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Early systemic inflammation induces neurodevelopmental disorders: results from ARTEMIS, a French multicenter study of juvenile rheumatisms and systemic autoimmune and auto-inflammatory disorders and meta-analysis

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Abstract

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, [I2 = 66%, Tau2 = 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.

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Fig. 1: Different neurodevelopmental scores depending on the subtype of juvenile idiopathic arthritis.
Fig. 2: Early age of onset and delayed initiation of background treatment disrupts the neurodevelopmental trajectory.
Fig. 3: Flow chart.
Fig. 4: Results of the meta-analysis for the association between jRSAID and NDD.

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Acknowledgements

The authors warmly thank Camille Aupiais and Charlène Da Silveira for their precious help in the inclusion of the patients.

Funding

The authors received funding from DM’UP (Robert Debré).

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Author notes

  1. These authors contributed equally: Pierre Ellul, Isabelle Melki.

Authors and Affiliations

  1. Excellence Centre for Autism & Neuro-developmental Disorders, Department of Child and Adolescent Psychiatry, Robert Debré Hospital, APHP, Paris Cité University, Paris, France

    Pierre Ellul, Stephanie Antoun, Laura Lavialle, Eric Acquaviva, Hugo Peyre & Richard Delorme

  2. Inflammation-Immunopathology-Biotherapy Department (i2B), AP-HP, Pitié-Salpêtrière Hospital, Paris, and Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université, INSERM, Paris, France

    Pierre Ellul, Michelle Rosenzwajg, Nicolas Tchitchek & David Klatzmann

  3. Reference Center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France

    Pierre Ellul, Isabelle Melki, Florence A. Aeschlimann, Brigitte Bader-Meunier, Glory Dingulu, Cecile Dumaine, Albert Faye, Marie-Louise Frémond, Ulrich Meinzer, Pierre Quartier, Isabelle Savioz & Caroline Vinit

  4. General Pediatrics, Infectious Disease and Internal Medicine Department, Hôpital Robert Debre, AP-HP, Paris Cité University Paris, Paris, France

    Isabelle Melki, Glory Dingulu, Cecile Dumaine, Albert Faye, Ulrich Meinzer, Isabelle Savioz & Caroline Vinit

  5. Université Paris Cité, Inserm UMR 1163, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France

    Isabelle Melki & Marie-Louise Frémond

  6. Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris Cité University, Paris, France

    Isabelle Melki, Florence A. Aeschlimann, Brigitte Bader-Meunier, Marie-Louise Frémond & Pierre Quartier

  7. Pediatric Nephrology, Rheumatology, Dermatology Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 Bd Pinel, 68677, Lyon, Bron Cedex, France

    Alexandre Belot

  8. Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France

    Richard Delorme

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Contributions

PE and IM: have designed the ARTEMIS study, did the statistics, and wrote the first draft of the article. IM, FA, BBM, AB, GD, CD, AF, MLF, UM, PQ, IS, CV: inclusion of ARTEMIS patients. LL: extracted the data of the patients included in ARTEMIS and participated in the first statistical analyses. NT: Supervision of ARTEMIS statistical analysis. PE and SA: Searched the studies for the meta-analysis, extracted the data, and did the statistics. HP: helped for meta-analysis statistics. RD and DK: Overall supervision and guidance of the whole article. All authors contributed significantly to the proofreading and improvement of the first draft. All authors confirm that they had full access to all the data and accept responsibility to submit for publication.

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Correspondence to Pierre Ellul.

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Ellul, P., Melki, I., Antoun, S. et al. Early systemic inflammation induces neurodevelopmental disorders: results from ARTEMIS, a French multicenter study of juvenile rheumatisms and systemic autoimmune and auto-inflammatory disorders and meta-analysis. Mol Psychiatry 28, 1516–1526 (2023). https://doi.org/10.1038/s41380-023-01980-w

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