Maria Favaro

Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study

OBJECTIVE To assess fetal and maternal outcomes in women with systemic sclerosis (SSc). METHODS Prospectively collected data on 99 women with SSc from 25 Italian centers were analyzed retrospectively. Women with SSc were observed during 109 pregnancies (from 2000 to 2011), and outcomes were compared to those in the general obstetric population (total of 3,939 deliveries). The maternal age at conception was a mean ± SD 31.8 ± 5.3 years, and the median disease duration at conception was 60 months (range 2-193 months). RESULTS SSc patients, compared to the general obstetric population, had a significantly increased frequency of preterm deliveries (25% versus 12%) and severe preterm deliveries (<34 weeks of gestation) (10% versus 5%), intrauterine growth restriction (6% versus 1%), and babies with very-low birth weight (5% versus 1%). Results of multivariable analysis showed that corticosteroid use was associated with preterm deliveries (odds ratio [OR] 3.63, 95% confidence interval [95% CI] 1.12-11.78), whereas the use of folic acid (OR 0.30, 95% CI 0.10-0.91) and presence of anti-Scl-70 antibodies (OR 0.26, 95% CI 0.08-0.85) were protective. The disease remained stable in most SSc patients, but there were 4 cases of progression of disease within 1 year from delivery, all in anti-Scl-70 antibody-positive women, 3 of whom had a disease duration of <3 years. CONCLUSION Women with SSc can have successful pregnancies, but they have a higher-than-normal risk of preterm delivery, intrauterine growth restriction, and babies with very-low birth weight. Progression of the disease during or after pregnancy is rare, but possible. High-risk multidisciplinary management should be standard for these patients, and pregnancy should be avoided in women with severe organ damage and postponed in women with SSc of recent onset, particularly if the patient is positive for anti-Scl-70 antibodies.

A combination therapy protocol of plasmapheresis, intravenous immunoglobulins and betamethasone to treat anti-Ro/La-related congenital atrioventricular block. A case series and review of the literature.

OBJECTIVES The aim of this report was to evaluate the efficacy and safety of a combined treatment protocol used to treat 2nd and 3rd degree anti-Ro/La-related congenital atrioventricular block (CAVB). METHODS Six consecutive women diagnosed with 2nd degree (three cases) or 3rd degree block (three cases) between 2009 and 2011 referred to our outpatient clinic underwent a combination therapy protocol composed of weekly plasmapheresis, fortnightly 1g/kg intravenous immunoglobulins (IVIG) and daily betamethasone (4mg/day) throughout pregnancy. IVIG (1g/kg) treatment in the neonates was begun at birth and administered every fifteen days until passive maternal antibodies became undetectable. RESULTS The fetuses affected with 2nd degree block (cases 1, 2 and 3) reverted to a normal atrioventricular conduction after combined therapy, while those with a 3rd degree block remained stable (case 4), showed an increase in the ventricular rate (case 5) or an improvement in cardiac function (case 6). None of the fetuses with 3rd degree CAVB had other cardiac complications such as cardiomyopathy or fetal hydrops. The follow-up of the children affected with 2nd degree CAVB revealed a complete regression of the block in cases 1 and 3, and no signs of relevant worsening in case 2. The infants affected with 3rd degree block (cases 4, 5, and 6) remained stable and until now only one has required a pacemaker at the age of 10months. CONCLUSIONS If these results are confirmed by large-scale studies, this protocol could lead to improved outcomes in the treatment of this devastating disease.

Treatment of 139 Pregnancies in Antiphospholipid-positive Women Not Fulfilling Criteria for Antiphospholipid Syndrome: A Retrospective Study

Objective. The effect of low-dose aspirin (LDA) on pregnancy outcome in antiphospholipid (aPL)-positive women not fulfilling the criteria for antiphospholipid antibody syndrome (APS) was evaluated retrospectively. Methods. We evaluated 139 pregnancies of 114 aPL-positive women not fulfilling the Sydney classification criteria for definite APS (104 treated with LDA, 35 untreated). Inclusion criteria consisted of (1) any titer of aPL and no previous pregnancy or no pregnancy losses (defined as aPL carriers); (2) any titer of aPL and 1 or 2 pregnancy losses before the 10th gestational week. No women had previous thrombosis. The rate of pregnancy loss, gestational age at delivery, and birth weight percentile were compared in the treated and untreated patients. Associations between clinical and laboratory characteristics and pregnancy outcomes were investigated. Results. The rate of pregnancy loss was low in both treated and untreated groups (7.7% vs 2.9%, respectively). There were no statistically significant differences in the rate of pregnancy loss, gestational age at birth, or birth weight percentile in the treated and untreated groups. There were significant associations between gestational age at birth ≤ 34th week and positivity for lupus anticoagulant (p = 0.025) and anti-ß2-glycoprotein I IgG antibodies at titers > 99th (p = 0.016). Conclusion. LDA treatment does not appear to improve pregnancy outcome in low-risk women not fulfilling the criteria for APS. Because antibody profile seems to influence pregnancy outcome, further studies of patients stratified according to their antibody profile are warranted.

Efficacy and safety of nadroparin in the treatment of pregnant women with antiphospholipid syndrome: a prospective cohort study

The optimal therapeutic management of patients with antiphospholipid syndrome (APS) during pregnancy is debatable. In the present prospective cohort study the use of a low molecular weight heparin (LMWH) (nadroparin), administered alone twice daily in 30 pregnant women who were diagnosed with APS on the basis of the current classification criteria, is evaluated. Dosage was adjusted according to anti-Xa levels in the patients as the pregnancies progressed. Three women, in whom an important gradual fall in platelet count in the first trimester did not respond to increased nadroparin doses, were shifted to a second-line treatment protocol. Fetal loss occurred in two of the 27 remaining women (7.40%), while 25 (92.59%) delivered 25 live infants, between the 32nd and 40th weeks of gestation. No fetal problems were registered during pregnancies, while maternal complications occurred in two of the 25 patients (8%). Moreover, there were no thrombotic events in any of the women during the study. Patient compliance was good and only minor side-effects were reported. The results of this study indicate that nadroparin alone is useful and safe in the management of pregnant patients with APS. However, in consideration of the good pregnancy outcome obtained in patients with only pregnancy morbidity when heparin and aspirin were used together, other studies comparing nadroparin twice daily with once daily plus Aspirin would be useful to ascertain which is more effective in these patients.

Apheresis and intravenous immunoglobulins used in addition to conventional therapy to treat high-risk pregnant antiphospholipid antibody syndrome patients. A prospective study.

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 studys 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.

The clinical relevance of early anti-adalimumab antibodies detection in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: A prospective multicentre study.

OBJECTIVES To evaluate the relevance of anti-adalimumab (anti-ADA) antibodies (Abs) and their relationship with clinical/laboratory features in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS Fifty-eight patients affected with RA, AS and PsA were prospectively enrolled. Clinical/laboratory characteristics, disease activity, anti-ADA, anti-nuclear (ANA), anti-double strand (ds)DNA, anti-extractable nuclear antigens (anti-ENA) and anti-phospholipid Abs (aPL) were evaluated at baseline, 4, 12 and 24 weeks of adalimumab treatment. RESULTS Anti-ADA Abs were observed in 11/58 (19%) patients; they were detected within the 4th week of therapy in 90.9% of the positive subjects. Anti-ADA positivity was associated with significantly lower mean adalimumab serum levels (P<0.05). Treatment failure was observed in 20/58 (34.5%) patients and was significantly associated with anti-ADA Abs (P<0.05). Mean adalimumab serum levels were significantly lower in patients with treatment failure than in the responders one, both in the whole cohort (P<0.01) and in the group of anti-ADA positive patients (P<0.01). Adverse events happened more often in anti-ADA positive then in anti-ADA negative patients (27.3% vs 14.9%). CONCLUSIONS Anti-ADA abs could be considered an early marker associated to a poor clinical response to adalimumab treatment. Routine ANA/anti-ENA/aPL monitoring did not reveal as useful tools to predict the development of anti-ADA abs.

Maternal autoantibody profiles at risk for autoimmune congenital heart block: a prospective study in high-risk patients

Objective This prospective study aimed to identify antibody profiles characterising mothers with fetuses developing congenital heart block (CHB) by comparing their antibody frequencies and levels with those in unaffected mothers. Methods Eighty-one consecutive pregnant patients positive to anti-Ro±anti-La antibodies, at high risk of developing fetal CHB were prospectively studied. The 16 patients with fetal CHB outcome were considered the study population and the 65 patients with normal pregnancy outcomes were considered the control cohort. Anti-Ro52, anti-Ro60, anti-p200 and anti-La antibodies were assayed using home-made ELISA assays. Results The prevalence of anti-p200 antibodies was significantly higher in the fetal CHB affected patients than in the controls (p=0.03). Combinations of anti-p200 with anti-Ro52 and anti-Ro60 antibodies were significantly more frequent in the women with fetuses developing CHB than in the controls (p=0.03 for all combinations). The women with fetal CHB had significantly higher mean anti-Ro52, anti-Ro60 and anti-p200 levels than the controls (p=0.003, p=0.0001 and p=0.04, respectively); mean anti-La/SSB level was not significantly different in the two cohorts (p=0.25). Conclusions Since anti-p200, anti-Ro52 and anti-Ro60 antibodies, especially at high level, seem to identify patients at increased risk of developing fetal CHB, their detection could recognise anti-Ro/La positive women at risk for having an infant with this rare, potentially dangerous disorder.

Risk-based secondary prevention of obstetric antiphospholipid syndrome

Treatment of pregnant women with antiphospholipid syndrome (APS) should be set apart from that from thrombotic APS patients. Patients with a history of pregnancy morbidity but no vascular thrombosis are usually treated with a prophylactic dose of heparin plus low-dose aspirin; whereas, those with previous vascular thrombosis alone or associated with previous pregnancy morbidity, are commonly treated with a therapeutic dose of heparin generally combined with low-dose aspirin. However, in about 20% of pregnant APS women these regimens fail. In this context, we conducted a case-control study on a large multicentre cohort of conventionally treated pregnancies to verify whether specific laboratory profiles and/or clinical characteristics are predictive of unsuccessful pregnancy outcome during conventional treatments. Multivariate analysis showed that pregnancy failure during conventional therapies was independently associated with a history of both thrombosis and pregnancy morbidity, the presence of systemic lupus erythematosus (SLE) or other systemic autoimmune diseases and triple antiphospholipid antibody positivity. With the aim to discover the most effective and safe treatments in high-risk pregnant APS women a large-scale multicentre study focusing on the effect of treatments on pregnancy outcome in women with APS and further risk factors for pregnancy failure has been designed.

Apheresis in high risk antiphospholipid syndrome pregnancy and autoimmune congenital heart block

In the first part a prospective cohort study was reported to evaluate the efficacy and safety of a treatment protocol including plasma exchange (PE) or PE plus intravenous immunoglobulins (IVIG) or immunoadsorption (IA) plus IVIG administered in addition to conventional therapy to 22 pregnant women with high-risk APS. The results indicate that PE or IA treatments administered along with IVIG and conventional antithrombotic therapy could be a valuable and safe therapeutic option in pregnant APS women with triple antiphospholipid antibody positivity along with a history of thrombosis and/or one or more severe pregnancy complications. In the second part the efficacy and safety of PE combined with IVIG and steroids were evaluated for the treatment of 10 patients with autoimmune congenital heart block (CHB) by comparing maternal features, pregnancy outcome and side effects with those of 24 CHB patients treated with steroids only. The patients treated with the combined therapy showed a statistically significant regression of 2nd degree blocks, an increase in heart rate at birth and a significantly lower prevalence of pacing in the first year of life. Moreover, no side effects were observed except for a few steroid-related events. If these results are confirmed by large-scale studies, the apheretic procedures could lead to improved outcomes in the treatment of these devastating diseases.

Unstabilized DNA Breaks in Lymphocytes of Patients with Different Subsets of Systemic Sclerosis

Abstract:  The clastogenic effects on DNA, proven by the presence of micronuclei (MN) and the protective cellular mechanisms normally used to stabilize DNA breaks were investigated in three subsets of patients with systemic sclerosis (SSc). The frequency of MN found in cultures of peripheral lymphocytes in patients with anticentromere and antitopoisomerase I antibodies was significantly higher than that in the control group. The group with anticentromere antibody showed a significantly higher frequency of MN than did the subjects with antitopoisomerase antibody (4.22% versus 2.34%, P < 0.001). Patients with anti‐RNA polymerase III, instead, had a low prevalence of typical micronucleated cells (0.98%), not significantly different from that of the healthy controls (0.82%). Moreover, when MN was characterized for the presence or absence of DNA fragments with free 3′‐OH ends by digoxigenin‐dUTP (DIG‐dUTP) using terminal deoxynucleotidil transferase, its frequency was found to be increased in the groups with anticentromere and antitopoisomerase I antibodies with respect to that in the controls. The increase was significantly higher in the lymphocytes of the patients with anticentromere than in those with antitopoisomerase I antibody (35% versus 20.08%, P < 0.001). Nonetheless, the prevalence of unstable DNA fragments in patients with anti‐RNA polymerase III antibody was low (2.05%) and not significantly different from that of the control group (1.18%). Our results indicate that there is a clastogenic effect on DNA and an interference in the protective cellular mechanisms normally stabilizing DNA breaks only in some subsets of SSc patients.