Monica Nuzzo

Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case–control study

OBJECTIVE To identify the risk factors associated with pregnancy failure in patients with APS treated with conventional therapy. METHODS A multicentre, case-control study was conducted to compare APS patients with successful and unsuccessful pregnancy outcomes. We retrospectively considered 410 pregnancies of women diagnosed with primary APS. The study focused on 57 unsuccessful pregnancies (considered the study population) and 57 successful pregnancies (considered the control population) matched for age and therapy. All the patients had been treated with conventional protocol treatments including low-dose aspirin and/or heparin. The clinical and laboratory features of the two groups of women diagnosed with APS were compared. RESULTS The independent risk factors for pregnancy failure were: (i) the presence of SLE or other autoimmune diseases [odds ratio (OR) 6.0; 95% CI 1.7, 20.8; P = 0.01]; (ii) history of both thrombosis and pregnancy morbidity (OR 12.1; 95% CI 1.3, 115.3; P = 0.03); and (iii) triple [Immunoglobulin (Ig) G/IgM aCLs plus IgG/IgM anti-β(2) glycoprotein I antibodies plus LA] aPL positivity (OR 4.1; 95% CI 1.0, 16.7; P = 0.05). APS patients diagnosed on the basis of a single positive test and/or history of pregnancy morbidity alone were generally found to have successful pregnancies. CONCLUSION It would seem from these findings that the risk of pregnancy failure in APS women planning to conceive can be stratified on the basis of some specific clinical and laboratory features.

Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy.

This cross‐sectional study shows that a high number of untreated adult patients with GHD develop radiological vertebral deformities. Patients undergoing GH replacement treatment showed a significantly lower prevalence of vertebral deformities versus treated patients in the presence of similar BMD, as assessed by DXA.

Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study

Objectives: To asses risk factors for a first thrombotic event in antiphospholipid antibody (aPL) positive carriers and evaluate the efficacy of prophylactic treatments. Methods: Recruitment criteria were age 18–65 years, no history of thrombosis, positivity for lupus anticoagulant and/or IgG/IgM anticardiolipin antibody (aCL) on ⩾2 occasions at least 6 weeks apart. Demographic, laboratory and clinical parameters were collected at enrolment and at the time of the thrombotic event. Results: 370 patients/subjects (mean (SD) age 34 (9.9) years) were analysed retrospectively for a mean (SD) follow-up of 59.3 (45.5) months. Thirty patients (8.1%) developed a first thrombotic event during follow-up. Hypertension and medium/high levels of IgG aCL were identified by multivariate logistic regression analysis as independent risk factors for thrombosis. Thromboprophylaxis during high-risk and long-term periods was significantly protective. Conclusions: Hypertension or medium/high titres of IgG aCL are risk factors for a first thrombotic event in asymptomatic aPL carriers and primary prophylaxis is protective.

Anti-β2-glycoprotein I IgG antibodies from 1-year-old healthy children born to mothers with systemic autoimmune diseases preferentially target domain 4/5: might it be the reason for their ‘innocent’ profile?

Background Anti-β2-glycoprotein-I (anti-β2GPI) were demonstrated to be pathogenic in the antiphospholipid syndrome (APS). However, they can be detected in patients with no features of APS, especially those affected by systemic autoimmune diseases (SAD), and so in healthy children. It has been suggested that anti-β2GPI against domain 1 (D1) associate with thrombosis, while those recognising domain 4/5 (D4/5) are present in non-thrombotic conditions. Objective To evaluate the fine specificity of anti-β2GPI in adults and infants. Methods Three groups were examined—group A: 57 1-year-old healthy children born to mothers with SAD; group B: 33 children with atopic dermatitis; group C: 64 patients with APS. Subjects were selected based on positive anti-β2GPI IgG results. Serum samples were tested for anti-β2GPI IgG D1 and D4/5 using research ELISAs containing recombinant β2GPI domain antigens. Results Children (A and B) displayed preferential IgG reactivity for D4/5, whereas patients with APS were mainly positive for D1. No thrombotic events were recorded in groups A and B. Conclusions The specificity for D4/5 suggests that anti-β2GPI IgG production in children born to mothers with SAD is a process neither linked to systemic autoimmunity nor related to the maternal autoantibody status. This unusual fine specificity might, at least partially, account for the ‘innocent’ profile of such antibodies.

European registry of babies born to mothers with antiphospholipid syndrome

Objectives This study aimed to describe the long-term outcome and immunological status of children born to mothers with antiphospholipid syndrome, to determine the factors responsible for childhood abnormalities, and to correlate the childs immunological profile with their mothers. Methods A prospective follow-up of a European multicentre cohort was conducted. The follow-up consisted of clinical examination, growth data, neurodevelopmental milestones and antiphospholipid antibodies (APL) screening. Children were examined at 3, 9, 24 months and 5 years. Results 134 children were analysed (female sex in 65 cases, birth weight 3000±500 g, height 48±3 cm). Sixteen per cent had a preterm birth (<37 weeks; n=22), and 14% weighted less than 2500 g at birth (n=19). Neonatal complications were noted in 18 cases (13%), with five infections (4%). During the 5-year follow-up, no thrombosis or systemic lupus erythematosus (SLE) was noted. Four children displayed behavioural abnormalities, which consisted of autism, hyperactive behaviour, feeding disorder with language delay and axial hypotony with psychomotor delay. At birth lupus anticoagulant was present in four (4%), anticardiolipin antibodies (ACL) IgG in 18 (16%), anti-β2 glycoprotein-I (anti-β2GPI) IgG/M in 16 (15%) and three (3%), respectively. ACL IgG and anti-β2GPI disappeared at 6 months in nine (17%) and nine (18%), whereas APL persisted in 10% of children. ACL and anti-β2GPI IgG were correlated with the same mothers antibodies before 6 months of age (p<0.05). Conclusion Despite the presence of APL in children, thrombosis or SLE were not observed. The presence of neurodevelopmental abnormalities seems to be more important in these children, and could justify long-term follow-up.

Renal Involvement in Primary Antiphospholipid Syndrome: Retrospective Analysis of 160 Patients

BACKGROUND AND OBJECTIVES The objective of this study was to evaluate the prevalence, clinicopathologic features, and outcome of renal involvement in a large cohort of patients with primary antiphospholipid syndrome (PAPS). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We retrospectively examined medical records of 160 patients with a diagnosis of PAPS of two general hospitals of northern Italy between 1985 and 2008. RESULTS There were 140 women and 20 men. Mean age was 35+/-12 yr. PAPS was characterized by thrombotic events in 41.2%, fetal loss in 39.4%, and both in 19.4%. Signs of renal abnormalities were present in 14 (8.7%) patients. All patients had proteinuria, in the nephrotic range in five; four patients had moderate chronic renal insufficiency, and one had end-stage kidney disease (ESKD). Two patients presented with acute renal failure and one with nephritic syndrome. Ten patients underwent a renal biopsy, which showed a membranous glomerulonephritis in four, proliferative glomerulonephritis in two, thrombotic microangiopathy in two, and vascular lesions consistent with chronic antiphospholipid antibodies nephropathy in two. Patients with renal involvement were older (41.8 versus 34.3 years; P=0.0269), more frequently lupus anticoagulant positive (92.3 versus 48.9%; P=0.0068), and had hypocomplementemia (P<0.05). CONCLUSIONS Renal abnormalities are present in approximately 9% of patients with PAPS. In addition to APS nephropathy, the prevailing picture is membranous nephropathy. Outcome and long-term follow-up usually are good. Not all of the clinical manifestations of PAPS can be ascribed to thrombotic mechanisms. The heterogeneity of renal involvement confirms the presence of a continuum between systemic lupus erythematosus and PAPS.

Autoimmunity and Pregnancy Autoantibodies and Pregnancy in Rheumatic Diseases

Abstract:  In women who suffer from rheumatic diseases (RDs) the risk of repeated fetal loss, intrauterine growth restriction, and preterm birth remains higher than in the general population. Antiphospholipid antibodies are frequently observed in patients with systemic lupus erythematosus (SLE). They are associated with recurrent pregnancy losses that may occur at any age of gestation. The cause of fetal death is believed to be intraplacental thrombosis, although other pathologic mechanisms have been described. A recent study has described the increased frequency of learning disabilities in the offspring of SLE patients; case reports of neonatal thrombosis are very rare. Transplacental passage of IgG anti‐Ro/SS‐A antibodies is linked to neonatal lupus (2%). The main manifestation is congenital heart block (CHB) due to the binding of anti‐Ro/SS‐A antibodies to cardiac conduction tissue and to the consequent inflammatory/fibroid reaction. Neonatal lupus also includes cutaneous, hematologic, and hepatobiliary manifestations, which are typically transient. Incomplete CHB can be treated with fluorinated corticosteroids to prevent the progression and decrease inflammation. Intravenous immunoglobulin, decreasing the tranplacental passage of anti‐Ro/SS‐A, has been proposed as prophylactic therapy in patients who had one or more child with CHB. Transplacental passage of antiplatelet antibodies, in about 10% of mothers with SLE, can induce thrombocytopenia in the fetus or the neonate. Patients with RD have a higher incidence of anxiety and depression compared to the general population, interfering with parenthood and the upbringing of children.

The Efficacy and Safety of Cyclosporin A in Pregnant Patients with Systemic Autoimmune Diseases

Cyclosporin A (CYS A) is an immunosuppressant agent administered in autoimmune diseases, and its use during pregnancy and lactation is a debated topic.

Antiphospholipid syndrome and pregnancy

Since the 1960s, antiphospholipid antibodies have been known to be associated with repeated miscarriages and fetal losses. Other complications of pregnancy, such as preterm birth, with pre-eclampsia or severe placental insufficiency were also frequently reported and are included in the current classification criteria of the antiphospholipid syndrome. The titer, isotype or antigen specificity of the antibodies may be important in risk determination. The pathogenesis of pregnancy failures is not only linked to the thrombophilic effect of antiphospholipid antibodies but also to a direct effect of antibodies on trophoblast differentiation and invasion. The study of experimental animal models provided sound evidence of the pathogenic role of antiphospholipid antibodies both in lupus-prone and -naive mice. The classification of pregnant antiphospholipid syndrome patients as being at a ‘high risk’ has completely changed their prognosis due to obstetric monitoring and the application of effective therapy. In fact, despite the high rates of complications and preterm delivery, a successful outcome can now be achieved in a large majority of cases.

THU0264 Efficacy and Safety of Cyclosporine-A During Pregnancy in Autoimmune Diseases

Background Cyclosporin-A (CYS-A) is an immunosuppressant agent widely used in the context of anti-rejection therapy. In Rheumatology it’s indicated for Rheumatoid Arthritis (RA) and Psoriasic Arthritis (PA), but it’s also administered to control other connective tissue diseases like Systemic Lupus Eritematosus (SLE) and Dermatomyositis (DM) and in patients suffering from vasculitis. These diseases often occur in fertile women, therefore, in recent years, the compatibility of the drug with pregnancy has been largely debated. FDA classifies CYS-A in class C, since there are no conclusive data about it’s safety and not recommended breastfeeding during therapy, even though several registries and retrospective studies seem to demonstrate its safety [1,2]. Most of the available data derive from exposed pregnancies in transplanted women [3] and no studies have shown adverse effects on newborns [4]. Objectives To analyze a series of patients suffering from autoimmune diseases, treated with CYS-A during pregnancy and to highlight any related maternal-fetal complications. Methods 25 pregnancies in 19 consecutive patients treated with CYS-A throughout gestation was analyzed, focusing on demographic characteristics, underlying disease activity and the onset of maternal and/or fetal complications. Results At the time of pregnancy, patients had an average age of 32.2 years and underlying diseases in stable remission. They suffered from RA (n=2), PA (n=2), SLE (n=13, 1with associated Kikuchi disease), Sjögren Syndrome (n=1), DM (n=1). Therapy was made of CYS-A, 3mg/kg (tapered to suspension before delivery in 5 patients: 20%), low-medium dosage steroids(n=20: 80%), aspirine (n=22: 88%), hydroxychloroquine (n=17: 68%), azathioprine (n=1: 4%) and low molecule weight heparin (n=4: 16%). We had 20 full-term pregnancies (80%), with a mean gestational age of 38weeks, 1 is still ongoing.1 PROM (4.8%) and 2 IUGR (10%), both evolved into SGA babies. 3 Spontaneous Abortions (12%)and 1 voluntary abruption because of the finding of Turner’s Syndrome and cystic hygroma (4%).11 pregnancies (55%) resulted in natural delivery, 9 (45%) in caesarean section. Newborns presented a mean birth-weight of 2857g and they all had normal apgar scores. We found 2 (10%) maternal disease flares during gestation and 2 (10%) in puerperium. 2 cases of gestational hypertension (1 of new onset) and 2 (10%) elevations of pre-existing proteinuria. Conclusions According to existing data we found no evidences justifying the suspension of CYS-A when a pregnancy occurs. The drug does not appear to increase maternal-fetal complications comparing with general population(PROM:4.8%vs10%, IUGR:10%vs4-8%, Gestational hypertension:10%vs4-10%)and it should be continued in patients who benefit from therapy. When possible, the drug should be tapered to suspension to allow breastfeeding. References Cimaz R, Meregalli E, Biggioggero M, et al:Alterations in the immune system of children from mothers treated with immunosuppressive agents during pregnancy. ToxicolLett2004,149:155-162. Østensen M, Khamashta M, Lockshin M, et al:Anti-inflammatory and immunosuppressive drugs and reproduction. ArthritisResTher2006, 8:209. McKay DB, Adams PL, Bumgardner GL, et al:Reproduction and pregnancy in transplant recipients:current practices. ProgTransplant.2006;16:127-32. Al-Khader AA, Basri N, Al-Ghamdi, et al:Pregnanciesin renal transplant recipients, with a focus on babies. AnnTransplant.2004;9:65-7. Disclosure of Interest None Declared