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1.  Angiogenic Factor Imbalance Early in Pregnancy Predicts Adverse Outcomes in Patients with Lupus and Antiphospholipid Antibodies: Results of the PROMISSE Study 
American journal of obstetrics and gynecology  2015;214(1):108.e1-108.e14.
Background
Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high risk population. In non-autoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction.
Objective
To determine whether early dysregulation of circulating angiogenic factors, can predict APO in high risk SLE and/or APL pregnancies.
Study Design
We used data and samples from the PROMISSE Study (Predictors of pRegnancy Outcome: BioMarkers In antiphospholipid antibody Syndrome and Systemic Lupus Erythematosus), a multi-center prospective study that enrolled 492 pregnant women with SLE and/or APL between September 2003 and August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) were measured monthly and subjects followed for APO, classified as severe (PE<34 weeks, fetal/neonatal death, indicated pre-term delivery <30 weeks) or moderate (PE≥34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE).
Results
Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and sEng levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio=17.3 comparing highest and lowest quartiles, 95% CI: 3.5-84.8; positive predictive value (PPV)=61%; negative predictive value (NPV)=93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/ml) and sFlt1 in highest quartile (>1872 pg/ml; odds ratio=31.1; 95% CI: 8.0-121.9; PPV=58%; NPV=95%). Severe APO rate in this high risk subgroup was 94% (95%CI: 70%-99.8%), if lupus anticoagulant or history of high blood pressure is additionally present. In contrast, among patients with both sFlt1 <1872 pg/ml and PlGF >70.3 pg/ml, rate of severe APO was only 4.6% (95% CI: 2.1%-8.6%).
Conclusions
Circulating angiogenic factors measured during early gestation have a high negative predictive value in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of healthcare resources.
doi:10.1016/j.ajog.2015.09.066
PMCID: PMC4698098  PMID: 26432463
Angiogenic factors; preeclampsia; systemic lupus erythematosus; antiphospholipid antibodies; placental insufficiency
2.  Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus 
Clinical immunology (Orlando, Fla.)  2015;161(2):157-162.
Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.
doi:10.1016/j.clim.2015.09.007
PMCID: PMC4658308  PMID: 26385092
systemic lupus erythematosus; leptin pathway; gene polymorphisms
3.  Predictors of Pregnancy Outcome in a Prospective, Multiethnic Cohort of Lupus Patients 
Annals of internal medicine  2015;163(3):153-163.
Background
Since systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy is a major concern.
Objective
To identify predictors of adverse pregnancy outcome (APO) in inactive or stable active SLE patients
Design
Prospective Cohort
Setting
Multicenter
Patients
385 patients (49% non-Hispanic White; 31% prior nephritis) with SLE in PROMISSE. Exclusion criteria were: proteinuria >1000 mg/24 hour, creatinine >1.2 mg/dL, prednisone >20 mg/day, or multi-fetal pregnancy.
Measurements
APO included: fetal/neonatal death; birth <36 weeks due to placental insufficiency, hypertension, or preeclampsia; and small for gestational age (SGA) <5%. Disease activity was assessed by SLEPDAI and physician's global assessment (PGA).
Results
APO occurred in 19.0% (95% CI: 15.2% - 23.2%) of pregnancies, fetal death (4%), neonatal death (1%), preterm delivery (9%), and SGA (10%). Severe flares in the second and third trimester occurred in 2.5% and 3.0%, respectively. Baseline predictors of APO included lupus anticoagulant positive (OR = 8.32, 95% CI: 3.59-19.26), antihypertensive use (OR = 7.05, 95% CI: 3.05 - 16.31), PGA>1 (OR = 4.02, 95% CI: 1.84 - 8.82) and platelets (OR = 1.33 per 50K decrease, 95% CI:1.09-1.63); non-Hispanic White was protective (OR = 0.45, 95% CI: 0.24-0.84). Maternal flares, higher disease activity, and smaller increase in C3 later in pregnancy also predicted APO. Among women without baseline risk factors, the APO rate was 7.8%. For those either LAC positive, or LAC negative but non-White or Hispanic and taking antihypertensives, APO rate was 58%; fetal/neonatal mortality 22%.
Limitations
Excluded patients with high disease activity.
Conclusions
In pregnant SLE patients with inactive or stable mild/moderate disease, severe flares are infrequent, and absent specific risk factors, outcomes are favorable.
Primary Funding Source
National Institutes of Health
doi:10.7326/M14-2235
PMCID: PMC5113288  PMID: 26098843
4.  Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study 
Annals of the Rheumatic Diseases  2016;75(11):1909-1916.
Objectives
The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE).
Methods
431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52.
Results
Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment.
Conclusions
Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity.
Trial registration number
NCT01283139; Results.
doi:10.1136/annrheumdis-2015-208562
PMCID: PMC5099191  PMID: 27009916
Systemic Lupus Erythematosus; Treatment; Autoimmune Diseases
5.  Autoantibody‐Positive Healthy Individuals Display Unique Immune Profiles That May Regulate Autoimmunity 
Objective
Antinuclear antibodies (ANAs) are detected in ∼18% of females, yet autoimmune disease develops in only 5–8%. Immunologic differences between ANA‐positive healthy individuals and patients with systemic lupus erythematosus (SLE) may elucidate the regulatory mechanisms by which ANA‐positive individuals avoid transition to clinical autoimmune disease.
Methods
Healthy individuals (n = 790) were screened for autoantibodies specific for 11 antigens associated with lupus, systemic sclerosis, and Sjögren's syndrome. From this screening, 31 European American ANA‐positive healthy individuals were selected and demographically matched to ANA‐negative controls and SLE patients. Serum cytokine profiles, leukocyte subset frequency, and reactivity were analyzed by multiplex assays, immunophenotyping, and phosphospecific flow cytometry.
Results
Of 790 individuals screened, 57 (7%) were ANA‐positive. The majority of proinflammatory cytokines, including interferon‐γ (IFNγ), tumor necrosis factor, interleukin‐17 (IL‐17), and granulocyte colony‐stimulating factor, exhibited a stepwise increase in serum levels from ANA‐negative controls to ANA‐positive healthy individuals to SLE patients (P < 0.0001). IFNα, IFNβ, IL‐12p40, and stem cell factor/c‐Kit ligand were increased in SLE patients only (P < 0.05). B lymphocyte stimulator (BlyS) was elevated in SLE patients but decreased in ANA‐positive individuals (P < 0.001). Further, IL‐1 receptor antagonist (IL‐1Ra) was down‐regulated in SLE patients only (P < 0.0001). ANA‐positive individuals had increased frequencies of monocytes, memory B cells, and plasmablasts and increased levels of pSTAT‐1 and pSTAT‐3 following IFNα stimulation compared with ANA‐negative controls (P < 0.05).
Conclusion
ANA‐positive healthy individuals exhibit dysregulation in multiple immune pathways yet differ from SLE patients by the absence of elevated IFNs, BLyS, IL‐12p40, and stem cell factor/c‐Kit ligand. Further, severely decreased levels of IL‐1Ra in SLE patients compared with ANA‐positive individuals may contribute to disease development. These results highlight the importance of IFN‐related pathways and regulatory elements in SLE pathogenesis.
doi:10.1002/art.39706
PMCID: PMC5042816  PMID: 27059145
6.  Impact of heart rate variability, a marker for cardiac health, on lupus disease activity 
Background
Decreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). We examined the relationship of HRV with SLE disease activity and selected cytokine pathways.
Methods
Fifty-three patients from the Oklahoma Lupus Cohort were evaluated at two visits each. Clinical assessments included the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group (BILAG) index, physician global assessment (PGA), and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index. HRV was assessed with a 5-minute electrocardiogram, and the following HRV parameters were calculated: square root of the mean of the squares of differences between adjacent NN intervals (RMSSD), percentage of pairs of adjacent NN intervals differing by more than 50 milliseconds (pNN50), high-frequency power (HF power), and low frequency to high frequency (LF/HF) ratio, which reflects sympathetic/vagal balance. Plasma cytokine levels were measured with a multiplex, bead-based immunoassay. Serum B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were measured with an enzyme-linked immunosorbent assay. Linear regression analysis was applied.
Results
Baseline HRV (pNN50, HF power, LF/HF ratio) was inversely related to disease activity (BILAG, PGA) and flare. Changes in RMSSD between visits were inversely related to changes in SLEDAI (p = 0.007). Age, caffeine, tobacco and medication use had no impact on HRV. Plasma soluble tumor necrosis factor receptor II (sTNFRII) and monokine induced by interferon gamma (MIG) were inversely related with all baseline measures of HRV (p = 0.039 to <0.001). Plasma stem cell factor (SCF), interleukin (IL)-1 receptor antagonist (IL-1RA), and IL-15 showed similar inverse relationships with baseline HRV, and weaker trends were observed for interferon (IFN)-α, interferon gamma-induced protein (IP)-10, and serum BLyS. Changes in the LF/HF ratio between visits were also associated with changes in sTNFRII (p = 0.021), MIG (p = 0.003), IFN-α (p = 0.012), SCF (p = 0.001), IL-1RA (p = 0.023), and IL-15 (p = 0.010). On the basis of multivariate linear regression, MIG was an independent predictor of baseline HRV after adjusting for plasma IL-1RA, SCF, IFN-α, IP-10, and serum BLyS. In a similar model, the sTNFRII impact remained significant after adjusting for the same variables.
Conclusions
Impaired HRV, particularly the LF/HF ratio, is associated with lupus disease activity and several cytokines related to IFN type II and TNF pathways. The strongest association was with MIG and sTNFRII, expanding previous immune connections of vagal signaling.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-1087-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-1087-x
PMCID: PMC5010705  PMID: 27590046
Systemic lupus erythematosus; Disease activity; Heart rate variability; Cytokines
7.  A Phase 3, Randomized, Placebo-Controlled Study of Belimumab, a Monoclonal Antibody That Inhibits BLyS, in Patients With Systemic Lupus Erythematosus 
Arthritis and rheumatism  2011;63(12):3918-3930.
Objective
To assess the efficacy/safety of the B-lymphocyte stimulator inhibitor belimumab/standard-of-care (SOC) versus placebo/SOC in active systemic lupus erythematosus (SLE).
Methods
In a multicenter, randomized, controlled, phase 3 trial, 819 antinuclear antibody- or anti-dsDNA-positive SLE patients with Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) ≥ 6 were randomized (1:1:1 ratio) to receive intravenous belimumab 1 or 10 mg/kg, or placebo on days 0, 14, and 28, and then every 28 days for 72 weeks. Primary efficacy analyses: SLE Responder Index (SRI) at week 52 (≥ 4-point reduction in SELENA-SLEDAI; no new British Isles Lupus Assessment Group A and < 2 new B organ domain scores; no worsening in Physician’s Global Assessment).
Results
Belimumab 10 mg/kg plus SOC met the primary efficacy endpoint: significantly greater SRI response at week 52 than placebo (43.2% versus 33.5%; P = 0.017); the rate with belimumab 1 mg/kg was 40.6% (P = 0.089). Week-76 response rates: 32.4%, 39.1%, and 38.5% with placebo, and belimumab 1 and 10 mg/kg, respectively. In post-hoc sensitivity analyses evaluating higher SELENA-SLEDAI thresholds, belimumab 10 mg/kg achieved better discrimination at weeks 52/76. Risk of severe SELENA-SLEDAI flares over 76 weeks was reduced with belimumab 1 mg/kg (34%; P = 0.023) and 10 mg/kg (23%; P = 0.13). Serious and severe adverse events including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups.
Conclusion
Belimumab plus SOC significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well-tolerated in SLE.
doi:10.1002/art.30613
PMCID: PMC5007058  PMID: 22127708
8.  Renal involvement in lupus is characterized by unique DNA methylation changes in naïve CD4+ T cells 
Journal of autoimmunity  2015;61:29-35.
Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement. The tyrosine kinase gene TNK2 involved in cell trafficking and tissue invasion, and the phosphatase gene DUSP5 which dephosphorylates and inhibits the ERK signaling pathway, were among the most hypomethylated. Independent of disease activity, renal involvement is characterized by more robust demethylation in interferon regulated genes differentially methylated in both sets of lupus patients with and without renal involvement (fold change 1.4, P = 0.0014). The type-I interferon master regulator gene IRF7 is only hypomethylated in lupus patients with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, IRF7, ISG15, ISG20, ITGAX, and PARP12 (P = 1.78 × 10−6). Among the CG sites only hypomethylated with renal involvement, CG10152449 in CHST12 has a sensitivity of 85.7% and a specificity of 64.3% for stratifying lupus patients for a history of renal involvement (P = 0.0029). Our data identified novel epigenetic susceptibility loci that are differentially methylated with renal involvement in lupus. These loci will help better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvement in lupus.
doi:10.1016/j.jaut.2015.05.003
PMCID: PMC4497927  PMID: 26005050
Lupus; Nephritis; Epigenetics; Methylation; Biomarker; EWAS
9.  Mood Disorders in Systemic Lupus Erythematosus 
Objective
To determine the frequency, clinical and autoantibody associations and outcome of mood disorders in a multi-ethnic/racial, prospective, inception cohort of SLE patients.
Methods
Patients were assessed annually for mood disorders (4 types as per DSM-IV) and 18 other neuropsychiatric (NP) events. Global disease activity (SLEDAI-2K), SLICC/ACR damage index (SDI) and SF-36 subscale, mental (MCS) and physical (PCS) component summary scores were collected. Time to event, linear and ordinal regressions and multi-state models were used as appropriate.
Results
Of 1,827 SLE patients, 88.9% were female, 48.9% Caucasian, mean ± SD age 35.1±13.3 years, disease duration 5.6±4.8 months and follow-up 4.73±3.45 years. Over the study 863 (47.2%) patients had 1,627 NP events. Mood disorders occurred in 232/1827 (12.7%) patients and 98/256 (38.3%) events were attributed to SLE. The estimated cumulative incidence of any mood disorder after 10 years was 17.7% (95%CI=[15.1%,20.2%]). There was a greater risk of mood disorder in patients with concurrent NP events (p ≤ 0.01) and lower risk with Asian race/ethnicity (p=0.01) and immunosuppressive drugs (p=0.003). Mood disorders were associated with lower mental health subscale and MCS scores but not with SLEDAI-2K, SDI scores or lupus autoantibodies. Antidepressants were used in 168/232 (72.4%) patients with depression. 126/256 (49.2%) mood disorders resolved in 117/232 (50.4%) patients.
Conclusion
Mood disorders, the second most frequent NP event in SLE patients, have a negative impact on HRQoL and improve over time. The lack of association with global SLE disease activity, cumulative organ damage and lupus autoantibodies emphasize their multifactorial etiology and a role for non-lupus specific therapies.
doi:10.1002/art.39111
PMCID: PMC4485527  PMID: 25778456
Systemic lupus erythematosus; Mood disorders; Inception cohort; Outcomes research
10.  25-Hydroxyvitamin D and Cardiovascular Disease in Patients With Systemic Lupus Erythematosus: Data From a Large International Inception Cohort 
Arthritis care & research  2014;66(8):1167-1176.
Objective
An association between 25-hydroxyvitamin D (25[OH]D; vitamin D) deficiency and increased cardiovascular (CV) risk factors and CV disease (CVD) has been shown in general population studies. Vitamin D deficiency has been noted in systemic lupus erythematosus (SLE), and CVD is a major cause of morbidity and mortality in SLE. The objectives of this study were to estimate the associations of 25(OH)D levels with CV risk factors and to determine whether low baseline 25(OH)D levels predict future CV events in patients participating in an international inception cohort.
Methods
Data were collected on 890 participants, including demographics, SLE activity and damage assessments, CV risk factors and events, medications, laboratory assessments of 25(OH)D levels, and inflammatory markers. Multiple logistic and Cox regressions were used to estimate the associations of baseline 25(OH)D levels with baseline CV risk factors and CVD events. The models were adjusted for age, sex, race, season, and country, with and without body mass index.
Results
Patients in the higher quartiles of 25(OH)D were less likely to have hypertension and hyperlipidemia and were more likely to have lower C-reactive protein levels and lower Systemic Lupus Erythematosus Disease Activity Index 2000 scores at baseline when compared with the first quartile. Vitamin D levels were not independently associated with CVD event incidence; however, hazard ratios for CVD event incidence decreased with successively higher quartiles.
Conclusion
Lower baseline 25(OH)D levels are associated with higher risk for CV risk factors and more active SLE at baseline. There may be a trend toward a lower likelihood of CVD events in those with higher baseline 25(OH)D levels.
doi:10.1002/acr.22291
PMCID: PMC4844829  PMID: 24470118
11.  Impact of standard of care treatments and disease variables on outcomes in systemic lupus erythematosus trials: analysis from the Lupus Foundation of America Collective Data Analysis Initiative 
Objective
Most clinical trials for systemic lupus erythematosus (SLE) study the efficacy and safety of investigational agents added to variable background immunosuppressants, which has resulted in high response rates in patients treated with placebo plus standard of care (SOC) plus rescue measures. This project compared the impact of different SOC treatments and disease variables on the outcomes of SLE trials.
Material and Methods
Data were obtained from 981 patients receiving only SOC treatments in three nephritis and three general SLE trials to compare response and flare rates on the basis of the British Isles Lupus Assessment Group (BILAG) index, a measure common to all trials.
Results
For subjects enrolled in general SLE trials (n=173), those receiving mycophenolate mofetil (MMF) had more severe baseline disease, included more patients of African descent, and were administered higher baseline steroid doses compared with those receiving azathioprine (AZA) or methotrexate (MTX). BILAG responses at week 12 were MMF 35%, AZA 49%, MTX 34%, and no immunosuppressant (NIS) 65%. At week 52, MMF response rates increased to 41% despite reducing the steroid doses, but fell in all others (p=0.07, adjusted for steroids). Patients with severe disease activity at baseline (SDAB) who were defined as ≥1 BILAG A (severe) organ score had lower response rates to AZA or MTX but higher rates to MMF or NIS. Interim flares were highest with MMF [flares/patient–year (pt–yr)]. For all flares, rates were as follows: AZA 1.24, MMF 1.87, MTX 1.42, and NIS 0.81 and severe flares were as follows: AZA 0.66, MMF 1.29, MTX: 1.20, and NIS 0.55. Interim flares occurred in 71% of MMF-endpoint responders, 54% of AZA, 50% of MTX, and 22% of NIS. Patients with SDAB had more flares than moderate patients in the MMF and MTX groups: MMF: 2.39 vs. 1.03 flares/pt–yr (p=0.01), MTX: 2.33 vs. 0.63 (p=0.0002), severe flares: 1.87 vs. 0.34 for MMF (p=0.0013), 2.13 vs. 0.40 for MTX (p<0.0001). In nephritis trials (n=808), MMF subjects received less steroids than intravenous cyclophosphamide and response rates were similar, but MMF-treated patients had fewer severe flares (p=0.03).
Conclusion
Compared with MMF, AZA and MTX were associated with lower response rates at week 52. AZA-treated subjects had fewer flares and remained more stable in trials while engendering lower placebo plus SOC responses. MMF-treated subjects had frequent responses but more flares, suggesting that flares should be included in endpoint definitions. Given the likelihood of treatment selection bias, these data do not provide conclusions regarding efficacy but may help future trial designs by distinguishing factors definable at entry that are predictive of outcomes.
doi:10.5152/eurjrheum.2015.0048
PMCID: PMC5042268  PMID: 27708963
Systemic lupus; clinical trials; immunosuppressants
12.  Differential Expression of the Transcription Factor ARID3a in Lupus Patient Hematopoietic Progenitor Cells1 
Although hematopoietic progenitor/stem cells (HPSCs) are used for transplantation, characterization of the multiple subsets within this population in man has lagged behind similar studies in mice. We found that expression of the DNA-binding protein, ARID3a, in mouse stem cells was important for normal development of hematopoietic lineages; however, progenitors expressing ARID3a in man have not been defined. We previously showed increased numbers of ARID3a+ B cells in nearly half of systemic lupus erythematosus (SLE) patients, and that total numbers of ARID3a+ B cells were associated with increased disease severity. Because expression of ARID3a in those SLE patients occurred throughout all B cell subsets, we hypothesized that ARID3a expression in patient HSPCs might also be increased relative to expression in healthy controls. Our data now show that ARID3a expression is not limited to any defined subset of HPSCs in either healthy controls or SLE patients. Numbers of ARID3a+ HSPCs in SLE patients were increased over numbers of ARID3a+ cells in healthy controls. While all SLE-derived HPSCs exhibited poor colony formation in vitro compared to controls, SLE HPSCs with high numbers of ARID3a+ cells yielded increased numbers of cells expressing the early progenitor marker, CD34. SLE HPSCs with high numbers of ARID3a+ cells also more readily generated autoantibody producing cells than HPSCs with lower levels of ARID3a in a humanized mouse model. These data reveal new functions for ARID3a in early hematopoiesis and suggest that knowledge regarding ARID3a levels in HPSCs could be informative for applications requiring transplantation of those cells.
doi:10.4049/jimmunol.1401941
PMCID: PMC4297684  PMID: 25535283
13.  Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA 
Annals of the Rheumatic Diseases  2014;75(1):242-252.
Objectives
Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.
Methods
Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.
Results
The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10−4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10−7, OR 0.71; case-only pmeta=1.9×10−4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.
Conclusions
These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.
doi:10.1136/annrheumdis-2014-205584
PMCID: PMC4717392  PMID: 25180293
Systemic Lupus Erythematosus; Autoantibodies; Gene Polymorphism; B cells
14.  The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share 
Kottyan, Leah C. | Zoller, Erin E. | Bene, Jessica | Lu, Xiaoming | Kelly, Jennifer A. | Rupert, Andrew M. | Lessard, Christopher J. | Vaughn, Samuel E. | Marion, Miranda | Weirauch, Matthew T. | Namjou, Bahram | Adler, Adam | Rasmussen, Astrid | Glenn, Stuart | Montgomery, Courtney G. | Hirschfield, Gideon M. | Xie, Gang | Coltescu, Catalina | Amos, Chris | Li, He | Ice, John A. | Nath, Swapan K. | Mariette, Xavier | Bowman, Simon | Rischmueller, Maureen | Lester, Sue | Brun, Johan G. | Gøransson, Lasse G. | Harboe, Erna | Omdal, Roald | Cunninghame-Graham, Deborah S. | Vyse, Tim | Miceli-Richard, Corinne | Brennan, Michael T. | Lessard, James A. | Wahren-Herlenius, Marie | Kvarnström, Marika | Illei, Gabor G. | Witte, Torsten | Jonsson, Roland | Eriksson, Per | Nordmark, Gunnel | Ng, Wan-Fai | Anaya, Juan-Manuel | Rhodus, Nelson L. | Segal, Barbara M. | Merrill, Joan T. | James, Judith A. | Guthridge, Joel M. | Hal Scofield, R. | Alarcon-Riquelme, Marta | Bae, Sang-Cheol | Boackle, Susan A. | Criswell, Lindsey A. | Gilkeson, Gary | Kamen, Diane L. | Jacob, Chaim O. | Kimberly, Robert | Brown, Elizabeth | Edberg, Jeffrey | Alarcón, Graciela S. | Reveille, John D. | Vilá, Luis M. | Petri, Michelle | Ramsey-Goldman, Rosalind | Freedman, Barry I. | Niewold, Timothy | Stevens, Anne M. | Tsao, Betty P. | Ying, Jun | Mayes, Maureen D. | Gorlova, Olga Y. | Wakeland, Ward | Radstake, Timothy | Martin, Ezequiel | Martin, Javier | Siminovitch, Katherine | Moser Sivils, Kathy L. | Gaffney, Patrick M. | Langefeld, Carl D. | Harley, John B. | Kaufman, Kenneth M.
Human Molecular Genetics  2014;24(2):582-596.
Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5–TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5–TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10−49; OR = 1.38–1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10−27–10−32, OR = 1.7–1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5–TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5–TNPO3.
doi:10.1093/hmg/ddu455
PMCID: PMC4275071  PMID: 25205108
15.  Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results 
Lupus Science & Medicine  2016;3(1):e000131.
Objective
We previously reported that lupus anticoagulant (LAC) is the main predictor of poor pregnancy outcome in antiphospholipid antibody (aPL)-positive patients. We sought to confirm this finding in an independent group of patients who were subsequently recruited into the PROMISSE study.
Methods
The PROMISSE study is a multicentre, prospective, observational study of pregnancy outcomes in women with aPL and/or systemic lupus erythematosus (SLE) that enrolled patients from 2003 to 2015. All consecutive, aPL-positive patients from the PROMISSE study who completed their pregnancy between April 2011 and January 2015 (after the previous PROMISSE report) are included in the current report. Patients were followed monthly until delivery, and aPL was tested at first, second and third trimesters of pregnancy and at 12 weeks post partum. Adverse pregnancy outcomes (APOs) were defined as fetal death after 12 weeks of gestation, neonatal death, delivery prior to 36 weeks of gestation due to pre-eclampsia or placental insufficiency or small-for-gestational age (birth weight <5th percentile).
Results
Forty-four aPL-positive patients are included in this paper. Thirteen patients had APOs, which occurred in 80% of cases during the second trimester of pregnancy. LAC was present in 69% of patients with APOs compared with 27% of patients without APOs (p=0.01). No association was found between anticardiolipin antibodies (aCL) or anti-β2 glycoprotein I antibodies (aβ2GPI) IgG or IgM positivity and APOs. Definite antiphospholipid syndrome (history of thrombosis and/or pregnancy morbidity and aPL) was found in 92% of patients with any APOs compared with 45% of patients without APOs (p=0.004). Conversely, the frequency of SLE was not statistically different between those with and without APOs (30% vs 39%).
Conclusions
Our findings, in an independent group of aPL-positive patients from the PROMISSE study, confirm that LAC, but not aCL and aβ2GPI, is predictive of poor pregnancy outcomes after 12 weeks of pregnancy.
Trial registration number
NCT00198068.
doi:10.1136/lupus-2015-000131
PMCID: PMC4716418  PMID: 26835148
Antiphospholipid Antibodies; Lupus Anticoagulant; Pregnancy; Antiphospholipid Syndrome; Systemic Lupus Erythematosus
16.  Antiglutamate Receptor Antibodies and Cognitive Impairment in Primary Antiphospholipid Syndrome and Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome have an increased risk to develop cognitive impairment. A possible role for antiphospholipid antibodies (aPL) and antiglutamate receptor (anti-NMDA) antibodies in the pathogenesis of neurological manifestations of these two conditions, have been suggested. In particular, the role of anti-NMDA antibodies in the pathogenesis of neuropsychiatric SLE is supported by several experimental studies in animal models and by the finding of a correlation between anti-NMDA positivity in cerebrospinal fluid and neurological manifestations of SLE. However, data from the literature are controversial, as several studies have reported a correlation of these antibodies with mild cognitive impairment in SLE, but more recent studies have not confirmed this finding. The synergism between anti-NMDA and other concomitant autoantibodies, such as aPL, can be hypothesized to play a role in inducing the tissue damage and eventually the functional abnormalities. In line with this hypothesis, we have found a high incidence of at least one impaired cognitive domain in a small cohort of patients with primary APS (PAPS) and SLE. Interestingly, aPL were associated with low scoring for language ability and attention while anti-NMDA titers and mini-mental state examination scoring were inversely correlated. However, when patients were stratified according to the presence/absence of aPL, the correlation was confirmed in aPL positive patients only. Should those findings be confirmed, the etiology of the prevalent defects found in PAPS patients as well as the synergism between aPL and anti-NMDA antibodies would need to be explored.
doi:10.3389/fimmu.2016.00005
PMCID: PMC4740786  PMID: 26870034
systemic lupus erythematosus; antiphospholipid syndrome; mild cognitive impairment; neuropsychological assessment; central nervous system involvement; anti-NMDA/glutamate receptor antibodies
17.  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
18.  Disease Activity in Lupus Correlates with Expression of the Transcription Factor ARID3a 
Objective
Systemic lupus erythematosus (SLE) is a complex and multifactorial autoimmune disease with striking clinical, immunologic and genetic heterogeneity, despite nearly ubiquitous antinuclear antibody (ANA) production. Multiple gene polymorphisms have been associated with the disease, but individually account for only a very small percentage of overall SLE risk. In earlier studies, constitutive expression of the DNA-binding protein, A+T rich interacting domain 3a (ARID3a) in transgenic mouse B lymphocyte lineage cells led to spontaneous ANA production and preferential development of B cells associated with production of polyreactive antibodies. Therefore, we asked if ARID3a was over-expressed in B lymphocytes of SLE patients and if ARID3a expression was associated with disease severity.
Methods
A cross section of SLE patients and age and gender-matched controls were analyzed longitudinally for lupus disease activity, numbers of ARID3a+ peripheral blood mononuclear B cells from multiple B cell subsets, immunoglobulin and cytokine levels.
Results
Fifty of 115 patients (43%) had dramatically increased numbers of ARID3a+ B cells compared to healthy controls. ARID3a is not expressed in naïve B cells of healthy controls, but was abundant in these precursors of antibody-secreting cells in SLE patients. Total numbers of ARID3a+ B cells correlated with increased disease activity as defined by SLE Disease Activity Index scores in individuals assessed at three time points.
Conclusion
These findings identify B cell anomalies in SLE that allow stratification of patient samples based on ARID3a expression and implicate ARID3a as a potential marker of CD19+ B lymphocytes correlated with disease activity.
doi:10.1002/art.38857
PMCID: PMC4245462  PMID: 25185498
19.  How should lupus flares be measured? Deconstruction of the Safety of Estrogen in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index flare index 
Rheumatology (Oxford, England)  2014;53(12):2175-2181.
Objective. Accurate assessment of lupus flares is critical but problematic in clinical trials. This study examined the impact of modifications to the classic Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI flare index (cSFI).
Methods. Ninety-one SLE patient records were evaluated at two visits at which the SLEDAI and BILAG had been scored prospectively. The cSFI was compared with an experimental version (eSFI) that eliminated medication criteria and separated the mild/moderate flare category into its components by clinical judgement based on records. The revised SFI (SFI-R) and some physician’s global assessments (PGAs) were also scored using chart notes.
Results. eSFI-rated moderate flares had higher PGA and BILAG scores than those rated as mild. When medication criteria were excluded, 42 of 55 cSFI severe flares and 15 of 49 mild/moderate flares were downgraded in severity. Comparing flares that remained severe with those that were downgraded, disease activity was higher by PGA (P < 0.001), SLEDAI (P < 0.001), BILAG (P < 0.001), number of active BILAG organs (P < 0.04) and flaring SFI-R organs (P < 0.01). PGA (P < 0.001) and the number of SFI-R domains flaring (P < 0.001) were higher in mild/moderate eSFI flares than in those that were downgraded. Twenty-one of 83 (25%) medication changes occurred with no flare. Forty-six of 52 (88%) medication changes defining severe flare by cSFI involved patients rated by physicians with no, mild or moderate flares.
Conclusion. A deconstructed flare index improves the discrimination of mild from moderate flares and selects more ill patients with true clinical worsening for each category of flare.
doi:10.1093/rheumatology/keu153
PMCID: PMC4542656  PMID: 24729400
systemic lupus erythematosus; outcome measures; SELENA-SLEDAI flare index; revised SELENA flare index; SLEDAI; BILAG; physician’s global assessment; medications
20.  Seizure disorders in Systemic Lupus Erythematosus 
Annals of the rheumatic diseases  2012;71(9):1502-1509.
Objective
To describe the frequency, attribution, outcome and predictors of seizures in SLE
Methods
The Systemic Lupus International Collaborating Clinics (SLICC) performed a prospective inception cohort study. Demographic variables, global SLE disease activity (SLEDAI-2K), cumulative organ damage (SLICC/ACR Damage Index (SDI)) and neuropsychiatric events were recorded at enrollment and annually. Lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor antibodies were measured at enrollment. Physician outcomes of seizures were recorded. Patient outcomes were derived from the SF-36 mental (MCS) and physical (PCS) component summary scores. Statistical analyses included Cox and linear regressions.
Results
The cohort was 89.4% female with a mean follow up of 3.5±2.9 years. 75/1631 (4.6%) had ≥1 seizure, the majority around the time of SLE diagnosis. Multivariate analysis indicated a higher risk of seizures with African race/ethnicity (HR(CI):1.97 (1.07–3.63); p=0.03) and lower education status (1.97 (1.21–3.19); p<0.01). Higher damage scores (without NP variables) were associated with an increased risk of subsequent seizures (SDI=1:3.93 (1.46–10.55)); SDI=2 or 3:1.57 (0.32–7.65); SDI≥4:7.86 (0.89–69.06); p=0.03). There was an association with disease activity but not with autoantibodies. Seizures attributed to SLE frequently resolved (59/78(76%)) in the absence of anti-seizure drugs. There was no significant impact on the MCS or PCS scores. Anti-malarial drugs in absence of immunosuppressive agents were associated with reduced seizure risk (0.07(0.01–0.66); p=0.03).
Conclusion
Seizures occurred close to SLE diagnosis, in patients with African race/ethnicity, lower educational status and cumulative organ damage. Most seizures resolved without a negative impact on health-related quality of life. Anti-malarial drugs were associated with a protective effect.
doi:10.1136/annrheumdis-2011-201089
PMCID: PMC4656036  PMID: 22492779 CAMSID: cams5144
Systemic lupus erythematosus; Neuropsychiatric; Seizures; Inception cohort
21.  DNA methylation patterns in naïve CD4+ T cells identify epigenetic susceptibility loci for malar rash and discoid rash in systemic lupus erythematosus 
Lupus Science & Medicine  2015;2(1):e000101.
Objective
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by heterogeneous clinical manifestations, autoantibody production and epigenetic dysregulation in T cells. We sought to investigate the epigenetic contribution to the development of cutaneous manifestations in SLE.
Methods
We performed genome-wide DNA methylation analyses in patients with SLE stratified by a history of malar rash, discoid rash or neither cutaneous manifestation, and age, sex and ethnicity matched healthy controls. We characterised differentially methylated regions (DMRs) in naïve CD4+ T cells unique to each disease subset, and assessed functional relationships between DMRs using bioinformatic approaches.
Results
We identified 36 and 37 unique DMRs that contribute to the epigenetic susceptibility to malar rash and discoid rash, respectively. These DMRs were primarily localised to genes mediating cell proliferation and apoptosis. Hypomethylation of MIR886 and TRIM69, and hypermethylation of RNF39 were specific to patients with SLE with a history of malar rash. Hypomethylation of the cytoskeleton-related gene RHOJ was specific to patients with SLE with a history of discoid rash. In addition, discoid rash-specific hypomethylated DMRs were found in genes involved in antigen-processing and presentation such as TAP1 and PSMB8. Network analyses showed that DMRs in patients with SLE with but not without a history of cutaneous manifestations are associated with TAP-dependent processing and major histocompatibility-class I antigen cross-presentation (p=3.66×10−18 in malar rash, and 3.67×10−13 in discoid rash).
Conclusions
We characterised DNA methylation changes in naïve CD4+ T cells specific to malar rash and discoid rash in patients with SLE. These data suggest unique epigenetic susceptibility loci that predispose to or are associated with the development of cutaneous manifestations in SLE.
doi:10.1136/lupus-2015-000101
PMCID: PMC4577980  PMID: 26405558
Systemic Lupus Erythematosus; Gene Polymorphism; Autoimmune Diseases
22.  Genetic Association of CD247 (CD3ζ) with SLE in a Large-Scale Multiethnic Study 
Genes and immunity  2015;16(2):142-150.
A classic T-cell phenotype in Systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters TCR signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multi-ethnic population. We typed 44 contiguous CD247 SNPs in 8 922 SLE patients and 8 077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99×10−4
doi:10.1038/gene.2014.73
PMCID: PMC4371129  PMID: 25569266
Annals of the Rheumatic Diseases  2014;74(9):1706-1713.
Background and aims
We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients.
Methods
The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually. We assessed relative rates of transition using maximum likelihood estimation in a multistate model. The Kaplan–Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality.
Results
We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry. Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs ≥1; p<0.001). Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage. Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to ≥1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)). Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)). Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point).
Conclusions
Damage in SLE predicts future damage accrual and mortality. We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.
doi:10.1136/annrheumdis-2013-205171
PMCID: PMC4552899  PMID: 24834926
Systemic Lupus Erythematosus; Outcomes research; Corticosteroids; Inflammation
Arthritis and rheumatism  2010;62(1):222-233.
Objective
B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE.
Methods
Patients entered with ≥1 British Isles Lupus Assessment Group (BILAG) A score or ≥2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182.
Results
In the intent-to-treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty-three percent of the patients had ≥1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG-defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab.
Conclusion
The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials.
doi:10.1002/art.27233
PMCID: PMC4548300  PMID: 20039413
Introduction
Blisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE).
Methods
SLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed.
Results
All subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for ≥ 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naïve B cells (24–76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD-CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0–6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects.
Conclusions
Blisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0–6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases.
Trial registration
Clinicaltrials.gov NCT02443506. Registered 11 May 2015. NCT02411136 Registered 7 April 2015.
doi:10.1186/s13075-015-0741-z
PMCID: PMC4545922  PMID: 26290435

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