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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 80% for all items, explaining the higher overall specificity of the criteria set. © 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

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. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Background A pooled analysis of the open-label BLISS LTE studies (BEL112233/BEL112234) reported low levels of organ damage accrual (measured by Systemic Lupus International Collaborating Clinics [SLICC]/American College of Rheumatology Damage Index [SDI]) in patients who received belimumab (BEL) plus standard therapy (SoC) over a 5 year period. However, the LTE studies had no SoC arm. This post-hoc study (206347) used PSM to match BLISS LTE patients to TLC patients to define a SoC treatment comparison cohort. Objectives To assess damage accrual in patients with SLE treated with BEL plus SoC compared with PSM patients from the TLC treated with SoC alone. Methods This analysis compared the mean SDI change from baseline (over 5 years), time to SDI event (on all patients with ≥1 year follow-up), and magnitude of year-to-year SDI change (over 5 years), from baseline to Year 5 in patients treated with BEL plus SoC (pooled United States [US] and non-US data from the BLISS LTE studies), and SoC alone. Patients in the LTE and TLC were 1:1 PSM based on 16 clinical variables with a propensity score calliper ±20%. Regression augmented inverse propensity score weighting (IPSW) tested the robustness of the PSM results. Results For the 5 year analysis, 181 LTE patients were matched to 181 TLC patients (mean bias 3.8%) from a larger pool of 973 patients (BLISS LTE n=592; TLC n=381). Time-to-event PSM resulted in 323 LTE and 323 TLC patients (mean bias 3.7%) from a larger pool of 1541 patients (BLISS LTE n=949; TLC n=592). The mean SDI score change from baseline in the BEL group was 0.265 (95% confidence interval [CI]: 0.180, 0.350) compared with 0.718 (95% CI: 0.547, 0.889) in the SoC group, resulting in a BEL treatment effect of –0.453 fewer SDI units (95% CI: –0.646,–0.260; p Conclusions This PSM analysis demonstrates that BEL plus SoC reduces, and slows the rate of organ damage progression and reduces the magnitude of progression compared with SoC alone. Acknowledgements Study funded by GSK. Emma Hargreaves, MA, of Fishawack Indicia Ltd, UK, provided editorial assistance funded by GSK. Disclosure of Interest M. Urowitz Grant/research support from: GSK, Consultant for: GSK, R. Ohsfeldt Employee of: GSK contractors with Medical Decision Modelling Inc., R. Wielage Employee of: GSK contractors with Medical Decision Modelling Inc., J. Dever Employee of: GSK contractors with Medical Decision Modelling Inc., M. Zakerifar Employee of: GSK contractors with Medical Decision Modelling Inc., Y. Asukai Shareholder of: GSK, Employee of: GSK, S. Ramachandran Shareholder of: GSK, Employee of: GSK, A. Joshi Shareholder of: GSK, Employee of: GSK

Background Previous studies described three patterns of disease activity over time in systemic lupus erythematosus (SLE), namely long quiescent, relapsing remitting and persistently active. However, they enrolled prevalent patients, many of whom in the late stages of the disease. As such, the patterns of disease course since diagnosis are not known. Objectives The aim of the present study was to assess the prevalence and characteristics of such patterns over 10 years of follow-up in an inception cohort. Methods The inception patients of a large lupus cohort (enrolled within 18 months of diagnosis, n=883), with at least 10 years of follow-up and no time interval >18 months between consecutive visits, were investigated. Monophasic (M) pattern was defined as a clinical SLEDAI-2K=0 [serology (anti-dsDNA antibodies and C3/C4 levels) excluded], achieved within five years since enrollment and maintained for ≥10 years after that. Relapsing-remitting (RR) pattern was defined based on ≥2 remission periods (a remission period equals two consecutive visits with a clinical SLEDAI-2K=0), while patients with no remission were categorised as persistently active (PA). Descriptive and regression analyses were used to compare the different groups regarding cumulative damage at 10 years, mortality and flare rate beyond 10 years. Results Of 267 patients who fulfilled the inclusion criteria, 27 (10.1%) were monophasics, 180 (67.4%) RR and 25 (9.4%) PA. Thirty-five patients (13.1%) had only one remission period (“hybrid”). There were no significant differences regarding the demographic, clinical, immunological and therapeutic characteristics among groups at enrollment. At 10 years, PA patients had received significantly more glucocorticosteroids [39.4±24.3 g vs. 16.6±10.7 g and 27.3±18.4 g for the M and RR groups, p Conclusions Approximately 70% of lupus patients followed a relapsing remitting course from diagnosis onwards, while 10% displayed a monophasic and another 10% a persistently active course. Black race and more severe disease over the first two years were associated with a worse disease course. Disclosure of Interest K. Tselios: None declared, D. Gladman: None declared, Z. Touma: None declared, J. Su: None declared, N. Anderson: None declared, M. Urowitz Consultant for: Consultant GlaxoSmithKline

Background/purpose Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) is one of the most commonly used disease activity indices in clinical practice and research but this index doesn’t account for severity within each descriptor. Moreover, in clinical trials, the use of standard of care (SoC), which includes glucocorticosteroid (GCS) often confounds trial results. We developed and validated a novel lupus disease activity index, SLEDAI-2K GCS (SLEDAI-2KG), that describes disease activity while accounting for GCS dose. SLEDAI-2KG has the same descriptors as SLEDAI-2K in addition to a new descriptor ‘GCS’ with different weight scores based on the dose of GCS. Furthermore, SLEDAI-2KG has a low administration burden and a simple scoring system similar to SLEDAI-2K. We aimed to compare the performance of SLEDAI-2K and SGI in identifying responders in response to SoC. Methods Patients have been followed prospectively according to a standard protocol between January 2011 and January 2014, at a single lupus centre, with active disease (SLEDAI-2K≥6), on prednisone ≥10 mg/day, and with follow up visits within 5–24 months were studied. Treatment was determined based on the judgment of the treating rheumatologist. Response to SoC therapy, at first follow up visit, was assessed by SLEDAI- 2K and SLEDAI-2KG. Responders were defined based on the decrease in SLEDAI-2K and SGI score by ≥4. The performance of SLEDAI-2K and SGI was also compared using different cut-off points; 5, 6 and 7. Descriptive analysis was used. Results 111 patients met the inclusion criteria of the study and were further analysed. Patients’ characteristics are represented in table 1. SLEDAI-2KG identified more responders at 6 months (94% vs 84%) and at 12 months (92% vs 76%) compared to SLEDAI-2K by cut off of 4. SLEDAI-2KG also identified more responders with cut off points 5, 6 and 7 (table 2). Conclusion The novel index, SLEDAI-2KG, is superior to SLEDAI-2K in identifying responders at 6 and 12 months accounting for steroid dose and thus adjusting for severity within each descriptor of SLEDAI-2K. SLEDAI-2KG has the ability to enhance analyses in clinical trials to differentiate between responders on minimal and moderate/large doses of GCS.

Background EULAR and ACR are supporting multi-phase development of SLE classification criteria based on weighted criteria and a continuous probability scale. Prior steps included criteria generation, criteria reduction through Delphi and Nominal Group Technique exercises, literature review for sensitivity/specificity of candidate criteria, and organization of candidate criteria into seven clinical and three immunologic domains. Objectives To refine definitions of candidate criteria, determine relative weights using multicriteria decision analysis, and determine a threshold score for SLE classification. Methods An SLE Expert Panel (9 North American, 8 European) submitted 167 unique cases with a range of SLE probability. Experts scored 20 representative cases using the candidate criteria and rank-ordered them. In a 2-day meeting, experts reviewed inter-rater reliability of scoring, refined criteria definitions, and participated in a multicriteria decision analysis (MCDA) exercise using 1000Minds TM software. Experts were presented a series of decisions between two cases, each with different criteria from two domains (e.g. oral ulcers [cutaneous] and acute pericarditis [serositis] vs. alopecia [cutaneous] and pleural effusion [serositis]) and anonymously voted for the case more likely to be classified as SLE. Votes were discussed until consensus was reached for each decision. Using the consensus decisions, 1000Minds™ calculated criteria weights, assigned a total score to each of remaining 147 cases and rank-ordered the cases. Experts voted on whether each case should be classified as SLE. MCDA was repeated for criteria whose calculated weights were inconsistent with expert opinion until group consensus was achieved. 1000Minds TM then re-calculated criteria weights and re-ranked cases once. The score of the last case for which expert consensus was achieved was the threshold score. Results Inter-rater reliability was good; human data entry error, not following instructions, and differing interpretations of criteria definitions accounted for discrepancies. Arthritis and pericarditis definitions were modified through group discussion. The MCDA involved 74 pairwise decisions. Cranial neuropathy and Class VI lupus nephritis were removed as they added little to SLE classification. MCDA was repeated for the arthritis and cutaneous domains as initial weights did not match expert opinion. After criteria weights and scores were re-calculated once, experts reached consensus for SLE classification for case score >83. Conclusions Using an iterative process, the expert panel refined definitions, weighted candidate criteria and determined a threshold score of >83 for SLE classification, which will undergo validation. Acknowledgements Joint support from EULAR and ACR Disclosure of Interest None declared

Background and aims To develop and validate a new index, SLEDAI-2K Glucocorticoids Index (SGI), to accurately describe disease activity while accounting for GC doses. Methods Phase 1: Identification of patient scenarios followed in a longitudinal cohort. Phase 2: Equation’s derivation explaining the association between SLEDAI-2K and GC dose while using physician global assessment (PGA) as Gold Standard. Phase 3: Validation of SGI against SLEDAI-2K in active patients. Scenarios were identified using the top 13 organ involvement combinations, then patients were grouped into 7 categories based on GC dose and 10 patients per category were selected. Scenario information included: SLEDAI-2K score, organ involvement combination and GC dose. 3 rheumatologists ranked disease activity with PGA. An independent cohort was used for the validation in phase 3. We hypothesised that in patients with improvement/worsening by SLEDAI-2K, the change in SLEDAI-2K and SGI will correlate. Results Scenario development is summarised in table 1. 131 scenarios were ranked by 3 rheumatologists leading to 393 records. Perfect LS agreement was achieved; ICC (2, k) of 0.89 (95% CI: 0.83, 0.89). A quadratic linear regression model relating GC and SLEDAI-2K was structured; SGI score=SLEDAI-2K score+[3.65+0.29*GC–0.0027(GC*GC)]. The weight score of GC doses was derived (Table 2). Construct Validity: 109 of the 158 patients improved, 38 remained unchanged, 11 worsened. SLEDAI-2K and SGI correlated highly (r=0.87) and changed in the same direction in patients with improvement/worsening proving the validity of SGI. Conclusions We developed and validated a novel lupus disease activity index, SGI, that describes disease activity while accounting for GC dose.

Background and aims The prevalence of ANA-negative SLE is reportedly 5%–20%. Cytoplasmic or mitotic cell indirect immunofluorescence (IIF) patterns are usually reported as ANA-negative. This study examined the prevalence of ANA-negativity (no intracellular IIF pattern) and pure cytoplasmic and/or mitotic IIF patterns (CMP) in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort and examined demographic, clinical and autoantibody associations. Methods Three groups were examined 1) ANA-positive (presence of nuclear IIF pattern), 2) ANA-negative (no IIF pattern), and 3) pure CMP. ANA were detected by IIF on HEp-2000 substrate, SLE-related autoantibodies by laser bead immunoassay, and anti-dsDNA and anti-dense fine speckles 70 (DFS70) by chemiluminescence immunoassay. Results 1137 patients were included; 89.9% were female. 92.3% were ANA-positive, 6.2% were ANA-negative, and 1.5% had a CMP. In the multivariate analysis (Tables 1 and 2), patients from Canada (Odds Ratio (OR) 2.07 [95% CI: 1.28, 3.36]) or with anti-DFS70 (OR 4.45 [95% CI: 1.37, 14.39]) were more likely to be ANA-negative or have CMP. Patients of Asian descent (OR 0.34 [95% CI: 0.13, 0.86]) or with anti-dsDNA (OR 0.53 [95% CI: 0.30, 0.94]), anti-SSA/Ro60 (OR 0.51 [95% CI: 0.30, 0.87]), or anti-UI-RNP (OR 0.35 [95% CI: 0.17, 0.70]) were less likely to be ANA-negative or CMP. Conclusions In newly diagnosed SLE, the prevalence of ANA-negativity was at the lower end (6.2%) of the range previously published and an additional 1.5% had a CMP pattern. The prevalence of true ANA-negativity will likely decrease as future guidelines are expected to recommend that non-nuclear patterns, such as CMP, are also reported.

Background and aims Antimalarial (AM)-induced cardiomyopathy is an extremely rare complication of AM treatment in systemic lupus erythematosus (SLE). The use of specific cardiac biomarkers may identify patients at risk. We sought to investigate the prevalence and associated factors for abnormal myocardial biomarkers in lupus patients. Methods Consecutive patients (n=179) attending the Toronto Lupus Clinic were enrolled. BNP (brain natriuretic peptide, assessing pressure and/or volume overload) and cTnI (cardiac troponin I, assessing myocardial necrosis) were measured simultaneously. None had ECG abnormalities suggestive of acute coronary syndrome. Analysis was performed with SAS 9.3; p Results Twenty-seven patients (15.1%) had elevated BNP and/or cTnI; 11 with prior history of heart failure, coronary artery disease, pulmonary hypertension and/or exertional dyspnea were excluded. Compared to subjects with normal biomarkers, the remaining patients (n=16) were older [54.7±15.1 vs. 47.8±12.2 years, p=0.037], had longer disease duration [22.6±10.4 vs. 15.5±10.1 years, p Conclusions Approximately 9% of unselected SLE patients had elevated myocardial biomarkers, in the absence of prior cardiac disease. Chronic AM therapy accompanied by persistent CPK elevation conferred an increased risk for abnormal BNP and cTnI, which might predict cardiomyopathy in such patients.

Purpose: The Medical Outcome Survey Short Form 36 (SF-36) is recommended to assess quality of life (QoL) in SLE. The aim of the current study was to assess QoL over time in the first 5 years of a multi-centered inception cohort of patients with SLE.. Methods: An inception SLE cohort has been assembled according to a standardized protocol between 2000 and 2012. In addition to clinical and laboratory assessments, patients completed the SF-36 at yearly intervals. Only patients who had at least 5 completed QoL questionnaires were included in these analyses. GEE models were run separately for each of the 8 subscales and for the physical and mental component summary scores (PCS and MCS), adjusting for repeated measures by patients. Results: 495 patients were included. The mean (� SD) disease duration at first visit was 5.3� 4.1 months. The mean age at enrolment was 35.8 � 13.2 years. All 8 subscales and 2 summary scores showed improvement in the first 2 years from enrolment. Between years 2 and 5 none of the subscales or summary scores showed any change. Minimal clinically important improvement was achieved by 35-55% of the patients and was influenced by demographic and disease factors. Conclusion: Unlike late stage lupus where QoL is stable over time, in patients with early disease all subscales improve in early follow-up up to 2 years. Therefore the SF-36 may be a sensitive outcome measure in early disease in patients with SLE. � 2014 American College of Rheumatology.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: “A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment.” The LFA proposes this definition for lupus flare on the basis of its high face validity.

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.

The objective of this study was to examine mortality rates related to cerebrovascular disease in systemic lupus erythematosus (SLE) compared to the general population. Our sample was a multisite Canadian SLE cohort (10 centres, n = 2688 patients). Deaths due to cerebrovascular disease were ascertained by vital statistics registry linkage using ICD diagnostic codes. Standardized mortality ratio (SMR, ratio of deaths observed to expected) estimates were calculated. The total SMR for death due to cerebrovascular disease was 2.0 (95% confidence interval [CI] 1.0, 3.7). When considering specific types of events, the category with the greatest increased risk was that of ill-defined cerebrovascular events (SMR 44.9, 95% CI 9.3, 131.3) and other cerebrovascular disease (SMR 8.4, 95% CI 2.3, 21.6). Deaths due to cerebral infarctions appeared to be less common than hemorrhages and other types of cerebrovascular events. Our data suggest an increase in mortality related to cerebrovascular disease in SLE patients compared to the general population. The large increase in illdefined cerebrovascular events may represent cases of cerebral vasculitis or other rare forms of nervous system disease; alternately, it may reflect diagnostic uncertainty regarding the etiology of some clinical presentations in SLE patients. The suggestion that more deaths are attributed to cerebral hemorrhage, as opposed to infarction, indicates that inherent or iatrogenic factors (eg, thrombocytopenia or anticoagulation) may be important. In view of the paucity of large-scale studies of mortality attributed to neuropsychiatric outcomes in SLE, our findings highlight the need for additional research in large SLE cohorts.

Objective. There is increasing evidence in support of an association between systemic lupus erythematosus (SLE) and malignancy, but in earlier studies the association could not be quantified precisely. The present study was undertaken to ascertain the incidence of cancer in SLE patients, compared with that in the general population. Methods. We assembled a multisite (23 centers) international cohort of patients diagnosed as having SLE. Patients at each center were linked to regional tumor registries to determine cancer occurrence. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. Cancers expected were determined by multiplying person-years in the cohort by the geographically matched age, sex, and calendar year-specific cancer rates, and summing over all person-years. Results. The 9,547 patients from 23 centers were observed for a total of 76,948 patient-years, with an average followup of 8 years. Within the observation interval, 431 cancers occurred. The data confirmed an increased risk of cancer among patients with SLE. For all cancers combined, the SIR estimate was 1.15 (95% confidence interval [95% CI] 1.05-1.27), for all hematologic malignancies, it was 2.75 (95% CI 2.13-3.49), and for non-Hodgkin's lymphoma, it was 3.64 (95% CI 2.63-4.93). The data also suggested an increased risk of lung cancer (SIR 1.37; 95% CI 1.05-1.76), and hepatobiliary cancer (SIR 2.60; 95% CI 1.25, 4.78). Conclusion. These results support the notion of an association between SLE and cancer and more precisely define the risk of non-Hodgkin's lymphoma in SLE. It is not yet known whether this association is mediated by genetic factors or exogenous exposures.

The Medical Outcomes Study Short Form 36 (SF-36) is recommended to assess quality of life (QOL) in systemic lupus erythematosus (SLE). The aim of the current study was to assess QOL over time in the first 5 years of a multicenter inception cohort of patients with SLE.An inception SLE cohort was assembled according to a standardized protocol between 2000 and 2012. In addition to clinical and laboratory assessments, patients completed the SF-36 at yearly intervals. Only patients who had ≥5 completed QOL questionnaires were included in these analyses. Generalized estimating equation models were run separately for each of the 8 subscales and for the physical and mental component summary scores, adjusting for repeated measures by patients.A total of 495 patients were included. The mean ± SD disease duration at the first visit was 5.3 ± 4.1 months. The mean ± SD age at enrollment was 35.8 ± 13.2 years. All 8 subscales and the 2 summary scores showed improvement in the first 2 years from enrollment. Between years 2 and 5, none of the subscales or summary scores showed any change. Minimum clinically important improvement was achieved by 35-56% of the patients and was influenced by demographic and disease factors.Unlike late-stage lupus, where QOL is stable over time, in patients with early disease, all subscales improve in early followup up to 2 years. Therefore, the SF-36 may be a sensitive outcome measure in early disease in patients with SLE.

Objective To investigate potential differences between childhood-onset and adult-onset systemic lupus erythematosus (SLE). Methods An inception cohort with childhood-onset SLE (n = 67) was compared with an inception cohort with adult-onset SLE (n = 131), each of whom was diagnosed between 1990 and 1998 and followed up until February 1999. Prospective information included data on medications, laboratory markers, and disease activity and damage as measured by the SLE Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), respectively. Results Eighty-five percent of patients with childhood-onset SLE and 88% of patients with adult-onset SLE were female; the mean duration of followup was 3.2 and 3.5 years, respectively. On average, the children had more-active disease than did the adults at the time of diagnosis and during followup. There was a higher incidence of renal disease in those with childhood-onset SLE (78% versus 52% in adults; P = 0.0005), and the adjusted mean SLEDAI renal score was higher in the children than in the adults (2.37 versus 0.82; P < 0.0001). Treatment with steroids (97% versus 72%; P < 0.0001) and immunosuppressive drugs (66% versus 37%; P = 0.0001) was used significantly more often in children with SLE. Four adult patients with SLE, but none of the children, died during the followup. At the end of the followup, the mean SDI scores in those with childhood-onset SLE were higher than those with adult-onset SLE (1.70 versus 0.76; P = 0.008). Conclusion Children with childhood-onset SLE have more active disease at presentation and over time than do adults with SLE, especially active renal disease. Compared with adults with SLE, children receive more intensive drug therapy and accrue more damage, often related to steroid toxicity.

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.

Background Late stage cognitive impairment is increasingly recognized in patients with systemic lupus erythematosus (SLE). Yet there is an unmet need for a clinical assessment of cognitive function that can be administered in an ambulatory setting. Objectives To determine: 1) the validity of the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) as screening tests of Cognitive Impairment (CI) in SLE and 2) associated factors with CI. Methods Consecutive patients with SLE visiting the Toronto Lupus Clinic since Feb 2014 that agreed to participate in all study9s phases were included. Patients underwent the battery of cognitive screening tests administered by 2 trained assessors: Hopkins Verbal Learning Test-Revised (HVLT-R) and Controlled Oral Word Association Test (COWAT) via telephone interview and MoCA and MMSE via face-to-face assessment. Patients completed the Perceived Deficits Questionnaire – 5-item (PDQ-5). Sensitivity (Se)/specificity (Sp) of MoCA and MMSE in detecting CI (HVLT-R external construct) were determined. Pearson correlation of MoCA and MMSE with HVLT-R and COWAT, were studied. PDQ-5 scores were compared in patients with and without CI. Center of Epidemiologic Studies Depression Scale (CES-D), Beck Anxiety Inventory (BAI), and Reynolds Intellectual Screening Test (RIST) were completed by patients. Logistic regression analyses were performed to test for possible associations with CI. Results 73 patients participated; 92% female, mean age 48±13 years, lupus disease duration 18±12 years, and SLE Disease Activity Index 2000 (SLEDAI-2K) 3.7±4.1. Prevalence of CI: 47% had CI using MoCA, 40% using HVLT-R, 16% using COWAT and 14% using MMSE. Patients with CI had marked impairment in attention, language and delayed recall in the domains of MoCA compared to normal controls (Table 1). Se/Sp: Sensitivity was higher for MoCA (69%) compared to MMSE (21%), though MMSE was more specific (91%) than MoCA (68%). Correlation: HVLT-R correlated with MoCA (r=0.43, p=0.0001). PDQ-5 showed higher scores in CI patients compared to patients without CI (10.16±4.60 vs. 8.41±3.95, p=0.11) [higher scores = greater perceived impairment]. Association: There was no significant difference in CES-D, BAI or RIST scores between patients with and without CI. The following variables were analyzed one by one univariate regressions for the outcome of cognitive impairment: age, sex, age at diagnosis, lupus disease duration, education years, SLEDAI-2K, CES, BAI and RIST (variables with p Conclusions CI among SLE patients was highly prevalent (47%) in this study using MoCA. Ease of use and time needed for an assessment, make the MoCA the preferential screening test for CI in patients with SLE compared to HTLV-R. Low intelligence scores were associated with CI but depression and anxiety were not. Disclosure of Interest None declared

Background Systemic lupus erythematosus (SLE) is a chronic relapsing and remitting condition in which long-term damage can accrue over time. Objectives To examine long-term organ damage and safety following 5 years of treatment with belimumab plus standard of care (SoC) in patients with SLE. Methods We examined pooled interim data (GSK201223) from two open-label studies that enrolled patients who completed the BLISS-52 and BLISS-76 studies. Patients received belimumab plus SoC every 4 weeks. Baseline was defined as prior to the first dose of belimumab. SLICC Damage Index (SDI) values were assessed every 48 weeks (yearly interval). Results 998 patients comprised the modified intent-to-treat population at baseline: 940 (94.2%) were female, with a mean (SD) age of 38.7 (11.49) years and disease duration of 6.69 (6.24) years. The mean (SD) SELENA-SLEDAI and SDI were 8.2 (4.18) and 0.7 (1.19), respectively. Reasons for study withdrawal included: subject request (16.8%), AEs (8.5%), other (7.0%), and investigator decision (4.8%). 411 (41.2%) patients had damage at baseline (SDI =1: 235 [23.5%]; SDI ≥2: 176 [17.6%]). At Years 5–6 (n=403), 343 (85.1%) patients had no change from baseline in SDI score (SDI +1: 46 [11.4%, SDI +2: 13 [3.2%], SDI +3: 1 [0.2%]). The mean (SD) change in SDI was +0.19 (0.481). Of patients with damage at baseline, 132/162 (81.5%) had no change in SDI (SDI +1: 22/162 [13.6%], SDI +2: 8/162 [4.9%], SDI +3: 0/162 [0%]), mean (SD) change in SDI was +0.23 (0.529). Of patients without baseline damage, 211/241 (87.6%) had no change in SDI (SDI +1: 24/241 [10.0%], SDI +2: 5/241 [2.1%], SDI +3: 1/241 [0.4%]), mean change (SD) in SDI was +0.15 (0.444). Overall, 433 (43.4%) of patients had a drug-related AE. The most common drug-related AEs were infections/infestations, 282 (28%) patients, and gastrointestinal disorders, 139 (14%) patients. 23 (2%) patients had an adjudicated opportunistic infection (OI); 4 (0.4%) patients had a serious OI. 87 (8.7%) patients had herpes zoster. 88 (8.8%) patients had an AE causing belimumab discontinuation. 11 deaths occurred during the study period; 2 deaths occurred after study exit. Conclusions Patients with moderate to severe SLE treated with belimumab plus SoC for 5 years had a low incidence of organ damage accrual and clinically manageable rates of AEs. Importantly, patients with pre-existing organ damage at study entry experienced similar rates of damage accrual compared with those with no baseline damage. As existing damage is a known risk for future damage accrual, our data suggest that belimumab may have a positive effect on risk factors for future damage that requires further evaluation. Acknowledgements Studies funded by GlaxoSmithKline (study #201223) and Human Genome Sciences. Louisa Pettinger, PhD, Fishawack Indicia Ltd, UK, assisted with the abstract submission and was funded by GSK. Disclosure of Interest I. Bruce Grant/research support from: UCB, GSK, Roche, Sanofi, Consultant for: UCB, Eli Lilly, GSK, Medimmune, Pfizer, Employee of: University of Manchester, Speakers bureau: UCB, GSK, Medimmune, M. Urowitz Grant/research support from: GSK, UCB, Eli Lilly, Consultant for: GSK, UCB, Eli Lilly, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo, Eli Lilly, GSK, Janssen, Merck, Pfizer, Roche, UCB, Vertex, C. Aranow Grant/research support from: GSK, UCB, Eli Lilly, Celgene, Janssen, Consultant for: GSK, UCB, Eli Lilly, Celgene, Janssen, J. Fettiplace Shareholder of: GSK, Employee of: GSK, M. Oldham Shareholder of: GSK, Employee of: GSK, E. Menius Shareholder of: GSK, Employee of: GSK, B. Wilson Shareholder of: GSK, Employee of: GSK, C. Molta Shareholder of: GSK, Employee of: GSK, D. Roth Shareholder of: GSK, Employee of: GSK, D. Gordon Shareholder of: GSK, Employee of: GSK

Background: Up to 35% of patients with SLE have abnormalities on myocardial perfusion imaging (MPI).It is postulated that endothelial dysfunction (EdF) is a precursor to atherosclerosis and may contribute to abnormalities on MPI. Aim: To determine the relationship between EdF measured using brachial artery Doppler ultrasound and MPI in patients with SLE. Method: This was a prospective study of 76 women with SLE, without clinical CAD. Assessment of EdF using brachial artery Doppler ultrasound was performed in all patients. Endothelium-dependent (ed) and independent (eid) flow mediated dilatation (FMD) was measured in response to post-ischemic reactive hyperemia and sublingual GTN respectively. All patients also underwent rest-stress MPI using SPECT 99mTc sestamibi using dipyridamole stress. MPI was interpreted using a 20 segment model. Summed stress score (SSS) were computed. Results: 40(52.6%) patients had both normal FMD and MPI. 7(9.2%) patients had both abnormal FMD and MPI. 8(10.5%) patients had abnormal FMD alone while 21(27.6%) patients had abnormal MPI alone. 36(47.4%) had an abnormality in either or both investigations. There was no agreement between FMD and MPI (Kappa=9.2%, correlation coefficient = −0.01, NS). However in an analysis of continuous variables, there was a statistically significant but weak negative correlation between eid and MPI (correlation coefficient = −0.35, p=0.002). Conclusion: In this study there was no agreement between FMD and MPI. Abnormal FMD with normal MPI is in keeping with the hypothesis that endothelial dysfunction is a precursor to myocardial ischemia, whereas normal FMD with abnormal MPI may reflect external influences such as treatment with statins at the time of study. Our findings indicate that brachial FMD and myocardial scintigraphy are complementary investigations in assessing the cardiovascular health of patients with SLE and should not be used interchangeably. When used in combination, brachial FMD and myocardial scanning identify around 47.4% of patients with SLE who may be at risk of developing clinical coronary artery disease.

To evaluate the prevalence of cytoplasmic (c) and peripheral (p) antineutrophil cytoplasmic antibodies (ANCA) using the indirect immunofluorescence (IIF) slide kit (INOVA) in patients with systemic lupus erythematosus (SLE) to correlate the presence of ANCA with disease activity and to determine if ANCA is associated with specific clinical manifestations.One hundred and fourteen consecutive patients with SLE seen at The Wellesley Hospital Lupus Clinic, Toronto, Ontario in May and June, 1992 were assessed clinically, and blood drawn for routine serology and ANCA. Disease activity was measured using the SLE Disease Activity Index (SLEDAI). ANCA was measured by IIF.Of the 114 patients, 12 (10.5%) had c-ANCA and 29 patients (25.4%) had p-ANCA. The titers of ANCA varied from 1:20 to 1:160. SLEDAI was 0 in 6 patients (5%), and 108 patients had some disease activity. Eighty-eight patients (77%) had mild to moderate active disease (SLEDAI10), and 20 (18%) patients had severe active disease (SLEDAIor = 10).No correlation was found between the presence of ANCA and SLEDAI either when analyzed as active-inactive (p = 0.75) or when correlated with degrees of disease activity (1-10:10) (p = 0.77). No correlation was found between p and c ANCA and the presence of vasculitis, renal, or CNS disease at the time of the assessment or at any time during the course of the disease. Thus ANCA was not associated with SLE disease activity or the presence of vasculitis in SLE.

Monocyte infiltration and activation of the coagulation system have been implicated in the pathophysiology of glomerulonephritis. In this study, spontaneous procoagulant activity (PCA) was measured in circulating mononuclear cells to determine whether elevated PCA correlated with the presence of proliferative glomerulonephritis in patients with systemic lupus erythematosus (SLE). No increase in PCA was found in 20 patients with end-stage renal failure, 8 patients with glomerulonephritis without SLE, and 10 patients undergoing abdominal surgical or orthopedic procedures as compared with 20 normal controls. In eight patients with SLE but with no apparent active renal disease, PCA was not elevated above normal basal levels. Seven additional patients with SLE who had only mesangial proliferation on biopsy also had no increase in PCA. In contrast, eight patients with focal or diffuse proliferative lupus nephritis, and one patient with membranous nephritis who ultimately developed a proliferative lesion, had a marked increase in PCA with greater than 100 times the base-line levels. The activity was shown to originate in the monocyte fraction of the mononuclear cells and was shown to be capable of cleaving prothrombin directly. The prothrombinase activity was not Factor Xa, because it was not neutralized by anti-Factor X serum and was not inhibited by an established panel of Factor Xa inhibitors. Monocyte plasminogen activator determinations did not correlate with renal disease activity. We conclude that monocyte procoagulant activity, a direct prothrombinase, seems to correlate with endocapillary proliferation in lupus nephritis and could be a mediator of tissue injury.

Antigen-specific suppressor cell activity of peripheral blood mononuclear cells was investigated in twenty-nine patients with systemic lupus erythematosus (SLE) and sixteen normal, age- and sex-matched healthy controls. Suppressor cell activity was generated by priming peripheral blood mononuclear cells with high dose antigen (ovalbumin) and adding the washed primed or control (unprimed) cells to autologous optimally stimulated target plaque-forming cell (PFC) cultures. The ability of the primed cells to interfere with an optimal ovalbumin-specific PFC response in the target cultures was used as a measure of antigen-specific suppressor cell activity. The results demonstrated reduced suppressor cell activity in the SLE patients relative to controls--46.8 +/- 3.6% vs 63 +/- 2.4% suppression respectively (P less than 0.01). Consistent with reduced suppressor cell activity was an increase in the plaque-forming cell response to ovalbumin in patients relative to controls (880 +/- 73 vs 763 +/- 102 PFC/10(6) cells respectively [P = 0.10]). No correlation was demonstrated between suppressor cell activity in SLE patients and disease activity or therapy.

The rheumatoid biologically active factor (RBAF) was characterized further with respect to its biological and physical characteristics. The histamine-releasing activity of the RBAF in the guinea-pig lung was influenced in the same manner as soluble immune complexes when the lungs were being perfused at 20°C or 45°C or when the perfusate lacked calcium or magnesium or contained N-ethylmaleimide, phenol, theophylline, adrenaline or succinate. The RBAF was consistently associated with complement-fixing activity and RBAF-positive synovial fluid showed a lower total haemolytic complement level than RBAF-negative fluid. However, RBAF activity was not lost following absorption with anti-human beta 1C globulin. There was a higher frequency of free DNA and/or single-stranded DNA in RBAF-positive than negative synovial fluid. RBAF-positive synovial fluid was more active than RBAF-negative fluid in neutrophil chemotaxis when examined at 1:10 but not when undiluted. Mixed IgG–IgM cryoprecipitates failed to show RBAF activity and aggregates seen on analytical ultracentrifugation of rheumatoid synovial fluid did not correspond with the RBAF. The RBAF was stable to freezing and thawing but was labile to acid pH and to heating at 56°C. It was concluded that the RBAF is likely to be a soluble immune complex consisting of IgG and a second constituent which is labile to acid and heat.

Figure S1. Overall hydroxychloroquine prescription dose trends. (DOCX 17 kb)

Figure S1. Overall hydroxychloroquine prescription dose trends. (DOCX 17 kb)