Systemic Lupus Erythematosus Damage Research Articles

The effect of smoking on cumulative damage in systemic lupus erythematosus: An incident cohort study.

To investigate the relationship between smoking history and pack-year exposure on the rate of end-organ damage in systemic lupus erythematosus (SLE). The SLE incident cohort included patients who met American College of Rheumatology (ACR) 1997 or SLE International Collaborating Clinics (SLICC) 2012 SLE criteria and had rheumatology encounters at a US academic institution (2008-16). The primary outcome was median time to SLICC/ACR damage index (SLICC/ACR-DI) increase or death. Main explanatory variables were smoking status and pack-years. Covariates included age, sex, race, ethnicity, receipt of Medicaid, neighborhood area deprivation index, and baseline SLE damage. Damage increase-free survival was evaluated by smoking status and pack-years using Kaplan-Meier and Cox proportional hazards methods. Patients of Black race and Medicaid recipients were more commonly current smokers (p's < 0.05). Former smokers were older and more likely to have late-onset SLE (54% versus 33% of never and 29% of current smokers, p = 0.001). Median time to SLICC/ACR-DI increase or death was earlier in current or former compared to never smokers (4.5 and 3.4 versus 9.0 yrs; p = 0.002). In multivariable models, the rate of damage accumulation was twice as fast in current smokers (HR 2.18; 1.33, 3.57) and smokers with a >10 pack-year history (HR 2.35; 1.15, 3.64) versus never smokers. In this incident SLE cohort, past or current smoking predicted new SLE damage 4-5 years earlier. After adjustment, current smokers and patients with a pack-year history of >10 years accumulated damage at twice the rate of never smokers.

Correlations of serum beta 2-microglobulin level with disease activity and renal involvement in patients with systemic lupus erythematosus

Abstract Objectives To determine correlations of serum beta 2-microglobulin (β2-MG) level with disease activity and renal involvement in patients with systemic lupus erythematosus (SLE). Methods Two hundred eligible SLE patients were assigned into remission and active stage groups according to SLE disease activity index (SLEDAI) scores. They were also assigned into kidney damage and no kidney damage groups. Serum β2-MG, Scr, ALB, BUN, anti-dsDNA, complements C3, C4 and 24-h urinary total protein (UTP) were detected. Estimated glomerular filtration rate (eGFR) was calculated. Correlations of β2-MG level with SLEDAI score and eGFR were subjected to Spearman analysis. Affecting factors were explored by logistic multivariate regression analysis, and predictive values of β2-MG level for SLE, disease activity and renal damage were assessed by ROC curves. Results β2-MG, Scr, ALB, C3, C4, anti-dsDNA and UTP levels, eGFR and SLEDAI score were different between patients with different disease activities, and, except for eGFR, also between patients with different renal damage degrees (p&lt;0.05). Serum β2-MG, Scr, ALB, C3, C4, anti-dsDNA, UTP, eGFR and SLEDAI score were independent factors for disease activity (p&lt;0.05), and β2-MG, ALB, C3, UTP, eGFR and SLEDAI score were factors affecting renal damage (p&lt;0.05). β2-MG level was correlated positively with SLEDAI score (r=0.877, p=0.000) and negatively with eGFR (r=−0.873, p=0.000). This level was highly valuable for predicting SLE, disease activity and renal damage. Conclusions Serum β2-MG levels in SLE patients are correlated positively with disease activity and negatively with renal involvement, being highly sensitive and specific for predicting SLE, disease activity and eGFR.

Long-term remission in patients with systemic lupus erythematosus.

Remission has been introduced as a desirable outcome and the primary target of treatment in systemic lupus erythematosus (SLE). The purpose of this study was to identify the number of patients in remission and the long-term outcome of the disease and their predictors. Of the 379 patients in our SLE Database, a total of 193 patients fulfilled the inclusion criteria. Remission was definition according to the definitions of remission in SLE. Three levels of remission were defined, including remission on-treatment, remission off-treatment and complete remission. In addition, we have defined a sustained remission for each level of remission in which the remission should last at least 5years. During a median follow-up of 96months, remission on-treatment and off-treatment, and complete remission were obtained in 49.2%, 38.9% and 19.2% of patients, respectively. Predictors of remission on-treatment in multivariate regression analysis were adherence to therapy and remission induction during 6months after treatment. Predictors of remission off-treatment were age ≥40 at the time of analysis and remission induction during 6months after treatment. Poor outcome (SLE Damage Index ≥1) was observed in 28% of the patients. Age at disease onset <30, kidney and nervous system involvement and SLEDAI-2K≥11 at the cohort entry were the risk factors of poor outcome in multivariate analysis. However, sustained remission on-treatment had a negative association with poor outcome. Treatment with glucocorticoids, antimalarials, immunosuppressants and biologics in sequential or in combination may cause durable remission. Patients with durable remission have significantly lower organ damage.

Analysis of multiple organ damage and clinical immunological characteristics in systemic lupus erythematosus patients with hematologic involvement.

Objective: To investigate clinical immunological characteristics and imaging findings of multiple organ damage of systemic lupus erythematosus (SLE) patients with hematologic involvement.Methods: SLE patients diagnosed in the Second Affiliated Hospital of Nanchang University from June 2015 to March 2019 were selected, including 93 SLE patients with hematologic involvement and 68 SLE patients without hematologic involvement. Immunological indicators such as autoantibodies, immunoglobulin G (IgG), complement 4 (C4) and imaging data of several organs were measured respectively. The results were statistically analyzed.Results: SLE patients with hematologic involvement were more likely to have autoimmune hemolytic anemia (AIHA) (20.43%, P<0.05). The erythrocyte sedimentation rate (ESR) of SLE patients with hematologic involvement was 75.82 (±35.33) mm/h, IgG was 28.84 (±6.00) g/L and C4 was 0.073 (±0.031) g/L (P< 0.05). The area under the curve (AUC) of IgG was the highest among the above indicators (P<0.01). The positive anti-RO-52 antibody (OR=15.926, P<0.05) was an independent risk factor for pulmonary inflammatory lesions in SLE patients with hematologic involvement.Conclusion: Compared with the control group, abnormal immunological indicators and multiple organs damage are more obvious. Positive anti-RO-52 antibody may play an important role in the pathogenesis of pulmonary inflammation in SLE patients.

Relation between cumulative damage in systemic lupus erythematosus and recognised disability by the National Social Security Institute of Spain (INSS)

IntroductionSystemic Lupus Erythematosus (SLE) is a multisystemic autoimmune disease that particularly affects young women during their second and third decades. Events attributed to SLE itself and others related to the disease may impact negatively on the quality of life, employment and disability. However, there are not many studies focused on the impact that the disease may have on patients regarding those aspects. In Spain, the evaluation of disability and the assignation of a pension is given by the National Social Security Institute of Spain, INSS (“Instituto Nacional de la Seguridad Social”). ObjectiveTo assess the relationship between cumulative damage regarding the affected organ and the percentage of disability recognised by the National Social Security Institute of Spain (INSS) in SLE patients. MethodsCross-sectional prospective study of SLE patients according to the SLICC-2012 criteria, from the Rheumatology Service of two Spanish hospitals. We collected clinical and demographic data through personal interview and the SLICC/ACR questionnaire, and classified patients regarding a recognised disability or not. Results142 patients were evaluated; 30% had some percentage of official disability. We found a positive correlation between percentage of recognised disability and the SLICC/ACR index score. Musculoskeletal system is the most affected system, without differences between both groups; but we found a higher proportion of damage in nervous system, renal and vasculitis in patients with a recognised disability. ConclusionThere is a positive correlation between percentage of recognised disability in Spain and the cumulative damage in SLE.

Impact of Limited Health Literacy on Patient-Reported Outcomes in Systemic Lupus Erythematosus.

Health disparities in patient-reported outcomes by income and education are well documented; however, the impact of health literacy on patient-reported outcomes has received less attention. We examined independent effects of income, education, and health literacy on patient-reported outcomes in systemic lupus erythematosus (SLE). Data from the California Lupus Epidemiology Study (n = 323 participants) were used. Health literacy was assessed with a validated 3-item measure (ability to understand written information, reliance on others to understand written information, confidence in completing written forms). Patient-reported outcomes were administered by interview in English, Spanish, Cantonese, or Mandarin. Generic and disease-specific patient-reported outcomes were examined using the following: 10 Patient-Reported Outcomes Measurement Information System (PROMIS) short forms; the 8 Short Form 36 (SF-36) health survey subscales; and 3 patient-reported SLE disease activity and damage measures. We conducted 2 sets of multivariable analyses: the first examined education, income, or health literacy individually; the second included all 3 simultaneously. All multivariable models included age, sex, race/ethnicity, language, disease duration, and physician-assessed disease activity and damage. More than one-third of participants (38%) had limited health literacy (LHL), including >25% with greater than high school education. In multivariable analyses simultaneously considering education, income, and health literacy, LHL was associated with significantly worse scores on all patient-reported outcomes except disease damage. In contrast, disparities by income were seen in only 3 PROMIS scales, 3 SF-36 subscales, and 1 disease activity measure. No disparities by education level were noted. We found significantly worse patient-reported outcome scores among individuals with LHL, even after controlling for disease activity and damage. Whether disparities are due to actual differences in health or measurement issues requires further study.

Aberrant Non-Coding RNA Expression in Patients with Systemic Lupus Erythematosus: Consequences for Immune Dysfunctions and Tissue Damage.

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with heterogeneous clinical manifestations. A diverse innate and adaptive immune dysregulation is involved in the immunopathogenesis of SLE. The dysregulation of immune-related cells may derive from the intricate interactions among genetic, epigenetic, environmental, and immunological factors. Of these contributing factors, non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs), and long non-coding RNAs (lncRNAs) play critical roles in the post-transcriptional mRNA expression of cytokines, chemokines, and growth factors, which are essential for immune modulation. In the present review, we emphasize the roles of ncRNA expression in the immune-related cells and cell-free plasma, urine, and tissues contributing to the immunopathogenesis and tissue damage in SLE. In addition, the circular RNAs (circRNA) and their post-translational regulation of protein synthesis in SLE are also briefly described. We wish these critical reviews would be useful in the search for biomarkers/biosignatures and novel therapeutic strategies for SLE patients in the future.

The Problem of Pain in Systemic Lupus Erythematosus: An Explication of the Role of Biopsychosocial Mechanisms.

To define biopsychosocial mechanisms of pain that go above and beyond disease activity and organ damage in systemic lupus erythematosus (SLE). We conducted a cross-sectional analysis of patient-reported data in a population-based registry of 766 people with SLE. Predictors of pain intensity and interference were examined using hierarchical linear regression. We built 2 main hierarchical regression models with pain intensity and interference as outcomes, both regressed on disease activity and organ damage. For each model, we sought to establish the relationship between pain outcomes and the primary exposures using sequential steps comprising the inclusion of each construct in 6 stages: demographic, socioeconomic, physical, psychological, behavioral, and social factors. We also conducted sensitivity analyses eliminating all overt aspects of pain in the disease activity measure and reestimated the models. Disease activity and organ damage explained 32-33% of the variance in pain intensity and interference. Sociodemographic factors accounted for an additional 4-9% of variance in pain outcomes, whereas psychosocial/behavioral factors accounted for the final 4% of variance. In the sensitivity analyses, we found that disease activity and organ damage explained 25% of the variance in pain outcomes. Disease activity only explained 33% of the variance in pain outcomes. However, there was an attenuation in these associations after accounting for psychosocial/behavioral factors, highlighting their roles in modifying the relationship between disease activity and pain. These findings suggest that multilevel interventions may be needed to tackle the negative effect of pain in SLE.

Association of STAT4 rs7574865 with Sysceptibility to Juvenile Onset Systemic Lupus Erythematous in Pakistani Population

Association of STAT4 (signal transducer and activator of transcription4) haplotype tagged by single nucleotide polymorphism (SNP) rs7574865 with systemic lupus erythematosus (SLE) was reported in different populations. This study was aimed to investigate a genetic association between STAT4 single nucleotide polymorphism (rs7574865) with susceptibility and clinical features of systemic lupus erythematosus in Pakistani population. A total of 75 clinically diagnosed individuals affected with SLE were enrolled from Children’s Hospital and Institute of Child Health Lahore. Sixty-eight healthy individuals of same ethnicity were also enrolled for this study. Clinical assessment of patients was done with the help of clinical features suggestive for SLE and some diagnostic tests specific for the disease were performed. SNP rs7574865 was genotyped by allele specific tetra ARMS PCR assay to check and compare the genotypic allele frequencies between SLE patients and healthy controls. Different statistical analysis ChiSquare, Fisher’s exact tests and binary Logistic Regression is performed to determine association of risk alleles with SLE in Pakistani population. p value less than >0.05 consider significant. This study showed the frequency of GG (28%), TT (12%), and GT alleles (60%) in SLE patients while controls showed allele frequencies of GG (5%), TT (29%) and GT (64%), respectively. The results showed that GG genotype and G allele in STAT4 rs7574865 was the risk allele for SLE while T allele proved to be the protective one for disease susceptibility when compared with healthy controls genotypic frequencies. This study suggests the strong association of SNP rs7574865 in STAT4 with the risk of SLE in Pakistani population. However, G allele showed no association with organ damage and immune disorder of SLE.

IgG1 antibodies against phosphorylcholine are associated with protection in SLE and atherosclerosis: potential underlying mechanisms

Abstract Background The risk of cardiovascular disease (CVD) and atherosclerosis is very high in SLE. This is a clinical problem, and could also shed light on immunity and atherosclerosis in general. IgM antibodies against phosphorylcholine (anti-PC) may be protective in atherosclerosis, cardiovascular disease (CVD) and systemic lupus erythematosus (SLE). We here study IgG1 and IgG2 anti-PC, with focus on atherosclerosis and SLE. Methods We determined anti-PC by ELISA in 116 SLE-patients and 110 age- and sex-matched controls. For functional studies, we used three in-house generated, fully human monoclonal IgG1 anti-PC (A01, D05, E01). Apoptosis was induced in Jurkat T-cells and pre-incubated with A01, D05, E01 or isotype control IgG1 and effects on efferocytosis by human macrophages studied. Anti-PC peptide/protein characterization was determined using a proteomics de novo sequencing approach. Results IgG1 but not IgG2 anti-PC levels were higher among SLE patients (p=0.02). IgG1 anti-PC was negatively associated with SLICC and SLEDAI (OR: 2,978 CI: 0.876–10.098, OR: 5.108 CI 1.3 20.067 respectively) and negatively associated with CVD, atherosclerotic plaques and echolucent (potentially vulnerable plaques) but the association for the two former was not significant after controlling for confounders. D05 had maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC associated neo-epitopes. Peptide analysis showed difference in the CDR3 region of the three anti-PC IgG1 clones which are crucial for recognition of PC on apoptotic cell surface and other neo-epitopes. Conclusion Anti-PC IgG1 is negatively associated with disease activity, and disease damage in SLE, but the negative association with CVD is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swedish Heart and Lung Foundation, Reumatikerfonden

Lupus Nephritis In Systemic Lupus Erythematosus

The pathogenesis, clinic, and treatment of kidney damage in patients with systemic lupus erythematosus (SLE) are considered. It is noted that if at the beginning of the disease signs of kidney damage are present in 25-50% of SLE patients, then later they are detected in almost 60% of adults and 80% of children. Variants of kidney damage in SLE are described. The pathogenesis of SLE is generally considered on the model of lupus nephritis. The morphological classification of lupus nephritis, features of the main nephrological syndromes, and clinical variants (active and inactive) are presented. It is indicated that the treatment strategy depends on the activity of the disease, the clinical and morphological variant of lupus nephritis.

Validation of the Japanese version of the Lupus Damage Index Questionnaire in a large observational cohort: A two-year prospective study

Objectives The Lupus Damage Index Questionnaire (LDIQ) is a validated patient-reported outcome measure to assess accumulated damage in systemic lupus erythematosus (SLE). We aimed to translate it into Japanese and further investigate its validity and reliability. Methods The English version of the LDIQ was translated into Japanese and administered to Japanese patients with SLE (n = 259) at our university clinic. Physicians simultaneously completed the Systemic Lupus International Collaborating Clinics Damage Index (SDI) and SLE Disease Activity Index 2000 (SLEDAI-2K). Patients were prospectively followed for a repeat assessment the following year. Results The median LDIQ score was 2.0. The LDIQ demonstrated substantial correlation with the SDI but poor correlation with the SLEDAI-2K (Spearman’s ρ = 0.75 and −0.08, respectively). These results suggested its convergent and discriminant validity. The LDIQ demonstrated good test-retest reliability (intraclass correlation coefficient = 0.85). When the effect size and standardized response mean for the LDIQ were assessed only in patients who had a change ≥1 in the SDI, they demonstrated a small to moderate responsiveness: 0.43 and 0.59, respectively. Conclusion The Japanese version of the LDIQ had acceptable reliability and validity and its performance was comparable with the original version.

Longitudinal Study of Fatigue, Stress, and Depression: Role of Reduction in Stress Toward Improvement in Fatigue.

Fatigue is common among individuals with systemic lupus erythematosus (SLE), but the causes are not well understood. Our objective was to examine perceived stress and depressive symptoms as predictors of fatigue in SLE. Data from 2 years of the Lupus Outcomes Study (n = 650 patients), obtained through annual structured interviews, were used. Fatigue was measured with the Short Form 36 (SF-36) vitality scale along with a variety of self-report measures of disease, depression, and stress. Multivariate linear regression models examined predictors of changes in fatigue. Model 1 tested the association of time 1 (T1) depression with time 2 (T2) fatigue; model 2 added T1 perceived stress to model 1, and final models added T1-to-T2 decrease in stress. All analyses controlled for T1 fatigue, age, sex, self-report of fibromyalgia, pain, and SLE duration, activity, and damage. Mean ± SD age was 51 ± 12 years, 92% of participants were women, and 68% were white. The mean ± SD SF-36 fatigue score was 55 ± 24. T1 depression significantly predicted T2 fatigue. When T1 stress was added, stress (β = 1.7 [95% confidence interval (95% CI) 1.1, 2.2]; P < 0.0001) significantly predicted T2 fatigue, but depression was no longer significant. The addition of T1-to-T2 decrease in stress was associated with a clinically meaningful decline in fatigue (β = -11.8 [95% CI -15.6, -8.9]; P < 0.0001). While depressive symptoms initially predicted subsequent fatigue, the effects were mediated by stress. A decrease in stress, in addition, was associated with a clinically meaningful decrease in fatigue. These results suggest that perceived stress plays an important role in SLE fatigue and may be an important focus of interventions for fatigue.

Sphingolipids and Diagnosis, Prognosis, and Organ Damage in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that involves multiple organs and disproportionality affects females, especially African Americans from 15 to 44 years of age. SLE can lead to end organ damage including kidneys, lungs, cardiovascular and neuropsychiatric systems, with cardiovascular complications being the primary cause of death. Usually, SLE is diagnosed and its activity is assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Systemic Lupus International Collaborating Clinics Damage Index (SLICC/ACR), and British Isles Lupus Assessment Group (BILAG) Scales, which unfortunately often occurs after a certain degree of systemic involvements, disease activity or organ damage already exists. There is certainly a need for the identification of early biomarkers to diagnose and assess disease activity as well as to evaluate disease prognosis and response to treatment earlier in the course of the disease. Here we review advancements made in the area of sphingolipidomics as a diagnostic/prognostic tool for SLE and its co-morbidities. We also discuss recent reports on differential sphingolipid metabolism and blood sphingolipid profiles in SLE-prone animal models as well as in diverse cohorts of SLE patients. In addition, we address targeting sphingolipids and their metabolism as a method of treating SLE and some of its complications. Although such treatments have already shown promise in preventing organ-specific pathology caused by SLE, further investigational studies and clinical trials are warranted.

Serum resistin, insulin resistance and carotid intima-media thickness as an indication of subclinical atherosclerosis in systemic lupus erythematosus patients

Aim of the workTo evaluate resistin level in systemic lupus erythematosus(SLE) patients and to assess the relationship with insulin resistance, disease characteristics, inflammatory markers and carotid intima-media thickness (CIMT) as a marker of subclinical atherosclerosis. Patients and methodsThirty adult SLE patients and twenty age and sex-matched control were enrolled. All patients were subjected to history taking, clinical examination and assessment of anthropometric measurements. Laboratory investigations included serum resistin, measures of insulin resistance, highly sensitive C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR) and lipid profile. Carotid duplex was performed for measurement of CIMT. SLE disease activity index (SLEDAI-2k) and damage index were evaluated. ResultsThe 30 patients were 23 (76.7%) females and 7 (23.3%) males (F:M 3.3:1) with a mean age of 30.9 ± 7.9 years. The disease duration was 4.8 ± 1.8 years. The mean serum resistin in patients was 7.7 ± 2.9 ng/dl and in control was 8.5 ± 5.1 ng/dl (p = 0.8). The ESR and hs-CRP were significantly increased (p < 0.001) and the high-density lipoprotein (HDL) decreased (p < 0.001). The mean CIMT was significantly increased in cases (0.62 ± 0.16 mm) compared to control (0.51 ± 0.11 mm)(p = 0.006). Serum resistin significantly correlated with hs-CRP, HDL and anti-nuclear antibody (p = 0.027, p < 0.001,p = 0.013 respectively). There was no significant correlation between resistin and markers of insulin resistance, SLEDAI-2 k and CIMT. ConclusionResistin expression in the serum of patients with SLE was not significantly higher than controls. Although resistin was correlated with two cardiovascular risk factors (HDL-C, hs-CRP), it did not correlate significantly with insulin resistance, disease activity, damage index and CIMT in SLE patients.

Frequency of Polyautoimmunity in Patients With Rheumatoid Arthritis and Systemic Lupus Erythematosus.

To describe the frequency of polyautoimmunity and multiple autoimmune syndrome in patients with rheumatoid arthritis (RA) and patients with systemic lupus erythematosus (SLE). This was a cross-sectional observational study of patients with RA, SLE, and controls without autoimmune rheumatic disease. Cases were those with RA according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria and SLE according to the 2019 American College of Rheumatology/European League Against Rheumatism criteria, consecutively recruited in a rheumatology clinic. Controls were subjects with no rheumatic autoimmune disease (AIDs) recruited in the same area. Patients filled out a questionnaire on polyautoimmunity. Variables of interest were polyautoimmunity (RA or SLE with other AIDs), whereas secondary variables were rheumatic, skin, endocrine, digestive, and neurological AIDs. Multiple autoimmune syndrome is defined as the presence of 3 or more AIDs and a family history of AIDs. Statistical analyses performed were descriptive, bivariate, and multivariate (dependent variable: polyautoimmunity). The study population comprised 109 patients with RA, 105 patients with SLE, and 88 controls. Polyautoimmunity was recorded in 15 patients with RA (13.8%), 43 with SLE (41%), and 2 controls (2.2%). The most frequent AID in RA was Sjögren syndrome (53.3%), followed by Hashimoto thyroiditis and psoriasis; the most frequent AIDs in SLE were Sjögren syndrome (55.8%) and antiphospholipid syndrome (30.2%), followed by Hashimoto thyroiditis. Obesity was associated with polyautoimmunity in RA (odds ratio [OR], 3.362; p = 0.034). In SLE, joint damage (OR, 2.282; p = 0.038) and anti-RNP antibodies (OR, 5.095; p = 0.028) were risk factors for polyautoimmunity, and hydroxychloroquine was a protective factor (OR, 0.190; p = 0.004). Polyautoimmunity is frequent in RA and even more frequent in SLE. It was associated with obesity in RA and with joint damage and anti-RNP in SLE. Hydroxychloroquine was a protector.

MFG-E8 accelerates wound healing in diabetes by regulating \u201cNLRP3 inflammasome-neutrophil extracellular traps\u201d axis

Sustained activation of NLRP3 inflammasome and release of neutrophil extracellular traps (NETs) impair wound healing of diabetic foot ulcers (DFUs). Our previous study reported that milk fat globule epidermal growth factor VIII (MFG-E8) attenuates tissue damage in systemic lupus erythematosus. However, the functional effect of MFG-E8 on “NLRP3 inflammasome-NETs” inflammatory loop in wound healing of diabetes is not completely elucidated. In this study, neutrophils from DFU patients are susceptible to undergo NETosis, releasing more NETs. The circulating levels of NET components neutrophil elastase and proteinase 3 and inflammatory cytokines IL-1β and IL-18 were significantly elevated in DFU patients compared with healthy controls or diabetic patients, in spite of higher levels of MFG-E8 in DFU patients. In Mfge8−/− diabetic mice, skin wound displayed exaggerated inflammatory response, including leukocyte infiltration, excessive activation of NLRP3 inflammasome (release of higher IL-1β, IL-18, and TNF-α), largely lodged NETs, resulting in poor angiogenesis and wound closure. When stimulated with high-dose glucose or IL-18, MFG-E8-deficient neutrophils release more NETs than WT neutrophils. After administration of recombinant MFG-E8, IL-18-primed NETosis of WT or Mfge8−/− neutrophils was significantly inhibited. Furthermore, NET and mCRAMP (component of NETs, the murine equivalent of cathelicidin LL-37 in human)-mediated activation of NLRP3 inflammasome and production of IL-1β/IL-18 were significantly elevated in Mfge8−/− macrophages compared with WT macrophages, which were also significantly dampened by the administration of rmMFG-E8. Therefore, our study demonstrated that as inhibitor of the “NLRP3 inflammasome-NETs” inflammatory loop, exogenous rMFG-E8 improves angiogenesis and accelerates wound healing, highlighting possible therapeutic potential for DFUs.

Update on antimalarials and systemic lupus erythematosus

The purpose of this review is highlighting the most recent evidence on the clinical efficacy and toxicity of antimalarials in systemic lupus erythematosus (SLE). New data confirm the effects of antimalarials in preventing SLE activity, damage and infections and in decreasing mortality. An important reduction in use of health resources is related to continued antimalarial use. Hydroxychloroquine (HCQ) may prevent preeclampsia in pregnant women with SLE. HCQ ocular toxicity is infrequent and could be associated with blood levels. Gastrointestinal and skin toxicity are underrecognized and could influence adherence. Prolongation of QT interval is extremely unusual with HCQ. Doses of HCQ of 200 mg/day seem to offer a good efficacy/toxicity balance. HCQ protection against herpes zoster and Pneumocystis jirovecii infection has been shown. On the contrary, HCQ prescription by doctors and adherence by patients are both under recommended standards. The recent coronavirus disease 2019 pandemic has resulted in a significant shortage of HCQ in many countries with possible consequences in the correct treatment of lupus patients. Recent evidence reinforces the central role of HCQ in SLE therapy. The reduction in activity, damage accrual and mortality is consistent across studies, countries and ethnical groups. On the contrary, and despite the well established beneficial effects of prolonged regular HCQ therapy, many SLE patients do never take this drug or it is eventually stopped in the setting of severe flares, pregnancy or presumed toxicity. Every effort must be made to assure the correct prescription of HCQ and not to withdraw the drug unless unequivocal signs of toxicity are present.

Low-Density Neutrophils in Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus (SLE) display increased numbers of immature neutrophils in the blood, but the exact role of these immature neutrophils is unclear. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low‐density neutrophils (LDNs). Far beyond antimicrobial functions, LDNs are emerging as decision‐shapers during innate and adaptive immune responses. Traditionally, neutrophils have been viewed as a homogeneous population. However, the various LDN populations identified in SLE to date are heterogeneously composed of mixed populations of activated mature neutrophils and immature neutrophils at various stages of differentiation. Controversy also surrounds the role of LDNs in SLE in terms of whether they are proinflammatory or polymorphonuclear myeloid‐derived suppressor cells. It is clear that LDNs in SLE can secrete increased levels of type I interferon (IFN) and that they contribute to the cycle of inflammation and tissue damage. They readily form neutrophil extracellular traps, exposing modified autoantigens and oxidized mitochondrial DNA, which contribute to autoantibody production and type I IFN signaling, respectively. Importantly, the ability of LDNs in SLE to perform canonical neutrophil functions is polarized, based on mature CD10+ and immature CD10− neutrophils. Although this field is still relatively new, multiomic approaches have advanced our understanding of the diverse origins, phenotype, and function of LDNs in SLE. This review updates the literature on the origin and nature of LDNs, their distinctive features, and their biologic roles in the immunopathogenesis and end‐organ damage in SLE.

Correlation between the level of urine interleukin-6 with microalbuminuria in Systemic Lupus Erythematosus (SLE) patients at Sanglah General Hospital, Bali, Indonesia

Background: Lupus Nephritis (LN) is one of the serious manifestations of SLE. Because of its role in the pathogenesis of LN, IL-6 is likely to be a potential marker, whereas for diagnosing kidney involvement at the subclinical stage, microalbuminuria can be examined. Therefore, early detection of kidney damage in SLE is needed to prevent the progression of NL to permanent kidney failure. This study aims to evaluate the relationship between IL-6 levels and microalbuminuria in SLE patients at Sanglah General Hospital Bali.Methods: This study used a cross-sectional analytic design, carried out in Sanglah General Hospital on SLE patients, conducted in May until July 2019. Blood and urine samples were taken to obtain the data needed to measure the Mex-SLEDAI score. Cytokine evaluation is done by quantitative examination using enzyme-linked immunosorbent assay (ELISA). Chi-square analysis was done using SPSS version 24 for Windows.Results: The results of the study were 85 subjects with SLE (94.1% women). The median age is 35 years (18-61 years), and the median duration of illness is three years (0.4-18 years). Most of the patients were in inactive clinical condition, 54 patients (63.53%) and laboratory results were still in the normal range. Steroids (94.1%) are the most widely used therapeutic options. Urine IL-6 levels were obtained with a mean of 0.41±0.21 pg/ml, while microalbuminuria levels were obtained with a median of 20 (0-100) mg/L. The results of data analysis stated that there was no significant relationship between urine IL-6 levels and microalbuminuria in SLE (p = 0.972).Conclusion: In this study, there was no significant relationship between urine IL-6 levels and microalbuminuria.