Central Nervous System Lupus Research Articles

Melatonin as a potential adjunct therapy for central nervous system lupus: evidence from the MRL/lpr mouse model.

Melatonin as a potential adjunct therapy for central nervous system lupus: evidence from the MRL/lpr mouse model.

Unfavorable Outcomes Associated With Glucocorticoid Use in Current Standard-of-Care Management of Systemic Lupus Erythematosus in Canada.

Our objective was to describe the administration of glucocorticoids (GCs) and characterize its association with organ damage in a longitudinal systemic lupus erythematosus (SLE) cohort over a time period spanning the introduction of biologics in Canada. A retrospective observational study was conducted using data from a large SLE cohort in Canada, including adults without lupus nephritis or central nervous system lupus. Patients were observed from time of entry into the cohort to the last available clinic visit (up to December 31, 2020), with a minimum of 24 months of follow-up. Demographic and clinical characteristics, including average disease activity, treatment administration, and prevalence of organ damage, were examined. Organ damage was stratified by GC administration. A total of 1,255 patients were included. The mean follow-up duration was 10.5 (SD 8.6) years. One hundred eighty-two (15%) patients had organ damage at baseline. More than 80% of patients were prescribed GCs over the follow-up period, almost all patients had long-term GC treatment, and only 5% of patients took any biologics. Organ damage was more frequent in patients with a higher average GC dose and greater years of GC exposure. In this large cohort of patients with SLE, the majority of patients continue to rely on GC for SLE symptom management, with limited administration of biologics. GC administration was correlated with increased irreversible organ damage. Access to novel GC-sparing treatment options is critical to improve long-term outcomes for patients with SLE, especially given the continued reliance on GC despite the introduction of biologics.

An Interesting Case Series of Neuropsychiatric Lupus: A Combination of Inflammatory and Thrombotic Origin

Systemic Lupus Erythematosus (SLE) is a versatile autoimmune disorder with multisystem organ involvement, most commonly involving the skin, joints, vasculature, and associated immunological abnormalities. The hallmark of SLE is the presence of circulating non organ specific humoral autoantibodies synthesised by so-called T cell-dependent B cells, which are germline encoded. Patients with SLE can exhibit symptoms of Central Nervous System (CNS) involvement, termed CNS Lupus, which may also have associated psychiatric manifestations, where the entity gets the designation of Neuropsychiatric SLE (NPSLE). CNS Lupus is often a diagnosis of exclusion, as there are many other aetiological factors that could result in seizures and encephalitis picture. A detailed examination of patients presenting with isolated late-onset seizures is very helpful in uncovering Connective Tissue Disorder (CTD) as the cause of seizures. The manifestations of NPSLE (19 Neuropsychiatric syndromes) can be focal and diffuse, ranging from non specific symptoms such as headache and cognitive impairment to severe manifestations such as memory loss, seizures, stroke, and suicidal intentions. Neuropsychiatric symptoms often occur during the first year of SLE but can rarely also be the presenting symptom of the disease. Antiphospholipid antibodies (Anticardiolipin, Lupus anticoagulant, Anti β2 glycoprotein) and Anti Ribosomal P antibodies are among the frequently associated antibodies in NPSLE, which, in turn, increase the risk of both focal and diffuse neurological complications. A single episode of abortion or miscarriage is a vital clue for a detailed work-up of female patients for the possibility of an underlying occult potential of CNS Lupus in the absence of seizures. The present case series focuses on five female patients who presented with NP symptoms, and finally, the cause was attributed to the involvement of CNS in SLE after excluding other possible organic causes.

Enigmatic CNS Lupus Vasculitis: A Heuristic Approach

Systemic lupus erythematosus is an autoimmune disease affecting all organs of the body. It has a higher incidence in women and can affect the central nervous system (CNS) in 10% to 20% of cases. Any structure in the CNS can be involved, resulting in a varied and often complex symptomatology. CNS lupus vasculitis is an even rarer manifestation characterized by small vessel inflammation that can result in vessel thrombosis and necrosis. We present the case of a 31-year-old woman with a history of systemic lupus erythematosus and Sjögren’s syndrome who was treated at our institution for an acute exacerbation of lupus complicated by CNS lupus vasculitis. This case was particularly challenging due to concurrent bacteremia and a travel history that broadened the differential diagnosis widely, thus requiring our input as infectious disease consultants. CNS lupus vasculitis is a diagnosis of exclusion that requires a high level of clinical suspicion to arrive at a prompt diagnosis paired with aggressive management to guarantee good outcomes. In this report, we share our stepwise approach to this challenging case in a didactic manner to benefit trainees and independent infectious diseases providers who may encounter similar clinical scenarios in their practice.

Transcranial direct current stimulation for focal status epilepticus or lateralized periodic discharges in four patients in a critical care setting.

Transcranial direct current stimulation (tDCS) has been advocated for various neurological conditions, including epilepsy. A 1-4-mA cathodal current applied to the scalp over a seizure focus can reduce spikes and seizures. This series of four patients with focal status epilepticus is among the first case series to demonstrate benefit of tDCS in the critical care setting. Patients in the intensive care unit were referred for tDCS treatment when focal status epilepticus or clinically relevant lateralized periodic discharges did not resolve with conventional antiseizure medications and anesthetics. Battery-powered direct cathodal current at 2mA was delivered by an ActivaDose (Caputron) tDCS device via a saline-soaked sponge on the scalp over the seizure focus. Anode was on the contralateral forehead or shoulder. Treatment was for 30 min, repeated twice in a day, then again 1-4 times more over the next few days. Three females and one male, aged 34-68 years, were treated. Etiologies of status epilepticus were posterior reversible encephalopathy syndrome in association with immunosuppressants for a liver transplant, perinatal hypoxic-ischemic injury, a prior cardioembolic parietal stroke, and central nervous system lupus. tDCS led to significant reduction of interictal spikes (.78 to .38/s, p< .0001) in three cases and electrographic seizures (3.83/h to 0/h, p< .001) in two cases. Medication reductions were enabled in all cases subsequent to tDCS. The only side effect of tDCS was transient erythema under the sponge in one case. Two patients died of causes unrelated to tDCS, one was discharged to a nursing home, and one became fully responsive as seizures were controlled with tDCS. Spikes and electrographic seizure frequency significantly improved within 1 day of tDCS. Results are potentially confounded by multiple ongoing changes in medications and treatments. These results might encourage further investigation of tDCS in the critical care setting, but verification by controlled studies will be required.

47 Systemic lupus erythematosus in Tunisian children: a case series

BackgroundChildhood–onset systemic lupus erythematosus (c-SLE) is the prototype of a multisystemic, inflammatory, heterogeneous autoimmune condition, characterized by simultaneous or sequential organ involvement. Compared with the adult onset form, c-SLE is thought to have a worse prognosis.ObjectivesTo review the epidemiological, and bio-clinical, characteristics of a c-SLE case series.MethodsThe files of patients diagnosed as c-SLE in the pediatrics department of Monastir, Tunisia from January 2004 to March 2022 were reviewed. Mean and standard-deviations were used to express normally-distributed variables, as verified by the Kolmogorov-Smirnov statistical test.ResultsFourteen patients were collected. Female to male ratio was 6:1. Mean ages at lupus onset and diagnosis were 9.9 ± 1.4 years, [5–13.8 years] and 10.75 ± 2.3 years [6–14 years], respectively. Only two children had a family history of autoimmune disease.The initial admission was motivated primarily by skin and musculoskeletal manifestations, in 64.3% and 51.7% of cases, respectively. General signs (fever, asthenia) were observed in 35.7% of cases, hematological and gastrointestinal manifestations in 28.6% of cases each. In 3 cases, upper gastric endoscopy was performed prior to admission, in view of abdominal pain and vomiting.The physical examination noted various anomalies. Malar rash (50%) and discoid lupus (28.6%) were the most frequent cutaneous manifestations, while skin biopsy was performed in three cases, all favorable for lupus. The musculoskeletal manifestations comprised arthralgia (71.4%), arthritis and myositis (14.3% each). Hematological manifestations included thrombocytopenia and leukopenia in 4 cases each, as well as 3 cases of auto-immune hemolytic anaemia and splenomegaly. Renal manifestations were dominated by proteinuria in 7 cases, followed by hematuria in 6 cases, and 2 cases of hypertension (associated with renal failure in one case). The renal biopsy was performed in one case showed a stage-2 lupus nephritis. Pleural effusion was observed in 3 cases, 3 cases of pneumonia, 2 cases of pericarditis, one case of myo-pericarditis and one case of central nervous system (CNS) lupus.Relevant results of the laboratory workup are illustrated in the following table:47 Table 1Laboratory testPerformed (%)Abnormal results (%)Erythrocyte sedimentation rate14 (100%)13 (92%)Antinuclear anti-bodies14 (100%)13 (92%)AntiDNA antibodies7 (50%)5 (71%)AntiSm antibodies8 (57%)5 (62%)Antiphospholipid antibodies8 (57%)5 (62%)Complement11 (78%)9 (81%)The formal diagnosis of SLE was established according to the ACR-1997 criteria in 7 cases (50%), the SLICC-2012 in 4 cases (28.6%) and EULAR/ACR-2019 in 3 cases (21.4%). The c-SLE diagnosis was associated with coeliac disease and Hashimoto thyroiditis in one case each.The therapeutic management was based on corticosteroids in 11 cases, followed by hydroxychloroquine in 3 cases, while cyclophosphamides and immunoglobulin were used for one case each.The outcomes were heterogeneous. Among 11 patients with sufficient follow-up, 6 cases of remission and 2 cases of relapse were noted. Major adverse events were not infrequent: one case each of cardiac tamponade, macrophage activation syndrome and severe CNS lupus were observed, all fatal.ConclusionChildhood–onset systemic lupus is a challenging disease, both to diagnose and to treat. The development of new criteria of higher specificity and sensitivity has greatly helped identify the incomplete types of lupus and allow for early stage diagnosis, and therefore prevent the serious complications of the disease.

85 Systemic lupus erythematosus in Tunisian children: a case series

BackgroundChildhood–onset systemic lupus erythematosus (c-SLE) is the prototype of a multisystem, inflammatory, heterogeneous autoimmune condition, characterized by simultaneous or sequential organ involvement. Compared with the adult-onset form, c-SLE have a worse prognosis.ObjectivesTo review the epidemiological, and bio-clinical, characteristics of a c-SLE case series.MethodsThe files of patients diagnosed as c-SLE in the pediatrics department of Monastir, Tunisia from January 2004 to March 2022 were reviewed. Mean and standard-deviation were used to express normally-distributed variables, as verified by the Kolmogorov-Smirnov statistical test.ResultsFourteen patients were collected. Female to male ratio was 6:1. Mean ages at lupus onset and diagnosis were 9.9 ± 1.4 years, [5–13.8 years] and 10.75 ± 2.3 years [6–14 years], respectively. Only two children had a family history of autoimmune disease.The initial admission was motivated primarily by skin and musculoskeletal manifestations, in 64.3% and 51.7% of cases, respectively. General signs (fever, asthenia) were observed in 35.7% of cases, hematological and gastrointestinal manifestations in 28.6% of cases each. In 3 cases, upper gastric endoscopy was performed prior to admission, in view of abdominal pain and vomiting.The physical examination noted various abnormalities. Malar rash (50%) and discoid lupus (28.6%) were the most frequent cutaneous manifestations, while skin biopsy was performed in three cases, all in keeping with lupus. The musculoskeletal manifestations were arthralgia (71.4%), arthritis and myositis (14.3%). Hematological manifestations included thrombocytopenia and leukopenia in 4 cases, as well as 3 cases of auto-immune hemolytic anaemia and splenomegaly. Renal manifestations were proteinuria in 7, haematuria in 6, and hypertension in 2 (with renal failure in one of the patients). The renal biopsy that was performed in one subject showed a class 2 lupus nephritis. Pleural effusion was observed in 3, pneumonia in 3, pericarditis in 2, myo-pericarditis in 1 and central nervous system (CNS) lupus in 1.Relevant results of the laboratory workup are illustrated in the following table:85 Table 1Laboratory testPerformed (%)Abnormal results (%)Erythrocyte sedimentation rate14 (100%)13 (92%)Antinuclear anti-bodies14 (100%)13 (92%)AntiDNA antibodies7 (50%)5 (71%)AntiSm antibodies8 (57%)5 (62%)Antiphospholipid antibodies8 (57%)5 (62%)Complement11 (78%)9 (81%)The formal diagnosis of SLE was established according to the ACR-1997 criteria in 7 cases (50%), the SLICC-2012 in 4 cases (28.6%) and EULAR/ACR-2019 in 3 cases (21.4%). The c-SLE diagnosis was associated with coeliac disease and Hashimoto thyroiditis in two of the subjects respectively.The therapeutic management was based on corticosteroids in 11 cases, hydroxychloroquine in 3, while cyclophosphamides and immunoglobulin were used for two subjects respectively.The outcomes were heterogeneous. Among 11 patients with sufficient follow-up, 6 cases of remission and 2 cases of relapse were noted. Major adverse events were not infrequent: one case each of cardiac tamponade, macrophage activation syndrome and severe CNS lupus were observed, all fatal.ConclusionChildhood–onset systemic lupus is a challenging disease, both to diagnose and to treat. The development of new criteria of higher specificity and sensitivity has greatly helped identify the incomplete types of lupus and allow for early-stage diagnosis, therefore preventing the serious complications of the disease.

Evaluation of anifrolumab safety in systemic lupus erythematosus: A meta-analysis and systematic review.

ObjectivesSystemic lupus erythematosus (SLE) is a chronic autoimmune disease, and type I interferon plays an important role in its pathogenesis. Anifrolumab is a new strategy for the treatment of systemic lupus erythematosus. It could antagonize the activity of all type 1 interferons by binding with type I interferon receptor subunit 1. The aim of our study was to evaluate the safety of anifrolumab in patients with moderate to severe SLE (excluding patients with active severe lupus nephritis or central nervous system lupus).MethodsFour databases (Embase, Cochrane, PubMed, Web of Science) were systematically searched from inception until December 2021 for randomized controlled trials (RCTs) evaluating the safety of anifrolumab versus placebo in SLE patients. Then, the incidence of adverse events in each study was aggregated using meta-analysis.ResultsA total of 1160 SLE patients from four RCTs were included in the analysis. Serious adverse events were less common in the anifrolumab group than in the placebo group (RR: 0.76, 95% CI: 0.59-0.98, p<0.03). The most common adverse events included upper respiratory tract infection (RR: 1.48, 95% CI: 1.13-1.94, P=0.004), nasopharyngitis (RR: 1.66, 95% CI: 1.25-2.20, P=0.0004), bronchitis (RR: 1.96, 95% CI: 1.32-2.92, P=0.0009), and herpes zoster (RR: 3.40, 95% CI: 1.90-6.07, P<0.0001).ConclusionAnifrolumab is considered a well-tolerated option for the treatment of SLE patients with good safety.Systematic Review Registration https://inplasy.com, identifier 202230054.

Exercise alleviates symptoms of CNS lupus

Systemic lupus erythematosus (lupus) is a global health problem where 20–80% patients display cognitive problems and central nervous system (CNS) dysfunction. Early diagnosis and treatment of lupus remains a clinical challenge. Exercise improves experimental lupus nephritis. However, the effects of exercise in CNS lupus remains unknown. This study investigates the effects of controlled exercise (CE) that consisted of treadmill walking (5 m/min for 10 min everyday) on experimental CNS lupus using the well-established mouse model, MRL/lpr mice. The MRL/lpr mice were subjected to CE from 8 weeks (preclinical) to 16 weeks (disease). Multiplex gene expression analysis revealed significant upregulation of genes involved in neurite growth, proliferation and synaptic plasticity, and a decrease in inflammatory genes including complement proteins, NFkB, chemokines and cytokines in exercised mice compared to the unmanipulated, age-matched controls. The loss of blood–brain barrier integrity, astrogliosis and edema seen in MRL/lpr mice were reduced with exercise. Exercised mice performed better in behavioral assessments such as open field, nesting, and tail suspension test. For the first time our results show that a supervised, well-regulated and controlled exercise regimen alleviates CNS lupus and could potentially serve as an intervention strategy to improve the quality of life. Exercise could also serve as an adjunct therapy for lupus and other neuroinflammatory diseases, thereby reducing the need for the current therapies with toxic side effects. The validity of the findings and a safe exercise regimen needs to be established by additional studies in patients.

Formal neurocognitive function and anti-N-methyl-D-aspartate receptor antibodies in paediatric lupus

ObjectiveSLE is a chronic multisystem autoimmune inflammatory disease impacting a number of organs, including the central nervous system (CNS). The pathophysiology of CNS lupus is multifactorial, making diagnosis problematic. Neurocognitive...

Pediatric Inflammatory and Autoimmune Neurologic Disorders at a Tertiary Medical Center.

To describe the spectrum of pediatric inflammatory neurologic diseases and compare the sensitivity of ancillary testing for these diagnoses. We analyzed clinical features and outcomes of 98 children with an immune-mediated central nervous system disorder. We compared sensitivities of each diagnostic modality. We identified the following diagnoses: acute cerebellar ataxia (n = 14; 14.3%), acute demyelinating encephalomyelitis (n = 13; 13.3%), multiple sclerosis (MS) (n = 18; 18.4%), anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDAR encephalitis) (n = 15; 15.3%), encephalitis not otherwise specified (n = 12; 12.2%), and "Other" (n = 26; 26.5%). "Other" included acute transverse myelitis, neuromyelitis optica, central nervous system lupus, primary central nervous system vasculitis, Rasmussen encephalitis, opsoclonus myoclonus ataxia syndrome, and clinically isolated syndrome. The mean age of onset of all diagnoses was 7.9 ± 5.5 years. The diagnostic sensitivity of magnetic resonance imaging (MRI) for acute demyelinating encephalomyelitis and multiple sclerosis was 92.3% and 94.4%, respectively. Cerebrospinal fluid was sensitive for multiple sclerosis in 92.3%, where 75% of patients had cerebrospinal fluid oligoclonal bands. Electroencephalogram (EEG) coupled with cerebrospinal fluid studies was highly sensitive for anti-NMDAR encephalitis (100%). EEG was sensitive for acute demyelinating encephalomyelitis and encephalitis not otherwise specified (77.8% and 80%). No diagnostic studies were sensitive for acute cerebellar ataxia. Seventy-three percent of patients with multiple sclerosis had residual deficits. Thirty-six percent of anti-NMDAR encephalitis patients were nonverbal and wheel-chair bound. We found that MRI is useful for detecting multiple sclerosis and acute demyelinating encephalomyelitis, cerebrospinal fluid is helpful in diagnosing multiple sclerosis and anti-NMDAR encephalitis, and EEG is often abnormal in suspected anti-NMDAR encephalitis, acute demyelinating encephalomyelitis, and encephalitis not otherwise specified. Neurologic outcome at follow-up was unfavorable in patients with multiple sclerosis and anti-NMDAR encephalitis.

Refractory Proteinuria in a Patient with Lupus Nephritis.

### Case Answer A 43-year-old woman with a 20-year history of SLE and a 13-year history of lupus nephritis was referred to our hospital for evaluation of worsening proteinuria. During the past 20 years, the patient had experienced multiple flares of SLE, including central nervous system lupus and biopsy-proven renal flares, and hence, had received several pulses of intravenous methylprednisolone and cyclophosphamide. Four years before presentation, kidney biopsy to investigate increased urinary protein excretion of 6 g/d demonstrated both active and chronic glomerular lesions of lupus nephritis, including mesangial proliferation; wire-loop lesions; and numerous deposits in the subendothelial, intramembranous, subepithelial, and mesangial areas. After another pulse therapy, mycophenolate mofetil 1000 mg was added to prednisolone 10–15 mg/d. Azathioprine therapy was attempted but discontinued due to pancytopenia. Tacrolimus was given for a short period but discontinued due to …

Central nervous system lupus presenting as rhombencephalitis responding to aggressive immunotherapy: A unique case

AbstractBackgroundSystemic lupus erythematosus (SLE) is the prototypic autoimmune connective tissue disorder (CTD) usually affecting young females. Central nervous system lupus is a serious complication encountered in SLE cases. Predominant involvement of rhombencephalon in patients of SLE at the first contact with health care professional has not been seen and described frequently in the literature. It still remains a diagnostic and therapeutic challenge.Case presentationThis paper describes a case of SLE in an adolescent female who was diagnosed as having rhombencephalitis, which is a rare presentation of SLE.ConclusionsCentral nervous system lupus should be included in the provisional diagnosis of any young female patient presenting with complicated neurologic manifestations over the background of joint pain or fever or headache or confusion or psychosis, to avoid misdiagnosis and aid in timely institution of aggressive immunotherapy.

Treatment patterns and medical cost of systemic lupus erythematosus patients in Japan: a retrospective claims database study

Aim: To describe the characteristics and medication treatment patterns, healthcare resource utilization (HRU), and associated costs in Japanese patients with systemic lupus erythematosus (SLE).Methods: Claims data from the Japan Medical Data Center (JMDC) database were used to identify patients with SLE-related claims from 2010 to 2017. Algorithms were developed to retrospectively categorize patients by disease severity, treatment experience, and SLE-related manifestations such as lupus nephritis and central nervous system lupus. Descriptive and multivariate analyses were used to describe treatment pattern and estimate HRU and associated costs for the SLE cohort overall and by disease severity and complications.Results: Among 4,733 eligible patients, 2,072 (43.8%) were treatment naïve, 2,214 (46.8%) were previously treated for SLE, and 447 (9.4%) did not receive any treatment. Mean (SD) age of the total SLE cohort was 45.2 (13.1) years and mean (SD) follow-up duration was 1,137.3 (758.0) d. Based on disease severity, 1,383 (29.2%) patients had mild, 2,619 (55.3%) patients had moderate, and 731 (15.4%) patients had severe SLE. Patients on glucocorticoids (both oral and parenteral) received add-on medications the most (35.5%, p < .001). Mean annual cost per SLE patient in the post-index period, inclusive of hospitalizations, outpatient visits, and pharmacy was ¥436,836; ¥1,010,772; and ¥2,136,780 for patients with mild, moderate, and severe SLE, respectively.Limitations: The database only captured information on patients up to 75 years of age. Due to the nature of the database, biases regarding conditions that attribute to the spectrum of SLE severity, flare incidences, or individual physical status cannot be ruled out.Conclusions: This study describes the treatment patterns and economic burden experienced by Japanese patients with SLE. The results highlight an unmet need to derive better treatment strategies for patients with SLE to effectively address the disease burden in Japan.

Characteristics and Symptom Severity of Patients Reporting Systemic Lupus Erythematosus in the PatientsLikeMe Online Health Community: A Retrospective Observational Study.

IntroductionOnline health communities and research networks such as PatientsLikeMe (PLM) capture patient perspectives of diseases, including systemic lupus erythematosus (SLE). We performed a retrospective observational study of data provided by patients in the PLM SLE community to characterize demographics, clinical characteristics, patient experience, and symptom impact.MethodsAdults who registered with PLM in 2011–2017 and reported SLE diagnosis and treatment with one or more SLE-related drug (antimalarials, immunosuppressives, corticosteroids, calcineurin inhibitors, or biologics) were included in the analysis. Information reported within 30 days from PLM registration was used to assess patient eligibility; demographics and clinical characteristics; and primary outcome measures of SLE treatments, symptoms, primary lupus manifestations, and comorbidities.ResultsAmong 21,101 PLM members included in this analysis, median ages at registration, onset of SLE symptoms, and SLE diagnosis were 46 years (interquartile range [IQR] 38–53, n = 21,101), 30 years (IQR 21–39; n = 6489), and 36 years (IQR 27–44; n = 6936), respectively. Most patients were female (96.8%, n = 20,370). Country of residence was reported by 19,502 patients (92.4%), of whom 18,491 (94.8%) were US residents. Race was recorded by 17,994 patients (85.3%), of whom 67.8% were white and 22.4% were black/African American. Patients reported a mean of 2.2 SLE-related medications, including antimalarials (83.8%), corticosteroids (78.8%), immunosuppressives (32.3%), and biologics (9.4%). Fatigue, pain, and joint pain were rated as moderate or severe by at least 80% of patients who reported these symptoms. Reported primary lupus manifestations and comorbidities included fibromyalgia (7.9%), discoid lupus (6.8%), lupus nephritis (6.3%), rheumatoid arthritis (4.8%), subacute cutaneous lupus (4.7%), central nervous system lupus (3.9%), Sjögren’s syndrome (3.9%), and lupus pneumonitis (3.1%).ConclusionsAge, sex, and race of patients in the PLM SLE community are broadly consistent with characteristics of the general SLE population in the United States. The PLM SLE population may provide valuable data on self-reported patient experience.Plain Language SummaryPlain language summary available for this article.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-020-00195-7) contains supplementary material, which is available to authorized users.

Update on the pathogenesis of central nervous system lupus.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is an emerging frontier in lupus care encompassing a wide spectrum of clinical manifestations. Its pathogenesis remains poorly understood because of the complexity of pathophysiologic mechanisms involved and limited access to tissue. We highlight recent advances in the pathophysiology of neuropsychiatric lupus. Disruption of blood-brain barrier (BBB) facilitating entrance of neurotoxic antibodies into the central nervous system (CNS), neuroinflammation and cerebral ischemia are the key mechanisms. Disruption of the BBB may occur not only at the traditional BBB, but also at the blood-cerebrospinal fluid barrier. Certain autoantibodies, such as anti-N-methyl-D-aspartate receptors, antiribosomal P and antiphospholipid antibodies may cause injury in subsets of patients with diffuse neuropsychiatric disease. Activation of microglia via autoantibodies, interferon-a or other immune reactants, may amplify the inflammatory response and promote neuronal damage. New inflammatory pathways, such as TWEAK/Fn14, Bruton's tyrosine kinase, Nogo-a and ACE may represent additional potential targets of therapy. Novel neuroimaging techniques suggest alterations in brain perfusion and metabolism, increased concentration of neurometabolites, indicative of glial activation, vasculopathy and neuronal impairment. NPSLE encompasses a diverse phenotype with distinct pathogenic mechanisms, which could be targeted by novel therapies or repositioning of existing drugs.

Establishment and characterization of induced pluripotent stem cells (iPSCs) from central nervous system lupus erythematosus

Involvement of the central nervous system (CNS) is an uncommon feature in systemic lupus erythematosus (SLE), making diagnosis rather difficult and challenging due to the poor specificity of neuropathic symptoms and neurological symptoms. In this work, we used human‐induced pluripotent stem cells (hiPSCs) derived from CNS‐SLE patient, with the aim to dissect the molecular insights underlying the disease by gene expression analysis and modulation of implicated pathways. CNS‐SLE‐derived hiPSCs allowed us to provide evidence of Erk and Akt pathways involvement and to identify a novel cohort of potential biomarkers, namely CHCHD2, IDO1, S100A10, EPHA4 and LEFTY1, never reported so far. We further extended the study analysing a panel of oxidative stress‐related miRNAs and demonstrated, under normal or stress conditions, a strong dysregulation of several miRNAs in CNS‐SLE‐derived compared to control hiPSCs. In conclusion, we provide evidence that iPSCs reprogrammed from CNS‐SLE patient are a powerful useful tool to investigate the molecular mechanisms underlying the disease and to eventually develop innovative therapeutic approaches.

Balancing immunosuppression and infection: recurrent enterovirus encephalitis in SLE

A young woman with systemic lupus erythematosus (SLE) developed recurrent enterovirus meningoencephalitis while taking prednisolone, azathioprine and rituximab. After reducing the immunosuppression, she developed a central nervous system (CNS) flare...

Monophasic Disease Course in Systemic Lupus Erythematosus.

Disease course in systemic lupus erythematosus (SLE) is primarily relapsing-remitting. Long quiescent and chronically active patterns are less frequent. We recently described an atypical "monophasic" course in a small number of patients. The aim of the present study was to assess the prevalence and characteristics of such patients in a defined SLE cohort. The inception patients of the University of Toronto Lupus Clinic (enrolled within 18 mos of diagnosis) were investigated. No time interval > 18 months was allowed between consecutive visits. A monophasic course was defined as Systemic Lupus Erythematosus Disease Activity Index 2000 = 0 (serology excluded), achieved within 5 years since enrollment and maintained for ≥ 10 years. Descriptive statistics were used. Of 267 inception patients, 27 (10.1%) achieved prolonged clinical remission (≥ 10 yrs) and 20 (7.5%) sustained remission for the entire followup (18 yrs on average). Twelve patients were receiving no maintenance treatment 10 years after achieving remission. Clinical manifestations at diagnosis (apart from skin and musculoskeletal involvement) included 25% in each of central nervous system involvement and lupus nephritis (LN). Half the patients were serologically active. Ten years after achieving remission, two-thirds of the patients had discontinued glucocorticosteroids; the remaining were treated with 5 mg/day on average. Seven patients relapsed after 10 years, 4 with arthritis, 2 LN, and 1 catastrophic antiphospholipid syndrome. A monophasic disease course was observed in 7.5% in this inception cohort. Patients sustained remission for 18 years on average, eventually without medications. Further study of such patients may provide unique pathophysiologic insights for SLE.

Microglia-dependent synapse loss in type I interferon-mediated lupus.

Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.