Pediatric Presentation of Antiphospholipid Syndrome: A Review of Recent Literature With Estimation of Local Prevalence.

We aimed to investigate the epidemiology, the clinical and laboratory characteristics of the pediatric involvement of antiphospholipid syndrome (APS), by performing a review of the current evidence and reviewing local experience in the Northwest Italy. To achieve this, we performed a detailed literature search to identify articles describing clinical and laboratory characteristics of pediatric APS. In concomitance, we conducted a registry-based study collecting data from the Piedmont and Aosta Valley Rare Disease Registry including pediatric patients diagnosed with APS in the last 11 years. The literature review led to inclusion of six articles with a total of 386 pediatric patients (65% females, 50% with systemic lupus erythematosus (SLE) as concomitant diagnosis). Rates of venous and arterial thrombosis were 57 and 35%, respectively. "Extra-criteria manifestations" included mostly hematologic and neurologic involvement. Almost one-quarter of patients (19%) reported recurrent events and 13% manifested as catastrophic APS. A total of 17 pediatric patients (mean age 15.1 ± 2.8, 76% female) developed APS in the Northwest of Italy. In 29% of cases, SLE was a concomitant diagnosis. Deep vein thrombosis was the most frequent manifestation (28%) followed by catastrophic APS (6%). The estimated prevalence of pediatric APS in Piedmont and Aosta Valley Region is 2.5/100,000 people, whereas the estimated annual incidence is 0.2/100,000 inhabitants. In conclusion, clinical manifestations of pediatric APS seem to be more severe and with a high prevalence of noncriteria manifestations. International efforts are needed to better characterize this condition and to develop new specific diagnostic criteria to avoid missed/delayed diagnosis in children with APS.

2023 ACR/EULAR classification criteria in existing research cohorts: an international study.

OBJECTIVE: Assessing the impact of the updated ACR/EULAR APS classification criteria to our research cohort. METHODS: Consecutive patients who tested persistently positive for at least one aPL in the last three years were enrolled. The first APS Sydney index event was considered and computed for the comparison between Sydney and 2023 APS criteria. When computing the 2023 APS criteria, additional manifestations were also considered. RESULTS: The cohort comprised 249 patients (185 with APS and 64 aPL carriers according to Sydney criteria). The 185 patients had as first index event VT in 55 cases (29.8%) AT in 63 (34%) and PM in 67 (36.2%). When applying the updated criteria, 90 subjects (48.7%) failed to reach the composite score of the new criteria. The percentage of thrombotic APS per Sydney criteria decreased from 47.3% to 34.9% because of high cardiovascular risk in 23 cases, IgM aPL profile in 6 cases and in 2 patients for both reasons. Patients with PM decreased from 26.9-3.2% (39 cases of recurrent early pregnancy loss and 20 of fetal losses). Consequently, the percentage of aPL carriers increased from 26% to 61%. When looking at the disease evolution at follow-up, 32 additional patients out of 90 (35.6%) fulfilled the new APS criteria, after developing additional clinical manifestation following index event. CONCLUSION: When applying the new APS criteria to our research cohort, not negligible differences exist in patients' classification. A multidisciplinary approach will be mandatory to assess the impact into research and, ultimately, patient's care of new criteria.

The estimated prevalence of antiphospholipid antibodies and criteria-antiphospholipid syndrome in subjects with renal thrombotic microangiopathy.

BACKGROUND: While the prevalence of antiphospholipid antibodies (aPL) in venous and arterial thrombotic events had already been estimated by previous studies, the prevalence of aPL in subjects with Thrombotic Microangiopathy (TMA) is still not fully elucidated. Thus, we conducted a systematic review to estimate the frequency of aPL in subjects with biopsy-proven renal TMA. METHODS: We conducted in the PubMed database a search for English-language studies investigating the presence of aPL in subjects with biopsy-proven renal TMA from January 1985 to December 2022. Keywords used in the search included: 'antiphospholipid syndrome', 'antiphospholipid antibodies' and 'thrombotic microangiopathy'. Cohorts of HUS patients were excluded due to the risk of over-estimating the prevalence of aPL in these populations. The median frequency for positive aPL including anticardiolipin antibodies (aCL), antibodies against ß2-glycoprotein-I (anti-ß2GPI) and lupus anticoagulant (LA) was then calculated. RESULTS: 522 articles were identified through the literature search. Six studies, assessing the prevalence of aPL in 211 subjects with renal TMA, were retrieved. The overall aPL prevalence was estimated as 24.4% (range 22-56). The estimated prevalence of aCL (IgG/IgM), anti-ß2GPI, (IgG/IgM) and LA was 4.0% (range 3-27), 4.0% (range 3-16) and 18.9% (range 13-25), respectively. APS was diagnosed in 16.3% (range 11-29) of the patients. Of note, a high level of heterogeneity was observed when comparing the reported aPL profiles for each study. CONCLUSIONS: This comprehensive systematic analysis of studies investigating the prevalence of aPL in renal TMA showed that, despite the high heterogeneity of the included studies, aPL are present in about one case out of four renal-TMA cases.

16th International congress on antiphospholipid antibodies task force report on antiphospholipid syndrome laboratory diagnostics and trends.

Classification criteria for antiphospholipid syndrome (APS) require IgG or IgM isotypes of the anticardiolipin (aCL) antibodies, anti-ß2 glycoprotein I (anti-ß2GPI) antibodies, and/or the lupus anticoagulant (LA) to satisfy the laboratory disease definition. Over the past 20 years, non-criteria antiphospholipid antibodies (aPL) directed to other proteins of the coagulation cascade (i.e. prothrombin and/or phosphatidylserine-prothrombin complex) or to some domains of ß2GPI have been proposed. This task force concentrated and reviewed the literature on data including aPS/PT, antibodies to domain 4/5 of ß2GPI and the newly described antibodies to protein/HLA-DR complex. In addition, we discussed testing of LA in the 'new' oral anticoagulants' era and the value of triple positivity in the risk assessment of aPL. The conclusions were presented at a special session during the 16th International Congress on aPL, Manchester, UK, September 2019.

Thrombosis and APS: Lessons Learned from Another Black Swan Tale.

Antiphospholipid syndrome (APS) is a chronic systemic autoimmune disease characterized by venous, arterial, and microvascular thromboses and/or recurrent pregnancy morbidity, that occur in the persistent presence of antiphospholipid antibodies (aPL). APS can present with a wide range of clinical manifestations often reffered as "extra-criteria". These features, although apparently less common, can severely impact patients' outcome. Here, we report the case of a patient with a newly diagnosed APS. He previously experienced a recurrence of venous thrombosis after discontinuation of anticoagulant therapy in association with cutaneous ulcerations as presenting symptoms. Interestingly, skin lesions did not improve with full anticoagulant treatment. Due to concomitant presence of thrombotic and microvascular involvement, immunomodulatory therapy with steroid pulses followed by intravenous injections of belimumab was started, with progressive and significant amelioration, leading to complete recovery. Following the presentation of the current case report, we highlight the importance of suspecting APS in young patients experiencing unprovoked thrombosis. We also emphasized the critical issue of testing aPL during anticoagulant treatment and focused on the need of aPL retesting in patients with positivity at high titers. We also highlight the double nature of aPL-mediated clinical manifestations. While most patients presented with pure thrombotic complications, one should always remember that APS is an autoimmune-mediated disease, which can benefit from alternative therapeutic approaches beyond anticoagulation.

Open-label, prospective, phase II descriptive pilot trial of belimumab therapy for refractory and/or non-criteria manifestations of antiphospholipid syndrome: study protocol.

OBJECTIVES: To evaluate the safety and tolerability of belimumab given for 24 months in patients persistently positive for antiphospholipid antibodies (aPL) with clinical features attributable to aPL [refractory and/or non-criteria manifestations of the antiphospholipid syndrome (APS)]. METHODS: In this investigator-initiated, single-centre, open-label, prospective, phase II descriptive pilot trial, belimumab will be administered in 15 patients attending San Giovanni Bosco Hospital (Turin) showing refractory and/or non-criteria manifestations of APS. Subjects will receive belimumab 10 mg/kg intravenously (in addition to their ongoing APS treatment) with regimen at 0, 2, 4 weeks and every 4 weeks thereafter (up to week 104). Study endpoints determined at 4, 16, 24, 36, 52 and 104 weeks will include: primary (safety and adverse events) and secondary outcomes, such as changes in clinical outcomes (recurrent thromboses, thrombocytopenia, haemolytic anaemia, cardiovascular events, skin ulcer, aPL-related nephropathy and cognitive dysfunction), laboratory outcomes (routine tests, aPL, ENA and anti-dsDNA tests, thrombin generation assay, interferon-signature analysis, lymphocytes immunophenotyping, BLyS determination) and QoL evaluation. RESULTS: Study endpoints determined at 4, 16, 24, 36, 52 and 104 weeks will include: primary (safety and adverse events) and secondary outcomes, such as changes in clinical outcomes (recurrent thromboses, thrombocytopenia, haemolytic anaemia, cardiovascular events, skin ulcer, aPL-related nephropathy and cognitive dysfunction), laboratory outcomes (routine tests, aPL, ENA and anti-dsDNA tests, thrombin generation assay, interferon-signature analysis, lymphocytes immunophenotyping, BLyS determination) and QoL evaluation. CONCLUSIONS: Targeting B-cells is emerging as an appealing strategy for patients with APS. Preliminary observations showed aPL negativisation after starting therapy with belimumab. The clinical relevance of these findings will be investigated in this prospective study. If confirmed, the current 'anti-thrombotic' approach to APS patients could be complemented, at least in selected cases, with an 'immunomodulatory' strategy.

Finding the Needle in the Haystack: Serological and Urinary Biomarkers in Behçet's Disease: A Systematic Review.

Urinary and serological markers play an essential role in the diagnostic process of autoimmune diseases. However, to date, specific and reliable biomarkers for diagnosing Behçet's disease (BD) are still lacking, negatively affecting the management of these patients. To analyze the currently available literature on serological and urinary BD biomarkers investigated in the last 25 years, we performed a systematic literature review using the Population, Intervention, Comparison, and Outcomes (PICO) strategy. One hundred eleven studies met the eligibility criteria (6301 BD patients, 5163 controls). Most of them were retrospective, while five (5%) were prospective. One hundred ten studies (99%) investigated serological biomarkers and only two (2%) focused on urinary biomarkers. One hundred three studies (93%) explored the diagnostic potential of the biomolecules, whereas sixty-two (56%) tested their effect on disease activity monitoring. Most articles reported an increase in inflammatory markers and pro-oxidant molecules, with a decrease in antioxidants. Promising results have been shown by the omics sciences, offering a more holistic approach. Despite the vast number of investigated markers, existing evidence indicates a persistent gap in BD diagnostic/prognostic indices. While new steps have been taken in the direction of pathogenesis and disease monitoring, international efforts for the search of a diagnostic marker for BD are still needed.

Disease evolution in a long-term follow-up of 104 undifferentiated connective tissue disease patients.

OBJECTIVES: To investigate the rate of disease evolution in a cohort of patients with undifferentiated connective tissue disease (UCTD) and to determine clinical and immunological features more frequently associated with disease progression. METHODS: This retrospective single-centre long-term follow-up cohort study included patients with UCTD diagnosis, ANA positive, with a follow-up of at least 2 years. RESULTS: A total of 100 UCTD patients were recruited. During the follow-up (6.2±2.1 years), 44 patients (44%) developed novel clinical and/or laboratory features (rate of development patient/year of 7%), and 21 patients (21%) evolved into a definite connective tissue disease (CTD) after a mean time of 7±5.5 years with a rate of disease evolution (patient/year) of 3%. New clinical manifestations (39 patients) included: joints (36%), haematological (30%), cutaneous (13%), pulmonary (10%) and renal (10%) involvement. New laboratory findings (17 patients (17%)) included: 2 anti-ENA positivity, 3 anti-dsDNA antibodies positivity and 6 low complement levels. At follow-up, 13 patients (61.9%) met the classification criteria for systemic lupus erythematosus, 1 patient (4.8%) for mixed CTD, 5 patients (23.8%) for systemic sclerosis and 2 patients (9.5%) for Sjögren's syndrome. Patients evolving towards a new diagnosis had longer disease duration (15.2±9.7 years vs. 10±5.8 years; respectively, p<0.005), had a higher prevalence of anti-Ro/SSA antibodies (63.2% vs. 28.4%; respectively, p<0.05) and anti-RNP antibodies (21.1% vs. 7.4%; respectively, p<0.05). The statistical difference was also confirmed after the multivariate analysis. CONCLUSIONS: Up to 45% of UCTD patients might develop novel clinical and/or laboratory features during the follow-up, leading to evolution into a definite CTD in 1 out 5 cases.

Serum Biomarkers of Renal Fibrosis: A Systematic Review.

Chronic kidney disease (CKD) is a widely diffuse pathological condition which deeply impacts upon an affected patient's quality of life and its worldwide rate is predicted to further rise. The main biological mechanism underlying CKD is renal fibrosis, a non-reversible process representing, for the affected system, a point of no return of tissue damage and dysfunction, deeply reducing the possible therapeutic strategies at the disposal of physicians. The best tool clinicians can use to address the extent of renal fibrosis at any level (glomeruli, tubule-interstitium, vasculature) is kidney biopsy that, despite its overall safety, remains an invasive procedure showing some shortcomings. Thus, the identification of novel non-invasive renal fibrosis biomarkers would be of fundamental importance. Here, when systematically reviewing the available evidence on serological biomarkers associated with renal fibrosis evaluated in patients suffering from CKD in the last five years, we found that despite the presence of several promising biomarkers, the level of observed evidence is still very scattered. Probably, the use of multiple measures capable of addressing different aspects involved in this condition would be the most suitable way to capture the high complexity characterizing the renal fibrotic process, having consequently a great impact on clinical practice by maximizing prevention, diagnosis, and management.

Renal Fibrosis in Lupus Nephritis.

Fibrosis can be defined as a pathological process in which deposition of connective tissue replaces normal parenchyma. The kidney, like any organ or tissue, can be impacted by this maladaptive reaction, resulting in persistent inflammation or long-lasting injury. While glomerular injury has traditionally been regarded as the primary focus for classification and prognosis of lupus nephritis (LN), increasing attention has been placed on interstitial fibrosis and tubular atrophy as markers of injury severity, predictors of therapeutic response, and prognostic factors of renal outcome in recent years. This review will discuss the fibrogenesis in LN and known mechanisms of renal fibrosis. The importance of the chronicity index, which was recently added to the histological categorization of LN, and its role in predicting treatment response and renal prognosis for patients with LN, will be explored. A better understanding of cellular and molecular pathways involved in fibrosis in LN could enable the identification of individuals at higher risk of progression to chronic kidney disease and end-stage renal disease, and the development of new therapeutic strategies for lupus patients.

Identifying phenotypes of patients with antiphospholipid antibodies: results from a cluster analysis in a large cohort of patients.

OBJECTIVES: To identify the aggregation of patients with aPL into different subgroups sharing common features in terms of clinical and laboratory phenotypes. METHODS: We applied a hierarchical cluster analysis from the multiple correspondence analysis to determine subgroups of patients according to clinical and laboratory characteristics in a cohort of subjects with confirmed aPL positivity who presented to our outpatient clinics from 2006 to 2018. RESULTS: A total of 486 patients [403 women; age 41.7 years (26)] were included, resulting in five clusters. Cluster 1 (n= 150) presented with thrombotic events (65.3% with venous thrombosis), with triple aPL positivity found in 34.7% of them (the highest rate among the different clusters). All the patients from cluster 2 (n = 91) had a confirmed diagnosis of SLE and the highest rate of anti-dsDNA positivity (91.7%). Cluster 3 included 79 women with pregnancy morbidity. Triple positivity was present in 3.8%, significantly lower when compared with Cluster 1 (34.7% versus 3.8%, P <0.01). Cluster 4 included 67 patients, 28 (41.8%) of whom with APS. Thrombotic events were observed in 23.9% patients. Cluster 4 had the highest rate of cytopenia, with thrombocytopenia as high 41.8% with no anti-dsDNA antibodies. Cluster 5 included 94 asymptomatic aPL carriers. CONCLUSION: While clusters 1, 2, 3 and 5 corresponded to well-known entities, cluster 4 might represent a bridging condition between pure primary APS and defined SLE, with lower thrombotic risk when compared with primary APS but higher general features such as ANA and cytopenia (mainly thrombocytopenia).

Endothelial dysfunction and cardiovascular risk in lupus nephritis: New roles for old players?

In systemic lupus erythematosus (SLE) patients, most of the clinical manifestation share a vascular component triggered by endothelial dysfunction. Endothelial cells (ECs) activation occurs both on the arterial and venous side, and the high vascular density of kidneys accounts for the detrimental outcomes of SLE through lupus nephritis (LN). Kidney damage, in turn, exerts a negative feedback on the cardiovascular (CV) system aggravating risk factors for CV diseases such as hypertension, stroke and coronary syndrome among others. Despite the intensive investigation on SLE and LN, the role of endothelial dysfunction, as well as the underlying mechanisms, remains to be fully understood, with no specifically targeted pharmacological treatment. It is not known, in fact, if the activation pathway(s) in venous ECs are similar to the one in arterial ECs and doubts persist on the shared manifestation of microcirculation compared to macrocirculation. In this work, we aim to review the recent literature about the role of endothelial activation and dysfunction in the development of CV complications in SLE and LN patients. We, therefore, focus on arteriovenous similarities and differences and on specific pathways of great vessels compared to capillaries. Critically summarising the available data is of pivotal importance for both basic researchers and clinicians in order to develop and test new pharmacological approaches in the treatment of basic components of SLE and LN.

Prognostic and Diagnostic Values of Novel Serum and Urine Biomarkers in Lupus Nephritis: A Systematic Review.

INTRODUCTION: While renal biopsy remains the gold standard for diagnosing lupus nephritis (LN), the prognostic and diagnostic role of non-invasive biomarkers for LN is currently debated. METHODS: Available studies published in last 5 years (2015-2020) assessing the diagnostic and prognostic value of urinary and/or serological biomarkers in subjects with LN were analyzed in this systematic review. RESULTS: Eighty-five studies were included (comprehending 13,496 patients with systemic lupus erythematosus [SLE], 8,872 LN, 487 pediatric LN, 3,977 SLE but no LN, 160 pediatric SLE but no LN and 7,679 controls). Most of the studies were cross-sectional (62; 73%), while 14 (17%) were prospective. In sixty studies (71%), the diagnosis of LN was biopsy-confirmed. Forty-four out of 85 (52%) investigated only serological biomarkers, 29 studies (34%) tested their population only with urinary biomarkers, and 12 (14%) investigated the presence of both. Outcome measures to assess the clinical utility of the analyzed biomarkers were heterogeneous, including up to 21 different activity scores, with the SLEDAI (in 60%) being the most used. Despite some heterogeneity, promising results have been shown for biomarkers such as urinary monocyte chemoattractant protein, urinary adiponectin, and urinary vascular cell adhesion protein 1. DISCUSSION/CONCLUSION: While serum and urine biomarkers have the potential to improve diagnostic and prognostic pathways in patients with LN, the vast heterogeneity across studies severely limits their applicability in current clinical practice. With the kidney biopsy still representing the gold standard, future efforts should focus on harmonizing study inclusion criteria and outcomes, particularly in clinical trials, in order to improve comparability and facilitate the implementations of available biomarkers into the daily practice.

16th International congress on antiphospholipid antibodies task force report on clinical manifestations of antiphospholipid syndrome.

The objectives of the 16th International Congress on Antiphospholipid Antibodies (aPL) Task Force on Clinical Manifestations of Antiphospholipid Syndrome (APS) were to critically analyze: a) the definition of "APS"; b) the current knowledge on non-traditional manifestations associated with aPL; and c) the risk stratification strategies in aPL-positive patients. The quality of evidence was assessed by the GRADE system. The task force concluded that: a) APS does not have a uniform definition given the heterogeneity of the clinical presentations and different aPL profiles; b) current literature supports the role for aPL testing in cases of thrombocytopenia and recurrent cardiac events but are limited by vast heterogeneity, providing an overall low-to-very low level of evidence; and c) risk stratification strategies in aPL-positive patients, such as aPL-Score and Global APS Score, can be useful in clinical practice. International multicenter studies are still highly needed to improve the quality of available evidence and consequently the strength of future recommendations.

Clinical manifestations in patients with antiphospholipid antibodies: Beyond thrombosis and pregnancy loss.

The clinical spectrum of the antiphospholipid syndrome (APS) encompasses additional manifestations other than thrombosis and pregnancy morbidity, which may potentially affect every organ and system. The pathophysiology of APS indeed cannot be explained exclusively by a prothrombotic state and the "extra-criteria" manifestations of the syndrome should be attributed to other mechanisms, such as inflammation, complement and platelet activation. In this case-series, we report patients with uncommon clinical APS presentations, to highlight relevant peculiarities of the syndrome, potentially paving the way for a further update of clinical as well as laboratory manifestations of this complex immunological condition.

The global antiphospholipid syndrome score in women with systemic lupus erythematosus and adverse pregnancy outcomes.

OBJECTIVES: To validate the global antiphospholipid syndrome score (GAPSS) in a cohort of women with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL). METHODS: This retrospective study included 143 women ever pregnant with SLE who presented in our outpatient clinic were included. Data on cardiovascular risk factors and aPL status were retrospectively collected and their individual GAPSS score was calculated. RESULTS: Significantly higher GAPSS values were found in women with any placental medicated complication (such as foetal death, placental abruption, prematurity, pre-eclampsia or intrauterine growth restriction (IUGR)) (GAPSS 8.2±3.0 vs. 3.5±3.0, p<0.001). Significantly higher GAPSS values were also found in those with recurrent miscarriages (RM) <10 weeks, foetal death, placental abruption, prematurity, pre-eclampsia or IUGR) (GAPSS 8.3±4.5 vs. 3.2±2.6, p<0.001). Patients with 3 or more consecutive early miscarriages (<10 weeks), foetal death, miscarriage <10 weeks' gestation, premature birth (<34 weeks), pre-eclampsia (<34 weeks), stillbirth, and placental infarction had significantly higher GAPSS values compared to those without previous pregnancy complications. The odds ratio of having any pregnancy morbidity when having a GAPSS value ≥8 was 20 compared to those with a GAPSS of ≤1 (p<0.001). CONCLUSIONS: Women with a history of aPL-related pregnancy complications had higher GAPSS values in this retrospective cohort compared to women without pregnancy complications. This study is the first step to assess the clinical utility of the GAPSS score in pregnancy. A prospective validation is needed.

Psychosocial burden in young patients with primary anti-phospholipid syndrome: an Italian nationwide survey (The AQUEOUS study).

OBJECTIVES: The AQUEOUS (Anti-phospholipid syndrome: a QUEstionnaire for yOUng patientS) study aimed to assess how the diagnosis of primary anti-phospholipid syndrome (PAPS) affects the psychosocial status of young patients. METHODS: Subjects with PAPS aged 18-45 years were invited to compile an ad hoc designed questionnaire and the Short Form-12 to assess quality of life (QoL). RESULTS: Ninety-two patients (83.7% females) were recruited in 10 Italian centres. Vascular and obstetric manifestations were equally represented. Nearly half of the patients perceived the need for psychological support, 89.2% when considering women after pregnancy complications. Social activities and working efficiency were reduced in APS patients, also intimacy was threatened. In all cases, fatigue appeared to be the main determinant. PAPS affected family planning, due to fears of treatment side-effects, disease hereditariness, inability to care for the newborn child. Fertility appeared to be conserved: the median time to pregnancy was 2 months; assisted reproduction techniques were pursued by 5 women. Our survey documented significantly lower rates of hospitalisation and learning disabilities in 51 children born after APS diagnosis as compared to 48 children born before. PAPS patients displayed lower QoL in physical and, to a greater extent, mental scores compared to the general Italian population. Both components were significantly lower in women and in patients with fatigue. CONCLUSIONS: The AQUEOUS study assessed for the first time the unmet needs of young PAPS patients, enabling the development of a future "youth-focused" strategy to reduce disease burden.

Treatment of antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is the most common acquired thrombophilia. The clinical manifestations of APS are mainly vascular thrombosis (venous and/or arterial) and/or recurrent pregnancy morbidity with the concomitant persistent presence of antiphospholipid antibodies (aPL). Therefore, the goals of the treatment of patients with APS are reducing the pregnancy morbidity and/or the prevention of thrombotic events during the follow-up. Optimal treatment of APS has long been discussed, due to the heterogeneity of the clinical manifestations and the consequent plurality in the medical specialties involved in managing this condition. This review summarizes the available evidence on primary thromboprophylaxis in aPL-positive individuals with no prior thrombotic events, secondary prophylaxis in patients with positive history for thrombotic events, the management of refractory or difficult cases and the current strategies for the management of APS during pregnancy.

A multicentre study of 244 pregnancies in undifferentiated connective tissue disease: maternal/fetal outcomes and disease evolution.

OBJECTIVES: To investigate fetal/perinatal and maternal outcomes from a large multicentre cohort of women diagnosed with UCTD. METHODS: This multicentre retrospective cohort study describes the outcomes of 224 pregnancies in 133 consecutive women with a diagnosis of UCTD, positive for ANA and aged <45 years old at study inclusion. RESULTS: Of the 224 pregnancies analysed, 177 (79%) resulted in live births, 45 (20.1%) in miscarriages (defined as pregnancy loss before 12 weeks' gestation), 2 (0.9%) in stillbirths (pregnancy loss after 20 weeks' gestation) and 6 (2.7%) cases showed intrauterine growth restriction. Miscarriages and stillbirths were strongly associated with the presence of aPL and ENA antibodies (P < 0.05). Maternal pregnancy complications were as follows: 5 (2.2%) cases developed pre-eclampsia, 11 (4.9%) cases gestational hypertension and 12 (5.4%) cases gestational diabetes. Joint involvement represented the most frequent clinical manifestation of the cohort (57.9%), followed by RP (40.6%), photosensitivity (32.3%) and haematological manifestations (27.1%). The rate of disease evolution of our cohort from a diagnosis of UCTD to a diagnosis of definite CTD was 12% within a mean time of 5.3 ± 2.8 years. With a total follow-up after first pregnancy of 1417 patient-years, we observed the evolution to a defined CTD in one out of every 88 patient- years. CONCLUSION: In our multicentre cohort, women with UCTD had a live birth rate of 79%. Women with UCTD should be referred to specialist follow-up when planning a pregnancy. ENA profiling and aPL testing should be mandatory in this setting, and further therapeutic approaches and management should be planned accordingly.

Global antiphospholipid syndrome score and anti-ß2-glycoprotein I domain I for thrombotic risk stratification in antiphospholipid syndrome: A four-year prospective study.

OBJECTIVE: This study aimed to assess prospectively the role of anti-ß2-glycoprotein I domain I antibody (aß2GPI-DI) and the Global Antiphospholipid Syndrome Score (GAPSS) in identifying antiphospholipid syndrome (APS) patients at higher risk of a new event. METHODS: Thrombotic APS patients were followed from May 2013 to July 2017. At baseline, we measured lupus anticoagulant, IgG/IgM anticardiolipin, anti-ß2-glycoprotein I, antiphosphatidylserine-prothrombin (aPS/PT) and IgG aß2GPI-DI, and calculated GAPSS for each patient. RESULTS: A total of 44 patients (age 43 ± 10 years, 89% female, 73% primary APS) were followed for 39 months (range 9-46 months). Four new thromboses occurred, two of them after vitamin K antagonist interruption. Recurrent patients presented higher GAPSS (median 20) and were triple and aß2GPI-DI positive; non-recurrent patients had lower GAPSS (median 10.5, range 0-20) and lower ratio of triple (33%) and aß2GPI-DI positivities (38%). aß2GPI-DI was associated with higher GAPSS (median 19 vs. 7, p < 0.001; Pearson correlation 0.82, p < 0.001) and had a greater proportion of triple (83% vs. 4%, p < 0.001) and aPS/PT positivity (94% vs. 50%, p = 0.002). CONCLUSION: Our data show a significant correlation between a validated risk score such as GAPSS and the novel antiphospholipid antibody aß2GPI-DI. Future studies are needed. However, one could speculate a role of aß2GPI-DI as a risk-stratifying tool for thrombotic events in APS.