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http://orcid.org/0000-0001-9374-5279 Diana Valdés Cabrera 1 ,
Tala El Tal 2 ,
Ibrahim Mohamed 2 ,
Santiago Eduardo Arciniegas 3 ,
Stephanie Fevrier 1 ,
Justine Ledochowski 4 and
Andrea M Knight 1 , 2
1 Neurosciences and Mental Health , The Hospital for Sick Children , Toronto , Ontario , Canada
2 Rheumatology , The Hospital for Sick Children , Toronto , Ontario , Canada
3 Child Health Evaluative Sciences , The Hospital for Sick Children , Toronto , Ontario , Canada
4 Psychology , The Hospital for Sick Children , Toronto , Ontario , Canada
Correspondence to Dr Andrea M Knight; andrea.knight{at}sickkids.ca

Background Cognitive dysfunction (CD) is highly prevalent in systemic lupus erythematosus (SLE), yet the underlying mechanisms are poorly understood. Neuroimaging utilising advanced MRI metrics may yield mechanistic insights. We conducted a systematic review of neuroimaging studies to investigate the relationship between structural and diffusion MRI metrics and CD in SLE.

Methods We systematically searched several databases between January 2000 and October 2023 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Retrospective and prospective studies were screened for search criteria keywords (including structural or diffusion MRI, cognitive function and SLE) to identify peer-reviewed articles reporting advanced structural MRI metrics and evaluating CD in human patients with SLE.

Results Eighteen studies (8 structural MRI, 9 diffusion MRI and 1 with both modalities) were included; sample sizes ranged from 11 to 120 participants with SLE. Neurocognitive assessments and neuroimaging techniques, parameters and processing differed across articles. The most frequently affected cognitive domains were memory, psychomotor speed and attention; while abnormal structural and/or diffusion MRI metrics were found more consistently in the hippocampus, corpus callosum and frontal cortex of patients with SLE, with and without clinically diagnosed central nervous system involvement.

Conclusion Advanced structural MRI analysis can identify total and regional brain abnormalities associated with CD in patients with SLE, with potential to enhance clinical assessment. Future collaborative, longitudinal studies of neuroimaging in SLE are needed to better characterise CD, with focus on harmonised neurocognitive assessments, neuroimaging acquisitions and postprocessing analyses and improved clinical characterisation of SLE cohorts.

Systemic Lupus Erythematosus
Magnetic Resonance Imaging
Health-Related Quality Of Life

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/lupus-2024-001214

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Cognitive dysfunction is a common symptom for patients with systemic lupus erythematosus (SLE), yet often difficult to attribute to neuropsychiatric SLE (NPSLE) using existing clinical tools such as conventional MRI. Utilising advanced neuroimaging to examine structural brain abnormalities that may increase our understanding of the mechanisms underlying cognitive dysfunction in SLE.

WHAT THIS STUDY ADDS

The results of this literature review examining structural MRI abnormalities in SLE and their associations to cognitive dysfunction indicate that memory and attention are the most consistently impaired cognitive domains, associated with abnormalities in the hippocampus and corpus callosum. Additionally, longer disease duration and higher cumulative glucocorticoid doses were reported in association with abnormal brain structural metrics in patients with SLE.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

The study identifies current gaps in the application or neuroimaging to understand cognitive dysfunction in NPSLE, and highlights opportunities to optimise utilisation of advanced neuroimaging through harmonised protocols and pipelines for collaborative research in NPSLE. It also highlights the need for more longitudinal studies, and additional research including children with SLE.

Introduction

Neuropsychiatric systemic lupus erythematosus (NPSLE) remains one of the most challenging manifestations of SLE due to the broad spectrum of symptoms (up to 19 clinical syndromes affecting either the central—CNS or the peripheral nervous system) and limited understanding of the underlying disease neurobiology. 1 These syndromes can be categorised into focal or diffuse, with the latter manifestations showing highest prevalence, mainly as cognitive dysfunction (CD, ~80%) 2 3 and mood disturbances (~65%). 1 3 In addition, neuropsychiatric involvement occurs more frequently in childhood-onset SLE (cSLE, up to 95%) than in adult-onset SLE (aSLE, 11%–81%), and it strikes during a critical period of neurodevelopment that may potentially lead to irreversible negative impact in cognitive function. 4

CD in SLE has been defined by the American College of Rheumatology (ACR) as a significant deficit in one or several of the following domains: attention, reasoning, executive skills, memory, visual-spatial processing, language and psychomotor speed, 5 with attention and memory among the most regularly affected cognitive domains. 6 7 CD due to NPSLE could be a consequence of several pathologic mechanisms related to vascular involvement, blood–brain barrier breach and cell-mediated inflammation. 8 Yet, NPSLE pathogenesis is still poorly understood, making diagnosis and monitoring particularly challenging. CD may also be due to other factors and, therefore difficult to attribute to NPSLE. 7 8

MRI is the gold-standard neuroimaging tool to diagnose and monitor NPSLE. 1 9 However, conventional structural MRI abnormalities, such as white matter (WM) hyperintensities, gross brain tissue atrophy and ventricular enlargement in response to this atrophy are not always observed in patients with NPSLE. 10 In contrast, more advanced postprocessing techniques enable the quantification of structural brain metrics beyond total tissue volumes from standard T1-weighted MRI, such as regional volumes, surface area and cortical grey matter (GM) thickness. 11 12 These metrics can be semiautomatically calculated from human brain atlases and can reveal subtle NPSLE-related brain abnormalities (eg, frontal cortex atrophy), not apparent with more conventional clinical tools. 10–12

In addition to these postprocessing methods, other less conventional structural MRI sequences, specifically diffusion MRI, have become a subject of interest in current NPSLE clinical research. 10 13 Diffusion MRI measures the random motion of water molecules (diffusion coefficient D) while they interact with tissue boundaries, cell membranes and other biological barriers, yielding structural metrics linked to axonal loss, inflammation and demyelination, particularly in the WM 14 ; thus, it can probe the status of brain tissue microstructure in relationship to neurological symptoms. Common metrics include the mean (MD), axial (AD) and radial (RD) diffusivities, which respectively characterise water diffusion in bulk, parallel and perpendicular to a WM tract, and fractional anisotropy (FA), which quantifies the degree of diffusion anisotropy or directionality in a voxel. 15 16 Additionally, diffusion-weighted imaging (DWI) can be used to weight the strength of WM connections by quantifying properties of brain-wide structural networks (eg, node strength, density), 17 and to evaluate intravoxel incoherent motion (IVIM), where the microcirculation of blood–water in the capillary network (D*), and tissue D and perfusion can be estimated. 18

An increasing number of studies are utilising advanced MRI to investigate NPSLE. 10 Altered tissue microstructure has been reported in several brain regions of patients with and without NPSLE diagnosis when compared with healthy controls, 11 19–21 and they have correlated with higher CD. 20 Overall, the presence of these associations, even in the absence of clinical NPSLE diagnosis, suggests that brain involvement could be underdetected in SLE. However, existing advanced neuroimaging research in SLE has been limited in generalisability and interpretation due to small cohorts and often incomplete characterisation of clinical features. In response to these knowledge gaps, we conducted a systematic review to evaluate (1) the effect of SLE on brain structure, (2) the neuroimaging correlates of CD in SLE and (3) potential disease-related contributors including but not limited to disease activity, duration and glucocorticoid exposure. A better understanding of these associations will help inform attribution of CD to SLE, characterisation of domain-specific CD trajectories, and possible new therapeutic strategies for protection of cognitive function in children and adults diagnosed with SLE.

Search strategy

This systematic review was conducted in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 22 The search was performed in PubMed, MEDLINE, Embase, Web of Science, Google Scholar and Cochrane databases, and it was aided by the web-based literature review manager Covidence. It included the following terms: ‘systemic lupus erythematosus (SLE)’, OR ‘neuropsychiatric lupus (NPSLE)’, OR ‘central nervous system (CNS) lupus’, OR ‘antiphospholipid syndrome SLE’; AND ‘magnetic resonance imaging (MRI, structural MRI)’; OR ‘diffusion MRI (diffusion tensor imaging—DTI, DWI)’. More details on the search strategy are included in online supplemental file 1 . The systematic review was registered into the Registry of Systematic Reviews/Meta-Analyses in Research Registry ( https://www.researchregistry.com/ ) with Review Registry Unique Identifying Number ‘reviewregistry1844’.

Supplemental material

Inclusion and exclusion criteria.

Inclusion criteria: (1) peer-reviewed articles, limited to human research, and published between January 2000 and October 2023, including observational, case series, cross-sectional, longitudinal, retrospective or prospective study designs of SLE populations; (2) neuroimaging studies that used structural (T1-weighted) and/or diffusion MRI; (3) evaluation of cognitive function/performance in SLE.

Exclusion criteria: (1) reviews, meta-analyses and manuscripts that do not refer to MRI data directly collected from SLE cohorts; (2) studies solely reporting conventional T1-weighted MRI metrics, such as total brain volumes (and not regional volumes), lateral ventricles volume and/or WM hyperintensities numbers/volumes.

Identification of eligible studies

Title and abstracts were reviewed for eligibility by six team members (DVC, TET, IM, SEA, SF and JL). A full-text review of potentially eligible articles according to inclusion and exclusion criteria was undertaken independently by two members (DVC and TET), and afterwards final articles were selected by consensus.

Data extraction and risk of bias assessment

Information extracted from studies included main publication details (first author, year, country), study design (cross-sectional, longitudinal), cohort demographics (sample size, age, sex, ethnicity), clinical variables (NPSLE clinical diagnosis, disease duration, SLE Disease Activity Index—SLEDAI scores, Systemic Lupus International Collaborating Clinic Damage Index – SDI scores, glucocorticoid use), CD assessments (cognitive domains, neuropsychological tests, CD definitions), MRI technical details (magnetic fields, voxel sizes, b-values, diffusion directions), protocol type (structural or diffusion MRI sequences) and structural (total GM, WM and regional volumes; cortical thickness) and diffusion MRI metrics (FA, MD, AD RD). Two reviewers (DVC and TET) individually extracted data from the included articles regarding associations between atypical structural and/or diffusion brain MRI metrics and CD in SLE. Associations between brain MRI abnormalities and other clinical variables were summarised when available. Risk of bias assessment was performed by two independent raters (DVC and TET) in agreement with The National Heart, Lung, and Blood Institute Study Quality Assessment Tools for Observational Cohort and Cross-Sectional Studies ( https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools ) and consensus was reached after discussions including the senior author (AMK) in case of major disagreements.

A total of 18 articles that evaluated the effect of SLE on brain structure and their links with CD were included in this review ( online supplemental file S1 ). 12 19–21 23–36 From these studies, eight used T1-weighted MRI, 12 28 29 31–33 35 36 nine focused on diffusion MRI 19–21 24–27 30 34 and one reported brain metrics from both modalities. 23 Most studies (15) were cross-sectional in design, while three studies assessed longitudinal changes in brain structure in their SLE cohorts at two different time points. 25 31 35 In terms of methodological quality and risk of bias assessment, half of the studied articles (9) were rated with an overall fair quality (unclear risk of bias), one-third (6) were rated as poor quality (high risk of bias), and three studies were rated as good quality (low risk of bias). Four of the six articles at high risk of bias had measuring bias (statistical analyses not adjusted for key potential confounding variables) while two articles had possible cohort selection bias (healthy and SLE cohorts with different demographic characteristics). Risk of bias assessments for each article are summarised in online supplemental figure S2 .

Sample sizes, demographics and clinical features

An overview of demographic and clinical characteristics of the SLE cohorts is presented in table 1 . SLE sample sizes ranged from 11 to 120 with a mean of 50 participants, and in all cohorts at least 80% were women (17 out of 18 papers reported biological sex as part of patient’s demographics), which is in line with the highest prevalence of SLE in women. 37 Three manuscripts reported information regarding race/ethnicity, and in two of them over half of the patients were African-American individuals (55% and 70% of their respective cohorts). 25 27 Cohort ages ranged 14.7–48.9 years on average with a pooled mean of 35.5 years; 16 studies examined adult patients with SLE, 2 included patients with cSLE 27 28 and one compared patients with aSLE versus cSLE. 26 Healthy controls with age and sex distributions comparable to their respective SLE cohorts were used for group comparisons in 16 studies. Only three studies longitudinally evaluated 56%, 65% and 100% of their SLE cohorts at follow-up time points that ranged 12–19 months from the date of their respective baseline MRI scans. 25 31 35

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Demographic and clinical characteristics of SLE cohorts (least to most recent publication date)

The number of patients with clinical NPSLE diagnosis was reported in 16 cohorts and it was quite variable (ranged 0%–100% of their respective cohorts), with half of these cohorts describing proportions over 50%, and three studies mentioning CD as a previous clinical NPSLE symptom. SDI ranged from 0 to 2.3 and it was the most frequently reported clinical variable (12 studies). Nine articles reported SLEDAI ranging from 2.0 to 15.3, whereas one manuscript used the systemic lupus activity measure (9.9±4.9). Disease duration was stated in 16 papers and spanned 0.5–38 years since SLE symptom onset. Additionally, information regarding glucocorticoid exposure, retrieved from either current or cumulative use, was provided in 14 papers, and in 10 of them over 75% of patients were exposed to some form of glucocorticoids.

Neurocognitive assessments

Studies assessed cognitive performance of SLE patients with diverse approaches classified into the following categories: neuropsychological batteries, computerised batteries, screening tests and incomplete/mixed designs. 38 A full neurocognitive characterisation of the reviewed SLE cohorts is available in table 2 .

Neurocognitive characterisation, cognitive domains, neuropsychological assessments and cut-offs for cognitive dysfunction (CD) classification in SLE cohorts

Comprehensive neuropsychological batteries comprised at least four tests sensitive to specific cognitive domains (≥2 assessed domains) that have been validated in SLE (including the ACR-SLE, and the modified version endorsed by the Childhood Arthritis & Rheumatology Research Alliance). 38 These included, for example: Wechsler Intelligence Scales (Adult—WAIS-3 and WAIS-4, Children—WISC-4 and Abbreviated—WASI in 7 studies, Continuous Performance Test (simple attention, 8 studies), Stroop Color-Word Test (attention and working memory, 5 studies), California Verbal Learning Test and Rey Auditory Verbal Learning Test (RAVLT)—verbal memory and learning, 3 studies each, Trail Making Test (visual-spatial processing, psychomotor speed and memory, 3 studies), Hayling Test (executive skills, specifically response initiation and inhibition, 3 studies).

Six studies included neuropsychological batteries. 23 24 27 28 30 36 While the above standard neuropsychological batteries were still the most frequently employed category, they require lengthy assessments that must be administered by clinical psychologists. 8 Thus, computerised batteries, such as CNS Vital Signs (3 studies) and Automated Neuropsychological Assessment Metrics (2 studies), have become more popular in SLE and they were used in five manuscripts. 19 21 25 29 33 These computerised batteries are shorter than traditional neuropsychological batteries, have demonstrated high sensitivity and specificity with the ACR-SLE battery and can be administered by less clinically specialised staff. 38 39

Screening tests are recurrently used to evaluate multiple domains and provide a quick global estimate of cognitive function. These screening tools were applied in six studies: Mini Mental State Examination (6 studies), 20 30–32 34 35 Montreal Cognitive Assessment (3 studies), 20 26 34 Addenbrooke’s Cognitive Examination (3 studies), 20 32 34 and National Adult Reading Test (2 studies). 20 34 The use of screening tests has increased during the last decade as they might complement subjective assessments and guide additional neuropsychological tests to evaluate specific cognitive domains of interest in patients with SLE. Mixed/incomplete designs that included a combination of these screening tests and/or less than four domain-specific neuropsychological tests were reported in three papers. 12 31 35

Lacking a generally accepted definition of CD in SLE, cut-offs for related deficits were selected in seven studies by choosing standardised z-scores −1.0 to −2.0 SD below the normative mean, either in at least two individual cognitive domains (if cut-off was lower than −1 SD) 27 28 or in only one domain (if cut-off was lower than −1.5 or −2 SD). 12 27 28 30 31 35 36 Two of these seven studies exclusively focused on verbal memory (RAVLT). 12 30

MRI technical details and brain structural findings

Technical parameters, postprocessing and group differences in MRI metrics are available in online supplemental table S1 . In 10 studies, brain MRI data were acquired with 3T scanners, while remaining studies were acquired at lower magnetic fields (2 studies at 2 T and 6 studies at 1.5 T). Regional volume was the most commonly evaluated structural MRI metric (8 out of 9 studies) and it was mainly calculated from automated segmentations (4 studies) and voxel-based morphometry (3 studies). Both postprocessing techniques employ semiautomated algorithms for volume quantification, reducing measurement susceptibility to operator skill. Additionally, segmentation methods (manual and automated) were targeted to specific brain regions in three studies (two in hippocampus, one in hippocampus and corpus callosum), therefore these studies did not evaluate potential abnormalities across the entire brain. 29 32 35 Diffusion MRI metrics from 9 DTI studies included FA (8 studies), mean and directional diffusivities (MD, RD, AD—4 studies) as well as FA-weighted global and local brain structural connectivity metrics (1 study). 34 They were mainly computed with tractography, tract-based spatial statistics or voxel-wise analyses. One tractography study focused on the corpus callosum, cingulum and uncinate fasciculus tracts 19 while another study solely retrieved metrics from corpus callosum automated segmentations. 26 IVIM-derived diffusion-perfusion metrics were examined in one study. 27

Structural MRI: a summary of the structural MRI abnormalities in SLE reported across the studies is depicted in figure 1 , including T1-weighted MRI segmentation maps of GM and WM structures and atlas-based parcellations of cortical structures. Lower total GM volume was reported in two SLE cohorts when compared with healthy controls. The hippocampus was the most frequently affected structure bilaterally, with smaller volumes reported in patients with SLE relative to controls (2 studies), 32 35 and worse hippocampus atrophy observed in patients with NPSLE (1 study) 29 or CD (1 study). 36 The next most frequent abnormalities were smaller frontal (2 studies) and temporal (2 studies) GM regions in adults and children with SLE and CD. 28 31 Additionally, regions within the frontal, temporal and parietal cortices of patients with SLE with memory deficits were thinner when compared with patients without memory deficits and controls. 12 Regarding longitudinal assessments, one study showed that the percentage of the SLE cohort with hippocampus atrophy increased by 23% when follow-up versus baseline MRI volumes were compared (from 47 out of 107 patients with hippocampus atrophy at baseline to 40 out of 60 patients at follow-up), 35 while lower corpus callosum, frontal, dorsolateral and medial temporal cortical volumes were reported in patients relative to controls during over a year follow-up period in another longitudinal study. 31

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Shown are T1-weighted MRI segmentation maps of GM and WM structures (A), and atlas-based parcellations of cortical structures (B) summarising findings from the reviewed articles. Compared to controls, lower total white matter, grey matter, cerebellum and hippocampus (hippo) volumes (A), and lower cortical volumes (particularly frontal cortex) and thickness (B) were commonly observed in patients with SLE (sagittal views). Structural MRI metrics were displayed from automatic segmentations and parcellations labelled from a human brain atlas (Desikan-Killiany). Beyond general cognitive function, memory, psychomotor speed and attention were the most frequently affected cognitive domains found to be associated with structural MRI findings in SLE (C). GM, grey matter; SLE, systemic lupus erythematosus; WM, white matter.

Diffusion MRI: a summary of the microstructural brain abnormalities on diffusion MRI in SLE reported across the studies in depicted in figure 2 , including WM atlas-based segmentations superimposed in a colour-encoded FA map and an example of a 3D-rendered tract. The corpus callosum was the WM pathway most frequently damaged in SLE (6 studies), with lower FA (5 studies), higher MD and RD (2 studies) and higher AD and free-water (1 study) in patients with SLE when compared with controls. 19 20 23 25 26 30 Other frequently affected WM pathways were the cingulum 19–21 25 and fascicles connecting the frontal cortex in four studies (inferior fronto-occipital fasciculus, inferior and superior longitudinal fasciculus, uncinate fasciculus), 21 23 25 30 and projection tracts in three studies (thalamic radiation, internal and external capsule, corticospinal tract, corona radiata). 20 23 30 One study evaluated diffusion metrics in GM and reported abnormalities in patients with cSLE, mainly higher D and D* in the precuneus/cuneus, occipital, postcingulate and parietal regions. 27 Within SLE subgroups, one study reported large affected areas in patients with SLE with and without memory deficits versus controls (lower FA and higher MD/RD). 30 Another study evaluated patients with cSLE versus aSLE and reported lower FA and higher diffusivities in the corpus callosum in the former relative to the latter subgroup, 26 while no diffusion differences were observed between NPSLE and non-NPSLE patients in two manuscripts. 19 24 No changes in diffusion metrics in patients with SLE after the follow-up period were observed in the DTI publication with longitudinal data. 25

Shown are brain maps (sagittal, coronal and axial views) depicting reported abnormal widespread white matter microstructure (A). Compared to controls, lower fractional anisotropy and higher diffusivities were reported in patients with SLE, with a predilection for the corpus callosum (CC) and periventricular/frontal tracts. Diffusion MRI metrics were mostly calculated with tractography (3D-rendered genu of the corpus callosum viewed from the top, A) or from WM tract labels with tract-based spatial statistics. Beyond general cognitive function, memory, psychomotor speed and attention were the most frequently affected cognitive domains found to be associated with diffusion MRI findings in SLE (B). Cg, cingulum; CR, corona radiata; IC/EC, internal/external capsula, IFOF, inferior fronto-occipital fasciculus; ILF/SLF, inferior/superior longitudinal fasciculus; WM, white matter.

Cognitive function and relationships between brain structural metrics

Poor overall cognition function was the most frequently reported metric of CD (8 studies). The cognitive domains most consistently impaired in SLE were: memory (visual, verbal, working, episodic, composite) in five articles, 12 24 25 31 35 followed by psychomotor speed and attention (simple, complex, sustained) in four 19 24 27 33 and three studies, 21 24 31 respectively. One longitudinal study reported that the prevalence of CD after the follow-up period remained the same, 25 while it increased by 34% (5 patients) after the follow-up period in another longitudinal study. 35 Brain structures/regions implicated in these cognitive domains, effect measures of these associations and the direction of the effects are summarised in table 3 , and their anatomic locations are shown in figures 1 and 2 .

Associations between brain structural MRI metrics, cognitive performance and other clinical features in SLE cohorts of previous studies

With regard to structural brain MRI metrics, lower GM and WM volumes were associated with worse overall cognitive function and a greater number of impaired cognitive domains in patients with SLE. 31 Smaller volumes in the temporal and frontal lobes were associated with worse composite memory, while smaller volumes in the parietal lobe correlated with worse attention. 31 Abnormal hippocampus metrics frequently related to CD (3 studies), with smaller volumes linked with worse overall cognitive function, 32 35 memory (composite and verbal) and recall. 35 Other cortical and subcortical areas showing associations with CD were frontal and precentral cortex (lower thickness with lower episodic memory) and the cerebellum (lower volumes and slower psychomotor speed). 12 33

With regard to diffusion MRI metrics, for total WM, higher MD was associated with lower overall cognitive function. 20 The corpus callosum was the WM structure that was most recurrently associated with CD (3 studies), with higher MD 26 and lower FA 24 correlating with worse overall cognitive function, lower FA 24 and higher free water 21 being associated with poor attention, and lower FA with visual memory and psychomotor speed. 24 Lower FA in the cingulum associated with slower psychomotor speed and worse cognitive flexibility (executive functioning domain), 19 while higher free water was associated with worse attention. 21 Lower FA in anterior portions of the corona radiata (2 studies), thalamic radiation (1 study) and right external capsula (1 study) correlated with lower overall cognitive function 24 and executive skills, 23 with anterior thalamic radiation also correlating with worse processing speed. 24 Lower FA in the superior longitudinal fasciculus (2 studies) was associated with lower overall cognitive function, visual memory, psychomotor speed, attention 24 and executive skills. 23 Lower FA in the inferior fronto-occipital and longitudinal fasciculus, respectively, correlated with lower visual and verbal memory in one study. 24 Additionally lower parahippocampal FA related to worse spatial memory, 25 higher node strength in the frontal cortex and in caudal/lingual regions, respectively, correlated to greater overall cognitive function and lower episodic memory, 32 and higher IVIM-derived perfusion in the precuneus associated with slower psychomotor speed and worse visual spatial processing. 25

Associations between clinical variables and abnormal brain structure (n=10) and CD (n=1)

Longer disease duration was related to lower total GM and WM volumes, 31 weaker network connectivity metrics in the whole brain 34 and lower FA in the corpus callosum. 19 Greater SLE damage was associated with lower nodal strength in caudate and in several cortical regions in all brain lobes, 34 higher disease activity with higher water diffusion and lower blood–water fraction in precuneus, 27 higher levels of DNRAb serum titres with lower FA in parahippocampal areas 25 and greater number of CNS manifestations with lower hippocampus volume 35 ( table 3 ). Cumulative glucocorticoid dose was linked to lower GM volumes 31 and higher free water in the corpus callosum, cingulum and WM tracts connecting to the frontal cortex. 21 Greater fatigue was linked to higher MD in total WM 20 and lower FA in the corpus callosum of patients with SLE, and to higher MD in the cingulum of patients with NPSLE. 19 One study reported worse overall cognitive function negatively associated with greater disease duration, higher expression of the inflammatory cytokine interleukin-6 and higher level of endothelial dysfunction antigens and activity (von Willebrand factor). 20

To our knowledge, this is the first systematic review of neuroimaging literature on structural MRI abnormalities in SLE in relationship to CD. Our work included 18 peer-reviewed manuscripts and summarised their results in terms of clinical characterisations of SLE cohorts, neurocognitive assessments and CD definitions, structural brain MRI abnormalities and their links to CD and other related clinical factors in patients with SLE. We found that memory and attention as well as psychomotor speed were the most consistently impaired cognitive domains in SLE when evaluated in relationship with structural brain alterations. CD in these domains correlated with abnormal MRI metrics (low volumes, abnormal microstructure), particularly in hippocampus and corpus callosum. Longer disease duration, higher cumulative glucocorticoid doses and fatigue were disease factors often linked to regional brain structure abnormalities.

CD was associated with injury in several areas, with a particular emphasis in periventricular and frontal WM pathways (eg, the corpus callosum), cortical frontal and parahippocampal regions and certain subcortical GM structures (eg, hippocampus) that are known to be involved in cognitive processes frequently affected in patients with SLE. Lower volumes and cortical thinning were observed in frontotemporal and hippocampal/parahippocampal regions in relationship to impairments in all cognitive domains in patients with SLE. Lower FA and higher diffusivities in WM tracts such as the corpus callosum and in subcortical structures, specifically the hippocampus, were used as indicators of microstructural brain alterations in NPSLE and non-NPSLE patients, and metrics in these regions were linked to poorer attention and impaired visual and working memory. Global and regional brain abnormalities in GM and WM were related to longer disease duration, NPSLE diagnosis, higher fatigue, greater disease activity and higher cumulative glucocorticoid use, which suggests that brain damage, specifically in periventricular regions, could worsen with progressive pathology directly or indirectly caused by SLE. These results aligned with a longitudinal study that showed that hippocampus volumes, although affected early in SLE, further decreased with time and in relationship to factors such as greater total glucocorticoid dose, CD and number of CNS manifestations. 35

The hippocampus proper and interconnected parahippocampal and periventricular regions are critical for memory and executive skills. 40 Neuronal injury in the hippocampus could extend to neighbouring WM tracts as a consequence of anterograde or retrograde axonal degeneration and this mechanism has been proposed as a mediator of CD in SLE 7 and MS. 41 Microstructural degeneration of these regions could be also related to their location in the brain, adjacent to cerebrospinal fluid and vascular spaces. This location makes them particularly vulnerable to SLE pathology and treatment, including but not limited to microglial activation, as reported from in vitro and mouse studies 42 and glucocorticoid use. 43 Microstructural alterations in these regions could precede regional and global brain atrophy, and both microstructural and macrostructural abnormalities could even lead CD in SLE. However, to our knowledge, there have been only three MRI studies longitudinally evaluating structural brain metrics, 10 31 35 and one cross-sectional study that has combined both advanced structural and diffusion metrics in relationship to CD in SLE. 23 Additionally, only two studies evaluated CD in paediatric SLE populations. 27 28 Children with cSLE are at higher risk for developing CNS manifestations due to NPSLE, and they represent an opportunity to investigate the effects of SLE on the brain with little presence of comorbid conditions. 44 Studies of CD utilising neuroimaging in cSLE may, therefore, provide particular insight into the mechanisms underlying the impact of SLE on the brain. In addition to structural brain abnormalities, factors that directly correlated to CD in patients with SLE included long disease duration and high expression of inflammatory cytokines. However, relationships between these factors and CD were only evaluated in one study. 20

It is important to note that several methodological issues limited our interpretation of the findings. These include (1) inadequately described demographic and disease-related features in heterogeneous SLE cohorts; (2) infrequent accounting of potential confounders such as glucocorticoid use, mood disorders, fatigue, disease activity and duration; large variability in (3) neuropsychological assessments utilised to evaluate CD; (4) technical details in MRI scanners and acquisitions in studies in patients with SLE; (5) lack of harmonised neuroimaging analyses that combine structural MRI metrics from different modalities to evaluate both brain tissue morphology and microstructure and (6) lack of longitudinal data.

Importantly, the above limitations indicate a critical need for collaboration, consensus and coordination of research on CD in SLE, and for NPSLE overall. Our review highlights the current inconsistent use of neuropsychological tools, MRI protocols and consideration of demographic and disease-related variables potentially impacting brain function. Future efforts are needed to develop consensus recommendations and guidelines regarding relevant demographic, clinical and cognitive function measures and suitable technical MRI parameters and processing/postprocessing pipelines. Additionally, developing a standard for clinical collection of harmonised neuropsychological measures and neuroimaging protocols would allow for multicentre studies utilising clinically collected data. Furthermore, consideration and inclusion of paediatric cSLE populations will be highly valuable to understand the impact of SLE on the developing brain and across the lifespan. Such recommendations would enable larger, collaborative studies in SLE on neuroimaging, CD and NPSLE across the globe, utilising common data elements. These efforts will require multidisciplinary teams inclusive of adult and paediatric rheumatologists, neuropsychologists, neuroimaging scientists, neurologists, neuroimmunologists and others with relevant expertise.

In conclusion, the results collected in this systematic review suggest that advanced structural MRI metrics can identify CNS abnormalities in patients with SLE and CD. Specifically, this systematic review indicates that despite the limitations, the existing literature shows structural and microstructural changes in brain regions and networks that are known to be involved in many aspects of cognition. The use of these advanced structural MRI metrics might enhance the knowledge of the underlying causes of CD and other neuropsychiatric symptoms such as mood disorders in SLE, and they could help to develop more objective biomarkers for the attribution of specific NPSLE syndromes. Together with functional and metabolic neuroimaging tools, these structural metrics could also serve as complementary diagnostic tools of NPSLE as well as outcome measures in clinical trials focusing on therapeutic interventions and neuroprotection and preserving cognitive function in SLE. However, improved characterisation of SLE cohorts, guidelines for neuroimaging acquisitions and analyses and more longitudinal studies are needed to further confirm the diagnostic and predictive ability of these metrics in SLE-related CD.

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Mohamed AS ,
Rogers S , et al
Husain SF ,
Appenzeller S ,
Pereira DR ,
Julio PR , et al
ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature
Kwan A , et al
Anderson E ,
Allameen NA ,
Tay SH , et al
Magro-Checa C ,
Steup-Beekman GM ,
Huizinga TW , et al
Toledano P ,
Calvo A , et al
Sanchez TA ,
Tukamoto G , et al
Reis F , et al
Le Bihan D ,
Mangin JF ,
Poupon C , et al
Valdes Cabrera D ,
Garcia JOD ,
Hagmann P ,
Gigandet X , et al
Nystedt J ,
Nilsson M ,
Jönsen A , et al
Wiseman SJ ,
Bastin ME ,
Hamilton IF , et al
Ng KK , et al
McKenzie JE ,
Bossuyt PM , et al
Shucard JL , et al
Chavez RS ,
Flores RA , et al
Tang CC , et al
Caldeira T ,
Pinheiro GR , et al
DiFrancesco MW ,
Altaye M , et al
Gitelman DR ,
Klein-Gitelman MS ,
Ying J , et al
Cannerfelt B ,
Corrêa DG ,
Zimmermann N ,
Borges RS , et al
Bonilha L ,
Rio PA , et al
Kiss E , et al
Mårtensson J ,
Rumetshofer T ,
Nystedt J , et al
Amft EN , et al
Carnevalle AD ,
Li LM , et al
Kubo TA , et al
Bingham K , et al
Tayer‐Shifman OE ,
Beaton DE , et al
Valdés Cabrera D ,
Blevins G ,
Smyth P , et al
Zhao Q , et al
Nguyen DM ,
Tustison NJ , et al
Trindade VC ,
Carneiro-Sampaio M ,
Bonfa E , et al

Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Data supplement 1
Data supplement 2

DVC and TET are joint first authors.

Contributors AMK is responsible for the overall content (as guarantor). DVC, TET and IM designed the search strategy. All authors (DVC, TET, IM, SEA, SF, JL, AMK) participated on the identification and screening of all the relevant articles. DVC and TET performed the full data extraction of eligible articles and the risk of bias assessment. DVC, TET and AMK wrote the first draft of the paper. All authors reviewed, contributed and approved the final manuscript.

Funding Funding for this project included a Lupus Foundation of America Career Development Award (TET), Lupus Research Alliance Administrative Supplement to Promote Diversity in Lupus Research (SEA), Canada Research Chair Tier 2 in Mental Health and Chronic Disease of Childhood (AMK) and Lupus Research Alliance Career Development Award to Promote Diversity in Lupus Research (AMK).

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer-reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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The 100 top-cited studies in systemic lupus erythematosus: A bibliometric analysis

Affiliations.

1 Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
3 Tianjin Institutes of Health Science, Tianjin, China.
4 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
5 West China School of Medicine, Sichuan University, Chengdu, China.
6 School of Clinical Medicine, Southwest Medical University, Luzhou, China.
7 Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.
PMID: 39149877
PMCID: PMC11328883
DOI: 10.1080/21645515.2024.2387461

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory tissue disease. In view of the explosive growth in research on SLE, bibliometrics was performed to evaluate the 100 top-cited papers in this realm. We performed the search with terms "systemic lupus erythematosus" the Web of Science Core Collection database on May 3, 2023. Relevant literatures were screened. Data were extracted and analyzed by SPSS. The citations of 100 top-cited SLE studies spanned from 472 to 13,557. Most studies (60 out of 100) were conducted in the United States. Total citation times were positively associated with ACY, which was negatively correlated with the length of time since publication. Approximately half of the studies focused on the underlying mechanisms of SLE. New biologic therapies garnered attention and development. Our findings provide valuable insights into the developments in crucial areas of SLE and shed contributions to future studies.

Keywords: Systemic lupus erythematosus; bibliometric analysis; bibliometrics; citations; literature review; research hotspots.

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No potential conflict of interest was reported by the author(s).

Institutions of the corresponding author…

Institutions of the corresponding author in the 100 top-cited studies.

Years of the 100 top-cited…

Years of the 100 top-cited studies on SLE.

Country distribution of the 100…

Country distribution of the 100 top-cited studies on SLE.

Correlation analysis between ACY and…

Correlation analysis between ACY and publication time.

Correlation analysis between total citation…

Correlation analysis between total citation times and ACY.

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Lupus Clinical Trials Unit

Sarfaraz hasni, m.d..

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Research Areas (IRP Lab Groups)

The Lupus Clinical Trials Unit (LCTU) is a part of the National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS). NIAMS is an institute of the National Institutes of Health (NIH) that is dedicated to clinical and translational research related to arthritis and musculoskeletal and skin disease.

The LCTU conducts innovative translational and clinical research into the causes, treatment, and prevention of systemic lupus erythematosus (SLE). We maintain a comprehensive clinical database of SLE patients that includes patient demographics, SLE disease activity, damage indices, patient-reported outcome tools, and other data for phenotyping our cohort. The unit's SLE Natural History and Pathogenesis protocol is crucial for understanding the disease's diversity, offering vital biological samples and clinical phenotyping for research. Our collaborative approach has resulted in significant biomarker discoveries and the development of new clinical trials.

We develop and implement clinical research protocols and conduct high impact, innovative clinical research based largely on the discoveries resulting from NIAMS translational research.

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As you prepare to visit the LCTU, there are a few things you’ll need to have ready. Here’s a quick list to help you stay organized.

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Please refer to our clinical trials for details of all current studies.

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Quality improvement (QI) is a framework used in health care to improve patient care, outcomes, and the development of health care professionals. It has been shown to improve morbidity and mortality. The LCTU has implemented several QI projects for our patient cohort.

A health maintenance section has been incorporated into all progress notes to address areas affected by SLE and the drugs that treat this disease.
Patients with lupus are at a higher risk of osteoporosis because of chronic inflammation and the adverse effects of therapeutic medications, including glucocorticoids. We are working with an interdisciplinary team to implement a standardized template for outpatient visits incorporating osteoporosis assessment and management guidelines.
A specific sun protection brochure to educate patients regarding SLE and photosensitivity.
Reproductive health is an important topic and should be a shared decision-making process between SLE patients and providers. We are currently working on implementing reproductive health counseling during patient visits.
Patient-reported outcome surveys are completed at every visit to help clinicians better understand the patient's perceived health status and empower them in their healthcare process.
A disease indices tool monitors disease activity and damage accrual for every patient visit.

For more information, please contact Jun Chu ([email protected]).

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Poster for the 2024 DCLC annual event featuring illustrations of various butterflies.

Clinical research trials are essential for understanding the pathogenesis of lupus and the development of new therapies. The lupus clinical research team believes that a platform for resource sharing, information exchange, and patient referral is critical in this process. Therefore, in 2016 we established the DC Lupus Consortium (DCLC) , a partnership amongst stakeholders in local academia, rheumatologists, nephrologists, patients and patient advocacy groups.

Join Us for the Next DCLC

NIH scientists, researchers, patient advocacy groups, and physicians both within and outside of NIH are welcome to join this consortium. If you would like to learn more about upcoming DCLC events, please contact Elaine Poncio ( [email protected] ) or Isabel Ochoa ( [email protected] ) to be added to the mailing list.

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Clinical Trials

Gonadotropin-releasing hormone agonist (gnrha) in ovarian preservation in sle subjects receiving cyclophosphamide as determined by questionnaires.

Systemic lupus erythematosus (SLE) is a disease that affects females nine times more often than males. People with SLE are often treated with cyclophosphamide (CYC). But CYC can damage a woman s ovaries; it may cause infertility. A drug called GnRHa is sometimes given to protect the ovaries during CYC therapy. But no one really knows how effective GnRHa treatment is. This natural history survey will compare women who received GnRHa during CYC therapy with those who did not.

Study of Systemic Lupus Erythematosus

This study enrolls patients with systemic lupus erythematosus. The goal is to identify clinical subsets of patient that might aid in understanding progress and determining appropriate therapies. The goals of this research study are to evaluate patients thought to have the disease to better understand how the disease begins and how it affects patients. Secondly, to follow patients during the course of the disease to understand how the disease changes over time and the effects of standard treatments.

The Natural History of Coronavirus Disease (COVID-19) in Systemic Autoimmune Diseases; An Observational Prospective Study

This is an observational study to characterize how COVID-19 modulates systemic inflammation, autoimmune features and vasculopathy in adult and pediatric patients with a prior diagnosis of systemic autoimmunity, and their overall outcomes including response to potential antiviral treatments or vaccines.

The Role of Anifrolumab in Improving Markers of Vascular Risk in Patients With Systemic Lupus Erythematosus

This is a double blind placebo-controlled study to characterize whether blocking type I IFN receptor signaling with anifrolumab will lead to improvements in vascular function, decreases in vascular inflammation and modulation of biomarkers of vascular risk in patients with systemic lupus erythematosus (SLE).

The Role of PPAR-Gamma Agonists in Immunomodulation and Vascular Prevention in SLE (PPAR-SLE)

Lupus causes a person's immune system to attack the body. It can cause blood vessel problems, heart attack, or stroke. Researchers want to see if the drug pioglitazone may help and to see how well pioglitazone improves blood vessel function and decreases blood vessel inflammation. To study its effect on lupus symptoms.

Scientific Publications

Selected recent publications, inhibition of jak-stat pathway corrects salivary gland inflammation and interferon driven immune activation in sjögren's disease., changes in cardiorespiratory function and fatigue following 12 weeks of exercise training in women with systemic lupus erythematosus: a pilot study., use of gonadotropin-releasing hormone agonists for ovarian preservation in patients receiving cyclophosphamide for systemic lupus erythematosus: a meta-analysis., peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus., long-term follow-up after lymphodepleting autologous haematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus., clinical images: cardiovascular magnetic resonance to detect and monitor inflammatory myocarditis in systemic lupus erythematosus., risk factors for covid-19 and rheumatic disease flare in a us cohort of latino patients., european league against rheumatism (eular)/american college of rheumatology (acr) sle classification criteria item performance., bite of the wolf: innate immune responses propagate autoimmunity in lupus., lox-1: a potential driver of cardiovascular risk in sle patients., using the circulating proteome to assess type i interferon activity in systemic lupus erythematosus., transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus., key publications, long-term follow-up after lymphodepleting autologous hematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus., phase 1 double-blind randomized safety trial of the janus kinase inhibitor tofacitinib in systemic lupus erythematosus., lupus-like autoimmunity and increased interferon response in patients with stat3-deficient hyper-ige syndrome., sex differences in neutrophil biology modulate response to type i interferons and immunometabolism., 2019 european league against rheumatism/american college of rheumatology classification criteria for systemic lupus erythematosus., safety and tolerability of omalizumab: a randomized clinical trial of humanized anti-ige monoclonal antibody in systemic lupus erythematosus., distinct functions of autoantibodies against interferon in systemic lupus erythematosus: a comprehensive analysis of anticytokine autoantibodies in common rheumatic diseases., news & highlights.

Mitochondria - several rounded, roughly rectangular shapes arranged in a random pattern

Exercise Energizes Patients With Autoimmune Disease

New treatment shows promise in reducing the risk of cardiovascular disease in people with lupus

Dr. Sarfaraz Hasni Receives 2021 Coleman Research Innovation Award

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Scientists say they have identified a root cause of lupus — one that could pave the way for new treatments

A key mystery behind one of the most common autoimmune diseases may finally have an answer.

Researchers at Northwestern Medicine and Brigham and Women’s Hospital say they’ve discovered a root cause of lupus, a disease that affects hundreds of thousands of people in the U.S.

Scientists have long suspected that a person’s genetics or hormones may predispose them to lupus, and that the disease may be triggered by environmental factors like a previous viral infection or exposure to certain chemicals.

Now, a study published Wednesday in the journal Nature outlines a clear pathway for how the disease likely develops, pointing to abnormalities in the immune systems of people with lupus.

“What we found was this fundamental imbalance in the types of T cells that patients with lupus make,” said Dr. Deepak Rao, one of the study authors and a rheumatologist at Brigham and Women’s Hospital in Massachusetts. T-cells are white blood cells that play a key role in the body’s immune response.

The study arrived at its findings by comparing blood samples from 19 people with lupus to blood samples from healthy individuals. The comparison showed that people with lupus have too much of a particular T cell associated with damage in healthy cells and too little of another T cell associated with repair.

A butterfly-shaped (malar) face rash is a common sign of Lupus.

At the heart of this imbalance is a protein called interferon, which helps defend the body against pathogens. Scientists have known for many years that people with lupus have excess amounts of type I interferon — but the new study links this issue to several negative effects.

First, too much type I interferon can block a protein called the aryl hydrocarbon receptor, which helps regulate the body’s response to bacteria or environmental pollutants.

Blocking this receptor hinders the production of T cells that can help heal wounds on the barrier of the skin, lungs and gut. It also stimulates the production of T cells involved in creating autoantibodies, which attack healthy cells and are a hallmark of lupus.

Rao said the theory could explain the vast majority of lupus cases.

“I think this is going to apply to essentially all patients with lupus,” he said.

But other experts questioned the idea that there’s a singular explanation for all instances of lupus.

“It’s very exciting research and very hopeful, but I think that it might be too early to say that it’s the root cause of the disease,” said Mara Lennard Richard, scientific program officer for the Lupus Research Alliance. The alliance is a private funder of lupus research and contributed grant funding to Rao’s study.

Because lupus symptoms are so varied and the contributing factors are manifold, “it’s been very hard to find one singular root cause for the disease,” Lennard Richard said. “Obviously, if this turns out to be the cause of lupus, that would be amazing and really fantastic for people living with lupus.”

Dr. Jill Buyon, director of the division of rheumatology and the Lupus Center at NYU Langone Health, said the theory would need to be tested in a larger sample of people.

“Until they study 100 patients prospectively, how are we going to know?” said Buyon, who was not involved in the study.

The Centers for Disease Control and Prevention estimates that more than 200,000 people in the U.S. have lupus, though the Lupus Foundation of America puts the total much higher: roughly 1.5 million people . Around 90% of people with lupus are women.

Common symptoms include extreme fatigue, joint pain or skin rashes. In rare cases, the disease may lead to kidney or heart damage, or weaken the immune system so the body can’t fight off infections. These issues can be fatal or life-threatening.

Lupus has historically been difficult to treat. Many of the current options broadly suppress the immune system, including beneficial T cells that fight infection. And for some people with the disease, standard treatments aren’t effective.

The new study hints at the possibility of better treatments in the future, which could take the forms of infusions or pills, said Dr. Jaehyuk Choi, one of the study authors and a dermatologist at Northwestern Medicine.

The study found that giving people with lupus anifrolumab, a drug that blocks interferon, prevented the T-cell imbalance that likely leads to the disease.

“We followed patients who received this as part of their clinical care and showed that in patients who got the drug, this cell imbalance was fixed or was on the way to getting fixed,” Choi said.

In blood samples of people with lupus, the researchers also tested the effects of adding a small molecule that activates the aryl hydrocarbon receptor. They found that it limited the accumulation of disease-promoting T cells.

The major challenge to developing a new treatment, according to Choi, is finding ways to administer it without activating aryl hydrocarbon receptors throughout the whole body, which may result in more side effects.

Even if such a treatment becomes available, Buyon said, it’s unlikely to work for everyone with lupus.

“We have come to the profound understanding that one drug will not do it all,” she said.

Aria Bendix is the breaking health reporter for NBC News Digital.

News Center

Scientists discover a cause of lupus and a possible way to reverse it, two cellular defects appear to drive disease in lupus.

Jaehyuk Choi, MD, PhD, the Jack W. Graffin Professor, an associate professor of Dermatology and a Northwestern Medicine dermatologist.

Northwestern Medicine and Brigham and Women’s Hospital scientists have discovered a molecular defect that promotes the pathologic immune response in systemic lupus erythematosus (known as lupus) and in a study published in Nature , show that reversing this defect may potentially reverse the disease.

Lupus affects more than 1.5 million people in the U.S. Until this new study, the causes of this disease were unclear. Lupus can result in life-threatening damage to multiple organs including the kidneys, brain and heart. Existing treatments often fail to control the disease, the study authors said, and have unintended side effects of reducing the immune system’s ability to fight infections.

“Up until this point, all therapy for lupus is a blunt instrument. It’s broad immunosuppression,” said co-corresponding author Jaehyuk Choi, MD, PhD , the Jack W. Graffin Professor, an associate professor of Dermatology and a Northwestern Medicine dermatologist. “By identifying a cause for this disease, we have found a potential cure that will not have the side effects of current therapies.”

“We’ve identified a fundamental imbalance in the immune responses that patients with lupus make, and we’ve defined specific mediators that can correct this imbalance to dampen the pathologic autoimmune response,” said co-corresponding author Deepak Rao, MD, PhD, an assistant professor of medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital and co-director of its Center for Cellular Profiling.

In the study, the scientists reported a new pathway that drives disease in lupus. There are disease-associated changes in multiple molecules in the blood of patients with lupus. Ultimately, these changes lead to insufficient activation of a pathway controlled by the aryl hydrocarbon receptor (AHR), which regulates cells’ response to environmental pollutants, bacteria or metabolites. Insufficient activation of AHR results in too many disease-promoting immune cells, called the T peripheral helper cells, that promote the production of disease-causing autoantibodies.

To show this discovery can be leveraged for treatments, the investigators returned the aryl hydrocarbon receptor-activating molecules to blood samples from lupus patients. This seemed to reprogram these lupus-causing cells into a cell called a Th22 cell that may promote wound healing from the damage caused by this autoimmune disease.

“We found that if we either activate the AHR pathway with small molecule activators or limit the pathologically excessive interferon in the blood, we can reduce the number of these disease-causing cells,” said Choi, who is also a member of the Robert H. Lurie Comprehensive Cancer Center . “If these effects are durable, this may be a potential cure.”

Choi, Rao and colleagues next want to expand their efforts into developing novel treatments for lupus patients. They are now working to find ways to deliver these molecules safely and effectively to people.

Other Northwestern authors are first author Calvin Law; Arundhati Pillai; Brandon Hancock; and Judd Hultquist, PhD , assistant professor of Medicine in the Division of Infectious Diseases . Brigham and Women’s Hospital authors include Vanessa Sue Wacleche, PhD; Ye Cao, PhD; John Sowerby, PhD; Alice Horisberger, MD; Sabrina Bracero; Ifeoluwakiisi Adejoorin; Eilish Dillon; Daimon Simmons, MD; Elena Massarotti, MD; Karen Costenbader, MD, MPH; Michael Brenner, PhD; and James Lederer, PhD.

The research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grants K08 AR072791, P30 AR070253, R01 AR078769 and P30 AR075049; National Institute of Allergy and Infectious Diseases grants R01 AI176599, P30 AI117943, R01 AI165236 and U54 AI170792; National Cancer Institute grants F31 CA268839 and CA060553, all of the National Institutes of Health (NIH); and NIH Director’s New Innovator Grant 1DP2AI136599-01, and grants from Lupus Research Alliance, Burroughs Wellcome Fund, Bakewell Foundation, Leukemia and Lymphoma Society and American Cancer Society.

Investigating the molecular mechanisms of ‘forgetting’, intercellular mechanisms regulate gene expression in cancer cells, investigators discover new therapeutic target for pediatric brain cancers.

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Systemic lupus erythematosus articles from across Nature Portfolio

Systemic lupus erythematosus is a potentially fatal autoimmune disease that is characterized by wide-spread inflammation and tissue damage that can affect any part of the body. Commonly affected sites include the liver, kidneys, blood vessels, skin, heart and joints. Patients are treated with immunosuppressive drugs.

Related Subjects

Lupus nephritis

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Amplification of autoimmune organ damage by nkp46-activated ilc1.

Stylianos-Iason Biniaris-Georgallis
Tom Aschman
Antigoni Triantafyllopoulou

High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus

Here, the authors use SNP-seq to screen 87 lupus risk loci for functional non-coding variants. Validation at one locus identified a risk variant through which enhanced Ikaros binding amplifies expression of the interferon / NFκB regulator IKKε.

Taehyeung Kim
Peter A. Nigrovic

The immunology of systemic lupus erythematosus

In this Review, the author outlines the complex immunology of systemic lupus erythematosus and how to treat it.

George C. Tsokos

Interferon subverts an AHR–JUN axis to promote CXCL13 + T cells in lupus

Insufficient AHR activation has been suggested in SLE, and augmenting AHR activation therapeutically may prevent CXCL13 + T PH /T FH differentiation and the subsequent recruitment of B cells and formation of lymphoid aggregates in inflamed tissues.

Vanessa Sue Wacleche
Deepak A. Rao

Elucidating the function of STING in systemic lupus erythematosus through the STING Goldenticket mouse mutant

Pichpisith Pierre Vejvisithsakul
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Active juvenile systemic lupus erythematosus is associated with distinct NK cell transcriptional and phenotypic alterations

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News and Comment

Ifn versus ahr-jun.

Laurie A. Dempsey

UNC93B1 variants promote SLE via TLR activation

Two studies have identified variants of UNC93B1 that are associated with enhanced TLR7 and TLR8 activity and the development of systemic lupus erythematosus.

Holly Webster

A humanized mouse that mounts specific and mature antibody and autoantibody responses

We constructed a humanized (THX) mouse by grafting non-γ-irradiated, genetically myeloablated immunodeficient mouse neonates with human cord blood CD34 + cells, followed by 17β-estradiol hormonal conditioning. THX mice develop a human lymphoid and myeloid immune system, mount mature antibacterial and antiviral neutralizing antibody responses, and are amenable to develop lupus autoimmunity.

Integrin-mediated ILC2 adhesion protects against lupus nephritis

Type 2 innate lymphoid cells protect against kidney inflammation in lupus nephritis, and enhancing their adhesion via integrin α4β7 upregulation, particularly through IL-33 treatment, could be a promising therapeutic approach.

Jessica McHugh

Two rare UNC93B1 variants contribute to childhood-onset lupus

This work identifies two rare genetic variants of UNC93B1 that contribute to the development of childhood-onset lupus. Mice that expressed one of these variants developed a lupus-like disease. UNC93B1 is known to regulate the localization of Toll-like receptors (TLRs) to the endosome, and UNC93B1 variants resulted in enhanced responses to TLR7 and TLR8 agonists.

Can transcriptomics guide the management of SLE-associated APS?

The management of antiphospholipid syndrome is hindered by heterogeneous clinical presentations. Whole-blood transcriptomics have the potential to identify previously unknown disease endotypes, which could inform new treatment strategies. However, such hypothesis-generating data must still account for the results of randomized clinical trials, such as those focused on direct oral anticoagulants in APS.

Jason S. Knight
Maria G. Tektonidou

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Tiny killers: How autoantibodies attack the heart in lupus patients

by Columbia University School of Engineering and Applied Science

Cardiovascular disease is the leading cause of death in patients suffering from lupus, an autoimmune disease in which our immune system attacks our own tissues and organs, the heart, blood, lung, joints, brain, and skin. Lupus myocarditis—inflammation of the heart muscle—can be very serious because the inflammation alters the regularity of the rhythm and strength of the heartbeat. However, the mechanisms underlying this complex disease are poorly understood and difficult to study.

A long-standing question about lupus is why some patients develop myocarditis while others remain unaffected. And why the clinical manifestations of affected patients range so dramatically, from no symptoms at all to severe heart failure. Lupus is characterized by a large number of autoantibodies, immune proteins that mistakenly target a person's own tissues or organs, with different specificities for various molecules. Like our genes, they may explain why different individuals experience different symptoms.

Researchers have long suspected that specific autoantibody signatures could hold the key to the puzzling clinical variations they observe in lupus patients. Thus far, identifying autoantibodies involved in heart damage has been incredibly challenging due to the lack of experimental models that can replicate the cardiac disease in lupus patients. The currently used animal models fall short because of differences in cardiac physiology, while human cell cultures simply cannot capture the complexity and function of the human heart.

Study shows that autoantibodies can directly affect heart disease in lupus patient

In a new study, published August 15 in Nature Cardiovascular Research , a team of researchers from Columbia Engineering, Columbia University Vagelos College of Physicians and Surgeons, and Harvard University report that autoantibodies alone directly affect heart function in lupus patients.

The team found that the binding patterns of the patients' autoantibodies to heart tissue depend on the type and severity of their myocardial damage. A subset of patients with severe myocarditis had unique autoantibody populations that primarily targeted dying cardiac cells, whereas patients with weakened heart pump function had autoantibodies that mostly targeted the surface of live cells.

Interestingly, the team discovered that the autoantibodies that were binding to live cardiac cells were able to exert potent biological effects on the tissues in the absence of immune cells, revealing potentially new mechanisms that could contribute to heart failure in lupus patients.

The study also identified four such autoantibodies that may directly affect the heart muscle. These findings may help identify lupus patients with the greatest risk of developing heart disease, inform the development of new therapeutic strategies, and allow extension to other autoimmune diseases.

"It's astounding that these tiny heart tissues we've engineered using human stem cells and 'organs-on-chip' technology have the ability to emulate organ-level functions in a patient-specific way, and for such a complex disease. We now live in the era of studying the progression and treatment of diseases using apparently simple yet highly controllable and predictive models of human organs. It feels like living in the future."

Engineers and clinicians use collaborative approach

The physicians provided blood samples containing lupus autoantibodies and detailed clinical data for the cohort of lupus patients. This enabled the Columbia Engineering team to assess the effects of patient-specific autoantibodies on heart function using engineered heart tissues and to correlate these effects to clinical symptoms.

"Myocarditis can be a diagnostically elusive and sometimes clinically ominous feature of lupus. The development of this functional mature cardiac tissue model is already opening multiple new pathways to advance our understanding and ultimately clinical management of this enigmatic autoimmune process," Winchester noted.

To learn more about the potential therapeutic targets, Vunjak-Novakovic's team also worked closely with Drs Christine and Jonathan Seidman from Harvard University. The team is now exploring ways to use their findings to better understand the underlying mechanisms of cardiac disease in lupus patients and to improve diagnostics and treatment of this complex and challenging disease.

"What's really cool about this study is that by leveraging our expertise in engineering and stem cells to develop models of the human heart, we were able to take an innovative approach to solving long-standing questions surrounding heart disease in lupus patients," said the study's first author Sharon Fleischer, who is a postdoc in Vunjak-Novakovic's lab. "The new framework we established in this study to investigate autoantibody interactions with human organs opens up unparalleled opportunities for understanding organ damage, not just in lupus but across a spectrum of autoimmune diseases."

"It was wonderful to be part of such a collaborative team that included engineers, physicians, and biologists working together to investigate a challenging clinical problem," said Trevor Nash, one of the study's co-first authors who is a recent graduate from the Vunjak-Novakovic lab and a MD/Ph.D. candidate in the Medical Scientist Training Program at the Vagelos College of Physicians and Surgeons.

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Engineered heart tissues uncover new mechanisms in lupus-related heart damage

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Cardiovascular disease is the leading cause of death in patients suffering from lupus, an autoimmune disease in which our immune system attacks our own tissues and organs, the heart, blood, lung, joints, brain, and skin. Lupus myocarditis--inflammation of the heart muscle-- can be very serious because the inflammation alters the regularity of the rhythm and strength of the heartbeat. However, the mechanisms underlying this complex disease are poorly understood and difficult to study.

New study shows that autoantibodies can directly affect heart disease in lupus patient

The researchers engineered millimeter-sized cardiac tissues from healthy adult human stem cells, matured them using metabolic and electromechanical signals, and then incubated them with the autoantibodies found in the blood of lupus patients with and without myocarditis. The team found that the binding patterns of the patients' autoantibodies to heart tissue depend on the type and severity of their myocardial damage. A subset of patients with severe myocarditis had unique autoantibody populations that primarily targeted dying cardiac cells, whereas patients with weakened heart pump function had autoantibodies that mostly targeted the surface of live cells. Interestingly, the team discovered that the autoantibodies that were binding to live cardiac cells were able to exert potent biological effects on the tissues in the absence of immune cells, revealing potentially new mechanisms that could contribute to heart failure in lupus patients.

"This finding is the first demonstration that autoantibodies can directly mediate myocardial injury in this complex autoimmune disease," said the team's leader Gordana Vunjak-Novakovic, University Professor and the Mikati Foundation Professor of Biomedical Engineering, Medical Sciences, and Dental Medicine at Columbia. "It's astounding that these tiny heart tissues we've engineered using human stem cells and 'organs-on-chip' technology have the ability to emulate organ-level functions in a patient-specific way, and for such a complex disease. We now live in the era of studying the progression and treatment of diseases using apparently simple yet highly controllable and predictive models of human organs. It feels like living in the future."

Engineers and clinicians use collaborative approach

Vunjak-Novakovic, a bioengineer renowned for her pioneering work in engineering functional human tissue for use in regenerative medicine, and her group have spent three decades working on modeling heart injury and disease and engineering tissues to combat them. For this study, the bioengineers teamed up with two physicians, Robert Winchester and Laura Geraldino-Pardilla, both rheumatologists at NewYork-Presbyterian/Columbia University Irving Medical Center. The physicians provided blood samples containing lupus autoantibodies and detailed clinical data for the cohort of lupus patients. This enabled the Columbia Engineering team to assess the effects of patient-specific autoantibodies on heart function using engineered heart tissues and to correlate these effects to clinical symptoms.

Myocarditis can be a diagnostically elusive and sometimes clinically ominous feature of lupus. The development of this functional mature cardiac tissue model is already opening multiple new pathways to advance our understanding and ultimately clinical management of this enigmatic autoimmune process." Robert Winchester, rheumatologist at NewYork-Presbyterian/Columbia University Irving Medical Center

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v.37(4); 2012 Apr

Lupus: An Overview of the Disease And Management Options

Lupus is a chronic inflammatory autoimmune disease with a wide range of clinical presentations resulting from its effect on multiple organ systems. There are four main types of lupus: neonatal, discoid, drug-induced, and systemic lupus erythematosus (SLE), the type that affects the majority of patients. Patients with lupus experience a loss of self-tolerance as a result of abnormal immunological function and the production of autoantibodies, which lead to the formation of immune complexes that may adversely affect healthy tissue.

Although the precise etiologic mechanism is unknown, genetic, hormonal, and environmental factors, as well as immune abnormalities, have been identified. Associations between lupus onset and age, sex, geography, and race have also been established. Management of this disease should be individualized and should include both pharmacological and nonpharmacological modalities for symptom relief and resolution as well as improved quality of life.

INTRODUCTION

Lupus is associated with multisystemic inflammation resulting from abnormal immunological function. Patients experience periodic flares of varying severity or instances in which no observable signs or symptoms are present. The four main types of lupus are neonatal and pediatric lupus erythematosus (NLE); discoid lupus erythematosus (DLE); drug-induced lupus (DIL); and systemic lupus erythematosus (SLE).

As a rare form of lupus observed in newborns, NLE is thought to result from maternal autoantibodies passing through the placenta. However, of those pediatric patients who have positive maternal autoantibodies, only about 1% develop NLE. Common clinical presentations involve the heart, liver, and skin. Significant morbidity and mortality, along with cardiac manifestations, have been noted; however, in most NLE patients with other organ involvement (e.g. skin, liver, and blood), signs and symptoms sometimes resolve spontaneously within 4 to 6 months. 1
DLE is manifested as a chronic scarring and atrophic photosensitive dermatosis, which may progress to SLE or may occur in patients with SLE. The cause is thought to be genetic, with the highest prevalence in women, African-Americans, and persons between 20 and 40 years of age. The diagnosis is frequently made by biopsy of a rash on the scalp, face, neck, or arms. Chemical and physical sunblocks, topical corticosteroids, or antimalarial agents are commonly used to prevent disease flares and to manage the clinical manifestations associated with DLE. 2
DIL occurs after exposure to a medication, causing an autoimmune response. Various organ systems may be affected, but clinical manifestations usually subside upon discontinuation of the responsible agent. DIL is discussed on page 242. 3
SLE is the most common type of lupus and is therefore the focus of this review. SLE is commonly referred to simply as “lupus,” but it is differentiated from other types by its multi-organ system effects. SLE is diagnosed in approximately 20 to 150 persons per 100,000 and is typically seen in females of child-bearing age; however, it may affect male or female patients at any age. 4 – 6 SLE is more commonly observed in African-Americans, Asians, Hispanics, and Native Americans. 7 , 8

Arriving at the correct diagnosis of lupus is a challenge, considering the multitude of clinical presentations observed. The disease can affect the kidneys, lungs, skin, nervous system, and musculoskeletal system as well as other organs of the body. If SLE is suspected, patients’ subjective complaints, as well as laboratory abnormalities and demographic characteristics, may help to pinpoint the diagnosis.

In recent decades, mortality rates attributed to SLE have declined as a result of earlier disease detection and advances in treatment. The average 10-year survival rate now exceeds 90%; three decades ago, the 10-year average survival rate was 76%. 9 – 11 The most common causes of death are related to early active SLE include SLE-induced and immunosuppressant-induced infectious complications. A common cause of late mortality related to SLE is an accelerated atherosclerosis that is associated with either the disease or the treatment. 9

PATHOPHYSIOLOGY

SLE is a chronic disease that affects various organ systems, primarily as a consequence of the formation and deposition of autoantibodies and immune complexes, leading to eventual organ damage. Hyperactive B cells, resulting from T-cell and antigen stimulation, increase the production of these antibodies against antigens that are exposed on the surface of apoptotic cells. 12

The antigens causing T-cell and B-cell stimulation in patients with SLE can be attributed to the inappropriate disposal of apoptotic cells. During the process of cellular death, pieces of cellular material form on the surface of the dying cell. Antigens that are normally absent on the surface of the cellular material, but instead are embedded within, are now present on the cell surface. Nucleosomes and anionic phospholipids are examples of antigens that have been identified in patients with SLE, and they have the potential to trigger an immune response. 12 , 13 It is believed that the removal of these apoptotic cells is compromised because of the impaired functioning of phagocytic cells, resulting in suboptimal disposal of dying cells and antigen recognition in patients with SLE. 14

SLE is thought to develop when a T-lymphocyte to an antigen-presenting cell (APC) is introduced. The T-cell receptor binds to the major histocompatibility complex (MHC) portion of the APC, which may lead to cytokine release, inflammation, and B-cell stimulation. 12 Stimulation of B-cell division and the production of immunoglobulin G (IgG) autoantibodies that can cause tissue damage also occur in SLE. 12 , 15 – 19 Unlike the situation in healthy adults, autoantigen-specific T cells and B cells may also interact and produce harmful autoantibodies. 12 , 20

Many of the autoantibodies identified in SLE—the antinuclear antibodies (ANAs)—target nuclear components of cells. The detection of ANAs in patients with SLE is essential to the diagnosis. Patients may have positive results for more than one ANA. 19 The ANAs that have been tested most extensively, with involvement confirmed in SLE, are the anti–double-stranded (ds) DNA antibodies. 21 These antibodies, which are linked to SLE-induced kidney and skin disease, are highly specific for SLE and are present in a significant number of patients. 12 ANAs also interact with single-stranded (ss) DNA as well as with RNA. Other examples of ANAs are the anti-Ro and anti-La antibodies that, when detected during pregnancy, have been linked to fetal heart damage as well as the anti-Smith (Sm) antibodies, which are a marker of kidney disease. 22 – 24

A second grouping of autoantibodies targets the phospholipid moiety of the prothrombin activator complex as well as cardiolipin. These antiphospholipid antibodies can lead to abnormal clotting as well as loss of pregnancy. 25

In summary, the presence of hyperactive B cells leading to the production of autoantibodies, in conjunction with the impaired removal of apoptotic cellular material, results in the formation of immune complexes. In the microvasculature, these complexes induce inflammatory reactions, causing the tissue inflammation and damage associated with SLE.

The etiologic mechanism of SLE remains unknown, but multiple associations have been identified as a result of decades of research. Genetic, hormonal, immunological, and environmental factors all play a role in the development of SLE.

Studies focusing on a potential connection between genetics and SLE have shown a genetic predisposition within families. First-degree relatives of patients with SLE are significantly more likely to have the disease compared with the rest of the population. A study focusing on children of mothers with SLE documented that 27% of 195 children tested positive for ANAs. 26 Multiple studies addressing the incidence of SLE in identical and fraternal twins have demonstrated a strong relationship, especially with identical twins. One study revealed concordance rates of 14% to 57% in identical twins sharing the same trait; a second study showed an incidence rate of 24% to 58%. 27 – 29 In another study of non-identical twins, concordance rates of 3% to 10% were documented. 29

The investigation of a genetic influence on SLE has led to the discovery of a number of gene variants linked to SLE expression. Typically, a combination of these genetic variants leads to the clinical manifestations of SLE. For example, the complement component C1q eliminates necrotic cellular waste (apoptotic material) in healthy individuals. In patients with SLE, a possible deficiency of the C1q component can lead to disease expression. A second example of genetic variance is a possible deficiency of the C4 complement, a component identified in the elimination of self-reactive B cells. When the overall genetic picture of a patient with SLE is taken into account, the additive effects of these genetic variances significantly increase the risk of SLE progression. 30

The effect of hormones on the rate of occurrence and the severity of SLE has been of particular interest to researchers. The mechanism by which hormones affect SLE prevalence remains unknown. One hypothesis focuses on the roles of estrogens, progesterone, testosterone, dehydroepiandrosterone (DHEA), and prolactin in immune system responsiveness.

Estrogen has been linked to the stimulation of T and B cells, macrophages, and cytokines. 31 , 32 Estradiol in mice has an inhibitory effect on apoptosis, allowing the survival of B cells that produce high-affinity anti-DNA antibodies. 33 DHEA, an androgen that is a precursor to testosterone, has immunosuppressive properties. In patients with SLE, DHEA levels may be suboptimal. 34 Progesterone also affects autoantibody production, and elevated prolactin levels have been associated with SLE flares. 35 – 37

Immunological involvement in SLE focuses on a patient’s loss of “self-tolerance.” The process of phagocytosis is compromised in SLE patients, leading to the inappropriate removal of apoptotic cells and immune complexes. The hallmark of SLE is the formation of autoantibodies that go on to form immune complexes (in combination with antigens), leading to inflammation and tissue damage.

Environmental factors include certain viruses and ultra-violet (UV) light. UV light stimulates keratinocytes, leading to B-cell stimulation and antibody production; it may also stimulate T-cell activity, resulting in additional autoantibody production. 13 , 38 , 39 Epstein–Barr virus (EBV) has also been linked to the onset of SLE in children. Patients with SLE have higher titers of antibodies to EBV. 40 Smoking, silica, and some hair products (e.g., dyes) may also be possible triggers of lupus.

EPIDEMIOLOGY

The incidence of SLE varies among ethnic groups and by geographic location, sex, and age. The reported prevalence of SLE in the general population is approximately 20 to 150 cases per 100,000 persons. 4 – 6

A report submitted by the National Arthritis Data Working Group estimated that SLA affects 250,000 Americans. 41 The prevalence of SLE in the U.S. demonstrates a distinct elevation among Asian, Afro-American, Afro-Caribbean, and Hispanic-Americans compared with Americans of Eastern European descent. 42 , 43 For example, the prevalence of SLE among Caucasian patients in Rochester, Minn., is approximately 40 cases per 100,000 persons, compared with Hispanic patients in Nogales, Arizona, where the rate is 100 cases per 100,000 persons. 44 , 45

Black persons in Africa have a much lower incidence of SLE than African-Americans in the U.S. 46 The incidence of SLE in various populations (e.g., urban versus rural areas) is also a topic in need of further investigation. Epidemiologic data utilizing lupus registries point to the need for larger, population-based studies with a large patient base. Such data are currently lacking because of potential obstacles, such as differing case definitions, small-source populations, and varying demographic group targets. 47

Sex and Age

SLE is more common in women, particularly those of child-bearing age. This increased incidence may be attributed to hormones, namely estrogen, as studies have shown women who had an early menarche or who used oral contraceptives or hormonal therapies had an increased risk of SLE. 48 , 49 The lower risk in men is similar to that in prepubertal or postmenopausal women. Klinefelter’s syndrome, which features an extra X chromosome in males, is linked to an elevated incidence of SLE, thereby providing further support for the association between SLE and a possible hormonal pathogenesis. 50

CLINICAL PRESENTATION

The presentation of SLE can be complex, considering the number of organ systems that can be affected by the disease. Patients experience flare-ups to varying degrees as well as periods of disease remission. Although certain signs and symptoms are common in SLE, every patient presents with a unique set of identifiers. General signs and symptoms observed in SLE include fever, fatigue, and weight loss. The skin, musculoskeletal system, and pulmonary system are primarily affected. 6 , 7

SLE patients who report symptoms involving the skin most commonly have a red rash on the nose and cheeks following exposure to the sun. This “butterfly” rash is identified in a significant number of SLE patients at some point during the disease course. Patients experiencing photosensitivity reactions also report skin rashes on other areas of the body that were exposed to the sun. Other symptoms associated with skin manifestations include alopecia, Reynaud’s phenomenon, and sores in the mouth or nose. Musculoskeletal involvement includes arthralgias, myalgias, and/or arthritis. Arthritis can affect any minor or major joints, commonly presenting as painful, stiff joints accompanied by either occasional or persistent inflammation. 11 , 12

Patients with pulmonary symptoms report painful breathing, coughing, and shortness of breath. Pleural effusion and pulmonary hypertension have also been reported. 51

SLE also affects the cardiovascular, gastrointestinal, renal, and hematological systems, as well as the central nervous system (CNS). Cardiovascular effects often include pericarditis, myocarditis, endocarditis, and coronary artery disease. 52 , 53 It has been theorized that certain drugs used to treat SLE (e.g., immunosuppressants and corticosteroids) are risk factors for coronary artery disease in SLE patients along with the traditional risk factors observed in the general population. 52

Signs of gastrointestinal involvement include nausea, vomiting, and abdominal pain. Hematological changes reported in SLE include anemia as well as leukopenia or thrombocyto-penia. 54 The presence of antiphospholipid antibodies in patients with SLE can lead to thrombosis and fetal loss. 55

SLE patients with CNS manifestations may experience headaches, depression, anxiety, seizures, stroke, or cognitive impairment. Renal involvement in SLE typically results in diminished kidney function, which may result in elevated serum creatinine levels and proteinuria. Patients with renal involvement have a poorer prognosis, with likely progression to end-stage renal disease, which can be life-threatening. Approximately 50% of lupus patients develop nephritis, which is a major cause of morbidity and mortality. Autoantibodies appear to be involved in the formation of immune complexes, which may be deposited in the kidneys, leading to renal infiltration by T cells, macrophages, and other cells. 56 , 57

The diagnosis of SLE is based on observed signs and symptoms, laboratory testing, and diagnostic testing tailored to each patient. The 1997 Update of the 1982 American College of Rheumatology (ACR) Revised Criteria for Classification of Systemic Lupus Erythematosus is a valuable resource in the assessment of patients when SLE is suspected. 58 If a patient displays four or more of the 11 criteria (either simultaneously or at different time points), the diagnosis of SLE can be made with 95% specificity and 85% sensitivity. 58 However, a study conducted in 2003, which compared ACR criteria with modified weighted criteria, demonstrated a higher sensitivity in favor of the weighted criteria (sensitivity, 90.3% vs. 86.5%; specificity, 60.4% vs. 71.9%). 59

Considering that almost all patients with SLE are ANA-positive, ANA testing is essential in the diagnosis of SLE. 60 A positive ANA result is sometimes reported in disorders other than SLE (e.g., rheumatoid arthritis), but lower titers are commonly observed with rheumatoid arthritis than with SLE. Anti-dsDNA and anti-Smith (Sm) are two specific autoanti-bodies that are highly diagnostic for SLE. 61 – 63

In addition to autoantibody testing, other commonly performed diagnostic laboratory analyses include a complete blood count (CBC) with differential, a complete metabolic profile, and a urinalysis to determine the creatinine clearance and the presence of proteinuria or active sediment. The testing of complement levels (C3 and C4) as potential markers during SLE flares is also useful and is being studied further. 64

Diagnostic testing may be individualized to address signs and symptoms affecting each patient. Radiography can be used to assess joint involvement; renal ultrasound, kidney size and impairment; chest radiography, pulmonary involvement; and electrocardiography, chest pain.

Drug-Induced Lupus

Each year, approximately 15,000 to 30,000 cases of lupus are induced by a pharmaceutical product. 3 , 65 , 66 Certain medications, when administered to susceptible patients, may initiate or exacerbate SLE or may independently lead to drug-induced lupus (DIL). Procainamide (e.g., Pronestyl, Bristol-Myers Squibb) and hydralazine (e.g., Apresoline, Novartis), although not frequently used today, have been commonly associated with DIL. 67 , 68 Penicillamine (e.g., Cuprimine, Merck), minocycline (Minocin Wyeth/Pfizer), isoniazid (formerly Nydrazid, no longer available in the U.S.), methyldopa (e.g., Aldomet, Merck), and anti–tumor necrosis factor (anti-TNF) agents have also been linked to DIL. Unlike that of idiopathic SLE, the incidence of DIL is similar among men and women; the disease primarily affects patients of advanced age. 3 , 63

The exact cause of DIL is unknown, but genetics are believed to be involved. Patients who are slow acetylators, particularly those taking procainamide or hydralazine, have a higher risk of developing DIL. 61 , 69 , 70

The presence of autoantibodies is a significant immunological finding in DIL. Antihistone antibodies, the predominant autoantibodies identified in DIL, are present in 95% of patients. 71 Anti–dsDNA antibodies have been identified in patients taking interferon-alpha or anti–TNF-related drugs, and antineutrophil cytoplasmic antibodies have been associated with necrotizing vasculitis in patients with DIL. 72

Procainamide and hydralazine are the two agents most often implicated in the development of DIL. Most patients test positive for ANAs if they were taking procainamide for more than 2 years, 67 especially true in patients with the slow acetylator phenotype. 68 It is estimated that symptoms develop in up to one-third of patients who take procainamide after 1 year of therapy. 39 , 73 The risk of DIL from hydralazine becomes a special concern in patients receiving increased doses (more than 200 mg daily), in female patients, in slow acetylators, and in patients with certain genetic mutations. 73 – 77

Patients with DIL commonly present with fever, fatigue, myalgia, arthralgia, pericarditis, and pleuritis. A diagnosis of DIL is made if a patient has taken a drug thought to have caused DIL, has no prior history of idiopathic SLE, has a combination of the symptoms listed, and has a positive ANA test result. 69 , 78 , 79

The remedy for DIL is to discontinue taking the offending agent. Nonsteroidal anti-inflammatory drugs (NSAIDs) help to relieve musculoskeletal symptoms. Antimalarials and corticosteroids may be given if the symptoms of DIL are considered to be very serious. Following discontinuation of the suspected drug, patients should experience improvement within days to weeks, although some cases of DIL may take a year or longer for the disease manifestations to resolve completely. 80

The approach to the treatment of signs and symptoms of lupus depends on the type and the severity of disease. General recommendations for all patients include sun protection, proper diet and nutrition, exercise, smoking cessation, appropriate immunizations, and management of comorbid conditions.

In patients with mild-to-moderate lupus, NSAIDs, anti-malarial agents, and corticosteroids are commonly used to treat signs and symptoms. As the disease progresses and clinical manifestations worsen, high-dose corticosteroids and immunosuppressive agents are used to help control disease progression. A list of drugs commonly used to treat SLE is presented in Table 1 . 81 , 82

Commonly Used Medications in the Treatment of Systemic Lupus Erythematosus


NSAIDs (including salicylates)	Block prostaglandin synthesis through inhibition of cyclooxygenase enzymes, producing anti-inflammatory, analgesic, and antipyretic effects	Various agents and dosages	Gastrointestinal irritation and bleeding, renal toxicity, hepatic toxicity, hypertension	Nausea, vomiting, abdominal pain, dark/tarry stool; baseline and annual CBC, SCr, LFTs, urinalysis
Antimalarials	Unclear; may interfere with T-cell activation and inhibit cytokine activity; also thought to inhibit intracellular TLRs	Hydroxychloroquine PO 200–400 mg daily	Macular damage, muscle weakness	Funduscopy and visual field examination at baseline and every 6 to 12 months
Corticosteroids	Multiple effects on immune system (e.g., blocking cytokine activation and inhibiting interleukins, γ-interferon and tumor necrosis factor-α)	Prednisone PO 0.5–2 mg/kg per day Methylprednisolone IV 500–1,000 mg daily for 3 to 6 days (acute flare)	Weight gain, hypertension, hyperglycemia, hyperlipidemia, osteoporosis, cataracts, edema, hypokalemia, muscle weakness, growth suppression, increased risk of infection, glaucoma	Baseline blood pressure, bone density, glucose, potassium, lipid panel; glucose every 3 to 6 months; annual lipid panel and bone density
Immunosuppressants	Multiple suppressive effect on immune system (e.g., reduction of T-cell and B-cell proliferation; DNA and RNA disruption)	Cyclophosphamide PO 1–3 mg/kg per day or 0.5–1 g/m IV monthly with or without a corticosteroid Azathioprine PO 1–3 mg/kg per day Mycophenolate PO 1–3 g daily	Myelosuppression, hepatotoxicity, renal dysfunction, infertility, increased risk of infection and cancer	Baseline and routine CBC, platelet count, SCr, LFTs, and urinalysis (depends on individual drug)
Monoclonal antibodies	Block binding of BLyS to receptors on B cells, inhibiting survival of B cells, and reducing B-cell differentiation into immunoglobulin-producing plasma cells	Belimumab IV 10 mg/kg (over a period of 1 hour), every 2 weeks for the first three doses, then every 4 weeks	Nausea, diarrhea, pyrexia, nasopharyngitis, insomnia, extremity pain, depression, migraine, gastroenteritis, infection (e.g., pneumonia, UTI, cellulitis, bronchitis)	Gastrointestinal complaints, infectious signs and symptoms, mood or behavioral changes, infusion reactions

BLyS = B-lymphocyte stimulator protein; CBC = complete blood count; DNA = deoxyribonucleic acid; IV = intravenous; LFTs = liver function tests; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth; RNA = ribonucleic acid; SCr = serum creatinine; TLRs = toll-like receptors; UTI = urinary tract infection.

NSAIDs may be used to alleviate musculoskeletal pain, swelling, and aches. These drugs possess pain-reducing, anti-inflammatory, and anticoagulant properties, which are beneficial in treating common lupus-associated manifestations; however, the potential for side effects (see Table 1 ) must be considered before clinicians prescribe NSAIDs for a patient with lupus. 81 , 82

Antimalarial Medications

Some antimalarial agents have proved effective in treating the various signs and symptoms of lupus and preventing subsequent flares. Although the exact mechanism is unclear (see Table 1 ), antimalarials may interfere with T-cell activation and inhibit cytokine activity. These agents may also inhibit intra-cellular toll-like receptors, which recognize and bind foreign materials, thereby contributing to activation of the immune system. 83 Hydroxychloroquine (e.g., Plaquenil, Sanofi) is the most commonly studied and used drug in its class, but it has the potential to cause serious visual and muscle disturbances.

Corticosteroids mimic naturally occurring hormones excreted by the adrenal gland and help regulate blood pressure and immune function. These agents decrease the swelling and pain associated with inflammation, which can occur in a lupus flare. Because of their serious long-term side effects (see Table 1 ), corticosteroids should be used at the lowest possible dose and only for periods necessary to control an active exacerbation of lupus. 81 , 82

Immunosuppressive Agents

Immunosuppressants are primarily used in more severe cases of lupus when high-dose corticosteroids or antimalarial treatments have failed to control the signs and symptoms of disease. They are also used when it is necessary to induce and maintain remission and to reduce flares or relapses. Immunosuppressants may be given with high-dose cortico steroids to control flares, to achieve a lower dose of each medication, or to reduce the occurrence of adverse events. The most commonly used agents in this class are cyclophosphamide (Cytoxan, Bristol-Myers Squibb) and azathioprine (Azasan, Salix; Imuran, GlaxoSmithKline). Mycophenolate (CellCept, Genentech/Roche) has also been used for lupus-related kidney problems. Side effects of this drug class are listed in Table 1 . 81 , 82

Monoclonal Antibodies

In March 2011, the FDA approved the first human monoclonal antibody for the treatment of lupus. Belimumab (Benlysta, Human Genome Sciences/GlaxoSmithKline) is the first agent in more than 50 years to be approved for patients with lupus. Belimumab inhibits the activation of B lymphocytes by interfering with a protein necessary for B-cell activity (BLyS). Previously known as LymphoStat-B, belimumab is recommended for patients with active SLE who are receiving standard therapy with NSAIDs, antimalarials, corticosteroids, and/or immunosuppressants. Common adverse effects are presented in Table 1 . 84

Belimumab is also discussed in this month’s Drug Forecast column, also by Dr. Hilas and colleagues, on page 212.

As a genetically engineered chimeric monoclonal antibody directed against the CD20 antigen, rituximab (Rituxan, Genentech/Roche) has also shown potential in the treatment of SLE. It is believed that B cells responsible for the production of pathogenic autoantibodies, and other immune-mediated substances associated with lupus, are depleted by rituximab. During the past few years, a number of open-label and retrospective studies have reported promising results with rituximab (when taken with corticosteroids and other immunosuppressants in the management of both pediatric-onset and adult-onset lupus).

Benefits of rituximab have also been noted in patients with lupus nephritis, arthralgia, arthritis, serositis, cutaneous vasculitis, mucositis, rashes, fatigue, and neurological and refractory symptoms. Adverse events were generally mild. Mild-to-moderate infusion reactions were reported most often. 85 , 86

A few randomized controlled studies have provided mixed results regarding the efficacy and role of rituximab in the treatment of SLE. In a study by Terrier et al., clinical responses were reported in 71% of patients who received rituximab, demonstrating a significant benefit in refractory lupus (with or without concomitant immunosuppressive therapy). Cutaneous, articular, renal, and hematological improvements were noted most often, along with an acceptable tolerance profile. 87

In a systematic review of 188 SLE patients treated with various regimens of rituximab, 91% showed a significant improvement in one or more systemic manifestations, particularly in patients with renal involvement (e.g., lupus nephritis). Adverse events were experienced by 23% of patients, and infections were reported most often. 88 However, two additional randomized, placebo-controlled studies, conducted since 2010, failed to demonstrate significant clinical improvements with rituximab in patients receiving concomitant steroid therapy. 89 , 90 Despite the favorable tolerability and safety profile of rituximab, further evaluation of this drug is required for patients with SLE.

Additional Treatment Options

Researchers have been particularly interested in the use of stem-cell transplantation to introduce healthy cells into the body in order to help rebuild the immune system. Both DHEA and rituximab have been studied in clinical trials and have provided improvements in patients’ quality of life. DHEA is believed to help in the regulation of sex hormones, whereas rituximab decreases the number of B cells and may be most beneficial in patients who do not respond to the other traditionally used immunusuppressants. 85 , 86

Women with SLE are at increased risk for serious medical and pregnancy complications, such as thrombosis, infection, thrombocytopenia, transfusion, pre-eclampsia, and death. 91 , 92 Because of the high risk of miscarriage, stillbirths, premature delivery, and exacerbation of SLE, it is recommended that women not become pregnant if they have active disease or significant organ involvement. Oral contraceptives must be given cautiously because high doses of estrogen can cause SLE exacerbations. 92 Pregnancy outcomes are improved if conception is delayed until SLE has been inactive for at least 6 months and if the patient’s medications are adjusted in advance.

Baseline and monthly monitoring (e.g., laboratory tests, ultrasonography, fetal surveillance tests, maternal echocardiography, and antibody testing) should be performed for all pregnant lupus patients, because signs and symptoms of lupus flares may be similar to those typical of pregnancy. 92 Neonates should be carefully evaluated for placental transfer of maternal antibodies, which could lead to cutaneous or cardiac complications (e.g., congenital heart block and cardiomyopathy). 93

If a woman is pregnant and has active SLE, corticosteroids may be prescribed with caution to manage the disease. Most steroids are Pregnancy Category C drugs. NSAIDs (Pregnancy Category C and D) have also been used, but to a lesser extent, and they should be avoided during early pregnancy and the last trimester.

If necessary, hydroxychloroquine may be used, but it is also a Pregnancy Category C drug. Therefore, therapy must be individualized and the drug’s benefits and risks must be carefully considered. Immunosuppressive agents are contraindicated in pregnancy, except for azathioprine, a Pregnancy Category C drug.

In women with SLE and antiphospholipid antibodies, prophylaxis with aspirin, low-molecular-weight heparin, or both, is indicated for the prevention of fetal loss. 91 , 92

Lupus continues to present many unanswered questions. Although no cure has been discovered for this autoimmune disease, many medications are available to help control flares, to maintain remission, and to manage symptoms. Pharmacists and other health care professionals can play a vital role in treatment by educating patients, monitoring their therapeutic regimens, and identifying preventable drug-associated adverse events. Current research is under way, with the hope that improved quality of life and increased survival can be achieved for the many patients affected by SLE each year.

Disclosure: The authors report no financial or commercial relationships in regard to this article.

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