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Type I interferons (IFN) causes inflammatory responses to pathogens, and can be elevated in autoimmune diseases such as systemic lupus erythematosus (SLE). We previously reported unexpected associations of increased numbers of B lymphocytes expressing the DNA-binding protein ARID3a with both IFN alpha (IFNα) expression and increased disease activity in SLE. Here, we determined that IFNα producing low density neutrophils (LDNs) and plasmacytoid dendritic cells (pDCs) from SLE patients exhibit strong associations between ARID3a protein expression and IFNα production. Moreover, SLE disease activity indices correlate most strongly with percentages of ARID3a(+) LDNs, but were also associated, less significantly, with IFNα expression in LDNs and pDCs. Hierarchical clustering and transcriptome analyses of LDNs and pDCs revealed SLE patients with low ARID3a expression cluster with healthy controls and identified gene profiles associated with increased proportions of ARID3a- and IFNα-expressing cells of each type. These data identify ARID3a as a potential transcription regulator of IFNα-related inflammatory responses and other pathways important for SLE disease activity.

Interactions between gut microbes and the immune system influence autoimmune disorders like systemic lupus erythematosus (SLE). Recently, Enterococcus gallinarum, a gram-positive commensal gut bacterium, was implicated as a candidate pathobiont in SLE. The present study was undertaken to evaluate the influence of E. gallinarum exposure on clinical parameters of SLE. Since circulating IgG antibodies to whole bacteria have been established as a surrogate marker for bacterial exposure, anti-E. gallinarum IgG antibodies were measured in banked serum samples from SLE patients and healthy controls in the Oklahoma Cohort for Rheumatic Diseases. The associations between anti-E. gallinarum antibody titers and clinical indicators of lupus were studied. Antibodies to human RNA were studied in a subset of patients. Our results show that sera from both patients and healthy controls had IgG and IgA antibodies reactive with E. gallinarum. The antibody titers between the two groups were not different. However, SLE patients with Ribosomal P autoantibodies had higher anti-E. gallinarum IgG titers compared to healthy controls. In addition to anti-Ribosomal P, higher anti-E. gallinarum titers were also significantly associated with the presence of anti-dsDNA and anti-Sm autoantibodies. In the subset of patients with anti-Ribosomal P and anti-dsDNA, the anti-E. gallinarum titers correlated significantly with antibodies to human RNA. Our data show that both healthy individuals and SLE patients were sero-reactive to E. gallinarum. In SLE patients, the immune response to E. gallinarum was associated with antibody response to a specific subset of lupus autoantigens. These findings provide additional evidence that E. gallinarum may be a pathobiont for SLE in susceptible individuals.

Previous studies on blood transcription profiles of patients with cutaneous lupus (CLE) have primarily used a gene expression approach. The large amount of data involved in these studies can make data analysis and interpretation cumbersome. Consequently, a novel approach in gene expression analyses was devised that groups genes into transcriptional modules (i.e., apoptosis, protein synthesis, inflammation) to identify important themes and relevant genes. This approach was used to study gene expression in systemic lupus patients and subsequently identified a unique interferon signature. Thus, we aim to use the modular analysis approach to identify unique modules and genes of CLE patients in order to better understand their disease pathophysiology. We conducted RNA sequencing of whole transcriptomes of blood from 66 CLE patients and 10 human controls and subsequently performed modular analyses. Based on module scores, we performed an unsupervised cluster analysis to identify subgroups of CLE patients with distinct gene expression patterns. Statistical analyses comparing module scores of these clusters was performed using the Kruskal-Wallis tests with Bonferroni’s correction. Modules were associated with patient subgroups distinguished by demographic, clinical, and laboratory features such as CLE subtypes, autoantibody profiles (BioPlex(®) 2200 ANA Screen with MDSS), and cytokine profiles (Thermo Scientific ProCarta xMAP cytokine assay kits). The unsupervised cluster analysis identified eight distinct clusters of CLE patients and controls. A neutrophilic predominant signature governed by azurophilic granule genes (i.e., BPI, LTF, MPO) and neutrophil chemotaxis genes (CEACAM6, CEACAM8) was seen in two groups of patients mostly with subacute lupus erythematosus (SCLE) [n=7 (77.8% of total SCLE)] or lupus erythematosus tumidus (LET) [n=6 (60% of total LET)] and European-American descent [n=28 (53.6% of total European-Americans)]. Four groups consisting of a majority of discoid lupus erythematosus (DLE) patients [n=29 (60% of total DLE)] had a predominant T cell signature driven by genes important for antigen presentation and T cell proliferation and differentiation (i.e., SKAP1, ITK). Our data suggests that unique cell populations may help differentiate CLE subgroups, which can potentially affect their disease course and treatment selection. Further studies examining individual gene and protein levels are necessary to confirm our hypotheses.

COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins., Infection with SARS-CoV2 and the development of Coronavirus disease 2019 (COVID-19) has been linked to induction of autoimmunity and autoantibody production. Here the authors characterise the new-onset IgG autoantibody response in hospitalised patients with COVID-19 which they correlate to the magnitude of the SARS-CoV2 response.

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease. Infections or infectious reactivation are potential triggers for initiation of autoimmunity and for SLE flares. Epstein-Barr virus (EBV) is gamma herpes virus that has been associated with several autoimmune diseases such as SLE, multiple sclerosis, Sjogren’s syndrome, and systemic sclerosis. In this review, we will discuss the recent advances regarding how EBV may contribute to immune dysregulation, and how these mechanisms may relate to SLE disease progression.

Background Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease with clinical sequelae such as itching, dyspigmentation and scarring. Objectives We applied a previously described modular analysis approach to assess the molecular heterogeneity of patients with CLE. Methods Whole-blood transcriptomes of RNA sequencing data from a racially and ethnically diverse group of patients with CLE (n = 62) were used to calculate gene co-expression module scores. An unsupervised cluster analysis and k-means clustering based on these module scores were then performed. We used Fisher's exact tests and Kruskal-Wallis tests to compare characteristics between patient clusters. Results Six unique clusters of patients with CLE were identified from the cluster analysis. We observed that seven inflammation modules were elevated in two clusters of patients with CLE. Additionally, these clusters were characterized by interferon, neutrophil and cell-death signatures, suggesting that interferon-related proteins, neutrophils and cell-death processes could be driving the inflammatory response in these subgroups. Three different clusters had a predominant T-cell signature, which were supported by lymphocyte counts. Conclusions Our data support a diverse molecular profile in CLE that further adds to the clinical variations of this skin disease, and may affect disease course and treatment selection. Future studies with a larger and diverse cohort of patients with CLE are warranted to confirm these findings.

Understanding how the brain allocates resources to match the demands of active neurons under physiological conditions is critically important. Increased metabolic demands of active brain regions are matched with hemodynamic responses known as neurovascular coupling (NVC). Several methods that allow noninvasive assessment of brain activity in humans detect NVC and early detection of NVC impairment may serve as an early marker of cognitive impairment. Therefore, non-invasive NVC assessments may serve as a valuable tool to detect early signs of cognitive impairment and dementia. Working memory tasks are routinely employed in the evaluation of cognitive task-evoked NVC responses. However, recent attempts that utilized functional near-infrared spectroscopy (fNIRS) or transcranial Doppler sonography (TCD) while using a similar working memory paradigm did not provide convincing evidence for the correlation of the hemodynamic variables measured by these two methods. In the current study, we aimed to compare fNIRS and TCD in their performance of differentiating NVC responses evoked by different levels of working memory workload during the same working memory task used as cognitive stimulation. Fourteen healthy young individuals were recruited for this study and performed an n-back cognitive test during TCD and fNIRS monitoring. During TCD monitoring, the middle cerebral artery (MCA) flow was bilaterally increased during the task associated with greater cognitive effort. fNIRS also detected significantly increased activation during a more challenging task in the left dorsolateral prefrontal cortex (DLPFC), and in addition, widespread activation of the medial prefrontal cortex (mPFC) was also revealed. Robust changes in prefrontal cortex hemodynamics may explain the profound change in MCA blood flow during the same cognitive task. Overall, our data support our hypothesis that both TCD and fNIRS methods can discriminate NVC evoked by higher demand tasks compared to baseline or lower demand tasks.

Infections may act as environmental triggers, inducing, promoting, and/or complicating systemic lupus erythematosus (SLE). Environmental exposures may influence SLE development in select individuals, and several mechanisms link these agents with lupus pathogenesis. Molecular mimicry, epitope spreading, exaggerated local activation of antigen-presenting cells, and priming of large numbers of T cells with broad specificities may have important roles in lupus autoimmunity. Polyclonal activation of infected B cells results in B-cell proliferation, enhanced antibody production, and generation of circulating immune complexes, as well as bystander T-cell activation, all of which may promote overt disease. At the genetic level, Epstein–Barr virus (EBV) broadly disrupts genetic regulation of immune responses through viral transcription factors such as Epstein–Barr virus nuclear antigen 2, and interactions between lupus-associated genetic variants and EBV may contribute to disease risk. Finally, infections can influence the SLE phenotype, trigger disease flares, and cause extensive morbidity and mortality in SLE patients. Interactions between infections and select lupus genetic polymorphisms influence the specific impact of infectious exposures. Work is ongoing to understand the complex interactions between environmental factors and SLE pathogenesis.

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.

Clostridioides difficile is a leading cause of nosocomial infection responsible for significant morbidity and mortality with limited options for therapy. Secreted C. difficile toxin B (TcdB) is a major contributor to disease pathology, and select TcdB-specific Abs may protect against disease recurrence. However, the high frequency of recurrence suggests that the memory B cell response, essential for new Ab production following C. difficile reexposure, is insufficient. We therefore isolated TcdB-specific memory B cells from individuals with a history of C. difficile infection and performed single-cell deep sequencing of their Ab genes. Herein, we report that TcdB-specific memory B cell–encoded antibodies showed somatic hypermutation but displayed limited isotype class switch. Memory B cell–encoded mAb generated from the gene sequences revealed low to moderate affinity for TcdB and a limited ability to neutralize TcdB. These findings indicate that memory B cells are an important factor in C. difficile disease recurrence., The C. difficile toxin-specific human memory B cell repertoire encodes low-affinity, non-neutralizing antibodies.

Background Immunologic aging leads to immune dysfunction, significantly reducing the quality of life of the elderly. Aged-related defects in early hematopoiesis result in reduced lymphoid cell development, functionally defective mature immune cells, and poor protective responses to vaccines and pathogens. Despite considerable progress understanding the underlying causes of decreased immunity in the elderly, the mechanisms by which these occur are still poorly understood. The DNA-binding protein ARID3a is expressed in a subset of human hematopoietic progenitors. Inhibition of ARID3a in bulk human cord blood CD34+ hematopoietic progenitors led to developmental skewing toward myeloid lineage at the expense of lymphoid lineage cells in vitro. Effects of ARID3a expression in adult-derived hematopoietic stem cells (HSCs) have not been analyzed, nor has ARID3a expression been assessed in relationship to age. We hypothesized that decreases in ARID3a could explain some of the defects observed in aging. Results Our data reveal decreased frequencies of ARID3a-expressing peripheral blood HSCs from aged healthy individuals compared with young donor HSCs. Inhibition of ARID3a in young donor-derived HSCs limits B lineage potential, suggesting a role for ARID3a in B lymphopoiesis in bone marrow-derived HSCs. Increasing ARID3a levels of HSCs from aged donors in vitro alters B lineage development and maturation. Finally, single cell analyses of ARID3a-expressing HSCs from young versus aged donors identify a number of differentially expressed genes in aged ARID3A-expressing cells versus young ARID3A-expressing HSCs, as well as between ARID3A-expressing and non-expressing cells in both young and aged donor HSCs. Conclusions These data suggest that ARID3a-expressing HSCs from aged individuals differ at both molecular and functional levels compared to ARID3a-expressing HSCs from young individuals.

Understanding immune responses to native antigens in response to natural infections can lead to improved approaches to vaccination. This study sought to characterize the humoral immune response to anthrax toxin components, capsule and spore antigens in individuals (n = 46) from the Kayseri and Malatya regions of Turkey who had recovered from mild or severe forms of cutaneous anthrax infection, compared to regional healthy controls (n = 20). IgG antibodies to each toxin component, the poly-γ-D-glutamic acid capsule, the Bacillus collagen-like protein of anthracis (BclA) spore antigen, and the spore carbohydrate anthrose, were detected in the cases, with anthrax toxin neutralization and responses to Protective Antigen (PA) and Lethal Factor (LF) being higher following severe forms of the disease. Significant correlative relationships among responses to PA, LF, Edema Factor (EF) and capsule were observed among the cases. Though some regional control sera exhibited binding to a subset of the tested antigens, these samples did not neutralize anthrax toxins and lacked correlative relationships among antigen binding specificities observed in the cases. Comparison of serum binding to overlapping decapeptides covering the entire length of PA, LF and EF proteins in 26 cases compared to 8 regional controls revealed that anthrax toxin-neutralizing antibody responses elicited following natural cutaneous anthrax infection are directed to conformational epitopes. These studies support the concept of vaccination approaches that preserve conformational epitopes. Copyright: © 2020 Dumas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

BackgroundSystemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further.ResultsWe perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody.ConclusionsWe demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.

Objective While prior Epstein–Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections. Methods Cases with pediatric‐onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses‐1 (HSV‐1) and ‐2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA‐DRB1:1501 status. Results A total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV‐viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5–12.0, P < 0.001). Seropositivity for HSV‐1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06–2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35–3.52, P < 0.001) and those negative for HLA‐DRB1*1501 (OR = 1.89, 95% CI 1.17–3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA‐DRB1*15:01 status. Interpretation EBV seropositivity is strongly associated with pediatric MS, as is HSV‐1 seropositivity in subjects negative for HLA‐DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

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.

OBJECTIVE To evaluate the clinical efficacy and safety of baminercept, a lymphotoxin β receptor IgG fusion protein (LTβR-Ig), for the treatment of primary Sjogren's syndrome (SS), and to explore the possible mechanisms of action of this treatment. METHODS In this multicenter trial, 52 patients with primary SS were randomized in a 2:1 ratio to receive subcutaneous injections of 100 mg of baminercept every week for 24 weeks or matching placebo. The primary end point was the change between screening and week 24 in the stimulated whole salivary flow (SWSF) rate. Secondary end points included the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI), as well as measurements of select chemokines and cytokines and enumeration of peripheral blood B and T cell subsets. RESULTS The change from baseline to week 24 in the SWSF rate was not significantly different between the baminercept and placebo treatment groups (baseline-adjusted mean change -0.01 versus 0.07 ml/minute; P = 0.332). The change in the ESSDAI during treatment was also not significantly different between the treatment groups (baseline-adjusted mean change -1.23 versus -0.15; P = 0.104). Although the incidence of adverse events was similar between the treatment groups, baminercept therapy was associated with a higher incidence of liver toxicity, including 2 serious adverse events. Baminercept also produced a significant decrease in plasma levels of CXCL13 and significant changes in the number of circulating B and T cells, consistent with its known inhibitory effects on LTβR signaling. CONCLUSION In this trial, treatment with baminercept failed to significantly improve glandular and extraglandular disease in patients with primary SS, despite evidence from mechanistic studies showing that it blocks LTβR signaling.

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.

Background The role of sleep in the etiology of systemic lupus erythematosus (SLE) has not been well studied. We examined whether sleep duration was associated with subsequent transitioning to SLE in individuals at risk for SLE. Methods Four hundred and thirty-six relatives of SLE patients who did not have SLE themselves at baseline were evaluated again an average of 6.3 (± 3.9) years later. Fifty-six individuals transitioned to SLE (≥ 4 cumulative American College of Rheumatology (ACR) criteria). Sleep duration, medication use and medical history were assessed by questionnaire; ACR criteria were confirmed by medical record review. Vitamin D was measured by ELISA. Generalized estimating equations, accounting for correlation within families, assessed associations between baseline sleep and the outcome of transitioning to SLE. Results Reporting sleeping less than 7 hours per night at baseline was more common in those who subsequently transitioned than those who did not transition to SLE (55% versus 32%, p = 0.0005; OR: 2.8, 95% CI 1.6–4.9). Those who transitioned to SLE were more likely to sleep less than 7 hours per night than those who did not transition to SLE adjusting for age, sex and race (OR: 2.8, 95% CI 1.6–5.1). This association remained after individual adjustment for conditions and early symptoms that could affect sleep, including prednisone use, vitamin D deficiency and number of ACR criteria (OR: 2.0, 95% CI 1.1–4.2). Conclusion Lack of sleep may be associated with transitioning to SLE, independent of early clinical manifestations of SLE that may influence sleep duration. Further evaluation of sleeping patterns and biomarkers in at-risk individuals is warranted.

Objective To better understand the role of B cells, the potential mechanisms responsible for their aberrant activation, and the production of autoantibodies in the pathogenesis of Sjogren's syndrome (SS), this study explored patterns of selection pressure and sites of N-glycosylation acquired by somatic mutation (acN-glyc) in the IgG variable (V) regions of antibody-secreting cells (ASCs) isolated from the minor salivary glands of patients with SS and non-SS control patients with sicca symptoms. Methods A novel method to produce and characterize recombinant monoclonal antibodies (mAb) from single cell-sorted ASC infiltrates was applied to concurrently probe expressed genes (all heavy- and light-chain isotypes as well as any other gene of interest not related to immunoglobulin) in the labial salivary glands of patients with SS and non-SS controls. V regions were amplified by reverse transcription-polymerase chain reaction, sequenced, and analyzed for the incidence of N-glycosylation and selection pressure. For specificity testing, the amplified regions were expressed as either the native mAb or mutant mAb lacking the acN-glyc motif. Protein modeling was used to demonstrate how even an acN-glyc site outside of the complementarity-determining region could participate in, or inhibit, antigen binding. Results V-region sequence analyses revealed clonal expansions and evidence of secondary light-chain editing and allelic inclusion, of which neither of the latter two have previously been reported in patients with SS. Increased frequencies of acN-glyc were found in the sequences from patients with SS, and these acN-glyc regions were associated with an increased number of replacement mutations and lowered selection pressure. A clonal set of polyreactive mAb with differential framework region 1 acN-glyc motifs was also identified, and removal of the acN-glyc could nearly abolish binding to autoantigens. Conclusion These findings support the notion of an alternative mechanism for the selection and proliferation of some autoreactive B cells, involving V-region N-glycosylation, in patients with SS.

Objective Sjogren's Syndrome (SS) patients are prone to develop malignant lymphomas and a correlation has been established between lymphoproliferations and the presence in patients’ blood of an unusual B cell population that downregulated complement receptor 2/CD21. We sought to determine from which B cell compartment lymphoproliferations in SS patients emerge and what are the mechanisms that promote these clonal B cell expansions. Methods Using a PCR-based approach that allows us to clone and express, in vitro, recombinant antibodies produced by single B cells, we tested the reactivity of antibodies expressed by CD19+CD10-CD27-IgM+CD21-/low cells from SS patients. Results We identified clonal expansions in CD21-/low B cells isolated from the blood of three SS patients. All three lymphoproliferations expressed B cell receptors (BCRs) that displayed somatic hypermutation lineage trees characteristic of strong selection by antigens, one of which was identified as a ribosomal self-antigen. When mutated BCR sequences expressed by SS expanded clones were reverted, in vitro, to their germline counterparts, one remained autoreactive. Conclusion Clonal lymphoproliferations in SS patients preferentially accumulate in the autoreactive CD21-/low B cell compartment, which is often amplified in these subjects, and (self)-antigen recognition may drive expansion while further refining BCR (self)-reactivity. This article is protected by copyright. All rights reserved.

Anthrax vaccine adsorbed (AVA) is a significant line of defense against bioterrorist attack from Bacillus anthracis spores. However, in a subset of individuals, this vaccine may produce a suboptimal quantity of anti-protective antigen (PA), antibodies that are poorly neutralizing, and/or antibody titers that wane over time, necessitating annual boosters. To study individuals with such poor responses, we examine the properties of anti-PA in a subset of vaccinated individuals that make significant quantities of antibody but are still unable to neutralize toxin. In this cohort, characterized by poorly neutralizing antibody, we find that increased IgG4 to IgG1 subclass ratios, low antibody avidity, and insufficient antibody targeting domain 4 associate with improper neutralization. Thus, future vaccines and vaccination schedules should be formulated to improve these deficiencies.

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:To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis.Methods:Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA-DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth.Results:Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups (p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics (p = 0.004) but not in blacks (p = 0.95) or whites (p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics (p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics.Conclusions:The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations.

Objective Systemic lupus erythematosus (SLE) and other autoimmune diseases cause significant morbidity. Identifying populations at risk of developing SLE is essential for curtailing irreversible inflammatory damage. The aim of this study was to identify factors associated with transition to classified disease that would inform our understanding of the risk of SLE. Methods Previously identified blood relatives of patients with SLE, who had

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:Trials and clinical observations have demonstrated the efficacy of mycophenolate mofetil (MMF) for SLE treatment. Long-term use of MMF is associated with adverse events, pregnancy risks, drug monitoring, and increased cost. Current management continues therapy indefinitely. Whether immunosuppression may be safely withdrawn or whether risks of withdrawal outweigh the benefits of continuation is unknown.Objectives:To compare rates of clinically significant disease reactivation (CSDR), major flares, and all flares in patients with quiescent SLE on stable MMF randomized to maintain or withdraw MMF. The goal is to provide guidance for clinicians and patients on the risks of MMF withdrawal.Methods:Adults with quiescent SLE (SELENA-SLEDAI without serologies Results:102 subjects were randomized (50 MA, 52 WA); 1 subject in each arm was ineligible and 10 terminated early (7 MA, 3 WA). Mean disease duration was 13 years; 76% had a history of nephritis; mean baseline SLEDAI was 2.2. 5 MA subjects (10%) had CSDR, compared to 9 WA (17%). Median time to CDSR was 38 weeks in both arms. BILAG A flares occurred in 1MA subject (pancreatitis) vs. 4 WA (cranial neuropathy, panniculitis, 2 nephritis). Kaplan-Meier curves overlapped for CDSR, BILAG A flares, and all SLEDAI flares (Figure). Based on these data, we are 86% confident that the increased risk of CDSR with MMF withdrawal is less than 15% over 60 weeks. AEs were similar between groups; infections occurred more commonly in MA (63 vs. 49).Conclusion:In this cohort of subjects with quiescent SLE on long term MMF serious flares occurred infrequently in subjects continuing or withdrawing MMF without differences in time to flare. MMF withdrawal may be considered in subjects with prolonged quiescent disease.Table 1.Baseline and Demographic CharacteristicsMaintenance armWithdrawal armTotalRandomized5052102Female, n (%)39 (78)47 (90)86 (84)White, n (%)25 (50)19 (37)44 (43)Black, n (%)19 (38)22 (42)41 (40)Hispanic/Latino, n (%)10 (20)12 (23)22 (22)Age, Years, mean (SD)42.4 (12.9)41.6 (12.5)42.0 (12.6)Disease Duration, Years, mean (SD)13.6 (8.2)12.2 (7.9)12.9 (8.0)H/O Lupus Nephritis, n (%)40 (80)38 (73)78 (76.5)On Baseline Steroids, n (%)18 (36)23 (44)41 (40)Prednisone Dose, mg, mean (SD)4.8 (2.7)3.3 (1.7)4.0 (2.3)MMF Duration, Years, mean (SD)6.8 (4.3)6.4 (4.3)6.6 (4.3)Baseline MMF Dose, mg, mean1,6121,6681,640SELENA-SLEDAI*, mean (SD)2.4 (1.76)1.9 (1.76)2.2 (1.77)Positive DsDNA, n (%)35 (70)27 (52)62 (61)Low C31, n (%)14 (28)9 (17)23 (23)Low C41, n (%)6 (12)5 (10)11 (11)Figure.Kaplan-Meier Estimates of Flare EndpointsDisclosure of Interests:Eliza Chakravarty: None declared, Tammy Utset: None declared, Diane L Kamen Consultant of: Consulted on SLE survey development for Lilly and consulted on SLE trial protocol development for EMD Serono in 2019, Gabriel Contreras Grant/research support from: Genentech, Merck, Consultant of: Genentech, Merck, William Joseph McCune: None declared, Kenneth C Kalunian: None declared, Cynthia Aranow: None declared, Megan Clowse Grant/research support from: GSK, Pfizer, Consultant of: UCB, Astra-Zeneca, Speakers bureau: UCB, Ellen Goldmuntz: None declared, Jessica Springer: None declared, Lynette Keyes-Elstein: None declared, Bill Barry: None declared, Ashley Pinckney: None declared, Judith James: None declared

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell–B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here, we evaluated the phenotypes of CD4(+) T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1(hi)CXCR5(–)CD4(+) T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1(hi)CXCR5(–)CD4(+) T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5(–) T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not T follicular helper (Tfh) cells, correlated with both clinical disease activity and the frequency of CD11c(+) B cells in SLE patients. PD-1(hi)CD4(+) T cells were found within lupus nephritis kidneys and correlated with B cell numbers in the kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells as a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.

EgeUn###, Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 3 102295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence. Copyright © 2019 by the American Thoracic Society, Háskóli Íslands, HI University of Chicago University of Ulsan, UOU Monash University, MU University of Nottingham University of Edinburgh University of Colorado Denver Universitat de Barcelona University of Pittsburgh, Pitt Harvard School of Dental Medicine Massachusetts General Hospital, MGH University of Pennsylvania, Penn University College Cork, UCC City, University of London, City University of California, San Francisco, UCSF School of Medicine, Vanderbilt University Ege Üniversitesi University of Virginia, UV Aarhus Universitetshospital Central Manchester University Hospitals NHS Foundation Trust Columbia University Novartis Sunovion COPD Foundation Pfizer National Heart, Lung, and Blood Institute, NHLBI: R01-HL097163, UH3-HL123442, P01-HL092870 U.S. Department of Defense, DOD: W81XWH-17-1-0597, U01 HL089897, U01 HL089856 AstraZeneca Siemens Foundation North Carolina GlaxoSmithKline Foundation, 1National Jewish Health, Denver, Colorado; 2School of Public Health; 3Department of Medicine, and 54Department of Immunology, University of Colorado Denver, Denver, Colorado; 4Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 5Brigham and Women’s Hospital, Harvard School of Medicine, Boston, Massachusetts; 6Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;7Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 8MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; 9Respiratory Medicine Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 10Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; 11Royal Brompton Hospital and Imperial College, London, United Kingdom; 12Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; 13Department of Medicine, University of California, San Francisco, San Francisco, California; 14Gilead Sciences, Foster City, California; 15Department of Medicine, University of Chicago, Chicago, Illinois; 16Department of Medicine, University of Virginia, Charlottesville, Virginia; 17Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; 18National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; 19National Hospital Organization Tokyo National Hospital, Tokyo, Japan; 20Helmholtz Zentrum München, Neuherberg, Germany; 21University Hospital Munich, Munich, Germany; 22Department of Pulmonology, Ege University Hospital, Bornova, Izmir, Turkey; 23Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia; 24Alfred Hospital and Monash University, Melbourne, Australia; 25Pulmonary Medicine, GB Morgagni Hospital, Forlì, Italy; 26Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy; 27Université Paris Diderot and Hôpital Bichat, Paris, France; 28Royal Papworth Hospital and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 29Respiratory Department, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain; 30National University Hospital of Iceland, University of Iceland, Reykjavik, Iceland; 31Department of Medicine, Columbia University Irving Medical Center, New York, New York; 32Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts; 33Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 34Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas,” México City, México; 35Universidad Nacional Autónoma de México, México City, México; 36Cork University Hospital and University College Cork, Cork, Ireland; 37St. Vincent’s University Hospital, Dublin, Ireland; 38School of Medicine, University College Dublin, Dublin, Ireland; 39Department of Respiratory Medicine, First Faculty of Medicine Charles University and Thomayer Hospital, Prague, Czech Republic; 40University of British Columbia, Vancouver, Canada; 41Tokyo Medical and Dental University, Tokyo, Japan; 42Institute for Respiratory Health and; 43Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Perth, Australia; 44Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; 45Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia; 46Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey; 47Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 48Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany; 49Department of Medicine, Tallaght University Hospital, Trinity College Dublin, Dublin, Ireland; 50CardioPulmonary Reserach Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico; 51Department of Internal Medicine, University of Genoa, Genoa, Italy; 52Biomedical Genomics Center, University of Minnesota; Minneapolis, Minnesota; and 53Northwest Genomics Center, University of Washington, Seattle, Washington -- This research was supported by grants from the NHLBI (R01-HL097163, P01-HL092870, and UH3-HL123442) and the Department of Defense (W81XWH-17-1-0597). The COPDGene project was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the NHLBI. The COPDGene project was also supported by the COPD Foundation through contributions made to an industry advisory board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

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