Irama Villar

Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus

Antimalarials have shown beneficial effects on systemic lupus erythematosus (SLE) activity. Our aim was to investigate whether antimalarials protect against thrombosis and influence survival in SLE patients. A prospective cohort including 232 patients with SLE were included in the study at the time of lupus diagnosis. End points were documented thrombosis and death due to any cause. A Cox regression-multiple-failure time survival analysis model was fitted to establish the effect of antimalarials on the development of thrombosis. Kaplan-Meier survival curves and propensity score adjusted-Cox regression analysis were performed to investigate the effect of antimalarials use on survival. Of our subjects, 204 patients (88%) were women. 230 patients (99%) were white. 150 patients (64%) had ever received antimalarials. Median time on antimalarials was 52 months (range three to 228 months). The Cox multiple-failure time survival analysis showed that taking antimalarials was protective against thrombosis (HR 0.28, 95%CI 0.08-0.90), while aPL-positivity (HR 3.16, 95%CI 1.45-6.88) and previous thrombosis (HR 3.85, 95%CI 1.50-9.91) increased the risk of thrombotic events. Twenty-three patients died, 19 of whom (83%) had never received antimalarials. No patient treated with antimalarials died of cardiovascular complications. Cumulative 15-year survival rates were 0.68 for never versus 0.95 for ever treated patients (P < 0.001). Age at diagnosis and propensity score-adjusted HR for antimalarials ever versus never users was 0.14 (95%CI 0.04-0.48). Our study shows a protective effect of antimalarials against thrombosis and an increased survival of SLE patients taking these drugs. These data support the routine use of antimalarials in all patients with SLE.

Transiently positive anticardiolipin antibodies and risk of thrombosis in patients with systemic lupus erythematosus.

Fluctuations in the titers of anticardiolipin antibodies (aCL) have been reported in systemic lupus erythematosus (SLE) patients, but their relation with thrombosis is not completely understood. Prospective inception cohort of 237 patients with SLE (American College of Rheumatology criteria). Positivity for antiphospholipid antibodies (aPL) was defined according to Sapporo criteria. aCL was defined as persistently positive when more than two-thirds of the determinations were positive during follow-up. Patients were classified into four groups: A [positive lupus anticoagulant (LA)], B (negative LA and persistently positive aCL), C (negative LA and transiently positive aCL) and D (negative LA and aCL). Of these 237 patients, 211 (89%) patients were women. Median age at diagnosis and follow-up were 32 (2—78) and 10 (1—31) years, respectively; 33 (13.9%), 23 (9.7%), 42 (17.7%) and 139 (58.6%) patients were classified in groups A, B, C and D, respectively. Thirty (12.6%) and 23 (9.7%) patients suffered arterial and venous thrombotic events, respectively. Adjusted risk for arterial thrombosis was increased in groups A [odds ratio (OR) 15.69, 95% confidential interval (CI) 4.79—51.42, P < 0.001] and B (OR 7.63, 95% CI 2.00—29.08, P = 0.003), but not in group C when compared with group D. Adjusted risk of venous thrombosis was increased in group A (OR 4.24, 95% CI 1.36—13.20, P = 0.013), but not in groups B or C when compared with group D. Risk of thrombosis is not increased in SLE patients with negative LA and transiently positive aCL, even fulfilling Sapporo laboratory criteria, when compared with aPL-negative SLE patients. Lupus (2007) 16, 810—816.

Pulmonary hypertension in systemic lupus erythematosus: prevalence, predictors and diagnostic strategy

OBJECTIVES To investigate the prevalence and predictors of pulmonary hypertension (PH) in patients with systemic lupus erythematosus (SLE) and to validate a diagnostic strategy. METHODS 245 patients with SLE entered a screening program. Possible PH was defined as two consecutive systolic pulmonary arterial pressure (PAP) values ≥ 40mmHg by echocardiography. The subsequent diagnostic procedure, including right heart catheterization if needed, confirmed or excluded the diagnosis of PH secondary to cardiopulmonary disease or SLE-related pulmonary arterial hypertension (PAH). Independent predictors of PH were identified by multivariant multiple linear or logistic regression models. The sensitivity (S), specificity (SP), positive (PPV) and negative predictive values (NPV) were calculated for different screening cutoff values. RESULTS 88% patients were women. The mean (SD) age at the time of enrolment was 45 (16) years. 12 cases of PH were detected, all secondary, with a resulting prevalence of 5%. Two consecutive echocardiographic PAP measurements ≥ 40mmHg performed best as the cutoff point for screening (S 100%, SP 97%, PPV 70, NPV 100), as compared with single PAP measurements ≥ 30mmHg or ≥ 40mmHg The age at the time of enrolment was the only variable independently associated with PAP values (p=0.0001), with the SLICC damage index score showing a borderline association (p=0.08). Only the age at the time of enrolment showed an independent association with PH (OR 1.10, 95% CI 1.06-1.17). CONCLUSION We found a low prevalence of PH. Screening echocardiograms in asymptomatic lupus patients are thus not recommended. Two consecutive PAP values ≥ 40mmHg by echocardiogram is the best screening cutoff for starting investigations in SLE patients with suspected PH.

Peripheral Arterial Disease in Systemic Lupus Erythematosus: Prevalence and Risk Factors

Objective. To analyze the prevalence of peripheral arterial disease (PAD) and cardiovascular (CV) risk factors in a cohort of patients with systemic lupus erythematosus (SLE) and to identify variables potentially related to PAD. Methods. The study included 216 patients with SLE from the Lupus-Cruces prospective observational cohort. The ankle brachial index (ABI) was determined in each patient, with values < 0.9 considered diagnostic of PAD. Demographic and clinical variables, presence of traditional risk factors and CV events, cardiovascular risk calculated by Systematic Coronary Risk Evaluation (SCORE), and treatments received by each patient were analyzed. Results. Ninety-two percent of patients were women. The mean age (SD) was 49 years (15), with a mean followup (SD) of 12 years (9). The prevalence of low ABI was 21%. CV risk factors were frequent: smoking, 30% of patients; high blood pressure, 32.7%; diabetes mellitus, 3.2%; hypercholesterolemia, 34.1%; and metabolic syndrome, 9.7%. The following variables were associated with low ABI in the univariate analysis: age (p < 0.001), hypertension (p = 0.002), diabetes (p = 0.018), hypercholesterolemia (p = 0.018), CV events (p < 0.001), SCORE (p = 0.004), cumulative dose of cyclophosphamide (p = 0.03), and fibrinogen levels (p = 0.002). In the multivariate analysis, the only independent variable in the final model was age (OR 1.04, 95% CI 1.02–1.07, p < 0.001), with a tendency for the presence of any vascular risk factor (diabetes, hypertension, hypercholesterolemia, or current smoking; OR 2.3, 95% CI 0.99–5.1, p = 0.053). Conclusion. The prevalence of low ABI in patients with SLE is higher than expected. While the association with CV risk factors and vascular disease in other territories was strong, we could not identify SLE-specific variables independently associated with PAD.

LDLR and PCSK9 Are Associated with the Presence of Antiphospholipid Antibodies and the Development of Thrombosis in aPLA Carriers.

Introduction The identification of the genetic risk factors that could discriminate non- thrombotic from thrombotic antiphospholipid antibodies (aPLA) carriers will improve prognosis of these patients. Several human studies have shown the presence of aPLAs associated with atherosclerotic plaque, which is a known risk factor for thrombosis. Hence, in order to determine the implication of atherosclerosis in the risk of developing thrombosis in aPLA positive patients, we performed a genetic association study with 3 candidate genes, APOH, LDLR and PCSK9. Material & Methods For genetic association study we analyzed 190 aPLA carriers -100 with non-thrombotic events and 90 with thrombotic events- and 557 healthy controls. Analyses were performed by χ2 test and were corrected by false discovery rate. To evaluate the functional implication of the newly established susceptibility loci, we performed expression analyses in 86 aPLA carrier individuals (43 with thrombotic manifestations and 43 without it) and in 45 healthy controls. Results Our results revealed significant associations after correction in SNPs located in LDLR gene with aPLA carriers and thrombotic aPLA carriers, when compared with healthy controls. The most significant association in LDLR gene was found between SNP rs129083082 and aPLA carriers in recessive model (adjusted P-value = 2.55 x 10−3; OR = 2.18; 95%CI = 1.49–3.21). Furthermore, our work detected significant allelic association after correction between thrombotic aPLA carriers and healthy controls in SNP rs562556 located in PCSK9 gene (adjusted P-value = 1.03 x 10−2; OR = 1.60; 95%CI = 1.24–2.06). Expression level study showed significantly decreased expression level of LDLR gene in aPLA carriers (P-value <0.0001; 95%CI 0.16–2.10; SE 0.38–1.27) in comparison to the control group. Discussion Our work has identified LDLR gene as a new susceptibility gene associated with the development of thrombosis in aPLA carriers, describing for the first time the deregulation of LDLR expression in individuals with aPLAs. Besides, thrombotic aPLA carriers also showed significant association with PCSK9 gene, a regulator of LDLR plasma levels. These results highlight the importance of atherosclerotic processes in the development of thrombosis in patients with aPLA.

Predictors of peripheral arterial disease in SLE change with patient’s age

Objective To analyse the differential influence of risk factors of peripheral artery disease (PAD) according to age in patients with SLE. Methods 216 patients from the Lupus-Cruces cohort were divided in three age groups: ≤34 years, 35–49 years and ≥50 years. A low ankle–brachial index defined PAD. Significant variables were identified by univariant and multivariant analysis in each age group. Results Different factors were identified in different age groups: antiphospholipid antibodies/antiphospholipid syndrome and glucocorticoids in patients ≤34 years; in patients 35–49 years old, hypertension was the only statistically significant predictor, although a trend was observed for fibrinogen levels; a trend was observed for hypercholesterolaemia in those ≥50 years. Conclusions Age may modulate the influence of risk factors for PAD in patients with SLE.

Prevalence and Significance of Persistently Positive Antiphospholipid Antibodies in Women with Preeclampsia

Objective. To determine the prevalence of antiphospholipid antibodies (aPL) and their association with obstetric outcomes in women with preeclampsia. Methods. The study included 150 patients. Clinical variables, risk factors, and severity criteria for preeclampsia and aPL were analyzed. Results. We found aPL in 4% of patients without risk factors for preeclampsia and in no women with risk factors (p = 0.03). Fifty percent of aPL-positive patients had a fetus with intrauterine growth restriction versus 13.9% (p = 0.04). No relation between aPL and severe preeclampsia was found. Conclusion. The prevalence of aPL among women with preeclampsia is low. aPL can predispose women without risk factors to preeclampsia.

Dr. Erdozain, et al reply

To the Editor: We thank Dr. Kawada1 for his interest in our study2 and acknowledge his comments, which we will try to address. Regarding the first issue, the prevalence of ankle brachial index (ABI) > 1.4 in our cohort was low: 2.77% (6/216 patients). It is true that high ABI values, with a cutoff value ranging between 1.3 and 1.4, have been related with higher cardiovascular mortality. The Strong Heart Study … Address correspondence to Dr. G. Ruiz-Irastorza, Unidad de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Universitario Cruces, 48903-Bizkaia, Spain. E-mail: r.irastorza{at}euskaltel.net

Tratamiento del síndrome antifosfolipídico en el embarazo

The antiphospholipid syndrome (APS) is a well known cause of pregnancy complications, including maternal thrombosis and preeclampsia as well as embryofetal losses. A multidisciplinary, medical-obstetric approach is of great importance in the clinical management of pregnant women with APS. Therapeutic interventions are based on the combination acilsalycilic acid-heparin. Although the specific combinations in different situations are still a matter of debate – due to important limitations of the available studies–, combined treatment with both drugs is usually recommended in women with previous thrombosis and/or fetal death. Aspirin alone is still a reasonable option for women with early losses, although controversy is particularly important in this group. In any situation, an adequate thromboprophylaxis in the peripartum period is warranted.