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.

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.

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.

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.

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.

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.

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.

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.

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.

Antiphospholipid-mediated thrombosis: interplay between type of antibodies and localisation of lung, and cardiovascular incidences in primary antiphospholipid syndrome.

OBJECTIVES: The aim of this study was to analyse prevalence and type of pulmonary manifestations in patients with primary antiphospholipid syndrome (PAPS), their association to antiphospholipid antibody (aPL) type and localisation of peripheral vascular thrombosis, and possible relationship to existing cardiac manifestations. METHODS: Our cross-sectional study comprised 318 PAPS patients, enrolled in the study as the Serbian APS Registry. aPL analysis included detection of aCL (IgG/IgM), ß2GPI (IgG/IgM) and LA, served to evaluate associations with cardiac and pulmonary manifestations. RESULTS: In patients with pulmonary embolism and infarction, we observed significant prevalence of myocardial infarction (p=0.044), unstable angina pectoris (p=0.001), venous thrombosis (p=0.007) arterial thrombosis (p=0.0001), deep venous thrombosis of the low extremities (p=0.008), and superficial thrombophlebitis of the low extremities (p=0.023). Patients with primary pulmonary hypertension were more prone to unstable angina pectoris (p=0.009), while patients with secondary pulmonary hypertension were more prone to venous thrombosis (p=0.04) and deep venous thrombosis of the inferior extremities (p=0.04). Patients with pulmonary microthrombosis were more prone to unstable angina pectoris (p=0.026), arterial thrombosis (p=0.002), venous thrombosis (p=0.001), deep venous thrombosis of the inferior extremities (p=0.001), and superficial thrombophlebitis of the inferior extremities (p=0.001). The presence of LA was significantly higher in patients with pulmonary embolism and infarction (p=0.001), secondary pulmonary hypertension (p=0.032), and pulmonary microthrombosis (p=0.001). CONCLUSIONS: Presence of LA was associated with distinct pulmonary manifestations in the Serbian APS cohort. There is a strong link between some cardiovascular and pulmonary manifestations in PAPS patients, suggesting complexity and evolutionary nature of PAPS.

Physical Activity Program Is Helpful for Improving Quality of Life in Patients with Systemic Lupus Erythematosus.

Given the crucial events in systemic lupus erythematosus (SLE) such as joint and muscle pain, fatigue, depression, obesity and osteoporosis, the very thought of exercising can be challenging. This prospective study included 60 patients diagnosed with SLE in stable condition. A randomly selected group of 30 women had aerobic training on a bicycle ergometer for a period of 15 minutes, 3 times per week for 6 weeks, while the second group of 30 women performed isotonic exercises (to stretch and lengthen muscles and improve the range of motion) for 30 minutes, 3 times per week during the same period. Fatigue Severity Scale (FSS), Short Form 36 (SF36) questionnaire on the quality of life and Beck depression inventory (BDI) were analyzed at baseline and after 6 weeks. At baseline FSS score was 53.8 ± 5.7 and after the physical activity FSS score was 29.1 ± 7.8 (FSS ≥ 36; fatigue is present). The largest number of patients (66.7%) was in a moderate depressed state at the baseline, while after physical activities 61.7% of patients, had a mild mood disturbance. There were significant differences (p < 0.001) in values of all areas of quality of life questionnaire SF36 before and after the implementation of physical activity. The type of physical activity had no influence in FSS and BDI values. Continuous physical activity, regardless of its type, significantly improved quality of life of SLE patients. We recommend regular physical activity as an integral part of modern therapeutic approach in this patient population.

Degradation of neutrophil extracellular traps is decreased in patients with antiphospholipid syndrome.

OBJECTIVES: A decreased ability to degrade neutrophil extracellular traps (NETs) is seen in a subgroup of patients with systemic lupus erythematosus (SLE) and correlates with the presence of autoantibodies. Antiphospholipid syndrome (APS) can develop secondary to SLE or as a primary disease. In the current study we investigated the ability of sera from patients with APS to degrade NETs. The presence of antibodies against NETs and neutrophil remnants were also determined in the same patients. METHODS: In the study, 106 patients with APS (73 primary and 33 secondary), 76 patients with systemic sclerosis (SSc) and 77 healthy donors as control samples were included. NETs generated from neutrophils isolated from healthy volunteers were incubated with patient sera, followed by measurement of degraded NETs or deposited IgG. RESULTS: Sera of APS patients had a decreased ability to degrade NETs compared to healthy controls, with no difference between primary and secondary APS. Sera from SSc patients did not differ significantly from healthy controls in the ability to degrade NETs. A decreased degradation of NETs correlated weakly to increased levels of antibodies against NETs/neutrophil remnants in patients with primary APS, but stronger in patients with secondary APS. CONCLUSIONS: The ability to degrade NETs is decreased in a subgroup of patients with APS and is associated with antibodies against NETs and specific clinical manifestations in those patients.

Association between cardiac manifestations and antiphospholipid antibody type and level in a cohort of Serbian patients with primary and secondary antiphospholipid syndrome.

BACKGROUND: Antiphospholipid syndrome (APS, also known as Hughes syndrome) may manifest itself as a primary or secondary disease, most commonly with systemic lupus erythemathosus (SLE) and various cardiac manifestations. OBJECTIVES: To report the first results from the Serbian National Cohort study, which was started in January 2000. METHODS: Our study included 374 patients: 260 primary APS patients and 114 SLE patients with secondary APS. Antiphospholipid antibody (aPL) analysis included detection of anticardiolipin antibodies (aCL) (immunoglobulin G and M), beta2-glycoprotein 1, and lupus anticoagulant. Echocardiography was performed in all patients, and data on myocardial infarction, unstable angina, chronic cardiomyopathy and acute heart failure were collected. RESULTS: There were 30.7% secondary APS patients and 9.2% primary APS patients with pseudo-infective endocarditis (P = 0.0001). Cardiac manifestations were observed in 28.7% of patients who had more than one type of antibody (category I), in 24.1% with category IIa, in 23.1% with category IIb, and in 27.8% with category IIc (P = 0.78). Age was confirmed as a significant factor for cardiac manifestations in APS patients (52.3 and 43.3 years, respectively, P = 0.001). aCL IgG and IgM positivity was related to valvular changes in all APS patients and high levels of those antibodies increased the risk of these manifestations. CONCLUSIONS: Patients with secondary APS had a higher prevalence ofvalvular lesions, and some aPL types and high levels of aPL were risk factors for specific cardiac manifestations in APS patients.

Association between non-thrombotic neurological and cardiac manifestations in patients with antiphospholipid syndrome.

OBJECTIVES: The aim of this study was to investigate the association between non-thrombotic neurological and cardiac manifestations in patients with antiphospholipd syndrome (APS), as well as their connection with type and level of antiphospholipid antibodies. METHODS: Our prospective study comprises 333 patients: 218 with primary and 115 with secondary APS. Antiphospholipid antibody (aPL) analysis included detection of aCL(IgG/IgM), ß2GPI(IgG/IgM) and LA and served to evaluate associations with distinct neurological manifestations. RESULTS: The presence of aCL IgG was more common (p=0.001) in SAPS and LA in PAPS patients (p=0.002). High ß2GPI IgM levels (>100PLU/ml) were more common in epilepsy (p=0.00001) in PAPS, and in transient ischaemic attack (p=0.029) in SAPS. High ß2GPI IgG levels (>100PLU/ml) were more common in epilepsy (p=0.035) in SAPS. Chorea, migraine and epilepsy occurred more often in SAPS and headache and depression in PAPS. We found statistical significance considering the presence of aCL IgG and acute ischaemic encephalopathy in SAPS, aCL IgM and epilepsy in SAPS, aCL IgM and migraine in PAPS, ß2GPI IgG and chorea in SAPS and ß2GPI IgM and TIA and epilepsy in PAPS. LA was linked to depression, transient global amnaesia and migraine in PAPS. Patients with non-stable angina pectoris were more likely to develop TIA in both PAPS and SAPS, epilepsy and transient global amnaesia in PAPS and acute ischaemic encephalopathy in SAPS. Patients with valve vegetations were more prone to epilepsy and depression. CONCLUSIONS: Certain aPL type and levels are associated with distinct neurological non-thrombotic manifestation, suggesting their predictive role. There is strong link between some non-thrombotic neurological and cardiac manifestations in APS patients, suggesting the complexity and evolutionary nature of APS.

Association between systemic non-criteria APS manifestations and antibody type and level: results from the Serbian national cohort study.

OBJECTIVES: The aim of this study was to investigate the importance of aPL type and level for non-criteria-related events in APS patients. METHODS: Our study included 374 patients: 260 with PAPS and 114 with APS associated with systemic lupus erythematosus (SLE). RESULTS: We discovered significant connection between migraine and LA absence, livedo reticularis and aCL-IgG, skin ulcerations with aCL-IgG and anti-ß2GPI-IgM, pseudovasculitis lesions with aCL-IgG, aCL-IgM and anti-ß2GPI-IgM, and thrombocytopenia with aCL-IgM, aCL-IgG and anti-ß2GPI-IgG. Thrombocytopenia occurred more frequently in patients with more than one aPL. In PAPS, epilepsy correlated with ß2GPI-IgM, migraine with aCL-IgM, and thrombocytopenia with aCL-IgM, aCL-IgG, anti ß2GPI-IgG and LA. Skin ulcerations occurred more frequently in IIc category patients and in patients with high levels of aCL-IgG and anti ß2GPI-IgG. Livedo reticularis was more prominent in PAPS with high levels of aCL-IgG. Significantly higher prevalence of thrombocytopenia was observed in patients with high levels of aCL-IgG and anti ß2GPI-IgG. Epilepsy was related to high levels of anti ß2GPI-IgM and thrombocytopenia in the SAPS was correlated with aCL-IgG. Skin ulcerations were more prevalent in aCL-IgM positive SAPS patients and epilepsy more frequently in SAPS patients with high levels of anti ß2GPI-IgG. CONCLUSIONS: Our study showed that certain aPL type with certain level correlated with non-criteria manifestations, suggesting their predictive role.

Helicobacter pylori serology in autoimmune diseases - fact or fiction?

BACKGROUND: The pathogenesis of autoimmunity is presumed to be a complex process including genetic predisposition, hormonal balance and environmental factors such as infectious agents. Helicobacter pylori, a common bacterial infectious agent has been associated with a variety of autoimmune disorders. However, this bacteria is also thought to play a protective role in the development of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). We tested various links between anti-H. pylori (anti-HP) antibodies and a wide profile of autoimmune diseases and autoantibodies. METHODS: A total of 1290 patients diagnosed with 14 different autoimmune diseases from two geographical areas (Europe and Latin America) and two groups of healthy matching controls (n=385) were screened for the presence of H. pylori IgG antibodies by "pylori detect" kit. In parallel, a large profile belonging to three groups of autoantibodies was tested in all sera (anti-nuclear antibodies, autoantibodies associated with thrombophilia and gastrointestinal diseases). RESULTS: Our data demonstrate associations between anti-HP antibodies and anti-phospholipid syndrome, giant cell arteritis, systemic sclerosis and primary biliary cirrhosis. Our data also support a previously known negative association between the prevalence of anti-HP antibodies and IBD. Additionally, links were made between seropositivity to H. pylori and the presence of anti-nuclear antibodies, dsDNA, anti-Ro and some thrombophilia-associated antibodies, as well as negative associations with gastrointestinal-associated antibodies. CONCLUSIONS: Whether these links are epiphenomenal or H. pylori does play a causative role in the autoimmune diseases remains uncertain. The negative associations could possibly support the notion that in susceptible individuals infections may protect from the development of autoimmune diseases.

Influenza vaccination in autoimmune rheumatic disease patients.

Patients suffering from autoimmune rheumatic diseases have significantly higher risk of developing various infections compared to the healthy population. Our study included patients suffering from systemic lupus erythematosus (n = 30), rheumatoid arthritis (n = 37) or Sjögren's syndrome (n = 32), with stable underlying diseases status. In November 2010, 47 patients, including 35 subjects vaccinated annually during 2006-2010, received immunization against influenza with trivalent inactivated split vaccine, whereas 52 patients did not accept proposed vaccination in that period. The presence of viral (primarily influenza) and bacterial infections, parameters of disease activity (from the date of vaccination until April 2011), and titers of antibodies against A H1N1 were then monitored in vaccinated and unvaccinated patients. We have identified the importance of predisposing factors for influenza occurrence (i.e. previous respiratory infections and vaccinations in last five years, age, sex, type of disease and duration, medications, smoking) in those groups of patients. The incidence of influenza or bacterial complications (bronchitis) among vaccinated patients was significantly lower, compared to the non-vaccinated group. Importantly, there was no case of exacerbation of the underlying disease. The last vaccination in 2010 reduced the risk of influenza by 87%, but previous bacterial infections (bronchitis and pneumonia) increased influenza risk significantly. In the present study, we have shown the efficiency, sufficient immunogenicity and safety of modern influenza vaccine application in patients suffering from systemic lupus erythematosus, rheumatoid arthritis or Sjögren's syndrome.

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.

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.