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Introduction: Neuropsychiatric (NP) involvement represents an emerging frontier in systemic lupus erythematosus (SLE), posing significant challenges due to its clinical diversity and obscure pathop...

Besides treating acute flares, the management of SLE should aim at preventing organ damage accrual and drug-associated harms, improving health-related quality of life and prolonging survival. At present, therapy is based on combinations of antimalarials (mainly HCQ), considered the backbone of SLE treatment, glucocorticoids and immunosuppressive drugs. However, these regimens are not universally effective and a substantial degree of damage can be caused by exposure to glucocorticoids. In this review we provide a critical appraisal of the efficacy and safety of available treatments as well as a brief discussion of potentially novel compounds in patients with SLE. We emphasize the use of methylprednisolone pulses for moderate–severe flares, followed by low–moderate doses of oral prednisone with quick tapering to maintenance doses of ≤5 mg/day, as well as the prompt institution of immunosuppressive drugs in the setting of severe disease but also as steroid-sparing agents. Indications for the use of biologic agents, namely belimumab and rituximab, in refractory or organ-threatening disease are also presented. We conclude by proposing evidence- and experience-based treatment strategies tailored to the clinical scenario and prevailing organ involvement that can aid clinicians in managing this complex disease.

Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is—by and large—a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents—used alone, in combination or sequentially—have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use.

The global coronavirus disease 2019 (COVID-19) situation threatens not only the health of populations, but also the coherence and function of health care systems. Patients with systemic inflammatory disorders feel the overwhelming strain of COVID-19, since their disease, administered treatments, and associated comorbidities may all contribute to increased vulnerability to infection. At the same time, monitoring the activity status of rheumatic diseases and adjusting the treatments where appropriate, are important for preventing flares and other complications, which could pose additional health risks. Considering the urgent need to maintain physical distancing and self-quarantine as much as possible, we herein discuss the challenges and possible solutions pertaining to the assessment and monitoring of patients with systemic inflammatory diseases. We also discuss issues related to the prescription and supply of anti-rheumatic drugs, as well as opportunities provided by the use of technological and wireless tools. From an optimistic viewpoint, the end of this pandemic may leave us with an important legacy in utilising and implementing e-health solutions that may both improve the clinical care standards for patients with systemic inflammatory diseases and also reduce the burden placed on healthcare systems.

Objectives Although neuropsychiatric involvement in SLE (NPSLE) is one of the most complex and troubling manifestations of the disease, validated outcome instruments to be used as sensitive endpoints in controlled clinical trials are lacking. We performed a systematic literature review (SLR) to identify outcome measurement instruments and domains used to assess NPSLE. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used. Articles available in English (1967–2020), listed in PubMed, Embase, PsycINFO, Cochrane Library and the EULAR outcome measures library were screened. All domains and outcome measurement instruments were characterized according to the OMERACT Filter 2.1, considering core areas (manifestations/abnormalities, life impact, death/lifespan, societal/resource use) and contextual factors. Results Of 3392 abstracts evaluated, 83 studies were included in the SLR (15 974 patients, females 89.9%). Eligible studies included domains and instruments pertinent to all core areas defined by the OMERACT, except for ‘societal/resource use’. The most common core areas were ‘manifestations/abnormalities’, covering 10 domains pertinent to laboratory and instrumental markers, indexes and neuropsychiatric dimension (cognitive, neurologic and psychiatric field), and ‘life impact’, covering 7 domains related to physical function (from both the perspective of the patient and the physician), pain and quality of life. Conclusion Our study revealed great heterogeneity in the instruments derived from populations with NPSLE and none of these had high-quality evidence. This supports the need to develop and further validate a core domain set and outcome measurement instruments to promote clinical research in this field, enhancing comparability across studies.

Background Cognitive impairment (CI) is one of the most frequent neuropsychiatric manifestations of systemic lupus erythematosus (SLE). Given that extensive neuropsychological testing is not always feasible in routine clinical practice, brief cognitive screening tools are desirable. The aim of this study was to evaluate the Montreal Cognitive Assessment (MoCA) as a screening tool for CI in SLE. Methods Consecutive SLE patients followed at a single centre were evaluated using MoCA and an extensive neuropsychological test battery (NPT), including the Digits Forward and Digits Backwards, Rey Auditory Verbal Learning Memory Test, Trail Making Test, Stroop Colour-Word Test, Semantic and Phonetic Verbal Fluency tests and a 25-problem version of the General Adult Mental Ability test. The criterion validity of MoCA was assessed through receiver operating characteristic (ROC) analyses using three different case definitions: i) against normative population data, ii) and iii) against average performance of a comparison group of rheumatoid arthritis (RA) patients, to adjust for possible confounding effects of chronic illness and inflammatory processes on cognitive performance. The effect of patient-related (age, years of education, anxiety, depression, fatigue and pain) and disease-related (activity, damage, age at diagnosis, disease duration, use of glucocorticoid, psychotropic and pain medication) parameters on the MoCA was examined. Results A total of 71 SLE patients were evaluated. MoCA significantly correlated with all NPT scores and was affected by education level ( p < 0.001), but not by other demographic or clinical variables. The optimal cutoff for detecting CI, as defined on the basis of normative population data, was 23/30 points, demonstrating 73% sensitivity and 75% specificity. A cutoff of 22/30 points, using neuropsychological profiles of the RA group as inflammatory disease controls, exhibited higher sensitivity (100%, based on both definitions) and specificity (87% and 90%, depending on the definition). The standard cutoff of 26/30 points displayed excellent sensitivity (91–100%) with significant expenses in specificity (43–45%). Conclusion The MoCA is an easily applied tool, which appears to be reliable for identifying CI in SLE patients. The standard cutoff score (26/30) ensures excellent sensitivity while lower cutoff scores (22–23/30) may, also, provide higher specificity.

ObjectiveTo achieve consensus on a definition of remission in SLE (DORIS).BackgroundRemission is the stated goal for both patient and caregiver, but consensus on a definition of remission has been lacking. Previously, an international task force consisting of patient representatives and medical specialists published a framework for such a definition, without reaching a final recommendation.MethodsSeveral systematic literature reviews were performed and specific research questions examined in suitably chosen data sets. The findings were discussed, reformulated as recommendations and voted on.ResultsBased on data from the literature and several SLE-specific data sets, a set of recommendations was endorsed. Ultimately, the DORIS Task Force recommended a single definition of remission in SLE, based on clinical systemic lupus erythematosus disease activitiy index (SLEDAI)=0, Evaluator’s Global Assessment ConclusionThe 2021 DORIS definition of remission in SLE is recommended for use in clinical care, education, and research including clinical trials and observational studies.

Genome wide association studies (GWAS) have identified autoimmune disease-associated loci, a number of which are involved in numerous disease-associated pathways. However, much of the underlying genetic and pathophysiological mechanisms remain to be elucidated. Systemic lupus erythematosus (SLE) is a chronic, highly heterogeneous auto-immune disease, characterized by differences in autoantibody profile, serum cytokines and a multi-system involvement. This study presents the Epione application, an integrated bioinformatics web-toolkit, designed to assist medical experts and researchers in more accurately diagnosing SLE. The application aims to identify the most credible gene variants and single nucleotide polymorphisms (SNPs) associated with SLE susceptibility, by using patient's genomic data to aid the medical expert in SLE diagnosis. The application contains useful knowledge of >70,000 SLE-related publications that have been analyzed, using data mining and semantic techniques, towards extracting the SLE-related genes and the corresponding SNPs. Probable genes associated with the patient's genomic profile are visualized with several graphs, including chromosome ideograms, statistic bars and regulatory networks through data mining studies with relative publications, to obtain a representative number of the most credible candidate genes and biological pathways associated with the SLE. Furthermore, an evaluation study was performed on a patient diagnosed with SLE and is presented herein. Epione has also been expanded in family-related candidate patients to evaluate its predictive power. All the recognized gene variants that were previously considered to be associated with SLE were accurately identified in the output profile of the patient, and by comparing the results, novel findings have emerged. The Epione application may assist and facilitate in early stage diagnosis by using the patients' genomic profile to compare against the list of the most predictable candidate gene variants related to SLE. Its diagnosis-oriented output presents the user with a structured set of results on variant association, position in genome and links to specific bibliography and gene network associations. The overall aim of the present study was to provide a reliable tool for the most effective study of SLE. This novel and accessible webserver tool of SLE is available at http://geneticslab.aua.gr/epione/.

BackgroundRemission and low disease activity (LDA) have been proposed as the treatment goals for patients with systemic lupus erythematosus (SLE). Several definitions for each have been proposed in the literature.ObjectiveTo assess the impact of remission/LDA according to various definitions on relevant outcomes in patients with SLE.MethodsThis systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses using PubMed (1946–week 2, April 2021), Cochrane library (1985–week 2, week 2, April 2021) and EMBASE (1974–week 2, April 2021). We included longitudinal and cross-sectional studies in patients with SLE reporting the impact of remission and LDA (regardless their definition) on mortality, damage accrual, flares, health-related quality of life and other outcomes (cardiovascular risk, hospitalisation and direct costs). The quality of evidence was evaluated using the Newcastle-Ottawa Scale.ResultsWe identified 7497 articles; of them, 31 studies met the inclusion criteria and were evaluated. Some articles reported a positive association with survival, although this was not confirmed in all of them. Organ damage accrual was the most frequently reported outcome, and remission and LDA were reported as protective of this outcome (risk measures varying from 0.04 to 0.95 depending on the definition). Similarly, both states were associated with a lower probability of SLE flares, hospitalisations and a better health-related quality of life, in particular the physical domain.ConclusionRemission and LDA are associated with improvement in multiple outcomes in patients with SLE, thus reinforcing their relevance in clinical practice.PROSPERO registration numberCRD42020162724.

We thank Zhou et al for their interest in our manuscript and their insightful comments.1 In figure 4 of our manuscript (Diagnostic approach to a patient with suspected systemic lupus erythematosus and the use of classification criteria to aid clinical diagnosis), we propose an algorithm to aid clinical diagnosis, especially in patients not fulfilling the classification criteria.2 As opposed to classification, diagnosis by definition may include the notion of probability (ie, possible systemic lupus erythematosus (SLE)). Moreover, as …

ObjectivesClassification criteria are biased towards classifying long-standing disease. We compared the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR)-2019, Systemic Lupus International Collaborating Clinics (SLICC)-2012 and ACR-1997 criteria in an early (median 48 months) systemic lupus erythematosus (SLE) cohort.MethodsPatients diagnosed with SLE (n=690) or control diseases (n=401). Sensitivity, specificity of the criteria and time-to-classification were calculated. Modified classification algorithms were derived from a random 80% and validated in the remaining 20% of the dataset running multiple iterations.ResultsAt last assessment, sensitivities of ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria were 85.7%, 91.3% and 88.6%, with specificities 93.0%, 93.8% and 97.3%, respectively. Both SLICC and EULAR/ACR enabled earlier classification. Only 76.7% of patients with SLE met all three criteria suggesting non-overlapping groups. Notably, unclassified patients had high prevalence of British Isles Lupus Assessment Group moderate/severe manifestations (43.3%–60%) and SLICC/ACR organ damage (30%–50%). At diagnosis, criteria missed 25.6%–30.5% of patients. Modification of EULAR/ACR and SLICC algorithms to include hypocomplementaemia and/or positive anti-phospholipid antibodies as alternative entry criterion, and/or allow classification with fewer clinical criteria from multiple organs, increased their sensitivity at diagnosis (median 82.0% and 86.2%) and overall (93.7% and 97.1%) with modest decreases in specificity. Importantly, patients who were still missed by the modified criteria had lower incidence of major organ involvement, use of immunosuppressive/biological therapies and organ damage.ConclusionsThe SLICC and EULAR/ACR are more sensitive than the ACR and the EULAR/ACR criteria have superior specificity in early SLE, although patients with significant disease can be missed. Combination and/or modification of the classification algorithms may enhance their sensitivity, allowing earlier classification and treatment of more patients with high disease burden.

Despite advancements in the care of lupus nephritis, a considerable proportion of patients may respond poorly or flare while on conventional immunosuppressive agents. Studies in murine and human lupus have illustrated a pathogenic role for several cytokines by enhancing T- and B-cell activation, autoantibodies production and affecting the function of kidney resident cells, therefore supporting their potential therapeutic targeting. To this end, there is limited post-hoc randomized evidence to suggest beneficial effect of belimumab, administered on top of standard-of-care, during maintenance therapy in lupus nephritis. Type I interferon receptor blockade has yielded promising results in preliminary SLE trials yet data on renal activity are unavailable. Conversely, targeting interleukin-6 and interferon-γ both failed to demonstrate a significant renal effect. For several other targets, preclinical data are encouraging but will require confirmation. We envision that high-throughput technologies will enable accurate patient stratification, thus offering the opportunity for personalized implementation of cytokine-targeting therapies.

The therapeutic armamentarium in Systemic Lupus Erythematosus (SLE) is expanding with the introduction of novel biologic and small-molecule agents. Complementary to randomized controlled trials, registry-based studies are advantageous due to the inclusion of a wider range of patients from daily practice and the potential for long-term monitoring of the efficacy and safety of therapies. Moreover, data from registries can be used to identify disease phenotypes that best respond to biologic agents, and to correlate clinical response with parameters such as co-administered therapies and comorbidities. In this project, we will use the configuration of the Hellenic Registry of Biologic Therapies for inflammatory arthritides in order to design a dedicated SLE module with variables pertaining to global and organ-specific disease activity, severity, flares, organ damage/outcome, comorbidities and adverse events. The second stage will involve the pilot implementation of this platform for the multicentric registration of SLE patients who are treated with belimumab. The significance lies in the development of a structured registry that enables the assessment of the disease burden and the long-term efficacy and safety of existing and future biological agents in SLE. Piloting the registry can serve as a basis for establishing nationwide collaborative efforts.

ObjectivesThe release of neutrophil extracellular traps (NETs) represents a novel neutrophil effector function in systemic lupus erythematosus (SLE) pathogenesis. However, the molecular mechanism underlying NET release and how NETs mediate end-organ injury in SLE remain elusive.MethodsNET formation and NET-related proteins were assessed in the peripheral blood and biopsies from discoid lupus and proliferative nephritis, using immunofluorescence, immunoblotting, quantitative PCR and ELISA. Autophagy was assessed by immunofluorescence and immunoblotting. The functional effects of NETs in vitro were assessed in a primary fibroblast culture.ResultsNeutrophils from patients with active SLE exhibited increased basal autophagy levels leading to enhanced NET release, which was inhibited in vitro by hydroxychloroquine. NETosis in SLE neutrophils correlated with increased expression of the stress-response protein REDD1. Endothelin-1 (ET-1) and hypoxia-inducible factor-1α (HIF-1α) were key mediators of REDD1-driven NETs as demonstrated by their inhibition with bosentan and L-ascorbic acid, respectively. SLE NETs were decorated with tissue factor (TF) and interleukin-17A (IL-17A), which promoted thrombin generation and the fibrotic potential of cultured skin fibroblasts. Notably, TF-bearing and IL-17A-bearing NETs were abundant in discoid skin lesions and in the glomerular and tubulointerstitial compartment of proliferative nephritis biopsy specimens.ConclusionsOur data suggest the involvement of REDD1/autophagy/NET axis in end-organ injury and fibrosis in SLE, a likely candidate for repositioning of existing drugs for SLE therapy. Autophagy-mediated release of TF-bearing and IL-17A-bearing NETs provides a link between thromboinflammation and fibrosis in SLE and may account for the salutary effects of hydroxychloroquine.

Systemic lupus erythematosus (SLE) is characterized by aberrant production of auto-antibodies and a sexual dimorphism both in the phenotypic expression and frequency of the disease between males and females. The striking female predominance was initially attributed primarily to sex hormones. However, recent data challenge this simplistic view and point more towards genetic and epigenetic factors accounting for this difference. More specifically, several SLE-associated single-nucleotide polymorphisms (SNPs) have been found to play an important role in the gender predilection in SLE. Their effect is mediated through their involvement in sex-hormone and immune system signalling and dysregulation of the expression of genes and miRNAs pertinent to the immune system. Additionally, the genetic factors are interchangeably associated with epigenetic modifications such as DNA methylation and histone modification, thus revealing a highly complex network of responsible mechanisms. Of importance, disturbance in the epigenetic process of X chromosome inactivation in females as well as in rare X chromosome abnormalities leads to increased expression of X-linked immune-related genes and miRNAs, which might predispose females to SLE. Microbiota dysbiosis has also been implicated in the sexual dimorphism by the production of oestrogens within the gut and the regulation of oestrogen-responsive immune-related genes. Sexual dimorphism in SLE is an area of active research, and elucidation of its molecular basis may facilitate ongoing efforts towards personalized care.

Background Low disease activity is a validated target of current systemic lupus erythematosus (SLE) therapy. The aim of this study was to assess the ability of belimumab to achieve low disease activity states in real-life settings. Methods Multicentre prospective observational study of consecutive SLE patients receiving belimumab for at least 3 months, due to active disease refractory to at least one conventional immunosuppressant. Disease activity, including the recently defined lupus low disease activity state (LLDAS) and remission (clinical SLEDAI-2K = 0), accrual of organ damage, flares and side effects were documented. Results Ninety-one patients were included [94.5% women, mean (SD) age 45.9 (12.5) years]. Most frequent manifestations were arthritis (76.7%), rash (72.5%), serologic activity (low C3/C4 and/or high anti-dsDNA; 54.9%), hair loss (47.2%) and mucosal ulcers (27.5%). Median (range) duration of treatment was 10.5 (3.0–42.1) months. Belimumab significantly decreased average SLEDAI-2K, physician global assessment (PGA) and daily prednisone dose over time, as early as 3 months after initiation, with over 20% of patients discontinuing corticosteroids. Although reduction in clinical (i.e., excluding serology) SLEDAI-2K was more pronounced in patients who were serologically active (from 8 to 1.5 at 12 months) as compared to serologically inactive (from 6 to 4) at baseline, attainment of LLDAS did not differ between the two groups and was reached by more than 40% of completer patients after 9–12 months. In addition, the number of flares and severe flares was reduced by 62% and 50%, respectively, during the first 12 months of treatment. Twenty patients (22.0%) discontinued treatment due to inadequate response and two due to side effects potentially related to the drug. Conclusions In real-life, belimumab is efficacious in achieving low disease activity in over 40% of unselected patients, in combination with reduction of corticosteroid dosage and number of flares. Both serologically active and inactive patients respond to the drug.

Background Prompt recognition of systemic lupus erythematosus (SLE) in hospitalized patients presenting with severe disease is essential to initiate treatment. We sought to characterize the phenotype of hospitalized patients with new-onset SLE and estimate potential diagnostic delays. Methods Observational study of 855 patients (“Attikon” SLE cohort). Clinical phenotype was categorized according to the leading manifestation that led to hospitalization. Disease features, time to diagnosis, classification criteria and the SLE Risk Probability Index (SLERPI) were recorded for each patient. Results 191 patients (22.3% of the total cohort) were hospitalized due to manifestations eventually attributed to SLE. Main causes of admission were neuropsychiatric syndromes (21.4%), cytopenias (17.8%), nephritis (17.2%) and thrombotic events (16.2%). Although 79.5% of patients were diagnosed within 3 months from hospitalization, in 39 patients diagnosis was delayed, particularly in those with hematological manifestations. At hospitalization, a SLERPI >7 (indicating high probability for SLE) was found in 87.4% of patients. Patients missed by the SLERPI had fever, thrombotic or neuropsychiatric manifestations not included in the algorithm. Lowering the SLERPI threshold to 5 in patients with fever or thrombotic events increased the diagnostic rate from 88.8% to 97.9% in this subgroup, while inclusion of all neuropsychiatric events yielded no additional diagnostic value. Conclusion One in five patients with new-onset SLE manifest disease presentations necessitating hospitalization. Although early diagnosis was achieved in the majority of cases, in approximately 20% diagnosis was delayed. A lower SLERPI cut-off (≥5) in patients with fever or thrombosis could enhance early diagnosis.

We would like to thank Batu et al 1 for the interest in our work and for evaluating the performance of SLE Risk Probability Index (SLERPI)2 in paediatric SLE patients. In their analysis using the simple scoring version of the index as a binary outcome, the sensitivity and specificity was 90.0% and 81.2%, respectively.1 Applying a more stringent cut-off of >8 resulted in a sensitivity of 81.2% and a specificity of 89.4%. Notably, the area under the receiver operating characteristic curve of the scoring version of SLERPI was 0.94 (95% CI 0.919 to 0.968), suggesting a …

RTX could be an effective and safe alternative treatment for refractory EF. Rituximab (RTX) is a successful therapeutic option for various autoimmune diseases. Our aim is to report our experience with RTX in eosinophilic fasciitis (EF) and review published data on its efficacy for the treatment of EF. We reviewed the medical charts of all patients with a diagnosis of EF treated with RTX from 2008 to 2020 in the Department of Rheumatology and Clinical Immunology in the University Hospital of Heraklion, Crete, Greece. We also reviewed the English literature for cases of EF treated with RTX. Demographics, clinical manifestations, laboratory findings, prior treatments, response to RTX, cumulative RTX dose, duration of treatment and follow-up are reported. We report three cases of EF refractory to conventional DMARDs (cDMARDs) that responded to RTX. Furthermore, literature review revealed five cases. In our case series in all patients, RTX was the first biologic. RTX could be effective in cases of (EF) refractory to standard immunosuppressive treatment.

Comorbidities and multimorbidity, often complicating the disease course of patients with chronic inflammatory rheumatic diseases, may be influenced by disease-intrinsic and extrinsic determinants including regional and social factors. We analyzed the frequency and co-segregation of self-reported comorbid diseases in a community-based Mediterranean registry of patients (n = 399) with systemic lupus erythematosus (SLE). Predictors for multimorbidity were identified by multivariable logistic regression, strongly-associated pairs of comorbidities by the Cramer’s V-statistic, and comorbidities clusters by hierarchical agglomerative clustering. Among the most prevalent comorbidities were thyroid (45.6%) and metabolic disorders (hypertension: 24.6%, dyslipidemia: 33.3%, obesity: 35.3%), followed by osteoporosis (22.3%), cardiovascular (20.8%), and allergic (20.6%) disorders. Mental comorbidities were also common, particularly depression (26.7%) and generalized anxiety disorder (10.7%). Notably, 51.0% of patients had ≥3 physical and 33.1% had ≥2 mental comorbidities, with a large fraction (n = 86) displaying multimorbidity from both domains. Sociodemographic (education level, marital status) and clinical (disease severity, neurological involvement) were independently associated with physical or mental comorbidity. Patients were grouped into five distinct clusters of variably prevalent comorbid diseases from different organs and domains, which correlated with SLE severity patterns. Conclusively, our results suggest a high multimorbidity burden in patients with SLE at the community, advocating for integrated care to optimize outcomes.

Background/objectives The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. Methods We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. Results Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia Conclusions Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.

BackgroundQuality of care is receiving increased attention in systemic lupus erythematosus (SLE). We developed quality indicators (QIs) for SLE based on the 2019 update of European League Against Rheumatism recommendations.MethodsA total of 44 candidate QIs corresponding to diagnosis, monitoring and treatment, were independently rated for validity and feasibility by 12 experts and analysed by a modified Research and Development Corporation/University of California Los Angeles model. Adherence to the final set of QIs and correlation with disease outcomes (flares, hospitalisations and organ damage) was tested in a cohort of 220 SLE patients with a median monitoring of 2 years (IQR 2–4).ResultsThe panel selected a total of 18 QIs as valid and feasible. On average, SLE patients received 54% (95% CI 52.3% to 56.2%) of recommended care, with adherence ranging from 44.7% (95% CI 40.8% to 48.6%) for diagnosis-related QIs to 84.3% (95% CI 80.6% to 87.5%) for treatment-related QIs. Sustained remission or low disease activity were achieved in 26.8% (95% CI 21.1% to 33.2%). Tapering of prednisone dose to less than 7.5 mg/day was achieved in 93.6% (95% CI 88.2% to 97.0%) while 73.5% (95% CI 66.6% to 79.6%) received the recommended hydroxychloroquine dose. Higher adherence to monitoring-related QIs was associated with reduced risk for a composite adverse outcome (flare, hospitalisation or damage accrual) during the last year of observation (OR 0.97 per 1% adherence rate, 95% CI 0.96 to 0.99).ConclusionWe developed QIs for assessing and improving the care of SLE patients. Initial real-life data suggest face validity, but a variable degree of adherence and a need for further improvement.

The use of alkylating agents such as cyclophosphamide, has decreased in recent years because of concerns for ovarian toxicity, and is limited to patients with severe disease or disease refractory to inhibitors of nucleotide synthesis such as mycophenolate acid or azathioprine. Because of a more favorable efficacy to toxicity ratio, mycophenolate acid is the drug of first choice in moderately severe lupus and can used both as induction and maintenance therapy. Azathioprine is predominantly used as a steroid-sparing agent and as maintenance treatment. Calcineurin inhibitors like cyclosporine A and tacrolimus are used less often- predominantly as steroid sparing agents or in patients with refractory disease-because of their metabolic and renal toxicity. Patients on cytotoxic-immunosuppressive agents have increased risk for both common and opportunistic infections.

Interleukin-33 (IL-33), a nuclear alarmin released during cell death, exerts context-specific effects on adaptive and innate immune cells eliciting potent inflammatory responses. We screened blood, skin and kidney tissues from patients with Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease driven by unabated type I interferon (IFN) production, and found increased amounts of extracellular IL-33 complexed with Neutrophil Extracellular Traps (NETs), correlating with severe, active disease. Using a combination of molecular, imaging and proteomic approaches, we show that SLE neutrophils -activated by disease immunocomplexes- release IL-33-decorated NETs that stimulate robust IFNα synthesis by plasmacytoid dendritic cells (pDCs) in an IL-33-receptor (ST2L)-dependent manner. IL33-silenced neutrophil-like cells cultured under lupus-inducing conditions generated NETs with diminished interferogenic effect. Importantly, SLE patient-derived NETs are enriched in mature bioactive isoforms of IL-33 processed by the neutrophil proteases elastase and cathepsin G. Pharmacological inhibition of these proteases neutralized IL-33-dependent IFNα production elicited by NETs. These data demonstrate a novel role for cleaved IL-33 alarmin decorating NETs in human SLE, linking neutrophil activation, type I IFN production and end-organ inflammation with skin pathology mirroring that observed in the kidneys.

Objective CNS demyelinating syndromes occurring in the context of SLE may represent a manifestation of neuropsychiatric lupus, or an overlap of SLE and multiple sclerosis (MS). We evaluated prospectively patients presenting with demyelinating syndrome for clinical and serological evidence of SLE and characterized the evolution of their clinical syndrome to a defined disease. Methods Patients with CNS demyelinating syndromes not fulfilling the criteria for MS were evaluated in a rheumatology unit for features of SLE and followed longitudinally (enrolment period 2016–20). Clinical, laboratory and neuroimaging data were recorded at every visit, following multidisciplinary evaluation. At end of follow-up, patients were assessed for their final neurological and rheumatological diagnosis, and classified accordingly. Results A total of 79 patients were included in the study [91.1% female, mean (s.d.) age at first demyelinating episode 38.4 (10.3) years, median (interquartile range) observation period 39 (57) months]. At last follow-up, 38 patients (48.1%) had evolved into MS. Of the remaining patients, 7 (17.1%) had SLE, while 34 (82.9%) had features of systemic autoimmunity without fulfilling classification criteria for SLE. The most common rheumatological features of these patients were inflammatory arthritis (73.5%), acute cutaneous lupus (47.1%) and positive ANA (72.1%). Importantly, these patients were less likely to have elevated IgG index (odds ratio 0.11, 95% CI 0.04, 0.32) and positive oligoclonal bands (odds ratio 0.21, 95% CI 0.08, 0.55). Conclusion A significant number of patients with demyelination do not fulfill criteria for either MS or SLE at follow-up. These patients exhibit lupus-like autoimmune features and may represent a distinct entity, ‘demyelination with autoimmune features’.

Funder: American College of Rheumatology Research and Education Foundation; FundRef: http://dx.doi.org/10.13039/100000960, Funder: National Institute of Arthritis and Musculoskeletal and Skin Diseases; FundRef: http://dx.doi.org/10.13039/100000069, Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. METHODS: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. RESULTS: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to

In chronic inflammatory diseases such as rheumatoid arthritis, attainment of a specific cut-off of low (or even absent) disease activity has been associated with favourable long-term disease outcomes. Systemic lupus erythematosus (SLE) is a complex, systemic disease where prognosis is determined by a variety of factors including disease activity and exposure to potentially toxic drugs particularly glucocorticoids. To this end, both increased activity (either persistent or exacerbations following a period of inactivity) and continuous intake of prednisone at doses above 5–7.5 mg/day have been correlated with accrual of irreversible dysfunction or damage in a variety of organs. Delineation of the optimal therapeutic goal in SLE is challenging, which is in part due to the inherent limitations of the available clinical instruments for monitoring the disease. Nonetheless, through an evidence- and consensus-based approach, an international expert panel has recently introduced various definitions of remission in SLE 1 namely: (a) complete remission (with normal serological markers); (b) clinical remission (irrespective of serological markers); (c) complete remission on-treatment (allowing intake of stable maintenance immunosuppressives and/or ≤5 mg/day of prednisone); and (d) clinical remission on-treatment. In the aforementioned definitions, remission is established by combination of absent disease activity (typically, SLEDAI=0 and physician-rated global disease activity [physician global assessment-PhGA] ≤0.5). In addition, an Asia-Pacific collaborative group has proposed lupus low disease activity state (LLDAS) 2 as minimally acceptable disease activity (including serological markers and allowing intake of stable maintenance immunosuppressives and/or ≤7.5 mg/day of prednisone) in patients with SLE. A SLEDAI cut-off of ≤4 with PhGA of ≤1 are included in this definition. Accordingly, a number of observational studies have shown that attainment of either remission or LLDAS is associated with improved patient outcomes such as prevention of flares and organ damage accrual.3 4 However, a number of issues pertaining to the definition of therapeutic target in SLE require clarification. First, although PhGA is useful in monitoring the disease by acting as a ‘safety net’ against the drawbacks of SLEDAI, it is still subject to inter-rater variability.5 Second, existing definitions of remission and LLDAS comprise of a combination of features such as an objective activity index, physician-rated activity and dose of glucocorticoids. The extent to which all these components are prognostically important is not clear and recent studies suggest that SLEDAI=0 alone may suffice for the definition of remission in SLE.6 Finally, it has been a matter of debate whether serology (serum C3/C4, anti-dsDNA) should be included in the definition of treatment targets (remission, LLDAS) or whether the latter should be based on the clinical parameters of SLE activity. This is due to the lack of absolute concordance between clinical and serological activity and the fact, that most patients with stable abnormal serology have favourable long-term prognosis. Further studies in large, well-characterised patient registries will be required to address the abovementioned issues, thus defining the optimal treatment goal in the disease. Learning Objectives Identify factors with an adverse impact on organ damage accrual in patients with SLE Demonstrate understanding of the existing definitions of remission and low disease activity state in SLE Discuss unresolved issues related to the definitions of remission and low disease activity and their implementations in clinical practice References van Vollenhoven R, Voskuyl A, Bertsias G, et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis 2017;76(3):554–61. Franklyn K, Lau CS, Navarra SV, et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis 2016;75(9):1615–21. Petri M, Magder LS. Comparison of Remission and Lupus Low Disease Activity State in Damage Prevention in a United States Systemic Lupus Erythematosus Cohort. Arthritis Rheumatol 2018;70(11):1790–95. Zen M, Iaccarino L, Gatto M, et al. Lupus low disease activity state is associated with a decrease in damage progression in Caucasian patients with SLE, but overlaps with remission. Ann Rheum Dis 2018;77(1):104–10. Chessa E, Piga M, Arnaud L. Physician global assessment in systemic lupus erythematosus: can we rely on its reliability?Ann Rheum Dis 2020 doi: 10.1136/annrheumdis-2020-217632 Saccon F, Zen M, Gatto M, et al. Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort. Ann Rheum Dis 2020 doi: 10.1136/annrheumdis-2020-217070 [published Online First: 2020/04/24].

Background The long-term outcome of rheumatoid arthritis (RA) patients who in clinical practice, exhibit persistent moderate disease activity (pMDA) despite treatment with biologics has not been adequately studied. Herein, we analyzed the 5-year outcome of the pMDA group and assessed for within-group heterogeneity. Methods We included longitudinally-monitored RA patients from the Hellenic Registry of Biologic Therapies with persistent (cumulative time ≥50% of a 5-year period) moderate (pMDA, 3.2Results We identified 295 patients with pMDA and 90 patients with pRLDA, the former group comprising of plMDA (n=133, 45%) and phMDA (n=162, 55%). pMDA was associated with worse 5-year functionality trajectory than pRLDA (+0.27 HAQ units, CI 95% +0.22 to +0.33; p0.22 (p=0.029) and lower average DAS28 during the first trimester since treatment initiation (p=0.001), independently predicted grouping into pRLDA. Conclusions In clinical practice, RA patients with pMDA while on bDMARDs have adverse long-term outcome compared to lower disease activity status, while heterogeneity exists within the pMDA group in terms of 5-year functionality and SAEs. Targeted studies to better characterize pMDA subgroups are needed, in order to assist clinicians in tailoring treatments.

Update on the diagnosis, treatment, and monitoring of lupus nephritis. The recent criteria enable the earlier classification of lupus nephritis based on kidney biopsy and compatible serology. Treatment of active nephritis includes low-dose intravenous cyclophosphamide or mycophenolate, followed by maintenance immunosuppression. Recent trials have suggested superiority of regimens combining mycophenolate with either calcineurin inhibitor or belimumab, although their long-term benefit/risk ratio has not been determined. Encouraging results with novel anti-CD20 antibodies confirm the effectiveness of B cell depletion. Achievement of low-grade proteinuria (

Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, Objective: To update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN). Methods: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. Results: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria 1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. Conclusions: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

Background and Aims Systemic Lupus Erythematosus (SLE) is a complex disease associated with non-synchronous multi-tissue dysfunction of varying severity. Involvement of major organs, such as kidneys, contributes significantly to morbidity and mortality. We sought to unravel new pathways to be used as potential biomarkers and therapeutic targets. To this end, we compared the patterns of gene transcription -as determined by the use of RNA-sequencing- across tissues between healthy and lupus-prone mice at different stages of the disease, and explored their implications for human disease and prediction of kidney involvement, in our whole blood RNA sequencing dataset comprised of 120 SLE [55 lupus nephritis (LN), 65 non-LN] patients and 58 healthy individuals (HI). Method NZB/W-F1 lupus-prone mice were sacrificed at the pre-puberty, pre-autoimmunity and nephritic stage. Age-matched C57BL/6 mice were used as controls. An “effector” tissue (spleen) and major end-organ tissues (kidneys, brain) were collected. Total RNA was isolated, and mRNA-sequencing was performed. Differential expression and time-series analyses were performed using DESeq2. Differentially expressed genes (DEGs) were hierarchically clustered and functionally interpreted using gProfiler enrichment analysis. Human orthologous genes of mouse common DEGs in each tissue and across all disease stages, were compared to human DEGs. Using machine learning techniques, human orthologs identified in the common DEGs across all stages in the kidneys of lupus-prone vs healthy mice were used to predict kidney involvement in the human dataset, which was split in training and validation sets. Results: Gene signatures: the common cross-tissue signature was identified by the comparison of DEGs between tissues of lupus-prone vs healthy mice at each stage of the disease. A total 134 genes (including C4A, LYRM7 and HDDC3) were found, suggesting their involvement in a common pathogenic mechanism across “effector” and end-organ tissues. Tissue-specific signatures showed enrichment of FCERI mediated NF-kB activation pathway in the spleen, steroid hormone biosynthesis pathway in the kidney and phosphatidylcholine metabolic process in the brain, suggesting distinct pathways implicated in end-organ injury. Comparative murine-human transcriptome analysis: 76 human orthologs (including CCL5, IFIT and HLA genes) identified in the murine spleen signature were also differentially expressed in SLE patients vs HI, suggesting their involvement in systemic autoimmunity. A total of 68 human orthologs (including FCGR2A, C1R and JAK1) identified in the mouse kidney-signature and 25 human orthologs (including APOA2) identified in the mouse brain-signature, were differentially expressed in LN patients vs HI and neuropsychiatric SLE patients vs HI, respectively. Kidney involvement prediction in human SLE: using a neural network model, 193 human orthologs predicted LN patients vs HI with high accuracy (accuracy=0.86, sensitivity=0.82, specificity=0.91 in the validation set). Using a support vector machine model, 30 human orthologs and age and gender were the best predictors of LN vs non-LN SLE patients (accuracy=0.71, sensitivity=0.73, specificity=0.69 in the validation set). Conclusion Murine RNA-sequencing uncovered both shared cross-tissue and tissue-specific gene signatures that could be potentially targeted in SLE. Murine-human comparative transcriptome analysis revealed common gene signatures suggesting that similar biological processes and pathways are disturbed across species, with murine kidney lupus signature predicting kidney involvement in human SLE. Validation in other datasets is ongoing.

We thank Drs Wu et al for their interest in our manuscript1 and the stimulating data they provide regarding the value of hydroxychloroquine (HCQ) in the prevention of chronic kidney disease (CKD) in patients with systemic lupus erythematosus (SLE).2 We agree with the authors that the evidence behind the recommendation for a 50% reduction in HCQ dose in patients with lupus nephritis (LN) and a glomerular filtration rate (GFR) less than 30% is not supported by high-level evidence (although it is known that excretion of the drug is carried out principally by direct renal clearance).3 4 Nevertheless, CKD is considered a risk factor for the most important side effect of HCQ, retinal toxicity ; …

ObjectivesTo analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations.MethodsAccording to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012.ResultsWe identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (ConclusionsThere is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression.

Background Innate immunity cells, cytokines and inflammatory pathways have been recognised as inducers and amplifiers of autoimmune responses and tissue injury in SLE. Methods Published experimental data during the last five years on the contribution of innate immunity, particularly neutrophils and type I interferon, are summarized and their clinical implications are discussed. Results Recent genome-wide expression studies have implicated neutrophils in human SLE and lupus nephritis. Through a combined transcriptomic, epigenetic, and functional analysis, distinct subtypes of these cells have been identified in patients with SLE, with low-density granulocytes exhibiting excessive death by generation of extracellular chromatin traps (NETs) that are decorated with immunostimulatory/alarmin molecules such as interleukin-33 and promote the activation of other immune cells, type I interferon (IFN) production and endothelial injury. Intracellular protein citrullination mediated by neutrophil peptidylarginine deiminases (PADs) is critical for NETs formation and accordingly, targeting PADs ameliorates lupus disease by reducing autoantibodies, type I IFN, immune cell activation, vascular dysfunction, and NET immunogenicity. Notably, activation of Toll-like receptors (TLR)-7/8 in neutrophils causes proteolytic cleavage of the N-terminal part of Fc-γ-receptors (FcgrIIA), thus abrogating their capacity to phagocytose immunocomplexes while promoting their death by NETosis. Mechanistically, recruitment of syntenin-1 by UNC93B1 has been reported to facilitate the sorting of TLR-7 into multivesicular bodies, therefore offering dynamic regulation of TLR-7 activation/signaling. Besides NETs, a number of other pathways may enhance IFN production in SLE such as apoptosis-derived membrane vesicles through activation of cGAS–STING, and photosensitivity-induced IFN-kappa released by keratinocytes. The latter is in line with clinical observations that therapeutic blockade of IFN or downstream signaling may be particularly beneficial in cutaneous manifestations of SLE. Remarkably, IFN signature is present in multiple immune cell types in SLE such as in B-cells where it causes breach of tolerance, promoting autoreactive B cell development into the autoantibody-forming cell and germinal center pathways. In T-cells, SLE patients who carry the STAT4 risk allele rs7574865[t] display augmented inflammatory responses to IL-12 and IFN-α, and vice versa, IFN-α may augment the IL-12-induced STAT4 activation, therefore highlighting a subgroup of patients who may benefit from IFNa/JAK/STATs targeting. Conclusions Culminating research further supports the critical role of neutrophils and innate immune pathways in SLE pathogenesis. Elucidation of intracellular pathways pertaining to production and regulation of important mediators such as IFN may provide novel insights towards development of targeted therapies. Acknowledgements This work was supported by Special Research Account of the University of Crete (grant no. 4718).

Immune cells have unique metabolic requirements to support the energetic and biosynthetic burden during their activation. Delineation of the metabolic tuning of immune cells could lead to novel strategies in treating metabolically-demanding processes including autoimmune diseases. Among innate effectors, monocytes have a distinct role in systemic lupus erythematosus (SLE) pathogenesis. We have previously described robust type-I interferon (IFNα) signaling in patients with SLE. IFNα-stimulated monocytes from healthy individuals (IFN-Mo) develop mitochondrial hyperpolarization and increased oxidative stress resembling SLE monocytes (SLE-Mo). Here we sought to delineate the metabolic repercussion of IFNα-mediated signaling that could explain metabolic shifts pertaining to autoimmunity. To this end, we combined transcriptomic data with metabolic flux analysis (Seahorse technology) and Gas Chromatography (GC-MS) in healthy monocytes, IFN-Mo and SLE-Mo. Our preliminary results indicate an increased, glucose-dose dependent glycolytic flux in IFNα-treated healthy monocytes recapitulating the SLE-Mo phenotype. Blockade of hexokinase 2 (HK-2)-dependent glycolysis with the use of 2-DG inhibitor attenuated proinflammatory cytokine secretion and the expression of surface markers characteristic of activated monocytes, supporting the deregulated metabolic profile in SLE autoimmunity. Combination of these data with targeted metabolomics (LC-MS) analyses and the application of pathway-specific inhibitors are implemented in vitro to reverse the inflammatory state of SLE monocytes. Together, our data are expected to yield unique insights into the role of immunometabolism in SLE and the potential use of metabolites as novel therapeutic targets in autoimmunity.

Background Supported by both the ACR and EULAR, the EULAR/ACR 2019 Classification Criteria for SLE employ positive ANA (ever) as an entry criterion and use a weighted scheme with values ranging from 2 to 10, for a classification cut-off of 10. Criteria items are attributed to SLE only if there is no more likely alternative diagnosis in the individual patients. Items are organized in domains, and only the highest ranking item within a domain is counted. These criteria have been validated in a cohort of 696 SLE patients and 574 non-SLE patients from a total of 21 centers, reaching an overall sensitivity of 96.1% and a specificity of 93.4%. To at least estimate the performance in groups underrepresented in the validation cohort of this transatlantic project, we analyzed this cohort for patient subsets with regard to sex, ethnicity, and disease duration. Methods The full EULAR/ACR 2019 classification criteria validation cohort was analyzed for female (n=1,098) and male (n=172) patients, Asian (n=118), Black (n=68), Hispanic (n=124) and White (n=941) patients, and patients with an SLE duration of less than 1 year (n=34), one to less than 3 years (n=196), 3 to less than 5 years (n=157), and 5 or more years (n=879). Sensitivity and specificity were calculated for the EULAR/ACR 2019 criteria, the SLICC 2012 criteria and the ACR 1997 criteria each. Results As shown in table 1, most of the point estimates for sensitivity and specificity in subsets lay within the 95% confidence intervals of the sensitivity and specificity of the EULAR/ACR 2019 criteria validation. In particular, sensitivity and specificity for all ethnic groups were within the confidence intervals or even higher. Formally, the sensitivity was slightly lower for male patients, corresponding to a higher specificity, but the male 95% confidence intervals (0.86–0.98 for sensitivity, 0.90–0.99 for specificity) overlapped. While sensitivity appeared independent of disease duration from year 1 on, sensitivity was only 89% in the first year of disease, identical to the SLICC criteria (89%) and numerically higher than the ACR criteria (56%), but all confidence intervals overlapped. Conclusion While not all subgroups of SLE patients in the validation cohort are of adequate size to fully explore the sensitivity and specificity of the EULAR/ACR 2019 SLE classification criteria in the respective subsets, the point estimates of sensitivity and specificity suggest that the new criteria perform at least reasonably well in all ethnic groups, in men and in early disease. Nevertheless, sensitivity and specificity should be independently validated in larger groups of Asian, Black and Hispanic patients, male patients and in early disease.

Objectives Evidence on comorbidity prevalence in antiphospholipid syndrome (APS) and its difference from high comorbidity burden rheumatic diseases is limited. Herein, we compare multiple comorbidities between APS and RA. Methods A total of 326 patients from the Greek APS registry [237 women, mean age 48.7 (13.4) years, 161 primary APS (PAPS), 165 SLE-APS] were age/sex matched (1:2 ratio) with 652 patients from a Greek multicentre RA cohort of 3115 patients. Prevalence of cardiovascular (CV) risk factors, stroke, coronary artery disease (CAD), osteoporosis, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), depression and neoplasms were compared between APS and RA patients using multivariate regression analysis. Results Ηyperlipidemia and obesity (ΒΜΙ ≥ 30 kg/m2) were comparable while hypertension, smoking, stroke and CAD were more prevalent in APS compared with RA patients. Osteoporosis and depression were more frequent in APS, while DM, COPD and neoplasms did not differ between the two groups. Comparison of APS subgroups to 1:2 matched RA patients revealed that smoking and stroke were more prevalent in both PAPS and SLE-APS vs RA. Hypertension, CAD and osteoporosis were more frequent only in SLE-APS vs RA, whereas DM was less prevalent in PAPS vs RA. Hyperlipidaemia was independently associated with CV events (combined stroke and CAD) in PAPS and SLE-APS, while CS duration was associated with osteoporosis in SLE-APS. Conclusion Comorbidity burden in APS (PAPS and SLE-APS) is comparable or higher than that in RA, entailing a high level of diligence for CV risk prevention, awareness for depression and CS exposure minimization.