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1.  T cells as a therapeutic target in SLE 
Lupus  2015;24(0):351-363.
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a loss of tolerance to multiple endogenous antigens. SLE etiology remains largely unknown, despite recent insight into the immunopathogenesis of the disease. T cells are important in the development of the disease by amplifying the immune response and contributing to organ damage. Aberrant signaling, cytokine secretion and tissue homing displayed by SLE T cells have been extensively studied and the underlying pathogenic molecular mechanisms are starting to be elucidated. T-cell targeted treatments are being explored in SLE patients. This review is an update on the T-cell abnormalities and related therapeutic options in SLE.
doi:10.1177/0961203314556139
PMCID: PMC4372812  PMID: 25801878
Systemic lupus erythematosus; T cells; Interleukin-2 (IL-2); epigenetics; treatment
2.  Elevated BLyS levels in patients with systemic lupus erythematosus: Associated factors and responses to belimumab 
Lupus  2015;25(4):346-354.
Introduction
Patients with systemic lupus erythematosus (SLE) with B-lymphocyte stimulator (BLyS) levels ≥ 2 ng/mL are at increased risk of flare. A regression analysis was undertaken to identify routine clinical measures that correlate with BLyS ≥ 2 ng/mL. Efficacy and safety of belimumab 10 mg/kg were examined in patients with BLyS ≥ 2 ng/mL and < 2 ng/mL.
Methods
Data from BLISS-52 and -76 (N = 1684) were pooled post hoc. A univariate logistic regression was employed to identify factors predictive of baseline BLyS ≥ 2 ng/mL. Factors significant at the 0.05 level then entered a stepwise logistic regression as covariates. Efficacy endpoints included SLE responder index (SRI), ≥ 4-point reduction in Safety of Estrogens in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and risk of severe flare over 52 weeks. Adverse events (AEs) were analyzed for each treatment arm and BLyS subgroup.
Results
Baseline predictors of BLyS ≥ 2 ng/mL included positive anti-Smith (≥ 15 U/mL), low complement (C) 3 (< 900 mg/L), anti-double-stranded DNA (anti-dsDNA) 80–200 and ≥ 200 IU/mL, immunosuppressant usage, proteinuria, elevated C-reactive protein (CRP), and low total lymphocyte count for all patients. Belimumab 10 mg/kg led to significantly greater SRI responses over 52 weeks versus placebo in both BLyS subgroups, though treatment differences were numerically greater at Week 52 in the BLyS ≥ 2 ng/mL group (24.1%, p < 0.0001) compared with BLyS < 2 ng/mL (8.2%, p = 0.0158). Results were similar for ≥ 4-point reduction in SELENA-SLEDAI. Risk of severe flare over 52 weeks was significantly reduced with belimumab 10 mg/kg versus placebo in the BLyS ≥ 2 ng/mL group (p = 0.0002). AEs were similar across treatment arms and BLyS subgroups.
Conclusions
Positive anti-Smith, low C3, anti-dsDNA ≥ 80 IU/mL, immunosuppressant usage, proteinuria, elevated CRP, and low total lymphocyte count were predictors of BLyS ≥ 2 ng/mL. Monitoring these factors could identify patients with BLyS ≥ 2 ng/mL who are at risk of flare.
doi:10.1177/0961203315604909
PMCID: PMC4785993  PMID: 26385220
BLyS; belimumab; systemic lupus erythematosus; BLISS trials; regression analysis
3.  Longitudinal expression of type I interferon responsive genes in systemic lupus erythematosus 
Lupus  2009;18(11):980-989.
Cross-sectional studies of patients with systemic lupus erythematosus (SLE) have demonstrated an association between activation of type I interferon (IFN) pathway and disease activity. This study examined longitudinal changes in IFN-regulated gene expression in peripheral blood using microarrays. A cross-section of 66 patients from the Autoimmune Biomarkers Collaborative Network SLE archive was evaluated. We also examined paired samples from a 15 patient subset collected during a period of low disease activity (Baseline) and at a subsequent flare event, and baseline scores of 29 patients who maintained low disease activity. IFN response (IFNr) scores were calculated from three IFN-regulated genes. Overall, higher IFNr scores were associated with increased disease activity. However, IFNr scores were not significantly different between the paired Baseline and Flare samples. An extended longitudinal analysis in 11 patients indicated little change in IFNr scores over time, even during dynamic disease activity. In patients with low disease activity, IFNr scores were not different between patients who experienced a subsequent flare and those who maintained low disease activity. In summary, although higher IFNr scores were associated with greater disease activity, IFNr scores of individual patients did not correlate with changes in disease severity or flare risk.
doi:10.1177/0961203309105529
PMCID: PMC4752166  PMID: 19762399
gene expression; longitudinal analysis; systemic lupus erythematosus; type I interferon
4.  Effects of Obesity on Health-Related Quality of Life in Juvenile-Onset Systemic Lupus Erythematosus 
Lupus  2014;24(2):191-197.
Objective
Evaluate the effects of obesity on health-related quality of life (HRQOL) measures in juvenile-onset SLE (jSLE).
Methods
Obesity was defined as a body mass index (BMI) ≥ 95th% according to the sex-specific Center for Disease Control body mass index-for-age charts and determined in a multicenter cohort of jSLE patients. In this secondary analysis, the domain and summary scores of the Pediatric Quality of Life (PedsQL) Inventory and the Child Health Questionnaire (CHQ) of obese jSLE patients were compared to those of non-obese jSLE patients as well as historical obese and non-obese healthy controls. Mixed-effects modeling was performed to evaluate the relationship between obesity and HRQOL measures.
Results
Among the 202 jSLE patients, 25% (n=51) were obese. Obesity had a significant negative impact on HRQOL in jSLE, even after adjusting for differences in current corticosteroid use, disease activity, disease damage, gender, and race between groups. Obese jSLE patients had lower physical functioning compared to non-obese jSLE patients, and to non-obese and obese healthy controls. Compared to their non-obese counterparts, obese jSLE patients also had worse school functioning, more pain, worse social functioning, and emotional functioning. Parents of obese jSLE patients worry more. The CHQ scores for obese jSLE patients were also worse compared to non-obese jSLE patients in several other domains
Conclusion
Our study demonstrates the detrimental effects of obesity on patient-reported outcomes in jSLE. This supports the importance of weight management for the therapeutic plan of jSLE.
doi:10.1177/0961203314555537
PMCID: PMC4305011  PMID: 25335488
SLE; Obesity; Children
5.  Anti-C1q Antibodies in Systemic Lupus Erythematosus 
Lupus  2014;24(1):42-49.
Objective
Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs. rheumatic disease controls) and the association with SLE manifestations in an international multi-center study.
Methods
Information and blood samples were obtained in a cross-sectional study from patients with SLE (n=308) and other rheumatologic diseases (n=389) from 25 clinical sites (84% female, 68% Caucasian, 17% African descent, 8% Asian, 7% other). IgG anti-C1q against the collagen-like region was measured by ELISA.
Results
Prevalence of anti-C1q was 28% (86/308) in patients with SLE and 13% (49/389) in controls (OR=2.7, 95% CI: 1.8-4, p<0.001). Anti-C1q was associated with proteinuria (OR=3.0, 95% CI: 1.7-5.1, p<0.001), red cell casts (OR=2.6, 95% CI: 1.2-5.4, p=0.015), anti-dsDNA (OR=3.4, 95% CI: 1.9-6.1, p<0.001) and anti-Smith (OR=2.8, 95% CI: 1.5-5.0, p=0.01). Anti-C1q was independently associated with renal involvement after adjustment for demographics, ANA, anti-dsDNA and low complement (OR=2.3, 95% CI: 1.3-4.2, p<0.01). Simultaneously positive anti-C1q, anti-dsDNA and low complement was strongly associated with renal involvement (OR=14.9, 95% CI: 5.8-38.4, p<0.01).
Conclusions
Anti-C1q was more common in patients with SLE and those of Asian race/ethnicity. We confirmed a significant association of anti-C1q with renal involvement, independent of demographics and other serologies. Anti-C1q in combination with anti-dsDNA and low complement was the strongest serological association with renal involvement. These data support the usefulness of anti-C1q in SLE, especially in lupus nephritis.
doi:10.1177/0961203314547791
PMCID: PMC4268323  PMID: 25124676
6.  Elevated C-reactive protein and self-reported disease activity in systemic lupus erythematosus 
Lupus  2014;23(14):1460-1467.
C-reactive protein (CRP), a biomarker of inflammation, has been associated with increased disease activity in rheumatoid arthritis. However, the association in systemic lupus erythematosus (SLE) remains unclear. We examined the association of CRP with self-reported disease activity in the Carolina Lupus Study and described differences by sociodemographic characteristics. The study included baseline and three-year follow-up data on 107 African-American and 69 Caucasian SLE patients enrolled at a median 13 months since diagnosis. Models estimated prevalence differences in the association of baseline CRP with self-reported flares, adjusting for age, sex, race and education. Active disease or flare was reported by 59% at baseline and 58% at follow-up. Higher CRP (>10 μg/ml vs. <3 μg/ml) was associated with a 17% (95% CI: −20, 53%) higher prevalence of flare at baseline and a 26% (95% CI: −9, 62%) higher prevalence of flare at follow-up. These CRP-flare associations were notably stronger in patients with lower education at baseline and in African Americans at follow-up. These findings suggest CRP may be a useful marker in studies of SLE health disparities.
doi:10.1177/0961203314543915
PMCID: PMC4233128  PMID: 25057037
systemic lupus erythematosus; C-reactive protein; flares; socioeconomic factors
7.  Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus 
Lupus  2015;24(13):1437-1442.
Introduction
ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage.
Methods
SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria.
Results
SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition.
Conclusions
SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate.
doi:10.1177/0961203315591031
PMCID: PMC4616909  PMID: 26085597
SLE; MRL/Lpr mouse; inflammation; antinuclear antibody (ANA); nephritis; parasitic helminth; ES-62; MyD88
8.  Mitochondrial DNA damage is associated with damage accrual and disease duration in patients with Systemic Lupus Erythematosus 
Lupus  2014;23(11):1133-1141.
Objective
To determine the extent of mitochondrial DNA (mtDNA) damage in systemic lupus erythematosus (SLE) patients compared to healthy subjects and to determine the factors associated with mtDNA damage among SLE patients.
Methods
A cross-sectional study was performed in 86 SLE patients (per American College of Rheumatology classification criteria) and 86 healthy individuals matched for age and gender. Peripheral blood mononuclear cells (PBMCs) were collected from subjects to assess the relative amounts of mtDNA damage. Quantitative polymerase chain reaction assay was used to measure the frequency of mtDNA lesions and mtDNA abundance. Socioeconomic-demographic features, clinical manifestations, pharmacologic treatment, disease activity, and damage accrual were determined. Statistical analyses were performed using t test, pairwise correlation, and Pearson’s chi-square test (or Fisher’s exact test) as appropriate.
Results
Among SLE patients, 93.0% were women. The mean (SD) age was 38.0 (10.4) years and the mean (SD) disease duration was 8.7 (7.5) years. SLE patients exhibited increased levels of mtDNA damage as shown by higher levels of mtDNA lesions and decreased mtDNA abundance as compared to healthy individuals. There was a negative correlation between disease damage and mtDNA abundance and a positive correlation between mtDNA lesions and disease duration. No association was found between disease activity and mtDNA damage.
Conclusion
PBMCs from SLE patients exhibited more mtDNA damage compared to healthy subjects. Higher levels of mtDNA damage were observed among SLE patients with major organ involvement and damage accrual. These results suggest that mtDNA damage have a potential role in the pathogenesis of SLE.
doi:10.1177/0961203314537697
PMCID: PMC4156531  PMID: 24899636
Systemic lupus erythematosus; disease activity; disease damage; mitochondrial DNA; mitochondrial dysfunction; oxidative stress
9.  Clinical Manifestations and Survival among Adults with Systemic Lupus Erythematosus according to Age at Diagnosis 
Lupus  2014;23(8):778-784.
Objectives
To determine the effect of clinical and laboratory manifestations, and medication prescribing, on survival according to patient age at diagnosis in a large academic systemic lupus erythematosus (SLE) cohort.
METHODS
We identified SLE patients with a diagnosis at age ≥ 18, seen between 1970 through 2011, and with more than 2 visits to our lupus center. Data collection included SLE manifestations, serologies, other laboratory tests, medications, dates and causes of death. We examined characteristics of those diagnosed before age 50 (adult-onset) compared to those diagnosed at or after age 50 (late-onset) using descriptive statistics. We used Kaplan Meier curves with log rank tests to estimate five- and ten-year survival in age-stratified cohorts. Predictors of ten-year survival were assessed using Cox regression models, adjusted for calendar year, race/ethnicity, sex, lupus nephritis and medication use.
RESULTS
Of 928 SLE patients, the mean age at diagnosis was 35. Among the adult-onset group, there was significantly higher prevalence of malar rashes and lupus nephritis. Glucocorticoids, azathioprine, mycophenolate and cyclophosphamide use were also more frequently in the adult-onset group compared to the late-onset group. Five-year survival rates were 99.5% and 94.9% and ten-year survival rates were 97.8% and 89.5%, among those diagnosed before and at or after age 50. In the entire cohort, increasing age at diagnosis, male sex and Black race were statistically significant predictors of reduced ten-year survival. Compared to those diagnosed before age 50, the late-onset group had a multivariable-adjusted hazard ratio for ten- year risk of death of 4.96 (95% CI 1.75–14.08). The most frequent cause of known death was a lupus manifestation, followed by cardiovascular disease and infection.
CONCLUSIONS
In our cohort, several demographic features, SLE manifestations, and medication prescribing differed between those with adult-onset and late-onset SLE. Ten-year survival rates were high for both groups, but relatively lower among late-onset patients. A lupus manifestation as the cause of death was more common among adult-onset compared with late-onset patients.
doi:10.1177/0961203314526291
PMCID: PMC4157121  PMID: 24608964
SLE (systemic lupus erythematosus); Survival Mortality; Outcomes; Age; Male
10.  Genetic Variation and Coronary Atherosclerosis in Patients with Systemic Lupus Erythematosus 
Lupus  2014;23(9):876-880.
Summary
Coronary artery disease is the major cause of mortality in patients with systemic lupus erythematosus (SLE). Increased cardiovascular risk in SLE is not explained by traditional risk factors. We examined the hypothesis that genetic variation contributes to the presence of coronary atherosclerosis in patients with SLE. The genotypes of single-nucleotide polymorphisms (SNP) in 152 candidate genes linked with autoimmune or cardiovascular risk were determined in 125 patients with SLE. Coronary artery calcium (CAC), a measure of coronary atherosclerosis, was detected in 32 patients (26%) by electron-beam computed tomography. Polymorphism in twenty of the candidate genes (ADAM33, ADIPOQ, CCL5, CCR7, CDKN2B, CSF1, IL4, IL12A, IL23R, INS, IRF5, MIF, MS4A1, PTGS1, PTPN22, RETN, SELE, TNFSF4, TNFRSF11B, and VCAM1) were nominally associated with the presence of CAC (p-values = 0.001–0.047 after adjustment for age, sex and race). Some of these are known susceptibility genes for SLE and others have been implicated in cardiovascular disease in other populations. No association withstood false discovery rate adjustment. Replication studies in additional cohorts of patients with SLE may be informative.
doi:10.1177/0961203314530019
PMCID: PMC4185017  PMID: 24699314
systemic lupus erythematosus; genetic variation; SNP; atherosclerosis
11.  Comparison of Renal Response Parameters for Juvenile Membranous Plus Proliferative Lupus Nephritis Versus Isolated Proliferative Lupus Nephritis: A Cross-Sectional Analysis of the CARRA Registry 
Lupus  2014;23(9):898-904.
Lupus nephritis (LN) affects many patients with juvenile systemic lupus erythematosus (SLE) and is a significant cause of disease morbidity. Membraneous plus proliferative LN (M+PLN) may represent a more difficult to treat subtype of juvenile LN, compared to isolated proliferative LN (PLN.) In this retrospective observational study, we utilized data from the Childhood Arthritis and Rheumatism Research Alliance (CARRA) registry to compare response rates for pediatric M+PLN versus PLN. Response was assessed at the most recent CARRA registry visit gathered ≥ 6 months after diagnostic kidney biopsy. Estimated glomerular filtration rate (GFR) less than 90 ml/min/1.73m2, indicating renal insufficiency, was found in 16.1% of patients with M+PLN and 6.1% of patients with PLN (P=0.071). We found no significant difference in achievement of response in either hematuria or proteinuria between PLN and M+PLN groups or between subgroups determined by presence of class III vs. class IV proliferative disease. Exposure rates to mycophenolate, cyclophosphamide, and rituximab were similar between groups. Future studies will be necessary to correlate pediatric LN renal histology data with treatment response as well as other disease outcome measures.
doi:10.1177/0961203314531841
PMCID: PMC4194184  PMID: 24729278
lupus; nephritis; response; membranous; proliferative; pediatric; CARRA registry
12.  Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE 
Lupus  2015;24(10):1087-1094.
Introduction
The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS.
Aims
The primary aim is to demonstrate, in patients with APS and previous VTE, with or without systemic lupus erythematosus (SLE), that the intensity of anticoagulation achieved with rivaroxaban is not inferior to that of warfarin. Secondary aims are to compare rates of recurrent thrombosis, bleeding and the quality of life in patients on rivaroxaban with those on warfarin.
Methods
Rivaroxaban in antiphospholipid syndrome (RAPS) is a phase II/III prospective non-inferiority RCT in which eligible patients with APS, with or without SLE, who are on warfarin, target international normalized ratio (INR) 2.5 for previous VTE, will be randomized either to continue warfarin (standard of care) or to switch to rivaroxaban. Intensity of anticoagulation will be assessed using thrombin generation (TG) testing, with the primary outcome the percentage change in endogenous thrombin potential (ETP) from randomization to day 42. Other TG parameters, markers of in vivo coagulation activation, prothrombin fragment 1.2, thrombin antithrombin complex and D-dimer, will also be assessed.
Discussion
If RAPS demonstrates i) that the anticoagulant effect of rivaroxaban is not inferior to that of warfarin and ii) the absence of any adverse effects that cause concern with regard to the use of rivaroxaban, this would provide sufficient supporting evidence to make rivaroxaban a standard of care for the treatment of APS patients with previous VTE, requiring a target INR of 2.5.
doi:10.1177/0961203315581207
PMCID: PMC4527976  PMID: 25940537
Antiphospholipid syndrome; systemic lupus erythematosus; venous thromboembolism; rivaroxaban; warfarin; thrombin generation
13.  Application and Feasibility of Systemic Lupus Erythematosus Reproductive Health Care Quality Indicators at a Public Urban Rheumatology Clinic 
Lupus  2014;24(2):203-209.
Objective
Quality indicators (QIs) are evidence-based processes of care designed to represent the current standard of care. Reproductive health QIs for the care of patients with systemic lupus erythematosus (SLE) have recently been developed, and examine areas such as pregnancy screening for autoantibodies, treatment of pregnancy associated antiphospholipid syndrome, and contraceptive counseling. This study was designed to investigate our performance on these QIs and to explore potential gaps in care and demographic predictors of adherence to the QIs in a safety net hospital.
METHODS
We performed a retrospective record review of patients with a diagnosis of SLE at Denver Health Medical Center (DH) through an electronic query of existing medical records and via chart review. Data was limited to female patients between the ages of 18–50 who were seen between July 2006 and August 2011.
RESULTS
One hundred and thirty-seven female patients between the ages of 18–50 were identified by ICD-9 code and confirmed by chart review to have SLE. Of these, 122 patients met the updated 1997 American College of Rheumatology SLE criteria and had an intact reproductive system. Only 15 pregnancies were documented during this 5-year period and adherence to autoantibody screening was 100 percent. We did not have any patients who were pregnant and met criteria for pregnancy associated antiphospholipid syndrome. Sixty-five patients (53%) received potentially teratogenic medications and 30 (46%) had documented discussions about these medications’ potential risk upon their initiation. Predictors of whether patients received appropriate counseling included younger age (OR 0.93, CI 0.87-0.98) and those who did not describe English as their primary language (OR 0.29, CI 0.09-0.96). These remained statistically significant in multivariate analysis.
CONCLUSIONS
We were able to detect an important gap in care regarding teratogenic medication education to SLE patients of childbearing potential in our public health academic clinic as only 1 in 2 eligible patients had documented appropriate counseling at the initiation of a teratogenic medication.
doi:10.1177/0961203314552832
PMCID: PMC4465250  PMID: 25267076
Systemic Lupus Erythematous; Quality Indicators Health Care; Reproductive Health; Teratogens; Contraception
14.  Aberrant regulation of the integrin very late antigen-4 in systemic lupus erythematosus 
Lupus  2013;22(3):297-306.
Integrin very late antigen-4 (VLA4) is induced during inflammation and can regulate monocyte migration. It has been implicated in atherogenesis, a significant concern in systemic lupus erythematosus (SLE). The aim of this study was to define VLA4 expression in SLE monocytes. Flow cytometry, reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry staining with confocal microscopy were used to evaluate VLA4 expression in SLE patients and controls. We found elevated expression of VLA4 in SLE patients with significantly increased VLA4 staining intracellularly compared to control. Exposure of control monocytes to SLE sera or immune complexes led to increased intracellular expression, and immune complexes were capable of driving redistribution of surface VLA4 to the cytoplasm. Therefore, VLA4 was found to be subject to complex regulation with SLE sera driving both RNA expression and redistribution of protein. Stimulation of SLE monocytes with a VLA4 ligand induced significant TNFα expression, confirming a functional effect. This behavior may contribute to increased atherosclerosis and monocyte infiltrates in end organs.
doi:10.1177/0961203313475691
PMCID: PMC4418519  PMID: 23439470
Integrin; monocyte; systemic lupus erythematosus; atherosclerosis; immune complex
15.  Environmental Exposures, Epigenetic Changes and the Risk of Lupus 
Lupus  2014;23(6):568-576.
A dose-dependent combination of environmental exposures, estrogenic hormones and genetic predisposition is thought to be required for lupus to develop and flare, but how the environment modifies the immune system in genetically predisposed people is unclear. Current evidence indicates that environmental agents that inhibit DNA methylation can convert normal antigen-specific CD4+ T lymphocytes into autoreactive, cytotoxic, pro-inflammatory cells that are sufficient to cause lupus-like autoimmunity in animal models, and that the same changes in DNA methylation characterize CD4+ T cells from patients with active lupus. Environmental agents implicated in inhibiting T cell DNA methylation include the lupus-inducing drugs procainamide and hydralazine, as well as diet, and agents causing oxidative stress, such as smoking, UV light exposure, and infections, which have been associated with lupus onset or disease activity. Other studies demonstrate that demethylated T cells cause only anti-DNA antibodies in mice lacking a genetic predisposition to lupus, but are sufficient to cause lupus-like autoimmunity in genetically predisposed mice and likely people, and that estrogens augment the disease. Collectively, these studies suggest that environmental agents that inhibit DNA methylation, together with lupus genes and estrogens or endocrine disruptors, combine in a dose-dependent fashion to cause lupus flares.
doi:10.1177/0961203313499419
PMCID: PMC4000546  PMID: 24763540
Lupus; epigenetics; environment; oxidative stress; mercury; endocrine disruptors; genetics
16.  Diet, Microbiota and Autoimmune Diseases 
Lupus  2014;23(6):518-526.
There is growing evidence that the commensal bacteria in the gastrointestinal tract (the gut microbiota) influence the development of autoimmunity in rodent models. Since humans have co-evolved with commensals for millennia, it is likely that people, who are genetically predisposed to autoimmunity, harbor gut microbial communities that similarly influence the onset and/or severity of disease. Beyond the current efforts to identify such disease-promoting or –preventing commensals (‘pathobionts’ or ‘symbionts’), it will be important to determine what factors modulate them. Dietary changes are known to affect both the composition and function of the gut microbial communities, which in turn can alter the innate and adaptive immune system. In this review, we focus on the relationships between diet, microbiota, and autoimmune diseases. We hypothesize that the beneficial and life-prolonging effects of caloric restriction on a variety of autoimmune models including lupus might partly be mediated by its effects on the gut microbiome and associated virome, the collection of all viruses in the gut. We give recent examples of the immunomodulatory potential of select gut commensals and their products or diet-derived metabolites in murine models of arthritis, multiple sclerosis and type 1 diabetes. Lastly, we summarize the published phenotypes of germ-free mouse models of lupus and speculate on any role of the diet-sensitive microbiome and virome in systemic lupus and the related antiphospholipid syndrome.
doi:10.1177/0961203313501401
PMCID: PMC4009622  PMID: 24763536
Microbiome; virome; caloric restriction; autoimmunity; molecular mimicry
17.  Pesticides, chemical and industrial exposures in relation to systemic lupus erythematosus 
Lupus  2014;23(6):527-536.
Growing evidence suggests exposure to chemicals and industrial pollutants may increase risk of SLE. Here we review research on SLE associations with occupational and industrial exposures, primarily drawing on studies in human populations and summarizing epidemiologic research published in the past decade. The association of occupational silica exposure with SLE is well established, but key questions remain, including the required dose and susceptibility factors, and SLE risk due to other silicate exposures. Research on SLE and other exposures is less well developed, though several potential associations merit further consideration due to the consistency of preliminary human findings, experimental animal research, and biologic plausibility. These include pesticides and solvents, for which experimental findings also support investigation of specific agents, including organochlorines and trichloroethylene. Experimental findings and biologic plausibility suggest research on SLE and occupational exposure to hydrocarbons (i.e., mineral oils) is warranted, especially given the widespread exposures in the population. Experimental and limited human findings support further investigation of SLE related to mercury exposure, especially in dental occupations. Research on environmental risk factors in risk-enriched cohorts (family based) is recommended, as is further investigation of exposures in relation to intermediate markers of effect (e.g., antinuclear antibodies), clinical features (e.g., nephritis) and outcomes.
doi:10.1177/0961203313511680
PMCID: PMC4020505  PMID: 24763537
Systemic Lupus Erythematosus; environmental risk factors; occupational exposures; silica; pesticides; epidemiology
18.  Smoking is not associated with autoantibody production in systemic lupus erythematosus patients, unaffected first-degree relatives, nor healthy controls 
Lupus  2014;23(4):360-369.
Objective
To examine whether smoking is associated with autoantibody production in systemic lupus erythematosus (SLE) patients, unaffected first-degree relatives (FDR) of individuals with SLE - a group at increased risk of developing SLE, or unaffected, unrelated controls.
Methods
Detailed demographic, environmental, clinical, and therapeutic information was collected by questionnaire on 1,242 SLE patients, 981 FDRs, and 946 controls in the Lupus Family Registry and Repository; a blood sample was obtained. All sera were tested for multiple lupus autoantibodies by immunofluorescence and luminex bead-based assays. Generalized estimating equations, adjusting for age, gender, and ethnicity and accounting for correlation within families, were used to assess smoking status with the dichotomous outcome variables of positivity for SLE status, positivity of ANA by immunofluorescence (≥ 1:120), positivity for ≥ 1 autoantibody by the luminex assay, and positivity for each of the 11 autoantibodies.
Results
Current smoking was associated with being positive for ≥ 1 autoantibody (excluding ANA) (adjusted OR=1.53, 95% CI 1.04–2.24) in our subjects with SLE. No association was observed in unaffected FDRs or healthy controls. Former smoking was associated with anti-Ro/SS-A60 in our unaffected FDRs. There was an increased association with anti-nRNP A seropositivity, as well as a decreased association with anti-nRNP 68 positivity, in current smokers in SLE subjects.
Conclusions
No clear association between smoking status and individual autoantibodies was detected in SLE patients, unaffected FDRs, nor healthy controls within this collection. The association of smoking with SLE may therefore manifest its risk through mechanisms outside of autoantibody production, at least for the specificities tested.
doi:10.1177/0961203314520838
PMCID: PMC3954895  PMID: 24449338
Smoking; autoantibodies; systemic lupus erythematosus
19.  Differential immunoglobulin class-mediated responses to components of the U1 small nuclear ribonucleoprotein in Systemic Lupus Erythematosus and Mixed Connective Tissue Disease 
Lupus  2013;22(13):10.1177/0961203313508444.
Summary
Objective
To determine whether patients with Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease (MCTD) possess differential IgM-and IgG-specific reactivity against peptides from the U1 small nuclear ribonucleoprotein particle (U1 snRNP).
Methods
The IgM- and IgG-mediated responses against 15 peptides from subunits of the U1 snRNP were assessed by indirect ELISAs in sera from patients with SLE and MCTD and healthy individuals (n = 81, 41 and 31, respectively). Additionally, 42 laboratory tests and 40 clinical symptoms were evaluated to uncover potential differences. Binomial logistic regression analyses (BLR) were performed to construct models to support the independent nature of SLE and MCTD. Receiver Operating Characteristic (ROC) curves corroborated the classification power of the models.
Results
We analyzed IgM and IgG anti-U1 snRNP titers to classify SLE and MCTD patients. IgG anti-U1 snRNP reactivity segregates SLE and MCTD from non-disease controls with an accuracy of 94.1% while IgM-specific anti-U1 snRNP responses distinguish SLE from MCTD patients with an accuracy of 71.3%. Comparison of the IgG and IgM anti-U1 snRNP approach with clinical tests used for diagnosing SLE and MCTD revealed that our method is the best classification tool of those analyzed (p ≤ 0.0001).
Conclusions
Our IgM anti-U1 snRNP system along with lab tests and symptoms provide additional molecular and clinical evidence to support the hypothesis that SLE and MCTD may be distinct syndromes.
doi:10.1177/0961203313508444
PMCID: PMC3875166  PMID: 24158973
Systemic Lupus Erythematosus (SLE); Mixed Connective Tissue Disease (MCTD); immunoglobulin M (IgM); U1 small nuclear ribonucleoprotein particle (U1 snRNP); auto-immune disorders; classification criteria
20.  Hypogammaglobulinemia in Pediatric Systemic Lupus Erythematosus 
Lupus  2013;22(13):1382-1387.
Objective
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease typically associated with elevated serum immunoglobulin G (IgG). Hypogammaglobulinemia in SLE patients has been attributed to immunosuppressive treatment or a transient effect associated with nephrotic syndrome. We retrospectively reviewed pediatric SLE patients from a single institution to identify patients with hypogammaglobulinemia and risk factors for hypogammaglobulinemia.
Methods
116 pediatric SLE cases from 1997–2011 were reviewed and patients with hypogammaglobulinemia (IgG <500 mg/dL) were identified. The two cohorts were evaluated for association with age, sex, presence of lupus nephritis at SLE diagnosis, disease activity at diagnosis, initial IgG level, and drug treatment.
Results
Eighty-six patients were included in our study, with a median age of 15 years and a median follow-up of 39.5 months. Seven percent (6/86) of patients had hypogammaglobulinemia with a median onset of 27 months (0–72 months) after SLE diagnosis. Significant associations were noted for white race (p-value 0.029), male sex (p-value 0.009), and the presence of lupus nephritis at SLE diagnosis (p-value of 0.004). Use of immunosuppressive treatment did not show a statistical association with hypogammaglobulinemia, although 2 of the patients with hypogammaglobulinemia did receive rituximab. Most patients with hypogammaglobulinemia received intravenous immunoglobulin (IVIG) replacement therapy due to infections and/or concern for infection.
Conclusion
Measurement of immunoglobulin levels during treatment in SLE could help identify patients with hypogammaglobulinemia that might require more aggressive follow-up to monitor for increased risk of infection and need of IVIG treatment. A prospective study is needed to validate associated risk factors identified in this study.
doi:10.1177/0961203313507990
PMCID: PMC3840537  PMID: 24106215
Systemic Lupus Erythematosus; Pediatrics; Hypogammaglobulinemia
21.  NADPH oxidase and nitric oxide synthase dependent superoxide production is increased in proliferative lupus nephritis 
Lupus  2013;22(13):1361-1370.
Objective
Lupus nephritis (LN) is an immune complex-mediated glomerulonephritis. Proliferative LN (PLN, International Society of Nephrology and Renal Pathology Society (ISN/RPS) classes III and IV)) often leads to renal injury or failure despite traditional induction and maintenance therapy. Successful targeted therapeutic development requires insight into mediators of inflammation in PLN. Superoxide (SO) and its metabolites are mediators of the innate immune response through their ability to mediate reduction-oxidation signaling. Endothelial nitric oxide synthase (eNOS) modulates inflammatory responses in endothelial cells. We hypothesized that markers of SO production would be increased in active PLN and that SO production would be dependent on the activity of select enzymes in the renal cortex.
Methods
Patients with systemic lupus erythematosus were enrolled at the time of renal biopsy for active LN of all classes. Serum collected at baseline was analyzed by HPLC with electrochemical detection for markers of SO production (durable modifications of serum protein Tyr ultimately requiring SO as a substrate). Renal cortex from MRL/MpJ-FASlpr (MRL/lpr) mice with and without functional eNOS was analyzed during active disease for superoxide (SO) production with and without inhibitors of SO producing enzymes.
Results
Serum protein modifications indicative of total SO production were significantly higher in patients with PLN. These markers were increased in association with more active, inflammatory PLN. Mice lacking functional eNOS had 80% higher levels of renal cortical SO during active disease, and inhibitors of nitric oxide synthase and NADPH oxidase reduced these levels by 60% and 77%, respectively.
Conclusion
These studies demonstrate that SO production is unique to active PLN in a NOS and NADPH oxidase-dependent fashion. These findings suggest the emulating or augmenting eNOS activity or inhibiting NADPH oxidase SO production may be targets of therapy in patients with PLN. The markers of SO production used in this study could rationally be used to select SO-modulating therapies and serve as pharmacodynamic indicators for dose titration.
doi:10.1177/0961203313507988
PMCID: PMC3839955  PMID: 24106214
Lupus nephritis; Systemic lupus erythematosus; Nitric oxide; Endothelial nitric oxide synthase; NADPH Oxidase; Proliferative lupus nephritis; Superoxide; Oxidation-reduction; Inflammation
22.  Annexin A5 anticoagulant activity in children with systemic lupus erythematosus and the association with antibodies to domain I of β2-glycoprotein I 
Lupus  2013;22(7):702-711.
Children with systemic lupus erythematosus (SLE) have a high prevalence of antiphospholipid (aPL) antibodies and are at increased risk for aPL-related thrombosis. We investigated the association between annexin A5 anticoagulant activity and antibodies to the domain I portion of β2-glycoprotein I (anti-DI antibodies), and propose a potential mechanism for the pathogenesis of aPL-related thrombosis. Using samples from 183 children with SLE collected during the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we examined resistance to the anticoagulant effects of annexin A5, using the annexin A5 resistance (A5R) assay, and evaluated for anti-DI IgG antibodies. Children with SLE had higher frequency of anti-D1 antibodies (p=0.014) and significantly reduced A5R compared to pediatric controls: mean A5R = 172 ± 30 % versus 242 ± 32 % (p<0.0001). Children with SLE and positive anti-DI antibodies had significantly lower mean A5R levels compared to those with negative anti-DI antibodies: mean A5R = 155 ± 24 % versus 177 ± 30% (p<0.0001). In multivariate analysis, anti-DI antibodies (p=0.013) and lupus anticoagulant (LA) (p=0.036) were both independently associated with reduced A5R. Children with SLE have significantly reduced annexin A5 anticoagulant activity that is associated with the presence of LA and anti-DI antibodies.
doi:10.1177/0961203313490241
PMCID: PMC4138827  PMID: 23690366
23.  Overexpression of methyl-CpG-binding protein 2 and autoimmunity: Evidence from MECP2 duplication syndrome, lupus, MECP2 transgenic and Mecp2 deficient mice 
Lupus  2013;22(9):870-872.
Methyl-CpG-binding protein 2 (MeCP2) is a key transcriptional regulator that can induce either silencing or activation of target genes. Genetic polymorphisms in the MECP2/IRAK1 locus have been associated with increased susceptibility to multiple autoimmune diseases such as lupus, primary Sjogren's syndrome, and more recently rheumatoid arthritis. Data from our group suggest that the disease risk variant in this locus is associated with gain of MeCP2 function. Recent findings indicate that MECP2 duplication in human results in defective T helper cell type 1 (TH1) response and IFN-γ production. Herein, we discuss the data from children with MECP2 duplication, human lupus, and from the human MECP2 transgenic and Mecp2 deficient mice to support a link between MECP2 overexpression and autoimmunity. We also provide findings from an Mecp2 deficient mouse that independently support a role for MeCP2 in the immune response and specifically in IFN-γ expression.
doi:10.1177/0961203313497119
PMCID: PMC3790641  PMID: 23861028
MeCP2; MECP2 duplication; lupus; autoimmunity; TH1 response
24.  Heart failure in a woman with SLE, anti-phospholipid syndrome and Fabry’s disease 
Lupus  2013;22(10):1070-1076.
We describe a female patient with systemic lupus erythematosus (SLE) also diagnosed with Fabry’s disease and anti-phospholipid antibody syndrome (APS). SLE and Fabry’s disease are both systemic diseases with variable clinical presentations. Recent studies have shown a relatively high incidence of late onset Fabry’s disease in female heterozygous individuals, suggesting that this condition could be under-diagnosed. We discuss a possible association between SLE and Fabry’s disease and consider the role of lipid abnormalities in the pathogenesis of SLE.
doi:10.1177/0961203313497116
PMCID: PMC4107795  PMID: 23864039
SLE; Fabry’s disease; Gb3
25.  Cancer complicating systemic lupus erythematosus – a dichotomy emerging from a nested case-control study 
Lupus  2013;22(9):919-927.
Objectives
We determined whether any individual cancers are increased or decreased in a cohort of 595 patients with systemic lupus erythematosus (SLE) followed for up to 32 years at the University College London Hospitals Lupus Clinic, looking for any associated clinical or serological factors and the prognosis after cancer diagnosis.
Methods
We undertook a careful retrospective review of the medical records and identified all individuals diagnosed with cancer. For controls, we selected three other patients in the cohort who had not developed cancer, carefully matched for age, sex, ethnicity and disease duration, to determine if any obvious differences emerged in a nested case-control design.
Results
Thirty-three patients developed cancer after being diagnosed with SLE. There was a statistically insignificant small increase in overall cancer risk, standardized incidence ratios (SIRs) 1.05 (95% CI 0.52–1.58) and increased SIRs for cervical, prostate, anal and pancreatic cancers and reduction in breast cancer SIRs.
Haematological and musculoskeletal manifestations, anticardiolipin and antithyroid globulin antibodies were found to be positively associated with cancer risk in multivariate analysis. There was no drug, dose or duration was associated with cancer risk. There was a reduction in survival with a cancer fatality rate of 84.2% (p < 0.0001).
Conclusion
We found a very small but statistically insignificant increased cancer risk with reduction in survival. Whereas some cancers appear to be more common in SLE, notably prostate and cervical cancer, others, particularly breast cancer, are less frequent. Multiple clinical and serological factors are involved in the increased risk of malignancy in SLE. No drug dose or duration effect was identified.
doi:10.1177/0961203313497118
PMCID: PMC4107831  PMID: 23857987
Systemic lupus erythematosus (SLE); neoplasm; risk factors; immunosuppressive therapy

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