Thrombotic microangiopathy in primary antiphospholipid syndrome is linked to stroke and less deep venous thrombosis.

OBJECTIVE: To compare clinical and laboratory data obtained from patients with primary Antiphospholipid Syndrome (pAPS) with and without Thrombotic Microangiopathy (TMA). PATIENTS AND METHODS: A cross-sectional study with 66 (83.3% female) pAPS patients was performed. Demographic, clinical, drug use, antiphospholipid antibodies data were evaluated. Patients were subdivided into one of two groups: pAPS with TMA and pAPS without TMA and were compared. RESULTS: In this sample, 5/66 (7.6%) of patients had TMA. Primary APS with TMA group exhibited a higher frequency of arterial events (100% vs. 54.1%, p=0.02), stroke (100% vs. 32.8%, p=0.001) and a lower frequency of deep venous thrombosis (0 vs. 68.9%, p=0.0009) compared to the patients without TMA. Analysis of therapy used in these patients showed a higher frequency of current (40% vs. 6.6%, p=0.0006) and previous glucocorticoid use (80% vs. 36%, p=0.0007) and statin use (50% vs. 22.9%, p=0.037) in the first group. The two groups exhibited no differences in the frequency of positive autoantibodies, except for higher IgG anticardiolipin titers (86 ± 52 vs. 34.5 ± 39 GPL, p=0.003). CONCLUSIONS: Patients with pAPS and TMA have distinct clinical and laboratory spectra from those without TMA, that is characterized by an increased frequency of arterial events, stroke, and higher titers of IgG anticardiolipin; they have deep venous thrombosis less frequently.

Validation of the adjusted global antiphospholipid syndrome score in systemic lupus erythematosus patients in Argentina.

INTRODUCTION: Assessment of risk both for pregnancy morbidity and thrombosis in the presence of anti-phospholipid antibodies (aPL) is still a challenge in Systemic Lupus Erythematosus (SLE) patients. The Global Antiphospholipid Syndrome Score (GAPSS) takes into account the aPL profile (criteria and non-criteria aPL), the conventional cardiovascular risk factors and the autoimmune antibody profile. An adjusted model of the score (aGAPSS) excluding anti-phosphatidylserine/Prothrombin (aPS/PT), suggests that the score is able to stratify patients for their rate of events making it widely applicable in daily clinical practice. OBJECTIVE: To validate the aGAPSS in a multicentric cohort of SLE patients in Argentina. PATIENTS AND METHODS: consecutive SLE patients with and with andwithout thrombotic events from seven Rheumatologist centers were included. Traditional cardiovascular risk factors, aPL antibodies and medications received (aspirin, hydroxychloroquine and anticoagulation) were collected. The score aGAPSS was calculated for each patient at the last visit by adding together the points corresponding to the risk factors: 1 for hypertension, 3 for dyslipidemia, 4 for LA and B2GPI (IgM or IgG) antibodies and 5 for aCL (IgM or IgG) antibodies. The discriminative ability of the aGAPSS was calculated by measuring the area under the receiver operating characteristic curve (AUC). Multivariate logistic regression analysis was performed to examine the impact of multiple cardiovascular risk factors and laboratory parameters on the occurrence of thrombosis. RESULTS: Two hundred and ninety-six SLE patients were included. One-hundred and twenty-one patients (40.9%) presented thrombotic and/or pregnancy complications. Median aGAPSS was significantly higher in patients who experienced an event (thrombosis and/or pregnancy morbidity) compared with those without [4 (IQR 1-9) versus 1 (IQR 0-5); p < 0.001]. The best cut off point for the diagnosis of thrombosis and/or pregnancy complications was aGAPSS ≥4. Multivariate logistic regression analysis showed that aCL antibodies [OR 2.1 (95% CI 1.16-3.90); p = 0.015] were an independent risk factors for thrombotic events. CONCLUSIONS: This score is a simple tool, easy to apply to SLE patients in daily practice. The use of the aGAPSS could change the non-pharmacologic and pharmacologic treatment in higher risk patients to improve their survival.

16th International Congress on Antiphospholipid Antibodies Task Force Report on Obstetric Antiphospholipid Syndrome.

Obstetric antiphospholipid syndrome (APS) remains a clinical challenge for practitioners, with several controversial points that have not been answered so far. This Obstetric APS Task Force met on the 16th International Congress on Antiphospholipid Antibodies in Manchester, England, to discuss about treatment, diagnostic and clinical aspects of the disease. This report will address evidence-based medicine related to obstetric APS, including limitations on our current management, the relationship between antibodies against domain 1 of ß2GPI and obstetric morbidity, hydroxychloroquine use in patients with obstetric APS and factors associated with thrombosis after obstetric APS. Finally, future directions for better understanding this complex condition are also reported by the Task Force coordinators.

Ophthalmologic manifestations in primary antiphospholipid syndrome patients: A cross-sectional analysis of a primary antiphospholipid syndrome cohort (APS-Rio) and systematic review of the literature.

OBJECTIVE: There is a broad spectrum of eye involvement in antiphospholipid syndrome (APS). The majority of descriptions are presented as case reports that include mostly APS patients secondary to systemic lupus erythematosus (SLE), with no compelling evidence in primary APS (PAPS). This study aimed to describe ocular manifestations in our well-defined PAPS cohort (APS-Rio) and then perform a systematic literature review (SLR) of ocular manifestations in patients with APS or positivity to aPL without SLE. METHODS: We retrospectively analyzed PAPS patients followed at our outpatient clinics. All patients fulfilled Sydney APS classification criteria (2006). We evaluated them for ocular symptoms and previous ocular diagnoses. Antiphospholipid antibodies and clinical APS manifestations were compared between patients with and without ocular manifestations. For the SLR, electronic databases were searched up to November 2019. RESULTS: We studied 105 PAPS patients; 90.5% were female and 56.2% were Caucasian. We found ocular manifestations in 37.1% of our cohort. Thrombosis was the main criteria manifestation (95.2%) and lupus anticoagulant was the most prevalent antibody. Ophthalmologic diagnoses were present in 7 patients, with 5 having retinal vessels thromboses. Amaurosis fugax was the leading complaint, present in 30 patients. In the univariate analysis, amaurosis fugax was related to livedo (p = 0.005), Raynaud's phenomenon (p = 0.048) and the presence of anticardiolipin antibody (≥40 GPL/MPL) (p = 0.041). Hemianopia was associated with arterial hypertension (p = 0.049). In the multivariate analysis, the only association found was between livedo and amaurosis fugax (OR 4.09, 95%CI 1.5-11.11, p = 0.006). Our SLR incorporated 96 articles of ocular manifestations in patients with PAPS or positivity to aPL without SLE. Ocular findings varied from 5 to 88%, including anterior and posterior segments, orbital and neuro-ophthalmologic changes. CONCLUSION: There is little evidence on ocular manifestations in PAPS. We described an association between livedo and amaurosis fugax. Prospective studies are needed to promote the best treatment and avoid blindness in PAPS patients.

Global antiphospholipid syndrome score and anti-ß2-glycoprotein I domain I for thrombotic risk stratification in antiphospholipid syndrome: A four-year prospective study.

OBJECTIVE: This study aimed to assess prospectively the role of anti-ß2-glycoprotein I domain I antibody (aß2GPI-DI) and the Global Antiphospholipid Syndrome Score (GAPSS) in identifying antiphospholipid syndrome (APS) patients at higher risk of a new event. METHODS: Thrombotic APS patients were followed from May 2013 to July 2017. At baseline, we measured lupus anticoagulant, IgG/IgM anticardiolipin, anti-ß2-glycoprotein I, antiphosphatidylserine-prothrombin (aPS/PT) and IgG aß2GPI-DI, and calculated GAPSS for each patient. RESULTS: A total of 44 patients (age 43 ± 10 years, 89% female, 73% primary APS) were followed for 39 months (range 9-46 months). Four new thromboses occurred, two of them after vitamin K antagonist interruption. Recurrent patients presented higher GAPSS (median 20) and were triple and aß2GPI-DI positive; non-recurrent patients had lower GAPSS (median 10.5, range 0-20) and lower ratio of triple (33%) and aß2GPI-DI positivities (38%). aß2GPI-DI was associated with higher GAPSS (median 19 vs. 7, p < 0.001; Pearson correlation 0.82, p < 0.001) and had a greater proportion of triple (83% vs. 4%, p < 0.001) and aPS/PT positivity (94% vs. 50%, p = 0.002). CONCLUSION: Our data show a significant correlation between a validated risk score such as GAPSS and the novel antiphospholipid antibody aß2GPI-DI. Future studies are needed. However, one could speculate a role of aß2GPI-DI as a risk-stratifying tool for thrombotic events in APS.

A high-risk laboratory profile of antiphospholipid antibodies and thrombosis is associated with a large number of extra-criteria manifestations in obstetric antiphospholipid syndrome.

Extra-criteria manifestations such as thrombocytopenia and livedo are described associated with antiphospholipid syndrome (APS) but are not included in the current classification criteria. Their clinical expression might be important, as they may be associated with a high-risk profile of antiphospholipid antibodies (aPL) and thrombosis. We evaluated the association between the presence of extra-criteria manifestations in primary obstetric-APS (POAPS) and aPL profiles. We also evaluated whether the presence of extra-criteria manifestations in POAPS patients increases the risk of developing thrombosis during the follow-up period (median follow-up 5 years; range 3-9 years). We selected 79 women who were included in our study only if they were first diagnosed with POAPS (with no history of previous thrombosis) and reevaluated for the presence of thrombosis after the follow-up period. We evaluated the association between the aPL profile and extra-criteria manifestations. We also evaluated the relationship of thrombosis during the follow-up period with extra-criteria manifestations and other risk factors. Patients with three or more extra-criteria manifestations presented high rates of triple positivity for the aPL profile (75%) (p < 0.001). We also found a relationship between the presence of extra-criteria manifestations and the presence of high titers of aPL: 91.7% of patients with three or more extra-criteria manifestations had high titers of aPL (p < 0.01). We further evaluated the group of POAPS patients according to thrombotic events during the follow-up. Among these patients, 6 (7.6%) presented thrombosis. Notably, 100% of patients with a thrombotic event during the follow-up had more than three extra-criteria manifestations. POAPS patients with extra-criteria manifestations might have a high-risk aPL profile and a major risk of developing thrombosis.

Oxidative stress in endothelial cells induced by the serum of women with different clinical manifestations of the antiphospholipid syndrome / Estrés oxidativo en células endoteliales inducido por el suero de mujeres con diferentes manifestaciones clínicas del síndrome antifosfolípido

Introduction: The antiphospholipid syndrome is characterized by the persistent presence of antiphospholipid antibodies and clinical manifestations of thrombosis or gestational morbidity that are associated with oxidative stress and endothelial dysfunction. Objective: To evaluate markers of oxidative stress in endothelial cells induced by the serum from women with different clinical manifestations of the antiphospholipid syndrome, and to analyze the antioxidant capacity of the sera. Materials and methods: We included 48 women who were classified as follows: presence of antiphospholipid antibodies and clinical criteria of gestational morbidity alone, vascular thrombosis only, and gestational morbidity/vascular thrombosis. Control groups included antiphospholipid antibodies negative women. In an in vitro model of endothelial cells stimulated with sera from women included in the groups, some markers of oxidative stress were determined by flow cytometry. The antioxidant capacity in the sera of these women was analyzed. Results: The sera from the groups of women with antiphospholipid syndrome that presented thrombosis, with or without gestational morbidity, generated a significant increase (p<0.05 and p<0.001) in endothelial oxidative stress markers in contrast to the control of normal human serum. There were no differences in the effect of the sera from the different study groups on endothelial lipid peroxidation. Also, there was also no difference in the antioxidant activity of the sera. Conclusion: Mitochondrial oxidative stress in the endothelium is associated with the presence of thrombosis; instead, its association with gestational morbidity generates intracellular oxidative stress.

Introducción. El síndrome antifosfolípido se caracteriza por la presencia persistente de anticuerpos antifosfolípidos y manifestaciones clínicas de trombosis o morbilidad gestacional, las cuales se asocian con estrés oxidativo y disfunción endotelial. Objetivo. Evaluar los marcadores de estrés oxidativo en células endoteliales, inducidos por el suero de mujeres con diferentes manifestaciones clínicas del síndrome antifosfolípido y analizar la capacidad antioxidante de los sueros. Materiales y métodos. Se incluyeron 48 mujeres que fueron clasificadas así: presencia de anticuerpos antifosfolípidos y criterios clínicos de morbilidad gestacional, trombosis vascular o ambas. Como grupos control se incluyeron mujeres negativas para anticuerpos antifosfolípidos. En un modelo in vitro de células endoteliales estimuladas con los sueros de las mujeres del estudio, se determinaron algunos marcadores de estrés oxidativo por citometría de flujo. También, se analizó la capacidad antioxidante de los sueros incluidos. Resultados. Los sueros de los grupos de mujeres con síndrome antifosfolípido que presentaban trombosis, con morbilidad gestacional o sin ella, generaron un incremento significativo (p<0,05 y p<0,001) en los marcadores de estrés oxidativo endotelial, en contraste con el control de suero humano normal. No se observaron diferencias en el efecto de los sueros de los diferentes grupos de estudio sobre la lipoperoxidación endotelial. Tampoco se encontró diferencia en la actividad antioxidante de los sueros. Conclusión. El estrés oxidativo mitocondrial en el endotelio se asocia con la presencia de trombosis. Sin embargo, cuando esta se asocia con morbilidad gestacional, también se genera estrés oxidativo intracelular.

Disease presentation of 1312 childhood-onset systemic lupus erythematosus: influence of ethnicity.

OBJECTIVE: To evaluate the influence of ethnicity in presentation of childhood-onset systemic lupus erythematosus (cSLE) patients. METHODS: This multicenter study included cSLE patients (American College of Rheumatology criteria) followed in 27 Pediatric Rheumatology services of Brazil. Ethnicities were classified in four groups according to the parents' and all four grandparents' self-reported ethnicity. The statistical analysis was performed using the Bonferroni's correction (p < 0.0027). RESULTS: According to ethnic groups, 1537 cSLE patients were classified in Caucasian (n = 786), African-Latin American (n = 526), Asian (n = 8), and others/unknown (n = 217). Comparisons between 1312 African-Latin American and Caucasian revealed similar median age at cSLE diagnosis [12.2(2.6-18) vs. 12.1(0.3-18) years, p = 0.234], time interval to diagnosis [0.25(0-12) vs. 0.3(0-10) years, p = 0.034], and SLEDAI-2K score [14(0-55) vs. 14(0-63), p = 0.781] in both groups. The mean number of diagnostic criteria according to SLICC (6.47 ± 1.911 vs. 5.81 ± 1.631, p < 0.0001) and frequencies of maculopapular lupus rash (8% vs. 3%, p < 0.0001), palate oral ulcers (17% vs. 11%, p = 0.001), tongue oral ulcers (4% vs. 1%, p = 0.001), and nonscarring alopecia (29% vs. 16%, p < 0.0001) were significantly higher in African-Latin American, whereas malar rash (45% vs. 58%, p < 0.0001) was more frequent in Caucasian. The presence of anti-phospholipid antibody (23% vs. 12%, p < 0.0001), low complement levels (58% vs. 41%, p < 0.0001), and isolated direct Coombs test (10% vs. 5%, p = 0.001) was also significantly higher in the former group. CONCLUSIONS: Our study demonstrated that disease presentation severity of African-Latin American cSLE patients is comparable with Caucasian. Mucocutaneous manifestations and autoantibodies profile were the only distinctive features of the former group. The unique mixed background of Brazilian patients probably minimized race diversity spectrum of these patients. Key Points • Our study demonstrated that disease presentation severity of African-Latin American cSLE patients is comparable with Caucasian. • Mucocutaneous manifestations and autoantibodies profile were the only distinctive features of African-Latin American cSLE patients. • African-Latin American cSLE patients had more often anti-phospholipid antibodies and hypocomplementemia. • The unique mixed background of Brazilian patients probably minimized race diversity spectrum of these patients.

Prevalence and associations of anti-phosphatidylserine/prothrombin antibodies with clinical phenotypes in patients with primary antiphospholipid syndrome: aPS/PT antibodies in primary antiphospholipid syndrome.

OBJECTIVE: The clinical significance of anti-phosphatidylserine/prothrombin (aPS/PT) in antiphospholipid syndrome (APS) is still controversial. We assessed the prevalence of aPS/PT antibodies, their association with other anti-phospholipid antibodies (aPL) and with different APS clinical phenotypes. METHODS: We included 95 primary APS patients according to the Sydney classification criteria, and patients with thrombocytopenia and/or hemolytic anemia who also fulfilled the serological APS criteria. We tested aCL, anti-ß2GP-I and aPS/PT antibodies (both IgG and IgM isotypes) and lupus anticoagulant (LA). We used χ2 test, Spearman's correlation coefficient, Mann-Whitney U test and logistic regression. RESULTS: Seventy-seven percent of patients had thrombosis, 50% hematologic involvement and 25% obstetric events (non-exclusive groups). Twenty patients had only hematologic features. The prevalence of IgG and IgM aPS/PT antibodies was 61% and 60%, respectively. Patients with LA+ had a higher prevalence and higher titers of IgG and IgM aPS/PT antibodies. aPS/PT antibodies correlated with aPL antibodies including LA. IgG aPS/PT antibodies were associated with thrombosis (OR 8.6 [95% CI 2.13-33.8, p = 0.002]) and pure hematologic features (OR 0.2, CI 95% 0.05-0.97, p = 0.004). IgM anti-ß2GP-I antibodies conferred high risk for both hematologic (OR 7.9, 95% CI 1.88-34.61, p = 0.006) and thrombotic involvement (OR 7.4, 95% CI 1.76-31.12, p = 0.006). CONCLUSIONS: aPS/PT antibodies were highly prevalent and correlated with other aPL antibodies. IgG aPTS/PT conferred a high risk for thrombosis, but not for pure hematologic involvement. aPS/PT antibodies may be a useful serological tool in the diagnosis and phenotypic characterization of APS patients.

Intravenous Immunoglobulin Therapy in Refractory Autoimmune Dysautonomias: A Retrospective Analysis of 38 Patients.

BACKGROUND: Intravenous immunoglobulin (IVIG) has recognized efficacy in autoimmune peripheral nerve disorders, but there has been limited study of the use of IVIG in autoimmune dysautonomias. STUDY QUESTION: To determine the efficacy and safety of IVIG in patients with disabling, refractory autoimmune dysautonomias, including patients with postural tachycardia syndrome and gastrointestinal dysmotility. STUDY DESIGN: Patients with one or more autonomic disorder(s) and persistent serological evidence for autoimmunity who were unable to work or attend school despite usual treatments for dysautonomia were treated with IVIG for at least 3 months at a dose of at least 1 gm/kg monthly. MEASURES AND OUTCOMES: Outcome measures included the composite autonomic symptom scale 31 survey and a functional ability score. RESULTS: There were 38 patients, 84% female and mean age of 28.4 years. Of patients, 83.5% improved on IVIG as defined by at least 20% improvement in the composite autonomic symptom scale 31 and/or functional ability score. The mean pretreatment functional ability score was 21% (mostly bedridden), which improved to a mean of 74% (nearing able to return to work/school) for responsive patients after at least 1 year of IVIG. The mean time to the first sign of response was 5.3 weeks. There were no serious adverse events. The Mayo autoimmune dysautonomia panel antibodies and traditional Sjögren antibodies were present in only 13% and 8% of patients, respectively, but antiphospholipid antibodies and novel Sjögren antibodies were present in 76% and 42% of patients, respectively. CONCLUSIONS: There is increasing evidence that IVIG is safe and effective in a subset of patients with autonomic disorders and evidence for autoimmunity. A 4-month IVIG trial should be considered in severely affected patients who are refractory to lifestyle and pharmacological therapies. Antiphospholipid antibodies and novel Sjögren antibodies are often present in these patients and correlate with a high response rate to IVIG.

Factors associated with first thrombosis in patients presenting with obstetric antiphospholipid syndrome (APS) in the APS Alliance for Clinical Trials and International Networking Clinical Database and Repository: a retrospective study.

OBJECTIVE: To evaluate the subsequent rate of thrombosis among women with obstetric antiphospholipid syndrome (Ob-APS) in a multicentre database of antiphospholipid antibody (aPL)-positive patients, and the clinical utility of the adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients. DESIGN: Retrospective study. SETTING: The Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking Clinical Database and Repository. POPULATION: Women with Ob-APS. METHODS: Comparison of clinical and laboratory characteristics and measurement of aGAPSS in women with Ob-APS, with or without thrombosis, after initial pregnancy morbidity (PM). MAIN OUTCOME MEASURES: Risk factors for thrombosis and aGAPSS. RESULTS: Of 550 patients, 126 had Ob-APS; 74/126 (59%) presented with thrombosis, and 47 (63%) of these women developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age at diagnosis of Ob-APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had a higher aGAPSS compared with women with Ob-APS alone [median 11.5 (4-16) versus 9 (4-13); P = 0.0089]. CONCLUSION: Based on a retrospective analysis of our multicentre aPL database, 63% of women with Ob-APS developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high-risk aPL profile increased the risk. Women with subsequent thrombosis after Ob-APS had a higher aGAPSS at entry to the registry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL-positive women. TWEETABLE ABSTRACT: More than 60% of women with obstetric antiphospholipid syndrome had thrombosis after initial pregnancy morbidity.

Anti-RNP/Sm antibodies in patients with systemic lupus erythematosus and its role in thrombosis: a case-control study.

OBJECTIVE: To validate the association of thrombotic events with positive lupus anticoagulant (LA) and co-presence of anti-RNP/Sm, as well as the diagnostic accuracy of this combination of antibodies for thrombosis. METHODS: Case-control study of patients with systemic lupus erythematosus (SLE) who presented thrombosis after SLE diagnosis and controls with SLE without thrombosis. Comorbidities, traditional risk factors, clinical variables, and treatment were evaluated. Antiphospholipid (aPL) and anti-RNP/Sm antibodies were determined. RESULTS: Sixty-three cases and 63 controls were studied, 88% women, median age of 40 years, and disease duration of 135 months at study inclusion. No differences were found between groups regarding age, comorbidities, or clinical characteristics at SLE diagnosis. Patients with thrombosis were more frequently positive for anti-RNP/Sm (p = 0.001), IgG aCL (p = 0.02), IgG anti-B2GPI (p = 0.02), IgM anti-B2GPI (p = 0.02), LA (p < 0.001), the combination of anti-RNP/Sm + LA (p < 0.001), and aPL triple marker (p = 0.002), compared to controls. The combination of anti-RNP/Sm + LA, SLEDAI-2 K, and prednisone dose was associated with thrombosis (p < 0.05). The combination of anti-RNP/Sm + LA showed 56% sensitivity, 79% specificity, 73% positive predictive value, 64% negative predictive value, positive likelihood ratio (LR) 2.69, and negative LR 0.56 for predicting thrombosis. No difference was found in the comparison of area under the curve between LA alone and the combination of anti-RNP/Sm + LA (p = 0.73). CONCLUSION: Thrombosis was associated with disease activity, dose of prednisone, and the combination of anti-RNP/Sm antibodies and LA. This combination of antibodies could be useful in the identification of SLE patients at risk of thrombosis.

Lupresan, a new drug that prevents or reverts the formation of nonbilayer phospholipid arrangements that trigger a murine lupus resembling human lupus.

Non-bilayer phospholipid arrangements (NPA) are lipid associations different from the bilayer, formed by the interactions of conic anionic lipids and divalent cations that produce an inverted micelle which is inserted between the lipid layers, so the polar heads of the outer lipids spread and expose new antigens. Since these structures are transient, they are not immunogenic, but if they are stabilized by drugs, such as chlorpromazine, they become immunogenic and induce anti-NPA antibodies that trigger a lupus-like disease in mice. Chloroquine is a drug used for the treatment of lupus; chloroquine has a quinoline ring and two positive charges that interact with conic anionic lipids and prevent or revert the formation of NPA. However, the polyamine spermidine is more effective, since it has three positive charges and interacts with more lipids, but polyamines cannot be used as drugs, because they are highly toxic. Here we report the design and synthesis of Lupresan, an analogous of chloroquine with its quinoline ring but with three positive charges. Lupresan is more effective in preventing or reverting the formation of NPA than chloroquine or spermidine, and as a consequence, it decreased auto-antibody titers and healed the malar rash in mice with lupus to a greater extent than chloroquine. A drug as Lupresan could be used for the treatment of human lupus.

Renal involvement in antiphospholipid syndrome.

This is a review of scientific publications on renal involvement in antiphospholipid syndrome (APS), with focus on clinical and histopathological findings and treatment. A search for English-language articles on renal involvement in APS covering the period 1980-2017 was conducted in Medline/PubMed and Scopus databases using the MeSH terms "antiphospholipid syndrome", "antiphospholipid antibodies", "glomerulonephritis" and "thrombotic microangiopathy" (TMA). APS nephropathy is primarily the result of thromboses in renal arteries or veins, intraparenchymatous arteries and glomerular capillaries. On histology, APS nephropathy is characterized by TMA, but chronic vaso-occlusive lesions are also commonly observed (fibrous intimal hyperplasia, focal cortical atrophy, fibrous occlusions of arteries). Anticardiolipin and lupus anticoagulant are the most prevalent antibodies in patients with APS nephropathy. The spectrum of renal manifestations includes renal vein thrombosis, renal artery thrombosis/stenosis, TMA, increased allograft vascular thrombosis and malignant hypertension. Anticoagulation is the standard treatment of thrombotic events. In systemic lupus erythematosus (SLE) patients with antiphospholipid antibodies (aPL), kidney failure due to SLE nephritis (immune-complex disease) should be clearly distinguished from kidney failure due to APS-related TMA. In such cases, renal biopsy is mandatory. SLE nephritis requires immunosuppressive therapy, whereas APS nephropathy is usually treated with anticoagulants. Recently, eculizumab and sirolimus have been proposed as a rescue therapy. Based on our review, APS nephropathy appears to be a distinct clinical condition. TMA is a characteristic histopathological finding in APS and is strongly associated with the presence of aPL. This has important therapeutic implications and allows distinguishing APS nephropathy from lupus nephritis.

Catastrophic antiphospholipid syndrome. Case report and literature review / Síndrome antifosfolípidos catastrófico. Reporte de caso y revisión bibliográfica.

The present document is the report of a case of a very rare clinical entity, which presents with acute multiorganic failure after a thrombotic storm related to antiphospholipid antibodies, the so-called catastrophic antiphospholipid syndrome, which began as a recurrent picture of mesenteric thrombosis, with a previous history of venous insufficiency and distal ulcers probably associated with an unidentified antiphospholipid; deserving management in intensive care and the consultation by the world expert, Dr. Ricard Cervera who confirmed the diagnosis and recommend treating as such entity, the patient's evolution was satisfactory so far. Final recommendations for diagnosis and current treatment options such as rituximab or eculizumab are made. The present case was added to the international registry that currently houses around 500 cases worldwide (International CAPS Registry).

Se reporta un caso de una condición clínica sumamente rara, la cual cursa con falla multiorgánica aguda posterior a una tormenta trombótica relacionada con anticuerpos antifosfolípidos, el denominado síndrome antifosfolípidos (SAF) catastrófico, el cual comenzó como un cuadro recurrente de trombosis mesentérica, con antecedentes de insuficiencia venosa y úlceras distales probablemente asociadas a un SAF no identificado, ameritando manejo en terapia intensiva y la consulta por el experto mundial Dr. Ricard Cervera, quien confirmó el diagnóstico y recomendó tratar como tal. La evolución del paciente fue satisfactoria hasta el momento. Se hacen recomendaciones finales de diagnóstico y se comentan las opciones de tratamiento actuales, como rituximab o eculizumab. El presente caso fue agregado al registro internacional de SAF catastrófico (International CAPS Registry), que actualmente alberga alrededor de 500 casos en todo el mundo.

The impact of antibody profile in thrombosis associated with primary antiphospholipid syndrome.

Triple positivity (TP) for antiphospholipid antibodies(aPL) may identify aPL carriers with poorer prognosis. The clinical impact of TP in primary antiphospholipid syndrome(PAPS) remains unclear and further clinical evidences are needed to validate TP as a marker of severity. The aim of this study was to evaluate the impact of TP on the clinical course of PAPS with thrombosis(t-PAPS). We performed a retrospective analysis of a cohort of t-PAPS patients, comparing groups of patients with TP and non-TP profiles according to their demographic, clinical and laboratory features. We included 105 patients with t-PAPS, the median follow-up time of 3.7 years. Twenty-two patients(21%) had TP; the demographic distribution, the presence of cardiovascular risk factors and the site of thrombosis were similar between TP and non-TP patients. The frequency of thrombotic events did not differ between TP and non-TP patients during the study period. Pregnancy morbidities were more frequent in women with t-PAPS and TP than in those with non-TP profile (80% vs. 52.8%, P = 0.05). Patients with t-PAPS and TP presented, at diagnosis, higher dRVVT ratio (median R = 2.44 vs. 1.57, P < 0.0001), higher aCL titer (median = 50UI vs. 35 UI, P < 0.0001), lower C3 levels (median = 1.08 vs. 1.30 mg dL-1 , P = 0.001), lower C4 levels (median = 0.22 vs. 0.25 mg dL-1 , P = 0.05) and higher frequency of positive ANA test (50% vs. 20%, P = 0.008) than patients with t-PAPS and non-TP. Lower-than-normal levels of C3 was independently associated with TP (OR = 5.1, P = 0.02). The presence of TP in patients with t-PAPS was associated with immune derangement, with no effect on the clinical course of the disease.

Total IgM and Anti-Phosphatidylcholine IgM Antibody Secretion Continue After Clearance of Mycobacterium bovis Bacillus Calmette-Guerin Pleural Infection.

The cellular immune response to Mycobacterium tuberculosis infection has been well characterized, while the humoral antibody response remains underexplored. We aimed to examine the total and anti-phospholipid IgM levels in the pleural lavage from mice with Mycobacterium bovis BCG extrapulmonary infection. We found that the levels of total and anti-phosphatidylcholine IgM antibodies remained significantly higher in infected mice as compared to non-infected mice up to day 90 after BCG infection, while the anti-cardiolipin IgM antibody levels decreased with bacteria clearance. Our findings suggest that IgM antibodies are secreted and their composition vary during early and late immune response to BCG pleurisy.

Modulation of antiphospholipid antibodies-induced trophoblast damage by different drugs used to prevent pregnancy morbidity associated with antiphospholipid syndrome.

PROBLEM: Women with antiphospholipid antibodies (aPLs) present a risk of pregnancy morbidity (PM), vascular thrombosis (VT), or both (PM/VT). aPLs affect trophoblast function, and the aim of this study was to determine the modulation of this aPL-induced damage by different drugs. METHOD OF STUDY: IgG was obtained from women with PM and PM/VT positive to aPLs. Binding of IgG to trophoblastic cells, proliferation, mitochondrial membrane integrity, and trophoblast invasion were assessed. The effect of enoxaparin, aspirin, and aspirin-triggered lipoxin (ATL) were evaluated as well as signal transducer and activator of transcription 3 (STAT3) phosphorylation. RESULTS: IgG from women with aPLs strongly binds to trophoblastic cells. Integrity of mitochondrial membrane was reduced, and proliferation was increased by IgG-PM/VT. Both IgG-PM and IgG-PM/VT decreased trophoblast invasion, which was restored by enoxaparin, aspirin, and ATL. IgG-PM triggered reduction in STAT3 phosphorylation. CONCLUSION: Some drugs used to prevent aPL-induced PM modulated the alteration of trophoblast function.

Síndrome antifosfolípido en mujeres con pérdidas recurrentes de embarazo: diagnóstico de laboratorio / Antiphospholipid syndrome in women with recurrent pregnancy loss: laboratory diagnosis

El síndrome antifosfolípido es el tipo de trombofilia adquirida más frecuente y se define como un estado de hipercoagulabilidad de causa autoimnune, que puede provocar trombosis arterial, venosa, o ambas; así como una amplia gama de complicaciones obstétricas por lo general asociadas a insuficiencia placentaria. Entre ellas están: la pérdida gestacional recurrente, la muerte fetal, la preclampsia grave precoz, la restricción del crecimiento intrauterino, el desprendimiento precoz de placenta y los partos prematuros. En general, en los países en vías de desarrollo se desconoce la magnitud del problema ocasionado por estos anticuerpos antifosfolípidos en mujeres con pérdidas recurrentes de embarazo, debido a que para el diagnóstico de esta entidad se precisa de pruebas que resultan costosas, que requieren de personal calificado para su interpretación y por otra parte, no existe uniformidad en los criterios de laboratorio utilizados por diferentes instituciones para realizar el diagnóstico. En Cuba contamos con posibilidades diagnósticas para la identificación de los anticuerpos antifosfolípidos, lo que constituye un pilar fundamental en el análisis diferencial de esta entidad obstétrica; por ello, la combinación de un diagnóstico adecuado, un minucioso seguimiento y un tratamiento certero redundarán en el éxito del embarazo(AU)

The antiphospholipid syndrome is the most common type of acquired thrombophilia and is defined as a hypercoagulable state of autoimmune cause, which can provoke arterial and/or venous thrombosis, as well as a wide range of adverse obstetric complications associated to placental insufficiency. Among them are the recurrent pregnancy loss, stillbirth, early severe preeclampsia, intrauterine growth restriction, premature placental abruption and premature births. In general, in developing countries the magnitude of the problem caused by these antiphospholipid antibodies in women with recurrent pregnancy losses is high, as tests of elevated cost for the diagnosis of this disease are needed, which also requires qualified personnel for the interpretation of results and there is no uniformity in the laboratory criteria used for diagnosis by different institutions In Cuba we have diagnostic possibilities for the identification of these antiphospholipids which is a fundamental pillar in the differential analysis of this obstetric entity; therefore, the combination of an accurate diagnosis, careful monitoring and the proper treatment, guarantees pregnancy success(AU)