Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus (jSLE)

Abstract

Systemic lupus erythematosus (SLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Approximately 15-20% of SLE patients develop the disease during childhood or adolescence (juvenile-onset SLE/jSLE). Patients with jSLE exhibit more variable and severe disease when compared to patients with disease-onset during adulthood. Neuropsychiatric (NP) involvement is a clinically heterogenous and potentially severe complication. Published reports on the incidence and prevalence of NP-jSLE are scarce, and the exact pathophysiology is poorly understood.This manuscript provides a review of the existing literature, suggesting NP involvement in 13.5-51% of jSLE patients. Among patients with NP-jSLE affecting the CNS, we propose two main subgroups: (i) a chronic progressive, predominantly type 1 interferon-driven form that poorly responds to currently used treatments, and (ii) an acutely aggressive form that usually presents early during the disease that may be primarily mediated by auto-reactive effector lymphocytes. While this hypothesis requires to be tested in large collaborative international cohort studies, it may offer future patient stratification and individualised care.

Keywords: CNS; Inflammation; Interferon; Juvenile; Lupus; NP-jSLE; Neurologic; Neuropsychiatric; SLE; Treatment; jSLE.

Fig. 1

Immune-mediated neurological disorders in jSLE. A Demyelinating syndrome (DS) in a 15-year-old patient. Transversal MRI images showing increased spotty signals in frontal white matter in Fluid attenuated inversion recovery (FLAIR) sequences. B Myelopathy in a 10-year-old patient. Sagittal MRI with high-signal of the myelin in T2-weighted images. C Guillain-Barré syndrome in a 12-year-old patient. Contrast enhancement of the cauda equina; sagittal T1-weighed images

Fig. 2

Cerebrovascular involvement in jSLE. A Infarction in a 15-year-old patient. Transversal MRI with diffusion disorder in right temporal lobe; DWI sequences. B Vasculitis of the arteria cerebri media with vascular irregularities in MR angiography (MRA)

Fig. 3

Neuromyelitis optica and retinitis in an 8-year-old jSLE patient. A Coronal MRI images showing perineural contrast enhancement of the right optic nerve in T1-weighted sequences (arrow). B Increased T2-weighted signal of the Nervus opticus and reduced signal of the nerve sheath (arrow) representing focal oedema of nerve and optic perineuritis. C Cotton-wool infiltrates resembling retinitis of the right eye in the same patient. The patient failed to respond to treatment with CPM and high-dose corticosteroids and was therefore treated with B cell depletion (rituximab), followed by repeated/cyclic immune-apheresis

Fig. 4

Proposed pathomechanisms of CNS vasculitis in NP-jSLE. Several, likely connected pathways may be involved in the pathogenesis of vasculitis in NP-jSLE. Circulating autoantibodies can recruit to vascular epithelia and/or form immune complexes that contribute to complement activation. Both, antibody binding and the presence of activated complement contribute to endothelial activation that, in turn, mediates the upregulation of adhesion molecules (including intercellular adhesion molecule 1/ICAM1 and vascular cell adhesion molecule 1/VCAM1) and the expression of pro-inflammatory cytokines, including IL-6 and IL-8. As a result, B and T lymphocytes are attracted, adhere to ICAM1/VCAM1 and infiltrate the perivascular region where they produce inflammatory cytokines and B cell survival factors (BAFF/BLys) [49]

Fig. 5

Molecular mechanisms of type 1 interferon production in jSLE. A In primary-type 1 interferonopathies, reduced metabolization/removal of cytoplasmic nucleic acid (e.g., through TREX1, SAMHD1, RNASEH2, ADAR1) or increased/spontaneous activation of cytoplasmic nucleic acid sensors (e.g., STING, MDA5) result in increased type 1 IFN expression (IFNA/B) and release. Release of type 1 interferons results in binding to and activation of type 1 IFN receptors (IFNAR), a mechanism that amplifies IFN expression through the Janus Kinase (JAK) signal transducer and activator of transcription (STAT) pathway. B In secondary type 1 interferonopathies but also “classic” SLE, deposition of immune complexes results in their detection by Toll-like receptors (namely TLR3, 7, 9), which triggers type 1 IFN expression and release. Interferons enhance their own expression through the JAK/STAT pathway and cause tissue damage through immune activation and the propagation of inflammation. This results in the release of cellular components and the generation of autoantibodies, which amplifies immune complex formation and deposition. C Type 1 IFN signalling can be inhibited using antiretroviral drugs (e.g., abacavir, lamivudine, zidovudine), IFN-I antibodies (sifalimumab, rontalizumab), or inactivating type 1 IFN receptor antibodies (anifrolumab)