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1.  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
2.  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
3.  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
4.  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 care & research  2014;66(8):1177-1185.
Objectives
To investigate risk factors in the subclinical atherosclerosis progression as measured by coronary artery calcium (CAC) and aorta calcium (AC) in women with Systemic Lupus Erythematosus (SLE) (cases) and in comparison with a control population.
Methods
A cohort of 149 cases and 124 controls participated in the Study of Lupus Vascular and Bone Long-term Endpoints (SOLVABLE). Demographic information, cardiovascular and SLE risk factors, and laboratory assessments were collected at an initial visit. CAC and AC were measured by electron beam computed tomography (CT) or multi-detector CT at an initial and a follow-up visit. Logistic regression models were used to identify predictors of progression in CAC and AC; multivariate models were adjusted for age, hypertension, and total cholesterol/HDL ratio.
Results
Higher modified ACR/SLICC-DI (OR 2.15, 95%CI 1.33–3.57), use of a corticosteroid (OR 2.93, 95%CI 1.14–7.86), and use of aspirin (OR 4.23, 95%CI 1.53–11.74) were associated with CAC progression in multivariate models. Presence of SLE (OR 2.64, 95%CI 1.26–5.72), lower C3 (OR 0.54, 95%CI 0.33–0.87), lower C4 (OR 0.49, 95% CI 0.27–0.86), use of a corticosteroid (OR 2.73, 95%CI 1.03–7.64), higher corticosteroid dose (OR 1.77, 95%CI 1.12–3.00), higher lipoprotein(a) (OR 1.80, 95%CI 1.11–2.98), higher homocysteine (OR 2.06, 95%CI 1.06–4.29) were associated with AC progression in multivariate models.
Conclusions
Higher disease damage at the first study visit, as measured by the modified ACR/SLICC-DI, may predict increased risk in CAC progression, whereas higher disease activity at the first study visit, as measured by hypocomplementemia and use of corticosteroids, may predict increased risk in AC progression.
doi:10.1002/acr.22271
PMCID: PMC4069201  PMID: 24376005
Annals of the Rheumatic Diseases  2014;74(8):1530-1536.
Background
The metabolic syndrome (MetS) may contribute to the increased cardiovascular risk in systemic lupus erythematosus (SLE). We examined the association between MetS and disease activity, disease phenotype and corticosteroid exposure over time in patients with SLE.
Methods
Recently diagnosed (<15 months) patients with SLE from 30 centres across 11 countries were enrolled into the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort from 2000 onwards. Baseline and annual assessments recorded clinical, laboratory and therapeutic data. A longitudinal analysis of factors associated with MetS in the first 2 years of follow-up was performed using random effects logistic regression.
Results
We studied 1150 patients with a mean (SD) age of 34.9 (13.6) years and disease duration at enrolment of 24.2 (18.0) weeks. In those with complete data, MetS prevalence was 38.2% at enrolment, 34.8% at year 1 and 35.4% at year 2. In a multivariable random effects model that included data from all visits, prior MetS status, baseline renal disease, SLICC Damage Index >1, higher disease activity, increasing age and Hispanic or Black African race/ethnicity were independently associated with MetS over the first 2 years of follow-up in the cohort.
Conclusions
MetS is a persistent phenotype in a significant proportion of patients with SLE. Renal lupus, active inflammatory disease and damage are SLE-related factors that drive MetS development while antimalarial agents appear to be protective from early in the disease course.
doi:10.1136/annrheumdis-2013-203933
PMCID: PMC4515988  PMID: 24692585
Systemic Lupus Erythematosus; Cardiovascular Disease; Inflammation
Objective
To investigate whether the FcγRIIIa-66R/H/L polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcγRIIIa-66R/H/L and FcγRIIIa-176F/V as well as copy number variation (CNV) confer risk for development of SLE and lupus nephritis.
Methods
FcγRIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG binding assays. FCGR3A SNP and CNV genotypes were determined by Pyrosequencing methodology in a cohort of 1728 SLE patients and 2404 healthy controls.
Results
The FcγRIIIa-66L/H/R (rs10127939) polymorphism influences ligand binding capacity in the context of the FcγRIIIa-176V (rs396991) allele. The low binding FcγRIIIa-176F allele was associated with SLE nephritis (p = 0.0609) in African Americans but not in European Americans (p > 0.10). Nephritis among African American SLE subjects was associated with FcγRIIIa low binding haplotypes containing the 66R/H/L and 176F variants (p = 0.03) and with low binding genotype combinations (p = 0.002). No association was observed in European American SLE patients. The distribution of FCGR3A CNV was not significantly different between controls and SLE patients with or without nephritis.
Conclusion
FcγRIIIa-66R/H/L influences ligand binding. The low binding haplotypes formed by 66R/H/L and 176F confer enhanced risk for lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or SLE nephritis in either African Americans or European Americans.
doi:10.1002/art.38337
PMCID: PMC4069204  PMID: 24782186
Frontiers in Genetics  2015;5:450.
Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3′ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10−10, OR 0.81 (0.75–0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
doi:10.3389/fgene.2014.00450
PMCID: PMC4288052  PMID: 25620976
lupus; PXK; fine-mapping; B cells; BCR
Annals of the rheumatic diseases  2013;73(1):10.1136/annrheumdis-2012-202099.
Objective
To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE).
Methods
We performed case–cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren’s syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses.
Results
We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls.
Conclusions
In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.
doi:10.1136/annrheumdis-2012-202099
PMCID: PMC3855611  PMID: 23303389
Lupus Science & Medicine  2014;1(1):e000068.
doi:10.1136/lupus-2014-000068
PMCID: PMC4276294  PMID: 25553253
Systemic Lupus Erythematosus; Treatment; Disease Activity
Objective
Thrombosis is a serious complication of systemic lupus erythematosus (SLE). Studies that have investigated the genetics of thrombosis in SLE are limited. We undertook this study to assess the association of previously implicated candidate genes, particularly Toll-like receptor (TLR) genes, with pathogenesis of thrombosis.
Methods
We genotyped 3,587 SLE patients from 3 multiethnic populations for 77 single-nucleotide polymorphisms (SNPs) in 10 genes, primarily in TLRs 2, 4, 7, and 9, and we also genotyped 64 ancestry-informative markers (AIMs). We first analyzed association with arterial and venous thrombosis in the combined population via logistic regression, adjusting for top principal components of the AIMs and other covariates. We also subjected an associated SNP, rs893629, to meta-analysis (after stratification by ethnicity and study population) to confirm the association and to test for study population or ethnicity effects.
Results
In the combined analysis, the SNP rs893629 in the KIAA0922/TLR2 region was significantly associated with arterial thrombosis (logistic P = 6.4 × 10−5, false discovery rate P = 0.0044). Two additional SNPs in TLR2 were also suggestive: rs1816702 (logistic P = 0.002) and rs4235232 (logistic P = 0.009). In the meta-analysis by study population, the odds ratio (OR) for arterial thrombosis with rs893629 was 2.44 (95% confidence interval 1.58–3.76), without evidence for heterogeneity (P = 0.78). By ethnicity, the effect was most significant among African Americans (OR 2.42, P = 3.5 × 10−4) and European Americans (OR 3.47, P = 0.024).
Conclusion
TLR2 gene variation is associated with thrombosis in SLE, particularly among African Americans and European Americans. There was no evidence of association among Hispanics, and results in Asian Americans were limited due to insufficient sample size. These results may help elucidate the pathogenesis of this important clinical manifestation.
doi:10.1002/art.38520
PMCID: PMC4269184  PMID: 24578102
Clinical immunology (Orlando, Fla.)  2013;149(3):10.1016/j.clim.2013.08.008.
Low-dose tolerance therapy with nucleosomal histone peptide epitopes blocks lupus disease in mouse models, but effect in humans is unknown. Herein, we found that CD4+CD25highFoxP3+ or CD4+CD45RA+FoxP3low T-cells, and CD8+CD25+FoxP3+ T-cells were all induced durably in PBMCs from inactive lupus patients and healthy subjects by the histone peptide/s themselves, but in active lupus, dexamethasone or hydroxychloroquine unmasked Treg-induction by the peptides. The peptide-induced Treg depended on TGFβ/ALK-5/ pSmad 2/3 signaling, and they expressed TGF-β precursor LAP. Lupus patients’ sera did not inhibit Treg induction. The peptide epitope-induced T cells markedly suppressed type I IFN related gene expression in lupus PBMC. Finally, the peptide epitopes suppressed pathogenic autoantibody production by PBMC from active lupus patients to baseline levels by additional mechanisms besides Treg induction, and as potently as anti-IL6 antibody. Thus, low-dose histone peptide epitopes block pathogenic autoimmune response in human lupus by multiple mechanisms to restore a stable immunoregulatory state.
doi:10.1016/j.clim.2013.08.008
PMCID: PMC3849335  PMID: 24211843
Systemic Lupus Erythematosus; Human, T cells; Peptide epitopes; Tolerance; Autoimmunity
Oncology  2013;85(4):10.1159/000350165.
Objective
To describe non-lymphoma hematological malignancies in SLE.
Methods
A large SLE cohort was linked to cancer registries. We examined the types of non-lymphoma hematological cancers.
Results
In 16, 409 patients, 115 hematological cancers (including myelodysplastic syndrome) occurred. Among these, 33 were non-lymphoma. Of the 33 non-lymphoma cases, 13 were of lymphoid lineage: multiple myeloma (N=5), plasmacytoma (N=3), B-cell chronic lymphocytic leukemia, B-CLL (N=3), precursor cell lymphoblastic leukemia (N=1), and unspecified lymphoid leukemia (N=1). The remaining 20 cases were of myeloid lineage: myelodysplastic syndrome, MDS (N=7), acute myeloid leukemia, AML (N=7), chronic myeloid leukemia, CML (N=2), and 4 unspecified leukemias. Most of these malignancies occurred in female Caucasians, except for plasma cell neoplasms (4/5 multiple myeloma and 1/3 plasmacytoma cases occurred in blacks).
Conclusions
In this large SLE cohort, the most common non-lymphoma hematological malignancies were myeloid types (MDS and AML). This contrasts to the general population, where lymphoid types are 1.7 times more common than myeloid non-lymphoma hematological malignancies. Most (80%) multiple myeloma cases occurred in blacks, which requires further investigation.
doi:10.1159/000350165
PMCID: PMC3880772  PMID: 24107608
Systemic lupus erythematosus; malignancy; cancer
The American journal of cardiology  2013;112(7):1025-1032.
Patients with systemic lupus erythematosus (SLE) are at increased risk for cardiovascular (CV) disease. The aim of this study was to investigate the association between subclinical CV disease as measured by carotid intima-media thickness (IMT) and plaque using B-mode carotid ultrasound and incident CV events in a combined cohort of female patients with SLE. This was a prospective, 2-center observational study of 392 adult women with SLE and no previous CV events with a mean 8 years of follow-up. Incident CV events confirmed by clinicians were defined as angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, fatal cardiac arrest, transient ischemic attack, and cerebrovascular accident. Incident hard CV events excluded angina and transient ischemic attack. The mean age was 43.5 years, and most patients were Caucasian (77.3%). During follow-up, 38 patients had incident CV events, and 17 had incident hard CV events. Patients with incident hard CV events had higher mean carotid IMT (0.80 vs 0.64 mm, p <0.01) and presence of carotid plaque (76.5% vs 30.4%, p <0.01) compared with those without incident hard CV events. Baseline carotid IMT and presence of plaque were predictive of any incident hard CV event (hazard ratio 1.35, 95% confidence interval 1.12 to 1.64, and hazard ratio 4.26, 95% confidence interval 1.23 to 14.83, respectively), independent of traditional CV risk factors and medication use. In conclusion, in women with SLE without previous CV events, carotid IMT and plaque are predictive of future CV events. This suggests that carotid ultrasound may provide an additional tool for CV risk stratification in patients with SLE.
doi:10.1016/j.amjcard.2013.05.040
PMCID: PMC3779482  PMID: 23827400
Lupus Science & Medicine  2014;1(1):e000056.
Objective
To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE).
Methods
The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (AUC), sensitivity and specificity.
Results
AUC for EC4d (0.82±0.02) and BC4d (0.84±0.02) was higher than those yielded by C3 (0.73±0.02) and C4 (0.72±0.02) (p<0.01). AUC for CBCAPS was also higher than the AUC yielded by anti-dsDNA (0.79±0.02), but significance was only achieved for BC4d (p<0.01). The combination of EC4d and BC4d in multivariate testing methodology with anti-dsDNA and autoantibodies to cellular and citrullinated antigens yielded 80% sensitivity for SLE and specificity ranging from 70% (Sjogren's syndrome) to 92% (rheumatoid arthritis) (98% vs. normal). A higher proportion of patients with SLE with higher levels of disease activity tested positive for elevated CBCAPS, reduced complement and anti-dsDNA (p<0.03).
Conclusions
CBCAPS have higher sensitivity than standard complement and anti-dsDNA measurements, and may help with the differential diagnosis of SLE in combination with other autoantibodies.
doi:10.1136/lupus-2014-000056
PMCID: PMC4225732  PMID: 25396070
Autoimmune Diseases; Systemic Lupus Erythematosus; Autoantibodies
Arthritis Research & Therapy  2014;16(4):R147.
Introduction
Our objectives were to examine mononuclear cell gene expression profiles in patients with systemic lupus erythematosus (SLE) and healthy controls and to compare subsets with and without atherosclerosis to determine which genes’ expression is related to atherosclerosis in SLE.
Methods
Monocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro-differentiated into macrophages. Subjects also underwent laboratory and imaging studies to evaluate for subclinical atherosclerosis. Whole-genome RNA expression microarray was performed, and gene expression was examined.
Results
Gene expression profiling was used to identify gene signatures that differentiated patients from controls and individuals with and without atherosclerosis. In monocytes, 9 out of 20 patients with SLE had an interferon-inducible signature compared with 2 out of 16 controls. By looking at gene expression during monocyte-to-macrophage differentiation, we identified pathways which were differentially regulated between SLE and controls and identified signatures based on relevant intracellular signaling molecules which could differentiate SLE patients with atherosclerosis from controls. Among patients with SLE, we used a previously defined 344-gene atherosclerosis signature in monocyte-to-macrophage differentiation to identify patient subgroups with and without atherosclerosis. Interestingly, this signature further classified patients on the basis of the presence of SLE disease activity and cardiovascular risk factors.
Conclusions
Many genes were differentially regulated during monocyte-to-macrophage differentiation in SLE patients compared with controls. The expression of these genes in mononuclear cells is important in the pathogenesis of SLE, and molecular profiling using gene expression can help stratify SLE patients who may be at risk for development of atherosclerosis.
doi:10.1186/ar4609
PMCID: PMC4227297  PMID: 25011540
Science translational medicine  2013;5(216):216ra175.
B cells are pivotal regulators of acquired immune responses and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can significantly alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides IgG-mediated negative modulation through a tyrosine-based inhibition motif which down-regulates B cell receptor initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. Here we report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and in B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax® vaccination in a human Anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of uni-directional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell targeted antibody-based therapy.
doi:10.1126/scitranslmed.3007097
PMCID: PMC3982386  PMID: 24353158
Rheumatology (Oxford, England)  2013;52(6):1101-1108.
Objective. To evaluate telomere length (TL) between patients with SLE and healthy controls and to test if TL is associated with carotid plaque.
Methods. A pilot study of 154 patients with SLE and 152 controls was performed from the SOLVABLE (Study of Lupus Vascular and Bone Long-Term Endpoints) cohort. Demographic and cardiovascular disease (CVD) factors were collected at baseline. The presence or absence of plaque was evaluated by B-mode US. Genomic DNA was isolated from whole peripheral blood. TL was quantified using real-time quantitative PCR.
Results. SLE women had a short TL compared with healthy controls (4.57 vs 5.44 kb, P = 0.03). SLE women showed shorter TL than controls across all age groups: <35 years (4.38 vs 6.37 kb), 35–44 years (4.52 vs 5.30 kb), 45–54 years (4.77 vs 5.68 kb) and ≥55 years (4.60 vs 4.71 kb). Among patients with SLE and carotid plaque there was a trend towards shorter TL at a younger age and it was significantly lower in the 35- to 44-year age group when compared with controls (P = 0.025). Multiple logistic regression analysis indicated a risk of carotid plaque with older age [odds ratio (OR) 1.09; 95% CI 1.06, 1.12] but not with TL (OR 1.05; 95% CI 0.97, 1.13).
Conclusion. SLE women had significantly shorter TL than controls. SLE women trended towards shorter TL at a younger age. When carotid plaque was identified, the younger SLE women had shorter TL. Only older age but not shorter TL was independently associated with carotid plaque. Additional studies are needed to confirm if TL is a novel biomarker for cardiovascular disease in SLE.
doi:10.1093/rheumatology/kes424
PMCID: PMC3651615  PMID: 23382361
systemic lupus erythematosus; cardiovascular disease; telomere length
Lupus Science & Medicine  2014;1(1):e000024.
Background/objective
Patients with systemic lupus erythematosus (SLE) are at increased risk for adverse pregnancy outcomes and cardiovascular disease (CVD). The objective of this exploratory study was to investigate the association between a history of adverse pregnancy outcomes and subsequent risk of subclinical CVD assessed by imaging studies and verified clinical CVD events in 129 women with SLE.
Methods
The occurrence of adverse pregnancy outcomes, specifically pre-eclampsia, preterm birth and low birth weight was ascertained by questionnaire. Subclinical CVD was assessed by coronary artery calcium (CAC) as measured by electron beam CT and carotid plaque measured by B mode ultrasound. Clinical CVD events were verified by medical record review. Logistic regression was used to estimate the association of pregnancy complications with occurrence of subclinical CVD and clinical CVD with a priori adjustment for age, which is associated with CVD and SLE disease duration as a measure of SLE disease burden.
Results
Fifty-six women reported at least one pregnancy complication while 73 had none. Twenty-six women had at least one pregnancy complicated by pre-eclampsia and were more likely to have a CAC score greater than or equal to 10 (adjusted OR=3.7; 95% CI 1.2 to 11.9), but the presence of plaque was not associated with this pregnancy complication, OR=1.1, (95% CI 0.4 to 2.8). Low birth weight and preterm birth were not associated with CAC or plaque.
Conclusions
Patients with SLE with a history of pre-eclampsia had a higher rate of subclinical CVD as measured by CAC score. Future studies are needed to confirm the relationship between adverse pregnancy outcomes and subsequent subclinical CVD and clinical CVD events.
doi:10.1136/lupus-2014-000024
PMCID: PMC4213826  PMID: 25379191
Cardiovascular Disease; Systemic Lupus Erythematosus; Pregnancy; Pre-eclampsia
Journal of autoimmunity  2013;42:130-135.
OBJECTIVE
To update estimates of cancer risk in SLE relative to the general population.
METHODS
A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers.
RESULTS
Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin’s lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61–0.88), endometrial (SIR 0.44, 95% CI 0.23–0.77), and possibly ovarian cancers (0.64, 95% CI 0.34–1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23).
CONCLUSION
These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.
doi:10.1016/j.jaut.2012.12.009
PMCID: PMC3646904  PMID: 23410586
Systemic Lupus Erythematosus; Epidemiology; Treatment; Disease Activity
Objective
Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
Methods
APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.
Results
Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10−9), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10−6). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ~2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).
Conclusion
APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
doi:10.1002/art.38220
PMCID: PMC4002759  PMID: 24504811

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