Neuropsychiatric lupus: new mechanistic insights and future treatment directions

Abstract

Patients with systemic lupus erythematosus (SLE) frequently show symptoms of central nervous system (CNS) involvement, termed neuropsychiatric SLE (NPSLE). The CNS manifestations of SLE are diverse and have a broad spectrum of severity and prognostic implications. Patients with NPSLE typically present with nonspecific symptoms, such as headache and cognitive impairment, but might also experience devastating features, such as memory loss, seizures and stroke. Some features of NPSLE, in particular those related to coagulopathy, have been characterized and an evidence-based treatment algorithm is available. The cognitive and affective manifestations of NPSLE, however, remain poorly understood. Various immune effectors have been evaluated as contributors to its pathogenesis, including brain-reactive autoantibodies, cytokines and cell-mediated inflammation. Additional brain-intrinsic elements (such as resident microglia, the blood-brain barrier and other neurovascular interfaces) are important facilitators of NPSLE. As yet, however, no unifying model has been found to underlie the pathogenesis of NPSLE, suggesting that this disease has multiple contributors and perhaps several distinct aetiologies. This heterogeneity presents a challenge for clinicians who have traditionally relied on empirical judgement in choosing treatment modalities for patients with NPSLE. Improved understanding of this manifestation of SLE might yield further options for managing this disease.

Fig. 1 |. Neuroimmune interfaces and postulated mechanisms by which they can be breached.

Damage to the blood–brain barrier (BBB) might enable neuropathic antibodies in the serum of patients with systemic lupus erythematosus to enter the central nervous system (CNS); however, several other interfaces could also serve as sites of leukocyte and pathogenic antibody transfer into the CNS. a | The arachnoid epithelium serves as the meningeal barrier between the cerebrospinal fluid (CSF) in the subarachnoid space and the blood in cerebral veins. Meningitis (both aseptic and infectious) can cause inflammation in the subarachnoid space, potentially leading to a breach of this barrier that enables circulating pathogenic antibodies, leukocytes and pro-inflammatory cytokines to enter into the CSF. b | The glymphatic pathway is a perivascular pseudolymphatic system that provides a conduit for interstitial fluid in the brain parenchyma. Brain antigens (such as microtubule-associated protein 2) might be recognized by indwelling antigen-presenting cells in the perivascular space, which can migrate to the cervical lymph nodes and initiate an adaptive response. c | Breach of the BBB has been observed under several circumstances, including infection (simulated by lipopolysaccharide administration), stress (simulated by adrenaline infusion), the mechanical and inflammatory sequelae of vascular occlusion and antibody-mediated endothelial cell activation. d | The fenestrated capillary plexus within the choroid plexus enables ready access of antibodies and leukocytes to the choroidal plexus stroma (a previously characterized site of immunosurveillance) and potentially into the CSF. AQP4, aquaporin 4.

Fig. 2 |. Pathogenetic mechanisms and potential treatment targets in diffuse NPSLE.

Several different but potentially complementary pathways and effectors in the central nervous system (CNS) microenvironment might be involved in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). a | Endothelial cells connected by tight junctions comprise the blood–brain barrier and are subject to activation by autoantibodies such as anti-endothelial cell antibodies (AECAs). Activated endothelial cells show upregulated expression of adhesion molecules (such as intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1)), which facilitate leukocyte infiltration into the CNS parenchyma. In addition, these activated endothelial cells secrete pro-inflammatory cytokines, including IL-6 and IL-8. Concurrently, immune complexes in the cerebral vasculature activate the complement system, which further promotes chemotaxis. The locally infiltrating leukocytes secrete pro-inflammatory cytokines, such as IFNγ, which in turn promotes B cell survival and activation via increasing local levels of B cell activating factor (BAFF). b | Microglia are consequently activated, most notably by interferons, the elevated intrathecal levels of which are commonly seen in patients with NPSLE. Activated microglia further propagate local cytokine and chemokine signalling cascades, in addition to direct phagocytic activity focused on neuronal surface signalling domains and synaptic termini. Finally, several neuropathic autoantibodies have been implicated in NPSLE, including antibodies to the NR2 subunit of the anti-N-methyl-d-aspartate receptor (NMDAR), anti-ribosomal P protein (RP; targeting neuronal surface P antigen (NSPA)) and anti-microtubule-associated protein 2 (MAP2) antibodies, which might have direct neurotoxic effects and provide a source of intrathecal immune complexes. Anti-aquaporin 4 (AQP4) antibodies, directed against the myelin sheath, are found in some patients with SLE who have demyelinating disease. The above pathogenetic mechanisms, along with studies in animal models, suggest that several drugs might prove to be effective in treating NPSLE, including belimumab (a BAFF inhibitor), anifrolumab (a type I interferon receptor antagonist), macrophage colony-stimulating factor-1 receptor (CSF1R) inhibitors (which block activation of microglia and infiltrating macrophages) and tyrosine-protein kinase BTK (also known as Bruton tyrosine kinase) inhibitors (BTKis), which interrupt inflammatory activation of B cells and macrophages or microglia.