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Cellular senescence is a dynamic stress response process that contributes to aging. From initiation to maintanence, senescent cells continuously undergo complex molecular changes and develop an altered transcriptome. Understanding how the molecular architecture of these cells evolves to sustain their non-proliferative state will open new therapeutic avenues to allievate or delay consequences of aging. Seeking to understand these molecular changes, we studied the transcriptomic profiles of endothelial replication-induced senescence and senescence induced by the inflammatory cytokine, TNF-α. The downregulated gene signature of both replicative and TNF-α senescence were highly overlapped: decreasing expression of several genes associated to cell cycle regulation, DNA replication, recombination, repair, chromatin structure, cellular assembly, and organization. We identified multiple targets of p53/p16-pRB-E2F-DREAM that are essential for proliferation, mitotic progression, resolving DNA damage, maintaining chromatin integrity, and DNA synthesis were repressed in senescent cells. Here we provide important molecular link between DREAM repressor complex and senescence, and identify pleothra of p53/p16-pRB-E2F-DREAM targets that controls the stability of the senescenct arrest. We propose stable repression of large number of mitotic genes by p53/p16-pRB-E2F-DREAM pathway contributes to the extended mitotic arrest and permanence of the senescent state.

Objectives To investigate the impact of thrombocytopenia on survival in patients with APS. Methods Thrombocytopenia and other predictors of outcome were retrospectively evaluated in an aPL-positive and APS cohort with 38-year follow-up (1980–2018). Thrombocytopenia was defined as Results Among 114 patients, 64% had primary APS, 25% secondary APS and 10% asymptomatic aPL. Mean follow-up was 19 (range 5–38) years. ANA [hazard ratio (HR) 1.8, 95% CI 0.8, 3.6, P = 0.10], arterial thrombotic events (HR 7.0, 95% CI 1.4, 3.5, P = 0.016), myocardial infarction (HR 8.3, 95% CI 1.1, 59, P = 0.03), intracardiac thrombosis (HR 17, 95% CI 1, 279, P = 0.04) and thrombocytopenia (HR 2.9, 95% CI 1.4, 6.1, P = 0.004) were risk factors for all-cause mortality, but in multivariate analysis only thrombocytopenia (HR 2.7, 95% CI 1.3, 6.0, P = 0.01) remained significant. Persistent (HR 4.4, 95% CI 2.1, 9.2, P = 0.001) and low–moderate thrombocytopenia (HR 2.8, 95% CI 1.2, 6.4, P = 0.01) were associated with a significant increase in mortality compared with acute (HR 1.6, 95% CI 0.5, 5.3, P = 0.40) and severe (HR 2.1, 95% CI 0.5, 9.2, P = 0.30) forms. APS patients with vs without thrombocytopenia were more frequently male (58 vs 24%, P = 0.001) with arterial thrombosis (55 vs 32%, P = 0.04), LA positivity (100 vs 87%, P = 0.04), type I aPL profile (89% vs 71%, P = 0.05) and anticoagulant treatment (89 vs 63%, P = 0.01). Thrombosis caused 13% of deaths in thrombocytopenic patients and 1% in those without (P = 0.01). Conclusion Thrombocytopenia is an aPL-related manifestation that identifies patients with severe disease phenotype and high thrombotic risk. Persistent low–moderate thrombocytopenia is associated with a reduced long-term survival.

Coronavirus disease-2019 (COVID-19) related to Coronavirus-2 (SARS-CoV-2) is a worldwide health concern. Despite the majority of patients will evolve asymptomatic or mild-moderate upper respiratory tract infections, 20% will develop severe disease. Based on current pathogenetic knowledge, a severe COVID-19 form is mainly a hyperinflammatory, immune-mediated disorder, triggered by a viral infection. Due to their particular immunological features, pregnant women are supposed to be particularly susceptible to complicate by intracellular infections as well as immunological disturbances. As an example, immune-thrombosis has been identified as a common immune-mediated and pathogenic phenomenon both in COVID-19, in obstetric diseases and in COVID-19 pregnant women. According to extensive published clinical data, is rationale to expect an interference with the normal development of pregnancy in selected SARS-CoV-2-infected cases, mainly during third trimester. This manuscript provides insights of research to elucidate the potential harmful responses to SARS-CoV-2 and /or other coronavirus infections, as well as bidirectional interactions between COVID-19 and pregnancy to improve their respective management.

Objectives An increased risk of adverse maternal and foetal pregnancy complications (including pre-eclampsia, intrauterine growth restriction, and small for gestational age) is well described in women with autoimmune rheumatic disease (ARD) compared with the general population (GenPop). It is less clear, however, whether this risk of adverse pregnancy outcome (APO) also exists in women with ‘preclinical ARD’ (pre-ARD) before they are diagnosed with an ARD many years post-partum. Therefore, we have undertaken a systematic review of the available evidence on APO in patients who subsequently were diagnosed with a rheumatic disease to identify whether there is an increased risk in pre-ARD. Methods The present study was reported in accordance with the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard. A systematic literature review was performed using the online PubMed database. Pre-SLE and pre-RA patients were defined as those who, over the subsequent years, developed SLE or RA according to international classification criteria. Results A total of 176 articles were screened, and 27 original articles were selected for final analysis. Pre-RA was the most studied group, with 15 studies and a total of >1600 pregnancies, and pre-SLE was the second-most studied pre-ARD in pregnancy, with 14 studies and a total of >1000 pregnancies. We found that patients who subsequently developed SLE had an increased burden of poor pregnancy outcomes compared with pregnant women from the GenPop, but fewer APOs compared with pregnancies of women with SLE. In contrast, a similar rate of APOs was found when pre-RA pregnancies were compared with GenPop pregnancies. Conclusion Our findings of an increased risk of APO in certain pre-ARDs highlights the relevance of taking an obstetric history during the first rheumatology appointment and the need for novel screening strategies for the prediction of APOs. Further research is required to elucidate the immune basis of APOs in preclinical and clinical ARD.

Objective This study aimed to analyze the effect of pravastatin on angiogenic factors, feto–maternal Doppler findings and pregnancy outcomes in women with early-onset fetal growth restriction (FGR) treated with pravastatin compared with nontreated controls. Study Design This was a pilot study conducted between March 2016 and September 2017. Women with single pregnancies and FGR diagnosed at ≤ 28 weeks of gestation were offered 40 mg of pravastatin daily. Doppler progression, soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) values, and pregnancy outcomes were assessed and compared with consecutive historical controls. Controls were matched to treated women for gestational age, maternal characteristics, maternal and obstetric history, Doppler severity classification, and angiogenic factors at diagnosis. The sFlt-1/PlGF was measured in maternal serum at two different times: before pravastatin was started (ratio M0) and during pravastatin treatment (ratio M1). Doppler severity was classified into four categories: normal, mild, moderate, and severe. Results A total of 38 women were enrolled in this study. No differences were observed in baseline characteristics between groups. However, when compared with the ratio M0, M1 was increased by a median (interquartile range) of 67.0 (−34.8 to 197.3) in the control group but decreased by a median (interquartile range) of −10.1 (−53.1 to −0.07) in the pravastatin treated group (p Conclusion In women with early-onset FGR, treatment with pravastatin 40 mg daily was associated with significant improvement in the angiogenic profile. Additionally, median pregnancy duration and median birthweight increased and the incidence of PE was reduced in treated women. Nevertheless, since this pilot study was underpowered, none of these differences were statistically significant. Key Points

Objectives(1) To assess the clinical utility of the adjusted global antiphospholipid syndrome score (aGAPSS) to predict new obstetric events during follow-up in primary obstetric antiphospholipid syndrome (POAPS) patients under standard-of-care treatment (SC) based on the use of low-dose aspirin (LDA) + heparin and (2) to study the risk of a first thrombotic event and to evaluate whether stratification according to this score could help to identify POAPS patients who would benefit from long-term thromboprophylaxis.MethodsThis is a retrospective, multicentre study. 169 women with POAPS were evaluated for the presence of a new obstetric event and/or a first thrombotic event during follow-up [time period: 2008–2020, median: 7 years (6–12 years)]. The outcomes of 107 pregnancies from these POAPS patients with SC were studied to evaluate relapses. Simple and multivariable logistic regression analyses were performed.ResultsRegarding obstetric morbidity, only triple positivity for antiphospholipid antibodies (aPLs) [OR = 8.462 (95% CI: 2.732–26.210); p < 0.0001] was found to be a strong risk factor independently associated with treatment failure. On the other hand, triple positivity for aPLs [OR=10.44 (95% CI: 2.161–50.469), p = 0.004] and an aGAPSS ≥7 [OR = 1.621 (95% CI: 1.198–2.193), p = 0.002] were independent risk factors associated with a first thrombotic event. LDA was marginally associated with a decrease in the risk of thrombosis only in patients with aGAPSS ≥ 7 ( p = 0.048).ConclusionaGAPSS appears to be useful in predicting the occurrence of a first thrombotic event in POAPS patients, and these stratification of patients could be helpful in selecting patients who would benefit from thromboprophylaxis with LDA.

BackgroundNot all patients fulfil criteria for specific autoimmune rheumatic diseases (ARDs) and are then defined as having non-criteria (nc)ARD. It is uncertain whether well-recognised associations with adverse pregnancy outcomes in patients with criteria ARD also exist in patients with ncARD or undifferentiated connective tissue disease (UCTD). Therefore, we undertook a systematic review of the prevalence of adverse pregnancy outcomes in various ncARD and UCTD compared with criteria ARD to identify whether there are increased risks and to examine for any benefits of treatment.MethodsThis study was conducted in accordance with the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard. A systematic literature review was performed using online databases including Medline and PubMed from inception to the beginning of April 2021 using appropriate keywords for various ARD and pregnancy outcomes.ResultsAfter screening 665 articles, 36 articles were chosen for full text review and 15 selected for final analysis. There were eight studies of nc antiphospholipid syndrome (APS) of more than 7000 pregnancies and seven studies of UCTD of more than 1000 pregnancies. No studies of any other ncARD in pregnancy were identified. We found that patients with either ncAPS or UCTD seem to have an increased burden of poor pregnancy outcomes compared with the general population. Despite the heterogeneity and poor quality of the studies, we also noted that ncAPS and criteria APS patients may have similar rates of obstetric complications with standard and/or non-standard APS treatment regimens.ConclusionOur findings of increased risks of poor pregnancy outcomes in patients with ncAPS or UCTD will be helpful for pre-pregnancy counselling and management of these patients in pregnancy and support their referral to specialist obstetric-rheumatology and obstetric-haematology clinics.

Background: We investigated the pattern of reported immune diseases in the international ASIA syndrome registry. Methods: Data from 500 subjects exposed to adjuvants from the ASIA syndrome international registry were analysed. Results: The patient mean age was 43 ± 17 years and 89% were female. Within the reported immune diseases, 69% were well-defined immune diseases (autoimmune, autoinflammation, and mixed pattern diseases). Among the well-defined immune diseases following the exposure to adjuvants, polygenic autoimmune diseases were significantly higher than autoinflammatory disorders (92.7% vs 5.8%, respectively, p < 0.001). Polygenic autoimmune diseases such as connective tissue diseases were significantly linked to the exposure to HBV vaccine (OR 3.15 [95%CI 1.08–9.23], p = 0.036). Polygenic autoinflammatory diseases were significantly associated with the exposure to influenza vaccination (OR 10.98 [95%CI 3.81–31.67], p < 0.0001). Conclusions: Immune conditions following vaccination are rare, and among these, polygenic autoimmune diseases represent the vast majority of the well-defined immune diseases reported under the umbrella ASIA syndrome. However, vaccines benefit outweighs their autoimmune side effects.

Antiphospholipid antibodies; Obstetric antiphospholipid syndrome; Thrombotic antiphospholipid syndrome Anticuerpos antifosfolípidos; Síndrome antifosfolípido obstétrico; Síndrome antifosfolípido trombótico Anticossos antifosfolípids; Síndrome antifosfolípid obstètric; Síndrome antifosfolípid trombòtic Antiphospholipid syndrome (APS) is a systemic autoimmune condition characterised by the presence of antiphospholipid antibodies (aPL) associated with vascular thrombosis and/or pregnancy complications. In a cohort of 74 yet diagnosed APS individuals fulfilling Sydney laboratory criteria (twice positive for lupus anticoagulant, anticardiolipin, aCL, and/or anti-β2glycoprotein I, aβ2GPI), 33 out of 74 were obstetric APS (OAPS) and 41 thrombotic APS (TAPS) patients. 39% of TAPS patients were women. Although aPL detection was persistent, we observed an oscillatory aPL positivity in 56.7% and a transient seroconversion in 32.4% of APS patients at enrolment. Thus, we tested their sera in a line immunoassay that simultaneously detected IgG or IgM for criteria (aCL and aβ2GPI) and non-criteria (anti-phosphatidylserine, aPS; anti-phosphatidic acid, aPA; anti-phosphatidylinositol, aPI; anti-annexin 5, aA5; anti-prothrombin, aPT; anti-phosphatidylethanolamine; anti-phosphatidylglycerol, and anti-phosphatidylcholine) aPL. OAPS and TAPS patients displayed different but overlapping clusters based on their aPL reactivities. Specifically, while OAPS patients showed higher aPA, aPS, aA5, aβ2GPI and aPT IgM levels than TAPS patients, the latter displayed higher reactivity in aCL, aPI and aA5 IgG. Eventually, with a cut-off of the 99th percentile established from a population of 79 healthy donors, TAPS patients significantly tested more positive for aCL and aA5 IgG than OAPS patients, who tested more positive for aPA, aPS and aβ2GPI IgM. Transiently seronegative APS patients showed non-criteria aPL positivity twice in sera obtained 3 months apart. Overall, our data show that APS patients presented clusters of aPL that define different profiles between OAPS and TAPS, and persistent non-criteria aPL positivity was observed in those who are transiently seronegative. This research was funded by Fundació Ona Futura (ONA-JAR-2021; Port d’Alcudia, Balearic Islands, Spain); and Gravida Fertilitat Avançada (GRA-JAR-2021; Barcelona, Spain).

Identification of differentially expressed proteins in antiphospholipid syndrome (APS) is a developing area of research for unique profiles of this pathology. Advances in technologies of mass spectrometry brings improvements in proteomics and results in assessment of soluble or cellular proteins which could be candidates for clinical biomarkers of primary APS. The use of blood as a source of proteins ease the acquisition of samples for proteomics analyses and later for disease diagnosis. We performed a systematic review to explore the proteomics studies carried out in circulating released proteins (serum, plasma) or cellular proteins (monocytes and platelets) of APS patients. The study groups differentiate among clinical APS cases with the aim to translate molecular findings to disease stratification and to improve APS diagnosis and prognosis. These studies also include the unravelling of new autoantibodies in non-criteria APS or how post-translational protein modifications provides clues about the pathological mechanisms of antigen-autoantibody recognition. Herein, we identified 82 proteins that were dysregulated in APS across eleven studies. Enrichment analysis revealed its connection to cellular activation and degranulation that eventually leads to thrombosis as the main biological process highlighted by these studies. Validation of APS-relevant proteins by functional and mechanistic studies will be essential for patient stratification and the development of targeted therapies for every clinical subtype of APS.

Villitis of unknown etiology (VUE) is characterized by lympho-histiocytic infiltrates, which are predominant within the villous stroma. VUE can be of low grade i.e. affecting less than 10 contiguous villi or high grade with either patchy or diffuse subgroups (the later concerning more than 30 % of distal villi). Several other placental lesions could be associated with VUE, in particular in diffuse subgroups, such as diffuse perivillous fibrin deposition and chronic intervillositis. One of the most characteristic features of VUE is the late onset of fetal growth restriction after 32 weeks of gestation, and earlier detection of villitis should first raise an infectious origin. High grade VUE has been associated with fetal growth restriction, prematurity, fetal deaths, recurrent pregnancy loss, central nervous system injury and is characterized by relatively high risk of recurrence (25-50 %). Prospective and well-designed studies are necessary to determine the real prevalence of these adverse pregnancy events associated with VUE. Data about the management of VUE are extremely scarce and thus no recommendation based on the literature review could be actually done.

Antiphospholipid antibodies (aPL) are related to poor pregnancy outcomes, but their effect on embryo implantation is unclear. We aimed to assess the prevalence of different aPL in women with recurrent implantation failure (RIF).We searched studies in PubMed (MEDLINE), Scopus and Cochrane Library. Quality of studies was scored by the Newcastle-Ottawa Scale and risk of bias assessment by items described in RevMan5 software. Statistical analyses were made using random-effects model and presented as pooled Odds Ratio (OR), 95% confidence interval (CI). Heterogeneity was assessed by IThis systematic review and meta-analysis included 17 studies and showed a high degree of variability in aPL positivity in RIF. In the latter, the risk of bias assessment suggested unclear bias on study performance with a median sample size and interquartile range for RIF patients and fertile women of 96 (57-417) and 100 (60.5-202.5), respectively. Among the criteria aPL, IgG anticardiolipin autoantibodies (OR 5.02, 95% CI [1.95, 12.93]) were associated with RIF. Within the non-criteria aPL, anti-β2 glycoprotein I-IgA (OR 64.8, 95% CI [9.74, 431.0]), and antiphosphatidylglycerol-IgG and IgM (OR 10.74, 95% CI [5.25, 22.0]; OR 4.26, 95% CI [1.76,10.31]; respectively) were associated with RIF, too.Anticardiolipin-IgG is a prevalent autoantibody in women with RIF. Three other non-criteria aPL, aβ2GP I-IgA, aPG-IgG and aPG-IgM also present a positive rate in RIF. Overall, these results advise about testing them as indicators of RIF risk in women seeking IVF treatment.

Objective. To evaluate the role played by anakinra in the treatment of patients with severe COVID-19 who fail to “accepted” standard of care and tocilizumab.Methods. We conducted a retrospective cohort study assessed in Althaia Health Network University and Vall d’Hebrón University Hospital, in Barcelona, Spain. We included patients with confirmed RT-PCR for SARS-CoV-2, moderate-to-severe acute respiratory distress syndrome [PaO2:FiO2] (PAFI) ≤200 mmHg, and hyperinflammation. All of them were primarily managed with non-invasive ventilation outside of the ICU and received standard of care with hydroxychloroquine, lopinavir/ritonavir, azithromycin, and enoxaparin supplemented with tocilizumab. These patients received an additional administration of 100 mg subcutaneous anakinra twice a day (low-dose) or every 6-8 hours (medium-dose). Mechanical ventilation-free survival, ICU admission, respiratory function changes (PAFI), inflammatory markers, and survival were analyzed.Results. Clinical and respiratory improvements were already present at 48 hours post-anakinra. PAFI increased 105.2% at 48 hours over anakinra administration and 166.9% at day 7. Respiratory function improvement was significant at day 7 (pConclusions. In severe ARDS related to SARS-CoV-2 refractory to standard of care plus tocilizumab, low-to-moderate doses of anakinra as a rescue therapy showed effectiveness and safety, avoiding mechanical ventilation and deaths.

Preeclampsia is caused by placental impairment with increased expression of sFlt-1 (soluble fms-like tyrosine kinase 1) and decreased PlGF (placental growth factor); it has been associated with cardiovascular morbidity and mortality later in life, but the underlying mechanism remains unknown. The aim of this study was to determine whether sFlt-1 and PlGF levels during preeclampsia are associated to long-term cardiovascular risk. We prospectively recruited 43 women with previous preeclampsia and 21 controls with uncomplicated pregnancies. Cardiovascular risk assessment ≈12 years later included maternal hemodynamic, cardiac function and structure, biomarker analysis, and carotid-intima thickness evaluation. Women with previous preeclampsia had higher prevalence of hypertensive disorders and dyslipidemia than controls. In addition, they had worse global longitudinal strain, thicker left ventricular septal and posterior walls, more myocardial mass and increased carotid intima-media thickness compared with controls. PlGF during pregnancy correlated positively with high-density lipoprotein ( r =0.341; P =0.006), and negatively with global longitudinal strain ( r =−0.581; P r =−0.251; P =0.045), and mean arterial blood pressure ( r =−0.252; P =0.045), when adjusted by study group. sFlt correlated negatively with high-density lipoprotein ( r =−0.372; P =0.002) and apolipoprotein A-1 ( r =−0.257; P =0.040), and positively with carotid intima-media thickness ( r =0.269; P =0.032) and left ventricular posterior wall thickness ( r =0.368; P =0.003). The antiangiogenic state present in preeclampsia is related to greater prevalence of cardiovascular risk factors ≈12 years after delivery. The knowledge of altered angiogenic factors may help detect women with a higher risk for premature cardiovascular disease, who will require earlier follow-up after delivery.

International audience; Background: Endometriosis is a multifactorial pathology dependent on intrinsic and extrinsic factors, but the immune deregulation seems to play a pivotal role. In endometriosis-associated infertility this could raise the benefit of immunomodulatory strategies to improve the results of ART. In this review, we will describe (1) sera and peritoneal fluid cytokines and immune markers; (2) autoantibodies; (3) immunomodulatory treatments in endometriosis with infertility.Methods: The literature research was conducted in Medline, Embase and Cochrane Library with keywords: "endometriosis", "unexplained miscarriage", "implantation failure", "recurrent implantation failure » and « IVF-ICSI », « biomarkers of autoimmunity", "TNF-α", "TNF-α antagonists", "infliximab", "adalimumab", "etanercept", "immunomodulatory treatment", "steroids", "intralipids", "intravenous immunoglobulins", "G-CSF", "pentoxyfylline".Results: Several studies analyzed the levels of pro-inflammatory cytokines in sera and peritoneal fluid of endometriosis-associated infertility, in particular TNF-α. Various autoantibodies have been found in peritoneal fluid and sera of infertile endometriosis women even in the absence of clinically defined autoimmune disease, as antinuclear, anti-SSA and antiphospholipid autoantibodies. In few uncontrolled studies, steroids and TNF-α antagonists could increase the pregnancy rates in endometriosis-associated infertility, but well-designed trials are lacking.Conclusion: Endometriosis is characterized by increased levels of cytokines and autoantibodies. This suggests the role of inflammation and immune cell deregulation in infertility associated to endometriosis. The strategies of immunomodulation to regulate these immune deregulations are poorly studied and well-designed studies are necessary.

Though the exact etiology of autoimmune diseases still remains unknown, there are various factors which are believed to contribute to the emergence of an autoimmune disease in a host including the genetic predisposition, the environmental triggers such as bacterial infections, including the gut microbiota, viral fungal and parasitic infections, as well as physical and environmental agents, hormonal factors and the hosts immune system dysregulation. All these factors interplay was coined by Shoenfeld et al., many years ago “The Mosaic of Autoimmunity” [[1], [2], [3], [4]]. The most prominent pathogenic viruses which have been proposed in the triggering and initiation of autoimmune diseases include: Parvovirus B19, Epstein-Barr-virus (EBV), Cytomegalovirus (CMV), Herpes virus-6, HTLV-1, Hepatitis A and C virus, and Rubella virus [[5], [6], [7], [8], [9], [10], [11]]. These viruses have been implicated in the initiation of chronic inflammatory or autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, primary billiary cholangitis, multiple sclerosis, polymoysitis, uveitis, Henoch Schonlein Puprpura, Systemic Juvenile Idiopathic arthritis, systemic sclerosis, Hashimoto thyroiditis and autoimmune hepatitis [12,13]. Suggested mechanisms of induction of the autoimmunity include both molecular mimicry [14] as well as “bystander activation” whereby the infection may lead to activation of antigen presenting cells that may in turn activate pre-primed auto-reactive T-cells, thus leading to the production of pro-inflammatory mediators, which in turn may lead to tissue damage [15]. Alternative suggested mechanisms include epitope spreading as well as presentation of cryptic antigens [16]. Corona viruses represent a major group of viruses mostly affecting human beings through zoonotic transmission. In the past two decades, this is the third instance of the emergence of a novel coronavirus, after the severe acute respiratory syndrome (SARS) in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 [17,18]. In December 2019 a novel outbreak of a new strain of coronavirus infection emerged in Wuhan, China the SARS-CoV-2 or the Covid-19. The disease which was declared as a pandemic in early March 2020, is characterized by fever, dry cough, myalgia and or extreme fatigue, may be asymptomatic or with minimal flu-like constitutional symptoms leading to a favorable outcome in many instances. However, some of the patients encounter a severe pneumonia with sepsis leading to an acute respiratory distress syndrome (ARDS) with respiratory failure requiring mechanical ventilation, and at times accompanied by hyperferritinemia and multiple organ involvement including hematological, gastrointestinal, neurological and cardiovascular complications leading to death [[19], [20], [21], [22], [23]]. The ARDS described in up to 20% of Covid-19 cases, is reminiscent of the cytokine release syndrome-induced ARDS and secondary hemophagocytic lymphohistiocytosis (sHLH) observed in patients with SARS-CoV and MERS-CoV as well as in leukemia patients receiving engineered T cell therapy. These cases with Covid-19 are those who develop through the excessive cytokine release and the uncontrolled immune activation, the multiorgan failure with a grave prognosis [24,25].

Importance We have performed a systematic search to summarize the role of statins for preventing and treating severe preeclampsia. Objective The aim of this study was to examine whether pravastatin is a useful and safe alternative for treating preeclampsia during pregnancy. Evidence Acquisition A systematic MEDLINE (PubMed) search was performed (1979 to June 2017), which was restricted to articles published in English, using the relevant key words of statins, pregnancy, preeclampsia, obstetrical antiphospholipid syndrome, and teratogenicity. Results The initial search provided 296 articles. Finally, 146 articles were related to the use of statins during pregnancy, regarding their effect on the fetus and the treatment of preeclampsia. Ten studies were related to in vitro studies, 25 in animals, and 24 in humans (13 case report series and 11 cohort studies). We found 84 studies on reviews of such guidelines on cardiovascular disease (35 studies), use of statins in the antiphospholipid syndrome (25 studies), statin's specific use during pregnancy (13 studies), or preeclampsia treatment (11 studies). Conclusions Although the studies are of poor quality, the rate of major congenital abnormalities in the newborn exposed to statins during pregnancy is no higher than the expected when compared with overall risk population. The review shows a potential beneficial role of statins in preventing and treating severe preeclampsia that needs to be evaluated through well-designed clinical trials. Relevance This update could influence positively the clinical practice, giving an alternative therapy for clinicians who treat preeclampsia, particularly in severe cases. Target Audience Obstetricians and gynecologists, family physicians. Learning Objectives After completing this activity, the learner should be better able to recall that statins exert a useful number of pleiotropic effects related to their antiproliferative and immunosuppressive actions; describe the potential role of statins as beneficial and safe drugs during pregnancy, thereby preventing and treating early and severe preeclampsia; and list the properties that make pravastatin the best statin to treat preeclampsia.

Cellular senescence is a cell fate program that entails essentially irreversible proliferative arrest in response to damage signals. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some types of senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways linking TNFα-related inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that TNFα induces permanent growth arrest and increases p21CIP1, p16INK4A, and SA-β-gal, accompanied by persistent DNA damage and ROS production. By gene expression profiling, we identified the crucial involvement of inflammatory and JAK/STAT pathways in TNFα-mediated senescence. We found that TNFα activates a STAT-dependent autocrine loop that sustains cytokine secretion and an interferon signature to lock cells into senescence. Furthermore, we show STAT1/3 activation is necessary for cytokine and ROS production during TNFα-induced senescence. However, inhibition of STAT1/3 did not rescue cells from proliferative arrest, but rather suppressed cell cycle regulatory genes and altered TNFα-induced senescence. Our findings suggest a positive feedback mechanism via the STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence.

Despite years of research, miscarriage, particularly when recurrent, continues to pose a medical challenge. An embryo chromosomal error is responsible for 50-60% of recurrent cases; however, up to 30-50% remains an enigma. Successful pregnancy involves different maternal physiologic changes and certain complex interactions between the fetus and the mother by cytokines, angiogenic mediators and hormones. To date, research lines have focused on genetic and epigenetic polymorphisms related mainly to immune response and inflammatory mediators, and have yielded a significant relationship between recurrent miscarriage and immune mechanisms. Thus, unknown causes of miscarriage could be due to an immune imbalance induced by T-helper Th1/Th2/Th17 cytokines and regulatory T cells. Furthermore, these genes and mediators have long been suspected of being blood markers for the clinical diagnosis and management of miscarriage; however, more evidence is required for them to be included in medical practice and obstetric guidelines.

Background: Preeclampsia (PE) and intrauterine growth restriction (IUGR) are major causes of maternal and perinatal morbidity and mortality. Previous studies have shown that intervention with low-dose aspirin resulted in a reduction in the occurrence of preterm PE. However, no data are currently available on the effect of low-molecular-weight heparin (LMWH) for the prevention of pregnancy complications in women enrolled at first trimester screening. Objective: We aimed to assess the effectiveness of LMWH in the prevention of PE, IUGR, fetal death, and abruptio placentae in women classified as high risk based on their medical history and in women selected by first trimester screening of PE. Study ­Design: This was a multicenter, randomized, open-label, parallel controlled trial in women without thrombophilia between 6.0 and 15.6 weeks of gestation. Inclusion criteria were severe PE or IUGR before 34 weeks of gestation and/or abruptio placentae or unexplained intrauterine death in a previous pregnancy; uterine artery mean pulsatility index Doppler >95th percentile and/or positive first trimester screening for PE. Pregnant women were randomly assigned to receive no intervention or LMWH until the 36th week of gestation. The primary composite outcome consisted of 1 or more of the following: development of PE, IUGR, abruptio placentae, and intrauterine fetal death. Results: A total of 278 pregnant women were randomly allocated to receive LMWH (n = 134) or no intervention (n = 144). Overall, 115 (41%) women experienced placental insufficiency complications, with no significant differences between the 2 arms: 50/144 (34.7%) in the LMWH arm and 43/134 (32%) in the control arm (p = 0.64, OR: 1.13, 95% CI: 0.68–1.85). Conclusion: LMWH did not reduce the incidence of placenta-mediated complications either in women with previous adverse obstetric history without thrombophilia or in women selected by first trimester screening for PE. Based on these results, we cannot recommend the use of LMWH alone in women at risk of placental complications.

Background Systemic autoimmune or granulomatous disorders related to biomaterials of human use have rarely been described Objectives The aim of this study was to report cases of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) related to biomaterial injections and prostheses, mainly silicone, hyaluronic acid, acrylamides and methacrylate compounds in a Spanish patient cohort. Methods This study is a retrospective analysis of clinical, laboratory, histopathological and follow-up data of 50 cases of patients suffering from late-onset, non-infectious inflammatory/autoimmune disorders related to bioimplants. Late onset was defined as 3 months or more post injection. Data were obtained through a further non-systematic but comprehensive review of the literature. Fifty cases of late-onset adverse reactions related to biomaterial injections or prostheses were reviewed. Results All cases had systemic complaints that could be categorised as ASIA. In all but five patients, inflammatory features at the implantation site preceded distant or systemic manifestations. Abnormal blood tests were common. Localised inflammatory nodules and panniculitis in 88.88% evolved into a variety of disorders, viz., primary biliary cirrhosis, Sjogren’s syndrome, sarcoidosis, human adjuvant disease, vasculitis, inflammatory bowel syndrome and inflammatory polyradiculopathy. 11.11% cases presented primarily with systemic autoimmune disorders. Conclusion Biomaterials and prostheses can provoke late-onset systemic autoimmune disorders fulfilling ASIA criteria, or present primarily local/regional inflammatory reactions that may eventually evolve into systemic autoimmune and/or granulomatous disorders which fall under ASIA References [1] Hanke CW, Rohrich RJ, Busso M, Carruthers A, Carruthers J, Fagien S, et al. Facial soft-tissue fillers: assessing the state of the science conference proceedings report. J Am Acad Dermatol. 2011;64(4 Suppl):S53–65. [2] Ellis DA, Makdessian AS, Brown DJ. Survey of future injectables. Facial Plast Surg Clin North Am. 2001;9:405–11. [3] American Society of Plastic Surgery. Statistics of 2010, http://www.surgery.org/site/default/stats2010_1.pdf (2010, Accessed 01 Aug 2011). Disclosure of Interests None declared

Background No absolute data on the treatment of antiphospholipid antibodies (aPL) related to refractory obstetric complications exist to date. TNF-α play a major role in this disorder. Objectives To assess the effectiveness of TNF-α blockers in 18 aPL-positive women with recurrent infertility after therapy with low-molecular-weight heparin (LMWH) plus aspirin (LDA) plus hydroxychloroquine (HCQ). Methods Prospective case-series of 12 women fulfilling Sydney criteria for obstetric antiphospholipid syndrome (OAPS) and 6 with incomplete forms (OMAPS). All women tested positive for aPL at least twice. Non-criteria aPL were tested in 15/18. Complement, TNF-α and IL-10 were also evaluated. Women were closely monitored for fetal well-being and possible malformations throughout gestation and the postpartum period. Results Sixteen patients were started on adalimumab and 2 on certolizumab. Twelve women completed gestation: 9 at term and 3 pre-term. Differences in laboratory categories and outcomes were observed when OAPS and OMAPS were compared. First trimester miscarriage or implantation failure recurred in 6 cases, all of the OAPS group. Malformations were not seen in the newborns. Conclusion Overall, good obstetric results were obtained in 70% of previous LMWH-LDA+HCQ refractory cases. TNF-α blockers were well tolerated without adverse effects. The combination of LMWH plus LDA plus TNF-α blockers appears to be a promising treatment for refractory obstetric complaints related to aPL; nevertheless, outcome differences between OAPS and OMAPS do exist. References [1] Yamaguchi Y, Noriyuki N, Kaburaki J, Kobayashi K, Matsuura E, Kuwana M. Excessive exposure to anionic surfaces maintains autoantibody response to B2-glycoprotein I in patients with antiphospholipid syndrome. Blood 2007;110:4312-18. [2] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost 2006; 4:295-306. [3] Alijotas-Reig J, Vilardell-Tarres M. Is obstetric antiphospholipid syndrome a primary nonthrombotic, proinflammatory, complement-mediated disorder related to antiphospholipid antibodies? Obstet Gynecol Surv 2010: 65:39-45. [4] Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 2005;174:1222-1226. [5] Meroni PL, Borghi MO, Raschi E,Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011;7:330-39. [6] Brogin Moreli J, Cirino Ruocco AM, Vernini JM, Rudge MV, Calderon IM. Interleukin 10 and tumor necrosis factor-alpha in pregnancy: aspects of interest in clinical obstetrics. ISRN Obstet Gynecol. 2012;2012:230742. Disclosure of Interests None declared

Background: The relapse rate in antiphospholipid syndrome (APS) remains high, 20% at 5 years in thrombotic APS and 28% in obstetrical APS (1). Hydroxychloroquine (HCQ) appears as an additional therapy, with immunomodulatory and antithrombotic effects (2-5). Objectives: The main aim of this trial is to assess the efficacy of treatment with Hydroxychloroquine in preventing new events in primary antiphospholipid syndrome patients. Methods: We have performed a retrospective multicentre open-labelled study (2002-2018). Results: 812 patients with APS from 53 international centres from 16 countries were included. In all cases, the previous standard treatment was inefficient. The mean follow-up was 20.2 months (8- 144 mo), the mean age 39.5 years old. The type of clinical manifestations is described in figure 1. The obstetrical manifestations were various as described in figure 2. The number of thrombotic events were 190 arterial and 187 venous. Triple antiphospholipid antibody (tAPL) positivity was found in 20% of patients and lupus anticoagulant (LA) in 22%. No bleeding was registered in 99,6% of cases with treatment by HCQ. HCQ use was associated with favourable outcome in 96% of cases (figure 3). In multivariate analysis, age more than 65 years was associated with arterial events (odds-ratio 0.13 95%CI 0.03-0.32, p 0.005). Conclusion: HCQ could be effective in cases of refractory APS but prospective studies are necessary. References: [1] Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, Buonaiuto V, Jacobsen S, Zeher MM, Tarr T, Tincani A, Taglietti M, Theodossiades G, Nomikou E, Galeazzi M, Bellisai F, Meroni PL, Derksen RH, de Groot PG, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quere I, Hachulla E, Vasconcelos C, Fernandez-Nebro A, Haro M, Amoura Z, Miyara M, Tektonidou M, Espinosa G, Bertolaccini ML, Khamashta MA. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74:1011-8. [2] Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev. 2015;14:358–62. [3] Nuri E, Taraborelli M, Andreoli L, Tonello M, Gerosa M, Calligaro A, Argolini LM, Kumar R, Pengo V, Meroni PL, Ruffatti A, Tincani A. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res. 2017;65:17-24. [4] Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost JTH. 2013;11:1927–9. Disclosure of Interests: Cristina Belizna: None declared, Ljudmila Stojanovich: None declared, Patrick Saulnier: None declared, Francesca Pregnolato: None declared, Jaume Alijotas-Reig: None declared, Enrique Esteve-Valverde: None declared, Omar Latino: None declared, Sebastien Udry: None declared, Natasa Stanisavljevic: None declared, Alexander Makatsariya: None declared, Jamilya Khizroeva: None declared, Maarten Limper Consultant for: GSK, Roche and Thermofisher, Speakers bureau: GSK and Roche, Angela Tincani Consultant for: UCB, Pfizer, Abbvie, BMS, Sanofi, Roche, GSK, AlphaSigma, Lillly, Jannsen, Cellgene, Novartis, Laura Andreoli: None declared, Francesca Regola: None declared, Cecilia Chighizola Speakers bureau: Inova Diagnostics, Maria Orietta Borghi: None declared, Sule Apras Bilgen: None declared, Levent Kilic: None declared, Arsene Mekinian: None declared, Valentina Canti: None declared, Katrien Devreese: None declared, Gilberto Pires Rosa: None declared, Laura Damian: None declared, Fatma Said: None declared, Yehuda Shoenfeld: None declared, Ricard Cervera: None declared, Pier Luigi Meroni Consultant for: Inova, Thermofisher, Teofarma, Zahir Amoura: None declared

Background The mollecular pathogenesis of antiphospholipid syndrome is complex (environmental triggers, predisposed individuals). Previous studies suggested that infection may lead to the development of transiently elevated non-thrombogenic aPL antibodies. However, there are increasing case reports of patients with viral infections who develop antiphospholipid antibodies and thromboembolic events. Objectives To evaluate the role of acute viral infections in the development of thrombotic events related to aPL transitory (or permanent) positivity. Methods We include patients with a current viral infection that was diagnosed before elevated aPL antibodies were identified. One positive laboratory test either LA, aCL, or anti β2 GPI antibodies after a prior diagnosis of infection was required ( Results From January 2014 to date we have collected 40 cases with a demonstrated acute virosis and an aPL positive result with a thrombotic manifestation. 9 cases (22.5%) for Epstein-Barr virus, 17 cases (42.5%) were positive for CMV, 8 (20%) for Parvovirus B19, 3 cases were positive for Influenza A H1N1,3 for HIV, 1 for RSV, 1 for HCV and 1 case for Rotavirus. Lupus anticoagulant (L A) positivity was showed in 22 cases (55%), 15 cases (37.5%) tested positive for IgM anticardiolipin antibody and 13 cases (32.5%) also tested positive for IgM anti-β2GPI antibodies. Unfortunately, anti-prothrombin antibodies could not been analysed. The clinical manifestations were: leg deep venous thrombosis (17 cases) (42.5%), pulmonary embolism (5 cases) (12.5%), superior limbs (3 cases)(7.5%) livedoid vasculopathy (3 cases) (7.5%), splenic infarction (1 case), ovarian venous thrombosis (1 case). Only four arterial thromboses were observed: superior limbs (2 cases), digital ischemia (1case) and transverse myelitis (1 case). We have observed how the IgM virus related antibody became negative and the aPL became negative in parallel in 20/40 cases (50%). Conclusion We hypothesized that thrombotic manifestations of aPL-related acute viral infections are underdiagnosed, and probably in predisposed host, some viral infections may induce the transient apparition of aPL, mainly those with LA activity with potential pathogenic thrombotic properties. References [1] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an Update of classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006Feb;4(2):295-306. [2] Ascer E, Marques M, Gidlund M. M pneumoniae infection, pulmonary thromboembolism and antphospholipid antibodies. BMJ Case Rep. 2011Apr19;2011. [3] Abuaf N, Laperche S, Rajoely B, et al. Autoantibodies to phospholipids and to the coagulation proteins in AIDS. Thromb Haemost1997; 77: 856–861. Disclosure of Interests None declared

Background: Optimal standard therapy in obstetrical antiphospholipid syndrome (APS) (aspirin and LMWH) is effective in 72- 80% of pregnancies (1). Intravenous immunoglobulins (IVIG) are not more efficient than standard therapy (2, 3) and seems to be reserved to high risk pregnant APS patients (4) and/or refractory cases (5). Objectives: The main aim of this study was to analyse the outcome of pregnancies in APS patients with recurrent obstetrical event despite conventional treatment, who received IVIG. Methods: We have performed a retrospective multicentre open-labelled study (2010-2018). Results: 103 patients (107 pregnancies) with obstetrical APS from 8 international centres were included. In all cases, the previous standard treatment was inefficient. Obstetrical APS was present in 73%, while 27% had obstetrical and thrombotic APS. Median age was 28 years. Triple antiphospholipid antibody (tAPL) positivity was found in 51% of patients and lupus anticoagulant (LA) in 60%. IV IG use was associated with favourable outcome in 101/107 pregnancies (94%). In multivariate analysis, previous history of prematurity and Ig use were associated with live-birth pregnancy (odds-ratio 0.12 95%CI 0.03-0.37, p 0.005). The dosages of IV IG were variable: 0.4g/kilo day-2g/kilo day but without differences on outcomes between patients (p 0.8). There were no differences in outcomes of pregnancies between patients with tAPLand/or LA positivity and patients with other antibodies profiles (p 0.8). Conclusion: IVIG could be effective in cases of refractory obstetrical APS but prospective studies are necessary. References [1] Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, Buonaiuto V, Jacobsen S, Zeher MM, Tarr T, Tincani A, Taglietti M, Theodossiades G, Nomikou E, Galeazzi M, Bellisai F, Meroni PL, Derksen RH, de Groot PG, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quere I, Hachulla E, Vasconcelos C, Fernandez-Nebro A, Haro M, Amoura Z, Miyara M, Tektonidou M, Espinosa G, Bertolaccini ML, Khamashta MA. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74:1011-8. [2] Branch DW, Porter TF, Paidas MJ, Belfort MA, Gonik B. Obstetric uses of intravenous immunoglobulin: successes, failures, and promises. J Allergy Clin Immunol. 2001;108:S133-8. [3] Dendrinos S, Sakkas E, Makrakis E. Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome. Int J Gynaecol Obstet. 2009;104:223-5. [4] Ruffatti A, Favaro M, Hoxha A, Zambon A, Marson P, Del Ross T, Calligaro A, Tonello M, Nardelli GB. Apheresis and intravenous immunoglobulins used in addition to conventional therapy to treat high-risk pregnant antiphospholipid antibody syndrome patients. A prospective study. J Reprod Immunol. 2016;115:14-9. [5] Prete M, Urso L, Fatone MC, Pinto V, Perosa F. Antiphospholipids Syndrome Complicated by a Systemic Capillary Leak-Like Syndrome Treated With Steroids and Intravenous Immunoglobulins: A Case Report. Medicine. 2016;95:e2648. Disclosure of Interests: None declared

Tumor necrosis factor-α (TNF-α) is a central regulator of inflammation, and TNF-α antagonists may be effective in treating inflammatory disorders in which TNF-α plays a major pathogenic role. TNF-α has also been associated with inflammatory mechanisms related to implantation, placentation, and pregnancy outcome. TNF-α is secreted by immune cells and works by binding to TNFR1 and TNFR2 cell receptors. TNF-α is also related to JAK/STAT pathways, which opens up hypothetical new targets for modifying. The accurate balance between Th1 cytokines, mainly TNF-α, Th17, and Th2, particularly IL-10 is essential to achieve good obstetric outcomes. TNF-α targeted therapy could be rational in treating women with obstetric complication related to overproduction of TNF-α, such as recurrent pregnancy loss, early and severe pre-eclampsia, and recurrent implantation failure syndrome, all "idiopathic" or related to aPL positivity. Along the same lines, Th1 cytokines, mainly TNF- α, play a leading pathogenic role in rheumatic and systemic autoimmune diseases occurring in women and, to a lesser extent, in men of reproductive age. These disorders have to be clinically silent before pregnancy can be recommended, which is usually only possible to achieve after intensive anti-inflammatory and immunosuppressive treatment, TNF-α blockers included. Physicians should be aware of the theoretic potential but low embryo-fetal toxicity risk of these drugs during pregnancy. From an updated review in May 2016, we can conclude that TNF-α blockers are useful in certain "refractory" cases of inflammatory disorders related to poor obstetric outcomes and infertility. Furthermore, TNF-α blockers can be safely used during the implantation period and pregnancy. Breastfeeding is also permitted with all TNF-α inhibitors. Since data on the actual mechanism of action of JAK-STAT in inflammatory obstetric disorders including embryo implantation are scarce, for the time being, therapeutic interventions in this setting should be discouraged. Finally, adverse effects on sperm quality, or causing embryo-fetal anomalies, in men treated with TNF inhibitors have not been described.

Resumen Las enfermedades reumaticas y autoinmunitarias afectan a mujeres y, en menor medida, tambien a hombres en edad fertil. Estas deben estar sin actividad clinica antes de la concepcion, lo que suele conseguirse con farmacos inmunodepresores/antiinflamatorios. Un 50% de los embarazos en este colectivo no seran planificados. Los profesionales debemos conocer los efectos embrio/fetotoxicos de estos farmacos, asi como sus consecuencias negativas sobre la gestacion y la lactancia. Esta revision actualizada hasta enero de 2016 permite concluir que la mayoria de los inmunodepresores disponibles, incluidos los inhibidores del TNF, se pueden utilizar antes y durante la gestacion, con la excepcion de ciclofosfamida, metotrexato, micofenolato y leflunomida. Se puede lactar exceptuando si se usa metotrexato, leflunomida, micofenolato y ciclofosfamida. Parece que abatacept, belimumab, rituximab, tocilizumab y anakinra son seguros durante la gestacion y la lactancia. Exceptuando ciclofosfamida y sulfasalazina, no se han comunicado efectos sobre la calidad espermatica ni un aumento de embriofetopatias en hombres tratados con inmunodepresores.

Objectives To ascertain whether screening for pre-eclampsia (PE) and intrauterine growth restriction (IUGR) by uterine artery (UtA) Doppler in the second trimester of pregnancy and targeted surveillance improve maternal and perinatal outcomes in an unselected population. Methods This was a multicenter randomized open-label controlled trial. At the routine second-trimester anomaly scan, women were assigned randomly to UtA Doppler or non-Doppler groups. Women with abnormal UtA Doppler were offered intensive surveillance at high-risk clinics of the participating centers with visits every 4 weeks that included measurement of maternal blood pressure, dipstick proteinuria, fetal growth and Doppler examination. The primary outcome was a composite score for perinatal complications, defined as the presence of any of the following: PE, IUGR, spontaneous labor < 37 weeks' gestation, placental abruption, stillbirth, gestational hypertension, admission to neonatal intensive care unit and neonatal complications. Secondary outcomes were a composite score for maternal complications (disseminated intravascular coagulation, maternal mortality, postpartum hemorrhage, pulmonary edema, pulmonary embolism, sepsis), and medical interventions (for example, corticosteroid administration and induction of labor) in patients developing placenta-related complications. Results In total, 11 667 women were included in the study. Overall, PE occurred in 348 (3.0%) cases, early-onset PE in 48 (0.4%), IUGR in 722 (6.2%), early-onset IUGR in 93 (0.8%) and early-onset PE with IUGR in 32 (0.3%). UtA mean pulsatility index > 90th percentile was able to detect 59% of early-onset PE and 60% of early-onset IUGR with a false-positive rate of 11.1%. When perinatal and maternal data according to assigned group (UtA Doppler vs non-Doppler) were compared, no differences were found in perinatal or maternal complications. However, screened patients had more medical interventions, such as corticosteroid administration (relative risk (RR), 1.79 (95% CI, 1.4–2.3)) and induction of labor for IUGR (RR, 1.36 (95% CI, 1.07–1.72)). In women developing PE or IUGR, there was a trend towards fewer maternal complications (RR, 0.46 (95% CI, 0.19–1.11)). Conclusions Routine second-trimester UtA Doppler ultrasound in an unselected population identifies approximately 60% of women at risk for placental complications; however, application of this screening test failed to improve short-term maternal and neonatal morbidity and mortality. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Obstetric antiphospholipid syndrome is an acquired autoimmune disorder that is associated with various obstetric complications and, in the absence of prior history of thrombosis, with the presence of antiphospholipid antibodies directed against other phospholipids, proteins called cofactors or PL-cofactor complexes. Although the obstetric complications have been related to the procoagulant properties of antiphospholipid antibodies, pathological studies of human placenta have shown the proinflammatory capacity of antiphospholipid antibodies via the complement system and proinflammatory cytokines. There is no general agreement on which antiphospholipid antibodies profile (laboratory) confers the greatest obstetric risk, but the best candidates are categories I and IIa. Combined treatment with low doses of aspirin and heparin achieves good obstetric and maternal outcomes. In this study, we also review the therapeutic possibilities in refractory cases, although the likelihood of progressing to other autoimmune diseases is low. We briefly comment on incomplete obstetric antiphospholipid syndrome, also known as antiphospholipid antibody-mediated pregnancy morbidity syndrome.

Severe Acute Respiratory Syndrome related to Coronavirus-2 (SARS-CoV-2), coronavirus disease-2019 (COVID-19) may cause severe illness in 20% of patients. This may be in part due to an uncontrolled immune-response to SARS-CoV-2 infection triggering a systemic hyperinflammatory response, the so-called “cytokine storm”. The reduction of this inflammatory immune-response could be considered as a potential therapeutic target against severe COVID-19. The relationship between inflammation and clot activation must also be considered. Furthermore, we must keep in mind that currently, no specific antiviral treatment is available for SARS-CoV-2. While moderate-severe forms need in-hospital surveillance plus antivirals and/or hydroxychloroquine; in severe and life-threating subsets a high intensity anti-inflammatory and immunomodulatory therapy could be a therapeutic option. However, right data on the effectiveness of different immunomodulating drugs are scarce. Herein, we discuss the pathogenesis and the possible role played by drugs such as: antimalarials, anti-IL6, anti-IL-1, calcineurin and JAK inhibitors, corticosteroids, immunoglobulins, heparins, angiotensin-converting enzyme agonists and statins in severe COVID-19., Higlights • Severe COVID-19 forms may be related to a hyperinflammatory syndrome. • Severe COVID-19 is associated with clot pathway hyperactivity and sometimes, with thromboses. • Immunosuppression may be a complementary therapy in COVID-19 patients. • Antimalarials, heparin, cytokine blockers, JAK-inhibitors, IVIG could be useful for treating severe COVID-19 patients. • In SARS-CoV-2 infections the effectiveness of the hyperimmune plasma remains uncertain.

Background:Although guidelines do not recommend antiphospholipid antibodies testing after 60 yo, recent data reported late onset antiphospholipid syndrome (APS).Objectives:To comparatively analyse the clinical, laboratory features and outcomes in 695 cases with primary APS between patients older and younger than 70 yo.Methods:we have performed an international study within the framework of the International Registry of primary APS patients treated with Hydroxychloroquine, HIBISCUS (an ongoing retrospective and prospective register launched in 2016). 28 centres from 17 countries participate. Data about late onset APS were analysed in 695 patients and were obtained from a standardized form registered in the database containing 66 items with respect to demographics, clinical and biological features.Results:Arterial events and especially stroke represented the main initial and recurrent clinical manifestation in 40 primary APS patients older than 70 yo. There were not statistically significant differences with respect to cardiovascular risk factors between the two groups of patients. A significant male predominance, a familial APS history, a higher prevalence of triple positivity, lower complement levels, and anticardiolipin antibodies (aCL) IgA isotype were found in older patients. Low anticoagulation regimens were safe and efficient, with a low relapse rate in older patients.Conclusion:we suggest that the detection of aPL antibodies should be included into the initial screening panel tests in elderly with thrombotic events, especially arterial, in particular those with recurrent stroke and familial APS.Our study further suggests that lower intensity anticoagulation regimens could be a therapeutic option in older APS patients, as no differences in outcomes and relapse rate were found between patients with high and low intensity anticoagulation regimens.References:[1]Grimaud F et al. Rheumatology. 2019;58:1006-10.[2]Goldman-Mazur S et al. Thromb Res. 2019;176:67-73.[3]Hirmerova J et al. 2017;36:167-73.Disclosure of Interests:Cristina Belizna: None declared, Omar Latino: None declared, Ljudmila Stojanovich: None declared, Patrick Saulnier: None declared, Katrien Devreese: None declared, Sebastien Udry: None declared, Natasa Stanisavljevic: None declared, Aleksandra Djokovic Speakers bureau: KRKA, Astra Zeneca, Actavis, Jaume Alijotas-Reig: None declared, Enrique Esteve-Valverde: None declared, Raquel Ferrer-Oliveras: None declared, Angela Tincani: None declared, Laura Andreoli: None declared, Francesca Regola: None declared, Maarten Limper: None declared, Alexander Makatsariya: None declared, Jamilya Khizroeva: None declared, Viktoria Bitsadze: None declared, Cecilia Chighizola: None declared, Francesca Pregnolato: None declared, Maria Orietta Borghi: None declared, Pier Luigi Meroni: None declared

Background No absolute data on the treatment of antiphospholipid antibodies (aPL) related to refractory obstetric complications exist to date. TNF-α play a major role in this disorder. Objective To assess the effectiveness of TNF-α blockers in 18 aPL-positive women with recurrent infertility after therapy with low-molecular-weight heparin (LMWH) plus aspirin (LDA) plus hydroxychloroquine (HCQ). Methods Prospective case-series of 12 women fulfilling Sydney criteria for obstetric antiphospholipid syndrome (OAPS) and 6 with incomplete forms (OMAPS). All women tested positive for aPL at least twice. Non-criteria aPL were tested in 15/18. Complement, TNF-α and IL-10 were also evaluated. Women were closely monitored for fetal well-being and possible malformations throughout gestation and the postpartum period. Results Sixteen patients were started on adalimumab and 2 on certolizumab. Twelve women completed gestation: 9 at term and 3 pre-term. Differences in laboratory categories and outcomes were observed when OAPS and OMAPS were compared. First trimester miscarriage or implantation failure recurred in 6 cases, all of the OAPS group. Malformations were not seen in the newborns. Conclusions Overall, good obstetric results were obtained in 70% of previous LMWH-LDA+HCQ refractory cases. TNF-α blockers were well tolerated without adverse effects. The combination of LMWH plus LDA plus TNF-α blockers appears to be a promising treatment for refractory obstetric complaints related to aPL; nevertheless, outcome differences between OAPS and OMAPS do exist.

Introduction Le syndrome des antiphospholipides (SAPL) seronegatif constitue une nouvelle entite avec la presence de caracteristiques cliniques de SAPL, en l’absence d’anticorps antiphospholipides conventionnels. Patients et methodes Nous avons realise un appel a observation europeen de patientes avec au moins un critere clinique de SAPL obstetrical (criteres de Sydney), en l’absence d’anticorps antiphospholipides conventionnels mais avec la presence d’au moins un anticorps antiphospholipides non criteria parmi : anticorps anti-annexine V, anti-phosphatidylethanolamine (anti-PE), anti-prothrombine/phosphatidylserine (anti-PS/PT), et/ou anti-beta2-glycoproteine 1 Immunoglobuline A (anti-β2GpI IgA). Resultats Nous avons inclus 187 patientes issues de 12 centres universitaires europeens (Italie, Autriche, Espagne, France), d’un âge median de 32 ans [18–44], dont 80 % de femmes caucasiennes (n = 150). Au moins un critere clinique de SAPL (criteres de Sydney) etait present chez toutes les femmes, avec 35 % de patientes ayant presente au moins 3 fausses couches precoces (n = 66), 32 % ayant un antecedent d’au moins une mort fœtale in utero (n = 60), 23 % ayant un antecedent d’au moins une naissance prematuree avant 34 semaines d’amenorrhee (SA) liee a une eclampsie, preeclampsie severe ou insuffisance placentaire (n = 43). Neuf patientes avaient un antecedent de thrombose veineuse profonde (5 %). Les anticorps non conventionnels presents chez toutes les femmes etaient : des anticorps anti-annexine V dans 23 % des cas (n = 43), anti-PE dans 62 % (n = 56) (IgG pour 34 %, et IgM 76 %), des anti-PS/PT dans 52 % (n = 98) (IgG pour 67 % et/ou IgM pour 70 %) et anti-β2GpI IgA dans 2 % (n = 1). Vingt-huit pour cent de patientes presentaient une positivite de plusieurs antiphospholipides non criteria (n = 53). Au moins une grossesse apres la mise en evidence de ces anticorps est survenue chez 79 % des patientes (n = 148). Un traitement pendant la grossesse etait prescrit dans 86 % de cas (n = 127) par : aspirine seule (n = 37 ; 29 %) ; association d’aspirine et d’HBPM (n = 82 ; 65 %), corticotherapie a faible dose (n = 16 ; 13 %) et/ou hydroxychloroquine (n = 17 ; 13 %). Une grossesse vivante etait obtenue dans 57 % des cas (n = 84) avec un terme median de 38 SA. Une complication maternelle et/ou fœtale etait notee dans 38 % des grossesses (n = 57) : preeclampsie ou HELLP syndrome (n = 11 ; 7 %), retard de croissance intra-uterin (n = 5 ; 3 %), oligoamnios (n = 2 ; 1 %) et pertes fœtales (n = 37 ; 25 %) (causes maternelles anatomiques, infectieuses, hormonales ou materno-paternelles chromosomiques exclues), sans aucun cas de thrombose. Conclusion Le SAPL seronegatif est donc une reelle entite clinique associee aux anticorps antiphospholipides non criteria. Le pronostic obstetrical de ces patientes est impacte avec des complications maternofœtales pour plus d’un tiers des grossesses dans notre serie europeenne. Cette etude plaide pour la recherche systematique des anticorps antiphospholipides non criteria en cas de SAPL clinique seronegatif afin d’encadrer et de traiter au mieux les grossesses pour en ameliorer leur devenir. Des etudes prospectives sont necessaires pour confirmer et approfondir ces donnees.

Systemic autoimmune or granulomatous disorders related to biomaterials of human use have rarely been described. The aim of this study was to report cases of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) related to biomaterial injections and prostheses, mainly silicone, hyaluronic acid, acrylamides and methacrylate compounds in a Spanish patient cohort. This study is a retrospective analysis of clinical, laboratory, histopathological and follow-up data of 45 cases of patients suffering from late-onset, non-infectious inflammatory/autoimmune disorders related to bioimplants. Late onset was defined as 3 months or more post injection. Data were obtained through a further non-systematic but comprehensive review of the literature. Forty-five cases of late-onset adverse reactions related to biomaterial injections or prostheses were reviewed. All cases had systemic complaints that could be categorised as ASIA. In all but four patients, inflammatory features at the implantation site preceded distant or systemic manifestations. Abnormal blood tests were common. Localised inflammatory nodules and panniculitis in 40/45 (88.88%) evolved into a variety of disorders, viz., primary biliary cirrhosis, Sjogren’s syndrome, sarcoidosis, human adjuvant disease, vasculitis, inflammatory bowel syndrome and inflammatory polyradiculopathy. Five (11.11%) cases presented primarily with systemic autoimmune disorders. Biomaterials and prostheses can provoke late-onset systemic autoimmune disorders fulfilling ASIA criteria, or present primarily local/regional inflammatory reactions that may eventually evolve into systemic autoimmune and/or granulomatous disorders which fall under ASIA.

Background and objectives: To compare clinical, laboratory, treatment and live birth rate data between women with aPL-related obstetric complications (OMAPS) not fulfilling the Sydney criteria and women fulfilling them (OAPS). Materials and methods: Retrospective and prospective multicentre study. Data comparison between groups from The European Registry on Antiphospholipid Syndrome included within the framework of the European Forum on Antiphospholipid Antibody projects. Results: 338 women were analysed: 247 fulfilled the Sydney criteria (OAPS group) and 91 did not (OMAPS group). In the OMAPS group, 24/91 (26.37%) fulfilled laboratory Sydney criteria (subgroup A) and 67/91 (74.63%) had a low titre and/or non-persistent aPL-positivity (subgroup B). Overall, aPL laboratory categories in OAPS vs. OMAPS showed significant differences: 34% vs. 11% (p < 0.0001) for category I, 66% vs. 89% (p < 0.0001) for category II. No differences were observed when current obstetric complications were compared (p = 0.481). 86.20% of OAPS women were treated vs. 75.82% of OMAPS (p = 0.0224), particularly regarding the LDA + LMWH schedule (p = 0.006). No differences between groups were observed in live births, gestational, puerperal arterial and/or venous thrombosis. Conclusions: Significant differences were found among aPL categories between groups. Treatment rates were higher in OAPS. Both OAPS and OMAPS groups had similarly good foetal-maternal outcomes when treated. The proposal to modify OAPS classification criteria, mostly laboratory requirements, is reinforced by these results.

The maternal immune system needs to adapt to tolerate the semi-allogeneic conceptus. Since maternal allo-reactive lymphocytes are not fully depleted, other local/systemic mechanisms play a key role in altering the immune response. The Th1/Th2 cytokine balance is not essential for a pregnancy to be normal. The immune cells, CD4+CD25+Foxp3+, also known as regulatory T cells (Tregs), step in to regulate the allo-reactive Th1 cells. In this review we discuss the role of Tregs in foeto-maternal immune tolerance and in recurrent miscarriage as well as their potential use as a new target for infertility treatment. Animal and human experiments showed Treg cell number and/or function to be diminished in miscarriages. Murine miscarriage can be prevented by transferring Tregs from normal pregnant mice. Tregs at the maternal-fetal interface prevented fetal allo-rejection by creating a "tolerant" microenvironment characterised by the expression of IL-10, TGF-β and haem oxygenase isoform 1 (HO-1) rather than by lowering Th1 cytokines. Tregs increase placental HO-1. In turn, HO-1 may lead to up-regulation of TGF-β, IL-10 and CTLA-4. In vivo experiments showed Tregs sensitisation from paternal antigens to be essential for maternal-fetal tolerance. Tregs increase throughout pregnancy and diminish in late puerperium. Recent data also support the capacity of Tregs to block maternal effector T cells, thereby reducing the maternal-fetal pathological responses to paternal antigens. These findings also permit us to consider new strategies for improving pregnancy outcomes, i.e., anti-TNF blockers and granulocyte-colony stimulating factors as well as novel approaches to therapeutically exploiting Treg + cell memory.