miR-19b-3p and miR-20a-5p are associated with the levels of antiphospholipid antibodies in patients with antiphospholipid syndrome.

Monocytes play a key role in pathophysiology of antiphospholipid syndrome (APS), nevertheless it is unclear if microRNA expression is associated with particular APS features. Identify whether miR-19b-3p and miR-20a-5p expression in monocytes are associated with hallmarks of the APS. Fifty-seven APS patients and 18 healthy controls were studied. Expression of miR-19b-3p and miR-20a-5p was measured in monocytes by RT-qPCR. Both miR-19b-3p (AUC = 0.835, 95% CI 0.733-0.938; P < 0.001) and miR-20a-5p (AUC = 0.857, 0.757-0.957; P < 0.001) discriminated APS patients from healthy individuals. A cut-off point of 1.98 for miR-19-3p and 2.18 for miR-20a-5p showed that APS patients with low microRNA expression had higher levels of IgM and IgG anticardiolipin antibodies than patients with high microRNA expression. In addition, APS patients with low microRNA expression had higher IgG anti-ß2 glycoprotein I antibody levels than their counterparts with high microRNA expression. Finally, miR-19b-3p and miR-20a-5p expression levels were significantly higher in APS patients using oral anticoagulants. Monocyte expression of miR-19b-3p and miR-20a-5p is low in APS, and patients with the lowest microRNA expression presented the highest levels of antiphospholipid antibodies.

Factors predictive of serious infections over time in systemic lupus erythematosus patients: data from a multi-ethnic, multi-national, Latin American lupus cohort.

AIM: The aim of this study was to identify factors predictive of serious infections over time in patients with systemic lupus erythematosus (SLE). METHODS: A multi-ethnic, multi-national Latin American SLE cohort was studied. Serious infection was defined as one that required hospitalization, occurred during a hospitalization or led to death. Potential predictors included were sociodemographic factors, clinical manifestations (per organ involved, lymphopenia and leukopenia, independently) and previous infections at baseline. Disease activity (SLEDAI), damage (SLICC/ACR Damage Index), non-serious infections, glucocorticoids, antimalarials (users and non-users), and immunosuppressive drugs use; the last six variables were examined as time-dependent covariates. Cox regression models were used to evaluate the predictors of serious infections using a backward elimination procedure. Univariable and multivariable analyses were performed. RESULTS: Of the 1243 patients included, 1116 (89.8%) were female. The median (interquartile range) age at diagnosis and follow-up time were 27 (20-37) years and 47.8 (17.9-68.6) months, respectively. The incidence rate of serious infections was 3.8 cases per 100 person-years. Antimalarial use (hazard ratio: 0.69; 95% confidence interval (CI): 0.48-0.99; p = 0.0440) was protective, while doses of prednisone >15 and ≤60 mg/day (hazard ratio: 4.18; 95 %CI: 1.69-10.31; p = 0.0019) and >60 mg/day (hazard ratio: 4.71; 95% CI: 1.35-16.49; p = 0.0153), use of methylprednisolone pulses (hazard ratio: 1.53; 95% CI: 1.10-2.13; p = 0.0124), increase in disease activity (hazard ratio: 1.03; 95% CI: 1.01-1.04; p = 0.0016) and damage accrual (hazard ratio: 1.22; 95% CI: 1.11-1.34; p < 0.0001) were predictive factors of serious infections. CONCLUSIONS: Over time, prednisone doses higher than 15 mg/day, use of methylprednisolone pulses, increase in disease activity and damage accrual were predictive of infections, whereas antimalarial use was protective against them in SLE patients.

Organ Damage and Quality of Life in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) affects young patients in the most productive years of their life, and the consequences of organic or tissue damage involve a decrease in health-related quality of life (HRQoL). While acute disease manifestations of APS are well known, information on the long-term prognosis and damage in affected patients is still very limited. Systemic lupus erythematosus (SLE) patients would be expected to experience long-term complications and even die as a consequence of APS. Organ damage in APS has been evaluated using different methods and definitions, including the SLICC/ACR Damage Index (SDI), which tend to underestimate aPL-related damage. A new damage index in APS has been proposed (DIAPS), and it seems to be more accurate than SDI. Given the implications for morbidity and mortality, it is imperative to assess accurately aPL-related damage and HRQoL in patients with APS.

Development and initial validation of a damage index (DIAPS) in patients with thrombotic antiphospholipid syndrome (APS).

INTRODUCTION: In antiphospholipid syndrome (APS), certain principal manifestations are associated with a worse prognosis and organ damage. OBJECTIVE: The objective of this paper is to describe the development and initial content, criterion and construct validity of a disease-specific cumulative damage index in patients with thrombotic APS (DIAPS). METHODS: Through expert panel agreement, 47 items were considered to reflect damage in APS. This preliminary version of the DIAPS was submitted to four local and international clinical and research experts in APS who ranked each item according to severity. A Delphi exercise resulted in a final 37 item instrument. In the second phase, a cross-sectional study was conducted applying the DIAPS in patients included in a multicenter electronic registry of patients with APS. Quality of life related to health status was evaluated with the EuroQol for construct validation. An α Cronbach and correlation with the EuroQol scale were calculated with SPSS 20.0 (p < 0.05). RESULTS: We evaluated the DIAPS in 156 patients, 77% female, with a mean age at diagnosis 34.7 ± 5.5 years. A total of 69% had primary APS. Common comorbidities included obesity, depression and dyslipidemia. The most frequent manifestations resulting in sequelae were deep venous thrombosis and ischemic stroke. Blindness, retinal occlusive vessel disease, myocardial infarction, cardiac valve requiring replacement, mesenteric thrombosis, and renal insufficiency also occurred. Homogeneity: α Cronbach 0.619. DIAPS items correlated with EuroQol domains with the exception of pulmonary, renal, gastrointestinal, and endocrine systems. CONCLUSION: This study demonstrates content, criterion and construct validity of a new physician-reported instrument to assess the DIAPS. In addition, the DIAPS correlated with the EuroQol.

Lupus in Latin-American patients: lessons from the GLADEL cohort.

The need for comprehensive published epidemiologic and clinical data from Latin American systemic lupus erythematosus (SLE) patients motivated the late Dr Alarcón-Segovia and other Latin American professionals taking care of these patients to spearhead the creation of the G: rupo L: atino A: mericano D: e E: studio del L: upus (GLADEL) cohort in 1997. This inception cohort recruited a total of 1480 multiethnic (Mestizo, African-Latin American (ALA), Caucasian and other) SLE patients diagnosed within two years from the time of enrollment from 34 Latin American centers with expertise in the diagnosis and management of this disease. In addition to the initial 2004 description of the cohort, GLADEL has contributed to improving our knowledge about the course and outcome of lupus in patients from this part of the Americas. The major findings from this cohort are highlighted in this review. They have had important clinical implications for the adequate care of SLE patients both in Latin America and worldwide where these patients may have emigrated.

What do we know about the cardiac valve lesion in the antiphospholipid syndrome (APS)?

Heart valve disease (HVD) is the most common cardiac manifestation in the antiphospholipid syndrome (APS). Valve lesions should be described according to the established definition. HVD is progressive despite anticoagulant/antiplatelet treatments. Around 4-6% of patients with HVD in APS will require valve replacement surgery, which is considered a very high risk procedure in APS. Unfortunately, no recommendations regarding medical treatment of antiphospholipid antibodies-associated HVD can be made at this moment. There are evidence-based data and strong pathophysiologic rationale for considering HVD as a manifestation of APS. Thus, HVD should be included as a criterion of definite APS.

Sueño y mujer / Sleep and Women

Introducción. Existe una estrecha relación entre las hormonas sexuales femeninas y el sueño. Esto conlleva la existencia de diferencias relacionadas con el género tanto en la estructura del sueño normal como en la incidencia de diferentes trastornos del sueño. Objetivo. Revisar los cambios en las características del sueño que experimentan las mujeres en diferentes etapas de su ciclo vital (edad fértil, menstruación, embarazo, menopausia y posmenopausia), así como las patologías del sueño más frecuentes en las que se da una mayor diferencia entre géneros (insomnio, apnea obstructiva del sueño, síndrome de piernas inquietas y narcolepsia-cataplejía). Desarrollo. En cuanto al sueño normal, se ha informado de que las mujeres tienen una mayor calidad de sueño objetiva en comparación con los hombres (mayor tiempo, menor latencia de inicio y mayor grado de eficiencia del sueño); sin embargo, se quejan más frecuentemente de problemas de sueño. Por otra parte, diferentes etapas en la vida de la mujer se asocian con importantes cambios hormonales y fisiológicos que favorecen la alteración del patrón de sueño normal y, con ello, un posible aumento del riesgo de manifestar trastornos del sueño. Conclusiones. Las razones que subyacen en las diferencias de género en los trastornos del sueño se atribuyen a las diferencias en el sueño normal, en las manifestaciones clínicas y factores de riesgo de los trastornos del sueño, y en la respuesta-dosis óptimas de tratamiento (AU)

Introduction. There is a strong link between female sex hormones and sleep. This implies the existence of sex differences both in the structure of sleep as in the incidence of various sleep disorders. Aim. To review the changes in the pattern of sleep experienced by women along different stages of their life cycle (fertile period, menstruation, pregnancy, menopause and postmenopause), as well as the most frequent sleeping pathologies in which there exist more gender differences (insomnia, obstructive sleep apnea syndrome, restless legs syndrome and narcolepsy). Development. About normal sleeping has been reported a higher quality of it, in women compared with men (increased sleeping time, reduced sleep onset latency, and a greater efficiency of sleeping), but they frequently complain of sleep problems. Moreover, different stages in the life of women are associated with significant physiological and hormonal changes that favour the disruption of normal sleep pattern and by this way, possibly, increase risk to suffer sleep disorders. Conclusions. The reasons that underlie in gender differences in sleeping disorders are attributed to differences in normal sleep pattern, in the clinical manifestations and risk factors for sleep disorders, and in the results and optimal dose of treatments (AU)

[Sleep and women]. / Sueño y mujer.

INTRODUCTION: There is a strong link between female sex hormones and sleep. This implies the existence of sex differences both in the structure of sleep as in the incidence of various sleep disorders. AIM: To review the changes in the pattern of sleep experienced by women along different stages of their life cycle (fertile period, menstruation, pregnancy, menopause and postmenopause), as well as the most frequent sleeping pathologies in which there exist more gender differences (insomnia, obstructive sleep apnea syndrome, restless legs syndrome and narcolepsy). DEVELOPMENT: About normal sleeping has been reported a higher quality of it, in women compared with men (increased sleeping time, reduced sleep onset latency, and a greater efficiency of sleeping), but they frequently complain of sleep problems. Moreover, different stages in the life of women are associated with significant physiological and hormonal changes that favour the disruption of normal sleep pattern and by this way, possibly, increase risk to suffer sleep disorders. CONCLUSIONS: The reasons that underlie in gender differences in sleeping disorders are attributed to differences in normal sleep pattern, in the clinical manifestations and risk factors for sleep disorders, and in the results and optimal dose of treatments.

Myocardial ischaemia in patients with primary APS: a 13N-ammonia PET assessment.

OBJECTIVE: Evaluate the presence and severity of myocardial ischaemia in a population of asymptomatic patients with primary APS (PAPS) using (13)N-ammonia PET. METHODS: We studied 36 patients, 18 with a diagnosis of PAPS and 18 healthy volunteers. All patients underwent a two-phase (rest-stress) (13)N-ammonia PET. Myocardial perfusion images were acquired and then analysed by two experts in the field. RESULTS: We found ischaemia in 7/18 asymptomatic PAPS patients (38.8%). The anterolateral wall was the most commonly affected cardiac territory [5/7 PAPS patients (71.4%)]. In a severity analysis, we found that five patients (71.4%) had mild ischaemia, one patient (14.2%) had moderate ischaemia and another one (14.2%) had severe defects. All the healthy volunteers studied showed normal myocardial perfusion images. CONCLUSION: An important proportion of PAPS patients, even when asymptomatic, showed myocardial perfusion defects assessed with PET. Most of the ischaemic patients had mild defects and the anterolateral wall was the territory mainly affected.

Myocardial perfusion defects in patients with autoimmune diseases: a prospective study. Analysis of two diagnostic tests.

A significant correlation between autoimmune diseases and premature or accelerated coronary atherosclerosis has been found. The objectives of the study were: (a) to evaluate myocardial perfusion defects in patients with autoimmune diseases by contrast echocardiography and nuclear imaging; and (b) to evaluate the prevalence of alterations in subclinical myocardial perfusion defects in autoimmune diseases. Myocardial perfusion in 37 patients was evaluated by contrast echocardiography at rest and with dobutamine and with nuclear imaging. The agreement between the two diagnostic tests at rest was 0.72 (P < 0.0001) and with dobutamine was 0.65 (P < 0.0001). The prevalence of abnormalities in myocardial perfusion in autoimmune diseases by contrast echocardiography and nuclear imaging was 27% and in patients with primary antiphospholipid syndrome was 30%. We concluded that there is a high level of agreement between contrast ecocardiography and nuclear imaging for assessment of myocardial perfusion defects in patients with autoimmune diseases, and their prevalence is similar to that reported in the literature.

Libman-Sacks endocarditis associated with antiphospholipid syndrome and infection.

INTRODUCTION: Antiphospholipid syndrome (APS) is a systemic autoimmune disease, associated not only with a hypercoagulable state and recurrent fetal loss but with many diverse clinical manifestations including heart involvement, neurological manifestations, as well as skin, kidney and hematologic abnormalities. Cardiac manifestations include coronary by-pass graft and angioplasty occlusions, cardiomyopathy, cyanotic congenital heart disease, intracardiac thrombus and complications of cardiovascular surgery. The valvular heart disease was defined as Libman-Sacks nonbacterial endocarditis. Previously, we have shown a linear subendothelial deposition of anti-cardiolipin/beta2 glycoprotein I (beta2GPI) antibodies in the valve specimens derived from APS patients. The involvement of complement C3c in the pathogenesis was documented. We assessed the beta2GPI-related target epitope recognized by the anti-beta2GPI Abs on the valves. MATERIALS AND METHODS: In order to find the beta2GPI-related target epitopes recognized by the anti-beta2GPI antibodies on the valves, we used beta2GPI-related synthetic peptides. The presence of anti-beta2GPI Abs on the studied valves was detected by anti-idiotypic antibody, followed by immunoperoxidase analysis. Biotin attached to the N-terminal of beta2GPI-related synthetic peptides and control peptide were used to identify the epitope addressed by the anti-beta2GPI Abs deposited on the patient's valve. The binding was probed by streptavidin-peroxidase and appropriate substrate. The specificity was confirmed by competition assays with control peptide and anti-idiotypic antibody. RESULTS: Among the beta2GPI-related synthetic peptides, two peptides were found in previous studies to mimic common pathogens either bacteriae or viruses, which raised a possible infectious origin for APS. One of these peptides, TLRVYK, is a specific target for anti-beta2GPI Abs deposited on the APS valves. This synthetic peptide was able to displace the anti-anti-beta2GPI anti-idiotypic Abs for binding the anti-beta2GPI Abs on the valve by a competition assay. CONCLUSION: We point to the possibility that Libman-Sacks nonbacterial endocarditis may have an infectious origin.

Vascular endothelial growth factor plasma levels in patients with systemic lupus erythematosus and primary antiphospholipid syndrome.

The objective of this study was to assess the possible role of vascular endothelial growth factor (VEGF) in the pathogenesis of systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (PAPS). We studied 28 patients with SLE, 10 patients with PAPS, and 24 healthy controls. VEGF plasma levels were measured by ELISA. Immunolocalization of VEGF was done in renal tissue from SLE patients and cadaveric controls. Our results showed that VEGF plasma levels were increased in SLE patients compared with PAPS and controls. The correlation between clinical manifestations and VEGF levels revealed that SLE patients with renal failure had significantly increased plasma VEGF levels (134.1 + 91.0 pg/ml) compared with SLE patients with normal renal function (42.9 + 19.0 pg/ml), PAPS patients (41.9 + 26.6 pg/ml), and controls (36.2 + 27.0 pg/ml; P < 0.01). Immunostaining showed a strong expression of VEGF in SLE renal tissue samples. Our preliminary results indicate that VEGF is increased in plasma from patients with lupus nephritis and a moderate degree of renal failure and is overexpressed in renal tissue from these patients.

Prognosis in antiphospholipid syndrome.

The results of prospective large cohort studies of patients with different clinical subsets of APS have been reported recently. A significant impact of the disease on long-term survival has been documented in these studies. Cumulative irreversible damage secondary to thrombosis results in organ dysfunction and morbidity. To assess prognosis and treatment in APS, it is imperative to quantify damage. We have recently created and validated an Antiphospholipid Damage Index, which is currently undergoing improvements. Having APS, whether primary or secondary, definitely confers a poor prognosis.

Two- and three-dimensional echocardiography in primary antiphospholipid syndrome: misdiagnosis as rheumatic valve disease.

This is a report of a woman in the fifth decade of life with primary antiphospholipid syndrome and involvement of a heart valve. Diagnosis was reached with echocardiography and serological studies.

Morphology of vascular, renal, and heart lesions in the antiphospholipid syndrome: relationship to pathogenesis.

A growing body of evidence suggests that aPL are not only serological markers of the antiphospholipid syndrome (APS), but may also directly contribute to the development of thrombosis and other manifestations, including the APS vasculopathy. The latter has been documented in leptmeninges, lung, skin, myocardium, peripheral arteries, and kidney. Renal lesions, a common feature of primary antiphospholipid syndrome (PAPS), include occlusion of principal renal arteries or their main branches, TMA, cortical ischemia, and renal vein thrombosis. Within the cardiac manifestations associated with aPL, valvular involvement is the most common. Histologic findings in valve specimens are consistent with a noninflammatory lesion characterized by intravalvular capillary thrombosis, laminar or verrucous superficial thrombosis, vascular proliferation, fibrosis, and calcification. Even though there is general consensus that endothelial damage triggers the chain of events that results in valve thickening, fusion, rigidity, and ultimately functional abnormalities, we believe that more experimental work remains to be done on the initial valve insult in APS.

Antiphospholipid (Hughes) syndrome in systemic lupus erythematosus.

APS is found in 20% to 35% of patients with SLE. PAPS and secondary APS have similar features and aPL specificities. The clinical course of the secondary syndrome is independent of the activity and severity of lupus, but the presence of APS worsens the prognosis of patients with lupus. Some features of SLE may result from thrombosis in patients with APS; thus, these patients require anticoagulation rather than corticosteroids. Novel preliminary classification criteria for APS were formulated during a postconference workshop held in Sapporo, Japan, following the Eight International Symposium on Antiphospholipid Antibodies. Treatment of APS remains empirical because of limited controlled prospective data. There is strong evidence that patients with aPL-associated thrombosis are subject to recurrences and require prophylactic therapy. APS is a treatable cause of recurrent fetal loss in women with SLE. The treatment of choice is anticoagulation with heparin, either standard unfractionated heparin or LMWH. One of the main reasons for the improving outcomes in APS pregnancies is closer obstetric surveillance.