Quantitative and Qualitative Characteristics of Atherosclerotic Plaques on Carotid Arteries in Patients with Antiphospholipid Syndrome: The Role of MDCT Angiography.

INTRODUCTION: Antiphospholipid syndrome (APS) is an autoimmune disease characterised by arterious and venous thrombosis, miscarriage, and the presence of antiphospholipid antibodies (aPL) in the blood. As we know, APS is also characterised by accelerated atherosclerotic degeneration with an increased risk of thrombosis in all blood vessels, including the carotid arteries. Carotid artery stenosis can manifest in many different ways. The aim of this study is to present the results of our multidetector computerised tomography angiography (MDCTA) analysis of the carotid arteries in patients with primary and secondary APS compared with a control group. MATERIALS AND METHODS: This study examined 50 patients with primary antiphospholipid syndrome (PAPS) and 50 patients with secondary antiphospholipid syndrome (SAPS). The results were compared with a control group also comprising 50 patients. The groups were analysed with respect to age, sex and the presence of well-established risk factors for vascular disease. The study was conducted using MDCTA, where we analysed the quantitative and qualitative (morphologic) characteristics of carotid artery lesions. RESULTS: Patients from the control group had significantly elevated levels of cholesterol and triglycerides in comparison with patients with PAPS and SAPS (p < 0.001 and p < 0.05). The results show that carotid artery lesions were significantly more common in patients with APS (PAPS, n = 40, CI95: 0.50-0.75, p = 0.0322 and SAFS, n = 54, CI95: 0.59-0.80, p = 0.0004) than within the control group (n = 23). There was a statistically significant difference between patients with APS and the control group with respect to lesions in the distal segments (n = 27, CI95: 0.67-0.95, p = 0.0001), bulbi and proximal segments (n = 21, CI95: 0.84-1.00, p = 0.000005). The number of patients with one lesion (L) (n = 27) was significantly greater than the number of those with three (n = 10, CI95: 0.56-0.86, p = 0.0051) or four (n = 3, CI95: 0.73-0.98, p = 0.00001) lesions. There were also more patients with two lesions (n = 24) than those with four (n = 3) (CI95: 0.71-0.97, p = 0.00005). Carotid artery stenosis was shown as a percentage of the carotid artery lumen diameter (%DS). Stenosis of up to 30%, was more common in patients in the PAPS group (n = 12) than in the control group (n = 3) (CI95: 0.52-0.96, p = 0.0201), while the SAPS group (n = 17) had an even larger disparity (CI95: 0.62-0.97, p = 0.0017). We observed a highly significant difference in the frequency of stenoses between 30% and 50% DS between the PAPS group (n = 24) and the control group (n = 7) (CI95: 0.59-0.90, p = 0.0023), as well as the SAPS group (n = 30) (CI95: 0.65-0.92, p = 0.0002). A qualitative analysis of plaque morphology revealed that patients with PAPS had significantly more soft tissue lesions (n = 23) compared with calcified lesions (n = 2) (CI95: 0.74-0.99, p = 0.00003), as well as more mixed plaques (n = 9) and calcified plaques (n = 2) (CI95: 0.48-0.98, p = 0.0348). Patients within the SAPS group had significantly more soft tissue (n = 35) than calcified lesions (n = 3) (CI95: 0.79-0.98, p = 0.00000021), as well as more mixed lesions (n = 21) compared with calcified (n = 3) (CI95: 0.68-0.97, p = 0.0002). CONCLUSIONS: Our study shows that subclinical manifestations of carotid artery lesions were more common in patients with APS. We came to the conclusion that MDCTA is an accurate diagnostic method because it is a safe method that provides us with a great quantity of accurate information about the characteristics of atheromatous plaques, which aids us in the further planning of treatment for patients with APS.

Humoral Response of Different Types of SARS-CoV-2 Vaccines in Patients with Autoimmune Rheumatic Diseases: Experiences from a Serbian Cohort.

BACKGROUND: Data are scarce on the immunogenicity of coronavirus disease 2019 vaccines in patients with autoimmune rheumatic diseases (ARD). OBJECTIVES: To measure the immunoglobulin G (IgG) response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization and to evaluate clinical characteristics associated with seropositivity. METHODS: Samples were collected after the second and third doses of the three different types of vaccines in ARD patients. Seroconversion rates and IgG antibody S1/S2 titers were measured. RESULTS: The type of ARD diagnosis and previous treatment had no significant impact on the serum IgG antibody levels measured after the second (P = 0.489 and P = 0.330, respectively) and boost dose (P = 0.441 and P = 0.446, respectively). What made a significant difference regarding serum IgG antibody levels after the second dose was the type of SARS-CoV-2 vaccine. The difference was highly statistically significant for all vaccine types (P = 0.001 with the highest odds ratio for the mRNA vaccine). After the boost with the mRNA vaccine, all patients achieved a high level of serum IgG antibody levels (t = 10.31, P = 0.001). No ARD patients experienced serious post-vaccinal reactions. Eight patients developed COVID-19 before the boost dose. CONCLUSIONS: In ARDs patients, the highest level of serum IgG antibody against S1/S2 proteins was achieved with the mRNA vaccine, irrespective of the therapy applied or the type of the disease. We recommend a booster dose with mRNA vaccine in all ARDs for the highest SARS-CoV-2 protection without serious post-vaccinal reactions observed.

Primary antiphospholipid syndrome as a cause of impaired left ventricular diastolic function: experience from a Serbian cohort.

OBJECTIVES: Cardiovascular manifestations, encountered in antiphospholipid syndrome, may develop as a consequence of acquired thrombophilia mediated by antiphospholipid antibodies and accelerated atherosclerosis as well. Our study aims to assess the impairment of the left ventricular diastolic performance, as early evidence of myocardial involvement in primary antiphospholipid syndrome (PAPS). METHODS: We analysed 101 PAPS patients, with the average age of 47.70±13.14y. Anticardiolipin antibodies (aCL IgG/IgM), anti-ß2 glycoprotein-I (anti-ß2GPI IgG/IgM), and lupus anticoagulant (LAC) were determined. Abnormal cut-off values used for left ventricular diastolic dysfunction (LVDD) were septal E ́<7 cm/sec, lateral E ́ <10 cm/sec, average E/E ́ ratio >14, LA volume index (LAVI) >34 mL/m2, and peak tricuspid regurgitation velocity >2.8 m/sec. LVDD was present if more than half parameters were with abnormal values. The results were compared to 90 healthy, age and sex-matched controls. RESULTS: LVDD was significantly more prevalent in PAPS patients compared to healthy controls (24.8% vs. 2.2%, p=0.001). In PAPS patients, it was signi cantly related to age, body mass index, hyperlipidaemia, thromboses and LAC positivity (p=0.0001, p=0.008, p=0.039, p=0.001, p=0.047 respectively). Patients with PAPS had higher LAVI (29.76±6.40 ml/m2 vs. 26.62±7.8 ml/m2, p=0.012), higher isovolumic relaxation time, lower lateral É velocity and lower E/É ratio compared to controls (p=0.0001, p=0.020, p=0.038, respectively). In multivariate analysis, thromboses in PAPS were significant, and independent predictors of LVDD. CONCLUSIONS: Thrombotic PAPS patients are at higher risk of LVDD development. Strong action against standard atherosclerotic risk factors and adequate therapy regimes seems to be crucial to preserve good diastolic performance of the left ventricle in PAPS.

Asymmetric Dimethylarginine Is a Marker of Endothelial Dysfunction in Thrombotic Antiphospholipid Syndrome Patients.

Objective: The potential contribution of asymmetric dimethylarginine (ADMA) and high-sensitivity C reactive protein (hsCRP) to endothelial dysfunction in APS patients has not been studied in detail, until now. The study involved 105 APS patients (59 diagnosed with primary APS (PAPS) and 46 APS associated with systemic lupus erythematosus (SAPS)) who were compared to 40 controls. Endothelial dysfunction was assessed by measurement of flow-mediated dilatation (FMD) and glyceryl trinitrate dilatation (NMD) of the brachial artery. ADMA (micromol/L) was analyzed by ELISA. Results: FMD in patients with APS was significantly lower than that of the controls (p < 0.001), with no difference between the PAPS and the SAPS groups. ADMA and hsCRP concentrations were significantly higher in the patient cohort than in the control group (p < 0.001, p = 0.006, respectively), as was the case with the SAPS group as compared to the PAPS group (p < 0.001, p = 0.022, respectively). FMD impairment correlated to ADMA (ρ 0.472, p < 0.001) and to hsCRP (ρ 0.181, p = 0.033). In the regression model, the ADMA concentration confirmed the strength of its association (B 0.518, SE 0.183, Wald 8.041, p = 0.005, Exp(B) 1.679, 95% CI 1.174−2.402) to FMD impairment. The synergistic probability model of ADMA and hsCRP caused FMD impairment when the positivity of ß2GPIIgG was added. ADMA may be used as a simple and low-cost tool for verifying the presence of endothelial dysfunction in APS patients. According to the results of the study, we could presume that hsCRP, together with aPL, has a preparatory effect on the endothelium in causing endothelial dysfunction.

Circulating immune-complexes of IgG/IgM bound to B2-glycoprotein-I associated with complement consumption and thrombocytopenia in antiphospholipid syndrome.

Background: Antiphospholipid syndrome (APS) is a multisystemic autoimmune disorder characterized by thrombotic events and/or gestational morbidity in patients with antiphospholipid antibodies (aPL). In a previous single center study, APS-related clinical manifestations that were not included in the classification criteria (livedo reticularis, thrombocytopenia, leukopenia) were associated with the presence of circulating immune-complexes (CIC) formed by beta-2-glycoprotein-I (B2GP1) and anti-B2GP1 antibodies (B2-CIC). We have performed a multicenter study on APS features associated with the presence of B2-CIC. Methods: A multicenter, cross-sectional and observational study was conducted on 303 patients recruited from six European hospitals who fulfilled APS classification criteria: 165 patients had primary APS and 138 APS associated with other systemic autoimmune diseases (mainly systemic lupus erythematosus, N=112). Prevalence of B2-CIC (IgG/IgM isotypes) and its association with clinical manifestations and biomarkers related to the disease activity were evaluated. Results: B2-CIC prevalence in APS patients was 39.3%. B2-CIC-positive patients with thrombotic APS presented a higher incidence of thrombocytopenia (OR: 2.32, p=0.007), heart valve thickening and dysfunction (OR: 9.06, p=0.015) and triple aPL positivity (OR: 1.83, p=0.027), as well as lower levels of C3, C4 and platelets (p-values: <0.001, <0.001 and 0.001) compared to B2-CIC-negative patients. B2-CIC of IgM isotype were significantly more prevalent in gestational than thrombotic APS. Conclusions: Patients with thrombotic events and positive for B2-CIC had lower platelet count and complement levels than those who were negative, suggesting a greater degree of platelet activation.

Analysis of Serbian Primary Antiphospholipid Syndrome Patients Confirmed a Strong Association Between Livedo Reticularis and Arterial Thrombosis: A National Cross-Sectional Cohort Study.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by antiphospholipid antibodies (aPLs) associated with thrombosis (arterial and/or venous) and/or obstetrical manifestations. However, various manifestations, which are considered to be noncriteria manifestations, are frequently found in APS. AIM: The purpose of this study was to evaluate whether noncriteria manifestations may be found more frequently in subjects with thrombotic and/or obstetrical APS ("criteria" manifestations) in a population of patients with primary APS (PAPS). This study presents the results from our national cohort. PATIENTS AND METHODS: This is a cross-sectional study of 360 PAPS patients. Data regarding the presence of thrombocytopenia, livedo reticularis, chorea, and valvulopathy were analyzed. The aPL analysis included the detection of anticardiolipin antibodies (aCLs: immunoglobulin G [IgG]/IgM), anti-ß 2 glycoprotein I (IgG/IgM), and lupus anticoagulant positivity. RESULTS: In our cohort, livedo reticularis was significantly related to arterial thromboses in the same way as valvular manifestations (valvular vegetations and valvular thickening and dysfunction not related to age) ( p = 0.0001, p = 0.013, respectively). Age was strongly related to all the noncriteria manifestations analyzed. Thrombocytopenia was significantly related to ß 2 glycoprotein I IgG and lupus anticoagulant positivity ( p = 0.043, p = 0.030, respectively), as well as to double and triple aPL positivity ( p = 0.041, p = 0.013 respectively). Moreover, in a multivariate model, livedo reticularis was strongly and independently related to arterial thrombosis in our cohort (odds ratio, 2.010; confidence interval, 1.229-3.288; p = 0.005). CONCLUSION: This cross-sectional analysis of a large cohort of Serbian PAPS patients confirmed a strong relationship between livedo reticularis and arterial thrombosis, suggesting a more cautious approach regarding the presence of noncriteria manifestations, especially livedo reticularis, in APS.

A Lower Level of Post-Vaccinal Antibody Titer against Influenza Virus A H1N1 May Protect Patients with Autoimmune Rheumatic Diseases from Respiratory Viral Infections.

Background and Objectives: The concentration of antibodies against virus influenza A H1N1 in the titer (≥1:32) positively correlates with resistance to flu in healthy persons. In elderly and immune-compromised patients, an influenza vaccine may be less immunogenic. Hypothesis: A lower post-vaccinal antibody titer (≥1:16) may be sero-protective against respiratory viral infections in patients with autoimmune rheumatic diseases. Materials and Methods: Fifty patients with autoimmune rheumatic diseases (Systemic Lupus Erythematosus-24; Rheumatoid Arthritis-15; and Sjögren's Syndrome-11), who were at least 65 years old or whose relative disease duration (disease duration/age) was greater than 1/8, were examined. Thirty-four of them were vaccinated with a trivalent inactivated non-adjuvant influenza vaccine. The antibody concentration against influenza virus A H1N1 was measured using the standardized hemagglutination inhibition test and patients who got any respiratory viral infection were registered. To test the hypothesis, a correlative analysis was applied, followed by a binary logistic regression that included potential confounding variables, such as age, disease duration and therapy (personal/health-related conditions). Results: Vaccinated patients were significantly less affected by respiratory viral infections (21% vs. 75%). The lower titer considered (≥1:16) was significantly present more often among vaccinated patients (68% vs. 6%). The correlation between its presence/absence and that of respiratory viral infections was -0.34 (p < 0.05). The binary logistic regression evidenced the relevance of this correlation, confirming the hypothesis. Vaccination was associated with the 87.3% reduction in the likelihood of getting respiratory viral infections, whereas the lower antibody titer (≥1:16) was associated with the 77.6% reduction in the likelihood of getting respiratory viral infections. The vaccine was well tolerated by all patients and after vaccination no exacerbation of the underlying disease was observed. Conclusions: A lower antibody titer (≥1:16) against influenza virus A H1N1 could be protective against respiratory viral infections for certain autoimmune rheumatic diseases patients, which confirms the clinical effectiveness of influenza vaccination.

Cardiac manifestations in primary antiphospholipid syndrome and their association to antiphospholipid antibodies' types and titers-cross-sectional study of Serbian cohort.

OBJECTIVES: Antiphospholipid syndrome (APS) is multisystem autoimmune coagulopathy with antiphospholipid antibodies (aPL) in its ground, manifested as a primary disease (PAPS) or in the setting of other conditions, most commonly systemic lupus erythematosus. The objective of this cross-sectional study was to investigate various cardiac manifestations and their possible relation to aPL type and titer in a Serbian cohort of PAPS patients. METHODS: A total of 360 PAPS patients were analyzed and aPL analysis included detection of anticardiolipin antibodies (aCL: IgG/IgM), anti-ß2glycoprotein I (ß2GPI: IgG/IgM), and lupus anticoagulant (LA). Cardiac manifestations investigated were valvular lesions (comprehending valvular thickening and dysfunction not related to age and pseudoinfective endocarditis), coronary artery disease (CAD) with specific insight for myocardial infarction (MI), chronic cardiomyopathy (CMP), and acute decompensated heart failure (ADHF) as well as pulmonary hypertension (PH) and intracardiac thrombus presence. RESULTS: The prevalence of cardiac manifestations overall was 19.6%. There was a strong association between age and the majority of cardiac manifestations, as well as standard atherosclerotic risk factors. aCL IgG-positive patients had a higher prevalence of valvular lesions (p = 0.042). LA presence was significantly related to MI (p = 0.031) and PH (p = 0.044). CMP and ADHF were significantly related to higher titers of aCl IgG (p = 0.033, p = 0.025 respectively). Age and smoking were independent risk predictors for MI in PAPS with meaningful risk for LA positivity (OR 2.567 CI 0.671-9.820 p = 0.168). CONCLUSIONS: Certain cardiac manifestations in PAPS were related to certain aPL type and/or titer levels, imposing confirmation in prospective studies. Preventive actions, comprehending proper anticoagulant/antithrombotic therapy, and intense action against standard atherosclerotic risk factors are of utmost importance in this group of patients. Key Points • In Serbian patients with primary antiphospholipid syndrome (PAPS), prevalence of non-criteria cardiac manifestations was 19.6% and they were significantly related to certain antiphospholipid antibodies and titers. • Lupus anticoagulant was a meaningful predictor of myocardial infarction, enabling possible risk stratification and proper preventive and therapeutical strategies in this subgroup of PAPS patients. • Patients with high titers of aCL IgG are more prone to acute decompensated heart failure occurence, imposing careful follow-up of these patients • Based on the analysis of the Serbian PAPS cohort, even being non-criterial, cardiology manifestations are significantly present and inclusion of cardiologists in treatment and follow-up of these patients should be implied from the diagnosis establishment.

Summary of the 12th Meeting of the European Forum on antiphospholipid antibodies ONLINE.

As a result of the current COVID-19 pandemic, the 12th meeting of the European Forum on Antiphospholipid Antibodies was held in a digital format on 26th March 2021. Even experienced for the first time in a virtual set-up, it kept its strength in continuation of the opportunity for more than 200 physicians from all continents and 20 countries to meet the experts in the field. Contemporary research in the area of antiphospholipid syndrome was presented, and proposals for the new research projects, as a distinguishing feature of the meeting, made a major contribution. Despite challenging times, this meeting enabled the highest number of registered participants to have interactive communication with presenters. This report summarizes major studies and new research projects presented during the online forum meeting.

Long-term efficacy of immunoglobulins in small fiber neuropathy related to Sjögren's syndrome.

The most common peripheral nervous system manifestations in Sjogren's syndrome are small fiber sensory neuropathies (SFPN) and axonal sensorimotor polyneuropathies. Currently, treatment in small fiber neuropathy is mainly symptomatic and based on anti-depressors and anti-epileptics. The benefit of treatment with polyvalent immunoglobulins for SFPN has been reported in small series of patients, although transient in several cases. The medium-to-long-term effects of polyvalent immunoglobulins (Ig) in SFPN in patients with Sjogren's syndrome who are refractory to conventional treatments remain an unmet medical need. We present our experience related to the persistent improvement of Ig in a case series of SFPN in Sjogren's syndrome and relevant data in the literature regarding the benefits of immunoglobulins, for this indication.

In utero exposure to Azathioprine in autoimmune disease. Where do we stand?

Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms. The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors. In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this field. TAKE HOME MESSAGES.

EULAR recommendations for the management of antiphospholipid syndrome in adults.

The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2-3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3-4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research.

Presence of Immune Complexes of IgG/IgM Bound to B2-glycoprotein I Is Associated With Non-criteria Clinical Manifestations in Patients With Antiphospholipid Syndrome.

Background: Antiphospholipid syndrome (APS) is an acquired autoimmune disorder defined by the presence of both clinical (thromboembolic events or pregnancy morbidity) and laboratory (antiphospholipid antibodies, aPL) manifestations. Despite their importance, several clinical manifestations strongly associated with APS such as livedo reticularis (LR), thrombocytopenia, sicca-ophthalmic(sicca), heart, or neurological manifestations are not included in the APS clinical classification criteria. Circulating immune complexes (CIC) formed by Beta-2-glycoprotein I (B2GPI) and aPL (B2-CIC) have been described and their presence has been related with thrombotic events. Methods: Cross-sectional and observational cohort study in APS patients with thrombotic symptomatology. Setting and Participants: Fifty-seven patients from the University Hospital Center Bezanijska Kosa (Belgrade, Serbia) who met the APS classification criteria (35 with primary APS and 22 with APS associated to systemic lupus erythematosus). This study aimed to determine the prevalence of B2-CIC in APS patients and to evaluate their association with clinical manifestations of APS not included in the classification criteria. Results: B2-CIC prevalence in APS patients was 19.3%. The presence of thrombocytopenia (OR:5.7), livedo reticularis (OR:5.6), sicca (OR:12.6), and leukopenia (OR:5.6) was significantly higher in patients with B2-CIC than in the rest of APS patients. C3 and C4 complement factor levels were significantly lower in B2-CIC positive patients, which suggests a greater consumption of complement. Patients with quadruple aPL positivity (triple aPL-positivity plus the presence of B2-CIC) showed a higher prevalence of thrombocytopenia, leucopenia and LR than those with single/double aPL-positivity. No significant differences were found in the frequencies observed in patients with triple-only vs. single/double aPL-positivity. There were no significant differences between patients with primary APS and lupus-associated APS regarding the prevalence of B2-CIC and outcomes. Conclusions: Presence of B2-CIC is strongly associated with several non-criteria clinical manifestations related to APS and to higher complement consumption. More studies are required to better understand the clinical significance of B2-CIC.

Primary antiphospholipid syndrome and antiphospholipid syndrome associated to systemic lupus: Are they different entities?

Primary antiphospholipid syndrome (PAPS) and antiphospholipid syndrome associated to lupus (SAPS) have several overlapping characteristics. As systemic manifestations are also reported in patients with PAPS, and as a subgroup of PAPS patients could evaluate to a SAPS, the differentiation between the two types of APS could be performed based on the clinical experience of the medical teams and is related to a variety of clinical, biological, histological and genetic features. Several data are available in the literature with respect to the identification of distinctive features between these two entities. However, there are some limitation in the interpretation of results issued from studies performed prior to updated Sydney criteria. Based on recent data, a certain number of features more frequent in one type of APS as compared to the other could be distinguished. The major differentiation between these two entities is genetical. New genetic data allowing the identification of specific subgroups of APS are ongoing.

Anti-annexin A5 antibodies and 25-hydroxy-cholecalciferol in female patients with primary antiphospholipid syndrome.

Vascular antiphospholipid syndrome (VAPS) and obstetric (OAPS) are different entities because some patients only develop thrombosis (without recurrent pregnancy losses) and vice versa. Only two articles have reported that low 25-hydroxy-cholecalciferol (vitamin D3, VD3) levels were not correlated with the presence of conventional antiphospholipid antibodies (aPL Abs: anticardiolipin (aCL), anti-beta2glycoprotein I (aß2gpI), and lupus anticoagulant (LA)), but no article analyzed the association of VD3 and anti-annexin A5 (aanxA5) Abs. The aim of our study was to investigate the association between VD3, multiple positivity of conventional aPL and aanxA5 Abs levels only in female OAPS vs. VAPS. Our study included 62 consecutive female PAPS patients. Concentrations of Abs were measured by ELISA, while VD3 levels were determined by immunochemiluminescence. Only 10/62 (16.13%) had sufficient (≥ 30 ng/ml) VD3 levels, while 48/62 (77.42%) and 4/62 (6.45%) had insufficiency and VD3 deficiency, respectively. Statistically significant VD3 deficiency was noticed in VAPS (vs. OAPS, P = 0.013). A negative correlation between VD3 levels and the age of patients was noticed (r = - 0.493, P = 0.032) only in VAPS subgroup. Multiple positivity of aPL and aanxA5 Abs was not associated with VD3 deficiency. Newly emerging aPL Abs, such as aanxA5 Abs, or their combinations with classical aPL Abs are not associated with VD3 deficiency in neither OAPS nor VAPS patients. Due to its immunomodulatory roles in B-Ly homeostasis, supplementation with VD3 should be considered in APS, at least in subgroup with severe form of the disease, i.e., VAPS.

Relationship between cerebrovascular and valvular manifestations in a Serbian cohort of patients with antiphospholipid syndrome.

OBJECTIVES: Antiphospholipid syndrome (APS) may manifest itself as a primary (PAPS) or secondary disease, most commonly in the context of systemic lupus erythematosus (SLE) with various neurological and cardiac manifestations in its occurrence. The objective of this study was to investigate the relationship between cerebrovascular (stroke and transient ischaemic attack (TIA)) and valvular manifestations in a Serbian cohort of APS patients. METHODS: This is cross sectional study of 508 APS patients: 360 PAPS and 148 APS patients associated with SLE (SAPS). aPL analysis included detection of anticardiolipin antibodies (aCL: IgG/IgM), anti-ß2glycoprotein I (ß2GPI: IgG/IgM), and LA. RESULTS: The prevalence of valvular manifestations (valvular vegetations and valvular thickening and dysfunction not related to age) in our cohort was significantly higher in SAPS group. (28.4% vs. 8.6%, p=0.0001). Age was strong predictor for stroke and TIA occurrence in both groups as well as gender (stroke more likely occurred in male SAPS and TIA in male PAPS patients). Presence of ß2GPI IgG in SAPS patients was significantly related to stroke (p=0.018), whereas ß2GPI IgG negative PAPS patients were more prone to TIA. Valvular manifestations were significantly related to TIA in both groups of patients and were independent risk factors for TIA in PAPS (OR 3.790 CI 1.597-8.998 p=0.003). CONCLUSIONS: In this cross-section analysis of a large cohort of Serbian APS patients, there was a strong relationship between valvular and cerebrovascular manifestations, suggesting a more cautious approach regarding neurological symptoms, especially in PAPS patients with valvular vegetations present.

Are the cutaneous manifestations in patients with primary antiphospholipid syndrome a marker for predicting lung manifestations?

OBJECTIVES: The aim of this study was to investigate association between pulmonary and skin manifestations in a large group of patients with primary antiphospholipid syndrome (PAPS) as well as their connection with antiphospholipid antibodies. METHODS: Our prospective study comprises of 390 patients with primary APS. Antiphospholipid antibody (aPL) analysis included detection of aCL (IgG/IgM), ß2GPI (IgG/IgM) and LA. Distinct pulmonary and skin associations were determined, as well as their associations with aPL. RESULTS: In PAPS patients the presence of LA was more common in PTE (p=0.005) and in pulmonary microthrombosis (p=0.003). We revealed statistical significance considering the presence of aCL IgM and pulmonary microthrombosis (p=0.05). Skin ulcerations correlated with positive titres aCL IgM and ß2 GPI IgM (p=0.03 and 0.04, respectively), while pseudovasculitis correlated with positive titres ß2 GPI IgM (p=0.02). PAPS patients were more more likely to develop pulmonary thromboembolisam if they had livedo reticularis (p=0.005), skin ulcerations (p=0.007), pseudovasculitic lesions (p=0.01), superficial cutaneous necrosis (p=0.005), and digital gangrene (p=0.02). Patients were also more prone to pulmonary microthrombosis if they already had livedo reticularis (p=0.03), skin ulcerations (p=0.007), pseudovasculitic lesions (p=0.05), superficial cutaneous necrosis (p=0.006), and digital gangrene (p=0.02). CONCLUSIONS: There is strong link between some pulmonary and skin manifestations in PAPS patients, suggesting complexity and evolutionary nature of APS. The presence of skin manifestations may be a high risk factor for several types of serious pulmonary manifestations in PAPS. Certain aPL types are associated with distinct pulmonary and skin manifestation, suggesting their predictive role.

Abdominal pain in patient with antiphospholipid syndrome-the role of MDCT angiography on visceral blood vessels.

Antiphospholipid syndrome (APS) is an autoimmune disease defined by accelerated atherosclerosis, arterial and venous thrombosis, fetal loss, and the presence of antiphospholipid antibodies (aPL) in the serum and which leads to the occurrence of various vascular events. Nonspecific abdominal pain can be one of the symptoms due to changes on visceral blood vessels. The goal of our work is to show the results we obtained in multidetector computed tomography (MDCT) angiography examination of visceral arteries, comparing patients with primary antiphospholipid syndrome (PAPS) and secondary antiphospholipid syndrome (SAPS) with control group. In this study, we analyzed 50 patients with primary PAPS and 50 patients, with secondary SAPS. The results were compared to 50 patients in the control group. The groups were compared in terms of age, gender, and the most common risk factors except for the lipid status, since controls had significantly higher levels of cholesterol and triglycerides. The study was conducted on 64-MDCT, on which we analyzed quantitative and morphological characteristics of the blood vessel lesions. Patients from the control group had statistically significant elevation of cholesterol and triglyceride levels compared to the patients with SAPS and PAPS (p < 0.001 and p < 0.05). The results showed that the frequency of changes is statistically (p < 0.05 and p < 0.001) more common in patients with PAPS and SAPS than in the control group. Statistically significant difference between the groups was found in superior and inferior mesentery arteries. Analyzing the number of lesions, there was statistically high difference between the patients with one and two lesions than in patients with four or more lesions (p < 0.001), lower difference compared to the patients with three lesions (p < 0.01), while there was low, but yet statistically important difference between the patients with three lesions and those with five or more blood vessel lesions (p < 0.05). Analyzing percentage of diameter stenosis, we established that the lesions in the groups of 0-30% diameter stenosis (DS) and 30-50% DS in patients with PAPS (n = 42) and SAPS (n = 44) are more common than in the control group (n = 18, p < 0.05). Analyzing the qualitative characteristics of plaques, we established significantly higher frequency of soft tissue and mixed lesions than calcified ones in patients with PAPS and SAPS (p < 0.001; p < 0.05). Our study showed that the subclinical manifestation of the changes on visceral arteries is more common in patients with APS. Patients with abdominal pain were those with two or more lesions, and according to our results, majority had PAPS. Because of its safety and accuracy, the method of choice is MDCT angiography in monitoring the progression of disease.

Effects of sustained i.c.v. infusion of lupus CSF and autoantibodies on behavioral phenotype and neuronal calcium signaling.

Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that is often accompanied by brain atrophy and diverse neuropsychiatric manifestations of unknown origin. More recently, it was observed that cerebrospinal fluid (CSF) from patients and lupus-prone mice can be neurotoxic and that acute administration of specific brain-reactive autoantibodies (BRAs) can induce deficits in isolated behavioral tasks. Given the chronic and complex nature of CNS SLE, the current study examines broad behavioral performance and neuronal Ca2+ signaling in mice receiving a sustained infusion of cerebrospinal fluid (CSF) from CNS SLE patients and putative BRAs (anti-NR2A, anti-ribosomal P, and anti-α-tubulin). A 2-week intracerebroventricular (i.c.v.) infusion of CSF altered home-cage behavior and induced olfactory dysfunction, excessive immobility in the forced swim test, and perseveration in a learning task. Conversely, sustained administration of purified BRAs produced relatively mild, both inhibitory and stimulatory effects on olfaction, spatial learning/memory, and home-cage behavior. In vitro studies revealed that administration of some CSF samples induces a rapid influx of extracellular Ca2+ into murine neurons, an effect that could be partially mimicked with the commercial anti-NR2A antibody and blocked with selective N-methyl-D-aspartate (NMDA) receptor antagonists. The current findings confirm that the CSF from CNS SLE patients can be neuroactive and support the hypothesis that intrathecal BRAs induce synergistically diverse effects on all domains of behavior. In addition, anti-NMDA receptor antibodies may alter Ca2+ homeostasis of central neurons, thus accounting for excitotoxicity and contributing to the heterogeneity of psychiatric manifestations in CNS SLE and other autoantibody-related brain disorders.

The interaction between anti-Ro/SSA and anti-La/SSB autoantibodies and anti-infectious antibodies in a wide spectrum of auto-immune diseases: another angle of the autoimmune mosaic.

OBJECTIVES: The presence of anti-Ro/SSA and anti-La/SSB antibodies has been linked with autoimmunity in general and with several autoimmune diseases (AID) in particular. In the current study we evaluated these antibodies in a wide spectrum of AID as well as the links between them and anti-infectious antibodies. METHODS: We examined 2082 sera from patients with 16 different AID compared to 524 sera from geographically-matched healthy controls, for the presence and titres of anti-Ro/SSA and anti-La/SSB. All samples were also tested for a variety of anti-infectious agents' antibodies using the BioPlex 2200-immunoassay (Bio-Rad, USA). RESULTS: Anti-Ro/SSA was more prevalent, with significantly higher titre in 5 autoimmune diseases namely Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) both primary and APS linked to SLE, systemic sclerosis (SSc) and primary biliary cirrhosis (PBC). Anti-La/SSB was more prevalent with higher titers in SS, SLE, APS linked to SLE and PBC. Prevalence, but not titers, of both antibodies were higher also in polymyositis (PM). Additionally, we found a correlation between anti-Ro/SSA antibodies and antibodies of the IgM and IgG subtypes directed at cytomegalovirus as well as IgG-antibodies directed at Epstein-Barr virus (EBV) and toxoplasma (p<0.001). Anti-La/SSB antibodies correlated with the presence of IgG antibodies against EBV early antigen (p<0.001). CONCLUSIONS: In a large cohort of patients with autoimmune diseases we found an association between anti-Ro/SSA and anti-La/SSB antibodies and 6 autoimmune diseases, amongst which primary APS and PM. Additionally, we observed linkages between these autoantibodies and anti-infectious antibodies directed at Epstein-Barr virus, toxoplasma and cytomegalovirus. Our findings support the concept of interplay between infectious agents and autoimmunity, such as the plausibility of an infectious agent that trigger the immune system to produce specific antibodies which will later result in a unique group of AID.