Stéphane Zuily

Validity of the global anti-phospholipid syndrome score to predict thrombosis: a prospective multicentre cohort study

OBJECTIVE To investigate the validity of the global APS score (GAPSS) to predict thrombosis in patients with autoimmune diseases. METHODS This prospective cohort study included consecutive patients with aPL or SLE. aPL, aPS-PT and GAPSS were determined. A Cox proportional hazards model assessed the validity of GAPSS and identified other potential independent predictors of thrombosis. RESULTS One hundred and thirty-seven patients [43.5 (s.d. 15.4) years old; 107 women] were followed up for a mean duration of 43.1 (s.d. 20.7) months. Mean GAPSS was significantly higher in patients who experienced a thrombotic event compared with those without [10.88 (s.d. 5.06) vs 8.15 (s.d. 5.31), respectively, P = 0.038]. In univariate analysis, age [hazard ratio (HR) = 1.04 (95% CI 1.01, 1.08)] and GAPSS above 16 [HR = 6.86 (95% CI 1.90, 24.77)] were each significantly associated with thrombosis during follow-up, while history of arterial thrombosis [HR = 2.61 (95% CI 0.87, 7.82)] failed to reach significance. Among aPL assays, IgG aPS/PT--a component of the GAPSS--was significantly associated with thrombosis [HR = 2.95 (95% CI 1.02, 8.51)]. In multivariate analysis, GAPSS above 16 remained the only significant predictor of thrombosis [HR = 6.17 (95% CI 1.70, 22.40)]. CONCLUSION This first external validation study confirmed that GAPSS can predict thrombosis in patients with aPL and associated autoimmune diseases.

Direct Oral Anticoagulants Use in Antiphospholipid Syndrome: Are These Drugs an Effective and Safe Alternative to Warfarin? A Systematic Review of the Literature

BackgroundThe cornerstone of thrombotic antiphospholipid syndrome (APS) patients’ management is to prevent recurrent thrombosis by long-term anticoagulation.Purpose of reviewThe purpose of the review is to summarize available literature on direct oral anticoagulants (DOACs) use in APS patients through a systematic review and to determine factors associated with thrombosis recurrence.Recent findingsThe recent RAPS trial demonstrated that APS patients treated with rivaroxaban had a significant twofold-increased thrombin potential, suggesting a higher thrombotic risk, in comparison with warfarin users. Furthermore, several reports of APS patients treated with DOACs have raised safety issues. Our systematic review identified 122 published APS patients treated with DOACs; among them, 19 experienced a recurrent thrombosis while on DOACs. Of note, triple positivity (positivity of all three laboratory criteria for APS) was associated with a 3.5-fold increased risk for recurrent thrombosis.SummaryIn conclusion, DOACs should be used with caution in APS patients and randomized control trials with clinical primary endpoints assessing clinical efficacy and safety are awaited to establish whether the prescription of DOACs could be a safe alternative to warfarin.

The Challenge of Bleeding in Antiphospholipid Antibody-Positive Patients

Antiphospholipid antibody-positive patients can develop bleeding due to capillaritis, microthrombosis, antiprothrombin antibodies, thrombocytopenia, and/or excessive antithrombotic therapy. Clinical characteristics of patients, e.g., renal impairment, elderly, or concomitant medications, are closely related to the risk of bleeding. The management of bleeding in antiphospholipid antibody (aPL)-positive patients is challenging due to the baseline increased risk of thrombosis. If anticoagulation is stopped, it should be restarted as soon as possible once the acute bleeding is controlled; the continuation of anticoagulation despite active bleeding may be required in selected cases. High-dose corticosteroid is the mainstay treatment for diffuse alveolar hemorrhage, lupus anticoagulant–hypoprothrombinemia syndrome, and severe thrombocytopenia; immunosuppressive drugs are also required to improve the long-term outcomes. Hydrocortisone is critical in adrenal hemorrhage patients due to concomitant adrenal insufficiency; despite bleeding, anticoagulation should be maintained as much as possible. Plasma exchange should be considered in catastrophic antiphospholipid syndrome patients with concurrent bleeding. This article will review the causes of bleeding in aPL-positive patients as well as the management strategies.

Pulmonary Hypertension in Antiphospholipid Syndrome

Pulmonary hypertension (PH) is a rare but life-threatening condition in antiphospholipid syndrome (APS) patients with or without systemic lupus erythematosus (SLE). The definition of PH is based on hemodynamic parameters estimated by transthoracic echocardiography (TTE) and confirmed by right heart catheterization (RHC). New evidence suggests that antiphospholipid antibodies (aPL) in SLE patients increase the risk of PH; however, studies yield conflicting results. Hypotheses regarding the impact of aPL on PH include large vessel and microvascular thrombosis, and endothelial remodeling. Natural history of PH is progressive worsening mainly due to recurrent pulmonary embolism. The management in APS patients includes anticoagulation; patients undergoing pulmonary endarterectomy need to be closely monitored because of an increased risk of thrombotic complications.

Superficial vein thrombosis, thrombin generation and activated protein C resistance as predictors of thromboembolic events in lupus and antiphospholipid patients. A prospective cohort study

INTRODUCTION Predicting thrombosis in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (aPL) is still challenging. Our objective was to determine risk factors for thrombotic events including activated protein C (APC) resistance proven by a thrombin generation (TG) assay in patients with SLE and/or aPL. MATERIALS AND METHODS We performed a prospective cohort study in a French University Hospital and tertiary care center. Ninety-two consecutive patients with SLE and/or aPL without ongoing anticoagulant treatment were enrolled. The outcome was time to thrombotic event. We evaluated clinical and laboratory variables including APC sensitivity ratio (APCsr) determined by TG. An APCsr>90th percentile of a control population indicated APC resistance. RESULTS Patients were followed-up for a median duration of 35 months (inter-quartile range: 26 to 62; 320 patient-years). Thrombosis during follow-up occurred in 18 patients. In univariate analysis, together with history of hypertension, superficial vein thrombosis (SVT) and arterial thrombosis, patients with both aPL and APC resistance had an increased risk for incident thromboembolic events (HR, 3.67 [95% confidence interval, 1.31 to 10.31]). In multivariate analysis, only history of hypertension (HR, 10.77 [95% confidence interval, 3.15 to 36.83]), SVT (HR, 7.45 [95% confidence interval, 2.25 to 24.66]) and arterial thrombosis (HR, 3.31 [95% confidence interval, 1.14 to 9.55]) remained independent risk factors. CONCLUSIONS History of thrombosis including seemingly benign SVT have a higher predictive value for incident thrombotic events in SLE or aPL patients than APC resistance proven by TG.

Impact of comorbidity on medication use in elderly patients with cardiovascular diseases: the OCTOCARDIO study

Background: Recommended medications are under-prescribed in elderly patients with atrial fibrillation (AF), coronary artery disease (CAD), and congestive heart failure (CHF). The relationship between under-prescribing and comorbidity is unclear. Design: Single-day observational study. Methods: Analysis of medications taken by patients aged 80 years or over at the time of their admission to cardiology units of 32 French hospitals. Comorbidity was measured using the Charlson comorbidity index (CCI). Results: The study included 510 patients (57% men, mean age 85 years). History of AF, CHF, and CAD was present in 213 (42%), 199 (39%), and 187 (37%) patients, respectively. CCI was 0 in 110 (22%), 1–2 in 215 (42%), and ≥3 in 185 (36%) patients. Vitamin K antagonists (VKA) were prescribed to 105 (49%) and aspirin to 86 (40%) patients with AF. CCI did not influence VKA prescription but influenced aspirin use, with lower prescription rates in patients with CCI 1–2 than CCI 0 or CCI ≥3 (p = 0.02). In CHF, angiotensin-converting enzyme inhibitors (ACEI) and β-blockers were prescribed to 80 (40%) and 96 (48%) patients, respectively. Rates of prescription of ACEI, β-blockers, statins, and aspirin in patients with CAD were 43%, 56%, 56%, and 66%, respectively. CCI level did not influence any medication use in CHF and CAD. Conclusion: Even in the absence of comorbidity, elderly patients with major cardiovascular diseases are denied from indicated medical treatments probably because of their age alone. Implementing measures to enhance awareness of treatment benefits and promote appropriate prescribing is necessary.

Antiphospholipid antibodies can identify lupus patients at risk of pulmonary hypertension: A systematic review and meta-analysis☆

BACKGROUND Pulmonary hypertension (PH) is a life-threatening condition that may affect outcomes in patients with systemic lupus erythematosus (SLE). The role of antiphospholipid antibodies (aPL) on the risk of PH is controversial. Therefore our objective was to estimate the risk of PH (WHO groups 1-5) including associated pulmonary arterial hypertension (APAH, WHO group 1 only) related to aPL in patients with SLE. METHODS Systematic review and meta-analysis were performed: MEDLINE, EMBASE, Cochrane Library, congress abstracts, and reference lists of eligible studies were searched through 2015. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcomes (PH including APAH). Two reviewers extracted study characteristics and outcome data from published reports. Estimates were pooled using random effects models and sensitivity analyses. PROSPERO registration number: CRD42015016872. RESULTS Of 984 identified abstracts, 31 primary studies (five cohorts, 13 case-control, 13 cross-sectional) met inclusion criteria, including 4480 SLE patients. Prevalence of PH in aPL-positive vs. aPL-negative SLE patients was 12.3% vs. 7.3%, respectively. The overall pooled odds ratio (OR) for PH was 2.28 (95% CI, 1.65 to 3.15) (I2=39%). The risk of APAH was also significantly increased (OR=2.62 [95% CI, 1.11-6.15]). The risk of PH was the highest for lupus anticoagulant (OR=1.96 [95% CI, 1.31-2.92]) and IgG anticardiolipin antibodies (OR=2.64 [95% CI, 1.30-5.36]) while other antibodies were not significantly associated with PH. CONCLUSIONS Among SLE patients, aPL can identify patients at risk for PH and APAH. These findings warrant implementation of effective screening and early treatment strategies.

Hydroxychloroquine in the primary thrombosis prophylaxis of antiphospholipid antibody positive patients without systemic autoimmune disease

Objective The objective of this study was to determine the efficacy of hydroxychloroquine (HCQ) in the primary thrombosis prevention of antiphospholipid antibody (aPL)-positive patients with no other systemic autoimmune diseases. Methods Under the auspices of Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking, a multicenter, international, randomized controlled trial (RCT) was initiated, in which persistently aPL-positive but thrombosis-free patients without systemic autoimmune diseases were randomized to receive HCQ or no treatment in addition to their standard regimen. The primary objective was the efficacy of HCQ in preventing the first thrombosis. The secondary objectives were the thrombosis incidence rate, and the effects of HCQ on aPL profile and mortality rate. Patients were risk-stratified based on antiplatelet agent use. The goal was to follow patients every 6 months for 5 years. Results We recruited 20 persistently aPL-positive patients (female: 19, mean age: 46.6 ± 9.9 years, and baseline antiplatelet medication: 14); 9/20 were randomized to HCQ. During the mean follow-up of 1.7 years, no patients developed thrombosis or a serious adverse event. The study was terminated early due to the low recruitment rate, exacerbated by the prolonged manufacturing shortage and significant price increase of HCQ in the United States. Conclusion Given that a small number of patients with a relatively short follow-up were enrolled in our RCT, and no patients developed thrombosis, we cannot accurately assess the effectiveness of HCQ for primary thrombosis prevention in persistently aPL-positive patients with no other systemic autoimmune diseases. Our experience suggests that conducting an international RCT, especially without pharmaceutical support, is an extremely challenging undertaking.

International and multidisciplinary expert recommendations for the use of biologics in systemic lupus erythematosus

BACKGROUND/PURPOSE Despite conventional immunosuppressants, active and steroid-dependent systemic lupus erythematosus (SLE) represents a therapeutic challenge. Only one biologic, belimumab, has been approved, but other biologics are sometimes used off-label. Given the lack of evidence-based data in some clinical situations encountered in real life, we developed expert recommendations for the use of biologics for SLE. METHODS The recommendations were developed by a formal consensus method. This method aims to formalize the degree of agreement among experts by identifying, through iterative ratings with feedback, the points on which experts agree, disagree or are undecided. Hence, the recommendations are based on the agreed-upon points. We gathered the opinion of 59 French-speaking SLE experts from 3 clinical networks dedicated to systemic autoimmune diseases (FLEUR, IMIDIATE, FAI2R) from Algeria, Belgium, France, Italy, Morocco, Switzerland and Tunisia. Represented medical specialities were internal medicine (49%), rheumatology (34%), nephrology (7%), dermatology (5%), pediatrics (3%) and cardiology (2%). Two methodologists and 3 strictly independent SLE expert groups contributed to developing these recommendations: a steering group (SG) (n=9), an evaluation group (EG) (n=28) and a reading group (RG) (n=22). Preliminary recommendations were drafted by the SG, then proposed to the EG. Each EG member rated the degree of agreement from 1 to 9 (1: lowest; 9: strongest) for each recommendation. After 2 rating rounds, the SG submitted a new version of the recommendations to the RG. With comments from the RG, the SG finalised the recommendations. RESULTS A total of 17 final recommendations were formulated by the SG, considering all agreement scores and comments by the EG and RG members and the two methodologists. These recommendations define the subset of patients who require a biologic; the type of biologics to use (belimumab, rituximab, etc.) depending on the organ involvement and associated co-treatments; what information should be given to patients; and how to evaluate treatment efficacy and when to consider discontinuation. CONCLUSION Overall, 17 recommendations for the good use of biologics in SLE were formulated by a large panel of SLE experts to provide guidance for clinicians in daily practice. These recommendations will be regularly updated according to the results of new randomized trials and increasing real life experience.

Dramatic Response to Tocilizumab Before Emergency Surgery in Severe Active Takayasu Disease

A 19-year-old man was admitted in our tertiary care center in August 2014 for a 10-kg weight loss in a few months (48 kg, 1.80 m, and body mass index, 14.8 kg/m2), claudication in the lower limbs after a 500-m distance and a postprandial abdominal pain associated with mild renal insufficiency and proteinuria with no hypertension (100/80 mm Hg). The patient had no medical history and was an active smoker (tobacco and cannabis, estimated consumption: 2 pack-years). Laboratory parameters were elevated leukocyte count (13×109/L), C-reactive protein level (55 mg/L), creatinine (14 mg/L), and B-natriuretic peptide (4246 pg/mL). No thrombophilia, autoimmune disorders, or viral infections were identified. The patient underwent a B-mode Doppler ultrasound that showed multiple proximal arterial occlusions and stenoses of large vessels confirmed by a computed tomographic angiography: occlusions of bilateral subclavian arteries, superior and inferior mesenteric arteries, and right renal artery with kidney atrophy were found (Figure 1A). Furthermore, significant stenoses of celiac artery, left renal artery (Figure 1B), right internal iliac artery, and bilateral superficial femoral arteries were identified. A discrete circumferential thickening of the abdominal aorta was suggestive of aortitis. Cervical magnetic resonance angiography showed a complete occlusion of both subclavian and vertebral arteries (Figure 2). Transthoracic echocardiography revealed a severe left ventricular (LV) systolic dysfunction (LV ejection fraction …