Bcl-3 inhibits lupus-like phenotypes in BL6/lpr mice.

Bcl-3 is an atypical member of the IκB family that modulates NF-κB activity in nuclei. lpr mice carry the lpr mutation in Fas, resulting in functional loss of this death receptor; they serve as models for lupus erythematosus and autoimmune lymphoproliferation syndrome (ALPS). To explore the biologic roles of Bcl-3 in this disease model, we generated BL6/lpr mice lacking Bcl-3. Unlike lpr mice on an MRL background, BL6/lpr mice present with very mild lupus- or ALPS-like phenotypes. Bcl-3 KO BL6/lpr mice, however, developed severe splenomegaly, dramatically increased numbers of double negative T cells - a hallmark of human lupus, ALPS, and MRL/lpr mice - and exhibited inflammation in multiple organs, despite low levels of autoantibodies, similar to those in BL6/lpr mice. Loss of Bcl-3 specifically in T cells exacerbated select lupus-like phenotypes, specifically organ infiltration. Mechanistically, elevated levels of Tnfα in Bcl-3 KO BL6/lpr mice may promote lupus-like phenotypes, since loss of Tnfα in these mice reversed the pathology due to loss of Bcl-3. Contrary to the inhibitory functions of Bcl-3 revealed here, this regulator has also been shown to promote inflammation in different settings. Our findings highlight the profound, yet highly context-dependent roles of Bcl-3 in the development of inflammation-associated pathology.

Blockade of anti-dsDNA ameliorates systemic lupus erythematosus in MRL/Faslpr mice through ameliorating inflammation via the PKCδ-NLRC4 axis.

Anti-double-stranded DNA (anti-dsDNA) is closely associated with the inflammatory burden in the brain after ischemic stroke. Here, we studied the inflammatory cascade and investigated the mechanisms behind the pro-inflammatory role of dsDNA in systemic lupus erythematosus (SLE). The serum levels of interleukin-1beta (IL-1ß) and IL-6 in SLE patients and the corresponding controls were evaluated using ELISA, and the expression level of caspase-1 was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). We found that the serum levels of IL-1ß and IL-6 were increased in the SLE patients. The expression of caspase-1 was upregulated and positively correlated with the levels of pro-inflammatory factors. The level of anti-dsDNA was also elevated and positively correlated with the results for the mean fluorescence intensity (MFI) of caspase-1. Additionally, we evaluated the functions of PRKCD encoding protein kinase c delta (PKCδ) and NLRC4, in vivo, in MRL/Faslpr mice. We found that renal injury was aggravated, and the levels of pro-inflammatory factors were increased in the MRL/Faslpr mice. We also found that increased levels of NLRC4 in the mice exacerbated renal injury and increased the levels of pro-inflammatory factors, whereas inhibition of PKCδ had the opposite results. These findings provide unique perspectives on pathogenesis of SLE and indicate that inhibition of anti-dsDNA could attenuate renal inflammatory burden, representing a promising therapeutic opportunity for SLE.

Influenza A/Singapore (H3N2) component vaccine in systemic lupus erythematosus: A distinct pattern of immunogenicity.

INTRODUCTION: Influenza A (H3N2) virus is the most important cause of seasonal influenza morbidity and mortality in the last 50 years, surpassing the impact of H1N1. Data assessing immunogenicity and safety of this virus component are lacking in systemic lupus erythematosus (SLE) and restricted to small reports with other H3N2 strains. OBJECTIVE: This study aims to evaluate short-term immunogenicity and safety of influenza A/Singapore (H3N2) vaccine in SLE. METHODS: 81 consecutive SLE patients and 81 age- and sex-matched healthy controls (HC) were vaccinated with the influenza A/Singapore/INFIMH-16-0019/2016(H3N2)-like virus. Seroprotection (SP) and seroconversion (SC) rates, geometric mean titers(GMT), and factor increase in GMT(FI-GMT) and adverse events were assessed before and 4 weeks post-vaccination. Disease activity and therapies were also evaluated. RESULTS: Before immunization, SLE and HC groups had high SP rates (89% vs 77%, p = 0.061) and elevated GMT titer with higher levels in SLE (129.1(104.1-154.1) vs 54.8(45.0-64.6), p < 0.001). Frequency of two previous years' influenza vaccination was high and comparable in SLE and HC (89% vs 90%, p = 1.000). Four weeks post-vaccination, median GMT increased for both groups and remained higher in SLE compared to HC (239.9(189.5-290.4) vs 94.5(72.6-116.4), p < 0.0001) with a comparable FI-GMT (2.3(1.8-2.9) vs 1.9(1.5-2.3), p = 0.051). SC rates were low and comparable for both groups (16% vs 11%, respectively, p = 0.974). Disease activity scores remained stable throughout the study (p = 1.000) and severe adverse events were not identified. CONCLUSION: Influenza A/Singapore (H3N2) vaccine has an adequate safety profile. The distinct immunogenicity pattern from other influenza A components characterized by a remarkably high pre- and post-vaccination SP rate and high GMT levels may be associated with previous influenza A vaccination. (www.clinicaltrials.gov, NCT03540823).

Association between alcohol intake and the risk of systemic lupus erythematosus: A systematic review and meta-analysis.

OBJECTIVES: Previous studies have reported inconsistent results on the relationship between alcohol intake and the risk of systemic lupus erythematosus (SLE). Therefore, we conducted a systematic review and meta-analysis to illustrate the potential role of alcohol intake on the progression of SLE. METHODS: An electronic search of the PubMed, EmBase, and the Cochrane library databases was conducted from their inception up to March 2020. Observational studies that investigated the role of alcohol intake on the risk of SLE were eligible for inclusion in this study. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated as an effect estimate using the random-effects model. RESULTS: Seven case-control studies (n = 3, 251) and three cohort studies (n = 322, 479) were selected for the final meta-analysis. Mild (OR: 0.85; 95% CI: 0.53-1.38; p = 0.515) or heavy (OR: 0.63; 95% CI: 0.37-1.09; p = 0.102) alcohol intake were not associated with the risk of SLE, while moderate alcohol intake could protect against the risk of SLE (OR: 0.71; 95% CI: 0.55-0.93; p = 0.012). Sensitivity analysis suggested that heavy alcohol intake was associated with a reduced risk of SLE (OR: 0.47; 95% CI: 0.32-0.67; p < 0.001). CONCLUSIONS: This study found that moderate alcohol intake could protect against the risk of SLE, while mild or heavy alcohol intake did not significantly affect the risk of SLE.

Effect of early eradication therapy on systemic lupus erythematosus risk in patients with Helicobacter pylori infection: a nationwide population-based cohort study.

BACKGROUND: This study aimed to investigate whether early eradication therapy influences systemic lupus erythematosus (SLE) risk in patients with Helicobacter pylori (HP) infection. METHODS: We identified 41,653 patients with HP infection in Taiwan from 2000 to 2013. The patient population was divided into early (within three months) and late (after three months) eradication cohorts. age, sex, co-morbidities and medical visits were matched at a 1:1 ratio. Multiple Cox regression, sensitivity analysis and stratified analysis were used to estimate SLE adjusted hazard ratios (aHR). RESULTS: The relative risk of SLE was 0.75 (95% confidence interval 0.43-1.31) in the early eradication cohort. After multivariate adjustment, the SLE risk was non-significantly lower in the early eradication cohort than in the late eradication cohort (aHR = 0.74, 95% CI 0.42-1.29). Stratified analysis revealed that early eradication could significantly reduce SLE risk during the three-year follow-up period (aHR = 0.16, 95% CI 0.05-0.53, p for interaction = 0.0013). Compared to eradication within three months of diagnosis, eradication within 3-36 months and >36 months corresponded with SLE aHRs of 4.78 (95% CI 1.19-19.20) and 7.66 (95% CI 2.17-27.05), respectively, when the follow-up period was less than three years. CONCLUSION: Early HP eradication could significantly reduce SLE risk, especially in the first three-year follow-up.

Endosomal Toll-like receptors in clinically overt and silent autoimmunity.

Toll-like receptors (TLRs), first identified as pattern recognition receptors, are now recognized to serve as a key interface between innate and adaptive immunity. Systemic lupus erythematosus (SLE) is characterized by both continuous and cyclic stimulation of the innate and adaptive immune system by endogenous nucleic acids released from apoptotic or necrotic cells. TLR7 and TLR9 function as innate sensors of viral infection as their ligands are ssRNA and dsDNA, respectively. Recognition of self nucleic acids by endosomal TLRs in B cells and pDCs is thought to be an important step in the pathogenesis of SLE, generating anti-nuclear antibodies and producing type I IFN. In this review, we take a specific look at how TLR7, non-coding RNA, and SSA/Ro60 can contribute to clinical autoimmunity and organ damage in the context of neonatal lupus (NL). Although 15 times less common than SLE, NL provides a unique opportunity to study two different aspects of autoimmunity: passively acquired tissue injury in a developing fetus and clinical progression of disease in an asymptomatic mother found to have anti-Ro60 autoantibodies only after identification of heart block/rash in a child. Finally, we discuss hydroxychloroquine (HCQ) use by asymptomatic subjects which may forestall the clinical expression of autoimmunity.

A20: A multifunctional tool for regulating immunity and preventing disease.

A20, also known as TNFAIP3, is a potent regulator of ubiquitin (Ub) dependent signals. A20 prevents multiple human diseases, indicating that the critical functions of this protein are clinically as well as biologically impactful. As revealed by mouse models, cell specific functions of A20 are linked to its ability to regulate diverse signaling pathways. Aberrant expression or functions of A20 in specific cell types underlie divergent disease outcomes. Discernment of A20's biochemical functions and their phenotypic outcomes will contribute to our understanding of how ubiquitination is regulated, how Ub mediated functions can prevent disease, and will pave the way for future therapeutic interventions.

Practice-based differences in paediatric discoid lupus erythematosus.

BACKGROUND: Children with discoid lupus erythematosus (DLE) are at risk for disfigurement and progression to systemic lupus erythematosus (SLE). Consensus is lacking regarding optimal care for children with DLE. OBJECTIVES: The aim of this study was to compare practice patterns among paediatric dermatologists/rheumatologists treating paediatric DLE. METHODS: An online survey was sent to 292 paediatric rheumatologists in the Childhood Arthritis and Rheumatology Research Alliance and 200 paediatric dermatologists in the Pediatric Dermatology Research Alliance. Consensus was defined as ≥ 70% agreement. RESULTS: Survey response rates were 38% (76 of 200) for dermatology and 21% (60 of 292) for rheumatology. Both specialties agreed that screening labs should include complete blood counts with differential, urinalysis, complement levels, erythrocyte sedimentation rate, antinuclear antibody and other autoantibodies, hepatic function and renal function/electrolytes. Both specialties agreed that arthritis or nephritis should prompt intensified evaluation for SLE. No other patient features achieved consensus as disease-modifying risk factors. Hydroxychloroquine was agreed upon as first-line systemic therapy, but consensus was lacking for second- or third-line treatment. CONCLUSIONS: We found few areas of consensus and significant practice differences between paediatric dermatologists and rheumatologists treating DLE. Knowledge gaps include risk factors for SLE, optimal screening and treatment of refractory skin disease.

Implementation and dissemination of an African American popular opinion model to improve lupus awareness: an academic-community partnership.

OBJECTIVE: Lupus is a chronic, autoimmune disease that disproportionately affects African Americans. We adapted the Centers for Disease Control and Prevention's Popular Opinion Leader model to implement an intervention tailored for African American individuals that leverages an academic-community partnership and community-based social networks to disseminate culturally appropriate lupus education. METHODS: Academic rheumatologists, social scientists, and researchers in Boston, MA and Chicago, IL partnered with local lupus support groups, community organizations, and churches in neighborhoods with higher proportions of African Americans to develop curriculum and recruit community leaders with and without lupus (Popular Opinion Leaders; POLs). POLs attended four training sessions focused on lupus education, strategies to educate others, and a review of research methods. POLs disseminated information through their social networks and recorded their impact, which was mapped using a geographic information system framework. RESULTS: We trained 18 POLs in greater Boston and 19 in greater Chicago: 97% were African American, 97% were female; and the mean age was 57 years. Fifty-nine percent of Boston POLs and 68% of Chicago POLs had lupus. POLs at both sites engaged members of their social networks and communities in conversations about lupus, health disparities, and the importance of care. Boston POLs documented 97 encounters with 547 community members reached. Chicago POLs documented 124 encounters with 4083 community members reached. CONCLUSIONS: An adapted, community-based POL model can be used to disseminate lupus education and increase awareness in African American communities. Further research is needed to determine the degree to which this may begin to reduce disparities in access to care and outcomes.

Lupus, Silica, and Dietary Omega-3 Fatty Acid Interventions.

Two environmental factors, crystalline silica (cSiO2), a toxic airborne particle encountered occupationally, and docosahexaenoic acid (DHA), a dietary omega-3 highly unsaturated fatty acid (HUFA), have the potential to influence the development of systemic lupus erythematosus (lupus). Using the NZBWF1 mouse, which spontaneously develops lupus, we found that intranasal exposure to cSiO2 significantly decreases latency and promotes rapid progression of the disease. Specifically, cSiO2 induces the development of ectopic lymphoid structures (ELS) containing germinal centers in the lungs that yield vigorous and diverse autoantibody responses locally and systemically. Transcriptomic analysis revealed that cSiO2 promotes a robust type I interferon gene signature that likely precipitates ELS neogenesis. Intriguingly, dietary supplementation with human-relevant doses of DHA impedes cSiO2-induced gene expression, ELS neogenesis, autoantibody elevation, and glomerulonephritis in this lupus-prone mouse model. Together, our findings point to the feasibility of enhancing tissue omega-3 HUFAs as a personalized nutritional intervention to impede onset and progression of environment-triggered autoimmune disease.

Conjugated linoleic acid prevents age-dependent neurodegeneration in a mouse model of neuropsychiatric lupus via the activation of an adaptive response.

Oxidative stress is a key mediator of autoimmune/neurodegenerative disorders. The antioxidant/anti-inflammatory effect of a synthetic conjugated linoleic acid (CLA) mixture in MRL/MpJ-Fas lpr mice (MRL/lpr), an animal model of neuropsychiatric lupus, was previously associated with the improvement of nuclear factor-E2-related factor 2 (Nrf2) defenses in the spleen and liver. However, little is known about the neuroprotective ability of a CLA mixture. This study investigated the age-dependent progression of oxidative stress and the hyperactivation of redox-sensitive compensatory pathways (macroautophagy, Nrf2) in old/diseased MRL/lpr mice brains and examines the effect produced by dietary CLA supplementation. Disrupted redox homeostasis was evidenced in the blood, liver, and brain of 21- to 22-week-old MRL/lpr (Old) mice compared with 8- to 10-week-old MRL/lpr (Young) animals. This alteration was associated with significant hyperactivation of compensatory mechanisms (macroautophagy, Nrf2, and astrocyte activation) in the brains of Old mice. Five-week daily supplementation with CLA (650 mg/kg-1 body weight) of 16-week-old (CLA+Old) mice diminished all the pathological hallmarks at a level comparable to Young mice or healthy controls (BALB/c). Such data demonstrated that MRL/lpr mice can serve as a valuable model for the evaluation of the effectiveness of neuroprotective drugs. Notably, the preventive effect provided by CLA supplementation against age-associated neuronal damage and hyperactivation of compensatory mechanisms suggests that the activation of an adaptive response is at least in part accountable for its neuroprotective ability.

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model.

IL-21 promotes B cell and CTL responses in vivo, conferring IL-21 with a role in both humoral and cellular responses. Because CTL can target and eliminate autoreactive B cells, we investigated whether IL-21R signaling in CD8 T cells would alter the expansion of autoreactive B cells in an autoimmune setting. We addressed this question using the parent→F1 murine model of acute and chronic (lupus-like) graft-versus-host disease (GVHD) as models of a CTL-mediated or T-dependent B cell-mediated response, respectively. Induction of acute GVHD using IL-21R-deficient donor T cells resulted in decreased peak donor CD8 T cell numbers and decreased CTL effector function due to impaired granzyme B/perforin and Fas/Fas ligand pathways and a phenotype of low-intensity chronic GVHD with persistent host B cells, autoantibody production, and mild lupus-like renal disease. CTL effector maturation was critically dependent on IL-21R signaling in Ag-specific donor CD8, but not CD4, T cells. Conversely, treatment of DBA/2J→F1 chronic GVHD mice with IL-21 strongly promoted donor CD8 T cell expansion and rescued defective donor anti-host CTLs, resulting in host B cell elimination, decreased autoantibody levels, and attenuated renal disease, despite evidence of concurrently enhanced CD4 help for B cells and heightened B cell activation. These results demonstrate that, in the setting of lupus-like CD4 T cell-driven B cell hyperactivity, IL-21 signaling on Ag-specific donor CD8 T cells is critical for CTL effector maturation, whereas a lack of IL-21R downregulates CTL responses that would otherwise limit B cell hyperactivity and autoantibody production.

mTOR regulates NLRP3 inflammasome activation via reactive oxygen species in murine lupus.

Inflammasomes are protein complexes responsible for the release of IL-1 family cytokines, and they play critical roles in immunity and inflammation. The best-characterized inflammasome, the NOD-like receptor protein 3 (NLRP3) inflammasome, is involved in the development of multiple autoimmune diseases. However, the underlying mechanisms of abnormal NLRP3 inflammasome activation in systemic lupus erythematosus (SLE) remain elusive. Here, western blot analysis was used to detect the level of NLRP3 components and mTORC1/2 substrate in the kidney tissues from B6.MRL-FASlpr/J lupus mice and C57BL/6 mice, and the results showed that mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) and the NLRP3 inflammasome were hyperactivated in B6.MRL-FASlpr/J lupus mice. The inhibition of mTOR by INK128, a novel mTORC1/2 inhibitor, suppressed LPS/ATP and LPS/nigericin-induced NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) in vitro. INK128 decreased both the mRNA and protein levels of NLRP3 in an NF-κB-independent manner. Moreover, we reported for the first time that the inhibition of mTOR suppressed mitochondrial reactive oxygen species (ROS) production in BMDMs stimulated by an NLRP3 agonist. Furthermore, N-acetyl-L-cysteine, a ROS inhibitor, decreased NLRP3 expression, and rotenone, a robust ROS inducer, partially reversed the inhibitory effect of INK128 on NLRP3. These results demonstrated that mTOR regulated the activation of the NLRP3 inflammasome at least partially via ROS-induced NLRP3 expression. Importantly, in vivo data demonstrated that INK128 treatment prominently attenuated lupus nephritis and suppressed NLRP3 inflammasome activation in B6.MRL-FASlpr/J lupus mice. Taken together, our results suggest that activation of mTOR/ROS/NLRP3 signaling may contribute to the development of SLE.

Poly IC pretreatment suppresses B cell-mediated lupus-like autoimmunity through induction of Peli1.

Noncanonical NF-κB pathway is essential for the B cell activation and antibody production, which centralize the critical role of B cells in regulating the pathogenesis of systemic lupus erythematosus (SLE). We have previously demonstrated that Pellino1 (Peli1) negatively regulates noncanonical NF-κB activation and lupus autoimmunity. Here, we showed that poly IC is a potent inducer of Peli1 protein in mouse splenic B cells in dose- and time-dependent manners, and poly IC-induced Peli1 protein dramatically suppressed the activation of noncanonical NF-κB pathway. In addition, poly IC-pretreated B cells failed to induce lupus-like disease in BM12 CD4+ T cell-immunized mice. Accordingly, the induction of antibody-producing plasma cells and germinal center B cells, as well as the production of autoantibodies were significantly impaired in immunized µMT mice that were transferred with poly IC-pretreated B cells. Our findings demonstrate that poly IC-induced Peli1 negatively regulates the noncanonical NF-κB pathway in the context of restraining the pathogenesis of lupus-like disease.

TIGIT signalling pathway negatively regulates CD4+ T-cell responses in systemic lupus erythematosus.

B-lymphocyte hyperactivity in systemic lupus erythematosus (SLE) is T-cell-dependent, and CD4+ T-cell activation is essential to SLE pathogenesis. However, the mechanism of the deregulation of CD4+ T cells in SLE is largely unknown. T-cell immunoglobulin and ITIM domain (TIGIT) is a new inhibitory receptor preferentially expressed on activated CD4+ T cells. Here, we address the role of TIGIT in the pathogenesis of SLE. Our results showed that TIGIT expression on CD4+ T cells was significantly elevated in patients with SLE and highly correlated with the activity of the disease. TIGIT+ CD4+ T cells from both healthy individuals and patients with SLE had a more activated phenotype than TIGIT- CD4+ T cells. In contrast, the activation, proliferation and cytokine production potential of TIGIT+ CD4+ T cells were significantly lower than those of TIGIT- CD4+ T cells. Furthermore, activation of the TIGIT pathway by using CD155 could substantially down-regulate the activities of CD4+ T cells from SLE patients in vitro, and in vivo administration of CD155 resulted in a delayed development of SLE in MRL/lpr mice. TIGIT is a powerful negative regulator of CD4+ T cells in SLE, which suggests that the TIGIT signalling pathway may be used as a potential therapeutic target for treating this disease.

Progress in the pathogenesis and treatment of cardiac manifestations of neonatal lupus.

PURPOSE OF REVIEW: To provide new insights into pathogenesis, prevention and management of cardiac manifestations of neonatal lupus (cardiac neonatal lupus) and issues pertinent to all anti-SSA/Ro positive individuals of childbearing age. RECENT FINDINGS: Antibody specificity with high risk for cardiac neonatal lupus remains elusive, but high titers of Ro60, Ro52 or Ro52p200 antibodies appear to be required. Varying antibody specificities to the p200 region of Ro52 can induce first-degree block in a rodent model. In consideration of the contribution of macrophages to inflammation and fibrosis in cardiac neonatal lupus, hydroxychloroquine (HCQ) is being considered as preventive therapy. Cord blood biomarkers support the association of fetal reactive inflammatory and fibrotic components with the development and morbidity of cardiac neonatal lupus. Data from U.S. and French registries do not provide evidence that the prompt use of fluorinated steroids in cases of isolated block significantly alters fetal/neonatal morbidity or mortality. SUMMARY: The search for a high-risk cardiac neonatal lupus antibody profile remains, but high-titer antibodies to Ro60 and R052 are a consistent finding, and this may guide the need for fetal echocardiographic surveillance. The uniform use of fluorinated steroids to prevent progression of cardiac neonatal lupus or reduce mortality does not appear justified. HCQ, based on diminishing an inflammatory component of cardiac neonatal lupus, is under consideration as a potential preventive approach.

Prenatal exposure to antimalarials decreases the risk of cardiac but not non-cardiac neonatal lupus: a single-centre cohort study.

Objective: Recent studies have suggested that prenatal exposure to HCQ reduces the risk of cardiac neonatal lupus. The aim of this study is to assess if maternal intake of antimalarials (AMs) throughout pregnancy lowered the risk of cardiac and non-cardiac neonatal lupus. Methods: Consecutive children seen between 1 January 1984 to 1 October 2013 born to women with a CTD and positive anti-Ro and/or anti-La antibodies were eligible for this single-centre retrospective cohort study. A total of 315 individuals were screened and 268 participants were included. Exposure to AMs was defined as HCQ or chloroquine throughout pregnancy. Outcomes were cardiac and non-cardiac neonatal lupus. Frequentist and Bayesian analyses were performed. We hypothesized that prenatal AM exposure would decrease the risk of cardiac but not non-cardiac neonatal lupus. Results: A total of 268 pregnancies were included; 73 were exposed to AMs throughout pregnancy. Ninety-nine children developed neonatal lupus, 117 remained unaffected and 52 children did not develop cardiac neonatal lupus but could not be categorized as unaffected since their full non-cardiac neonatal lupus status was unknown. Logistic regression suggested a protective effect of AM on cardiac neonatal lupus, but results were not statistically significant [odds ratio (OR) 0.21; P = 0.07]. Bayesian analysis showed that the probability of obtaining a protective effect (OR < 1.0) for cardiac neonatal lupus was significant (98.7%). The effect of AMs on non-cardiac neonatal lupus was not significant (OR 0.78; P = 0.21). Conclusion: In this large single-centre cohort study, exposure to AMs throughout pregnancy was associated with a decreased probability of developing cardiac but not non-cardiac neonatal lupus.

Hydroxychloroquine Dose per Ophthalmology Guidelines and the Risk of Systemic Lupus Erythematosus Flares.

This study of an academic medical center patient cohort with systemic lupus erythematosus (SLE) investigates the association between hydroxychloroquine dose based on current guidelines and risk of lupus flares.

Preventing the development of SLE: identifying risk factors and proposing pathways for clinical care.

Although challenging, developing evidence-based approaches to an early and accurate diagnosis of systemic lupus erythematosus is a key approach to preventing disease and lupus-associated morbidity and mortality. Advances in our understanding of preclinical and incomplete lupus erythematosus have enabled the identification of risk factors that may predict disease and the development of potential strategies aimed at primary prevention. Emerging data support the notion that there is a temporal disease progression from initial asymptomatic autoimmunity (preclinical lupus) through early clinical features of the disease (incomplete lupus erythematosus) to finally becoming fully classifiable systemic lupus erythematosus (complete lupus erythematosus). Here, we review the demographic, clinical, biomarker as well as genetic and environmental features that are reported to increase the risk of disease progression. Based on these risk factors, we propose a clinical care pathway for patients with early disease. We envisage that such a pathway, through early identification of disease, may improve patient outcomes, while reducing health care costs.

The potential protective role of hepatitis B virus infection in pristane-induced lupus in mice.

OBJECTIVE: The objective of this study was to investigate whether hepatitis B virus (HBV) infection plays a role in the regulation of autoimmunity for systemic lupus erythematosus (SLE). METHOD: A total of 21 female BALB/c mice and 21 female HBV transgenic BALB/c mice aged two months were randomly divided into four groups: BALB/c mice, HBV(Tg) mice, pristane-injected BALB/c mice, and pristane-injected HBV(Tg) mice. BALB/c mice and HBV(Tg) mice were given an intraperitoneal injection of 0.5 ml normal saline, and the mice in the other two groups were given an intraperitoneal injection of 0.5 ml pristane. ANA and anti-dsDNA levels in serum were detected by indirect immunofluorescence. Interleukin 2 (IL-2), IL-4, IL-6, IL-17, and TNF-α were measured by Luminex technology. The serum BAFF level was measured using an Elisa kit. Twenty-four weeks after pristane administration, kidneys were removed, dissected, and stained with hematoxylin and eosin and periodic-acid Schiff. RESULT: At six months after injecting, the ANA titers in pristane-injected HBV(Tg) mice were significantly lower than pristane-injected BALB/c mice. IL-17, TNF-α, and BAFF levels were significantly higher in pristane-injected BALB/c mice than BALB/c mice and pristane-injected HBV(Tg) mice. IL-2, IL-4, and IL-6 levels were much higher in pristane-injected HBV(Tg) mice than pristane-injected BALB/c mice. In pristane-injected HBV(Tg) mice and HBV(Tg) mice, fewer glomerulonephritis changes were found in the kidneys. CONCLUSIONS: Our results showed that the incidence of SLE was much lower in HBV(Tg) mice, and that HBV infection helped the SLE mice survive high levels of inflammatory cytokines and severe renal damage. All these findings demonstrated the protective role of HBV in SLE patients via the immunoregulatory networks of the cytokines.