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Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies.

ABSTRACT: OBJECTIVE:Studies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies. METHODS:The PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly. APOs were: fetal/neonatal death, preterm delivery <36 weeks because of placental insufficiency or preeclampsia and/or growth restriction <5th percentile. Complement activation products were measured on serial blood samples obtained at each monthly visit. RESULTS:APO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12-15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12-15 weeks remained significantly associated with APO (ORadj=1.41 per SD increase; 95%?CI 1.06 to 1.89; P=0.019?and ORadj=1.37 per SD increase; 95%?CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12-15 weeks and APOs became stronger (ORadj=2.01 per SD increase; 95%?CI 1.16 to 3.49; P=0.013). CONCLUSION:In pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.

SUBMITTER: Kim MY

PROVIDER: S-EPMC6037302 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies.

Kim Mimi Y MY Guerra Marta M MM Kaplowitz Elianna E Laskin Carl A CA Petri Michelle M Branch D Ware DW Lockshin Michael D MD Sammaritano Lisa R LR Merrill Joan T JT Porter T Flint TF Sawitzke Allen A Lynch Anne M AM Buyon Jill P JP Salmon Jane E JE

Annals of the rheumatic diseases 20180125 4

<h4>Objective</h4>Studies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies.<h4>Methods</h4>The PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly. APOs we ...[more]

PMID: 29371202

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Project description:APS is the association of antiphospholipid antibodies (aPL) with thromboses and/or recurrent pregnancy loss (RPL). Among patients with SLE, one-third have aPL and 10-15% have a manifestation of secondary APS. Animal studies suggested that complement activation plays an important role in the pathogenesis of thrombosis and pregnancy loss in APS. We performed a cross-sectional study on complement proteins and genes in 525 patients with aPL. Among them, 237 experienced thromboses and 293 had SLE; 111 had both SLE and thromboses, and 106 had neither SLE nor thrombosis. Complement protein levels were determined by radial immunodiffusion for C4, C3 and factor H; and by functional ELISA for mannan binding lectin (MBL). Total C4, C4A and C4B gene copy numbers (GCN) were measured by TaqMan-based realtime PCR. Two to six copies of C4 genes are frequently present in a diploid genome, and each copy may code for an acidic C4A or a basic C4B protein. We observed significantly (a) higher protein levels of total C4, C4A, C4B, C3, and anticardiolipin (ACLA) IgG, (b) increased frequencies of lupus anticoagulant and males, and (c) decreased levels of complement factor H, MBL and ACLA-IgM among patients with thrombosis than those without thrombosis (N = 288). We also observed significantly lower GCNs of total C4 and C4A among aPL-positive patients with both SLE and thrombosis than others. By contrast, aPL-positive subjects with SLE had significantly reduced protein levels of C3, total C4, C4A, C4B and ACLA-IgG, and higher frequency of females than those without SLE. Patients with thrombosis but without SLE (N = 126), and patients with SLE but without thrombosis (N = 182) had the greatest differences in mean protein levels of C3 (p = 2.6 × 10-6), C4 (p = 2.2 × 10-9) and ACLA-IgG (p = 1.2 × 10-5). RPL occurred in 23.7% of female patients and thrombotic SLE patients had the highest frequency of RPL (41.0%; p = 3.8 × 10-10). Compared with non-RPL females, RPL had significantly higher frequency of thrombosis and elevated C4 protein levels. Female patients with homozygous C4A deficiency all experienced RPL (p = 0.0001) but the opposite was true for patients with homozygous C4B deficiency (p = 0.017). These results provide new insights and biomarkers for diagnosis and management of APS and SLE.

Project description:BackgroundEffectively predicting the risk of adverse pregnancy outcome (APO) in women with systemic lupus erythematosus (SLE) during early and mid-pregnancy is a challenge. This study was aimed to identify potential markers for early prediction of APO risk in women with SLE.MethodsThe GSE108497 gene expression dataset containing 120 samples (36 patients, 84 controls) was downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was performed, and differentially expressed genes (DEGs) were screened to define candidate APO marker genes. Next, three individual machine learning methods, random forest, support vector machine-recursive feature elimination, and least absolute shrinkage and selection operator, were combined to identify feature genes from the APO candidate set. The predictive performance of feature genes for APO risk was assessed using area under the receiver operating characteristic curve (AUC) and calibration curves. The potential functions of these feature genes were finally analyzed by conventional gene set enrichment analysis and CIBERSORT algorithm analysis.ResultsWe identified 321 significantly up-regulated genes and 307 down-regulated genes between patients and controls, along with 181 potential functionally associated genes in the WGCNA analysis. By integrating these results, we revealed 70 APO candidate genes. Three feature genes, SEZ6, NRAD1, and LPAR4, were identified by machine learning methods. Of these, SEZ6 (AUC = 0.753) showed the highest in-sample predictive performance for APO risk in pregnant women with SLE, followed by NRAD1 (AUC = 0.694) and LPAR4 (AUC = 0.654). After performing leave-one-out cross validation, corresponding AUCs for SEZ6, NRAD1, and LPAR4 were 0.731, 0.668, and 0.626, respectively. Moreover, CIBERSORT analysis showed a positive correlation between regulatory T cell levels and SEZ6 expression (P < 0.01), along with a negative correlation between M2 macrophages levels and LPAR4 expression (P < 0.01).ConclusionsOur preliminary findings suggested that SEZ6, NRAD1, and LPAR4 might represent the useful genetic biomarkers for predicting APO risk during early and mid-pregnancy in women with SLE, and enhanced our understanding of the origins of pregnancy complications in pregnant women with SLE. However, further validation was required.

Project description:INTRODUCTION:Systemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage. METHODS:Fifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum levels of ANA, anti-dsDNA, anti-cardiolipin, anti-?(2)-glycoprotein I, anti-P ribosomal, anti-endothelial cell, and anti-Nedd5 antibodies. SLEDAI-2000 and SLICC were used to assess disease activity and chronic damage. Patients were administered a test battery specifically designed to detect fronto-subcortical dysfunction across five domains: memory, attention, abstract reasoning, executive function and visuospatial function. For each patient, the raw scores from each test were compared with published norms, then transformed into Z scores (deviation from normal mean), and finally summed in the Global Cognitive Dysfunction score (GCDs). RESULTS:Nineteen percent of patients had mild GCDs impairment (GCDs 2-3), 7% moderate (GCDs 4-5) and 5% severe (GCDs?6). The visuospatial domain was the most compromised (MDZs?=?-0.89±1.23). Anti-cardiolipin IgM levels were associated with visuospatial domain impairment (r?=?0.331, P?=?0.005). SLEDAI correlated with GCDs, and attentional and executive domains; SLICC correlated with GCDs, and with visuospatial and attentional domains impairment. CONCLUSIONS:Anti-phospholipids, disease activity, and chronic damage are associated with cognitive dysfunction in SLE. The use of a wide spectrum of tests allowed for a better selection of the relevant factors involved in SLE cognitive dysfunction, and standardized neuropsychological testing methods should be used for routine assessment of SLE patients.

Project description:To investigate which serologic and clinical findings predict adverse pregnancy outcome in patients with antiphospholipid antibody (aPL) and to test the hypothesis that a pattern of clinical and serologic variables can identify women at highest risk of adverse pregnancy outcome.Women enrolled in a multicenter prospective observational study of risk factors for adverse pregnancy outcome in patients with aPL (lupus anticoagulant [LAC], anticardiolipin antibody [aCL], and/or antibody to ?2-glycoprotein I [anti-?2 GPI]) and/or systemic lupus erythematosus (SLE) were recruited for the present prospective study. Demographic, clinical, serologic, and treatment data were recorded at the time of the first study visit. The relationship between individual and combined variables and adverse pregnancy outcome was assessed by bivariate and multivariate analysis.Between 2003 and 2011 we enrolled 144 pregnant patients, of whom 28 had adverse pregnancy outcome. Thirty-nine percent of the patients with LAC had adverse pregnancy outcome, compared to 3% of those who did not have LAC (P<0.0001). Among women with IgG aCL at a level of ?40 units/ml, only 8% of those who were LAC negative had adverse pregnancy outcome, compared to 43% of those who were LAC positive (P=0.002). IgM aCL, IgG anti-?2 GPI, and IgM anti-?2 GPI did not predict adverse pregnancy outcome. In bivariate analysis, adverse pregnancy outcome occurred in 52% of patients with and 13% of patients without prior thrombosis (P=0.00005), and in 23% with SLE versus 17% without SLE (not significant); SLE was a predictor in multivariate analysis. Prior pregnancy loss did not predict adverse pregnancy outcome. Simultaneous positivity for aCL, anti-?2 GPI, and LAC did not predict adverse pregnancy outcome better than did positivity for LAC alone.LAC is the primary predictor of adverse pregnancy outcome after 12 weeks' gestation in aPL-associated pregnancies. Anticardiolipin antibody and anti-?2 GPI, if LAC is not also present, do not predict adverse pregnancy outcome.

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Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies.

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Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies.

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