Cecilia Nalli

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.

Clinical Characterization of Antiphospholipid Syndrome by Detection of IgG Antibodies Against β2‐Glycoprotein I Domain 1 and Domain 4/5: Ratio of Anti–Domain 1 to Anti–Domain 4/5 As a Useful New Biomarker for Antiphospholipid Syndrome

It has been suggested that only antibodies against domain 1 (D1) of β2‐glycoprotein I (β2GPI) are pathogenic and diagnostic. The role of antibodies against other β2GPI domains is still debated. This study was undertaken to evaluate the clinical relevance of domain specificity profiling of anti‐β2GPI IgG antibodies in antiphospholipid syndrome (APS) patients and in control groups of patients with systemic autoimmune rheumatic diseases and in asymptomatic antiphospholipid antibody (aPL) carriers.

The Pathogenicity of Anti-β2GP1-IgG Autoantibodies Depends on Fc Glycosylation

To analyze the glycosylation of anti-β2GP1, we investigated purified IgG from healthy children, patients with APS, and asymptomatic adult carriers of antiphospholipid antibodies. We observed that in the sera of healthy children and of patients with APS, IgG3 and IgG2 were predominant, respectively. The potentially protective anti-β2GP1-IgM was lower in the sera of healthy children. Although anti-β2GP1-associated C1q did not differ between children and patients with antiphospholipid syndrome, the associated C3c was significantly higher in the sera of healthy children. This indicates a more efficient clearance of anti-β2GP1 immune complexes in the healthy children. This clearance is not accompanied by inflammation or coagulatory events. It is likely that the most important pathogenic factor of the anti-β2GP1-IgG is related to the different glycosylation observed in healthy and diseased individuals. We detected a significantly higher sialylation of anti-β2GP1-IgG isolated from the sera of healthy children and asymptomatic adults when compared with that of patients with clinically apparent antiphospholipid syndrome. Low sialylated IgG reportedly ameliorates inflammation and inflammation promotes hyposialylation. Thus, both reactions create a vicious circle that precipitates the pathology of the antiphospholipid syndrome including thrombus-formation. We conclude that the increased sialylation of anti-β2GP1-IgG of sera of healthy individuals limits their pathogenicity.

The effects of lupus and antiphospholipid antibody syndrome on foetal outcomes

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that primarily affects women of childbearing-age. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder defined by the occurrence of venous and arterial thrombosis, often multiple, and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Recently, the long-term outcome of children born to patients with lupus and APS has become a major topic of interest both to patients and physicians. One of the major problems related to maternal disease is preterm delivery with all the consequences that this condition may bring. Prematurity may also be due to the presence of aPL; however, aPL do not generally display any thrombotic potential on neonates. Another complication may be neonatal lupus (NL), mediated by the presence of maternal antibodies (anti-Ro/SSA and anti-La/SSB). In addition, behaviour and neuropsychological outcomes have also been a matter of interest, but there are currently few data available. Beyond the biological influence of both maternal disease and autoimmune background, it is important to focus on the possible influence of maternal chronic illness on the neuropsychological development of her children. Whether aPL exposure could have a direct effect on brain development is still being debated. In children of mothers with APS, language delays have been noted and learning disabilities were described with a higher rate than the general age-school population. Several studies were performed on children born to lupus mothers: even if maternal lupus does not seem to impair intelligence levels, it may increase the occurrence of learning disabilities and particularly dyslexia in male children. To the best of our knowledge, no studies are available on the long-term outcome of children born to mothers with lupus or APS and particularly regarding the development of autoimmune diseases. Nevertheless, common experience of experts in the field is that these children do not show a significantly increased risk of displaying the same autoimmune disease as their mothers. The purpose of this paper is to answer the frequently asked questions of patients with lupus and APS who desire to become mothers, based on the little information available.

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.

Antiphospholipid antibodies mediate autoimmunity against dying cells

The Antiphospholipid Syndrome (APS) is characterized by thrombosis and pregnancy loss, clinical events mediated by pathogenic anti-phospholipid autoantibodies (aPL). β2-glycoprotein I (β2GPI) is the major autoantigens recognized by aPL. β2GPI is a cationic protein that binds to negatively charged surfaces such as those of apoptotic cells. This feature may lead to two major events: i) immunization with β2GPI fosters the Fc-receptor-mediated uptake by antigen presenting cells of apoptotic material decorated with β2GPIand the activation ofβ2GPI-specific T cells which in turn provide help to β2GPI-specific B cells for the production of anti-β2GPI; ii) apoptotic bodies decorated with β2GPI can be opsonized by anti-β2GPI and shifted towards a pro-inflammatory clearance by macrophages; epitope spread can occur with the generation of autoimmunity against nuclear autoantigens. In the presence of a predisposing genetic background and of a particular cytokine environment (type I interferons), the sequential emergence of autoantibodies can evolve into overt clinical disease. The spectrum of clinical phenotypes of the patients can be modulated by several factors affecting the pathogenicity of anti-β2GPI (e.g. domain specificity). We conclude that dying cells may play a dual role in APS: (I) as immunogen for the induction of aPL (etiology) and (II) as targets of aPL for the chronification of inflammation and the development of autoimmune diseases (pathology).

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.

Long-term neurodevelopmental outcome of children born to prospectively followed pregnancies of women with systemic lupus erythematosus and/or antiphospholipid syndrome

Background Systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) are autoimmune diseases that affect women of childbearing age. Maternal IgG antiphospholipid antibodies (aPL) can cross the placenta during pregnancy and theoretically reach the fetal brain. Some studies showed an increased number of learning disabilities in these children. Objectives To evaluate the long-term neurodevelopmental outcome of 40 children (median age 7.4 years) born to mothers with SLE and/or APS carrying positive IgG aPL during the third trimester of pregnancy. Methods Children were checked for neurological physical exam and intellectual/cognitive functioning by the Wechsler scale for corrected age. We submitted to the mothers the Child Behavior CheckList (CBCL) and a homemade set of questions created by pediatric neurologists. Results In all children neurological physical exam and intelligence levels were found to be normal. A cognitive impairment or a discrepant cognitive profile was found in 3 (7%) and 11 (28%) children, respectively. Learning disabilities were diagnosed in 3 children (19% of school-age children), all born to mothers with triple aPL positivity. A history of epilepsy was shown in four children (10%). Conclusions: Children born to women with SLE and/or APS may need a long-term follow-up focusing on milestones of neurodevelopment in order to detect and correct any alteration as early as possible.

Children born to SLE and APS mothers.

Background Systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) are autoimmune diseases that affect women of childbearing age. Pregnancies in these patients carry several complications such as prematurity. Maternal IgG antiphospholipid antibodies (aPL) can cross the placenta but they don’t generally cause any neonatal thrombotic event. Because of the incompleteness of the fetal blood-brain barrier, aPL could theoretically reach the fetal brain. Whether this can have an effect on brain development is still under investigation. Some studies performed in children of patients with SLE and/or APS showed an increased number of learning disabilities without impairment in intelligence level. Objectives The objectives of this article are to evaluate the neurodevelopment outcome in 30 children (median age 9 years) born to mothers with SLE and/or APS with IgG anti-beta2-glycoprotein I during the third trimester of pregnancy and found positive for the same antibodies at birth. Methods A neurological physical exam was performed in all children. We submitted some questionnaires to the mothers: the Child Behavior CheckList (CBCL) and a homemade set of questions obtained by a team composed of rheumatologists and pediatric neurologists. Intellectual functioning was determined by the Wechsler scale for corrected age. Results In all children neurological physical exam and intelligence levels were found to be normal but mild behavior disorders and history of neurological manifestations were shown in three children. Conclusions Offspring of patients with SLE and/or APS are generally healthy. We and others observed the occurrence of minor neurological disorders that might be related to maternal disease or to prematurity. The limited number of the available data on this sensitive issue supports the need for further studies.

Antirheumatic drugs and reproduction in women and men with chronic arthritis

The impact of rheumatic disease on fertility and reproduction can be remarkable. Many disease-related factors can influence patients’ sexual functioning, perturb fertility and limit family planning. Antirheumatic pharmacological treatment can also have a crucial role in this field. Proper counselling, preferably provided by a multidisciplinary team of rheumatologists, obstetricians, gynaecologists and neonatologists, is recommended for patients taking antirheumatic drugs, not only at the beginning, but also during the course of treatment. Paternal exposure to antirheumatic drugs was not found to be specifically associated with congenital malformation and adverse pregnancy outcome, therefore discontinuation of these drugs while planning for conception should be weighed against the risk of disease flare. Drugs in Food and Drug Administration (FDA) category ‘X’ should be withdrawn in a timely manner in women who desire a pregnancy. Meanwhile, disease control can be achieved with anti-tumour necrosis factor (TNF)-α agents, which are not teratogenic drugs. If maternal disease control is permissive, they can be stopped as soon as the pregnancy test turns positive and be resumed during pregnancy in case of a flare.