Laura Andreoli

Estimated Frequency of Antiphospholipid Antibodies in Patients With Pregnancy Morbidity, Stroke, Myocardial Infarction, and Deep Vein Thrombosis: A Critical Review of the Literature

Antiphospholipid Syndrome Alliance For Clinical Trials and International Networking (APS ACTION) is an international research network devoted to conducting well‐designed clinical trials in persistently antiphospholipid antibody (aPL)–positive patients. One of the first needs of APS ACTION was to know the true aPL frequency in patients with pregnancy morbidity (PM), stroke (ST), myocardial infarction (MI), and deep venous thrombosis (DVT).

14th International Congress on Antiphospholipid Antibodies Task Force report on obstetric antiphospholipid syndrome.

Pregnancy morbidity is one of the clinical manifestations used for classification criteria of antiphospholipid syndrome (APS). During the 14th International Congress on Antiphospholipid Antibodies (aPL), a Task Force with internationally-known experts was created to carry out a critical appraisal of the literature available regarding the association of aPL with obstetric manifestations present in actual classification criteria (recurrent early miscarriage, fetal death, preeclampsia and placental insufficiency) and the quality of the evidence that treatment(s) provide benefit in terms of avoiding recurrent adverse obstetric outcomes. The association of infertility with aPL and the effectiveness of the treatment of patients with infertility and positive aPL was also investigated. This report presents current knowledge and limitations of published studies regarding pregnancy morbidity, infertility and aPL, identifying areas that need better investigative efforts and proposing how critical flaws could be avoided in future studies, as suggested by participants of the Task Force. Except for fetal death, there are limitations in the quality of the data supporting the association of aPL with obstetric complications included in the current APS classification criteria. Recommended treatments for all pregnancy morbidity associated to APS also lack well-designed studies to confirm its efficacy. APL does not seem to be associated with infertility and treatment does not improve the outcomes in infertile patients with aPL. In another section of the Task Force, Dr. Jane Salmon reviewed complement-mediated inflammation in reproductive failure in APS, considering new therapeutic targets to obstetric APS (Ob APS).

Novel aspects of Sjögren’s syndrome in 2012

Sjögren’s syndrome (SS) is a systemic progressive autoimmune disease characterized by a complex pathogenesis requiring a predisposing genetic background and involving immune cell activation and autoantibody production. The immune response is directed to the exocrine glands, causing the typical ‘sicca syndrome’, but major organ involvement is also often seen. The etiology of the disease is unknown. Infections could play a pivotal role: compared to normal subjects, patients with SS displayed higher titers of anti-Epstein-Barr virus (EBV) early antigens, but lower titers of other infectious agent antibodies such as rubella and cytomegalovirus (CMV) suggest that some infections may have a protective role against the development of autoimmune disease. Recent findings seem to show that low vitamin D levels in patients with SS could be associated with severe complications such as lymphoma and peripheral neuropathy. This could open new insights into the disease etiology. The current treatments for SS range from symptomatic therapies to systemic immunosuppressive drugs, especially B cell-targeted drugs in cases of organ involvement. Vitamin D supplementation may be an additional tool for optimization of SS treatment.

EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome.

Objectives Develop recommendations for womens health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). Methods Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. Results Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. Conclusions Recommendations for womens health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

State of the art: reproduction and pregnancy in rheumatic diseases

Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the etiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with rheumatoid arthritis (RA) affects their childrens birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Pre-conceptional counseling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes.

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.

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.

Antinucleosome antibodies in primary antiphospholipid syndrome: A hint at systemic autoimmunity?

BACKGROUND Antinucleosome antibodies (anti-NCS) are reported to be highly sensitive and specific for systemic lupus erythematosus (SLE) and to correlate with disease activity. They may appear in early stages of the disease, in particular before anti-dsDNA antibodies, being a potential marker for identifying patients susceptible to SLE. Patients with primary antiphospholipid syndrome (PAPS) may develop full-blown SLE but there is no evidence for markers predictive for that. AIM To evaluate whether anti-NCS may be predictors for full-blown or lupus like disease (LL) in a cohort of PAPS patients. METHODS A multicentric cohort of 105 PAPS patients was tested for IgG/IgM anti-NCS by using a home made assay with H1-stripped chromatin as antigen. RESULTS Eighty-one out of 105 (77%) of the patients were positive for anti-NCS; medium-high titre results were present only in 49/105 (46%). Anti-NCS were more frequently detected in PAPS+LL, but no relationship with clinical/serological features was found, except for a weak correlation with anti-dsDNA antibodies. Two PAPS patients evolved into full-blown SLE during the follow-up and displayed high titre anti-NCS many years before. CONCLUSIONS Our findings suggest that anti-NCS might be added to the mosaic of autoimmune phenomena characterizing PAPS patients and in particular those with more chance to evolve to SLE.

The estimated frequency of antiphospholipid antibodies in young adults with cerebrovascular events: a systematic review

Background Around 10% of all thrombotic cerebrovascular events (CVE) occur in young population and in a large proportion of those the trigger remains undetermined. Antiphospholipid antibodies (aPL) are recognised risk factors for ischaemic stroke and recurrent thrombotic events; however, the frequency of aPL in young people with CVE is still an unresolved issue. Objectives To estimate the frequency of aPL in young adults with CVE and to determine whether aPL-positive young individuals are at greater risk of CVE when compared with individuals without aPL by systematically reviewing the literature. Methods Medline reports published between 1970 and 2013 investigating the presence of aPL in young patients (<50 years old) with CVE were included. The median frequency for positive aPL, including lupus anticoagulant, anticardiolipin antibodies (aCL) and antibodies against β2Glycoprotein I (anti-β2GPI), was calculated for stroke and transient ischaemic attacks. Findings This systematic review is based on available data from 5217 patients and controls from 43 studies analysing the frequency of aPL in young patients with CVE. The overall aPL frequency was estimated as 17.4% (range 5%–56%) for any CVE, 17.2% (range 2%–56%) for stroke and 11.7% (range 2%–45%) for transient ischaemic attack (TIA). The presence of aPL increased the risk for CVE by 5.48-fold (95% CI 4.42 to 6.79). Based on available data, the frequency of aPL in young patients with CVE can be estimated at 17%, rising up to 22% for aCL in patients with stroke. The presence of aPL seems to confer a fivefold higher risk for stroke or TIA when compared with controls. However, variability in test reproducibility and cut-off definition still represent an important methodological limitation for the current diagnostic testing for aPL. These observations should be confirmed by appropriately designed population studies.

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.