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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  Effects of rituximab-based B-cell depletion therapy on skin manifestations of lupus erythematosus – report of 17 cases and review of the literature 
Lupus  2013;22(9):932-939.
Cutaneous manifestations occur frequently in systemic lupus erythematosus (SLE) and are pathognomonic in subacute-cutaneous lupus erythematosus (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Although B-cell depletion therapy (BCDT) has demonstrated efficacy in SLE with visceral involvement, its usefulness for patients with predominant skin manifestations has not been fully established. In this single-centre, retrospective study 14 consecutive SLE, one CCLE and two SCLE patients with recalcitrant skin involvement were treated with 2 × rituximab 1 g, and 1 × cyclophosphamide 750 mg.
Six months after BCDT, nine of 17 (53%) patients were in complete (CR) or partial remission (PR). Relapses occurred in 12 patients (71%) at a mean time of 10 ± 1.8 months after BCDT. A second cycle of BCDT achieved a more sustained remission in seven of nine patients (78%) lasting for a mean time of 18.4 ± 2.7 months. Minor adverse events were experienced by three patients. Mean follow-up was 30 months.
Our own results and the literature review demonstrate that BCDT based on rituximab is well tolerated and may be effective for cutaneous lesions of lupus erythematosus. Randomized controlled trials are necessary to further evaluate the value of BCDT for this group of patients.
doi:10.1177/0961203313497115
PMCID: PMC4107853  PMID: 23894047
Cutaneous lupus; discoid lupus; subacute lupus erythematosus; systemic lupus erythematosus
8.  Diagnosis of antiphospholipid syndrome in routine clinical practice 
Lupus  2013;22(1):18-25.
The updated international consensus criteria for definite antiphospholipid syndrome (APS) are useful for scientific clinical studies. However, there remains a need for diagnostic criteria for routine clinical use. We audited the results of routine antiphospholipid antibodies (aPLs) in a cohort of 193 consecutive patients with aPL positivity-based testing for lupus anticoagulant (LA), IgG and IgM anticardiolipin (aCL) and anti-ß2glycoprotein-1 antibodies (aß2GPI). Medium/high-titre aCL/aβ2GPI was defined as >99th percentile. Low-titre aCL/aβ2GPI positivity (>95th < 99th percentile) was considered positive for obstetric but not for thrombotic APS. One hundred of the 145 patients fulfilled both clinical and laboratory criteria for definite APS. Twenty-six women with purely obstetric APS had persistent low-titre aCL and/or aβ2GPI. With the inclusion of these patients, 126 of the 145 patients were considered to have APS. Sixty-seven out of 126 patients were LA-negative, of whom 12 had aCL only, 37 had aβ2GPI only and 18 positive were for both. The omission of aCL or aβ2GPI testing from investigation of APS would have led to a failure to diagnose APS in 9.5% and 29.4% of patients, respectively. Our data suggest that LA, aCL and aβ2GPI testing are all required for the accurate diagnosis of APS and that low-titre antibodies should be included in the diagnosis of obstetric APS.
doi:10.1177/0961203312460722
PMCID: PMC4108293  PMID: 22988029
9.  Is Familial Lupus Different from Sporadic Lupus?: Data from LUMINA, a Multiethnic US Cohort 
Lupus  2010;19(11):1331-1336.
Purpose
To characterize the clinical features of familial lupus, and determine its influence on damage accrual and survival using data from LUMINA, a longitudinal multiethnic US cohort.
Method
Familial lupus was defined as patients with a first degree relative with SLE. Relative risks were estimated by logistic regression; odds ratios (OR) and their 95% confidence intervals (CI) were the measure of association for familial lupus. Hazard Ratios (HR) were calculated using Cox proportional hazard adjusted for potential confounders for damage and survival.
Results
Thirty-two of 644 patients had familial and 612 had sporadic lupus; both groups were of comparable age (~ 36 years). Familial lupus patients were in decreasing order of frequency siblings, parents and children. In multivariable analyses, mucosal ulcers (OR=1.92, 95% CI 0.65–5.70), mitral valve prolapse (OR=1.74, 95% CI 0.50–6.10), cerebrovascular disease (OR=4.18, 95% CI 0.98–17.76) and oral contraceptive use (ever/never; OR=2.51, 95% CI 0.88–7.19) were more likely in familial lupus but a history of low platelet count (<150,000/mm3; OR=0.31, 95% CI 0.08–1.17) and pulmonary disease activity (OR=0.39, 95% CI 0.14–1.20) were less likely. However, none of these associations reached statistical significance. Familial lupus was not significantly associated with a shorter time to either damage accrual or death (HR=0.77, 95% CI 0.37–1.59, p = 0.4746 and HR=0.20, 95% CI 0.03–1.47, p = 0.2020, respectively).
Conclusions
Although some clinical differences were observed in patients with familial and sporadic lupus, familial lupus was not associated with a significantly greater disease burden (damage, survival) than sporadic lupus.
doi:10.1177/0961203310375264
PMCID: PMC4078734  PMID: 20696771
familial lupus; lupus; sporadic lupus; LUMINA; multiethnic cohort
10.  Estradiol Differentially Regulates Calreticulin: A Potential Link with Abnormal T Cell Function in Systemic Lupus Erythematosus? 
Lupus  2013;22(6):583-596.
Objective
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects women nine times more often than men. The present study investigates estradiol-dependent control of the calcium buffering protein, calreticulin, to gain further insight into the molecular basis of abnormal T cell signaling in SLE T cells.
Methods
T cells were purified from blood samples obtained from healthy females and SLE patients. Calreticulin expression was quantified by real time polymerase chain amplification. Calreticulin and estrogen receptor-α were co-precipitated and analyzed by Western blotting to determine if the proteins associate in T cells.
Results
Calreticulin expression increased (p= 0.034)in activated control T cells, while estradiol decreased (p = 0.044) calreticulin in resting T cells. Calreticulin expression decreased in activated SLE T cell samples and increased in approximately 50% of resting T cell samples. Plasma estradiol was similar (p > 0.05) among SLE patients and control volunteers. Estrogen receptor-αand calreticulin co-precipitated from nuclear and cytoplasmic T cell compartments.
Conclusions
The results indicate that estradiol tightly regulates calreticulin expression in normal human T cells and the dynamics are different between activated and resting T cells. The absence of this tight regulation in SLE T cells could contribute to abnormal T cell function.
doi:10.1177/0961203313482742
PMCID: PMC4072130  PMID: 23535532
SLE; human T cells; estradiol; calreticulin; estrogen receptor-α
11.  Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort 
Lupus  2010;19(11):1315-1325.
As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homo-cysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R2 for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.
doi:10.1177/0961203310373937
PMCID: PMC4049625  PMID: 20861207
atherosclerosis; cardiovascular; lipid; pediatric; SLE; systemic lupus erythematosus
12.  Epitope mapping of the U1 small nuclear ribonucleoprotein particle in patients with systemic lupus erythematosus and mixed connective tissue disease 
Lupus  2011;20(3):274-289.
Systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) are autoimmune illnesses characterized by the presence of high titers of autoantibodies directed against a wide range of ‘self ’ antigens. Proteins of the U1 small nuclear ribonucleoprotein particle (U1 snRNP) are among the most immunogenic molecules in patients with SLE and MCTD. The recent release of a crystallized U1 snRNP provides a unique opportunity to evaluate the effects of tertiary and quaternary structures on autoantigenicity within the U1 snRNP. In the present study, an epitope map was created using the U1 snRNP crystal structure. A total of 15 peptides were tested in a cohort of 68 patients with SLE, 29 with MCTD and 26 healthy individuals and mapped onto the U1 snRNP structure. Antigenic sites were detected in a variety of structures and appear to include RNA binding domains, but mostly exclude regions necessary for protein–protein interactions. These data suggest that while some autoantibodies may target U1 snRNP proteins as monomers or apoptosis-induced, protease-digested fragments, others may recognize epitopes on assembled protein subcomplexes of the U1 snRNP. Although nearly all of the peptides are strong predictors of autoimmune illness, none were successful at distinguishing between SLE and MCTD. The antigenicity of some peptides significantly correlated with several clinical symptoms. This investigation implicitly highlights the complexities of autoimmune epitopes, and autoimmune illnesses in general, and demonstrates the variability of antigens in patient populations, all of which contribute to difficult clinical diagnoses.
doi:10.1177/0961203310387180
PMCID: PMC4026168  PMID: 21362751
autoimmune disease; pre-mRNA splicing; autoantigen; spliceosome
13.  Predictors of the Rate of Change in Disease Activity over Time in LUMINA, a Multiethnic US Cohort of Patients with Systemic Lupus Erythematosus: LUMINA LXX 
Lupus  2010;19(6):727-733.
The objectives of the present study were (1) to clarify and quantify the relationship between age and disease duration with the rate of change in disease activity over time in patients with systemic lupus erythematosus (SLE) and (2) to explore other possible factors associated with this rate of change. To this end, SLE patients from LUMINA were studied if they had ≥3 visits in which disease activity (Systemic Lupus Activity Measure-Revised or SLAM-R) had been ascertained. Variables associated with the rate (slope) of change in disease activity (obtained by regressing the SLAM-R scores against the length of time from diagnosis to last visit) were examined by univariable and multivariable analyses. Five-hundred forty-two of the 632 patients had ≥3 SLAM-R scores. In multivariable analyses Caucasians exhibited the fastest decline in disease activity; Texan Hispanics exhibited the slowest, trailed by the African Americans. Longer disease duration and HLA-DRB1*1503 positivity were associated with a slower decline whereas a greater number of ACR criteria and abnormal laboratory parameters (white blood cell and platelet counts, hematocrit and serum creatinine) were associated with a faster decline. These findings complement existing knowledge on SLE disease activity and are potentially useful to clinicians managing these patients.
doi:10.1177/0961203309359289
PMCID: PMC3964002  PMID: 20118158
Lupus; disease activity; rate of change; ethnicity; cohort
14.  Mestizos with Systemic Lupus Erythematosus Develop Renal Disease Early while Antimalarials Retard its Appearance: Data from a Latin American Cohort 
Lupus  2013;22(9):899-907.
Objectives
To assess the predictors of time-to-lupus renal disease in Latin American patients.
Methods
SLE patients (n=1480) from GLADEL’s (Grupo Latino Americano De Estudio de Lupus) longitudinal inception cohort were studied. Endpoint was ACR renal criterion development after SLE diagnosis (prevalent cases excluded). Renal disease predictors were examined by univariable and multivariable Cox proportional hazards regression analyses. Antimalarials were considered time-dependent in alternative analyses.
Results
Of the entire cohort, 265 patients (17.9%) developed renal disease after entering the cohort. Of them, 88 (33.2%) developed persistent proteinuria, 44 (16.6%) cellular casts and 133 (50.2%) both; 233 patients (87.9%) were women; mean (± SD) age at diagnosis was 28.0 (11.9) years; 12.8% were African-Latin Americans, 52.5% Mestizos, 34.7% Caucasians (p=0.0016). Mestizo ethnicity (HR 1.61, 95% CI 1.19–2.17), hypertension (HR 3.99, 95% CI 3.02–5.26) and SLEDAI at diagnosis (HR 1.04, 95% CI 1.01–1.06) were associated with a shorter time-to-renal disease occurrence; antimalarial use (HR 0.57, 95% CI 0.43–0.77), older age at onset (HR 0.90, 95% CI 0.85–0.95, for every 5 years) and photosensitivity (HR 0.74, 95% CI 0.56–0.98) were associated with a longer time. Alternative model results were consistent with the antimalarial protective effect (HR 0.70, 95% CI 0.50–0.99).
Conclusions
Our data strongly support the fact that Mestizo patients are at increased risk of developing renal disease early while antimalarials seem to delay the appearance of this SLE manifestation. These data have important implications for the treatment of these patients regardless of their geographic location.
doi:10.1177/0961203313496339
PMCID: PMC3943422  PMID: 23857989
15.  C6 knock-out Mice Are Protected from Thrombophilia Mediated by Antiphospholipid Antibodies 
Lupus  2012;21(14):1497-1505.
Background
Complement activation plays a role in pathogenesis of the Antiphospholipid Syndrome (APS), but the involvement of the C5b-9 membrane attack complex (MAC) is unknown. Here we studied the effects of human polyclonal antiphospholipid (aPL) antibodies on thrombosis and tissue factor (TF) up-regulation in C6 deficient (C6-/-) mice.
Methods
C6-/- or the wild-type (C3H/HeJ) C6+/+ mice were injected twice with IgG-APS (n=2) or IgM-APS (n=1) isolated from APS patients or with the corresponding control Igs (IgG-NHS or IgM-NHS). Then, the size of induced thrombi in the femoral vein were determined 72 hours after the first injection. Tissue factor was determined in homogenates of carotid arteries and in peritoneal macrophages.
Results
Thrombus sizes were significantly larger in C6+/+ treated with IgG-APS1 or with IgG-APS2 or with IgM-APS when compared with C6+/+ mice treated with IgG-NHS or with IgM-NHS, respectively. The sizes of thrombi were significantly smaller in the C6-/- mice injected with IgG-APS1, IgG-APS2 or IgM-APS (p<0.001), compared to their C6+/+ counterparts showing an important abrogation of thrombus formation in mice lacking C6. The TF expression and activity in the C6-/- mice treated with IgG-APS were diminished when compared to C6+/+ treated with the same immunoglobulins. All mice injected with IgG-APS and IgM-APS had medium-high titers of aCL and aβ2GPI antibodies.
Conclusions
These data indicate that the C6 component of the complement system mediates aPL-thrombogenic effects, underscoring an important pathogenic mechanism and indicating the possibility of inhibiting complement to ameliorate APS-related manifestations.
doi:10.1177/0961203312458839
PMCID: PMC3923322  PMID: 22933620
16.  A systemic lupus erythematosus gene expression array in disease diagnosis and classification: a preliminary report 
Lupus  2010;20(3):10.1177/0961203310383072.
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease diagnosed on the presence of a constellation of clinical and laboratory findings. At the pathogenetic level, multiple factors using diverse biochemical and molecular pathways have been recognized. Succinct recognition and classification of clinical disease subsets, as well as the availability of disease biomarkers, remains largely unsolved. Based on information produced by the present authors’ and other laboratories, a lupus gene expression array consisting of 30 genes, previously claimed to contribute to aberrant function of T cells, was developed. An additional eight genes were included as controls. Peripheral blood was obtained from 10 patients (19 samples) with SLE and six patients with rheumatoid arthritis (RA) as well as 19 healthy controls. T cell mRNA was subjected to reverse transcription and PCR, and the gene expression levels were measured. Conventional statistical analysis was performed along with principal component analysis (PCA) to capture the contribution of all genes to disease diagnosis and clinical parameters. The lupus gene expression array faithfully informed on the expression levels of genes. The recorded changes in expression reflect those reported in the literature by using a relatively small (5ml) amount of peripheral blood. PCA of gene expression levels placed SLE samples apart from normal and RA samples regardless of disease activity. Individual principal components tended to define specific disease manifestations such as arthritis and proteinuria. Thus, a lupus gene expression array based on genes previously claimed to contribute to immune pathogenesis of SLE may define the disease, and principal components of the expression of 30 genes may define patients with specific disease manifestations.
doi:10.1177/0961203310383072
PMCID: PMC3880791  PMID: 21138984
gene array; principal component analysis; systemic lupus erythematosus
17.  Erythrocyte sedimentation rate is a predictor of renal and overall SLE disease activity 
Lupus  2013;22(8):10.1177/0961203313492578.
Objective
To assess whether erythrocyte sedimentation rate levels correlate with the level of disease activity at each visit and whether a change in ESR could be useful in predicting changes in disease activity.
Methods
Thousands of visits in a prospective SLE cohort were analyzed to assess the association of ESR and level of disease activity. We explored whether ESR was cross-sectionally associated with disease activity, whether changes in ESR were associated with changes in disease activity, and whether changes in ESR predicted future changes in disease activity. Visits when patients had cancer, infection, pregnancy or were in renal failure were excluded.
Results
After adjusting for confounding factors, mild (25–50mm/hr), moderate (51–75mm/hr), and marked ( > 75mm/hr) elevations in ESR levels at a given visit correlated with the SELENA-SLEDAI, the physician global assessment(PGA), fatigue, renal, joint, rash, serositis, hematological visual analogue scale (VAS), hematuria and proteinuria (p<0.0001) levels at that visit. A change in ESR between two visits was highly correlated with a concurrent change in physician global assessment (PGA), renal, fatigue and joint VAS (p<0.0001). There was no statistically significant correlation between change in ESR between two visits and change in disease activity at a future visit. The subgroup analysis of patients who do not have anti-dsDNA and low complement levels as a feature of their disease showed ESR to be positively associated with SLEDAI, PGA, renal and joint visual analogue scale at that visit (p<0.0001), but there were few significant assocations between changes in ESR and changes in disease activity.
Conclusion
ESR is associated with disease activity in SLE measured by the SELENA-SLEDAI, the physician global assessment (PGA), and with organ specific activity including serositis, rash, joint, renal and hematological visual analogue scales. Grouping baseline ESR into 4 levels does associate with both global and organ specific disease activity. A change in ESR between two visits was highly correlated with a change in physician global assessment (PGA), renal, fatigue and joint visual analogue scale (VAS). In patients without anti-dsDNA and low complement levels, ESR was positively associated with SLEDAI, PGA, renal and joint visual analogue scale at the same visit. Until more specific biomarkers are validated, serial ESR does have some utility in following disease activity in SLE.
doi:10.1177/0961203313492578
PMCID: PMC3703841  PMID: 23761098
erythrocyte sedimentation rate; ESR; systemic lupus erythematosus; disease activity
18.  Designing an Intervention for Women with Systemic Lupus Erythematosus from Medically Underserved Areas to Improve Care: A Qualitative Study 
Lupus  2012;22(1):52-62.
Objective
Systemic lupus erythematosus (lupus) disproportionately affects women, racial/ethnic minorities and low-income populations. We held focus groups for women from medically underserved communities to discuss interventions to improve care.
Methods
From our Lupus Registry, we invited 282 women, > 18 years, residing in urban, medically underserved areas. Hospital-based clinics and support groups also recruited participants. Women were randomly assigned to 3 focus groups. 75-minute sessions were recorded, transcribed and coded thematically using interpretative phenomenologic analysis and single counting methods. We categorized interventions by benefits, limitations, target populations and implementation questions.
Results
29 women with lupus participated in 3 focus groups, (n=9, 9, 11). 80% were African American and 83% were from medically underserved zip codes. Themes included the desire for lupus education, isolation at the time of diagnosis, emotional and physical barriers to care, and the need for assistance navigating the healthcare system. 20 of 29 participants (69%) favored a peer support intervention; 17 (59%) also supported a lupus health passport. Newly diagnosed women were optimal intervention targets. Improvements in quality of life and mental health were proposed outcome measures.
Conclusion
Women with lupus from medically underserved areas have unique needs best addressed with an intervention designed through collaboration between community members and researchers.
doi:10.1177/0961203312463979
PMCID: PMC3543784  PMID: 23087258
Disparities; qualitative research; African Americans; systemic lupus erythematosus
19.  Free Fatty Acids are Associated with Metabolic Syndrome and Insulin Resistance, but not Inflammation in SLE Patients 
Lupus  2012;22(1):26-33.
Free fatty acids (FFAs) are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines promote lipolysis and increase FFAs, a cause of endothelial dysfunction and increased atherosclerosis risk. We hypothesized that increased inflammation is associated with increased FFAs, resulting in insulin resistance and atherosclerosis in patients with systemic lupus erythematosus (SLE). We measured clinical variables, serum FFAs, homeostasis model assessment for insulin resistance (HOMA), inflammatory cytokines, markers of endothelial activation, cholesterol concentrations, and coronary artery calcium in 156 patients with SLE and 90 controls. We compared FFAs in patients with SLE and controls using Wilcoxon rank sum tests and further tested for the independent association between FFAs and disease status with adjustment for age, race, and sex using multivariable regression models. We assessed the relationship between FFA and continuous variables of interest using Spearman correlation and multivariable regression analysis. FFAs levels were higher in patients with SLE than controls (0.55 mmol/l [0.37- 0.71] vs. 0.44 mmol/l [0.32- 0.60], P=0.02). FFAs remained significantly higher among patients with SLE after adjustment for age, race, and sex (P=0.03), but not after further adjustment for BMI (P=0.13). FFA levels did not differ according to current immunosuppressive medication use in univariate and adjusted analysis (all P>0.05). Among patients with SLE, concentrations of FFAs were higher among those with metabolic syndrome compared to those without (0.66 mmol/l [0.46-0.81] vs. 0.52 mmol/l [0.35- 0.66], P<0.001). FFAs were positively correlated with insulin resistance (HOMA) (rho=0.23, P=0.004, P adjusted=0.006) and triglyceride levels (rho=0.22, P=0.01, P adjusted=0.004). FFAs were not associated with inflammatory cytokines (IL-6, TNF-α) (all P>0.05), but were positively associated with levels of E-selectin (rho=0.33, P=<0.001, P adjusted=0.001) and ICAM-1 (rho=0.35, P<0.001, P adjusted=0.001). FFAs were correlated with coronary artery calcium score (rho=0.20, P=0.01), but this was attenuated after adjustment for age, race and sex (P=0.33). FFAs are elevated in patients with SLE, particularly those with metabolic syndrome. FFAs in SLE are not associated with markers of generalized inflammation but are associated with insulin resistance and markers of endothelial activation.
doi:10.1177/0961203312462756
PMCID: PMC3684362  PMID: 23060481
cardiovascular disease; systemic lupus erythematosus; free fatty acids; metabolic syndrome; endothelial activation; insulin resistance
20.  Chemosis as a presenting symptom of systemic lupus erythematosus 
Lupus  2010;19(8):10.1177/0961203310367919.
We present a case of chemosis (conjunctival edema) as an early manifestation of severe systemic lupus erythematosus affecting multiple organs, including the central nervous system and the kidneys.
doi:10.1177/0961203310367919
PMCID: PMC3872738  PMID: 20581021
Chemosis; neuro-psychiatric lupus; SLE
21.  Evidence that abnormally large seasonal declines in vitamin D status may trigger SLE flare in non-African Americans 
Lupus  2012;21(8):10.1177/0961203312439640.
Cross-sectional studies have shown that low vitamin D (25-hydroxyvitamin D (25(OH)D)) is associated with increased systemic lupus erythematosus (SLE) activity. This study is the first to assess the temporal relationship between 25(OH)D levels and onset of SLE flare. This assessment was made possible because of the specimen bank and database of the Ohio SLE Study (OSS), a longitudinal study of frequently relapsing SLE that involved regular bimonthly patient follow-up. We identified for this study 82 flares from 46 patients that were separated by at least 8 months from previous flares. Serum 25(OH)D levels were measured at 4 and 2 months before flare, and at the time of flare (a flare interval). We found that for flares occurring during low daylight months (LDM, Oct-Mar), 25(OH)D levels were decreased at the time of flare, but only in non-African American (non-AA) patients (32% decrease at flare, compared to 4 months prior, p < 0.001). To control for seasonal effects, we also measured 25(OH)D levels in the LDM “no-flare” intervals, which were intervals that matched to the same calendar months of the patients’ LDM flare intervals, but that didn’t end in flare (n = 24). For these matches, a significant decrease occurred in 25(OH)D levels during the flare intervals (18.1% decrease, p < 0.001), but not during the matching no-flare intervals (6.2% decrease, p = 0.411). For flares occurring during high daylight months (HDM), 25(OH)D levels changed only in non-AA patients, increasing slightly (5.6%, p = 0.010). Analysis of flare rates for the entire OSS cohort (n = 201 flares) revealed a tendency for higher flare rates during LDM compared to HDM, but again only in non-AA patients (p = 0.060). Flare rates were lower during HDM for non-AA patients compared to AA patients (p = 0.028). In conclusion, in non-AA SLE patients, unusually large declines in 25(OH)D during LDM may be mechanistically related to SLE flare, whereas relatively high 25(OH)D levels during HDM may protect against flare.
doi:10.1177/0961203312439640
PMCID: PMC3839052  PMID: 22433915
Vitamin D; systemic lupus erythematosus; disease flare
22.  An Exploratory Dose-Escalating Study Investigating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous Atacicept in Patients with Systemic Lupus Erythematosus 
Lupus  2009;18(6):547-555.
Atacicept, a recombinant fusion protein containing the extracellular, ligand-binding portion of the transmembrane activator and calcium modulator and cyclophilin-ligand interactor receptor, and the Fc portion of human immunoglobulin (Ig) G, is designed to block the activity of B-lymphocyte stimulator and a proliferation-inducing ligand, and may have utility as a treatment for B-cellmediated diseases, such as systemic lupus erythematosus (SLE). This Phase Ib study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of intravenous (i.v.) atacicept in patients with mild-to-moderate SLE. Patients (n = 24) were randomised (5:1) to receive atacicept (single dose: 3, 9 or 18 mg/kg; or multiple dose: 2 × 9 mg/kg) or matching placebo. Patients were followed for 6 weeks after dosing (9 weeks in the 2 × 9 mg/kg cohort). Local tolerability of atacicept was comparable with that of placebo, with only mild injection-site reactions reported with atacicept. Atacicept i.v. was generally well tolerated, both systemically and locally, in patients with mild-to-moderate SLE. Atacicept displayed non-linear PK, which was predictable across doses and between single and repeat doses. The biological activity of atacicept was demonstrated by its marked effect in reducing B-cells and Ig levels in patients with SLE. This supports the utility of this therapeutic approach in the treatment of autoimmune diseases, such as SLE.
doi:10.1177/0961203309102803
PMCID: PMC3835146  PMID: 19395457
APRIL; atacicept; biological agents; BLyS; systemic lupus erythematosus; TACI-Ig
23.  Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort 
Lupus  2012;21(8):10.1177/0961203312437270.
Objective
We sought to determine the effect of hydroxychloroquine therapy on the levels proinflammatory/prothrombotic markers and disease activity scores in patients with systemic lupus erythematosus (SLE) in a multiethnic, multi-center cohort (LUMINA).
Methods
Plasma/serum samples from SLE patients (n=35) were evaluated at baseline and after hydroxychloroquine treatment. Disease activity was assessed using SLAM-R scores. Interferon (IFN)-α2, interleukin (IL)-1β, IL-6, IL-8, inducible protein (IP)-10, monocyte chemotactic protein-1, tumor necrosis factor (TNF)-α and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Anticardiolipin antibodies were evaluated using ELISA assays. Thirty-two frequency-matched plasma/serum samples from healthy donors were used as controls.
Results
Levels of IL-6, IP-10, sCD40L, IFN-α and TNF-α were significantly elevated in SLE patients versus controls. There was a positive but moderate correlation between SLAM-R scores at baseline and levels of IFN-α (p=0.0546). Hydroxychloroquine therapy resulted in a significant decrease in SLAM-R scores (p=0.0157), and the decrease in SLAM-R after hydroxychloroquine therapy strongly correlated with decreases in IFN-α (p=0.0087).
Conclusions
Hydroxychloroquine therapy resulted in significant clinical improvement in SLE patients, which strongly correlated with reductions in IFN-α levels. This indicates an important role for the inhibition of endogenous TLR activation in the action of hydroxychloroquine in SLE and provides additional evidence for the importance of type I interferons in the pathogenesis of SLE. This study underscores the use of hydroxychloroquine in the treatment of SLE.
doi:10.1177/0961203312437270
PMCID: PMC3808832  PMID: 22343096
Lupus; hydroxychloroquine; biomarkers of inflammation; biomarkers of thrombosis
24.  Predictors of kidney biopsy complication among patients with systemic lupus erythematosus 
Lupus  2012;21(8):848-854.
Kidney biopsy is essential for the diagnosis and management of lupus nephritis. The risk of bleeding complication, however, is not defined in the systemic lupus erythematosus population. A retrospective cohort study was conducted to determine predictors of major and minor complications among patients with systemic lupus erythematosus undergoing percutaneous ultrasound-guided kidney biopsy. Major complications included bleeding necessitating intervention, hypotension requiring vasopressors or higher level of care or death. Minor complications included moderate or large (≥ 4 cm in largest diameter) perinephric hematoma, gross hematuria or voiding difficulties. All patients were observed for at least 23 h post-procedure. The overall incidence of bleeding was 10.5% (2.7% major, 7.8% minor). Adjusted logistic regression showed that for every 10,000 cells/mm3 decrease in platelet count, risk for major and any complication increased by 27% (odds ratio 1.27; 95% confidence intervals 1.06–1.51; p=0.01) and 8% (odds ratio 1.08; 95% confidence intervals 1.02–1.15; p=0.01), respectively. Patients with a platelet count <150,000 cells/mm3 were 30 times more likely to experience a major complication (p=0.002). Other candidate predictors, including steroid exposure, kidney function, hematocrit and histopathology, were not significant. Kidney biopsies are well tolerated in patients with systemic lupus erythematosus. However, patients with pre-biopsy platelet counts <150,000 cells/mm3 are at markedly increased risk for a major bleeding complication.
doi:10.1177/0961203312439334
PMCID: PMC3767126  PMID: 22415926
Renal lupus; nephritis; systemic lupus erythematosus; kidney biopsy; bleeding complication
25.  Time to Neuropsychiatric Damage Occurrence in LUMINA: A Multiethnic Lupus Cohort 
Lupus  2009;18(9):822-830.
The aims of this study were to examine the predictors of time-to-neuropsychiatric (NP) damage and its impact on mortality in 632 systemic lupus erythematosus (SLE) African American, Hispanic and Caucasian LUMINA patients, age ≥ 16 years and disease duration ≤ 5 years at baseline (T0). Time-to-NP damage and its impact on mortality were examined by Cox proportional hazards regressions. One-hundred eighty-five (29.3%) patients developed NP-damage over a mean (SD) disease duration of 5.6 (3.7) years. After adjusting for neuropsychiatric manifestations present, older age [Hazard ratio (HR)=1.02; 95% [Confidence interval (CI) 1.00–1.04)], Caucasian ethnicity (HR=1.87; 95% CI 1.22-2.87), disease activity over the disease course (HR=1.16; 95% CI 1.12–1.21), diabetes (HR=3.47; 95% CI 1.44–8.38) and abnormal illness-related behaviors (HR=1.05; 95% CI 1.02–1.08) were associated with a shorter time to NP-damage. Photosensitivity (HR=0.65; 95% CI 0.44–0.95), anemia (HR=0.56; 95% CI 0.31–0.98), Raynaud’s phenomenon (HR=0.49; 95% CI 0.34–0.72), a medium dose of prednisone (HR=0.56; 95% CI 0.35–0.92) and hydroxychloroquine use (HR=0.58; 95% CI 0.36–0.93) were associated with a longer time. NP-damage did not contribute to mortality. Older age, Caucasian ethnicity, disease activity and abnormal illness-related behaviors are associated with a shorter time-to-NP damage; hydroxychloroquine and a medium dose of prednisone with a longer time.
doi:10.1177/0961203309104392
PMCID: PMC3759150  PMID: 19578107

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