Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007–12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.

ObjectiveTo update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN).MethodsFollowing 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.ResultsThe 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 <0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or 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.ConclusionsWe have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

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.

Systemic lupus erythematosus (SLE) is a multiorgan disease with protean manifestations. Because SLE is uncommon and heterogeneous, its diagnosis can pose a considerable challenge, especially for clinicians with limited expertise of the disease. This is particularly true at the early stages of SLE, when an inadequate number of features to secure the diagnosis might be present, and for patients presenting with uncommon features, which can nonetheless be severe and require prompt treatment. Furthermore, the suboptimal performance of immunological testing in patients referred for possible SLE has been highlighted. As a result, SLE remains largely a clinical diagnosis that is made after excluding alternative diagnoses. Diagnostic criteria can expedite diagnosis and treatment, but are not available for SLE. Thus, SLE classification criteria are often used, but strict adherence to these criteria could delay diagnosis. Therefore, while eagerly awaiting diagnostic criteria for this disease, we propose interim potential solutions to facilitate its diagnosis.

ObjectivesSystemic lupus erythematosus (SLE) diagnosis and treatment remain empirical and the molecular basis for its heterogeneity elusive. We explored the genomic basis for disease susceptibility and severity.MethodsmRNA sequencing and genotyping in blood from 142 patients with SLE and 58 healthy volunteers. Abundances of cell types were assessed by CIBERSORT and cell-specific effects by interaction terms in linear models. Differentially expressed genes (DEGs) were used to train classifiers (linear discriminant analysis) of SLE versus healthy individuals in 80% of the dataset and were validated in the remaining 20% running 1000 iterations. Transcriptome/genotypes were integrated by expression-quantitative trail loci (eQTL) analysis; tissue-specific genetic causality was assessed by regulatory trait concordance (RTC).ResultsSLE has a ‘susceptibility signature’ present in patients in clinical remission, an ‘activity signature’ linked to genes that regulate immune cell metabolism, protein synthesis and proliferation, and a ‘severity signature’ best illustrated in active nephritis, enriched in druggable granulocyte and plasmablast/plasma–cell pathways. Patients with SLE have also perturbed mRNA splicing enriched in immune system and interferon signalling genes. A novel transcriptome index distinguished active versus inactive disease—but not low disease activity—and correlated with disease severity. DEGs discriminate SLE versus healthy individuals with median sensitivity 86% and specificity 92% suggesting a potential use in diagnostics. Combined eQTL analysis from the Genotype Tissue Expression (GTEx) project and SLE-associated genetic polymorphisms demonstrates that susceptibility variants may regulate gene expression in the blood but also in other tissues.ConclusionSpecific gene networks confer susceptibility to SLE, activity and severity, and may facilitate personalised care.

Background:Lupus nephritis (LN) affects ~ 40% of patients with systemic lupus erythematosus (SLE) and is associated with significant morbidity. New data has emerged since the publication of the EULAR/ERA-EDTA recommendations for the management of LN, involving a multidisciplinary panel of experts.Objectives:To analyze the current evidence, in order to inform the 2019 update of the EULAR/ERA-EDTA recommendations for the management of LN.Methods:According to the EULAR standardised operating procedures, a Medline systematic literature review (SLR) was performed, from January 2012 until 31 December 2018. The final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including the LoE of the 2012 recommendations.Results:We identified 542 relevant articles. High-quality evidence supports the use of immunosuppressive treatment for class III and IV LN (LoE 1a) there is moderate quality evidence for immunosuppression in pure class V LN, with nephrotic-range proteinuria (LoE 2b). Treatment should aim for a 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (< 500-700 mg/day) at 12 months (LoE 2a-2b). Strong evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) for the initial treatment of class III/IV LN (LoE 1a,Table); Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a,Table). There is little evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease due to LN, all methods of kidney replacement treatment have been used, but transplantation is accompanied by the most favourable outcomes (LoE 2b).Table.Randomized trials for induction therapy in LNConclusion:There is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment. There is low quality evidence to guide treatment of class V, monitoring and optimal duration of immunosuppression.Disclosure of Interests: :Antonis Fanouriakis Paid instructor for: Paid instructor for Enorasis, Amgen, Speakers bureau: Paid speaker for Roche, Genesis Pharma, Mylan, Myrto Kostopoulou: None declared, Kim Cheema: None declared, George Bertsias Grant/research support from: GSK, Consultant of: Novartis, David Jayne Grant/research support from: ChemoCentryx, GSK, Roche/Genentech, Sanofi-Genzyme, Consultant of: Astra-Zeneca, ChemoCentryx, GSK, InflaRx, Takeda, Insmed, Chugai, Boehringer-Ingelheim, Dimitrios Boumpas: None declared

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.

By the use of a comprehensive methodology, we describe the full spectrum of SLE from the community to tertiary care, with almost half of the cases having mild disease, yet with significant damage accrual. SLE is not rare, affects predominantly middle-aged women and is increasingly recognised in men. Neuropsychiatric disease is an emerging frontier in lupus prevention and care.