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Objective: To determine if serum interferon (IFN)-α levels at the time of a lupus nephritis (LN) flare are associated with renal outcomes., Methods: Patients with an LN flare who had a preflare estimated glomerular filtration rate (eGFR) ≥60 mL/min were included in the study. The following outcomes were ascertained: (1) Time to first and second LN flares during follow-up, (2) Time to a sustained decline in eGFR by 30% and 50%, and progression to end-stage renal disease (ESRD, <15 mL/min), and (3) Time to an adverse renal event (≥2 renal flares and/or at least a 30% sustained decline in eGFR during follow-up). Serum IFN-α was measured by Simoa., Results: 92 patients with active LN were included in the study. Elevated serum baseline levels of IFN-α predicted poor renal outcomes. Patients with higher baseline IFN-α had a greater risk of having two or more subsequent LN flares (HR: 1.31 (1.08-1.59), p=0.006), sustained 30% decline in eGFR (HR: 1.27 (1.14-1.40), p<0.001), 50% decline in eGFR (HR: 1.27 (1.12-1.33), p<0.001) and progressing to ESRD (HR: 1.29 (1.14-1.47), p<0.001). Receiver operating characteristic analysis identified an IFN-α cut-off, 0.6 pg/ml, for predicting an adverse renal event., Conclusions: Elevated serum IFN-α levels measured at the time of an LN flare are associated with poor renal outcomes, including the development of ≥2 LN flares, and a clinically meaningful decline in kidney function., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate modified versions of the Belimumab International Study in Lupus Nephritis (BLISS-LN) belimumab study primary efficacy renal response (mPERR) and complete renal response (mCRR) criteria (excluding mandatory corticosteroid tapering) as predictors of real-world, long-term renal outcomes among patients with lupus nephritis (LN)., Methods: This retrospective, observational study (GSK Study 212866) used deidentified data between 1970 and 2015 from the University of Toronto Lupus Cohort from adults diagnosed with systemic lupus erythematosus and biopsy-proven Class III±V, IV±V or V LN. At 24 months postbiopsy, patients were retrospectively indexed as responders/non-responders based on mPERR (estimated glomerular filtration rate (eGFR) ≤20% below biopsy value/≥60 mL/min/1.73 m 2 and urine protein:creatinine ratio (uPCR) ≤0.7 g/day) or mCRR (eGFR ≤10% below biopsy value/≥90 mL/min/1.73 m 2 and uPCR ≤0.5 g/day) criteria. The association between index mPERR (primary outcome) or mCRR (secondary outcome) status and long-term (up to 25 years, until censoring or death) renal survival (no progression to end-stage kidney disease (eGFR <30 mL/min/1.73 m 2 , dialysis or transplant) or death) was assessed., Results: Overall, 179 patients were included in the analysis (mPERR responders, n=128; non-mPERR responders, n=51). Most patients were female (87.2%); the mean (SD) age was 34.1 (11.3) years.Long-term renal survival was attained for 78.9% of mPERR responders and 60.8% of non-mPERR responders; achieving mPERR was associated with an increased likelihood of long-term renal survival versus not achieving mPERR (log-rank p=0.0119). Overall, 102 patients were mCRR responders, and 77 were non-mCRR responders. Long-term renal survival was attained for 80.4% of mCRR responders and 64.9% of non-mCRR responders; achieving mCRR was associated with an increased likelihood of long-term renal survival than not achieving mCRR (log-rank p=0.0259)., Conclusions: Achieving mPERR or mCRR was associated with improved long-term renal survival, highlighting that these statuses are suitable predictors of long-term renal outcomes in patients with LN., Competing Interests: Competing interests: MU has received grant/research support from GSK and consulting fees from GSK, UCB, Lilly and AstraZeneca, and has been a speaker for GSK, UCB, Lilly and AstraZeneca. ZT has received grant/research support from GSK and AZ and consulting fees from GSK, AbbVie, UCB and AstraZeneca, and has been a speaker for GSK, UCB and AstraZeneca. He has salary support from the Department of Medicine and holds the Dr MU Chair in Lupus Research at UHN. MEG, QF and RAL are employees of GSK and hold stock/shares in the company. PCJ was an employee of GSK at the time of the study and holds stock/shares in the company and is a current employee of RTI Health Solutions. KG was an employee of GSK at the time of the study and holds stocks and shares in GSK, and a current employee of AstraZeneca. JS, NA, JPDM and AM have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine if the serum levels of neutrophil extracellular trap (NET) remnants (Elastase-DNA and HMGB1-DNA complexes) at the time of a lupus nephritis (LN) flare predict renal outcomes in the following 24 months., Methods: This was a retrospective study performed in prospectively followed cohorts. The study included two cohorts: an exploratory cohort to assess the association between NET remnant levels and the presence of active LN, and a separate LN cohort to determine the utility of NET remnants to predict renal outcomes over the subsequent 24 months., Results: Ninety-two individuals were included in the exploratory cohort (49 active systemic lupus erythematosus (SLE), 23 inactive SLE and 20 healthy controls (HC)). NET remnants were significantly higher in patients with SLE patients compared with HC (p<0.0001 for both complexes) and those with active LN (36%) had significantly higher levels of NET remnants compared with active SLE without LN (Elastase-DNA: p=0.03; HMGB1-DNA: p=0.02). The LN cohort included 109 active LN patients. Patients with proliferative LN had significantly higher levels of NET remnants than non-proliferative LN (Elastase-DNA: p<0.0001; HMGB1-DNA: p=0.0003). Patients with higher baseline levels of NET remnants had higher odds of not achieving complete remission (Elastase-DNA: OR 2.34, p=0.007; HMGB1-DNA: OR 2.61, p=0.009) and of progressing to severe renal impairment (Elastase-DNA: OR 2.84, p=0.006; HMGB1-DNA: OR 2.04, p=0.02) at 24 months after the flare., Conclusions: Elastase-DNA and HMGB1-DNA complexes predict renal outcomes, suggesting they could be used to identify patients requiring more aggressive therapy at flare onset., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: SRJ reports grants from Bayer, Boehringer Ingelheim, Corbus, GSK, Roche and Merck, and personal fees from Boehringer Ingelheim and Ikaria.

Objectives: A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes., Methods: Demographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset., Results: Cluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2., Conclusion: Four discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk., Competing Interests: Competing interests: MYC has received consulting fees from Janssen, AstraZeneca, Mallinckrodt Pharmaceuticals and MitogenDx. AEC has received consulting fees, speaking fees and/or honoraria from AstraZeneca, Bristol Myers Squibb and GlaxoSmithKline (

Objective: To evaluate hydroxychloroquine (HCQ)-related retinal toxicity in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort., Methods: Data were collected at annual study visits between 1999 and 2019. We followed patients with incident SLE from first visit on HCQ (time zero) up to time of retinal toxicity (outcome), death, loss-to-follow-up or end of study. Potential retinal toxicity was identified from SLICC Damage Index scores; cases were confirmed with chart review. Using cumulative HCQ duration as the time axis, we constructed univariate Cox regression models to assess if covariates (ie, HCQ daily dose/kg, sex, race/ethnicity, age at SLE onset, education, body mass index, renal damage, chloroquine use) were associated with HCQ-related retinal toxicity., Results: We studied 1460 patients (89% female, 52% white). Retinal toxicity was confirmed in 11 patients (incidence 1.0 per 1000 person-years, 0.8% overall). Average cumulative time on HCQ in those with retinal toxicity was 7.4 (SD 3.2) years; the first case was detected 4 years after HCQ initiation. Risk of retinal toxicity was numerically higher in older patients at SLE diagnosis (univariate HR 1.05, 95% CI 1.01 to 1.09)., Conclusions: This is the first assessment of HCQ and retinal disease in incident SLE. We did not see any cases of retinopathy within the first 4 years of HCQ. Cumulative HCQ may be associated with increased risk. Ophthalmology monitoring (and formal assessment of cases of potential toxicity, by a retinal specialist) remains important, especially in patients on HCQ for 10+ years, those needing higher doses and those of older age at SLE diagnosis., Competing Interests: Competing interests: All the following relationships are outside the submitted work. AEC—consulting fees from AstraZeneca, Bristol Myers Squibb, Exagen Diagnostics and GlaxoSmithKline (GSK). CG—consulting fees from the Centers for Disease Control (CDC), Morton Grove Pharmaceutical (MGP), Sanofi and UCB. RR-G—consulting fees from GSK, Immuncor and ThermoFisher. DI—consulting fees from Amgen, Merck Serono, AstraZeneca and Eli Lilly (the honoraria are passed onto a local arthritis charity). AR—consulting fees from Lilly. PRF—participation in advisory boards from AbbVie, AstraZeneca and Lilly. MK—consulting fees from GSK. MI—consulting fees from AbbVie, UCB, Novartis, Janssen and Lilly., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objective: To determine the independent impact of different definitions of remission and low disease activity (LDA) on damage accrual., Methods: Patients with ≥2 annual assessments from a longitudinal multinational inception lupus cohort were studied. Five mutually exclusive disease activity states were defined: remission off-treatment: clinical Systemic Lupus Erythematosus Disease Activity Index (cSLEDAI)-2K=0, without prednisone or immunosuppressants; remission on-treatment: cSLEDAI-2K score=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; low disease activity Toronto cohort (LDA-TC): cSLEDAI-2K score of ≤2, without prednisone or immunosuppressants; modified lupus low disease activity (mLLDAS): Systemic Lupus Erythematosus Disease Activity Index-2K score of 4 with no activity in major organ/systems, no new disease activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants; active: all remaining visits. Only the most stringent definition was used per visit. Antimalarials were allowed in all. The proportion of time that patients were in a specific state at each visit since cohort entry was determined. Damage accrual was ascertained with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Univariable and multivariable generalised estimated equation negative binomial regression models were used. Time-dependent covariates were determined at the same annual visit as the disease activity state but the SDI at the subsequent visit., Results: There were 1652 patients, 1464 (88.6%) female, mean age at diagnosis 34.2 (SD 13.4) years and mean follow-up time of 7.7 (SD 4.8) years. Being in remission off-treatment, remission on-treatment, LDA-TC and mLLDAS (per 25% increase) were each associated with a lower probability of damage accrual (remission off-treatment: incidence rate ratio (IRR)=0.75, 95% CI 0.70 to 0.81; remission on-treatment: IRR=0.68, 95% CI 0.62 to 0.75; LDA: IRR=0.79, 95% CI 0.68 to 0.92; and mLLDAS: IRR=0.76, 95% CI 0.65 to 0.89))., Conclusions: Remission on-treatment and off-treatment, LDA-TC and mLLDAS were associated with less damage accrual, even adjusting for possible confounders and effect modifiers., Competing Interests: Competing interests: All the following relationships are outside the submitted work. MF-UG: research support from Janssen and Pfizer. CG: consulting fees from the AbbVie, Amgen, AstraZeneca, Centers for Disease Control, Morton Grove Pharmaceutical (MGP), Sanofi and UCB. AEC: consulting fees from AstraZeneca, Bristol Myers Squibb, Exagen Diagnostics and GlaxoSmithKline. DAI: consulting fees from Amgen, Merck Serono, AstraZeneca and Eli Lilly (the honoraria are passed onto a local arthritis charity). AR: consulting fees from Lilly. PRF: participation on advisory boards from AbbVie, AstraZeneca and Lilly. MAK: consulting fees from GSK. MI: consulting fees from AbbVie, UCB, Novartis, Janssen and Lilly., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: A perception derived from cross-sectional studies of small systemic lupus erythematosus (SLE) cohorts is that there is a marked discrepancy between antinuclear antibody (ANA) assays, which impacts on clinicians' approach to diagnosis and follow-up. We compared three ANA assays in a longitudinal analysis of a large international incident SLE cohort retested regularly and followed for 5 years., Methods: Demographic, clinical and serological data was from 805 SLE patients at enrolment, year 3 and 5. Two HEp-2 indirect immunofluorescence assays (IFA1, IFA2), an ANA ELISA, and SLE-related autoantibodies were performed in one laboratory. Frequencies of positivity, titres or absorbance units (AU), and IFA patterns were compared using McNemar, Wilcoxon and kappa statistics, respectively., Results: At enrolment, ANA positivity (≥1:80) was 96.1% by IFA1 (median titre 1:1280 (IQR 1:640-1:5120)), 98.3% by IFA2 (1:2560 (IQR 1:640-1:5120)) and 96.6% by ELISA (176.3 AU (IQR 106.4 AU-203.5 AU)). At least one ANA assay was positive for 99.6% of patients at enrolment. At year 5, ANA positivity by IFAs (IFA1 95.2%; IFA2 98.9%) remained high, while there was a decrease in ELISA positivity (91.3%, p<0.001). Overall, there was >91% agreement in ANA positivity at all time points and ≥71% agreement in IFA patterns between IFA1 and IFA2., Conclusion: In recent-onset SLE, three ANA assays demonstrated commutability with a high proportion of positivity and titres or AU. However, over 5 years follow-up, there was modest variation in ANA assay performance. In clinical situations where the SLE diagnosis is being considered, a negative test by either the ELISA or HEp-2 IFA may require reflex testing., Competing Interests: Competing interests: MYC has received consulting fees from Janssen and MitogenDx (less than US$10 000). AEC has received consulting fees from AstraZeneca, BristolMyersSquibb, and Glaxo Smith Kline (less than US$10 000 each). KCH has consulted for or collaborated on research projects with Janssen, Glaxo Smith Kline, Exagen Diagnostics, Eli Lilly, Merck Serono, Astra Zeneca and Neutrolis (less than US$10 000 each). CG has received consulting fees, speaking fees, and/or honoraria from AstraZeneca, Abbvie, Amgen, UCB, GlaxoSmithKline, Merck Serono and BMS (less than US$10 000 each) and grants from UCB. Grants from UCB were not to CG but to Sandwell and West Birmingham Hospitals NHS Trust. DDG received consulting fees, speaking fees, and/or honoraria from GlaxoSmithKline (less than $10 000). INB has received consulting fees, speaking fees and/or honoraria from Eli Lilly, UCB, Roche, Merck Serono, MedImmune (less than US$10 000 each) and grants from UCB, Genzyme Sanofi and GlaxoSmithKline. EMG has paid consultation with investment analysts Guidepoint Global Gerson Lerman Group.Dr. Kalunian has received grants from UCB, Human Genome Sciences/GlaxoSmithKline, Takeda, Ablynx, Bristol-Myers Squibb, Pfizer and Kyowa Hakko Kirin, and has received consulting fees from Exagen Diagnostics, Genentech, Eli Lilly, Bristol-Myers Squibb, and Anthera (less than US$10 000 each). MJF is Director of Mitogen Diagnostics Corporation (Calgary, AB Canada) and a consultant to Werfen International (Barcelona, Spain), Grifols (Barcelona, Spain), Janssen Pharmaceuticals of Johnson & Johnson and Alexion Canada (less than US$10 000 each). The remainder of the authors have no disclosures., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance., Methods: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare., Results: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts., Conclusions: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful., Competing Interests: Competing interests: All the following relationships are outside the submitted work. Dr AEC: consulting fees from AstraZeneca, Bristol Myers Squibb, Exagen Diagnostics and GlaxoSmithKline. Dr CG: consulting fees from the Centers for Disease Control (CDC), Morton Grove Pharmaceutical (MGP), Sanofi and UCB. Dr RR-G: consulting fees from GSK, Immuncor and ThermoFisher. Dr DAI: consulting fees from Amgen, Merck Serono, AstraZeneca and Eli Lilly (the honoraria are passed onto a local arthritis charity). Dr AR: consulting fees from Lilly. Dr PRF: participation on advisory boards from AbbVie, AstraZeneca and Lilly. Dr MAK: consulting fees from GSK. Dr MI: consulting fees from AbbVie, UCB, Novartis, Janssen and Lilly., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objective: Multiple guidelines recommend continuing hydroxychloroquine (HCQ) for SLE during pregnancy based on observational data. The goal of this individual patient data meta-analysis was to identify the potential benefits and harms of HCQ use within lupus pregnancies., Methods: Eligible studies included prospectively collected pregnancies in women with lupus. After a systematic literature search, seven datasets meeting inclusion criteria were obtained. Pregnancy outcomes and lupus activity were compared for pregnancies with a visit in the first trimester in women who did or did not take HCQ throughout pregnancy. Birth defects were not systematically collected. This analysis was conducted in each dataset, and results were aggregated to provide a pooled OR., Results: Seven cohorts provided 938 pregnancies in 804 women. After selecting one pregnancy per patient with a first trimester visit, 668 pregnancies were included; 63% took HCQ throughout pregnancy. Compared with pregnancies without HCQ, those with HCQ had lower odds of highly active lupus, but did not have different odds of fetal loss, preterm delivery or pre-eclampsia. Among women with low lupus activity, HCQ reduced the odds of preterm delivery., Conclusions: This large study of prospectively-collected lupus pregnancies demonstrates a decrease in lupus activity among woman who continue HCQ through pregnancy and no harm to pregnancy outcomes. Like all studies of HCQ in lupus pregnancy, this study is confounded by indication and non-adherence. As this study confirms the safety of HCQ and diminished SLE activity with use, it is consistent with current recommendations to continue HCQ throughout pregnancy., Competing Interests: Competing interests: MC: Funding: AHRQ, Arthritis Foundation; Grants: GSK; Consulting and Advisory Board: UCB. AE: Grant funding: NIH NCATS Award 1KL2TR002554. SB: Grants: NIH, US FDA, PCORI, RRF, CARRA; Consulting: UCB; Travel: FDA; Leadership: CARRA Assistant Scientific Director. DDG: Grants and/or consulting fees from AstraZeneca; Leadership: Member of the Systemic Lupus International Collaborating Clinics group; served on the Medical advisory board of the Lupus foundation of America. MAP: Grant NIH RO-1 AR069572., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence., Methods: We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966-October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with <5 years of follow-up, <50 patients, different outcomes and special populations were excluded., Results: We selected 49 articles including 16 224 patients, 14 755 (90.9%) female with a mean age and disease duration of 35.1 years and of 37.1 months. The mean follow-up time was 104.9 months. For individual damage items, the average daily GC dose was associated with the occurrence of overall cardiovascular events and with osteoporosis with fractures. A higher average cumulative dose adjusted (or not)/number of follow-up years and a higher proportion of patients on GC were associated with the occurrence of osteonecrosis., Conclusions: We confirm associations of GC use with three specific damage items. In treating patients with SLE, our aim should be to maximise the efficacy of GC and to minimise their harms., Competing Interests: Competing interests: JB and RFvV are Editors-in-Chief of Lupus Science & Medicine., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement., 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the ominosity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Systemic Lupus Erythematosus Classification Criteria by determining its predictive role for disease severity in the first 5 years following diagnosis., Methods: 867 patients with systemic lupus erythematosus (SLE) from the Toronto Lupus Clinic were included (all first 12 months after SLE diagnosis). The EULAR/ACR criteria score was calculated based on baseline information. To determine disease severity in the first 5 years after diagnosis, adjusted mean SLE Disease Activity Index 2000 (AMS), flares, remission and immunosuppressive treatment were used as outcomes. The Systemic Lupus International Collaborating Clinics (SLICC) registry comprised the validation cohort., Results: Based on receiver operating characteristic analysis, a EULAR/ACR score of 20 was used as a threshold to compare outcomes between groups. In the first 5 years of disease course, patients with a score of ≥20 had higher AMS scores (p<0.001) and were more likely to ever experience a flare (p<0.001). These patients had lower probabilities of achieving remission and higher requirements for immunosuppressives. Results were confirmed in the SLICC validation cohort. Patients with a score of ≥20 had higher AMS during the first 5 years of disease (5.4 vs 3.1% and ≥20 vs <20 respectively, p≤0.001). The score correlated with AMS (r=0.43, p≤0.001) in the same time frame., Conclusion: A EULAR/ACR score of ≥20 is an indicator of ominosity in SLE. Patients with a score of ≥20 were characterised by a more active disease course throughout the first 5 years. These criteria provide prognostic information regarding disease severity in the first 5 years following diagnosis., Competing Interests: Competing interests: SRJ reports grants from Bayer, Boehringer Ingelheim, Corbus, GSK, Roche, Merck and personal fees from Boehringer Ingelheim and Ikaria., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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 <3 years (n=196) and ≥5 years (n=879). Among patients with 1 to <3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 81%). The EULAR/ACR criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). Among women, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 83%) and better specificity than the SLICC criteria (94% vs 82%). Among white patients, the EULAR/ACR criteria had better sensitivity than the ACR criteria (95% vs 83%) and better specificity than the SLICC criteria (94% vs 83%). The EULAR/ACR criteria performed well among black patients (sensitivity of 98%, specificity 100%), and had better sensitivity than the ACR criteria among Hispanic patients (100% vs 86%) and Asian patients (97% vs 77%)., Conclusions: The EULAR/ACR 2019 criteria perform well among patients with early disease, men, women, white, black, Hispanic and Asian patients. These criteria have superior sensitivity than the ACR criteria and/or superior specificity than the SLICC criteria across many subgroups., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The 2017 American College of Cardiology/American Heart Association guidelines defined hypertension at ≥130/80 mm Hg. Studies on patients with connective tissue diseases were not considered. Our aim was to assess the impact of this definition on atherosclerotic vascular events (AVEs) in systemic lupus erythematosus., Patients Methods: Individuals from the Toronto Lupus Clinic with at least 2 years of follow-up and no prior AVE were divided in three groups according to their mean blood pressure (BP) over that period (≥140/90 mm Hg, 130-139/80-89 mm Hg and <130/80 mm Hg). They were followed until the first occurrence of an AVE (fatal or non-fatal coronary artery disease, cerebrovascular event and peripheral vascular disease) or last visit. Groups were compared as per the baseline atherosclerotic risk factors. A multivariable time-dependent analysis was performed to adjust for the presence of other risk factors., Results: Of 1532 patients satisfying the inclusion criteria, 155 (10.1%) had a BP ≥140/90 mm Hg, 316 (20.6%) 130-139/80-89 mm Hg and 1061 (69.3%) were normotensives. After a mean follow-up of 10.8 years, 124 AVEs were documented. The incidence rates were 18.9, 11.5 and 4.5 per 1000 patient-years for the three groups, respectively (p=0.0007 between the 130-139/80-89 mm Hg group and the normotensives). A mean BP of 130-139/80-89 mm Hg over the first 2 years was independently associated with the occurrence of AVEs (HR 1.73, 95% CI 1.13 to 2.65, p=0.011)., Conclusion: Patients with lupus with a sustained mean BP of 130-139/80-89 mm Hg over 2 years had a significantly higher incidence of AVEs compared with normotensive individuals. This BP level should be the target for antihypertensive therapy to minimise their cardiovascular risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR)., Methods: This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects., Results: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria., Conclusion: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Survival in systemic lupus erythematosus (SLE) has improved substantially in the last 50 years. The aim of the present study was to assess the evolution of the all-cause, cause-specific and age-specific standardised mortality ratios (SMRs) of patients with lupus in Ontario, Canada., Patients and Methods: Between 1971 and 2013, 1732 patients were followed in the Toronto Lupus Clinic. Causes of death were retrieved from death certificates, autopsy reports, hospital records or the records of the family physicians. They were categorised as atherosclerotic, infectious, malignancy, active lupus and others. For the calculation of the SMR (indirect standardisation method), data from the general population of Ontario, Canada were used (Statistics Canada)., Results: Two hundred and forty-nine patients (205 women) died (infections 24.5%, atherosclerosis 15.7%, active lupus 13.3%, malignancy 9.6%); mean age was 53.2±16.6 years and mean disease duration 15.2±11.7 years. The all-cause SMR was substantially decreased from the 1970s (13.5, 95% CI 8.6 to 18.5) to recent years (2.2, 95% CI 1.4 to 3.1). Similar trends were observed for atherosclerosis, infections and malignancies over time. The all-cause age-specific SMR was particularly high in younger (19-39 years old) patients (SMR=12.4, 95% CI 9.7 to 15.1) as compared with individuals older than 40 years (SMR=3.1, 95% CI 2.6 to 3.6). The cause-specific SMR was also higher in younger patients, particularly for infections and malignancies., Conclusions: The all-cause and cause-specific SMR significantly decreased over time, likely reflecting the advances in the management of SLE and certain comorbidities. The all-cause and cause-specific SMR was particularly high for younger patients (<40 years old)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

European League Against Rheumatism and are jointly supporting multiphase development of systemic lupus erythematosus (SLE) classification criteria based on weighted criteria and a continuous probability scale. Prior steps included item generation, item reduction and hierarchical organisation of candidate criteria using an evidence-based approach. Our objectives were to determine relative weights using multicriteria decision analysis (MCDA) and to set a provisional threshold score for SLE classification. An SLE Expert Panel (8 European, 9 North American) submitted 164 real, unique cases with a wide range of SLE probability in a standardised format. Using the candidate criteria, experts scored and rank-ordered 20 representative cases. At an in-person meeting, experts reviewed inter-rater reliability of scoring, further refined criteria definitions and participated in an MCDA exercise. Based on expert consensus decisions on pairwise comparisons of criteria, 1000minds software calculated criteria weights and rank-ordered the remaining 144 cases based on their additive scores. The score of the lowest-ranked case for which complete expert consensus was achieved defined the provisional threshold classification score. Inter-rater reliability of scoring cases with the candidate criteria was good. MCDA involved 74 pairwise decisions and was repeated for the arthritis and mucocutaneous domains when the initial ranking of some cases did not match expert opinion. After criteria weights and additive scores were recalculated once, experts reached consensus for SLE classification for all cases scoring>83. Using an iterative process, the candidate criteria definitions were refined, preliminary weights were calculated and a provisional threshold score for SLE classification was determined., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with diffuse immune cell dysfunction. CD40-CD40 ligand (CD40L) interaction activates B cells, antigen-presenting cells and platelets. CD40L blockade might provide an innovative treatment for systemic autoimmune disorders. We investigated the safety and clinical activity of dapirolizumab pegol, a polyethylene glycol conjugated anti-CD40L Fab' fragment, in patients with SLE., Methods: This 32-week randomised, double-blind, multicentre study (NCT01764594) evaluated repeated intravenous administration of dapirolizumab pegol in patients with SLE who were positive for/had history of antidouble stranded DNA/antinuclear antibodies and were on stable doses of immunomodulatory therapies (if applicable). Sixteen patients were randomised to 30 mg/kg dapirolizumab pegol followed by 15 mg/kg every 2 weeks for 10 weeks; eight patients received a matched placebo regimen. Randomisation was stratified by evidence of antiphospholipid antibodies. Patients were followed for 18 weeks after the final dose., Results: No serious treatment-emergent adverse events, thromboembolic events or deaths occurred. Adverse events were mild or moderate, transient and resolved without intervention. One patient withdrew due to infection.Efficacy assessments were conducted only in patients with high disease activity at baseline. Five of 11 (46%) dapirolizumab pegol-treated patients achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment response (vs 1/7; 14% placebo) and 5/12 (42%) evaluable for SLE Responder Index-4 responded by week 12 (vs 1/7; 14% placebo). Mechanism-related gene expression changes were observed in blood RNA samples., Conclusions: Dapirolizumab pegol could be an effective biological treatment for SLE. Further studies are required to address efficacy and safety., Trial Registration Number: NCT01764594., Competing Interests: Competing interests: CC, PJC, GIJ, CO and MZ are full-time employees of UCB Pharma and hold stock awards and/or options. CS is a full-time employee of UCB Biosciences GmbH and holds stock awards and/or options. AMR was a full-time employee and stock holder of Biogen at the time the study was conducted. LCB is a full time employee and stockholder of Biogen. FH has received consultancy fees from UCB, Sanofi, Eli Lilly, Baxter, BMS and research grants from Deutsche Forschungsgemeinschaft, IMI (PRECISESADS) and attended speakers’ bureau for GSK, Roche Pharma and Pfizer. TD has received consultancy fees and research grants from UCB, Biogen, Roche, Sanofi, Eli Lilly, Jansen and research grants from Deutsche Forschungsgemeinschaft and EU Horizon 2020 (Harmonics). MU has served as Chair of the Data and Safety Monitoring Committee for the study., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE., Methods: An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%., Results: The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life., Conclusions: The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Aims: To compare the British Isles Lupus Assessment Group (BILAG) 2004, the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare index (SFI) and physician's global assessment (PGA) in assessing flares of disease activity in patients with systemic lupus erythematosus (SLE)., Methods: Sixteen patients with active SLE were assessed by a panel of 16 rheumatologists. The order in which the patients were seen was randomised using a 4×4 Latin square design. Each patient's flare status was determined at each assessment using the BILAG 2004 activity index; the SFI and a PGA. A group of five specialists designated each patient into severe, moderate, mild or no flare categories., Results: The rate of complete agreement (95% CI) of the four individual examining physicians for any flare versus no flare was 81% (55% to 94%), 75% (49% to 90%) and 75% (49% to 90%) for the BILAG 2004 index, SELENA flare instrument and PGA, respectively. The overall agreement between flare defined by BILAG 2004 and the SFI was 81% and when type of flare was considered was 52%. Intraclass correlation coefficients (95% CI), as a measure of internal reliability, were 0.54 (0.32 to 0.78) for BILAG 2004 flare compared with 0.21 (0.08 to 0.48) for SELENA flare and 0.18 (0.06 to 0.45) for PGA. Severe flare was associated with good agreement between the indices but mild/moderate flare was much less consistent., Conclusions: The assessment of flare in patients with SLE is challenging. No flare and severe flare are identifiable but further work is needed to optimise the accurate 'capture' of mild and moderate flares.

Objective: To study the longitudinal expression of interferon (IFN)-inducible genes in systemic lupus erythematosus (SLE) and determine their suitability as disease biomarkers., Methods: RNA was isolated from the peripheral blood of 94 patients with SLE and 11 controls and reverse transcribed into cDNA. The expression levels of five IFN-responsive genes (LY6E, OAS1, IFIT1, ISG15 and MX1) were determined by quantitative PCR, normalised to GAPDH and summed to generate a global IFN score. Patients were followed longitudinally for a period of 3-12 months, and the association between disease activity, as measured by the SLE disease activity index (SLEDAI-2K), and other clinical and laboratory variables was examined., Results: The expression of all five IFN-responsive genes was significantly higher in patients with SLE than in controls. The expression of LY6E, OAS1, IFIT1 and the global IFN score was associated with high disease activity. The global IFN score was also associated with active renal disease, a decreased C3, and the presence of anti-dsDNA or anti-RNA binding protein antibodies at a single point in time. However, there was a poor correlation between changes in this score and changes in disease activity, C3 or anti-dsDNA antibody levels in patients followed longitudinally. In most patients the levels of IFN-induced gene expression remained relatively stable over 3-12 months despite marked changes in disease activity. Nevertheless, in patients with low/moderate disease activity, those with high IFN scores had a more recent history of sustained high disease activity., Conclusion: The findings indicate that IFN-induced gene expression has limited clinical utility as a biomarker of acute changes in disease activity.

Objective: To examine if, in systemic lupus erythaematosus (SLE), exposure to immunosuppressive therapy (cyclophosphamide, azathioprine, methotrexate) increases cancer risk., Methods: A case-cohort study was performed within a multi-site international SLE cohort; subjects were linked to regional tumour registries to determine cancer cases occurring after entry into the cohort. We calculated the hazard ratio (HR) for cancer after exposure to an immunosuppressive drug, in models that controlled for other medications (anti-malarial drugs, systemic glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin), smoking, age, sex, race/ethnicity, geographic location, calendar year, SLE duration, and lupus damage scores. In the primary analyses, exposures were treated categorically (ever/never) and as time-dependent., Results: Results are presented from 246 cancer cases and 538 controls without cancer. The adjusted HR for overall cancer risk after any immunosuppressive drug was 0.82 (95% CI 0.50-1.36). Age > or = 65, and the presence of non-malignancy damage were associated with overall cancer risk. For lung cancer (n = 35 cases), smoking was also a prominent risk factor. When looking at haematological cancers specifically (n = 46 cases), there was a suggestion of an increased risk after immunosuppressive drug exposures, particularly when these were lagged by a period of 5 years (adjusted HR 2.29, 95% CI 1.02-5.15)., Conclusions: In our SLE sample, age > or = 65, damage, and tobacco exposure were associated with cancer risk. Though immunosuppressive therapy may not be the principal driving factor for overall cancer risk, it may contribute to an increased risk of haematological malignancies. Future studies are in progress to evaluate independent influence of medication exposures and disease activity on risk of malignancy.

Background: Recent evidence supports an association between systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL)., Objectives: To describe demographic factors, subtypes, and survival of patients with SLE who develop NHL., Methods: A multi-site cohort of 9547 subjects with definite SLE was assembled. Subjects at each centre were linked to regional tumour registries to determine cancer cases occurring after SLE diagnosis. For the NHL cases ascertained, descriptive statistics were calculated, and NHL subtype frequency and median survival time of patients determined., Results: 42 cases of NHL occurred in the patients with SLE during the 76,948 patient-years of observation. The median age of patients at NHL diagnosis was 57 years. Thirty six (86%) of the 42 patients developing NHL were women, reflecting the female predominance of the cohort. In the patients, aggressive histological subtypes appeared to predominate, with the most commonly identified NHL subtype being diffuse large B cell (11 out of 21 cases for which histological subtype was available). Twenty two of the patients had died a median of 1.2 years after lymphoma diagnosis., Conclusions: These data suggest aggressive disease in patients with SLE who develop NHL. Continuing work should provide further insight into the patterns of presentation, prognosis, and aetiology of NHL in SLE.