Pathogenesis and Treatment of Neuropsychiatric Lupus Erythematosus

Pathogenesis and Treatment of Neuropsychiatric Lupus Erythematosus: History

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Neuropsychiatric systemic lupus erythematosus (NPSLE) has a broad spectrum of sub-types with diverse severities and prognoses. Ischemic and inflammatory mechanisms, including autoantibodies and cytokine-mediated pathological processes, are key components of the pathogenesis of NPSLE. Additional brain-intrinsic elements (such as the brain barrier and resident microglia) are also important facilitators of NPSLE. An improved understanding of NPSLE may provide further options for managing this disease. The attenuation of neuropsychiatric disease in mouse models demonstrates the potential for novel targeted therapies. Conventional therapeutic algorithms include symptomatic, anti-thrombotic, and immunosuppressive agents that are only supported by observational cohort studies, therefore performing controlled clinical trials to guide further management is essential and urgent. The latest pathogenetic mechanisms of NPSLE are presented, and the progress in its management is discussed.

neuropsychiatric lupus erythematosus
pathogenesis
management

1. Pathogenesis of NPSLE

The exact immunopathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is complex and unclear. Ischemic and autoimmune-mediated neuroinflammatory pathways are now considered two main, and probably complementary, pathogenetic mechanisms leading to NPSLE.

1.1. Ischemic Pathway

Ischemic injury to large- and small- blood vessels, mediated by antiphospholipid (aPL) antibodies, immune complexes, and complement activation leads to focal (e.g., stroke) and diffuse (e.g., cognitive dysfunction) neuropsychiatric events. Among these, aPL antibodies play a predominant role in the intravascular thrombosis ^[1]. Some studies have reported that SLE patients positive for aPL antibodies are approximately twice as likely to develop NPSLE than aPL-negative patients. aPL antibodies may also increase the risk of subclinical atherosclerosis, leading to a propensity for cerebral ischemia. The central nervous system is more susceptible than most tissues to thrombus formation, which accounts for the increased risk of stroke and transient ischemic attack seen in aPL antibody-positive patients ^[2]. Apart from thrombosis, aPL antibody positivity has also been correlated with other NPSLE manifestations, such as seizures, chorea, cognitive dysfunction, and myelopathy ^[3]^[4]^[5], especially psychosis ^[6]^[7]^[8]. Recent evidence suggests that aPL antibodies are also linked to direct neuronal damage by inducing oxidative stress and damage to neuronal cell membranes via the β2-glycoprotein. In an in vitro study, aPL antibodies bound to neurons and other CNS cells, and the intracerebroventricular injection of aPL induced a hyperactive behavior in animal models ^[9], thereby supporting a direct effect of these antibodies on the brain.

1.2. Neuroinflammatory Pathway

Autoimmune-mediated neuroinflammatory pathways with complement activation, enhanced the permeability of the blood–brain barrier (BBB), the intrathecal migration of neuronal autoantibodies, and the local production of pro-inflammatory cytokines, and other inflammatory mediators are associated with mostly diffuse neuropsychiatric manifestations, such as psychosis, mood disorders, and cognitive dysfunction ^[10]^[11]^[12]^[13].

2. Current Management of NPSLE

The management of NPSLE can be challenging, because of the complexity of its pathogenesis, difficulty in its accurate diagnosis, and a lack of clinical trials in NPSLE. Current treatment options for NPSLE are usually derived from observational studies and refer to the experience of treatment of other SLE subtypes, such as lupus nephritis and similar neuropsychiatric disorders ^[10]^[14].

First, symptomatic therapy is necessary: anti-epileptics for seizures, and anxiolytics, antidepressants, mood-stabilizers, or antipsychotics should be administered as appropriate. Neurotrophic and neuroleptic agents were generally adopted in case with peripheral nervous system involvement ^[15]. The treatment of the underlying SLE process should be undertaken based on whether the pathogenesis is primarily related to an inflammatory or ischemic disease pathway (Figure 1).

Figure 1. Management for patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Created with BioRender.com.

2.1. Inflammatory pathway therapies

Glucocorticoids have been a cornerstone in the treatment of various manifestations of NPSLE, especially in those associated with an immune-inflammatory pathogenesis ^[16]^[17]. High-dose glucocorticoids, alone or in combination with cyclophosphamide, azathioprine, and mycophenolate mofetil, are reported to be effective, but their use is mainly based on patient’s clinical experience of disease severity and their clinician’s preference. Given the evidence linking glucocorticoids use to cumulative organ damage in SLE ^[18] and its associated psychiatric symptoms ^[19]^[20], alternative therapeutic strategies are essential.

2.2. Ischemic Pathway Therapies

Cerebral ischemia attributed to NPSLE, such as transient ischemic attacks and stroke attributed to NPSLE events and is thought to be correlated with aPL antibodies. Thus, the primary prevention of cerebral ischemia in NPSLE is linked to a reduction in prothrombotic risk.

3. Promising Targeted Therapies

Due to the lack of understanding of the exact pathogenic mechanisms behind this condition as well as its diverse neuropsychiatric manifestations, we have limited experience in targeted therapies for patients with NPSLE. The attenuation of neuropsychiatric diseases in related animal models demonstrates the potential for targeted therapies, which are based on a current understanding of the pathogenesis of NPSLE (Table 1).

Table 1. Promising targeted therapies in NPSLE.

Promising Targeted Therapies	Underlying Mechanisms and Clinical Findings	Experimental Arrangement	Potential Drugs
Complement inhibitors	Complement signaling promotes the loss of BBB integrity. Blocking the complement cascades relieved the symptoms of NPSLE. Complement deposits were present in most of patients with NPSLE.	Human brain autopsies	Eculizumab
BBB-targeted therapy	BBB disruption is essential in the neuronal damage process. Restoration of normal BBB function may reduce the development of neuropsychiatric manifestations	Human and mouse cells; C57 BL/6J mice, respectively	GW0742, a peroxisome proliferator-activated receptor β/δ agonist; KD025, a rho kinase inhibitor.
MMPs inhibitors	There is an association between CSF/serum levels of MMP-9, psychiatric NPSLE, and markers for neuronal/astrocytic damage. MMP-9 may contribute to the pathogenesis of psychiatric NPSLE by stimulating T-cell migration	-	-
IFN-α/β receptor antagonists	IFN receptor inhibition decreased microglia-related synaptic loss and attenuated anxiety-like behavior and cognitive deficits in animal models.	564Igi lupus-prone mice	Anifrolumab
BTK inhibitors	Use of BI-BTK-1 (an inhibitor of BTK) in MRL/lpr mice, decreased the infiltration of macrophages, T cells, and B cells in the choroid plexus, and improved cognitive function.	MRL/lpr mice	Ibrutinib; Evobrutinib
S1P receptor modulator	S1P receptor modulators decreased proinflammatory cytokine secretion by microglia and significantly improved spatial memory and depression-like behavior. Fingolimod (a S1P receptor modulator) treatment attenuated neuropsychiatric manifestations, reversed the entry of immune components, and decreased BBB leakage. Fingolimod-treated microglia revealed down- regulated of multiple immune-mediated pathways, including NF-kB signaling and the IFN response with the negative regulation of type I IFN-mediated signaling.	MRL/lpr mice	Fingolimod
ACE inhibitors	ACE inhibitors treatment suppressed microglial activation and promoted cognitive status.	BALB/c mice	Captopril; Perindopril
CSF1R inhibitors	CSF1R is essential in both macrophage and microglia function. Inhibition of CSF1R signaling in MRL/lpr mice reduced the brain expression of proinflammatory cytokines and attenuated depression performance.	MRL/lpr mice	GW2580, a small CSF-1R kinase inhibitor; depletion of microglia
Nogo-a/NgR1 antagonists	Nogo-a/NgR1 in the CSF is significantly increased in NPSLE. Nogo-a/NgR1 antagonists improved cognitive function, decreased the expression of pro-inflammatory components, and reduced axonal degeneration and demyelination.	MRL/lpr mice	Nogo-66
JAK inhibitors	JAK inhibitors penetrate the BBB and reduce the production of several cytokines, including type I IFNs.	-	Tofacitinib

This entry is adapted from the peer-reviewed paper 10.3390/jcm11174955

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