 5 low-risk articles, 4 high-risk articles, and the remaining 30 articles contained unknown risk bias, with a total of 13 treatment measures. The results of network meta-analysis: (1) In ACR20, infliximab combined with methotrexate (OR=5.54, 95%CI: 1.33-23.01, P < 0.05), abatacept+methotrexate tablets (OR=3.21, 95%CI: 1.13-9.10, P < 0.05), and tocilizumab (OR=2.95, 95%CI: 1.61-5.44, P < 0.05) were better than methotrexate tablets. The probabilistic ranking of ACR20 was: infliximab+methotrexate tablets > abatacept+methotrexate tablets > tocilizumab > certlizumab > etanercept+methotrexate tablets. (2) In the aspect of ACR50, etanercept combined with methotrexate tablets (OR=4.04, 95%CI: 2.13-7.66, P < 0.05), infliximab combined with methotrexate tablets (OR=4.79, 95%CI: 1.19-19.26, P < 0.05), and tocilizumab combined with methotrexate tablets (OR=3.54, 95%CI: 1.36-9.22, P < 0.05) had better therapeutic effects than methotrexate tablets. The probabilistic ranking of ACR50 was: etanercept+methotrexate tablets > infliximab+methotrexate tablets > tocilizumab+methotrexate tablets > tocilizumab > certlizumab+methotrexate tablets. (3) In terms of ACR70, the therapeutic effects of infliximab combined with methotrexate tablets (OR=8.00, 95%CI: 2.31-27.69, P < 0.05), etanercept combined with methotrexate tablets (OR=4.26, 95%CI: 2.51-7.21, P < 0.05), and tocilizumab combined with methotrexate tablets (OR=3.51, 95%CI:1.82-6.80, P < 0.05) were better than methotrexate tablets. The probabilistic ranking of ACR70 was infliximab+methotrexate tablets > etanercept+methotrexate tablets > tocilizumab+methotrexate tablets > certlizumab > adalimumab+methotrexate tablets. (4) In erythrocyte sedimentation rate, etanercept combined with methotrexate tablets (SMD=-9.23, 95%CI: -16.55 to -1.92, P < 0.05) was better than etanercept and methotrexate tablets (SMD=14.59, 95%CI: 7.28-21.91, P < 0.05). The probabilistic ranking of erythrocyte sedimentation rate was etanercept+methotrexate tablets > infliximab+methotrexate tablets > etanercept > adalimumab+methotrexate tablets > methotrexate tablets. (5) In terms of adverse reactions, placebo (OR=0.62, 95%CI: 0.39-0.99, P < 0.05) was better than infliximab and certlizumab (OR=0.44, 95%CI: 0.25-0.78, P < 0.05). The probabilistic ranking of adverse reactions was placebo > infliximab > etanercept+methotrexate tablets > certlizumab > etanercept.
CONCLUSION: Based on evidence from 39 randomized controlled trials, infliximab combined with methotrexate tablets (highly recommended) can be the first choice in clinic, and etanercept combined with methotrexate tablets (highly recommended) can be the second choice in terms of good effectiveness and safety.

Key words: biological agent, rheumatoid arthritis, entanercept, infliximab, methotrexate tablets, tocilizumab, adalimumab, certlizumab, abatacept, network meta-analysis

CLC Number:

Jia Hongsheng, Wang Fan, Chen Chun, Sun Bo, Fang Shengqi. Network meta-analysis on efficacy and safety of different biological agents in treatment of rheumatoid arthritis[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(29): 4748-4756.

Figures/Tables 14

2.4.4 红细胞沉降率指标直接Meta分析及一致性检验结果运用直接Meta分析及亚组分析对各研究间异质性进行分析，结果显示，整体I2=6.5%，P > 0.05，提示各临床研究间一致性良好，故在固定效应模型下进行分析。红细胞沉降率直接Meta分析结果显示：依那西普、依那西普+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片治疗措施效果优于甲氨蝶呤片，差异有显著性意义(P < 0.05)，阿达木单抗+甲氨蝶呤片措施与甲氨蝶呤片措施之间无显著差异(P > 0.05)，依那西普+甲氨蝶呤片治疗措施效果优于依那西普(P < 0.05)。对纳入研究进行不一致性检验，结果显示P=0.059 4，P > 0.05说明研究数据一致性良好；并运用节点分裂法进行局部的一致性检验，检验结果P > 0.05，显示研究间具有一致性，故在一致性模型下进行网状Meta分析。并对闭环进行一致性检验，闭环IF=13.24，95%CI：0.00-27.00，检验结果显示一致性良好。 2.4.5 不良反应指标直接Meta分析及一致性检验结果运用直接Meta分析及亚组分析对各研究间异质性进行分析，结果显示，整体I2=42.9%，P > 0.05，提示各临床研究间一致性良好，故在固定效应模型下进行分析。不良反应指标直接Meta 分析结果显示：依那西普措施不良反应发生情况优于甲氨蝶呤片，差异有显著性意义(P < 0.05)，依那西普+甲氨蝶呤片、托珠单抗、英夫利昔单抗+甲氨蝶呤片、阿达木单抗+甲氨蝶呤片、阿巴西普+甲氨蝶呤片治疗措施不良反应发生情况与甲氨蝶呤片措施无显著差异(P > 0.05)，甲氨蝶呤片措施在不良反应发生情况方面优于培塞利珠单抗+甲氨蝶呤片(P < 0.05)，依那西普+甲氨蝶呤片措施在不良反应发生情况方面优于依那西普(P < 0.05)，托珠单抗+甲氨蝶呤片措施与英夫利昔单抗+甲氨蝶呤片措施无显著差异(P > 0.05)，托珠单抗+甲氨蝶呤片，英夫利昔单抗，阿达木单抗，培塞利珠单抗措施在不良反应发生情况方面不如安慰剂安全，差异有显著性意义。对文献进行一致性检验，P=0.210，P > 0.05,研究间无明显异质性，对局部进行节点分裂法进行不一致性检验，结果显示P > 0.05，无明显异质性，故在一致性模型下进行网状分析。对闭环依那西普-依那西普+甲氨蝶呤片-甲氨蝶呤片进行不一致性检验，IF=1.96，95%CI：0.67-3.25，结果显示一致性良好。 2.5 结局指标两两比较结果 2.5.1 ACR20指标在改善病情达到ACR20方面：与安慰剂措施相比，依那西普+甲氨蝶呤片和甲氨蝶呤片治疗效果与其无显著差异，剩余治疗措施治疗效果优于安慰剂；与依那西普相比，依那西普+甲氨蝶呤片、托珠单抗、托珠单抗+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片、阿巴西普+甲氨蝶呤片的治疗效果优于依那西普，其他治疗措施治疗效果与其无显著差异；与甲氨蝶呤片相比，英夫利昔单抗、阿达木单抗、阿达木单抗+甲氨蝶呤片、培塞利珠单抗的效果与其无显著差异，其他治疗措施治疗效果明显优于甲氨蝶呤片；依那西普+甲氨蝶呤片、托珠单抗、托珠单抗+甲氨蝶呤片、英夫利昔单抗、英夫利昔单抗+甲氨蝶呤片、阿达木单抗、阿达木单抗+甲氨蝶呤片、培塞利珠单抗、培塞利珠单抗+甲氨蝶呤片、阿巴西普+甲氨蝶呤片之间，除了英夫利昔单抗+甲氨蝶呤片、托珠单抗的治疗效果优于阿达木单抗，其他治疗措施之间无显著差异。由此可见，不同生物制剂间的疗效差距不明显，联合用药的效果要优于单独用药。 2.5.2 ACR50指标在改善病情达到ACR50方面：与安慰剂措施相比，除英夫利昔单抗治疗效果无区别外，其他治疗措施治疗效果均优于安慰剂。与英夫利昔单抗相比，依那西普+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片、托珠单抗+甲氨蝶呤片措施治疗效果优于英夫利昔单抗，其他治疗措施效果同英夫利昔单抗无显著差异。与甲氨蝶呤片相比，依那西普、阿达木单抗、培塞利珠单抗、阿巴西普+甲氨蝶呤片治疗效果同甲氨蝶呤片无显著差异，安慰剂差于甲氨蝶呤片、剩余治疗措施均优于甲氨蝶呤片。与阿达木单抗相比，依那西普+甲氨蝶呤片、托珠单抗、托珠单抗+甲氨蝶呤片，英夫利昔单抗+甲氨蝶呤片、培塞利珠单抗+甲氨蝶呤片、阿达木单抗+甲氨蝶呤片的治疗效果优于阿达木单抗，阿达木单抗优于安慰剂，剩余治疗措施同阿达木单抗无显著差异。依那西普、依那西普+甲氨蝶呤片、托珠单抗、托珠单抗+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片、阿达木单抗+甲氨蝶呤片、培塞利珠单抗、培塞利珠单抗+甲氨蝶呤片、阿巴西普+甲氨蝶呤片治疗措施之间比较，依那西普+甲氨蝶呤片优于依那西普，剩余措施均无显著差异。由此可见，不同生物制剂间的疗效差异不显著，联合用药的效果要优于单独用药。 2.5.3 ACR70指标在改善病情达到ACR70方面：与安慰剂措施相比，英夫利昔单抗、阿达木单抗、培塞利珠单抗、甲氨蝶呤片治疗效果与安慰剂无显著差异，剩余治疗措施治疗效果均好于安慰剂。与甲氨蝶呤片相比，英夫利昔单抗、阿达木单抗、培塞利珠单抗，安慰剂与甲氨蝶呤片无显著差异，剩余治疗措施效果优于甲氨蝶呤片。与英夫利昔单抗相比，依那西普+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片治疗措施效果优于英夫利昔单抗，剩余治疗措施与英夫利昔单抗无显著差异。与阿达木单抗相比，依那西普、英夫利昔单抗、培塞利珠单抗、阿巴西普+甲氨蝶呤片、甲氨蝶呤片、安慰剂治疗效果同阿达木单抗无显著差异，依那西普+甲氨蝶呤片、托珠单抗、托珠单抗+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片、阿达木单抗+甲氨蝶呤片、培塞利珠单抗+甲氨蝶呤片治疗措施优于阿达木单抗。依那西普、依那西普+甲氨蝶呤片、托珠单抗+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片、阿达木单抗、阿达木单抗+甲氨蝶呤片、培塞利珠单抗、培塞利珠单抗+甲氨蝶呤片、阿巴西普+甲氨蝶呤片治疗措施之间比较，依那西普+甲氨蝶呤片优于依那西普和阿巴西普+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片优于阿巴西普+甲氨蝶呤片，剩余治疗措施的治疗效果无显著差异。由此可见，不同生物制剂间的疗效差异不显著，联合用药的效果要优于单独用药。 2.5.4 红细胞沉降率指标在改善红细胞沉降率指标方面：依那西普、依那西普+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片、阿达木单抗+甲氨蝶呤片、甲氨蝶呤片措施之间比较，依那西普+甲氨蝶呤片措施优于依那西普和甲氨蝶呤片，剩余措施间治疗效果无显著差异。 2.5.5 不良反应指标两两比较结果在不良反应发生情况方面：与安慰剂措施相比，安慰剂措施的不良反应发生情况好于托珠单抗+甲氨蝶呤片，英夫利昔单抗，阿达木单抗治疗措施，剩余治疗措施同安慰剂无显著差异。与英夫利昔单抗相比，安慰剂措施优于英夫利昔单抗措施，英夫利昔单抗措施优于托珠单抗+甲氨蝶呤片、阿达木单抗措施，剩余治疗措施同英夫利昔单抗无显著差异。与依那西普+甲氨蝶呤片措施相比，依那西普+甲氨蝶呤片措施优于培塞利珠单抗+甲氨蝶呤片措施，剩余治疗措施同依那西普+甲氨蝶呤片措施无显著差异。依那西普、托珠单抗、托珠单抗+甲氨蝶呤片、英夫利昔单抗+甲氨蝶呤片、阿达木单抗、阿达木单抗+甲氨蝶呤片、培塞利珠单抗、培塞利珠单抗+甲氨蝶呤片、阿巴西普+甲氨蝶呤片、甲氨蝶呤片治疗措施间不良反应发生情况无显著差异。由此可知，不同生物制剂治疗类风湿性关节炎的不良反应发生情况没有明显差异。 2.6 结局指标网状Meta分析SUCRA 排序结果 2.6.1 ACR20指标不同生物制剂改善ACR20的排序结果，见图8，英夫利昔单抗+甲氨蝶呤片(88.1%)>阿巴西普+甲氨蝶呤片(75.5%)>托珠单抗(75.4%)>培塞利珠单抗(69.9%)>依那西普+甲氨蝶呤片(68.7%)>托珠单抗+甲氨蝶呤片(68.1%)>培塞利珠单抗+甲氨蝶呤片(54.0%)>阿达木单抗+甲氨蝶呤片(51.7%)>英夫利昔单抗(29.4%)>阿达木单抗(28.4%)>甲氨蝶呤片(23.9%)>依那西普(15.2%)>安慰剂(1.9%)。由此可知，生物制剂联合用药在临床应用时可作为首选应用以提高疗效。"

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