A systematic review of pharmacological therapies and their effectiveness on health-related quality of life outcomes in patients with juvenile-onset systemic lupus erythematosus.

Juvenile-onset systemic lupus erythematosus (JSLE) presents with an aggressive course and high morbidity associated with disease and treatment. JSLE patients have a poorer health-related quality of life (HRQoL) when compared with age-matched patients with other rheumatologic disorders. We aim to summarize the impact of current pharmacological therapies on the HRQoL of JSLE patients. Search strategies were developed across seven databases. Randomized clinical trials (RCTs) and cohort studies comparing interventions to standard therapy, placebo or pre-post cohort comparisons for more than 4 weeks were included. The outcome included self-reported scales compared at baseline and a therapeutic time point. Risk of bias was evaluated by using the Cochrane risk of bias tool and the Newcastle-Ottawa quality assessment scale. A total of 2812 articles were narrowed down to 309 for full-text screening. Four RCTs and one prospective cohort study, with a total of 634 JSLE patients, met the inclusion criteria. Four of the studies had a controlled intervention plus standard therapy compared with standard therapy alone or placebo. Multiple indices were used to evaluate HRQoL. These included the Pediatric Quality of Life Inventory, Childhood Health Assessment Questionnaire, Simple Measure of Impact of Lupus Erythematosus in Youngsters tool, Kids Fatigue Severity Scale and Child Depression Inventory. A single study reported a significant improvement while remaining studies reported no difference or failed to report the statistical analysis. Although HRQoL is significantly impaired in JSLE, evidence regarding its improvement is limited due to the small number of eligible studies, heterogeneity in scales, and HRQoL domains. A universal HRQoL questionnaire for JSLE needs to be established and used in both the research and clinical setting. All studies should adhere to reporting guidelines.

Remission and low disease activity state (LDAS) are protective of intermediate and long-term outcomes in SLE patients. Results from LUMINA (LXXVIII), a multiethnic, multicenter US cohort.

OBJECTIVE: The objective of this report is to determine the impact of remission and low disease activity state (LDAS) on damage accrual and mortality in systemic lupus erythematosus (SLE) patients. PATIENTS AND METHODS: Visits from the Lupus in Minority populations: Nature vs. Nurture (LUMINA) cohort were categorized into remission (Systemic Lupus Activity Measure (SLAM) score = 0 and prednisone ≤ 5 mg/day and no immunosuppressants), LDAS ((not on remission), SLAM score ≤ 3, prednisone ≤ 7.5 mg/day, no immunosuppressants), or neither: active. Remission and LDAS visits were combined because of the relatively small number of remission visits. Their impact on damage accrual and mortality were examined by Poisson and logistic multivariable regressions adjusting for variables known to affect these outcomes. RESULTS: A total of 3879 visits for 558 patients (28% Caucasian, 37% African descent, 35% Hispanic) were studied. These visits corresponded to 71 in remission, 585 in LDAS, and 3223 active. The longer the percentage of time the patients were in remission/LDAS, the less damage accrual observed (rate ratio 0.1773 (95% confidence interval (CI) 0.1216 to 0.2584) p < 0.0001). A trend was observed in terms of mortality although statistical significance was not reached (odds ratio 0.303 (95% CI 0.063 to 1.456), p = 0.1360). CONCLUSIONS: The longer the patient's state on Remission/LDAS, the less damage accrual that occurs. The protective effect on mortality was not statistically significant.

DNA barcoding of large oak-living cerambycids: diagnostic tool, phylogenetic insights and natural hybridization between Cerambyx cerdo and Cerambyx welensii (Coleoptera: Cerambycidae).

Three large saproxylic cerambycids with different pest/legal status co-occur in the Iberian oak woodlands, Cerambyx welensii (Cw), Cerambyx cerdo (Cc) and Prinobius myardi (Pm): Cw is an emerging pest, Cc is a protected but sometimes harmful species and Pm is a secondary/minor pest. A precise taxonomic diagnosis is necessary for research, management or protection purposes, but may be problematic mainly because Cw and Cc larvae are morphologically indistinguishable. To resolve this constraint, we genotyped adults, larvae and eggs collected over a wide geographical range using the mitochondrial barcoding of the cytochrome c oxidase subunit I (COI). A Neighbour-Joining tree phylogram revealed three distinct clusters corresponding to Cw, Cc and Pm. We further first sequenced for Cw and Cc two mitochondrial (12S rRNA and 16S rRNA) and one nuclear (28S rRNA) gene fragments. For the first two genes, interspecific divergence was lower than in COI, and for the 28S (lower mutation rate), the two species shared identical haplotypes. Two approaches for species delimitation (General Mixed Yule Coalescent (GMYC), Barcode Index Number (BIN)) confirmed the species distinctiveness of Cc and Cw. The Bayesian COI gene tree showed a remarkable genetic divergence between Cc populations from Iberia and the rest of Europe. Such divergence has relevant taxonomic connotations and stresses the importance of a wide geographical scale sampling for accurate DNA barcoding species identification. Incongruities between morphology/lineage and COI barcodes in some individuals revealed natural hybridization between Cw and Cc. Natural hybridization is important from a phylogenetic/evolutionary perspective in these cerambycids, but the prevalence of (and the behavioural/ecological factors involved in) interspecific cross-breeding remain to be investigated.

Factors associated with disease expression patterns in systemic lupus erythematosus patients: results from LUMINA (LXXVII), a multiethnic US cohort.

Objective The objective of this study was to determine the association of disease expression patterns with demographic and clinical characteristics in SLE. Methods Patients from a multi-ethnic SLE cohort were included. Disease expression patterns were defined as acute SLE and insidious SLE; this group was divided into those who accrued three ACR criteria and then accrued the fourth (insidious pattern A) and those who have one or two and then accrued four criteria (insidious pattern B). Disease activity was ascertained with the SLAM-R and disease damage with SLICC/ACR damage index. Variables were compared using analysis of variance for numeric variables and χ2 for categorical variables. Multivariable analyses adjusting for possible confounders were performed. Results Six hundred and forty patients were included; the most frequent pattern was the insidious pattern B, with 415 (64.8%) patients, followed by the acute SLE group with 115 (18.0%) and the insidious pattern A with 110 (17.2%) patients. Patients from the insidious pattern A were older at diagnosis (pattern A: 39.8 vs pattern B: 36.7 vs acute: 32.4 years; p < 0.0001), more educated (13.6 vs 13.1 vs 12.1; p = 0.0008) and with a less active disease at baseline (8.8 vs 9.2 vs 10.7; p = 0.0227). Caucasian and Hispanic (Puerto Rico) ethnicities were overrepresented in this group (40.0% vs 27.7% vs 19.1% and 18.2% vs 17.1% vs 9.6%; p = 0.0003). Conclusions More insidious onset is associated with older age, Caucasian ethnicity, higher level of education, and lower disease activity than those with acute onset. However, after multivariable analyses, disease activity was not associated with any disease expression pattern.

A unique antiphospholipid assay recognizing phospholipid mixture compared with criteria antiphospholipid immunoassays in lupus patients.

Background While essential for the classification of antiphospholipid syndrome (APS), anticardiolipin (aCL) assays lack specificity and anti-ß2glycoproteinI (anti-ß2GPI) assays lack sensitivity in this regard. Our aim was to perform a comparative analysis of the APhL ELISA assay (IgG/IgM) and criteria antiphospholipid (aPL) immunoassays in identifying APS-related clinical manifestations in a large group of patients with systemic lupus erythematosus (SLE). Methods Serum samples from 1178 patients from the Hopkins ( n = 543), LUMINA ( n = 588) and Jamaican SLE cohorts ( n = 47) were examined for IgG/IgM positivity in aCL (in-house), anti-ß2GPI (two commercial kits) and APhL (Louisville APL) ELISA assays. Correlation of assay positivity with clinical manifestations and sensitivity, specificity, positive and negative predictive values and likelihood ratios were evaluated. A case series analysis was also performed in patients for whom there was isolated positivity in the specific aPL assays. Results The prevalence of aCL positivity was 34.9%, anti-ß2GPI kit A was 22.6%, APhL was 11.5% and anti-ß2GPI kit B was 7.6% in the study population. Anti-ß2GPI kit B, aCL and APhL assays were correlated with venous thrombosis, while only APhL was significantly correlated with arterial thrombosis and consistently correlated with pregnancy-related morbidity. No significant correlations were noted for anti-ß2GPI kit A. Sensitivity was greatest for aCL assays followed by anti-ß2GPI kit A, APhL and anti-ß2GPI kit B, while specificity was greatest and equal for anti-ß2GPI kit B and APhL assays. Conclusions Overall, APhL antibodies, especially IgG, represent a promising biomarker for the classification of APS patients in the context of autoimmunity and in risk assessment with regards to pregnancy morbidity and thrombotic manifestations.

Reproductive biology of the great capricorn beetle, Cerambyx cerdo (Coleoptera: Cerambycidae): a protected but occasionally harmful species.

Cerambyx cerdo (Cc) is a protected saproxylic beetle in Europe, although it is increasingly reported as an oak 'pest'. Cc ecological features are relatively well known, but, its reproductive biology is still poorly understood. Hence, we investigated the reproductive traits of Cc under laboratory conditions. In females, body length was 44.1 ± 0.9 mm, 28-53 (mean ± SE, range); fecundity 143 ± 11 eggs, 33-347; fertility 78 ± 1%, 65-93; oviposition period 44 ± 3 days, 13-128 and longevity 59 ± 5 days, 16-157. Fecundity was positively correlated with female size, longevity and oviposition period. Daily fecundity was 3.5 ± 0.2 eggs/day, 0.9-6.5 showing a fluctuating synovigenic pattern with a slight decreasing trend over time. Egg length was 3.74 ± 0.01 mm, 2.3-6.0 and egg volume 5.45 ± 0.04 mm3, 2.4-9.6. Egg size was correlated with female size, but, the relative size of eggs was larger in smaller females. Incubation time was 13.5 ± 0.1 days, 7-28. Hatching was superior in larger eggs and neonate size was positively correlated to egg volume. Females were polyandrous (up to 19 matings), but, multiple mating did not enhance fecundity or fertility. In males, body length was 41.8 ± 0.8 mm, 29-53 and longevity 49 ± 3 days, 9-124. Male longevity was unrelated to body size. Males were polygynous (up to 16 matings) and mating number did not affect male longevity. Overall, females were larger and lived longer than males. Cc reproductive traits are compared with those other Cerambycidae, especially with the congeneric pest Cerambyx welensii. Our data may be valuable to improve the protection/management measures of Cc in dehesa woodlands and other oak forests.

Reproductive traits and number of matings in males and females of Cerambyx welensii (Coleoptera: Cerambycidae) an emergent pest of oaks.

The longhorn beetle Cerambyx welensii is an emerging pest involved in oak decline episodes, whose damage is increasingly reported in dehesa open woodlands. Knowledge of the reproductive biology of C. welensii is a crucial goal due to its new pest status. In this study, we assess the reproductive traits of both sexes in the laboratory (25°C and 60% relative humidity ). In females, body length was 44.9 ± 0.9 mm (mean ± SE), fecundity 132 ± 12 eggs, fertility 70 ± 1 %, longevity 70 ± 3 days, preoviposition period 2 ± 0.2 days, oviposition period 44 ± 3 days and postoviposition period 19 ± 3 days. Fecundity was positively correlated with female size, longevity and oviposition period. Daily fecundity was 3.0 ± 0.2 eggs/day and showed a fluctuating synovigenic pattern with a slight decreasing trend over time. Egg length was 4.24 ± 0.01 mm and egg volume 8.14 ± 0.04 mm3. Egg size was correlated with female size but the relative size of eggs was larger in smaller females. Incubation time was 13.9 ± 0.1 days and hatching did not depend on egg size. Neonate size was positively correlated with egg length. Females were polyandrous (more than 20 lifetime matings) but multiple mating did not increase fecundity, fertility or longevity. In males, body length was 43.7 ± 0.6 mm and longevity 52 ± 3 days. Unlike with females, longevity was positively correlated with male size. Males were polygynous (up to 30 lifetime matings) but mating history did not affect male longevity. Rather to the contrary, long-lived males mated more times because they had more mating chances. Lastly, C. welensii reproductive traits were compared with those other Cerambycidae species and discussed from an adaptive perspective. Our data will be useful to improve management of C. welensii in order to prevent or mitigate its impact in dehesa woodlands and other oak forests.

Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study.

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor 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 multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.

Lymphocyte sensitivity assay as a marker for glucocorticoid resistance in lupus: report of two sisters with systemic lupus erythematosus.

Glucocorticoid sensitivity can be measured in vitro using the lymphocyte sensitivity assay (LSA). In this test, dexamethasone is used to inhibit the proliferation of peripheral blood mononuclear cells (PBMC) in response to mitogens. If the proliferation of PBMC is suppressed the subjects are considered to be GC sensitive; if not, they are considered to be resistant. The LSA has been used to test GC sensitivity in some inflammatory diseases but its clinical value in systemic lupus erythematosus (SLE) has not been determined. Herein, we present the results of the LSA from two sisters with SLE who had different disease outcomes. Patient 1 presented with higher disease activity and damage accrual, and poorer response to corticosteroids than patient 2. In the LSA, patient 1 had a lower dexamethasone suppression of mitogen-stimulated PBMC than patient 2 and one control subject. The LSA could be helpful in identifying patients with GC resistance, thus allowing the consideration of alternative immunosuppressive drugs.

Mitochondrial DNA damage is associated with damage accrual and disease duration in patients with systemic lupus erythematosus.

OBJECTIVE: To determine the extent of mitochondrial DNA (mtDNA) damage in systemic lupus erythematosus (SLE) patients compared to healthy subjects and to determine the factors associated with mtDNA damage among SLE patients. METHODS: A cross-sectional study was performed in 86 SLE patients (per American College of Rheumatology classification criteria) and 86 healthy individuals matched for age and gender. Peripheral blood mononuclear cells (PBMCs) were collected from subjects to assess the relative amounts of mtDNA damage. Quantitative polymerase chain reaction assay was used to measure the frequency of mtDNA lesions and mtDNA abundance. Socioeconomic-demographic features, clinical manifestations, pharmacologic treatment, disease activity, and damage accrual were determined. Statistical analyses were performed using t test, pairwise correlation, and Pearson's chi-square test (or Fisher's exact test) as appropriate. RESULTS: Among SLE patients, 93.0% were women. The mean (SD) age was 38.0 (10.4) years and the mean (SD) disease duration was 8.7 (7.5) years. SLE patients exhibited increased levels of mtDNA damage as shown by higher levels of mtDNA lesions and decreased mtDNA abundance as compared to healthy individuals. There was a negative correlation between disease damage and mtDNA abundance and a positive correlation between mtDNA lesions and disease duration. No association was found between disease activity and mtDNA damage. CONCLUSION: PBMCs from SLE patients exhibited more mtDNA damage compared to healthy subjects. Higher levels of mtDNA damage were observed among SLE patients with major organ involvement and damage accrual. These results suggest that mtDNA damage have a potential role in the pathogenesis of SLE.

Effects of statins on proinflammatory/prothrombotic biomarkers and on disease activity scores in SLE patients: data from LUMINA (LXXVI), a multi-ethnic US cohort.

OBJECTIVES: We sought to determine the effect of statin therapy on the levels of proinflammatory/prothrombotic markers and disease activity scores in patients with SLE in a multi-ethnic, multi-centre cohort (LUMINA). METHODS: Plasma/serum samples from SLE patients placed on statins (n=21) therapy taken before and after at least 6 months of treatment were tested. Disease activity was assessed using SLAM-R scores. Interleukin (IL)-1ß, IL-6, IL-8, tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF) and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Soluble intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and anticardiolipin (aCL) antibodies were evaluated using ELISA assays while high sensitivity C-reactive protein (hsCRP) was assessed by nephelometry. Plasma/serum samples from frequency- matched healthy donors were used as controls. RESULTS: Levels of IL-6, VEGF, sCD40L and TNF-α were significantly elevated in SLE patients versus controls. Statin therapy resulted in a significant decrease in SLAM-R scores (p=0.0199) but no significant changes in biomarker levels were observed. There was no significant association of biomarkers with SLAM-R scores. CONCLUSIONS: Statin therapy resulted in significant clinical improvement in SLE patients, underscoring the use of statins in the treatment of SLE.

Polyandry-fecundity relationship in insects: methodological and conceptual problems.

Polyandry is perhaps the most puzzling component of mating systems because the fitness benefits for females of mating with more than one male during lifetime are poorly understood. The occurrence and extent of polyandry varies considerably both among and within species, and a positive association between polyandry and fecundity is widespread but not universal. The scenario is further complicated because the scientific literature on this issue includes studies that are often inconclusive or contradictory even for the same target species. A previous meta-analysis detected the crucial importance of two usually neglected aspects that potentially bias the interpretation of primary studies about the polyandry-fecundity relationship: the methodological approach--experimental or descriptive--and the polyandry concept itself--realized or potential. In this paper, we experimentally test the effect of these aspects with the moth Lobesia botrana. We used an innovative protocol in which the experimental and the descriptive methods were conducted simultaneously on the same target population and the results were then interpreted from the perspective of both concepts of polyandry. The results clearly showed that 1) the conclusions about the polyandry-fecundity relationship were strongly dependent on the methodological approach used and 2) the concept of polyandry invoked by the researcher was a confounding effect that potentially biases data interpretation. We suggest that greater attention must be paid to intraspecific variation among females in their propensity to remate. The differentiation in experimental studies between potentially polyandrous and monandrous phenotypes could greatly improve our knowledge about the maintenance of female mating polymorphism in most species and the adaptive significance of polyandry.

Efficacy of low-dose intravenous cyclophosphamide in systemic lupus erythematosus presenting with Guillain-Barre syndrome-like acute axonal neuropathies: report of two cases.

There are few cases of Guillain-Barré syndrome (GBS), particularly of atypical variants, occurring in association with systemic lupus erythematous (SLE). Reports addressing a specific therapy thus remain almost anecdotal. It is therefore challenging to determine the treatment that is best suited for this subset of patients, especially if initial conventional therapy for GBS fails. We present two cases of GBS-like acute axonal neuropathies, one with acute motor axonal neuropathy (AMAN), and another with acute motor sensory axonal neuropathy (AMSAN), presenting early in the course of SLE. The first case failed to respond to therapy with intravenous immunoglobulins (IVIG) and plasmapheresis, but achieved a favorable outcome when high-dose glucocorticoids along with low-dose intravenous (IV) cyclophosphamide pulses were given. The second case responded favorably to high-dose glucocorticoids, IVIG, and low-dose IV cyclophosphamide pulses. Both patients have remained in clinical remission and without neurologic sequelae after 10 and three years of follow-up, respectively.

Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P < 2.03 × 10(-3) were observed between LN and MYH9 in EAs (N = 4620), with the most pronounced association at rs2157257 (P = 4.7 × 10(-4), odds ratio (OR) = 1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

Long-term membranous glomerulonephritis as the presenting manifestation of systemic lupus erythematosus in a patient with human immunodeficiency virus infection.

The coexistence of human immunodeficiency virus (HIV) infection and systemic lupus erythematosus (SLE) is unusual, but the occurrence of SLE after HIV infection is even less common. Both conditions share similar clinical features including constitutional symptoms, facial rash, oral ulcers, alopecia, arthralgias, arthritis, seizures, cytopenias, glomerulonephritis, and antinuclear and antiphospholipid antibodies. This clinical overlap makes the diagnosis of SLE in a patient with pre-existing HIV infection difficult. Furthermore, immune complex glomerulonephritis with features resembling lupus nephritis has been described in HIV-positive patients. We present the case of a 45-year-old Hispanic woman with long-standing HIV infection who developed membranous glomerulonephritis with histological features of lupus nephritis. Five years after onset of renal disease she developed clinically evident SLE.

Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort.

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)-1ß, 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.

Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.

Is familial lupus different from sporadic lupus? Data from LUMINA (LXXIII), a multiethnic US cohort.

The aim of this study was 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. Familial lupus was defined as patients with a first-degree relative with systemic lupus erythematosus. Relative risks were estimated by logistic regression; odds ratios (ORs) and their 95% confidence intervals (CIs) were the measure of association for familial lupus. Hazard ratios were calculated using Cox proportional hazards adjusted for potential confounders for damage and survival. Of 644 patients, 32 had familial and 612 had sporadic lupus; both groups were of comparable age (~36 years). Patients with familial lupus 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/mm(3); 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). We conclude that although some clinical differences were observed between patients with familial and sporadic lupus, familial lupus was not associated with a significantly greater disease burden (damage, survival) than sporadic lupus.

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.

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 at least three visits in which disease activity (Systemic Lupus Activity Measure-Revised [SLAM-R]) had been ascertained. Variables associated with the rate (slope) of change in disease activity (obtained by regressing the SLAM-R score against the length of time from diagnosis to visit date) were examined by univariable and multivariable analyses. Five hundred and forty two of the 632 patients had at least three SLAM-R score. In multivariable analyses, Whites 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 American College of Rheumatology criteria and abnormal laboratory parameters (white blood cell 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.