Excellence Centre for Autism & Neuro-developmental Disorders, Department of Child and Adolescent Psychiatry, Robert Debré Hospital, APHP, Paris Cité University, Paris, France.
Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP, Pitié-Salpêtrière Hospital, Paris, and Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université, INSERM, Paris, France.
Mol Psychiatry. 2023 Apr;28(4):1516-1526. doi: 10.1038/s41380-023-01980-w. Epub 2023 Feb 6.
Prenatal immune-mediated events are known risk factors for neurodevelopmental disorders in the offspring (NDD). Although the brain continues to develop for years after birth and many postnatal factors alter the regular trajectory of neurodevelopment, little is known about the impact of postnatal immune factors. To fill this gap we set up ARTEMIS, a cohort of juvenile rheumatisms and systemic autoimmune and auto-inflammatory disorders (jRSAID), and assessed their neurodevelopment. We then complemented our results with a systematic review and meta-analysis. In ARTEMIS, we used unsupervised and supervised analysis to determine the influence of jRSAID age at onset (AO) and delay in introduction of disease-modifying therapy (DMT) on NDD (NCT04814862). For the meta-analysis, we searched MEDLINE, EMBASE, PsycINFO, Cochrane, and Web of Science up to April 2022 without any restrictions on language, or article type for studies investigating the co-occurence of jRSAID and NDD (PROSPERO- CRD42020150346). 195 patients were included in ARTEMIS. Classification tree isolated 3 groups of patients (i) A low-risk group (AO > 130 months (m)) with 5% of NDD (ii) A medium-risk group (AO < 130 m and DMT < 2 m) with 20% of NDD (iii) and a high-risk-group (AO < 130 m and DMT > 2 m) with almost half of NDD. For the meta-analysis, 18 studies encompassing a total of (i) 46,267 children with jRSAID; 213,930 children with NDD, and 6,213,778 children as controls were included. We found a positive association between jRSAID and NDD with an OR = 1.44 [95% CI 1.31; 1.57] p < 0.0001, [I = 66%, Tau = 0.0067, p < 0.01]. Several sensitivity analyses were performed without changing the results. Metaregression confirmed the importance of AO (p = 0.005). Our study supports the association between jRSAID and NDD. AO and DMT have pivotal roles in the risk of developing NDD. We plead for systematic screening of NDD in jRSAID to prevent the functional impact of NDD.
产前免疫介导的事件是后代神经发育障碍（NDD）的已知风险因素。尽管大脑在出生后仍会继续发育多年，并且许多产后因素会改变神经发育的正常轨迹，但对于产后免疫因素的影响知之甚少。为了填补这一空白，我们建立了一个幼年特发性关节炎和全身自身免疫性和自身炎症性疾病（jRSAID）队列，并评估了他们的神经发育情况。然后，我们通过系统综述和荟萃分析补充了我们的结果。在 ARTEMIS 中，我们使用无监督和监督分析来确定 jRSAID 发病年龄（AO）和疾病修饰治疗（DMT）引入延迟对 NDD 的影响（NCT04814862）。对于荟萃分析，我们在 MEDLINE、EMBASE、PsycINFO、Cochrane 和 Web of Science 中进行了搜索，截至 2022 年 4 月，没有任何语言或文章类型的限制，以调查 jRSAID 和 NDD 同时发生的研究（PROSPERO-CRD42020150346）。ARTEMIS 纳入了 195 名患者。分类树分离出三组患者：（i）低风险组（AO＞130 个月（m）），NDD 发生率为 5%；（ii）中风险组（AO＜130 m 和 DMT＜2 m），NDD 发生率为 20%；（iii）高风险组（AO＜130 m 和 DMT＞2 m），NDD 发生率接近一半。对于荟萃分析，共纳入 18 项研究，其中包括（i）46267 名患有 jRSAID 的儿童；213930 名患有 NDD 的儿童和 6213778 名作为对照的儿童。我们发现 jRSAID 和 NDD 之间存在正相关，OR=1.44[95%CI 1.31；1.57]，p＜0.0001，[I=66%，Tau=0.0067，p＜0.01]。进行了几次敏感性分析，但结果没有改变。元回归证实了 AO 的重要性（p=0.005）。我们的研究支持 jRSAID 和 NDD 之间的关联。AO 和 DMT 在发生 NDD 的风险中起着关键作用。我们呼吁系统筛查 jRSAID 中的 NDD，以防止 NDD 的功能影响。
