EULAR recommendations for the management of systemic lupus erythematosus: 2023 update.

OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.

The SLE-DAS provides an accurate and feasible flare tool in the clinical setting: a validation study.

OBJECTIVE: To assess the criterion validity of the SLE disease activity score (SLE-DAS) flare tool and compare its performance in identifying flares against other instruments. METHODS: Patients with SLE fulfilling SLE-DAS low disease activity at baseline were included from two academic lupus clinics. During follow-up, flares were identified by the senior attending clinician, applying the expert-consensus-based definition as gold-standard. The first clinical flare from flaring patients, and the first visit after baseline in patients without flares were analysed. In each no flare/flare visits, we assessed flares by SLE-DAS (score increase ≥1.72), classic-SELENA Flare Index (c-SELENA FI), revised-SELENA FI (r-SELENA FI), and SLEDAI-2K (score increase ≥4). We estimated the sensitivity, specificity, and Cohen's Kappa agreement of each flare tool against the gold-standard. RESULTS: A total of 442 patients were included and followed-up for 22.9 (14.2) months. Incidence of flares was 8.19/100 patient-years, with 69 patients experiencing flares. The SLE-DAS identified 96.6% of the expert-defined flares implying a treatment change and classified 28.0% of those as moderate/severe. Sensitivity and specificity for the gold-standard flare definition were: SLE-DAS 97.1% and 97.3%, c-SELENA FI 88.4% and 98.1%, r-SELENA FI 88.4% and 96.8%, SLEDAI-2K 56.5% and 99.2%, respectively. Kappa coefficients of these instruments were 0.902 (95% CI: 0.847, 0.957), 0.870 (95% CI: 0.805, 0.935), 0.832 (95% CI: 0.761, 0.903), and 0.663 (95% CI: 0.557, 0.769), respectively. The number of flare misclassifications was lowest with the SLE-DAS, and highest with the SLEDAI-2K. CONCLUSION: The SLE-DAS accurately identifies and categorizes flares as mild or moderate/severe. It is feasible and, thus, may help the physicians' treatment decisions in the clinical practice setting.

Risk of chronic kidney disease in 260 patients with lupus nephritis-analysis of a nationwide multicentre cohort with up to 35 years of follow-up.

OBJECTIVES: To compare proliferative (PLN) and membranous (MLN) lupus nephritis (LN) regarding clinical and laboratory presentation and long-term outcomes; To investigate predictors of progression to chronic kidney disease (CKD). METHODS: Multicentre observational study, with retrospective analysis of a prospective cohort, using data from the Rheumatic Diseases Portuguese Registry-Reuma.pt. Patients with biopsy-proven PLN, MLN and mixed LN were included. Cox regression survival analysis was used to investigate predictors of CKD. RESULTS: 260 patients were included. Median follow-up was 8 years (IQR 11; minimum 1, maximum 35 years). MLN patients presented with significantly lower serum creatinine (0.70 (IQR 0.20; minimum 0.50, maximum 1.30) mg/dl vs 0.80 (IQR 0.31; minimum 0.26, maximum 2.60) in PLN, p= 0.003). Proteinuria levels did not differ between groups (p= 0.641). Levels of complement were reduced in PLN but nearly normal in MLN patients, and there were fewer patients with positive anti-dsDNA antibodies in the MLN group (p< 0.001). One year after the beginning of treatment, 62% of the patients achieved EULAR/ERA-EDTA complete response, with further 5% achieving partial response. Patients with lower proteinuria at diagnosis were more likely to achieve a complete renal response at one year, however, proteinuria at diagnosis or at one year did not predict long term CKD. Estimated glomerular filtration rate (eGFR) ≤75 mL/min/1.73 m2 at one year was the strongest predictor of progression to CKD (HR 23 [95% CI 8-62], p< 0.001). Other possible predictors included the use of azathioprine for induction of remission, older age at diagnosis and male sex. CONCLUSION: Proteinuria levels did not predict LN histologic class in our cohort. eGFR cutoff of 75 mL/min/1.73 m2 after one year of treatment was strongly predictive of progression to CKD.

Does remission in systemic lupus erythematosus according to the 2021 DORIS definition match the treating rheumatologist's judgement?

OBJECTIVES: To assess agreement between the 2021 Definition Of Remission In SLE (DORIS) and physician-judged lupus activity. METHODS: A cross-sectional analysis was conducted of data from a Spanish prospective multicentre study of SLE patients. We applied the 2021 DORIS criteria and assessed whether remission status based on this definition agreed with remission as per physician clinical judgement and reasons for disagreement between them. RESULTS: Out of 508 patients [92% women; mean age (s.d.): 50.4 years (13.7)] studied, 267 (54.4%) met the criteria for 2021 DORIS remission. Based on physicians' judgement, 277 (55.9%) patients were classified as in remission or serologically active clinically quiescent (SACQ). The overall rate of agreement between these assessments was 81.2% (95% CI: 79.9, 82.9%) with a Cohen's kappa of 0.62 (0.55-0.69). Overall, 46 (9.1%) patients were classified as in remission/SACQ by rheumatologists but did not meet the 2021 DORIS criteria for remission. The main reasons for discrepancies were a clinical SLE Disease Activity Index (cSLEDAI) score >0 in 39 patients, a Physician Global Assessment score >0.5 in five patients, and prednisone >5 mg/day in another five patients. CONCLUSIONS: The 2021 DORIS remission is an achievable target in clinical practice. There is substantial agreement between the DORIS definition and physician-judged remission. The discordance was mainly due to physicians classifying some patients with ongoing mild disease activity as in remission. Thus, the standardized DORIS definition should be used to define the target in a treat-to-target strategy for the management of SLE.

Anti-SSA Ro52 and anti-Ro60 autoantibodies: association with clinical phenotypes.

OBJECTIVES: Anti-SSA autoantibodies can be differentiated according to their antigenic target proteins as anti-Ro60 (60 kDa) or anti-Ro52 (52 kDa). Anti-SSA(Ro60) antibodies are clearly associated with connective tissue diseases (CTD), but the clinical significance of anti-SSA(Ro52) antibodies remains unclear. The aim of the present study was to analyse the disease phenotype of patients with anti-Ro52 and/or anti-Ro60 antibodies. METHODS: A multicentre, cross-sectional study was carried out of positive anti-Ro52 and/or Ro60 antibodies patients followed at 10 Rheumatology centres from January 2018 until December 2021. Patients were categorised into 3 groups: group 1 (Ro52+/Ro60-); group 2 (Ro52-/Ro60+); group 3 (Ro52+/Ro60+). Antinuclear antibodies were evaluated by indirect immunofluorescence assay and further screened for anti-extractable nuclear antigen (ENA) antibodies. Demographicsand clinical data were compared between the 3 groups, by patients' medical chart review. Univariate analysis was performed and subsequently logistic regression was used to identify intergroup differences and calculate the odds ratio with a 95% confidence interval (95% CI). RESULTS: We included 776 patients [female: 83.1%; median age: 59 (46-71) years]. Groups 1, 2, and 3 comprised 31.1%, 32.6%, and 36.3% of the patients, respectively. Anti-Ro52 antibody alone was more frequently associated with non-rheumatic diseases, older age, and men (p<0.05). Among patients with CTD, the diagnosis of systemic lupus erythematosus is 3 and 2 times more prevalent in groups 2 and 3, respectively, than in group 1 [OR 2.8 (95% CI 1.60, 4.97), p<0.001; OR 2.2 (95% CI 1.28, 3.86), p<0.01]. In group 2, the diagnosis of undifferentiated CTD is more frequent than in the other groups. Group 1 was more frequently associated with inflammatory myositis than group 2 [OR 0.09 (95% CI 0.01, 0.33), p<0.001] or group 3 [OR 0.08 (95% CI 0.01, 0.29), p<0.001]. Group 1 was also more frequently associated with arthritis (p<0.01), interstitial lung disease (p<0.01), and myositis (p<0.01). CONCLUSIONS: Anti-Ro52+ antibody alone is frequently found in patients with non-rheumatic diseases. In addition, anti-Ro52+ antibody is also prevalent in patients with CTD and associated with clinical phenotypes that are different from anti-Ro60+ antibody.

Predictors of flare in SLE patients fulfilling lupus low disease activity state: a cohort study of 292 patients with 36-month follow-up.

OBJECTIVES: The treatment target in SLE should be maintained stable by preventing flares. The objectives were to identify predictors of flare in patients attaining lupus low disease activity state (LLDAS), and to assess whether remission with no glucocorticoids is associated with lower risk of flares. METHODS: This was a cohort study of SLE patients followed in a referral centre over 3 years. Baseline was the first visit where each patient attained LLDAS. Flares up to 36 months' follow-up were identified by three instruments: revised Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) Flare Index (r-SFI), SLEDAI-2000 (SLEDAI-2K) and SLE Disease Activity Score (SLE-DAS). Demographic, clinical and laboratory parameters at baseline were evaluated as predictors of flare, with distinct models for each flare instrument, using survival analysis with univariate followed by multivariate Cox regression. Hazard ratios (HR) were determined with 95% CI. RESULTS: A total of 292 patients fulfilling LLDAS were included. Over follow-up, 28.4%, 24.7% and 13.4% of the patients developed one or more flare, according to r-SFI, SLE-DAS and SLEDAI-2K definitions, respectively. After multivariate analysis, the predictors of SLE-DAS flares were presence of anti-U1-ribonucleoprotein (anti-U1RNP) (HR = 2.16, 95% CI 1.30, 3.59), SLE-DAS score at baseline (HR = 1.27, 95% CI 1.04, 1.54) and immunosuppressants (HR = 2.43, 95% CI 1.43, 4.09). These predictors were equally significant for r-SFI and SLEDAI-2K flares. Remitted patients with no glucocorticoids presented a lower risk of SLE-DAS flares (HR = 0.60, 95% CI 0.37, 0.98). CONCLUSION: In patients with LLDAS, anti-U1RNP, disease activity scored by SLE-DAS and SLE requiring maintenance immunosuppressants predict higher risk of flare. Remission with no glucocorticoids is associated with lower risk of flares.

Does expert opinion match the definition of lupus low disease activity state? Prospective analysis of 500 patients from a Spanish multicentre cohort.

OBJECTIVES: To apply the lupus low disease activity state (LLDAS) definition within a large cohort of patients and to assess the agreement between the LLDAS and the physician's subjective evaluation of lupus activity. METHODS: We conducted a cross-sectional analysis of a prospective multicentre study of SLE patients. We applied the LLDAS and assessed whether there was agreement with the clinical status according to the physician's opinion. RESULTS: A total of 508 patients [92% women; mean age 50.4 years (s.d. 3.7)] were recruited and 304 (62.7%) patients were in the LLDAS. According to physician assessment, 430 (86.1%) patients were classified as remission or low activity. Overall agreement between both evaluations was 71.4% (95% CI: 70.1, 70.5) with a Cohen's κ of 0.3 [interquartile range (IQR) 0.22-0.37]. Most cases (96.1%) in the LLDAS were classified as remission or low activity by the expert. Of the patients who did not fulfil the LLDAS, 126 (70.4%) were classified as having remission/low disease activity. The main reasons for these discrepancies were the presence of new manifestations compared with the previous visit and a SLEDAI 2K score >4, mainly based on serological activity. CONCLUSIONS: Almost two-thirds of SLE patients were in the LLDAS. There was a fair correlation between the LLDAS and the physician's evaluation. This agreement improves for patients fulfilling the LLDAS criteria. The discordance between both at defining lupus low activity, the demonstrated association of the LLDAS with better outcomes and the fact that the LLDAS is more stringent than the physician's opinion imply that we should use the LLDAS as a treat-to-target goal.

Definition of low disease activity state based on the SLE-DAS: derivation and validation in a multicentre real-life cohort.

OBJECTIVES: To derive and validate a definition of low disease activity (LDA) for SLE based on the SLE Disease Activity Score (SLE-DAS), in a real-life multicentre cohort of SLE patients. METHODS: Derivation was conducted using data from a monocentric cohort of SLE (Portugal), and validation was performed in a multicentre cohort (Italy, France and Spain). The Lupus Low Disease Activity State (LLDAS) was used as comparator. We applied receiver operating characteristics curve analysis against the LLDAS to determine the cut-off of SLE-DAS for LDA using bootstrap methodology. In a second step, we tested a definition of SLE-DAS LDA that included: (i) the statistically derived SLE-DAS upper threshold for LDA and (ii) prednisone dose ≤7.5 mg/day. In the multicentre validation cohort, we assessed the classification performance of this SLE-DAS LDA definition. RESULTS: We included 774 patients, 300 in the derivation and 474 in the validation cohort. In the derivation cohort, the optimal cut-off to identify patients in LLDAS was SLE-DAS ≤2.48, presenting an area under the curve of 0.965 (95% CI 0.935, 0.994). When applied to the multicentre validation cohort, the SLE-DAS LDA definition showed a sensitivity of 97.1% and a specificity of 97.7% for LLDAS and an almost perfect agreement (Cohen's Kappa = 0.933; P < 0.001). McNemar's test found no significant differences between the two definitions (P = 0.092). CONCLUSION: The SLE-DAS LDA is a validated, accurate and easy-to-use definition for classifying SLE patients in LDA state.

Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) enables accurate and user-friendly definitions of clinical remission and categories of disease activity.

OBJECTIVES: There is an unmet need for accurate and user-friendly definitions of systemic lupus erythematosus (SLE) disease activity and remission. We aimed to derive and validate the SLE Disease Activity Score (SLE-DAS) definitions for disease activity categories and clinical remission state. METHODS: Derivation was conducted at Padova Lupus Clinic (Italy). Validation was prospectively performed at Cochin Lupus Clinic (France) and by post hoc analysis of BLISS-76 trial. At each clinic, an expert classified patients in three categories: remission, mild or moderate/severe activity. The SLE-DAS cut-offs were derived using the receiver operating characteristic curve analysis in Padova cohort; its performance was assessed against expert classification in Cochin cohort and British Isles Lupus Assessment Group (BILAG) index in BLISS-76. Gold standard for clinical remission state was the fulfilment of Definition Of Remission In SLE. A Boolean and an index-based definitions of remission were sustained by chi-square automatic interaction detection algorithm. An SLE-DAS online calculator was developed and tested. RESULTS: We included 1190 patients with SLE: 221 in the derivation cohort and 969 in the validation cohorts (150 from Cochin; 819 from BLISS-76). Derived cut-offs were: remission, SLE-DAS ≤2.08; mild activity, 2.087.64. Regarding validation in Cochin cohort, sensitivity and specificity are above 90%, 82% and 95% for remission, mild and moderate/severe activity, respectively. The SLE-DAS Boolean-based and index-based remission showed sensitivity of 100% and specificity above 97%. CONCLUSION: The SLE-DAS is an accurate and easy-to-use tool for defining SLE clinical remission state and disease activity categories, validated against expert assessment and BILAG.

Early predictors of renal outcome in patients with proliferative lupus nephritis: a 36-month cohort study.

OBJECTIVES: To identify predictors of complete renal response (CRR) and renal flares in SLE patients with active proliferative LN. METHODS: This was a retrospective cohort study over 36 months including patients with biopsy-proven proliferative LN (class III/IV), from two European tertiary centres. CRR and renal flare were defined as proteinuria <0.5 g/day with normal renal function and proteinuria >1 g/day after CRR attainment, respectively. Demographic, clinical and analytic parameters were evaluated as early predictors of renal outcome, using survival analysis. Candidate variables were tested as predictors for CRR at time 0, 3 and 6 months after starting induction treatment. Potential predictors for renal flare were evaluated at time of reaching CRR. Variables with P < 0.10 on univariate analysis with log-rank tests were further tested with multivariate Cox proportional hazards regression models. RESULTS: We included 104 patients [81.7% female, mean (s.d.) age at baseline 32.0 (13.3) years]. Over follow-up, 91.7% reached CRR, within a median time of 6.0 months. Proteinuria <2 g/day at baseline [hazard ratio (HR) = 1.80, 95% CI 1.16, 2.79, P < 0.01] and 3 months (HR = 2.32, 95% CI 1.24, 4.32, P < 0.01) after starting induction therapy were independent predictors of CRR. Renal flares occurred in 18.4% of patients reaching CRR, after a mean time of 16.5 (8.6) months. Age up to 25 years at time of LN diagnosis (HR = 5.41, 95% CI 1.72, 16.97, P < 0.01) and positive anti-RNP (HR = 3.52, 95% CI 1.21, 10.20, P = 0.02) were independent predictors of renal flares. CONCLUSION: In patients with SLE and proliferative LN, factors assessed at baseline and 3 months from starting induction treatment can predict CRR and renal flares once CRR is achieved.