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1.  Improving clinical trial accrual by streamlining the referral process 
Objective
Poor accrual rates impede clinical trial efficiency and significantly contribute to development costs for new interventions. Many providers recognize investigational treatments are their patients’ best opportunities for improvement, but operational clinical burdens impede providers’ awareness of, and ability to leverage, such opportunities. We aimed to develop a new workflow for non-intrusively apprising providers of trial opportunities for their patients and enabling providers to efficiently refer potential trial candidates to study teams for preliminary eligibility review.
Materials and methods
We developed a small information system to monitor institutional systems, identify patients potentially eligible for ongoing clinical trials, and give providers a non-intrusive, one-click method to refer such patients to study teams for preliminary eligibility vetting.
Results
In 18 months of pilot experience, providers invited study teams to vet 11% of 1844 patients found potentially eligible for 38 trials registered with the system. Seventy-nine patients were conservatively estimated to be accrued. Accrual rates were boosted for several trials. Results of a survey indicated most users were satisfied with the system.
Discussion
Providers’ time constraints impede their pursuit of investigational opportunities for their patients. In pilot experience, our novel approach to facilitating such pursuits yielded improved accrual, benefiting trials and presumably patients, too. Our approach may bear particular fruit for cross-disciplinary referrals for screening.
Conclusion
Systems for assisting providers in making investigational opportunities available to their patients may benefit from careful attention to provider workflow and time constraints. Our system might further benefit from improved patient/trial matching and shorter messages.
doi:10.1016/j.ijmedinf.2014.09.001
PMCID: PMC5225661  PMID: 25256066
Clinical trials; Clinical trial accrual; Clinical trial information systems; Clinical research workflow
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.  Safety and efficacy of belimumab in systemic lupus erythematosus academic clinical practices 
The Journal of rheumatology  2015;42(12):2288-2295.
Objective
Belimumab (Benlysta) is a human monoclonal antibody that inhibits soluble B-lymphocyte stimulator and was approved by the FDA for treatment of adults with systemic lupus erythematosus (SLE). This study evaluates the use and efficacy of belimumab in academic SLE practices.
Methods
Invitations to participate and complete a one-page questionnaire for each patient prescribed belimumab were sent to 16 physicians experienced in SLE Phase III clinical trials. The outcome was defined as the physician’s impression of improvement in the initial manifestation(s) being treated without worsening in other organ systems.
Results
Of 195 patients treated with belimumab at 10 academic centers, 96% were on background medications for SLE at initiation of belimumab, with 74% on corticosteroids. The main indications for initiation of belimumab were arthritis, rash, and/or worsening serologic activity, with 30% of patients unable to taper corticosteroids. Of the 120 patients on belimumab for at least 6 months, 51% responded clinically and 67% had ≥25% improvement in laboratory values. While numbers are limited, black patients showed improvement at 6 months. In a subset of 39 patients with childhood-onset SLE, 65% responded favorably at 6 months, and 35% discontinued corticosteroids.
Conclusion
Our data demonstrate favorable clinical and laboratory outcomes in patients with SLE at 6 months across all racial and ethnic groups, with similar improvement seen among patients with childhood-onset SLE.
doi:10.3899/jrheum.150470
PMCID: PMC5031077  PMID: 26523030
belimumab; lupus treatment; childhood-onset lupus
4.  Longitudinal measures of perfluoroalkyl substances (PFAS) in serum of Gullah African Americans in South Carolina: 2003–2013 
Environmental research  2015;143(0 0):82-88.
Background
Charleston Harbor has elevated concentrations of PFAS in dolphins, but local human exposure data are limited.
Objectives
We sought to describe PFAS serum concentrations’ temporal trends among Gullah African American residents of coastal South Carolina.
Methods
Longitudinal measures of PFAS in blood serum from a Gullah clinical sample, without lupus, were examined using spaghetti plots and visit-to-visit change scores (e.g., differences in concentrations between visits) among the 68 participants with repeated measures available. We also modeled population-level trends among the 71 participants with any data using proportionate percentile models, accounting for clustering through robust standard errors. In a post-hoc analysis we examined heterogeneity of temporal trends by age through mixed-effects models for the log-transformed PFAS compounds.
Results
Population concentrations of PFOS dropped approximately 9 (95% CI: 8, 10) percent each year over 2003–2013. This was concordant with individual PFOS trajectories (median PFOS change score −21.7 ng/g wet weight, interquartile range of PFOS change scores: −32.8, −14.9) and reports for other populations over this time period. Several other compounds including PFOA, PFHxS, and PFuNDA also showed a population-level decrease. However, examination of individual trajectories suggested substantial heterogeneity. Post-hoc analyses indicated that PFAS trajectories were heterogeneous by age.
Conclusions
Many PFAS compounds are decreasing in a sample of Gullah African Americans from coastal South Carolina. There may be age differences in the elimination kinetics of PFASs. The possible role of age as a modifier of PFAS serum trends merits further research.
doi:10.1016/j.envres.2015.03.012
PMCID: PMC4583839  PMID: 25819541
PFAS; Gullah; PFOA; PFOS; biomonitoring; contaminant trends
5.  A pilot randomized, controlled trial of vitamin D repletion to determine if endothelial function improves in patients with systemic lupus erythematosus 
The endothelium is important not only in regulating vascular tone but also in modulating inflammation. Patients with systemic lupus erythematosus (SLE) have deficits in these endothelial functions. Vitamin D is a nuclear hormone that regulates vascular endothelial nitric oxide synthase activity and expression. Many SLE patients have insufficient levels of vitamin D. The effect of this hormone on vascular endothelial function in SLE patients is not known. This study was designed to determine the effect size of repleting vitamin D levels on endothelial function in patients with SLE and vitamin D deficiency. SLE patients with 25(OH) vitamin D (25(OH)D) levels < 20 ng/ml were randomized to oral vitamin D3 (D3) doses that did or did not raise 25(OH)D levels to ≥ 32 ng/ml. Endothelial function was measured with flow-mediated dilation (FMD) before and after 16 weeks of vitamin D3 supplementation. Half of those who achieved 25(OH)D levels of ≥32 ng/ml experienced increases in FMD, while none of those with continued low 25(OH)D levels did. Those with increases in FMD had significantly higher final 25(OH)D levels. Using the effect size from this study, future studies designed to test the effect of repleting 25(OH)D on FMD in vitamin D deficient SLE patients will require 35 patients in each group. These results suggest a potential role for vitamin D in SLE-related endothelial dysfunction and that an adaptive multi-arm treat-to-target serum level trial design may increase the efficiency and likelihood of success of such a study.
doi:10.1097/MAJ.0000000000000556
PMCID: PMC4589474  PMID: 26351776
6.  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
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
Objective
Vitamin D modulates the immune response and blocks induction of an interferon signature by SLE sera. We investigated the effects of vitamin D supplementation on the IFN signature in SLE patients.
Methods
57 SLE patients with stable, inactive disease, a serum 25OH vitamin D (25OHD) ≤20ng/ml, elevated anti-DNA antibodies and an IFN signature (determined by measurement of 3 interferon responsive genes) were randomized into a 12 week double-blind placebo controlled trial of 0, 2000IU or 4000IU of vitamin D3. An IFN signature response required a 50% reduction in expression of 1 gene or a 25% decrease in 2 genes. Disease activity, adverse events and endocrine effects were assessed.
Results
Baseline characteristics of the 3 treatment groups were similar. No subjects receiving placebo repleted (achieved 25OHD levels ≥30ng/ml) compared to 16 of 33 subjects receiving vitamin D3. The percent of subjects achieving an IFN signature response did not differ between treatment groups. Moreover, there was no difference in the IFN signature response in vitamin D deficient versus repleted subjects. Modular microarray analysis of a subset (n=40) revealed no changes in any modules including the IFN-inducible module between any treatment group, nor when comparing expression data from vitamin D repleted to persistently deficient subjects. Vitamin D3 was well-tolerated with no safety concerns.
Conclusions
Vitamin D3 supplementation up to 4000IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D deficient SLE patients. Higher 25OHD levels sustained for longer duration may be required to affect immunological outcomes.
doi:10.1002/art.39108
PMCID: PMC4732716  PMID: 25777546
Vitamin D3; SLE; interferon signature
Objective
Recent studies have reported an increased risk of fracture among patients with systemic lupus erythematosus (SLE) in comparison to the general population. The aim of this study was to examine associations between SLE status and bone geometry in Caucasian and African American women.
Methods
We compared hip bone mineral density (BMD) and bone geometry parameters among SLE women and controls using hip structure analysis (HSA). 153 DXA scans from the Study of Lupus Vascular and bone Long Term Endpoints (68.7% Caucasian and 31.3% African American) and 4920 scans from the third National Health and Nutrition Examination Survey (59.3% Caucasian and 40.7% African American) were analyzed. Linear regression was used to examine BMD and bone geometry differences by SLE status and by race/ethnicity after adjusting for age and body mass index.
Results
Significant differences were detected between SLE women and control. Among Caucasians, age-adjusted BMD (g/cm2), section modulus (cm3) and cross sectional areas (cm2) were lower among SLE subjects in comparison to control at the narrow neck (0.88 vs. 0.83, 1.31 vs. 1.11 and 2.56 vs. 2.40; p<0.001, <0.01 and <0.0001 respectively), while buckling ratio was increased (10.0 vs. 10.6, p<0.01). Likewise, BMD, section modulus and cross sectional areas were decreased among African American SLE women at all sub regions, while buckling ratios were increased.
Conclusions
There were significant bone geometry differences between SLE women and control at all hip sub-regions. Bone geometry profiles among SLE subjects were suggestive of increased fragility.
doi:10.1002/jbmr.466
PMCID: PMC4847947  PMID: 21755534
Osteoporosis; Inflammation; Biomechanics; Modeling and Remodeling; Bone densitometry
Lupus science & medicine  2014;1(1):e000020.
Objective
In a study of Gullah African–Americans, we compared pregnancy outcomes before and after systemic lupus erythematosus (SLE) diagnosis to controls to test whether there is a predisease state that negatively affects pregnancy outcomes.
Design
Cases and controls reporting at least one pregnancy were included. Controls were all Gullah African-American females. We collected demographic, socioeconomic and pregnancy data. We modelled pregnancy outcome associations with case status using multiple logistic regression to calculate ORs.
Results
After adjustment for age, years of education, medical coverage and pregnancy number, compared with controls, cases were more likely to have any adverse outcome (OR 2.35, 95% CI 1.78 to 3.10), including stillbirth (OR 4.55, 95% CI 1.53 to 13.50), spontaneous abortion (OR 2.05, 95% CI 1.40 to 3.00), preterm birth (OR 2.58, 95% CI 1.58 to 4.20), low birth weight (OR 2.64, 95% CI 1.61 to 4.34) and preeclampsia (OR 1.80, 95% CI 1.08 to 3.01). The odds of adverse pregnancy outcomes all increased after SLE diagnosis compared with before diagnosis, even after adjustment for age, years of education, pregnancy number and medical coverage.
Conclusion
From a large cohort of African–American women, our findings suggest there may be a predisease state that predisposes to adverse pregnancy outcomes.
doi:10.1136/lupus-2014-000020
PMCID: PMC4211631  PMID: 25360323
Vitamin D is an essential steroid hormone, with well-established effects on mineral metabolism, skeletal health, and recently established effects on the cardiovascular and immune systems. Vitamin D deficiency is highly prevalent and evidence is mounting that it contributes to the morbidity and mortality of multiple chronic diseases, including systemic lupus erythematosus (SLE). Patients with SLE avoid the sun because of photosensitive rashes and potential for disease flare, so adequate oral supplementation is critical. This review will describe the prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency, and review current vitamin D recommendations for patients with rheumatic diseases.
PMCID: PMC4185297  PMID: 20969555
Lupus Science & Medicine  2014;1(1):e000020.
Objective
In a study of Gullah African–Americans, we compared pregnancy outcomes before and after systemic lupus erythematosus (SLE) diagnosis to controls to test whether there is a predisease state that negativelyaffects pregnancy outcomes.
Design
Cases and controls reporting at least one pregnancy were included. Controls were all Gullah African-American females. We collected demographic, socioeconomic and pregnancy data. We modelled pregnancy outcome associations with case status using multiple logistic regression to calculate ORs.
Results
After adjustment for age, years of education, medical coverage and pregnancy number, compared with controls, cases were more likely to have any adverse outcome (OR 2.35, 95% CI 1.78 to 3.10), including stillbirth (OR 4.55, 95% CI 1.53 to 13.50), spontaneous abortion (OR 2.05, 95% CI 1.40 to 3.00), preterm birth (OR 2.58, 95% CI 1.58 to 4.20), low birth weight (OR 2.64, 95% CI 1.61 to 4.34) and preeclampsia (OR 1.80, 95% CI 1.08 to 3.01). The odds of adverse pregnancy outcomes all increased after SLE diagnosis compared with before diagnosis, even after adjustment for age, years of education, pregnancy number and medical coverage.
Conclusion
From a large cohort of African–American women, our findings suggest there may be a predisease state that predisposes to adverse pregnancy outcomes.
doi:10.1136/lupus-2014-000020
PMCID: PMC4211631  PMID: 25360323
systemic lupus erythematosus; pregnancy
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
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
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
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
In a 10-wk Wii Fit™ home-based program, exercise logs exhibited marginally acceptable agreement with Wii estimation of exercise duration at a group level, illustrating the tendency of participants to overreport.
OBJECTIVE. We examined agreement of data between self-reported and objectively assessed exercise adherence among women with systemic lupus erythematosus.
METHOD. Eleven participants completed weekly exercise logs on date and duration of exercise during a 10-wk Wii Fit™ home-based program. Afterward, exercise data from the log were compared with those recorded in the Wii console.
RESULTS. Of the paired data, the mean duration of exercise recorded in the Wii was 29.5 min and that recorded in the log was 33.3 min. The composite intraclass correlation for exercise duration between exercise log and the Wii Fit was 0.4. The 95% limits of agreement indicated large between-subjects variability.
CONCLUSION. Exercise logs exhibit a marginally acceptable agreement with Wii estimation of exercise duration at a group level. However, caution should be applied when using the exercise log as a measure of a person’s exercise behavior because of the tendency to overreport.
doi:10.5014/ajot.2013.007575
PMCID: PMC3722661  PMID: 23791324
exercise therapy; home care services; lupus erythematosus, systemic; patient compliance; self report
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
Dermato-endocrinology  2012;4(2):146-151.
Systemic lupus erythematosus (SLE) is a complex multi-system autoimmune disease. Vitamin D deficiency has been proposed as an environmental trigger of disease onset and as a contributor to increased SLE activity. SLE patients are prone to develop vitamin D deficiency because of photosensitivity leading to sun avoidance and other sun protective measures. The impact of vitamin D on immune function previously seen in vitro and in cross-sectional studies has now been shown in prospective human studies, strengthening the evidence that there is a connection between SLE and vitamin D status. This review describes the role of vitamin D on immune function, prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency in SLE patients, and review current vitamin D recommendations for patients with SLE.
doi:10.4161/derm.20443
PMCID: PMC3427193  PMID: 22928070
systemic lupus erythematosus; vitamin D; autoimmune disease; review
doi:10.1016/j.rdc.2014.05.003
PMCID: PMC4198387  PMID: 25034153
Systemic lupus erythematosus; etiology; vitamin D; environment; risk factors
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
Perfluorinated compounds, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), have been shown to alter various immune functions suggesting they are immunotoxic. This study assessed the effects of PFOS and PFOA on interleukin (IL)-2 production in the human Jurkat T-cell line and PFOS in healthy human primary T cells. Jurkat cells were stimulated with phytohemagglutinin (PHA)/phorbol myristate acetate (PMA), anti CD-3/anti CD-28, or anti CD-3, and dosed with 0, 0.05, 0.1, 0.5, 1, 5, 10, 50, 75, or 100 μg ml−1 PFOS or 0, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, or 10 μg ml−1 PFOA. Jurkat cells stimulated with PHA/PMA or anti CD-3 exhibited decreased IL-2 production beginning at 50 μg PFOS ml−1 and 5 μg PFOS ml−1 respectively, but stimulation with anti-CD3/anti-CD28 resulted in no changes compared with the control. Addition of the PPAR-alpha antagonist GW6471 to PFOS-dosed cells stimulated with PHA/PMA resulted in decreases in IL-2 production starting at 50 μg PFOS ml−1, which suggests PFOS affected T-cell IL-2 production via PPAR-alpha-independent mechanisms. Exposure to PFOA, PFOA + GW6471, or PFOS + PFOA in Jurkat cells resulted in no significant differences in IL-2 production. In vitro dosing studies using healthy primary human CD4+ T cells were consistent with the Jurkat results. These data demonstrated that PFOA did not impact IL-2 production, but PFOS suppressed IL-2 production in both a human cell line and human primary cells at dose levels within the high end of the human exposure range. A decrease in IL-2 production is characteristic of autoimmune diseases such as systemic lupus erythematosus and should be further investigated.
doi:10.1002/jat.3037
PMCID: PMC4305032  PMID: 25056757
PFOS; PFOA; IL-2 production; immunology; ppar-alpha; perfluorinated compounds; cytokine; human T cells; in vitro; immunosuppression
Lupus  2014;23(4):360-369.
Objective
To examine whether smoking is associated with autoantibody production in systemic lupus erythematosus (SLE) patients, unaffected first-degree relatives (FDR) of individuals with SLE - a group at increased risk of developing SLE, or unaffected, unrelated controls.
Methods
Detailed demographic, environmental, clinical, and therapeutic information was collected by questionnaire on 1,242 SLE patients, 981 FDRs, and 946 controls in the Lupus Family Registry and Repository; a blood sample was obtained. All sera were tested for multiple lupus autoantibodies by immunofluorescence and luminex bead-based assays. Generalized estimating equations, adjusting for age, gender, and ethnicity and accounting for correlation within families, were used to assess smoking status with the dichotomous outcome variables of positivity for SLE status, positivity of ANA by immunofluorescence (≥ 1:120), positivity for ≥ 1 autoantibody by the luminex assay, and positivity for each of the 11 autoantibodies.
Results
Current smoking was associated with being positive for ≥ 1 autoantibody (excluding ANA) (adjusted OR=1.53, 95% CI 1.04–2.24) in our subjects with SLE. No association was observed in unaffected FDRs or healthy controls. Former smoking was associated with anti-Ro/SS-A60 in our unaffected FDRs. There was an increased association with anti-nRNP A seropositivity, as well as a decreased association with anti-nRNP 68 positivity, in current smokers in SLE subjects.
Conclusions
No clear association between smoking status and individual autoantibodies was detected in SLE patients, unaffected FDRs, nor healthy controls within this collection. The association of smoking with SLE may therefore manifest its risk through mechanisms outside of autoantibody production, at least for the specificities tested.
doi:10.1177/0961203314520838
PMCID: PMC3954895  PMID: 24449338
Smoking; autoantibodies; systemic lupus erythematosus
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

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