Irene Cecchi

Non-vitamin K antagonist oral anticoagulants and antiphospholipid syndrome

The current treatment of thrombotic APS patients includes long-term anticoagulation with oral vitamin K antagonists (VKAs), with warfarin being the one most commonly used. However, the use of VKAs can be challenging, especially in patients with APS. VKAs monitoring in patients with aPL is complicated by the heterogeneous responsiveness to LAs of reagents used in the International Normalized Ratio test, potentially resulting in instability of anticoagulation. For decades, VKAs were the only available oral anticoagulants. However, non-VKA oral anticoagulants, including a direct thrombin inhibitor (dabigatran etexilate) and direct anti-Xa inhibitors (rivaroxaban, apixaban and edoxaban), are currently available. The use of these agents may represent a major step forward since, unlike VKAs, they have few reported drug interactions and they do not interact with food or alcohol intake, thereby resulting in more stable anticoagulant intensity. Most importantly, monitoring their anticoagulant intensity is not routinely required due to their predictable anticoagulant effects. In this review, we discuss the clinical and laboratory aspects of non-VKA oral anticoagulants, focusing on the available evidence regarding their use in patients with APS.

Expanding the therapeutic options for renal involvement in lupus: eculizumab, available evidence.

In this study, we aimed to systematically review available literature on the efficacy of eculizumab for the treatment of renal involvement in patients with systemic lupus erythematosus (SLE). We conducted a literature search developed a priori, to identify articles reporting clinical experience with the use of eculizumab in SLE patients, focusing on renal involvement. The search strategy was applied to Ovid MEDLINE, EMBASE, In-Process and Other Non-Indexed Citation, Cochrane Central Register of Controlled Trials and Scopus from 2006 to present. Abstracts from EULAR and ACR congresses were also screened. We included six publications describing the renal outcome in SLE patients receiving eculizumab. Five out of six cases described the occurrence of thrombotic microangiopathy (TMA) in renal biopsies of patients with known SLE; three cases with biopsy-proven lupus nephritis (LN) and two patients with SLE-related antiphospholipid syndrome without histologic evidence of LN. One study reported the outcome of a patient with severe refractory LN successfully treated with eculizumab. All patients, regardless of the presence of concomitant LN, presented with severe hypocomplementemia and renal function impairment. All patients showed a sustained improvement of renal function and normalization of complement parameters after treatment with eculizumab[median follow-up 9 months (1–17)]. Despite the limitations of the currently available evidence, existing data are promising and provide preliminary support for the use of eculizumab in selected cases of SLE with renal involvement, especially in the presence of TMA, or in patients with refractory LN.

Prevalence and Thrombotic Risk Assessment of Anti-β2 Glycoprotein I Domain I Antibodies: A Systematic Review

Background To date, the exact prevalence of anti‐&bgr;2 glycoprotein I domain I (anti‐&bgr;2 GPI‐DI) antibodies in patients with antiphospholipid syndrome (APS) and their role when assessing thrombosis risk is uncertain. Objectives To estimate the prevalence of anti‐&bgr;2 GPI‐DI in patients with APS and to determine whether anti‐&bgr;2 GPI‐DI‐positive individuals are at greater risk of thrombosis, as compared with individuals without anti‐&bgr;2 GPI‐DI, by systematically reviewing the literature. Methods A detailed literature search was applied a priori to Ovid MEDLINE In‐Process and Other Non‐Indexed Citation 1986 to present and to abstracts from the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR)/Association for Rheumatology Health Professionals (ARHP) Annual Meetings (2011–2015). Results A total of 11 studies, including 1,585 patients, were analyzed. Patients were distributed as follow: 1,218 patients APS (45.4% anti‐&bgr;2 GPI‐DI‐positive; in more detail: 504 primary APS [55.4% anti‐&bgr;2 GPI‐DI‐positive], 192 secondary APS [43.2% anti‐&bgr;2 GPI‐DI‐positive], and 522 not specified), 318 with systemic lupus erythematosus (SLE; 26.7% anti‐&bgr;2 GPI‐DI‐positive), 49 asymptomatic carriers of antiphospholipid antibodies (aPL) (30.6% anti‐&bgr;2 GPI‐DI‐positive), and 1,859 healthy controls. When considering the five studies eligible for thrombotic risk assessment, four studies found a significant association of anti‐&bgr;2 GPI‐DI‐positivity with thrombotic events, whereas one study found no predictive correlation with thrombosis (overall odds ratio [OR] for pooled data: 1.99; 95% confidence interval [CI]: 1.52–2.6; p < 0.0001). Conclusion We report an overall estimated median prevalence of anti‐&bgr;2 GPI‐DI antibodies of 44.3% in patients with APS and/or SLE and a significantly higher prevalence among patients with APS compared with SLE alone. Anti‐&bgr;2 GPI‐DI antibodies might represent a promising tool when assessing thrombotic risk in patients with APS.

The adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) for risk stratification in young APS patients with acute myocardial infarction

BACKGROUND Young adults with acute myocardial infarction are a critical group to examine for the purpose of risk factor stratification and modification. In this study we aimed to assess the clinical utility of the adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) for the risk stratification of acute myocardial infarction in a cohort of young patients with antiphospholipid syndrome (APS). METHODS The analysis included 83 consecutive APS patients (≤50years old) who presented with arterial or venous thromboembolic events. Data on cardiovascular risk factors and antiphospholipid antibodies (aPL) positivity were retrospectively collected. The aGAPSS was calculated by adding the points corresponding to the risk factors, based on a linear transformation derived from the ß-regression coefficient as follows: 3 for hyperlipidaemia, 1 for arterial hypertension, 5 for aCL IgG/IgM, 4 for anti-b2 glycoprotein I IgG/IgM and 4 for LA. RESULTS Higher aGAPSS values were observed in patients with acute myocardial infarction when compared to the others [mean aGAPSS 11.9 (S.D. 4.15, range 4-18) Vs. mean aGAPSS 9.2 (S.D. 5.1, range 1-17); T test: p<0.05]. Significantly higher aGAPSS values were also seen in patients with acute coronary syndrome compared to patients with a history of peripheral or cerebrovascular arterial thrombotic events [mean aGAPSS 11.9 (S.D. 4.15, range 4-18) Vs. mean aGAPSS 6.7 (S.D. 5.7, range 1-17); T test: P<0.005]. CONCLUSIONS The aGAPSS is based upon a quantitative score and could aid risk stratifying APS patients younger than 50years for the likelihood of developing coronary thrombotic events and may guide pharmacological treatment for high-risk patients.

Ubiquinol Effects on Antiphospholipid Syndrome Prothrombotic Profile: A Randomized, Placebo-Controlled Trial

Objective— Antiphospholipid syndrome (APS) leukocytes exhibit an oxidative perturbation, directly linked to alterations in mitochondrial dynamics and metabolism. This disturbance is related to the patients’ prothrombotic status and can be prevented by in vitro treatment with coenzyme Q10. Our aim was to investigate short-term effects of in vivo ubiquinol (reduced coenzyme Q10 [Qred]) supplementation on markers related to inflammation and thrombosis in APS through a prospective, randomized, crossover, placebo-controlled trial. Approach and Results— Thirty-six patients with APS were randomized to receive Qred (200 mg/d) or placebo for 1 month. Thirty-three patients with APS completed the intervention, which increased plasma coenzyme Q10. Qred improved endothelial function and decreased monocyte expression of prothrombotic and proinflammatory mediators, inhibited phosphorylation of thrombosis-related protein kinases, and decreased peroxides and percentage of monocytes with depolarized mitochondria; mitochondrial size was increased, and mitochondrial biogenesis–related genes were upregulated. Qred ameliorated extruded neutrophil extracellular traps in neutrophils and downregulated peroxides, intracellular elastase, and myeloperoxidase. Nanostring microRNA profiling revealed 20 microRNAs reduced in APS monocytes, and 16 of them, with a preponderance of cardiovascular disease–related target mRNAs, were upregulated. Monocytes gene profiling showed differential expression of 29 atherosclerosis-related genes, 23 of them changed by Qred. Interaction networks of genes and microRNAs were identified. Correlation studies demonstrated co-ordinated effects of Qred on thrombosis and endothelial function–associated molecules. Conclusions— Our results highlight the potential of Qred to modulate the overexpression of inflammatory and thrombotic risk markers in APS. Because of the absence of clinically significant side effects and its potential therapeutic benefits, Qred might act as safe adjunct to standard therapies in APS. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02218476

Clinical utility of the global anti-phospholipid syndrome score for risk stratification: A pooled analysis

Objective Recently, our group conceived a risk score for clinical manifestations of APS (the global APS score, or GAPSS) that takes into account the combination of independent cardiovascular risk factors and the aPL positivity profile. These include hyperlipidaemia, arterial hypertension, aCL, anti-β2 glycoprotein-I, aPS-PT and the LA. A complementary version, the adjusted GAPSS (aGAPSS), which excludes aPS-PT, was also designed. The aim of our study was to systematically review the literature to assess the clinical utility of the GAPSS and aGAPSS for risk stratification of any APS clinical manifestation. Methods We pooled data from available cohort studies, including a total of 10 studies, comprising 2273 patients, in which the GAPSS has been applied. A search strategy was developed a priori to identify an available cohort that reported findings which investigated the clinical utility of GAPSS or aGAPSS. Results Seven studies used the GAPSS in their cohort, whereas three studies used the aGAPSS. In brief, we found a statistically significant difference in the cumulative GAPSS and aGAPSS between patients that experienced an arterial and/or venous thrombotic event [cumulative mean GAPSS (s.d.) 10.6 (4.74) and aGAPSS 7.6 (3.95)], patients without any thrombotic manifestation [cumulative GAPSS 7.01 (5.46) and aGAPSS 4.9 (4.33)] and patients with pregnancy morbidity [cumulative GAPSS 8.79 (2.59) and aGAPSS 6.7 (2.8)]. The highest levels of GAPSS were found in patients that experienced arterial thrombosis [mean GAPSS 12.2 (5.2)] and patients that experienced any recurrences of clinical manifestations of APS [mean GAPSS 13.7 (3.1)]. Conclusion GAPSS may represent a useful tool to assess the thrombosis or pregnancy loss risk in aPL-positive patients, switching from the concept of aPL as a sole diagnostic antibody to aPL as risk factors for clinical events.

The risk of ischaemic stroke in primary APS patients: a prospective study

The most common neurological manifestation of antiphospholipid syndrome (APS) is ischaemic stroke. Identifying patients with APS at high risk for developing any thrombotic event remains a major challenge. In this study, the aim was to identify predictive factors of ischaemic stroke in a cohort of primary APS (PAPS) patients who presented with new onset symptoms suggestive of acute stroke.

Immunotherapies in phase II and III trials for the treatment of systemic lupus erythematosus

ABSTRACT Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by highly heterogeneous clinical manifestations and a multi systemic involvement. SLE is prone to relapses and remissions, which makes the management challenging. Moreover, conventional therapies may have considerable side-effects, which highlights the demand for new therapeutic strategies. The progress towards a better understanding of the underlying pathogenesis has led to the development of biological therapies targeted directly against crucial molecular mediators of SLE. Areas covered: In this review we analyzed available biological therapies, phase II and III trials and upcoming new therapies that are currently under development for SLE treatment. Expert opinion: The complex pathogenesis of SLE is far from being fully understood. Evidence towards a better understanding of the pathogenic pathways, the cellular and molecular mediators involved in SLE are emerging. Henceforth, new biological therapeutic options targeting crucial molecular mediators involved in the pathogenesis of SLE are being developed. In the future, the management of SLE could profit from the use of biological therapies that are tailored towards the individual patient’s specific clinical manifestations, taking into account their genetic background and pathogenic fingerprint.

Long-term effect of B-cells depletion alone as rescue therapy for severe thrombocytopenia in primary antiphospholipid syndrome

OBJECTIVES To investigate the long-term effect of B-cell depletion therapy with Rituximab (RTX) alone as rescue therapy in primary antiphospholipid syndrome (PAPS) patients with severe thrombocytopenia. METHODS We retrospectively retrieved data from patients who met the following inclusion criteria: (a) persistent antiphospholipid antibodies (aPL) positivity and fulfilled the Sydney criteria for PAPS (b) presented with severe thrombocytopenia (platelets <50,000/mm3) (c) were treated with RTX as a rescue therapy (d) had at least 1 year of follow-up after B-cells depletion therapy. RESULTS This retrospective study included 6 consecutive female PAPS patients [median age 49.5 (range 38-66)] who presented with severe thrombocytopenia (platelets <50,000/mm3, mean value 31,000 ± 9000/mm3). We observed a full response (defined as >150,000 platelets/mm3) after treatment with RTX in 5 out of 6 patients (83.3%). Among responders, after a median follow-up of more than 4 years, we observed a median time free from relapse of 43 months (range 12-97). One patient did not respond to the B-cell depletion therapy and was treated with a splenectomy 1 month after RTX therapy and platelets levels normalized after 3 months. No adverse events were reported, no patients developed significant infections. Importantly, the patients required no further maintenance therapy for the thrombocytopenia. CONCLUSION In one of the longest-term observational (median 43 months) studies, sustained clinical remission of severe thrombocytopenia without immunosuppressive maintenance therapy was obtained by RTX alone in patients with PAPS and severe thrombocytopenia intolerant or refractory to conventional therapy.

Circulating microRNAs as biomarkers of disease and typification of the atherothrombotic status in antiphospholipid syndrome

We aimed to identify the plasma miRNA profile of antiphospholipid syndrome (APS) patients and to investigate the potential role of specific circulating miRNAs as non-invasive disease biomarkers. Ninety APS patients and 42 healthy donors were recruited. Profiling of miRNAs by PCR-array in plasma of APS patients identified a set of miRNAs differentially expressed and collectively involved in clinical features. Logistic regression and ROC analysis identified a signature of 10 miRNA ratios as biomarkers of disease. In addition, miRNA signature was related to fetal loss, atherosclerosis, and type of thrombosis, and correlated with parameters linked to inflammation, thrombosis, and autoimmunity. Hard clustering analysis differentiated 3 clusters representing different thrombotic risk profile groups. Significant differences between groups for several miRNA ratios were found. Moreover, miRNA signature remained stable over time, demonstrated by their analysis three months after the first sample collection. Parallel analysis in two additional cohorts of patients, including thrombosis without autoimmune disease, and systemic lupus erythematosus without antiphospholipid antibodies, each displayed specific miRNA profiles that were distinct from those of APS patients. In vitro, antiphospholipid antibodies of IgG isotype promoted deregulation in selected miRNAs and their potential atherothrombotic protein targets in monocytes and endothelial cells. Taken together, differentially expressed circulating miRNAs in APS patients, modulated at least partially by antiphospholipid antibodies of IgG isotype, might have the potential to serve as novel biomarkers of disease features and to typify patients’ atherothrombotic status, thus constituting a useful tool in the management of the disease.