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Abstract：
OBJECTIVE: Neuropsychiatric (NP) events are found in patients with rheumatic diseases, commonly in systemic lupus erythematosus (SLE) and Sjögren\'s syndrome (SS). The standard nomenclature and case definitions for 19 NPSLE syndromes by the American College of Rheumatology (ACR) Committee on Research cover a wide range of NP events seen in both SLE and SS. Despite advances in the understanding of SLE and SS, NP syndromes continue to pose diagnostic challenges. Correct attribution of NP events is critical in determining the correct treatment and prognosis. Anti-N-methyl-d-aspartate receptor subunits NR2A/B (anti-NR2A/B) antibodies have been demonstrated in the sera of SLE and SS patients and have been associated with collective or specific NP syndromes, though not consistently. Interpretation of anti-NR2A/B antibody data in the medical literature is rendered difficult by small sample size of patient groups. By combining different studies to generate a pooled effect size, a meta-analysis can increase the power to detect differences in the presence or absence of NP syndromes. Hence, we set out to perform a meta-analysis to assess the association between anti-NR2A/B antibodies and NP syndromes in SLE and SS.
METHODS: A literature search was conducted using PubMed and other databases from inception to June 2016. We abstracted data relating to anti-NR2A/B antibodies from the identified studies. The random effects model was used to calculate overall combined odds ratio (OD) with its corresponding 95% confidence interval (CI) to evaluate the relationship between anti-NR2A/B antibodies and NP syndromes in SLE and SS patients with and without NP events. We also included our own cohort of 57 SLE patients fulfilling the ACR 1997 revised classification criteria and 58 healthy controls (HCs).
RESULTS: In total, 17 studies with data on anti-NR2A/B antibodies in 2212 SLE patients, 66 SS patients, 99 disease controls (DCs) (e.g. antiphospholipid syndrome, myasthenia gravis and autoimmune polyendocrine syndrome I) and 538 HCs were used in this analysis. Overall pooled prevalence of serum/plasma anti-NR2A/B antibodies was higher in SLE patients [24.6% (95% CI 18.5-32.0%)] and SS patients [19.7% (95% CI 11.8-31.0%)] compared to DCs [14.8% (95% CI 2.2-56.9)] and HCs [7.6% (95% CI 4.6-12.4%)] (p=0.001). There was a significantly greater proportion of SLE and SS patients with NP syndromes who demonstrated positivity for serum/plasma anti-NR2A/B antibody [pooled OR=1.607 (95% CI 1.041-2.479), p=0.032] as compared to SLE and SS patients without NP syndromes in 13 studies. Usable data for cerebrospinal fluid anti-NR2A/B antibodies were available in only 4 studies [pooled OR=0.831 (95% CI 0.365-1.888), p=0.658]. Among the 19 NP syndromes, serum/plasma anti-NR2A/B antibodies were not specifically associated with any NP syndrome, including cognitive dysfunction (p=0.259) and mood disorder (p=0.503). Meta-regression identified proportion of anti-double-stranded deoxyribonucleic acid antibody positivity (p=0.009) and SLE Disease Activity Index (p=0.028) as moderators for the heterogeneity of serum/plasma anti-NR2A/B antibodies.
CONCLUSIONS: Circulating anti-NR2A/B antibody testing has a diagnostic value for NP syndromes in SLE and SS collectively. However, the evidence to date suggests that anti-NR2A/B antibody positivity cannot distinguish specific NP syndromes.
METHODS: A literature search was conducted using PubMed and other databases from inception to June 2016. We abstracted data relating to anti-NR2A/B antibodies from the identified studies. The random effects model was used to calculate overall combined odds ratio (OD) with its corresponding 95% confidence interval (CI) to evaluate the relationship between anti-NR2A/B antibodies and NP syndromes in SLE and SS patients with and without NP events. We also included our own cohort of 57 SLE patients fulfilling the ACR 1997 revised classification criteria and 58 healthy controls (HCs).
RESULTS: In total, 17 studies with data on anti-NR2A/B antibodies in 2212 SLE patients, 66 SS patients, 99 disease controls (DCs) (e.g. antiphospholipid syndrome, myasthenia gravis and autoimmune polyendocrine syndrome I) and 538 HCs were used in this analysis. Overall pooled prevalence of serum/plasma anti-NR2A/B antibodies was higher in SLE patients [24.6% (95% CI 18.5-32.0%)] and SS patients [19.7% (95% CI 11.8-31.0%)] compared to DCs [14.8% (95% CI 2.2-56.9)] and HCs [7.6% (95% CI 4.6-12.4%)] (p=0.001). There was a significantly greater proportion of SLE and SS patients with NP syndromes who demonstrated positivity for serum/plasma anti-NR2A/B antibody [pooled OR=1.607 (95% CI 1.041-2.479), p=0.032] as compared to SLE and SS patients without NP syndromes in 13 studies. Usable data for cerebrospinal fluid anti-NR2A/B antibodies were available in only 4 studies [pooled OR=0.831 (95% CI 0.365-1.888), p=0.658]. Among the 19 NP syndromes, serum/plasma anti-NR2A/B antibodies were not specifically associated with any NP syndrome, including cognitive dysfunction (p=0.259) and mood disorder (p=0.503). Meta-regression identified proportion of anti-double-stranded deoxyribonucleic acid antibody positivity (p=0.009) and SLE Disease Activity Index (p=0.028) as moderators for the heterogeneity of serum/plasma anti-NR2A/B antibodies.
CONCLUSIONS: Circulating anti-NR2A/B antibody testing has a diagnostic value for NP syndromes in SLE and SS collectively. However, the evidence to date suggests that anti-NR2A/B antibody positivity cannot distinguish specific NP syndromes.
摘要：
目的：风湿性疾病患者出现神经精神（NP）事件，常见于系统性红斑狼疮（SLE）和干燥综合征（SS）。美国风湿病学会（ACR）研究委员会对19种NPSLE综合征的标准命名法和病例定义涵盖了SLE和SS中广泛的NP事件。尽管对SLE和SS的理解有所进步，NP综合征继续提出诊断挑战。NP事件的正确归因对于确定正确的治疗和预后至关重要。抗N-甲基-d-天冬氨酸受体亚基NR2A/B（抗NR2A/B）抗体已在SLE和SS患者的血清中得到证实，并与集体或特定的NP综合征相关，虽然不一致。医学文献中抗NR2A/B抗体数据的解释由于患者组的小样本量而变得困难。通过组合不同的研究来产生一个汇集效应的大小，荟萃分析可以提高检测是否存在NP综合征差异的能力.因此，我们着手进行荟萃分析,以评估SLE和SS中抗NR2A/B抗体与NP综合征之间的关联.
方法：从开始到2016年6月，使用PubMed和其他数据库进行了文献检索。我们从鉴定的研究中提取了与抗NR2A/B抗体相关的数据。随机效应模型用于计算总组合比值比（OD）及其相应的95％置信区间（CI），以评估有或没有NP事件的SLE和SS患者抗NR2A/B抗体与NP综合征之间的关系。我们还纳入了我们自己的57名符合ACR1997修订分类标准的SLE患者和58名健康对照(HCs)的队列。
结果：总计，关于2212例SLE患者的抗NR2A/B抗体的17项研究，66例SS患者，99个疾病对照（DC）（例如抗磷脂综合征，本分析使用重症肌无力和自身免疫性多内分泌综合征I）和538例HC。与DC[14.8%(95%CI2.2-56.9)]和HC[7.6%(95%CI4.6-12.4%)]相比,SLE患者[24.6%(95%CI18.5-32.0%)]和SS患者[19.7%(95%CI11.8-31.0%)]的血清/血浆抗NR2A/B抗体总体汇集患病率较高(p=0.001)。患有NP综合征的SLE和SS患者中，血清/血浆抗NR2A/B抗体阳性的比例明显更高[合并OR=1.607（95％CI1.041-2.479），与13项研究中没有NP综合征的SLE和SS患者相比，p=0.032]。脑脊液抗NR2A/B抗体的可用数据仅在4项研究中可用[合并OR=0.831（95％CI0.365-1.888），p=0.658]。在19个NP综合征中，血清/血浆抗NR2A/B抗体与任何NP综合征均无特异性相关，包括认知功能障碍(p=0.259)和情绪障碍(p=0.503)。Meta回归确定抗双链脱氧核糖核酸抗体阳性比例（p=0.009）和SLE疾病活动指数（p=0.028）作为血清/血浆抗NR2A/B抗体异质性的调节因子。
结论：循环抗NR2A/B抗体检测对SLE和SS共同的NP综合征具有诊断价值。然而,迄今为止的证据表明,抗NR2A/B抗体阳性不能区分特定的NP综合征.
方法：从开始到2016年6月，使用PubMed和其他数据库进行了文献检索。我们从鉴定的研究中提取了与抗NR2A/B抗体相关的数据。随机效应模型用于计算总组合比值比（OD）及其相应的95％置信区间（CI），以评估有或没有NP事件的SLE和SS患者抗NR2A/B抗体与NP综合征之间的关系。我们还纳入了我们自己的57名符合ACR1997修订分类标准的SLE患者和58名健康对照(HCs)的队列。
结果：总计，关于2212例SLE患者的抗NR2A/B抗体的17项研究，66例SS患者，99个疾病对照（DC）（例如抗磷脂综合征，本分析使用重症肌无力和自身免疫性多内分泌综合征I）和538例HC。与DC[14.8%(95%CI2.2-56.9)]和HC[7.6%(95%CI4.6-12.4%)]相比,SLE患者[24.6%(95%CI18.5-32.0%)]和SS患者[19.7%(95%CI11.8-31.0%)]的血清/血浆抗NR2A/B抗体总体汇集患病率较高(p=0.001)。患有NP综合征的SLE和SS患者中，血清/血浆抗NR2A/B抗体阳性的比例明显更高[合并OR=1.607（95％CI1.041-2.479），与13项研究中没有NP综合征的SLE和SS患者相比，p=0.032]。脑脊液抗NR2A/B抗体的可用数据仅在4项研究中可用[合并OR=0.831（95％CI0.365-1.888），p=0.658]。在19个NP综合征中，血清/血浆抗NR2A/B抗体与任何NP综合征均无特异性相关，包括认知功能障碍(p=0.259)和情绪障碍(p=0.503)。Meta回归确定抗双链脱氧核糖核酸抗体阳性比例（p=0.009）和SLE疾病活动指数（p=0.028）作为血清/血浆抗NR2A/B抗体异质性的调节因子。
结论：循环抗NR2A/B抗体检测对SLE和SS共同的NP综合征具有诊断价值。然而,迄今为止的证据表明,抗NR2A/B抗体阳性不能区分特定的NP综合征.
