Article

Predictors of neuropsychiatric damage in systemic lupus erythematosus: Data from the Maryland lupus cohort

January 2005
British Journal of Rheumatology 43(12):1555-60

January 2005
43(12):1555-60

DOI:10.1093/rheumatology/keh384

Source
PubMed

Authors:

Jamal Mikdashi

University of Maryland, College Park

To identify factors predictive of significant neuropsychiatric (NP) damage in systemic lupus erythematosus (SLE). One hundred and thirty patients with SLE were followed at the University of Maryland Lupus Clinic from 1992 until 2003. NP manifestations were defined according to the revised American College of Rheumatology (ACR) nomenclature and case definitions for NP-SLE syndromes. Disease activity was measured using the SLE Disease Activity Index (SLEDAI), organ damage using the Systemic Lupus International Collaborating Clinics Damage Index SLICC/ACR (SDI); NP damage (NPDI) was measured with the corresponding domain of the SDI. At end of study period, 64 patients exhibited no NP damage (NPDI = 0) and 66 patients developed significant NP damage (defined as NPDI > or =1). The baseline features for these two patient groups were compared, and variables found to be significantly different were examined by multivariable analyses to determine their contribution to NP damage. Significant NP damage is common in SLE; mortality is infrequent and the cause of death is unrelated to NP damage. Independent predictors of significant NP damage were disease activity, Caucasian ethnicity and the presence of antiphospholipid antibodies and anti-Ro/SSA antibody. Certain clinical features at baseline predicted specific NP damage. For example, higher disease activity at baseline was predictive of psychosis and cognitive impairment, anti-dsDNA was predictive of polyneuropathy, and antiphospholipid antibodies were predictive of seizures and cerebrovascular accidents. In this longitudinal SLE cohort, significant cumulative NP damage occurred. Early aggressive therapy targeted towards NP manifestations may prevent the occurrence of NP damage.

Determinants of neuropsychiatric flares in patients with systemic lupus erythematosus: results from five phase III trials of belimumab

Article

Full-text available

May 2023

Objective: To identify determinants of neuropsychiatric (NP) flares in patients with systemic lupus erythematosus (SLE) treated for active SLE yet no ongoing severe NPSLE with non-biologic standard therapy plus belimumab or placebo. Methods: We analysed data from five phase III trials (BLISS-52, BLISS-76, BLISS-NEA, BLISS-SC, EMBRACE; N = 3638) after exclusion of patients with baseline NP BILAG A. Factors associated with NPSLE flare, defined as a new NP BILAG A or B, were investigated using Cox regression. In a subgroup analysis, we studied patients with baseline NP BILAG E for determinants of de novo NPSLE flare. Organ damage was assessed using the SLICC/ACR Damage Index (SDI). Results: We documented 105 (2.9%) NPSLE flares. In multivariable analysis, male sex (HR = 2.37; 95% CI: 1.31-4.28; p = 0.004), baseline NP BILAG B-D (HR = 5.91; 95% CI: 3.86-9.06; p < 0.001), and increasing SDI scores (HR = 1.35; 95% CI: 1.21-1.50; p < 0.001) were strongly associated with NPSLE flare. Belimumab use yielded no association at any dose or administration form. In analysis of SDI domains, NP damage was the strongest determinant of NPSLE flare (HR = 3.25; 95% CI: 2.72-3.88; p < 0.001), holding true for cognitive impairment (HR = 14.29; 95% CI: 9.22-22.14; p < 0.001), transverse myelitis (HR = 21.89; 95% CI: 5.40-88.72; p < 0.001), and neuropathy (HR = 8.87; 95% CI: 5.59-14.09; p < 0.001). Male sex was the strongest determinant of de novo NPSLE flare (HR = 3.26; 95% CI: 1.51-7.04; p = 0.003). Conclusion: Male sex, NPSLE history, and NP damage were strong determinants of impending NPSLE flare. No clear protection or predisposition was conferred from add-on belimumab.

Cognitive Impairment in Anti-Phospholipid Syndrome and Anti-Phospholipid Antibody Carriers

Article

Full-text available

Feb 2022
BSRCCS

Cognitive impairment is frequently reported among anti-phospholipid syndrome (APS) patients as well as anti-phospholipid antibody (aPL) carriers, but it is less studied than other manifestations of this condition. Moreover, the exact prevalence of cognitive impairment in these patients has not been accurately determined, mainly due to inconsistency in the tools used to identify impairment, small sample sizes, and variability in the anti-phospholipid antibodies measured and positivity cutoffs. The notion of a direct pathogenic effect is supported by the observation that the higher the number of aPLs present and the higher the load of the specific antibody, the greater the risk of cognitive impairment. There is some evidence to suggest that besides the thrombotic process, inflammation-related pathways play a role in the pathogenesis of cognitive impairment in APS. The cornerstone treatments of APS are anti-coagulant and anti-thrombotic medications. These treatments have shown some favorable effects in reversing cognitive impairment, but solid evidence for the efficacy and safety of these treatments in the context of cognitive impairment is still lacking. In this article, we review the current knowledge regarding the epidemiology, pathophysiology, clinical associations, and treatment of cognitive impairment associated with APS and aPL positivity.

Factors associated with neuropsychiatric involvement in Latin American patients with systemic lupus erythematosus

Article

Jun 2021

Introduction Factors related to presentation of neuropsychiatric (NP) SLE manifestations, early in the course of the disease, and during follow up have not been clearly established. Purpose To identify disease and non-disease related factors associated with NP manifestations in early SLE. Methods We included 1193 patients from the GLADEL inception cohort free of NP involvement at cohort entry. We evaluated the association of demographic, clinical and laboratory data with NP involvement during follow-up. Statistical methods Independent factors associated with NP involvement were identified using a multivariable Cox regression model. Results Factors independently associated with NP manifestations were: mestizo ethnicity (HR 1.701, 95% CI 1.282–2.258, p = 0.0002), myalgias/myositis (HR 1.832, 95% CI 1.335–2.515, p = 0.0002), pneumonitis (HR 2.476, 95% CI 1.085–5.648, p = 0.0312), shrinking lung (HR 2.428, 95% CI 1.074–5.493, p = 0.0331) and hemolytic anemia (HR 1.629, 95% CI 1.130–2.347, p = 0.0089). Longer disease duration at cohort entry (13 to 24 months) was associated with a lower risk of developing NP manifestations (HR 0.642, 95% CI 0.441–0.934, p = 0.0206). Conclusions Patients with myalgias/myositis, pneumonitis, shrinking lung and hemolytic anemia are at higher risk of NP involvement, whereas longer disease duration at cohort entry is associated with a lower risk of developing NP involvement.

Neuropsychiatric manifestations in systemic lupus erythematosus: correlation with neuropsychiatric damage and disease activity

Article

May 2014

The conundrum of neuropsychiatric systemic lupus erythematosus: Current and novel approaches to diagnosis

Article

Full-text available

Mar 2023

Recognising neuropsychiatric involvement by systemic lupus erythematosus (SLE) is of growing importance, however many barriers to this exist at multiple levels of our currently available diagnostic algorithms that may ultimately delay its diagnosis and subsequent treatment. The heterogeneous and non-specific clinical syndromes, serological and cerebrospinal fluid (CSF) markers and neuroimaging findings that often do not mirror disease activity, highlight important research gaps in the diagnosis of neuropsychiatric SLE (NPSLE). Formal neuropsychological assessments or the more accessible screening metrics may also help improve objective recognition of cognitive or mood disorders. Novel serum and CSF markers, including autoantibodies, cytokines and chemokines have also shown increasing utility as part of diagnosis and monitoring, as well as in distinguishing NPSLE from SLE patients without SLE-related neuropsychiatric manifestations. Novel neuroimaging studies also expand upon our existing strategy by quantifying parameters that indicate microarchitectural integrity or provide an assessment of neuronal function. Some of these novel markers have shown associations with specific neuropsychiatric syndromes, suggesting that future research move away from considering NPSLE as a single entity but rather into its individually recognized neuropsychiatric manifestations. Nevertheless, it is likely that a composite panel of these investigations will be needed to better address the gaps impeding recognition of neuropsychiatric involvement by SLE.

Low C4 as a risk factor for severe neuropsychiatric flare in patients with systemic lupus erythematosus

Article

Full-text available

Jul 2020

Objective This study aimed to explore the risk factors for ‘severe’ neuropsychiatric (NP) flare in patients with systemic lupus erythematosus (SLE). Methods This retrospective study comprised newly diagnosed 184 adult SLE patients who visited Hokkaido University Hospital between 2006 and 2017. In this study, severe NP flare was defined as the occurrence of at least one newly developed British Isles Lupus Assessment Group A score in the neurological domain. Overall severe NP flare-free survival was estimated by Kaplan–Meier analysis. Clinical and demographic profiles at SLE diagnosis were assessed as potential risk items in the adjusted multivariate Cox regression model. Results The median follow-up period was 7.9 years (interquartile range (IQR) 4.6–12.3) years. A total of 28 (15.2%) patients had one or more severe NP flares during the observation period. The median time from patient enrolment date to severe NP flare occurrence was 3.1 years (IQR 0.9–6.3 year). The 2- and 10-year severe NP flare-free survival rates were 92.7% and 86.0%, respectively. Among the manifestations of severe NP flare, psychosis was the most frequent (19.1%). In the multivariate model, low serum levels of C4 (hazard ratio (HR) = 3.67, p = 0.013) and severe NP manifestations at SLE diagnosis (HR = 7.11, p < 0.001) emerged as independent risk factors for developing severe NP flare. Conclusion The first severe NP flare presented early in the course of SLE. Low C4 level and severe NP manifestations at SLE diagnosis could predict the development of severe NP flare.

Systemic lupus erythematosus may have an early effect on peripheral nerve function in patients without clinical or electrophysiological neuropathy: comparison with age- and gender-matched controls

Article

Full-text available

Feb 2021
RHEUMATOL INT

Asymptomatic electrophysiological peripheral neuropathy is described in systemic lupus erythematosus (SLE) patients. To determine if SLE could have an even earlier effect on peripheral nerve function even before the development of electrophysiological abnormalities, we compared nerve conduction studies (NCS) of SLE patients without electrophysiological or clinical peripheral neuropathy with healthy controls. Consecutive SLE patients without clinical neuropathy (or other known causes of neuropathy) underwent sensory and motor NCS of all four limbs. Results of 61 patients without electrophysiological criteria of neuropathy were compared with age- and gender-matched controls. Although still within the laboratory’s range of normal values, significant differences were found in several NCS parameters between patients and controls. SLE patients had lower amplitudes for ulnar, fibular, and tibial compound muscle action potentials (CMAP) and sural sensory nerve action potentials (SNAP); slower conduction velocities for median, ulnar, and fibular motor nerves, and median, ulnar and sural sensory nerves. SLE patients also had longer minimum F-wave latencies for median, ulnar, fibular, and tibial nerves. H reflexes were more often absent in patients. Correlations were found between the number of disease relapses and motor conduction velocities of the fibular and tibial nerves. SLE may have early effect on peripheral nerve function in patients even before they develop electrophysiological or clinical neuropathy.

Combined Brain/Heart Magnetic Resonance Imaging in Systemic Lupus Erythematosus

Article

Full-text available

Aug 2019

Cardiovascular Disease (CVD) in Systemic Lupus Erythematosus (SLE) and Neuropsychiatric SLE (NPSLE) has an estimated prevalence of 50% and 40%, respectively and both constitute major causes of death among SLE patients. In this review, a combined brain/heart Magnetic Resonance Imaging (MRI) for SLE risk stratification has been proposed. The pathophysiologic background of NPSLE includes microangiopathy, macroscopic infarcts and accelerated atherosclerosis. Classic brain MRI findings demonstrate lesions suggestive of NPSLE in 50% of the NPSLE cases, while advanced MRI indices can detect pre-clinical lesions in the majority of them, but their clinical impact still remains unknown. Cardiac involvement in SLE includes myo-pericarditis, valvular disease/endocarditis, Heart Failure (HF), coronary macro-microvascular disease, vasculitis and pulmonary hypertension. Classic and advanced Cardiovascular Magnetic Resonance (CMR) indices allow function and tissue characterization for early diagnosis and treatment follow-up of CVD in SLE. Although currently, there are no clinical data supporting the combined use of brain/heart MRI in asymptomatic SLE, it may have a place in cases with clinical suspicion of brain/heart involvement, especially in patients at high risk for CVD/stroke such as SLE with antiphospholipid syndrome (SLE/APS), in whom concurrent cardiac and brain lesions have been identified. Furthermore, it may be of value in SLE with multi-organ involvement, NPSLE with concurrent cardiac involvement, and recent onset of arrhythmia and/or heart failure.

Relationship of Antiphospholipid Antibodies to Risk of Dementia: A Systematic Review

Article

May 2019

Antiphospholipid antibodies (aPL) are well-known risk factors for venous and arterial thrombosis, but their association with cognitive dysfunction has not been widely investigated in the general population and in patients with primary and secondary antiphospholipid syndrome (APS).We performed a systematic review searching MEDLINE via PubMed and Cochrane (CENTRAL) databases for observational studies reporting on the association between aPL and dementia in the general population, in subjects carrying aPL, in patients with cognitive disorder/dementia, and in primary and secondary APS. Prevalence of anticardiolipin (aCL) IgG ranged from 5.9% to 31.1% in the general population, with aCL titers being more elevated in subjects with functional decline of cognitive functions or with neurological alterations as detected by imaging. The prevalence of aPL ranged from 6.0 to 56.6% in patients with vascular dementia. Regarding patients with primary and secondary APS, a severe cognitive deficit has been described in up to 60% of patients, 33.3% of systemic lupus erythematosus (SLE)-APS and 22.2% of SLE patients without aPL. Five studies included patients with primary APS with divergent results, while 18 studies investigated the association between aPL and cognitive impairment in patients with SLE. Of these, 14 reported a positive association between aPL, mostly aCL and LAC, and cognitive impairment while little evidence on anti b2-Glycoprotein I exists. Mechanisms leading to cognitive dysfunction are not well characterized and may include vascular aPL-induced micro and macro-thrombosis and immune-mediated neuronal toxicity pathways in the cerebral district.

Cognitive dysfunction in pediatric systemic lupus erythematosus: current knowledge and future directions

Article

Full-text available

Oct 2023

Cognitive dysfunction (CD) is a neurologic complication of pediatric systemic lupus erythematosus (SLE) that remains poorly understood and understudied, despite the potential negative effects of CD on long-term socioeconomic status and quality of life. Data regarding the prevalence and risk factors for CD in pediatric SLE as well as the optimal screening, treatment, and long-term outcomes for CD are lacking. In this review, we present current knowledge on CD in pediatric SLE with a focus on the application to clinical practice. We discuss the challenges in diagnosis, clinical screening methods, potential impacts, and interventions for this complication. Finally, we discuss the remaining gaps in our knowledge of CD in pediatric SLE, and avenues for future research efforts.

The clinical features and potential mechanisms of cognitive disorders in peripheral autoimmune and inflammatory diseases

Article

Full-text available

Dec 2022

According to a study from World Health Organization's Global Burden of Disease, mental and neurological disorders have accounted for 13% of global diseases in recent years and are on the rise. Neuropsychiatric conditions or neuroinflammatory disorders are linked by the presence of an exaggerated immune response both peripherally and in the central nervous system (CNS). Cognitive dysfunction (CD) encompasses a complex group of diseases and has frequently been described in the field of autoimmune diseases, especially in multiple non-CNS-related autoimmune diseases. Recent studies have provided various hypotheses regarding the occurrence of cognitive impairment in autoimmune diseases, including that abnormally activated immune cells can disrupt the integrity of the blood-brain barrier (BBB) to trigger a central neuroinflammatory response. When the BBB is intact, autoantibodies and pro-inflammatory molecules in peripheral circulation can enter the brain to activate microglia, inducing CNS inflammation and CD. However, the mechanisms explaining the association between the immune system and neural function and their contribution to diseases are uncertain. In this review, we used clinical statistics to illustrate the correlation between CD and autoimmune diseases that do not directly affect the CNS, summarized the clinical features and mechanisms by which autoimmune diseases trigger cognitive impairment, and explored existing knowledge regarding the link between CD and autoimmune diseases from the perspective of the field of neuroimmunology.

Neuropsychiatric Events in Systemic Lupus Erythematosus: Predictors of Occurrence and Resolution in a Longitudinal Analysis of an International Inception Cohort

Article

Dec 2021

Objective: To determine predictors of change in neuropsychiatric (NP) event status in a large, prospective, international inception cohort of patients with systemic lupus erythematosus (SLE). // Methods: Upon enrollment and annually thereafter, NP events attributed to SLE and non-SLE causes and physician-determined resolution were documented. Factors potentially associated with the onset and resolution of NP events were determined by time-to-event analysis using a multistate modeling structure. // Results: NP events occurred in 955 (52.3%) of 1,827 patients, and 593 (31.0%) of 1,910 unique events were attributed to SLE. For SLE-associated NP (SLE NP) events, multivariate analysis revealed a positive association with male sex (P = 0.028), concurrent non-SLE NP events excluding headache (P < 0.001), active SLE (P = 0.012), and glucocorticoid use (P = 0.008). There was a negative association with Asian race (P = 0.002), postsecondary education (P = 0.001), and treatment with immunosuppressive drugs (P = 0.019) or antimalarial drugs (P = 0.056). For non-SLE NP events excluding headache, there was a positive association with concurrent SLE NP events (P < 0.001) and a negative association with African race (P = 0.012) and Asian race (P < 0.001). NP events attributed to SLE had a higher resolution rate than non-SLE NP events, with the exception of headache, which had comparable resolution rates. For SLE NP events, multivariate analysis revealed that resolution was more common in patients of Asian race (P = 0.006) and for central/focal NP events (P < 0.001). For non-SLE NP events, resolution was more common in patients of African race (P = 0.017) and less common in patients who were older at SLE diagnosis (P < 0.001). // Conclusion: In a large and long-term study of the occurrence and resolution of NP events in SLE, we identified subgroups with better and worse prognosis. The course of NP events differs greatly depending on their nature and attribution.

Heterogeneity of Stroke in Patients with Systemic Lupus Erythematosus

Article

Full-text available

Oct 2022
INTERNAL MED

Objective The underlying pathophysiology varies according to stroke subtype. However, stroke heterogeneity among patients with systemic lupus erythematosus (SLE) remains unstudied. We hypothesized that the contribution of SLE to stroke might vary according to its subtype and investigated the associations of SLE and various stroke subtypes. Methods Diagnostic codes and electronic medical records were used to identify 70 patients with SLE who developed acute cerebral infarction or intracerebral hemorrhaging at four tertiary referral hospitals between 2008 and 2018. Intracerebral hemorrhaging was classified as lobar or deep, while cerebral infarction was classified according to the SSS-TOAST criteria. Physician notes were used to identify SLE activity, and their prevalences were compared among stroke subtypes. Outcomes were collected from the patients' medical records. Results The most common stroke subtype in patients with SLE was that of undetermined causes (31%), followed by small artery occlusion (16%), cardioaortic embolism (13%), other causes (11%), lobar hemorrhaging (10%), deep hemorrhaging (10%), and large artery atherosclerosis (9%). Stroke onset occurred during a period of high SLE activity in 21 patients (30%). The proportion of patients with high SLE activity varied according to stroke subtype (p=0.039) and was highest for cerebral infarction with undetermined causes. Stroke recurrence or death was observed in 40% of patients within 5 years after the initial stroke onset. Conclusion The contributions of SLE to stroke varied significantly according to the stroke subtype. Given the unfavorable prognosis, close stroke subtype-specific observation by rheumatologists and stroke specialists is recommended after stroke events.

Progress in the Pathogenesis and Treatment of Neuropsychiatric Systemic Lupus Erythematosus

Article

Full-text available

Aug 2022

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

Differentiating central nervous system demyelinating disorders: The role of clinical, laboratory, imaging characteristics and peripheral blood type I interferon activity

Article

Full-text available

Aug 2022

Objective: While multiple sclerosis (MS) is considered the cornerstone of autoimmune demyelinating CNS disorders, systemic autoimmune diseases (SADs) are important MS mimickers. We sought to explore whether distinct clinical, laboratory, and imaging characteristics along with quantitation of peripheral blood type I interferon (IFN) activity could aid in differentiating between them. Methods: A total of 193 consecutive patients with imaging features suggesting the presence of CNS demyelinating disease with or without relevant clinical manifestations underwent full clinical, laboratory, and imaging evaluation, including testing for specific antibodies against 15 cellular antigens. Expression analysis of type I IFN-inducible genes (MX-1, IFIT-1, and IFI44) was performed by real-time PCR, and a type I IFN score, reflecting type I IFN peripheral activity, was calculated. After joint neurological/rheumatological evaluation and 1 year of follow-up, patients were classified into MS spectrum and CNS autoimmune disorders. Results: While 66.3% (n = 128) of the patients were diagnosed with MS spectrum disorders (predominantly relapsing–remitting MS), 24.9% (n = 48) were included in the CNS autoimmune group, and out of those, one-fourth met the criteria for SAD (6.7% of the cohort, n = 13); the rest (18.1% of the cohort, n = 35), despite showing evidence of systemic autoimmunity, did not fulfill SAD criteria and comprised the “demyelinating disease with autoimmune features” (DAF) subgroup. Compared to the MS spectrum, CNS autoimmune patients were older, more frequently females, with increased rates of hypertension/hyperlipidemia, family history of autoimmunity, cortical dysfunction, anti-nuclear antibody titers ≥1/320, anticardiolipin IgM positivity, and atypical for MS magnetic resonance imaging lesions. Conversely, lower rates of infratentorial and callosal MRI lesions, CSF T2 oligoclonal bands, and IgG-index positivity were observed in CNS autoimmune patients. Patients fulfilling SAD criteria, but not the DAF group, had significantly higher peripheral blood type I IFN scores at baseline compared to MS spectrum [median (IQR)]: 50.18 (152.50) vs. −0.64 (6.75), p -value: 0.0001. Conclusion: Our study suggests that underlying systemic autoimmunity is not uncommon in patients evaluated for possible CNS demyelination. Distinct clinical, imaging and laboratory characteristics can aid in early differentiation between MS and CNS-involving systemic autoimmunity allowing for optimal therapeutic strategies. Activated type I IFN pathway could represent a key mediator among MS-like-presenting SADs and therefore a potential therapeutic target.

Insights into the role of neutrophils in neuropsychiatric systemic lupus erythematosus: Current understanding and future directions

Article

Full-text available

Aug 2022

Central nervous system (CNS) involvement of systemic lupus erythematosus (SLE), termed neuropsychiatric SLE (NPSLE), is a major and debilitating manifestation of the disease. While patients with SLE mostly complain of common neuropsychological symptoms such headache and mild mood disorders that may not even be technically attributed to SLE, many SLE patients present with life-threatening NPSLE syndromes such as cerebrovascular disease, seizures and psychosis that are equally challenging in terms of early diagnosis and therapy. While we are just beginning to unravel some mysteries behind the immunologic basis of NPSLE, advancements in the mechanistic understanding of the complex pathogenic processes of NPSLE have been emerging through recent murine and human studies. The pathogenic pathways implicated in NPSLE are multifarious and various immune effectors such as cell-mediated inflammation, autoantibodies and cytokines including type I interferons have been found to act in concert with the disruption of the blood-brain barrier (BBB) and other neurovascular interfaces. Beyond antimicrobial functions, neutrophils are emerging as decision-shapers during innate and adaptive immune responses. Activated neutrophils have been recognized to be involved in ischemic and infective processes in the CNS by releasing neutrophil extracellular traps (NETs), matrix metalloproteinase-9 and proinflammatory cytokines. In the context of NPSLE, these mechanisms contribute to BBB disruption, neuroinflammation and externalization of modified proteins on NETs that serve as autoantigens. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low-density neutrophils (LDNs) or low-density granulocytes. LDNs are a proinflammatory subset of neutrophils that are increased with SLE disease activity and are primed to undergo NETosis and release cytokines such as interferon-α and tumor necrosis factor. This review discusses the immunopathogenesis of NPSLE with a focus on neutrophils as a core mediator of the disease and potential target for translational research in NPSLE.

Evaluation of depression and general health assessment among systemic lupus erythematosus patients in relation to disease activity and damage

Article

Full-text available

Dec 2022

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune illness defined by involvement of several systems and a variety of clinical symptoms among them the neuropsychiatric manifestations. The purpose of the study was to evaluate the presence of depression and to assess overall health in individuals with SLE, as well as their relation to SLE disease activity and damage. Sixty adult SLE patients were enrolled, along with sixty age and sex-matched controls. For the presence of major depression, all patients were examined using the Beck Depression Inventory (BDI-II) and the General Health Questionnaire (GHQ-12) for mental distress. Antinuclear antibody, anti-ds DNA, complements 3 and 4, and anti-ribosomal P antibody were performed for SLE patients. The SLEDAI-2 K and SLEDDI were assessed. Results The 60 patients were 52 (86.7%) females and 8 (13.3%) men, with a mean age of 32.5 ± 11.5 years and disease duration of 3.57 ± 3.55 years. Patients with depression accounted for 43 (71.6%) of the total, whereas controls accounted for just 14 (23.3%). Patients with substantial depression had significantly higher SLEDAI-2 K, SLEDDI, and illness duration than those without major depression ( p = 0.047, p = 0.043, and p = 0.033, respectively). The patients’ mean GHQ-12 score was 17 ± 5.96, whereas the control group's was 10.0 ± 67.30, with a p value of 0.002. SLEDAI-2 K, SLEDDI, and depression score had a substantial positive association ( p = 0.001, p = 0.042), while BDI-II and GHQ-12 had a significant positive correlation ( p 0.001). Conclusions Depression and psychological distress were both common in SLE patients. Depression severity was linked to illness duration, activity, and damage.

Immunological findings in patients with migraine and other primary headaches: a narrative review

Article

Full-text available

Nov 2021

Experimental findings suggest an involvement of neuroinflammatory mechanisms in the pathophysiology of migraine. Specifically, preclinical models of migraine have emphasized the role of neuroinflammation following the activation of the trigeminal pathway at several peripheral and central sites including dural vessels, the trigeminal ganglion and the trigeminal nucleus caudalis. The evidence of an induction of inflammatory events in migraine pathophysiological mechanisms has prompted researchers to investigate the Human leukocyte antigen (HLA) phenotypes as well as cytokine genetic polymorphisms in order to verify their potential relationship with migraine risk and severity. Furthermore, the role of neuroinflammation in migraine seems to be supported by evidence of an increase in pro-inflammatory cytokines, both ictally and interictally, together with the prevalence of Th1 lymphocytes and a reduction in regulatory lymphocyte subsets in peripheral blood of migraineurs. Cytokine profiles of cluster headache patients and those of tension-type headache patients further suggest an immunological dysregulation in the pathophysiology of these primary headaches, although evidence is weaker than for migraine. The present review summarizes available findings to date from genetic and biomarker studies that have explored the role of inflammation in primary headaches.

Long-term Outcomes of Patients with Systemic Lupus Erythematosus: A Multicenter Cohort Study from CSTAR Registry

Article

Full-text available

Dec 2021

Objective To study the long-term outcomes, in the context of both mortality and organ damage in patients with systemic lupus erythematosus (SLE) in the Chinese SLE Treatment and Research group (CSTAR) registry cohort. Methods Patients were enrolled from April 2009 to February 2010 and they were followed up. The demographic data, clinical manifestations, labs test results and imaging examinations, disease activity (SLEDAI-2K), damage scores (SLLIC/Damage Index [SDI]), and medications were collected. Data were censored at either the last clinic visit or telephonic interview. Survival rate was analyzed by Kaplan–Meier (KM) method. COX proportional hazard model was adopted to perform the analysis of predicting factors for mortality and organ damage. Logistic regression analysis was employed to discuss the relationship among mortality, organ damage, and flare. Results A total of 2104 patients were recruited at baseline and 1494 patients were followed up. The cumulative 1-year, 3-year, and 5-year survival rates were 98.3%, 96.9%, and 95.7%, respectively. Seventy-eight patients died during follow-up, and the main causes of death were infection (34.6%), active disease (26.9%), cardiovascular and cerebrovascular events (5.13%), and malignancy (5.13%). At entry, 247 patients presented with irreversible organ damage and it increased to 398 patients at the endpoint. The major accumulated organ damages were kidney (25.9%), musculoskeletal disease (20.2%), neuropsychiatric disease (12.2%), and pulmonary damage (10.9%). Cox regression analysis further showed that male, late disease onset, delayed diagnosis (diagnosis from disease onset >1 year), baseline organ damage, and specific organ involvements predicted for higher mortality. In addition, early disease onset was a protecting factor for organ damage, and anti-SSA was an independent predicting factor for new organ damage. Logistic regression analysis showed that flare predicted for more organ damage. Conclusion The 5-year survival rate of Chinese SLE patients has improved and is comparable to Caucasians SLE patients. Disease flare impact on prognosis is the increasing risk of damage development. Early diagnosis, prevention for flare and damage to maintain remission, may improve outcome.

Headache and immunological/autoimmune disorders: a comprehensive review of available epidemiological evidence with insights on potential underlying mechanisms

Article

Full-text available

Nov 2021
J NEUROINFLAMM

Several lines of evidence support a role of the immune system in headache pathogenesis, with particular regard to migraine. Firstly, alterations in cytokine profile and in lymphocyte subsets have been reported in headache patients. Secondly, several genetic and environmental pathogenic factors seem to be frequently shared by headache and immunological/autoimmune diseases. Accordingly, immunological alterations in primary headaches, in particular in migraine, have been suggested to predispose some patients to the development of immunological and autoimmune diseases. On the other hand, pathogenic mechanisms underlying autoimmune disorders, in some cases, seem to favour the onset of headache. Therefore, an association between headache and immunological/autoimmune disorders has been thoroughly investigated in the last years. The knowledge of this possible association may have relevant implications in the clinical practice when deciding diagnostic and therapeutic approaches. The present review summarizes findings to date regarding the plausible relationship between headache and immunological/autoimmune disorders, starting from a description of immunological alteration of primary headaches, and moving onward to the evidence supporting a potential link between headache and each specific autoimmune/immunological disease.

Fatal cerebral venous sinus thrombosis as a manifestation of uncontrolled systemic lupus erythematosus in a young African female

Article

Full-text available

Jul 2021

In a young patient with systemic lupus erythematosus presenting with status epilepticus and neurological deficits, early brain imaging, risk factor identification and prompt treatment of underlying lupus flare‐up and cerebral venous sinus thrombosis could significantly improve the management and prognosis. In a young patient with systemic lupus erythematosus presenting with status epilepticus and neurological deficits, early brain imaging, risk factor identification and prompt treatment of underlying lupus flare‐up and cerebral venous sinus thrombosis could significantly improve the management and prognosis.

Neuropsychiatric Events in Systemic Lupus Erythematosus: Predictors of Occurrence and Resolution in a Longitudinal Analysis of an International Inception Cohort

Article

Full-text available

Oct 2021

Objective To determine predictors of change in neuropsychiatric (NP) event status in a large, prospective, international inception cohort of patients with systemic lupus erythematosus (SLE). Methods Upon enrollment and annually thereafter, NP events attributed to SLE and non‐SLE causes and physician‐determined resolution were documented. Factors potentially associated with the onset and resolution of NP events were determined by time‐to‐event analysis using a multistate modeling structure. Results NP events occurred in 955 (52.3%) of 1,827 patients, and 593 (31.0%) of 1,910 unique events were attributed to SLE. For SLE‐associated NP (SLE NP) events, multivariate analysis revealed a positive association with male sex (P = 0.028), concurrent non‐SLE NP events excluding headache (P < 0.001), active SLE (P = 0.012), and glucocorticoid use (P = 0.008). There was a negative association with Asian race (P = 0.002), postsecondary education (P = 0.001), and treatment with immunosuppressive drugs (P = 0.019) or antimalarial drugs (P = 0.056). For non‐SLE NP events excluding headache, there was a positive association with concurrent SLE NP events (P < 0.001) and a negative association with African race (P = 0.012) and Asian race (P < 0.001). NP events attributed to SLE had a higher resolution rate than non‐SLE NP events, with the exception of headache, which had comparable resolution rates. For SLE NP events, multivariate analysis revealed that resolution was more common in patients of Asian race (P = 0.006) and for central/focal NP events (P < 0.001). For non‐SLE NP events, resolution was more common in patients of African race (P = 0.017) and less common in patients who were older at SLE diagnosis (P < 0.001). Conclusion In a large and long‐term study of the occurrence and resolution of NP events in SLE, we identified subgroups with better and worse prognosis. The course of NP events differs greatly depending on their nature and attribution.

Cerebral venous sinus thrombosis and subdural hematoma in a female patient with systemic lupus erythematosus: a case report and literature review

Article

Full-text available

May 2021

Cerebral venous sinus thrombosis (CVST) and subdural hematoma (SDH) are extremely rare in patients with systemic lupus erythematosus (SLE), and when conditions are severe, it can endanger the life of the patients. We report a case of a 44-year-old woman who was admitted to our hospital due to multiple paroxysmal headaches, dizziness, and seizures for 20 days. In the past 2 years, she had severe thrombocytopenia. Her brain computed tomography (CT) and magnetic resonance venography (MRV) demonstrated CVST and a SDH near the right parietal occipital lobe and left temporal parietal lobe. After admission, she was eventually diagnosed with SLE based on the seizures, thrombocytopenia, positive antinuclear antibodies, and anti-ds DNA antibodies. After treatment, the patient's headaches and symptoms completely disappeared, and the myodynamia of the left limbs improved to grade 4. Her platelet count rose to 199×109 /L. The second brain MRV and MRI demonstrated partial reopening of the right superior sagittal sinus, transverse sinus, and sigmoid sinus, and the improvement of bilaterally SDH, which revealed that the treatment with an anticoagulant, pulse methylprednisolone therapy, and intravenous gamma globulin was effective. We summarized possible mechanisms in this case, which can improve our understanding of CVST and SDH in SLE. And we consider that such patients should be treated as soon as possible, and the outcome can be good.

Organ damage in systemic lupus erythematosus

Article

May 2021

Damage reflects the irreversible changes that occur in systemic lupus erythematosus (SLE) patients as a consequence of the disease, its treatment or comorbidities. The pattern of damage increases in a steady linear fashion over time. At least half of all patients with SLE will have some form of organ damage 10 years after their diagnosis. Factors associated with the occurrence of damage include older age, disease duration, male gender, non-Caucasian ethnicity, disease activity, corticosteroid use, poverty, hypertension and abnormal illness behaviors. In contrast, antimalarials are protective against damage. Since damage predicts further damage and mortality, prevention of damage accrual should be a major therapeutic goal in SLE. Novel therapies for SLE that achieve better control of the disease and with corticosteroid-sparing properties, may lead to improved outcomes in patients as they will reduce damage accrual and improve survival.

Treatment of neuropsychiatric systemic lupus erythematosus: clinical challenges and future perspectives

Article

Full-text available

Mar 2021

Introduction : Neuropsychiatric (NP) involvement represents an emerging frontier in systemic lupus erythematosus (SLE), posing significant challenges due to its clinical diversity and obscure pathophysiology. The authors herein discuss selected aspects in the management of NPSLE based on existing literature and our experience, aiming to facilitate routine medical care. Areas covered : Research related to diagnosis, neuroimaging, treatment and outcome is discussed, focusing on data published in PubMed during the last 5 years. Selected translational studies of clinical relevance are included. Expert opinion : Identification of NPSLE patients who may benefit from appropriate treatment can be facilitated by attribution algorithms. Immunosuppressants are typically indicated in recurrent seizures, optic neuritis, myelopathy, psychosis and peripheral nerve disease, although a low threshold is recommended for cerebrovascular disease and other NP manifestations, especially when SLE is active. With the exception of stroke with positive antiphospholipid antibodies, anti-coagulation is rarely indicated in other syndromes. Refractory NPSLE can be treated with rituximab, whereas the role of other biologics remains unknown. Advances in the fields of biomarkers, neuroimaging for brain structural, perfusion or functional abnormalities, and design of novel compounds targeting not only systemic autoimmunity, but also inflammatory and regenerative pathways within the nervous system, hold promise for optimizing NPSLE management.

Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus

Article

Full-text available

Sep 2020

Neuropsychiatric disorders in juvenile-onset systemic lupus erythematosus (SLE) stay in the focus of attention in recent decades due to significant influence of CNS lesions on SLE course in general, necessity to optimize therapeutic interventions and outline prognosis. This paper considers the prevalence of neurolupus in children and adolescents, specific features of the clinical picture, possible relationships with other SLE manifestations and immunological disorders, aspects of neuropsychiatric disorders pathogenesis and potential influence of growing and developing nervous system on SLE course, resulting in varying neurolupus manifestations and prognosis.

The immunologic etiology of psychiatric manifestations in systemic lupus erythematosus: A narrative review on the role of the blood brain barrier, antibodies, cytokines and chemokines

Article

Full-text available

Jun 2020
AUTOIMMUN REV

Introduction The aim of this narrative review is to provide an overview of the literature on the possible immunologic pathophysiology of psychiatric manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE). Methods A systematic search on PubMed was conducted. English studies with full text availability that investigated the correlation between blood-brain barrier (BBB) dysfunction, intrathecal synthesis of antibodies, antibodies, cytokines, chemokines, metalloproteinases, complement and psychiatric NPSLE manifestations in adults were included. Results Both transient BBB-dysfunction with consequent access of antibodies to the cerebrospinal fluid (CSF) and intrathecal synthesis of antibodies could occur in psychiatric NPSLE. Anti-phospholipid antibodies, anti-NMDA antibodies and anti-ribosomal protein p antibodies seem to mediate concentration dependent neuronal dysfunction. Interferon-α may induce microglial engulfment of neurons, direct neuronal damage and production of cytokines and chemokines in psychiatric NPSLE. Several cytokines, chemokines and matrix metalloproteinase-9 may contribute to the pathophysiology of psychiatric NPSLE by attracting and activating Th1-cells and B-cells. Discussion This potential pathophysiology may help understand NPSLE and may have implications for the diagnostic management and therapy of psychiatric NPSLE. However, the presented pathophysiological model is based on correlations between potential immunologic etiologies and psychiatric NPSLE that remain questionable. More research on this topic is necessary to further elucidate the pathophysiology of NPSLE.

Neuroinflammation in systemic lupus erythematosus - a review

Article

Full-text available

Jan 2019

Neuroinflammation is a complex process that contributes to the pathogenesis of both immune mediated and neurodegenerative pathologies. Systemic lupus erythematosus (SLE) is the prototype of connective tissue diseases that can present the complete spectrum of neurological and psychiatric dysfunctions. The precise etiological diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is rather difficult to be established and it is still controversial the exact timing of neuropsychiatric (NPS) events: either central nervous system (CNS) is the initial target of autoimmune abnormalities, either NPS symptoms are a part of multisystem involvement. Ischemic and inflammatory mechanisms have an important input on NPSLE pathogenesis. Neuroinflammation, consequent to blood-brain barrier (BBB) damage, local and systemic production of autoantibodies, determine neuronal injury and apoptosis, further responsible for diffuse cerebral events, mostly cognitive dysfunction and psychotic disorder. Moreover, SLE complications or therapy complications can interfere and contribute to complex clinical manifestations that can be present in SLE patients. Understanding the role of each pathogenic way can provide not only an early diagnosis, but a more accurate therapeutic approach of these patients.

Clinical and laboratory manifestations of systemic lupus erythematosus in patients with neuropsychiatric disorders (eurasian renaissance register)

Article

Full-text available

Nov 2019

Objective: to investigate the clinical and laboratory manifestations of systemic lupus erythematosus (SLE) with nervous system lesions in a Kyrgyz cohort.Subjects and methods. The prospective study enrolled 460 patients with SLE who fulfilled American College of Rheumatology (ACR) 1987 and SLICC 2012 criteria, and had been followed up at Academician M. Mirrahimov National Center for Cardiology and Therapy, from January 2012 to December 2017 according to the Eurasian RENAISSANCE Register program. The 1999 ACR classification criteria were used to evaluate the neuropsychiatric manifestations of SLE (NPSLE). A psychiatrist diagnosed neuropsychiatric disorders according to the ICD-10. A psychologist identified cognitive impairment, by using the specific Mini-Mental State Examination (MMSE) (a minischeme for examining a patient's mental status).Results and discussion. Various NPSLEs were detected in 103 (22.39%) of the 460 patients. According to the 1999 ACR criteria, 103 patients were diagnosed as having 155 different NPSLEs, including 123 (79.35%) patients who had central nervous system (CNS) disorders and 32 (20.65%) with peripheral nervous system (PNS) damages. There were 76 (61.79%) focal 47 (38.21%) diffuse CNS disorders. Most patients with diffuse NPSLEs were observed to have psychosis, the main manifestations of which were visual and auditory hallucinations (72.34%). The patients with focal NPSLEs had cerebrovascular disease (43.42%) with increase of level of antinuclear antibodies, antibodies against double-stranded DNA and hypocomplementemia (95.56, 86.52, and 73.85%, respectively). Patients with CNS lesions were significantly more likely than those with PNS to have lupus nephritis and hematological disorders (leukopenia, lymphopenia, and thrombocytopenia), as well as high immunological activity.Conclusion. Most patients with diffuse NPSLEs were observed to have psychosis with visual and auditory hallucinations (72.34%), and those with focal NPSLEs had cerebrovascular disease (43.42%) with a high frequency of immunological disorders. Lupus nephritis and hematological disorders with high immunological activity were significantly more common in patients with CNS lesions than in those with PNS ones.

Prevalence of cognitive impairment and cognitive improvement in patients with systemic lupus erythematosus during a 6-month follow-up study

Article

Aug 2023
LUPUS

Objectives: The Montreal Cognitive Assessment (MoCA) is a simple and reliable screening tool for early detection for cognitive impairment in systemic lupus erythematosus (SLE). Most previous studies were cross-sectional with small samples. Research on long-term cognitive changes and reversibility is limited. This study aimed to establish the prevalence of cognitive impairment and changes in SLE patients after 6 months and the associated factors. Methods: A prospective study was conducted in 200 patients with SLE between April 2021 and March 2022. Demographic data, disease activity, and medications were recorded. MoCA was administered at baseline and 6 months; for Thais, scores 17-24 indicate mild cognitive impairment, while ≤16 signifies severe impairment. Multivariate analysis identified factors associated with cognitive impairment and improvement. Results: The patients' median age was 44 years (range: 19-73), 96% were female, and 55% had < 12 years of education. The median disease duration was 11 years (range: 0-51.8), and 79% of patients had inactive disease. Cognitive impairment was found in 70% of patients (mild, 63%; severe, 7%). The most often affected domains were delayed recall (82%), abstraction (80.5%), language (76%) and visuospatial/executive function (70.5%), whereas orientation and naming were the least involved. Factors significantly associated with cognitive impairment were age > 40 years (OR, 3.71; 95% CI, 1.72-8.00), formal education < 12 years (OR, 3.11; 95% CI, 1.45-6.63), and prednisolone use (OR, 2.21; 95% CI, 1.08-4.51). Sixty-six (38.2%) of 173 patients completing the 6-month re-evaluation exhibited cognitive changes (52 [30.1%] improved; 14 [8.1%] deteriorated). Except for delayed recall, all commonly affected domains showed significant improvement. Disease activity, prednisolone, antimalarials, or immunosuppressant use did not predict cognitive improvement. Conclusions: Mild cognitive impairment is prevalent among patients with SLE. Due to the possibility of reversibility, early recognition and additional research to identify relevant factors are required.

Clinical and serological predictors of neuropsychiatric manifestations in patients with systemic lupus erythematosus

Article

Jul 2023

Organ damage in Systemic Lupus Erythematosus patients: A multifactorial phenomenon

Article

Jun 2023
AUTOIMMUN REV

The prevention of chronic damage, especially in early disease phases, remains an unmet need in the management of Systemic Lupus Erythematous (SLE) patients, despite the application of a so-called treat-to-target strategy. The high proportion of SLE patients developing chronic damage suggests a multifactorial aetiology. Thus, besides disease activity, other factors may contribute to the development of damage. The revision of data published so far underlines that, next to disease activity, it is possible to identify other factors playing a relevant role in damage development and progression. In summary, the presence of antiphospholipid antibodies and drugs used to treat SLE patients, in particular glucocorticoids, is strongly associated with SLE-related damage. Furthermore, recent data suggests the possible role of genetic background in determining the development of specific organ damage, in particular renal and neurological. Nonetheless, demographic factors, such as age, sex and disease duration could exert a role along with the presence of comorbidities. The contribution of different factors in determining damage development suggests the need for new outcomes to assess a comprehensive disease control including not only the assessment of disease activity, but also the evaluation of chronic damage development.

Factors associated with cardiovascular events in systemic lupus erythematosus in a monocentric cohort with up to 40 years of follow-up

Article

May 2023
SEMIN ARTHRITIS RHEU

Objectives: Systemic lupus erythematosus (SLE) is associated with an increased cardiovascular risk. Several traditional and disease-specific risk factors have been shown to correlate with the occurrence of cardiovascular events (CVE) in patients with SLE. However, results of previous studies are diverse. The objectives of this study were to report number, type and those factors associated with CVE in patients with SLE in a large, single-center, ethnically diverse cohort with a long follow-up duration. Methods: Medical records of patients treated at the Lupus Clinic at University College London Hospital (UCLH) between 1979 and 2020 were retrospectively reviewed. Data about CVE, traditional cardiovascular risk factors, demographic and disease features, and treatment history were collected. Only patients with complete available information were included in the study. Regression analyses were performed to identify factors associated with CVE. Results: Four hundred and nineteen patients were included in the study. Maximum follow-up length was 40 years. Seventy-one (17%) patients had at least one CVE. Multivariable analysis showed that only antiphospholipid antibody positivity (p-value<0.001) was associated with CVE. When analysing different types of CVE, antiphospholipid antibodies were specifically associated with both venous thromboembolic events (p-value<0.001) and cerebrovascular events (p-value=0.007). Dedicated subanalyses revealed that cumulative glucocorticoid dose (p-value=0.010) and a diagnosis of SLE before 2000 (p-value<0.001) were significantly associated with CVE. Conclusions: Cardiovascular disease is highly prevalent among patients with SLE and is associated with antiphospholipid antibodies, glucocorticoid therapy, and diagnosis before 2000.

Clinical associations of cognitive dysfunction in systemic lupus erythematosus

Article

Full-text available

Feb 2023

Objective: Cognitive dysfunction in SLE is common, but clinical risk factors are poorly understood. This study aims to explore the associations of cognitive dysfunction in SLE with disease activity, organ damage, biomarkers and medications. Methods: We performed cross-sectional cognitive assessment using a conventional neuropsychological test battery, with normative values derived from demographically matched healthy subjects. Endpoints included two binary definitions of cognitive dysfunction and seven individual cognitive domain scores. Clinical parameters included disease activity (SLEDAI-2K) and organ damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We performed regression analyses to determine associations between clinical parameters and cognitive endpoints. Results: 89 patients with SLE were studied, with median age of 45 and disease duration of 15 years. Organ damage was significantly associated with severe cognitive dysfunction (OR 1.49, CI 1.01-2.22) and worse cognitive test performance in three of the seven individual cognitive domains. In contrast, no significant associations were found between SLEDAI-2K at the time of cognitive assessment and any cognitive endpoints on multivariate analysis. Higher time-adjusted mean SLEDAI-2K was associated with better verbal memory scores but had no significant associations with other cognitive endpoints. The presence of anti-dsDNA antibodies and high IFN gene signature were negatively associated with severe cognitive dysfunction; there were no significant associations with the other autoantibodies studied or any medications. Substance use was significantly associated with lower psychomotor speed. Only 8% of patients who had cognitive dysfunction on testing had been recognised by clinicians on their SDI score. Conclusions: In SLE, cognitive dysfunction was positively associated with organ damage, but not associated with disease activity, and serological activity and high IFN signature were negatively associated. Cognitive dysfunction was poorly captured by clinicians. These findings have implications for preventative strategies addressing cognitive dysfunction in SLE.

Reduced homovanillic acid, SDF-1α, and SCGF-β levels in cerebrospinal fluid are related to depressive states in systemic lupus erythematosus

Article

Feb 2023

Objective: This study aimed to seek a new method of evaluation and surrogate markers for diffuse neuropsychiatric systemic lupus erythematosus (NPSLE). Methods: We enrolled 44 patients with SLE between 2017 and 2020 who fulfilled at least one of three specific inclusion criteria: high disease activity, abnormal findings (cerebrospinal fluid [CSF] examination, brain MRI, or electroencephalography), or history of neuropsychiatric illness. Psychiatric symptom rating scales (PSYRATS) were evaluated retrospectively. The primary end point was the PSYRATS positivity rate in SLE patients who had not been diagnosed with diffuse NPSLE. Results: Based on the 1999 ACR classifications, 7 out of the 44 patients evaluated using PSYRATS had been diagnosed with diffuse NPSLE. PSYRATS positivity was seen in 13 out of 37 SLE patients (35.1%) who had not been diagnosed with diffuse NPSLE, and all these patients were positive for Montgomery-Åsberg Depression Rating Scale (MADRS), an indicator of depression state in PSYRATS. Additionally, in the 20 SLE patients exhibiting depression symptoms who were MADRS-positive, CSF concentrations of the neuroinflammatory markers, homovanillic acid (HVA; p= 0.0400), stromal cell-derived factor-1α (SDF-1α; p= 0.0431), and stem cell growth factor-β (SCGF-1β; p= 0.0061), were significantly reduced compared with that in the 24 MADRS-negative SLE patients, and the levels of HVA, SDF-1α, and SCGF-1β correlated with one another (p< 0.05). Conclusion: Many patients with active SLE have subclinical depression, and MADRS evaluation of neuropsychiatric symptoms is useful for detecting them. Additionally, the decrease in CSF levels of HVA, SDF-1 α, and SCGF-1β reflect the same pathology, and these may serve as surrogate markers.

Posterior reversible encephalopathy syndrome and autoimmunity

Article

Dec 2022
AUTOIMMUN REV

Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by acute or subacute onset of neurological symptoms (e.g., headache, seizure, confusion, vomiting, and diminished eyesight) and impaired endothelial barrier function of the cerebral circulation that leads to bilateral subcortical vasogenic edema, while exhibiting a “reversible” feature in most cases. Clinically, various predisposing or precipitating conditions have been identified, such as hypertension, autoimmune diseases, renal dysfunction/failure, preeclampsia/eclampsia, post-transplantation conditions, and certain therapeutic agents. Among several putative mechanisms, the immune activation hypothesis prevails, as up to 50% of patients with PRES harbor abnormalities related to autoimmunity, such as concurrent systemic lupus erythematosus. In this Review, we summarize the clinical and laboratory evidence that places PRES in the context of autoimmunity.

Central nervous system involvement in systemic lupus erythematosus: Data from the Spanish Society of Rheumatology Lupus Register (RELESSER)

Article

Oct 2022
SEMIN ARTHRITIS RHEU

Objectives To analyse the prevalence, incidence, survival and contribution on mortality of major central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). Methods Patients fulfilling the SLE 1997 ACR classification criteria from the multicentre, retrospective RELESSER-TRANS (Spanish Society of Rheumatology Lupus Register) were included. Prevalence, incidence and survival rates of major CNS neuropsychiatric (NP)-SLE as a group and the individual NP manifestations cerebrovascular disease (CVD), seizure, psychosis, organic brain syndrome and transverse myelitis were calculated. Furthermore, the contribution of these manifestations on mortality was analysed in Cox regression models adjusted for confounders. Results A total of 3591 SLE patients were included. Of them, 412 (11.5%) developed a total of 522 major CNS NP-SLE manifestations. 61 patients (12%) with major CNS NP-SLE died. The annual mortality rate for patients with and without ever major CNS NP-SLE was 10.8% vs 3.8%, respectively. Individually, CVD (14%) and organic brain syndrome (15.5%) showed the highest mortality rates. The 10% mortality rate for patients with and without ever major CNS NP-SLE was reached after 12.3 vs 22.8 years, respectively. CVD (9.8 years) and organic brain syndrome (7.1 years) reached the 10% mortality rate earlier than other major CNS NP-SLE manifestations. Major CNS NP-SLE (HR 1.85, 1.28-2.67) and more specifically CVD (HR 1.99, 1.28-3.08), organic brain syndrome (HR 1.92, 1.08-3.42) and seizure (HR 1.72, 1.02-2.88) accounted as independent prognostic factors for poor survival. Conclusion The presentation of major CNS NP-SLE during the disease course contributes to a higher mortality, which may differ depending on the individual NP manifestation. CVD, organic brain syndrome and seizure are associated with the highest mortality rates.

Neuropsychiatric lupus erythematosus: Focusing on autoantibodies

Article

Aug 2022
J AUTOIMMUN

Patients with systemic lupus erythematosus (SLE) frequently suffer from nervous system complications, termed neuropsychiatric lupus erythematosus (NPLE). NPLE accounts for the poor prognosis of SLE. Correct attribution of NP events to SLE is the primary principle in managing NPLE. The vascular injuries and neuroinflammation are the fundamental neuropathologic changes in NPLE. Specific autoantibody-mediated central nerve system (CNS) damages distinguish NPLE from other CNS disorders. Though the central antibodies in NPLE are generally thought to be raised from the periphery immune system, they may be produced in the meninges and choroid plexus. On this basis, abnormal activation of microglia and disease-associated microglia (DAM) should be the common mechanisms of NPLE and other CNS disturbances. Improved understanding of both characteristic and sharing features of NPLE might yield further options for managing this disease.

Manifestations neuropsychiatriques au cours du lupus érythémateux systémique: à propos de 108 cas au Cameroun

Article

Full-text available

Jul 2022

Few data on neuropsychiatric disorders in systemic lupus erythematosus (NPSLE) are available in sub-Saharan Africa. The purpose of this study was to determine their frequency and describe their features in Cameroon. We conducted a retrospective study collecting all the medical records of patients with systemic lupus erythematosus (SLE) hospitalized in the department of rheumatology of 3 hospitals in Cameroon from 2009 to 2019. Lupus activity was assessed using the SLE activity index (SLEDAI). A total of 108 records of patients with a mean age of 40.2 ± 13.7 years were included in the study. The frequency of NPSLE was 55.5% (n=60). Neuropsychiatric disorders were diagnosed concomitantly with SLE (37.0%; n = 40) while in 20 patients with SLE (18.5%) they occurred during the first year. When NPSLE were inaugural, central nervous system involvement was dominant, with demyelinating syndrome 27.8% (n=30) and headaches 21.3% (n=23). Mononeuropathy was the most frequent peripheral nervous system involvement (15.7%; n=17). Factors associated with NPSLE occurrence were malar rash (p=0.024), alopecia (p=0.024), very high lupus activity (p=0.011), arthralgia (p<0.001), anti-nuclear factor (p=0.002). NPSLE did not appear to influence either lupus activity (log rank p=0.227) or the probability of new onset lupus (log rank p=0.233). More than half of patients had NPSLE during the first year. The presence of cutaneous and articular signs, high lupus activity, and anti-nuclear factor were associated with the occurrence of NPSLE.

Clinical Associations of Cognitive Dysfunction in Systemic Lupus Erythematosus (SLE)

Article

Jan 2022

Central Nervous System Involvement in Systemic Lupus Erythematosus: Data from the Spanish Society of Rheumatology Lupus Register (RELESSER)

Article

Jan 2022

The role of anti-ribosomal P autoantibodies in the prediction of neuropsychiatric damage in systemic lupus erythematosus based on CSTAR cohort (XIV)

Article

Jan 2022

Objectives: To identify the predictive value of anti-ribosomal P protein (anti-RibP) antibodies on the accrual of neuropsychiatric damage in systemic lupus erythematosus (SLE) patients in a large cohort in the Chinese SLE Treatment and Research group (CSTAR) database. Methods: This single-center prospective study was conducted based on data from the CSTAR registry. At baseline, we collected demographic characteristics, autoantibody profiles, clinical manifestations, disease activity status, and organ damage. Follow-up data were collected by reviewing clinical records and telephone interviews. Anti-RibP antibodies were identified by immunoblot containing all three native RibP (P0, P1, P2) antigenic proteins. Results: Of 2395 SLE patients with complete follow-up data, 659 (27.5%) were anti-RibP antibody positive. At baseline, positive anti-RibP antibodies were associated with a higher proportion of neurological involvement (𝑃 < 0.05). During follow-up, patients with positive anti-RibP antibodies were more likely to accumulate neuropsychiatric damage (adjusted HR = 3.8, 95% CI 2.7-57), p < 0.001). What is more, the cumulative probability of new-onset neurological involvement increased gradually in anti-RibP antibody-positive patients. Conclusion: Anti-RibP antibodies can provide information about not only organ involvement at baseline, but also neuropsychiatric damage accrual and new-onset neurological involvement during follow-up. We suggested that anti-RibP antibody detection should be done in the newly diagnosed SLE patients to predict organ involvement and even the accumulation of neuropsychiatric damage. Key points: • Positive anti-RibP antibodies were associated with baseline neurological involvement. • Baseline positive anti-RibP antibodies can predict the neuropsychiatric damage accrual and new-onset neurological involvement.

Predictores clínicos y serológicos de manifestaciones neuropsiquiátricas en pacientes con lupus eritematoso sistémico

Article

Jan 2022

Resumen Introducción El lupus eritematoso sistémico es una enfermedad autoinmune crónica con severidad variable; las manifestaciones neuropsiquiátricas comprenden un amplio espectro de síndromes definidos de acuerdo con su compromiso central y periférico. Diversos mecanismos fisiopatológicos tienen relación con el desarrollo de estas manifestaciones, entre los cuales se mencionan la disrupción de la barrera hematoencefálica y la toxicidad celular asociada con autoanticuerpos como antiacuaporina, anti-p ribosomal y antifosfolípidos; aún no se conocen elementos predictores relacionados con la aparición del compromiso neuropsiquiátrico, los cuales se explorarán a partir de modelos de predicción en este trabajo. Metodología Estudio analítico retrospectivo de corte transversal; para el análisis se emplearon modelos de predicción a partir de árboles de decisión, bayesiano ingenuo, K vecinos más cercanos y modelos lineales generalizados; se seleccionó el mejor modelo. Resultados Se incluyeron 122 pacientes, de los cuales 100 (81,9%) fueron mujeres y 22 (18,1%) hombres; la prevalencia del compromiso neuropsiquiátrico fue del 59%, siendo los trastornos de ansiedad, la cefalea y los trastornos del afecto los más frecuentes. En el análisis bivariado, las úlceras orales (OR 2,52, IC 95% 1,09-6,08, p = 0,02), la alopecia no cicatrizal (OR 4,06, IC 95% 1,76-9,68, p < 0,01), la artritis (OR 2,5, IC 95% 0,99-6,94, p = 0,04), la leucopenia (OR 2,81, IC 95% 1,18-7,09, p = 0,04), así como los pacientes sin daño acumulado medido por el score de daño SLICC/ACR-DI (2,1, IC 95% 0,98-4,93, p = 0,01), se asociaron con mayor compromiso neuropsiquiátrico. El mejor modelo de predicción fue el de árboles de decisión, en el cual la alopecia no cicatrizal, las úlceras orales y el anti-Ro/SSA se comportaron como variables independientes relacionadas con el compromiso neuropsiquiátrico, con una precisión del 75,6%. Conclusiones La prevalencia de compromiso neuropsiquiátrico en lupus fue del 59%, las variables independientes que mejor predijeron estas manifestaciones fueron la seropositividad anti-Ro/SSA, la alopecia no cicatrizal y las úlceras orales, por medio de árboles de decisión.

2019-EULAR/ACR classification criteria domains at diagnosis: predictive factors of long-term damage in systemic lupus erythematosus

Article

Nov 2021

The objective of this study is to assess the role of the 2019-European League Against Rheumatism/American College of Rheumatology (2019-EULAR/ACR) classification criteria at diagnosis and its domains in predicting long-term damage in systemic lupus erythematosus(SLE). We performed a retrospective analysis using an electronic chart database utilized in routine clinical care of SLE patients and established in 2000 in a tertiary hospital. Two hundred and nine consecutive SLE patients with disease onset ≥18 years old and long disease duration were included. Cumulative damage at the last visit was scored using the SLICC/ACR-Damage Index (SDI). The median age at SLE diagnosis was 28 years (18–63), disease duration was 14 years (8–25), and 88% were females. Damage (SDI≥1) was observed in 116/209 (55%). Patients with (SDI≥1, n=116) and without damage (SDI=0, n=93) had similar median disease duration [14 (8–25) vs. 12 (8–25) years, p=0.090] and age at diagnosis [23 (18–55) vs. 23 (18–56) years, p=0.998]. No correlation was observed between total 2019-EULAR/ACR score at diagnosis and SDI at last visit (r=0.007, p=0.913). Presence of renal domain at diagnosis was associated with renal damage at last visit (OR=3.6, 95%CI 1.2–10.4, p=0.017) and antiphospholipid antibodies domain predicted neuropsychiatric damage (OR=3.0, 95%CI 1.2–7.6, p=0.015). A ROC analysis identified that a cut-off >24 in 2019-EULAR/ACR score could predict a trend for renal damage (p=0.077) with a lower renal survival (Kaplan-Meier curve) for patients above this limit (p=0.029). A multivariate logistic regression analysis revealed that 2019-EULAR/ACR score >24 at diagnosis (OR 4.583, 95%CI 1.052–19.962, p=0.043) was independently associated with renal damage. Specific domains in the 2019-EULAR/ACR criteria at diagnosis were associated with long-term organ-specific damage, particularly renal and neuropsychiatric harm. A 2019-EULAR/ACR score >24 predicted worse renal survival. Key Points• Presence of renal domain of the 2019-EULAR/ACR classification criteria at diagnosis was associated with long-term renal damage.• Presence of antiphospholipid antibodies domain at diagnosis was associated with long-term neuropsychiatric damage.• A 2019-EULAR/ACR overall score >24 at diagnosis was independently associated with renal damage and predicted worse renal long-term survival. Key Points • Presence of renal domain of the 2019-EULAR/ACR classification criteria at diagnosis was associated with long-term renal damage. • Presence of antiphospholipid antibodies domain at diagnosis was associated with long-term neuropsychiatric damage. • A 2019-EULAR/ACR overall score >24 at diagnosis was independently associated with renal damage and predicted worse renal long-term survival.

Assessment of Cognitive Function in Systemic Lupus Erythematosus

Chapter

Jul 2021

Cognitive impairment (CI) is common in patients with systemic lupus erythematosus (SLE), with a pooled prevalence of 38% (95% confidence interval: 33–43%). While common, screening and diagnosing CI can be challenging. Cognitive impairment is often associated with physiological and psychological factors that can greatly impact the quality of life of patients with SLE. This chapter covers several topics under the umbrella of cognitive functioning in patients with SLE, including an overview of the definition and prevalence of CI in patients with SLE, instruments for measuring cognitive function, the ongoing heterogeneity of CI definition and assessment in patients with SLE, changes in cognition over time, the association between cognition and other comorbidities such as depression and anxiety, the relationship between cognition and patient health-related quality of life, and the association between cytokines and antibodies in relation to cognition.

Assessment of Health-Related Quality of Life in Systemic Lupus Erythematosus

Chapter

Jul 2021

With the improving life expectancy in systemic lupus erythematosus (SLE), the assessment of health-related quality of life (HRQoL) has become an important outcome measure in these patients. SLE is an autoimmune multisystem disease that tends to affect women of childbearing age and has a significant impact on the HRQoL comparable to that of more common rheumatological and medical illnesses. Assessing HRQoL alongside disease activity and damage captures the patients’ perspective of the impact of the disease and its treatment on their lives. Generic questionnaires, in particular, the SF-36, are the most common questionnaires for assessing HRQoL in SLE. However, in the last 15 years, SLE-specific questionnaires have been developed and validated, and they have the added advantage of assessing issues more relevant to patients with SLE. They are more sensitive to the changes in HRQoL and therefore more useful when assessing patient-reported outcomes in clinical trials of new interventions for SLE patients. This chapter describes the content of generic and SLE-specific measures and presents evidence for the quality of the scale development and psychometric evaluation of the SLE-specific HRQoL scales.

Neurovascular Consequences of Systemic Disease: Lupus and Primary Hyperparathyroidism

Chapter

Aug 2020

Cognitive dysfunction is a common feature in systemic lupus erythematosus (SLE) patients, with a prevalence of ranging from 55–80% in SLE patients (Ainiala et al., Arthritis Rheum 45:419–423, 2001; Brey et al., Neurology 58:1214–1220, 2002; Hanly et al., J Rheumatol 31:2156–2162, 2004; Sanna et al., J Rheumatol 30:985–992, 2003; Sibbitt et al., J Rheumatol 29:1536–1542, 2002). Cognitive impairment often involves the subcortical brain, causing difficulties with working memory as well as a reduction in information-processing and executive functioning, such as planning, organizing, or multi-tasking (Leritz et al., J Int Neuropsychol Soc 6:821–825, 2000). The etiology of cognitive dysfunction in SLE is still under investigation, with current studies demonstrating that cognitive dysfunction cannot be fully explained by SLE disease activity or treatments or prior strokes (Brey et al., Neurology 58:1214–1220, 2002; Rivest et al., J Rheumatol 27:680–684, 2000). Alternative explanations, such as infection, malignancy, medication adverse effect (e.g. steroid-induced psychosis), metabolic disturbances (e.g. uremia) need to be aggressively evaluated and excluded (“The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes,” Arthritis Rheum, 42:599–608, 1999; Futrell et al., Neurology 42:1649–1657, 1992; West et al., Am J Med 99:153–163, 1995).

Autoimmune and Autoantibody-Associated Encephalomyelopathies

Chapter

Jan 2020

Autoimmune central nervous system (CNS) affection comprises an expanding group of potentially treatable disorders that should be included in the differential diagnosis of any type of encephalitis or myelitis. The extent of CNS involvement in systemic immunopathic disorders such as lupus erythematosus, rheumatoid arthritis (RA), or sarcoidosis has been recognized since long. However, the identification of underlying pathogenic mechanisms has led to the development of revolutionary antibody (Ab)-based therapies improving the prognosis of this group of patients. Further advances in autoimmune involvement of the nervous system have led to the identification of new clinical syndromes, associated with antineuronal Abs that have transformed the diagnostic and therapeutic approach to these disorders. Starting with auto-Abs to the acetylcholine receptor for myasthenia gravis and against intracellular antineuronal nuclear Ab 1 (ANNA-1) (Hu) antigen, there is still a continuous expansion of the number of cell surface, synaptic, and intracellular molecules, which expose antigenic epitopes for autoimmune neurological disorders. Numerous of these Abs were associated with an extraneural malignancy, causing “paraneoplastic neurological syndromes,” while others occur as primary autoimmune diseases. Furthermore, identification of several Abs targeting glial antigens, such as aquaporin-4 (AQP4), has enabled the classification of these disorders as distinct clinical entities. The particular focus of this chapter is on autoimmune disorders associated with encephalitis or myelitis, subdivided into two groups: (1) systemic diseases with CNS manifestations and (2) Ab-associated disorders of the CNS.

Laboratory Testing: Neurologic Manifestations with Rheumatic Diseases—Associated Findings and Recommended Laboratory Evaluation

Chapter

Jun 2019

In this chapter, laboratory tests relevant to major disorders in rheumatology that can affect the nervous system are discussed. While laboratory tests can be helpful in evaluating patients with suspected or established rheumatic disease, they are often not diagnostic due to imperfect sensitivity and specificity. Therefore, it is particularly important to recognize that the pretest probability of disease is the driving factor in determining the utility of any laboratory value. Laboratory testing may make a particular diagnosis more or less likely, but ultimately, consideration of the clinical context is essential for disease diagnosis. In many cases, laboratory testing is more helpful to rule out disease than to rule in disease.

Neuropsychiatric Manifestations of Systemic Lupus Erythematosus

Chapter

Jun 2019

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with variable clinical presentation and disease course. The estimated prevalence ranges from 20 to 70 per 100,000 persons, with non-Caucasian populations at higher risk. Neuropsychiatric SLE is an all-encompassing term for a variety of complex neurologic and psychiatric manifestations that can be found in SLE patients. The pathophysiology is poorly understood, and diagnosis remains challenging due to heterogeneity in presentation and course. Distinguishing between SLE-related neuropsychiatric manifestation and other causes of neurologic symptoms is often best done through multidisciplinary evaluation by rheumatology, neurology, and psychiatry.

A critical evaluation of enzyme immunoassays for detection of antinuclear autoantibodies of defined specificities: I. Precision, sensitivity, and specificity

Article

Full-text available

Mar 1999
ARTHRIT RHEUM-ARTHR

Objective To determine the performance characteristics of enzyme‐based immunoassay (EIA) kits for the detection of antinuclear and other autoantibodies of defined specificities. Methods Nine manufacturers of EIA kits to detect antibodies of defined specificities participated in a study in which they received coded sera from the Centers for Disease Control and Prevention. These coded sera contained different dilutions of antibody of one specificity mixed with sera containing antibodies of other specificities. The manufacturers were asked to use their standard technology to determine antibody content and send the data to a committee of the International Union of Immunological Societies for analysis. The data were analyzed for sensitivity and specificity in the detection of anti–double‐stranded DNA (anti‐dsDNA), anti–single‐stranded DNA, antihistone, anti‐Sm, anti–U1 RNP, anti‐SSA/Ro, anti‐SSB/La, anti–Scl‐70 (DNA topoisomerase I), anticentromere, and anti–Jo‐1 antibodies. In addition, replicate samples were included in the coded sera to evaluate the precision of each EIA method. Results Lack of sensitivity and specificity was most evident in the anti‐dsDNA and anti‐Sm kits, although 2 kits for anti‐dsDNA achieved acceptable sensitivity and specificity. Generally, anti‐SSA/Ro, anti‐SSB/La, anti–Scl‐70, anticentromere, and anti–Jo‐1 kits performed well. Many false‐positive results were obtained with a multiple myeloma serum containing cryoprecipitates, but multiple myeloma sera without cryoprecipitates presented no problem in the EIA system. Precision, based on evaluation of replicate samples, varied from very good to poor. Conclusion No single manufacturer was clearly superior to others in terms of their products' overall sensitivity, specificity, and precision. Areas that needed improvement were in kits for the detection of antibodies to dsDNA and to Sm antigen. Some EIA kits achieved good sensitivity and specificity. Individual manufacturers were informed of the performance of their respective kits so they could take measures to correct perceived deficiencies and thus improve the reliability of a group of important diagnostic assays used in the evaluation of systemic rheumatic diseases.

SLICC/ACR Damage Index is valid, and renal and pulmonary organ scores are predictors of severe outcome in patients with systemic lupus erythematosus

Article

Full-text available

Apr 1996

We investigated the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index as a predictor of severe outcome and an indicator of morbidity in different ethnic groups, and in regard to its validity. We retrospectively studied disease course within 10 yr of diagnosis in an inception cohort of 80 patients with systemic lupus erythematosus (SLE). The mean renal damage score (DS) at 1 yr after diagnosis was a significant predictor of endstage renal failure and the mean pulmonary DS at 1 yr significantly predicted death within 10 yr of diagnosis. Compared to Caucasians, Afro-Caribbeans and Asians had significantly higher mean total DS at 5 and 10 yr, and higher mean renal DS at 10 yr. At 5 yr, the mean renal DS in Afro-Caribbeans and the mean neuropsychiatric DS in Asians were significantly higher than in Caucasians. The rate of endstage renal failure in Caucasians was significantly lower than in the other ethnic groups. Our results confirm the validity of the SLICC/ACR Damage Index.

Assessing the Usefulness of Anticardiolipin Antibody Assays A Cautious Approach Is Suggested by High Variation and Limited Consensus in Multilaboratory Testing

Article

Full-text available

Nov 2002

An anticardiolipin antibody (ACA) assay has become a laboratory standard for the detection of antiphospholipid antibodies. We evaluated data from a quality assurance program to assess ACA assay usefulness. Cross-laboratory (n = 56) testing of 12 serum samples yielded interlaboratory coefficients of variation (CVs) for lgG ACA and IgM ACA that were higher than 50% in 17 (71%) of 24 cases. The situation for testing consensus was of equal concern. Total consensus occurred in 6 (25%) of 24 cases. General consensus (interlaboratory agreement, 90% or more) was obtained in 10 (42%) of 24 cases. In the majority of test cases, laboratories could not agree on whether a serum sample tested was ACA-positive or ACA-negative. Differing method-related issues also were evident; some methods tended toward higher or lower ACA values. Method-based majority consensus differed from participant majority consensus on many test occasions. Exceedingly high interlaboratory result variation, combined with a general lack of test result grading consensus and method-based variation, indicate that a cautious clinical approach toward laboratory findings is prudent. Laboratory tests should be repeated at least once before making a clinical diagnosis of any anti-phospholipid syndrome-like disorder.

A comparison between the Farr radioimmunoassay and a new automated fluorescence immunoassay for the detection of antibodies against double stranded DNA in serum

Article

Full-text available

Jan 2003

To compare test characteristics of the Farr radioimmunoassay and an automated fluorescence immunoassay (ELIA dsDNA test) for the diagnosis of systemic lupus erythematosus (SLE). A cross sectional study comprising 440 samples from 440 patients, sent to the laboratory over a three month period for anti-dsDNA testing. Chart review was performed, blinded for test results, to count for each patient the number of American College of Rheumatology criteria for the classification of SLE that were fulfilled. At least four criteria were met by 248 (56%) patients (SLE), one to three criteria by 77 (18%) (lupus-like disease, LLD), and no criterion by 115 (26%) (non-SLE/non-LLD). Results from serum samples from the non-SLE/non-LLD and SLE groups were used to calculate receiver operating characteristic curves. For the Farr assay, specificities of 95% and 99% corresponded to sensitivities of 72% and 56% respectively. For the ELIA dsDNA test these levels of specificity corresponded to sensitivities of 44% and 17% respectively. The Farr radioimmunoassay is superior to the ELIA dsDNA test for identifying patients with SLE.

Association of damage with autoantibody profile, age, race, sex and disease duration in systemic lupus erythematosus

Article

Full-text available

Mar 2003

To determine if there is any association between autoantibody profile and damage in a cohort of patients with systemic lupus erythematosus (SLE). A prospective cohort of SLE patients attending two SLE clinics in Birmingham was analysed. All patients fulfilled ARA criteria for SLE. Detailed clinical and serological information was recorded at each visit. Damage according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI) was recorded 6-monthly and the last score in the year 2000 or prior to death was used in the analysis. Univariate analysis was performed with the chi(2) test, Fisher's exact test or univariate analysis of variance. Multivariate analysis was done with binary logistic regression. A total of 348 patients (326 females) were studied, comprising 208 Caucasians, 65 Afro-Caribbeans, 59 Asians, four Orientals and 12 others. There were 32 (9.2%) deaths and 156 (44.8%) patients had damage recorded during follow-up. The presence of damage showed no significant association with race, sex or anti-cardiolipin, anti-Ro, anti-La, anti-Sm, anti-RNP and anti-dsDNA antibodies. Only age, disease duration and other antibodies to extractable nuclear antigens (ENA) were found to be associated with the presence of damage. When individual organ damage was analysed, the only significant associations were of anti-Ro with ocular damage and of other anti-ENA antibodies (anti-Scl-70 and/or anti-Jo-1) with premature gonadal failure. Other autoantibodies were not predictive of damage in individual organs. Although autoantibodies are useful in diagnosis and predicting disease activity in SLE, they do not appear to be useful in predicting damage in SLE.

Systemic lupus erythematosus in three ethnic groups. XX. Damage as a predictor of further damage

Article

Full-text available

Feb 2004

To examine the predictors of damage in a multiethnic cohort of systemic lupus erythematosus (SLE) patients with a specific focus on damage at baseline. Patients and SLE patients from a multiethnic US (Hispanic, African-American and Caucasian) cohort (LUMINA: Lupus in Minority populations, Nature versus nurture) were included if they had > or =6 months of follow-up in the cohort. Damage was measured with the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI). The dependent variable was the change in SDI score between study visits. Predictors were from the preceding visit. Variables known to affect damage accrual in SLE were included in the analyses. Three hundred and fifty-two patients (82 Hispanics, 153 African-Americans and 117 Caucasians) representing 1795 patient visits were included. Previous damage was found to be a significant predictor of subsequent damage accrual (P < 0.0001). Other variables predictive of subsequent damage accrual were disease activity (P < 0.0001), older age (P = 0.041) and use of corticosteroids (P = 0.0048). Once damage occurs in SLE, further damage is expected to occur. This is more likely to be the case if disease activity persists. These data have clinical implications for the management of SLE patients.

Prevalence and Correlates of Accelerated Atherosclerosis in Systemic Lupus Erythematosus

Article

Full-text available

Dec 2003
NEW ENGL J MED

Although systemic lupus erythematosus is associated with premature myocardial infarction, the prevalence of underlying atherosclerosis and its relation to traditional risk factors for cardiovascular disease and lupus-related factors have not been examined in a case-control study. In 197 patients with lupus and 197 matched controls, we performed carotid ultrasonography, echocardiography, and an assessment for risk factors for cardiovascular disease. The patients were also evaluated with respect to their clinical and serologic features, inflammatory mediators, and disease treatment. The risk factors for cardiovascular disease were similar among patients and controls. Atherosclerosis (carotid plaque) was more prevalent among patients than the controls (37.1 percent vs. 15.2 percent, P<0.001). In multivariate analysis, only older age, the presence of systemic lupus erythematosus (odds ratio, 4.8; 95 percent confidence interval, 2.6 to 8.7), and a higher serum cholesterol level were independently related to the presence of plaque. As compared with patients without plaque, patients with plaque were older, had a longer duration of disease and more disease-related damage, and were less likely to have multiple autoantibodies or to have been treated with prednisone, cyclophosphamide, or hydroxychloroquine. In multivariate analyses including patients with lupus, independent predictors of plaque were a longer duration of disease, a higher damage-index score, a lower incidence of the use of cyclophosphamide, and the absence of anti-Smith antibodies. Atherosclerosis occurs prematurely in patients with systemic lupus erythematosus and is independent of traditional risk factors for cardiovascular disease. The clinical profile of patients with lupus and atherosclerosis suggests a role for disease-related factors in atherogenesis and underscores the need for trials of more focused and effective antiinflammatory therapy.

“Mini-Mental State”. A practical method for grading the cognitive state of patients for the clinician

Book

Dec 1975
J PSYCHIATR RES

Criteria for the classification of systemic lupus erythematosus (proposed 1982 revision)

Article

Jan 1982
ARTHRIT RHEUM-ARTHR

One Hundred Anti-Ro (SS-A) Antibody Positive Patients

Article

May 1995

Prevalence and Correlates of Accelerated in Systemic Lupus Erythematosus

Article

Mar 2004

HOPKINS LUPUS COHORT

Article

May 2000
RHEUM DIS CLIN N AM

Michelle Petri

Morbidity of systemic lupus erythematosus: Role of race and socioeconomic status*1

Article

Oct 1991
AM J MED

Michelle Petri

objective: To determine if differences in morbidity of systemic lupus erythematosus (SLE) as measured by (1) important renal disease, (2) number of hospitalizations, and (3) neurologic disease can be explained by race, socioeconomic status (SES), or measures of compliance.

Quality of life in systemic lupus erythematosus patients during more and less active disease states: Differential contributors to mental and physical health

Article

Jun 2001
ARTHRIT RHEUM-ARTHR

Objective To identify determinants of mental and physical health as a function of disease state in patients with systemic lupus erythematosus (SLE).MethodsA sample of 129 SLE patients (mean age 42.01 years; SD 11.09) was recruited from 9 immunology/rheumatology clinics across Canada. Patients completed questionnaires assessing psychological distress, social support, coping, stress, and health-related quality of life. Physicians rated disease activity (using the revised Systemic Lupus Activity Measure; SLAM-R) and damage (using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). Mental and physical health composite scores were derived from the Medical Outcomes Study Short Form 36. Patients were subdivided into more active (SLAM-R ≥ 10; n = 38) or less active disease states (n = 91).ResultsBetter mental health was predicted by more education and less emotion-oriented coping in the patients in a more active disease state (P = 0.0001; R2 = 0.46). Better mental health was predicted by less stress, less emotion-oriented coping, and more task-oriented coping in patients during a less active disease state (P = 0.0001; R2 = 0.45). Better physical health was predicted by more emotion-oriented coping in patients in a more active disease state (P = 0.04; R2 = 0.11). Better physical health was predicted by less stress and younger age in patients during a less active disease state (P = 0.0001; R2 = 0.20).Conclusion The positive association between emotion-oriented coping and better physical health in patients during a more active disease state suggests that this style of coping may be more adaptive in situations that are considered uncontrollable (e.g., SLE flare). Predictors of mental health were similar to those found in the literature, especially for SLE patients in a less active disease state.

A critical evaluation of enzyme immunoassays for detection of antinuclear autoantibodies of defined specificities: I. Precision, sensitivity, and specificity

Article

Mar 1999
ARTHRIT RHEUM-ARTHR

Objective To determine the performance characteristics of enzyme-based immunoassay (EIA) kits for the detection of antinuclear and other autoantibodies of defined specificities.Methods Nine manufacturers of EIA kits to detect antibodies of defined specificities participated in a study in which they received coded sera from the Centers for Disease Control and Prevention. These coded sera contained different dilutions of antibody of one specificity mixed with sera containing antibodies of other specificities. The manufacturers were asked to use their standard technology to determine antibody content and send the data to a committee of the International Union of Immunological Societies for analysis. The data were analyzed for sensitivity and specificity in the detection of anti–double-stranded DNA (anti-dsDNA), anti–single-stranded DNA, antihistone, anti-Sm, anti–U1 RNP, anti-SSA/Ro, anti-SSB/La, anti–Scl-70 (DNA topoisomerase I), anticentromere, and anti–Jo-1 antibodies. In addition, replicate samples were included in the coded sera to evaluate the precision of each EIA method.ResultsLack of sensitivity and specificity was most evident in the anti-dsDNA and anti-Sm kits, although 2 kits for anti-dsDNA achieved acceptable sensitivity and specificity. Generally, anti-SSA/Ro, anti-SSB/La, anti–Scl-70, anticentromere, and anti–Jo-1 kits performed well. Many false-positive results were obtained with a multiple myeloma serum containing cryoprecipitates, but multiple myeloma sera without cryoprecipitates presented no problem in the EIA system. Precision, based on evaluation of replicate samples, varied from very good to poor.Conclusion No single manufacturer was clearly superior to others in terms of their products' overall sensitivity, specificity, and precision. Areas that needed improvement were in kits for the detection of antibodies to dsDNA and to Sm antigen. Some EIA kits achieved good sensitivity and specificity. Individual manufacturers were informed of the performance of their respective kits so they could take measures to correct perceived deficiencies and thus improve the reliability of a group of important diagnostic assays used in the evaluation of systemic rheumatic diseases.

Update of the American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematosus

Article

Sep 1997
ARTHRIT RHEUM-ARTHR

Marc C Hochberg

Reliability and validity of six systems for the clinical assessment of disease activity in SLE

Article

Sep 1989
ARTHRIT RHEUM-ARTHR

Six systems for defining and evaluating disease activity in patients with systemic lupus erythematosus (SLE) (the Ropes system, the National Institutes of Health [NIH] system, the New York Hospital for Special Surgery system, the British Isles Lupus Assessment Group [BILAG] scale, the University of Toronto SLE Disease Activity Index [SLE-DAI], and the Systemic Lupus Activity Measure [SLAM]) were tested on 25 SLE patients who were selected to represent a range of disease activity. The patients were evaluated independently by 2 physicians on 2 occasions approximately 1 month apart. Differences between patients demonstrated the largest source of variation in scores, accounting for 56–84% of the total variance, depending on the instrument. Differences between physicians (i.e., error) showed the next largest variation, 11–28% of the total variance, and differences between visits made up 5–16% of the total. The BILAG, SLE-DAI, and SLAM had the best inter-visit and inter-rater reliability. Convergent validity was shown by the strong correlations of scores among the different instruments (r = 0.81–0.97). All instruments correlated highly with the physicians' clinical impression of disease but less well with their evaluation of disease severity. The number of American Rheumatism Association criteria for SLE that were met by the patients correlated poorly with the physicians' global evaluation and with the scores of the instruments. The patients' self-reported disease activity scores correlated highly with the physicians' assessments of disease activity (r = 0.85–0.91), and the mean values from self-reports and from physicians' assessments were nearly equal. In contrast, severity scores correlated less well between self-reports and physician assessments (r = 0.49–0.69), and mean self-reported severity values were lower than the means from physicians. The BILAG, SLE-DAI, and SLAM systems appear to have better psychometric properties than the others for clinical research.

Systemic lupus erythematosus in three ethnic groups: IX. Differences in damage accrual

Article

Dec 2001
ARTHRIT RHEUM-ARTHR

Objective To determine the factors predictive of damage in a multiethnic (Hispanic, African American, and Caucasian) LUMINA (lupus in minority populations, nature versus nurture) cohort of patients with systemic lupus erythematosus (SLE) with disease duration of ≤5 years at enrollment (T0).Methods Variables (socioeconomic/demographic, clinical, immunologic, immunogenetic, behavioral, and psychological) were measured at T0 and annually thereafter. Disease damage was measured with the Systemic Lupus International Collaborating Clinics Damage Index (SDI), and disease activity was measured with the Systemic Lupus Activity Measure. The relationship between the different variables and the SDI at the last visit (TL) was examined (mean followup from diagnosis to TL 61 months; adjusted for disease duration). Poisson regression was used to identify the independent association between the different variables and SDI scores at TL.ResultsSeventy-two Hispanics, 104 African Americans, and 82 Caucasians were included. One-half of patients had not accrued any damage. Caucasians had the lowest SDI scores at T0, and Hispanics had the highest scores at TL. Renal damage occurred more frequently among Hispanics and African Americans, while integument damage was more frequent among African Americans. Neuropsychiatric (20%), renal (16%), and ocular (15%) damage occurred most frequently among all patients. Independent predictors of SDI at TL were age, corticosteroid use (maximum dose at T0), number of American College of Rheumatology (ACR) criteria met, disease activity, and abnormal illness-related behaviors. Other variables were less consistently associated with damage accrual (poverty in African Americans, lack of HLA–DRB1*0301 in Hispanics, presence of HLA–DQB1*0201 and acute onset of SLE in Caucasians).Conclusion Damage in SLE occurs from the outset in some, but not all, patients; Hispanics accrue damage more rapidly. Disease factors (corticosteroid use, number of ACR criteria met, disease activity, and acute-onset type) are important, but age and abnormal illness-related behaviors also contribute to overall damage in SLE.

Damage in systemic lupus erythematosus and its association with corticosteroids

Article

Aug 2000
ARTHRIT RHEUM-ARTHR

Objective To evaluate the association between corticosteroid use and organ damage in patients with systemic lupus erythematosus (SLE).Methods The occurrence and date of organ damage, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, were determined for 539 patients enrolled in the Hopkins Lupus Cohort Study. The risk of damage associated with the cumulative prednisone dose, high-dose prednisone (≥60 mg/day for ≥2 months), and pulse methylprednisolone (1,000 mg intravenously for 1–3 days) was estimated using Cox proportional hazards regression analyses, controlling for age, race, and sex. Risk estimates for the cumulative prednisone dose were based on a reference dose of 36.5 gm (e.g., 10 mg of prednisone daily for 10 years [or equivalent]).ResultsThe cumulative prednisone dose was significantly associated with the development of osteoporotic fractures (relative risk [RR] 2.5, 95% confidence interval [95% CI] 1.7, 3.7), symptomatic coronary artery disease (RR 1.7, 95% CI 1.1, 2.5), and cataracts (RR 1.9, 95% CI 1.4, 2.5). Each intravenous pulse was associated with a small increase in the risk of osteoporotic fractures (RR 1.3, 95% CI 1.0, 1.8); however, this result failed to reach statistical significance (P = 0.07). Each 2-month exposure to high-dose prednisone was associated with a 1.2-fold increase in the risk of both avascular necrosis (95% CI 1.1, 1.4) and stroke (95% CI 1.0, 1.5).ConclusionSLE patients receiving long-term prednisone therapy were at significant risk of morbidity due to permanent organ damage. Additional research is required to determine the relative contributions of SLE disease activity and corticosteroids to the pathogenesis of specific types of organ damage. Furthermore, new steroid-sparing therapies are needed in order to treat disease activity and minimize cumulative and high-dose prednisone exposure.

Neuropsychiatric manifestations of systemic lupus erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease

Article

Aug 1976

1. Among patients with SLE, 71 (51%) had significant neuropsychiatric problems during the course of the disease. In 52 (37%), the nervous system manifestations were secondary to SLE. 2. The most frequent manifestations were psychiatric dysfunction, seizures, long tract signs, cranial neuropathy, and peripheral neuropathy. 3. Psychiatric abnormalities secondary to SLE were characterized by organic features (present in 22 of 24) and by the association of neurologic lesions which were often diffuse or multifocal. 4. An abnormal cerebrospinal fluid was found in 32% of neuropsychiatric episodes in which specimens were obtained. The most frequently abnormal study was the electroencephalogram (71%), and the least frequent was the brain scan (8%). These studies did not correlate with specific clinical patterns. 5. In 63% of the patients, NP manifestations preceded the diagnosis of SLE or occurred within the first year of diagnosed disease, and in most episodes were associated with evidence of clinical and/or serologic activity of the underlying illness. 6. Only two clinical features showed significant and striking correlations with neuropsychiatric involvement, namely vasculitis and thrombocytopenia. The possible pathogenic implications have been discussed. 7. Only 2 of the 140 patients were felt to have steroid-induced psychoses. In approximately one-half of the NP episodes secondary to SLE, patients were receiving no corticosteriods on presentation. Of those developing while patients were on steroids, the majority occurred on low doses or after tapering from higher levels. 8. The immediate prognosis for improvement in neuropsychiatric function was good with 84% of episodes showing complete or partial resolution. Corticosteroids appeared to be of benefit in a substantial number of patients although their precise role is difficult to quantitate. 9. Five and 10 years survivals for the overall population were 94% and 82%, respectively. There were no significant differences in survival for patients with or without nervous system involvement.

Central nervous system disease in systemic lupus erythematosus. Therapy and prognosis

Article

Jun 1975
AM J MED

The effect of corticosteroid therapy in 28 patients with 52 episodes of neuropyciatric disease in systemic lupus erythematosus (SLE) was elevated. Categories of organic central nervous system disease were seizures (eight patients), organic brain syndromes (nine patients), aseptic meningitis (four patients) and a variety of focal neurologic findings (seven patinets). Fourteen pateints had 15 episodes of functional psychosis without other evidence of neurologic disease. Although there was a general correlation between clinical and serologic evidnce of active SLE and the development of organic neurolgic disease, there was no evidence that therapy with very large doses of corticosteroids was beneficial. Of the deaths in this series, two were due to probable active SLE involving the central nervous system wheras five were attributable to complications of therapy. The long-term morbidity, likewise, was high in the patients who recieved large doses of corticosteroids. In all, 12 patients had major complications of corticosteroid therapy. Functional psychosis was usually preciptated by corticsoteroid therapy and respond to a reduction in steroid dosage and administration of psychotropic drugs.

The incidence and prognosis of central nervous system in SLE

Article

Feb 1992

In a review of our experience with systemic lupus erythematosus (SLE) since 1975, we found 48 of 266 patients with major central nervous system (CNS) manifestations for which a non-SLE explanation could not be identified. Eleven patients developed more than one type of CNS event. The commonest symptom was seizure (18 patients), followed by brainstem dysfunction (12 patients), psychosis (11 patients), organic brain syndrome (11 patients) and stroke (7 patients). In 19% of cases, CNS manifestations were accompanied by a flare of multisystem SLE disease activity. Anticonvulsants were able to be discontinued safely in the majority of patients with seizures. Most CNS events were self-limited, reversible and not associated with poor outcome unless accompanied by multisystem disease activity. Therapy with corticosteroids did not appear to offer substantial benefit.

Morbidity of systemic lupus erythematosus: Role of race and socioeconomic status

Article

Nov 1991
AM J MED

To determine if differences in morbidity of systemic lupus erythematosus (SLE) as measured by (1) important renal disease, (2) number of hospitalizations, and (3) neurologic disease can be explained by race, socioeconomic status (SES), or measures of compliance. The interrelationship of black race, SES, and the physician's assessment of compliance as risk factors for morbidity was examined in a cohort of 198 patients with SLE (179 female, 115 black). SES was measured with Nam-Powers scores for education (years), income, and job status, and source of insurance; compliance was assessed by physician global assessment and percent of protocol visits kept. Morbidity outcomes were important renal disease (creatinine level 1.5 mg/dL or greater, renal failure, nephrotic syndrome), neurologic involvement, and number of hospitalizations. The Johns Hopkins Rheumatology Faculty Practice, in which both private and clinic patients are seen. Black patients had significantly lower SES on all measures (p less than 0.0001) and were also less compliant by physician global assessment (odds ratio [OR] = 0.39, p = 0.002). Univariate analyses showed that blacks had a higher frequency of important renal disease (OR = 2.07, 95% confidence interval [CI] 1.05 to 4.11) and hypertension (OR = 1.80, 95% CI 1.01 to 3.23). Important renal disease was associated with the physician global assessment of compliance (p = 0.009) and hypertension (p less than 0.001). Multiple regression models for important renal disease, including race, physician global assessment of compliance, hypertension, SES, age, and gender, identified significant associations with only physician global assessment of compliance (OR = 0.40, 95% CI 0.17 to 0.91) and hypertension (OR = 5.37, 95% CI 2.40 to 11.98); black race was not significant (OR = 1.60, 95% CI 0.68 to 3.76). The second morbidity measure, number of hospitalizations, was associated with renal disease, neurologic disease, mouth ulcers, duration of disease, and public insurance but not with black race, in the best log-linear model. Neither race, SES variables, nor physician assessment of compliance was significantly associated with neurologic disease, the third morbidity measure. These data fail to support an independent association of black race with morbidity in SLE; rather, they suggest that noncompliance (as measured by physician global assessment) and type of medical insurance are important factors in morbidity. Classical epidemiologic measures of SES (education, income, occupation) do not appear to be significant confounders of the relationship of race to morbidity in SLE.

Detection of autoantibodies to Sm antigen in systemic lupus erythematosus by immunodiffusion, ELISA and immunoblotting: Variability of incidence related to assays and ethnic origin of patients

Article

Sep 1990

Autoantibodies to small nuclear ribonucleoproteins (snRNP) were studied using the techniques of immunodiffusion, ELISA, and immunoblotting in the sera of 150 patients with systemic lupus erythematosus (SLE), and of 29 patients with mixed connective tissue disease; 900 control patients and 100 normal blood donors were examined simultaneously. The incidence of anti-Sm antibodies in French SLE patients was low compared with the occurrence observed in similar studies in USA (even when highly sensitive assays were used) but was of the same magnitude as European results. Frequency of anti-Sm antibodies in SLE patients varied moderately when detected by immunodiffusion (12%), or by immunoblotting (17%), however, it seems that the ethnic and/or genetic background of patients induces more significant differences. SLE patients from the French West Indies had anti-Sm antibodies in 39% of cases when detected by immunodiffusion and in 50% when immunoblotting was used. In these patients the incidence of the antibodies was five times more frequent than that of mainland French patients. Immunization against snRNP does not seem to be a common feature of all SLE patients.

SPECIAL ARTICLE - THE 1982 REVISED CRITERIA FOR THE CLASSIFICATION OF SYSTEMIC LUPUS-ERYTHEMATOSUS

Article

Nov 1982

The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification. The 1982 revised criteria include fluorescence antinuclear antibody and antibody to native DNA and Sm antigen. Some criteria involving the same organ systems were aggregated into single criteria. Raynaud's phenomenon and alopecia were not included in the 1982 revised criteria because of low sensitivity and specificity. The new criteria were 96% sensitive and 96% specific when tested with SLE and control patient data gathered from 18 participating clinics. When compared with the 1971 criteria, the 1982 revised criteria showed gains in sensitivity and specificity.

Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death

Article

Aug 1995

To study the causes of death in patients with SLE, followed prospectively in a single center. The study population comprised 665 patients with systemic lupus erythematosus (SLE). Causes of death were determined by review of hospital files, autopsy reports, and death certificates. Nonparametric lifetable models were used to calculate Kaplan-Meier estimates of survival probabilities. One hundred and twenty-four patients (18.6%) had died. The primary causes of death were active SLE in 20 (16%), infection in 40 (32%), acute vascular event in 19 (15.4%), sudden death in 10 (8.1%), organ failure in 6 (4.8%), malignancy in 8 (6.5%), others in 8 (6.5%), and unknown in 13 (10.5%). Death as a result of active SLE was more common in patients who died within 5 years of diagnosis compared to those dying after 5 years (p = 0.021), and deaths due to vascular events and end organ failure not related to active lupus were more frequent in the late death group (p = 0.028). The overall 5, 10, 15, and 20 year survival rates were 93, 85, 79, and 68%, respectively. Patients with SLE had a 4.92 fold increased risk for death compared with the general population. Survival rates continue to improve in SLE but causes of mortality vary at different stages.

One hundred anti-Ro (SS-A) antibody positive patients: A 10-year foliow-up

Article

Jun 1995

To explore further the varied clinical expression of anti-Ro(SS-A) antibody positive patients and to determine the outcomes of these patients, we followed 100 anti-Ro(SS-A) antibody positive patients, originally seen at the Johns Hopkins Medical Institutions in 1982 and 1983, over a 10-year period. The results of this study indicate that anti-Ro(SS-A) antibody positive patients have a diverse clinical presentation and that the anti-Ro(SS-A) antibody response generally persists for years. Some of these patients appear to have a static disease process for years. However, 65% (51, including 13 deaths, of 78 patients) of the patients for whom we had follow-up data had a chronic (10 years or greater) progressive disease process. Black patients, in general, have an earlier onset of disease and may have a more severe disease than white patients. At least 25% of our anti-Ro(SS-A) antibody positive patients demonstrated a dynamic change in clinical presentation with the development of Sjögren syndrome and/or a progressive "rheumatoid-like" arthritis. Interstitial pulmonary disease, central nervous system disease, and vasculitic insults occur frequently in these patients. Renal disease occurred in 19 anti-Ro(SS-A) positive patients, and in 47% of these renal disease patients, no anti-DNA antibodies (dsDNA or ssDNA) were detected. Cutaneous manifestations are prominent in anti-Ro(SS-A) antibody positive patients with lupus. Photosensitivity and a malar dermatitis were the most common features. Twenty percent of lupus patients had discoid lesions, and 20% had SCLE lesions. Based on this study, we believe that anti-Ro(SS-A) antibody positive patients should be routinely evaluated for the emergence of systemic features. Since these systemic features are at least in part, if not solely, the result of inflammation, early treatment with steroids and/or immunosuppressive agents may minimize the damage and influence in a positive manner the significant morbidity and mortality observed in some anti-Ro(SS-A) antibody positive patients.

Neuwelt C, Lacks S, Kaye B, Ellman J, Borenstein D. Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus. Am J Med 1995;

Article

Feb 1995
AM J MED

We assessed the outcome of 31 patients with severe neuropsychiatric (NP) systemic lupus erythematosus (NPSLE) treated with intravenous cyclophosphamide (IV-CYC), and identified clinical predictors of response to therapy. The authors performed a retrospective chart review and classified patients by NP manifestation and response to therapy as measured by serial anatomic imaging and neurodiagnostic studies coupled with clinical assessment of improvement. Neuropsychiatric manifestations occurred with the following frequencies: organic brain syndromes (OBS) 55%, stroke syndromes 35%, peripheral or mononeuropathy 32%, seizures 29%, psychiatric symptoms 26%, transverse myelitis 16%, cranial neuropathies 13%, other 16%. Most patients had multiple NP manifestations, with a median of two. Ninety percent of patients had failed therapy with corticosteroids with or without cytotoxic drugs prior to treatment with IV-CYC. Eight patients received synchronous plasmapheresis along with IV-CYC. After treatment with IV-CYC, NP deficits substantially improved in 61% (group I), stabilized in 29% (group S), and progressively deteriorated in 10% (group P). Patients in group I had significantly fewer NP manifestations than combined group S+P, two versus four, and a lower frequency of OBS, 37% versus 83%. Intravenous cyclophosphamide appears to be an effective treatment for some patients with severe NPSLE refractory to other forms of therapy. Higher number of NP manifestations and presence of OBS may predict poor outcome and identify a group of patients for whom early aggressive therapy may be indicated.

Long-term survival in systemic lupus erythematosus. Patient characteristics associated with poorer outcomes

Article

Feb 1995

To investigate the associations of age, sex, race, and socioeconomic status with long-term survival in patients with systemic lupus erythematosus (SLE). We examined survival in an inception cohort of 408 patients with SLE. The cohort included 177 black females, 162 white females, 49 white males, and 20 black males. The median duration of followup was 11 years (range 0.1-22 years). One hundred forty-four patients died during the study. The 5-, 10-, and 15-year survival estimates for the entire cohort were 82%, 71%, and 63%, respectively. In univariate analyses, mortality rates increased with age and were higher among males, blacks, those without private medical insurance, and those living in census tracts with lower household incomes. In multivariate analyses, age, sex, and both socioeconomic indicators were associated with total mortality (mortality from any cause), while race was not. Lower socioeconomic status and increased age were also associated with higher rates of death from SLE. Socioeconomic status, but not race, is associated with mortality in SLE. SLE-related mortality also tends to increase with age, which suggests that SLE may not be less severe when it occurs later in life.

Drenkard C, Villa AR, Alarcon-Segovia D, Perez-Vazquez ME. Influence of the antiphospholipid syndrome in the survival of patients with systemic lupus erythematosus. J Rheumatol. 21: 1067-1072

Article

Jul 1994

To determine prognostic factors for mortality in a cohort of 667 patients with systemic lupus erythematosus (SLE) including those variables associated with the presence of antiphospholipid antibodies (aPL) as well as antiphospholipid syndrome (APS) itself. Analysis of the cohort under a nested case control design by means of Cox proportional hazards regression with and without stepwise method. During the 2039 person-years of followup, there were 49 deaths (cases). Thrombocytopenia, arterial occlusions, and hemolytic anemia were the aPL related manifestations that were associated with decreased survival in univariate analyses. The first 2 were also selected among risk factors for mortality in stepwise Cox multivariate analysis. The syndrome itself was also associated with increased mortality rates, independently of other variables. APS is among the variables that confer decreased survival on patients with SLE. This decreased survival is due to some (e.g., thrombocytopenia or arterial occlusions), but not all, of the manifestations of APS.

The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus

Article

Mar 1996

To develop and perform an initial validation of a damage index for systemic lupus erythematosus (SLE). A list of items considered to reflect damage in SLE was generated through a nominal group process. A consensus as to which items to be included in an index was reached, together with rules for ascertainment. Each center submitted 2 assessments, 5 years apart, on 2 patients with active and 2 with inactive disease, of whom 1 had increased damage and the other had stable disease. Analysis of variance was used to test the factors physician, time, amount of damage, and activity status. Nineteen physicians completed the damage index on 42 case scenarios. The analysis revealed that the damage index could identify changes in damage seen in patients with both active and inactive disease. Patients who had active disease at both time points had a higher increase in damage. There was good agreement among the physicians on the assessment of damage in these patients. This damage index for SLE records damage occurring in patients with SLE regardless of its cause. The index was demonstrated to have content, face, criterion, and discriminant validity.

Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus

Article

Oct 1997

Marc C Hochberg

Association between clinical factors, socioeconomic status, and organ damage in recent onset systemic lupus erythematosus

Article

Apr 2000

To determine the prevalence and socioeconomic and clinical predictors of early organ damage in a cohort of patients with systemic lupus erythematosus (SLE) of 2-7 years' duration randomly sampled at 5 centers and balanced by socioeconomic status and race. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index was measured in 200 patients who met the ACR criteria for SLE with a mean disease duration of 3.8 years. The SLICC/ACR scores for each organ system and the prevalence of damage within organ systems were assessed. Logistic regression analyses evaluated the simultaneous effects of age at diagnosis, disease duration, disease activity, and sociodemographic factors. Sixty-one percent of the patients had damage within 7 years of onset (mean 3.8 yrs). Neuropsychiatric (20.5%) and musculoskeletal (18.5%) systems were the most frequently involved, followed by renal (15.5%) and skin (12.5%) systems, all with median SLICC/ACR organ system scores of 1. In multivariate models, African-American race was associated with skin damage but not with damage in other specific organ systems. Socioeconomic status was not associated with organ system damage. Older age at diagnosis correlated with cardiovascular, musculoskeletal, gastrointestinal, ocular, and pulmonary damage. Clinical factors such as longer disease duration correlated with higher renal and cardiovascular damage, and greater disease activity at diagnosis of SLE correlated with greater renal, musculoskeletal, and pulmonary damage. There is evidence of organ system damage in SLE within a mean of 3.8 years after onset. We found little evidence for differences in early organ damage according to race or socioeconomic status. Damage to most organ systems was related to age at diagnosis of SLE and clinical factors such as disease duration.

Hopkins Lupus Cohort: 1999 Update

Article

Jun 2000
RHEUM DIS CLIN N AM

Muhammad Helmi Petri

The Hopkins Lupus Cohort is a decade-long prospective study, now numbering 800 patients with systemic lupus erythematosus. In this article, predictors of disease activity, disease damage (including accelerated atherosclerosis and antiphospholipid antibody syndrome) and health status are reviewed.

Development of the Antinuclear and Anticytoplasmic Antibody Consensus Panel by the Association of Medical Laboratory Immunologists

Article

Jun 2000

The Association of Medical Laboratory Immunologists (AMLI) have developed a panel of antinuclear and anticytoplasmic antibody consensus sera that can be useful for enzyme immunoassay (EIA), Ouchterlony, and immunofluorescence assay methods. It was developed to assist in the evaluation of newly available EIA methods for the detection of autoantibodies. The panel of sera was evaluated in several clinical laboratories and a large number of laboratories owned by manufacturers of clinical autoantibody testing kits. The majority of sera performed well for the EIAs in both the clinical laboratories and the manufacturers' laboratories, but some samples had discrepant results. A major source of discrepancy is the current inability of the EIA results to be directly compared in a quantitative way as no standardization exists. The evaluation demonstrated lower sensitivity of detection by the Ouchterlony method. The limited evaluation of the sera with immunoblotting and Western blotting did not show good agreement with other methods. Further work must be done to standardize blotting methods prior to their use in routine clinical testing. The sera are now available to vendors and clinical laboratories for use in the detection of SS-A, SS-B, Sm, U1-RNP, Scl-70, Jo-1, double-stranded DNA, and centromere antibodies. The availability of the consensus sera will help evaluate and improve the EIA methods currently being used.

Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome

Article

Sep 2000

We assessed whether initial clinical presentations suggestive of antiphospholipid syndrome (APS) predicted the subsequent rate and type of serious clinical outcomes. Eighty-two consecutive patients with anticardiolipin antibodies or lupus anticoagulant were followed for 814 person-years after a first event suggestive of APS (livedo reticularis, thrombocytopenia, autoimmune haemolysis, thrombosis, central nervous system manifestations, recurrent abortions). The hazard of developing a second event was largest in patients with antibodies recognizing beta2 glycoprotein I who had autoimmune haemolysis as the first event (hazard ratio HR 2.70, p=0.018) and smallest in patients without such antibodies who had recurrent abortions as their first event (HR 0.37, p=0.028). Subsequent serious events in patients with venous and arterial thromboses, recurrent abortions, central nervous system manifestations and autoimmune haemolytic anaemia were likely to be of the same type as the presenting event (odds ratio (OR) 3.76, 5.90, 77.7, 6.92, and 7.13, respectively. Adjusting for therapy, the rate of subsequent serious events was 6.86-fold higher (p=0.0001) in patients presenting with two events, 1.56-fold higher (p=0.038) in autoimmune haemolysis presentations, 1.69-fold higher (p=0.004) in patients with anti-beta2-glycoprotein-I antibodies, and 46% (p=0.063) lower in thrombocytopenia presentations. Initial clinical features determine the long-term evolution of APS, and specific types of clinical manifestations cluster during the course of the disease.

Prediction of short term mortality in Systemic Lupus erythematosus with time dependent measures of disease activity

Article

Sep 2000

To identify predictors of short term mortality in systemic lupus erythematosus (SLE) in terms of time dependent clinical indicators of disease activity from the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). We studied data collected on patients followed at the University of Toronto Lupus Clinic. Clinical and laboratory indicators of disease activity are recorded at each clinic visit and a SLEDAI summary score is calculated. Survival analyses were conducted in which the prognostic value of the time dependent indicators of disease activity was examined on 6-month mortality through a multivariate Cox regression model. Relative risks, confidence intervals, and significance levels were obtained for each indicator to reflect their clinical importance and statistical significance. The sample consisted of 806 patients followed for a median of 6.6 years; 702 (87%) were female, 671 (83%) were Caucasian, and the mean age at first clinic visit was 36 years. Seventy-two patients died within 6 months of their last clinic visit. In a univariate regression model, a categorical variable reflecting total SLEDAI score was highly prognostic for mortality (p < 0.001) and yielded increasing relative risks of 1.28 for SLEDAI 1-5 vs 0, 2.34 for SLEDAI 6-10 vs 0, 4.74 for SLEDAI 11-19 vs 0, and 14.11 for SLEDAI > 20 vs 0. In a separate multivariate Cox model examining the individual components of SLEDAI, presence of organic brain syndrome, retinal changes, cranial nerve involvement, proteinuria, pyuria, pleurisy, fever, thrombocytopenia, and leukopenia each significantly increased the risk of death, while new rash and anti-DNA antibodies conferred protective effects. This time dependent Cox regression analysis identified the extent to which SLE disease activity, revealed by SLEDAI, is prognostic for short term mortality. Further, important individual components were identified and their prognostic value for death was estimated.

Do present damage and health perception in patients with systemic lupus erythematosus predict extent of future damage?: a prospective study

Article

Nov 2000

To study whether either initial damage, disease activity, disease duration, age, a drug score, or health status would predict an increase in damage in patients with systemic lupus erythematosus (SLE) within the next three years. A three year prospective longitudinal study of a cohort of 141 consecutive patients with SLE attending a specialist lupus outpatient clinic from their first assessment between July 1994 and February 1995. Disease activity was assessed using the BILAG system, health status by the Medical Outcome Survey Short Form 20 with an extra question about fatigue (SF-20+), and damage by the SLICC/ACR Damage Index (SDI). Damage was reassessed three years later. Statistical analysis was carried out using logistic regression analysis (logXact). 133 female and 8 male patients with SLE (97 white subjects, 16 Afro-Caribbeans, 22 Asians, and 6 others) were included. Their mean (SD) age at inclusion was 41.1 (12.5) years and their disease duration 10.2 (6. 3) years. The mean measures at inclusion were: total BILAG 5.2 (range 0-17), total SDI 1.2 (0-7), drug score 1.2 (0-3); SF-20+: physical 58 (0-100), role 54 (0-100), social functioning 71 (0-100), mental health 64 (16-100), health perception 44 (0-100), pain 53 (0-100), fatigue 59 (0-100). Four patients were lost to follow up because they had moved. At three years in 33 patients the total SDI had increased to a mean of 1.5 (0-7) (n=130). Moreover, seven patients had the maximum damage as they had died during the follow up period. The only variables with an independent and significant contribution in predicting damage at three years were the total damage score (odds ratio (OR)=1.46; 95% CI 1.04 to 2.05), and health perception (OR=0.96; 95% CI 0.93 to 0.99) at inclusion. Of all the variables at inclusion only the total damage score and SF-20+: health perception, significantly predicted an increase in damage, for patients with SLE, three years later.

Predictors of clinical outcome and radiologic progression in patients with neuropsychiatric manifestations of systemic lupus erythematosus

Article

Jan 2001
AM J MED

We sought to identify the predictors of clinical outcome and of the evolution of cerebral abnormalities in patients with neuropsychiatric systemic lupus erythematosus (SLE). Thirty-two patients with SLE (including 14 with the antiphospholipid syndrome) who had been hospitalized with primary neuropsychiatric disease were observed prospectively for at least 2 years. Laboratory and clinical characteristics and data from magnetic resonance imaging (MRI) studies obtained during the hospitalization and 2 years later were evaluated. We ascertained nonreversible or new MRI changes and clinical outcomes, including neuropsychiatric events, during follow-up. Cranial MRI scans on admission were abnormal in 26 (81%) of the 32 patients. Patients with the antiphospholipid syndrome were more likely to have focal cerebral white matter lesions (odds ratio [OR] = 12, 95% confidence interval [CI]: 2.0 to 72). After 2 years, neuropsychiatric deficits substantially improved in 22 (69%) of the patients, stabilized in 6 (19%), and deteriorated in 4 (12%). The number of prior neuropsychiatric events was associated with persistent MRI lesions (OR = 4.8 per each event, 95% CI: 1.1 to 21) and unfavorable clinical outcome (OR = 4.3 per each event, 95% CI: 1.4 to 13) at 2 years. The antiphospholipid syndrome also predicted an unfavorable clinical outcome at 2 years (OR = 11, 95% CI: 1.7 to 65). Among patients with SLE who have neuropsychiatric disease, prior neuropsychiatric events and the antiphospholipid syndrome increase the risk of adverse outcomes.

Early damage as measured by the SLICC/ACR damage index is a predictor of mortality in systemic lupus erythematosus

Article

Feb 2001

The aim of this study was to determine whether early damage accrued in SLE as measured by the SLICC/ACR Damage Index predicts mortality in an inception cohort of lupus patients that have been followed prospectively in a single centre. SLE patients from the University of Toronto Lupus Clinic presenting within 1 y of their diagnosis prior to 1988 were included. This enabled all patients to be potentially followed for at least 10 y. Yearly SLICC/ACR Damage Index scores were determined for each patient. Early damage was defined as a score > or = 1 and no damage as a score of 0 at the initial assessment. Log rank test was used to compare the survival experience between those with and without damage, with all patients being censored at 10 y. Two-hundred and sixty-three patients were identified in this inception cohort who were followed for 10 y. One-hundred and ninety patients (72%) had a SLICC/ACR Damage Index score of 0 (no damage) while 73 patients (28%) had at least one SLICC/ACR Damage Index item scored (early damage). Twenty-five percent of lupus patients who exhibited damage at their first SLICC/ACR Damage Index assessment died within 10 y of their illness as compared to only 7.3% who had no early damage (log rank P-value = 0.0002). SLE patients who died within 10 y were more likely to have renal damage (P = 0.013), and a trend toward more cardiovascular disease (P = 0.056), compared to patients who were alive. Early damage as reflected by the initial SLICC/ACR Damage Index is associated with a higher rate of mortality.

International Society on Antiphospholipid Antibodies, Tours, France, 12–16 September 2000

Article

Apr 2001

Thomas Exner

Risk factors for damage in childhood-onset systemic lupus erythematosus: Cumulative disease activity and medication use predict disease damage

Article

Mar 2002

Objective: The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index measures damage in adult patients with systemic lupus erythematosus (SLE), but its usefulness in patients with childhood-onset SLE has not been examined. This study was conducted to evaluate the sensibility of the SLICC/ACR Damage Index, to investigate how cumulative disease activity is related to damage in childhood-onset SLE, and to identify other risk factors for damage in childhood-onset SLE. Methods: Disease activity and damage in 66 patients with newly diagnosed childhood-onset SLE were assessed retrospectively, and information on potential risk factors for damage (age, race, sex, medications, duration of disease, hypertension, body mass index, antiphospholipid antibodies, kidney disease, acute thrombocytopenia) was obtained. In addition, a group of physicians was surveyed to establish the sensibility of the SLICC/ACR Damage Index in childhood-onset SLE. Results: The SLICC/ACR Damage Index was found to have face, content, and construct validity when used in children. The mean SLICC/ACR Damage Index score of the patients was 1.76 (mean followup 3.3 years). Cumulative disease activity over time was the single best predictor of damage (R(2) = 0.30). Other, possibly important risk factors for damage were corticosteroid treatment, the presence of antiphospholipid antibodies, and acute thrombocytopenia. It was determined that immunosuppressive agents may be protective. Conclusion: The SLICC/ACR Damage Index, though useful in childhood-onset SLE, may benefit from the introduction of weightings and redefinition of some of the items. Ongoing disease activity leads to disease damage, and treatment should be prompt. Prolonged use of high-dose corticosteroids may further increase damage, but use of immunosuppressive agents may protect against disease damage; this latter finding may have potential implications for the treatment of childhood-onset SLE and deserves further study. The relationship between disease activity and concomitant use of medication also requires further investigation.

High predictive value of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for survival in systemic lupus erythematosus

Article

Jul 2002

We previously reported high Systemic Lupus International Collaborating Clinics (SLICC) scores in fatal cases of systemic lupus erythematosus (SLE) from our inception cohort. This study was done to clarify if the SLICC damage scores 5 years after diagnosis predicted the outcome. We studied 80 patients with SLE (70 women, 10 men), all enrolled and diagnosed during the years 1981 through 1991 in our inception cohort, and all alive 5 years after inclusion into the cohort. In all patients the SLICC/American College of Rheumatology (ACR) damage index (DI) was scored at 5 years after SLE diagnosis, and these scores were tested for predictive value. The outcomes were survival or late mortality within the following median observation period of 7 years. All surviving patients were followed through 1999, and no patient was lost to followup. At study entry, 5 years after the diagnosis of SLE, 37 patients had no damage to score with SLICC. Of the remaining 43 patients, 25 had a score of 1 and 18 had a score of 2 or more. In total, 14 fatalities occurred within 7 years after study entry, 7 among the 18 with initial SLICC/ACR DI of 2 or more compared with 7 fatalities among the 62 with less or no damage (p < 0.01). Cardiovascular or cerebrovascular SLICC/ACR DI items were more common in fatal cases than in survivors (p < 0.001). A SLICC score at 5 years of 2 or more increased the relative risk for fatality by 3.4 (95% CI 1.5-14.4), and had a predictive value of 38%. A SLICC score of 0 at 5 years gave an odds ratio in favor of survival of 0.06 (95% CI 0.0-0.5) and had a predictive value for survival of 97%. During an extended followup for one more year the predictive value of damage for fatalities was even more pronounced (p = 0.003, log-rank). SLICC damage scores registered 5 years after SLE diagnosis have a high predictive value for survival during the following median observation time of 7 years. These data provide strong evidence that the items included in the SLICC score are clinically relevant.

Lowering anti-dsDNA antibodies - What's new?

Article

Feb 2002

Antibodies to dsDNA are specific to SLE and are pathogenic, both due to their ability to deposit in tissues through a variety of mechanisms, and to their ability, when present in immune complexes, to activate inflammatory cells. The relationship of serum anti-dsDNA antibody levels to disease activity is a complex one and the factors that determine whether or not such antibodies will be pathogenic in an individual SLE patient are incompletely understood. Although anti-dsDNA antibodies can be made by naïve B cells and B cells belonging to the B1 and marginal zone subsets, pathogenic anti-dsDNA antibodies have the hallmarks of germinal center development and exposure to T cell help, including accumulation of somatic mutations and class switching to the IgG isotype. Epitope spreading may result in aquisition of cross-reactivities with multiple target organ antigens and aquisition of a memory phenotype will allow these B cells to acquire antigen presentation functions that amplify the autoreactive response. In the early stages of disease, or after remission induction protocols, autoreactive B cells may be susceptible to treatments that target T cell costimulation or that deplete or tolerize naïve and mature B cells. Therapeutic approaches targeting innate immune responses or regulatory T cells are starting to be tested in pre-clinical models. In later disease stages, memory and plasma cell accumulation may render patients more resistant to this type of therapeutic approach. Deposition of anti-dsDNA antibodies in target tissues can stimulate an inflammatory cascade that leads to tissue damage. A number of murine models have now been developed that show that interruption of this cascade can prevent or reverse such damage. This type of approach may be beneficial for individuals with established disease. As we learn more about the specific defects that cause SLE, it may become possible to individualize therapy based on patient specific biologic markers.

Sanna G, Bertolaccini ML, Cuadrado MJ, Laing H, Khamashta MA, Mathieu A, Hughes GR. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies

Article

May 2003

To apply the new American College of Rheumatology nomenclature for neuropsychiatric systemic lupus erythematosus (NPSLE), determine the prevalence of the different neuropsychiatric (NP) syndromes, and evaluate which of these manifestations correlates with the presence of antiphospholipid antibodies (aPL). Methods. Clinical, serological, and imaging data of 323 consecutive patients with SLE were retrospectively reviewed. Neuropsychometric testing was applied by a neuropsychologist. Univariate and multivariate statistical analyses were applied to evaluate the association bewteen NP manifestations, magnetic resonance imaging (MRI) abnormalities, and aPL. In total, 185 patients (57.3%) had NP manifestations at any time during followup. Headache was the most frequent manifestation, present in 78 patients (24%). Cerebrovascular disease (CVD) was diagnosed in 47/323 patients (14.5%), with a total of 57 events. Mood disorders were found in 54 (16.7%), cognitive disorders in 35 (10.8%), and seizures in 27 patients (8.3%). Psychosis was diagnosed in 25 (7.7%), anxiety disorder in 24 (3.7%), and acute confusional state in 12 patients (3.7%). Less common manifestations were polyneuropathy, mononeuritis, myasthenia gravis, cranial neuropathy, myelopathy, chorea, demyelinating disease, and Guillain-Barré syndrome. The presence of aPL was associated with NP manifestations (p < 0.001). Multivariate analysis showed that aPL were independently associated with CVD (OR 6.17, 95% CI 2.94-12.9, p = 0.001), headache (OR 2.04, 95% CI 1.17-3.55, p = 0.01), and seizures (OR 2.89, 95% CI 1.18-7.10, p = 0.02). The presence of lupus anticoagulant (LAC) was independently associated with white matter hyperintensity lesions on MRI (OR 3.0, 95% CI 1.12-8.05, p = 0.027). The new ACR criteria for NPSLE are useful to define NP manifestations in SLE with accuracy. NP manifestations are significantly associated with aPL. CVD, headache, and seizures were independently associated with these antibodies.

Clinical, immunogenetic and outcome features of Hispanic systemic lupus erythematosus patients of different ethnic ancestry

Article

Feb 2003

The aim of this study was to compare and contrast the clinical, immunogenetic and outcome features of two subgroups of Hispanic patients with systemic lupus erythematosus (SLE), one from Northern Spain (Spaniards) and one of from the USA (Hispano-Americans: Hispanics primarily of Mexican ancestry (Amerindian and Spaniard backgrounds). Patients with SLE as per the American College of Rheumatology classification criteria, from two University-affiliated Hospitals (Universidad de Cantabria) and disease of five or less years in duration (n = 28) and with four years of follow up constituted the Spaniard subgroup. Fifty-two patients of Hispano-American ancestry from the LUMINA (Lupus in Minority populations: Nature versus Nurture) cohort constituted the Hispano-American subgroup. Patients were studied using a similar protocol. In short, sociodemographic, clinical, immunological, immunogenetic and psychosocial and behavioral features were obtained at enrollment into the study (baseline visit) and yearly thereafter. The relationship between these variables and disease activity at baseline and over time, as measured by the systemic lupus activity measure (SLAM) and disease damage, as measured by the SLICC (Systemic Lupus International Collaborating Clinics) Damage Index (SDI) were determined. Variables found to be significant at P = 0.10 were then entered into multivariable linear regression models with disease activity at baseline and over time, and damage as the outcome measures. Patients of Hispano-American and Spaniard ethnicity had comparable sociodemographic features except for home density, which was higher among the Hispano-Americans. HLA-DRB1*08 was associated with SLE among the Hispano-Americans but not among the Spaniards. Hispano-American patients had more severe disease as manifested by more frequent clinical manifestations (renal and neurological), higher SLAM scores at baseline and over time and higher SDI scores at the year 4 visit (that despite the fact that Hispano-American patients had overall shorter disease duration than the Spaniard patients). Hispano-American ethnicity, younger age at disease onset and the number of ACR criteria at baseline and over time were consistently associated with disease activity, whereas increased home density and the absence of HLA-DRB1*0301 were significant predictors only over time. Disease damage was associated with disease activity over time, the number of ACR criteria at baseline, increased home density and the presence of HLA-DRB1*08. This is the first longitudinal study of SLE in two different Hispanic subgroups. Hispanics with a strong Amerindian background have a more serious disease than that observed in Spaniards. Genetic and socio-economic differences between these two Hispanic subgroups probably account for these findings.

Damage accrual in southern Chinese patients with systemic lupus erythematosus

Article

Aug 2003

To study the predictive factors of damage accrual in a large cohort of southern Chinese patients with systemic lupus erythematosus (SLE). A cohort of consecutive Chinese patients with SLE was recruited in 1998 and prospectively followed for 3 years. Demographic data, disease manifestations and activity, medication use, and damage scores were recorded. Organ damage was assessed using the SLE International Collaborating Clinics Damage Index (SDI), which was scored at study entry and then annually. Disease flares and new damage were recorded during followup visits. Predictive factors of new damage were studied by statistical analysis. The cohort consisted of 242 consecutive patients with SLE (221 women, 21 men; F:M = 10.5:1). All fulfilled at least 4 American College of Rheumatology criteria for the classification of SLE. At entry, mean age was 35.7 +/- 10.7 years and mean disease duration was 75.3 +/- 79 months. Ninety (38%) patients had damage. The mean SDI score at year 0 was 0.76 +/- 1.3 (range 0-8), and this increased significantly to 1.33 +/- 1.7 (range 0-9) at year 3 (p < 0.001). The most frequent organ damage at entry was musculoskeletal (26.5%), followed by damage in central nervous system (18.4%), renal (15.1%), and cardiovascular (12.4%) systems. The increase in SDI scores over the 3 year period was primarily caused by the increase in renal, musculoskeletal, and gonadal damage. Twelve patients died. Multiple regression revealed that the number of major disease flares and the use of cyclophosphamide were independent factors predictive of damage accrual. An increase in SDI scores was associated with mortality risk (OR 1.47 per 1 point, 95% CI 1.03-2.11, p = 0.04). The damage scores of our SLE cohort increased significantly over 3 years. Severe disease flares and the use of cyclophosphamide predicted new damage. Increase in damage was associated with mortality risk. Judicious use of immunosuppressive agents to achieve prompt control of disease activity was essential in minimizing damage and improving survival of our patients with SLE.

Neuronal and Astrocytic Damage in Systemic Lupus Erythematosus Patients with Central Nervous System Involvement

Article

Oct 2003

Symptoms originating from the central nervous system (CNS) frequently occur in patients with systemic lupus erythematosus (SLE). CNS involvement in lupus is associated with increased morbidity and mortality. Currently, reliable markers for activity in this condition are absent. The goal of this study was to determine the level of the light subunit of the neurofilament triplet protein (NFL) and that of glial fibrillary acidic protein (GFAP) in the cerebrospinal fluid of SLE patients with clinically verified CNS involvement and compare them with the levels in SLE patients without CNS involvement. We assessed cerebrospinal fluid obtained from 99 patients with SLE and 99 age-matched controls for the presence of soluble molecules indicating neuronal destruction and astrogliosis-NFL and GFAP, respectively. Patients were evaluated clinically, with magnetic resonance imaging (MRI) of the brain, cerebrospinal fluid analyses, and neuropsychiatric tests. In the group of lupus patients with CNS involvement, intrathecal levels of NFL and GFAP were increased an average of 7-fold (P </= 0.0001) and 3-fold (P </= 0.05), respectively, compared with the levels in SLE patients without overt CNS disease. Intrathecal levels of NFL correlated significantly with cerebrospinal fluid levels of interleukin-6 (IL-6) (P </= 0.005), IL-8 (P </= 0.005), pleocytosis (P </= 0.05), the albumin ratio (P </= 0.0005), and the presence of oligoclonal IgG bands (P </= 0.005). Cerebrospinal fluid levels of both NFL and GFAP also showed a significant correlation with MRI abnormalities (P </= 0.001). Successful cyclophosphamide treatment of CNS lupus resulted in significantly decreased levels of both proteins; levels of GFAP reached those observed in healthy subjects. This study is the first to show biochemical signs of neuronal and astrocytic damage in patients with neuropsychiatric lupus. It is suggested that biochemical markers of brain damage should be used as a followup tool in this patient group.

Cerebral hypoperfusion detected by SPECT in patients with systemic lupus erythematosus is related to clinical activity and cumulative tissue damage

Article

Feb 2003

Cerebral single-photon emission computed tomography (SPECT) is a sensitive technique for the detection of central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). The objective was to determine whether a relationship exists between cerebral hypoperfusion as detected by cerebral SPECT, cumulative tissue damage and the clinical activity of SLE. Cerebral technetium-99m-L,L-ethyl cysteinate dimer (99mTc-ECD) SPECT was performed in two groups of patients: 10 women with SLE (Group A) who had no previous history of major neuropsychiatric (NPS) manifestations and no minor NPS symptoms in the last six months, and 57 unselected women with SLE (Group B). In the same week that SPECT was performed, the SLE disease activity index (SLEDAI), SLICC/ACR damage index, native anti-DNA antibodies (ELISA) and erythrocyte sedimentation rate (ESR) were determined. In Group A, cerebral SPECT showed moderate or severe hypoperfusion (abnormal SPECT) in five patients without NPS symptoms, unrelated to age (mean 24.8 versus 27.8 years) or disease duration (mean 6.8 versus 9 years). Patients with significant cerebral hypoperfusion had greater clinical disease activity (mean SLEDAI 13.6 versus 7.6) (SLEDAI > 7 in 5/5 versus 1/5; Fisher: 0.023; OR: 33; 95% CI: 2.3-469.8) and ESR (mean 43.6 versus 9.8; P < 0.05). In Group B, the mean age of the 57 unselected women with SLE was 37 years (SD 6.3) and the mean duration of the disease was 9.7 years (SD 6.3). Cerebral SPECT revealed normal perfusion or mild hypoperfusion (normal SPECT) in 30 patients (52.6%), and moderate or severe hypoperfusion in 27 (47.4%). Hypoperfusion was unrelated to age, duration of SLE or concentrations of anti-DNA antibodies and C3 and C4 fractions. Patients with significant cerebral hypoperfusion had more active clinical disease (mean SLEDAI 13.92; SD 8.44 versus 4.56; SD 4.15) (Mann-Whitney, P < 0.005), more cumulative tissue damage (mean SLICC 2.66; SD 2.84 versus 1.03; SD 1.51) (Mann-Whitney, P = 0.035), and higher ESR values (mean 28.7; SD 22.5 versus 17.7; SD 13.3) (Mann-Whitney, P = 0.023) than patients with normal SPECT studies. Significant cerebral hypoperfusion was related both to NPS manifestations present at the time of the study (17 of 27, 63% versus 3 of 30, 10%) (OR: 15.3) and cumulative manifestations (19 of 27, 70.4% versus 8 of 30, 26.7%) (OR: 6.5), whether mild (OR: 5.5) or severe (OR: 8.2). In conclusion, cerebral hypoperfusion detected by SPECT in patients with SLE is related to clinical activity (SLEDAI), cumulative tissue damage (SLICC) and concomitant or previous NPS manifestations.

Ribosomal P antibodies and CNS lupus

Article

Feb 2003

M Reichlin

Within two years of the recognition of autoantibodies to ribosomal P proteins in patients with systemic lupus erythematosus (SLE) an association with anti-P autoantibodies with psychosis was noted. While there has been some controversy about this association, ample evidence suggests a meaningful relationship between anti-P antibodies and central nervous system (CNS) disease. This evidence consists of 1) seven independent studies showing a strong relationship between anti-P antibodies and CNS disease; 2) longitudinal studies showing fluctuations of anti-P antibodies with episodes of psychosis; 3) correlation of anti-P antibodies with general disease activity; and 4) acid eluates form lupus renal tissue were found to contain anti-P antibodies enriched 30-fold with respect to their specific activity in serum heralding a direct role of anti-P antibodies in disease expression. Finally, there is evidence that the P protein resides on normal cells in an immunologically accessible way and evidence exists that anti-P antibodies are able to bind and penerate cells in culture, and once inside cells can affect a profound inhibition of protein synthesis in living cells. Taken together, these observations provide evidence linking anti-P antibodies to various forms of CNS disease. While this is true, there are other autoantibodies in SLE patients such as anti-dsDNA and antiglial fibrillary protein which may also play a role in the CNS disease of SLE patients. Continued study will inform us of the relative contribution of these autoantibodies to CNS disease in SLE patients.

Predictors of neuropsychiatric damage in systemic lupus erythematosus: Data from the Maryland lupus cohort

Abstract

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