Objectives The aim of this study was to evaluate whether certolizumab pegol, a tumour necrosis factor α inhibitor with little or no transport across the placenta, added to standard treatment with low molecular weight heparin plus low dose aspirin, reduces rates of adverse pregnancy outcome (APO) in high-risk pregnancies with antiphospholipid syndrome (APS). Methods We assessed treatment with certolizumab in pregnant patients with APS and lupus anticoagulant, administered gestational weeks 8 through 28, in addition to standard treatment. The primary APO was a composite of fetal death ≥10 weeks’ gestation or pre-eclampsia with severe features or placental insufficiency requiring delivery <34 weeks’ gestation. Target sample size was 45 with expected APO rate of 20% with certolizumab versus 40% in historical controls from a prospectively observed population of similarly managed APS pregnancies. Results Fifty-one patients were enrolled, and 9 had primary APO (17.6%; 95% CI, 8.4%-30.9%). Excluding 6 patients who had a pregnancy loss <10 weeks’ gestation or fetal loss due to genetic abnormalities, primary APO occurred in 9 of the 45 patients (20%; 95% CI, 9.6%-34.6%), meeting predetermined criteria for efficacy of certolizumab and significantly lower than rates in historical controls. Median gestational age at delivery in certolizumab-treated patients was 36.5 weeks and was after 30 weeks in those who met the primary outcome of pre-eclampsia. Neonatal survival to hospital discharge was 93%. There were no serious infections and no new cases or severe flares of lupus. Conclusions Certolizumab appears effective in preventing placenta-mediated adverse outcomes in high-risk patients with APS.

Preeclampsia is a common pregnancy-specific vascular disorder that develops during the second half of pregnancy. Preeclampsia shares features with thrombotic microangiopathies. Here we analyzed whether sequence variants in the coagulation system genes predispose to preeclampsia. We performed targeted exomic sequencing of 58 genes in a total of 615 preeclamptic women and 2094 controls. A common missense variant rs1800385 (Val1565Leu) in the gene coding for von Willebrand Factor (VWF) (OR=1.72, p-value=3.57E-4) and a low-frequency missense variant rs41314453 (Ala732Val) in the gene coding for a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (OR=1.97, p-value=0.044) were associated with preeclampsia. rs41314453 is known to decrease ADAMTS13 expression and activity. Thus, the reduced enzyme activity could promote the formation of large vWF polymers on endothelial cells and platelets and thereby increase vascular prothrombotic activity in preeclampsia. Our results support a role for an impaired ability of ADAMTS13 to limit VWF polymerization in the pathogenesis of PE. Ultralarge multimers of VWF could mediate platelet accumulation in the turbulent intervillous spaces in preeclamptic placentae, calling upon novel therapeutics to control the VWF-ADAMTS13 axis in severe cases having low ADAMTS13 in the presence of high VWF levels and multimerization.

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.

Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study of 609 women with preeclampsia and 2092 non-preeclamptic controls, we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to preeclampsia (rs200674959: I1296V, OR (CI95) = 24.13 (1.25-467.43), p value = 0.01 and rs147430470: I330T, OR (CI95) = 22.75 (1.17-440.78), p value = 0.01). In addition, one predisposing rare variant and one protective rare variant were discovered in C6 (rs41271067: D396G, OR (CI95) = 2.93 (1.18-7.10), p value = 0.01 and rs114609505: T190I, 0.02 OR (CI95) = 0.47 (0.22-0.92), p value = 0.02). The results suggest that variants in the terminal complement pathway predispose to preeclampsia.

In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known. Sphingosine 1 -phosphate receptor 1 (S1PR1), widely expressed on ECs, maintains the vascular barrier. Here, we assessed the contribution of vascular integrity and EC S1PR1 signaling to joint damage in mice exposed to serum -induced arthritis (SIA). EC -specific deletion of S1PR1 or pharmacological blockade of S1PR1 promoted vascular leak and amplified SIA, whereas overexpression of EC S1PR1 or treatment with an S1PR1 agonist delayed SIA. Blockade of EC S1PR1 induced membrane metalloproteinase-dependent cleavage of vascular endothelial cadherin (VE-cadherin), a principal adhesion molecule that maintains EC junctional integrity. We identified a disintegrin and a metalloproteinase domain 10 (ADAM10) as the principal VE-cadherin "sheddase." Mice expressing a stabilized VE-cadherin construct had decreased extravascular VE-cadherin and vascular leakage in response to S1PR1 blockade, and they were protected from SIA. Importantly, patients with active rheumatoid arthritis had decreased circulating S1P and microvascular expression of S1PR1, suggesting a dysregulated S1P/S1PR1 axis favoring vascular permeability and vulnerability. We present a model in which EC S1PR1 signaling maintains homeostatic vascular barrier function by limiting VE-cadherin shedding mediated by ADAM10 and suggest this signaling axis as a therapeutic target in inflammatory arthritis.

Objective Omega-3 polyunsaturated fatty acids (PUFAs) play a critical role in regulating inflammation and lipid metabolism. This study sought to ascertain the frequency of omega-3 deficiency in patients with SLE and investigate whether supplementation with krill oil concentrate (KOC) could replenish omega-3 levels and decrease SLE disease activity.Methods A multicentre, randomised, double-blind, placebo-controlled trial was conducted in adult patients with active SLE. Eligible patients were randomised to receive 4 g/day KOC or placebo (vegetable oil mixture) for the first 24 weeks, and thereafter patients could opt to enter an open-label extension. The primary end point was improvement of the red blood cell Omega-3 Index from baseline to week 24. Changes in clinical features, including SLE Disease Activity Index 2000 (SLEDAI-2K) disease activity scores, were also monitored.Results Seventy-eight patients met eligibility criteria and were randomised to a treatment group (n=39 per group). The baseline Omega-3 Index in the total SLE cohort was a mean 4.43% (±SD 1.04%). After 4 weeks of KOC treatment, the Omega-3 Index rapidly increased to 7.17%±1.48% (n=38) and after 24 weeks to 8.05%±1.79% (n=25) (each p<0.001 vs baseline), whereas no significant change from baseline was noted in patients receiving placebo. Increases in the Omega-3 Index in KOC-treated patients persisted through week 48. After patients switched from placebo to KOC at 24 weeks, the mean Omega-3 Index showed a rapid and significant increase (from 4.63%±1.39% at week 24 (n=26) to 7.50%±1.75% at week 48 (n=12); p<0.001). Although there were no changes in disease activity in the study population overall, SLEDAI-2K scores decreased significantly in the KOC group during the 24-week randomised period among those who had high disease activity at baseline (SLEDAI-2K ≥9) (p=0.04, p=0.02 and p=0.01 vs placebo at 4, 8 and 16 weeks, respectively; n=9 per group). KOC was well-tolerated, with no significant safety concerns.Conclusion KOC corrected omega-3 deficiency in patients with SLE. Supplementation with KOC was safe and decreased disease activity in those with more active disease. These findings warrant further evaluation of omega-3 fatty acid supplementation with KOC in the management of SLE.Trial registration number NCT03626311.

ObjectiveLeveraging the Manhattan Lupus Surveillance Program (MLSP), a population-based registry of cases of systemic lupus erythematosus (SLE) and related diseases, we investigated the proportion of SLE with concomitant rheumatic diseases, including Sjögren’s disease (SjD), antiphospholipid syndrome (APLS), and fibromyalgia (FM), as well as the prevalence of autoantibodies in SLE by sex and race/ethnicity.MethodsPrevalent SLE cases fulfilled one of three sets of classification criteria. Additional rheumatic diseases were defined using modified criteria based on data available in the MLSP: SjD (anti-SSA/Ro positive and evidence of keratoconjunctivitis sicca and/or xerostomia), APLS (antiphospholipid antibody positive and evidence of a blood clot), and FM (diagnosis in the chart).Results1,342 patients fulfilled SLE classification criteria. Of these, SjD was identified in 147 (11.0%, 95% CI 9.2–12.7%) patients with women and non-Latino Asian patients being the most highly represented. APLS was diagnosed in 119 (8.9%, 95% CI 7.3–10.5%) patients with the highest frequency in Latino patients. FM was present in 120 (8.9%, 95% CI 7.3–10.5) patients with non-Latino White and Latino patients having the highest frequency. Anti-dsDNA antibodies were most prevalent in non-Latino Asian, Black, and Latino patients while anti-Sm antibodies showed the highest proportion in non-Latino Black and Asian patients. Anti-SSA/Ro and anti-SSB/La antibodies were most prevalent in non-Latino Asian patients and least prevalent in non-Latino White patients. Men were more likely to be anti-Sm positive.ConclusionData from the MLSP revealed differences among patients classified as SLE in the prevalence of concomitant rheumatic diseases and autoantibody profiles by sex and race/ethnicity underscoring comorbidities associated with SLE.

ObjectivePreterm birth (PTB) is one of the most frequent complications of pregnancies in women with systemic lupus erythematosus (SLE). The high indicated PTB proportion due to hypertensive disorders of pregnancy and/or fetal growth restriction is well known, and preventive measures as well as screening for early detection are performed. The risk of spontaneous PTB is less well recognized. The purpose of this study is to determine the proportions of spontaneous and indicated PTB in pregnancies of women with SLEData sourcesA systematic literature search using Pubmed, Embase, Web of Science and Google Scholar was performed in June 2021Study eligibility criteriaStudies in pregnant women with SLE reporting spontaneous and indicated PTB rates were selected. Original research articles published from 1995 to June 2021 were includedStudy appraisal and synthesis methodsQuality 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.ResultsWe included 21 articles, containing data of 8157 pregnancies in women with SLE. On average 31% (95% prediction interval [0.14; 0.50]) of the pregnancies resulted in PTB, including 14% (95% prediction interval [0.04; 0.27]) spontaneous, and 16% (95% prediction interval [0.03; 0.35])indicated PTBConclusionsIn pregnant women with SLE, spontaneous as well as indicated PTB proportions are high. This information should be applied in (pre-pregnancy) counselling 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 PTB in SLE pregnancies

OBJECTIVE:To investigate the value of anti-β2 glycoprotein-I domain 1 (aD1) and antiphosphatidylserine-prothrombin antibodies for predicting adverse pregnancy outcomes in an at-risk population and to describe the relationship among aD1, antiphosphatidylserine-prothrombin, lupus anticoagulant, and other antiphospholipid antibodies (aPL). METHODS:Data were obtained from a prospective cohort of pregnant patients with aPL, with systemic lupus erythematosus (SLE) (n=59) or without SLE (n=106), or SLE without aPL (n=100) (PROMISSE [Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus and Antiphospholipid Syndrome] study; NCT00198068). Levels of aD1 and antiphosphatidylserine-prothrombin were quantified with the QUANTA Flash and QUANTA Lite systems, respectively, in sera collected at less than 18 weeks of gestation. Adverse pregnancy outcome was defined as delivery at before 34 weeks of gestation for preeclampsia or placental insufficiency or fetal death after 12 weeks of gestation. Receiver operating characteristic (ROC) analysis assessed the diagnostic properties of aD1 and antiphosphatidylserine-prothrombin for adverse pregnancy outcomes. Bivariate comparisons were made between each biomarker. Multivariable regression modeling of adverse pregnancy outcomes was performed, and backward selection determined variables for a final model for adverse pregnancy outcomes. Logistic regression of lupus anticoagulant quantified the association with aD1 and antiphosphatidylserine-prothrombin. The rate of adverse pregnancy outcomes was described by combined results of lupus anticoagulant, aD1, and antiphosphatidylserine-prothrombin immunoglobulin G (IgG). RESULTS:Of 265 individuals, 45 (17.0%) experienced adverse pregnancy outcomes. Area under the curve from ROC analysis for aD1 was 0.734 (95% CI, 0.664-0.805), for antiphosphatidylserine-prothrombin IgG was 0.83 (95% CI, 0.751-0.899), and for antiphosphatidylserine-prothrombin immunoglobulin M (IgM) was 0.612 (95% CI, 0.520-0.703). Markers associated with adverse pregnancy outcomes were aD1 (P<.001), anticardiolipin IgG (P<.001), β2-glycoprotein I IgG (P=.003), antiphosphatidylserine-prothrombin IgG (P<.001), antiphosphatidylserine-prothrombin IgM (P=.03), and lupus anticoagulant (P<.001). Backward selection identified lupus anticoagulant, aD1, and antiphosphatidylserine-prothrombin IgG for final adverse pregnancy outcome modeling: lupus anticoagulant odds ratio (OR) 7.0 (95% CI, 3.4-14.4), aD1 OR 12.1 (95% CI, 3.64-40.2), and antiphosphatidylserine-prothrombin IgG OR 11.4 (95% CI, 5.2-25.2). Both aD1 and antiphosphatidylserine-prothrombin IgG remained significant when lupus anticoagulant was removed from the model. Both aD1 and antiphosphatidylserine-prothrombin IgG performed the best in ruling in adverse pregnancy outcomes. With a likelihood ratio less than 0.1, aD1 or antiphosphatidylserine-prothrombin IgG performed well for ruling out adverse pregnancy outcomes. Both aD1 and antiphosphatidylserine-prothrombin IgG were associated with lupus anticoagulant positivity: OR 27.9 (95% CI, 12.1-64.0) if both were positive. Adverse pregnancy outcomes were highest in those with positive lupus anticoagulant, aD1, and antiphosphatidylserine-prothrombin IgG (47.6%). CONCLUSION:In pregnant individuals with aPL, with or without SLE, aD1 and antiphosphatidylserine-prothrombin IgG are significant independent predictors of adverse pregnancy outcomes and are strongly associated with lupus anticoagulant. Combined use may identify patients at greatest risk for severe obstetric complications.

The Manhattan Lupus Surveillance Program (MLSP), a population-based retrospective registry of patients with systemic lupus erythematosus (SLE), was used to investigate the prevalence of cardiovascular disease events (CVE) and compare rates among sex, age and race/ethnicity to population-based controls. Patients with prevalent SLE in 2007 aged ≥ 20 years in the MLSP were included. CVE required documentation of a myocardial infarction or cerebrovascular accident. We calculated crude risk ratios and adjusted risk ratios (ARR) controlling for sex, age group, race and ethnicity, and years since diagnosis. Data from the 2009–2010 National Health and Nutrition Examination Survey (NHANES) and the 2013–2014 NYC Health and Nutrition Examination Survey (NYC HANES) were used to calculate expected CVE prevalence by multiplying NHANES and NYC HANES estimates by strata-specific counts of patients with SLE. Crude prevalence ratios (PRs) using national and NYC estimates and age standardized prevalence ratios (ASPRs) using national estimates were calculated. CVE occurred in 13.9

Women with antiphospholipid syndrome (APS) are at high risk for miscarriage and preeclampsia. Unlike pro-thrombotic systemic APS, obstetric APS is associated with insufficient placentation, as well as inflammation and vascular dysfunction at the maternal-fetal interface. Antiphospholipid antibodies (aPL) can target the placental trophoblast and induce inflammation. We reported that aPL trigger trophoblast cells to produce elevated levels of IL-8 through activation of Toll-like receptor 4 (TLR4). Downstream of TLR4, we found this IL-8 response is mediated by a TLR8-activating microRNA (miR), miR-146a-3p, which is also released by the trophoblast via extracellular vesicles (EVs). Since endothelial dysfunction is a feature of obstetric APS, we sought to determine if other miRs that can activate the RNA sensors, TLR7 and/or TLR8, are released by the trophoblast via EVs after exposure to aPL, and if these EVs can activate human endometrial endothelial cells (HEECs). Using a human first trimester extravillous trophoblast cell line we found that aPL elevated their release of small EVs (<150 nm). These extracellular vesicles released from trophoblast cells exposed to aPL expressed elevated levels of TLR7/8-activating miR-21a and miR-29a, in addition to the previously reported miR-146a-3p. Extracellular vesicles from aPL-exposed human trophoblast cells triggered human endometrial endothelial cells to generate an inflammatory IL-8 response, in part through TLR7. This study highlights EVs as a mode of communication between the placenta and the maternal vasculature, as well as a potential role for TLR7/8-activating miRs in contributing to inflammation at the maternal-fetal interface in obstetric APS.

Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of the complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to preeclampsia (rs200674959: I1296V, OR (CI95) = 24.13 (1.25–467.43), p-value = 0.01 and rs147430470: I330T, OR (CI95) = 22.75 (1.17–440.78), p-value = 0.01). In addition, one predisposing rare variant and one protective rare variant were discovered in C6 (rs41271067: D396G, OR (CI95) = 2.93 (1.18–7.10), p-value = 0.01 and rs114609505: T190I, 0.02 OR (CI95) = 0.47 (0.22–0.92), p-value = 0.02). The results suggest that variants in terminal complement pathway predispose to preeclampsia.