Systemic Lupus Erythematosus Subgroups Research Articles

Limited Association between Antibodies to Oxidized Low-Density Lipoprotein and Vascular Affection in Patients with Established Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus (SLE) are at an increased risk of cardiovascular disease. We aimed to evaluate whether antibodies to oxidized low-density lipoprotein (anti-oxLDL) were associated with subclinical atherosclerosis in patients with different SLE phenotypes (lupus nephritis, antiphospholipid syndrome, and skin and joint involvement). Anti-oxLDL was measured by enzyme-linked immunosorbent assay in 60 patients with SLE, 60 healthy controls (HCs) and 30 subjects with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Intima-media thickness (IMT) assessment of vessel walls and plaque occurrence were recorded using high-frequency ultrasound. In the SLE cohort, anti-oxLDL was again assessed in 57 of the 60 individuals approximately 3 years later. The levels of anti-oxLDL in the SLE group (median 5829 U/mL) were not significantly different from those in the HCs group (median 4568 U/mL), while patients with AAV showed significantly higher levels (median 7817 U/mL). The levels did not differ between the SLE subgroups. A significant correlation was found with IMT in the common femoral artery in the SLE cohort, but no association with plaque occurrence was observed. The levels of anti-oxLDL antibodies in the SLE group were significantly higher at inclusion compared to 3 years later (median 5707 versus 1503 U/mL, p < 0.0001). Overall, we found no convincing support for strong associations between vascular affection and anti-oxLDL antibodies in SLE.

Heterogeneity of echocardiographic variables in systemic lupus erythematosus among clinical subgroups according to non-cardiac organ involvement

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Cardiac involvement is rare but plays an important prognostic role. The degree of cardiac involvement according to SLE subsets defined by non-cardiac manifestations is unknown. The objective of this study was to identify differences in TTE parameters associated with different SLE subgroups. One hundred and eighty-one patients fulfilling the ACR/EULAR 2019 classification criteria for SLE and had a TTE were included in this cross-sectional study. We defined four subsets of SLE based on the predominant clinical manifestations. A multivariate multinomial regression analysis was performed to determine whether TTE parameters differ between the subsets. The first subset (n = 37) of patients showed features of mixed connective tissue disease (MCTD); the second subset (n = 76) had primarily cutaneous involvement; the third subset (n = 18) exhibited serositis and the last subset (n = 50) had severe disease with significant organ involvement, including renal involvement. Forty TTE parameters were assessed in each patient. Using a multivariate multinomial regression analysis, 3 parameters differed between groups: early diastolic tricuspid annular velocity (RV-E′, P < 0.0001), RV-S′ (RV-pulse DTI systolic peak wave, P = 0.0031), and RV end-diastole diameter (P = 0.0419). The degree of RV dysfunction was lowest in patients with primarily cutaneous involvement. Four distinct clinical subsets based on clinical manifestations differed in terms of TTE parameters of right heart function and diastolic dysfunction. This could help to tailor the cardiac follow-up required by the different clinical subsets of SLE.

Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjögren's Syndrome.

Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n=958) or primary SS (n=911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P=2 × 10-9 ) and impaired function of the classical complement pathway (P=0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.

Evaluation of subclinical retinal microvascular changes in systemic lupus erythematosus patients using optical coherence tomography angiography and its relationship with disease activity.

This study aimed to investigate subclinical retinal microvascular changes with optical coherence tomography angiography (OCTA) in patients with systemic lupus erythematosus (SLE) and healthy controls (HCs), and to evaluate the relationship between OCTA findings and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). In this study, 47 eyes of SLE and 41 eyes of healthy control (HC) were evaluated. The SLE patients were divided into two subgroups: low disease activity (LDA) (SLEDAI≤5) and high disease activity (HDA) (SLEDAI>6). The results of OCTA were compared between SLE patients and HCs as well as the SLE subgroups. The relationship between OCTA results and SLEDAI-2K was evaluated. There were no differences in foveal avascular zone (FAZ) areas between the SLE patients and HCs. Central foveal thickness (CFT) was lower in SLE patients (p = .046). Superficial capillary plexus (SCP) vessel density (VD) in SLE patients was significantly lower only in the foveal area compared to that in HCs (p = .006). Deep capillary plexus (DCP) VD in SLE patients was significantly lower in all areas except the temporal parafoveal area compared to that in the HCs. There was no statistically significant difference between SLE groups with LDA and HDA in FAZ or any of the other areas, including SCP and DCP. When the correlation between OCTA findings and SLEDAI-2K was examined, both SCP and DCP VD were found to be negatively correlated. It was observed that DCP VDs were affected in SLE patients with LDA, and SCP VDs were also affected in addition to DCP with HDA. This suggests that DCP may be the first capillary plexus to be comprised in SLE. VDs were negatively correlated with disease activity. It was concluded that OCTA can be a useful tool in assessing subclinical retinal microvascular pathology and disease activity in patients with SLE.

Characterization and clinical significance of biventricular mechanics in patients with systemic lupus erythematosus by 3T cardiovascular magnetic resonance tissue tracking.

Detecting impaired left ventricle (LV) or right ventricle (RV) mechanics could aid in fully understanding the process of cardiac involvement in patients with systemic lupus erythematosus (SLE). This study aimed to evaluate biventricular strain parameters derived from cardiac magnetic resonance (CMR) tissue tracking in SLE patients and their association with other clinical variables. A group of 47 SLE patients and 27 healthy controls were enrolled and underwent CMR examination, including cine and late gadolinium enhancement (LGE) imaging. Aside from RV strain parameters in the radial direction, biventricular global peak strain and peak systolic/diastolic global strain rate in radial, circumferential, and longitudinal directions were assessed for each participant. Multivariate linear regression analysis was used to analyze the factors related to the biventricular strain parameters. Receiver operating characteristic (ROC) analysis was used to identify RV dysfunction. Compared with the controls, part of the biventricular strain parameters in the SLE subgroup with preserved ejection fraction (EF) were impaired, which was more significant in the SLE subgroup with reduced EF (all P<0.05). The SLE patients with RV dysfunction (15/47) included patients with LV dysfunction (8/47). The RVEF was associated with impaired LV global peak strain and peak diastolic strain rate in the SLE patients (absolute value of β=0.406-0.715, all P<0.05). The LV LGE in SLE patients (12/47) was associated with LV global longitudinal peak strain and peak diastolic global longitudinal strain rate (β=0.378 and -0.342; all P<0.05). There were independent correlations between pulmonary arterial hypertension and RV global longitudinal peak strain, anti-ribonucleoprotein (RNP) antibody and RV global circumferential peak strain, and pericardial effusion and RV peak diastolic global circumferential strain rate, respectively (β=0.319, 0.359, and -0.285, respectively; all P<0.05). The LV global longitudinal peak strain had greater diagnostic accuracy for RV dysfunction RV dysfunction [area under curve (AUC): 0.933, cut-off value: -13.38%). Biventricular strain parameters derived from CMR are sensitive markers of subclinical ventricular function impairment before EF reduction at an early stage of SLE. Biventricular strain analysis could be considered for inclusion in early cardiac functional assessment in SLE patients, particularly LV global longitudinal peak strain, which might assist in therapeutic decision-making and disease monitoring.

LАТЕ ONSET OF SLE IN MALES: A MISDIAGNOSED DISEASE

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antibodies to components of the cell nucleus in association with a diverse array of clinical manifestations. When the immune system attacks its own tissues, it causes widespread inflammation and tissue damage in affected organs. It can affect the joints, skin, brain, lungs, kidneys, and blood vessels. The primary pathological findings in patients with SLE are those of inflammation, vasculitis, immune complex deposition, and vasculopathy. Late-onset SLE represents a specific subgroup of SLE and is often initially missed leading to a significant delay in diagnosis.&nbsp; Elderly patients frequently present to hospital with nonspecific symptoms such as fatigue, recurrent fever of an unknown cause, weight loss, serositis (pleural and/or pericardial effusions), and acute kidney injury. We are describing a case of late onset SLE in a male patient that has been previously only syptomaticaly treated for the complications of the disease itself, whilst it took a longer period for physicians to think of SLE and make further investigations about it, because of the age and sex of the patient.&nbsp; Keywords: systemic lupus erythematosus, male, late onset, pleural effusion, myocadritits. &nbsp;

Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA-DRB1 Genotype Associations and Immunological and Clinical Manifestations.

ObjectiveThe heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA‐DRB1 alleles and immunological and clinical data.MethodsAn unsupervised cluster analysis was performed based on detection of 13 SLE‐associated autoantibodies (double‐stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm/RNP, Sjögren's syndrome antigen A [SSA]/Ro52, SSA/Ro60, Sjögren's syndrome antigen B [SSB]/La, cardiolipin [CL]‐Immunoglobulin G [IgG], CL–Immunoglobulin M [IgM], and β2 glycoprotein I [β2GPI]–IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with HLA‐DRB1 alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446).ResultsOur analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti‐SSA/Ro60/Ro52/SSB autoantibodies and was strongly associated with HLA‐DRB1*03 (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52‐4.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18‐2.47). Subgroup 2 (28.7%) was dominated by anti‐nucleosome/SmRNP/DNA/RNPA autoantibodies and associated with HLA‐DRB1*15 (OR = 1.62, 95% CI = 1.41‐1.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14‐2.26). Subgroup 3 (23.8%) was characterized by anti‐ß2GPI‐IgG/anti‐CL–IgG/IgM autoantibodies and a higher frequency of HLA‐DRB1*04 compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2‐2.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with HLA‐DRB1. Additionally, the levels of eight cytokines significantly differed among the disease subgroups.ConclusionOur findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. These four SLE subgroups differ regarding associations with HLA‐DRB1 alleles and immunological and clinical features, suggesting dissimilar disease pathways.

Restless legs syndrome in systemic lupus erythematosus: A case-control study.

Sleep disturbances in systemic lupus erythematosus (SLE) are not well understood. The restless legs syndrome (RLS) is one of the frequent occurring sleep disturbances in SLE. The aim of this study was to evaluate the prevalence of RLS and its characteristics in SLE. We evaluated, in a prospective case-control study, 26 patients with SLE and 26 patients without SLE in an age- and sex-matched control group. An RLS-positive diagnosis met International RLS Study Group (IRLSSG) criteria. We used standardized questionnaires, which included demographic data, medical history and sleep assessment. We used validated questionnaires and scales to assess sleep. There were 23/26 females (88.46%) in each group; the mean patient age in the SLE subgroup was 51.65 years, while in the control subgroup, 52.07 years (range 30-74). Nine (34.2%) patients had RLS-positive criteria in the SLE group and 2 (7.69%) of 26 in the control group. Eight out of 9 patients described RLS onset after SLE was diagnosed. In the SLE group, 8 cases were of moderate severity and 1 was considered mild. The control group had one mild and one moderate case of RLS. RLS prevalence in SLE is higher and the quality of sleep is poorer compared with the control group.

Evaluation of optical coherence tomography angiography parameters in patients treated with Hydroxychloroquine

BackgroundOne of the major side effects of Hydroxychloroquine (HCQ) is retinopathy. The aim of this study was to evaluate the Optical coherence tomography angiography (OCTA) parameters in a group of patients who have Hydroxychloroquine-induced retinopathy based on Multifocal electroretinography (mfERG) with a group who do not have retinopathy.MethodThis is a Cross-Sectional Study. In this study, patients with Rheumatoid arthritis (RA) or Systemic lupus erythematosus (SLE) who had been taking Hydroxychloroquine for at least 7 years were included. MfERG and OCTA imaging were performed for all patients. Patients were divided into Normal mfERG and Abnormal mfERG groups based on mfERG results. OCTA parameters were studied in these two groups.ResultSixty-one patients (61 eyes) were included. Forty-one patients had SLE and 20 patients had RA. Forty patients (66.7%) had Abnormal mfERG. The mean vascular density (VD) in Superficial capillary plexus (SCP) layer was not significantly different between Normal mfERG and Abnormal mfERG groups (P-Value> 0.05). Mean VD in SCP layer was not significantly different between Normal mfERG and Abnormal mfERG groups (P-Value> 0.05). In RA subgroup, mean VD in SCP layer in PeriFovea region in Abnormal mfERG group was significantly lower than normal group (P-Value < 0.05). Mean VD in deep capillary plexus (DCP) layer in Whole Image, Superior Hemi, Inferior Hemi, PeriFovea area in Abnormal mfERG group was significantly lower than normal group (P-Value < 0.05). This discrepancy was also observed in the RA subgroup but not in the SLE subgroup. The mean of none of the parameters of foveal avascular zone (FAZ) (mm2), Flow Area of Outer Retina (mm2) and Flow Area of Choriocapillaris (mm2) were not statistically significant between the groups Abnormal mfERG and Normal mfERG. (p-value> 0.05).ConclusionVD in the DCP layer decreased in abnormal mfERG patients compared to patients with normal mfERG. But it seems that VD in SCP layer, FAZ Area and Flow Area are similar in both groups. OCTA may be used as a non-invasive tool in the diagnosis of early stages of HCQ-induced retinopathy, especially in RA patients, but further studies are needed.

Transcriptomic analysis of immune cells in a multi-ethnic cohort of systemic lupus erythematosus patients identifies ethnicity- and disease-specific expression signatures

Systemic lupus erythematosus (SLE) is an autoimmune disease in which outcomes vary among different racial groups. We leverage cell-sorted RNA-seq data (CD14+ monocytes, B cells, CD4+ T cells, and NK cells) from 120 SLE patients (63 Asian and 57 White individuals) and apply a four-tier approach including unsupervised clustering, differential expression analyses, gene co-expression analyses, and machine learning to identify SLE subgroups within this multiethnic cohort. K-means clustering on each cell-type resulted in three clusters for CD4 and CD14, and two for B and NK cells. To understand the identified clusters, correlation analysis revealed significant positive associations between the clusters and clinical parameters including disease activity as well as ethnicity. We then explored differentially expressed genes between Asian and White groups for each cell-type. The shared differentially expressed genes across cells were involved in SLE or other autoimmune-related pathways. Co-expression analysis identified similarly regulated genes across samples and grouped these genes into modules. Finally, random forest classification of disease activity in the White and Asian cohorts showed the best classification in CD4+ T cells in White individuals. The results from these analyses will help stratify patients based on their gene expression signatures to enable SLE precision medicine.

Quantitative susceptibility mapping in the thalamus and basal ganglia of systemic lupus erythematosus patients with neuropsychiatric complaints

Systemic lupus erythematosus (SLE) is an auto-immune disease characterized by multi-organ involvement. Although uncommon, central nervous system involvement in SLE, termed neuropsychiatric SLE (NPSLE), is not an exception. Current knowledge on underlying pathogenic mechanisms is incomplete, however, neuroinflammation is thought to play a critical role. Evidence from neurodegenerative diseases and multiple sclerosis suggests that neuroinflammation is correlated with brain iron accumulation, making quantitative susceptibility mapping (QSM) a potential hallmark for neuroinflammation in vivo. This study assessed susceptibility values of the thalamus and basal ganglia in (NP)SLE patients and further investigated the in vivo findings with histological analyses of postmortem brain tissue derived from SLE patients. We used a 3T MRI scanner to acquire single-echo T2*-weighted images of 44 SLE patients and 20 age-matched healthy controls. Of the 44 patients with SLE, all had neuropsychiatric complaints, of which 29 were classified as non-NPSLE and 15 as NPSLE (seven as inflammatory NPSLE and eight as ischemic NPSLE). Mean susceptibility values of the thalamus, caudate nucleus, putamen, and globus pallidus were calculated. Formalin-fixed paraffin-embedded post-mortem brain tissue including the putamen and globus pallidus of three additional SLE patients was obtained and stained for iron, microglia and astrocytes. Susceptibility values of SLE patients and age-matched controls showed that iron levels in the thalamus and basal ganglia were not changed due to the disease. No subgroup of SLE showed higher susceptibility values. No correlation was found with disease activity or damage due to SLE. Histological examination of the post-mortem brain showed no increased iron accumulation. Our results suggest that neuroinflammation in NPSLE does not necessarily go hand in hand with iron accumulation, and that the inflammatory pathomechanism in SLE may differ from the one observed in neurodegenerative diseases and in multiple sclerosis.

Dysregulation of cell-free long non-coding RNAs (NEAT2, CTC-471J1.2 and lnc-DC) in Egyptian systemic lupus and lupus nephritis patients

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder; lupus nephritis (LN) is the main cause of disability and death in SLE patients. Although long noncoding RNAs (lncRNAs) lack a protein-coding ability, they have a significant role in the regulation of gene expression. We aimed to evaluate cell-free lncRNAs (NEAT2, CTC-471 J1.2 and lnc-DC) as biomarkers for SLE and LN. Quantification of the expression level of cell-free lncRNAs (NEAT2, CTC-471J1.2 and lnc-DC) was performed by real-time PCR in 90 controls and 139 patients with SLE, who were further subdivided into 70 patients with LN and 69 patients without LN. The expression levels of the NEAT2 and lnc-DC genes were significantly up-regulated and that of the CTC-471J1.2 gene was down-regulated in patients with SLE versus controls. Additionally, NEAT2 showed the best performance to differentiate SLE patients from controls, with a sensitivity of 92% and a specificity of 89%. To predict the future development of LN, CTC-471J1.2 showed the highest sensitivity (87%) and specificity (90%). A significantly positive correlation was found between lnc-DC expression and the activity of SLE (as assessed by the SLEDAI score) in LN patients, and a negative correlation was found between CTC471J1.1 expression and the SLEDAI score in both SLE subgroups. We concluded that cell-free NEAT2 is the most sensitive biomarker for SLE diagnosis and that circulating CTC-471J1.2 is the most specific and sensitive diagnostic biomarker for LN. Both lnc-DC and CTC-471J1.2 could be considered predictive biomarkers for SLE activity and LN development.

Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann–Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (padjusted = 3 × 10−9, 3 × 10−6, and 5 × 10−6 respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sj\xf6gren\u2019s syndrome differ in molecular signatures and treatment perspectives

BackgroundPrevious studies and own clinical observations of patients with systemic lupus erythematosus (SLE) suggest that SLE harbors distinct immunophenotypes. This heterogeneity might result in differences in response to treatment in different subgroups and obstruct clinical trials. Our aim was to understand how SLE subgroups may differ regarding underlying pathophysiology and characteristic biomarkers.MethodsIn a cross-sectional study, including 378 well-characterized SLE patients and 316 individually matched population controls, we defined subgroups based on the patients’ autoantibody profile at inclusion. We selected a core of an antiphospholipid syndrome-like SLE (aPL+ group; positive in the lupus anticoagulant (LA) test and negative for all three of SSA (Ro52 and Ro60) and SSB antibodies) and a Sjögren’s syndrome-like SLE (SSA/SSB+ group; positive for all three of SSA (Ro52 and Ro60) and SSB antibodies but negative in the LA test). We applied affinity-based proteomics, targeting 281 proteins, together with well-established clinical biomarkers and complementary immunoassays to explore the difference between the two predefined SLE subgroups.ResultsThe aPL+ group comprised 66 and the SSA/SSB+ group 63 patients. The protein with the highest prediction power (receiver operating characteristic (ROC) area under the curve = 0.89) for separating the aPL+ and SSA/SSB+ SLE subgroups was integrin beta-1 (ITGB1), with higher levels present in the SSA/SSB+ subgroup. Proteins with the lowest p values comparing the two SLE subgroups were ITGB1, SLC13A3, and CERS5. These three proteins, rheumatoid factor, and immunoglobulin G (IgG) were all increased in the SSA/SSB+ subgroup. This subgroup was also characterized by a possible activation of the interferon system as measured by high KRT7, TYK2, and ETV7 in plasma. In the aPL+ subgroup, complement activation was more pronounced together with several biomarkers associated with systemic inflammation (fibrinogen, α-1 antitrypsin, neutrophils, and triglycerides).ConclusionsOur observations indicate underlying pathogenic differences between the SSA/SSB+ and the aPL+ SLE subgroups, suggesting that the SSA/SSB+ subgroup may benefit from IFN-blocking therapies while the aPL+ subgroup is more likely to have an effect from drugs targeting the complement system. Stratifying SLE patients based on an autoantibody profile could be a way forward to understand underlying pathophysiology and to improve selection of patients for clinical trials of targeted treatments.

White matter lesions and brain atrophy in systemic lupus erythematosus patients: correlation to cognitive dysfunction in a cohort of systemic lupus erythematosus patients using different definition models for neuropsychiatric systemic lupus erythematosus.

Aim The aim of this study was to evaluate the extent of white matter lesions, atrophy of the hippocampus and corpus callosum, and their correlation with cognitive dysfunction (CD), in patients diagnosed with systemic lupus erythematosus (SLE). Methods Seventy SLE patients and 25 healthy individuals (HIs) were included in the study. To evaluate the different SLE and neuropsychiatric SLE (NPSLE) definition schemes, patients were grouped both according to the American College of Rheumatology (ACR) definition, as well as the more stringent ACR-Systemic Lupus International Collaborating Clinics definition. Patients and HIs underwent a 3 Tesla brain MRI and a standardized neuropsychological test. MRI data were evaluated for number and volume of white matter lesions and atrophy of the hippocampus and corpus callosum. Differences between groups and subgroups were evaluated for significance. Number and volume of white matter lesions and atrophy of the hippocampus and corpus callosum were correlated to cognitive dysfunction. Results The total volume of white matter lesions was significantly larger in SLE patients compared to HIs ( p = 0.004). However, no significant differences were seen between the different SLE subgroups. Atrophy of the bilateral hippocampus was significantly more pronounced in patients with NPSLE compared to those with non-NPSLE (right: p = 0.010; left p = 0.023). Significant negative correlations between cognitive test scores on verbal memory and number and volume of white matter lesions were present. Conclusion SLE patients have a significantly larger volume of white matter lesions on MRI compared to HIs and the degree of white matter lesion volume correlates to cognitive dysfunction, specifically to verbal memory. No significant differences in the number or volume of white matter lesions were identified between subgroups of SLE patients regardless of the definition model used.

Elevated uric acid levels in premenopausal female systemic lupus erythematosus patients: Association with potential or existing renal damage

Do premenopausal female systemic lupus erythematosus (SLE) patients have a low incidence of hyperuricaemia (HU) as healthy premenopausal females? As of yet, there have been few studies. This study aims to investigate the serum uric acid (UA) levels of premenopausal female SLE patients and the associated clinical risk factors. 107 premenopausal female SLE patients were divided into two groups: the high UA SLE group (n = 45) and the normal UA SLE group (n = 62). In total, 50 age-matched healthy premenopausal females served as the control group. Serum UA concentration, kidney damage index, lupus index, disease activity score of lupus and serum lipid index were collected and compared between the SLE subgroups. Binary logistic regression and multiple linear regression analyses were used to analyse the association of high UA levels with clinical features. The mean UA level of the SLE group was significantly higher than that of the control group (509.73 ± 150.28 μmol/L vs 296.78 ± 69.87 μmol/L, P &lt; 0.001), as was the incidence of HU (42.06% vs 14.00%, P = 0.01). The UA levels of the high UA SLE group and the normal UA SLE group were 515.91 ± 120.64 μmol/L and 245.71 ± 63.18 μmol/L, respectively, which was statistically significant ( P &lt; 0.001). None of the patients with HU had current or previous gout attacks. The frequency of patients with renal manifestations in the high UA SLE group was significantly higher than that in the normal UA SLE group (χ2 = 26.278, P &lt; 0.001). In the SLE group, the medications azathioprine and cyclosporine were not associated with HU ( P = 0.689), as analysed by binary linear regression. Using multiple linear regression analysis, it was found that urinary blood ( P = 0.048), creatinine ( P = 0.016), triglycerides ( P = 0.029), peripheral white blood cells ( P = 0.007) and renal manifestation ( P &lt; 0.001) were associated with HU in the SLE group. Our results demonstrate that premenopausal SLE patients had higher levels of UA than healthy premenopausal females, which may be associated with potential or existing renal damage.

Late-Onset Systemic Lupus Erythematosus With Lupus Nephritis in a 74-Year-Old Male: A Brief Case and Review.

Rationale:Late-onset systemic lupus erythematosus (SLE) represents a specific subgroup of SLE, and although there is no strict age cut-off, 50 years is commonly used as the minimum age for disease onset. In this report, we present a case of a 74-year-old male with late-onset SLE and biopsy-proven lupus nephritis (LN).Presenting concerns of the patient:A 74-year-old male was referred to the nephrology clinic with a rapidly rising creatinine from a baseline of 60 µmol/L to 176 µmol/L. His labs showed pancytopenia, a positive antinuclear antibodies (ANA), and hypocomplementemia.Diagnoses:Renal biopsy showed focal proliferative glomerulonephritis that was immune-mediated and immunofluorescence showed C3, IgM, IgA, IgG, lambda, and C1q diffuse mesangial and glomerular basement membrane staining. Together these findings were in keeping with a diagnosis of stage III LN.Interventions:Treatment included hemodialysis and induction with pulse methylprednisone and cyclophosphamide. He was then placed on the Euro-Lupus Protocol.Outcomes:One year after the diagnosis, he was off dialysis, had no signs of fluid retention or uremia, and his creatinine had stabilized at ~ 330 µmol/L.Lessons learned:To the best of our knowledge, this case represents the oldest known biopsy-confirmed case of late-onset SLE and LN. Late-onset SLE is uncommon and often overlooked as classical symptoms such as malar rash or photosensitivity may not be present. The American College of Rheumatology (ACR) guidelines for treatment of LN can be applied to these patients but physicians should be cognizant of the fact that these patients may not tolerate immunosuppressive therapy as well as younger patients.

Depressed serum IgM levels in SLE are restricted to defined subgroups

Natural IgM autoantibodies have been proposed to convey protection from autoimmune pathogenesis. Herein, we investigated the IgM responses in 396 systemic lupus erythematosus (SLE) patients, divided into subgroups based on distinct autoantibody profiles. Depressed IgM levels were more common in SLE than in matched population controls. Strikingly, an autoreactivity profile defined by IgG anti-Ro/La was associated with reduced levels of specific natural IgM targeting phosphorylcholine (PC) antigens and malondialdehyde (MDA) modified-protein, as well as total IgM, while no differences were detected in SLE patients with an autoreactivity profile defined by anti-cardiolipin/β2glycoprotein-I. We also observed an association of reduced IgM levels with the HLA-DRB1*03 allelic variant among SLE patients and controls. Associations of low IgM anti-PC with cardiovascular disease were primarily found in patients without antiphospholipid antibodies. These studies further highlight the clinical relevance of depressed IgM. Our results suggest that low IgM levels in SLE patients reflect immunological and genetic differences between SLE subgroups.

Relationship of miRNA-146a to primary Sjögren's syndrome and to systemic lupus erythematosus: a meta-analysis.

Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE) are common systemic autoimmune diseases, which impact not only patient health but also their quality of life. miRNA-146a is a microRNA that participates in the pathophysiology of SjS and SLE. In this investigation, we conducted a meta-analysis to determine the relationship of miR-146a to primary SjS (PSS) and to SLE. The following databases were interrogated; Pubmed, Cochrane Central Register of Controlled Trials, WANFANG, Chinese National Knowledge Infrastructure, and WEIPU. Standard mean difference with 95% confidence intervals (CI) were used to study the relationship between miRNA-146a expression and thee diseases by random-effects model. A total of six studies, with 158 cases and 124 controls were included for the meta-analysis. The meta-analysis shows that miRNA-146a expression is associated with the risk of PSS (MD=6.32, p=0.005). No relationship between miR-146a expression and SLE was identified (MD=-0.86, p=0.26). SLE subgroup analysis (peripheral blood mononuclear cells and serum) confirmed this result. The risk for PSS is related to miR-146a expression, while miRNA-146a expression is not related to SLE. As such, miRNA-146a may serve as a novel biomarker for the diagnosis of PSS, but not SLE.

RNA-seq Analysis Reveals Unique Transcriptome Signatures in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Specificities.

Systemic lupus erythematosus (SLE) patients exhibit immense heterogeneity which is challenging from the diagnostic perspective. Emerging high throughput sequencing technologies have been proved to be a useful platform to understand the complex and dynamic disease processes. SLE patients categorised based on autoantibody specificities are reported to have differential immuno-regulatory mechanisms. Therefore, we performed RNA-seq analysis to identify transcriptomics of SLE patients with distinguished autoantibody specificities. The SLE patients were segregated into three subsets based on the type of autoantibodies present in their sera (anti-dsDNA+ group with anti-dsDNA autoantibody alone; anti-ENA+ group having autoantibodies against extractable nuclear antigens (ENA) only, and anti-dsDNA+ENA+ group having autoantibodies to both dsDNA and ENA). Global transcriptome profiling for each SLE patients subsets was performed using Illumina® Hiseq-2000 platform. The biological relevance of dysregulated transcripts in each SLE subsets was assessed by ingenuity pathway analysis (IPA) software. We observed that dysregulation in the transcriptome expression pattern was clearly distinct in each SLE patients subsets. IPA analysis of transcripts uniquely expressed in different SLE groups revealed specific biological pathways to be affected in each SLE subsets. Multiple cytokine signaling pathways were specifically dysregulated in anti-dsDNA+ patients whereas Interferon signaling was predominantly dysregulated in anti-ENA+ patients. In anti-dsDNA+ENA+ patients regulation of actin based motility by Rho pathway was significantly affected. The granulocyte gene signature was a common feature to all SLE subsets; however, anti-dsDNA+ group showed relatively predominant expression of these genes. Dysregulation of Plasma cell related transcripts were higher in anti-dsDNA+ and anti-ENA+ patients as compared to anti-dsDNA+ ENA+. Association of specific canonical pathways with the uniquely expressed transcripts in each SLE subgroup indicates that specific immunological disease mechanisms are operative in distinct SLE patients’ subsets. This ‘sub-grouping’ approach could further be useful for clinical evaluation of SLE patients and devising targeted therapeutics.