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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.

How do generative linguistic knowledge and knowledge of item-specific usage preferences jointly contribute to language processing? We investigated this using the test case of binomial expression ordering preferences (e.g. bread and butter vs. butter and bread), which are driven both by a) generative constraints referencing phonological, semantic, or other lexical properties of the elements in a binomial, e.g. a short-beforelong constraint; and b) item-specific experience in which an order is preferred purely because it has been experienced more often. In a forced-choice task looking at items that span the frequency continuum from very low to very high frequency, we asked how these two factors jointly determine binomial ordering preferences, and how their contributions vary based on expression frequency. We found that generative knowledge exerts a consistent role across the frequency continuum, while relative frequency plays an increasingly large role with increased expression frequency. We also found substantial reliance on item-specific knowledge at much lower frequencies than has been suggested previously. Our findings bring a quantitative perspective to the debate over the joint roles of generative and item-specific knowledge in language processing. We additionally connect our findings to models of language change, providing a test case for a unified account of how speakers use both generative and item-specific knowledge in processing to accommodate the existing structure of the language, and how these processing strategies in turn maintain the balance of generative structure versus idiosyncrasies in the language over time.

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.

During real-time language comprehension, our minds rapidly decode complex meanings from sequences of words. The difficulty of doing so is known to be related to words' contextual predictability, but what cognitive processes do these predictability effects reflect? In one view, predictability effects reflect facilitation due to anticipatory processing of words that are predictable from context. This view predicts a linear effect of predictability on processing demand. In another view, predictability effects reflect the costs of probabilistic inference over sentence interpretations. This view predicts either a logarithmic or a superlogarithmic effect of predictability on processing demand, depending on whether it assumes pressures toward a uniform distribution of information over time. The empirical record is currently mixed. Here we revisit this question at scale: we analyze six reading datasets, estimate next-word probabilities with diverse statistical language models, and model reading times using recent advances in nonlinear regression. Results support a logarithmic effect of word predictability on processing difficulty, which favors probabilistic inference as a key component of human language processing.

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as "unmet needs", such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data.

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.

ObjectiveTo generate comparative efficacy evidence of belimumab versus anifrolumab in SLE that can inform treatment practices.MethodsThe SLE Responder Index (SRI)-4 response at 52 weeks of belimumab versus anifrolumab was evaluated with an indirect treatment comparison. The evidence base consisted of randomised trials that were compiled through a systemic literature review.A feasibility assessment was performed to comprehensively compare the eligible trials and to determine the most appropriate indirect treatment comparison analysis method. A multilevel network meta-regression (ML-NMR) was implemented that adjusted for differences across trials in four baseline characteristics: SLE Disease Activity Index-2K, anti–double-stranded DNA antibody positive, low complement (C)3 and low C4. Additional analyses were conducted to explore if the results were robust to different sets of baseline characteristics included for adjustment, alternative adjustment methods and changes to the trials included in the evidence base.ResultsThe ML-NMR included eight trials: five belimumab trials (BLISS-52, BLISS-76, NEA, BLISS-SC, EMBRACE) and three anifrolumab trials (MUSE, TULIP-1, TULIP-2). Belimumab and anifrolumab were comparable in terms of SRI-4 response (OR (95% credible interval), 1.04 (0.74–1.45)), with the direction of the point estimate slightly favouring belimumab. Belimumab had a 0.58 probability of being the more effective treatment. The results were highly consistent across all analysis scenarios.ConclusionsOur results suggest that the SRI-4 response of belimumab and anifrolumab are similar at 52 weeks in the general SLE population, but the level of uncertainty around the point estimate means we cannot rule out the possibility of a clinically meaningful benefit for either treatment. It remains to be seen if specific groups of patients could derive a greater benefit from anifrolumab or from belimumab, and there is certainly an unmet need to identify robust predictors towards more personalised selection of available biological agents in SLE.

Summary Background Belimumab is approved for the treatment of active systemic lupus erythematosus (SLE). Although clinical trials showed a favourable benefit–risk profile, numerical differences in the incidence of mortality and adverse events of special interest (AESIs) have been reported. We assessed the frequency of these events in patients with SLE receiving belimumab or placebo plus standard therapy. Methods BASE was a double-blind, randomised, placebo-controlled, phase 4 trial done in 33 countries. Adults with active SLE were randomly assigned (1:1) to receive intravenous belimumab (10 mg/kg) or placebo, plus standard therapy, for 48 weeks. The primary endpoints were incidences of all-cause mortality and AESIs during the on-treatment period (first-to-last study drug dose + 28 days). Safety analyses were done in the as-treated population (patients grouped by actual treatment received >50% of the time). This study was registered with ClinicalTrials.gov ( NCT01705977 ). Findings Between Nov 27, 2012, and July 28, 2017, we randomly assigned 4018 patients. The as-treated population included 2002 patients in the belimumab group versus 2001 in the placebo group. Ten (0·50%) patients in the belimumab group died versus eight (0·40%) in the placebo group (difference 0·10%, 95% CI −0·31 to 0·51). Incidences were similar in the belimumab and placebo groups for serious infections (75 [3·75%] of 2002 vs 82 [4·10%] of 2001; difference −0·35%, 95% CI −1·55 to 0·85), opportunistic infections and other infections of interest (36 [1·80%] vs 50 [2·50%]; −0·70%, −1·60 to 0·20), non-melanoma skin cancers (4 [0·20%] vs 3 [0·15%]; 0·05%, −0·21 to 0·31) and other malignancies (5 [0·25%] vs 5 [0·25%]; 0·00%, −0·31 to 0·31). A higher proportion of patients in the belimumab group than in the placebo group had infusion and hypersensitivity reactions (8 [0·40%] vs 2 [0·10%]; 0·30%, −0·01 to 0·61), serious depression (7 [0·35%] vs 1 [0·05%]; 0·30%, 0·02 to 0·58), treatment-emergent suicidality (28 [1·42%] of 1972 patients vs 23 [1·16%] of 1986; 0·26%, −0·44 to 0·96), and sponsor-adjudicated serious suicide or self-injury (15 [0·75%] of 1972 patients vs 5 [0·25%] of 1986; post hoc difference 0·50%, 0·06 to 0·94). Interpretation In line with previously published data, incidences of all-cause mortality and AESIs were similar in patients given belimumab and placebo, except for serious infusion or hypersensitivity reactions, serious depression, treatment-emergent suicidality, and sponsor-adjudicated serious suicide or self-injury events. Funding GSK.

ObjectiveDescribe available data on birth defects and pregnancy loss in women with systemic lupus erythematosus (SLE) exposed to belimumab.MethodsData collected from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports up to 8 March 2020 were described. Belimumab exposure timing, concomitant medications and potential confounding factors were summarised descriptively.ResultsAmong 319 pregnancies with known outcomes (excluding elective terminations), 223 ended in live births from which birth defects were identified in 4/72 (5.6%) in belimumab-exposed pregnancies and 0/9 placebo-exposed pregnancies across 18 clinical trials, 10/46 (21.7%) belimumab-exposed pregnancies in the BPR prospective cohort (enrolled prior to pregnancy outcome) and 0/4 belimumab-exposed pregnancies in the BPR retrospective cohort (enrolled after pregnancy outcome), and 1/92 (1.1%) in belimumab-exposed pregnancies from postmarketing/spontaneous reports. There was no consistent pattern of birth defects across datasets. Out of pregnancies with known outcomes (excluding elective terminations), pregnancy loss occurred in 31.8% (35/110) of belimumab-exposed women and 43.8% (7/16) of placebo-exposed women in clinical trials; 4.2% (2/48) of women in the BPR prospective cohort and 50% (4/8) in the BPR retrospective cohort; and 31.4% (43/137) of belimumab-exposed women from postmarketing/spontaneous reports. All belimumab-exposed women in clinical trials and the BPR received concomitant medications and had confounding factors and/or missing data.ConclusionsObservations reported here add to limited data published on pregnancy outcomes following belimumab exposure. Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.

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.

Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as “unmet needs”, such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data.

Lupus is a complex disease that is often difficult to diagnose. Risks of diagnostic delays include non-specific signs and symptoms that mimic other diseases and a lack of diagnostic criteria and referral pathways for non-specialists. To address these issues, we convened a series of virtual meetings with members of our Addressing Lupus Pillars for Health Advancement clinical care team. Meeting participants included lupus physicians, treatment developers from biotechnology, patient advocacy group representatives from the Lupus Foundation of America and advocacy/government consultants. Causes and consequences of ambiguity in diagnosis and diagnostic delays were evaluated through historical, experiential and evidence-based accounts (survey data, literature reviews and patient testimonials). Discussions highlighted the need for a clearer understanding of the definition of lupus, the natural history of the disease and the need for advancements in biotechnology to support an accurate and timely diagnosis with the potential development of a lupus spectrum.

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.

IntroductionLupus nephritis (LN) is more prevalent in patients with SLE of Asian ethnicity than in Caucasian patients. Belimumab became available in Japan in 2017 to treat patients with SLE, including those with LN. In the BLISS-LN trial (NCT01639339), belimumab showed a favourable effect on renal outcomes when combined with standard therapy (ST) starting at the induction treatment phase for active LN, but real-world effectiveness of belimumab in LN has not been extensively studied. Here we describe the protocol for the MOONLIGHT (post-Marketed effectiveness of belimumab cOhOrt and JapaN Lupus NatIonwide ReGistry (LUNA) coHorT) study, which will use data from a Japan postmarketing surveillance study and the Lupus Registry of Nationwide Institutions (LUNA) to evaluate the real-world effectiveness of belimumab plus ST versus ST alone in patients with a history of active LN who are not in the induction phase.Methods and analysisThis multicentre, retrospective, observational study (GSK Study 214710) will enrol adults with SLE and a history of active LN, holding ≥3 years of complete follow-up data from the initiation of belimumab (no continuous treatment required). Data for patients with belimumab plus ST treatment (postmarketing registry data, belimumab cohort) will be compared with those for patients with ST only treatment (LUNA data, comparison cohort). Patients who discontinue/initiate belimumab after the start of the follow-up may be included in the comparison/belimumab cohort, respectively. The primary endpoint will be the occurrence of renal flares, for which belimumab’s effectiveness will be estimated using a marginal structural model to consider time-dependent treatment and confounding factors. Secondary endpoints will include change in corticosteroid dose, renal disease activity, extrarenal disease activity, disease severity/activity biomarkers, LN class changes, end-stage kidney disease events and hospitalisations.Ethics and disseminationThis study will be conducted according to the Declaration of Helsinki and the local ethical guidelines. Findings will be submitted to peer-reviewed journals and presented at scientific meetings.

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.