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Organ damage is a key determinant of poor long-term prognosis and early death in patients with systemic lupus erythematosus (SLE). Prevention of damage is a key treatment goal of the 2019 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for SLE management. Belimumab is a monoclonal antibody that inhibits B lymphocyte stimulator (BLyS) and is the only therapy approved for both SLE and lupus nephritis. Here, we review the clinical trial and real-world data on the effects of belimumab on organ damage in adult patients with SLE. Across 4 phase III studies, belimumab in combination with background SLE therapy demonstrated consistent reductions in key drivers of organ damage including disease activity, risk of new severe flares, and glucocorticoid exposure compared to background therapy alone. Long-term belimumab use in SLE also reduced organ damage progression measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, as reported in open-label extension studies, and propensity score–matched comparative analyses to background therapy alone. Results from a clinical trial showed that in patients with active lupus nephritis, belimumab treatment improved renal response, reduced the risk of renal-related events, and impacted features related to kidney damage progression compared to background therapy alone. The decrease of organ damage accumulation observed with belimumab treatment in SLE, including lupus nephritis, suggest a disease-modifying effect.

Objective The present study aimed to analyse the frequency of premature rupture of membranes (PROMs) among 190 women with systemic lupus erythematosus (SLE) followed up at the Hospital Universitário Pedro Ernesto from 2011 to 2018 and to review the literature on PROM in patients with SLE. Methods A cohort study of SLE patients was conducted by analysing the following variables: sociodemographic characteristics, clinical manifestations of lupus, modified disease activity index for pregnancy, drugs used during pregnancy, intercurrent maternal infections and obstetric outcomes. Additionally, seven electronic databases (PubMed, Embase, Cochrane, Scielo, Scielo Brazil, Virtual Health Library Regional Portal and Google Scholar) were systematically searched. The search was updated on 3 February 2020. Results Infections (relative risk (RR): 3.26, 95% confidence interval (CI): 1.5–6.7, p = .001), history of serositis (RR: 2.59, 95% CI: 1.31–5.11, p = .006) and anti-RNP positivity (RR: 3.08, 95% CI: 1.39–6.78, p = .005) were associated risk factors for PROM, while anti-RNP positivity (RR: 3.37, 95% CI: 1.35–8.40; p = .009) were associated with premature PROM (PPROM). The prevalence of PROM and PPROM was 28.7% and 12.9%, respectively. In the systematic review, the prevalence of PROM and PPROM was 2.7%–35% (I2 = 87.62%) and 2.8%–20% (I2 = 79.56%), respectively. Conclusions PROM, both at term and preterm, occurs more frequently in women with lupus than in the general population. A history of serositis, anti-RN, infections and immunosuppression during pregnancy may increase the susceptibility to PROM. The systematic review did not find any study with the main objective of evaluating PROM/PPROM in women with lupus.

Objective The objective of this study was to evaluate the potential impact of irreversible damage accrual in women with systemic lupus erythematosus (SLE) and adverse maternal and/or fetal/neonatal outcomes. Methods Retrospective cohort study with SLE pregnant patients was carried out from January 2011 to January 2020 at the Hospital University Pedro Ernesto (HUPE) of the State University of Rio de Janeiro, Brazil. Irreversible damage was defined according to SLICC/ACR damage index (SDI). The association of SDI on pregnancy outcomes was established by univariate and multivariate regression models and included demographic and clinical variables. Results This study included data from 260 patients in their first pregnancies after SLE diagnosis, with a quarter of them (67/260) scoring one or more points on SDI at the beginning of prenatal care. These patients presented more frequently adverse maternal events, namely, disease activity during pregnancy ( p = 0.004) and puerperium ( p = 0.001), active lupus nephritis ( p = 0.04), and hospitalizations ( p = 0.004), than those with no SDI score. Similarly, the risks of adverse fetal and neonatal outcomes were also higher among the patients with SDI ≥ 1 (59.7% vs 38.3% p = 0.001) even after controlling data for disease activity (SLEPDAI > 4). Patients with SDI ≥ 1 presented more frequently preterm deliveries (46.3% vs 31.6%; p = 0.01), small for gestational age infants (28.3% vs 18.1%; p = 0.04), and neonatal intensive care unit admission (26.9% vs 1.5%; p < 0.001). The multivariate analyses showed that SDI ≥ 1 is an independent risk factor for hospitalization due to obstetric complications ( p = 0.0008) and preterm delivery ( p = 0.009). Conclusion Pregnant SLE patients who present irreversible damage accrual may have higher risk of maternal and fetal adverse outcomes, independently of disease activity. These results should be validated in further prospective studies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting both adults and children. Belimumab is the only biologic approved for SLE, and the first in a class of drugs known as B-lymphocyte stimulator-specific inhibitors. The introduction of intravenous belimumab in 2011 was a major advance, being the first new therapy approved for SLE in over 50 years. As of April 2021, more than 7200 people with SLE have received belimumab in clinical studies, and it is approved in over 75 countries for the treatment of adults with SLE. A subcutaneous, self-injectable belimumab formulation was licensed in 2017 by both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Belimumab was then approved for use in children in Europe, the USA and Japan in 2019, and China and Brazil in 2020. Recently, belimumab became the first FDA-approved drug for the treatment of adults with active lupus nephritis (LN), the most-common severe manifestation of SLE. Over the past 10 years, belimumab has established its position as a disease modifier in the SLE treatment paradigms. Robust evidence from randomised clinical studies and observational, real-world studies has demonstrated the tolerability and efficacy of belimumab for reducing disease activity and the risk of new, severe SLE flares. This enables patients to taper their glucocorticoid use, which limits damage accumulation. Significantly more patients with active LN met the criteria for renal responses and were at less risk of a renal-related event or death after receiving belimumab plus standard therapy, compared with standard therapy on top of mandatory steroid reduction. Ongoing clinical studies are evaluating belimumab’s effectiveness in various indications beyond SLE. Post-marketing and registry studies are gathering additional data on key areas such as pregnancy outcomes after belimumab exposure and belimumab co-administration with other biologics.

Objective The understanding of systemic lupus erythematosus (SLE) and lupus nephritis (LN) pathogenesis remains incomplete. This review assessed LN development in SLE, within-LN progression and progression to end-stage renal disease (ESRD). Methods A keyword-based literature search was conducted, and 26 publications were included. Results Overall, 7–31% of patients had LN at SLE diagnosis; 31–48% developed LN after SLE diagnosis, most within 5 years. Class IV was the most commonly found LN class and had the worst prognosis. Histological transformation occurred in 40–76% of patients, more frequently from non-proliferative rather than proliferative lesions. Cumulative 5- and 10-year ESRD incidences in patients with SLE were 3% and 4%, respectively, and 3–11% and 6–19%, respectively, in patients with SLE and LN. Conclusions Elevated serum creatinine was identified as a predictor of worsening disease state, and progression within LN classes and from SLE/LN to ESRD. This review highlights the substantial risk for developing LN and progressing to ESRD amongst patients with SLE.

Endothelial dysfunction is an initial stage of the atherogenic process, which can be evaluated by a noninvasive method (flow-mediated dilation - FMD) and has a well-established prognostic value for cardiovascular (CV) risk. Currently, there is no evidence of increased CV mortality in Behc¸et's disease (BD), although its association with endothelial dysfunction has been described. There are still doubts in the literature whether the presence of chronic vascular inflammation might trigger the development of atherosclerosis, despite BD remission, which is why this study was conducted.We analyzed 24 subjects in this cross-sectional study (12 patients with BD in remission and 12 subjects matched by gender age). Endothelial function was analyzed via FMD.The lowest median for FMD was presented by the BD group (2.025% - interquartile range (IQR) 7.785 versus 5.46% - IQR 3.625, P ¼ .18). The median total cholesterol in the BD group was lower than the controls (168 mg dL-1 - IQR 46 and 216.5 mg dL-1 - IQR 54, respectively, P ¼ .0193). In the right carotid artery, the intima-media thickness was equal to 0.740 - IQR 0.16 for the patients and 0.740 - IQR 0.11 for the controls (P ¼ .9473); on the left, 0.725 - IQR 0.13 and 0.745 - IQR 0.120 (P ¼ .4333), respectively.The lower median trend of FMD in patients with BD suggests endothelial dysfunction, despite clinical remission of the inflammatory disease, although our study is limited by the sample size and greater use of statins in BD group.

Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE.We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on ‘disease manifestations’ (ie, signs, symptoms and patient-reported outcomes) and on ‘disease outcomes’ (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested.Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE.

Background/objective The epidemiology of vasculitis is variable in different geographic areas, and this issue has not been approached in Brazil yet. The objective of this study was to assess the frequency of vasculitis in specialized centers in Brazil. Methods This cross-sectional study was performed in 9 vasculitis outpatient clinics from 6 different states mainly from the Southeast and the Northeast regions of Brazil between 2015 and 2017. Diagnosis and/or classification criteria for Behcet disease (BD), Takayasu arteritis (TA), giant cell arteritis (GCA), polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and cryoglobulinemic vasculitis (CryoVas) were used to include patients with at least 6 months of follow-up in this hospital-based survey. Results A total of 1233 patients with systemic vasculitis were included from the Southeast region. Behcet disease was the most frequent vasculitis (35.0%) followed by TA (26.4%), GPA (16.2%), PAN (5.8%), GCA (5.8%), EGPA (4.3%), MPA (3.4%), and CryoVas (3.0%). Up to 7.8% of vasculitis patients had a juvenile onset, and the frequency of vasculitides found in children and adolescents was as follows: TA (52.6%), BD (24.7%), GPA (12.4%), and PAN (10.3%). No cases of EGPA, MPA, and CryoVas were diagnosed before the age of 18 years. As a comparator, 103 vasculitis patients were included in the Northeast of Brazil where TA was found in 36.9% and BD in 31.1% of vasculitis cases. No GCA cases were found in the Northeast part of Brazil. Conclusions Similar to the epidemiology of vasculitis in Asia, BD and TA are the most frequent vasculitis in Southeastern Brazilian referral centers.

The objectives of the 16th International Congress on Antiphospholipid Antibodies (aPL) Task Force on Clinical Manifestations of Antiphospholipid Syndrome (APS) were to critically analyze: a) the definition of “APS”; b) the current knowledge on non-traditional manifestations associated with aPL; and c) the risk stratification strategies in aPL-positive patients. The quality of evidence was assessed by the GRADE system. The task force concluded that: a) APS does not have a uniform definition given the heterogeneity of the clinical presentations and different aPL profiles; b) current literature supports the role for aPL testing in cases of thrombocytopenia and recurrent cardiac events but are limited by vast heterogeneity, providing an overall low-to-very low level of evidence; and c) risk stratification strategies in aPL-positive patients, such as aPL-Score and Global APS Score, can be useful in clinical practice. International multicenter studies are still highly needed to improve the quality of available evidence and consequently the strength of future recommendations.

ObjectiveThere 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.MethodsWe 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.ResultsWe 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.ConclusionThere 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.

To analyse maternal variables associated with occurrence of small for gestational age (SGA) newborns in pregnancies of women with systemic lupus erythematosus (SLE), considering clinical and laboratory characteristics prior to conception, during gestation and comorbidities.Retrospective cohort study with SLE pregnant patients and singleton deliveries after 22 weeks. SGA newborn was defined as birth weight below 10th percentile and SLE activity at conception and during gestation was measured using the SLE Pregnancy Disease Activity Index (SLEPDAI). Univariate analysis was employed to evaluate individual influence of demographic and clinical variables on the SGA newborn outcome, while variables with p0.20 were included in multivariate regression.Among 151 pregnancies, 28 (18.5%) had SGA newborns. History of proliferative nephritis (RR=3.84, CI 1.63-9.3) and positivity for anti-RNP and anti-Sm antibodies (RR=2.67, CI 1.11-6.43; 2.78, CI 1.44-5.32) were more frequent in the study group. Active proliferative nephritis at conception (RR=3.29, CI 1.75-6.18) and during gestation (RR=3.63, CI 1.97-6.71), as well as complement C3 consumption (RR=2.70, CI 1.09-6.67) and venous pulse therapy with methylprednisolone (RR=20.3, CI 2.18-190), were also associated with SGA newborns, the latter being independently associated in multivariate regression. Adverse perinatal outcomes, such as stillbirths (4.3 times) and neonatal intensive care unit admissions (3.2 times), were more frequent among SGA infants.Active proliferative lupus nephritis during pregnancy was associated with SGA newborns, while its treatment with venous pulse therapy with methylprednisolone may play a significant role in this context. Presence of previous proliferative nephritis, SLEPDAI ≥4, C3 consumption and presence of anti-RNP and anti-Sm antibodies were additional variables associated with SGA newborns in this population.

OBJECTIVE To evaluate mean serum levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and soluble Flt-1 (sFlt-1) in pregnant patients with systemic lupus erythematosus (SLE) with inactive disease, active lupus nephritis, and preeclampsia for differential diagnosis between these conditions. METHODS Pregnant women with SLE, with singleton pregnancies and no other autoimmune diseases, were classified according to disease activity (inactive SLE and active lupus nephritis) and the presence of preeclampsia. Serum samples were collected within 3 weeks of delivery and frozen for subsequent blinded analysis through the enzyme-linked immunosorbent assay method. RESULTS A total of 71 women were included, with 41 classified as having inactive SLE (group 1; Systemic Lupus Erythematosus Pregnancy Disease Activity Index [SLEPDAI] score

Background Elevated B lymphocyte stimulator (BLyS) levels in patients with systemic lupus erythematosus (SLE) correlate positively with disease activity; BLyS expression is directly linked to interferon (IFN) pathway activation. This post hoc meta-analysis of BLISS-52 and BLISS-76 explored the relationship between baseline BLyS mRNA/protein levels and/or type 1 IFN-inducible gene signature (IFN-1) and responses to the BLyS-targeting monoclonal antibody belimumab in SLE. Methods In BLISS-52 and BLISS-76, patients with autoantibody-positive SLE and a SELENA-SLEDAI score ≥ 6 and receiving stable standard SLE therapy were randomised to intravenous belimumab 10 mg/kg or placebo, plus standard of care (SoC), for 52 or 76 weeks. For this post hoc meta-analysis, patients with an appropriate mRNA sample were stratified by BLyS mRNA expression (tertiles: high/medium/low; revised quantiles: high/low), IFN-1 mRNA expression (high/low) and BLyS protein level (high/low). Co-primary endpoints were correlation between baseline BLyS and IFN-1 mRNA levels and SLE Responder Index (SRI)4 response at week 52 within BLyS/IFN-1 subgroups. Secondary endpoints included time to first severe SELENA-SLEDAI Flare Index (SFI) flare. Results Of 554 patients included in this analysis, 281 had received belimumab and 273 had received placebo. Baseline BLyS and IFN-1 mRNA levels were highly correlated (Spearman’s rank correlation coefficient 0.7799; 95% confidence interval [CI] 0.7451, 0.8106; p p = 0.0153), high BLyS mRNA quantile (OR 1.58; 95% CI 1.02, 2.44; p = 0.0402), high IFN-1 mRNA (OR 1.58; 95% CI: 1.08, 2.31; p = 0.0186) and high BLyS protein (OR 3.57; 95% CI 1.63, 7.83; p = 0.0015) subgroups only. The risk of severe SFI flare was significantly lower with belimumab than placebo in the high BLyS mRNA quantile (hazard ratio [HR] 0.59; 95% CI 0.36, 0.97; p = 0.0371) and high BLyS protein (HR 0.39; 95% CI 0.19, 0.79; p = 0.0090) subgroups. Conclusions This post hoc meta-analysis demonstrated a tendency towards improved response to add-on intravenous belimumab 10 mg/kg versus SoC alone in patients with high baseline BLyS protein and IFN-1 mRNA levels and medium/high BLyS mRNA levels.

Autoimmunity is believed to play an important causative role in the pathogenesis of epilepsy. There are evidences for the presence of autoantibodies in patients with epilepsy. To date, many studies have assessed the presence of antiphospholipid antibodies (aPLs) in epilepsy patients, though the relationship has been inconclusive.The aim of this systematic review and meta-analysis was to evaluate the presence of aPLs in epileptic patients as compared to healthy controls.Five electronic databases (PubMed, Web of Science, Embase, Scopus and Google Scholar) were searched systematically. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. Quality assessment was carried out by using the modified 9-star Newcastle-Ottawa Scale (NOS). L'Abbé plots were generated to visually inspect heterogeneity while publication bias was evaluated via visualization of contour- enhanced funnel plots, and Begg's and Egger's tests.Based on the inclusion criteria, 14 studies were selected involving 1248 epilepsy patients and 800 healthy controls. The majority of epilepsy was categorised as generalised or partial and none had comorbidity with autoimmune diseases. Significant presence of both anticardiolipin (aCL) antibodies (OR: 5.16, 95% CI: 3.21-8.28, p 0.00001) and anti-β2- glycoprotein I (anti-β2-GPI) antibodies (OR: 2.95, 95% CI: 1.07-8.11, p = 0.04) exhibited comorbid association with epilepsy patients as compared to healthy controls. Subgroup analyses revealed that presence of aCL antibodies was more specifically observed in paediatrics (OR: 4.57, 95% CI: 2.57-8.15, p 0.00001) than adults (OR: 4.24, 95% CI: 1.80-10.01, p = 0.001). The odds of aCL antibody presence was higher in partial epilepsy patients (OR: 7.88, 95% CI: 3.23-19.24, p 0.00001) than that of generalised (OR: 3.76, 95% CI: 2.15-6.59, p 0.00001) and in Asian epileptic patients (OR: 9.56, 95% CI: 2.69-33.95, p = 0.0005) than Europeans (OR: 4.35, 95% CI: 2.74-6.92, p 0.00001). The presence of anti-β2-GPI antibodies was significant in paediatric (OR: 6.44, 95% CI: 1.39-29.89, p = 0.02) and African population with epilepsies (OR: 10.59, 95% CI: 1.22-92.25, p = 0.03). NOS of the majority of the studies (11/14) indicated a high methodological quality. No substantial heterogeneity was observed either from the quantitative analysis or from the L'Abbé plots while no significant publication bias was detected from funnel plots; Begg's and Egger's tests.Since none of the epilepsy subjects exhibited any comorbid autoimmune disorders, significant presence of aCL and anti-β2-GPI antibodies indicate towards their contribution in immune-mediated general pathogenesis of epilepsy.

Summary Antiphospholipid syndrome (APS) is an autoimmune disease characterized by antiphospholipid antibodies (aPL) associated with thrombosis and/or pregnancy morbidity. Most APS events are directly related to thrombotic events, which may affect small, medium or large vessels. Other clinical features like thrombocytopenia, nephropathy, cardiac valve disease, cognitive dysfunction and skin ulcers (called non-criteria manifestations) add significant morbidity to this syndrome and represent clinical situations that are challenging. APS was initially described in patients with systemic lupus erythematosus (SLE) but it can occur in patients without any other autoimmune disease. Despite the autoimmune nature of this syndrome, APS treatment is still based on anticoagulation and antiplatelet therapy. Resumo A síndrome antifosfolipídide (APS) é uma doença autoimune caracterizada por tromboses e morbidade gestacional associadas à positividade de antiphospholipid antibodies (aPL). A maioria das manifestações da APS está diretamente relacionada aos eventos trombóticos, que podem afetar pequenos, médios ou grandes vasos. Outras manifestações como trombocitopenia, nefropatia, valvulopatia, disfunção cognitiva e úlceras cutâneas (chamadas de manifestações não critérios) agregam significativa morbidade e muitas vezes são refratárias ao tratamento convencional. Embora tenha sido inicialmente descrita em pacientes com lúpus eritematoso sistêmico (LES), a síndrome antifosfolípide também pode ocorrer em pacientes sem outras doenças autoimunes associadas. Apesar do caráter autoimune dessa síndrome, o tratamento da APS ainda é baseado na anticoagulação e na antiagregação plaquetária.

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 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 (pÂ

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.

ObjectivesTreat-to-target recommendations have identified ‘remission’ as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE.MethodsAn international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%.ResultsThe task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life.ConclusionsThe work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.

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 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 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.

Background The APS ACTION International Clinical Database and Repository includes a secure web-based data capture system storing patient information including demographics, antiphospholipid antibodies (aPL)-related medical history, and aPL tests. Despite efforts at harmonization, inter-assay variability remains a problem in aPL testing. As a clinical repository open to researchers, ensuring comparability between assays and consistency in results between APS ACTION laboratories is essential to the validity of studies emerging from this network. Objective To assess the level of agreement between an aPL-registry inclusion and core laboratory (core lab) anticardiolipin antibody (aCL) and anti-β2-glycoprotein-I antibody (aβ2GPI) ELISA testing results. Methods Patients are recruited from 25 international centers based on positive aPL tests at inclusion. All samples are retested at the corresponding national APS ACTION core lab to confirm aPL positivity based on standard validated protocols. We analysed the categorical agreement, degree of linear association, and correlation between inclusion (local laboratory) and core lab aPL tests. Samples were included in this study only if results of aPL testing with ELISA at baseline were available. Results 497 registry samples underwent confirmatory aPL tests. Categorical agreement between the inclusion and core lab values, as expressed by Cohen's kappa coefficients, ranged between 0.61 and 0.80 (as substantial agreement). The correlation between quantitative results in the aCL and aβ2GPI was better for IgM and IgA compared to IgG (Spearman rho 0.789 and 0.666 vs. 0.600 for aCL and rho 0.892 and 0.744 vs. 0.432 for aβ2GPI). Conclusions The results of inclusion for aCL and aβ2GPI tests used for recruitment into the registry were in agreement to the results obtained by the APS ACTION core laboratories; aCL and aβ2GPI results showed very good categorical agreement. This agreement increased when considering high titer (>40 units) samples. APS ACTION is a reliable and useful research resource for APS.

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.

The crucial issue for a better pregnancy outcome in women with autoimmune rheumatic diseases is appropriate planning, with counseling of the ideal timing and treatment adaptation. Drugs used to treat rheumatic diseases may interfere with fertility or increase the risk of miscarriages and congenital abnormalities. MTX use post-conception is clearly linked to abortions as well as major birth defects, so it should be stopped 3months before conception. Leflunomide causes abnormalities in animals even in low doses. Although in humans, it does not seem to be as harmful as MTX, when pregnancy is detected in a patient on leflunomide, cholestyramine is given for washout. Sulfasalazine can be used safely and is an option for those patients who were on MTX or leflunomide. Azathioprine is generally the immunosuppressive of choice in many high-risk pregnancy centers because of the safety profile and its steroid-sparing property. Cyclosporine and tacrolimus can also be used as steroid-sparing agents, but experience is smaller. Although prednisone and prednisolone are inactivated in the placenta, we try to limit the dose to the minimal effective one, to prevent side effects. Antimalarials have been broadly studied and are safe during pregnancy and breastfeeding. Among biologic disease modifying anti-rheumatic agents (bDMARD), the anti-TNFs that have been used for longer are the ones with greater experience. The large monoclonal antibodies do not cross the placenta in the first trimester, and after conception, the decision to continue medication should be taken individually. The experience is larger in women with inflammatory bowel diseases, where anti-TNF is generally maintained at least until 30weeks to reduce fetal exposure. Live vaccines should not be administrated to the infant in the first 6months of life. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab, ustekinumab, belimumab, and tofacitinib are limited and their use in pregnancy cannot currently be recommended.

The term autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) or Shoenfeld's syndrome refers to a wide group of immune-mediated diseases triggered by external agents. Several substances, such as vaccine adjuvants, squalene and silicone implants, are implied in the pathogenesis of ASIA syndrome. Treatment and prognosis of this complex condition are not completely known due to lack of good quality evidence. After a brief introductory literature review on ASIA, we report here two cases of patients that developed rapidly progressive systemic sclerosis clinical features after multiple intramuscular local injections of a substance recommended by a non-medical professional called ADE. ADE is an oily vitamin complex for veterinary use, and it was used in these cases for cosmetic muscular definition and enhancement purpose. To our knowledge, this is the first paper to describe the relation between injections of ADE and the development of ASIA with severe systemic sclerosis phenotype. Further investigation is needed to better understand the pathophysiology and to provide the basis for the treatment of this condition.

The eye is divided anatomically in three layers: an outer or fibrous layer (cornea/sclera), middle or vascular layer (uvea — iris, ciliary body, and choroid) and an inner or sensorineural layer (retina). They compose the several anatomic and functional layers that enable the immune protection of the eye. The first layer involves an intact anatomic border with the blood–ocular barrier and immunosuppressive neuropeptides in the native aqueous humor. The second layer trusts on the capability of the eye to reestablish an immunosuppressive micro-environment by activating latent TGF-β and reestablishing the anterior chamber-associated immune deviation. The third layer involves a mechanism that is not yet completely recognized, but that has the ability to overcome a predominantly Th1 intraocular immune response and to reestablish anterior chamber-associated immune deviation. Understanding the comprehensive mechanisms of these pathways, will lead to the development of new treatments strategies in order to prevent damage to the eye from persistent or exacerbated inflammation, directed at first to pathogens, but that may develop an autoimmune reaction.

Objective To investigate the effect of rituximab on microcirculation in long-term SSc. Results Four patients with diffuse SSc over 3 years of disease received rituximab cycles of two 1-g infusions every 6 months for 2 years. Videocapillaroscopy was performed at baseline, 12 months, and 24 months and semi-quantitative scoring of videocapillaroscopy abnormalities was performed and the microangiopathy evolution score (MES: range 0–9) was calculated. The mean disease duration was 5 years (range 3–15). On videocapillaroscopy, giant capillaries and hemorrhages remained stable from baseline to 24 months. Capillary loss, abnormally-shaped capillaries, and MES stabilized at 12 months and increased by 24.5% and 28% at 24 months. Rituximab improves microcirculation in long-term SSc. Stabilization and reduced progression of microcirculation abnormalities were achieved at 12 and 24 months, respectively. Electronic supplementary material The online version of this article (10.1186/s13104-018-3994-1) contains supplementary material, which is available to authorized users.

This article describes three complicated cases in rheumatology and pregnancy. The first case elucidates the challenges in treating SLE in conjunction with pulmonary arterial hypertension, while the second case features an SLE-affected pregnancy with development of portal hypertension secondary to portal vein thrombosis related to APS. The third case is a pregnant woman with stable SLE who developed thrombotic microangiopathy caused by atypical haemolytic uraemic syndrome, and failed to improve despite multiple measures including biopsy and elective preterm delivery. There are grave and unique challenges for women with autoimmune disease, but adverse outcomes can sometimes be avoided with careful and multidisciplinary medical management. Pre-conception counselling with regard to medications and disease treatment should also include discussion of the advisability of pregnancy, which may be difficult for a patient, but present the best course for optimizing health outcomes.

Tuberculosis (TB) is a millenarian chronic infection and, yet, remains a major global health problem. The interaction between systemic lupus erythematosus (SLE) and TB is complex, as one seems to be a risk factor for the development of the other. SLE patients are more likely to develop TB, that is more frequently extrapulmonary, with more extensive pulmonary involvement, and with a higher relapse rate.Different studies suggest that TB is more prevalent in SLE patients and that TB may actually be a risk factor for the development of the disease. Molecular and epidemiological data suggest that TB may be involved in the pathogenesis of SLE.We reviewed the most relevant aspects of TB infection in SLE patients, including the burden of TB, its role in inducing flare and its perpetuation, risk evaluation and prevention, and pearls and pitfalls when assessing extrapulmonary TB in SLE patients. We conclude that a high suspicion of TB in SLE patients from endemic countries should be kept in mind, especially in those with nephritis and high cumulative doses of corticosteroids.

Modern medicine is in a continuous state of flux given the relentless development of new evidence; thus, it is quite difficult for clinicians to remain abreast of all advances as they happen. Trustworthy clinical practica guidelines (CPGs) rigorously developed following a transparent methodology (http://www.gradeworkinggroup.org/) and including the best available evidence represent one of the best solutions to overcome these problems...

Background In scleroderma, excessive collagen production can alter tracheal geometry, and computed tomography (CT) volumetry of this structure may aid in detecting possible abnormalities. The objectives of this study were to quantify the morphological abnormalities in the tracheas of ​​patients with scleroderma and to correlate these findings with data on clinical and pulmonary function. Methods This was a cross-sectional study in which 28 adults with scleroderma and 27 controls matched by age, gender and body mass index underwent chest CT with posterior segmentation and skeletonization of the images. In addition, all participants underwent pulmonary function tests and clinical evaluation, including the modified Rodnan skin score (mRSS). Results Most patients (71.4%) had interstitial lung disease on CT. Compared to controls, patients with scleroderma showed higher values ​​in the parameters measured by CT trachea volumetry, including area, eccentricity, major diameter, minor diameter, and tortuosity. The tracheal area and equivalent diameter were negatively correlated with the ratio between forced expiratory flow and forced inspiratory flow at 50% of forced vital capacity (FEF50%/FIF50%) (r = -0.44, p = 0.03 and r = -0.46, p = 0.02, respectively). The tracheal tortuosity was negatively correlated with peak expiratory flow (r = -0.51, p = 0.008). The mRSS showed a positive correlation with eccentricity (r = 0.62, p < 0.001) and tracheal tortuosity (r = 0.51, p = 0.007), while the presence of anti-topoisomerase I antibody (ATA) showed a positive correlation with tracheal tortuosity (r = 0.45, p = 0.03). Conclusions In a sample composed predominantly of scleroderma patients with associated interstitial lung disease, there were abnormalities in tracheal geometry, including greater eccentricity, diameter and tortuosity. In these patients, abnormalities in the geometry of the trachea were associated with functional markers of obstruction. In addition, tracheal tortuosity was correlated with cutaneous involvement and the presence of ATA.

The current treatment for antiphospholipid syndrome (APS) with thrombotic manifestation is long-term anticoagulation. Vitamin K antagonists (VKA) are usually the agents of choice. However, VKA limitations, such as unpredictable anticoagulation effects due to interaction with diet and other drugs, require regular monitoring. This may impact on patients' quality of life. Since the approval of new oral anticoagulants (NOAC) for non-valvular atrial fibrillation and deep vein thrombosis prevention, much has been speculated about its use in APS patients. We report here a series of eight APS patients with failure of thrombotic prevention during rivaroxaban use. All patients had venous thrombosis as the initial manifestation of APS, and two of them also had arterial manifestations. Three patients had triple antibody positivity. Five patients developed arterial events during the treatment with rivaroxaban. Until the results of ongoing trials of rivaroxaban for APS are presented, NOAC should not be recommended to APS patients. Our preliminary experience as well cases previously reported in the literature suggest that there is a high-risk group that is less protected with rivaroxaban, namely those with previous arterial thrombosis or triple positivity. VKA remains to be the mainstay treatment for thrombotic APS.

Current therapeutic recommendations for thrombosis prevention in patients with antiphospholipid syndrome (APS) are limited to anticoagulation with vitamin K antagonists (VKA) or heparins and to anti-platelet aggregating agents. Maintaining optimized anticoagulation to prevent recurrent thrombosis or bleeding remains a therapeutic challenge. Although there are important ongoing trials with direct oral anticoagulants, they still aim the same target. New insights about pathophysiology in APS have revealed a myriad of potential pathways to be investigated as treatment targets. A radical shift from a hematological/coagulative approach to an immunological one will probably represent the near future of APS treatment. We reviewed the therapeutic trends and potential future treatments.

Chikungunya fever has become a relevant public health problem in countries where epidemics occur. Until 2013, only imported cases occurred in the Americas, but in October of that year, the first cases were reported in Saint Marin island in the Caribbean. The first autochthonous cases were confirmed in Brazil in September 2014; until epidemiological week 37 of 2016, 236,287 probable cases of infection with Chikungunya virus had been registered, 116,523 of which had serological confirmation. Environmental changes caused by humans, disorderly urban growth and an ever-increasing number of international travelers were described as the factors responsible for the emergence of large-scale epidemics. Clinically characterized by fever and joint pain in the acute stage, approximately half of patients progress to the chronic stage (beyond 3 months), which is accompanied by persistent and disabling pain. The aim of the present study was to formulate recommendations for the diagnosis and treatment of Chikungunya fever in Brazil. A literature review was performed in the MEDLINE, SciELO and PubMed databases to ground the decisions for recommendations. The degree of concordance among experts was established through the Delphi method, involving 2 in-person meetings and several online voting rounds. In total, 25 recommendations were formulated and divided into 3 thematic groups: (1) clinical, laboratory and imaging diagnosis; (2) special situations; and (3) treatment. The first 2 themes are presented in part 1, and treatment is presented in part 2. Resumo A febre chikungunya tem se tornado um importante problema de saúde pública nos países onde ocorrem as epidemias. Até 2013, as Américas haviam registrado apenas casos importados quando, em outubro desse mesmo ano, foram notificados os primeiros casos na Ilha de Saint Martin, no Caribe. No Brasil, os primeiros relatos autóctones foram confirmados em setembro de 2014 e até a semana epidemiológica 37 de 2016 já haviam sido registrados 236.287 casos prováveis de infecção pelo chikungunya vírus (CHIKV), 116.523 confirmados sorologicamente. As mudanças ambientais causadas pelo homem, o crescimento urbano desordenado e o número cada vez maior de viagens internacionais têm sido apontados como os fatores responsáveis pela reemergência de epidemias em grande escala. Caracterizada clinicamente por febre e dor articular na fase aguda, em cerca de metade dos casos existe evolução para a fase crônica (além de três meses), com dor persistente e incapacitante. O objetivo deste trabalho foi elaborar recomendações para diagnóstico e tratamento da febre chikungunya no Brasil. Para isso, foi feita revisão da literatura nas bases de dados Medline, SciELO e PubMed, para dar apoio às decisões tomadas para definir as recomendações. Para a definição do grau de concordância foi feita uma metodologia Delphi, em duas reuniões presenciais e várias rodadas de votação on line. Foram geradas 25 recomendações, divididas em três grupos temáticos: (1) diagnóstico clínico, laboratorial e por imagem; (2) situações especiais e (3) tratamento. Na primeira parte estão os dois primeiros temas e o tratamento na segunda.

Chikungunya fever has become an important public health problem in countries where epidemics occur because half of the cases progress to chronic, persistent and debilitating arthritis. Literature data on specific therapies at the various phases of arthropathy caused by chikungunya virus (CHIKV) infection are limited, lacking quality randomized trials assessing the efficacies of different therapies. There are a few studies on the treatment of musculoskeletal manifestations of chikungunya fever, but these studies have important methodological limitations. The data currently available preclude conclusions favorable or contrary to specific therapies, or an adequate comparison between the different drugs used. The objective of this study was to develop recommendations for the treatment of chikungunya fever in Brazil. A literature review was performed via evidence-based selection of articles in the databases Medline, SciELO, PubMed and Embase and conference proceedings abstracts, in addition to expert opinions to support decision-making in defining recommendations. The Delphi method was used to define the degrees of agreement in 2 face-to-face meetings and several online voting rounds. This study is part 2 of the Recommendations of the Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia - SBR) for the Diagnosis and Treatment of chikungunya fever and specifically addresses treatment. Resumo A febre chikungunya tem se tornado um importante problema de saúde pública nos países onde ocorrem as epidemias, visto que metade dos casos evolui com artrite crônica, persistente e incapacitante. Os dados na literatura sobre terapêuticas específicas nas diversas fases da artropatia ocasionada pela infecção pelo vírus chikungunya (CHIKV) são limitados, não existem estudos randomizados de qualidade que avaliem a eficácia das diferentes terapias. Há algumas poucas publicações sobre o tratamento das manifestações musculoesqueléticas da febre chikungunya, porém com importantes limitações metodológicas. Os dados atualmente disponíveis não permitem conclusões favoráveis ou contrárias a terapêuticas específicas, bem como uma adequada avaliação quanto à superioridade entre as diferentes medicações empregadas. O objetivo deste trabalho foi elaborar recomendações para o tratamento da febre chikungunya no Brasil. Foi feita uma revisão da literatura com seleção de artigos baseados em evidência, nas bases de dados Medline, SciELO, PubMed e Embase e de resumos de anais de congressos, além da opinião dos especialistas para dar apoio às decisões tomadas para definir as recomendações. Para a definição do grau de concordância foi feita uma metodologia Delphi, em duas reuniões presenciais e várias rodadas de votação on line. Este artigo refere-se à parte 2 das Recomendações da Sociedade Brasileira de Reumatologia para Diagnóstico e Tratamento da Febre Chikungunya, que trata especificamente do tratamento.

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.

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.

A major cause of morbidity and mortality in the context of the antiphospholipid syndrome (APS) is the occurrence of thrombotic events. Besides the pathogenic roles of antiphospholipid antibodies (aPL), other risk factors and medical conditions, which are conditions for traditional risk of an individual without the APS, can coexist in this patient, raising their risk of developing thrombosis. Therefore, the clinical and laboratory investigation of comorbidities known to increase cardiovascular risk in patients with antiphospholipid antibody syndrome is crucial for the adoption of a more complete and effective treatment. Experimental models and clinical studies show evidence of association between APS and premature formation of atherosclerotic plaques. Atherosclerosis has major traditional risk factors: hypertension, diabetes mellitus, obesity, dyslipidemia, smoking, and sedentary lifestyle that may be implicated in vascular involvement in patients with APS. The influence of nontraditional risk factors as hyperhomocysteinemia, increased lipoprotein a, and anti-oxLDL in the development of thromboembolic events in APS patients has been studied in scientific literature. Metabolic syndrome with all its components also has been recently studied in antiphospholipid syndrome and is associated with arterial events.

Ocular inflammatory diseases can present as isolated conditions but also as part of systemic inflammatory diseases. Anterior uveitis is closely related to SpA and shares the common genetic background of HLA-B27. Other ocular manifestations, such as episcleritis and scleritis, may also occur, although less frequently. Therefore, ocular involvement has been included as one of the important clinical features of SpA in the recently published classification criteria for axial and peripheral disease. However, there are a wide variety of aetiologies for ocular diseases and this must be considered in assessment of SpA.

Biologics are increasingly being used to modify the course of immune-mediated inflammatory diseases. Some main agents are monoclonal antibodies and a fusion-protein that target TNF. This group includes adalimumab, infliximab, certolizumab pegol, golimumab and etanercept. Although the efficacy of anti-TNFs is supported by numerous randomized clinical trials, their pharmacokinetics depend on many factors, in particular immunogenicity, which can cause marked and rapid clearance and a consequent decrease in efficacy. Kinetics involve receptors that recognize the Fc fragment of the antibody and are responsible for various processes. Pharmacological advances permit optimizing the pharmacokinetics of anti-TNFs. In this review, we examine the kinetics of anti-TNF biologics, and consequent therapeutic implications, and overview some latest developments in the field. First draftsubmitted: 17 May 2016; Accepted for publication: 15 September2016; Published online: 14 October 2016

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.

The multiple autoimmune syndromes (MAS) consist on the presence of three or more well-defined autoimmune diseases (ADs) in a single patient. The aim of this study was to analyze the clinical and genetic characteristics of a large series of patients with MAS. A cluster analysis and familial aggregation analysis of ADs was performed in 84 patients. A genome-wide microsatellite screen was performed in MAS families, and associated loci were investigated through the pedigree disequilibrium test. Systemic lupus erythematosus (SLE), autoimmune thyroid disease (AITD), and Sjögren's syndrome together were the most frequent ADs encountered. Three main clusters were established. Aggregation for type 1 diabetes, AITD, SLE, and all ADs as a trait was found. Eight loci associated with MAS were observed harboring autoimmunity genes. The MAS represent the best example of polyautoimmunity as well as the effect of a single genotype on diverse phenotypes. Its study provides important clues to elucidate the common mechanisms of ADs (i.e., autoimmune tautology).

Recurrent early miscarriages (excluding chromosomal anomalies), late fetal loss, and maternal thrombosis are characteristic of obstetric antiphospholipid syndrome (APS). Obstetric complications such as preeclampsia, fetal growth restriction, premature delivery, and fetal death also occur in higher frequency in APS patients than in the general population. A high-risk obstetric center is needed for proper evaluation of and intervention with pregnant women with APS. Association with lupus carries additional risk of thrombosis when antiphospholipid antibodies (aPLs) are present. Gestational results with live births are improved to about 80% when antithrombotic therapy is used, but failure in 20% to 30% of the cases despite correct treatment with low-dose aspirin with or without heparin reveals new pathways for pregnancy loss in APS and unmet needs. At the moment, there is no recommendation to investigate patients with infertility for the presence of aPLs.

The Antiphospholipid Syndrome (APS) Clinical Research Task Force (CRTF) was one of six Task Forces developed by the 13th International Congress on Antiphospholipid Antibodies (aPL) organization committee with the purpose of: a) evaluating the limitations of APS clinical research and developing guidelines for researchers to help improve the quality of APS research; and b) prioritizing the ideas for a well-designed multicenter clinical trial and discussing the pragmatics of getting such a trial done. Following a systematic working algorithm, the Task Force identified five major issues that impede APS clinical research and the ability to develop evidence-based recommendations for the management of aPL-positive patients: (1) aPL detection has been based on partially or non-standardized tests, and clinical (and basic) APS research studies have included patients with heterogeneous aPL profiles with different clinical event risks; (2) clinical (and basic) APS research studies have included a heterogeneous group of patients with different aPL-related manifestations (some controversial); (3) thrombosis and/or pregnancy risk stratification and quantification are rarely incorporated in APS clinical research; (4) most APS clinical studies include patients with single positive aPL results and/or low-titer aPL ELISA results; furthermore, study designs are mostly retrospective and not population based, with limited number of prospective and/or controlled population studies; and (5) lack of the understanding the particular mechanisms of aPL-mediated clinical events limits the optimal clinical study design. The Task Force recommended that there is an urgent need for a truly international collaborative approach to design and conduct well-designed prospective large-scale multi-center clinical trials of patients with persistent and clinically significant aPL profiles. An international collaborative meeting to formulate a good research question using ‘FINER’ (Feasible; Interesting; Novel; Ethical; and Relevant) criteria took place in November 2010.

Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus.Patients (aged ≥18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction ≥4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [0·3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476.867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1·55 [95% CI 1·10-2·19]; p=0·0129) and 10 mg/kg (167 [58%], 1·83 [1·30-2·59]; p=0·0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1·51 [1·07-2·14]; p=0·0189) and 10 mg/kg (169 [58%], 1·71 [1·21-2·41]; p=0·0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1·38 [0·93-2·04]; p=0·1064) and 10 mg/kg (236 [81%], 1·62 [1·09-2·42]; p=0·0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1·68 [1·15-2·47]; p=0·0078) and 10 mg/kg (231 [80%], 1·74 [1·18-2·55]; p=0·0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (1%), two (1%), and no patients, respectively. No malignant diseases were reported.Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease.Human Genome Sciences and GlaxoSmithKline.

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. Lupus (2014) 23, 1292–1294.

A consensus meeting of representatives of 18 Latin-American and Caribbean countries gathered in Reñaca, Chile, for 2 days to identify problems and provide recommendations for the care of patients with rheumatoid arthritis (RA) in Latin America, a region where poverty and other health priorities make the efforts to provide effective and high quality care difficult. This report includes recommendations for health professionals, patients, and health authorities in Latin America, with an emphasis on education and therapeutic issues.Fifty-one rheumatologists (list available only online on the JCR website) from 18 Latin-American and Caribbean countries with a special interest in RA participated in the consensus meeting. Participants were experts identified and appointed by the National Societies of Rheumatology affiliated with the Pan-American League of Associations for Rheumatology (PANLAR) and by the Grupo Latino Americano De Estudio de Artritis Reumatoide (GLADAR)-an independent group of Latin American rheumatologist researchers were also invited to the meeting. Eight topics were identified as priorities: patient, community and allied health professional education, health policy and decision making, programs for early detection and appropriate treatment of RA, role of classic disease modifying antirheumatic drugs (DMARDs), role of biologic therapy, and drug safety surveillance. To reach consensus, a survey with questions relevant to the topic of interest was sent to all participants before the meeting. During a 2 day meeting, the answers of the survey were reviewed and discussed by each group, with final recommendations on action items.The specific topic of the survey was answered by 86% of the participants and 68% of them answered the entire survey. It was agreed that RA and rheumatic diseases which are currently not but should be public health priorities in Latin America, because of their prevalence and impact on quality of life.Strategic areas identified as priorities for our region included: early diagnosis and access to care by multidisciplinary teams, creation of databases to identify infections with the use of biologic agents in RA which are relevant to Latin America, and overall efforts to improve the care of RA patients in accordance with international standards. Implementation of educational programs aimed to improve self-management for patients with RA was also considered crucial.

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.

In addition to the well-defined neurologic events due to arterial and venous thrombotic vascular occlusions of antiphospholipid syndrome (APS), a broad spectrum of neuropsychiatric has been related to antiphospholipid (aPL). Experimental evidence of a pathogenic role of aPL in mice with impaired neurological function disclosed inflammatory reaction as a hallmark. The process that leads to neurological dysfunction seems to be both structurally destructive and functionally impairing. The most modern resources of neuroimmaging also suggest that, in addition to the micro-infarcts that occur in strategic areas, other metabolic impairments are related to progressive dementia and aPL presence. Although there is a lot of confusion among APS and lupus' cognitive involvement, there is a body of experimental and clinical evidence that aPL causes this kind of damage.

There is a high incidence of thrombosis in cancer patients. Retrospective studies indicate that lupus anticoagulant (LA) antibodies can be a thrombosis risk factor in cancer. In 77 patients with different forms of cancer LA and thrombosis incidence were retrospectively evaluated. In a prospective study, with 42 lung adenocarcinoma patients, we measured plasma LA, fibrinogen, factor VIII (FVIII), and thrombosis incidence. A high frequency of LA and thrombosis were observed in both studies. In isolation LA, increased levels of FVIII and fibrinogen could not be considered good markers for the development of thrombosis.