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Background The rate of antiphospholipid antibody (aPL) negativization in antiphospholipid syndrome (APS) patients is uncertain, but it is estimated to be as high as 8%. Currently, a consensus definition of aPL negativization is lacking, as well as international recommendations on how to approach treatment in patients with a persistent aPL-negative seroconversion. Aim The aim of the Delphi survey was to evaluate the clinical approach and level of consensus among experts from the APS Study Group of the Italian Society for Rheumatology (SIR-APS) in different clinical scenarios. Methods Experts of SIR-APS were contacted using a survey methodology. Results A structured survey was circulated among 30 experts. Up to 90% of the interviewed experts agreed on defining aPL negativization as the presence of two negative determinations, 1 year apart (90%). Almost full consensus exists among experts in some clinical settings, including: (1) the role of aPL negativization in the management of a thrombotic event determined by concomitant presence of cardiovascular risk factors, both modifiable and not modifiable (90%); (2) approach to young patients with triple aPL positivity who experienced pulmonary arterial thrombotic events and tested negative for aPL detection after 5 years of vitamin K antagonist (VKA) treatment (90%); (3) the use of “extra criteria” aPL antibody testing before pondering VKA suspension (93%). Conclusion A substantial agreement exists among experts on how to define aPL negativization. VKA suspension should be embraced with extreme caution, particularly in case of previous thrombotic events and/or triple aPL positivity. Nevertheless, VKA cessation might be considered when risk factors are carefully monitored/treated and the presence of “extra criteria” aPL is ruled out.

Objective: Data on the safety of anti-SARS-CoV-2 vaccines in patients with rare rheumatic diseases, such as systemic vasculitis (SV), are limited. Aim of this study was to evaluate the occurrence of a disease flare and the appearance of adverse events (AEs) following administration of anti-SARS-CoV-2 vaccine in a multicenter cohort of patients with SV. Methods: Patients with SV and healthy controls (HCs) from two different Italian rheumatology centers were asked to complete a questionnaire assessing disease flares occurrence, defined as new onset of clinical manifestations related to vasculitis needing an implementation of therapy, and local/systemic AEs appearance following anti SARS-CoV-2 vaccination.Results: 107 patients with SV (57 ANCA-associated) and 107 HCs were enrolled. A disease flare occurred in only one patient (0.93%) with microscopic polyangiitis after the first dose of an mRNA vaccine. Both after the first and the second vaccine dose administration, no significant differences in AEs between patients with SV and HCs were observed; no serious AEs were reported as well. Conclusions: This data suggest a good risk profile for anti-SARS-CoV-2 vaccine in patients with systemic vasculitis.

Objective We aimed to analyse the prevalence of non-criteria anti-phospholipid (aPL) antibodies and their role in the diagnosis, treatment and prognosis in a cohort of patients with clinical features consistent with a diagnosis of antiphospholipid syndrome (APS), but persistently negative for criteria aPL – anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2-GPI) and lupus anticoagulant (LA) – named seronegative APS (SN-APS). Methods Sera from SN-APS patients were tested for aCL by TLC-immunostaining, anti-vimentin/cardiolipin (aVim/CL) and anti-phosphatidylserine/prothrombin (anti-PS/PT) by ELISA. Control groups of our study were APS patients and healthy controls. Results We enrolled 114 consecutive SN-APS patients, 69 (60.5%) resulted positive for at least one non-criteria test in two occasions 12 weeks apart. Among the persistently positive patients to these tests, 97% resulted positive for aCL by TLC-immunostaining, 52.3% for aVim/CL and 17.4% for aPS/PT. SN-APS patients with double positivity (aCL by TLC-immunostaining and aVim/CL) showed a likelihood positive ratio of 8 to present mixed thrombotic and obstetrical features. Among SN-APS patients tested positive, after the therapeutic changes, three cases of recurrent thrombosis were observed [median follow-up 41 months (IQR 39.5)]. Twenty pregnancies were recorded in 17 SN-APS patients after the detection of unconventional aPL and 12 of them (60%) experienced a good outcome under conventional treatment for APS. Conclusions This is the largest monocentric study demonstrating that aCL tested by TLC-immunostaining and aVim/CL can detect aPL positivity in SN-APS. It may encourage clinicians to monitor and provide adequate targeted therapy, which improve SN-APS prognosis.

Objectives Antiphospholipid syndrome (APS) is a prothrombotic condition defined by recurrent thrombosis, pregnancy complications and circulating antiphospholipid antibodies (aPL), including anti-β2-glycoprotein I (β2-GPI). In clinical practice it is possible to find patients with APS persistently negative for the aPL tests according to Sydney criteria (‘seronegative APS’, SN-APS). Recently, several autoimmune responses have been described as a consequence of post-translational modifications of their target autoantigens. This study was undertaken to test carbamylated-β2-GPI (Carb-β2-GPI) as a new autoantigen of APS. Methods β2-GPI was carbamylated by potassium cyanate and used to investigate its effect on monocyte-derived dendritic cell (moDC) phenotype and function. Sera from 114 SN-APS patients, 60 APS, 20 patients with RA, 20 non-APS thrombosis and 50 healthy donors were analysed for anti-Carb-β2-GPI by ELISA. Results Carb-β2-GPI is able to activate moDCs, inducing upregulation of CD80, CD86 and CD40, activation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and nuclear factor-κB, and IL-12p70 release. Serological results showed that both 37/114 SN-APS (32.46%) and 23/60 APS (38.33%) patients resulted positive for anti-Carb-β2-GPI. Interestingly, SN-APS patients who tested positive for anti-Carb-β2-GPI showed a higher prevalence of thrombocytopenia (P = 0.04, likelihood positive ratio of 3.9). Conclusion Data obtained from both functional tests on moDCs and immunological approaches prompted identification of Carb-β2-GPI as a ‘new’ antigenic target in APS. In particular, anti-Carb-β2-GPI revealed a potential usefulness in identification of a significant proportion of SN-APS patients. Moreover, since patients who tested positive for anti-Carb-β2-GPI reported a high risk of thrombocytopenia, this test may be considered a suitable approach in the clinical evaluation of SN-APS.

Purpose Aim of the study was to investigate whether aPL positivity correlated with thrombosis in COVID-19 patients and whether it was transient or persistent. Methods We enrolled COVID-19 patients who underwent aPL tests: Lupus Anticoagulant (LA); IgM, IgG, IgA anticardiolipin antibodies (aCL); and IgM, IgG anti-β2-Glycoprotein-I antibodies (aβ2GPI). Results Twenty-eight out of 73 (38.4%) patients resulted positive for at least one aPL assay: 32.8% for IgA aCL, 6.8% for IgM aCL and 4.1% for IgM aβ2GPI. No patients tested positive for IgG aPL or LA at the first determination. Seven (9.6%) patients developed thrombotic events during hospitalization, with 4 of them resulting positive for aPL. In patients with thrombotic events during hospitalization the risk of death was increased 9-fold (LR+8.9, p=0.003). Patients with double positivity for aCL and aβ2GPI IgM had a LR+ of 6.3 to have thrombotic events (p=0.012) and a LR+ of 4.9 to have elevated D-dimer levels (p=0.027). In 10 out of 28 positive patients, aPL was detected in a second occasion at least 12-weeks apart and two patients confirmed the positivity. Conclusion Results suggest that double positivity for aCL and aβ2GPI IgM increases the risk of thrombosis in COVID-19, unlike IgA aCL positivity. APL positivity may be persistent, and it is advisable to monitor it over time.

Vaccine induced thrombotic thrombocytopenia is a new syndrome recently described in young adults within two weeks from the first dose of the ChAdOx1 nCoV-19 vaccine and characterized by cerebral venous thrombosis. We report two cases of malignant middle cerebral artery (MCA) infarct and thrombocytopenia within 10 days after vaccination with ChAdOx1 nCoV-19. Patient 1 was a 57-year-old woman who underwent decompressive craniectomy despite two successful mechanical thrombectomies. Patient 2 was a 55-year-old woman who developed a fatal bilateral malignant MCA infarct. Both the patients had pulmonary and portal vein thrombosis and high level of antibodies to platelet factor 4-polyanion complexes.

Objective The EULAR recommendations underline the use of MMF for Lupus Nephritis (LN) but also for the treatment of moderate/severe non-renal manifestations (NLN). This study aims at evaluating the 5-years drug retention rate (DRR) of MMF in a SLE cohort in a real-life scenario. Secondly, we investigated the MMF influence to control chronic damage progression. Methods We performed a longitudinal study including all the SLE patients starting MMF in our Lupus Clinic (from 2008 to 2020). The DRR was estimated using the Kaplan-Meier method. Results We evaluated 162 SLE patients (M/F 22/140). The most frequent indications for prescribing MMF were LN (101 patients, 62.3%) and musculoskeletal manifestations (39, 24.1%) followed by NPSLE (10, 6.2%) and other manifestations (12, 7.4%). We registered a median treatment duration of 30 months (IQR 55). At 60 months follow-up we observed a DRR of 61.1% for LN patients, which was similar to that registered for patients without renal involvement (60.5%). The DRR was higher in the subgroup of patients with joint involvement (75.4%, P non-significant). During the overall observation period, 92 patients (59.2%) discontinued MMF. The main cause of withdrawal was the achievement of remission, observed in 20 patients (21.7%). Moreover, MMF resulted able to control chronic damage progression, as demonstrated by the lack of significant increase in the median SDI values (baseline: 0.6, IQR 1; last: 0.93, IQR 1). Conclusions Our finding suggested that MMF is a safe and effective drug for SLE manifestations other than LN, especially for joint involvement. Moreover, it was able to control the chronic damage progression.

In this longitudinal study, we assessed the role of musculoskeletal ultrasound (US) in predicting the efficacy of JAK inhibitors (JAKi) in rheumatoid arthritis (RA) patients.We enrolled RA patients starting baricitinib or tofacitinib. All patients were evaluated at baseline and after 4, 12, 24, 48 weeks. Disease activity was calculated by Disease Activity Score 28 (DAS28CRP); US examination in 22 joints (I-V MCPs and PIPs, wrists) aimed at evaluating inflammatory features (synovial effusion and hypertrophy, power Doppler-PD), scored through a semi-quantitative scale (0-3). The total US (0-198) and PD (0-66) scores were calculated. We scanned bilateral flexor (I-V fingers of hands) and extensor compartments (1-6) tendons: tenosynovitis was scored as absent/present (0/1), resulting in a total score ranging from 0 to 22.We studied 102 patients (M/F 15/87; median age 59.2 years, IQR 17.75; median disease duration 144 months, IQR 126), 61 treated with baricitinib and 41 with tofacitinib. At baseline, the median total US score was 18 (IQR 19) and the median PD score 2 (4). We observed a significant reduction in both total and PD US scores at all time-points (p0.0001). At baseline, 75.4% of patients showed tenosynovitis involving at least one tendon, with a median score of 2 (IQR 3.5) significantly decreasing after 24 weeks (p=0.02). At multivariate analysis, PD and tenosynovitis score significantly correlated with changes in DAS28CRP.The present study confirmed the early efficacy of JAKi in RA patients by using US evaluation. Furthermore, we found that power Doppler and tenosynovitis scores could play a predictive role in response to treatment.

Objectives We evaluated a monocentric SLE cohort in order to assess the frequency of Lupus comprehensive disease control (LupusCDC), a condition defined by the achievement of remission and the absence of damage progression. Methods Our longitudinal analysis included SLE patients with 5-years follow-up and at least one visit per year. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and three different remission levels were evaluated (Complete Remission, CR; Clinical remission off-corticosteroids; clinical remission on-corticosteroids). Chronic damage was assessed according to SLICC Damage Index (SDI). LupusCDC was defined as remission achievement for at least one year plus absence of chronic damage progression in the previous one year. A machine learning based analysis was carried out, applying and comparing Nonlinear Support Vector Machines (SVM) models and Decision Trees (DT), whereas features ranking was performed with the ReliefF algorithm. Results We evaluated 172 patients [M/F 16/156, median age 49 years (IQR 16.7), median disease duration 180 months (IQR 156)]. SDI values (baseline mean±SD 0.7 ± 1.1) significantly increased during the follow-up period. In all time-points analyzed, LupusCDC including CR was the most frequently detected. The failure to reach this condition was significantly associated with renal involvement and with the intake of immunosuppressant drugs and glucocorticoid (GC). Ten patients (5.8%) have maintained LupusCDC during the whole 5-year follow-up: these patients had never presented renal involvement and showed lower prevalence of anti-phospholipid antibodies (p = 0.0001). Finally, the prevalence of GC intake was significantly lower (p = 0.0001). The application of machine learning models showed that the available features were able to provide significant information to build predictive models with an AUC score of 0.703 ± 0.02 for DT and 0.713 ± 0.02 for SVM. Conclusions Our data on a monocentric cohort suggest that the LupusCDC can efficaciously merge into one outcome SLE-related disease activity and chronic damage in order to perform an all-around evaluation of SLE patients.

Objective SLE is an autoimmune disease, mainly affecting women of childbearing age, with possible impact on pregnancy. In this study, we evaluated pregnancy outcomes in all pregnant patients affected by SLE, followed in the context of a rheumatology/gynaecology multi-disciplinary team. Methods Since 2008, we evaluated 70 consecutive pregnancies occurring in 50 SLE patients referring to the Lupus Clinic of Sapienza University of Rome; as controls we evaluated 100 consecutive pregnancies in 100 women without autoimmune diseases. Results By comparing SLE patients and controls, we did not find differences in terms of pregnancy outcomes, except for the occurrence of small for gestational age, which was significantly higher in the SLE group (22.8% vs 11%, P =0.003). Small for gestational age was associated with the positivity for anti-dsDNA, anti-Sm and anti-RNP (P =0.009, P =0.02, P =0.002, respectively). A disease flare was reported in 28 pregnancies (40%) and in 31 puerperium periods (44.3%). Flare during pregnancy was associated with anti-SSA (P =0.02), while puerperium relapse with previous MMF treatment (P =0.01) and haematological flare during pregnancy (P =0.03). Conclusion The present study confirms how pre-gestational counselling and a multi-disciplinary approach could result in positive pregnancy outcomes for SLE patients. The high percentage of disease relapse justifies even more the need for multi-disciplinary management.

Anti‐phospholipid syndrome (APS) is a systemic autoimmune disorder defined by the simultaneous presence of vascular clinical events, pregnancy morbidity and anti‐phospholipid antibodies (aPL). In clinical practice, it is possible to find patients with APS who are persistently negative for the routine aPL tests (seronegative APS; SN‐APS). Recently, the identification of aPL immunoglobulin (Ig)A and/or anti‐β2‐glycoprotein‐I (β2‐GPI) IgA was shown to represent a further test in SN‐APS patients. In this study we analyzed the presence of anti‐vimentin/cardiolipin (aVim/CL) IgA in a large cohort of patients with SN‐APS, evaluating their possible association with clinical manifestations of the syndrome. This study includes 60 consecutive SN‐APS patients, 30 patients with APS and 40 healthy donors. aVim/CL IgA were detected by enzyme‐linked immunosorbent assay (ELISA). Results show that 12 of 30 APS patients (40%) and 16 of 60 SN‐APS patients (26.7%) resulted positive for aVim/CL IgA. Interestingly, SN‐APS patients who tested positive for aVim/CL IgA showed a higher prevalence of arterial thrombosis (p = 0.017, likelihood positive ratio = 5.7). This study demonstrates for the first time, to our knowledge, the presence of aVim/CL IgA in sera of patients with APS. In particular, they revealed a potential usefulness in identification of a significant proportion of SN‐APS patients. Moreover, as patients tested positive for aVim/CL IgA reported a high likelihood ratio to have the clinical features of APS, this test may be considered a suitable approach in the clinical evaluation of SN‐APS., This study demonstrates the presence of aVim/CL IgA in patients with APS. They revealed potential usefulness in the identification of a significant proportion of ‘seronegative’ APS patients (SN‐APS). Patients tested positive for aVim/CL IgA showed a higher prevalence of arterial thrombosis, suggesting that this test may be considered a suitable approach in the evaluation of SN‐APS patients.

Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers’ pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed (p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss (p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss.

Introduction Joint involvement represents the major determinant in quality of life (QoL)in Systemic Lupus Erhytematosus (SLE) patients. However, QoLhas been generally evaluated by non-specific questionnaires. We evaluated the relationship between SLE musculoskeletal manifestations and QoL, assessed by LupusQoL. Methods Patients with joint involvement (group A) were compared with those without this feature (group B). Disease activity was assessed by SLEDAI-2k in the whole population, while DAS28 and swollen to tender ratio were applied to assess joint activity. LupusQoL was administered to all the patients. Results Group A included 110 patients [M/F 8/102; median age 49 years (IQR 13), median disease duration 156 months (IQR 216)], group B 58 [M/F 11/47; median age 40 years (IQR 15), median disease duration 84 months (IQR 108)].We found significanlty lower values in all the LupusQoL domains except for one (burden to others) in group A in comparison with group B. A significant correlation between DAS28 values and all the LupusQoL domains in group A was found; only three domains correlated with SLEDAI-2k. Conclusions SLE-related joint involvement significantly influences disease-specific QoL. DAS28 better correlated with LupusQoL domains in comparison with SLEDAI-2k, confirming the need for specific musculoskeletal activity indices.

Background Mycophenolate mofetil (MMF) is an immunosuppressive drug currently used to treat Systemic Lupus Erythematosus (SLE). In addition to clinical efficacy, MMF use is also supported by a favorable profile of tolerance, with main side effects being nausea, diarrhea, headache, and, less frequently, leucopoenia. Acne is a relatively frequent adverse reaction to MMF that requires specific treatment and drug suspension. Investigations Herein, we describe four cases of MMF-induced acne, none reporting past medical history of acne. The patients were diagnosed with SLE and lupus nephritis and treated with MMF. They developed papulo-pustular and nodular skin lesions consistent with acne. The lesions occasionally showed the appearance of macrocomedones or of unusual, nodular, oedematous lesions in gluteal region, or they had abscess-like features. Culture test demonstrated the presence of Staphylococcus Aureus. They resolved after MMF withdrawal and therapy with tetracycline and local pseudomonic-acid. Conclusions Staphylococcus Aureus skin-localized infections inducing inflammatory/infectious acne may be a relatively frequent side-effect of MMF therapy in SLE. As soon as generalized, severe infections, due to Staphylococcus Aureus, may also occur in patients treated with MMF and even if antibiotics therapy is usually relatively effective, at least temporary MMF suspension may be suggested.

Background:In Systemic Lupus Erythematosus (SLE) patients the incidence of lupus nephritis (LN) is about 40% (1). The rate of progression to end stage renal disease (ESRD) is 4.3-10.1% (2) and renal involvement is a strong predictor of morbidity and mortality.Objectives:To describe clinical, histological features and renal outcomes of LN patients included in our single-center registry reporting data from more than 30 years. Moreover, we examined the correlation between clinical features at LN diagnosis and therapeutic lines used during the course of a 24 years follow-up.Methods:A total of 71 patients were diagnosed with LN from 1989 to 2020. Demographic features and laboratory abnormalities (serum creatinine, 24 hours urine protein, urinary sediment, ds-DNA) at the time of LN diagnosis and at last available follow-up, were evaluated. We also examined renal biopsy performed and the histological classes (proliferative vs non-proliferative). We considered the increase number of therapeutic lines adopted as a negative prognostic factor in response to therapy.Mean (SD) or median (IQR) were used according the variable distribution. T-test and Chi square and Mann-Whitney were used and p-value Results:Among 71 patients with LN, 63 (88.7%) were females and 8 (11.3%) males, with a F/M ratio of 6. Median SLE duration was 180 (162) months. The median age at the onset of nephritis was 28 (19.5) years and occurred in median after 12 (60) months from SLE diagnosis.Sixty patients underwent a biopsy: the histology showed class III or IV prolipherative glomerulonephritis in 49 patients (81.6%) and a non-proliferative class in 11 (18.3%) (p< 0.0001). Median serum creatinine value, 24 hours urine protein, urinary sediment, anti-ds-DNA at LN onset are reported in Table 1. Induction therapy was performed with cyclofosfamide in 14.5% of cases, mycophenolate in 21.1%, rituximab in 1.3%, cyclosporine A in 1.9% and azathioprine in 4.6%. The lines of therapies adopted during the follow-up ranged between a minimum of 0 and a maximum of 6 lines with a median value of 1.Overall, the median follow-up was 180 (111) months and 30 (21.3%) patients had at least 120 months of follow-up. Median serum creatinine value, 24 hours urine protein, urinary sediment and eGFR last available follow-up are reported in Table 1.Three patients underwent dialysis and 3 kidney transplantation.Eight patients underwent a re-biopsy: 7 (87.5%) had a proliferative class and 1 (12.5%) had a membranous class (p=0.01). Median serum creatinine value, 24 hours urine protein, urinary sediment at re-biopsy are reported in Table 1. In re-bioptized subgroup patients, induction therapies were cyclofosfamide in 50% of cases, mycophenolate in 12.5%, cyclosporine A in 25% and azathioprine in 12.5%.There were not statistically significant differences among the age on LN onset, the time from renal onset to the onset of the disease and the number of therapeutic lines adopted (Figure 1).Conclusion:Among patients with LN the proliferative classes are the most common. At the 15-year follow-up 2,1% had renal transplantation and 2,1% dyalisis. We did not detect any association between age at diagnosis, time from renal impairment and the number of therapeutic lines.References:[1]Fanouriakis A et al. Update EULAR/ERA–EDTA recommendations for the management of lupus nephritis. Ann Rheum Dis 2019.[2]Hanly JG et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology 2016.Table 1.Laboratory features in SLE patients at LN onset, at last available follow-up and in re-bioptized patients.LN onset(n 71)AFTER 10 years long FOLLOW-UP(n 30)P valueRe-bioptized patients(n 8)Serum creatinine (mg/dl)0.81 (+/- 0.4)0.87 (+/- 0.60)0,071.05 (0.45)24 hours urine protein (mg/24 h)3000 (+/- 3707)330 (+/- 793)5068 (2392)Active urinary sediment64 patients (45,44%)2 patients (6.66%)8 patients (100%)Anti-ds-DNA +30 patientseGFR 12 patients (3.6%)Disclosure of Interests:None declared

Background:Since the beginning of the SARS-CoV-2 outbreak, antiphospholipid antibodies (aPL), a known thrombotic risk factor, have been studied in COVID-19 patients, in whom thromboembolic events have been associated with poor prognosis. To date, the pathogenetic role of aPL and the trend over time is still unknown.Objectives:Aim of the study was to investigate whether aPL positivity was correlated with thrombosis in COVID-19 patients and whether it was a transient or persistent.Methods:We included all consecutive COVID-19 patients hospitalized at Policlinico Umberto I, Sapienza University of Rome from April 1, 2020 to June 7, 2020. In these patients, serum levels of anti-cardiolipin (aCL) IgM, IgG, IgA, anti-β2glycoprotein I (aβ2GPI) IgM, IgG were measured by enzyme-linked immunosorbent assay (ELISA) and Lupus Anticoagulant (LA) was detected with coagulatory tests in patients not in treatment with anticoagulant drugs.Results:Five out of 73 (6.8%) patients resulted positive for aCL IgM, 3 of them also tested positive for aβ2GPI IgM. aCL IgA were tested positive in 14 out of 46 patients (30.4%). Overall 18 patients resulted positive for at least one test. Seven (9.6%) patients developed thrombotic events during hospitalization, 3 of them resulting positive for aPL (Table 1. below).Table 1.Clinical and demographic features of the 7 Covid-19 patients that presented thrombotic eventsFeaturesPatient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7Age - yr67788343707495SexfemalefemalefemalemalemalefemalemaleMedical HistoryMalignancy, HypertensionStrokeChronic obstructive pulmonary diseaseNo medical historyChronic obstructive pulmonary disease, HypertensionMalignancy,HypertensionInitial findingsSigns and symptomsDyspneaDyspneaDyspneaFever, ageusia/anosmia, chest painFever, coughDyspneaDyspneaHRCT chest: Bilateralground glass opacityyesyesyesyesyesyesyesBaseline laboratory valuesLymphocytecount, cells x 106/L2202102330158016806001390Lactatedehydrogenase, U/L223321199227226349199Ferritin mcg/L6143172133874622455197D-dimer mcg/L7301213291228268812981097PaO2:FIO2, mm Hg132120442534348493314Anticoagulant therapy at the time of the thrombotic eventTherapeutic dosageProphylactic dosageProphylactic dosageNot administeredTherapeutic dosageTherapeutic dosageTherapeutic dosageThrombotic eventsStrokePulmonary embolismPeripheral venous thrombosisMyocardial infarctionPulmonary embolismMyocardial infarction, peripheral arterial thrombosis, peripheral venous thrombosisPeripheral venous thrombosisAntiphospholipid antibodiesnegativeAnti-cardiolipin IgM low title, anti-β2glicoprotein I IgM low titlenegativenegativenegativeAnti-cardiolipin IgM low title, anti-β2glicoprotein I IgM low titleAnti-cardiolipin IgA low titleOutcomeExitusExitusSuicideDischargedDischargedDischargedExitusAntiphospholipid antibodies tested after at least 12 weeksNPNPNPNPNPNegativeNPWe observed that patients showing double positivity for aCL IgM and aβ2GPI IgM had a likelihood positive ratio of 6.3 for thrombotic events (p=0.012) and a likelihood positive ratio of 4.9 for increased D-dimer levels (p=0.027). aCL IgA, the most prevalent aPL in this cohort, was not associated with thrombosis. Of the 18 aPL positive patients, 5 died, 3 were lost to follow-up, and 10 were tested on a second occasion at least 12 weeks, two patients confirmed positivity without clinical signs suggestive of APS.Conclusion:These results suggest that double positivity for aCL and aβ2GPI IgM increases the risk of thrombosis in COVID-19 patients, unlike aCL IgA. APL positivity may be persistent and it is advisable to monitor it over time.Disclosure of Interests:None declared

Background:The role of complement in the antiphospholipid (aPL) related pathology has been widely studied in animal models. Antiphospholipid antibodies can induce fetal loss in experimental animals but mice deficient in specific complement components (C4, C3, C5) appear somehow protected. In addition, in pregnant mice injected with aPL, antibody deposition has been found at decidual level causing focal necrosis, apoptosis and neutrophil infiltrates and supporting aPL pathogenetic potential. On the other hand, human studies did find hypocomplementemia associated to pregnancy complications in patients with obstetric antiphospholipid syndrome (APS). These results, however, are not unanimously confirmed and, in addition, some studies only show increased levels of complement activation products (i.e. Bb) and not decreased levels of C3 and/or C4. A recently study focusing on complement level in early pregnancy and before pregnancy showed a significant correlation with pregnancy complications and loss in a large cohort of primary APS.Objectives:To investigate if the simple detection of low C3 and/or C4 could be considered a risk factor for adverse pregnancy outcome in APS and aPL carriers pregnancies.Methods:We performed a multicentric study including patients from 10 Italian and 1 Russian Centers. Data on pregnancies in women with primary APS (n=434) and asymptomatic carriers with persistently positive aPL but not fulfilling clinical criteria for APS (n=218) were retrospectively collected. Serum C3 and C4 levels were evaluated by nephelometry; hypocomplementemia was defined by local laboratory reference values. Statistical analysis was performed using GraphPad.Results:Preconceptional complement levels and gestational outcome were available for 107 (25%) pregnancies in APS out of 434 and for 196 (90%) pregnancies in aPL carriers women out of 218. In pregnancies with low preconceptional C3 and/or C4, a significantly higher prevalence of pregnancy losses was observed (p=0.019). A subgroup analysis focusing on triple aPL positive patients was also performed. Preconceptional low C3 and/or C4 levels were found to be associated with an increased rate of pregnancy loss (p = 0.027) in this subgroup also. Otherwise, adverse pregnancy outcomes in single or double aPL positive women were not related to preconception complement levels (p = 0.44) (Table 1). Of note, all the pregnancy losses in the triple positive group occurred in patients treated with low dose aspirin and low molecular weight heparin from the time of positive pregnancy test.Conclusion:Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of adverse outcome. This has been seen only in in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss. test positivity.References:[1]De Carolis S, et al. Complementemia and obstetric outcome in pregnancy with antiphospholipid syndrome. Lupus (2012) 21:776–8.[2]Kim MY, et al. Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies. Ann Rheum Dis (2018) 77:549–55.[3]Fredi M, et al. Risk Factors for Adverse Maternal and Fetal Outcomes in Women With Confirmed aPL Positivity: Results From a Multicenter Study of 283 Pregnancies. Front Immunol. 2018 May 7;9:864.Triple aPL positivitySingle or double aPL positivityGestational outcomeLow C3/C4 (n=49)Normal C3/C4(n=17)pLow C3/C4 (n=57)Normal C3/C4(n=165)pTerm live birth (>37w)15 (31%)6 (35%)ns34 (60%)110 (67%)nsPreterm live birth (≤37w)22 (45%)11 (65%)ns15 (26%)38 (23%)nsPregnancy losses (abortion and miscarriages)12 (24%)0 (0%)0.0278 (14%) 17 (10%)nsDisclosure of Interests:None declared

Background:Antimalarials have been associated with QT prolongation in COVID19 patients but are generally safe in patients with rheumatologic disease.Objectives:Aim of the study was to compare the prevalence of QTc prolongation between COVID19 and Systemic Lupus Erythematosus (SLE) patients treated with hydroxychloroquine (HCQ).Methods:We included consecutive patients with SARS-CoV-2 infection confirmed by nasopharyngeal swab and patients taking HCQ for SLE. A prolonged QTc was defined as an increase in QTc intervals >60 ms (compared with baseline) or as a QTc of ≥500 ms.Results:We enrolled 58 COVID19 patients (median age 70.5 years, IQR 25). HCQ, without or with azithromycin, was given to 26 (44.8%) and 15 patients (25.9%), respectively; 17 (29.3%) had not received either drug. The median baseline QTc was 432 (IQR 36) and prolonged QTc was observed in 15 (26%) patients (12 QTc≥500 ms and 3 patients ΔQTc>60 ms). We didn’t find significant differences in QTc prolongation among the three treatment groups. Baseline QTc (OR 111.5) and D-dimer (OR 78.3) were independently associated to QTc prolongation.Compared to the 50 SLE patients (median age of 38.5 years, IQR 22), chronically treated with HCQ, patients with COVID19 showed significantly longer QTc (p < 0.001) (Table 1).Conclusion:This is the first study demonstrating that, differently from COVID19 patients, patients with SLE are not susceptible to HCQ-induced long QT syndrome and arrhythmia. The combined arrhythmogenic effect of SARS-CoV-2 infection and HCQ could account for the excess of QTc prolongation and fatal arrhythmias described in patients with COVID19.Table 1.Difference in clinical and demographic features between Systemic Lupus Erythematosus and COVID19 patients.Demographic FeaturesSLE patientsCovid-19 patientsp-ValueN°5058Female4323< 0.001Age (years)45 (17)70.5 (25)< 0.001Comorbidities N %Hypertension15 (30)24 (48)0.2Cardiovascular diseses8 (16)13 (22.4)0.4COPD1 (2)9 (15.5)0.016Thyroid disease8 (16)8 (13.8)0.75Chronic kidney disease4 (8)5 (8.6)0.91Population characteristics Median (IQR)HCQ (mg/die)400 (125)400< 0.001HCQ Time (days)3255 (5790)7< 0.001QTc (ms)SLEDAI-2KSDI432 (36.25)0 (4)0395 (80)--< 0.001--Disclosure of Interests:None declared

Pregnancy problems are common in patients with rheumatic disease; indeed, autoimmune disorders and autoantibodies can affect pregnancy progress and lead to maternal complications. Recent studies have highlighted a close association between HMGB1, chronic inflammation, and autoimmune diseases. Thus, in this investigation, we analyzed serum levels of HMGB1, an alarmin which plays a pivotal role in inducing and enhancing immune cell function. Sera from 30 patients with antiphospholipid syndrome (11 primary and 19 secondary APS), 35 subjects with pregnancy morbidity, and 30 healthy women were analysed for HMGB1 and its putative receptor RAGE (sRAGE) by Western blot and for TNF-α by ELISA. Results revealed that APS patients showed significantly increased serum levels of HMGB1, sRAGE, and the proinflammatory cytokine TNF-α, as compared to healthy women. However, also, the pregnancy morbidity subjects showed significantly increased levels of HMGB1 and sRAGE as well as TNF-α compared to healthy women. Our findings suggest that in subjects with pregnancy morbidity, including obstetric APS, elevated levels of HMGB1/sRAGE may represent an alarm signal, indicating an increase of proinflammatory triggers. Further studies are needed to evaluate the role of HMGB1/sRAGE as a possible tool to evaluate the risk stratification of adverse pregnancy outcomes.

Background:Joint involvement is one of the most common features observed in Systemic Lupus Erythematosus (SLE), potentially involving up to 90% of patients [1]. Several patients’ reported outcomes (PROs) have been employed to measure Quality of life (QoL) in SLE patients, but frequently not specifically developed for SLE patients. More recently, the LupusQoL has been validated, a disease specific questionnaire[2,3].Objectives:We focused at assessing the relationship between musculoskeletal manifestations and QoL in a large SLE cohort, by using the LupusQoL.Methods:SLE patients with a clinical history of joint involvement (arthralgia/arthritis – group A) were enrolled in the present study. SLE diagnosis was performed according to the revised 1997 ACR criteria. As a control group, we enrolled SLE patients without history of joint involvement (group B).Disease activity was assessed by the SLE Disease Activity Index-2000 (SLEDAI-2k). The activity of joint involvement was assessed by using the disease activity score on 28 joints (DAS28ESR). The LupusQoL was administered to the enrolled patients (Group A and Group B). It consists of 34 items referring to eight domains: physical health (PH), pain (P), planning (PL), intimate relationships (IR), burden to others (BO), emotional health (EH), body image (BI) and fatigue (F).Results:Group A included 110 patients [M/F 8/102; median age 49 years (IQR 13), median disease duration 156 months (IQR 216)], while group B included 58 patients [M/F 11/47; median age 40 years (IQR 15), median disease duration 84 months (IQR 108)]. Group A showed a significantly lower disease duration and mean age in comparison with group B (P< 0.001 for both comparisons). As represented in figure 1, group A showed significantly lower values in all LupusQoL domains except for “burden to others” domain. Moreover, we observed an inverse correlation between DAS28ESRand all the LupusQoL domains in group A patients [PH (r=-0.5, P>0.0001), P (r=-0.5, PFigure 1.Conclusion:In the present study, by using a disease specific PRO, we found a poorer QoL in SLE patients with joint involvement in comparison with those without this manifestation. Moreover,DAS28ESRsignificantly correlated with all LupusQol domains, differently from SLEDAI-2k, suggesting the need to evaluate joint involvement with a specific activity index.References:[1]Cervera R et al. Medicine 1993[2]McElhone K. et al. Arthritis Rheum 2007.[3]Conti F et al. Lupus 2014Group (A)Group (B)pPH80,38 ± 21,4362,88 ± 23.28< 0.0001P82,36 ± 25.0862,30± 26.02< 0.0001PL83,04 ± 27.8270,58± 29.450.001IR84,49± 25.9965,36± 36.330.0005BO69,58 ± 28.4663,45± 28.950.129EH71,98 ± 24.6964,69± 23.050.0169F73,69 ± 24.2959,78±26.060.0004B78,14 ± 24.6156,28±30.14Disclosure of Interests:Francesco Natalucci: None declared, Fulvia Ceccarelli: None declared, enrica cipriano: None declared, Giulio Olivieri: None declared, Carlo Perricone: None declared, Francesca Romana Spinelli Grant/research support from: Pfizer, Consultant of: Novartis, Gilead, Lilly, Sanofi, Celgene, Speakers bureau: Lilly, Simona Truglia: None declared, Francesca Miranda: None declared, cristiano alessandri Grant/research support from: Pfizer, fabrizio conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi, Guido Valesini: None declared

Background: Lupus nephritis (LN) occurs up to 50% of patients affected by Systemic Lupus Erythematosus (SLE) representing one of the major causes of morbidity and mortality in lupus population (1). Kidney biopsy is a fundamental tool for the diagnosis and management of lupus nephritis. The presence of pathological changes such as inflammatory infiltrate in glomeruli and/or in tubulo-interstitium are relevant in terms of prognosis and response to therapy (2). Objectives: The aim of the study was to correlate the clinical and laboratory findings and the response to therapy with presence of glomerular and/or interstitial infiltrate in kidney section of patients with a biopsy-proven LN. Methods: Kidney sections of patients with SLE undergoing a renal biopsy for diagnostically purpose were studied; samples were classified according to the 2004 International Society of Nephrology/Renal Pathology Society classification criteria (3). Clinical, laboratory and histological data were collected in a standardized, computerized and electronically filled form, including demographics, past medical history, autoantibody profile, previous and concomitant treatments. We assessed the disease activity by using SLEDAI-2K and remission in response to therapy was defined as the absence of renal impairment and as a score 0 of renal SLEDAI (proteinuria Results: We evaluated 53 kidney samples from patients with LN (F:M = 51:2, mean age at biopsy 35±7.7 years; mean disease duration at date of biopsy 8±8.3 years). Class IV (46%) was the most common class followed by class III (29%), class II (13%), class V (11.5%) and class VI (0,5%). Tubulo-interstitial infiltrate was found in 33 kidney specimens, with germinal centres (GC)-like features in 13 renal samples (Figure 1). During the follow up (6±3.8 years) the tubulo-insterstitial infiltrate, either diffuse or with GC-like feature, was negatively correlated with renal remission (P=0.03). Conclusion: Assessment and management of patients with LN are greatly facilitated by information obtained by renal biopsy. In the present study we demonstrate that the presence of tubulo-interstital infiltrate is associated with a worse outcome in response to therapy. Our data highlight the importance of tubulo-interstitium damage, scarcely considered in the current classification criteria, since it represents a key point to predict long-term prognosis. References: [1] Schwartz N, et al. Curr Opin Rheumatol. (2014) [2] Giannakakis K, et al. Clinic Rev Allerg Immunol (2011) [3] Weening JJ, et al. J Am Soc Nephrol (2004) [4] Gladman DD, et al. J Rheumatol (2002) [5] Houssiau FA, et al. Arthritis Rheum (2002) [6] Hahn BH, et al. Arthritis Care & Research (2012) Disclosure of Interests: None declared

Background The PDE4-inhibitor apremilast has been recently introduced in the treatment of Psoriatic Arthritis (PsA). It acts by down-regulating intracellular inflammatory mediators synthesis by elevating cAMP levels. Tregs, a subset of FOXP3+ CD4 T cells, play a key role in preventing immune responses and could exert their suppressive function via cAMP (1). Reduced frequencies of circulating Tregs have been observed in inflammatory disorders, nonetheless very few data are available on PsA patients. Objectives We evaluated peripheral Tregs in a cohort of PsA patients treated by apremilast. Methods Seventeen PsA patients (M/F 3/14; median age 56.0 years, IQR 20.0; median disease duration 15.0 years, IQR 11.0) with polyarticular subset treated by apremilast, were evaluated at baseline (T0) and after 6 (T1) and 12 weeks (T1). Clinimetric evaluation included DAS28, DAPSA, CDAI, and SDAI. Moreover, US assessment was performed at wrists, metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints: synovial effusion/hypertrophy and power Doppler were scored by a semi-quantitative scale (0-3), obtaining a total score (0-198). Treg frequency was assessed in peripheral blood mononuclear cells by flow cytometry, as the percentage of CD127low FOXP3+ in live CD4+ T cells (%Treg). Results At baseline we identified a median%Tregs of 4.6 (IQR 1.1), inversely correlating with DAS28 (r=-0.5, p=0.02), DAPSA (r=-0.7, p=0.003), CDAI (r=-0.6, p=0.01), SDAI (r=-0.6, p=0.003 and US inflammatory score (r=-0.6, p=0.01) (Figure 1). Treatment with apremilast was able to induce a significant improvement in all activity indices at T1 (DAS28, P=0.009; DAPSA, P=0.01; CDAI, P=0.005; SDAI, P=0.006; US score, P Conclusion The results of our study demonstrate that%Treg is a marker of disease activity in PsA patients. Moreover, the baseline value of Tregs could predict the response to apremilast after 12 weeks of treatment. Reference: [1] Chavele KMet al, FEBS Lett2011. Disclosure of Interests Fulvia Ceccarelli: None declared, Ilenia Pacella: None declared, Ramona Lucchetti: None declared, Arianna Forniti: None declared, francesca spinelli: None declared, enrica cipriano: None declared, Carlo Perricone Speakers bureau: BMS; Lilly, Celgene, Sanofi, Simona Truglia: None declared, Francesca Miranda: None declared, Rossana Scrivo: None declared, cristiano alessandri: None declared, Vincenzo Barnaba: None declared, Guido Valesini: None declared, Silvia Piconese: None declared, fabrizio conti: None declared

Background The introduction of TNF inhibitors have revolutionized the outcome of patients affected by Rheumatoid Arthritis (RA). In the last years, pharmaco-economic implications determined the introduction of biosimilar as alternative to originator biological drugs. Phase I and head-to-head phase III clinical studies demonstrated pharmacokinetic equivalence and comparability in terms of efficacy, safety, immunogenicity and tolerability. However, biosimilar drugs demonstrated some differences related to charge and glycosylation, not influencing the function and the ability to bind the soluble TNF. To date, very few data are available concerning the use of biosimilar drugs in a real-life setting. Results from DANBIO registry suggested a lower retention rate in RA patients switchers from Etanercept originator (ETA) to biosimilar (SB4) versus the historic ETA cohort and higher in comparison with historic SB4 patients (1). Objectives To compare the efficacy of ETA versus SB4 in a cohort of RA patients in a real life setting. Methods In this monocentric case-control prospective study, we consecutively enrolled RA patients starting ETA or SB4 treatment from 2015. RA diagnosis was made according with ACR/EULAR 2010 criteria (2). Data were collected and entered into a standardized, computerized, electronically filled-in form. We included patient demographics, date of diagnosis, comorbidities and previous and concomitant medications. The clinical evaluation included the count of swollen and tender joints and the patient‘s and physician’s global disease assessment based on a visual analogue scale (VAS; range, 0 to 100 mm). Disease activity was measured according to the disease activity score in 28 joints (DAS28ESR) (3). The patients were asked to fill in the Health Assessment Questionnaire (HAQ). All the patients were evaluated at the beginning of treatment (T0) and after 4 (T1) and 12 months (T2). Clinical response to treatment was evaluated by using EULAR criteria (4). Results We evaluated 35 RA patients treated with SB4 (M/F 2/33; median age 63 years, IQR 21; median disease duration 108 months, IQR 138) and 40 with ETA (M/F 5/35; median age 60.5 years, IQR 20; median disease duration 102 months, IQR 141). Biologic drug was prescribed as first-line biological treatment in 71.4% of SB4 cohort and in 80.0% of ETA. At T0 no significant differences were observed among the two groups in terms of DAS28ESR [SB4 median 4.6 (IQR 1.8), ETA 4.3 (IQR 1.9), p=ns] and HAQ [SB4: median 1 (IQR 1.05), ETA median 1 (IQR 0.85), p=ns]. In both groups we observed a significant reduction of DAS28 values at T1 (BS4 p=0.01; ETA p Conclusion The results of our study confirmed in a real-life setting the efficacy of SB4 in RA patients, as demonstrated by the significant reduction of DAS28ESR values after 4 and 12 months of treatment, similarly to ETA. Nonetheless, ETA seems to be able to induce a remission status earlier than SB4. References [1] Glintborg B, et al. Ann Rheum Dis. 2018 [2] Aletaha D, et al. Arthritis Rheum. 2010 [3] Anderson JK, et al. Arthritis Care Res. 2011 [4] van Gestel AM, et al. Arthritis Rheum. 1996 Disclosure of Interests Ramona Lucchetti: None declared, Fulvia Ceccarelli: None declared, Carlo Perricone Speakers bureau: BMS; Lilly, Celgene, Sanofi, Simona Truglia: None declared, Francesca Miranda: None declared, Manuela Di Franco: None declared, Valeria Riccieri: None declared, Rossana Scrivo: None declared, Antonio Sili Scavalli: None declared, francesca spinelli: None declared, cristiano alessandri: None declared, Guido Valesini: None declared, Roberta Priori: None declared, fabrizio conti: None declared

Background Post-translational-modifications (PTMs) are implicated in the pathogenesis of autoimmune diseases, leading to the break of self-tolerance, generation of new autoantigens and production of autoantibodies. Anti-citrullinated-proteins antibodies (ACPA) play a key role in the pathogenesis of rheumatoid arthritis (RA) and many evidences showed that they are related to bone loss in RA. Osteoclasts are the primary targets of ACPA in the joint site, displaying citrullinated antigens on their surface. Carbamylation is another PTM generating the production of anti-carbamylated proteins antibodies (anti-CarP), recently proposed as a new biomarker for RA. Anti-CarP have been also studied in patients with systemic lupus erythematosus (SLE) with predominant joint involvement, showing a prevalence of 46.1%. Moreover, in SLE patients these autoantibodies have been also associated to bone erosive damage. The pathogenic mechanism of these autoantibodies is not completely clarified so far. Objectives The aim of the present study was to investigate the possible pathogenic role of anti-CarP in the induction of osteoclastogenesis. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from a buffy coat from healthy donors using a Ficoll Hypaque gradient. Cells were cultured for 14 days in α-MEM complete medium, supplemented with 25 ng/ml of macrophage-colony-stimulating-factor (MCSF) and 30 ng/ml of receptor activator of nuclear-factor-kappa-β-ligand (RANKL), for the differentiation of monocytes in osteoclasts. Simultaneously, PBMCs were co-cultured in presence of anti-carbamilated-vimentin autoantibodies (anti-Vim CarP) purified from sera of 3 patients with RA and 3 patients with SLE with a predominant joint involvement at 100 ng/ml and 1 μg/ml. As control, intravenous immunoglobulin (IVIg) were used at the same concentrations. After 14 days, osteoclast differentiation was evaluated by staining cells for tartrate-resistant acid phosphatase (TRAP), using leukocyte acid phosphatase kit. Results Anti-VimCarP purified from RA patients at 100 ng/ml were able to increase the median number of osteoclasts per well significantly more than untreated and IVIg at 100 ng/ml and 1 μg/ml (P=0.0008; P=0.0009 and P=0.0009, respectively). The same results were observed treating cells with 1 μg/ml of anti-VimCarP from RA patients (P=0.0008, P=0.002 and P=0.002, respectively). Similarly, anti-VimCarP purified from SLE patients at 100 ng/ml significantly increased the median number of osteoclasts than untreated and IVIg at 100 ng/ml and 1 μg/ml (P=0.002, P=0.004 and P=0.003, respectively). Analogously, we observed similar results co-culturing cells with 1 μg/ml of anti-VimCarP from SLE patients (P=0.002, P=0.02 and P=0.006, respectively). Conclusion For the first time, we demonstrated that anti-Vim CarP purified from RA and SLE patients are able to induce osteoclastogenesis, suggesting their potential role as a biomarker of joint erosiveness in these autoimmune diseases. Disclosure of Interests Laura Massaro: None declared, Tania Colasanti: None declared, francesca spinelli: None declared, Fulvia Ceccarelli: None declared, Riccardo Mancini: None declared, Arbi Pecani: None declared, enrica cipriano: None declared, Carlo Perricone Speakers bureau: BMS; Lilly, Celgene, Sanofi, Francesca Miranda: None declared, Simona Truglia: None declared, Francesco Natalucci: None declared, Martina Leopizzi: None declared, Valeria Di Maio: None declared, Carlo Della Rocca: None declared, cristiano alessandri: None declared, Guido Valesini: None declared, fabrizio conti: None declared

Background Women suffering from autoimmune diseases, such as Systemic Lupus Erythematosus (SLE), could develop menopause at a younger age in comparison with healthy population. In particular, a higher frequency of abnormal ovarian function has been described in SLE cohorts1-4. The presence of a cause-effect link between the disease and such modifications remains poorly understood. The role of disease activity and chronic damage, combined with the intake of some drugs, such as cyclophosphamide (CYC), has been suggested2. Objectives We evaluated the age at natural menopause and the prevalence of premature ovarian failure (POF) in a monocentric Caucasian SLE cohort. Additionally, we analyzed the possible association with the disease features. Methods We performed a cross-sectional case-control study, enrolling consecutive SLE women and reporting their clinical and laboratory data. As control group (healthy controls - HC), women without autoimmune diseases were enrolled. By using an interview, gynecological characteristics were investigated in patients and controls: in particular, we registered age at menarche, occurrence and age of menopause, history of hysterectomy. Natural menopause was defined as the absence of menses for at least 12 months in women aged ≥40 years and POF as amenorrhea of at least 12 months in women Results We enrolled 196 Caucasian women with SLE (median age 47.0 years, IQR 16.7; median disease duration 132 months, IQR 180) and 90 HC (median age 49.9 years, IQR 15.0). Ninety-four SLE patients (48.0%) and 26 HC (23.4%) referred a condition of menopause: the median age at occurrence was significantly lower in SLE than HC (47 years, IQR 8.0 versus 50.5 years, IQR 4; P=0.0001). Among the SLE patients, a natural menopause was observed in 70 subjects (74.4%), surgical in 7 (7.4%), iatrogenic in 17 (18.1%). In particular, 13 (13.8%) SLE patients referred the occurrence of menopause after CYC exposure. Excluding SLE patients with surgical menopause, we registered POF in 16 patients (17%); this prevalence was significantly higher in comparison with HC group, in which none of subjects experienced POF (P=0.0001). The comparison between SLE patients developing POF and those with natural menopause history demonstrated a significant higher prevalence of anti-Sm (31.2% versus 10.2%; P=0.0004), anti-RNP (25.0% versus 12.8%; P=0.02), anti-cardiolipin (aCL) IgG/IgM (50.0% versus 26.9%; P=0.0008) and lupus anticoagulant (37.5% versus 17.9%; P=0.002). As expected, a significant more frequent CYC treatment was identified in patients developing POF (56.0% versus 11.0%; P=0.0001). Moreover, POF subjects showed a significant more frequent history of treatment with azathioprine (62.5% versus 30.7; P=0.0001), mycophenolate mofetil (50% versus 20.5%; P=0.0001) and cyclosporine A (37.5% versus 19.2%; P=007). No significant differences were found in terms of clinical manifestations and mean SLICC/ACR damage index (SDI). Conclusion In the present study, we observed a significantly lower age at menopause in SLE patients in comparison with HC; in addition, a significantly higher frequency of POF was observed. POF was associated with a more active disease, in terms of autoantibodies prevalence and use of immunosuppressant drugs. Finally, for the first time, it was found an association between POF and antiphospholipid positivity, suggesting a possible role of these antibodies, in particular aCL, in POF development. References [1] Mayorga J, et al. Lupus 2016 [2] Malheiro, et al. Gynecol Endocrinol 2014 [3] Fatnoon NN, et al. Singapore Med J 2008 [4] Lawrenz, et al. Lupus 2011. Disclosure of Interests Valeria Orefice: None declared, Fulvia Ceccarelli: None declared, Giuseppina Perrone: None declared, Carmelo Pirone: None declared, Carlo Perricone Speakers bureau: BMS; Lilly, Celgene, Sanofi, Simona Truglia: None declared, Francesca Miranda: None declared, viviana antonella pacucci: None declared, francesca spinelli: None declared, Paola Galoppi: None declared, cristiano alessandri: None declared, Guido Valesini: None declared, fabrizio conti: None declared

Antiphospholipid Syndrome (APS) is the commonest treatable cause of recurrent miscarriage and pharmacological treatment of pregnant patients with antiphospholipid antibodies (aPL) should aim at preventing obstetric complications and maternal thrombotic events. Conventional treatment for patients with an established diagnosis of obstetric APS (OAPS), generally resulting in over 70-80% successful pregnancies. Since seropositive (SP)-APS and seronegative (SN)-APS patients had shown similar clinical profiles, patients with SN- OAPS, as well as SP-OAPS, should receive combined treatment in order to improve the pregnancy prognosis; indeed, current standard of care increased good pregnancy outcome in SN-APS, with similar effect to confirmed APS. The above data suggest that there are patients with the clinical manifestations of OAPS but persistently negative to conventional aPL that need to be identified to ensure adequate therapy and therefore a better prognosis. The clinical utility of non-criteria aPL in the diagnosis of SN-APS is still a matter of debate. In the last decade more and more studies have reported the presence of patients suffering from SN-APS in which non-conventional ("non-criteria") aPL might be present or antibodies may be detected using methodological approaches different from the traditional assays. To improve test standardization large prospective, multicenter, and multinational studies are needed. Therefore, when assessing a patient with clinical manifestations consistent with OAPS but aPL negative using the conventional available assays, the clinician should consider the possibility that the patient is affected with SN-APS.

Apremilast, PDE4 competitive inhibitor, has been recently introduced in the treatment of adult psoriatic arthritis (PsA) patients, but only preliminary data are available on imaging evaluation. Thus, we evaluated the response to apremilast in PsA patients by ultrasonographic (US) assessment.Thirty-four patients (M/F 7/27; median age 61 years, IQR 15; median disease duration 10 years, IQR 13) treated for polyarticular involvement were longitudinally evaluated. All the patients were assessed at baseline (T0), and after 6 (T1), 12 (T2), and 24 weeks (T3) by DAS28, CDAI, SDAI, and DAPSA. At the same time-points, US assessment was performed in 22 sites (wrists, MCPs, PIPs): synovial effusion/hypertrophy and power Doppler were scored with a semi-quantitative scale (0-3). A total score, corresponding to patient's inflammatory status, was obtained by their sum (0-198). We assessed also the presence of tenosynovitis of flexorWe found a significant reduction in the US inflammatory score values after 6 weeks (T0, median 15 (IQR 11.2); T1, 6 (10.0); P = 0.0002), confirmed at T2 (4.0 (4.0), P = 0.0002) and T3 (4.0 (6.0); P = 0.0003). Finally, US-detected tenosynovitis was observed in 44.1% of patients: a significant improvement in tenosynovitis score was identified at 6 weeks (T0, median 4 (IQR 4); T1, 1 (2); P 0.0001) and maintained at T2 (0 (IQR 1); P 0.0001) and T3 ((IQR 1.25); P 0.0001).Apremilast is able to induce an early and sustained improvement of ultrasonographic inflammatory status at articular and peri-articular level. Key points •Apremilast induces a significant, early, and sustained improvement of inflammatory joint status in psoriatic arthritis patients. •Ultrasonographic assessment is able to monitor articular and peri-articular response to apremilast.

Background Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. Methods Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. Results PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. Conclusions Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA. Electronic supplementary material The online version of this article (10.1186/s13075-019-1818-x) contains supplementary material, which is available to authorized users.

Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and/or venous thrombosis, pregnancy morbidity in the presence of circulating “anti-phospholipid antibodies” (aPL). One of the main target antigens of aPL is β2-glycoprotein I (β2-GPI). APS may occur as a primary syndrome or associated with Systemic Lupus Erythematosus (SLE). High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein which is secreted from different type of cells during activation and/or cell death and may act as a proinflammatory mediator through ligation to its receptors, including RAGE. There is accumulating evidence that HMGB1 contributes to the pathogenesis of inflammatory and autoimmune diseases, especially SLE. In a previous study we demonstrated increased serum levels of HMGB1 in both primary and secondary APS patients. In this work we analyzed: (i) in vitro whether anti-β2-GPI antibodies from APS patients may induce both a HMGB1 cellular relocation by activation of its putative receptor RAGE in platelets and monocytes and, (ii) ex vivo, serum levels of HMGB1/soluble RAGE (sRAGE) in APS patients and their possible correlation with clinical manifestations. Platelets and monocytes from healthy donors were incubated with affinity purified anti-β2-GPI antibodies. HMGB1 and RAGE expression were analyzed by Western Blot. Sera from 60 consecutive APS patients (primary or secondary), diagnosed according to the Sydney Classification Criteria, were enrolled. As a control, 30 matched healthy subjects were studied. Serum levels of HMGB1 and sRAGE were analyzed by Western Blot. In vitro results showed that anti-β2-GPI antibodies were able to induce RAGE activation and HMGB1 cellular relocation in both monocytes and platelets. HMGB1 and sRAGE serum levels were significantly increased in APS patients in comparison with healthy subjects (p

Background:Lupus nephritis (LN) occurs in up to 60% of patients affected by Systemic Lupus Erythematosus (SLE). The presence of inflammatory infiltrates in glomeruli and/or in tubulo-interstitium (TI) plays an important role in terms of prognosis (1). Ectopic lymphoid structures (ELSs) are clusters of organized lymphoid infiltrates forming at sites of chronic inflammation in non-lymphoid organs (2). Data on ELSs in kidneys of SLE patients are scant (3-5).Objectives:The aim of the study was to evaluate the tubule-interstitial infiltrates (TI-I) organization and to investigate the presence of ELSs.Methods:Kidney sections of SLE patients undergoing a renal biopsy for diagnostic purpose were studied; LN was diagnosed according to the 2003 International Society of Nephrology / Renal Pathology Society classification criteria. Clinical, laboratory and histological data were collected in a standardized, computerized and electronically filled form, including past medical history. The presence of lymphoid aggregates and ELS in the kidney sections were firstly evaluated by hematoxylin-eosin (HE). By using immunohistochemistry (IHC), we characterized the infiltrates by identification of T cells (CD3), B cells (CD20) and follicular dendritic cells (CD21).Results:By HE we evaluated 53 kidney samples from LN patients (F:M = 51:2, mean age at biopsy ± SD years 35±7.7; mean disease duration at date of biopsy ± SD 8±8.3 years). TI-I were found in 33 kidney specimens. By HE we identified a well-defined infiltrate pattern resembling ELS in 13 renal samples. In these samples, we confirmed the presence of organized infiltrates by IHC, with evidence of segregated T and B cells areas in most of them. In one sample, the CD21 staining was positive confirming the presence of ELS (Figure 1). Interestingly, this last patient, who failed ciclophosphamide and mycofenolate, responded to rituximab administration and is now in complete LN remission. Moreover TII was negatively correlated with renal remission after induction therapy (P=0.03) independent of the histological class and the induction treatment.Figure 1.Biopsy specimens showing tubulo-interstitial ELS by IHC (10x).Conclusion:Assessment and management of LN patients are greatly facilitated by information obtained by renal biopsy. In the present study the evaluation by HE of 53 kidney samples from patients with LN showed TI-I in 62% of the specimens and a well-defined infiltrate pattern with GC-like features in 39% of those specimens with TI-I, confirmed in IHC. The presence of TII was associated with a worse outcome in response to therapy. Our preliminary results obtained by IHC suggest that ELS could be considered as a biomarker of renal response to B-cell depleting therapy supporting the importance of TI disease.References:[1]Giannakakis K. & Faraggiana T. Histopathology of Lupus Nephritis. Clinic Rev Allerg Immunol 2011[2]Bombardieri M et al. Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. Nat Rev Rheumatol 2017[3]Chang A et al. In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol 2011[4]Shen Y et al. Association of intrarenal B-cell infiltrates with clinical outcome in lupus nephritis: a study of 192 cases. Clin Dev Immunol 2012[5]Neusser MA et al. Intrarenal production of B-cell survival factors in human lupus nephritis. Mod Pathol 2011Disclosure of Interests:viviana antonella pacucci: None declared, Francesca Romana Spinelli Grant/research support from: Pfizer, Speakers bureau: Lilly, BMS, Celgene, Konsantinos Giannakakis: None declared, Serena Colafrancesco: None declared, Simona Truglia: None declared, Fulvia Ceccarelli: None declared, Cristina Garufi: None declared, cristiano alessandri Grant/research support from: Pfizer, Fabrizio Conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi

Background:The main outcomes in SLE patients management are represented by the remission achievement and chronic damage prevention. Even though activity and damage are intimately connected, to date indices including both these outcomes are not available.Objectives:In the present study, we aimed at assessing the application of a new index, the Lupus comprehensive disease control (LupusCDC), including disease activity and chronic damage progression.Methods:We performed a longitudinal analysis, including SLE patients according to ACR 1997 criteria, followed-up in the period between January 2014 and December 2018, and with at least one visit per year. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and three different remission levels were evaluated, as reported in Table 1 (1).Table 1.Remission levels considered in the study (1).Remission levelDefinitionComplete Remission(CR)No clinical and serological activity (SLEDAI-2K=0) in corticosteroid-free and immunosuppressant-free patients (antimalarials allowed)Clinical remission off-corticosteroids(ClR-GCoff)Serological activity with clinical quiescent disease according to SLEDAI-2K in corticosteroid-free patients (stable immunosuppressive therapy and antimalarials allowed)clinical remission on-corticosteroids(ClR-GCon)Clinical quiescent disease according to SLEDAI-2K in patients on prednisone 1–5 mg/day (stable immunosuppressants and antimalarials allowed)Chronic damage was registered according to SLICC damage index (SDI). All the patients were evaluated at baseline (T0) and every 12 months (T1, T2, T3, T4). At each time-point, we calculated the prevalence of LupusCDC, defined as remission achievement plus absence of chronic damage progression in the previous one year. We calculated this outcome including separately the different remission levels.Results:According with inclusion criteria, 172 SLE patients were evaluated in the present analysis [M/F 16/156, median age 49 years (IQR 16.7), median disease duration 180 months (IQR 156)]. At first assessment, we observed a mean±SD SDI value of 0.7±1.1. In details, 56 patients (32.5%) showed damage in at least one organ/system and the presence of damage was significantly associated with age (pIn figure 1A and 1B we reported the proportion of patients achieving the different levels of remission and LupusCDC, respectively. In particular, the LupusCDC definition including CR was the most frequently detected in all time-points evaluated (T1: 18.0%; T2: 31.9%; T3: 27.9%; T4: 24.4%), with a significant difference at T2 [LupusCDC(CR)versusLupusCDC(ClR-GCoff), p=0.0002; LupusCDC(CR)versusLupusCDC(ClR-GCon) p=0.0002)], T3 [LupusCDC(CR)versusLupusCDC(ClR-GCoff), p=0.03; LupusCDC(CR)versusLupusCDC(ClR-GCon) p=0.006], T4 [LupusCDC(CR)versusLupusCDC(ClR-GCon), p=0.002]. No significant differences were found when comparing the prevalence of different remission levels and the prevalence of LupusCDC including the corresponding remission.Conclusion:In the present analysis we proposed for the first time a new index including disease activity and chronic damage, in order to evaluate the proportion of SLE patients reaching a comprehensive disease control. We found that CR is most frequently associated with the absence of damage progression.References:[1]Zen M et al. Ann Rheum Dis 2017.Disclosure of Interests:Fulvia Ceccarelli: None declared, Giulio Olivieri: None declared, Lorenzo Dominici: None declared, Alessandra Ida Celia: None declared, enrica cipriano: None declared, Cristina Garufi: None declared, Silvia Mancuso: None declared, Francesco Natalucci: None declared, Valeria Orefice: None declared, Carlo Perricone: None declared, Carmelo Pirone: None declared, viviana antonella pacucci: None declared, Francesca Morello: None declared, Simona Truglia: None declared, Francesca Miranda: None declared, Francesca Romana Spinelli Grant/research support from: Pfizer, Consultant of: Novartis, Gilead, Lilly, Sanofi, Celgene, Speakers bureau: Lilly, cristiano alessandri Grant/research support from: Pfizer, fabrizio conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi

Background:Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease, affecting prevalently women in childbearing age. Thanks to pre-gestational counseling and multi-disciplinary approach, adopted in daily clinical practice, SLE patients are experiencing even more uncomplicated pregnancies.Objectives:Here, we evaluated pregnancy outcome in a large SLE cohort, compared to a control group including pregnant women without autoimmune diseases.Methods:Pregnant SLE patients (diagnosis made according to ACR 1997 criteria) were included in the present study, conducted in the context of a joint rheumatology/gynecology multi-disciplinary team. For each patient we collected demographic information, medical history, treatments, disease activity (SLEDAI-2K) chronic damage (SLICCdamage index), clinical and laboratory data, including serum complement level and autoantibodies. Pregnancy outcomes were reported longitudinally as well as disease relapses occurring during pregnancy and puerperium. Flares were defined as new onset or worsening disease-related manifestation in any organ/system.Results:Since 2008, 70 consecutive pregnancies occurred in 50 SLE patients [(median age at diagnosis 25 years (IQR 12.2), median age at first pregnancy 33 years (IQR 7), median disease duration 72 months (IQR 120)]. As controls, we evaluated 100 consecutive pregnancies in 100 women without autoimmune diseases [(median age 31 years (IQR 9)]. Table 1 reports the obstetric, fetal and neonatal outcomes of SLE patients compared to control group. A positive outcome in terms of live born infants was experienced in 88.6% of SLE pregnancies and in 88% of control group (p=NS). There were no statistically significant differences in any of the pregnancy outcomes evaluated; however, the percentage of small for gestational ages (SGA) was significantly higher in SLE group (22.8%versus11.0% P=0.003). A statistical association was found between SGA and positivity for anti-dsDNA, anti-SSA ed anti-SSB (p=0.0001, p=0.01, p=0.04 respectively). Miscarriage was significantly associated with disease-related serologic abnormalities [anti-dsDNA (p=0.0001), low C3 (p=0.0001) and low C4 (p=0.006)] and past smokinghabitus(p=0.0001); preterm birth was associated with anti-dsDNA, anti-CL and anti-B2GPI (p=0.001, p=0.0005, p=0.01 respectively). A disease flare was reported in 28 pregnancies (40%) and in 31 puerperium (44.3%). Figure 1 reports SLE relapses divided according to organ involvement. Flare during pregnancy was associated with positivity for anti-SSA (p=0.001), anti-SSB (p=0.01) and a-CL (p=0.006), whilepuerperiumrelapses were associated with previous renal involvement (p=0.0005), flare during pregnancy (p=0.01) and chronic damage (p=0.0001).Table 1.Pregnancy outcomes in 50 SLE and 100 controls.LES(Pregnancies N=70)Controls(Pregnancies N=100)POBSTETRIC OUTCOMEPreterm birth N/%18/25.719/19NSGestational hypertension N/%5/7.13/3NSGestational diabetes N/%5/7.15/5NSPre-eclampsia N/%2/2.91/1NSFETAL OUTCOMEMiscarriages N/%8/11.412/12NSPR interval elongation N/%4/6.4––IUGR N/%3/51/1NSNEONATAL OUTCOMESGA< 10° centile N/%16/22.811/110.003Weight at birth median-I.Q.R.2850-6883250-8140.003Apgar 1’ median-I.Q.R.8-18-1NSApgar 5’ median-I.Q.R.9-110-1NSFigure 1.Disease flares during and after 70 SLE pregnancies divided according to organ involvement.Conclusion:The present study confirms the role of pre-gestational counseling and a multi-disciplinary approach in the outcome of SLE pregnancies. Moreover, the high prevalence of disease relapse even more justifies the need for a combined rheumatology/gynecology multi-disciplinary approach.Disclosure of Interests:Carmelo Pirone: None declared, Fulvia Ceccarelli: None declared, Aikaterini Selntigia: None declared, Carlo Perricone: None declared, Simona Truglia: None declared, viviana antonella pacucci: None declared, Francesca Romana Spinelli Grant/research support from: Pfizer, Speakers bureau: Lilly, BMS, Celgene, cristiano alessandri Grant/research support from: Pfizer, Guido Valesini: None declared, Giuseppina Perrone: None declared, fabrizio conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi

Background:Seronegative antiphospholipid syndrome (SN-APS) is the term proposed to describe patients with clinical signs highly suggestive of APS but persistently negative for conventional antiphospholipid antibodies (aPL) assays. Therefore, new antigenic targets or different methodological approaches have been investigated to detect aPL in SN-APS [1].Objectives:The aim of this study was to describe the clinical follow-up of a monocentric cohort of SN-APS patients.Methods:The study included all consecutive SN-APS patients examined from 2014 to 2018. In all patients other possible causes of thrombosis or obstetric morbidity were ruled out. APL were investigated through two tests: 1. anti-cardiolipin/vimentin antibodies (aCL/Vim) by enzyme-linked immunosorbent assay (ELISA) 2. anti-cardiolipin antibodies (aCL) by thin-layer chromatography (TLC)-immunostaining.Results:We enrolled 121 patients (all Caucasian except one Asian and one Hispanic women). Clinical and demographic characteristics are reported in Table 1.Table 1.Clinical and demographic characteristicsFeaturesSN-APSn= 121 (%)Male/Female14/107Mean age in years (from-to)42.58 (16-78)PAPS/SAPS78/43 (64.5/35.5)SLE28 (23.1)Others autoimmune diseases15 (12.4)Pregnancy morbidity56/107 (52.3) Spontaneous abortions49 (45.8) Normal fetus deaths22 (20.6) Premature births7 (6.54)Thrombosis72 (59.5) Arterial thrombosis36 (29.8) Venous thrombosis48 (39.7) Recurrent thrombosis28 (23.1)Thrombosis + Pregnancy morbidity8 (6.6)Non-criteria APS features45 (37.2) Livedo reticularis18 (14.9) Thrombocytopenia12 (9.9) Migraine19 (15.7) Seizures5 (4) Others11 (9)Cardiovascular risk factors50 (41.3) Hypercholesterolemia8 (6.6) Smoking22 (18.2) Hypertension22 (18.2) OC/HRT7 (5.8) Diabetes4 (3.3)Sixty-nine out 121 patients (57%) resulted positive for at least one non-conventional test in two occasions more than 12 weeks apart (Figure 1). The agreement between first and second test resulted respectively of K=0,703 e K=0,655 (Cohen’s K test). Figure 2 shows the prevalence of aCL (TLC-immunostaining) and aCL/Vim. We found a significant correlation between aCL (by TLC-immunostaining) and aCL/Vim (p= 0.027), brain MRI ischemic changes (p= 0.012) and age (p= 0.023). ACL/Vim was significantly correlated with livedo reticularis (p = 0.015).Patients with double positivity showed a higher prevalence of mixed thrombotic and obstetrical features than patients with single positivity (p < 0.001, likelihood positive ratio 8.2).Non-conventional aPL positivity better supported the diagnosis of APS and, following the therapeutic changes implemented, in a median follow up of 41 months (IQR 39.5) only 3 cases of recurrent thrombosis (2 cases of arterial thrombosis during treatment with antiaggregant therapy and one case of venous thrombosis in treatment with new oral anticoagulant therapy) were observed. During the follow-up, 35 patients with obstetric morbidity who resulted positive for the tests had 20 pregnancies; 12 of them (60%) experienced a good outcome under conventional treatment for classical APS.Conclusion:The results demonstrate that new methods – TLC-immunostaining – or new antigens - CL/Vim – allow to detect aPL in so-called “SN-APS” patients and, consequently, to prescribe the most appropriate therapy.References:[1]Conti F et al. The Mosaic of “Seronegative” Antiphospholipid Syndrome. J Immunol Res. 2014;2014:389601Disclosure of Interests:Silvia Mancuso: None declared, Simona Truglia Speakers bureau: Lilly, BMS, Serena Recalchi: None declared, Gloria Riitano: None declared, Francesca Romana Spinelli Grant/research support from: Pfizer, Speakers bureau: Lilly, BMS, Celgene, Fulvia Ceccarelli: None declared, Maurizio Sorice: None declared, cristiano alessandri Grant/research support from: Pfizer, fabrizio conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi