Lupus and the Nervous System: A Neuroimmunoloigcal Update on Pathogenesis and Management of Systemic Lupus Erythematosus with Focus on Neuropsychiatric SLE

Abstract

An autoimmune condition is characterized by a misdirected immunological system that interacts with host antigens. Excess activation of T- and B-lymphocytes, autoantibody generation, immune complex deposition, and multi-organ injury are found in systemic lupus erythematosus (SLE), an early autoimmune condition with a substantial hereditary element. A number of environmental factors and lifestyle changes also play a role in the development of SLE. The imbalanced immunity could take part in the dysfunction and injury of different biological organs, including the central and peripheral nervous systems. Neuropsychiatric SLE (NPSLE) can present with focal and diffuse involvements. Clinical manifestations of NPSLE vary from mild cognitive deficits to changed mental status, psychosis, and seizure disorders. Headaches, mood, and cognitive problems are the most common neuropsychiatric presentations associated with SLE. NPSLE could be found in 40% of all people who have SLE. The diagnostic inference of NPSLE can be made solely following these secondary causes have been ruled out. The present chapter provides an updated discussion of the clinical presentation, molecular processes, diagnosis, management, and therapy of SLE with emphasizing on NPSLE.

1. Introduction

Autoimmune diseases occur due to the response of the adaptive immune system to self-antigens and mediators as well as tissue damage, leading to breaking self-tolerance. Autoimmune diseases can be divided into two groups. The first group particularly involves an organ, such as type 1 diabetes mellitus (T1DM) and thyroiditis. The second group, however, presents itself in the form of systemic complications [1]. Systemic disorders affect some organs and tissues such as the eye and optic nerve, skin, and joints. Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) are good examples of autoimmune diseases with multiorgan involvement [2, 3].

SLE is a long-lasting, febrile, proinflammatory multiorgan disease of the connective tissue, primarily involving the skin, joints, and serosal membranes [2, 4]. Moreover, SLE is associated with various diseases including neurological conditions (stroke, seizure, cranial neuropathy, and cognitive dysfunction), serositis, leukopenia, thrombocytopenia, antiphospholipid syndrome, lymphadenopathy, autoimmune hemolytic anemia, fever, arthritis, Livedo reticularis, renal disease, Raynaud’s phenomenon, oral ulcer, and malar rash [5]. The disease often affects women, Black, Hispanic, and Asian populations (ten times more frequently in women compared to men).

NPSLE or central nervous system (CNS) lupus denotes the condition where lupus influences the brain, spinal cord, and other nerves. Interestingly, SLE can affect the nervous system as neurological (N) and psychiatric (P) syndromes that are known as neuropsychiatric SLE (NPSLE) [6, 7]. NPSLE could be found in 40% of all people who have SLE. The prevalence and incidence of SLE vary based on the region, sex distribution, ethnicity, and socioeconomic factors. For example, the incidence rate of SLE in the US Medicare population varies between 3.7 and 49.0 in 100,000 person-year and the prevalence rate varies from 48 to 366.6 in 100,000 person-year. But in Europe, the incidence rate of SLE ranges from 1.5 to 7.4 per 100,000 person-year and the prevalence rate ranges from 29.3 to 210 (Global incidence rate ranges from 1.5 to 11 per 100,000 person-year and the prevalence rate varies between 13 and 7,773.5 per 100,000 person-year). It is expected that the mortality rate will decrease in the future [8]. By contrast, several essays show an increase in case numbers [9, 10].

To understand and increase information about the pathology, etiology, and treatment of this disease, animal models are used. Several articles on the pathology of NPSLE have been carried out in various aspects, such as genetic model design, complement system, cytokine involvement, and auto-antibody against brain antigens [11]. NPSLE leads to disruption and augmented the penetrability of the blood-brain barrier (BBB). Environmental factors (e.g., viruses such as Epstein-Barr virus, smoking, vitamin D level, air pollution, and medication drugs) affect the neuroimmunopathogenesis of SLE [12, 13].

Scientists have been facing many research difficulties within the field of SLE. In lupus, the inflammation happens due to the attack of the immune system against tissues and organs. Yet, the precise details of mechanisms underlying SLE are unclear. Diagnosing NPSLE is difficult because clinicians have to rule out other causes, including tumors and infections. Current treatments aim to inhibit the excessive activities of the immune system and prevent organ failure. Drugs used for patients depend on the symptoms that appear [14].

The present chapter rapidly reviews recent research into the clinical presentation, molecular mechanisms, diagnosis, management, and treatment of SLE with a focus on NPSLE. Finally, our discussion offers novel insights into the role of Immunoinformatics in future clinical research.

2. Epidemiology, definition, and classification of SLE: an overview

Systemic lupus erythematosus (SLE) is a nonhomogeneous clinical disorder that has autoimmunity roots. It can be recognized via the presence of autoantibodies produced toward nuclear antigens. According to a classic description, SLE is a multiorgan condition, and affected individuals may show symptoms in highly dissimilar formats. Classification criteria have been established, partly to try to maintain homogeneity within the SLE cases in order to facilitate research efforts. The American College of Rheumatology (ACR) disseminated these criteria that were modified in 1982 [1]. These guidelines integrate clinical presentations with irregularities found in blood exams including a detection of nuclear resistant antibodies or thrombocytopenia. Once again, these criteria were corrected in 1997 to better represent the significance of phospholipid-targeting antibodies in SLE cases [15].

SLE is an insufficiently explained syndrome. Etiology and pathogenesis are not known to date. Still, SLE is a seminal condition that has been a challenge to be resolved for immunologists, biologists, geneticists, and clinicians. The condition can be detected through various, seemingly unrelated presentations. Surprisingly, these symptoms could take place in many stochastically interconnected clusters; despite this, single gene deficits could enhance a narrower range of signs/items often observed in SLE. A lack of internal coherence exists among features (criteria) that contribute to the disease. Such features are considered in the ACR and the systemic lupus collaborating clinics (SLICC) descriptions to categorize SLE. Yet, SLE is a concept because the ACR/SLICC definitions enable scientists to describe hundreds of various SLE subtypes clinically [16].

3. Neuropsychiatric SLE (NPSLE)

3.1 Clinical presentations

3.1.1 Criteria and classification

Based on the manifestations, NPSLE can be categorized into focal and diffuse. Clinical presentations of NPSLE vary from mild impairment of cognition to altered mental status, psychosis, and seizure disorders. Headaches, cognitive deficits, and mood disorders are the most commonly found neuropsychological features in SLE. Also, epileptic disorders, cerebrovascular dysfunctions, neuropathic disease, and acute confusion conditions are the common presentations linked to NPSLE [17].

The American College of Rheumatology (ACR) introduced a consensus statement that classified 19 neuropsychiatric (NP) syndromes. These neuropsychiatric syndromes can be categorized into twelve central nervous systems (CNS) and seven peripheral nervous systems (PNS) syndromes. In addition, these were divided into diffuse neuropsychiatric diseases and focal nervous system disorders [18]. The frequency of these manifestations ranges from 0.08 to 80%. Some syndromes are more common (6.4%–80%), and the other syndromes are common (7%–20%), uncommon (0.6%–11%), or scarce (0.08%–2%). Neuropsychiatric manifestations including neuromyelitis optica spectrum disorder, chronic inflammatory demyelinating polyneuropathy, and small fiber neuropathy, are as well reported in SLE; however, these are not considered in this categorization. This categorization is not based on any precise pathological and physiological process: yet, it helps the diagnosis of SLE in the case of nervous system influence [19, 20].

3.1.2 General NPSLE presentations

Headaches, cognitive dysfunction, and psychiatric disorders (major depressive disorder (MDD), anxiety) are the most prevalent NPSLE symptoms. Neuropsychiatric manifestations usually develop in the initial stages of SLE. Previous evidence reported that up to 40% of neuropsychological presentations are detected within the initial year of being diagnosed with SLE. NPSLE manifestations can be devastating symptoms of SLE [21]. As mentioned above, NPSLE manifestations can be classified as CNS and/or PNS manifestations.

3.1.3 Pediatric NPSLE

In children, a recent work explored the presentations, therapy, and outcome of NPSLE cases. The charts of 185 children with SLE diagnosed from 1985 to 2005 in a medical center were investigated respectively. NPSLE was characterized by the ACR NPSLE descriptions. NPSLE was found in about a third of the cases. The average age of onset was 15.2 years. A fifth showed NP presentations when initially diagnosed with SLE. The most commonly observed NP findings were epileptic disorder (84.4%), cerebral infarction (28.1%), and psychosis (21.9%). Elevated average C3/C4 quantities, a reduced proportion of anti-dsDNA antibodies increased, and an amplified proportion of raised anticardiolipin antibodies were reported in NPSLE individuals compared to non-NPSLE individuals. NPSLE is common in SLE children. It is linked to heterogeneous presentations and a significant mortality rate [22].

3.1.4 CNS manifestations of NPSLE

3.1.4.1 Depression

Depressive disorder is the most frequent mood disturbance in NPLSE. Its prevalence over the course of life could reach about two-thirds of cases, however, mania is less frequent. Lately, evidence showed that depression in SLE is linked to several factors. High-dose prednisone was found most remarkable independent element, while global disease activity was not associated. Other influential elements were a new diagnosis of SLE, cutaneous problems, longitudinal myelitis, and belonging to an ethnic group other than Asia. Therefore, in certain cases, SLE-associated depressive condition is linked to adverse effects of treatment rather than with disease activity. Based on this notion, clinicians are encouraged to reduce prednisone doses or avoid its use [23]. A link between depressive disorders and exclusive antibodies produced against at NMDA receptor, ribosomal-P, and other neural epitopes has been found. More study is required to decipher the underpinnings of SLE-related depression and further therapy.

3.1.4.2 Headache

The association between SLE and headache has been well-researched, however, the findings were inconsistent. Although some previous reports have found enhanced headache occurrence in SLE cases, other experiments have not reported an elevation in the headache prevalence in comparison the healthy individuals.

Primary headaches, in particular tension-type headaches (TTH) and migraine, are frequent findings in NPSLE. However, secondary etiology of headache must be ruled out, such as cerebral venous sinus thrombosis, brain vasculitis, meningitis, and subarachnoid hemorrhage. The phrase ‘SLE headache’ is defined as a critical chronic headache for which narcotic painkillers are not effective. Lupus headache is defined as an element within the disease spectrum and therefore was classified as one of 19 neuropsychiatric diseases in ACR criteria for NPSLE [24].

3.1.4.3 Seizure

Generalized and focal seizures could occur in 10 to 20% of SLE cases. Seizures usually develop soon after the diagnosis of SLE [25].

3.1.4.4 Cerebrovascular disease

The occurrence of temporary ischemic attacks and stroke is increased among SLE patients [26]. Cerebrovascular accident in SLE is strongly related to the presence of aPL antibodies, Libman-Sacks endocarditis, accelerated atherosclerosis, and cardio-embolism due to heart valvular abnormalities [25].

3.1.4.5 Demyelinating syndromes

Clinical findings of demyelination were reported in 0.3% of SLE cases. SLE-related-demyelination is not yet clearly understood. Therefore, notable investigation toward its diagnosis and management is required. These syndromes may include clinically isolated syndrome (CIS), could be similar to other CNS demyelinating syndromes (for instance, multiple sclerosis (MS)), result from medication, and, in certain conditions, the diagnosis could be made solely by long-term follow-up [27].

3.1.4.6 Transverse myelitis

Transverse myelitis is estimated to affect 1.5% of cases in SLE. Lately, researchers have linked transverse myelitis-SLE to aPL antibodies [28], thereby highlighting spinal cord degeneration as a result of thrombosis as an underlying mechanism. In certain situations, a similarity between Devic’s disease with the existence of anti-NMO immunoglobulins is presumed. In the rest of the situations, transverse myelitis could turn into MS [25].

3.1.4.7 Movement disorders

Chorea is the most frequent movement problem in SLE and develops in 2 to 3% of SLE cases and this percentage is more in children, while ataxia, Parkinsonism, and hemiballismus are somewhat scarce symptoms in SLE patients. Chorea often occurs during the first years of SLE diagnosis and is found by aPL antibodies in up to 92% of patients [29, 30]. It has been proposed that such antibodies pass through the BBB, attach to nerve cells’ antigens, and ultimately lead up to this symptom [31].

3.1.4.8 Aseptic meningitis

Aseptic meningitis can be a neurological finding of ongoing SLE. Other etiology of aseptic meningitis, including pharmacotherapy, cancer, and infections are to be excluded [25].

3.1.4.9 Cognitive dysfunction

Cognitive deficit is extremely common in lupus cases, varying within the range of 20–80% [32, 33]. It may, however, not be reasonable to attribute deficit in cognition to the activity of the disorder, SLE burden, and corticosteroid treatment [32].

3.1.4.10 Psychosis

Organic psychosis may influence 2 to 11 percent of SLE cases. In about 60% of such cases, it emerges as the SLE-symptom [34]. SLE psychosis is often associated with SLE activity and is affected by immunosuppressive treatments. One important differential diagnosis is corticosteroid-activated psychosis. However, it is not more prevalent in SLE in comparison with the rest of autoimmune conditions [35]. Studies have also detected a positive linkage between SLE and the danger of being affected by schizophrenia [36, 37].

3.1.4.11 Acute confusional state

An acute confusion condition is a diffuse CNS disease that presents as a changing grade of consciousness and loss of orientation and is equal to the concept of delirium as defined within the DSM-IV [38]. Because of a lack of a precise definition, its frequency is hard to calculate, varying within the range of 0-7% [39].

3.1.5 PNS manifestations

Peripheral nervous system (PNS) presentations influence about 10 to 15% of NPSLE patients, and multiple concepts are taken into account in the late 1990s ACR-NPSLE patient descriptions. The greater part of patients present with peripheral neuropathy [40], which comprises mono-neuropathy, poly-neuropathy, cranial-neuropathy, hyperinflammatory demyelinating poly-radiculoneuropathy, and plexopathy. A report noted that 17% of SLE-associated peripheral neuropathies are small-fiber neuropathy [41]. Small-fiber neuropathies are able to cause severe burning pain by targeting non-myelinated C fibers and finely myelinated A fibers. The diagnosis is verified via obtaining a cutaneous sample that exhibits injury to the dorsal root ganglia along with distal axons. The rest of the PNS presentations comprise autonomic disorders and myasthenia gravis [25].

3.2 Molecular mechanisms

3.2.1 Cellular and molecular processes in neuropsychiatric systemic lupus erythematosus (NPSLE)

Overactive adaptive immune cells, autoantibody generation, immunological complex accumulation, and multisystem damage are features common in SLE, an early autoimmune disorder with a strong hereditary component. As previously stated, different elements could play a role in the development of SLE. Mutations in immunity-related genes, such as C1q, C1r, C1s, C2, or C4, which are essential elements of the complement cascade, are one of these reasons. These supplements play a role in the detection and opsonization of apoptotic cells, as well as the clearance of critical immune complexes, and their absence can result in the creation of autoantigens, as well as the stimulation of interferon (IFN) types 1 and 2 [42, 43].

Other mutations in genes that regulate nucleic acid metabolism, including TREX1, RNASEH2B (A, C), ADAR, IFIH1, and SAMHD1, trigger SLE-like symptoms that are mediated by a type I chronic response to IFN. Alleles associated with the B cell response (BLK, BANK1, FCGR2A, and PTPN22) as well as alleles associated with the innate immunological response (IRF5, STAT4, TNFAIP3, and TNFSF4) are also associated with SLE [44, 45].

In SLE, epigenetic modifications include DNA methylation, histone modifications, and noncoding transcripts. DNA methylation suppressors can induce T cell reactivity and lupus symptoms in mice and humans. In addition, T cells from patients with SLE have less methylation than T cells from healthy individuals. Studies of single-site methylation reveal that SLE patients had unique mutations in the PRF1, TNFSF7 (CD70), ITGAL, and CD40LG genes, among others [46, 47]. SLE pathogenesis is associated with aberrant histone acetylation, which is associated with higher histone H3 and H4 acetylation in human CD4 SLE T cells [48]. In SLE patients, the expression of miR-126-3p, miR-let7d-5p, miR-15a-5p, miR-326, miR98-5p, miR143-3p, miR-7, miR 21, and miR22 increased, whereas miR-31 and miR-146a, the negative regulator of IFN type I signaling, decreased. Negative regulators of IFN type I signaling, miR-31 and miR-146a, were decreased in SLE patients. In SLE B cells, miR-7, miR-21, and miR-22 levels were all elevated relative to the control group, and all three miRs suppressed PTEN expression. Reduced PTEN expression in SLE B cells correlates with B cell hyperactivity and the potential failure of B cell tolerance, suggesting that this microRNA may play a role in the etiology of SLE. Let 7 levels were seen to fluctuate in lupus nephritis samples, suggesting that it suppresses NFkB signaling. SLE patients and lupus nephritis tissue samples exhibit increased NFkB signaling in B cells. Reduced miR-31 expression is associated with lower IL-2 expression in SLE patients, indicating that miR-31 plays a mechanical role in the disease [49, 50, 51].

3.2.2 NR2A/B antibodies of anti-N-methyl-d-aspartate (NMDA) receptor subunit

Neurons contain the glutamate receptor and ion channel NMDA. 30–40% of SLE patients’ sera include antibodies against the NR2A/B subunit of the NMDA receptor. After establishing evidence of R4A antibody (as anti-dsDNA antibody) interaction with NRDA NR2A and NR2B receptor subunits, researchers sought similar antigenic characteristics in polyclonal anti-dsDNA antibodies in SLE patients. Anti-NR2A/B antibodies induce apoptotic cell death in cell culture, according to prior investigations. Anti-NR2A/B antibodies were injected into the hippocampus of C57BL/6 mice, causing neuronal death. In addition, intravenous administration of anti-NR2A/B antibodies to BALB/c mice treated with LPS resulted in antibody binding to hippocampal neurons and nerve damage [52, 53].

3.2.3 Matrix metalloproteinases (MMPs)

MMPs are a class of zinc- and calcium-dependent endoproteinases involved in the degradation and regeneration of extracellular matrix proteins. MMPs, especially MMP-9, are able to degrade basal layer components such as collagen type IV, fibronectin, and laminin, as well as aid in proteolyzing the basal layer, resulting in BBB disruption. Numerous immune-type cells (granulocytes, lymphocytes, and monocytes) release MMP-9, with neutrophils being one of the most prolific sources. Serum and CSF levels of MMP-9 in SLE patients with CNS involvement are elevated, according to the available evidence. MMP-9 levels in the CSF are also associated with tau protein and glial fibrillar acid, markers of neurodegeneration and astrocytic degeneration, respectively, in SLE patients [54, 55].

3.2.4 Neutrophil extracellular traps (NETs)

Neutrophils are guardians of the innate immune system that migrate from the bloodstream to infection sites to combat pathogens by phagocytosis, degranulation, and the release of neutrophil extracellular traps (NETs). Neutrophil extracellular vesicles (NETs), which are produced by active neutrophils, are a distinct kind of cell death from necrosis and apoptosis. NETs with fibrous structures contain histones (H1, H2A, H2B, H3, and H4) and granule-derived enzymes, including neutrophil elastase, myeloperoxidase, and MMP-9. Antibacterial characteristics exist within histones. In addition to elevated reactive oxygen species (ROS) in neutrophils, transmission across activated endothelium in vivo stabilizes NET formation and may result in cell death. Neutrophils in SLE patients have altered functional characteristics due to the overexpression of granulopoiesis-related genes, such as decreased phagocytic capabilities, increased intravascular activation, increased platelet-neutrophil accumulation, and increased production of reactive oxygen species [56, 57].

3.2.5 Pro-inflammatory mediators

In the hippocampus of animal models with NPSLE, infiltration of CD3+ T cells and enhanced mRNA expression of proinflammatory mediators including IL-1, IL-6, IL-10, interferon (IFN)- and transforming growth factor were observed. In the CNS, cytokines are produced by neurons and microglia. Studies have indicated that neurons and microglial cells are capable of synthesizing IL-2, IL-6, IL-8, and IL10 intrathecally. Levels of IL-6 in the cerebrospinal fluid (CSF) were associated with abnormal brain MRI signals in human NPSLE, which were predominantly white matter intensities weighted with T2. In 119 SLE patients, IL-6 CSF levels were related to MMP-9 CSF levels, suggesting that BBB failure may be involved in the development of brain MRI abnormalities in patients with NPSLE [58, 59].

3.3 Diagnosis

NPSLE is challenging to treat in clinical practice due to the variety of clinical presentations, the shortage of pathology specimens to diagnose the underlying etiology, and the paucity of evidence-based therapies [60]. Before making a definitive diagnosis of NPSLE, professionals must rule out other probable causes, such as infections and cancers, due to the disease’s difficulty to identify [32, 61]. Neuropsychiatric manifestations of SLE comprise a broad spectrum of symptoms that impair patient prognosis and quality of life. Recent advances have been achieved in both improving the diagnosis of NPSLE and elucidating its etiology. For the diagnosis of NPSLE, there is no gold standard [62]. In all patients with unexplained neuropsychiatric symptoms or presentations indicative of neuropsychiatric (NP) disease, the first step would be to investigate and characterize the NP symptoms while ruling out other common causes, such as infections, metabolic disorders, or drug use. Thrombotic events, atherosclerotic disease, cardiovascular risk factors, and general SLE activity are evaluated in greater detail [61]. Different clinical, serological, immunological, electrophysiological, and neuroimaging tests are utilized to diagnose NPSLE. Various imaging modalities and the presence of autoantibodies can aid in diagnosing the cause and the optimal treatment protocol [63]. Neuroimaging can be used to differentiate SLE patients from healthy controls, but further research is required to differentiate among lupus patients with and without neuropsychiatric symptoms. As potential markers for a more objective and accurate diagnosis, higher levels of certain substances in the cerebrospinal fluid and serum, as well as the presence of particular autoantibodies, have been detected [20, 64].

To accurately classify NP, imitators must be excluded with care. However, NP episodes must be associated with SLE in order to receive immunosuppressive therapy. To improve clinical care and research outcomes, a number of attribution models have been developed [65, 66]. Numerous practitioners now employ the well-established language of the American College of Rheumatology (ACR) to define NPSLE episodes in clinical practice [18]. Most commonly utilized are the ACR criteria from 1999, which have been validated in an external cohort with a sensitivity and specificity of 45% [67]. The ACR criteria must be amended and updated, including the addition of new manifestations, notwithstanding the considerable progress made since their release (e.g., posterior reversible encephalopathy syndrome, small fiber neuropathy, and chronic inflammatory progressive demyelination). Various classification criteria have been developed over time [18, 68, 69, 70, 71]. Another criterion devised an attribution method that produces a probability value between 0 and 10. This algorithm evaluates four subjects during model construction, three of which are identical to those used in ACR standards. In this context, issues discussed include the existence of mild or common neuropsychiatric episodes as well as EULAR-suggested SLE risk factors [72]. As the ACR criteria displayed a high sensitivity (91%) but a low specificity (46%), Zhang et al. presented their own criteria based on five symptoms (disease activity, antibodies, thrombosis, skin lesions, and manifestations) whose positive and negative prognostic values were greater than 70% [17].

SLE patients could be evaluated for cognitive impairment, anxiety, and depression using a number of screening procedures established for neurodegenerative illnesses. ACR’s ad hoc interdisciplinary committee recommended specific neuropsychological tests (NPTs) for identifying cognitive dysfunction (CD) in SLE [18]. Even for limited inspections, NPTs are time-consuming, costly, and inaccessible in a variety of situations. The Automated Neuropsychologic Assessment Metrics (ANAM), a computerized method, measures many of the same cognitive categories as the Neuropsychological Tests (NPTs) [73]. NPT and ANAM are time-consuming, somewhat costly, and difficult to obtain; hence, a simple and sensitive screening test is necessary for clinical therapy [74]. According to preliminary studies, the Montreal Cognitive Assessment Questionnaire (MoCA) is a brief and affordable screening tool that may be useful for the early detection of CD in SLE [75, 76]. In comparison to normal individuals or patients with rheumatoid arthritis, the MoCA demonstrated moderate sensitivity and specificity for cognitive impairments (0.83–0.94 and 0.27–0.46, respectively) [77]. Other cognitive decline screening instruments, such as the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), have been utilized in the elderly. The IQCODE is a questionnaire that is completed by the patient’s family or an appropriate informant who knows the patient well and can determine if the patient’s cognitive function has decreased in relation to regular daily activities over time. The IQCODE is not affected by the patient’s educational level, premorbid IQ , or proficiency in the culture’s predominant language, but it can be influenced by the quality of the informant-patient relationship [78].

Self-informed surveys, for example, the hospital anxiety and depression scale (HADS), the Center for Epidemiologic Studies-Depression Scale (CES-D), and beck anxiety inventory (BAI) are low-cost and widely used screening utilities for depression and anxiety in the general inhabitants; however, only a handful of researches have inspected their function in SLE patients [79, 80]. Previously reported in a cross-sectional study of 159 consecutive consenting SLE adults to determine the reliability of assessment in these questionnaires’ test-retest, prevalence of depression and anxiety in SLE patients, and study their diagnostic correctness (HADS-A), the prevalence of anxiety ranged from 45% (BAI) to 50% (CES-D) (CES-D) and the prevalence of depression ranged from 29% (HADS-D) to 52% (CES-D). According to the authors’ conclusion, both surveys have the potential to serve as NPSLE screening tools [74].

None of the laboratory or neuroimaging biomarkers for diagnosing NPSLE have been proven accurate or reliable in clinical practice, despite extensive clinical research. Novel biomarkers may permit a more objective evaluation [81]. It might be as easy as measuring the concentration of a certain biomarker in the blood. Autoantibodies, the defining characteristic of lupus, may be useful as biomarkers. Numerous autoantibodies have been linked to NPSLE, but their role in pathogenesis remains unproven [82]. One of the potential biomarkers is 2-glycoprotein 1 and cardiolipin, which have been associated with focal neuropsychiatric diseases including cerebrovascular disease, seizures, and chorea, as well as diffuse neuropsychiatric disorders like cognitive impairment, psychosis, sadness, and headache [83, 84]. Ribosomal P protein, which is associated with NPSLE by demonstrating greater titers during active SLE in serum and CSF, is not a helpful biomarker for discriminating between disease subtypes [85, 86, 87]. Antibodies against NR2, a subunit of the N-methyl D-aspartate receptor (NMDAR), are associated with spatial memory impairment in both mice and lupus patients. NR2 is essential for synaptic plasticity and memory in the brain [81, 88, 89, 90, 91, 92, 93]. Using primary brain micro-vessel endothelial cells, it was demonstrated that anti-NR2 antibodies can breach the BBB and enter the brain [94]. Several additional biomarkers, such as Microtubule-associated protein 2, were indicated to have a connection with NPSLE that was either significant or contentious (MAP-2) [95], U1 ribonucleoprotein (U1RNP) [96], and Glial fibrillary acidic protein (GFAP) [88, 97]. Although autoantibodies have been suggested as a potential biomarker, only a few antibodies, such as antineuronal, anti-ribosomal P, and anti-NR2 antibodies, have met the exploratory criteria and are being utilized in diagnosis and therapeutic decisions [98, 99].

In addition, numerous neuroimaging techniques, such as nuclear medicine techniques and magnetic resonance imaging (MRI), have enabled the assessment of functional and structural irregularities in SLE patients, thereby facilitating a greater comprehension of the underlying pathophysiology and subsequent pathophysiological alterations [6]. Since the 1980s, aberrant brain MRI has been described in SLE and NP-SLE [100, 101]. On conventional MRI (cMRI), a significant proportion of patients with NP-SLE show no abnormalities, and global markers such as lesion load or brain atrophy do not correlate with symptom severity [102, 103]. Innovative MRI techniques and software may be more precise in identifying brain variations in NPSLE patients. Researchers were able to map the microstructure of the brain utilizing mean diffusivity and fractional anisotropy (DTI), sophisticated MRI methods including white matter hypersensitivity volumetry, diffusion-tensor imaging (DTI), and voxel-based morphometry (VBM) [104]. However, there is yet a radiological and clinical contradiction. To eliminate this uncertainty, a broad strategy and imaging surveys are required.

3.4 Management and treatment

The management of NPSLE could be challenging at multiple phases, including problems in classifying them as SLE, diagnosis based on ambiguous symptoms, and the limited and imprecise arsenal of available therapies. Initially, a thorough evaluation should be conducted to rule out alternative reasons, such as metabolic diseases, infection, cancer, and severe drug reactions. Once the symptoms are mostly attributed to SLE and these confounding variables have been ruled out, the management goals are increased. First, symptomatic medication should be administered, including antiepileptics for seizures, treatment of hypertension and metabolic abnormalities, and mood stabilizers, anxiolytics, antidepressants, or antipsychotics, as indicated, for psychiatric symptoms. Until then, therapy of the underlying SLE process should be administered in accordance with whether the neuropsychiatric manifestations are attributable to a widespread, inflammation-driven condition or a process [61]. Before further actions, it is necessary to consider the challenges associated with NPSLE management.

First, concerns unrelated to SLE should be addressed appropriately with non-SLE-related therapies. A study described the beneficial effects of psychotherapy on reducing sadness and anxiety and boosting life satisfaction [105]. Anxiolytics and antidepressants are also used to improve cognitive skills in SLE patients with anxiety and depression; however, their use in mood disorders is inconsistent [106]. Effective antiepileptics and antipsychotics are used to treat SLE psychosis and seizures, respectively [107, 108]. The cognitive dysfunction caused by SLE is managed to utilize a technique known as meta-context behavioral rehabilitation. A nonrandomized study of rehabilitation strategies revealed a 100 percent retention rate with memory self-efficacy and an improvement in quality of life [109]. This emphasizes the relevance of non-SLE concerns in the quality of life of patients. In addition, non-SLE therapies offer the potential for ameliorating these problems. To unravel the pharmacological components of this strategy, a controlled trial should be conducted.

In the absence of controlled clinical trials, certain NPSLE therapies are experimental. Depending on the underlying pathophysiology, pharmaceutical therapy in the clinical environment is aimed at reducing inflammation or preventing thrombotic events [110]. In patients with immune-mediated damage or global lupus, immunosuppressants such as corticosteroids must be provided alone, or in combination with additional immunosuppressive medications such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Immunotherapy’s primary objective is to treat or relieve symptoms [61]. Only oral prednisolone and intravenous cyclophosphamide have demonstrated efficacy in the treatment of NPSLE [111]. Seizures are less likely to occur in people receiving antimalarials [108]. Other co-administered medications include statins for patients with arterial or recurrent venous thromboembolism, as well as nonsteroidal anti-inflammatory medicines (NSAID) for pain management [112]. Nonetheless, the use of NSAIDs in SLE is associated with an increased likelihood of recurrent aseptic meningitis. Anticoagulants and antiplatelet treatments are used to treat ischemic NPSLE, especially in patients with positive antiphospholipid (aPL) antibodies. Typically, inflammatory and ischemic NPSLE coexist; we advise a combination of antiplatelet treatment, anticoagulation, and immunosuppressive drugs [20]. All thromboses caused by aPL-antibody require lifelong anticoagulation with warfarin as the primary treatment [113]. Since the safety profile of antimalarials and statins is promising, they should be evaluated as alternatives to warfarin, particularly in patients with persistent thrombosis. In addition, low-dose aspirin is recommended for people with cardiovascular risk factors. Although randomized clinical trials are now underway, the available data are insufficient to recommend direct oral anticoagulants (as well as novel oral anticoagulants) to prevent aPL-antibody-mediated thromboembolic events. It is recommended to administer intravenous immunoglobulin infusions, pulse corticosteroids, and/or plasmapheresis to patients with NPSLE and severe anti-phospholipid syndrome (APS). Numerous small series and case reports found that the use of eculizumab into these treatments was beneficial [114]. There is a vast variety of pharmacotherapies for NPSLE, each of which requires careful evaluation, illustrating the sensitivity of treatment selection for this disease.

In addition, six months of oral cyclophosphamide therapy followed by azathioprine maintenance medication was successful in treating lupus psychosis. The addition of Rituximab (or a different anti-CD20 monoclonal antibody) to the NPSLE therapy procedure requires consideration, notwithstanding the unreliability of the data supporting this practice. The efficacy of Rituximab was evaluated in ten patients with persistent NPSLE who saw rapid and considerable improvement in clinical symptoms and signs, consistent with radiological findings [115]. In a retrospective study of pediatric patients with NPSLE, Rituximab was also effective and largely safe [116]. These results demonstrate that the CD20 receptor plays a critical role in the pathogenesis of NPSLE, consistent with the immune cells that express this receptor, highlighting the importance of immune system-induced inflammation in this disease.

4. Remarks for future clinical research: the role of bioinformatics and immunoinformatics

Immunological investigations are defined with the help of the generation of rapidly piling quantities of information, that is backed via genetics and proteomics projects and large-scale evaluation of pathogen- and antigen and host reactions. The need to store, handle and evaluate this quickly expanding source of biological, clinical as well as epidemiological information led to the conception of the field known as computational immunology or Immunoinformatics. Immunoinformatics employs computerized approaches or sources that can be utilized in the exploring of immune system actions. This field resides at the crossroad of experimental and computer sciences and utilizes domain-exclusive databanks, computer simulations, and approaches drawn from artificial intelligence. For instance, computational or artificial intelligence simulations are rapidly being utilized in order to trigger as well as enhance scientists’ comprehension of immunity patterns, including antigen modification and antigen-presenting, and for assessment of host and pathogenic genomes [117].

Immunoinformatics has been utilized to shift the immune profile by designing immunogenic candidates which implement various epitopes that play a role in disease. We suggest that a pipeline should be developed to identify differentially expressed genes and biomarkers by Bioinformatics [118, 119] and shift the immune system via Immunoinformatics/in silico efforts (e.g., reverse vaccinology) [120, 121, 122]. Moreover, Bioinformatics can help to recognize plausible therapeutic targets by the detection of differentially expressed genes [123].

There is no definitive treatment for COVID-19 and vaccines, despite bringing major success, have failed to completely eradicate the disease and have side effects [124, 125].

In addition, guideline makers should take into account the influence of the current Coronavirus disease-2019 (COVID-19) pandemic on SLE and its CNS involvements, which are well-known [126]. A study showed that COVID-19 morbidity could be moderately raised in most SLE cases, even though restricted data can be inferred on more critical patients [127].

Cytokines and hyperinflammatory responses are common features of COVID-19 and SLE [128, 129]. Inflammasomes are valuable therapeutic targets that are implicated in a wide range of disorders, such as neuropsychiatric and neurodegenerative diseases [130], eye disorders [131], cardiovascular disorders, and others [132]. Inflammasomes have also been shown to be involved in SLE. Induction of the inflammasome, a multimeric complex that triggers caspase-1. After that, the cytokines IL-1β and IL-18 mature, which are key to SLE pathogenesis [133].

Finally, we suggest that novel antibodies other than classical factors included in SLE criteria are developed. For instance, autoantibodies to the δ-Opioid Receptor act as opioid inducers and exhibit immunomodulatory function. Anti-DOR autoantibodies may function to stimulate the cell-mediated/Th1 arm. In SLE patients, therefore, elevated levels of anti-MOR Abs could worsen the disease, whereas increasing the anti-DOR autoantibodies could aid to deviate to Th1-type immune feedback [134, 135].

5. Conclusions

Research efforts have characterized NPSLE and SLE. The significance of NPSLE, in particular, has been underrated as it affects a great portion of SLE cases. More studies should aim the development of novel treatments because, despite clinical experiment, none of the laboratory or neuroimaging biomarkers for diagnosing NPSLE have been found accurate or reliable in clinical practice. New biomarkers may enable clinicians to make a more objective assessment of patients’ conditions. NPSLE therapy and management may be complicated at different phases. These difficulties are assigning patients to SLE, diagnosis based on vague presentations, and the restrictions and imprecise currently available therapy armamentarium. Development of treatments for SLE could be facilitated via Immunoinformatics/in silico technology to engineer and evaluate candidates rapidly. Finally, we believe the next-generation combinational therapeutic regimen should be tested to enable major advancements.

Acknowledgments

We thank the members of USERN MUBabol Office for their support.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

None.

Appendix A

Yu HH, Lee JH, Wang LC, Yang YH, Chiang BL. Neuropsychiatric manifestations in pediatric systemic lupus erythematosus: A 20-year study. Lupus. 2006;15(10):651-657

Costa Reis P, Nativ S, Isgro J, Yildirim-Toruner C, Imundo L, Eichenfield A. Neuropsychiatric lupus in children. Pediatric and Rheumatolology Online Journal. 2011;9(Suppl. 1):P264

Torreggiani S, D’Errico MM, Di Landro G, Cuoco F, Petaccia A, Cappellari A, et al. Neuropsychiatric manifestations in juvenile systemic lupus erythematosus: What’s the weight of headache? Pediatric Rheumatology. 2014;12(1):1-2

Zhang E, Jorgensen TN. Neuropsychiatric SLE: From immune mechanisms to clinical management. Lupus-New Advances and Challenges. 2018