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A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

Objective Neuropsychiatric events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. This study examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrolment predicted subsequent neuropsychiatric events. Methods Patients with a recent SLE diagnosis were assessed prospectively for up to 10 years for neuropsychiatric events using the American College of Rheumatology case definitions. Decision rules of graded stringency determined whether neuropsychiatric events were attributable to SLE. Associations between the first neuropsychiatric event and baseline autoantibodies (lupus anticoagulant (LA), anticardiolipin, anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression. Results Disease duration at enrolment was 5.4±4.2 months, follow-up was 3.6±2.6 years. Patients were 89.1% female with mean (±SD) age 35.2±13.7 years. 495/1047 (47.3%) developed one or more neuropsychiatric event (total 917 events). Neuropsychiatric events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrolment 21.9% of patients had LA, 13.4% anticardiolipin, 15.1% anti-β2 glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. LA at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (HR 2.54, 95% CI 1.08 to 5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR 3.92, 95% CI 1.23 to 12.5, p=0.02). Other autoantibodies did not predict neuropsychiatric events. Conclusion In a prospective study of 1047 recently diagnosed SLE patients, LA and anti-ribosomal P antibodies are associated with an increased future risk of intracranial thrombosis and lupus psychosis, respectively.

This 24-week randomized, open-label, noninferiority trial compared oral mycophenolate mofetil with monthly intravenous cyclophosphamide as induction therapy for active lupus nephritis. Mycophenolate mofetil appeared more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis, with a more favorable safety profile. Mycophenolate mofetil appeared to be more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis, with a more favorable safety profile. Intravenous cyclophosphamide has been the standard of care for treating severe lupus glomerulonephritis 1 ; however, its use is limited by potentially severe toxic effects including bone marrow suppression, hemorrhagic cystitis, opportunistic infections, malignant diseases, and premature gonadal failure. 2 Clinical trials of treatment with intermittent intravenous cyclophosphamide combined with corticosteroids show greater long-term renal survival but not overall survival, as compared with treatment with corticosteroids alone. 3 – 6 Furthermore, failure to achieve remission, which is associated with an increased rate of progression to renal failure, is reported in 18 to 57 percent of patients who received cyclophosphamide. 7 – 10 Mycophenolate mofetil, an immunosuppressive . . .

Objective Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs rheumatic disease controls) and the association with SLE manifestations in an international multicenter study. Methods Information and blood samples were obtained in a cross-sectional study from patients with SLE (n = 308) and other rheumatologic diseases (n = 389) from 25 clinical sites (84% female, 68% Caucasian, 17% African descent, 8% Asian, 7% other). IgG anti-C1q against the collagen-like region was measured by ELISA. Results Prevalence of anti-C1q was 28% (86/308) in patients with SLE and 13% (49/389) in controls (OR = 2.7, 95% CI: 1.8–4, p < 0.001). Anti-C1q was associated with proteinuria (OR = 3.0, 95% CI: 1.7–5.1, p < 0.001), red cell casts (OR = 2.6, 95% CI: 1.2–5.4, p = 0.015), anti-dsDNA (OR = 3.4, 95% CI: 1.9–6.1, p < 0.001) and anti-Smith (OR = 2.8, 95% CI: 1.5–5.0, p = 0.01). Anti-C1q was independently associated with renal involvement after adjustment for demographics, ANA, anti-dsDNA and low complement (OR = 2.3, 95% CI: 1.3–4.2, p < 0.01). Simultaneously positive anti-C1q, anti-dsDNA and low complement was strongly associated with renal involvement (OR = 14.9, 95% CI: 5.8–38.4, p < 0.01). Conclusions Anti-C1q was more common in patients with SLE and those of Asian race/ethnicity. We confirmed a significant association of anti-C1q with renal involvement, independent of demographics and other serologies. Anti-C1q in combination with anti-dsDNA and low complement was the strongest serological association with renal involvement. These data support the usefulness of anti-C1q in SLE, especially in lupus nephritis.

Objectives To determine the frequency, accrual, attribution and outcome of neuropsychiatric (NP) events and impact on quality of life over 3 years in a large inception cohort of patients with systemic lupus erythematosus (SLE). Methods The study was conducted by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of SLE diagnosis. NP events were identified using the American College of Rheumatology case definitions, and decision rules were derived to determine the proportion of NP disease attributable to SLE. The outcome of NP events was recorded and patient-perceived impact determined by the SF-36. Results 1206 patients (89.6% female) with a mean (±SD) age of 34.5±13.2 years were included in the study. The mean disease duration at enrolment was 5.4±4.2 months. Over a mean follow-up of 1.9±1.2 years, 486/1206 (40.3%) patients had ≥1 NP events, which were attributed to SLE in 13.0–23.6% of patients using two a priori decision rules. The frequency of individual NP events varied from 47.1% (headache) to 0% (myasthenia gravis). The outcome was significantly better for those NP events attributed to SLE, especially if they occurred within 1.5 years of the diagnosis of SLE. Patients with NP events, regardless of attribution, had significantly lower summary scores for both mental and physical health over the study. Conclusions NP events in patients with SLE are of variable frequency, most commonly present early in the disease course and adversely impact patients' quality of life over time. Events attributed to non-SLE causes are more common than those due to SLE, although the latter have a more favourable outcome.

Background:The Treatment Response Measure for Systemic Lupus Erythematosus (TRM-SLE) is a novel clinical outcome assessment (COA) to define meaningful improvement in disease activity for the purpose of SLE randomised clinical trials (RCTs), being developed by an international taskforce of clinicians, patient partners and industry representatives. To support regulatory approval of new treatments, contemporary guidelines require that clinical trials must demonstrate treatment benefit relevant to how patients “feel, function or survive”, as measured by COAs specific for the RCT context of use [1].Objectives:The aim of this study was to establish consensus on the outcome domains with which to define meaningful improvement in disease activity in the novel TRM-SLE instrument, considering both patient and clinician perspectives as well as clinical trial utility.Methods:Candidate domains identified by surveying TRM-SLE Taskforce members were rated in a two-stage modified Delphi study. Each stage comprised two online survey rounds, separated by a structured discussion meeting. In Stage 1 clinicians and patient partners rated domain “importance” (impact on SLE symptoms, function or survival). In Stage 2, clinicians rated “important” domains on three further characteristics relevant to RCT utility: “appropriateness” for evaluating disease activity, “representation” among patients with active SLE, and “measurability” in an RCT context. Ratings of “importance” and “representation” were supported by the results of targeted literature reviews. The prespecified consensus threshold for each Delphi round was a rating of 7 or more (0-9) by at least 70% of participants, with consensus on all four characteristics rated across the two Delphi stages required for inclusion in TRM-SLE.Results:The domain generation survey completed by 36/59 (61%) TRM-SLE Taskforce members yielded 34 candidate outcome domains. Of 118 invitees to the modified Delphi study, 87/102 (85%) clinicians with a median (IQR) of 21 (11, 30) years’ experience and 13/16 (81%) patient partners with median (IQR) disease duration 19 (16,33) years completed at least one Delphi round, with representation from six continents. In Stage 1, 14 domains met consensus on “importance” in both clinician and patient groups, and 11 domains met consensus on “importance” amongst patients only (Table 1). These 25 “important” domains were rated in Stage 2, after which eight domains (alopecia, arthritis, haemolytic anaemia, mucosal ulcers, nephritis, rash, serositis and thrombocytopenia) also reached consensus on all of “appropriateness”, “representation” and “measurability” (Table 2). Notably, two domains ultimately meeting consensus for inclusion in TRM-SLE were rated “important” in Stage 1 by patients only, highlighting the vital contribution of the patient perspective.Conclusion:We reached consensus on eight domains (alopecia, arthritis, haemolytic anaemia, mucosal ulcers, nephritis, rash, serositis and thrombocytopenia) which will define meaningful change in disease activity in TRM-SLE, considering patient and clinician perspectives on importance, and utility in an RCT context. In the next stage of the TRM-SLE project working groups will reach consensus on the measurement, scoring and thresholds defining response for each of these domains.REFERENCES:[1] FDA Patient Focused Drug Development Guidance: Selecting, Developing or Modifying Fit-for-Purpose Clinical Outcome Assessments. https://www.fda.gov/media/159500/downloadTable 1. Proportion of participants rating domains highly based on “importance”, defined as being associated with how a patient feels, functions or survives when assessing treatment effect in an SLE clinical trial, after two Delphi voting rounds.Table 2. Proportion of participants rating “important” domains highly on “appropriateness”, “representation” and “measurability” when assessing treatment effect in an SLE clinical trial, after two Delphi voting rounds.Acknowledgements:We would like to acknowledge all members of the TRM-SLE Taskforce and those who generously contributed their time and expertise to our Delphi study.Disclosure of Interests:Kathryn Connelly: None declared, Rachel Koelmeyer: None declared, Darshini Ayton: None declared, John May: None declared, Kate Gregory: None declared, Laura Eades: None declared, Raychel Barallon: None declared, Rangi Kandane-Rathnayake GSK, Novartis (Institutional research grants), Vera Golder: None declared, Afia Anzum: None declared, Maisarah Mydin: None declared, Munni Akther: None declared, Alan Friedman Abbvie, Anca Askanase Investigator/Consultant for Abbvie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer and UCB, Cynthia Aranow AstraZeneca, GSK, Kezar Inc, Bristl Myers Squibb, Kezar Inc., Edward M. Vital Novartis, AstraZeneca, UCB, Novartis, Roche, Pfizer, UCB, AstraZeneca, Novartis, Abbvie, Merck, Lilly, Otsuka, AstraZeneca, Sandoz, Guillermo Pons-Estel Boehringer Ingelheim, GSK, Janssen, Novartis and Pfizer, AstraZeneca, Boehringer Ingelheim, GSK, Janssen, Novartis, Pfizer and RemeGen, Janssen, Hermine Brunner AZ, BI, Novartis, Pfizer, UCB, BMS, TAKEDA, Kenneth C. Kalunian BMS, GSK, Artiva, Cabaletta Bio, Roche/Genentech, AstraZeneca, Artiva, Eli Lilly, Kezar, Aurinia, Abbvie, Khadija Dantata: None declared, Laurent Arnaud Alexion, Amgen, Astra-Zeneca, Abbvie, Biogen, BMS, Boehringer-Ingelheim, Cêmka, GSK, Grifols, Janssen, LFB, Lilly, Menarini France, Medac, Novartis, Oséus, Pfizer, Roche-Chugaï, Sêmeia, UCB, Laurie Burke Multiple across many different therapeutic areas; no active consulting in SLE., Lee Simon: None declared, Qing Zuraw: None declared, Sandra Garces Amgen, Amgen- Executive role, Victoria Werth Gilead, Lilly, BMS, Nektar, Abbvie, Akira, Viela, GSK, EMD Serona, Sanofi, Xencor, ONO, Cabaletta, Pfizer, Corbus, Amgen, Janssen, Biogen, Gilead, Viela, Ventus, Regeneron, Argenx, Ying Sun Yes, Merck KGaA, Darmstadt, Germany, Yoshiya Tanaka Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho, Mitsubishi-Tanabe, Eisai, Chugai, Taisho, Youmna Lahoud Biogen, Biogen, Alain Cornet: None declared, Alessandro Sorrentino: None declared, Anisur Rahman Lilly, Anna Stevens Multiple - Abbvie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer and UCB, Catherine Barbey Biogen, Biogen, Dzifa Dey Pfizer, Roche, Elaine Karis Amgen Inc, Amgen Inc, Eloisa Bonfa: None declared, Erika Noss Johnson and Johnson Innovative Medicine, Eve MD Smith: None declared, George Stojan UCB, Jeanette Andersen: None declared, Joan Merrill UCB, GlaxoSmithKline, Abbvie, EMD Serono, Janssen, Lilly, Genentech, Aurinia, Provention, Remegen, Celgene/Bristo Myers Squibb, AstraZeneca, Amgen, Astellas, Alexion, Sanofi, Zenas, Joseph F. Merola Consultant and/or investigator for multiple complanies - Amgen, Astra-Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Abbvie, Dermavant, Eli Lilly, Incyte, Moonlake, Novartis, Janssen, UCB, Sanofi-Regeneron, Sun Pharma, Biogen, Pfizer and Leo Pharma, Jorge A. Ross Terres Genentech/Roche, Genentech/Roche, Joy Buie Novartis, Aurinia, Justine Maller Genentech/Roche, Genentech/Roche, Karen Costenbader BMS, GSK, Cabaletta Bio, Merck, Gilead, Marta Mosca GSK, Astra Zeneca, Janssen, ASTRA ZENECA, ABBVIE, UCB, GKS, OTSUKA, GSK, Maja Hojnik Eli Lilly and Company (Lilly), Maria Dall’Era Genentech, Aurinia, GSK, AstraZeneca, Janssen, Nikolay Delev BMS, Richard A. Furie AZ; GSK, BMS, GSK, Genentech, AZ, Biogen, GMS, GSK, Genentech, Biogen, Kyverna, Ronald F. van Vollenhoven AbbVie, AstraZeneca, BMS, Galapagos, GSK, Janssen, Pfizer, UCB, AbbVie, AstraZeneca, Biogen, BMS, Galapagos, GSK, Janssen, Pfizer, RemeGen, UCB, AstraZeneca, BMS, Galapagos, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Subhashis Banerjee BMS, BMS, Eric Morand AstraZeneca, Merck, Gilead, Roche, EMD Serono, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Novartis, AbbVie, Galapagos, IgM, AbbVie, Amgen, AstraZeneca, Biogen, BMS, Eli Lilly, EMD Serono, Genetech, GSK, Janssen, UCB (all institutional).

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 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 ⩾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 ⩾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.

ObjectiveTo describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up.MethodsThe systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used.Results31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors.ConclusionsIn some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis.

BackgroundDespite case series suggesting efficacy, controlled trials of anti-CD20 in lupus nephritis (LN) did not confirm benefit;Arthritis Rheum 201264:1215 and 2013;65:2368).ObjectivesOne possible explanation for this failure stems from the fact that B cell depletion stimulates production of B cell activating factor (BAFF) which, in turn, facilitates maturation of autoreactive B cells in lymphoid organs or during B cell repopulation. The CALIBRATE study (NCT 02260934) was designed to test this hypothesis, to determine whether addition of anti-BAFF could enhance the clinical effects of anti-CD20, and to assess safety of the combination.MethodsForty-three patients with active LN despite conventional treatment enrolled in a prospective randomised open-label trial that compared two treatment strategies. All subjects received iv rituximab (1000 mg), CTX (750 mg), and methylprednisolone (100 mg) at wks 0 and 2, followed by 40 mg/d prednisone tapered to 10 mg/d by wk 12. At wk 4, subjects received either belimumab (10 mg/kg iv at wks 4, 6, 8 and then every 4 wks) plus prednisone (n=21) or prednisone alone (n=22). Complete response (CR) was defined as: (i) urine protein:creatinine ratio (UPCR) <0.5; (ii) eGFR ≥120 or, if <120, eGFR >80% of screening; and (iii) prednisone tapered to 10 mg/d. The definiton of partial response (PR) differed only in the UPCR criterion (>50% reduction).ResultsThe clinical outcome at wk 24 was similar in both groups (table 1). The CR rate was 24% in the belimumab group (RCB) and 23% in the control group (RC). Three subjects in each group withdrew (WD) prior to wk 24 (two withdrawals in each group due either to progressive nephritis or an infusion reaction, and one in each group for reasons unrelated to SLE or its treatment). B cell depletion from blood was virtually absolute in both groups at wk 12, but the pace of recovery differed. Six subjects experienced serious adverse events between wks 0 and 24; three subjects in the RC group (pneumonia followed by LN flare; deep vein thrombosis; SLE flare); and three subjects in the RCB group (anti-CD20 infusion reaction; soft-tissue abscesses prior to anti-BAFF treatment; quadriceps tendon rupture).Median B Cell Count Median IgG LevelCR PR NR WD Wk 0 Wk 12 Wk 24 Wk 0 Wk 24RC Group 23%–23% 41%–14% 105 1 31 1050 1100RCB Group 24% 24% 38% 14% 143 1 3 984 837ConclusionsAn interim analysis of data from CALIBRATE shows: (i) anti-BAFF following anti-CD20 for LN did not improve clinical outcome at week 24; (ii) anti-BAFF delayed blood B cell reconstitution following B cell depletion; and (iii) anti-BAFF following anti-CD20 was not associated with hypogammaglobulinemia or an increase in serious infections. Further analyses at 48 weeks and beyond will address how anti-BAFF therapy affects quantitative and qualitative recovery of B cells as well as long-term clinical outcome.AcknowledgementsConducted by ITN with support from NIAID (UM1AI109565) and Genentech.Disclosure of InterestC. Aranow Grant/research support from: GlaxoSmithKline, Consultant for: GlaxoSmithKline, M. Dall’Era Consultant for: Genentech, M. Byron: None declared, L. Ding: None declared, D. Smilek: None declared, B. Diamond: None declared, D. Wofsy Consultant for: GlaxoSmithKline, Celgene, Novartis, UCB, Sanofi