M.G. Lazzaroni

The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study.

In European multicenter study, we aimed to describe the real-life hydroxychloroquine use in APS patients during pregnancy and determine its benefit in refractory obstetrical APS. We analyzed the outcome of pregnancies treated by hydroxychloroquine in patients with APS or asymptomatic antiphospholipid (aPL) antibodies carriers. Thirty patients with APS with 35 pregnancies treated by hydroxychloroquine were analyzed. Comparing the outcome of pregnancies treated by the addition of hydroxychloroquine to previous pregnancies under the conventional treatment, pregnancy losses decreased from 81% to 19% (p<0.05), without differences in the associated treatments. The univariate analysis showed that the previous intrauterine deaths and higher hydroxychloroquine amount (400mg per day) were the factors associated with pregnancy outcome. Considering 14 patients with previous refractory obstetrical APS (n=5 with obstetrical and thrombotic primary APS and n=9 with purely obstetrical APS), all with previous pregnancy losses under treatment (aspirin with LMWH in 11 cases and LMWH in 3 cases), the addition of hydroxychloroquine resulted in live born babies in 11/14 (78%) cases (p<0.05). Our study shows the benefit of hydroxychloroquine addition in patients with refractory obstetrical APS and raises the need of prospective studies to confirm our preliminary study.

Systemic vasculitis and pregnancy: A multicenter study on maternal and neonatal outcome of 65 prospectively followed pregnancies

OBJECTIVE Systemic vasculitis (SV) are uncommon diseases that rarely affect women during their reproductive age; little data, mainly retrospective, is available on this topic. The aim of our study was to evaluate maternal/neonatal outcome and disease course before, during and after pregnancy. METHODS Sixty-five pregnancies in 50 women with SV were followed by a multispecialistic team in 8 institutions between 1995 and 2014. Clinical data on pregnancy, 1year before and 1year after delivery was retrospectively collected. The rate of pregnancy complications was compared to that of a General Obstetric Population (GOP) of 3939 women. RESULTS In 2 patients the diagnosis of SV was done during pregnancy; 59 out of the remaining 63 started when maternal disease was quiescent. We recorded 56 deliveries with 59 live births, 8 miscarriages and 1 fetal death. In SV, preterm, particularly early preterm (<34weeks) deliveries and cesarean sections appeared significantly more frequent than in GOP (11.3% vs 5.0%, p=0.049 and 48.2% vs 31.0%, p=0.009). Vasculitis-related complications occurred in 23 pregnancies (35.4%), with 5 severe events (7.7%) including 3 cases of transient ischemic attack (TIA). Data about the post-partum period were available for 56 pregnancies: 12 flares (21.4%) occurred, with 1 severe event (1.8%). CONCLUSION SV patients can have successful pregnancies (especially during a disease remission phase) despite an increased rate of preterm delivery. Severe flares were limited, but the occurrence of 3 TIA suggests that particular attention should be given to possible thrombotic complications in SV patients during pregnancy and puerperium.

A comprehensive review of the clinical approach to pregnancy and systemic lupus erythematosus.

Nowadays, most of the young women affected by Systemic Lupus Erythematosus (SLE) can carry out one or more pregnancies thanks to the improvement in treatment and the consequent reduction in morbidity and mortality. Pregnancy outcome in these women has also greatly improved in the last decades. A correct timing for pregnancy (tailored on disease activity and established during a preconception counselling), together with a tight monitoring during the three trimesters and the post-partum period (to timely identify and treat possible obstetric complications or maternal disease flares), as well as the concept of multidisciplinary management, are currently milestones of the management of pregnancy in SLE patients. Nevertheless, the increasing knowledge on the compatibility of drugs with pregnancy has allowed a better treatment of these patients, by choosing medications that control maternal disease activity without harming the foetus. However, particular attention and strict monitoring should be dedicated to SLE pregnant women in particular clinical settings: patients with lupus nephritis and patients with aPL positivity or Antiphospholipid syndrome, who are at higher risk for maternal and foetal complications, but also patients with anti-Ro/SSA and/or anti-La/SSB antibodies, because of the risk of neonatal lupus. A discussion on family planning, as well as counselling on contraception, should be part of the everyday-practice for physicians caring for SLE women during their reproductive age. Another issue is the possible reduction of fertility in these women, that can be due to different reasons. Consequently, the request for assisted reproduction techniques has been increasing in the last years, so that rheumatologists and gynaecologists should be prepared to counsel SLE patients also in this particular setting.

Malignancies in patients with anti-RNA polymerase III antibodies and systemic sclerosis : analysis of the EULAR Scleroderma Trials and Research cohort and possible recommendations for screening

Objective. To analyze the characteristics of anti-RNA polymerase III antibodies (anti-RNAP3)− positive patients with systemic sclerosis (SSc) in the European League Against Rheumatism Scleroderma Trials and Research group (EUSTAR) registry with a focus on the risk of cancer and the characteristics of malignancies, and the aim to provide guidelines about potential cancer screening in these patients. Methods. (1) Analysis of the EUSTAR database: 4986 patients with information on their anti-RNAP3 status were included. (2) Case-control study: additional retrospective data, including malignancy history, were queried in 13 participating EUSTAR centers; 158 anti-RNAP3+ cases were compared with 199 local anti-RNAP3− controls, matched for sex, cutaneous subset, disease duration, and age at SSc onset. (3) A Delphi exercise was performed by 82 experts to reach consensus for cancer screening in anti-RNAP3+ patients. Results. In the EUSTAR registry, anti-RNAP3 were associated in multivariable analysis with renal crisis and diffuse cutaneous involvement. In the case-control study, anti-RNAP3 were associated with gastric antral vascular ectasia, rapid progression of skin involvement, and malignancies concomitant to SSc onset (OR 7.38, 95% CI 1.61–33.8). When compared with other anti-RNAP3+ patients, those with concomitant malignancies had older age (p < 0.001) and more frequent diffuse cutaneous involvement (p = 0.008). The Delphi exercise highlighted the need for malignancy screening at the time of diagnosis for anti-RNAP3+ patients and tight followup in the following years. Conclusion. Anti-RNAP3+ patients with SSc have a high risk of concomitant malignancy. These results have implications for clinical practice and suggest regular screening for cancer in anti-RNAP3+ patients.

Refractory obstetrical antiphospholipid syndrome: Features, treatment and outcome in a European multicenter retrospective study☆

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

The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus

Objectives The objective of this study was to assess the contribution of clinically significant antiphospholipid antibodies (aPL) to organ damage in systemic lupus erythematosus (SLE). Methods Patients with disease duration of less than 10 years and at least 5 years of follow-up were identified from two SLE registries. A clinically significant antiphospholipid antibody (aPL) profile was defined as: positive lupus anticoagulant, anticardiolipin IgG/M ≥ 40 G phospholipid units (GPL)/M phospholipid units (MPL), and/or anti-β2-glycoprotein-I IgG/M ≥ 99th percentile on two or more occasions, at least 12 weeks apart. Organ damage was assessed by the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Univariate and multivariate analysis compared SLE patients with and without SDI increase during a 15-year follow-up. Results Among 262 SLE patients, 33% had a clinically significant aPL profile, which was associated with an increased risk of organ damage accrual during a 5-year follow-up in univariate analysis, and during a 15-year follow-up in the multivariate analysis adjusting for age, gender, race, disease duration at registry entry, and time. In the multivariate analysis, older age at diagnosis and male gender were also associated with SDI increase at each time point. Conclusion A clinically significant aPL profile is associated with an increased risk of organ damage accrual during a 15-year follow-up in SLE patients.

Beyond thrombosis: Anti-β2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome

Antibodies against β2 glycoprotein I (anti-β2GPI) have been identified as the main pathogenic autoantibody subset in anti-phospholipid syndrome (APS); the most relevant epitope is a cryptic and conformation-dependent structure on β2GPI domain (D) 1. Anti-β2GPI domain profiling has been investigated in thrombotic APS, leading to the identification of antibodies targeting D1 as the main subpopulation. In contrast, scarce attention has been paid to obstetric APS, hence this study aimed at characterizing the domain reactivity with regards to pregnancy morbidity (PM). To this end, 135 women with persistently positive, medium/high titre anti-β2GPI IgG, without any associated systemic autoimmune diseases and at least one previous pregnancy were included: 27 asymptomatic carriers; 53 women with obstetric APS; 20 women with thrombotic APS; and 35 women with both thrombotic and obstetric complications. Anti-D1 and anti-D4/5 antibodies were tested using a chemiluminescent immunoassay and a research ELISA assay, respectively (QUANTA Flash® β2GPI Domain 1 IgG and QUANTA Lite® β2GPI D4/5 IgG, Inova Diagnostics). Positivity for anti-D1 antibodies, but not anti-D4/5 antibodies, was differently distributed across the 4 subgroups of patients (p < 0.0001) and significantly correlated with thrombosis (χ2 = 17.28, p < 0.0001) and PM (χ2 = 4.28, p = 0.039). Patients with triple positivity for anti-phospholipid antibodies displayed higher anti-D1 titres and lower anti-D4/5 titres compared to women with one or two positive tests (p < 0.0001 and p = 0.005, respectively). Reactivity against D1 was identified as a predictor for PM (OR 2.4, 95% confidence interval [CI] 1.2-5.0, p = 0.017); in particular, anti-D1 antibodies were predictive of late PM, conveying an odds ratio of 7.3 (95% CI 2.1-25.5, p = 0.022). Positivity for anti-D1 antibodies was not associated with early pregnancy loss. Anti-D4/5 antibodies were not associated with clinical APS manifestations. As a whole, our data suggest that anti-D1 antibodies are significantly associated not only with thrombosis, but also with late PM, while positive anti-D4/5 antibodies are not predictive of thrombosis or PM.

The role of clinically significant antiphospholipid antibodies in systemic lupus erythematosus

The objective is to investigate the role of clinically significant antiphospholipid antibodies (aPL) in a cohort of systemic lupus erythematosus (SLE) patients. All SLE patients followed for at least 5 years and with available aPL profile at the beginning of the follow-up in our center were studied. Clinically significant aPL were defined as: positive lupus anticoagulant test, anti-cardiolipin and/or anti- β2Glycoprotein I IgG/IgM >99th percentile on two or more occasions at least 12 weeks apart. Patients with and without clinically significant aPL were compared by univariate (Chi square or Fishers exact test for categorical variables and Students t or Mann-Whitney test for continuous variables) and multivariate analysis (logistic regression analysis). P values <0.05 were considered significant. Among 317 SLE patients studied, 117 (37%) had a clinically significant aPL profile at baseline. Such patients showed at univariate analysis an increased prevalence of deep venous thrombosis, pulmonary embolism, cardiac valvular disease, cognitive dysfunction and antiphospholipid syndrome (APS), but a reduced prevalence of acute cutaneous lupus and anti-extractable nuclear antigens (ENA) when compared with patients without clinically significant aPL. Multivariate analysis confirmed the association between clinically significant aPL and reduced risk of acute cutaneous lupus [p=0.003, odds ratio (OR) 0.43] and ENA positivity (p<0.001, OR 0.37), with increased risk of cardiac valvular disease (p=0.024, OR 3.1) and APS (p<0.0001, OR 51.12). Triple positivity was the most frequent profile and was significantly associated to APS (p<0.0001, OR 28.43). Our study showed that one third of SLE patients had clinically significant aPL, and that this is associated with an increased risk, especially for triple positive, of APS, and to a different clinical and serological pattern of disease even in the absence of APS.

FRI0411 A Multicenter Prospective Evaluation of the Risk Profile in Pregnant Patients with Persistent Positivity for Antiphospholipid Antibodies (APL)

Background Antiphospholipd antibodies positivity (aPL) are considered as risk factors for a poor obstetric outcome. Several clinical and laboratory features have been associated with the risk of a pregnancy failure. Objectives To determine risk factors of having poor pregnancy outcome in patients (pts) with established aPL positivity with or without a diagnosis of primary antiphospholipid syndrome (APS) despite the administration of the accepted “conventional treatment” (low dose aspirin (LDA) and heparin (H)) when indicated. Methods We considered 276 pregnancies in 193 women prospectively followed in the 3 Institutions involved between 2000 and 2014. None of the pts had a concomitant systemic autoimmune disease. Data were collected from clinical charts using a common database and included the 3 assays to detect aPL. We considered as “poor pregnancy outcome” the occurrence of a pregnancy loss (early miscarriages and fetal loss), perinatal deaths, preterm deliveries before the 34 weeks and HELLP Syndrome. Results Among the 193 pts, 127 fulfilled the classification criteria for APS and 66 did not. According to their clinical history and/or the laboratory, the patients were divided in 4 groups: 87 pts with pure obstetric APS (O-PAPS, 121 pregnancies), 40 thrombotic with or without obstetric APS (T-PAPS, 66 pregnancies), 32 incomplete APS (incomplete clinical or laboratory criteria, 47 pregnancies) and 34 aPL carriers without any clinical manifestation prior to the index pregnancy (42 pregnancies). The mean age at the pregnancy onset was 32.5 years (SD 5.09), the global rate of live births was 86.9%; poor obstetrical outcome was observed in 48 pregnancies (17.4%); the outcome in the groups is detailed in table 1. In the table 2 we reported the several features that resulted, at the univariate analysis, with a significant prevalence among the pts with poor obstetric outcome regardless of the group. A thrombotic event occurred in 5 pts: 2 during pregnancies (1 O-APS and 1 aPL carrier) and 3 during puerperium, with 2 deep venous thrombosis with pulmonary embolism in 1 O-APS and 1 T-APS and 1 myocardial infarction after an early miscarriage in a T-APS. Finally 1 T-APS had a catastrophic syndrome during puerperium, and 3 pts (2 T-APS and 1 aPL carrier) had an onset or a relapse of mild-moderate thrombocytopenia (without HELLP syndrome). The combination of LDA plus H was administered in 94% of pregnancies that fulfilled the criteria for APS, while the rate was 57% for the incomplete APS and 39% for aPL carriers. Conclusions Our preliminary results show that, regardless of a high rate of use of the conventional therapy, a poor obstetrical outcome and the occurrence of several severe maternal complications were not uncommon, especially in T-PAPS and aPL carriers. Several factors (irrespectively of the diagnosis) seem to be associated with serological, clinical and acquired features. Disclosure of Interest None declared

Risk Factors for Adverse Maternal and Fetal Outcomes in Women With Confirmed aPL Positivity: Results From a Multicenter Study of 283 Pregnancies

Objective Antiphospholipid antibodies positivity (aPL) is considered as a risk factor for adverse pregnancy outcome (APO). The aim of this study was to determine the risk factors for APO in patients with confirmed aPL positivity, isolated (aPL carriers) or associated with a definite primary antiphospholipid syndrome (PAPS). Methods The clinical and laboratory features of 283 pregnancies occurring between 2000 and 2014 in 200 women were collected in three institutions. Results The rate of live birth was 87.9% and APO was observed in 50 cases (17.7%). Multivariate analysis showed that the independent variables related to APO were the concomitant diagnosis of an organ-specific autoimmune disease (p = 0.012, odds ratio (OR) 3.29, confidence interval (CI) 95% 1.29–8.38) and the presence of low complement levels during the first trimester (p = 0.02, OR 2.3, CI 95% 1.17–9.15). No statistical differences were found in APO occurrence among patients treated with low-dose aspirin (LDA) versus those treated with LDA plus heparin (LMWH), but LDA + LMWH was more frequently administered in patients with triple aPL positivity (p = 0.001, OR 3.21, CI 95% 1.48–7.11) and with PAPS (p < 0.001, OR 8.08, CI 95% 4.3–15.4). Based on clinical history, the patients were divided into four groups: obstetric, thrombotic, non-criteria antiphospholipid syndrome (clinical non-criteria), and aPL carriers. APOs were more frequent in the thrombotic group (24%). Seven patients had a thrombotic event during pregnancy or puerperium (2.4%). Conclusion Maternal and fetal complications were observed in some aPL-positive patients despite their efficient management according to the current recommendations. A higher risk of APO was observed in patients with a previous thrombosis and/or more complex autoimmune phenotype.