Association between ambient air pollution exposure in pregnant women with antiphospholipid syndrome in Nanjing, China.

Antenatal exposure to air pollutants is thought to be associated with a variety of maternal blood markers as well as adverse birth outcomes. However, the dysgenic influence of air pollutants on the antiphospholipid syndrome (APS) in mothers and their pregnancy outcomes remains unclear. In the current study, 371 mother-infant pairs (189 healthy: 182 APS) from Nanjing Maternal and Child Health Hospital as well as air pollutants concentration from their living environment were used to investigate correlations between air pollution with maternal blood indicators and fetal birth weight in the groups of APS and healthy mothers. Generalized linear model was used to evaluate the contributions of air pollutant exposure during pregnancy to the blood indicators variation. The relationships between birth weight with specific air pollutant and blood index were analyzed using ridge regression. Results showed that APS fetal birth weight was significantly impacted by air pollutant exposure during pregnancy, in particular, the birth weight decreased significantly along with increasing fine particulate matter 2.5 (PM2.5) and fine particulate matter 10 (PM10) exposure concentrations throughout pregnancy. In contrast, birth weight increased significantly with sulfur dioxide (SO2) exposure. In addition, APS-related blood indicators comprised of platelet distribution width (PDW), total bilirubin (TBIL), mean platelet volume (MPV), platelet-larger cell ratio (P_LCR), homocysteine (HCY), alkaline phosphatase (ALP), direct bilirubin (DBIL), basophilic granulocyte (BAS), platelet thrombocytocrit (PCT), preprandial glucose levels (OGTT0), monocytes (MON), and monocytes ratio (MON_ratio) were also strongly related with prenatal exposure to PM2.5 and PM10, in which PDW levels showed most strongly negative impaction on fetal birth weight. Together, we showed that prenatal exposure to air pollutant (PM2.5 and PM10) may exacerbate the poor birth outcomes of low birth weight by impacting APS maternal blood indicators especially for PDW.

Catastrophic antiphospholipid syndrome in lupus-associated immune thrombocytopenia treated with eltrombopag A case series and literature review.

BACKGROUND: Eltrombopag, a thrombopoietin receptor (TPO-R) agonist, is considered a second-line treatment for patients with refractory immune thrombocytopenia (ITP). Systemic lupus erythematosus (SLE) is frequently associated with ITP. In some cases, thrombocytopenia in SLE patients is attributed to concurrent antiphospholipid antibodies (APLA). Currently, data regarding treatment with TPO-R agonists for ITP in SLE or APLA patients are limited. The incidence of SLE flare or antiphospholipid syndrome while on TPO-R agonists has not been well-studied. CASES: We report 2 cases of female patients with SLE and concurrent triple positive APLA, without thrombotic events in their medical history, in our rheumatology clinic, who were treated for refractory ITP with eltrombopag. Both developed catastrophic antiphospholipid syndrome a few weeks after beginning treatment with eltrombopag. They were admitted to the intensive care unit and treated with solumedrol, plasmapheresis, anticoagulation and rituximab. CONCLUSIONS: We describe a severe possible side-effect of eltrombopag as a trigger of catastrophic antiphospholipid syndrome, a rare initial manifestation of antiphospholipid syndrome, in SLE patients with APLA. We suggest that APLA should be tested before initiating eltrombopag in patients with SLE-associated ITP. The safety of this treatment should be considered in these cases.

Predictive value of the adjusted Global Anti-Phospholipid Syndrome Score on clinical recurrence in APS patients: a longitudinal study.

OBJECTIVE: To assess the effect of the average adjusted global APS score (aGAPSS) over time on recurrence of clinical manifestations in APS patients through a retrospective longitudinal study. MATERIAL AND METHODS: The study included 200 patients with APS. The aGAPSS was calculated for each patient at baseline and on a yearly basis for either up to 6 years (minimum 3 years) or just before the clinical event in patients who experienced clinical recurrence. The mean score per patient was computed. In patients under vitamin K antagonists (VKA) the percentage of time spent within the therapeutic range (TTR) was calculated. Cox regression analysis was performed to determine the cut-off value of the aGAPSS with the strongest association with clinical recurrence. RESULTS: Higher average aGAPSS values were found in patients who experienced clinical recurrence in comparison to patients who did not [8.81 (95% CI 7.53, 10.08) vs 6.38 (95% CI 5.64, 7.12), P = 0.001], patients with thrombotic recurrence compared with patients with obstetric recurrence [9.48 (95% CI 8.14, 10.82) vs 4.25 (95% CI 0.85, 7.65), P = 0.006] and patients with arterial thrombosis compared with patients with venous thrombosis [10.66 (S.D. 5.48) vs 6.63 (S.D. 4.42), P = 0.01]. aGAPSS values >13 points were associated with the highest risk of recurrence in multivariate analysis [HR = 3.25 (95% CI 1.93, 5.45), P < 0.0001]. TTR was not statistically different between patients who had thrombosis recurrence and patients who had not. CONCLUSIONS: Our data support the role of periodic (annual) monitoring of the aGAPSS score in predicting clinical recurrence in patients with APS.

Direct oral anticoagulants versus warfarin in patients with antiphospholipid syndrome: A meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) versus warfarin in patients with antiphospholipid syndrome (APS). METHODS: We performed a literature search using MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. We also performed a meta-analysis of randomized controlled trials (RCTs) investigating the effectiveness and safety of DOACs versus warfarin in patients with APS. RESULTS: Five RCTs involving 648 patients with APS (330 in DOAC-treated and 318 in control groups) were included in the meta-analysis. Among the patients included in the analysis, 29 (8.8%) patients experienced recurrent thrombosis in the DOAC treatment group, and 10 patients (3.1%) had thrombosis recurrence in the warfarin treatment group, resulting in a higher incidence in DOAC-treated than in the warfarin-treated groups [odds ratio (OR) = 2.163, 95% CI = 0.985-4.748, p = 0.055]. Incidence of arterial thrombosis was significantly higher in DOAC-treated patients than in warfarin-treated patients (OR = 5.168, 95% CI = 1.567-17.04, p = 0.007). Stroke and thrombosis occurrences were significantly higher in the triple positivity group than in the warfarin therapy group (OR = 12.03, 95% CI = 2.249-64.36, p = 0.004; OR = 2.940, 95% CI = 1.016-8.504, p = 0.047). However, venous thrombosis occurrences did not differ significantly between the DOAC-treated and warfarin-treated groups. There were no significant differences between the DOAC and warfarin groups in terms of any bleeding, major bleeding, minor bleeding, and all-cause mortality. CONCLUSION: DOACs were associated with higher rates of arterial thrombosis than warfarin in patients with APS, especially in the triple-positive group. However, a higher risk of recurrent venous thrombosis was not found in APS patients treated with DOACs compared to those treated with warfarin.

Drug-induced antiphospholipid syndrome: Analysis of the WHO international database.

OBJECTIVE: As with drug-induced lupus, some drugs may induce an antiphospholipid syndrome (APS). With the always growing numbers of new molecules, the list of the liable treatments evolves rapidly. We herein analyzed VigiBase, the international pharmacovigilance database, to identify drugs suspected of inducing APS. METHODS: All the reported cases associated with "anti-phospholipid syndrome" using the preferred term level of medDRA (dictionary of regulated drug activity) when associated with anti-phospholipid antibodies in VigiBase were analyzed. For each treatment, a Bayesian disproportionality indicator (i.e. information component, IC) was calculated. A drug was significantly associated with APS if the 95% lower-end of the IC credibility interval was positive (IC025 > 0). Drugs with potential protopathic bias were excluded. RESULTS: From 01/11/2000 to 25/07/2021, 790 reports of suspected drug-induced APS were found in VigiBase. After excluding drugs reported by a single country and drugs with protopathic bias, fourteen drugs (n = 359 reports) were associated with APS with an IC0 25 > 0. These drugs were hormons: ethinylestradiol-etonogestrel and drospirenone-ethynilestradiol; platelet growth factors: eltrombopag, romiplostim; vaccines: Human Papillomavirus vaccine, hepatitis A and B vaccines and typhoid vaccine; antibiotics: minocycline; nonstreroidal anti-inflammatory: rofecoxib; biotherapy: interferon beta-1-a, etanercept; anti-hypertensive drug: hydralazine; bisphosphonates: alendronic acid and antipsychotic: olanzapine. The mean age at diagnosis of drug-induced APS was 39.2 years [29.3;47.9] and there were 63.5% of female patients. The mean delay from first exposition to drug-induced APS was 19.7 months [4.5; 38.8]. Drug-induced APS was reported as a severe side effect in 66.3% of cases: 8.4% with a life-threatening event and 2.5% of death (n = 9). A third (n = 118, 32.9%) pulmonary embolism events were reported and 4.2% (15) cerebral infarctions. 14.8% (53) cases were associated with a systemic lupus, a sub-analysis without lupus cases showed the same severity of cases. CONCLUSION: This study identified 14 drugs potentially associated with drug-induced APS that may prove useful in the investigational work-up in any new diagnosis of APS. TRIAL REGISTRATION NUMBER: NCT03994302.

Effect of statins on the prevention of recurrent thrombosis in thrombotic antiphospholipid syndrome.

OBJECTIVE: To assess the effect of statins on the prevention of recurrent thrombosis in patients with thrombotic APS. METHODS: This retrospective cohort study included 184 patients with thrombotic APS. The effect of statins on recurrent thrombosis was investigated in the total study population and in an inverse probability of treatment weighting (IPTW)-adjusted population. Multivariable and IPTW-adjusted Cox proportional hazard regression analyses were performed on the total study population and the IPTW-adjusted population, respectively, to estimate the hazard ratios (HRs) with 95% CIs for recurrent thrombosis, according to the use of statins. RESULTS: Of the 184 patients, 103 (56.0%) received statins, while the other 81 (44.0%) did not. Recurrent thrombosis occurred in 22 (12.0%) patients during the mean observation period of 48.5 (34.9) months. In the multivariable Cox regression analyses, the use of statins was associated with a lower risk of recurrent thrombosis: (i) model 1 adjusted for risk factors of arterial and venous thrombosis, HR 0.24, 95% CI: 0.09, 0.63, P = 0.004; (ii) model 2 adjusted for the use of anticoagulants, antiplatelets and HCQ, HR 0.28, 95% CI: 0.10, 0.76, P = 0.012; and (iii) model 3 adjusted for the antiphospholipid autoantibody profile, HR 0.26, 95% CI: 0.10, 0.67, P = 0.005. The IPTW-adjusted Cox regression analysis also showed a lower risk of recurrent thrombosis with the use of statins (HR 0.28, 95% CI: 0.12, 0.65, P = 0.003). CONCLUSION: Our data suggest that statins could be effective in reducing the risk of recurrent thrombosis in patients with thrombotic APS.

Digital ischaemia secondary to adalimumab-induced antiphospholipid syndrome.

A 50-year-old woman with a history of Crohn's disease treated with adalimumab presented with left hand pain and duskiness. Angiogram showed non-filling of the radial and digital arteries of the hand. Antiphospholipid antibody testing was positive, leading to a diagnosis of antitumour necrosis factor-induced antiphospholipid syndrome. Adalimumab was discontinued, and she was treated with the vitamin K antagonist warfarin and low-dose aspirin. Upon resolution of the antiphospholipid antibodies, she was transitioned to aspirin alone without recurrence of thrombosis.

Primary antiphospholipid syndrome during aromatase inhibitors therapy: A case report and review of the literature.

RATIONALE: Aromatase inhibitors (AIs) are a class of drugs widely used in the treatment of estrogen sensitive breast and ovarian cancer which convert testosterone to estradiol and androstenedione to estrogen. The AIs of third generation, including anastrazole, letrozole and exemestane, have actually become the standard of care of estrogen-receptor-positive breast cancer in menopausal women and are recommended as adjuvant treatment after surgery in place of/or following tamoxifen. Their main side-effects include reduction in bone mineral density, occurrence of menopausal manifestations and development of musculoskeletal symptoms which are, usually, transient, but sometimes evolve into a typical form of arthritis, such as rheumatoid arthritis (RA). Recently, a pathogenic linkage with other autoimmunity diseases, such as Sjogren syndrome (SjS), anti-synthetase antibody syndrome (ASAS), systemic sclerosis (SS) and subacute cutaneous lupus erythematosus (SCLE), was also described. PATIENT CONCERNS: Here, we report the first case of a patient with primary antiphospholipid syndrome (APS) developed during treatment with anastrazole. DIAGNOSIS: The patient developed a sudden onset of speech disturbance and disorientation, due to ischemic lesions, after 6 months of AIs therapy and the laboratory examination showed the positivity of anti-Cardiolipin antibodies, anti-ß2 Glycoprotein 1 antibodies and Lupus Anticoagulant, so a certain diagnosis of APS was achieved. INTERVENTIONS: The patient was treated with warfarin associated to hydroxychloroquine and monthly cycles of low doses intravenous immunoglobulins. OUTCOMES: A good control of the disease was obtained despite the continuation of anastrazole; the patient's clinical and laboratory situation remained not modified after AIs withdrawal. LESSONS: We discussed the possible role of anastrazole treatment in inducing APS in our patient, reporting the available literature data about the association between AIs treatment and autoimmune diseases. Furthermore, we analyzed the mechanism of action of estrogens in the pathophysiology of autoimmune rheumatic disorders.

Antiphospholipid score is a novel risk factor for idiopathic osteonecrosis of the femoral head in patients with systemic lupus erythematosus.

OBJECTIVE: Idiopathic osteonecrosis of the femoral head (ION) is a common complication of SLE associated with CS therapy. Although the pathogenesis of ION involves local bone ischaemia favoured by thrombophilia, the involvement of aPL in lupus ION remains to be elucidated. We have previously reported the aPL score (aPL-S) as a quantitative marker of aPL and the development of thrombotic events in autoimmune diseases. The aim of this study was to identify the impact of aPL on the development of ION using aPL-S. METHODS: This was a single-centre retrospective study comprising 88 consecutive SLE patients who underwent MRI of the hip joints from January 2000 to March 2017. Baseline characteristics, pharmacotherapy and total hip arthroplasty performed during follow-up were evaluated. RESULTS: The presence of ION was confirmed by MRI scan in 38 patients (43.1%). Male gender, positivity of any aPL, aPL-S, high aPL-S (≥30) and high dose of CS were identified as risk factors for ION by univariate analysis. Multivariate analysis revealed high aPL-S (odds ratio 5.12, 95% CI 1.18-29.79) and use of high-dose CS (odds ratio 10.25, 95% CI 3.00-48.38) as independent variables. Kaplan-Meier analysis showed that patients with high aPL-S received total hip arthroplasty more frequently than those without aPL (P = 0.010). CONCLUSIONS: We newly identified high aPL-S as an important risk factor for ION development in SLE, suggesting the involvement of aPL-induced coagulopathy in the pathophysiology of lupus ION.

Hydroxychloroquine partially prevents endothelial dysfunction induced by anti-beta-2-GPI antibodies in an in vivo mouse model of antiphospholipid syndrome.

BACKGROUND: Antiphospholipid syndrome is associated with endothelial dysfunction, which leads to thrombosis and early atheroma. Given that hydroxychloroquine has anti-thrombotic properties in lupus, we hypothesized that it could reduce endothelial dysfunction in an animal model of antiphospholipid syndrome. We evaluated the effect of hydroxychloroquine in preventing endothelial dysfunction in a mouse model of antiphospholipid syndrome. METHODS: Antiphospholipid syndrome was induced by an injection of monoclonal anti-beta-2-GPI antibodies. Vascular reactivity was evaluated in mesenteric resistance arteries isolated from mice 3 weeks (APL3W) after receiving a single injection of anti-beta-2-GPI antibodies and after 3 weeks of daily oral hydroxychloroquine treatment (HCQ3W) compared to control mice (CT3W). We evaluated endothelial dysfunction by measuring acetylcholine-mediated vasodilation. A pharmacological approach was used to evaluate NO synthase uncoupling (tetrahydrobiopterin) and the generation of reactive oxygen species (Tempol). RESULTS: Impaired acetylcholine-mediated dilation was evidenced in mice 3 weeks after anti-beta-2-GPI antibodies injection compared to CT3W, by reduced maximal dilation (p<0.0001) and sensitivity (pKd) (p = 0.01) to acetylcholine. Hydroxychloroquine improved acetylcholine-dependent dilation, on pKd (p = 0.02) but not maximal capacity compared to untreated mice. The addition of tetrahydrobiopterin (p = 0.02) and/or Tempol (p = 0.0008) improved acetylcholine-mediated dilation in APL3W but not in HCQ3W. CONCLUSIONS: We demonstrated that endothelial dysfunction in mouse resistance arteries persisted at 3 weeks after a single injection of monoclonal anti-beta-2-GPI antibodies, and that hydroxychloroquine improved endothelium-dependent dilation at 3 weeks, through improvement of NO synthase coupling and oxidative stress reduction.

Decreased hippocampal cell proliferation in mice with experimental antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, which may trigger vascular thrombosis with consecutive infarcts. However, cognitive dysfunctions representing one of the most commonest neuropsychiatric symptoms are frequently present despite the absence of any ischemic brain lesions. Data on the structural and functional basis of the neuropsychiatric symptoms are sparse. To examine the effect of APS on hippocampal neurogenesis and on white matter, we induced experimental APS (eAPS) in adult female Balb/C mice by immunization with ß2-glycoprotein 1. To investigate cell proliferation in the dentate gyrus granular cell layer (DG GCL), eAPS and control mice (n = 5, each) were injected with 5-bromo-2'-deoxyuridine (BrdU) once a day for 10 subsequent days. Sixteen weeks after immunization, eAPS resulted in a significant reduction of BrdU-positive cells in the DG GCL compared to control animals. However, double staining with doublecortin and NeuN revealed a largely preserved neurogenesis. Ultrastructural analysis of corpus callosum (CC) axons in eAPS (n = 6) and control mice (n = 7) revealed no significant changes in CC axon diameter or g-ratio. In conclusion, decreased cellular proliferation in the hippocampus of eAPS mice indicates a limited regenerative potential and may represent one neuropathological substrate of cognitive changes in APS while evidence for alterations of white matter integrity is lacking.

Miocardiopatía dilatada y fosfolipidosis inducida por hidroxicloroquina: de los cuerpos curvilíneos a la sospecha clínica / Dilated cardiomyopathy and hydroxychloroquine-induced phospholipidosis: from curvilinear bodies to clinical suspicion

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Reversible drug-induced antiphospholipid syndrome.

We report an original case of reversible antiphospholipid syndrome (APS) due to minocycline in a young male patient who experienced recurrent strokes while taking minocycline. He started minocycline therapy (50 mg twice daily) at 15 years old for acne. After three years of treatment, the patient experienced a lateral medullary syndrome. He was treated with aspirin while minocycline was continued. Eighteen months later, the patient complained about horizontal binocular diplopia. MRI revealed an infarct of the oculomotor nerve nucleus. Laboratory investigations revealed high titers of anti-beta 2 glycoprotein 1 (antiß2GP1) antibodies of 470 U/ml (normal range <15 U/ml) and antiphosphatidylethanolamine antibodies of 137.4 U/ml (normal range <18 U/ml). Other laboratory tests were normal. Six weeks after discontinuation of minocycline, anti-ß2GP1 antibodies decreased to 335 U/ml and to 36 U/ml at six months and then remained negative for six years. Many drugs have been considered as possibly causing APS but only in a limited number of patients. To our knowledge this is the first case of drug-induced APS with complete disappearance of high titers of anti-ß2GP1 antibodies after minocycline withdrawal. This case also illustrates the need to monitor the levels of antiphospholipid antibodies, even though initial values are high and confirmed after 12 weeks.

Emerging therapeutic uses of direct-acting oral anticoagulants: An evidence-based perspective.

Direct-acting oral anticoagulants (DOACs) were claimed to cause a potential paradigm shift in the therapeutic scenario of patients requiring short- and long-term anticoagulation, by virtue of their pharmacological properties, perceived as innovative. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirmed that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy and effectiveness and unequivocally documented a consistent and clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). Interestingly, two parallel paths can be identified in the current research scenario: A) in the aforementioned consolidated therapeutic indications, an innovative approach is directed towards tailored treatment strategies, to identify patients most likely to benefit from one of the different anticoagulant drugs, in particular subpopulations at increased risk of adverse events (e.g., bleeding); B) in unconventional settings, DOACs are gaining interest for potential use in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk-benefit profile of DOACs, as compared to VKAs or heparins, is less defined. The aim of this review is to critically assess the body of evidence underlying emerging therapeutic uses of DOACs (e.g., heparin-induced thrombocytopenia, anti-phospholipid antibody syndrome), including evolving issues in special populations (e.g., patients with VTE and cancer or cirrhosis). This will be achieved by analyzing the strength (i.e., systematic reviews, randomized clinical trials, observational studies, case report/series) and consistency (i.e., concordance) of both published and unpublished evidence registered in major public repositories.

Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of ß2-glycoprotein I in a mouse model of anti-phospholipid antibody-induced thrombosis.

OBJECTIVE: IgG aPL against domain I of ß2-glycoprotein I (ß2GPI) [anti-DI (aDI)] is associated with the pathogenesis of APS, an autoimmune disease defined by thrombosis and pregnancy morbidity. To date, however, no study has demonstrated direct pathogenicity of IgG aDI in vivo. In this proof-of-concept study, we designed a novel system to affinity purify polyclonal aDI aPL in order to assess its prothrombotic ability in a well-characterized mouse microcirculation model for APS. METHODS: Two polyclonal IgG fractions were isolated from serum of a patient with APS, both with high aPL activity but differing in aDI activity (aDI-rich and aDI-poor). These IgG fractions were tested for their pathogenic ability in an in vivo mouse model of thrombosis. Male CD1 mice were injected intraperitoneally with either aDI-rich or aDI-poor IgG; as a control, IgG isolated from healthy serum was used. A pinch injury was applied to the right femoral vein and thrombus dynamics and tissue factor activity in isolated tissue were evaluated. RESULTS: Both aDI-rich and aDI-poor IgG retained aCL and anti-ß2GPI activity, while only aDI-rich IgG displayed high aDI activity, as defined by our in-house cut-offs for positivity in each assay. aDI-rich IgG induced significantly larger thrombi in vivo compared with aDI-poor IgG (P < 0.0001). Similarly, aDI-rich IgG significantly enhanced the procoagulant activity of carotid artery endothelium and peritoneal macrophages isolated from experimental animals (P < 0.01). CONCLUSION: These data directly demonstrate that the ability to cause thrombosis in vivo is concentrated in the aDI fraction of aPL.