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Clinical trials for systemic lupus erythematosus (SLE) currently depend on outcome measures that were originally developed for epidemiological or outcomes research and never optimized to discriminate treatment effects. Because these systems were devised to encompass simultaneous assessment of multiple organs, their interpretation can be complicated, requiring specialized training. Not surprisingly, there has been minimal adaptation of these disease activity scales in clinical practice, leaving clinicians without practical or reproducible methods for tracking progress, justifying treatment approvals, or documenting quality assurance. This chapter focuses on two of the most widely used SLE measures, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG) index. Definitions and scoring rules for these instruments were originally conceived through expert consensus, followed by formal validation studies to test reliability of their use over time and between clinicians. Both the SLEDAI and BILAG have demonstrated reliability, relevance, and sensitivity to change in disease severity, but when these mature, well-validated instruments began to be applied in registrational trials of investigational treatments, significant pitfalls were recognized. Subsequent accommodations in how the instruments are applied to study endpoints has led to more interpretable results in some recent trials, but continue to illuminate ongoing obstacles to successful treatment development, and to the ability, in clinic, to accurately track progress in a complex patient population. The solution may lie in the development of a measure that is not first keyed to established algorithms, then later tested for validity, but is originally scaled to live patient outcomes in the clinic to discriminate real world, clinically significant disease changes from minor fluctuations.

Due to the complex and unpredictable nature of lupus, clinical trials have been problematic to design, conduct, analyze, and interpret. Despite more than 30 treatments entering human development since the early 1990s, only one, belimumab, has been approved by regulatory agencies. This chapter addresses major impediments to lupus trials, including substantial disease heterogeneity, implications of standard of care polypharmacy, and difficulties in trial design and management. Also reviewed is evidence suggesting that current understanding may be yielding better trial outcomes. More clarity in results has been observed under conditions ensuring active enough disease at baseline, tapering of background medications, and use of more robust endpoints. Additional strategies that may facilitate identification of effective treatments include improved statistical approaches to address “between-subject” and “within-subject” heterogeneity, valid ways of handling protocol deviations and missing data, and novel trial designs that can offer greater flexibility and efficiency in lupus drug development.

ObjectiveAlthough SLE disproportionately affects minority racial groups, they are significantly under-represented in clinical trials in the USA. This may lead to misleading conclusions in race-based subgroup analyses. We conducted focus groups to evaluate the perceptions of diverse patients with lupus about clinical trial participation.MethodsA qualitative research design employed three 90 min focus groups led by a trained moderator and guided by the Theory of Planned Behaviour. Open-ended questions about trial participation included advantages and disadvantages (behavioural beliefs), approving and disapproving significant others (normative beliefs), and participation enhancers and barriers (control beliefs). Discussions were recorded, transcribed and analysed to identify emerging themes.ResultsPatients with SLE (n=23) aged 21–72, with increased proportion of minority groups (65%), participated. Reported advantages of trial participation included altruism and personal benefit. Disadvantages included uncertainties, disappointment, information burden, and life–health balance. Although some patients had discussed research participation with approving or disapproving family or friends, self-approval superseded external approval. Barriers included logistics and time, and facilitators included flexibility in scheduling, advance notice of studies, streamlined forms, and hope for SLE improvement.ConclusionsKnowledge about potential benefits of clinical trial participation was high. Minority patients demonstrated confidence in making their own informed decisions, but major barriers for all participants included burdensome forms, travel, childcare, and work. These suggest a major impact on minority and all recruitment from behavioural and control aspects, which should be considered in the logistics of trial design. This does not minimise the potential importance of improved access and education about clinical research.

Objectives Atacicept reduced SLE disease activity in the phase 2b ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. Methods In the 24-week, randomized, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary endpoint. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. Results In total, 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4–93.2%), and 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. Conclusion Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT02070978.

Background: Biological agents (also termed biologics or biologicals) play a growingly central role in the treatment of immunological diseases. However, the numerous studies published on biologics complicate the decision on the most appropriate biologic for a given disease. We aim to address this problem by publishing a series of systematic reviews evaluating the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. This article assesses the safety and efficacy of atacicept, a recombinant fusion protein consisting of the binding portion of transmembrane activator and CAML interactor (TACI; also known as tumor necrosis factor receptor superfamily member 13B), which is able to bind the cytokines B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Objective: To evaluate atacicept's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics. Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. Results: The literature search identified 118 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, ten articles were finally included in a narrative synthesis. Conclusions: Atacicept failed to show an effect in multiple sclerosis, optic neuritis, rheumatoid arthritis, and systemic lupus erythematosus. In patients with systemic lupus erythematosus, atacicept led to increased infection rates, but this adverse effect was not seen in the other treated diseases.

Objective: In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE. Methods: A large 33-center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient-years, and univariable and multivariable relative risk regression models. Results: Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow-up visit after enrollment, for a total of 13,666 patient-years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient-years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32–0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55–10.30]) and a body mass index of >40 kg/m2 (HR 2.74 [95% CI 1.04–7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17–9.27], P < 0.001). Conclusion: The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors.

Objective: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) has been shown to predict mortality, but its association with other important outcomes is unknown. We examined the association of baseline SLICC FI values with damage accrual in the SLICC inception cohort. Methods: The baseline visit was defined as the first visit at which both organ damage (SLICC/American College of Rheumatology Damage Index [SDI]) and health-related quality of life (Short Form 36) were assessed. Baseline SLICC FI scores were calculated. Damage accrual was measured by the increase in SDI between the baseline assessment and the last study visit. Multivariable negative binomial regression was used to estimate the association between baseline SLICC FI values and the rate of increase in the SDI during follow-up, adjusting for relevant demographic and clinical characteristics. Results: The 1,549 systemic lupus erythematosus (SLE) patients eligible for this analysis were mostly female (88.7%) with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9–1.5 years) at baseline. The mean ± SD baseline SLICC FI was 0.17 ± 0.08. Over a mean ± SD follow-up of 7.2 ± 3.7 years, 653 patients (42.2%) had an increase in SDI. Higher baseline SLICC FI values (per 0.05 increase) were associated with higher rates of increase in the SDI during follow-up (incidence rate ratio [IRR] 1.19 [95% confidence interval 1.13–1.25]), after adjusting for age, sex, ethnicity/region, education, baseline SLE Disease Activity Index 2000, baseline SDI, and baseline use of glucocorticoids, antimalarials, and immunosuppressive agents. Conclusion: Our findings indicate that the SLICC FI predicts damage accrual in incident SLE, which further supports the SLICC FI as a valid health measure in SLE.

Objective.To construct a Frailty Index (FI) as a measure of vulnerability to adverse outcomes among patients with systemic lupus erythematosus (SLE), using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.Methods.The SLICC inception cohort consists of recently diagnosed patients with SLE followed annually with clinical and laboratory assessments. For this analysis, the baseline visit was defined as the first study visit at which sufficient information was available for construction of an FI. Following a standard procedure, variables from the SLICC database were evaluated as potential health deficits. Selected health deficits were then used to generate a SLICC-FI. The prevalence of frailty in the baseline dataset was evaluated using established cutpoints for FI values.Results.The 1683 patients with SLE (92.1% of the overall cohort) eligible for inclusion in the baseline dataset were mostly female (89%) with mean (SD) age 35.7 (13.4) years and mean (SD) disease duration 18.8 (15.7) months at baseline. Of 222 variables, 48 met criteria for inclusion in the SLICC-FI. Mean (SD) SLICC-FI was 0.17 (0.08) with a range from 0 to 0.51. At baseline, 27.1% (95% CI 25.0–29.2) of patients were classified as frail, based on SLICC-FI values > 0.21.Conclusion.The SLICC inception cohort permits feasible construction of an FI for use in patients with SLE. Even in a relatively young cohort of patients with SLE, frailty was common. The SLICC-FI may be a useful tool for identifying patients with SLE who are most vulnerable to adverse outcomes, but validation of this index is required prior to its use.

ObjectiveThe Lupus Foundation of America Rapid Evaluation of Activity in Lupus (LFA-REAL) clinician-reported outcome (ClinRO) and the LFA-REAL patient-reported outcome (PRO) were developed in order to capture manifestations of SLE from the perspective of both the clinician and the patient. The aim of this study is to compare the LFA-REAL ClinRO and PRO with other lupus disease activity measures.MethodsA cross-sectional analysis of patients from a single-centre cohort was performed using Spearman’s correlation. Disease activity measures included were LFA-REAL ClinRO (range 0–1400), LFA-REAL PRO (range 0–1200), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), clinical SLEDAI-2K and Physician Global Assessment (PGA, range 0–100).ResultsTwo hundred and twenty-seven patients with SLE were studied. The mean age was 46.3 (SD: 13.8); 212 (93.4%) were female. The mean (SD) LFA-REAL ClinRO was 25.4 (34.7), LFA-REAL PRO was 241.1 (187.6), PGA was 11.9 (15.4), SLEDAI-2K was 2.3 (3.3) and clinical SLEDAI-2K was 1.6 (2.9). The LFA-REAL ClinRO correlated with PGA (r=0.758, pConclusionsThe LFA-REAL ClinRO and the LFA-REAL PRO had good and weak correlations, respectively, with several physician-based disease activity measures in a cross-sectional study, suggesting their potential usefulness in establishing disease severity. Longitudinal studies will be required to determine their value in monitoring patients with SLE.

Objective: To determine the frequency, clinical characteristics, associations, and outcomes of different types of peripheral nervous system (PNS) disease in a multiethnic/multiracial, prospective inception cohort of systemic lupus erythematosus (SLE) patients. Methods: Patients were evaluated annually for 19 neuropsychiatric (NP) events including 7 types of PNS disease. SLE disease activity, organ damage, autoantibodies, and patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate. Results: Of 1,827 SLE patients, 88.8% were female, and 48.8% were white. The mean ± SD age was 35.1 ± 13.3 years, disease duration at enrollment was 5.6 ± 4.2 months, and follow-up was 7.6 ± 4.6 years. There were 161 PNS events in 139 (7.6%) of 1,827 patients. The predominant events were peripheral neuropathy (66 of 161 [41.0%]), mononeuropathy (44 of 161 [27.3%]), and cranial neuropathy (39 of 161 [24.2%]), and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with a history of neuropathy, older age at SLE diagnosis, higher SLE Disease Activity Index 2000 scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower Short Form 36 (SF-36) physical and mental component summary scores versus no NP events. According to physician assessment, the majority of neuropathies resolved or improved over time, which was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. Conclusion: PNS disease is an important component of total NPSLE and has a significant negative impact on health-related quality of life. The outcome is favorable for most patients, but our findings indicate that several factors are associated with longer time to resolution. (Less)

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A—C—B—DRB1—DQA—DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA– B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA–C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

Lupus disease measures such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG) index are challenging to interpret. The Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL) is intended to provide an efficient application of anchored visual analog scores, each representing the individual severity of active symptoms, with the sum of individual scores deriving an overall disease activity assessment. Our objective was to compare the performance of LFA-REAL to systemic lupus erythematosus disease activity assessments and compare scores between trained lupus clinical investigators and clinicians.Investigators scored the SLEDAI, BILAG, physician's global assessment (PGA), and LFA-REAL, while the clinicians scored the LFA-REAL. The level of agreement between physicians and instruments was determined.The study included 99 patients (93% women, 31% white, mean ± SD ages 43.4 ± 13.2 years). At the first visit, the mean ± SD SLEDAI score was 5.5 ± 4.5, BILAG score 6.7 ± 7.8, and PGA score 33.6 ± 24.5. The mean ± SD investigator LFA-REAL score was 46.2 ± 42.9, and clinician LFA-REAL score 56.1 ± 53.6. At the second visit, the mean ± SD investigator LFA-REAL score was 41.3 ± 36.7, and clinician LFA-REAL score 48.3 ± 42.6. Total LFA-REAL scores correlated positively with PGA, SLEDAI, and BILAG (ρ = 0.58-0.88, P0.001). LFA-REAL scores produced correlation coefficients of ρ0.7 for musculoskeletal, mucocutaneous, and renal BILAG domains. The intraclass correlation coefficient between the LFA-REAL scores of investigators and clinicians was 0.79 for visit 1 (P0.001) and 0.86 for visit 2 (P0.001).The LFA-REAL provides a reliable surrogate for more complicated disease activity measures when used by lupus clinical investigators or clinicians.

Objective To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis. Methods In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169. Conclusion AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.

Objective To evaluate the efficacy and safety of atacicept, an antagonist of B lymphocyte stimulator/APRIL–mediated B cell activation, in patients with systemic lupus erythematosus (SLE). Methods ADDRESS II is a 24‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐arm, phase IIb study evaluating the safety and efficacy of atacicept in patients with SLE (ClinicalTrials.gov identifier NCT01972568). Patients with active, autoantibody‐positive SLE receiving standard therapy were randomized (1:1:1) to receive atacicept (75 mg or 150 mg) or placebo for 24 weeks. The primary end point was the SLE responder index 4 (SRI‐4) at week 24. Results The intent‐to‐treat (ITT) population included 306 patients. There was a trend toward an improved SRI‐4 response rate with atacicept 75 mg (57.8%; adjusted odds ratio [OR] 1.78, P = 0.045) and 150 mg (53.8%; adjusted OR 1.56, P = 0.121) at week 24 as compared with placebo (44.0%) (primary analysis; using the screening visit as baseline). In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI‐4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI‐4 and SRI‐6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo. Conclusion Atacicept treatment showed evidence of efficacy in SLE, particularly in HDA and serologically active patients. Reductions in disease activity and severe flare were observed with atacicept treatment, with an acceptable safety profile.

ObjectiveStudies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies.MethodsThe PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at ResultsAPO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12–15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12–15 weeks remained significantly associated with APO (ORadj=1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and ORadj=1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12–15 weeks and APOs became stronger (ORadj=2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013).ConclusionIn pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.

Background:Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors involved in innate and adaptive immune cell development and homeostasis, and linked to the genetic risk for systemic lupus erythematosus (SLE). A phase 2, placebo-controlled study evaluated the efficacy and safety of iberdomide in patients (pts) with moderate to severe SLE.Objectives:To examine the effect of iberdomide on cutaneous manifestations in SLE pts.Methods:Adult autoantibody-positive SLE pts with a SLE Disease Activity Index 2000 (SLEDAI 2K) score ≥6 were randomized (2:2:1:2) to oral iberdomide (0.45, 0.3, 0.15 mg) or placebo once daily (QD) for 24 weeks while continuing standard background lupus medications. The Cutaneous Lupus Area and Severity Index Activity score (CLASI-A) was assessed every 4 weeks through week 24. As prespecified, exploratory analyses, change from baseline and the proportion of pts who achieved ≥50% reduction from baseline (CLASI-50) were evaluated for all pts, pts with baseline CLASI-A ≥8, and by cutaneous lupus subtypes (acute [ACLE], subacute [SCLE], chronic [CCLE]). CLASI-A outcomes were also evaluated post hoc for subgroups with high baseline expression of IKZF3 or the type 1 interferon (IFN) gene signatures in the blood.Results:Of 288 randomized pts, the mean and median (range) baseline CLASI-A scores were 6.9 and 5.0 (0-49), with 28% of pts having a score ≥8. 56% of pts had ACLE, 29% CCLE, and 16% SCLE. CLASI-50 responses were not significantly different comparing iberdomide to placebo in all pts and pts with baseline CLASI-A ≥8 at week 24, where high placebo response rates were observed (Table). Numerically greater mean improvement from baseline in CLASI-A scores in pts with baseline CLASI-A ≥8 was observed for iberdomide 0.45 mg vs placebo beginning at week 4, with continuous improvement through week 24. For pts with SCLE or CCLE, CLASI-50 response rates were significantly higher with iberdomide 0.45 mg vs placebo (PPIKZF3 or type 1 IFN gene signatures, with statistical significance achieved for SCLE pts but not CCLE pts (Figure).Table 1.CLASI-50 Response Rates by Subgroups at Week 240.15 mg QD0.3 mg QD0.45 mg QD(n=42)(n=82)(n=81)PlaceboSubgroup(n=83)0.15 mg QD vs Placebo0.3 mg QD vs Placebo0.45 mg QD vs Placebon/m (%)n/m (%)Str Diff in % (95% CI)P valuen/m (%)Str Diff in % (95% CI)P valuen/m (%)Str Diff in % (95% CI)P valueAll pts37/83 (44.6)19/42 (45.2)0.4 (-17.33, 18.55) P=0.96141/82 (50.0)5.3 (-9.93, 20.11) P=0.49945/81 (55.6)10.9 (-4.30, 25.51) P=0.163CLASI-A ≥810/20 (50.0)8/13 (61.5)15.9 (-17.42, 45.45) P=0.39913/24 (54.2)12.1 (-17.57, 39.97) P=0.45816/24 (66.7)15.1 (-15.51, 42.49) P=0.368ACLE23/50 (46.0)15/30 (50.0)4.8 (-17.22, 26.31) P=0.66220/43 (46.5)-3.3 (-22.95, 16.67) P=0.73817/38 (44.7)-3.0 (-23.20, 17.65) P=0.782SCLE9/17 (52.9)5/9 (55.6)2.6a (-33.04, 36.33) P=0.9663/9 (33.3)-6.6 (-38.98, 31.86) P>0.99911/12 (91.7)38.7a(4.54, 61.75) P=0.035CCLE5/18 (27.8)7/14 (50.0)22.2a (-10.51, 50.00) P=0.19810/23 (43.5)23.8 (-6.89, 48.88) P=0.12918/29 (62.1)34.1 (4.43, 56.16) P=0.029CI, confidence interval; Str Diff, stratified difference.aUnstratified difference.Conclusion:Iberdomide showed beneficial effects on skin manifestations in pts with SLE. Efficacy appears to be more pronounced in pts with SCLE and CCLE skin subtypes, and in pts with high IKZF3 or IFN gene expression signatures.Δ, treatment difference of adjusted means; CCLE, chronic cutaneous lupus erythematosus; CLASI-A, Cutaneous Lupus Erythematosus Disease Area and Severity Index-activity score; IFN, interferon; SCLE, subacute cutaneous lupus erythematosus.Acknowledgements:This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.Disclosure of Interests:Victoria Werth Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Joan Merrill Consultant of: UCB, GlaxoSmithKline, AbbVie, EMD Serono, Remegen, Celgene/Bristol Myers Squibb, AstraZeneca, Lilly, Immupharma, Amgen, Janssen, Resolve, Alpine, Aurinia, Astellas, Alexion, and Provention, Grant/research support from: GlaxoSmithKline and AstraZeneca, Richard Furie Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Thomas Dörner Consultant of: support for clinical studies and honoraria for scientific advice: AbbVie, Bristol Myers Squibb Company, Celgene, Eli Lilly, Janssen, Novartis, Roche, Employee of: Charite Universitätsmedizin, Berlin and DRFZ Berlin, Germany, Ronald van Vollenhoven Speakers bureau: UCB, AbbVie, Galapagos, Janssen, Pfizer, Paid instructor for: support for educational programs: Pfizer, Roche, Consultant of: AstraZeneca, Biogen, Biotest, Celgene, Gilead, Servier, UCB, AbbVie, Galapagos, Janssen, Pfizer, Grant/research support from: Bristol Myers Squibb, GlaxoSmithKline, Eli Lilly, UCB, Peter Lipsky Employee of: RILITE Foundation, Michael Weiswasser Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shimon Korish Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Peter Schafer Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Mark Stern Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Zhaohui Liu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shaojun Tang Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Nikolay Delev Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb

Background:Remission, LDA and LDAS have been proposed as treatment goals for SLE. However, the independent impact of these states on damage accrual has not been fully evaluated.Objectives:To determine the independent impact of remission (both off & on treatment), LDA, and LLDAS on damage accrual.Methods:We studied a long-term longitudinal multinational SLE cohort, including patients completing at least two annual assessments. Remission off-treatment was defined as a SLEDAI (excluding serology) =0, without prednisone and immunosuppressive (IS) drugs. Remission on-treatment was defined as a SLEDAI (excluding serology) =0, prednisone daily doseResults:There were 1,652 patients, 1464 (88.6%) were female, mean age at diagnosis was 34.6 (SD 13.4) years and mean baseline disease duration was 5.5 (SD 4.1) months. Patients had a mean follow-up of 6.5 (SD 4.3) years, 11686 visits were included. 763 patients (46.2%) had an increase in SDI score ≥1 during follow-up. 2483 (21.2%) of the visits were classified as remission off-treatment, 2276 (19.5%) as remission on-treatment, 544 (4.7%) as LDA, 657 (5.6%) as LLDAS and 5726 (49.0%) as not-optimally controlled. Being in remission off-treatment, remission on-treatment, LDA and LLDAS were predictive of a lower probability of damage accrual [remission off-treatment IRR=0.403, 95% CI 0.301-0.541); remission on-treatment IRR=0.313 (95% CI 0.218-0.451) LDA: IRR=0.469 (CI 95% CI 0.272-0.809); LLDAS IRR=0.440 (95% CI 0.241-0.803)]. The multivariable model is summarized in Table 1.Table 1.Multivariable GEE model of the impact of disease activity states on damage accrual.Incidence Rate Ratio95% CIDisease activity stateRemission off treatment0.4030.301-0.541Remission on treatment0.3130.218-0.451LDA0.4690.272-0.809LLDAS0.4400.241-0.803Gender, male1.2741.086-1.495Age at diagnosis1.0241.020-1.029EthnicityCaucasian USRef.Caucasian other1.0170.849-1.217African1.4671.211-1.776Asian0.8630.693-1.075Hispanic1.2661.034-1.550Other1.1210.759-1.656Educational level, years0.9770.957-0.996Disease duration at baseline0.9600.801-1.150Follow-up time0.9420.923-0.960Antimalarial use0.7860.681-0.908Highest prednisone dose before baseline1.0021.001-1.007SDI before1.1001.050-1.1152LLDAS: Low lupus disease activity state LDA: Low disease activity SDI: SLICC/ACR Damage IndexConclusion:Remission on- and off-treatment, LDA and LLDAS were associated with less damage accrual, even adjusting for possible confounders and effect modifiers. This highlights the importance of treating to target in SLE.Disclosure of Interests:Manuel F. Ugarte-Gil Grant/research support from: Pfizer, Janssen, John Hanly: None declared, Murray B Urowitz: None declared, Caroline Gordon Speakers bureau: UCB, Consultant of: Center for Disease Control, Astra-Zeneca, MFP, Sanofi, UCB, Sang-Cheol Bae: None declared, Juanita Romero-Diaz: None declared, Jorge Sanchez-Guerrero: None declared, Sasha Bernatsky: None declared, Ann E Clarke Consultant of: AstraZeneca, BristolMyersSquibb, GlaxoSmithKline, and Exagen Diagnostics, Daniel J Wallace Grant/research support from: Exagen, David Isenberg: None declared, Anisur Rahman: None declared, Joan T Merrill: None declared, Paul Fortin: None declared, Dafna D Gladman Consultant of: Abbvie, Janssen, Pfizer, Novartis, Amgen, Grant/research support from: Abbvie, Janssen, Pfizer, Novartis, Amgen, Ian N. Bruce: None declared, Michelle A Petri: None declared, Ellen M Ginzler Grant/research support from: Aurinia pharmaceutical, M.A. Dooley: None declared, Rosalind Ramsey-Goldman: None declared, Susan Manzi: None declared, Andreas Jonsen: None declared, Ronald van Vollenhoven Speakers bureau: AbbVie, Galapagos, GSK, Janssen, Pfizer, UCB, Consultant of: Abbvie, AstraZeneca, Biogen, Biotest, Celgen, Galapagos, Gilead, Janssen, Pfizer, Sanofie, Servier, UCB, Vielabo, Grant/research support from: BMS, GSK, Lilly, UCB, Cynthia Aranow: None declared, Meggan Mackay: None declared, Guillermo Ruiz-Irastorza: None declared, S. Sam Lim: None declared, Murat Inanc: None declared, Kenneth C Kalunian Consultant of: Roche, Biogen, Janssen, AstraZeneca, Eli Lilly, Genetech, Gilead, ILTOO, Nektar, Viela, Equillium, Bristol-Meyers Squibb, Soren Jacobsen Grant/research support from: BMS, Christine Peschken: None declared, Diane L Kamen: None declared, Anca Askanase Consultant of: Abbvie, Grant/research support from: Glaxo Smith Kline, Astra Zeneca, Janssen, Eli Lilly and Company, Mallinckrodt, Pfizer, Bernardo Pons-Estel Consultant of: GSK, Janssen, Graciela S Alarcon: None declared.

Background:Treatment with the type I interferon (IFN) receptor antibody anifrolumab was associated with clinical improvements in mucocutaneous and musculoskeletal disease activity in patients with systemic lupus erythematosus (SLE) in the phase 2 MUSE trial (NCT01438489) and phase 3 TULIP trials.1–4 Because rash and arthritis are the most common manifestations of SLE, the effect of anifrolumab on these symptoms can be examined in biomarker-defined subsets, as previously reported for the MUSE trial.2Objectives:To evaluate the effect of anifrolumab on rash and arthritis in patients with SLE, and the impact of IFN gene signature (IFNGS) on treatment response, using disease measures of different stringency in pooled data from the phase 3 TULIP trials.Methods:TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) were placebo-controlled, 52-week trials of intravenous anifrolumab administered every 4 weeks in patients with moderate to severe SLE.3,4 In this post hoc analysis, outcomes of rash and arthritis were evaluated using mucocutaneous and musculoskeletal domains of the SLE Disease Activity Index 2000 (SLEDAI-2K) and the British Isles Lupus Assessment Group (BILAG) index. In addition, the modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI) score was used to evaluate rash, and tender and swollen joint counts were used to assess arthritis.Results:360 patients received anifrolumab 300 mg (IFNGS test–high, n=298; IFNGS test–low, n=62) and 366 patients were given placebo (IFNGS test–high, n=302; IFNGS test–low, n=64). Change from baseline to Week 52 compared with placebo was measured by outcomes, ordered by their stringency. More anifrolumab-treated patients achieved rash improvement using SLEDAI-2K (complete resolution: difference 13.5%, nominal PP0: difference 15.6%, nominal PPPPP=0.029), BILAG severity lessening (difference 11.8%, nominal P=0.002), and ≥50% decrease in tender/swollen joint counts, when ≥6 at baseline (difference 12.6%, nominal P=0.016). Results were comparable in the IFNGS test–high subset (SLEDAI-2K: difference 11.7%, nominal P=0.005; BILAG: difference 12.9%, nominal P=0.003; joint counts: difference 11.3%, nominal P=0.054). In IFNGS test–low patients, there was a trend toward anifrolumab-associated arthritis improvement when measured using BILAG, and the effect of anifrolumab on the number of swollen/tender joint counts was similar to the IFNGS test–high group, although the IFNGS test–low sample size in this analysis was very small (Figure).Conclusion:In pooled data from the TULIP trials, anifrolumab treatment was associated with improvements in rash and arthritis using measures of different stringency. The SLEDAI-2K findings were largely driven by the subset of patients who were IFNGS test–high. However, using measures that were more sensitive to change, despite small sample sizes, IFNGS test–low patients may also have benefit.References:[1]Furie R, et al. Arthritis Rheumatol. 2017;69:376–86.[2]Merrill JT, et al. Lupus Sci Med. 2018;5:e000284.[3]Furie RA, et al. Lancet Rheumatol. 2019;1:e208–19.[4]Morand EF, et al. N Engl J Med. 2020;382:211–21.Acknowledgements:Writing assistance by Victoria Alikhan, PhD, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests:Joan T Merrill Consultant of: AstraZeneca, AbbVie, Amgen, Aurinia, BMS, EMD Serono, GSK, Remegen, Janssen, Provention, and UCB, Grant/research support from: BMS and GSK, Victoria Werth Speakers bureau: University of Pennsylvania, who own the copyright for the CLASI and SDASI, Consultant of: AbbVie, Amgen, Argenx, AstraZeneca, Biogen, BMS, Celgene, Chrysalis, CSL Behring, Cugene, Eli Lilly, EMD Serono, Genentech, GSK, Incyte, Idera, Janssen, Kirin, Medimmune, Medscape, Nektar, Octapharma, Pfizer, Principa, Regeneron, Resolve, and Viela Bio, Grant/research support from: AstraZeneca, Biogen, Celgene, Corbus Pharmaceuticals, Genentech, Gilead, Janssen, Pfizer, Syntimmune, and Viela Bio, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, J Michelle Kahlenberg Consultant of: Admirex Pharmaceuticals, AstraZeneca, Aurinia Pharmaceuticals, BMS, Boehringer Ingelheim, Eli Lilly, and Ventus Therapeutics, Grant/research support from: BMS/Celgene and Q32 Bio, Gabriel Abreu Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca

Objective Incomplete lupus erythematosus (ILE) involves clinical and/or serologic manifestations consistent with but insufficient for systemic lupus erythematosus (SLE) classification. Because the nature of ILE is poorly understood and no treatment recommendations exist, we examined the clinical manifestations, medication history, and immunologic features in a diverse collection of ILE and SLE patients. Methods Medical records of subjects enrolled in the Lupus Family Registry and Repository were reviewed for medication history and American College of Rheumatology (ACR) classification criteria to identify ILE patients (3 ACR criteria; n = 440) and SLE patients (≥4 ACR criteria; n = 3,397). Participants completed the Connective Tissue Disease Screening Questionnaire. Anticardiolipin and plasma B lymphocyte stimulator (BLyS) were measured by enzyme-linked immunosorbent assay, antinuclear antibodies (ANAs) by indirect immunofluorescence, and 13 autoantibodies by bead-based assays. Results On average, ILE patients were older than SLE patients (46.2 years versus 42.0 years; P < 0.0001), and fewer ILE patients were African American (23.9% versus 32.2%; P < 0.001). ILE patients exhibited fewer autoantibody specificities than SLE patients (1.3 versus 2.6; P < 0.0001) and were less likely to have ANA titers ≥1:1,080 (10.5% versus 19.5%; P < 0.0001). BLyS levels were intermediate in ILE patients (controls < ILE; P = 0.016; ILE < SLE; P = 0.008). Pericarditis, renal, or neurologic manifestations occurred in 12.5% of ILE patients and were associated with non–European American race/ethnicity (P = 0.012). Hydroxychloroquine use increased over time, but was less frequent in ILE than SLE patients (65.2% versus 83.1%; P < 0.0001). Conclusion Although usually characterized by milder symptoms, ILE manifestations may require immunomodulatory treatments. Longitudinal studies are necessary to understand how ILE affects organ damage and future SLE risk, and to delineate molecular pathways unique to ILE.

Objective The SLE Responder Index (SRI) is a composite endpoint used in SLE trials. This investigation examined the clinical trial elements that drive response measured by the SRI. Methods Analyses are based on data from two phase 3 trials (n = 2262) that evaluated the impact of an anti-B-cell activating factor antibody on disease activity using SRI-5 as the primary endpoint (ClinicalTrials.gov NCT01196091 and NCT01205438). Results The SRI-5 response rate at week 52 for all patients was 32.8%. Non-response due to a lack of SLEDAI improvement, concomitant medication non-compliance or dropout was 31, 16.5 and 19.1%, respectively. Non-response due to deterioration in BILAG or Physician's Global Assessment after SLEDAI improvement, concomitant medication compliance and trial completion was 0.5%. Disease activity in three SLEDAI organ systems was highly prevalent at baseline: mucocutaneous, 90.6%; musculoskeletal, 82.9%; and immunologic, 71.6%. Disease activity in each of the other organ systems was

Background and objectives Kidney disease is a critical concern in counseling patients with lupus considering pregnancy. This study sought to assess the risk of renal flares during pregnancy in women with previous lupus nephritis in partial or complete remission, particularly in those with antidouble-stranded DNA antibodies and low complement levels, and the risk of new-onset nephritis in patients with stable/mildly active SLE. Design, setting, participants, & measurements We assessed active nephritis (renal flares and de novo kidney disease) and associated predictors during pregnancy in patients with lupus with urine protein ≤1000 mg and serum creatinine 500 mg and/or red blood cell casts. Results Of 118 patients with previous kidney disease, 13 renal flares (11%) occurred (seven of 89 in complete remission and six of 29 in partial remission) compared with four with de novo kidney involvement (2%) in 255 patients without past kidney disease (P Conclusions De novo kidney involvement in SLE, even in ethnic/racial minorities, is uncommon during pregnancy. Past kidney disease and low C4 at baseline independently associate with higher risk of developing active nephritis. Antibodies to dsDNA alone should not raise concern, even in patients with past kidney disease, if in remission.

Objective To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52-week, randomized, placebo-controlled, double-blind studies in which patients were treated with the BAFF-blocking IgG4 monoclonal antibody tabalumab. Methods Patient samples were obtained from SLE patients from the ILLUMINATE-1 and ILLUMINATE-2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0 and NanoString. Results At baseline, expression of the interferon (IFN) response gene was elevated in patients compared with controls, with 75% of patients being positive for this IFN response gene signature. There was, however, substantial heterogeneity of IFN response gene expression and complex relationships among gene networks. The IFN response gene signature was a predictor of time to disease flare, independent of anti–double-stranded DNA (anti-dsDNA) antibody and C3 and C4 levels, and overall disease activity. Pharmacodynamically induced changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell–related and immunoglobulin genes, and were consistent with other pharmacodynamic changes including anti-dsDNA antibody, C3, and immunoglobulin levels. Conclusion SLE patients demonstrated increased expression of an IFN response gene signature (75% of patients had an elevated IFN response gene signature) at baseline in ILLUMINATE-1 and ILLUMINATE-2. Substantial heterogeneity of gene expression was detected among individual patients and in gene networks. The IFN response gene signature was an independent risk factor for future disease flares. Pharmacodynamic changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.

Objective To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate-to-severe systemic lupus erythematosus (SLE). Methods Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (

Background:We recently reported Phase 2 SLE trial results of obexelimab, an FcγRIIb agonist (suppressor of B cell activation). Obexelimab did not meet the primary endpoint (% of patients without flare at Day 225) (p=0.183) but other endpoints such as time to flare (p=0.025) were met.Objectives:1. To assign SLE patients to phenotypic subsets based on patterns of gene expression in immune-related pathways.12. To explore the association of immune patterns and clinical response to obexelimab.Methods:This analysis included 71 of the 104 participants in the obexelimab study, those who either completed the protocol or terminated for disease flare, if there were adequate blood samples (biomarker subset). At screening, patients were assigned to clusters based on 41 SLE co-expression signature modules from the Human Immune Phenotyping Consortium via unsupervised random forest and K-means clustering.2Other markers of SLE disease were also examined. TheBOLD3study design mandated withdrawal of background immunosuppressants, supporting less ambiguous pharmacodynamic analysis as the trial progressed.Results:Immune pathway expression patterns of 7 patient clusters (Fig 1a) confirmed our prior characterization of 200 non-overlapping SLE patients.2The biomarker subset retained a trend of longer time to first flare in patients receiving obexelimab (n=38) vs placebo (n=33) (Fig1b, HR 0.61, p=0.11). A smaller set of only Clusters 3 and 6 demonstrated marked increased time to flare in the obexelimab group (n=13) compared to placebo (n=14) (Fig 1c, HR 0.22, p=0.025). Obexelimab had no effect on other clusters (Fig 1d). The responder clusters shared low expression of inflammation modules (p < 0.001) compared to other clusters and high expression of T Cell, immune response, cell cycle, mitochondrial modules (all p < 0.001) and B Cell modules (p=0.006). We therefore sorted patients by these specific features regardless of cluster assignment. Figure 2 shows significant impact of obexelimab on time to flare in 64 patients with B Cell pathway activation (HR 0.5, p=0.038), although less robust by itself than found in Clusters 3 and 6. In a group with high B or plasma cell modules but low inflammation (n=46), treatment effect increased (HR 0.35, p=0.019). Between Screening and Baseline, as brief steroids were given and background treatments withdrawn, expression of B Cell and Plasma Cell pathways increased. Both then decreased after treatment with obexelimab but not placebo (p< 0.0001 and p< 0.001 respectively), an effect not seen with other immune pathway modules.Conclusion:Precision medicine for SLE has been hampered by heterogenous immune signals with variable expression. Clustering of patients by gene co-expression pathways enabled an efficient, hierarchical array that reduplicated results of a prior SLE cohort, suggesting these are not random phenotypes. Of these 7 reproducible SLE subsets, the combination of clusters 3 and 6 distinguished an obexelimab responder population of 27 out of 71 subjects (38%) with high expression of B and T Cell modules and cell activation pathways. Focus on the defining features shared by these clusters revealed specific factors associated with response, enabling inclusion of some patients from other clusters in an optimized responder population of 46/71 (65% of subjects). B Cell and Plasma Cell pathways demonstrated mechanism-related pharmacodynamic effects of obexelimab. Lack of responders with high expression of inflammation modules could implicate inhibitory factors to obexelimab within inflammatory pathways, potentially targetable by complementary treatments.References:[1]Banchereau Cell 165:1548 2016[2]Lu ACR Abstract #2977 2017[3]Merrill Arthritis Rheumatol 69: 1257 2017Disclosure of Interests: :Joan T Merrill Grant/research support from: Xencor, Bristol Myers Squibb, Glaxo Smith Kline, Consultant of: Xencor, Abbvie, UCB, Glaxo Smith Kline, EMD Serono, Astellas, Remegen, Celgene/Bristol Myers Squibb, Exagen, Astra Zeneca, Amgen, Jannsen, Servier, ILTOO, Daitchi Sankyo, Lilly, Paid instructor for: Abbvie, Bristol Myers Squibb, Joel Guthridge Grant/research support from: Xencor, Bristol Myers Squibb, DXterity, Debra Zack Shareholder of: Xencor, Employee of: Xencor, Paul Foster Shareholder of: Xencor Inc, Employee of: Xencor Inc, Bart Burington Shareholder of: Xencor Inc, Employee of: Xencor Inc, Ly Tran: None declared, Miles Smith: None declared, Judith A. James Grant/research support from: Progentec Diagnostics, Inc, Consultant of: Abbvie, Novartis, Jannsen

Background Autoimmune diseases comprise a spectrum of illnesses and are on the rise worldwide. Although antinuclear antibodies (ANAs) are detected in many autoimmune diseases, up to 20% of healthy women are ANA-positive (ANA+) and most will never develop clinical symptoms. Furthermore, disease transition is higher among ANA+ African Americans compared with ANA+ European Americans. Objective We sought to determine the immune features that might define and prevent transition to clinical autoimmunity in ANA+ healthy individuals. Methods We comprehensively phenotyped immune profiles of African Americans and European Americans who are ANA-negative (ANA−) healthy, ANA+ healthy, or have SLE using single cell mass cytometry, next-generation RNA-sequencing, multiplex cytokine profiling, and phospho-signaling analyses. Results We found that, compared with both ANA− and ANA+ healthy individuals, patients with SLE of both races displayed T-cell expansion and elevated expression of type I and II interferon pathways. We discovered a unique immune signature that suggests a suppressive immune phenotype and reduced CD11C+ autoimmunity-associated B cells in healthy ANA+ European Americans that is absent in their SLE or even healthy ANA− counterparts, or among African American cohorts. In contrast, ANA+ healthy African Americans exhibited elevated expression of T-cell activation markers and higher plasma levels of IL-6 than did healthy ANA+ European Americans. Conclusions We propose that this novel immune signature identified in ANA+ healthy European Americans may protect them from T-cell expansion, heightened activation of interferon pathways, and disease transition.

Background Central nervous system (CNS) involvement accounts for over 90% of neuropsychiatric (NP) events compared to involvement of the peripheral nervous system (PNS) which accounts for most of the other events. Although there is a large body of work on CNS disease in SLE patients, involvement of the PNS is less well established. Objectives In a multi-ethnic/racial, prospective SLE inception cohort, to determine the clinical characteristics, associations and outcomes in different types of peripheral nervous system (PNS) disease. Methods Patients were evaluated annually for 19 NP events including seven types of PNS disease. Standardized case definitions and attribution models for each type of PNS event were used. SLE disease activity (SLEDAI-2K), organ damage (SLICC/ACR damage index), autoantibodies, patient (SF-36) and physician (Likert score) assessment of outcome were measured. Time to event and linear regressions were used as appropriate. Results Of 1,827 SLE patients, 88.8% were female, 48.8% Caucasian. The mean±SD age was 35.1±13.3 years, disease duration at enrollment 5.6±4.2 months and follow-up 7.6±4.6 years. There were 161 PNS events in 139/1,827 (7.6%) patients. The predominant events were peripheral neuropathy [66/161 (41.0%)], mononeuropathy [44/161 (27.3%)] and cranial neuropathy [39/161 (24.2%)] and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with prior history of neuropathy, older age at SLE diagnosis, higher SLEDAI-2K scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower SF-36 physical and mental component summary scores versus patients without NP events. By physician assessment, the majority of neuropathies resolved or improved over time and this was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. Conclusion PNS disease is an important component of total NPSLE and has a significant negative impact on health related quality of life. The outcome is favourable for most patients, but several factors associated with longer time to resolution were identified. Disclosure of Interests John Hanly Consultant for: Eli Lilly Canada, Qiuju Li: None declared, Li Su: None declared, Murray B Urowitz Grant/research support from: GSK, Consultant for: BMS, Celgene, GSK, Lilly, UCB, Caroline Gordon Grant/research support from: Sandwell and West Birmingham Hospitals NHS Trust have received funding from UCB to support research work done by my research group that was unrelated to any pharmaceutical product or clinical trial., Consultant for: I have provided consultancy advice and taken part in scientific advisory boards on the design and analysis of clinical trials and the management of lupus for GSK, EMD Serono and UCB. I have taken part in adjudication and safety monitoring committees for BMS., Speakers bureau: I have been paid by UCB for speaking at meetings., Sang-Cheol Bae: None declared, Juanita Romero-Diaz: None declared, Jorge Sanchez-Guerrero: None declared, Sasha Bernatsky: None declared, Ann E Clarke: None declared, Daniel J Wallace: None declared, David Isenberg: None declared, Anisur Rahman: None declared, Joan T Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen, Paul Fortin: None declared, Dafna D Gladman Grant/research support from: AbbVie, Amgen, Celgene, Lilly, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GlaxoSmithKline, Consultant for: AstraZeneca, Eli Lilly, GlaxoSmithKline, ILTOO Pharma, MedImmune, Merck Serono, Speakers bureau: GlaxoSmithKline, UCB Pharma, Michelle A Petri Shareholder of: Pfizer, Merck, Grant/research support from: AstraZeneca, Exagen, Consultant for: Eli Lilly, GSK, Merck EMD Serono, Janssen, Amgen, Novartis, Quintiles, Exagen, Inova Diagnostics, AstraZeneca, Blackrock, Glenmark, UCB, and the Annenberg Center for Health Sciences, Ellen M Ginzler: None declared, M.A. Dooley: None declared, Kristjan Steinsson: None declared, Rosalind Ramsey-Goldman: None declared, Asad A Zoma: None declared, Susan Manzi: None declared, Ola Nived: None declared, Andreas Jonsen: None declared, Munther Khamashta: None declared, Graciela S Alarcon: None declared, Ronald F van Vollenhoven: None declared, Elisabet Svenungsson: None declared, Cynthia Aranow: None declared, Meggan Mackay: None declared, Guillermo Ruiz-Irastorza: None declared, Manuel Ramos-Casals: None declared, S. Sam Lim: None declared, Murat Inanc: None declared, Kenneth C Kalunian: None declared, Soren Jacobsen: None declared, Christine Peschken Consultant for: AstraZeneca, Diane L Kamen: None declared, Anca Askanase: None declared, Chris Theriault: None declared, Vernon Farewell: None declared

Background A major concern for SLE clinical trials is the possibility that some patients who technically meet entry criteria may not have active disease. Antinuclear antibody (ANA) is known to lack specificity for SLE, permitting inclusion of inappropriate patients. Typically, ANA≥1:80 and/or positive anti-double stranded DNA (DNA) are required screening elements, but lately other autoantibody variables have been utilized. Objectives To examine serologic features that promote entry of active SLE patients into trials while supporting reasonable recruitment rates. Methods Serologic features of 1411 individual subjects who had full laboratory data at screening (N=783) and/or baseline (N=1019) in 4 phase 2 multicenter SLE trials were examined. Complement levels, percent of patients with low C3 or C4, and elevated DNA were used as markers of active disease. Serological profiles consistent with active SLE were tested on screened population for effects on potential screen failure rates. Results Of 1019 patients who qualified for the studies (baseline population), 399 (39.2%) were positive for DNA and 670 (65.8%) had anti-Extractable Nuclear Antibodies (ENA). Patients with positive DNA or ENA (even in absence of DNA) had lower complement levels and were more likely to have low C3/C4. (Table 1) In patients at screening, higher titers of ANA were associated with lower complement levels and higher rates of patients with low C3/C4 and elevated DNA. ENA impacted complement levels even in the absence of ANA. Compared to traditional entry criteria (ANA≥1:80 and/or DNA), patients defined by positive DNA or ENA or ANA≥1:640 had significantly lower complement levels and greater rates of low C3/C4, suggesting a more active patient population. (Table 1) Compared to a 22.5% screen failure rate with the typical requirement for ANA≥1:80 or DNA, testing DNA or ENA or low C3/C4 as entry criteria resulted in 30.7% exclusion. Adding high titer (≥1:640) ANA as an additional optional criterion would decrease the screen failure to 25.7%. (Table 2) Conclusion The following entry criteria may help increase the likelihood that trial subjects have active SLE: ANA≥1:640, or DNA, or ENA, or low C3 or C4. To the extent that a modest loss of recruitment increases the probability of entering true, active SLE patients, these alternative constructs should be considered in future SLE trials. Disclosure of Interests: Ewa Olech Grant/research support from: Bristol Myers Squibb, Eduard van Rijen: None declared, Alexander Kant: None declared, Ali Ashrafzadeh Employee of: Employee of IQVIA, Joan T Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen

Background Regional differences have been identified as potential confounders of SLE clinical trial results. Recently, no difference between treatment and placebo was observed in the US lupus patients when a significant treatment effect was observed in Europe1. Objectives To compare SLE serologic features/markers of active disease between different geographic regions in recent multinational clinical trials. Methods Laboratory data of 1005 subjects from four global randomized SLE clinical trials at baseline were examined. Mean/median C3 and C4 complement levels, prevalence of low C3 or C4 (Low C3/C4), positive anti-double stranded DNA (DNA), anti-Extractable Nuclear Antibodies (ENA), and high-titer Antinuclear Antibody (ANA≥1:640) in North America (NA) patients were compared to Asia (AS), Latin America (LA), Africa (AF), Western Europe (WE), and Eastern Europe (EE) Results NA patients were significantly older than patients in LA, AF, or AS but not WE or EE. Not surprisingly, they also had higher complement levels and the lowest rates of low C3/C4, DNA, ENA, and ANA ≥1:640. Our data confirm that age is an important factor in the prevalence of low complement and autoantibodies. However, there remained a marked difference in serologic activity between NA and EE, despite being close in age. Asian patients were the youngest, had the lowest complement levels and the highest rate of ENA & DNA consistent with high disease activity. Low complement, but not DNA, was relatively common in Europe. LA patients, like Asians, had high rates of serologic activity but less incidence of low C3/C4, suggesting that this population may have intrinsic disease severity without being as acutely active. Conclusion SLE patients entering studies from North America are strikingly less likely to have markers of active disease than other regions, raising concerns for their suitability for trials. This appears to be associated, at least in part, with age, although more aggressive treatments cannot be ruled out. Asian subjects have the greatest prevalence of autoantibodies and low complement. Latin American patients have high prevalence of ANA≥1:640 and other autoantibodies, but less evidence of low complements. These findings may help to explain regional differences in treatment/placebo responses and emphasize the importance of geographical stratification and improved methods to screen out patients unsuitable for SLE trials. Reference [1] www.immupharma.co.uk Disclosure of Interests Ewa Olech Grant/research support from: Bristol Myers Squibb, Eduard van Rijen: None declared, Ali Ashrafzadeh Employee of: Employee of IQVIA, Alexander Kant: None declared, Joan T Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen

Background Abatacept (ABA) is a fusion protein of the extracellular domain of CTLA4 and the Fc domain of human IgG1, constructed to inhibit B/T cell co-stimulation. Previous studies of ABA in lupus failed to show benefit in overall disease activity, but improvement in arthritis was suggested. Objectives This 6-month randomized, double-blind, placebo-controlled (PBO) study withdrew background medications to facilitate the assessment of ABA in patients with SLE arthritis. Methods Patients were entered with moderate to severe arthritis [BILAG A or B with ≥3 swollen and ≥3 tender joints (28 joint count)]. All DMARDs except prednisone (up to 20mg daily) were withdrawn by baseline and patients were randomized 1:1 to weekly sc ABA or PBO. One or more DepoMedrol injections (≤320mg total) was allowed by end of Month 2. Additional steroids or immune suppressants (IMS) at any time, and transition to open label ABA at Month 3 or later, were allowed, but designated non-response. The primary endpoint was BICLA response at Month 6 compared to screening. Secondary objectives included SRI-4, SLEDAI 4-point improvement, SLEDAI arthritis resolution, BILAG A/B musculoskeletal (MSK) improvement, as well as low disease activity defined by either SLEDAI 2 or Lupus Low Disease Activity State (LLDAS) at Month 6. Flares were evaluated by the modified SELENA-SLEDAI flare index (1) in patients followed after baseline. Results 66 patients were randomized and received at least one dose of the study drug, 31 ABA and 35 PBO. 7 withdrew prior to Month 6. Placebo response rates were lower than in most SLE trials, but no primary or secondary endpoints were met, see table (Fischer’s exact test). Flares were evaluable in 64 patients (31 on ABA, 33 on PBO). 14 (45%) patients on ABA vs. 18 (55%) on PBO had a moderate/severe flare by Month 6. 22 (71%) patients on ABA vs. 23 (70%) on PBO experienced flare or treatment failure (early drop off or off protocol steroids or IMS) by Month 6. Rates of flare and treatment failure by Month 6 did not differ between groups (Log-Rank test, p=0.688 and p=0.631, respectively). The safety profile of ABA was consistent with known effects of the treatment. Conclusion ABA did not demonstrate improvement vs placebo in controlling disease activity or flare in SLE patients in a protocol that mandated IMS withdrawal. Placebo response rates of ≤23% support the validity of these results. Since some evidence suggests potential efficacy of ABA for certain biologic subsets of SLE (2), immunophenotyping may prove helpful. References [1] Thanou A, Chakravarty E, James JA, Merrill JT. Rheumatology (Oxford) 2014;53(12):2175-81. [2] Bandyopadhyay S, Connolly SE, Jabado O, Ye J, Kelly S, Maldonado MA, Westhovens R, Nash P, Merrill JT, Townsend RM. Lupus Sci Med. 2017 4 (1): e000206. Disclosure of Interests Aikaterini Thanou Grant/research support from: Bristol-Myers Squibb, Consultant for: Neovacs, Cristina Arriens Grant/research support from: Bristol-Myers Squibb, GSK/HGS, Consultant for: GSK, AstraZeneca, Teresa Aberle: None declared, Eliza Chakravary: None declared, Samera Vaseer: None declared, Joe Rawdon: None declared, Judith A. James: None declared, Joan Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen

Background: XmAb5871 is a humanized anti-CD19 antibody Fc-engineered for increased affinity to FcγRIIb. Co-ligation of CD19 and FcγRIIb inhibits B lineage cells key to SLE pathogenesis. Objectives: This Phase 2 study was designed to minimize background medications and placebo responses to improve interpretation of a small trial in a complex, heterogenous disease. Methods: SLE patients were enrolled with active disease, ameliorated during screening with ≥160 mg of IM Depo-Medrol. Improvement was required before randomization, defined by decrease in SLEDAI ≥4 points or ≥1 grade in a BILAG A or B score. Immunosuppressive drugs were stopped except antimalarials and/or ≤10 mg/day prednisone or equivalent. Subjects were randomized to IV XmAb5871 (5 mg/kg) or placebo and given Depo-Medrol 80 mg IM on Days 1 and 15, after which, steroid impact was expected to withdraw gradually. Study treatments were given Q14 days for up to 16 doses or loss of improvement (LOI), defined as SLEDAI increase ≥4 points OR new BILAG A or B, with investigator-determined significance. At LOI, patients could receive immediate standard treatments. The primary endpoint was the proportion with no LOI by Day 225 in the efficacy evaluable group (those completing Day 225 or withdrawn for LOI or drug-related adverse event). Results: 104 subjects were randomized: 99 female, median age 45 (20-65). The primary endpoint was met by 21 (42%) of XmAb5871-treated patients vs 12 (28.6%) of the placebo group (p=0.18). All but one responder also fulfilled the SRI-4 response definition from screening to completion. Results did not differ in those with or without anti-dsDNA and/or ENA antibodies. Time to flare was significantly longer in the XmAb5871 group (p=0.025) (figure 1). XmAb5871-treated patients with LOI had less recurrent disease after IM steroid cessation than those in the placebo group; 6 (20%) of placebo patients developed BILAG A scores vs 3 (13%) in the active arm. 9 (30%) of worsening placebo patients had SLEDAI increase ≥7 vs 0 in the XmAb5871 group. SLEDAI scores were higher and increased sooner after disease nadir with placebo vs XmAb5871 (figure 2); 16 (30.8%) of XmAb5871 patients vs 7 (13.5%) placebo patients sustained LLDAS (low disease) during months 6-8 (p=0.0453). Transient, infusion-related gastrointestinal side effects occurred in XmAb5871-treated patients during the 1st or 2nd infusion. There were 8 SAEs in 7 XmAb5871-treated subjects, 5 in 4 placebo patients, no opportunistic infections, and no deaths. Infection rate was low compared to other SLE trials. Conclusion: XmAb5871 was well-tolerated. Preliminary data from this small trial indicates suppression of disease recurrence after treatment withdrawal, supporting further evaluation of XmAb5871 in SLE. Disclosure of Interests: Joan Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen, Joshua June: None declared, Fotios Koumpouras: None declared, Wambui Machua: None declared, Mohammad Faisal Khan: None declared, Anca Askanase: None declared, Arezou Khosroshahi: None declared, Saira Sheikh: None declared, Judith A. James: None declared, Joel Guthridge: None declared, Gaurav Rathi Shareholder of: Xencor Inc, Employee of: Xencor Inc, Bart Burington Shareholder of: Xencor Inc, Employee of: Xencor Inc, Paul Foster Shareholder of: Xencor Inc, Employee of: Xencor Inc, Debra Zack Shareholder of: Xencor Inc, Employee of: Xencor Inc

Patients with systemic lupus erythematosus (SLE) face lifelong challenges from chronic and disabling symptoms. The toolkit for assessing patient progress lacks a simple, scalable index that includes both physician assessments and patient experiences. Clinician and patient reported outcomes (ClinROs and PROs) were developed in isolation and discrepancies in their results promote confusion. The Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL™) was designed as a simple, versatile instrument of simple additive scales. Dual physician and patient components allow for a complete evaluation of disease activity. This report presents the early development of the LFA-REAL™ PRO.An initial focus group was conducted consisting of 10 SLE patients who ranked 32 areas of health and identified additional domains that are important to people with lupus. Subsequently, 19 domains were ranked by 100 consecutive patients with SLE from New York and Oklahoma City.The 10 focus group participants were female and had a mean age of 38.6. The dimensions they identified were generally in two categories: symptoms and impacts. The main symptoms were fatigue, joint and muscle pain, and general pain. The main impacts were sleep, drug side effects, and physical well-being. The 100 patients with SLE (90% female, mean age 37.5 years) ranked the 19 fields of health in order of importance. The top eight domains ranked were joint and muscle pain, fatigue, experience of quality of life, general pain, physical well-being, emotional well-being, organ involvement, and family life. Clinicians reviewed the data and decided on an instrument that would differentiate between lupus related symptoms and impact on quality of life as well as differentiate active symptoms from chronic damage. The disease activity instrument draft included all the identified symptoms: rash, joint symptoms (pains, stiffness, and swelling), muscle pain, fatigue, organ involvement symptoms (fever, chest pain, shortness of breath, leg swelling, and other), and hair loss.The PRO derived here is a composite disease activity instrument to accompany the physician reported assessment. The ClinRO and the PRO will provide the spectrum of lupus disease activity and bring the patient's experience and provide essential quantitative data to the evaluation of lupus in routine clinical care and clinical research.

Background Lupus Nephritis (LN) usually presents within five years of SLE diagnosis. Male gender, Hispanic and African American race, and childhood-onset SLE portend greater risk of early nephritis. However, patients with late-occurring nephritis are poorly characterized. Since proliferative nephritis is a more aggressive class of nephritis than membranous and mesangial, we hypothesized that female gender, Caucasian race, adult-onset SLE, and membranous pathology would be associated with a later onset of nephritis. Methods A single large urban medical center was the source for retrospective record review of patients who underwent kidney biopsy between 1999 and 2015. Patients with biopsy-proven LN were evaluated to determine whether gender, race, age at SLE diagnosis, age at first biopsy, or histopathologic classification were associated with time between SLE diagnosis and first renal biopsy. Results 630 patients were screened. After elimination of duplicates, those without initial biopsy, biopsy findings other than LN, and unknown date of SLE diagnosis, 293 subjects had adequate data available for analysis. Those with late onset SLE, diagnosis after age 50, were excluded from further analysis due to known differences in this subgroup. The remaining 278 patients had characteristics shown in table 1. Twenty-nine percent of patients in this cohort developed nephritis more than 5 years after initial SLE diagnosis. Multivariable linear regression identified greater age at first biopsy and race as the strongest predictors of time between SLE diagnosis and first renal biopsy. Hispanic patients were more likely to present with LN earlier in their course and Asian patients were more likely to present later, with African American and Caucasian groups between them. The model accounts for 27% of the variability in the time elapsed between diagnosis and biopsy. Histopathologic class did not make a significant contribution, and proliferative nephritis was noted in similar numbers of patients who developed LN after 5 years and those in the early presenting group. Conclusions Surprisingly, more than a quarter of known LN patients at this large US center present after 5 years of SLE, higher than expected based on low numbers of late onset nephritis in other cohorts. This appears to be more common in Caucasian and Asian subgroups. Older patients are more likely to develop nephritis later, but aggressive histopathology is not less likely in later presentations. The data underscore the importance of remaining vigilant about nephritis risk in patients of diverse demographics five years and more after diagnosis with SLE. Funding Source(s): Mallinckrodt Research Fellowship, NIH:T32DK007257,UL1TR001105,U54GM104938,P30AR053483,U01AI101934,U19AI082714

Background Low disease activity (LDA) and remission are important goals in the treatment of patients with SLE.1 2 Lupus Low Disease Activity State (LLDAS) is associated with reduced damage accrual,2 and has been shown to be a feasible clinical trial endpoint.3 In patients with high disease activity (HDA; SLEDAI-2K ≥10) enrolled in the ADDRESS II study, atacicept improved SLE responder index (SRI)-6 response rates and flare prevention at Week 24 vs placebo. Atacicept also demonstrated an acceptable safety profile.4 We present a post-hoc analysis of data from ADDRESS II and its long-term extension, describing 48-week LDA and remission rates in patients with HDA at Screening. Methods In ADDRESS II, patients were randomized (1:1:1) to weekly subcutaneous atacicept 75 or 150 mg or placebo for 24 weeks. Atacicept-completers continued at the same dose in the extension study, while placebo-treated patients were switched to atacicept 150 mg (placebo/atacicept 150 mg). This post-hoc analysis assessed: LDA (SLEDAI-2K ≤2), LLDAS (SLEDAI-2K ≤4 without major organ activity, no new disease activity vs previous visit, Physician’s Global Assessment [PGA] ≤1, prednisone-equivalent ≤7.5 mg/day, and stable immunosuppressants),2 and remission (clinical SLEDAI-2K=0, PGA Results Of 306 ADDRESS II patients, 158 (51.6%) had HDA at Screening. At Week 24, 42.4% achieved SRI-6, 23.4% attained LDA, 15.8% LLDAS and 10.8% remission. At Week 48, 52.5% achieved SRI-6, 26.6% attained LDA, 19.0% LLDAS and 10.8% remission. Among 83 patients with HDA at Screening who had an SRI-6 response at Week 48, 49.4% (n=41) attained LDA, 34.9% (n=29) LLDAS and 20.5% (n=17) remission. At 48 weeks, LDA, LLDAS and remission rates were higher in patients treated with atacicept 150 mg vs atacicept 75 mg and vs placebo/atacicept 150 mg (figure 1). Conclusions ADDRESS II patients with HDA at Screening who received atacicept 150 mg were more likely to attain LDA, LLDAS and remission at Week 48 than those treated with atacicept 75 mg or placebo/atacicept 150 mg. These endpoints were more stringent and discriminatory than SRI-6, confirming LLDAS, LDA, and remission to be robust and meaningful endpoints for SLE trials. In addition, these data further support future studies of atacicept in SLE. Funding Source(s): Merck KGaA, Darmstadt, Germany References Van Vollenhoven et al. Ann Rheum Dis 2017. Franklyn et al. Ann Rheum Dis 2016. Morand et al. Ann Rheum Dis 2018. Merrill et al. Arthritis Rheum 2018.

Background A universal hallmark of systemic lupus erythematosus (SLE) is the presence of antinuclear antibodies (ANAs). While their cognate antigens and ANA levels can associate with SLE subphenotypes, many individuals develop ANAs years prior to autoimmune disease manifestations or never develop any clinical symptoms. At present, the mechanisms governing the transition from autoantibody production to disease onset remain unknown. Methods To ascertain differences in immune cell populations and their transcriptional state, we performed scRNA-seq on peripheral blood mononuclear cells from 30 patients, including African and European American individuals with lupus-associated autoantibodies (n=10), SLE patients (n=10), and ANA- healthy controls (n=10). Transcriptomes were analyzed using canonical correlation analysis, the results of which were used by a smart local moving algorithm to identify cell population clusters and by Uniform Manifold Approximation and Projection for visualization. Differential expression of genes was assessed using Model-based Analysis of Single Cell Transcriptomics. Results Distinct cell populations could be identified for each disease classification. EA ANA +individuals showed a decrease in the number of naive B cells relative to SLE and healthy individuals; in contrast, AA ANA +individuals had higher numbers of centrocytes. Additionally, AA SLE patients demonstrated an enrichment of plasma cells relative to both ANA +and healthy individuals while FCRL5, a marker of dysfunctional B cells, was increased only in SLE memory B cells. Overall, AA ANA +cell populations showed an upregulation in a number of heat shock genes in ANA+ (HSPA6, HSPA1A, DNAJB1). Multipotent progenitor (MPP) cells from SLE patients of both ethnicities were marked by upregulation of interferon stimulated genes; ANA +MPPs, however, differed in that cells from AA individuals had an upregulation of housekeeping genes (GAPDH, PGK1) while anti-inflammatory NFKB1A was increased in EA MPPs. Comparison of a manually curated list of regulatory factors demonstrated dysregulation of several genes, including upregulation of TGFB across all AA ANA +cell clusters and an increase in CD46 in EA ANA +clusters. Similarly, gene set enrichment analysis of differentially regulated genes indicated activation of stress response pathways in AA and EA ANA +individuals. Conclusions These data indicate that substantial transcriptional and cell population differences exist among immune cells from ANA+, SLE, and healthy individuals, including an activated stress response and enhanced immune regulation in the cells from ANA +individuals. Our results suggest that cells from ANA +individuals may be regulating reactions to stimulation, and exhaustion of that response may allow for transition to SLE. Funding Source(s): NIH U54GM104938, U01AI101934, U19AI082714, and P30AR053483.

Background Anti-nuclear antibody (ANA) positivity is a principal feature of individuals with an autoimmune disease, yet up to one in five healthy individuals are ANA-positive (ANA+) and will never develop overt disease. Understanding differences in immune cell physiology between ANA+healthy individuals and individuals with clinical SLE remains a critical goal in the understanding of SLE pathogenesis across ethnicities. Methods Blood specimens and information on disease activity were collected from European (EA) and African American (AA) individuals classified and matched in groups as ANA- healthy controls (n=24), ANA +healthy (n=24) or SLE patients (n=24). Single-cell analysis of cell surface markers was completed by mass cytometry on PBMCs and cellular heterogeneity was visualized using tSNE (figure 1A–B) and manual gating. Further, phospho-specific flow cytometry was used to measure basal levels of pERK, pPLCg2 and p38 and expression following CD3/CD28 (TCR) and anti-IgG and IgM (BCR) stimulation. Whole genome RNA-sequencing was performed on flow cytometry sorted T cells, B cells and monocytes from 35 matched ANA-, ANA +and SLE patients followed by weighted correlation network analysis (WGCNA) and pathway enrichment analyses. Results Both European and African American SLE patients were distinguished from healthy individuals by T cell proliferation (p=0.002) (figure 1C), plasmacytoid dendritic cell activation (p=0.021) and elevated stem cell factor (p=0.0003). EA ANA+healthy individuals exhibited greater immune regulation with reduced T cell numbers (p=0.002) (figure 1C), decreased activation of dendritic cells (p=0.039) and transitional B cells (0.033), and elevated expression of the inhibitory receptor CD85j (p=0.042) on specific immune cell subsets compared to ANA- healthy subjects. Further, a module associated with hematopoiesis, T cell activation and intrinsic apoptosis signaling pathways is expressed at a higher level in T cells of EA ANA+individuals. In contrast, AA ANA+healthy individuals had elevated plasma levels of IL-6 (p=0.018) and reduced inhibitory receptor expression (p=0.0089) compared to ANA- healthy controls. Gene expression modules associated with viral responses and type I IFN pathway activation were identified in AA SLE patient B cells, while similar expression modules were only found in the monocytes of European American SLE patients. Conclusions These results highlight the importance of stem cell factor and T cell expansion in SLE pathogenesis, and suggest that mechanisms of SLE pathogenesis differ by ethnicity. ANA +European Americans may have more effective regulatory mechanisms in place to prevent transition to classified autoimmune disease. Funding Source(s): This work was supported by the NIH under award numbers U54GM104938, U01AI101934, U19AI082714, and P30AR053483.

Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by unpredictable organ and tissue involvement. Immunosuppressive drugs and corticosteroids (CS) are central to control serious SLE flares, but long-term use is associated with significant morbidity and may obscure distinctions between investigational treatments and placebo. BMS-986165 is an oral, selective TYK2 inhibitor that blocks cytokine signaling pathways key to SLE pathophysiology. A phase 2 trial of this agent is underway, designed to address some of these issues seen in lupus trials. Methods In this randomized, double-blind, placebo-controlled, global study (ClinicalTrials.gov: NCT03252587), adults diagnosed with SLE at least 24 weeks before screening, and with antinuclear antibody titer of 1:80 or who were positive for anti-double-stranded DNA or anti-Smith antibodies, are being randomized (1:1:1:1) to placebo or 1 of 3 doses of BMS-986165 (figure 1). The primary endpoint is the SLE Responder Index 4 (SRI-4) response rate at Week 32. Secondary endpoints include Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) response rate, British Isles Lupus Assessment Group-based Composite Lupus Assessment response rate, both at Week 32, and safety. Key inclusion criteria include SLE Disease Activity Index 2000 (SLEDAI-2K) of 6 points, with active joint and/or skin involvement. Eligible patients must have received standard of care background immune modulators for 12 weeks. CS are permitted. Trial designs that encourage CS tapering or other limitations to background treatments have been associated with increased discrimination between treatments and placebo by lowering relative rates of placebo responses. In the current study, CS tapering is required for all patients whose disease has not worsened. Results Planned enrollment is 360 patients (90 per cohort) at approximately 170 sites in 15 countries. A monitored review of medically appropriate disease activity scoring and tapering of CS is a part of the administration of this trial. Accrual into the PAISLEY study is ongoing. Conclusions This study will characterize the efficacy and safety of BMS-986165, which works by a novel mechanism of TYK2 inhibition, in patients with moderate to severe manifestations of SLE. Funding Source(s): Bristol-Myers Squibb

Background XmAb5871 is a humanized anti-CD19 antibody Fc-engineered for increased affinity to FcgammaRIIb. Co-ligation of CD19 and FcgammaRIIb inhibits B lineage cells key to lupus pathogenesis. This Phase 2 study in SLE was designed to minimize background medications and placebo responses to improve interpretation of a small trial in a complex, heterogenous disease. Methods Patients were enrolled with active, non-organ threatening disease, and treated until improved with 160 mg of IM Depo-Medrol. Immunosuppressive drugs were withdrawn except antimalarials or 10 mg/day prednisone or equivalent before randomization to IV XmAb5871 (5 mg/kg) or placebo. Study treatments were given Q14 days until Day 225 or loss of improvement (LOI), defined as SLEDAI increase 4 points OR new BILAG A or B, with investigator-rated clinical significance. At LOI, patients resumed standard of care. The primary endpoint was the proportion of subjects without LOI by Day 225 in the efficacy evaluable group (those who completed Day 225 or discontinued due to LOI or a drug-related adverse event). Patients who withdrew for other reasons were excluded from this analysis. Results 104 patients were randomized. In the efficacy evaluable population, 42% of XmAb5871-treated subjects reached Day 225 without LOI vs 28.6% of the placebo group (p=0.18) with 40.4% vs 23.1% (p=0.06) achieving this endpoint in the ITT population. In those with LOI, no (0%) XmAb5871 patients vs 9 (30%) placebo had SLEDAI increase 7 with 3 (13%) vs 7 (23%) developing BILAG A scores. Six XmAb5871-treated patients were withdrawn for infusion-related events. The efficacy evaluable population excluded 10 placebo patients vs 2 XmAb5871 for other reasons, increasing placebo response proportions compared to the ITT population. Time to LOI was significantly longer in XmAb5871-treated patients than placebo (p=0.025, see figure 1). The most common AEs in XmAb5871-treated patients were transient, infusion-related gastrointestinal side effects during the 1 st or 2nd infusion. There were 8 SAEs in 7 XmAb-treated subjects, 5 in 4 placebo patients, no opportunistic infections, and no deaths. Infection rate was low compared to other SLE trials. Conclusions Results from this small trial, designed to maximize interpretability, supports further evaluation of XmAb5871 in SLE. Funding Source(s): This study was funded by Xencor Inc.

Background Although systemic lupus erythematosus (SLE) disproportionately affects minority racial groups, they are significantly under-represented in clinical trials. This produces underpowered conclusions in race-based sub-group analyses. The decision to participate in clinical research is complex. Primary care providers (PCPs) have the ability to introduce the idea of clinical trials and to refer to specialists who participate in clinical trials. We evaluated SLE knowledge and implicit bias in clinical research participation in both PCPs and lupus patients. Methods Lupus patients and PCPs completed a pre-test consisting of knowledge and belief questions followed by an educational program about lupus, clinical research, and human subjects protections. The same questions were repeated as part of the post-test. Responses to knowledge questions were analyzed by Fishers exact test for between group (patients vs. PCPs) comparisons or McNemars test for within group (pre-test vs. post-test) comparisons. Belief questions were scored on a Likert scale and analyzed by Mann-Whitney or Wilcoxon matched pairs for between group and within group comparisons. Results 55 providers and 32 lupus patients completed the questionnaires and educational program. Knowledge topics included 1) triggers of SLE, 2) lupus racial differences, and 3) informed consent. There was a statistically significant difference between PCPs and patients on the pre-test informed consent topic (PCP 46% correct and patient 15%, p=0.0005). Post-test results were similar between groups. The education program resulted in improvement in knowledge scores for PCPs (Q1 42% to 85%, p Conclusions Beliefs about race, education, and poverty may impact referral to clinical trial centers and clinical trial participation. More than a third of PCPs believe that indigent people are poor candidates for clinical trials. Despite a shift away from this attitude following an educational program, providers remained much more likely than lupus patients to hold this opinion. Funding Source(s): HHS-OMH-CPI-MP-17-002-1

OBJECTIVE: To determine, in a large, multiethnic/multiracial, prospective inception cohort of patients with systemic lupus erythematosus (SLE), the frequency, attribution, clinical, and autoantibody associations with lupus psychosis and the short- and long-term outcomes as assessed by physicians and patients.METHODS: Patients were evaluated annually for 19 neuropsychiatric (NP) events including psychosis. Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and the Short Form 36 (SF-36) were recorded. Time to event and linear regressions were used as appropriate.RESULTS: Of 1,826 SLE patients, 88.8% were female and 48.8% were Caucasian. The mean ± SD age was 35.1 ± 13.3 years, the mean ± SD disease duration was 5.6 ± 4.2 months, and the mean ± SD follow-up period was 7.4 ± 4.5 years. There were 31 psychotic events in 28 of 1,826 patients (1.53%), and most patients had a single event (26 of 28 [93%]). In the majority of patients (20 of 25 [80%]) and events (28 of 31 [90%]), psychosis was attributed to SLE, usually either in the year prior to or within 3 years of SLE diagnosis. Positive associations (hazard ratios [HRs] and 95% confidence intervals [95% CIs]) with lupus psychosis were previous SLE NP events (HR 3.59 [95% CI 1.16-11.14]), male sex (HR 3.0 [95% CI 1.20-7.50]), younger age at SLE diagnosis (per 10 years) (HR 1.45 [95% CI 1.01-2.07]), and African ancestry (HR 4.59 [95% CI 1.79-11.76]). By physician assessment, most psychotic events resolved by the second annual visit following onset, in parallel with an improvement in patient-reported SF-36 summary and subscale scores.CONCLUSION: Psychosis is an infrequent manifestation of NPSLE. Generally, it occurs early after SLE onset and has a significant negative impact on health status. As determined by patient and physician report, the short- and long-term outlooks are good for most patients, although careful follow-up is required.

OBJECTIVE: To evaluate the properties of a frailty index (FI), constructed using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort, as a novel health measure in systemic lupus erythematosus (SLE).METHODS: For this secondary analysis, the baseline visit was defined as the first study visit at which both organ damage (SLICC/American College of Rheumatology Damage Index [SDI]) and health-related quality of life (Short-Form 36 [SF-36] scores) were assessed. The SLICC-FI was constructed using baseline data. The SLICC-FI comprises 48 health deficits, including items related to organ damage, disease activity, comorbidities, and functional status. Content, construct, and criterion validity of the SLICC-FI were assessed. Multivariable Cox regression was used to estimate the association between baseline SLICC-FI values and mortality risk, adjusting for demographic and clinical factors.RESULTS: In the baseline data set of 1,683 patients with SLE, 89% were female, the mean ± SD age was 35.7 ± 13.4 years, and the mean ± SD disease duration was 18.8 ± 15.7 months. At baseline, the mean ± SD SLICC-FI score was 0.17 ± 0.08 (range 0-0.51). Baseline SLICC-FI values exhibited the expected measurement properties and were weakly correlated with baseline SDI scores (r = 0.26, P < 0.0001). Higher baseline SLICC-FI values (per 0.05 increment) were associated with increased mortality risk (hazard ratio 1.59, 95% confidence interval 1.35-1.87), after adjusting for age, sex, steroid use, ethnicity/region, and baseline SDI scores.CONCLUSION: The SLICC-FI demonstrates internal validity as a health measure in SLE and might be used to predict future mortality risk. The SLICC-FI is potentially valuable for quantifying vulnerability among patients with SLE, and adds to existing prognostic scores.

OBJECTIVE: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE. METHODS: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI). RESULTS: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03-1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007). CONCLUSION: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease. This study was funded by grants from the Swedish RheumatismAssociation, the Region Östergötland (ALF Grants), the King Gustaf V's80-year Anniversary Foundation, and the King Gustaf V and QueenVictoria's Freemasons Foundation. Dr. Bruce is a National Institute forHealth Research (NIHR) Senior Investigator and is funded by VersusArthritis, the NIHR Manchester Biomedical Research Centre, and theNIHR/Welcome Trust Manchester Clinical Research Facility. Dr.Caroline Gordon is supported by Lupus UK, the Sandwell and WestBirmingham Hospitals NHS Trust, and the National Institute for HealthResearch (NIHR)/Wellcome Trust Birmingham Clinical ResearchFacility. The views expressed are those of the author(s) and are notnecessarily those of the NHS, the NIHR or the Department of Health.Rosalind Ramsey-Goldman's work was supported by the NIH (grants8UL1TR000150, formerly UL-1RR-025741, K24-AR-02318 andP60AR064464, formerly P60-AR-48098). Dr. Sang-Cheol Bae's workwas supported in part by funding (NRF-2017M3A9B4050335) from theNational Research Foundation of Korea.

Objective. In cross-sectional studies, elevated osteopontin (OPN) levels have been proposed to reflect, and/or precede, progressive organ damage and disease severity in systemic lupus erythematosus (SLE). We aimed, in a cohort of patients with recent-onset SLE, to determine whether raised serum OPN levels precede damage and/or are associated with disease activity or certain disease phenotypes. Methods. We included 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who had 5 years of followup data available. All patients fulfilled the 1997 American College of Rheumatology (ACR) criteria. Baseline sera from patients and from age-and sex-matched population-based controls were analyzed for OPN using ELISA. Disease activity and damage were assessed at each annual followup visit using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the SLICC/ACR damage index (SDI), respectively. Results. Compared to controls, baseline OPN was raised 4-fold in SLE cases (p amp;lt; 0.0001). After relevant adjustments in a binary logistic regression model, OPN levels failed to significantly predict global damage accrual defined as SDI amp;gt;= 1 at 5 years. However, baseline OPN correlated with SLEDAI-2K at enrollment into the cohort (r = 0.27, p amp;lt; 0.0001), and patients with high disease activity (SLEDAI-2K amp;gt;= 5) had raised serum OPN (p amp;lt; 0.0001). In addition, higher OPN levels were found in patients with persistent disease activity (p = 0.0006), in cases with renal involvement (p amp;lt; 0.0001) and impaired estimated glomerular filtration rate (p = 0.01). Conclusion. The performance of OPN to predict development of organ damage was not impressive. However, OPN associated significantly with lupus nephritis and with raised disease activity at enrollment, as well as over time. Funding Agencies|Swedish Rheumatism Association; County Council of Ostergotland; Swedish Society of Medicine; King Gustaf V and Queen Victorias Freemasons foundation; King Gustaf Vs 80-year anniversary foundation; Hanyang University [201600000001387]; Lupus UK; NIHR/Wellcome Trust Clinical Research Facility; US National Institutes of Health (NIH) [AR43727]; Singer Family Fund for Lupus Research; Arthritis Research UK; NIHR Manchester Biomedical Research Centre; NIHR/Wellcome Trust Clinical Research Facility at Manchester University National Health Service (NHS) Foundation Trust; Danish Rheumatism Association [A1028]; NIH [RR00046]

SLE is a clinically heterogeneous disease characterized by an unpredictable relapsing-remitting disease course. Although the etiology and mechanisms of SLE flares remain elusive, Epstein-Barr virus (EBV) reactivation is implicated in SLE pathogenesis. This study examined the relationships between serological measures of EBV reactivation, disease activity, and interferon (IFN)-associated immune pathways in SLE patients. Sera from adult SLE patients (n = 175) and matched unaffected controls (n = 47) were collected and tested for antibodies against EBV-viral capsid antigen (EBV-VCA; IgG and IgA), EBV-early antigen (EBV-EA; IgG), cytomegalovirus (CMV; IgG), and herpes simplex virus (HSV-1; IgG). Serological evidence of EBV reactivation was more common in SLE patients compared to controls as demonstrated by seropositivity to EBV-EA IgG (39% vs 13%; p = 0.0011) and EBV-VCA IgA (37% vs 17%; p = 0.018). EBV-VCA, CMV1, and HSV-1 IgG seropositivity rates did not differ between SLE patients and controls. Furthermore, concentrations of EBV-VCA (IgG and IgA) and EBV-EA (IgG) were higher in SLE patients. SLE patients with high disease activity had increased concentrations of EBV-VCA IgA (mean ISR 1.34 vs. 0.97; p = 0.041) and EBV-EA IgG levels (mean ISR 1.38 vs. 0.90; p = 0.007) compared with those with lower disease activity. EBV reactivation was associated with enhanced levels of the IFN-associated molecule IP-10 (p, Highlights • Serologic markers of EBV reactivation are more common in SLE patients. • Elevated EBV reactivation is associated with higher SLE disease activity. • EBV serologic reactivation correlates with elevated IP-10, IL-10, and BLyS levels. • EBV reactivation occurs in SLE clusters with robust inflammatory and IFN responses.

Objective Antinuclear antibodies (ANAs) are detected in ∼18% of females, yet autoimmune disease develops in only 5–8%. Immunologic differences between ANA-positive healthy individuals and patients with systemic lupus erythematosus (SLE) may elucidate the regulatory mechanisms by which ANA-positive individuals avoid transition to clinical autoimmune disease. Methods Healthy individuals (n = 790) were screened for autoantibodies specific for 11 antigens associated with lupus, systemic sclerosis, and Sjogren's syndrome. From this screening, 31 European American ANA-positive healthy individuals were selected and demographically matched to ANA-negative controls and SLE patients. Serum cytokine profiles, leukocyte subset frequency, and reactivity were analyzed by multiplex assays, immunophenotyping, and phosphospecific flow cytometry. Results Of 790 individuals screened, 57 (7%) were ANA-positive. The majority of proinflammatory cytokines, including interferon-γ (IFNγ), tumor necrosis factor, interleukin-17 (IL-17), and granulocyte colony-stimulating factor, exhibited a stepwise increase in serum levels from ANA-negative controls to ANA-positive healthy individuals to SLE patients (P < 0.0001). IFNα, IFNβ, IL-12p40, and stem cell factor/c-Kit ligand were increased in SLE patients only (P < 0.05). B lymphocyte stimulator (BlyS) was elevated in SLE patients but decreased in ANA-positive individuals (P < 0.001). Further, IL-1 receptor antagonist (IL-1Ra) was down-regulated in SLE patients only (P < 0.0001). ANA-positive individuals had increased frequencies of monocytes, memory B cells, and plasmablasts and increased levels of pSTAT-1 and pSTAT-3 following IFNα stimulation compared with ANA-negative controls (P < 0.05). Conclusion ANA-positive healthy individuals exhibit dysregulation in multiple immune pathways yet differ from SLE patients by the absence of elevated IFNs, BLyS, IL-12p40, and stem cell factor/c-Kit ligand. Further, severely decreased levels of IL-1Ra in SLE patients compared with ANA-positive individuals may contribute to disease development. These results highlight the importance of IFN-related pathways and regulatory elements in SLE pathogenesis.

Objective Systemic lupus erythematosus (SLE) is a relapsing autoimmune disease that affects multiple organ systems. T cells play an important role in the pathogenesis of lupus; however, early T cell events triggering disease flares are incompletely understood. This study was undertaken to examine DNA methylation in naive CD4+ T cells from lupus patients to determine if epigenetic remodeling in CD4+ T cells is an early event in lupus flares. Methods A total of 74 lupus patients with an SLE Disease Activity Index score of 0-18 were included. Naive CD4+ T cells were isolated from peripheral blood samples, and DNA was extracted for genome-wide methylation assessment. RNA was also extracted from a subset of patients to determine the relationship between epigenetic changes and transcription activity using RNA sequencing and microRNA arrays. Results We demonstrated that naive CD4+ T cells in lupus undergo an epigenetic proinflammatory shift, implicating effector T cell responses in lupus flare. This epigenetic landscape change occurs without changes in expression of the corresponding genes, poises naive CD4+ T cells for Th2, Th17, and follicular helper T cell immune responses, and opposes inhibitory transforming growth factor β signaling. Bioinformatics analyses indicate that the epigenetic modulator EZH2 might play an important role in shifting the epigenetic landscape, with increased disease activity in lupus naive CD4+ T cells. Further, the expression of microRNA-26a, which is sensitive to glucose availability and targets EZH2, was negatively correlated with disease activity in lupus patients. Conclusion An epigenetic landscape shift in naive CD4+ T cells that favors T cell activation and non-Th1 immune responses predates transcription activity and correlates with lupus activity. A role for EZH2 dysregulation in triggering lupus flares warrants further investigation.

OBJECTIVE To measure variance in antiphospholipid antibody (aPL) levels during pregnancy and to determine if variation affects pregnancy outcomes. METHODS We used data from the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study, a multicenter prospective study of pregnant women with aPL and/or systemic lupus erythematosus (SLE). Antiphospholipid antibodies were considered present if any of the following were positive: anticardiolipin (aCL), anti-β2 -glycoprotein I (anti-β2 GPI) titers ≥40 IgG phospholipid (GPL) or IgM phospholipid (MPL) units, and/or lupus anticoagulant (LAC). Antiphospholipid antibodies were measured every trimester and postpartum. Adverse pregnancy outcomes were defined as fetal/neonatal death, preterm delivery (

Objective: To study bidirectional change and predictors of change in estimated glomerular filtration rate (GFR) and proteinuria in lupus nephritis (LN) using a multistate modeling approach. Methods: Patients in the Systemic Lupus International Collaborating Clinics inception cohort were classified annually into estimated GFR state 1 (>60 ml/minute), state 2 (30–60 ml/minute), or state 3 (3.0 gm/day), or end-stage renal disease (ESRD) or death. Using multistate modeling, relative transition rates between states indicated improvement and deterioration. Results: Of 1,826 lupus patients, 700 (38.3%) developed LN. During a mean ± SD follow-up of 5.2 ± 3.5 years, the likelihood of improvement in estimated GFR and estimated proteinuria was greater than the likelihood of deterioration. After 5 years, 62% of patients initially in estimated GFR state 3 and 11% of patients initially in estimated proteinuria state 3 transitioned to ESRD. The probability of remaining in the initial states 1, 2, and 3 was 85%, 11%, and 3%, respectively, for estimated GFR and 62%, 29%, and 4%, respectively, for estimated proteinuria. Male sex predicted improvement in estimated GFR states; older age, race/ethnicity, higher estimated proteinuria state, and higher renal biopsy chronicity scores predicted deterioration. For estimated proteinuria, race/ethnicity, earlier calendar years, damage scores without renal variables, and higher renal biopsy chronicity scores predicted deterioration; male sex, presence of lupus anticoagulant, class V nephritis, and mycophenolic acid use predicted less improvement. Conclusion: In LN, the expected improvement or deterioration in renal outcomes can be estimated by multistate modeling and is preceded by identifiable risk factors. New therapeutic interventions for LN should meet or exceed these expectations. (Less)