Systemic lupus erythematosus is associated with an increased frequency of spontaneous preterm births: systematic review and meta-analysis.

OBJECTIVE: Preterm birth is one of the most frequent complications of pregnancy in women with systemic lupus erythematosus. The high indicated preterm birth proportion due to hypertensive disorders of pregnancy and/or fetal growth restriction is well known, and preventive measures and screening for early detection are performed. The risk of spontaneous preterm birth is less well recognized. This study aimed to determine the proportions of spontaneous and indicated preterm birth in pregnancies of women with systemic lupus erythematosus. DATA SOURCES: A systematic literature search using Pubmed, Embase, Web of Science, and Google Scholar was performed in June 2021. STUDY ELIGIBILITY CRITERIA: Studies in pregnant women with systemic lupus erythematosus reporting spontaneous and indicated preterm birth rates were selected. Original research articles published from 1995 to June 2021 were included. METHODS: Quality and risk of bias of the included studies were assessed using the Newcastle-Ottawa quality assessment scale. To estimate the pooled event rates and 95% confidence intervals, meta-analysis of single proportions with a random-effects model was performed. RESULTS: We included 21 articles, containing data of 8157 pregnancies in women with systemic lupus erythematosus. On average, 31% (95% prediction interval, 0.14-0.50) of the pregnancies resulted in preterm birth, including 14% (95% prediction interval, 0.04-0.27) spontaneous and 16% (95% prediction interval, 0.03-0.35) indicated preterm birth. CONCLUSION: In pregnant women with systemic lupus erythematosus, spontaneous and indicated preterm birth proportions are high. This information should be applied in (prepregnancy) counseling and management in pregnancy. The knowledge obtained by this meta-analysis paves the way for further research of associated risk factors and development of interventions to reduce spontaneous preterm birth in systemic lupus erythematosus pregnancies.

Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-Dependent Adaptation.

The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2) modulate cell-cell interactions by mediating the release of membrane proteins such as TNFα (Tumor necrosis factor α) and EGFR (Epidermal growth factor receptor) ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here, we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of more than a thousand OR genes in mice. iRhom2-/- mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in iRhom2-/- OE, OSNs expressing ORs that are enriched in iRhom2-/- OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2/ADAM17, we investigated if ORs could activate iRhom2/ADAM17. Activation of an olfactory receptor that is ectopically expressed in keratinocytes (OR2AT4) by its agonist Sandalore leads to ERK1/2 phosphorylation, likely via an iRhom2/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.

Population-based prevalence and incidence estimates of mixed connective tissue disease from the Manhattan Lupus Surveillance Program.

OBJECTIVE: Epidemiological data for MCTD are limited. Leveraging data from the Manhattan Lupus Surveillance Program (MLSP), a racially/ethnically diverse population-based registry of cases with SLE and related diseases including MCTD, we provide estimates of the prevalence and incidence of MCTD. METHODS: MLSP cases were identified from rheumatologists, hospitals and population databases using a variety of International Classification of Diseases, Ninth Revision codes. MCTD was defined as one of the following: fulfilment of our modified Alarcon-Segovia and Kahn criteria, which required a positive RNP antibody and the presence of synovitis, myositis and RP; a diagnosis of MCTD and no other diagnosis of another CTD; and a diagnosis of MCTD regardless of another CTD diagnosis. RESULTS: Overall, 258 (7.7%) cases met a definition of MCTD. Using our modified Alarcon-Segovia and Kahn criteria for MCTD, the age-adjusted prevalence was 1.28 (95% CI 0.72, 2.09) per 100 000. Using our definition of a diagnosis of MCTD and no other diagnosis of another CTD yielded an age-adjusted prevalence and incidence of MCTD of 2.98 (95% CI 2.10, 4.11) per 100 000 and 0.39 (95% CI 0.22, 0.64) per 100 000, respectively. The age-adjusted prevalence and incidence were highest using a diagnosis of MCTD regardless of other CTD diagnoses and were 16.22 (95% CI 14.00, 18.43) per 100 000 and 1.90 (95% CI 1.49, 2.39) per 100 000, respectively. CONCLUSIONS: The MLSP provided estimates for the prevalence and incidence of MCTD in a diverse population. The variation in estimates using different case definitions is reflective of the challenge of defining MCTD in epidemiologic studies.

Protein Phosphatase 2A Activation Via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome.

[Figure: see text].

Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study.

OBJECTIVE: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia. DESIGN: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls. SETTING: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven. POPULATION: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts. METHODS: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type. MAIN OUTCOME MEASURES: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations. RESULTS: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V. CONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.

SARS-CoV-2 incidence among teaching staff in primary and secondary schools-Wales, 2020-2021.

BACKGROUND: During the COVID-19 pandemic, face-to-face delivery of education in schools across Wales was disrupted with repeated school closures to limit risk of infection. Evidence describing the incidence of infection amongst school staff during times when schools were open is limited. A previous research study found infection rates were higher in English primary school settings when compared with secondary. An Italian study suggested teachers weren't at greater risk of infection in comparison to the general population. The aim of this study was to identify whether educational staff had higher incidence rates than their counterparts in the general population in Wales, and secondly whether incidence rates amongst staff differed between primary and secondary school settings and by teacher age. METHODS: We performed a retrospective observational cohort study using the national case detection and contact tracing system implemented during the COVID pandemic. Age stratified person-day COVID-19 incidence rates amongst teaching staff linked to primary or secondary schools in Wales were calculated for the autumn and summer terms during 2020-2021. RESULTS: The observed pooled COVID-19 incidence rates for staff across both terms was 23.30 per 100,000 person days (95% CI: 22.31-24.33). By comparison, the rate in the general population aged 19-65, was 21.68 per 100,000 person days (95%: CI 21.53-21.84). Incidence among teaching staff was highest in the two youngest age groups (< 25 years and 25-29 years). When compared to the age matched general population, incidence was higher in the autumn term amongst primary school teachers aged ≤ 39 years, and in the summer term higher only in the primary school teachers aged < 25 years. CONCLUSION: The data were consistent with an elevated risk of COVID-19 amongst younger teaching staff in primary schools when compared to the general population, however differences in case ascertainment couldn't be excluded as a possible reason for this. Rate differences by age group in teaching staff mirrored those in the general population. The risk in older teachers (≥ 50 years) in both settings was the same or lower than in the general population. Amongst all age groups of teachers maintaining the key risk mitigations within periods of COVID transmission remain important.

Clinical integration of patient-reported outcome measures to enhance the care of patients with SLE: a multi-centre prospective cohort study.

OBJECTIVE: To assess the feasibility and impact of integrating electronic patient-reported outcome measures (PROMs) into the routine outpatient care of patients with SLE. METHODS: We conducted a prospective cohort study, utilizing a mixed-methods sequential explanatory design, of SLE outpatients receiving rheumatology care at two academic medical centres. Participants completed electronic PROMs at enrolment and then prior to their next two routine rheumatology visits. PROM score reports were shared with patients and rheumatologists before visits. Patients and rheumatologists completed post-visit surveys evaluating the utility of PROMs in the clinical encounters. Focus groups of patients and interviews with treating rheumatologists were conducted to further explore their experience utilizing PROMs. RESULTS: A total of 105 SLE patients and 17 rheumatologists participated in the study. Patients completed PROMs in 159 of 184 encounters (86%), with 93% of surveys completed remotely. Patients reported that PROMs were 'quite a bit' or 'very' useful (55% of encounters) and beneficial to communication (55% of encounters). In contrast, physicians found PROMs useful (20%) and beneficial to communication (17%) less frequently. There was no significant change in visit length, health-related quality of life or disease activity after implementation of PROMs; however, patient satisfaction improved slightly. Qualitative analyses revealed that patients felt PROMs provided utility primarily by facilitating communication, particularly when physicians discussed the surveys. CONCLUSION: The remote capture and integration of electronic PROMs into clinical care was feasible in a diverse cohort of SLE outpatients. PROMs were useful to patients and enhanced their clinical experience primarily by facilitating communication.

ADAM17 stabilizes its interacting partner inactive Rhomboid 2 (iRhom2) but not inactive Rhomboid 1 (iRhom1).

The metalloprotease ADAM17 (a disintegrin and metalloprotease 17) is a key regulator of tumor necrosis factor α (TNFα), interleukin 6 receptor (IL-6R), and epidermal growth factor receptor (EGFR) signaling. ADAM17 maturation and function depend on the seven-membrane-spanning inactive rhomboid-like proteins 1 and 2 (iRhom1/2 or Rhbdf1/2). Most studies to date have focused on overexpressed iRhom1 and -2, so only little is known about the properties of the endogenous proteins. Here, we show that endogenous iRhom1 and -2 can be cell surface-biotinylated on mouse embryonic fibroblasts (mEFs), revealing that endogenous iRhom1 and -2 proteins are present on the cell surface and that iRhom2 also is present on the surface of lipopolysaccharide-stimulated primary bone marrow-derived macrophages. Interestingly, very little, if any, iRhom2 was detectable in mEFs or bone marrow-derived macrophages lacking ADAM17, suggesting that iRhom2 is stabilized by ADAM17. By contrast, the levels of iRhom1 were slightly increased in the absence of ADAM17 in mEFs, indicating that its stability does not depend on ADAM17. These findings support a model in which iRhom2 and ADAM17 are obligate binding partners and indicate that iRhom2 stability requires the presence of ADAM17, whereas iRhom1 is stable in the absence of ADAM17.

Impact of the first wave of the COVID-19 pandemic on systemic lupus erythematosus patients: Results from a multi-center prospective cohort.

OBJECTIVE: The aim of this study was to evaluate the initial impact of the COVID-19 pandemic on individuals with systemic lupus erythematosus (SLE). METHODS: Patients with SLE participating in a multi-center longitudinal cohort study in New York and Boston were invited to complete a supplemental web-based questionnaire in the summer of 2020. Participants completed standardized patient-reported outcome (PRO) measures and a combination of Likert scale and open-ended questions exploring the impact of the COVID-19 pandemic on their health and access to health care. Changes in PROs were evaluated with paired t-tests and frequencies of worsened symptoms were calculated. A thematic qualitative analysis was conducted on free text responses. RESULTS: Of 97 patients invited, 63 (65%) completed a supplemental questionnaire. Nearly 50% of respondents exhibited increases in anxiety (47.5%) and depression (48.3%) and over 40% scored worse in measures of pain interference, fatigue, and cognitive abilities. Respondents with pre-existing diagnoses of anxiety did not differ from other participants in PRO scores, but were more than three times as likely to report worsened health status. Patients denied difficulties accessing medications (85%) or medical care (84%) and over 50% participated in telehealth visits. Anxiety and increased health risks due to immunosuppression were recurring themes in free text responses. CONCLUSIONS: SLE patients experienced a significant physical and emotional toll in the initial months of the COVID-19 pandemic. Comprehensive patient-centered care, including monitoring and addressing anxiety and health-related quality of life, is critical to improving health outcomes in this population during the ongoing health crisis.

COVID-19 and antiphospholipid antibodies: A position statement and management guidance from AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION).

Coronavirus disease 2019 (COVID-19) is associated with a high rate of thrombosis. Prolonged activated partial thromboplastin times (aPTT) and antiphospholipid antibodies (aPL) are reported in COVID-19 patients. The majority of publications have not reported whether patients develop clinically relevant persistent aPL, and the clinical significance of new aPL-positivity in COVID-19 is currently unknown. However, the reports of aPL-positivity in COVID-19 raised the question whether common mechanisms exist in the pathogenesis of COVID-19 and antiphospholipid syndrome (APS). In both conditions, thrombotic microangiopathy resulting in microvascular injury and thrombosis is hypothesized to occur through multiple pathways, including endothelial damage, complement activation, and release of neutrophil extracellular traps (NETosis). APS-ACTION, an international APS research network, created a COVID-19 working group that reviewed common mechanisms, positive aPL tests in COVID-19 patients, and implications of COVID-19 infection for patients with known aPL positivity or APS, with the goals of proposing guidance for clinical management and monitoring of aPL-positive COVID-19 patients. This guidance also serves as a call and focus for clinical and basic scientific research.

Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans.

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium.

In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of ß2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (apoER2)-dependent processes. How apoER2 molecularly links these events is unknown. Here, we show that, in endothelial cells, the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase 2A (PP2A). Disabled-2 (Dab2) recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently, Src homology domain-containing transforming protein 1 (SHC1) recruits the PP2A scaffolding subunit to the proline-rich apoER2 C terminus along with 2 distinct regulatory PP2A subunits that mediate inhibitory dephosphorylation of Akt and eNOS. In mice, the coupling of these processes in endothelium is demonstrated to underlie aPL-invoked thrombosis. By elucidating these intricacies in the pathogenesis of APS-related thrombosis, numerous potential new therapeutic targets have been identified.

Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway.

Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder hemophilia A. HA typically begins with hemophilic synovitis that resembles inflammatory arthritides, such as rheumatoid arthritis, and frequently results in bone loss in patients. A major cause of rheumatoid arthritis is inappropriate release of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by the TNF-α convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-α also has a pivotal role in mediating HA. Here, we show that addition of blood or its components to macrophages activates iRhom2/ADAM17-dependent TNF-α shedding, providing the premise to study the activation of this pathway by blood in the joint in vivo. For this, we turned to hemophilic FVIII-deficient mice (F8-/- mice), which develop a hemarthrosis following needle puncture injury with synovial inflammation and significant osteopenia adjacent to the affected joint. We found that needle puncture-induced bleeding leads to increased TNF-α levels in the affected joint of F8-/- mice. Moreover, inactivation of TNF-α or iRhom2 in F8-/- mice reduced the osteopenia and synovial inflammation that develops in this mouse model for HA. Taken together, our results suggest that blood entering the joint activates the iRhom2/ADAM17/TNF-α pathway, thereby contributing to osteopenia and synovitis in mice. Therefore, this proinflammatory signaling pathway could emerge as an attractive new target to prevent osteoporosis and joint damage in HA patients.

16th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends.

Antiphospholipid syndrome (APS), an acquired autoimmune thrombophilia, is characterised by thrombosis and/or pregnancy morbidity in association with persistent antiphospholipid antibodies. The 16th International Congress on Antiphospholipid Antibodies Task Force on APS Treatment Trends reviewed the current status with regard to existing and novel treatment trends for APS, which is the focus of this Task Force report. The report addresses current treatments and developments since the last report, on the use of direct oral anticoagulants in patients with APS, antiplatelet agents, adjunctive therapies (hydroxychloroquine, statins and vitamin D), targeted treatment including rituximab, belimumab, and anti-TNF agents, complement inhibition and drugs based on peptides of beta-2-glycoprotein I. In addition, the report summarises potential new players, including coenzyme Q10, adenosine receptor agonists and adenosine potentiation. In each case, the report provides recommendations for clinicians, based on the current state of the art, and suggests a clinical research agenda. The initiation and development of appropriate clinical studies requires a focus on devising suitable outcome measures, including a disease activity index, an optimal damage index, and a specific quality of life index.

Trends in Maternal and Fetal Outcomes Among Pregnant Women With Systemic Lupus Erythematosus in the United States: A Cross-sectional Analysis.

Background: Although pregnancy in systemic lupus erythematosus (SLE) carries a high risk for mother and fetus, outcomes may be improving. Objective: To assess nationwide trends and disparities in maternal and fetal complications among pregnant women with SLE. Design: Retrospective cohort study. Setting: United States, 1998 to 2015. Patients: Adult pregnant women with and without SLE who had hospitalizations recorded in the National Inpatient Sample (NIS) database. Measurements: Outcome measures were in-hospital maternal mortality, fetal mortality, preeclampsia or eclampsia, caesarean sections, non-delivery-related admissions, and length of stay. To assess whether trends in outcomes over time differed between patients with SLE and those without SLE, logistic or linear regression with an interaction term between year and SLE (yes or no) was used. Nationwide population estimates incorporating sampling and poststratification weights were obtained. Results: An estimated 93 820 pregnant women with SLE and 78 045 054 without SLE were hospitalized in the United States from 1998 through 2015. Outcomes improved during those 18 years. In-hospital maternal deaths (per 100 000 admissions) declined among patients with as well as those without SLE (442 vs. 13 for 1998 to 2000 and <50 vs. 10 for 2013 to 2015), although the decrease was greater in women with SLE (difference in trends, P < 0.002). The percentage of patients with SLE in all pregnancy-related, as well as delivery-related, admissions increased significantly. Limitations: The sample for this analysis was identified by using diagnostic codes; detailed information on hospital-specific trends, SLE disease activity, and medications was not available. Race trends could not be analyzed. Given that NIS uses weighted estimates, the incidence of outcomes reported may not be exact. Conclusion: In this large study examining SLE and non-SLE pregnancies over 18 years, in-hospital maternal mortality and overall outcomes improved markedly, particularly among women with SLE. However, improvement is still needed, because SLE pregnancy risks remain high. Primary Funding Source: None.

Hydroxychloroquine and Chloroquine in COVID-19: A Survey of Prescription Patterns Among Rheumatologists.

OBJECTIVE: With hydroxychloroquine (HCQ) and chloroquine (CQ) emerging as potential therapies for coronavirus disease 2019 (COVID-19), shortages have been reported. We aimed to understand how rheumatologists, one of the most common prescribers of HCQ/CQ, prescribed these medications to manage COVID-19 and to understand if their patients are affected by shortages. METHODS: Between April 8 and April 27, 2020, an online survey was distributed to a convenience sample of rheumatologists who practice medicine in a diverse range of settings globally, resulting in 506 responses. Adjusted Poisson regression models were calculated. RESULTS: Only 6% of respondents prescribed HCQ/CQ for COVID-19 prophylaxis, and only 12% for outpatient treatment of COVID-19. Compared to the United States, the likelihood of prescribing HCQ/CQ for prophylaxis was higher in India (adjusted risk ratio [aRR], 6.7; 95% confidence interval [CI], 2.7-16.8; p < 0.001). Further, compared to the United States and those with 1 to 5 years of experience, rheumatologists in Europe (aRR, 2.9; 95% CI, 1.6-5.3; p < 0.001) and those with 10+ years of experience (11-20 years: aRR, 2.5; 95% CI, 1.2-5.3; p = 0.015; 21+ years: aRR = 3.3; 95% CI, 1.4-7.4; p = 0.004) had a higher likelihood of prescribing HCQ/CQ for outpatient treatment. Of note, 71% of all rheumatologists reported that their patients were directly affected by HCQ/CQ shortages. CONCLUSION: The results suggest that only a small percentage of rheumatologists are prescribing HCQ/CQ for prophylaxis or outpatient treatment of COVID-19. Medication shortages experienced by large numbers of autoimmune disease patients are concerning and should play a role in decisions, especially given poor efficacy data for HCQ/CQ in COVID-19.

Role of NOD2 in antiphospholipid antibody-induced and bacterial MDP amplification of trophoblast inflammation.

Women with antiphospholipid antibodies (aPL) are at high risk for pregnancy complications, such as preeclampsia. We previously demonstrated that aPL recognizing ß2GPI promote an extravillous trophoblast pro-inflammatory, anti-migratory and anti-angiogenic profile similar to that seen in preeclampsia. Since preeclampsia in the absence of aPL may have an underlying infectious element, women with aPL may be at increased risk for preeclampsia or other adverse outcomes if an infection is present. Our objective was to determine the impact the common bacterial component, muramyl dipeptide (MDP), has on trophoblast responses to aPL. Herein, we report that bacterial MDP amplifies trophoblast IL-1ß expression, processing, and secretion in the presence of aPL through activation of NOD2. In the absence of MDP, NOD2 also mediates anti- ß2GPI antibody-induced trophoblast IL-1ß and VEGF secretion. Additionally, we report a role for extravillous trophoblast vimentin as a novel danger signal that contributes to the aPL-induced trophoblast IL-1ß production. Together our data indicate that NOD2 mediates trophoblast inflammatory and angiogenic responses to aPL alone, and mediates trophoblast inflammation in the presence of bacterial MDP. These findings suggest that a bacterial infection at the maternal-fetal interface may exacerbate the impact aPL have on trophoblast inflammation and, thus, on pregnancy outcome.

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

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.