. 2023 Apr;43(3):615-624.

doi: 10.1007/s10875-022-01407-1. Epub 2022 Dec 5.

Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers

Mathilde Labouret^{1

2

3}, Stefania Costi⁴, Vincent Bondet⁵, Vincent Trebossen^{6

7}, Enora Le Roux^{8

9}, Alexandra Ntorkou¹⁰, Sophie Bartoli¹, Stéphane Auvin^{11

12

13}, Brigitte Bader-Meunier^{14

15}, Véronique Baudouin¹⁶, Olivier Corseri^{1

2}, Glory Dingulu^{1

2

17}, Camille Ducrocq^{1

2}, Cécile Dumaine^{1

2}, Monique Elmaleh¹⁰, Nicole Fabien¹⁸, Albert Faye^{1

2

7

9}, Isabelle Hau¹⁹, Véronique Hentgen²⁰, Théresa Kwon¹⁶, Ulrich Meinzer^{1

2

7

21

22}, Naim Ouldali^{1

2

7}, Cyrielle Parmentier²³, Marie Pouletty^{1

2}, Florence Renaldo²⁴, Isabelle Savioz^{1

2}, Flore Rozenberg²⁵, Marie-Louise Frémond^{14

26}, Alice Lepelley²⁶, Gillian I Rice²⁷, Luis Seabra²⁶, Jean-François Benoist^{28

29}, Darragh Duffy⁵, Yanick J Crow^{26

30}, Pierre Ellul^#^{6

31}, Isabelle Melki^#^{32

33

34

35}

Affiliations

¹ General Paediatrics, Department of Infectious Disease and Internal Medicine, Robert Debré Mother-Child University Hospital, AP-HP, Paris, France.
² Reference Centre for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Paris, France.
³ Sorbonne Université, Paris, France.
⁴ University of Milan, Milan, Italy.
⁵ Translational Immunology Unit, Institut Pasteur, Université Paris Cité, 75015, Paris, France.
⁶ Department of Child and Adolescent Psychiatry, Robert Debré Mother-Child University Hospital, APHP, Paris, France.
⁷ Université Paris Cité, UFR de Médecine Paris Nord, Paris, France.
⁸ CIC 1426 UEC, Robert Debré Mother-Child University Hospital, APHP, INSERM, Paris, France.
⁹ Université Paris Cité, INSERM, ECEVE, Paris, France.
¹⁰ Department of Paediatric Radiology, Robert Debré Mother-Child University Hospital, APHP, Paris, France.
¹¹ Department of Paediatric Neurology, Center for Rare Epilepsies & Epilepsy Unit, Robert Debré Mother-Child University Hospital, APHP, Paris, France.
¹² Université Paris Cité, INSERM NeuroDiderot, Paris, France.
¹³ Institut Universitaire de France (IUF), Paris, France.
¹⁴ Department of Paediatric Haematology-Immunology and Rheumatology, Necker-Enfants-Malades University Hospital, AP-HP Centre Université Paris Cité, Paris, France.
¹⁵ Laboratory of Immunogenetics of Paediatric Autoimmune Diseases, UMR 1163, Imagine Institute, INSERM, Université Paris Cité, Paris, France.
¹⁶ Department of Paediatric Nephrology, Robert Debré Mother-Child University Hospital, AP-HP, Paris, France.
¹⁷ Department of General Paediatrics, Centre Hospitalier Sud Francilien, 40, Avenue Serge Dassault, 91106 Corbeil-Essonnes Cedex, Paris, France.
¹⁸ Immunology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France.
¹⁹ Department of General Paediatrics, Centre Hospitalier Intercommunal de Créteil, Creteil, France.
²⁰ Department of General Paediatrics, Hospital Centre Versailles, French Reference Centre for Autoinflammatory Diseases and Amyloidosis (CEREMAIA), Versailles Hospital, Le Chesnay, France.
²¹ Center for Research On Inflammation, Université Paris Cité, INSERM, UMR 1149, Paris, France.
²² Biology and Genetics of Bacterial Cell Wall Unit, Pasteur Institute, Paris, France.
²³ Department of Paediatric Nephrology, Armand-Trousseau Childrens' Hospital, APHP, Paris, France.
²⁴ Department of Paediatric Neurology, Center for Neurogenetic Diseases, Armand-Trousseau Childrens' Hospital, APHP, Paris, France.
²⁵ Assistance-Publique Hôpitaux de Paris, Groupe Hospitalier Universitaire Paris Centre, Service de Virologie, Université Paris Cité, 75014, Paris, France.
²⁶ Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Université Paris Cité, INSERM UMR 1163, Paris, France.
²⁷ Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
²⁸ Reference Centre for Inherited Metabolic Diseases, Necker-Enfants-Malades University Hospital, AP-HP, Paris, France.
²⁹ Université Paris Saclay, UFR Pharmacie, Chatenay-Malabry, France.
³⁰ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
³¹ Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université, Paris, France.
³² General Paediatrics, Department of Infectious Disease and Internal Medicine, Robert Debré Mother-Child University Hospital, AP-HP, Paris, France. isabelle.melki@aphp.fr.
³³ Reference Centre for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Paris, France. isabelle.melki@aphp.fr.
³⁴ Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Université Paris Cité, INSERM UMR 1163, Paris, France. isabelle.melki@aphp.fr.
³⁵ Paediatrics, Rheumatology and Paediatric Internal Medicine, Children's Hospital, Bordeaux, France. isabelle.melki@aphp.fr.

^# Contributed equally.

PMID: 36469191
PMCID: PMC9957825
DOI: 10.1007/s10875-022-01407-1

Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers

Mathilde Labouret et al. J Clin Immunol. 2023 Apr.

. 2023 Apr;43(3):615-624.

doi: 10.1007/s10875-022-01407-1. Epub 2022 Dec 5.

Authors

Affiliations

¹ General Paediatrics, Department of Infectious Disease and Internal Medicine, Robert Debré Mother-Child University Hospital, AP-HP, Paris, France.
² Reference Centre for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Paris, France.
³ Sorbonne Université, Paris, France.
⁴ University of Milan, Milan, Italy.
⁵ Translational Immunology Unit, Institut Pasteur, Université Paris Cité, 75015, Paris, France.
⁶ Department of Child and Adolescent Psychiatry, Robert Debré Mother-Child University Hospital, APHP, Paris, France.
⁷ Université Paris Cité, UFR de Médecine Paris Nord, Paris, France.
⁸ CIC 1426 UEC, Robert Debré Mother-Child University Hospital, APHP, INSERM, Paris, France.
⁹ Université Paris Cité, INSERM, ECEVE, Paris, France.
¹⁰ Department of Paediatric Radiology, Robert Debré Mother-Child University Hospital, APHP, Paris, France.
¹¹ Department of Paediatric Neurology, Center for Rare Epilepsies & Epilepsy Unit, Robert Debré Mother-Child University Hospital, APHP, Paris, France.
¹² Université Paris Cité, INSERM NeuroDiderot, Paris, France.
¹³ Institut Universitaire de France (IUF), Paris, France.
¹⁴ Department of Paediatric Haematology-Immunology and Rheumatology, Necker-Enfants-Malades University Hospital, AP-HP Centre Université Paris Cité, Paris, France.
¹⁵ Laboratory of Immunogenetics of Paediatric Autoimmune Diseases, UMR 1163, Imagine Institute, INSERM, Université Paris Cité, Paris, France.
¹⁶ Department of Paediatric Nephrology, Robert Debré Mother-Child University Hospital, AP-HP, Paris, France.
¹⁷ Department of General Paediatrics, Centre Hospitalier Sud Francilien, 40, Avenue Serge Dassault, 91106 Corbeil-Essonnes Cedex, Paris, France.
¹⁸ Immunology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France.
¹⁹ Department of General Paediatrics, Centre Hospitalier Intercommunal de Créteil, Creteil, France.
²⁰ Department of General Paediatrics, Hospital Centre Versailles, French Reference Centre for Autoinflammatory Diseases and Amyloidosis (CEREMAIA), Versailles Hospital, Le Chesnay, France.
²¹ Center for Research On Inflammation, Université Paris Cité, INSERM, UMR 1149, Paris, France.
²² Biology and Genetics of Bacterial Cell Wall Unit, Pasteur Institute, Paris, France.
²³ Department of Paediatric Nephrology, Armand-Trousseau Childrens' Hospital, APHP, Paris, France.
²⁴ Department of Paediatric Neurology, Center for Neurogenetic Diseases, Armand-Trousseau Childrens' Hospital, APHP, Paris, France.
²⁵ Assistance-Publique Hôpitaux de Paris, Groupe Hospitalier Universitaire Paris Centre, Service de Virologie, Université Paris Cité, 75014, Paris, France.
²⁶ Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Université Paris Cité, INSERM UMR 1163, Paris, France.
²⁷ Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
²⁸ Reference Centre for Inherited Metabolic Diseases, Necker-Enfants-Malades University Hospital, AP-HP, Paris, France.
²⁹ Université Paris Saclay, UFR Pharmacie, Chatenay-Malabry, France.
³⁰ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
³¹ Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université, Paris, France.
³² General Paediatrics, Department of Infectious Disease and Internal Medicine, Robert Debré Mother-Child University Hospital, AP-HP, Paris, France. isabelle.melki@aphp.fr.
³³ Reference Centre for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Paris, France. isabelle.melki@aphp.fr.
³⁴ Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Université Paris Cité, INSERM UMR 1163, Paris, France. isabelle.melki@aphp.fr.
³⁵ Paediatrics, Rheumatology and Paediatric Internal Medicine, Children's Hospital, Bordeaux, France. isabelle.melki@aphp.fr.

^# Contributed equally.

PMID: 36469191
PMCID: PMC9957825
DOI: 10.1007/s10875-022-01407-1

Abstract

Introduction: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated.

Objectives: To identify central nervous system (CNS) disease biomarkers of j-NPSLE.

Methods: A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations.

Results: Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (R_s = 0.832, p < 0.0001, n = 23 paired samples).

Conclusion: CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE.

Keywords: Biomarker; Central nervous system; Interferon-alpha; Juvenile systemic lupus erythematosus; Neopterin; Neuropsychiatric.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Comparison of CSF neopterin and IFN-α concentrations in non-NPSLE (j-SLE controls), active and inactive j-NPSLE patients. A Comparison of CSF neopterin concentration assessed by liquid chromatography coupled with mass spectrometry during active j-NPSLE in red (n = 18), inactive j-NPSLE in green (n = 11) and in non-NPSLE patients in blue (j-SLE controls, n = 7). B CSF pan-IFN-α concentration during active j-NPSLE in red (n = 9), inactive j-NPSLE in green (n = 5) and in non-NPSLE patients in blue (j-SLE controls, n = 3). C Correlation of pan-IFN-α measurement with neopterin assessment in the CSF in patients with j-NPSLE (n = 21) and j-SLE without NPSLE (n = 2). Spearman’s correlation was calculated Rs = 0.832, p < 0.0001, n = 23. D Serum pan-IFN-α concentration during active j-NPSLE in red (n = 8), inactive j-NPSLE in green (n = 5) and in non-NPSLE patients in blue (j-SLE controls, n = 3). Median levels are indicated by horizontal black bars, normal levels are indicated by horizontal dotted line. For A, B, D, tests were performed two by two with a Mann–Whitney’s test: the first compared active j-NPSLE and inactive j-NPSLE, the second test compared active j-NPSLE and j-SLE controls. *p < 0.05, ** < 0.01, ***p < 0.001, NS non-significant. CSF cerebrospinal fluid; IFN interferon; j-NPSLE juvenile neuropsychiatric systemic lupus erythematosus; j-SLE juvenile systemic lupus erythematosus; Simoa single-molecule array

**Fig. 2**
Correlation of pan-IFN-α concentrations by Simoa in the CSF and in the serum during active and inactive j-NPSLE, and j-SLE controls. A pan-IFN-α concentration in the CSF and in the serum during active j-NPSLE (8 patients). B pan-IFN-α concentration in the CSF and in the serum during inactive j-NPSLE (5 patients). All serum concentrations were higher than those in the CSF, except for one patient with Aicardi-Goutières syndrome (P8). C pan-IFN-α concentration in the CSF and in the serum during j-SLE controls (3 patients). CSF cerebrospinal fluid; IFN interferon; j-NPSLE juvenile neuropsychiatric systemic lupus erythematosus; j-SLE juvenile systemic lupus erythematosus; Simoa single-molecule array

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Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers

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Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers

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