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.

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.

The antiphospholipid/cofactor syndromes: a primary variant with antibodies to beta 2-glycoprotein-I but no antibodies detectable in standard antiphospholipid assays.

BACKGROUND: Most systemic lupus erythematosus (SLE) patients with two or more clinical manifestations of the antiphospholipid syndrome (APS) and negative antiphospholipid antibodies (aPL) have antibodies to beta 2-glycoprotein-I (a beta 2 GP-I). Herein we describe a similar set of circumstances, but in patients without evidence of SLE. PATIENTS AND METHODS: We studied 6 patients with recurrent venous and/or arterial thromboses without aPL as detected by routine assays nor clinical or serological evidence of other autoimmune disease. Immunoglobin (Ig) G and IgM antibodies to bovine and human phospholipid-free beta 2 GP-I were studied by Western blot test and by enzyme-linked immunosorbent assay (ELISA) utilizing radiated and nonirradiated plates. We also tested antibodies to cardiolipin, phosphatidylserine, and phosphatidylethanolamine by ELISA. As controls, 54 normal sera were studied. RESULTS: All 6 patients had recurrent arterial and/or venous thromboses. Three also had thrombocytopenia, 1 had livedo reticularis, and 2 had valvular heart disease. None of the patients had aPL, but all had serum IgG reactivity against human and bovine beta 2 GP-I (P < 0.001 versus controls for both). Titers of anti-bovine beta 2 GP-I were higher when studied in irradiated plates but were also higher than normal in nonirradiated plates (P < 0.001). These antibodies did not recognize human or bovine beta 2 GP-I bound to cardiolipin in solid phase. We confirmed by Western blot that these autoantibodies recognize human beta 2 GP-I. We found no IgM a beta 2 GP-I. CONCLUSIONS: We describe a primary condition akin to the antiphospholipid syndrome with negative aPL, but with serum IgG antibodies to human and bovine beta 2 GP-I. These antibodies recognize beta 2 GP-I epitopes that are not accessible when beta 2 GP-I is bound to cardiolipin.

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.

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.

Acute rheumatic fever.

The diagnosis of acute rheumatic fever has become difficult. A growing number of diseases that were not recognized in the past could fulfill its diagnostic criteria. We emphasize its changing incidence, current knowledge of its pathogenesis, and lesser known clinical features such as pneumonitis, encephalitis and glomerulonephritis.

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.

Antiphospholipid syndrome in patients with cyanotic congenital heart disease.

Patients with cyanotic congenital heart disease exhibit an increased incidence of thrombotic episodes and are frequently thrombocytopenic. We studied the sera of 15 patients with this type of heart malformation, searching for anticardiolipin antibodies. 3/15 had positive results. The three of them were adult females; two had thrombotic episodes and a false positive VDRL. Thus, cyanotic congenital heart disease may be another disease entity associated with the antiphospholipid syndrome.

[Cytomorphology of the cerebrospinal fluid. I. Tumors of the central nervous system (author's transl)]. / Citomorfología del líquido cefalorraquídeo. I. Tumores del sistema nervioso central.

A cytomorphological study of the cerebrospinal fluid corresponding to 42 patients with tumors of the central nervous system has been performed. The group of 31 patients with primary tumors accounted for an overall cytological positivity of 32.2 percent; according to the type of tumor cytological positivities were as follows: glioblastoma multiforme (44.4 percent); grade I/III astrocytoma (33.3 percent); oligodendroglioma (33.3 percent); ependymoma (25 percent), and meningioma (16.6 percent). In the group of 11 patients with metastatic tumors, neoplastic cells were observed in two cases (cytological positivity 18.1 percent). Cytological study of the cerebrospinal fluid is a useful diagnostic method for some primary and secondary neoplasms of the central nervous system.

[Behçet's disease: report of ten cases and of a new clinical manifestation (portal vein thrombosis) (author's transl)]. / Enfermedad de Behçet: presentación de 10 casos y de una nueva manifestación clínica (trombosis portal).

Ten patients (seven males and three females) with the diagnostic criteria for Behçet's disease are reported. Symptoms began between ages 14 and 37 (mean age 27.9 years), and the time of evolution of the disease varied between one and 23 years (mean 5.7 years). Initial presentation was aphthous stomatitis (three cases), ocular inflammation (three cases), erythema nodosum (one case), arthritis (one case), thrombophlebitis (one case), and hemorrhagic proctocolitis (one case). During the course of the disease the commonest clinical manifestations were oral and genital ulcerations (100%) and ocular (70%), cutaneous (70%), articular (40%), neurological (40%), venous (40%), gastrointestinal (40%) and arterial (10%) involvement. Increased erythrocyte sedimentation rate was a constant feature in all patients. HLA-B5 antigen was determined in four patients, being positive in two of them. Cerebrospinal fluid alterations were present in the four patients with neurological involvement even though three of them never had meningeal symptoms. One patient developed portal hypertension secondary to portal vein thrombosis, and its clinical manifestations are described.

[Morbidity in hospital admission for stroke]. / Morbilidad por hospitalización en el ictus.

INTRODUCTION: In spite of advances in the prevention and treatment of ischemic vascular disease, this continues to be one of the main causes of disablement and prolonged hospitalization in developed countries. Also, hospitalization itself leads to complications which have a negative effect on the morbi-mortality of these patients during the time spent in hospital. OBJECTIVE: We decided to study the effect of systemic complications during the period of hospital stay, on the functional recovery of patients which ictusl. MATERIAL AND METHODS: A prospective study was made of 47 patients admitted to our unit for neurological deficit of more than 24 hours evolution and of cerebrovascular aetiology. Functional recovery was evaluated by means of the index of Barthel on discharge and after a period of 3 months with respect to the degree of neurological involvement (Canadian scale on admission), glycemia on admission, time spent in hospital and the occurrence of systemic complications in hospital. RESULTS: These were no differences between the groups of patients with and without systemic complications regarding age, glycemia and Canadian scale on admission. Nor wes there any difference between the groups regarding the number of patients with significant deterioration of their neurological condition (decrease > 20% in the EC). Functional recovery on hospital discharge was worse in the group with systemic complications (IB: 43.05 +/- 34.1: as compared with IB: 72.8 +/- 22.7 in the group without complications). This difference persisted after 3 months. CONCLUSIONS: Systemic complications related to hospitalization have a negative effect on the functional recovery of patient with ictus and also prolong the time spent in hospital.

[Muscular biopsy in ceroid lipofuscinosis: 3 case reports of juvenile form]. / Biopsia muscular en la ceroidolipofuscinosis: estudio de tres casos de la forma juvenil.

Ceroid lipofuscinosis (CLF) is a progressive hereditary neurodegenerative disease characterised by deposits in the central nervous system and other tissues of ceroid lipopigment. Symptomatology and clinical course of the disease are heterogeneous and up to ten types have been distinguished, although the most frequent and best known are the Santavuori-Haltia infantile form, the Jansky-Bielschowsky late infantile form, the Spielmeyer-Vogt juvenile form and the Kufs adult form. We present here three cases diagnosed as having juvenile ceroid lipofuscinosis by means of muscular biopsy. Although morphological and ultrastructural findings in CLF have already been described in literature, the use of muscular biopsy as a means of diagnosis is not usual and its usefulness is not very well known. For this reason, we especially recommend this method for its simplicity and diagnostic specificity.

[Disseminated encephalic cryptococcosis as a form of presentation of idiopathic T-CD4 lymphocytopenia]. / Criptococosis encefálica diseminada como forma de presentación de una linfocitopenia T-CD4 idiopática.

INTRODUCTION: The term idiopathic T-CD4 lymphocytopenia is used to describe a new syndrome, defined as reduced T-CD4 lymphocytes in persons with no evidence of HIV infection or other causes which would explain the immunosuppression (secondary to neoplasties, immunosuppressive treatment, hereditary immunodeficiencies, infections, etc.). The reduced number of T-CD4 lymphocytes leads to deterioration in cellular immunity and therefore this leads to a predisposition to develop tumors and opportunist infections in patients with such defects. CLINICAL CASE: We describe a case of depletion of T-CD4 lymphocytes, associated with disseminated encephalic cryptococcosis (multiple cortical, capsulo-ganglionar, thalamic and cerebellar cryptococcomas) in a patient with no evidence of HIV infection. The case we present fulfilled diagnostic criteria for idiopathic T-CD4 lymphocytopenia, a clinical condition seldom described in this country. We discuss the pathogenic mechanisms of cryptococcosis, the different varieties of Cryptococcus neoformans and their different roles as the cause of opportunist infections in humans. CONCLUSIONS: In view of the neurotrophism of this fungus, the neurological signs and symptoms should make one suspect the presence of Cryptococcus neoformans infection in non-HIV carriers with cellular immunity defects such as those present in idiopathic T-CD4 lymphocytopenia.

[Takayasu arteritis; IV. Absence of autoantibodies and coagulation/fibrinolysis abnormalities]. / Arteritis de Takayasu; IV. Ausencia de autoanticuerpos y anomalías de la coagulación/fibrinolisis.

The etiopathogenesis of the non-specific arteritis known as Takayasu's arteritis, an inflammatory occlusive disease of the aorta and its main branches, is unknown. We searched for abnormalities in clotting and fibrinolytic systems, as well as the presence of non-organ specific autoantibodies, including those potentially reactive with vascular endothelium, in 21 untreated patients. There were only minor abnormalities in coagulation and fibrinolysis in a few patients, and the occasional presence of non-organ specific antibodies, including antiphospholipid antibodies. The findings had no clinical relevance. This study suggests that there is no support for a significative role of humoral immunity, coagulation and fibrinolysis in the pathogenesis of Takayasu's arteritis.