Airway autoantibodies are determinants of asthma severity.

BACKGROUND: Local airway autoimmune responses may contribute to steroid dependence and persistent eosinophilia in severe asthma. Auto-IgG antibodies directed against granule proteins such as eosinophil peroxidase (EPX), macrophage scavenger receptor with collagenous structure (MARCO) and nuclear/extranuclear antigens (antinuclear antibodies (ANAs)) have been reported. Our objective was to describe the prevalence and clinical characteristics of asthmatic patients with airway autoreactivity, and to assess if this could be predicted from clinical history of autoreactivity. METHODS: We analysed anti-EPX, anti-MARCO and ANAs in 218 sputum samples collected prospectively from 148 asthmatic patients, and evaluated their association with lung function parameters, blood/airway inflammation, severity indices and exacerbations. Additionally, 107 of these patients consented to fill out an autoimmune checklist to determine personal/family history of systemic autoimmune disease and symptoms. RESULTS: Out of the 148 patients, 59 (40%) were anti-EPX IgG+, 53 (36%) were anti-MARCO IgG+ and 64 out of 129 (50%) had ≥2 nuclear/extranuclear autoreactivities. A composite airway autoreactivity score (CAAS) demonstrated that 82 patients (55%) had ≥2 airway autoreactivities (considered as CAAS+). Increased airway eosinophil degranulation (OR 15.1, 95% CI 1.1-199.4), increased blood leukocytes (OR 3.5, 95% CI 1.3-10.1) and reduced blood lymphocytes (OR 0.19, 95% CI 0.04-0.84) predicted CAAS+. A third of CAAS+ patients reported an exacerbation, associated with increased anti-EPX and/or anti-MARCO IgG (p<0.05). While no association was found between family history or personal diagnosis of autoimmune disease, 30% of CAAS+ asthmatic patients reported sicca symptoms (p=0.02). Current anti-inflammatory (inhaled/oral corticosteroids and/or adjunct anti-interleukin-5 biologics) treatment does not attenuate airway autoantibodies, irrespective of eosinophil suppression. CONCLUSION: We report 55% of moderate-severe asthmatic patients to have airway autoreactivity that persists despite anti-inflammatory treatment and is associated with exacerbations.

Response to placebo in non-renal, non-neuropsychiatric systemic lupus erythematosus: a systematic review and pooled analysis.

OBJECTIVES: Most randomized controlled trials (RCTs) in SLE have failed to reach their respective end points, with the rates of response to placebo (plus standard-of-care treatment) being unexpectedly high. The aim of this systematic review was to quantify the response to placebo in non-renal, non-neuropsychiatric lupus. METHODS: The PubMed database was searched (from 2000 to December 2019) for phase II/III RCTs assessing the efficacy and safety of biologics in non-renal, non-neuropsychiatric SLE. Data on the efficacy and safety of the placebo-treated patients were collected in a pre-established data retrieval form. Descriptive statistics were used. RESULTS: A total of 24 RCTs (n = 11128 in total) were included. Placebo-treated patients (n = 3899) were mostly females (93.5%), Caucasians (60.2%), of mean age 39.7 years, and having a mean disease duration of 7.4 years. Their mean initial SLEDAI 2000 was 10.4, whereas 60.5% had positive anti-dsDNA antibodies, 41.9% low C3 and 35.6% low C4 at randomization. Standard-of-care treatment included glucocorticosteroids in 85.9%, antimalarials in 72.8% and immunosuppressives in 48.5%. The response to placebo was 36.2% for the primary end point (as defined in each study), 39.8% for the SLE Responder Index-4 (SRI-4), 29.2% for SRI-5, 28.4% for SRI-6 and 30.9% for BILAG-based Combined Lupus Assessment response. Regarding safety, there were serious adverse events in 16.3% of patients, serious infections in 5.5% and malignancies in 0.3%, and death occurred in 0.56% of patients. CONCLUSION: More than one-third of the placebo-treated patients achieved their respective primary end points in RCTs with biologics in non-renal, non-neuropsychiatric SLE. The response rate was higher for certain end points, such as the SRI-4, while it decreased with more stringent end points.

Impact of the new American College of Cardiology/American Heart Association definition of hypertension on atherosclerotic vascular events in systemic lupus erythematosus.

BACKGROUND: The 2017 American College of Cardiology/American Heart Association guidelines defined hypertension at ≥130/80 mm Hg. Studies on patients with connective tissue diseases were not considered. Our aim was to assess the impact of this definition on atherosclerotic vascular events (AVEs) in systemic lupus erythematosus. PATIENTS METHODS: Individuals from the Toronto Lupus Clinic with at least 2 years of follow-up and no prior AVE were divided in three groups according to their mean blood pressure (BP) over that period (≥140/90 mm Hg, 130-139/80-89 mm Hg and <130/80 mm Hg). They were followed until the first occurrence of an AVE (fatal or non-fatal coronary artery disease, cerebrovascular event and peripheral vascular disease) or last visit. Groups were compared as per the baseline atherosclerotic risk factors. A multivariable time-dependent analysis was performed to adjust for the presence of other risk factors. RESULTS: Of 1532 patients satisfying the inclusion criteria, 155 (10.1%) had a BP ≥140/90 mm Hg, 316 (20.6%) 130-139/80-89 mm Hg and 1061 (69.3%) were normotensives. After a mean follow-up of 10.8 years, 124 AVEs were documented. The incidence rates were 18.9, 11.5 and 4.5 per 1000 patient-years for the three groups, respectively (p=0.0007 between the 130-139/80-89 mm Hg group and the normotensives). A mean BP of 130-139/80-89 mm Hg over the first 2 years was independently associated with the occurrence of AVEs (HR 1.73, 95% CI 1.13 to 2.65, p=0.011). CONCLUSION: Patients with lupus with a sustained mean BP of 130-139/80-89 mm Hg over 2 years had a significantly higher incidence of AVEs compared with normotensive individuals. This BP level should be the target for antihypertensive therapy to minimise their cardiovascular risk.

All-cause, cause-specific and age-specific standardised mortality ratios of patients with systemic lupus erythematosus in Ontario, Canada over 43 years (1971-2013).

BACKGROUND: Survival in systemic lupus erythematosus (SLE) has improved substantially in the last 50 years. The aim of the present study was to assess the evolution of the all-cause, cause-specific and age-specific standardised mortality ratios (SMRs) of patients with lupus in Ontario, Canada. PATIENTS AND METHODS: Between 1971 and 2013, 1732 patients were followed in the Toronto Lupus Clinic. Causes of death were retrieved from death certificates, autopsy reports, hospital records or the records of the family physicians. They were categorised as atherosclerotic, infectious, malignancy, active lupus and others. For the calculation of the SMR (indirect standardisation method), data from the general population of Ontario, Canada were used (Statistics Canada). RESULTS: Two hundred and forty-nine patients (205 women) died (infections 24.5%, atherosclerosis 15.7%, active lupus 13.3%, malignancy 9.6%); mean age was 53.2±16.6 years and mean disease duration 15.2±11.7 years. The all-cause SMR was substantially decreased from the 1970s (13.5, 95% CI 8.6 to 18.5) to recent years (2.2, 95% CI 1.4 to 3.1). Similar trends were observed for atherosclerosis, infections and malignancies over time. The all-cause age-specific SMR was particularly high in younger (19-39 years old) patients (SMR=12.4, 95% CI 9.7 to 15.1) as compared with individuals older than 40 years (SMR=3.1, 95% CI 2.6 to 3.6). The cause-specific SMR was also higher in younger patients, particularly for infections and malignancies. CONCLUSIONS: The all-cause and cause-specific SMR significantly decreased over time, likely reflecting the advances in the management of SLE and certain comorbidities. The all-cause and cause-specific SMR was particularly high for younger patients (<40 years old).

Arterial stiffness and peripheral arterial disease in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is associated with increased cardiovascular risk. We aimed to evaluate arterial stiffness and the ankle brachial index (ABI), two markers of subclinical cardiovascular disease, in SLE. We studied 55 patients with SLE (12.7% males, age 53.3 ± 15.3 years) and 61 age- and gender-matched controls. Arterial stiffness was evaluated by measuring pulse wave velocity (PWV), augmentation index (AIx) and central systolic, diastolic, pulse and mean blood pressure (BP). Peripheral arterial disease was defined as ABI ≤ 0.90. Regarding markers of arterial stiffness, patients with SLE had lower PWV and AIx than controls (p < 0.01 and p < 0.05, respectively). However, after adjusting for differences in cardiovascular risk factors between patients with SLE and controls, PWV and AIx did not differ between the two groups. Central systolic, diastolic, pulse and mean BP also did not differ between the two groups. In patients with SLE, PWV correlated independently with systolic BP (B = 0.05, p < 0.001) and waist/hip ratio (B = 6.72, p < 0.05). Regarding ABI, the lowest ABI was lower in patients with SLE than in controls (p < 0.005). However, after adjusting for differences in cardiovascular risk factors between patients with SLE and controls, the lowest ABI did not differ between the two groups. The prevalence of PAD also did not differ between patients with SLE and controls (10.0 and 5.4%, respectively; p = NS). Markers of arterial stiffness and the ABI do not appear to differ between patients with SLE and age- and gender-matched controls. However, given the small sample size, larger studies are needed to clarify whether SLE promotes arterial stiffness and PAD.

T regulatory cells: a promising new target in atherosclerosis.

T regulatory cells (Tregs) comprise the cardinal mechanism of peripheral immune tolerance by modulating the function of virtually each immune cell. Given that atherosclerosis is a chronic inflammation of the arterial wall, certain components of the immune system have been proven to have a central role in its pathogenesis. Consequently, various clinical and experimental studies have been conducted to elucidate the role of Tregs in suppressing this immune-mediated inflammation. In this review, current experimental and clinical knowledge on the role of Tregs in the atherogenic process is presented after a short introduction to their generation and function. Based on these data, Treg-targeted therapeutic approaches are discussed in regard to their potential for clinical application.

CD4+CD25highFOXP3+ T regulatory cells as a biomarker of disease activity in systemic lupus erythematosus: a prospective study.

OBJECTIVES: Several studies have reported low numbers of T regulatory cells (Tregs) in active systemic lupus erythematosus (SLE). However, it is not evident if these cells may be utilised as a biomarker in assessing disease activity. METHODS: Tregs (CD4+CD25highFOXP3+) were prospectively assessed by flow cytometry in 285 separate blood samples from 100 white Caucasian SLE patients and 20 healthy controls. Patients were divided, according to disease activity (as measured by SLEDAI) into groups A (n=39, samples=94, SLEDAI=0), B (n=33, samples=92, SLEDAI=1-5), C (n=10, samples=53, SLEDAI=6-10) and D (n=18, samples=46, SLEDAI>10). Longitudinal measurements were performed in 131 cases (37 relapses, 44 remissions and 50 cases with stable disease activity) during three years. Statistics were performed by Student's t-test or one-way ANOVA; correlations with Pearson co-efficient, while p<0.05 was considered significant. RESULTS: Tregs were found significantly lower in severely active disease (group D), compared to healthy controls, inactive disease, mild and moderate disease activity (0.57±0.16% vs. 1.49±0.19%, 1.19±0.34% and 1.05±0.36%, 0.72±0.21%, p<0.05, respectively). There was a strongly inverse correlation between Tregs and SLEDAI (r=-0.644, p<0.001). Alterations in disease activity were characterised by inverse alterations in Tregs: relapse (from 1.23±0.44% to 0.64±0.19%, p<0.001, mean change 0.59±0.41%), remission (from 0.65±0.27% to 1.17±0.30%, p<0.001, mean change 0.52±0.35%). In cases with unaltered disease activity, Treg numbers remained stable (from 0.98±0.35% to 1.03±0.34%, p=0.245). Tregs were practically halved during relapse (mean reduction 42.6±22.2%), and doubled during remission (mean increment 113±120.9%). Mean change of Tregs in stable disease was significantly lower (7.3±20.6%, p<0.001). A clinically significant change in SLEDAI (sum of cases with relapse and remission, n=81) was followed by a significant (>20%) inverse change in Tregs in 71/81 cases (sensitivity 87.7%). In 50 cases of stable disease activity, Tregs were significantly changed (>20%) in 13 cases (specificity 74%). Positive predictive value (PPV) was 84.5% and negative predictive value (NPV) was 78.7%. CONCLUSIONS: CD4+CD25highFOXP3+ T regulatory cells displayed a strongly inverse correlation to disease activity in the long term. Treg alterations reflected changes in SLEDAI with high sensitivity. These cells may be a reliable biomarker for the assessment of disease activity in SLE by longitudinal measurements.

Managing Cardiovascular Risk in Systemic Lupus Erythematosus: Considerations for the Clinician.

A significant improvement in the survival of patients with systemic lupus erythematosus (SLE) over recent decades is largely attributed to the impact of disease-modifying therapies on end-organ damage. Thus, cardiovascular disease now represents the leading cause of mortality in SLE. Various disease-specific mechanisms are responsible for advanced atherosclerosis, as they lead to premature endothelial dysfunction, arterial stiffness, arterial wall thickening, and plaque formation. Consequently, in the assessment of cardiovascular risk in SLE, we must not only consider traditional risk factors (ie, age, gender, dyslipidemia) but also the additional role of non-traditional risk factors such as persistent disease activity and prolonged corticosteroid use. Cardiovascular risk assessment incorporates general cardiovascular screening, as existing risk prediction scores underestimate cardiovascular risk in this patient population. There is also an expanding role of imaging modalities in screening. Risk reduction strategies integrate unique considerations for the use of low-dose aspirin and more stringent hypertension targets. Hydroxychloroquine is the only disease-modifying therapy with known cardiovascular benefit in SLE, though this is a promising area of study.

Medium Versus High Initial Prednisone Dose for Remission Induction in Lupus Nephritis: A Propensity Score-Matched Analysis.

OBJECTIVE: The existing guidelines for lupus nephritis (LN) recommend initial prednisone doses of 0.3-1.0 mg/kg/day. However, recent studies reported noninferior outcomes with lower doses. The aim of this study was to compare the complete renal response rates in LN patients treated with prednisone ≤30 mg/day or ≥40 mg/day. METHODS: Patients with new-onset LN and standard immunosuppressive treatment were followed for at least 12 months, divided into medium (≤30 mg/day) and high prednisone groups (≥40 mg/day) and matched (propensity score) based on the baseline differences. Complete renal response was defined as proteinuria <0.5 gm/day and no worsening in renal function. Glucocorticoid-related damage was also assessed. RESULTS: High-dose prednisone patients (n = 103; mean ± SD dose 48.6 ± 12.3 mg/day) achieved better rates of complete response compared to the medium group (n = 103; mean ± SD dose 24.2 ± 4.6 mg/day) (61.8% versus 38.2%; P = 0.024) at 12 months. The difference in response rates was reproduced for several subgroups (concomitant immunosuppressive treatment, proliferative/nonproliferative LN). Complete remission rates were higher at 2 years (67.8% versus 39%; P = 0.002) and 3 years (64.9% versus 49.1%; P = 0.025) after LN diagnosis. Cumulative glucocorticoid dose was comparable at 2 and 3 years. Glucocorticoid-related damage was accelerated in both groups for the same period. CONCLUSION: Higher initial prednisone doses (median 45 mg/day) achieved significantly better rates of complete renal response at 12 months in new-onset LN. Cumulative glucocorticoid dose and damage accrual were not different at 2 and 3 years after LN. Damage was more prominent in the late phases of LN in both groups, underlining the importance of rapid tapering and the need to implement alternative strategies.

Perspective of 2D Integrated Electronic Circuits: Scientific Pipe Dream or Disruptive Technology?

Within the last decade, considerable efforts have been devoted to fabricating transistors utilizing 2D semiconductors. Also, small circuits consisting of a few transistors have been demonstrated, including inverters, ring oscillators, and static random access memory cells. However, for industrial applications, both time-zero and time-dependent variability in the performance of the transistors appear critical. While time-zero variability is primarily related to immature processing, time-dependent drifts are dominated by charge trapping at defects located at the channel/insulator interface and in the insulator itself, which can substantially degrade the stability of circuits. At the current state of the art, 2D transistors typically exhibit a few orders of magnitude higher trap densities than silicon devices, which considerably increases their time-dependent variability, resulting in stability and yield issues. Here, the stability of currently available 2D electronics is carefully evaluated using circuit simulations to determine the impact of transistor-related issues on the overall circuit performance. The results suggest that while the performance parameters of transistors based on certain material combinations are already getting close to being competitive with Si technologies, a reduction in variability and defect densities is required. Overall, the criteria for parameter variability serve as guidance for evaluating the future development of 2D technologies.

Influenza A/H1N1 septic shock in a patient with systemic lupus erythematosus. A case report.

BACKGROUND: Immunocompromised patients, such as systemic lupus erythematosus (SLE) sufferers have an increased risk of mortality, following influenza infection. In the recent pandemic, influenza A H1NI virus caused 18449 deaths, mainly because of adult respiratory distress syndrome or bacterial co-infections. CASE PRESENTATION: In this case report, an SLE patient with viral-induced septic shock, without overt pulmonary involvement, is discussed. The patient was administered oseltamivir and supportive treatment, including wide-spectrum antibiotics, vasopressors and steroids, according to the guidelines proposed for bacterial sepsis and septic shock. She finally survived and experienced a lupus flare soon after intensive care unit (ICU) discharge. CONCLUSIONS: To our knowledge, this is the first case to report severe septic shock from influenza A/H1N1 virus, without overt pulmonary involvement.

Gradual Glucocorticosteroid Withdrawal Is Safe in Clinically Quiescent Systemic Lupus Erythematosus.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) are usually treated with glucocorticosteroids even during periods of clinically quiescent disease. A recent study showed that abrupt glucocorticoid withdrawal was associated with an increased likelihood of flare in the next 12 months. The aim of the present study was to assess clinical flare rates and damage accrual in patients who tapered glucocorticosteroids gradually. METHODS: Patients from the Toronto Lupus Clinic with 2 consecutive years of clinically quiescent disease were retrieved from the database. Individuals who maintained a low prednisone dose (5 mg/day) comprised the maintenance group, whereas patients who gradually tapered prednisone within these two years comprised the withdrawal group. All individuals were followed for 2 years after prednisone discontinuation or the corresponding date for the maintenance group. Propensity score matching was implemented to adjust for certain baseline differences. Outcomes included clinical flares and damage accrual. RESULTS: Of 270 eligible patients, 204 were matched (102 in each group). Flare rate (any increase in clinical SLE Disease Activity Index 2000) was lower in the withdrawal group both at 12 (17.6% versus 29.4%; P = 0.023) and 24 months (33.3% versus 50%; P = 0.01). Moderate to severe flares (requiring systemic treatment escalation) were not different at 12 months (10.8% versus 13.7%; P = 0.467) but were less frequent at 24 months (14.7% versus 27.5%; P = 0.024). Damage accrual was less frequent in the withdrawal group (6.9% versus 17.6%; P = 0.022). No predictors for clinical flares were identified. CONCLUSION: Gradual glucocorticoid withdrawal is safe in clinically quiescent SLE and is associated with fewer clinical flares and less damage accrual at 24 months.

Factors Associated With Rapid Progression to Endstage Kidney Disease in Lupus Nephritis.

OBJECTIVE: Lupus nephritis (LN) may lead to endstage kidney disease (ESKD) in 22% of patients over a period of 15 years, with the risk being particularly higher in diffuse proliferative forms. The rate of kidney function decline varies. However, a catastrophic course leading to ESKD within a few years from onset is uncommon. The aim of the present study was to assess the factors associated with rapid progression to ESKD in patients with LN. METHODS: Patients from the Toronto Lupus Clinic with biopsy-proven LN at presentation and estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m2, who developed ESKD within 3 years were retrieved. Pathology reports were reviewed with particular emphasis on distinct histopathologic features. Demographic, clinical, laboratory, and therapeutic variables were also analyzed. RESULTS: Ten patients (1.8% of the total LN population) developed ESKD within 3 years of diagnosis. Their mean age was 34.2 ± 7.3 years, mean time to ESKD 19.2 ± 12.4 months, initial eGFR 90.2 ± 24.9 mL/min/1.73 m2, proteinuria 2.7 ± 1.04 g/24 h. The median rate of kidney function decline was > 43 mL/min/1.73 m2/year. One patient had LN class III, 5 had LN class IV, 2 had membranous LN (class V), and another 2 had mixed IV/V. Moreover, 2 patients had extensive thrombotic microangiopathy, 1 collapsing glomerulonephritis, and 1 concomitant antiglomerular basement membrane (anti-GBM) nephropathy. Four patients showed no unusual kidney pathology; all of them had severe noncompliance (discontinued all medications to follow alternative treatment). CONCLUSION: Catastrophic progression to ESKD is uncommon in LN. The major associated factors are poor compliance and distinct histopathologic features such as thrombotic microangiopathy, collapsing glomerulopathy, and concomitant anti-GBM nephropathy.

Hydroxychloroquine against COVID-19: A critical appraisal of the existing evidence.

Hydroxychloroquine (HCQ) has sparked much interest in the therapeutics of the Coronavirus Disease 2019 (COVID-19) pandemic. Its antiviral properties have been studied for years; regarding the Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2), it has been shown that HCQ may act at multiple levels. These extend from the initial attachment of the virus to the respiratory epithelium to the inhibition of its replication by the alkalinisation of the phagolysosome's microenvironment and the post-translational modification of certain viral proteins. Preliminary clinical evidence from China and France showed significant virological and clinical benefit in HCQ-treated patients, while other studies, mostly including critically ill patients, did not show favorable results. In this review, we critically appraise the existing evidence on HCQ against SARS-CoV-2 with particular emphasis on its protective and therapeutic role. Safety concerns that are relevant to the short-term HCQ use are also discussed. In the context of the rapid evolution of the COVID-19 pandemic that strains the health care systems worldwide and considering limited population-wide testing rates in most of the vulnerable countries, early empiric short-term administration of HCQ in symptomatic individuals, may be a promising, safe and low-cost strategy.

Advanced Chronic Kidney Disease in Lupus Nephritis: Is Dialysis Inevitable?

OBJECTIVE: Advanced chronic kidney disease (CKD) carries an increased risk for progression to endstage renal disease (ESRD). We aimed to determine the rate of progression and the factors that drive the decline of renal function in lupus nephritis (LN). METHODS: Patients with advanced LN-related CKD were identified from our longterm longitudinal cohort. Advanced CKD was defined as stage 3b [estimated glomerular filtration rate (eGFR) = 30-44 ml/min/1.73 m2] and stage 4 (eGFR = 15-29 ml/min/1.73 m2). All individuals were followed until progression to ESRD or the last visit and were divided into "progressors" and "non- progressors." Demographic, clinical, immunological, and therapeutic variables were compared at baseline. Multivariable Cox regression analysis (both time-dependent and independent) was performed to identify predictors for progression. RESULTS: One hundred eighteen patients (74 CKD 3b and 44 CKD 4) were included. Forty-five patients progressed (29 to ESRD and 16 from CKD 3b to CKD 4) after 6 years on average. No significant decline in the renal function was observed in 73 patients ("non-progressors") after 10 years on average. Active serology (high anti-dsDNA titers and low complements C3/C4) at the time of CKD diagnosis and any increase of the daily prednisone dose after baseline were strongly associated with progression. Treatment with renin angiotensin system (RAS) blockers was associated with less risk for progression. CONCLUSION: Dialysis is not inevitable in LN-related advanced CKD because 62% of our patients did not progress over 10 years of followup on average. Certain predictors were identified to affect progression to ESRD.

How can we define low disease activity in systemic lupus erythematosus?

BACKGROUND: In recent years, low disease activity emerged as a state that is associated with improved long-term outcomes in systemic lupus erythematosus (SLE). Our aim was to review the current concepts for low disease activity in SLE in order to serve as the basis of a future consensus for standardization. METHODS: The PubMed database was searched for relevant articles from inception up to July 2018. Medical Subject Headings (MeSH terms) included "lupus" AND "low disease activity" OR "minimal disease activity". RESULTS: Three different definitions of low disease activity in lupus have been proposed. Minimal disease activity (MDA) is defined as a clinical SLE Disease Activity Index 2000 (SLEDAI-2K)≤1 on antimalarials, immunosuppressives in standard doses and prednisone ≤5 mg/day. Low disease activity (LDA) allows for a clinical SLEDAI-2K≤2 maintained on antimalarials only. Lupus Low Disease Activity State (LLDAS) accepts a SLEDAI-2K≤4 with no activity from major organ systems, a Physician's Global Assessment of ≤1 with no new activity, prednisone dose ≤7.5 mg/day and standard doses of antimalarials, immunosuppressives and biologics. Active serology (anti-dsDNA and complement C3/C4) is not included in the MDA and LDA but counts towards disease activity in the LLDAS definition. All definitions were associated with less damage-accrual and mortality in the long-term that were comparable to those of clinical remission. CONCLUSIONS: There is solid evidence that low disease activity is associated with improved outcomes in SLE and could serve as a therapeutic target in daily practice and clinical trials. Future research should focus on advancing a consensus for the best possible definition.