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The short and long-term outcomes of children with anti-Ro/La-related congenital heart block treated with a combined maternal-neonatal therapy protocol were compared with those of controls treated with other therapies.Sixteen mothers were treated during pregnancy with a therapy consisting of daily oral fluorinated steroids, weekly plasma exchange and fortnightly intravenous immunoglobulins and their neonates with intravenous immunoglobulins (study group); 19 mothers were treated with fluorinated steroids alone or associated to intravenous immunoglobulins or plasma exchange (control group).The combined-therapy children showed a significantly lower progression rate from 2nd to 3rd degree block at birth, a significant increase in heart rate at birth and a significantly lower number of pacemaker implants during post-natal follow-up with respect to those treated with the other therapies.The combined therapy produced better short and long term outcomes with respect to the other therapies studied.

ObjectivesPatients with APS and triple-positive for aPL are at high risk of recurrent events. As COVID-19 and COVID-19 vaccination may induce thrombotic complications, the objective of the study was to assess the course of COVID-19 and adverse events after vaccination in these patients.MethodsThis is a nationwide multicentre survey conducted in nine APS referral centres by means of a questionnaire. Included patients are thrombotic APS with triple-positive aPL confirmed 12 weeks apart. Reference specialist physicians used a four-graded scale of severity for COVID-19 [from 0 (asymptomatic) to 3 (hospitalization in intensive care unit)] and a six-graded scale for adverse reactions to vaccination [from 0 (transient local injection site sign/symptoms) to 5 (potentially life-threatening reactions)]. Outcomes were considered within a 30-day period.ResultsOut of 161 patients interviewed, 18 (11%) had COVID-19. All of them fully recovered without any progression to severe disease nor thromboembolic event. A total of 146 patients received the first (92%) and 129 (80%) the second dose of vaccine; side effects were minimal and, in most cases (83% after the first and 68% after the second vaccination) limited to a sore arm. Fifteen patients (9%) were unvaccinated. Most of them raised doubts on the need for vaccination, complained of poor safety and in general were reluctant about COVID-19 vaccination.ConclusionPatients with triple-positive thrombotic APS did not suffer from severe COVID-19 outcomes. Importantly, COVID-19 vaccination was well tolerated. These data may reassure patients and physicians and contribute to reducing hesitancy in unvaccinated patients.

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.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract including Crohn's disease and ulcerative colitis, which may result in several extraintestinal complications (∼20–30% of cases), such as increased risk of venous thromboembolism (VTE). The main pathophysiological mechanism of VTE is an inflammation-induced hypercoagulable state, and recent data have shown that endothelial dysregulation due to gut and systemic inflammation may also lead to a prothrombotic state. Several prothrombotic alterations have been described, such as the activation of the coagulation system, platelet abnormalities, and dysregulation of fibrinolysis. Furthermore, the dysregulation of the gut microbiome seems to play a vital role in increasing systemic inflammation and thus inducing a procoagulant state. Our review aims to examine the main correlations between IBD and VTE, the underlying pathophysiology, and current therapeutic options.

High plasma C5a and C5b-9 levels are considered a clear sign of complement activation. We aimed to evaluate the clinical significance of these two complement activation products during quiescent phases of thrombotic antiphospholipid syndrome (APS) by comparing their plasma levels in the different clinical subsets and relating them to the clinical characteristics and antiphospholipid antibody profile of the patients.The three patient subsets studied were: i) thrombotic patients responsive to anti-vitamin K therapy (TAPS); ii) patients with refractory to vitamin K antagonists recurrent thrombosis (RAPS); iii) patients diagnosed with catastrophic APS (CAPS). Plasma C5a and C5b-9 levels were assessed using commercial ELISA assays.Sixty-two quiescent APS patients were recruited: 40 were affected by TAPS, 13 by RAPS and 9 by CAPS. Data analysis showed that the TAPS patients had significantly lower levels of both complement activation products with respect to the RAPS and CAPS patients. In addition, C5a and/or C5b-9 significantly prevailed in the patients with small-vessel thrombosis, just as C5b-9 did in the triple antiphospholipid antibody positive patients. The ROC curve showed that the best cut-offs for C5a and C5b-9 levels had a higher sensitivity, specificity and likelihood ratio in the CAPS and RAPS groups than they did in the TAPS subset.These results suggest that the persistence of high plasma C5b-9 and C5a levels during quiescent phases identifies APS patients with more severe disease who may develop rethrombosis and benefit from complement inhibition treatment during an acute disease phase.

Objective Gout treatment is largely suboptimal in clinical practice. We aimed to assess the predictors of disease-activity at 12 months in a real-life setting. Methods Consecutive patients referred to Rheumatology Units for suspected acute crystal-induced arthritis were enrolled in a multicentre-cohort study. Only patients with clinical diagnosis of gout were eligible. Disease-activity was evaluated by the Patient Acceptable Symptom State (PASS) on a visual analogue scale (VAS, 0=unsatisfactory, 100=satisfactory) at 0 (T0) and 12 months (T12), and the composite score called Gout Activity Score (GAS) calculated on the number of arthritic attacks (flare count), serum uric acid (sUA), cumulative number of tophi, VAS (T12), PtGA (T12). Multivariate linear regression model was performed to assess predictors of gout disease-activity at T12 with PASS and GAS as outcomes. Results: 201 patients had gout (diagnosis on synovial fluid in 45%, tophi in 26%, mean sUA 7.4±1.9 mg/L, 85% with urate-lowering therapy (ULT) in progress/initiated at T0); mean age 63±13 years, 88% men, median (interquartile range) disease duration 2.9 years (0.7-9.4). Follow-up visits were performed in 113 (56%) patients at T12. Mean PASS observed at T0 and at T12 were 38±27 and 74±23, respectively, whereas GAS at T12 was 10±8. A significant association was observed between the presence of tophi and PASS at T12 (-15.3, 95% CI -25.5, -5.2; p=0.003) and GAS at T12 (+4.0, 95% CI 0.6,7.4; p=0.02), adjusted for age, sex, disease duration, sUA

Mixed cryoglobulinaemic vasculitis (MCV) is an immune-complex-mediated systemic vasculitis characterised by heterogeneous clinical manifestations mainly involving lymphatic system, skin, kidney and peripheral nervous system. Although MCV patients have been included in priority programs for vaccination against SARS-CoV-2 in Italy, limited information is available for these patients. Aims of this multicentre Italian study were to investigate SARS-CoV-2 vaccination rate in MCV patients and its safety profile.All MCV patients referring to participating centres were assessed with an interview-based survey about vaccination, reasons for not getting vaccinated, adverse events (AE), and disease flares within a month after vaccination.A total of 416 patients were included in the study. Among participants, 7.7% did not get vaccinated, mainly for fear related to vaccine side-effects (50%) or medical decision (18.8%). They were more frequently treated with chronic glucocorticoids or rituximab (p=0.049 and p=0.043, respectively). Mild and self-limiting AE were recorded in 31.7% of cases, while post-vaccination vasculitis flares were observed in 5.3% of subjects. Disease relapses were mainly observed in patients with peripheral neuropathy or skin vasculitis (40% and 25%, respectively).Vaccination against SARS-CoV-2 has been performed in a high percentage of MCV patients with encouraging safety profile. Vasculitis flares rate was in line with that observed for other autoimmune diseases, despite patients with purpura or peripheral neuropathy seem to be at risk for symptoms' exacerbation. Patients' hesitancy, rituximab and glucocorticoids treatment were the main reasons for delaying vaccination.

Antiphospholipid syndrome (APS) is characterized by thrombotic events and obstetric complications in the presence of persistently positive antiphospholipid antibodies. Obstetric manifestations include, recurrent miscarriages, fetal death at or beyond the 10th week of gestation, and premature birth due to pre-eclampsia/placental insufficiency. Even now, both clinical features and laboratory parameters are controversial. Both can be used to stratify women with APS in terms of risk of adverse pregnancy outcome, and thus adjust treatment. APS pregnancies should be classified into low, medium and high-risk classes based on clinical and laboratory features. Depending on the risk class, the most appropriate therapy must be then selected. Heparin plus LDA is considered the standard of care for patients with a confirmed diagnosis of obstetric APS and generally results in over 70–80% successful pregnancies. The 20–30% pregnancies in which treatment fails are defined as “high-risk” or “refractory” pregnancies. Numerous treatments have been used in addition to standard of care, to treat these patients, but no well-designed trial has yet been conducted. New insights into the etiopathogenetic mechanisms of obstetric APS have led to the testing of new therapeutic approaches, that may soon change the way we manage this condition.

Introduction Therapeutic apheresis (TA) represents a treatment option for pre-existing conditions or diseases occurring during gestation. Although pregnancy is not a contraindication per se, due to the lack of evidence-based guidelines and presumed risk of maternal/fetal adverse events there is a general resistance to its application. Material and methods Between January 2005 and August 2017, at the Apheresis Unit of the University Hospital of Padua 936 TA procedures were performed during 57 pregnancies in 48 patients: 813 Plasma Exchange sessions, 119 Immunoadsorptions, 4 Red Blood Cell exchanges. The treated disease were as follows: antiphospholipid syndrome (18 patients), autoimmune congenital heart block (18), myasthenia gravis (3), Rh alloimmunization (2), systemic sclerosis (1), suspected autoimmune encephalitis (1), severe hypertriglyceridaemia (1), post partum hemolytic-uremic syndrome (1), sickle cell disease (1), lupus nephritis (1) and thrombotic thrombocytopenic purpura (1). Results In the time period considered the apheresis sessions applied to pregnant women were 7.1% of the total (n = 13.251). The median age at the first treatment was 33 years. The median week of gestation (WG) at the beginning of treatments was 21. Twenty (2.1%) sessions were complicated by adverse events, none requiring or prolonging hospitalization. There were 50 live births, 5 spontaneous abortions and 2 voluntary terminations of pregnancy. Median WG at delivery was 35 and caesarean section was performed in 46 cases. Conclusions Our data showed that TA in pregnancy is well tolerated. Close collaboration between clinician, obstetrician and TA specialist is crucial to ensure a good outcome of high-risk pregnancies.

Objective We aimed to assess the performance of the 2015 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) gout classification criteria in an Italian cohort of patients with crystal-induced arthritis stratified by disease duration and gender in a real-life setting. Methods Consecutive patients referred to Rheumatology Units for suspected acute crystal-induced arthritis were enrolled in a multicentre cohort study by the Italian Society of Rheumatology which was designed to improve the management of crystal-induced arthritis (ATTACk). To test the performance of the criteria (sensitivity and specificity), the presence of monosodium urate (MSU) crystals in synovial fluid (SF) was used as gold standard. Subgroup analyses by gender and disease duration were performed. Results Two hundred and seventy-seven patients were enrolled. SF analysis was available in 137 (49%) patients. Complete SF analysis and ACR/EULAR scores were obtained in 44% of patients. MSU crystals were found in 66% of patients. The sensitivity and the specificity of all criteria sets were 78% (95%CI, 67–86) and 98% (95%CI, 87–100), respectively; only clinical criteria yielded 70% (95%CI, 59–80) sensitivity and 93% (95%CI, 80-98) specificity, respectively. In early-stage disease (

Accumulating evidence suggests that complement activation is a critical contributor to catastrophic antiphospholipid syndrome (CAPS). While complement activation and C5b-9 levels have been documented in acute CAPS, Ruffati et al report that patients with a history of CAPS have higher levels of C5a and C5b-9 even in the quiescent phase, suggesting an underlying defect in complement regulation.

OBJECTIVES: We aimed to assess the performance of the 2015 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) gout classification criteria in an Italian cohort of patients with crystal-induced arthritis stratified by disease duration and gender in a real-life setting. METHODS: Consecutive patients referred to Rheumatology Units for suspected acute crystal-induced arthritis were enrolled in a multicentre cohort study by the Italian Society of Rheumatology which was designed to improve the management of crystal-induced arthritis (ATTACk). To test the performance of the criteria (sensitivity and specificity), the presence of monosodium urate (MSU) crystals in synovial fluid (SF) was used as gold standard. Subgroup analyses by gender and disease duration were performed. RESULTS: Two hundred and seventy-seven patients were enrolled. SF analysis was available in 137 (49%) patients. Complete SF analysis and ACR/EULAR scores were obtained in 44% of patients. MSU crystals were found in 66% of patients. The sensitivity and the specificity of all criteria sets were 78% (95%CI, 67–86) and 98% (95%CI, 87–100), respectively; only clinical criteria yielded 70% (95%CI, 59–80) sensitivity and 93% (95%CI, 80-98) specificity, respectively. In early-stage disease (

Background: Trial of Rivaroxaban in AntiPhospholipid Syndrome was a prospective randomized, open-label, noninferiority study conducted in 14 centers in Italy. Rivaroxaban was compared with warfarin for the prevention of thromboembolic events, major bleeding, and vascular death in high-risk, triple-positive patients with antiphospholipid syndrome. Objective: The aim of this paper is to report the events during the 2-year follow-up after the study closure. Methods: On January 28, 2018, the trial was prematurely stopped by adjudication and safety committee for an excess of events in the rivaroxaban group. Randomized patients were advised on trial results and those randomized to rivaroxaban were solicited to switch to warfarin. All 14 participating centers were asked and accepted to follow their patients for clinical events. This report describes the rate of events that occurred between January 28, 2018, and January 28, 2020. Results: Of 120 randomized patients, 115 were available for follow-up. Outcome events were two in six (33.3%) patients who remained on direct oral anticoagulants (DOACs) and six in 109 (5.7%) patients on warfarin (hazard ratio [HR] 6.9; 95% confidence interval [CI] 1.4-34.5, P=.018). The two patients on DOACs (one taking dabigatran and one taking rivaroxaban) suffered from thromboembolic events, whereas of the six patients with composite outcomes on warfarin, three had thromboembolic events (HR for thrombosis 13.3; 95% CI 2.2-79.9, P=.005). Conclusion: These data further support the use of warfarin in high-risk patients with antiphospholipid syndrome.

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.

The most efficacious strategy to manage pregnant patients with antiphospholipid syndrome (APS) refractory to conventional heparin/low-dose aspirin treatment or at high risk of adverse pregnancy outcomes has not been determined with any degree of certainty. The study set out to evaluate the efficacy and safety of the second-line treatments most frequently used in addition to conventional therapy, and the data were analyzed to identify which is/are associated to the best pregnancy outcomes.A systematic review of the literature on studies concerning second-line treatments for refractory and/or high risk pregnant APS women published between February 2006 and February 2020 was conducted. The records were retrieved by searching Medline via Pubmed, the Web of Science platform, the Cochrane library database and clinicaltrials.gov.Fourteen studies met the eligibility criteria of the review: six retrospective cohort studies, one case-control, one case-series and six case reports. The results of single treatment protocols based upon hydroxychloroquine (HCQ), low-dose steroids (LDS), intravenous immunoglobulins (IVIG), plasma exchange (PE) or pravastatin and of combination protocols based upon HCQ+LDS, IVIG+LDS, PE+LDS and PE+IVIG used during 313 pregnancies in 303 APS women were analyzed and compared. The second-line treatments produced 261/313 (83.4%) live births; severe pregnancy complications were registered in 75/313 (24%) pregnancies. Drug side-effects were observed in 3/313 (0.9%) pregnancies. Statistical analysis identified a significantly higher live birth rate and/or a significantly lower number of severe complications in the pregnancies treated with IVIG, HCQ, pravastatin, PE+IVIG and PE+LDS.Our results suggest using low-dose IVIG (2 g/Kg/month) or HCQ 400 mg/day starting before pregnancy in women with APS refractory to conventional therapy, while high-dose IVIG (2 g/Kg/month) associated with PE or alone in those with high risk±refractory APS.

Background:Giant cell arteritis (GCA) is the most frequent systemic vasculitis after the age of 50 years old. Recent interest in the processes of immune and vascular aging have been proposed as a disease risk factor. Data on the impact of age at diagnosis of GCA on the clinical course of the disease are scarceObjectives:To assess the role of age at diagnosis of GCA on the risk and time to relapseMethods:Centres participating in the Italian Society of Rheumatology Vasculitis Study Group retrospectively enrolled patients with a diagnosis of GCA until December 2019. The cohort was divided in tertiles according to age at diagnosis (≤ 72; 73-79; > 79 years old). Negative binomial regression was used to assess the relapse rate according to age groups, and Cox regression for time to first relapse.Results:Of 720 patients enrolled in 14 Italian reference centres, 711 had complete follow-up data (female 50%; mean age 75±7). Median follow-up duration was 34 months (IQR 16;70). Patients in the older group at diagnosis (> 79 years) had more frequent visual loss compared to the 73-79 and ≤ 72 age groups (31% vs 20% vs 7%; p 50 mg/L) and general symptoms were independent predictors of relapse.Conclusion:Age at diagnosis of GCA influenced the clinical presentation and risk of ischaemic complications, but did not affect the relapse rate during follow-up. LV-GCA occurred more frequently in younger patients and was an independent predictor of relapse risk, highlighting the need for a correct characterization of the clinical subtype at the early stages of disease.Disclosure of Interests:Sara Monti: None declared, Lorenzo Dagna Grant/research support from: Abbvie, BMS, Celgene, Janssen, MSD, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, SG, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Novartis, Pfizer, Roche, SG, and SOBI, Corrado Campochiaro Speakers bureau: Novartis, Pfizer, Roche, GSK, SOBI, Alessandro Tomelleri: None declared, Giovanni Zanframundo: None declared, Catherine Klersy: None declared, Francesco Muratore: None declared, Luigi Boiardi: None declared, Roberto Padoan: None declared, Mara Felicetti: None declared, Franco Schiavon: None declared, Milena Bond: None declared, Alvise Berti: None declared, Roberto Bortolotti: None declared, Carlotta Nannini: None declared, Fabrizio Cantini: None declared, Alessandro Giollo: None declared, Edoardo Conticini: None declared, angelica gattamelata: None declared, Roberta Priori: None declared, Luca Quartuccio Consultant of: Abbvie, Bristol, Speakers bureau: Abbvie, Pfizer, Elena Treppo: None declared, Giacomo Emmi: None declared, Martina Finocchi: None declared, Giulia Cassone: None declared, Ariela Hoxha Speakers bureau: Celgene, UCB, Novartis, Sanofi, Werfen, Rosario Foti Consultant of: lilly, sanofi, MSD, Janssen, Abbvie, BMS, celgene, roche, Speakers bureau: lilly, sanofi, MSD, Janssen, Abbvie, BMS, celgene, roche, Michele Colaci: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB, Carlo Salvarani: None declared, Carlomaurizio Montecucco: None declared

The aim of this study was to evaluate the effect of an oral preparation containing a naturally occurring matrix of hydrolyzed collagen type II, chondroitin sulfate (CS), and hyaluronic acid (HA), and bioactive oligopeptides of natural hydrolyzed keratin (K) in patients affected by knee OA through the evaluation of synovial fluid (SF) and clinical changes before and after treatment. Thirty patients with knee OA and swollen joint were included in the study and submitted to arthrocentesis. Patients were randomized in two groups: 1) the treatment group (N.15) took a dietary supplement containing 120 mg HA, 240 mg CS and 300 mg K once a day for 4 weeks; 2) the control group (N.15) was only submitted to arthrocentesis. Patient symptoms were evaluated at the beginning and at the end of the study by the WOMAC self-assessment questionnaire, the Lequesne algofunctional index, and the VAS forms. SF changes were evaluated by measuring local inflammatory indices, cytokines IL-1β, IL-8, IL-6, IL-10 and GM-CSF. The group of patients treated with the oral supplement showed an improvement in the clinical indices WOMAC (p

The current study evaluates the efficacy and safety of different treatment strategies for pregnant patients with antiphospholipid syndrome. One hundred twenty-seven consecutive pregnancies were assessed; 87 (68.5%) with a history of pregnancy morbidity alone were treated with prophylactic low molecular weight heparin (LMWH) + low-dose aspirin (LDA, 100 mg) (group I) and 40 (31.5%) with a history of thrombosis and/or severe pregnancy complications with therapeutic LMWH + LDA (group II). LMWH doses were increased throughout the pregnancies depending on the patients' weight gain, and treatment was switched to a more intensive one at the first sign of maternal/fetal complications. The study's primary outcome was live births. There were no significant differences in live birth rate between group I (95.4%) and group II (87.5%). Even fetal complication rate was similar in the two groups; group II nevertheless had a higher prevalence of maternal and neonatal complications (p = 0.0005 and p = 0.01, respectively) and registered a significantly lower gestational age at delivery and birth weight (p = 0.0001 and p = 0.0005, respectively). Two patients in group I switched to group II therapy, six patients in group II switched to a more intensive treatment strategy (weekly plasma exchange + fortnightly intravenous immunoglobulins in addition to therapeutic LMWH + LDA). The multivariate analysis uncovered that triple antiphospholipid antibodies positivity was an independent factor leading to a more intensive therapy. All eight switched patients achieved a live birth. Study results revealed that adjusted LMWH doses and switching therapy at first signs of severe pregnancy complications led to a high rate of live births in antiphospholipid syndrome patients.

Objective.Antibodies that recognize the phosphatidylserine/prothrombin complex (antiphosphatidylserine/prothrombin antibodies; aPS/PT) might reveal enhanced thrombotic risk in patients with systemic lupus erythematosus. Little is known about their association with pregnancy complications in the antiphospholipid syndrome (APS).Methods.We enrolled 55 patients with APS who were seeking pregnancy in 2 Italian hospitals. Antiphospholipid antibodies (aPL), including anticardiolipin antibodies, anti-β2-glycoprotein I antibodies, lupus-like anticoagulant, and aPS/PT antibodies were assessed, and the patients were prospectively followed for 24 months.Results.There were 65% (36/55) of the APS patients who had aPS/PT antibodies. Forty-seven pregnancies were followed, including 33 of aPS/PT+ patients. Forty-one of the 47 patients (87%) who initiated a pregnancy eventually gave birth to a child. The pregnancy duration and the mean newborn weight at delivery were significantly lower in aPS/PT+ than in aPS/PT− patients (33.1 ± 4.7 vs 36.2 ± 3.4 wks of gestation, respectively, and 2058 ± 964 g vs 2784 ± 746 g, respectively, p < 0.05). Late pregnancy complications, including intrauterine fetal death, preterm delivery, preeclampsia, and intrauterine growth restriction (IUGR), were more frequent in aPS/PT+ patients, independent of the therapy. Titers of aPS/PT IgG were significantly inversely correlated with the neonatal weight at delivery. Vascular injury, as reflected by thrombosis, fibrinoid necrosis, ischemic and hemorrhagic areas, and presence of chorangiomas characterized the IUGR placentas in the presence of aPS/PT.Conclusion.The aPS/PT antibodies might represent markers of aPL-related pregnancy complications, IUGR/preeclampsia in particular, and could help identify beforehand patients who may require additional treatment.

Resume Objectif Comme de nombreux rhumatismes inflammatoires affectent les patients en âge de procreer, un certain nombre de questions se posent au sujet de la securite des biotherapies pendant la grossesse. Cette etude a evalue les effets des agents anti-TNF alpha sur le devenir de la grossesse et de l’enfant. Methodes Trente-huit grossesses ont ete suivies de facon prospective de novembre 2008 a fevrier 2015. Les renseignements sur l’exposition des patients aux anti-TNFα, l’activite de la maladie, le traitement de fond, le devenir de la grossesse et de l’enfant ont ete enregistres. Resultats Vingt-quatre sur trente-huit (71,1 %) grossesses ont ete exposees aux anti-TNFα a la conception/1 er trimestre, 11/38 (28,9 %) avant la conception et 3 (11,1 %) apres exposition paternelle. Il y avait deux malformations congenitales : un enfant (4,2 %) avait une hernie diaphragmatique congenitale et un mega uretere obstructif ; la mere avait ete exposee a l’adalimumab a la conception/1 er trimestre. Tandis qu’un fœtus (9,1 %) avait une trisomie 16, la mere de 38 ans avait suspendu l’etanercept 4 semaines avant la conception. Il n’y avait aucune difference significative sur le devenir de la grossesse et de l’enfant entre les deux groupes. Il n’y avait pas non plus de difference significative sur le devenir de la grossesse et de l’enfant dans les differents groupes traites par differents antagonistes anti-TNFα. Aucune malformation congenitale ne fut constatee apres exposition paternelle. Conclusion Les resultats suggerent que les medicaments anti-TNFα peuvent etre sans danger lorsqu’ils sont administres apres exposition paternelle, autour de la conception ou au cours du premier trimestre.

Background:The most efficacious strategy to manage pregnant patients with antiphospholipid syndrome (APS) who are at high risk of adverse pregnancy outcomes ± refractory to conventional heparin/low-dose aspirin treatment is currently unknown (1, 2).Objectives:The purposes of this study were to investigate the efficacy and safety of a second-line treatment protocol administered in addition to twice daily low molecular weight heparin and low-dose aspirin to pregnant patients affected with high-risk ± refractory primary APS.Methods:Patients were included in the study if satisfying the following criteria were: 1) the presence of triple antiphospholipid antibody positivity (IgG/IgM anticardiolipin + IgG/IgM anti-β2 Glycoprotein I antibodies + lupus anticoagulant), 2) previous thrombosis and/or a history of one or more early and severe pregnancy complications. The second-line treatment protocol included weekly plasmapheresis or immunoadsorption and fortnightly 1g/kg intravenous immunoglobulins.Results:Twenty-four pregnancies occurring between 2002 and 2019 in 19 primary APS patients, (mean age 35.1 ± 3.5 SD) were monitored. Triple antiphospholipid positivity was detected in all 19 cases (100%). Seven of these women (36.8%) had a history of thrombosis, five (26.3%) one or more previous failed pregnancies associated to severe pregnancy complications and seven (36.8%) both clinical criteria. Twenty- three pregnancies (95.8%) produced live neonates (13 females and 10 males), all born between the 26th and 38th week of gestation (mean 33.6 ± 3.5 SD); birth weight percentile was 35.8 ± 24.1 SD and mean Apgar score at 5 min 8.7 ± 1.1 SD. Due to premature birth (24th week) complicated by fetal sepsis, one pregnancy (4.2%) had a negative outcome. During the treated pregnancy there were no episodes of thrombosis; there were five cases (20.8%) of severe maternal complications during pregnancy or puerperium and four of fetal complications (16.6%), all followed by complete recovery after delivery. No side-effects of the treatment were registered.Conclusion:Given the high live birth rate and the safety associated to it, the second-line treatment protocol described here could be taken into consideration when the treatment of a high-risk APS pregnancy ± refractory to conventional therapy is being evaluated.References:[1]Tektonidou MG, et al. Ann Rheum Dis 2019;0:1–9. doi:10.1136/annrheumdis-2019-215213[2]Giacomelli et al. Autoimmun Rev. 2020;102738. doi.org/10.1016/j.autrev.2020.102738Disclosure of Interests:None declared

Background:Many patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) are in their childbearing years. Concerns exist regarding the interplay between the rheumatic diseases and the pregnancy (1).Objectives:Actually, there are contradictory data regarding the pregnancy outcome in patients with RA and SpA (2). Thus, we performed this longitudinal retrospective study to evaluate the effect of RA and SpA on pregnancy outcome.Methods:The data of 78 pregnancies of 60 women followed from April 2017 to December 2020 at pregnancy clinic of Internal Medicine Unit, San Bortolo Hospital, Vicenza and Rheumatology Unit, University of Verona were reviewed. Fifty (64.1%) women were affected by RA and 28 (35.9%) by SpA. Information regarding demographic data, disease activity, drug exposure and maternal/foetal outcomes were collected in an electronic database. Details concerning pregnancy complications and congenital malformation were also collected. We compared pregnancy and foetal/neonatal outcome, medication use and disease activity between women affected by RA and SpA. Moreover, we evaluated the effect of disease activity on pregnancy outcome.Results:Overall, there were 70 (86.4%) live births, 10 (12.3%) miscarriages and 1 (1.2%) foetal death. There were three twin pregnancies. Even there was a higher rate of glucocorticoids and bDMARDs use in RA than in SpA group, respectively 40% vs 21% and 70% vs 57,1%, there were no statistical differences regarding drug exposure at conception. Moreover, there were no differences concerning disease activity at conception. Still, a higher rate of glucocorticoids and bDMARDs, respectively 26% vs 10.7% and 46% vs 39.3% were used in RA than in SpA patients during pregnancy. Furthermore, we did not find any statistical differences regarding maternal and foetal/neonatal outcome between pregnancies in the RA and those in the SpA groups. There were four (4.9%), congenital malformation, two (3.8%) in RA group and two (6.9%) in SpA group. About one-third of patients 24 (30.7%) presented a moderate disease activity at conception as evaluated by DAS28PCR and BASDAI. However, there were no significant differences, on maternal and foetal/neonatal outcome in patients with moderate activity disease with respect of those in clinical remission.Conclusion:Even a higher rate of glucocorticoids and bDMARDs were used in RA than in SpA patients, there was no differences on pregnancy outcome between them.References:[1]Ostensen M. Nat Rev Rheumatol. 2017;13:485-493. doi: 10.1038/nrrheum.2017.102.[2]Polachek et al. J Rheumatol 2020;47:161-163. doi: 10.3899/jrheum.190631.Disclosure of Interests:None declared

Background:Congenital heart block (CHB) is due to placental transfer of maternal anti-Ro/SSA autoantibodies to the fetus. The prevalence of CHB has been estimated as 1-2% in anti-Ro/SSA women while the recurrence rate is 16-19% (1). This condition is associated with a high rate of fetal/neonatal mortality and most of the cases requires pacemaker (PM) pacing. Given the rarity of CHB, limited data are available regarding the long-term follow-up of the offspring other than the cardiovascular complications.Objectives:The results of the Italian Registry of the autoimmune congenital heart block were recently described (2). A peculiarity of this cohort was that most of the mothers had an established diagnosis of systemic autoimmune disease at CHB detection, in contrast with other registries where CHB was mostly incidentally detected in healthy women. Here we report an update, with the preliminary data regarding the long-term outcome of patients with CHB, their unaffected siblings and health controls born from mothers positive for Ro/SSA.Methods:Data regarding demography, treatment, maternal, neonatal outcome, and follow-up were collected through an online electronic datasheet. A dedicated questionnaire was created with the aim to investigate general health, cardiovascular follow-up, and frequency of autoimmune diseases.Results:One-hundred and five cases of CHB in 99 patients were included from 1969 to December 2020. CHB was mostly detected in utero (97 cases, 92.3%) with 8 neonatal cases. Third degree CHB occurred in 71 cases (67.6%). Child mortality was observed in 29 (27.6%) cases: 20 in utero, 7 during neonatal period and 2 during childhood. Overall, a PM was implanted in 54 out of the 85 live births (63.5%). Then, our cohort was divided into 2 subgroups: pregnancy that occurred before (N=61) and after 2010 (N=44) with the aim to evaluate possible differences among the subgroups. Whereas mortality, PM, CHB degree were similar, CHB more frequently occurred in the last 10 years among Ro/SSA asymptomatic carriers than in the group of pregnancies before 2010 (53.6% vs 32.8%, p=0.038). Questionnaires from 14 surviving CHB cases, 8 unaffected siblings 12 controls born from mothers Ro/SSA positive were collected. Among CHB cases, 6 were males and 8 females, median age 12 years (range 6-28). All presented a third degree CHB, 10 required a neonatal PM pacing and one had an implantable ECG recorder. PM was substituted at least once in 9 patients, the oldest patient had to change it four times. No dilated cardiomyopathy occurred and most of the patients maintain an annual follow-up. Two cases of autoimmune diseases were registered among CHB cases, one idiopathic juvenile arthritis and one Cogan’s vasculitis, both born from mothers with Sjogren Syndrome. Four cases of neurodevelopmental disorders occurred: three cases of learning disabilities (one in each group) and one case of speech disorder in the sibling group. In addition, a CHB case presented a stress disorder linked to frequent hospitalizations.Conclusion:This registry is an ongoing project aiming at collecting all Italian CHB. Moreover, here we reported the preliminary data concerning the evaluation of long-term follow-up of CHB patients. Our data, even if need to be confirmed in larger cohort, seems reassuring: no differences were reported comparing CHB patients with unaffected siblings or controls.References:[1]Brito-Zéron et al. Nat Rev Rheumatol 2015;11:301-312.[2]Fredi M et al. Front Cardiovasc Med. 2019 Feb 28;6:11.Disclosure of Interests:None declared

Congenital heart block (CHB) is an autoantibody mediated disorder presumably caused by placental transmission of maternal autoantibodies to Ro/SSA 52 kd, p200, Ro/SSA 60 kd, La/SSB ribonucleoproteins. This study investigated the clinical significance of isolated anti-Ro/SSA 52 kd, anti-p200, anti-Ro/SSA 60 kd, and anti-La/SSB antibodies in positive pregnant patients. One hundred sixty-three pregnant women positive to anti-Ro/SSA 52 kd and/or anti-Ro/SSA 60 kd and/or anti-La/SSB antibodies were prospectively enrolled in the study. Anti-Ro52, anti-Ro60, anti-p200, and anti-La antibodies were assayed using home-made ELISA assays. Isolated antibody positivity was found in 25 women (15.3%), while multiple antibody positivity in 138 (84.7%). Twenty-four developed CHB, and the 139 had a favorable pregnancy outcome. The prevalence of isolated anti-Ro/SSA 60 kd antibodies was significantly higher (p

Lupus anticoagulant (LAC) is an in vitro phenomenon determining a phospholipid-dependent elongation of clotting times. The presence of LAC associated with anticardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies is strongly associated with thrombosis and pregnancy morbidity. Direct oral anticoagulants (DOACs) targeting thrombin and factor Xa are currently widely use to prevent and treat venous and arterial thromboembolism. Some concern has, however, been expressed about the possibility of false laboratory results during LAC assessment in patients taking these drugs. Several in vitro studies, spiking DOACs into normal plasma as well as ex vivo at peak levels in treated patients, led in false-positive LAC. The dilute Russell Viper Venom time is the assay that is most influenced by rivaroxaban, edoxaban, dabigatran and less by apixaban. Both screening and confirmatory tests have resulted equally prolonged for activated partial thromboplastin time and have not led to false-positive results, but this may depend on the type of reagent used for the test. Taipan/Ecarin snake venoms ratios, has been recommend by some investigators as they do not seem to be affected by rivaroxaban or edoxaban, but these tests are neither standardized nor generally available in clinical practice. In conclusion, for the time being it does not seem advisable to carry out LAC testing during anti-factor Xa and anti-factor IIa treatment because of the risk of false-positive results. Whenever needed in deciding the suspension of DOACs or in case of recurrent thrombosis, LAC determination should be carried out at trough better if DOAC concentration is known.

Resume Objectifs Evaluer la pertinence des anti-anticorps, (Ac) anti-adalimumab (ADA) et leur relation avec les caracteristiques cliniques et biologiques dans la polyarthrite rhumatoide (PR), la spondylarthrite ankylosante (SpA) et le rhumatisme psoriasique (RP). Methodes Cinquante-huit patients atteints de PR, SpA et RP ont ete inclus de facon prospective. Les caracteristiques cliniques et biologiques, l’activite de la maladie, les anticorps anti-ADA, anti-nucleaires (ANA), anti-ADN double-brin (db), anti-antigenes nucleaires solubles (anti-ENA) et anti-phospholipides (aPL) ont ete evalues a l’inclusion et apres 4, 12 et 24 semaines de traitement par l’adalimumab. Resultats Des Ac anti-ADA ont ete observes chez 11/58 (19 %) des patients. Ils ont ete detectes a partir de la quatrieme semaine de traitement chez 90,9 % des sujets positifs. Une reponse anti-ADA positive a ete associee de maniere significative a des niveaux seriques moyens d’adalimumab plus faibles (p = 0,028). L’echec du traitement a ete observe chez 20/58 (34,5 %) des patients et a ete associe de maniere significative a des Ac anti-ADA (p = 0,035). Les taux seriques moyens d’adalimumab etaient significativement plus faibles chez les patients presentant un echec de traitement que chez les repondeurs, a la fois dans l’ensemble de la cohorte (p = 0,005) et dans le groupe de patients positifs pour les anti-ADA (p = 0,006). Des evenements indesirables sont survenus plus souvent chez les patients ayant des anti-ADA que chez les patients qui n’en n’avaient pas (27,3 vs. 14,9 %). Conclusions Les Ac anti-ADA pourraient etre consideres comme un marqueur precoce d’une mauvaise reponse clinique au traitement par l’adalimumab. Le suivi des ANA/anti-ENA/aPL en routine ne s’est pas revele comme un outil utile pour predire le developpement des Ac anti-ADA.

Objective: Neonatal Lupus (NL) is a rare syndrome caused by placental transfer of maternal anti-SSA/Ro and anti-La/SSB autoantibodies to the fetus. The rarity of this condition requires the establishment of multidisciplinary registries in order to improve our knowledge.Method: Inclusion criteria in this retrospective study were the maternal confirmed positivity for anti-SSA/Ro and/or anti-SSB/La antibodies, and the presence of II or III degree congenital heart block (CHB) in utero or neonatal period (up to 27 days after birth).Result: Eighty-nine cases of CHB were observed in 85 women with 88 pregnancies that occurred between 1969 and 2017. CHB was mostly detected in utero (84 cases, 94.2%), while five cases were observed in the neonatal period. A permanent pacemaker was implanted in 51 of 73 children born alive (69.8), whereas global mortality rate was 25.8% (23 cases): 16 in utero, five perinatal, and two during childhood. By univariate analysis, factors associated with fetal death were pleural effusion (p = 0.005, OR > 100; CI 95% 2.88->100 and hydrops (p = 0.003, OR = 14.09; CI 95% 2.01–122). Fluorinated steroids (FS) were administered in 71.4% pregnancies, and its use was not associated with better survival. Some centers treated all cases with fluorinated steroids and some centers did not treat any case. CHB was initially incomplete in 24 fetuses, and of them five cases of II degree block reverted to a lower degree block after treatments. Recurrence rate in subsequent pregnancies was 17.6% (3 out of 17). A prophylactic treatment was introduced in 10 of these 16 subsequent (58.8%) pregnancies, mostly with FS or high dose intravenous immunoglobulins.Conclusion: This is the first report from the Italian Registry of neonatal lupus/CHB. The live birth rate was nearly 80%, with nearly two thirds of the children requiring the implantation of a pacemaker. The management of fetuses diagnosed with CHB was heterogeneous across Italian Centers. The registry at present is mainly rheumatological, but involvement of pediatric cardiologists and gynecologists is planned.

Objectives The aim was to determine whether assisted reproductive technologies (ARTs) confer additional risk in rheumatic patients (in terms of disease flare and fetal–maternal complications) and whether, if performed, their efficacy is affected by maternal disease. Methods Sixty infertile rheumatic women undergoing 111 ART cycles were included. Clinical pregnancy rate, live birth rate, maternal disease flares and maternal–fetal complications were recorded. Results One hundred and eleven ART cycles in 60 women were analysed. We reported 46 pregnancies (41.4%), 3 (3.1%) cases of ovarian hyperstimulation syndrome and no cases of thrombosis during stimulation, pregnancy and puerperium. One or more maternal complication was reported in 13 (30.2%) pregnancies, and fetal complications occurred in 11 fetuses (21.1%). The live birth rate was 98%, but we reported three (6%) perinatal deaths in the first days of life. During puerperium, we recorded one (2.5%) post-partum haemorrhage and one (2.5%) articular flare. Conclusion The safety and efficacy of the ARTs, demonstrated in the general population, seems to be confirmed also in rheumatic patients. No evidence was found to advise against their application, and the choice of therapy should be made depending on the patient’s risk profile, irrespective of whether the pregnancy is natural or artificial induced.

The clinical significance of IgG/IgM antiphosphatidylserine/prothrombin (aPS/PT) antibodies was prospectively evaluated in a cohort of 191 antiphospholipid antibody (aPL) carriers using commercial ELISA assays. IgG aPS/PT antibodies were detected in 40 (20.9%) and IgM aPS/PT in 102 (53.4%) of the carriers. Both IgG and IgM aPS/PT antibodies were significantly associated with triple aPL positivity (Lupus anticoagulants [LAC] plus anti-β2Glycoprotein I plus anticardiolipin antibodies) (p = 0.0000 for both). There was a significant prevalence of IgM aPS/PT in the individuals with isolated LAC positivity (p = 0.005). Fourteen of the aPL carriers (7.3%) developed a first thrombotic event. There was a significant prevalence of IgG aPS/PT antibodies but not of IgM aPS/PT in the thrombotic patients (p = 0.015). The cumulative incidence rate of thrombotic events was significantly higher in the IgG aPS/PT positive (p = 0.035) but not in the IgM aPS/PT positive carriers. Logistic regression analysis assessing the independent effect of IgG /IgM aPS/PT antibodies, triple aPL positivity, genetic/acquired thrombosis risk factors and autoimmune disorders on thrombosis development uncovered a significant association only for the risk factors (Odds Ratio = OR: 12.451, 95% Confidence Interval = CI: 2.519–61.537, p = 0.002) and for triple aPL positivity (OR: 4.725, 95% CI: 1.135–19.674, p = 0.033). Logistic regression evaluating the independent effect of IgG and IgM aPS/PT on thrombosis development uncovered a significant association only for the former (OR: 3.962, 95% CI: 1.174–13.37, p = 0.026). The risk score for thrombosis in aPL carriers could be more effective if IgG aPS/PT antibodies are added to triple aPL positivity and thrombosis risk factors.

Summary Congenital heart block (CHB) is a potentially lethal condition characterized by a third-degree atrioventricular block (AVB). Despite anti-Ro52 antibodies being detected in nearly 90% of mothers of affected children, CHB occurs in only 1–2% of anti-Ro/Sjögren's-syndrome-related antigen A (SSA) autoantibody-positive pregnancies. Maternal antibodies have been suggested to bind molecules crucial to fetal cardiac function; however, it remains unknown whether a single antibody profile associates with CHB or whether several specificities and cross-reactive targets exist. Here, we aimed to define further the reactivity profile of CHB-associated antibodies towards Ro52p200 (amino acid 200-239). We first analysed reactivity of a monoclonal anti-Ro52 antibody shown to induce AVB in rats (7.8C7) and of sera from anti-Ro52p200 antibody-positive mothers of children with CHB towards a panel of modified Ro52p200 peptides, and subsequently evaluated their potential to induce AVB in rats upon transfer during gestation. We observed that CHB maternal sera displayed a homogeneous reactivity profile targeting preferentially the C-terminal part of Ro52p200, in contrast to 7.8C7 that specifically bound the p200 N-terminal end. In particular, amino acid D233 appeared crucial to maternal antibody reactivity towards p200. Despite low to absent reactivity towards rat p200 and different binding profiles towards mutated rat peptides indicating recognition of different epitopes within Ro52p200, immunoglobulin (Ig)G purified from two mothers of children with CHB could induce AVB in rats. Our findings support the hypothesis that several fine antibody specificities and cross-targets may exist and contribute to CHB development in anti-Ro52 antibody-positive pregnancies.

Pregnant women with triple antibody positive antiphospholipid syndrome (APS) who have had thrombosis or a history of early, severe pregnancy complications are generally considered at high risk of pregnancy loss. The objectives of this study were to investigate the efficacy and safety of a relatively new treatment protocol used in addition to conventional therapy in high-risk pregnant patients affected with primary APS. The study's two inclusion criteria were: (1) the presence of triple antiphospholipid positivity, (2) previous thrombosis and/or a history of one or more early, severe pregnancy complications. Eighteen pregnancies occurring between 2002 and 2015 in 14 APS patients, (mean age 34.8±3.6 SD) were monitored. All 14 (100%) patients had triple antiphospholipid positivity. In addition, six of them (42.8%) had a history of thrombosis, four (28.6%) had one or more previous early and severe pregnancy complications, and four (30.8%) met both clinical study criteria. The study protocol included weekly plasmapheresis or immunoadsorption and fortnightly 1g/kg intravenous immunoglobulins. Seventeen of the pregnancies (94.4%) produced live neonates, all born between the 26th and 37th weeks of gestation (mean 33.1±3.5 SD). One female (5.5%), born prematurely at 24 weeks, died of sepsis a week after birth. There were two cases (11.1%) of severe pregnancy complications. No treatment side effects were registered. Given the high live birth rate and the safety associated to it, the study protocol described here could be taken into consideration by medical teams treating high-risk APS pregnant patients.

Objectives Because it has been suggested that the IgM isotype of antiphospholipid (aPL) antibodies should no longer be included in the laboratory criteria for antiphospholipid syndrome (APS) classification, we assess the clinical relevance of IgM isotype of aPL in a cohort of patients with vascular APS. Patients/methods Mean age, sex, the presence of autoimmune diseases other than systemic lupus erythematosus, risk factors for thrombosis, the type/s and site/s of thromboembolic events, the levels of C3 and C4, and autoantibody profile were evaluated in a large cohort of persistently aPL positive patients fulfilling the Sydney criteria for APS. Patients with isolated IgM isotype were compared for each variable with those with any other aPL antibody combination. Results One hundred six patients were assessed; of these 55 (51.9%) had venous thromboembolism, 48 (45.3%) arterial thrombosis, and 3 (2.8%) small vessel thrombosis. Positivity to only IgM aPL made possible to classify 13 patients (12.3%) as vascular APS. In all cases the presence of IgM aPL was at medium–high titer, confirmed, and found to be stable in the time. There were four patients with retinal thrombosis (3.8%) and the prevalence of this event was significant in the isolated IgM isotype positive patients (p = 0.005). Conclusions Data from this investigation give clinical value to the IgM isotype of aPL and suggest to consider aCL and anti-β2GPI of IgM class as valid laboratory criteria for APS classification, especially when they are associated and stable overtime.

Background:While it is generally agreed that pregnant APS patients should receive personalized treatment, evidence-based guidelines for these patients continue to be lacking.Objectives:The current study was designed as a management cohort study aiming to evaluate the efficacy and safety of different treatment strategies for pregnant APS patients in the attempt to provide some practical suggestions for attending physicians.Methods:One-hundred-twenty-seven consecutive pregnancies were assessed; 87 (68.5%) with a history of pregnancy morbidity alone were treated with prophylactic low molecular weight heparin (LMWH)+low-dose aspirin (LDA, 100 mg) [Group I] and 40 (31.5%) with a history of thrombosis and/or severe pregnancy complications with therapeutic LMWH+LDA [Group II]. LMWH doses were increased throughout the pregnancies depending on the patients’ weight gain, and treatment was switched to a more intensive one at the first sign of maternal/fetal complications. The study’s primary outcome was live births.Results:There were no significant differences in live birth rate between Group I (95.4%) and Group II (87.5%). Even, fetal complication rate was similar in the two groups; the Group II nevertheless had a higher prevalence of maternal and neonatal complications (p=0.0005 and p=0.01, respectively) and registered a significantly lower gestational age at delivery and birth weight (p=0.0001 and p=0.0005, respectively). Two patients in Group I switched to Group II therapy, six patients in Group II switched to a more intensive treatment strategy (weekly plasma exchange+ fortnightly intravenous immunoglobulins in addition to therapeutic LMWH+LDA). Comparison of the clinical and laboratory characteristics between patients who had shifted to a more intensive therapy and those who did not showed a significant prevalence of history of thrombosis ± pregnancy morbidity (p=0.02, OR 5.96, 95% CI 1.33-26.62) previous pregnancy complications (p=0.02, OR 8.32, 95% CI 1.67-41.3), triple aPL positivity (p Conclusion:Using adjusted LMWH doses and upgrading therapy at the first signs of pregnancy complications led to a high rate of live births in a relatively large group of APS patients. The study outlines the criteria for prescribing appropriate therapy for various subsets of these patients and for switching/upgrading the treatment protocol when it is no longer sufficient. Unfortunately, for the moment there are no evidence-based guidelines on the ideal additional treatment in refractory to conventional therapy APS patients. The present results will hopefully help point the direction of future clinical trials investigating the efficacy and safety of the different therapies on large numbers of APS pregnant patients in order to identify the benefits and limits of different treatment strategies administered from the beginning of pregnancy.Disclosure of Interests:Ariela Hoxha Speakers bureau: Celgene, UCB, Novartis, Sanofi, Werfen, Maria Favaro: None declared, Antonia Calligaro: None declared, Teresa Del Ross: None declared, Alessandra Teresa Ruffatti: None declared, Chiara Infantolino: None declared, Marta Tonello: None declared, Elena Mattia: None declared, Amelia Ruffatti: None declared

Background:Therapeutic apheresis (TA) represents a therapeutic option in pre-existing conditions or rheumatic diseases that occur during gestation. Although pregnancy is not a contraindication itself, due to the lack of evidence-based guidelines and the alleged risk of maternal and/or fetal adverse events, there is general resistance to its application during pregnancy.Objectives:In this observational study we aimed to evaluate the efficacy and safety of TA in high-risk pregnancies in patients with rheumatic diseases, followed over a decade in a tertiary Center.Methods:Between January 2005 and April 2019, 843 TA procedures were performed during 51 pregnancies in 43 patients: 745 plasma exchange sessions and 98 immunoabsorption sessions. TA was performed in 29 (57%) pregnancies of 21 (48.8%) patients with antiphospholipid antibody syndrome (APS), in 20 (39.2%) pregnancies of 20 (46.5%) patients with congenital heart block (CHB), in 1 (1.9%) pregnancy of 1 (2.3%) patient with systemic sclerosis (SSc) and 1 (1.9%) pregnancy of 1 (2.3%) patient affected by lupic nephritis (SLE).Results:During the period considered, apheresis sessions applied to pregnant women were 7.1% of the total (n = 13.251). The average age at the first treatment was 33 years (range 24-43). The mean management age at the first apheretic treatment was 21 weeks (range 4-32). Twelve (1.4%) apheresis sessions were complicated by adverse events, none required or prolonged hospitalization. There were 44 (86.3%) live births, 3 (5.9%) spontaneous abortions and 2 (3.9%) voluntary terminations of pregnancy, 2 (3.9%) lost to follow-up. The average gestational age at birth was 35 weeks (range 24-37) and cesarean section was performed in 41 (80.4%) cases. TA was added to conventional therapy in 24/29 (82.7%) patients with APS, to the detection of fetal cardiac activity, while in 5/26 (17.3%) it was introduced when the first signs of pregnancy complications such as mild preclampsia, HELLP and IUGR were detected. TA was started within 24 hours of atrioventricular block (AVB) detection; 10/20 (50%) mothers with CHB were diagnosed with 2nd degree AVB, 9/20 (45%) with 3rd degree AVB and one (5%) with sinus bradycardia and endocardial fibroelastosis. The patient with SSc was treated with TA twice a week from the 32nd SG until delivery, which occurred at the 36th SG, due to severe IUGR and oligohydramnios. The patient with SLE complicated by lupic nephritis was treated with TA twice a week, from the 26th SG until the birth, which took place at the 31st SG.Conclusion:Our data have shown that TA in pregnancy is well tolerated. Close collaboration between rheumatologist, obstetrician and specialist in TA is essential to ensure a successful outcome of high-risk pregnancies.Disclosure of Interests: :Anna Colpo: None declared, Piero Marson: None declared, Tiziana Tison: None declared, Alessandra Zambon: None declared, Annalisa La Rosa: None declared, Ermella Zanetti: None declared, Amelia Ruffatti: None declared, Giustina De Silvestro: None declared, Ariela Hoxha Speakers bureau: Celgene, UCB, Novartis, Sanofi, Werfen

Background Cardiac neonatal lupus is due to placental transfer of maternal anti-Ro/SSA and anti-La/SSB autoantibodies to the fetus and mainly includes congenital heart block (CHB) and dilated cardiomyopathy. The prevalence of CHB has been estimated as 1%–2% in anti-Ro/SSA women while the recurrence rate is 16%–19%(.1 This condition is associated with a high rate of fetal/neonatal mortality and in the majority of cases requires pacemaker pacing.2–6 Objectives The rarity of this condition requires the establishment of collaborative registries in order to improve our knowledge. Here we report the data of the ongoing Italian Registry of the autoimmune congenital heart block (Lu.Ne), which was created in 2016 Methods The aim was to collect retrospective and prospective pregnancies complicated with CHB in patients with antibodies. Data regarding demography, treatment, maternal and neonatal outcome and follow-up were collected through an online electronic datasheet prepared in a Research Electronic Data Capture platform. Results Eighty-six cases of CHB were collected in 82 women with 85 pregnancies that occurred between 1969–2016. CHB was mostly detected in utero (81 cases, 90.6%) with 5 neonatal CHB. Demographic description of the mothers, pregnancy outcomes and treatment are reported in table 1. Child mortality was observed in 22 (25.5%) cases: 12 fetal, 5 termination of pregnancy and 5 postnatal. Maternal and fetal risk factors for fetal mortality were analysed and, at univariate analysis, factors associated with death were an earlier detection of CHB (20.9±0.9 weeks vs 24.8±5.4 weeks; p=0.007), hydrops (p=0.002;OR=11.3;CI95%1.84–69.2) and pericardial effusion (p=0.025;OR >100;CI95%2.88->100). Conclusions The Lu.Ne registry is an ongoing project aiming at collecting all Italian CHB. Our data showed similar rate of fetal/neonatal death and of PM implantation previously reported. We confirmed that hydrops and pericardial effusion are risk factors for fetal death. A peculiarity of our cohorts is that the majority of the mothers (59%) had an established diagnosis of systemic autoimmune disease at CHB detection. This is in contrast with other registries showing that usually CHB was incidentally detected in healthy women and related to the recruiting Centres all belonging to Rheumatology Society. The collection of cases from Gynaecological and Paediatric Centres, planned in the next months, will complete our analysis References [1] Brucato, et al. Arth Rheum2001;1831–35. [2] Eliasson H, et al. Circulation2011;124:1919–26. [3] Izmirly PM, et al. Circulation2011;124:1927–35. [4] Levesque K, et al. Autoimmun Rev2015;14:1154–60. [5] Lopes LM, et al. Circulation2008;118:1268–75. [6] Van den Berg NW, et al. Int J Cardiol2016;225:167–171. Acknowledgements This project was funded by Italian Society of Rheumatology Disclosure of Interest None declared

Background There seems to be a clear correlation between antibodies against domain I (anti-DI) of β2Glycoprotein I and severe clinical profiles in antiphospholipid syndrome (APS) patients. We investigated the clinical significance of anti-DI antibodies in a cohort of aPL carriers. Methods One hundred and five carriers persistently positive for IgG anti-β2Glycoprotein 1 antibodies (a-β2GPI) and/or IgG anticardiolipin (aCL) and/or lupus anticoagulants (LAC) were tested for the presence of anti-DI antibodies using the QUANTA Flash® Beta2GPI-Domain I chemiluminescence immunoassay. Results Anti-DI antibodies were detected in 44 aPL carriers (41.9%) and they were significantly associated to triple aPL positivity (LAC plus IgG a-β2GPI plus IgG aCL antibodies). Isolated LAC and a-β2GPI antibodies were significantly associated to anti-DI negative aPL carriers. During a 82.2 month mean follow-up, ten aPL carriers (9.5%) developed a first thrombotic event so becoming APS patients. Anti-DI antibodies, triple aPL positivity, thromboembolic risk factors and autoimmune disorders significantly prevailed in carriers becoming APS. Logistic regression analysis showed that anti-DI positivity was an independent risk factor for thrombosis. Conclusions Anti-DI antibody positivity can be considered a new risk factor predictive of the first thrombotic event in aPL carriers, instead, negative anti-DI may be useful to identify low-risk aPL carriers.

The study aimed to evaluate the clinical significance of laboratory findings in patients with catastrophic antiphospholipid syndrome (CAPS) and to report the effects of a well-defined treatment protocol in 14 consecutive cases. Thirteen patients (12 presenting one and one presenting two episodes of CAPS) were consecutively treated and monitored between 1986 and 2017. Antiphospholipid antibody (aPL) characteristics of the patients were compared with those of 64 matched controls (45 antiphospholipid syndrome patients and 19 aPL carriers) who did not develop CAPS during the same mean follow-up period (12 years ± 9.9 SD). Triple aPL positivity (IgG/IgM anticardiolipin + IgG/IgM anti-β2Glycoprotein I + lupus anticoagulants) significantly prevailed in the CAPS patients with respect to the controls (p = 0.003). IgG anticardiolipin and IgG anti-β2Glycoprotein I mean antibody titers of the CAPS patients were significantly higher than those of the controls (p = 0.0018 and p = 0.003, respectively). Triple therapy (anticoagulation + plasma exchange + steroids) was administered to all the CAPS cases except for one. Beginning in 2009, intravenous immunoglobulin infusion has also been included in the triple therapy protocol (six patients). All the patients recovered from CAPS; five showed renal failure and one a I-II class New York Heart Association (NYHA) dilated cardiomyopathy. Long-term outcomes of CAPS included a gradual worsening of renal failure in one patient who required hemodialysis 30 years after the acute episode. Renal function improved in the other four patients. The patient affected with dilated cardiomyopathy worsened to a II class NYHA over a five year period. Currently all the patients are alive. A specific antiphospholipid antibody profile could be considered a risk factor associated to CAPS. Early use of a defined treatment protocol based on triple therapy either or not associated with IVIG was associated with recovery in all CAPS patients.

Background: Anti-p200 antibodies have been receiving growing interest in view of findings associating their presence to risk of fetal autoimmune congenital heart block (CHB). The study compares and evaluates the performance of two assays currently being used for their detection. Methods: One hundred and sixteen pregnant women positive for anti-SSA/Ro52 antibodies were considered as the study population. Fifty women negative for anti-SSA/Ro52 antibodies were considered as the control population. Anti-p200 antibodies were analyzed using two home-made ELISA assays: one with biotinylated antigen and the other with free antigen. Results: The specificity of the p200-free assay was significantly higher with respect to that of the p200-biotin assay (p=0.023). Both methods showed a high area under curve (AUC), thus, a good accuracy. There was a significant prevalence of anti-p200 antibodies when the p200-free assay was used to analyze the sera of the pregnant women with CHB fetuses (p=0.007). Cohen’s κ and Spearman’s ρ coefficients showed a good concordance (0.71) and a high correlation (0.93), respectively. Conclusions: The p200-free assay with respect to the biotin-based method was more specific in detecting p200 antibodies in women positive for anti-SSA/Ro52 antibodies. In addition, only the p200-free method significantly found p200 antibodies in patients with fetal CHB.