Diagnostic value of IP-10 in rheumatoid arthritis: a systematic review and Meta-analysis
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摘要:
目的 分析类风湿关节炎(rheumatoid arthritis, RA)中干扰素诱导蛋白10(interferon-inducible protein 10, IP-10)表达水平的变化，评估其在RA中的诊断价值及与疾病活动的相关性。 方法 通过电子文献检索，在Cochrane图书馆、Scopus和PubMed数据库(截至2020年9月16日)搜索相关的文献，采用诊断准确性研究的质量评估工具2(quality assessment of diagnostic accuracy studies-2, QUADAS-2)对文献进行评价，并进行定量、综合分析。 结果 最终纳入文献17篇，RA患者IP-10表达水平高于健康对照(healthy control, HC)[标准化均数差(standard mean difference, SMD)=0.93, 95% CI : 0.51~1.35]。此外，IP-10表达水平在RA与骨关节炎(osteoarthritis, OA)中也存在差异(SMD=3.84, 95% CI: 0.76~6.92)，但在RA和系统性红斑狼疮(systemic lupus erythematosus, SLE)之间差异无统计学意义。IP-10用于RA诊断的合并诊断比值比(diagnostic odds ratio, DOR)为65.70(95% CI: 1.52~2 844.43)，曲线下面积(area under the curve, AUC)为0.889 6。 结论 IP-10表达水平在RA患者与HC和OA患者之间存在差异，可作为潜在的诊断性生物标志物。 Abstract:Objective We aimed to analyze the changes of interferon-inducible protein 10 (IP-10) in rheumatoid arthritis (RA) and evaluate the diagnostic value of IP-10 in RA and its correlation with disease activity. Methods We collected articles related to our research topic through an electronic literature search from the Cochrane Library, Scopus, and Pubmed (up to Sep16th, 2020). Quality assessment of diagnostic accuracy studies (QUADAS-2) tool was used to assess the quality of collected articles, and quantitative and comprehensive analysis was conducted. Results 17 studies were finally included in this study. IP-10 level in RA patients was higher than health controls [pooled standard mean difference (SMD) = 0.93, 95% CI= 0.51-1.35]. Besides, IP-10 levels in RA patients differed from osteoarthritis (OA) controls, with a pooled SMD and 95% CI being 3.84 (0.76-6.92). We found no significant difference in IP-10 levels between RA patients and systemic lupus erythematosus (SLE) controls. The pooled diagnostic odds ratio (DOR) value for IP-10 to diagnose RA was 65.70 (1.52-2 844.43) and AUC value was 0.899 6. Conclusion IP-10 levels differ from RA patients to HC and OA controls, it may be a potential diagnostic biomarker. -
图 2 QUADAS-2工具对合格文献的质量评价
Figure 2. Quality assessment of eligible literature by QUADAS-2 tool
图 3 12篇RA患者与HC的IP-10表达水平研究的Meta分析
Figure 3. Meta-analysis of 12 studies reporting the IP-10 level in RA compared with HC
图 4 关于RA与OA的IP-10表达水平的4篇文献Meta分析
Figure 4. Meta-analysis of 4 studies reporting the IP-10 level in RA compared with OA
图 5 IP-10试验用于诊断RA的敏感性、特异性、诊断比值比和受试者工作特征曲线森林图
Figure 5. Forest plots of pooled sensitivity, specificity, diagnostic odds ratio and summary receiver operating characteristic curve for IP-10 to diagnose RA
表 1 入选文献的特征描述
Table 1. Feature description of selected literature in research
第一作者(发表年份) 国家 RA HC SLE/OA 诊断标准 样本来源 检测方法 n 年龄(岁) a 女/男 病程(年) a n 年龄(岁) 女/男 n 年龄(岁) a 女/男 病程(年) a Narumi S [10], 2000 日本 12 38.0±10.0 10/2 NA 25 41.0±13.0 21/4 SLE: 28 b Ⅰ: 38.0±10.0 Ⅱ: 40.0±14.0 26/2 NA ACR 血清 ELISA Patel DD 11], 2001 美国 38 NA NA NA - - - - - - - NA 血清/滑膜组织 ELISA 10 NA NA NA - - - OA: 10 NA NA NA ELISA Nishioji K [12], 2001 日本 16 63.8±7.7 15/1 NA 20 46.4±14.4 10/10 - - - - ACR 血清 ELISA Hanaoka R [13], 2003 日本 32 NA NA NA - - - OA: 10 NA NA NA NA 滑膜液 ELISA Ueno A, [14] 2005 日本 20 58.5±12.3 17/3 8.5±6.7 - - - OA: 20 71.5±8.5 13/7 NA ACR 血清 & 滑膜液/滑膜组织 ELISA 10 64.7±9.9 8/2 24.1±7.7 - - - OA: 5 74.0±5.4 3/2 NA ELISA Deane KD [15], 2010 美国 73 39.1±8.4 30/43 NA 73 39.9±10.3 30/43 - - - - ACR 1987 血清 Bead-Based 14-Plex Assay Kuan WP, 2010 [16] 中国 28 49.0±13.0 26/2 7.3±6.0 40 38.0±9.0 39/1 - - - - ACR 1987 血清 Cytometric Bead Array Kåss AS [17], 2010 挪威 20 58.0 (34.0~79.0) 14/6 18.0 (0.3~49.0) 19 56.0 (32.0~79.0) 13/6 - - - - ACR 血清 Bead-Based Fluorescence Immunoassay Shah D [18], 2011 印度 30 24.2±10.4 25/5 4.5±1.5 30 26.7±5.4 27/3 SLE: 30 26.5±7.5 26/4 5.1±2.2 ACR 血清 ELISA Sato M, 2011 [19] 日本 20 60.1±3.2 19/1 10.4±1.9 20 NA NA - - - - ACR 1987 血清 ELISA Eriksson C [20], 2013 瑞典 21 53.4±14.2 6/3 < 1 9 53.2±4.9 6/3 SLE: 3 55.3±11.5 3/0 19.5 (0.5~45) ACR 血清 ELISA Hampel U [21], 2013 德国 16 64.2±12.8 16/5 NA - - - OA: 21 73.1±8.0 14/2 NA NA 滑膜液 9-Plex Chemokine array Dhir V [22], 2014 印度 36 NA NA NA 15 NA NA - - - - NA 血清 ELISA Rodríguez-Carrio J [23], 2017 西班牙 113 53.4 (22.0~87.0) 92/21 NA 113 53.8 (23.1~80.0) 82/31 - - - - ACR/EULAR 2010 血清 ELISA Rico MC [24], 2018 芬兰 20 51.0±8.2 95% NA 13 NA NA - - - - ACR 1987 血浆 Microarray by RCA Imam AM [25], 2019 埃及 60 c Ⅰ: 40.6±12.0 Ⅱ: 45.4±9.2 Ⅰ: 27/3; Ⅱ: 28/2 Ⅰ: 1.3±4.3 Ⅱ: 10.1±7.3 30 42.9±9.3 27/3 - - - - ACR/EULAR 2010 血清 ELISA Muhsin HY [26], 2019 伊拉克 77 46.8±13.2 54/23 NA 79 34.2±9.6 55/24 - - - - ACR/EULAR 2010 血清 ELISA 注：a以(x±s)和中位数(范围)表示数值; bⅠ组为活动期SLE组，Ⅱ组为非活动期SLE组，Ⅰ组为13例，Ⅱ组为15例; cⅠ组为早期RA组，Ⅱ组为长期RA组，两组分别为30例；NA：无法获取，原始文献数据不充分；ACR：美国风湿病学会；EULAR：欧洲风湿病防治联合会；-：原始文献无相应研究。 
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表 2 纳入研究的诊断性研究文献特征
Table 2. Characteristics of diagnostic studies included in the Meta-analysis
作者 年份 国家 RA HC 敏感度(%) 特异度(%) TP TN FP FN 年龄(x±s, 岁) n 年龄(x±s, 岁) n Deane KD [18] 2010 美国 40.00±10.30 73 39.90±10.30 73 56.2 65.8 41 48 25 32 Imam AM [25] 2019 埃及 ER: 40.60±11.99 LR: 45.43±9.17 60 42.87±9.31 30 88.3 90.0 53 27 3 7 Muhsin HY [26] 2019 伊拉克 46.80±13.20 77 34.20±9.60 79 100.0 96.2 77 76 3 0
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表 3 RA和HC的IP-10表达水平亚组分析
Table 3. Subgroup analysis of IP-10 levels in RA and HC
分组 文献数量/研究分支 病人数量(n) SMD(95% CI)值 异质性检验 发表偏倚 I2(%) P值 t值 P值 总体 12/14 453 0.93(0.51~1.35) 87.6 < 0.001 2.11 0.056 样本大小 ≥30 5/6 287 1.08(0.51~1.64) 88.7 < 0.001 6.89 0.055 < 30 8/8 166 0.86(0.08~1.54) 87.8 < 0.001 7.67 0.036 年龄(岁) ≥50 6/7 218 0.74(0.07~1.41) 89.3 < 0.001 3.32 0.315 < 50 5/6 199 1.20(0.71~1.68) 78.5 < 0.001 4.37 0.142 地区 亚洲 4/5 219 0.74(0.13~1.35) 88.1 < 0.001 0.88 0.837 欧洲 7/7 174 1.25(0.31~2.18) 91.4 < 0.001 5.64 0.074 非洲 1/2 60 1.16(0.77~1.55) 注：发表偏倚使用Egger检验结果。
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表 4 RA病例组和对照组的IP-10表达水平
Table 4. IP-10 level in RA and disease control group
文献数量/研究分支 病例数 SMD(95% CI)值 P值 异质性分析 发表偏倚b I2(%) P值 t值 P值 RA与OA的IP-10表达水平 总体 4/5 88 3.84(0.76~6.92) 0.015 96.5 < 0.001 16.26 < 0.001 滑膜液 3/3 68 3.20(-0.99~7.39) 0.134 97.8 < 0.001 16.26 0.102 滑膜组织 2/2 20 4.87(3.48~6.26) < 0.001 0.0 0.065 RA与SLE的IP-10表达水平a 2/3 42 -1.60(-3.36~0.15) 0.074 93.0 < 0.001 注：a两篇文献研究都使用的是血清标本；b发表偏倚采用Egger检验。
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