The impact of different classes of lupus nephritis on maternal and fetal outcomes: a cohort study of 147 pregnancies.

OBJECTIVE: To analyze the impact of different classes of lupus nephritis as risk variables for maternal and fetal adverse outcomes in a cohort of pregnant lupus patients. METHODS: This is a cohort study with retrospective and prospective data collection, conducted at the University Hospital of State University of Rio de Janeiro, Brazil, from 2011 to 2016. A total of 147 pregnancies of 137 systemic lupus erythematosus patients of whom 66 had lupus nephritis were included. Demographic and clinical features, as well as maternal and fetal outcomes were observed for each nephritis histological class among systemic lupus erythematosus patients and compared with those without nephritis. Categorical variables were expressed as absolute and relative frequencies and numerical variables as means and standard deviation. The chi-square test with Fisher's correction and Student's t-test were used for statistical analysis. A pvalue < 0.05 was considered statistically significant. RESULTS: Systemic lupus erythematosus patients with proliferative nephritis (classes III/IV, n = 54) presented more frequent disease flares ( p = 0.02), continuous active disease during pregnancy and puerperium ( p = 0.006), hospitalization due to systemic lupus erythematosus ( p < 0.001), hospitalization not directly associated to systemic lupus erythematosus ( p = 0.04), higher frequency of cesarean delivery ( p = 0.03) and preeclampsia ( p = 0.01) than patients without nephritis. Permanent damage measured by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index was more frequent in classes III/IV than among the other patients. The frequency of adverse fetal outcomes such as prematurity and admission to neonatal intensive care unit were not different among systemic lupus erythematosus patients with or without nephritis. However, perinatal deaths were more frequent in patients with all classes of nephritis ( p = 0.003). CONCLUSION: Systemic lupus erythematosus patients with proliferative nephritis (classes III/IV) have a higher frequency of adverse maternal outcomes. This is probably due to the major impact of proliferative forms of nephritis on women's global heath, which is corroborated by the higher Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index findings, although we cannot exclude the negative influence of disease activity for the maternal adverse events. The findings indicate a need for further lupus nephritis classification beyond the nonspecific term nephritis in the context of lupus pregnancy as the impact on maternal and fetal outcomes varies according to histological class.

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.

Gestational outcomes in patients with neuropsychiatric systemic lupus erythematosus.

This study analyzed maternal and fetal outcomes of pregnancies of neuropsychiatric systemic lupus erythematosus patients followed in a reference unit. This retrospective cohort study included 26 pregnancies of patients seen between 2011 and 2015 included with history and/or active neuropsychiatric systemic lupus erythematosus among 135 pregnancies. Three patients had active neuropsychiatric systemic lupus erythematosus at conception, but only one remained with neurological activity during gestation, characteristically related to the inadvertent suspension of medications. Twenty six percent of the newborns were small for gestational age and 40% of live births were premature, with no neonatal death or early complications of prematurity. Preeclampsia was diagnosed in nine pregnancies, with two cases of early severe form that resulted in intrauterine fetal death. Patients with neuropsychiatric systemic lupus erythematosus had more prematurity and preeclampsia compared to patients without neuropsychiatric disease. However, when concomitant lupus nephritis was excluded, the gestational results of neuropsychiatric systemic lupus erythematosus patients were more favorable.

Ventilation distribution and small airway function in patients with systemic sclerosis.

BACKGROUND: Despite the importance of traditional pulmonary function tests (PFTs) in managing systemic sclerosis (SSc), many patients with pulmonary disease diagnosed by computed tomography (CT) present with normal PFTs. OBJECTIVE: To evaluate the efficacy of the nitrogen single-breath washout (N2SBW) test in diagnosing SSc and to correlate N2SBW parameters with the PFT indexes used in the follow-up of these patients, clinical data, and CT findings. METHODS: Cross-sectional study in which 52 consecutive SSc patients were subjected to spirometry, body plethysmography, analysis of the diffusing capacity for carbon monoxide (DLCO), analysis of respiratory muscle strength, N2SBW testing, and CT analysis. RESULTS: Twenty-eight patients had a forced vital capacity (FVC) that was <70% of the predicted value. In the N2SBW test, 44 patients had a phase III slope (Phase III slopeN2SBW) that was >120% of the predicted value, while 15 patients had a closing volume/vital capacity (CV/VC) that was >120% of the predicted value. A significant difference in Phase III slopeN2SBW was observed when the patients with predominant traction bronchiectasis and honeycombing were compared to the patients with other CT patterns (p<0.0001). The Phase III slopeN2SBW was correlated with FVC (rs=-0.845, p<0.0001) and DLCO (rs=-0.600, p<0.0001), and the CV/VC was correlated with FVC (rs=-0.460, p=0.0006) and residual volume/total lung capacity (rs=0.328, p=0.017). CONCLUSION: Ventilation heterogeneity is a frequent finding in SSc patients that is associated with restrictive damage, changes in pulmonary diffusion, and CT patterns. In addition, approximately one-third of the patients presented with findings that were compatible with small airway disease.

Efficacy of belimumab on renal outcomes in patients with systemic lupus erythematosus: A systematic review.

Both BLISS-52 and BLISS-76 international phase III trials in Systemic Lupus Erythematosus (SLE) met their primary outcomes; however, they were not designed to assess the efficacy of belimumab for the treatment of lupus nephritis (LN). LN is a frequent cause of SLE-associated morbidity and mortality, and emerging evidence suggests a potential therapeutic role for agents that target B lymphocyte stimulator (BLyS). We conducted a systematic review to identify data on the effect of belimumab on LN. A total of 2004 patients with SLE were identified from 11 studies. Three hundred and twenty-six patients had LN at baseline and 234 (71.8%) of those received belimumab. Thirteen patients out of 234 (5.5%) received belimumab for active LN. Due to the heterogeneous definitions of treatment response, clinical presentation and renal involvement, it was not possible to compare results using a single outcome parameter. However, the majority of these studies defined clinical response in terms of rates of renal flare, renal remission, and/or renal organ disease improvement. One hundred twenty-nine (55.1%) of the 234 patients with LN at baseline showed an improvement in renal parameters after treatment with belimumab. In patients with baseline proteinuria>0.2g/24h, (n=687), those receiving belimumab had a median reduction in proteinuria during follow-up as high as 38%. When focusing on patients with proteinuria≥1g/24h (n=228), 70.7% of those treated with belimumab (n=157) achieved a renal response. In the pooled population of patients receiving belimumab, we found an overall annual renal flare rate of 1.7% [24/1448, mean observation time 1,1years (0,5-3)]. Despite the limitations of the studies included in this analysis, available data are promising and provide preliminary support for targeting BlyS to induce or maintain a renal response. Further trials should examine whether belimumab (alone or following rituximab) represents an additional therapeutic option in the treatment of LN.

Antiphospholipid Syndrome On Cloud (APSOnCloud): web-based monitoring of oral anticoagulation.

Antiphospholipid Syndrome (APS) is an autoimmune disease characterized by recurrent thromboses and fetal losses with the presence of antiphospholipid antibodies. The main treatment to prevent recurrent thrombotic events is oral anticoagulation with vitamin K antagonist (VKA), which requires frequent monitoring and dosage adjustments. Outpatient anticoagulation monitoring has its limitations, such as patients spending long hours between the testing procedure and waiting for the results to be adjusted. To optimize this adjustment and to improve APS patients-doctors relationship, we developed a website to help monitor APS patients, called Antiphospholipid Syndrome On Cloud or APSOnCloud. To test it, since March 2014 to March 2016, we registered 20 patients with APS that have inserted 132 international normalized ratio (INR) values. Sixty two percent were out of range and it took on average 7 hours for the doctor in charge to adjust these values. The mean time in therapeutic range was 58.1%. Our preliminary experience in monitoring VKA oral anticoagulation on APSOnCloud suggests that patients with APS might benefit from this web-based monitoring.

Patient-health care provider relationship: how can it impact on APS (Hughes' syndrome) adherence to treatment?

Adherence to treatment is fundamental for its success. It comprises compliance combined with persistency and should be constantly reassessed. This is true in all medical situations. In antiphospholipid syndrome (or Hughes' syndrome), in addition to taking the medication at the planned time so that its effect on blood can be assessed and the dose adjusted if necessary, all patients must incorporate healthy habits with a treatment that is lifelong and will be influenced by dietary changes and the use of many other medications. Following a regime for the treatment to be effective, and to avoid serious complications, often creates the sensation of 'living on a tightrope' for both the patients and the health care providers. Patient education along with constant monitoring using proper communication settings and tools are certain to improve adherence and outcomes.

Using the GRADE system in diagnostic strategy: the case of antiphospholipid syndrome.

Diagnostic strategy studies commonly focus on the accuracy of tests in diagnosing, and grading this body of evidence is a challenge in itself because (1) standard tools for grading evidence were designed for questions about treatment rather than diagnostic testing; and (2) the clinical usefulness of a diagnostic strategy depends on multiple links in a chain of evidence connecting the performance of a test to changes in clinical outcomes. The application of the GRADE approach requires a shift in clinicians' thinking to clearly recognize that, whatever their accuracy, diagnostic tests are valuable only if they result in improved outcomes for patients.

The use of angiogenic and antiangiogenic factors in the differential diagnosis of pre-eclampsia, antiphospholipid syndrome nephropathy and lupus nephritis.

Pre-eclampsia (PE) is a major cause of maternal mortality and morbidity, perinatal deaths, preterm birth and intrauterine growth restriction. Differential diagnosis with antiphospholipid syndrome (APS) nephropathy and systemic lupus erythematosus (SLE) nephritis during pregnancy is difficult, if not sometimes impossible, as all three diseases may present hypertension and proteinuria. Improvement in diagnosis of PE has also offered new paths for differential diagnosis with other conditions and the analysis of angiogenic (vascular endothelial growth factor, placental growth factor) and antiangiogenic factors (serum soluble fms-like tyrosine kinase 1, soluble endoglin) is promising for differentiation between PE, APS nephropathy and SLE nephritis. This article reviews published studies about those factors in non-pregnant and pregnant patients with APS and SLE, comparing with patterns described in PE.

Safety profile of belimumab: pooled data from placebo-controlled phase 2 and 3 studies in patients with systemic lupus erythematosus.

Safety data were pooled and analyzed from one phase 2 and two phase 3 double-blind, placebo-controlled, repeat-dose systemic lupus erythematosus (SLE) trials of belimumab 1, 4 (phase 2 only), and 10 mg/kg. Types and rates of adverse events (AEs) were similar across treatment groups. Rates of patients experiencing any serious AE were 16.6%, 19.5%, 13.5%, and 18.0% with placebo, and belimumab 1, 4, and 10 mg/kg, respectively; rates of serious infusion reactions (including hypersensitivity reactions) occurring on the same days as infusions were 0.4%, 0.9%, 0%, and 0.9%, and rates of serious infections were 5.5%, 7.1%, 6.3%, and 5.3%. Malignancy rates/100 patient-years (excluding non-melanoma skin cancer) were 0.29 with placebo vs. 0.20 with all belimumab doses combined; mortality rates/100 patient-years were 0.43 vs. 0.73. These data support the conclusion that belimumab in combination with standard SLE therapy was generally well tolerated in a predominantly autoantibody-positive population with active SLE.

Increased expression of tissue factor and protease-activated receptor-1 does not correlate with thrombosis in human lung adenocarcinoma.

A correlation between cancer and hypercoagulability has been described for more than a century. Patients with cancer are at increased risk for thrombotic complications and the clotting initiator protein, tissue factor (TF), is possibly involved in this process. Moreover, TF may promote angiogenesis and tumor growth. In addition to TF, thrombin seems to play a relevant role in tumor biology, mainly through activation of protease-activated receptor-1 (PAR-1). In the present study, we prospectively studied 39 lung adenocarcinoma patients in relation to the tumor expression levels of TF and PAR-1 and their correlation with thrombosis outcome and survival. Immunohistochemical analysis showed TF positivity in 22 patients (56%), most of them in advanced stages (III and IV). Expression of PAR-1 was found in 15 patients (39%), most of them also in advanced stages (III and IV). Remarkably, no correlation was observed between the expression of TF or PAR-1 and risk for thrombosis development. On the other hand, patients who were positive for TF or PAR-1 tended to have decreased long-term survival. We conclude that immunolocalization of either TF or PAR-1 in lung adenocarcinoma may predict a poor prognosis although lacking correlation with thrombosis outcome.

Obstetric antiphospholipid syndrome: still a challenge.

Obstetric complications such as fetal death, premature delivery, preeclampsia and recurrent abortions (since chromosomal or anatomic defects have been excluded) are characteristic manifestations of antiphospholipid syndrome (APS). They can occur in patients with known APS with previous arterial or venous events in any tissue or organ, or be its first and only manifestation. Pregnancy in a patient with APS is considered high risk and the full prenatal clinical follow-up must be carried with this in mind, eliminating or minimizing concomitant thrombotic risk factors.

Increased expression of tissue factor and protease-activated receptor-1 does not correlate with thrombosis in human lung adenocarcinoma

A correlation between cancer and hypercoagulability has been described for more than a century. Patients with cancer are at increased risk for thrombotic complications and the clotting initiator protein, tissue factor (TF), is possibly involved in this process. Moreover, TF may promote angiogenesis and tumor growth. In addition to TF, thrombin seems to play a relevant role in tumor biology, mainly through activation of protease-activated receptor-1 (PAR-1). In the present study, we prospectively studied 39 lung adenocarcinoma patients in relation to the tumor expression levels of TF and PAR-1 and their correlation with thrombosis outcome and survival. Immunohistochemical analysis showed TF positivity in 22 patients (56 percent), most of them in advanced stages (III and IV). Expression of PAR-1 was found in 15 patients (39 percent), most of them also in advanced stages (III and IV). Remarkably, no correlation was observed between the expression of TF or PAR-1 and risk for thrombosis development. On the other hand, patients who were positive for TF or PAR-1 tended to have decreased long-term survival. We conclude that immunolocalization of either TF or PAR-1 in lung adenocarcinoma may predict a poor prognosis although lacking correlation with thrombosis outcome.

Functional contrast-enhanced CT for evaluation of acute ischemic stroke does not increase the risk of contrast-induced nephropathy.

BACKGROUND AND PURPOSE: Concerns have recently grown regarding the safety of iodinated contrast agents used for CTA and CTP imaging. We tested whether the incidence of AN, defined by a >or=25% increase in the post-contrast scan creatinine level, was higher among patients with ischemic stroke who underwent a functional contrast-enhanced CT protocol compared with those who had no iodinated contrast administration. MATERIALS AND METHODS: The contrast-exposed group consisted of 575 patients with acute ischemic stroke who underwent CTA (n = 313), CTA/CTP (n = 224), or CTA/CTP followed by conventional angiography (n = 38) within 24 hours of stroke onset and were consecutively enrolled in a prospective cohort study. The nonexposed group consisted of 343 patients with ischemic stroke, consecutively admitted to the same institution, who did not receive iodinated contrast material. Patients were stratified by baseline eGFR. In the primary analysis, the Fisher exact test was used to compare the incidence of AN between the contrast-exposed and the nonexposed patients at 24, 48, and 72 hours and on a cumulative basis. A secondary analysis compared the incidence of AN in patients who underwent conventional angiography following CTA/CTP versus patients who underwent CTA/CTP only. RESULTS: The incidence of AN was 5% in the exposed and 10% in the nonexposed group (P = .003). Patients who underwent conventional angiography after contrast CT were at no greater risk of AN than patients who underwent CTA/CTP alone (26 patients, 5%; and 2 patients, 5%, respectively; P = .7). CONCLUSIONS: Administration of a contrast-enhanced CT protocol involving CTA/CTP and conventional angiography in selected patients does not appear to increase the incidence of CIN.

Infections and autoimmunity: a panorama.

For more than 2,000 years, it was thought that malignant spirits caused diseases. By the end of nineteenth century, these beliefs were displaced by more modern concepts of disease, namely, the formulation of the "germ theory," which asserted that bacteria or other microorganisms caused disease. With the emergence of chronic degenerative and of autoimmune diseases in the last century, the causative role of microorganisms has been intensely debated; however, no clear explanatory models have been achieved. In this review, we examine the current available literature regarding the relationships between infections and 16 autoimmune diseases. We critically analyzed clinical, serological, and molecular associations, and reviewed experimental models of induction of and, alternatively, protection from autoimmune diseases by infection. After reviewing several studies and reports, a clinical and experimental pattern emerges: Chronic and multiple infections with viruses, such as Epstein-Barr virus and cytomegalovirus, and bacteria, such as H. pylori, may, in susceptible individuals, play a role in the evolvement of autoimmune diseases. As the vast majority of infections pertain to our resident microbiota and endogenous retroviruses and healthy carriage of infections is the rule, we propose to focus on understanding the mechanisms of this healthy carrier state and what changes its configurations to infectious syndromes, to the restoration of health, or to the sustaining of illness into a chronic state and/or autoimmune disease. It seems that in the development of this healthy carriage state, the infection or colonization in early stages of ontogenesis with key microorganisms, also called 'old friends' (lactobacilli, bifidobacteria among others), are important for the healthy living and for the protection from infectious and autoimmune syndromes.

[Lucio phenomenon. Vasculitis or occlusive vasculopathy?]. / Lucio-Phänomen. Vaskulitis oder okklusive Vaskulopathie?

Lucio's phenomenon (LP) occurs in patients with Lucio leprosy (LuL). Some interpret the cutaneous lesions and their histopathology as a thrombotic/occlusive condition, while others consider it leukocytoclastic vasculitis. The clinical similarities between the cutaneous manifestations of LP and antiphospholipid syndrome (APS) led us to investigate the relationship between these two pathological conditions. We studied the clinical, laboratory and histopathologic aspects of LuL and LP in one patient and compare these results to APS. The examination of antiphospholipid antibodies showed positive anticardiolipin (aCL) and lupus anticoagulant (LAC). The histopathological slides of cutaneous biopsies were stained by hematoxylin-eosin and Fite-Faraco. They showed the typical features of LuL, as well as thrombi, endothelial proliferation, vessel wall thickening and obliteration of the lumen. Leukocytoclastic vasculitis was not found. The clinical pattern of LuL in our case is identical to that described by Lucio and Latapi. The necrotic lesions of LP in our patient resembled APS. This suggests that LP could be considered APS secondary to LuL. Multidrug treatment for multibacillary patients (MDT-MP) was successful, with no need for thalidomide or systemic corticosteroids.

Contractile cells and fibrillin-1 distribution is disturbed in terminal villi of placentae from patients with preeclampsia and systemic lupus erythematosus.

Placentae from patients with preeclampsia (PE) and systemic lupus erythematosus (SLE) present many alterations that may impair materno-fetal exchange. We investigated the distribution of contractile cells and fibrillin-1 in terminal villi of term placentae from patients with PE or SLE and compared to control placentae. Stroma in terminal villi exhibited intense labelling for fibrillin-1. The fibrillin-1 villi surface fraction was greater in PE and SLE placentae than in controls (13+/-0.4%, 14+/-0.5%, 10+/-0.4%; p=0.0001). Immunohistochemistry for alpha-smooth muscle (SM) actin showed few contractile cells in control terminal villi stroma, localized around fetal capillaries and showed rare processes in vasculo-syncytial membrane. PE and SLE placentae exhibited an increase in the number of capillaries presenting alpha-SM actin adventitial positive cells. The presence of alpha-SM actin processes interposed in the vasculo-syncytial membrane was greater in SLE villi than in PE and controls. Ultrastructural observations confirmed in SLE and PE terminal villi the presence of these processes in vasculo-syncytial membrane and also showed a thickened trophoblastic basement membrane. The present study demonstrates that an important myofibroelastic system is present in term terminal villi, and that this system is actively remodelled in PE and SLE placentae.