Primary Antiphospholipid Syndrome Patients Research Articles

Cerebrovascular disease in patients with antiphospholipid antibody syndrome: a transcranial Doppler and magnetic resonance imaging study.

Transcranial Doppler (TCD) and brain MRI may be useful in evaluating patients with APS, helping to stratify the risk of cerebrovascular ischaemic events in this population. This study aimed to assess the frequency of brain MRI abnormalities in patients with primary antiphospholipid syndrome, secondary antiphospholipid syndrome and SLE and correlate to TCD findings. The study, conducted over four years at two autoimmune disease referral centres, included 22 primary antiphospholipid syndrome patients, 24 secondary antiphospholipid syndrome patients, 27 SLE patients without APS and 21 healthy controls. All participants underwent TCD to assess cerebral haemodynamics, detect microembolic signals and evaluate right-to-left shunts, followed by brain MRI and magnetic resonance angiography. MRI scans were reviewed for acute microembolism, localized cortical infarctions, border infarctions, lacunar infarctions, ischaemic lesions, white matter hyperintensity, micro and macro haemorrhages and arterial stenosis ≥50% of the cervical carotid artery, by two neuroradiologists blinded to the clinical data. Brain MRI findings were similar between the groups, except for lacunar infarction, more frequent in patients with secondary antiphospholipid syndrome (P = 0.022). Patients with intracranial stenosis detected by TCD had a higher frequency of territorial infarction (40% vs 7.5%, P = 0.02), lacunar (40% vs 11.3%, P = 0.075) and border zone infarcts (20% vs 1.9%, P = 0.034). Patients with intracranial stenosis presented a higher frequency of territorial, lacunar and border zone infarcts, suggesting that evaluating the intracranial vasculature should not be neglected in patients with APS and stroke.

Type I interferon pathway activation across the antiphospholipid syndrome spectrum: associations with disease subsets and systemic antiphospholipid syndrome presentation.

While the type I interferon (IFN-I) pathway is crucial in autoimmunity, its role in antiphospholipid antibody (aPL)-positive subjects, including aPL carriers and antiphospholipid syndrome (APS) patients, is poorly understood. This study aims at characterizing IFN-I pathway activation within the spectrum of aPL-positive subsets. A total of 112 patients [29 aPL carriers, 31 primary APS (PAPS), 25 secondary APS (SAPS), 27 systemic lupus erythematosus (SLE) patients without aPL, and 44 healthy controls (HCs)] were recruited. IFI6, IFI44, IFI44L, MX1, IFI27, OAS1, and RSAD2 gene expression was evaluated in whole blood, and a composite index (IFN score) was calculated. An overall activation of the IFN-I pathway was observed across the entire APS spectrum, with differences among genes based on the specific disease subset. The composite score revealed quantitative differences across subsets, being elevated in aPL carriers and PAPS patients compared to HCs (both p < 0.050) and increasing in SAPS (p < 0.010) and SLE patients (p < 0.001). An unsupervised cluster analysis identified three clusters, and correspondence analyses revealed differences in clusters usage across APS subsets (p < 0.001). A network analysis revealed different patterns characterizing different subsets. The associations between IFN-I pathway activation and clinical outcomes differed across APS subsets. Although no differences in gene expression were observed in systemic APS, the network analyses revealed specific gene-gene patterns, and a distinct distribution of the clusters previously identified was noted (p = 0.002). IFN-I pathway activation is a common hallmark among aPL-positive individuals. Qualitative and quantitative differences across the APS spectrum can be identified, leading to the identification of distinct IFN-I signatures with different clinical values beyond traditional categorization.

Vitamin D Status in Patients with Primary Antiphospholipid Syndrome (PAPS): A Systematic Review and Meta-Analysis.

Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disorder, characterised by consistently high levels of antiphospholipid antibodies, thrombosis, and/or pregnancy morbidity. Due to various suspected causes, deficient or insufficient levels of vitamin D in the serum have been reported in patients with PAPS; however, the reports have been sporadic and inconclusive. This systematic review and meta-analysis aimed to comprehensively evaluate the serum vitamin D levels in patients with PAPS compared to controls. A protocol was registered in PROSPERO (Registration No. CRD42019132128) and a systematic literature search was conducted through Google Scholar, PubMed, Web of Science, Scopus, and ScienceDirect databases without restricting language and year. Pooled prevalence, mean difference (MD), and odds ratio (OR) along with 95% confidence intervals (CI) were determined by using a random effects model. Study quality was assessed by the Joana Brigg's Institute (JBI) protocol and publication bias was evaluated by a trim and fill funnel plot, Begg's, and Egger's tests. The pooled prevalence of vitamin D deficiency and insufficiency was found to be 32.2% [95% CI: 16.3-48.2] and 61.5% [95% CI: 40.2-82.8], respectively. Serum levels of vitamin D were considerably lower in the PAPS patients compared to controls (MD: -5.75, 95% CI: -9.73 to -1.77; p = 0.005). Multiple sensitivity analyses showed that the results remained statistically significant, demonstrating the robustness of this meta-analysis. No significant publication bias was detected in determining the MD of serum vitamin D levels in PAPS and controls. In conclusion, PAPS patients had greater rates of vitamin D deficiency or insufficiency, higher frequency of thrombosis, and lower serum vitamin D levels than healthy individuals.

Cardiovascular risk in rare autoimmune diseases, lessons from a primary antiphospholipid syndrome patients

Abstract Background Antiphospholipid syndrome is a thrombo-inflammatory disease driven by circulating autoantibodies (aPL) that recognize cell surface phospholipids and phospholipid-binding proteins. In the absence of an underlying connective tissue disorder, the persistent presence of these antibodies associated with recurrent fetal losses and arterial or venous thrombosis is defined as a primary antiphospholipid syndrome (PAPS) with a prevalence of 1/2000 people, predominantly female. Purpose Estimation of cardiovascular risk presence based on markers of subclinical cardiovascular impairment. Methods 100 PAPS patients, with an average age of 47.70±13.14y, 93.7% females, were included in the study. 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 ́&amp;lt;7 cm/sec, lateral E ́ &amp;lt;10 cm/sec, average E/E ́ ratio &amp;gt;14, LA volume index (LAVI) &amp;gt;34 mL/m2, and peak tricuspid regurgitation velocity &amp;gt;2.8 m/sec. LVDD was present if more than half parameters were with abnormal values. Endothelial dysfunction was assessed through ultrasound measurement of brachial artery flow-mediated dilation (FMD) and atherosclerosis progression by ultrasound assessment of intima-media thickness (cIMT) on carotid arteries (common carotid artery, CCA, internal carotid artery, ICA). 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). FMD was significantly lower in PAPS patients (10.76±5.15% vs. 14.20±6.76%, p=0.0001) and cIMT values were significantly higher (left ICA 0.80±0.29mm vs 0.56±0.20mm, p=0.001). All markers of subclinical atherosclerosis were significantly related to age and standard atherosclerotic risk factors present. Regarding aPL profile, anti-ß2GPI IgG positive PAPS patients had higher levels of cIMT ICA left (p=0.049) and LAC positive higher prevalence of LVDD (p=0.047) CONCLUSIONS: PAPS patients impose significantly higher prevalence of subclinical cardiovascular involvement compare to healthy population. Timely recognition, along with vigorous control of standard atherosclerotic risk factors and a proper therapeutic (antithrombotic and/or anticoagulant) regime, is of great importance.

Small-Extracellular-Vesicle-Derived miRNA Profile Identifies miR-483-3p and miR-326 as Regulators in the Pathogenesis of Antiphospholipid Syndrome (APS).

Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disease associated with recurrent thrombosis and/or obstetric morbidity with persistent antiphospholipid antibodies (aPL). Although these antibodies drive endothelial injury and thrombophilia, the underlying molecular mechanism is still unclear. Small extracellular vesicles (sEVs) contain miRNAs, key players in intercellular communication. To date, the effects of miRNA-derived sEVs in PAPS are not well understood. We characterised the quantity, cellular origin and miRNA profile of sEVs isolated from thrombotic APS patients (PAPS, n = 50), aPL-carrier patients (aPL, n = 30) and healthy donors (HD, n = 30). We found higher circulating sEVs mainly of activated platelet origin in PAPS and aPL patients compared to HD, that were highly engulfed by HUVECs and monocyte. Through miRNA-sequencing analysis, we identified miR-483-3p to be differentially upregulated in sEVs from patients with PAPS and aPL, and miR-326 to be downregulated only in PAPS sEVs. In vitro studies showed that miR-483-3p overexpression in endothelial cells induced an upregulation of the PI3K-AKT pathway that led to endothelial proliferation/dysfunction. MiR-326 downregulation induced NOTCH pathway activation in monocytes with the upregulation of NFKB1, tissue factor and cytokine production. These results provide evidence that miRNA-derived sEVs contribute to APS pathogenesis by producing endothelial cell proliferation, monocyte activation and adhesion/procoagulant factors.

Immune Thrombocytopenia Could be an Independent Clinical Phenotype of Antiphospholipid Syndrome: A Prospective Cohort Study.

Patients with persistent positive antiphospholipid antibodies (aPLs) and immune thrombocytopenia (ITP) hardly develop thrombosis but share many similar characteristics with antiphospholipid syndrome (APS). This is a prospective cohort study consecutively enrolling thrombocytopenic patients with continuous positive aPLs. Patients developing thrombotic events are classified as the APS group. Then we compare the clinical characteristics and prognosis between aPLs carriers and patients with APS. This cohort included 47 thrombocytopenic patients with continuous positive aPLs and 55 with diagnosed primary APS. The proportion of smoking and hypertension are higher in the APS group (p = 0.03, 0.04, 0.03, respectively). The platelet count of aPLs carriers at admission was lower than APS patients [26 × 109/l (9 × 109/l, 46 × 109/l) vs. 64 × 109/l (24 × 109/l, 89 × 109/l), p = 0.0002]. Triple aPLs positivity is more common in primary APS patients with thrombocytopenia [24 (51.1%) vs. 40 (72.7%), p = 0.04]. Regarding the treatment response, the complete response (CR) rate is similar between aPLs carriers and primary APS patients with thrombocytopenia (p = 0.2). Nonetheless, the proportion of response, no response, and relapse differed significantly between the two groups [13 (27.7%) vs. 4 (7.3%), p < 0.0001; 5 (10.6%) vs. 8 (14.5%), p < 0.0001; 5 (10.6%) vs. 8 (14.5%), p < 0.0001, respectively]. In Kaplan-Meier analysis, primary APS patients had significantly more thrombotic events than aPLs carriers (p = 0.0006). In the absence of other high-risk factors for thrombosis, thrombocytopenia could be an independent and long-lasting clinical phenotype of APS.

Ocular involvement in primary antiphospholipid syndrome: results of an extensive ophthalmological evaluation performed in the APS-Rio cohort.

To study ophthalmological manifestations in a well-characterized primary antiphospholipid syndrome (PAPS) cohort (APS-Rio) and compare them with a healthy control group. We examined PAPS patients and controls with an extensive ophthalmological evaluation, which included anamnesis, visual acuity, slit-lamp biomicroscopy, binocular indirect ophthalmoscopy, and retinography of the anterior and posterior segments of the eye. PAPS group also underwent angiography exam and optical coherence tomography using spectral domain technology (SD-OCT). 98 PAPS patients and 102 controls were included. The most common symptom in PAPS was amaurosis fugax (34.7% vs. 6.9%; p = .001). In the multivariate analyses, Raynaud's phenomenon was associated with amaurosis fugax (OR 3.71, CI:1.33-10.32; p = .012), and livedo correlated with hemianopia (OR 6.96, CI:1.11-43.72, p = .038) and diplopia (OR 3.49, CI:1.02-11.53, p = .047). After ophthalmological evaluation, 84 PAPS patients had ocular involvement (1.0% glaucoma, 94.0% posterior findings, 62.7% anterior findings, and 56.6% both posterior and anterior findings). Vascular tortuosity was more frequent in the PAPS group (63.2% vs. 42.2%; p = .002), as well as peripheral tortuosity (29.6% vs. 7.8%; p < .001). After excluding patients with atherosclerotic risk factors, peripheral vascular tortuosity was still statistically associated with PAPS (35.0 vs. 7.8%, p < .001). Triple positivity was more frequent in PAPS patients with peripheral vascular tortuosity than in those without this ocular finding (34.5% vs. 15.9%, p = .041). Vasomotor phenomena are importantly related to ocular symptoms in PAPS. Vascular tortuosity was a frequent finding in PAPS patients. Peripheral vascular tortuosity was associated with triple positivity and might be a biomarker of ischemic microvascular retinopathy due to PAPS.

LncRNAs dysregulation in monocytes from primary antiphospholipid syndrome patients: a bioinformatic and an experimental proof-of-concept approach.

Antiphospholipid syndrome (APS) is the main cause of acquired thrombophilia where peripheral circulating cells such as monocytes have a key role. Currently, several studies have linked long non-coding RNAs (lncRNAs) in different inflammatory and autoimmune processes, including lupus. However, the role of lncRNAs in antiphospholipid syndrome is unknown, therefore, we aimed to select and measure expression levels of three lncRNAs based on its abundancein monocytes from APS patients. Selection of lncRNAs candidates were carried out based on its abundancein monocytes and their relationship with Perez-Sanchez miRNA signature by using miRNet 2.0 bioinformatic tool, then lncRNAs expression levels was measured in monocytes by RT-qPCR. This is the first study to report that lncRNAs: FGD5-AS1, OIP5-AS1 and GAS5 are promising candidates for play a role on APS monocytes and they are expressed differently between patients and controls. OIP5-AS1, FGD5-AS1 and GAS5 are downregulated on monocytes from APS patients.

Primary Anti-Phospholipid Antibody Syndrome: Real-World Defining Features of Rethrombosis in the Course of Disease.

We aimed to identify features that allow differentiation of primary antiphospholipid syndrome (PAPS) patients that suffer recurrent thrombotic events (RTE) despite anticoagulation, from the other diagnosed PAPS patients. This was an exploratory study of anticoagulated PAPS patients attending an Autoimmune Diseases Unit (1998-2018). From 2016, anti-phospholipid antibodies and lupus anticoagulant were determined for each patient at consecutive visits, collected together with retrospective clinical characteristics, laboratory, and therapeutic markers and compared according to the occurrence of thrombotic events during follow-up. Overall, two thirds of the patients were female, 93% were Caucasian, with a median age of 40 years at diagnosis, for a median time of 11.5 years in follow-up. Out of 54 patients, 10 were identified with RTE. There were no significant differences among the RTE and non-RTE patients as far as classical risk factors for clotting disorders. The RTE group was characterized by a higher proportion of younger patients, male sex and positivity for all laboratory markers, and initially and over follow-up as well as a sustained high-risk profile based on APS laboratory markers. Anticardiolipin IgG at onset was the only statistically significant marker of the RTE group. At the end of follow-up, consistent reversion to negative status was a rare event, observed in 20% of RTE vs. 25% of non-RTE patients. Despite therapy, we were able to identify features associated to thrombotic events in patients with PAPS. Prospectively regular clinical and laboratory monitoring might be warranted in order to treat APS more assertively.

Ocular findings in asymptomatic patients with primary antiphospholipid syndrome.

Primary antiphospholipid syndrome (PAPS) is characterized by the presence of antiphospholipid antibodies (aPL), repetitive fetal loss, and arterial/venous thrombosis and no association with other autoimmune rheumatic disease. Ocular involvement can also occur including retinal vascular thrombosis and neuro-ophthalmological manifestations, such as optic neuropathy and amaurosis fugax. Early detection of ocular changes is crucial to minimize functional loss. To perform a multimodal evaluation, including the use of Optical Coherence Angiotomography (OCTA), in patients with PAPS without ocular complaints and compare with healthy individuals. We performed a complete structural and functional ophthalmological evaluation using OCTA and microperimetry exam in patients with PAPS, followed at a tertiary Rheumatology outpatient clinic. We included 104 eyes of 52 subjects [PAPS without ocular complaints (N = 26) and healthy individuals (N = 26)]. Among PAPS patients, 21 were female (80.8%) and 21 (80.8%) were Caucasians. PAPS manifestations were venous (65.4%), arterial thrombosis (34.6%), and obstetrical (34.6%) and all of them had lupus anticoagulant. Ophthalmologic findings were more frequent in PAPS compared to healthy individuals (19.2% vs. 0%, p = 0.05). The most common retinal change was paracentral acute middle maculopathy (PAMM) (3 patients, 5 eyes), followed by drusen (1 patient, 2 eyes) and pachychoroid pigment epitheliopathy (PPE) (1 patient, 1 eye). Hypertension and hyperlipidemia were present in 100% of the PAPS patients with PAMM, while only six patients (26.1%) with PAPS without PAMM presented these two risk factors together (p = 0.03). We provide novel evidence that approximately 20% of our asymptomatic PAPS patients without ocular symptoms have ophthalmologic findings that require early identification and careful surveillance focusing on minimizing systemic and vascular risk factors.

Primary and secondary antiphospholipid syndrome characteristics in an Egyptian cohort

Aim of the workTo describe the clinical and laboratory characteristics of patients with primary and secondary antiphospholipid syndrome (APS) in an Egyptian cohort. Patients and methodsSixty APS patients were enrolled. 12 had primary APS and 48 had secondary. Patients were further classified according to the presence of double or triple antiphospholipid antibodies (aPL). ResultsThe study included 55 (91.7 %) females and 5 (8.3 %) males, with a mean age of 33.9 ± 9.1 years, and mean disease duration of 6.2 ± 93.04 years. The obstetric complication in the form of fetal loss was the commonest manifestation of APS (70 %), followed by lower limb deep venous thrombosis (DVT) (50 %), recurrent abortion (45 %), thrombocytopenia (25 %), cutaneous manifestations (20 %), and Raynaud’s phenomenon (18.3 %). Urinary findings are mostly related to secondary APS. 15 (25 %) patients were thrombocytopenic and 1 (1.7 %) had autoimmune hemolytic anemia. Primary APS patients showed higher frequency of cutaneous manifestations compared to secondary (50 % vs 12.5 %; p = 0.04), and higher levels of β2 glycoprotein I IgG (71.8 ± 22.4 U/ml vs 59.3 ± 17.1 U/ml; p = 0.047). Secondary APS patients showed positive antinuclear antibodies (ANA) and anti-double stranded deoxyribonucleic acid antibodies (anti-dsDNA) in 97.9 % and 93.8 % respectively and were negative in all primary APS patients. On comparing patients with double (n = 34) and triple (n = 26) aPL, no differences were found between both groups except for platelet count being significantly lower in the triple aPL (p = 0.045). ConclusionEgyptian APS patients showed a high frequency of obstetric complications and lower limb DVT. Primary APS patients had higher frequency of cutaneous manifestations.

COVID-19 vaccine affects neither prothrombotic antibody profile nor thrombosis in primary anti-phospholipid syndrome: a prospective study.

ObjectiveTo explore whether inactivated coronavirus disease 2019 vaccine influences the profile of prothrombotic autoantibodies and induces thrombotic events in primary APS patients.MethodsWe enrolled 39 primary APS patients who received two doses of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (BBIBPCorV, Sinopharm, Beijing, China) voluntarily in this prospective cohort. Prothrombotic autoantibodies were determined before vaccination and 4 weeks after the second dose of vaccination. Thrombotic disorders were evaluated via hospital site visits and assessments.ResultsThere was no significant difference in the presence of all 11 autoantibodies detected before and 4 weeks after vaccination: for aCL, IgG (14 vs 16, P = 0.64), IgM (13 vs 19, P = 0.34), IgA (2 vs 3, P = 0.64); anti-β2GP1, IgG (12 vs 12, P = 1.00), IgM (5 vs 8, P = 0.36), IgA (4 vs 3, P = 0.69); anti-PS/PT IgG (13 vs 16, P = 0.48), IgM (17 vs 22, P = 0.26); LAC (22 vs 28, P = 0.16); aPF4-heparin (0 vs 0, P = 1.00) and ANA (23 vs 26, P = 0.48). Notably, the distribution of the aPL profile in the pre- and post-vaccination cohorts was not affected by SARS-CoV-2 vaccination: for patients with a low-risk aPL profile (11 vs 10, P = 0.799) and patients with a high-risk aPL profile (28 vs 29, P = 0.799), respectively. Furthermore, no case exhibited symptoms of the thrombotic disorder during a minimum follow-up period of 12 weeks. There was no adjustment to the ongoing treatment regimens following SARS-CoV-2 vaccination.ConclusionInactivated SARS-CoV-2 vaccine does not influence the profile of anti-phospholipid antibodies and anti-PF4-heparin antibodies nor induces thrombotic events in primary APS patients.

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

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. 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. 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-β 2 glycoprotein I (IgG/IgM), and lupus anticoagulant positivity. 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 β 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). 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.

Disability and cognitive impairment are interdependent in primary antiphospholipid syndrome.

Cognitive impairment (CI) occurs at a high frequency in primary antiphospholipid syndrome (PAPS). Its psychosocial-related factors are of interest. We aimed to determine disability and perceived stress and their correlation with CI in PAPS. First study phase: a longitudinal study including patients with PAPS and paired controls for cardiovascular risk factors, age, and sex, determining CI with Montreal Cognitive Assessment (MoCA) and then repeating the measurement 1 year later. Second study phase: a cross-sectional analytical study by quantification of disability with the World Health Organization Disability Assessment Schedule (WHODAS 2.0) and perceived stress with the Perceived Stress Scale (PSS-14). Descriptive statistics and Spearman correlation coefficient were used. Sixty-three patients with PAPS and 60 controls were studied. In PAPS, age (range, 48.0 ± 13.5years), thrombotic artery events (TAE) (44.4%), and stroke/TIA (42.8%) were found. Disability was documented in the majority of WHODAS 2.0 domains and the total score for this was higher in participation and mobility, the stress level was normal, and 65.1% had CI. PAPS exhibited greater deterioration in the WHODAS 2.0 total score (p .017) and the MoCA test (p < .0001). Personal domains and the total WHODAS 2.0 score correlated inversely with MoCA. Life activities (rho = -0.419) and self-care (rho = -0.407) were those that correlated to the greatest degree. Stroke conferred risk for CI. Disability in PAPS and CI are interdependent. New treatment options and neurocognitive stimulation strategies are necessary to maintain functionality and prevent further cognitive dysfunction in PAPS patients.

Immunogenicity, safety, and antiphospholipid antibodies after SARS-CoV-2 vaccine in patients with primary antiphospholipid syndrome.

ObjectiveCoronavirus disease 19 (COVID-19) has an increased risk of coagulopathy with high frequency of antiphospholipid antibodies (aPL). Recent reports of thrombosis associated with adenovirus-based vaccines raised concern that SARS-CoV-2 immunization in primary antiphospholipid syndrome (PAPS) patients may trigger clotting complications. Our objectives were to assess immunogenicity, safety, and aPL production in PAPS patients, after vaccinating with Sinovac-CoronaVac, an inactivated virus vaccine against COVID-19.MethodsThis prospective controlled phase-4 study of PAPS patients and a control group (CG) consisted of a two-dose Sinovac-CoronaVac (D0/D28) and blood collection before vaccination (D0), at D28 and 6 weeks after second dose (D69) for immunogenicity/aPL levels. Outcomes were seroconversion (SC) rates of anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies (NAb) at D28/D69 in naïve participants. Safety and aPL production were also assessed.ResultsWe included 44 PAPS patients (31 naïve) and 132 CG (108 naïve) with comparable age (p=0.982) and sex (p>0.999). At D69, both groups had high and comparable SC (83.9% vs. 93.5%, p=0.092), as well as NAb positivity (77.4% vs. 78.7%, p=0.440), and NAb-activity (64.3% vs. 60.9%, p=0.689). Thrombotic events up to 6 months or other moderate/severe side effects were not observed. PAPS patients remained with stable aPL levels throughout the study at D0 vs. D28 vs. D69: anticardiolipin (aCL) IgG (p=0.058) and IgM (p=0.091); anti-beta-2 glycoprotein I (aβ2GPI) IgG (p=0.513) and IgM (p=0.468).ConclusionWe provided novel evidence that Sinovac-CoronaVac has high immunogenicity and safety profile in PAPS. Furthermore, Sinovac-CoronaVac did not trigger thrombosis nor induced changes in aPL production.

Preliminary Study on the Imbalance Between Th17 and Regulatory T Cells in Antiphospholipid Syndrome.

ObjectivePatients with antiphospholipid syndrome (APS) have immune cell abnormalities that remain poorly understood. This study compared primary APS (PAPS) and secondary APS (SAPS) patients with healthy controls with respect to peripheral blood lymphocytes, CD4+T cell subsets, and cytokine levels. The correlation between antiphospholipid antibody titres and T helper 17 (Th17) and T regulatory (Treg) cell subsets was also analyzed, together with the correlations between cytokine profiles and the clinical characteristics of APS patients.MethodsThe retrospective study population consisted of 67 APS patients (12 with PAPS, 55 with SAPS) and 40 healthy controls. Absolute numbers of peripheral blood lymphocyte subsets and CD4+ T cell subsets were detected by flow cytometry, and serum cytokine levels by flow cytometry bead array.ResultsPatients with SAPS had lower absolute values of T, B and CD4+T cells than the healthy control group, while only natural killer (NK) cell levels were decreased in patients with PAPS. Absolute numbers of T, B, NK, and CD4+T cells were significantly higher in the PAPS than SAPS group. The trends in CD4+T cell subsets were the same in PAPS and SAPS patients as in healthy controls, with increased Th1, decreased Th2, and decreased Treg levels, and thus an increased Th17/Treg ratio. Th2, Th17, and Treg cell counts were higher in the PAPS than SAPS group. Cytokine analysis showed that only IL-10 levels differed between the two APS groups. However, the levels of all of the studied cytokines were higher in APS patients than healthy controls, and correlated with the clinical characteristics of the patients. In the PAPS group, the titres of two autoantibodies correlated positively with the Th17/Treg ratio and negatively with the levels of D-dimer and Treg subsets.ConclusionsOur study clearly showed that APS patients have immune disturbances, the most prominent of which is an increase in the Th17/Treg ratio, due to a decrease in the number of Treg cells. These abnormalities may be involved in the occurrence and progression of APS. An additional finding was a higher level of peripheral blood lymphocytes in PAPS than SAPS patients, which may be related to the immunosuppressive treatment of SAPS patients.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in primary antiphospholipid syndrome. The multicenter ATHERO-APS study

BackgroundThe proprotein convertase subtilisin/kexin type 9 (PCSK9) is emerging as a novel cardiovascular risk factor. Levels of PCSK9 in thrombotic primary antiphospholipid syndrome (PAPS) have never been investigated. MethodsCross sectional comparison of baseline characteristics of 91 PAPS patients enrolled in the multicenter prospective ATHERO-APS cohort study. PCSK9 levels were categorized into tertiles and the association with arterial and recurrent thrombosis were assessed by univariable and multivariable logistic regression analysis. ResultsMedian age was 51 years and 71.4% (n = 65) were women. Overall, 33% (n = 30) experienced an arterial event while 31% (n = 28) had recurrent thrombotic events. Median PCSK9 levels were 1243 (1100–1650) pg/ml. Patients in the third PCSK9 tertile (>1458 pg/ml) showed a higher prevalence of dyslipidemia, lupus anticoagulant positivity and a history of previous arterial and recurrent thrombosis than patients in the first and second tertile. PCSK9 levels were higher in arterial than venous thrombosis (1502 vs. 1180 pg/ml, p = 0.002), and in patients with recurrent vs isolated thrombosis (1680 vs. 1150 pg/m, p < 0.001). High plasma PCSK9 levels were associated with a 4-fold increase risk for arterial events and with a 10-fold increase risk for recurrent thrombosis after adjustment for confounding factors. ConclusionThese preliminary data suggest that PCSK9 levels are increased in PAPS patients with arterial and recurrent thrombosis. Its role as a possible therapeutic target in PAPS needs further studies.

Sirolimus Monotherapy for Thrombocytopenia in Primary Antiphospholipid Syndrome: A Pilot Study From a Tertiary Referral Center.

BackgroundThrombocytopenia (TP) is considered as a warning sign of high-risk antiphospholipid syndrome (APS) and sometimes a paradoxical sign of anti-thrombosis treatment. Currently, there is an extreme paucity of effective and safe drugs for long-term management of TP in primary APS patients; therefore, we explored the efficacy and safety of sirolimus monotherapy.MethodsIn this real-world study, we included 7 consecutive patients with primary APS who received sirolimus monotherapy for TP. Oral sirolimus was initiated at a dose of 1–2 mg once daily and then adjusted primarily based on clinical efficacy and tolerance, with consideration of the sirolimus trough concentration of ≤15 ng/ml.ResultsOf included patients, the median age was 58 years with a median disease course of 1.5 years and 4 patients were treatment-naïve. All patients completed 6 months of sirolimus therapy with a median follow-up of 6 months (range: 6–15). All patients received sirolimus monotherapy for TP during the entire follow-up, without any additional agents. Overall, the platelet count exhibited a substantially increasing trend after sirolimus administration during the first 6 months (p < 0.001) and stability later. Specifically, the median platelet count was significantly increased from 59 × 109/l before sirolimus to 90 × 109/l at month 1 (p = 0.028), 131 × 109/l at 3 months (p = 0.028), and 178 × 109/l at 6 months (p = 0.018). Overall and complete responses were respectively achieved in 6 (85.7%) and 5 (71.4%) patients at month 6. Importantly, overall response was achieved in all 4 treatment-naïve patients. Additionally, there were different extents of decline in the titers of antiphospholipid antibodies after sirolimus treatment. Regarding safety, only one patient experienced an elevated cholesterol level with recovery after atorvastatin treatment.ConclusionSirolimus monotherapy confers good efficacy and tolerance for TP in primary APS patients and therefore may be considered as a first-line therapy.

Clinical and prognostic significance of antinuclear antibodies in primary antiphospholipid syndrome: A multicenter retrospective study.

The antiphospholipid syndrome (APS) (1) is defined by the development of vascular thrombosis, or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL). Antinuclear antibodies (ANA) can be detected in primary APS patients without any clinical systemic autoimmune disease. The presence of ANA antibodies could confer a specific phenotype in primary APS. To evaluate the characteristics of APS patients with antinuclear antibodies without other autoimmune disease (ANA positive APS patients) in comparison with primary APS without ANA or secondary APS patients with associated systemic lupus erythematosus (SLE). Clinical and biologic data from 195 APS were retrospectively collected and patients were classified as primary APS with positive ANA (ANA-positive APS), primary APS without any ANA (ANA-negative APS), and SLE-associated APS (SLE-APS). Fourty patients (21%) were classified into ANA-positive APS group, 77 (39%) in ANA-negative APS and 78 (40%) in SLE-APS. In ANA-positive APS patients, 20 patients (51%) had arterial thrombosis, 14 (41%) had veinous thrombosis and 19% had obstetrical complications. There was no difference between the three groups for the frequency of thrombotic manifestations and obstetrical complications. ANA-positive APS patients had more non-criteria manifestations than ANA-negative APS (48% versus 25%; P≤0.01). ANA-positive APS had more triple aPL positivity (59% versus 18%; P<0.001) and more thrombosis and obstetrical recurrences (63% versus 36%; P<0.01) in comparison with ANA-negative APS patients. ANA-positive APS had more triple aPL positivity than SLE-APS patients (54% versus 33%; P<0.05). ANA-positive APS and SLE-APS patients had similar clinical manifestations, and recurrences. Despite a limited follow-up (28 months (11-50)) none of the ANA-positive APS develop SLE. Antiplatelet and anticoagulant therapies were similar for the three groups. SLE-APS patients received more immunomodulatory therapies. ANA positivity in patients with APS enables to individualize a subset of patients with a more severe phenotype. Whereas the ANA positivity does not seem to be associated with the risk to develop SLE, prospective studies with a longer follow-up are necessary, in particular to evaluate the effect of additional therapies in this subset of APS.

Clinical and therapeutic value of the adjusted Global Antiphospholipid Syndrome Score in primary obstetric antiphospholipid syndrome.

(1) To assess the clinical utility of the adjusted global antiphospholipid syndrome score (aGAPSS) to predict new obstetric events during follow-up in primary obstetric antiphospholipid syndrome (POAPS) patients under standard-of-care treatment (SC) based on the use of low-dose aspirin (LDA) + heparin and (2) to study the risk of a first thrombotic event and to evaluate whether stratification according to this score could help to identify POAPS patients who would benefit from long-term thromboprophylaxis. This is a retrospective, multicentre study. 169 women with POAPS were evaluated for the presence of a new obstetric event and/or a first thrombotic event during follow-up [time period: 2008-2020, median: 7years (6-12years)]. The outcomes of 107 pregnancies from these POAPS patients with SC were studied to evaluate relapses. Simple and multivariable logistic regression analyses were performed. Regarding obstetric morbidity, only triple positivity for antiphospholipid antibodies (aPLs) [OR = 8.462 (95% CI: 2.732-26.210); p < 0.0001] was found to be a strong risk factor independently associated with treatment failure. On the other hand, triple positivity for aPLs [OR=10.44 (95% CI: 2.161-50.469), p = 0.004] and an aGAPSS ≥7 [OR = 1.621 (95% CI: 1.198-2.193), p = 0.002] were independent risk factors associated with a first thrombotic event. LDA was marginally associated with a decrease in the risk of thrombosis only in patients with aGAPSS ≥ 7 (p = 0.048). aGAPSS appears to be useful in predicting the occurrence of a first thrombotic event in POAPS patients, and these stratification of patients could be helpful in selecting patients who would benefit from thromboprophylaxis with LDA.