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The management of lupus nephritis (LN) and concomitant thrombotic microangiopathy (TMA), with or without antiphospholipid antibodies (aPL), remains controversial, and few studies are available to inform clinical management.1–4 The purpose of this multicentre retrospective study was to analyse the impact of anticoagulation (vitamin K antagonists (VKAs) and/or heparins) in addition to conventional immunosuppression on kidney outcomes (assessed at 12 months, according to the Kidney Disease: Improving Global Outcomes-KDIGOguidelines5) in patients with biopsy-proven LN and concomitant TMA. Data source, population and statistical analysis are detailed in the online supplementary material 1. Anticoagulation was considered if given for at least three consecutive months after TMA diagnosis.### Supplementary data [annrheumdis-2018-214559supp002.docx] We retrospectively identified 97 patients with biopsy-proven LN and TMA (2007–2017). See online supplementary table 1 for clinical and demographic characteristics. Laboratory parameters were collected at the time of the biopsy. The mean age of patients was 38.9±15.2 years (13–69) and 85 females (87.6%). Most had proliferative LN (class …

Background:Lupus nephritis (LN) is a common and severe manifestation of systemic lupus erythematosus (SLE) affecting 50% of SLE patients and leading to end-stage kidney disease (ESKD) in up to 30% of patients with LN.1 Previous studies have reported higher healthcare costs in patients with SLE that develop LN compared to patients without LN.2-5 These studies captured overall treatment costs associated with LN, regardless of disease activity or severity, and were conducted in small patient populations.Objectives:The aim of this study was to assess the real-world economic implications of achieving low disease activity compared to active disease or ESKD in a large LN population.Methods:This study was a retrospective observational analysis of patients with LN within Optum’s health plan identified with ICD9 or ICD10 codes to have LN between January 1, 2015, and December 31, 2019. Patients were ≥18 years of age and had ≥2 months of follow-up data available. Patients were followed until death, loss to follow-up, or December 31, 2019. Low disease activity was defined by evidence of glucocorticoid doses ≤5 mg/day, evidence of mycophenolate mofetil (MMF) doses ≤2 g/day, and no use of cyclophosphamide for ≥6 consecutive months. Follow-up time that could not be defined as low disease activity was defined as active disease periods, except for periods with evidence of ESKD. Healthcare payer costs for medical and pharmacy services were compared between periods of low disease activity, active disease, and ESKD. A univariate generalized estimating equation model accounting for interdependence was used to compare differences in costs between periods of active and low disease activity.Results:A total of 21,251 patients with LN met study criteria with a mean follow-up time of 31.0 months. The mean age was 60.3 years; 86.9% of patients were female and 35.2% of patients were non-White race. Low disease activity was evident in 51.3% of patients with a mean duration of 27.5 months. Mean monthly medical costs were $2,523 during periods of low disease activity and $4,777 during periods of active disease. After factoring in pharmacy costs, mean monthly total costs were $3,584 during periods of low activity and $6,612 during periods of active disease (PConclusion:Achieving low disease activity in patients with LN is associated with reduced economic burden to healthcare payers, with monthly medical costs averaging $2,254 less and total monthly costs averaging $3,028 less than costs during periods of active disease.References:[1]Parikh SV et al. Update on Lupus Nephritis: Core Curriculum 2020. Am J Kidney Dis. 2020;76(2):265-281.[2]Bartels-Peculis L et al. Treatment patterns and health care costs of lupus nephritis in a United States payer population. Open Access Rheumatol. 2020;12:117-124.[3]Furst DE et al. Medical costs and healthcare resource use in patients with lupus nephritis and neuropsychiatric lupus in an insured population. J Med Econ. 2013;16(4):500-509.[4]Li T et al. Long-term medical costs and resource utilization in systemic lupus erythematosus and lupus nephritis: a five-year analysis of a large Medicaid population. Arthritis Rheum. 2009;61(6):755-763.[5]Pelletier EM et al. Economic outcomes in patients diagnosed with systemic lupus erythematosus with versus without nephritis: results from an analysis of data from a US claims database. Clin Ther. 2009;31(11):2653-2664.Disclosure of Interests:Maria Dall’Era Speakers bureau: Consulting agreement with Aurinia for Advisory Boards and educational lectures, Tim Hermes Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Michael Eaddy Consultant of: Aurinia Pharmaceuticals Inc., Augustina Ogbonnaya Consultant of: Aurinia Pharmaceuticals Inc., Eileen Farrelly Consultant of: Aurinia Pharmaceuticals Inc., Paola Mina-Osorio Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a considerable impact on patients’ quality of life. Despite the plethora of clinical trials for SLE since the turn of the millennium, only one new treatment has been approved for the condition, and the overall pace of successful drug development remains slow. Nevertheless, the myriad of clinical studies has yielded insights that have informed and refined our understanding of eligibility criteria, outcome measures and trial design in SLE. In this review, we highlight the achievements of clinical trials as well as the major pitfalls that have been identified in drug development for SLE and, in doing so, identify areas where collaboration and consensus will be important to facilitate progress.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems triggered by the production of autoantibodies. Previous clinical studies in humans and murine models suggest that type I interferons (IFNs) are important for the initiation and potentiation of SLE activity. Methods: 65 consecutive patients with SLE were identified from the University of California, San Francisco Lupus Clinic with moderate-severe disease activity. 94 serological samples were collected. Type I IFN levels and the ability of plasma to induce expression of several surface markers of dendritic cell maturation were measured. Results: Type I IFN levels correlated with the presence of cutaneous manifestations, and there was a trend towards correlation with renal disease. No correlation was found between type I IFN levels and neurological disease. Type I IFN levels correlated positively with the SLEDAI score and anti-dsDNA levels and inversely with C3 levels. Interestingly, type I IFN levels were highest in African American patients. SLE plasma also induced the expression of MHC class I, CD38, and CD123 on monocytes, and was blocked by the addition of a monoclonal antibody to IFNAR1. Conclusions: The pathogenic role of type I IFN is suggested by the induction of cell surface markers for dendritic cell maturation. The potential therapeutic utility of antibodies directed to either type I IFN or IFNAR1/IFNAR2 may be of interest in further studies.

Background Immune complexes (ICs) containing RNA are thought to play a central role in driving interferon (IFN) production and systemic inflammation in systemic lupus erythematosus (SLE) via activation of intracellular Toll-Like Receptors (TLRs). However, quantitation of IC-bound RNAs in SLE patient plasma has not previously been performed. Objectives To quantify IC-associated U1 and Y1 RNA and relate the findings to the interferon (IFN) signature and SLE clinical activity. Methods Medications and SLEDAI measurements were completed on 228 SLE patients. Autoantibodies were quantified by a Bioplex assay. Peripheral blood transcript profiles for 186 selected genes were quantified by a dynamic array QPCR analysis. ICs were isolated from plasma by protein A bead capture and associated RNA quantified by QPCR using primer/probes designed to detect small, noncoding U1 and Y1 RNA transcripts. Results The autoantibodies anti-SmRNP and anti-Ro60 displayed the strongest associations with IC-bound U1 and Y1 RNA levels, respectively. When patients were grouped into 4 categories based on the presence of ICs containing U1 and/or Y1 RNA, blood gene expression changes in the U1-/ Y1- group were significantly lower than observed in the three groups possessing U1 alone, Y1 alone, or both RNA molecules. Within the U1 RNA-positive groups, the top 10 up-regulated genes were increased 10–48 fold compared to healthy volunteers (associated p values exceeding 10 –15 ) and corresponded to known IFN-inducible transcripts. IC-bound U1 and Y1 RNA levels showed significant correlations with each other and also with disease activity (SLEDAI) (p Conclusions The enhanced expression of IFN-inducible transcripts in blood from patients possessing IC-bound U1 and/or Y1 RNA lends further support to the hypothesis that these RNA molecules are involved in triggering TLR7 and stimulating interferon production in SLE patients. Therapeutic strategies that seek to reduce the quantities of RNA associated with ICs may be an attractive approach to blocking downstream IFN production and immune system activation. Disclosure of Interest None declared

Background Data from the Euro-Lupus Nephritis Trial (ELNT) indicated that a proteinuria Objectives The current analysis is aimed at testing the validity of this proteinuria cutoff level in another lupus nephritis (LN) patient population, taking advantage of the long-term MAINTAIN Nephritis Trial data set (2). Methods The MAINTAIN Nephritis Trial is an European-based randomized trial performed in 105 LN patients comparing azathioprine and mycophenolate mofetil as maintenance therapy, after induction with low-dose Euro-Lupus intravenous cyclophosphamide. Renal relapse rate was similar in the two groups and early proteinuria decrease within the first year predicted long-term renal function (2). For this analysis, aimed at defining the best cutoff proteinuria level, we selected patients with at least 7 years of follow-up for whom proteinuria measurement was available at month 3 (n=81), 6 (n=80) or 12 (n=80). Good and poor long-term renal outcome was defined as serum creatinine ≤1mg/dl and >1mg/dl at last follow-up, respectively. Sensitivity and specificity were calculated for each proteinuria level, as predictor of good long-term renal outcome. Receiver Operating Characteristic (ROC) curves (area under the curve; AUC) were drawn and the best proteinuria cutoff value at each time point was determined based on Youden index. 95% confidence intervals (CI) were calculated. Results The best proteinuria cutoff value ( i. e. the point on the ROC curve furthest to the equality line, defined by Youden index) at month 3, 6 and 12 is indicated in the Table below, as well as their sensitivity and specificity (±95%CI) as predictor of good renal outcome. The AUCs (between 0.73 and 0.78) confirmed accuracy of the test. A proteinuria cutoff of 0.7g/day optimized sensitivity and specificity at month 12. Quite interestingly, this value is very close to the 0.8g/day at month 12 computed from the ELNT data (1). Conclusions A 24-hour proteinuria cutoff level of 0.7 gram after 12 months of treatment best predicts long-term renal outcome in LN, confirming the ELNT data. We suggest that this target value be used as primary outcome in LN induction trials. References Dell9Ara M et al. Predictors of Long-Term Renal Outcome in Lupus Nephritis Trials: Lessons Learned from the Euro-Lupus Nephritis Cohort. Arthritis Rheumatol 2015; in press. Tamirou F et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann Rheum Dis 2015; in press. Disclosure of Interest None declared

Background Certain baseline factors in the BLISS trials were associated with high disease activity and identified as predictors of improved belimumab response. Objectives We examined clinical effectiveness of belimumab 10 mg/kg plus standard therapy in systemic lupus erythematosus (SLE) patients with high disease activity in US clinical practice. Methods OBSErve US (BLM117295) is a multicentre, retrospective, medical chart review study. Rheumatologists (n=92) randomly identified SLE patients who had received ≥8 belimumab infusions as part of usual care. Clinical measures were assessed 6 months (m) before belimumab initiation (index date), and every 6 m after, up to 2 years. Primary outcome was physician impression of overall change in SLE disease manifestations every 6 m, relative to the previous timepoint. Post hoc analyses examined three patient subgroups with high disease activity at index date: high anti-dsDNA and low complement (C3/C4); steroid dose ≥7.5 mg/day; SELENA-SLEDAI (SS) >10. Safety was not assessed. We present 18-m results. Results Of the 501 patient charts examined at 0–6 m, 121 were lost to follow-up/had outstanding data and 46 discontinued by 12 m (multiple reasons permitted: 16 patient request, 12 medication not effective, 9 lack of patient compliance, 8 disease progression, 3 insurance/reimbursement loss, 2 sepsis, 2 depression). 334 patients remained at 12–18 m; at index date 70.7% received steroid doses ≥7.5 mg/day; 53.0% had high anti-dsDNA and low C3/C4; 74.5% of 102 patients with available SS data scored >10. Characteristics across groups at index date appear similar (Table). SLE disease manifestations improved from 12–18 m (Table 1); only changes in the high anti-dsDNA and low C3/C4 subgroup were significantly different vs the remaining sample. Since index date all groups had mean SS score reductions of ≥8.5 at 18 m (in patients with available data) and mean steroid dose reductions of ≥14.9 mg/day (Table 1). Conclusions Based on physician impression, overall clinical response improved from 12–18 m with belimumab plus standard therapy; high anti-dsDNA and low C3/C4 patients had better responses vs the remaining sample. Disclosure of Interest C. Collins Consultant for: GlaxoSmithKline, M. Dall9Era Consultant for: GlaxoSmithKline, C. Macahilig Grant/research support: GlaxoSmithKline, R. Pappu Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, C. Molta Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, H. Kan Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, V. Koscielny Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline DOI 10.1136/annrheumdis-2014-eular.4968

Background There is controversy about what outcome measure in a lupus nephritis (LN) trial can be relied upon to predict longterm preservation of renal function. Objectives This analysis was undertaken to determine which of the outcome measures commonly employed in LN trials, used alone or in combination, correlate with longterm preservation of renal function and which measure has the greatest positive and negative predictive value. Methods We analyzed data from 81 of the 90 participants in the Euro-Lupus Nephritis Trial (ELNT) who have been followed for 5-12 yrs (median 10 yrs). Longterm data were not available for the other 9 subjects. Renal parameters were analyzed at 3, 6, and 12 mos after initiation of therapy, and those results were then correlated with the final serum creatinine (creat) measurement 5-12 years later. For the purpose of this analysis, the complete response (CR) targets were defined as: (i) proteinuria (prot) ≤500 mg/24 hrs; (ii) creat no worse than 0.2 mg/dL above baseline; and (iii) ≤5 RBCs/hpf on urinalysis. Partial response (PR) required a 50% improvement in proteinuria and creat no worse than 0.2 mg/dL above baseline, but did not require absence of RBCs. We tested three definitions for longterm preservation of renal function at the final visit: (i) creat ≤1.0 mg/dL; (ii) creat ≤1.3 mg/dL; and (iii) creat no worse than 0.2 mg/dL above the value at entry into ELNT. Results 89% of subjects who met prot criteria for CR at 12 mos had creat Conclusions Data from the ELNT support the conclusion that inclusion of an RBC component substantially weakens the positive predictive value of an early proteinuria drop in predicting longterm preservation of renal function. The clinical status at 3 or 6 mos does not correlate as well with longterm outcome as the status at 12 mos. Taken together, these data suggest that the primary outcome measure in LN trials should be based on improvement in proteinuria alone. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1646

Background Post hoc analyses of belimumab BLISS trials identified baseline factors generally associated with high disease activity as predictors of improved response to treatment, such as SELENA-SLEDAI (SS)> 10, low complement levels, anti-dsDNA positivity and glucocorticoid therapy. Objectives We examined clinical outcomes in patients with high disease activity treated with belimumab in U.S. clinical practice settings in 2012. Methods OBSErve (BLM117295) is a multicenter retrospective medical chart review study. 92 rheumatologists from U.S. non-academic centers who treat >10 SLE patients annually and have >5 years of practice experience were randomly recruited. Physicians randomly identified adult SLE patients who had received ≥8 infusions of belimumab as part of usual-care. Index date is the first belimumab infusion date. This post-hoc analysis was conducted among patients with low complement and high anti-dsDNA, steroids ≥7.5mg/day, and SS>10 at index date. Results were reported for the 3 subgroups and the entire sample. The primary outcome was the change in overall SLE disease manifestations 6 months after index date based on physician judgement. Changes from index date in SS and oral steroid dose (when available at index date) were also analyzed. Results 501 eligible patient charts were abstracted. Key patient characteristics at index date were mean age 41.3 yrs; female 89%; Caucasian 53%, black/African American 24%, Hispanic 18%; and SLE disease duration≤5yrs 56%. 50% (n=252) had hypocomplementemia and high anti-dsDNA, 69% (n=347) had steroid dose≥7.5mg/day, and 86 (70%) out of 122 with available SS had SS>10 at index date. Physician impression of overall change in disease manifestations over 6 months was similar in the subgroups of high disease activity compared to the entire sample. Within the 3 subgroups, mean SS scores decline ranged from 6.8-7.5 (51-53%), and mean steroid reduction ranged from 11.5-15.0 mg/day (58-61%) over 6 months. Conclusions Among the SLE patients with markers of high disease activity treated with at least 6 months of belimumab in clinical practice settings, clinicians observed improvement in overall SLE clinical manifestations, reduction in SELENA-SLEDAI, and reduction in steroid dose 6 months after belimumab initiation with no control arm. Disclosure of Interest H. Kan Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, C. Collins Consultant for: GlaxoSmithKline, M. Dall’Era Consultant for: GlaxoSmithKline, M. McGuire Grant/research support from: GlaxoSmithKline, V. Koscielny Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, R. Pappu Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, C. Molta Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline