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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.

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

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.

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.

Even though manufacturers claim that the dermal fillers are nontoxic and nonimmunogenic, adverse events may occur. Clinically and histologically, most of the late onset adverse events present as an inflammatory response. To assess whether HLA polymorphisms are associated with late-onset inflammatory adverse events related to dermal fillers. A total of 211 patients were included, of whom 129 experienced late-onset inflammatory adverse events to different fillers (Inflammation group) and 82 who did not (Reference group). Patients completed a standardized questionnaire and provided a blood sample or oral swap for HLA testing. The study population consisted of 188 (89%) women and 23 (11%) men. The two study groups were similar in the distributions of filler type, location of injecting, allergy, autoimmune disease, gender, age, ethnicity, and smoking status. Of the 211 patients in the sample, 25 had the combination of HLA subtype-B*08 and HLA subtype-DRB1*03. This was 16.3% of the inflammatory group and 4.9% of the reference group. This combination of HLA subtypes was associated with an almost 4-fold increase in the odds of developing immune mediated adverse events (odds ratio = 3.79, 95% CI 1.25-11.48). Genetic polymorphisms such as HLA combinations may identify patients at risk of developing late onset immune mediated adverse events to dermal fillers.

BACKGROUND The combination of low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH) until the end of gestation are the currently the accepted standard of care for the treatment of antiphospholipid-related obstetric disorders. In refractory cases, hydroxychloroquine (HCQ) can be added to this standard of care. OBJECTIVE To evaluate the haemostatic safety of LDA and LMWH (medium to high prophylactic doses) during pregnancy and the puerperium in women with both full-blown obstetric antiphospholipid syndrome (OAPS) (Sydney criteria) and noncriteria - incomplete - OAPS. STUDY DESIGN Retrospective/prospective multicentre observational study. Obstetric background, laboratory categories, delivery mode, antithrombotic regimens and bleeding complications were compared. SETTING A total of 30 tertiary European hospitals. PATIENTS Mainly, Caucasian/Arian pregnant women were included. Other ethnicities were minimally present. Women were controlled throughout pregnancy and puerperium. MAIN OUTCOME MEASURES The primary end-point was to evaluate the number of major and minor haemorrhagic complications in this cohort of women. Neuraxial anaesthetic bleeding complications were particularly assessed. Secondly, we aimed to compare local/general bleeding events between groups. RESULTS We studied 1650 women, of whom 1000 fulfilled the Sydney criteria of the OAPS and 650 did not (noncriteria OAPS). Data on antithrombotic-related complications were available in 1075 cases (65.15%). Overall, 53 (4.93%) women had bleeding complications, with 34 being considered minor (3.16%) and 19 major (1.76%). Neither obstetric complications nor laboratory categories were bleeding-related. Assisted vaginal delivery and caesarean section were related to local haemorrhage. Heparin doses and platelet count were not associated with major bleeding. CONCLUSIONS LDA and medium to high prophylactic LMWH during pregnancy in women with full-blown OAPS/noncriteria OAPS are safe. A slight increase in bleeding risk was noted in instrumental deliveries. No women who underwent spinal or epidural anaesthesia suffered bleeding complications. No haemorrhage was observed in cases where HCQ was added to standard therapy.

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.

International audience; Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms. The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors. In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this field

ObjectiveTo compare characteristics, pregnancies and treatments during pregnancies of seronegative and seropositive antiphospholipid syndrome (APS), to analyse factors associated with obstetrical outcome.Patients and methodsInclusion criteria were: (1) thrombotic and/or obstetrical APS (Sydney criteria); (2) absence of conventional antiphospholipid antibodies (APL); (3) at least one persistent non-conventional APL among IgA anticardiolipin antibodies, IgA anti-B2GPI, anti-vimentin G/M, anti-annexin V G/M, anti-phosphatidylethanolamine G/M and anti-phosphatidylserine/prothrombin G/M antibodies. The exclusion criteria were: (1) systemic lupus erythematosus ( SLE) or SLE-like disease; and (2) other connective tissue disease.ResultsA total of 187 women (mean 33±5 years) with seronegative APS were included from 14 centres in Austria, Spain, Italy, Slovenia and France and compared with 285 patients with seropositive APS. Seronegative APS has more obstetrical rather than thrombotic phenotypes, with only 6% of venous thrombosis in comparison to seropositive APS. Cumulative incidence of adverse obstetrical events was similar in seronegative and seropositive APS patients, although higher rates of intrauterine deaths (15% vs 5%; p=0.03), of preeclampsia (7% vs 16%, p=0.048) and lower live birth term (36±3 vs 38±3 weeks of gestation; p=0.04) were noted in seropositive APS. The cumulative incidence of adverse obstetrical events was significantly improved in treated versus untreated seronegative APS (log rankConclusionSeveral non-criteria APL can be detected in patients with clinical APS features without any conventional APL, with various rates. The detection of non-criteria APL and thus the diagnosis of seronegative APS could discuss the therapeutic management similar to seropositive APS, but well-designed controlled 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.

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

International audience; The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS [2, 3].Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4–16].Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency.Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial.This trial consists in two parts: a retrospective and a prospective study.The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

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.

International audience; Primary antiphospholipid syndrome (PAPS) and antiphospholipid syndrome associated to lupus (SAPS) have several overlapping characteristics. As systemic manifestations are also reported in patients with PAPS, and as a subgroup of PAPS patients could evaluate to a SAPS, the differentiation between the two types of APS could be performed based on the clinical experience of the medical teams and is related to a variety of clinical, biological, histological and genetic features. Several data are available in the literature with respect to the identification of distinctive features between these two entities. However, there are some limitation in the interpretation of results issued from studies performed prior to updated Sydney criteria. Based on recent data, a certain number of features more frequent in one type of APS as compared to the other could be distinguished. The major differentiation between these two entities is genetical. New genetic data allowing the identification of specific subgroups of APS are ongoing.

The effect of additional treatments combined with conventional therapy on pregnancy outcomes was examined in high-risk primary antiphospholipid syndrome (PAPS) patients to identify the most effective treatment strategy. The study's inclusion criteria were (1) positivity to lupus anticoagulant alone or associated with anticardiolipin and/or anti-β2 glycoprotein I antibodies; (2) a history of severe maternal–foetal complications (Group I) or a history of one or more pregnancies refractory to conventional therapy leading to unexplained foetal deaths not associated with severe maternal–foetal complications (Group II). Two different additional treatments were considered: oral—low-dose steroids (10–20 mg prednisone daily) and/or 200 to 400 mg daily doses of hydroxychloroquine and parenteral—intravenous immunoglobulins at 2 g/kg per month and/or plasma exchange. The study's primary outcomes were live birth rates and pregnancy complications. A total of 194 pregnant PAPS patients attending 20 tertiary centres were retrospectively enrolled. Hydroxychloroquine was found to be linked to a significantly higher live birth rate with respect to the other oral treatments in the Group II patients. The high (400 mg) versus low (200 mg) doses of hydroxychloroquine (p = 0.036) and its administration before versus during pregnancy (p = 0.021) were associated with a significantly higher live birth rate. Hydroxychloroquine therapy appeared particularly efficacious in the PAPS patients without previous thrombosis. Parenteral treatments were associated with a significantly higher live birth rate with respect to the oral ones (p = 0.037), particularly in the Group I patients. In conclusion, some additional treatments were found to be safe and efficacious in high-risk PAPS pregnant women.

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.

Aim The aim of this study was to demonstrate that women with severe early-onset preeclampsia and concomitant risk factors benefit from expectant management. Methods This retrospective study was conducted between January 2009 and December 2010. Stable women with severe preeclampsia between 23+6 and 33+6weeks of gestation were admitted to the IOCU for conservative management. They were classified into two groups: those with concomitant risk factors, i.e. associated medical conditions, HELLP syndrome, severe oligohydramnios, fetal growth restriction and multiple pregnancies (group A) and those without (group B). P values lesser than 0.05 were considered statistically significant. Results No significant differences were found in maternal and perinatal outcomes between groups. Neither were differences observed in pregnancy prolongation (mean: 8.42days (SD±7.462) in group A and 10.5days (SD±8.235) in group B ( p =0.391)). At the start of expectant management, 31.8% of fetuses had an abnormal middle cerebral artery Doppler; prior to delivery, this percentage was 77.4%. Conclusion Pregnant women with severe early-onset preeclampsia and associated risk factors benefited from expectant management. During expectant management using a continuous magnesium sulfate regimen, the majority of fetuses showed cerebral vasodilatation. The exact clinical value of this finding should be clarified in further studies

Background An increasing number of persons seek medical solutions for esthetic indications and for diverse pathological conditions, such as malformations, trauma, or cancer. Despite manufacturers' and different authors' claims that fillers are non-immunogenic or that complications are uncommon, unwanted adverse reactions do occur. Objectives To review the literature regarding the multiple types of immune-mediated adverse reactions related to medical dermal filler injections/prosthesis. Methods A comprehensive MEDLINE, PubMed, and Google Scholar electronic database search was performed (2000–January 2012). Selected articles published before 2000 referring to general concerns regarding the studied topic were also included. The search provided almost 300 articles. Finally, 235 studies were selected and included. Results All known fillers present in the market have been shown to be able to provoke early- and late-onset inflammatory adverse reactions. Their true prevalence is unknown but appears to be significant. The majority of the late-onset adverse effects are inflammatory and immune-mediated in nature. Edema, granulomas, sarcoid-like disorders, and panniculitis are the findings most commonly seen. Rarely, systemic granulomatous and autoimmune diseases, and to lesser extent acute hypersensitivity reactions can be seen. Conclusions All implanted, injected, and blood-contact biomaterials trigger a wide variety of adverse reactions that may appear early or late and range from local to systemic. Most fillers act more as adjuvants than as direct T-cell activators, on a background of genetic predisposition. Their treatment has not been the subject of well-designed studies. Management of both acute and systemic reactions is often difficult and requires anti-inflammatory and occasionally immunosuppressive therapy.

Pregnancy is a proinflammatory and hypercoagulable state. Miscarriage concerns approximately 15% of pregnancies. Recurrent miscarriage is a rather rare condition with an estimated incidence of 1% to 3%. However, despite years of investigation, the etiology is not established in up to 50% of cases. A multidisciplinary approach in the evaluation of miscarriage is essential to understand the cause and risk of recurrence. Although genetic factors are the major cause of spontaneous miscarriages, their relationship with recurrent miscarriage is less frequent. Recently, many kinds of genetic polymorphisms have also been found to be associated. Endocrine disorders such as poorly controlled diabetes, polycystic ovary syndrome, and hypothyroidism are linked with recurrent miscarriage. The relationship between recurrent miscarriage and subclinical thyroid disorders and thyroid autoimmunity is disputed, especially in early miscarriages. Uterine malformations should be considered as a cause of recurrent miscarriage. Although autoimmune-based recurrent miscarriage has been described, mainly antiphospholipid antibodies, the role of alloimmune mechanisms remains poorly understood. The influence of congenital thrombophilia is controversial. Antiphospholipid syndrome or antiphospholipid antibody-related recurrent miscarriage, and some endocrinologic disorders, have a specific and effective treatment. Still, the effectiveness of some common treatments needs to be demonstrated.

Aim To describe the consecutive pregnancy outcome and treatment in refractory obstetrical antiphospholipid syndrome (APS). Methods Retrospective multicenter open-labelled study from December 2015 to June 2016. We analyzed the outcome of pregnancies in patients with obstetrical APS (Sydney criteria) and previous adverse obstetrical event despite low-dose aspirin and low-molecular weight heparin LMWH (LMWH) conventional treatment who experienced at least one subsequent pregnancy. Results Forty nine patients with median age 27 years (23 − 32) were included from 8 European centers. Obstetrical APS was present in 71%, while 26% had obstetrical and thrombotic APS. Lupus anticoagulant was present in 76% and triple antiphospholipid antibody (APL) positivity in 45% of patients. Pregnancy loss was noted in 71% with a median age of gestation of 11 (8–21) weeks. The presence of APS non-criteria features (35% vs 17% in pregnancies without adverse obstetrical event; p = 0.09), previous intrauterine death (65% vs 38%; p = 0.06), of LA (90% vs 65%; p = 0.05) were more frequent in pregnancies with adverse pregnancy outcome, whereas isolated recurrent miscarriage profile was more frequent in pregnancies without any adverse pregnancy outcome (15% vs 41%; p = 0.04). In univariate analysis considering all pregnancies (index and subsequent ones), an history of previous intrauterine death was associated with pregnancy loss (odds-ratio 2.51 (95% CI 1.274.96); p = 0.008), whereas previous history of prematurity related to APS (odds-ratio 0.13 95%CI 0.04 0.41, P = 0.006), steroids use during the pregnancy (odds-ratio 0.30 95% CI 0.11–0.82, p = 0.019) and anticardiolipids isolated profile (odds-ratio 0.51 95% CI 0.26–1.03, p = 0.0588) were associated with favorable outcome. In multivariate analysis, only previous history of prematurity, steroids use and anticardiolipids isolated profiles were associated with live-birth pregnancy. Conclusion The main features of refractory obstetrical APS were the high rates of LA and triple APL positivity. Steroids could be effective in this APS profile, but prospective studies are necessary.

An ever-increasing number of persons seek medical solutions to improve the appearance of their aging skin or for aesthetic and cosmetic indications in diverse pathological conditions, such as malformations, trauma, cancer, and orthopedic, urological, or ophthalmological conditions. Currently, physicians have many different types of dermal and subdermal fillers, such as non-permanent, permanent, reversible, or non-reversible materials. Despite the claims of manufacturers and different authors that fillers are non-toxic and non-immunogenic or that complications are very uncommon, unwanted side effects do occur with all compounds used. Implanted, injected, and blood-contact biomaterials trigger a wide variety of adverse reactions, including inflammation, thrombosis, and excessive fibrosis. Usually, these adverse reactions are associated with the accumulation of large numbers of mononuclear cells. The adverse reactions related to fillers comprise a broad range of manifestations, which may appear early or late and range from local to systemic. Clinicians should be aware of them since the patient often denies the antecedent of injection or is unaware of the material employed. Most of these adverse effects seem to have an immunological basis, the fillers acting more as adjuvants than as direct T-cell activators, on a background of genetic predisposition. Their treatment has not been the subject of well-designed studies; management of both acute and systemic reactions is often difficult, and requires anti-inflammatory and occasionally immunosuppressive therapy. The clinical, pathological, and therapeutic aspects of inflammatory and immune-mediated late-onset adverse reactions related to soft tissue filler injections are thoroughly reviewed herein.

Rheumatic and systemic autoimmune diseases occur in women and, to a lesser degree, men of reproductive age. These disorders have to be clinically nonactive before conception, which is usually only possible after anti-inflammatory and immunosuppressive treatment. We must be alert since 50% of pregnancies are unplanned. Physicians should know the embryo-foetal toxicity of these drugs during pregnancy and lactation. This January 2016-updated review allows us to conclude that the majority of immunosuppressives available -anti-TNF inhibitors included- can be used before and during pregnancy, with the exception of cyclophosphamide, methotrexate, mycophenolate and leflunomide. Lactation is permitted with all drugs except methotrexate, leflunomide, mycophenolate and cyclophosphamide. Although data on abatacept, belimumab, rituximab, tocilizumab and anakinra are scant, preliminary reports agree on their safety during pregnancy and, probably, lactation. Cyclophosphamide and sulfasalazine apart, no negative effects on sperm quality, or embryo-foetal anomalies in men treated with immunosuppressives have been described.

Objective To date, there are no reliable data regarding the actual treatment received by women with refractory obstetric antiphospholipid syndrome (OAPS). The aim of this study was to assess current clinical evidence and new trends in the treatment of refractory OAPS. Methods A non-systematic but comprehensive literature search using relevant keywords was made to identify relevant articles published in English from different computerized databases: PubMed (Medline), Google Scholar electronic database search and The Cochrane Library, from January 2000 to March 2012. Studies on the treatment of poor obstetric outcomes in women with OAPS were included. Prospective randomized clinical trials, cohort studies, reviews, systematic reviews and meta-analysis were retrieved. Results A total of 130 articles were finally selected for this review, including 17 randomized clinical trials and four meta-analyses. The majority of articles were non-randomized original papers and basic and clinical reviews. Conclusion Up to 20% of women with OAPS do not receive the currently recommended therapeutic regimen. Unfortunately, well-designed studies regarding the usefulness of new drugs in refractory OAPS are scarce. Hydroxychloroquine and low-dose prednisolone appear to be useful when added to standard therapy. Current data do not support the use of intravenous immunoglobulins in this field. The role played by double anti-aggregant therapy, fondaparinux, vitamin D, pentoxifylline and TNF-targeted therapies should be tested in well-designed studies.

Jaume Alijotas-Reig *, Manel Sole b y Maria Angels Martinez c a Servicio de Medicina Interna-Enfermedades Sistemicas Autoinmunes, Hospital Universitari Vall d’Hebron, Departamento de Medicina, Universitat Autonoma, Barcelona, Espana b Servicio de Anatomia Patologica, Centro de Diagnostico Biomedico, Hospital Clinic, Barcelona, Espana c Servicio de Obstetricia, Ginecologia y Neonatologia, Instituto Clinico de Ginecologia y Obstetricia, Hospital Clinic, Barcelona, Espana

Background Although currently not authorized in many countries, medical-grade silicone (MGS) injections have been used for 50 years. Sometimes chronic and severe adverse effects refractory to usual therapy other than corticosteroids appear. Objective To evaluate the effectiveness of tacrolimus in the treatment of refractory cases of late-onset adverse effects related to MGS injections. Methods Case-series study of seven patients with late-onset adverse effects related to MGS injections. Cases had been treated with a mean of six drugs with poor response before low-tacrolimus dose was introduced. Patients who had received MGS injections with immediate adverse effects or drug responsiveness were excluded. Patients underwent clinical management and follow-up. Results Average latency period to onset of symptoms was 65 months (range: 6–144 months). Large, tender, inflammatory nodules; plaques; angioedema; and severe panniculitis were commonly seen. An average of 18 months after tacrolimus administration, five patients were experiencing mild, sparse bouts of inflammatory processes, including nodules, plaques, angioedema, and panniculitis. that were rapidly reversible, and two were in remission. No side effects related to tacrolimus had appeared. Conclusion Tacrolimus is an effective and well-tolerated drug in cases of severe and refractory late-onset inflammatory reactions, including large panniculitis, that complicate silicone gel injections.