Systemic Lupus Erythematosus Disease Severity Research Articles

Clinical algorithm model based on cfDNA to predict SLE disease activity.

Circulating cell-free DNA (cfDNA) has been widely used as a new liquid-biopsy marker. Dysregulation of cfDNA has been found in patients with systemic lupus erythematosus (SLE). However, the detailed association between cfDNA and SLE has not been thoroughly studied. Plasma samples were collected from 88 patients with active SLE and 39 patients with inactive SLE. The cfDNA concentration was determined, and the length and distribution of cfDNA fragments were verified. cfDNA concentrations were significantly higher in patients with active SLE than in patients with inactive SLE (0.4 [0.18-0.897] ng/µL vs 0.249 [0.144-0.431] ng/µL; p = .043). cfDNA fragments were enriched in the ranges of 153-198 bp and 300-599 bp. cfDNA concentrations were associated with the reduction of the anti-double-stranded DNA (dsDNA) antibodies titer (r = -0.301, p = .034). The presence of anti-U1 ribonucleoprotein (p = .012), anti-Sjogren syndrome A (p = .024), anti-dsDNA (p = .0208), and anti-nucleosome antibodies (p = .0382) might associate to the variation of cfDNA concentration. Reduced cfDNA concentration was associated with renal damage in active SLE patients (0.31 [0.11-0.73] ng/µL vs 0.65 [0.27-1.53] ng/µL; p = .009). The Active index, a combination model including cfDNA concentration and other clinical indices, had an area of 0.886 under the receiver operating characteristics curve for distinguishing active SLE. The Active index was positively correlated with the SLE disease activity index score (r = 0.6724, p < .0001). Through systematic stratified analysis and clinical algorithm model, this study found that plasma cfDNA concentration is closely related to SLE disease severity, which has guiding significance for the future clinical application of cfDNA in SLE.

Cost-of-illness changes before and after the diagnosis of systemic lupus erythematosus: a nationwide, population-based observational study in Korea

Abstract Objectives To estimate the direct healthcare cost progression from before to after systemic lupus erythematosus (SLE) diagnosis and to compare healthcare costs by disease severity. Methods Patients with incident SLE diagnosed between 2008 and 2018 were identified from the Korean National Health Insurance database. Annual direct healthcare costs for 5 years before and after SLE were estimated and compared with those of age-, sex- and calendar month-matched (1:4) controls, without SLE. Direct healthcare costs were compared by disease severity of SLE using regression analysis. Results Among 11 173 patients with SLE and 45 500 subjects without SLE, annual direct healthcare costs per person increased in the year before SLE diagnosis and peaked in the first year after diagnosis. They were 7.7-fold greater in the SLE patients than in the subjects without SLE ($5871 vs $759). Severe SLE was associated with 3.284-fold (95% CI: 3.075, 3.507) higher annual costs than mild SLE during the year after diagnosis. Older age (age 60–79 years), lupus nephritis, interstitial lung diseases, and comorbidities such as avascular necrosis and chronic kidney disease were associated with higher annual direct healthcare costs (times [95% CI]) in the first year after diagnosis: age 60–69: 1.119 (1.034, 1.211); age 70–79: 1.470 (1.342, 1.611); lupus nephritis: 1.794 (1.711, 1.881); interstitial lung diseases: 1.435 (1.258, 1.638); avascular necrosis: 6.208 (4.541, 8.487); and chronic kidney disease: 1.858 (1.673, 2.064). Conclusion Patients with SLE incurred significantly higher direct healthcare costs than subjects without SLE during the first year after diagnosis. Disease severity, older age, major organ involvements and comorbidities were associated with increased healthcare costs.

Higher CD4+CD40+ T cells (Th40 cells) associate with systemic lupus erythematosus activity

The aim of this study was to investigate the characteristics of CD4+CD40+ T cells (Th40 cells) in Chinese systemic lupus erythematosus (SLE) patients. Flow cytometry was used to identify the percentage of Th40 cells in peripheral blood from 24 SLE patients and 24 healthy individuals and the level of IL-2, IL-4, IL-6, IL-10, IFN-r, and TNF-α in serum (22 cases) from the SLE patients. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2000) was used to assess the SLE disease active state. The percentage of Th40 cells in T cells from SLE patients (19.37 ± 17.43) (%) was significantly higher than that from healthy individuals (4.52 ± 3.16) (%) (P < 0.001). The percentage of Th40 cells was also positively associated with SLEDAI-2000 (P = 0.001) and negatively associated with complement C3 (P = 0.007). The Th40 cell percentage was different in SLE patients with different organs involved. The Th40 cell percentage in SLE patients with lupus serositis (29.29 ± 22.19) was significantly higher than that in patients without serositis (13.41 ± 10.79; P = 0.040), and the percentage in SLE patients with lupus pneumonia involvement (29.11 ± 11.88) was significantly higher than that in patients without lupus pneumonia (16.80 ± 17.99; P = 0.043). After 4 weeks treatment, the Th40 cell percentage decreased significantly (P = 0.005). However, Th40 cell expression was not related to cytokines (IL-2, IL-4, IL-6, IL-10, IFN-r, and TNF-α; P > 0.05). A significantly higher percentage of Th40 cells was found in SLE patients, and the Th40 cell percentage was associated with SLE activity. Thus, Th40 cells may be used as a predictor for SLE disease activity and severity and therapeutic efficacy.

Platelet LGALS3BP as a Mediator of Myeloid Inflammation in Systemic Lupus Erythematosus.

Platelets are mediators of inflammation with immune effector cell properties and have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study investigated the role of platelet-associated lectin, galactoside-binding, soluble 3 binding protein (LGALS3BP) as a mediator of inflammation in SLE and as a potential biomarker associated with clinical phenotypes. We performed RNA sequencing on platelets from patients with SLE (n=54) and on platelets from age-, sex-, and race/ethnicity-matched healthy controls (n=18) and measured LGALS3BP levels in platelet releasate and in circulating serum. We investigated the association between LGALS3BP levels and the prevalence, disease severity, and clinical phenotypes of SLE and studied platelet-mediated effects on myeloid inflammation. Platelets from patients with SLE exhibited increased expression of LGALS3BP (fold change 4.0, adjusted P=6.02 × 10-11 ). Platelet-released LGALS3BP levels were highly correlated with circulating LGALS3BP (R=0.69, P < 0.0001), and circulating LGALS3BP levels were correlated with the severity of disease according to the SLE Disease Activity Index (r=0.32, P=0.0006). Specifically, circulating LGALS3BP levels were higher in SLE patients with lupus nephritis than in patients with inactive disease (4.0 μg/ml versus 2.3 μg/ml; P < 0.001). Interferon-α induced LGALS3BP transcription and translation in a megakaryoblastic cell line (MEG-01) in a dose-dependent manner. Recombinant LGALS3BP and platelet releasates from SLE patients enhanced proinflammatory cytokine production by macrophages. Our results support that platelets act as potent effector cells that contribute to the pathogenesis of SLE by secreting proinflammatory LGALS3BP, which also represents a novel biomarker of SLE clinical activity.

Dyslipidemia is associated with inflammation and organ involvement in systemic lupus erythematosus

IntroductionDisturbed lipid metabolism was observed in systemic lupus erythematosus (SLE) patients. This study aimed to evaluate the relationships between dyslipidemia and visceral organ involvement, disease severity, inflammatory factors, and drug intake in SLE patients.MethodInpatients with SLE (n = 105) and healthy controls (HC) (n = 75) were recruited in this study. Clinical and laboratory data were collected from patient records. The concentrations of tumor necrosis factor receptors superfamily member1A (TNFRSF1A), member1B (TNFRSF1B) and adipokine angiopoietin-like 4 (ANGPTL4) in plasma were measured by ELISA.ResultCompared to HC, serum levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and apolipoprotein B (ApoB) were significantly increased, while high-density lipoprotein (HDL) and apolipoprotein A1 (ApoA1) were decreased in SLE patients. Patients with higher disease activity and renal damage suffered from more severe dyslipidemia. Renal functional parameters were closely correlated with serum lipid levels. Inflammatory factors were associated with dyslipidemia. The levels of TNFRSF1A and TNFRSF1B were obviously increased and associated with kidney involvement in SLE patients. Patients with high-dose glucocorticoid intake showed more severe dyslipidemia.ConclusionsAttention should be paid to the dyslipidemia of SLE. Dyslipidemia is associated with inflammation and organ involvement in SLE. These findings might provide a new strategy for the treatment of SLE.Key Points• Serum levels of TG, TC, LDL, and ApoB were significantly increased, while HDL and ApoA1 were decreased in SLE patients.• Patients with higher disease activity and renal damage suffered from more severe dyslipidemia. Renal functional parameters and inflammatory factors were closely correlated with serum lipid levels.• Patients with high-dose glucocorticoid intake showed more severe dyslipidemia.• These findings might provide a new strategy for the treatment of SLE.

Intraindividual Change in Cognitive Function Among Adults With Systemic Lupus Erythematosus: A Markov Analysis Over 7 Years.

Cognitive impairment is prevalent in systemic lupus erythematosus (SLE). There remain gaps in understanding cognition and SLE longitudinally. We studied intraindividual change in cognition in SLE over time. Data were from the University of California, San Francisco Lupus Outcome Study, which included 1281 adults with SLE. The Hopkins Verbal Learning Test-Revised (HVLT-R) and the Controlled Oral Word Association Test (COWAT) were administered annually over 7 years. A two-state Markov analysis was used to model transition intensities for probabilities of change in cognition. Logistic regression examined the association between clinical variables and cognitive change. Minimal transition between cognitive states was observed in the Markov analysis. Using the COWAT, higher levels of self-reported depression were associated with decreased likelihood of cognitive improvement (Relative Risk [RR]: 0.98; 95% confidence interval [CI]: 0.96-0.99), and higher self-reported disease severity was associated with cognitive decline (RR: 1.05; 95% CI: 1.02-1.09). Using the HVLT-R, increasing age (RR: 1.02; 95% CI: 1.01-1.03) and higher education level (RR: 1.82; 95% CI: 1.28-2.58) were associated with cognitive improvement, and higher self-reported disease severity (RR: 1.02; 95% CI: 1.01-1.03) and depression (RR: 1.05; 95% CI: 1.03-1.07) were associated with cognitive decline. Most individuals with SLE did not transition between states of high (Z score ≥ -1.5) or low (Z score < -1.5) cognition in a Markov analysis over a 7-year assessment period, highlighting a degree of relative stability in cognition over time. Increasing age and higher education levels were associated with greater likelihood of cognitive improvement. Greater self-reported SLE disease severity and depression were associated with cognitive decline.

Association of - 717 A > G (rs2794521) CRP polymorphism with high cardiovascular risk by C-reactive protein in systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is an autoimmune disease where genetic factors have been related to SLE susceptibility and disease severity. CRP polymorphisms have been associated with high C-reactive protein (CRP) serum levels, cardiovascular disease (CVD), and high clinical disease activity in SLE patients; however, the evidence is still inconclusive. This study was aimed to assess the association of the - 717 A > G, - 409 G > A, + 1444 C > T, and + 1846 C > T CRP polymorphisms with genetic susceptibility, clinical disease activity, and CVD risk in Mexican-mestizo SLE patients. A comparative cross-sectional study was conducted on 369 unrelated women: 183 with SLE according to the 1997 SLE-ACR criteria and 186 healthy subjects (HS). The clinical disease activity was assessed by the Mex-SLEDAI score; CRP and lipid profile were quantified by turbidimetry and colorimetric-enzymatic assays, respectively. The CRP polymorphisms genotyping was carried out by allelic discrimination. SLE patients with - 717 AA genotype had higher CRP serum levels than SLE carriers of AG and GG genotypes (AA = 5mg/L vs. AG = 3.2mg/L vs. GG = 2.4mg/L; p = 0.01), and the AA genotype was associated with high CVD risk by CRP in SLE patients (OR = 3; CI: 1.2-7.6; p < 0.01). The - 717 A > G CRP polymorphism is a risk factor for high CRP levels and high CVD risk in Mexican-mestizo SLE patients. Key Points • Cardiovascular disease is one of the major causes of death in SLE patients due to the higher prevalence of traditional and non-traditional cardiovascular risk factors. • C-reactive protein is a liver-derived acute-phase protein suggested as one powerful independent risk predictor factor for cardiovascular disease. • Single nucleotide polymorphisms in CRP have been suggested as genetic susceptibility factors that could modify the SLE pathophysiology outcomes. • Mexican-mestizo SLE patients carrying the -717 A>G CRP AA genotype had 3-fold high cardiovascular disease risk than SLE patients with AG or GG genotypes.

Sex-based comparison of CD4+ T cell DNA methylation in lupus reveals proinflammatory epigenetic changes in men

Systemic lupus erythematosus (SLE) is more common in women than men, but the disease is more severe when it affects men. Lupus CD4+ T cells demonstrate dysregulated DNA methylation patterns. The purpose of this study was to investigate genome-wide CD4+ T cell differential DNA methylation between men (n = 12) and women (n = 10) with SLE. DNA methylation was evaluated using the Infinium MethylationEPIC array, and differences between male versus female SLE patients were calculated with probe-wise linear regressions with adjustment for age and disease activity. We identified 198 hypomethylated and 108 hypermethylated CpG sites in CD4+ T cells isolated from male compared to female SLE patients, annotated to 201 and 102 genes, respectively. A great proportion of these genes were related to apoptosis and immune functions. Among differentially methylated genes, CASP10, which is involved in the extrinsic apoptotic pathway, and multiple genes involved in T cell function and differentiation such as ELAVL1, UHRF1, and SMAD2, were hypomethylated in men compared to women with SLE. Importantly, network analysis of differentially methylated genes revealed a pattern consistent with increased activation of ROCK, PP2A, PI3K, and ERK1/ERK2 in men compared to women with SLE. These data provide epigenetic evidence suggesting activation of key T cell pathways in men compared to women with SLE and shed new light into possible mechanisms underlying increased SLE disease severity in men.

High Disease Severity Among Asian Patients in a US Multiethnic Cohort of Individuals With Systemic Lupus Erythematosus.

Knowledge about systemic lupus erythematosus (SLE) outcomes among US Asian patients is lacking. The present study was undertaken to examine SLE disease activity, severity, and damage among Asian patients of primarily Chinese and Filipino descent in a multiethnic cohort. California Lupus Epidemiology Study (n = 328) data were analyzed. Data were collected in English, Cantonese, Mandarin, or Spanish using validated instruments for disease activity (Systemic Lupus Erythematosus Disease Activity Index), disease severity (Lupus Severity Index [LSI]), and disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We assessed differences in SLE outcomes among racial/ethnic groups using multivariable linear regression including interaction terms for age at diagnosis and race/ethnicity. Asian was the largest racial/ethnic group (38% [Chinese = 22%; Filipino = 9%; Other = 7%]). Average age at diagnosis was younger among Asian patients (27.9 years), particularly Filipino patients (22.2 years), compared with White (29.4 years) and Black patients (34.0 years). After adjustment, disease activity and damage were not significantly different across groups. Disease severity among Asian patients was significantly higher than among White patients (LSI score 7.1 versus 6.5; P < 0.05) but similar among Black and Hispanic patients. Early age at diagnosis was associated with greater organ damage among Asian, Black, and Hispanic patients, but not White patients. SLE was more severe among US Asian patients compared to White patients. Filipinos were affected at strikingly young ages. Asian patients and non-White groups with younger age at diagnosis had greater organ damage than White patients. Such racial/ethnic distinctions suggest the need for heightened clinical awareness to improve health outcomes among Asian patients with SLE. Further study of SLE outcomes across a range of US Asian subgroups is important.

Serum Renalase Level as A Marker of Activity and Severity in Lupus Nephritis Cases

- Introduction: &nbsp;&nbsp;Lupus nephritis (LN) is a substantial risk factor for death and morbidity in patients with Systemic Lupus Erythematosus (SLE) (SLE). Despite excellent immunosuppressive therapy, it nevertheless leads to a disproportionate percentage of persons developing chronic kidney disease (CKD) or end-stage renal disease (ESRD). Renalase is a distinctive cytokine-like protein generated by the kidneys that promote cell survival. It has been recently linked to the etiology of LN and may be an ideal candidate as a sensitive biomarker&nbsp;for flare-ups and LN remission. -Aim of the work: &nbsp;The purpose of this study was to evaluate the utility of human serum renalase as a biomarker for assessing disease activity and severity in SLE, as well as to evaluate if it can be used as a sensitive biomarker in this capacity. -Methods: &nbsp;This study consists of around 23 healthy controls and 46 individuals with LN. These participants were separated into two equal groups according to disease activity as determined by the SLEDAI (SLE Disease Activity Index): 23 cases with LN who had disease activity and 23 cases who did not. The concentration of human serum Renalase (RNLS) was evaluated using a very sensitive commercial enzyme immunoassay that captures renalase from serum using (RNLS) antibody. - Results: Renalase concentrations were significantly greater in LN cases than in healthy controls (P-value &lt;0.001). Additionally, cases with active LN exhibited significantly greater serum renalase concentrations than those with inactive LN (P-value &lt;0.005). Serum renalase concentrations were positively connected with 24-h urine protein excretion,&nbsp;SLEDAI,&nbsp;ESR, CRP, and ds-DNA but were negatively related to serum C3 and the class (particularly in the proliferative type) (Class III, IV, more than class V). -Conclusion: &nbsp;Serum renalase levels were associated with disease symptoms&nbsp;in LN and may serve as a biomarker for disease activity in LN.

Retrospective Analysis of Disease Severity, Health Care Resource Utilization, and Costs Among Patients Initiating Belimumab for the Treatment of Systemic Lupus Erythematosus

The goal of this study was to evaluate clinical and economic outcomes associated with the initiation of intravenous (IV) belimumab for the treatment of systemic lupus erythematosus (SLE) in clinical practice in the United States. This retrospective study used administrative claims data from the IBM MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental and Coordination of Benefits Database. Data for patients with SLE who initiated (index) IV belimumab were collected for the 12 months before (pre-index) and the 12 months after (post-index) belimumab initiation. Outcomes included SLE disease severity and flares, all-cause health care resource utilization (HCRU) and health care costs, and hospital-based costs and service visits. Post hoc analyses of total hospital-based costs were conducted to further explore drivers of mean post-index costs. Baseline characteristics (N=908) are as follows: female, 93.4%; mean (SD) age, 45.6 (11.9) years; mean Charlson Comorbidity Index score, 0.9 (2.0); and moderate or severe disease, 94.9%. Disease activity (SLE flare episodes) was significantly reduced between the pre-index and post-index periods (severe flares, 16.4% vs 10.1% [P < 0.0001]; moderate flares, 92.1% vs 85.6% [P < 0.0001]; and mild flares, 77.4% vs 71.1%; [P=0.0003]). The proportion of patients receiving oral corticosteroids (OCS) was reduced between the pre-index and post-index periods, especially among patients at higher OCS thresholds (prednisone-equivalent dose: ≥60 mg/d, 7.3% vs 4.2%; >40 mg/d, 14.1% vs 7.9%). From the pre-index to the post-index period, few differences in HCRU were observed, although all-cause physician office visits, outpatient visits, and unique prescriptions filled increased significantly. In the 12-month post-index period, patients had a mean of 12.2 (9.0) encounters (eg, outpatient visit or prescription) associated with IV belimumab. All-cause total, medical, and pharmacy costs increased from the pre-index to the post-index period. Mean all-cause hospital-based costs increased from the pre-index to the post-index period ($7735 [26,603] vs $11,030 [88,086]; P=0.396). However, the 75th, 90th, and 95th percentile costs decreased from the pre-index to the post-index period ($305, $2107, and $3861, respectively). After initiation of IV belimumab, disease activity (number of moderate and severe SLE flares) and use of OCS were significantly reduced. However, HCRU and costs, including hospital-based costs, were generally greater in the post-index period. Further studies will increase understanding of SLE, with the specific goals of incorporating disease activity measures and long-term outcomes in studies of HCRU, costs, and patient outcomes.

Increased TIM-3+PD-1+ NK cells are associated with the disease activity and severity of systemic lupus erythematosus

It is well established that natural killer (NK) cells are dysregulated in systemic lupus erythematosus (SLE) patients. However, the functions of NK cells and the mechanisms regulated by them in SLE remain incompletely understood. Patients with SLE were recruited from The First Affiliated Hospital of Nanchang University, and their clinical characteristics and treatments were recorded. The expression levels of T cell immunoglobulin mucin-3 (TIM-3) and programmed cell death protein 1 (PD-1) on NK cells were examined using flow cytometry. The correlations between the increase in TIM-3+PD-1+ NK cells in the SLE patients and clinical traits, including inflammatory markers, auto-antibodies, disease activity and severity of SLE, were examined. The TIM-3+NK cells, PD-1+NK cells and TIM-3+PD-1+ NK cells were significantly increased in the SLE patients. The increase in TIM-3+PD-1+ NK cells in the patients with SLE was associated with erythrocyte sedimentation rate, C-reactive protein, anti-double stranded DNA, anti-ribosomal P, SLE disease activity index and clinical features. The frequency of TIM-3+PD-1+NK cells in SLE patients with a cardiovascular disease (CVD) was significantly lower than that in SLE patients without a CVD. Moreover, the increased TIM-3+PD-1+ NK cells were significantly decreased in SLE patients following treatment. The present study suggested that the increased TIM-3+PD-1+ NK cells were associated with the disease activity and severity of SLE and may play a role in SLE pathogenesis.

HLA-DRB1*04 as a Risk Allele to Systemic Lupus Erythematosus and Lupus Nephritis in the Malay Population of Malaysia.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease afflicting multiple organs. Lupus nephritis (LN) is a serious complication of SLE and remains a major cause of mortality and morbidity. Curative therapy remains unavailable as etiology from genetic and environmental factors is still unclear. The present study was conducted to elucidate the link between HLA-DRB1 gene polymorphisms with SLE and LN through clinical and laboratory/biological presentations in a population of Malaysian Malay females with SLE. A total of 100 Malay female SLE patients inclusive of 70 SLE patients without LN and 30 patients with LN were included in this study. HLA-DRB1 allele examination in SLE patients was performed using PCR-SSO, and the alleles' frequencies were compared with 951 publicly available datasets representing Malay healthy controls in Malaysia. Cytokines and free radical levels were detected by ELISA and bead-based multiplexed Luminex assays. The association between HLA-DRB1 alleles with clinical and serological manifestations and immune mediators was analyzed using different statistical approaches whenever applicable. Our study showed that HLA-DRB1*0405, HLA-DRB1*1502, and HLA-DRB1*1602 were associated with the increased risk of SLE while HLA-DRB1*1201 and HLADRB1*1202 alleles were associated with a lower risk of SLE development. Furthermore, HLA-DRB1*04 showed significant association to LN and arthritis while HLA-DRB1*15 was significantly associated with oral ulcer in Malay SLE patients. Association analysis of HLA-DRB1*04 with clinical and biological factors revealed that HLA-DRB1*04 was significantly associated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, anti-nuclear antibody (ANA), C-reactive protein (CRP) in the blood, and total protein in the urine. SLE carriers with the HLA-DRB1*04 allele were significantly correlated to the increased levels of cytokines (IFN-y, GM-CSF, IL-17F, IL-18, IL-21, and VEGF) and were significantly showing negative correlation to IL-5 and free radicals (LPO and catalase enzyme) levels compared to SLE carriers without HLA-DRB1*04 allele. The results suggested that disease severity in SLE may be determined by HLA-DRB1 alleles. The risk of HLA-DRB1*04 allele with LN was supported by the demonstration of an intense inflammatory response in Malay SLE patients in Malaysia. More studies inclusive of a larger and multiple SLE cohorts in the future are warranted to validate these findings.

Systemic lupus erythematosus in the intensive care unit: a systematic review.

Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous pathophysiologic mechanisms and diverse clinical manifestations. SLE is a frequent cause of intensive care unit (ICU) admissions. Multiple studies with controversial findings on the causes, evolution and outcomes of ICU-admitted patients with SLE have been published. The aim of this paper is to review the literature reporting the clinical characteristics and outcomes, such as mortality and associated factors, in such patients. Among the main causes of ICU admissions are SLE disease activity, respiratory failure, multi-organ failure and infections. The main factors associated with mortality are a high Acute Physiology and Chronic Health Evaluation (APACHE) score, the need for mechanical ventilation, and vasoactive and inotropic agent use. Reported mortality rates are 18.4%-78.5%. Therefore, it is important to evaluate SLE disease severity for optimizing clinical management and patient outcomes.

The Value of Screening for Celiac Disease in Systemic Lupus Erythematosus: A Single Experience of a Tertiary Medical Center.

IntroductionSystemic lupus erythematosus (SLE) is a multi-organ inflammatory disease associated with autoimmune diseases. The aim of the study is to assessed the frequency of celiac disease (CD) in adults and children with SLE (aSLE and cSLE, respectively) and compare them with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) patients; the study also explored the clinical impact of CD serologic markers on SLE disease activity and severity.MethodsThis was a cross-sectional study. Patients with SLE who had regular follow-up in rheumatology clinics were evaluated for laboratory and clinical variables using serology and the SLE Disease Activity Index (SLEDAI). To assess the occurrence of CD serology in cSLE and aSLE and the clinical impact of CD serologic markers on SLE, patients were tested for antigliadin (AGA), anti-endomysium (EmA) and anti-tissue transglutaminase (tTG) antibodies. RA and JIA patients were included for comparison. Duodenal biopsy was conducted in patients who exhibited CD markers.ResultsThe CD marker was found in 29 (11.6%) of the 250 patients. AGA was present in seven aSLE patients and tTG in two (11.1%). Among cSLE patients, the autoantibody was present in 17.6% (AGA in four, tTG in two, and EmA in three). For RA patients, five had AGA and tTG and one had EmA, with an overall positivity of 9.7%. Five JIA patients had AGA (four with EmA and five with tTG) with overall positivity of 10.9%; the serum IgA level was normal in all patients except one. Duodenal endoscopic biopsy was performed in patients with positive CD markers (two declined). Histologic confirmation of CD was reported in one RA and one JIA patient but in none of the SLE patients. There was no correlation between the presence of CD markers and autoantibodies in SLE.ConclusionCD antibodies did not influence SLE activity. Thus, SLE patients may not need to be screened for CD antibodies.

Correlation of the levels of DNA-binding inhibitor Id3 and regulatory T cells with SLE disease severity

E proteins, a subset of basic helix-loop-helix (bHLH) proteins, are transcription activators and their functions are inhibited by DNA-binding inhibitor (Id) 1–4. Studies have shown that Treg levels are decreased in Id3 knockout mice. Mice over-expressing Id1 in CD4 T cells possessed a greater number of regulatory T cells (Treg) and exhibited attenuated experimental autoimmune encephalomyelitis (EAE). The significance of Id proteins in human systemic lupus erythematosus (SLE) remains unclear. In this study, we systematically analyzed Id transcription in naïve, memory CD4 cells and regulatory T cells in peripheral blood mononuclear cells (PBMCs) in patients with active or inactive SLE. In parallel, Treg subsets in PBMCs were analyzed using different strategies. Id expression levels were correlated with Treg numbers as well as clinical indicators. We found that Id genes expressed in human peripheral CD4 cells were mainly Id2 and Id3. Id3 levels were significantly elevated in CD4+CD25hi T cells of patients with active SLE. Likewise, Id3 levels were positively correlated with increased CD4+FoxP3+ and CD4+Helios+FoxP3+ Treg cells in these patients. Id3 levels were found to be positively correlated with erythrocyte sedimentation rate (ESR), lupus anticoagulant (LAC), ribosomal antibody and SLE Disease Activity Index (SLEDAI) in patients with active SLE. Mice overexpressing Id1 in CD4+ T cells possessed significantly higher Treg levels in spleen and lower autoantibody concentrations in serum. Our results suggest that during the pathogenesis of SLE, up-regulation of Id3 can promote Treg differentiation to play an inhibitory effect on autoimmune responses.

Immune-phenotyping IRF5 genetic risk and in vivo targeting of Irf5 hyper-activation in mouse models of lupus

Abstract Genetic variations within interferon regulatory factor 5 (IRF5) associate with risk of systemic lupus erythematosus (SLE) and mice lacking Irf5 are protected from lupus onset and severity. Exactly how IRF5 functions in the context of SLE disease progression remains unclear. We sought to determine how IRF5 genetic risk contributes to SLE disease onset and severity, and whether targeting IRF5 with select inhibitors would alleviate disease severity and mortality. Studies were performed in blood from genotyped healthy donors, SLE patients and mouse models of murine lupus. In NZB/W F1 lupus mice, we found that Irf5 is already hyper-activated before clinical onset in a cell type-specific manner. In healthy donors carrying IRF5 genetic risk, we detected IRF5 hyper-activation in the myeloid compartment that drives a pre-symptomatic SLE immune-phenotype. In SLE patients, IRF5 hyper-activation correlates with SLEDAI and dsDNA titers. To test whether IRF5 hyper-activation is a targetable function, we developed novel inhibitors that are cell permeable, non-toxic and selectively bind to the inactive IRF5 monomer. Treatment of NZB/W F1 and MRL/lpr mice with inhibitor attenuated lupus pathology by reducing serum ANA and dsDNA titers. In NZB/W F1 mice, we detected significant reductions in the number of circulating plasma cells and age- or autoimmune-associated B cells (ABCs), which alleviated kidney pathology and improved overall survival. In ex vivo human studies, the inhibitor blocked SLE serum-induced IRF5 activation in healthy immune cells and reversed basal IRF5 hyper-activation in SLE immune cells. This study provides the first in vivo pre-clinical support for treating SLE patients with an IRF5 inhibitor.

Exploring the Perceived Impact of the Chronic Disease Self-Management Program on Self-Management Behaviors among African American Women with Lupus: A Qualitative Study.

ObjectiveTo qualitatively explore the processes through which the Chronic Disease Self‐Management Program (CDSMP)—a peer‐led, group‐based educational intervention for people with chronic conditions—affects self‐management behaviors among African American women with systemic lupus erythematosus (SLE).MethodsUsing a longitudinal pre‐ and postintervention design, we conducted two waves of one‐on‐one, semistructured interviews with 24 purposefully sampled participants. Wave 1 interviews explored self‐management behaviors at baseline; wave 2 interviews focused on changes in these behaviors postintervention. Transcripts were analyzed using thematic analysis methods.ResultsStudy participants perceived the CDSMP to be a valuable resource that helped them improve fundamental self‐management behaviors, including exercise, relaxation, diet, and medication adherence. We found, with few exceptions, that in this sample, women's reported changes in self‐management behaviors did not vary by participant age, education, SLE disease severity, or depression status. Our analysis suggests that the CDSMP had the most widespread perceived effects on relaxation and exercise. Strategies that generated improvements in relaxation and exercise included goal setting, action planning, encouragement to pursue low‐impact physical activity, and introduction of mindfulness techniques to better manage SLE symptoms.ConclusionOur findings suggest that African American women with SLE perceived the CDSMP as an effective educational self‐management intervention. The program can potentially catalyze improvements in self‐management behaviors in this population, regardless of demographic or disease characteristics.

Host-Microbial Interactions in Systemic Lupus Erythematosus and Periodontitis.

Background: Systemic lupus erythematosus (SLE) is a potentially fatal complex autoimmune disease, that is characterized by widespread inflammation manifesting tissue damage and comorbidities across the human body including heart, blood vessels, joints, skin, liver, kidneys, and periodontal tissues. The etiology of SLE is partially attributed to a deregulated inflammatory response to microbial dysbiosis and environmental changes. In the mouth, periodontal environment provides an optimal niche for local and systemic inflammation. Our aim was to evaluate the reciprocal impact of periodontal subgingival microbiome on SLE systemic inflammation.Methods: Ninety-one female subjects were recruited, including healthy (n = 31), SLE-inactive (n = 29), and SLE-active (n = 31). Patients were screened for probing depth, bleeding on probing, clinical attachment level, and classified according to CDC/AAP criteria with or without periodontal dysbiosis. Serum inflammatory cytokines were measured by human cytokine panel and a targeted pathogenic subgingival biofilm panel was examined by DNA-DNA checkerboard from subgingival plaque samples.Results: The results showed significant upregulation of serum proinflammatory cytokines in individuals with SLE when compared to controls. Stratification of subject's into SLE-inactive (I) and SLE-active (A) phenotypes or periodontitis and non-periodontitis groups provided new insights into SLE pathophysiology. Ten proinflammatory cytokines were upregulated in serum of SLE-I only and one in SLE-A only. Four molecules overlapped in SLE-A and SLE-I. Anti-inflammatory cytokines included IL-4 IL-10, which were upregulated in SLE-I sera (but not SLE-A), controlling clinical phenotypes. Out of 24 significant differential oral microbial abundances found in SLE, 14 unique subgingival bacteria profiles were found to be elevated in SLE. The most severe oral pathogens (Treponema denticola and Tannerella forsythia) showed increase abundances on SLE-A periodontal sites when compared to SLE-I and healthy controls. Inflammation as measured by cytokine-microbial correlations showed that periodontal pathogens dominating the environment increased proinflammatory cytokines systemically.Conclusions: Altogether, low-grade systemic inflammation that influenced SLE disease activity and severity was correlated to dysbiotic changes of the oral microbiota present in periodontal diseases.

New Frontiers: ARID3a in SLE.

Systemic lupus erythematosus (SLE) is a devastating and heterogeneous autoimmune disease that affects multiple organs, and for which the underlying causes are unknown. The majority of SLE patients produce autoantibodies, have increased levels of type-I inflammatory cytokines, and can develop glomerulonephritis. Recent studies indicate an unexpected but strong association between increased disease activity in SLE patients and the expression of the DNA-binding protein ARID3a (A + T rich interaction domain protein 3a) in a number of peripheral blood cell types. ARID3a expression was first associated with autoantibody production in B cells; however, more recent findings also indicate associations with expression of the inflammatory cytokine interferon alpha in SLE plasmacytoid dendritic cells and low-density neutrophils. In addition, ARID3a is expressed in hematopoietic stem cells and some adult kidney progenitor cells. SLE cells expressing enhanced ARID3a levels show differential gene expression patterns compared with homologous healthy control cells, identifying new pathways potentially regulated by ARID3a. The associations of ARID3a expression with increased disease severity in SLE, suggest that it, or its downstream targets, may provide new therapeutic targets for SLE.