Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by a wide range of clinical and immunologic manifestations, most prominently, the production of autoantibodies to nuclear components (ANAs). A previous study delineated four SLE patient clusters based on autoantibody expression to common antigens. To further assess autoantibody diversity within these clusters, we surveyed serum autoantibody expression using a novel autoantigen discovery technology, the Antigenome Platform. This phage-based system assesses serum antibody interactions with large protein fragments (up to 250 amino acids) spanning approximately 90% of the human genome. Bound autoantibody targets were identified through next-generation sequencing and robust bioinformatics and statistical analysis. Our study revealed 88, 49, 10, and 24 autoantibodies that expand the characterization of four SLE clusters, including 24 autoantibodies that characterize a cluster of patients lacking common autoantibodies by conventional assays. Further, some autoantibodies identified have potential links to patient disease features. Although SLE is characterized by antinuclear antibody expression, a significant proportion of autoantigens (ranging from 28% to 54%) in each cluster localized to the cytoplasm, which suggests extensive autoreactivity beyond targets in the cell nucleus that formed the original basis of clustering. This study identifies new markers to aid in the clustering and understanding of SLE disease subtypes and provides a rationale for elucidating autoantibody expression in SLE beyond antinuclear antibodies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by protean clinical manifestations that are associated with immune system dysregulation. Of these manifestations, pain and pain-related symptoms such as fatigue, mood disturbance and cognitive impairment are the most common features reported by patients and represent important determinants of quality of life. Nevertheless, the relationship of these symptoms to underlying immune mechanisms is unclear. To advance scientific study and patient-centric care, this Review will consider the origin of pain in SLE and the clinical ramifications. Although many of the inflammatory aspects of SLE, including arthritis, serositis and skin disease, can be associated with nociceptive pain, patients frequently report pain that seems out of proportion to the degree of inflammation. In many of these patients, pain might reflect central and peripheral nervous system sensitization that mediates nociplasticity, a change in brain processing; with nociplasticity, changes in neuronal function and brain connections can amplify the experience of pain and pain-related symptoms. The close interplay between the immune and the nervous systems means that widespread pain and the associated symptoms can be considered as essential features of SLE; these features might share pathogenic mechanisms with other autoimmune diseases and nociplastic pain syndromes such as fibromyalgia. In systemic lupus erythematosus (SLE), pain is one of the most commonly reported and debilitating symptoms. The authors of this Review highlight the importance of understanding the mechanisms of pain in SLE and addressing pain and pain-associated symptoms in the management of SLE.

The interaction of cell-free DNA with biological particles has been linked to autoimmune diseases such as systemic lupus erythematosus, but mechanistic details are lacking. Our recent work has shown that DNA adsorbed on the surface of synthetic particles, forming a DNA "corona," leads to an enhanced immunostimulatory response in macrophages, providing a model system to understand how DNA-particle interactions may lead to autoimmune diseases. This current study provides a detailed examination of DNA (500-600 base pairs and ∼10,000 base pairs) interacting with synthetic particles (40 nm to 10 μm) and planar surfaces. Of specific interest is how DNA adsorbed on the surface of particles is resistant to degradation by DNase 1, a common nuclease. DNA-particle complexes are characterized by a colorimetric DNA concentration assay (PicoGreen), spectroscopy (NanoDrop), dynamic light scattering (DLS), confocal fluorescence microscopy, and transmission electron microscopy. These studies show that the protective effect of the particle is size dependent, with smaller (40 and 200 nm) particles providing less protection. Correlated with this lack of protection is significantly increased particle aggregation, suggesting that a DNA corona formed on the larger particles is protective, whereas particle aggregation, which dominates the smaller particles, is not protective. The formation of a single-stranded DNA corona leads to the opposite protective effect, with smaller (200 nm) particles leading to near-complete protection of DNA from nuclease degradation. Overall, this study provides an important biophysical basis for the interaction of DNA with particles with the goal of guiding future in vitro and in vivo studies of cell-free DNA and particles in autoimmune disease.

PV228 / #365 Poster Topic:AS23 - SLE-Diagnosis, Manifestations, & Outcomes In SLE, autoantibodies (ANAs) can promote pathogenesis by forming immune complexes (ICs) that activate complement. While antibodies to DNA (anti-DNA) are known to be associated with complement levels, the role of other ANAs in activating complement is less clear. To elucidate better serological biomarkers in the context of novel therapies to decrease immunoglobulin levels or B cells, we modeled the relationship between autoantibodies (anti-DNA, other ANAs, anti-C1q) and complement. Adult SLE patients (SLICC or ACR/EULAR criteria) were enrolled during routine clinic visits from June 2020 to June 2024. At each visit, treating rheumatologists scored the PGA and SLEDAI, medications were recorded, and autoantibodies were measured. Autoantibodies including anti-DNA, anti-RNA-binding proteins (RBPs), and anti-C1q were measured by ELISA. Complement activation was defined as (1) low C3, (2) low C4, (3) low C3 and low C4, and (4) low C3 or low C4. Potential predictors of complement activation were modeled in 4 steps: (1) anti-DNA; (2) anti-DNA, anti-RBPs (Ro-52, Ro-60, Sm, La, U1RNP, RNP-70), and anti-C1q; (3) anti-DNA, anti-RBPs, anti-C1q, and medications; and (4) anti-DNA, anti-RBPs, anti-C1q, and disease activity. To identify linear and possible nonlinear relationships between predictors and complement activation, we considered both generalized linear models (GLMs; specifically, logistic regression with LASSO regularization) and decision tree models, each with continuous predictors. Models were trained and tuned on 80% of patients and evaluated on the remaining 20%. The study included 526 visits in 257 patients (mean age 42 years; mean disease duration 13 years; 88% female; 58% Black, 29% White; 6% Hispanic). Almost one-quarter of visits had low C3 or C4; anti-DNA was positive at 40% of visits. In Lasso regression models, the presence of anti-DNA accurately predicted complement levels (AUC: 0.71-0.79; Table 1); model performance improved with the inclusion of anti-RBPs and anti-C1q (AUC: 0.73-0.84). The inclusion of medications or disease activity led to limited improvement in model performance. Across outcomes of complement activation, anti-DNA and anti-C1q were consistently associated with low complement (Figure 1). For the outcome of low C3, a 1 standard deviation increase in anti-DNA levels increased the odds of having low C3 by approximately 123%; a 1 standard deviation increase in anti-C1q levels was associated with an 82% increase in the odds of having low C3. Results were similar for low C4. The results of the decision tree models (Table 1) align with the findings from Lasso logistic regression models. For both low C3 and low C4, the decision tree consistently selected anti-DNA and anti-C1q as the primary splitting variables, further affirming their predictive power. Table 1. Model performance of serologies, medications, and disease activity to predict low complement. Figure 1. Coefficients of anti-DNA, anti-RBPs and anti-C1q on low C3 and low C4. Error bars indicate 95% confidence intervals obtained via bootstrapping (1000 resamples) the development set. These results support the important role of anti-DNA antibodies in complement activation as reflected in levels of C3 and/or C4; the effects of other ANAs in the model were less marked, perhaps reflecting a more limited ability of these antibodies to form ICs that activate complement. The association of anti-C1q with low C3 and/or C4 is consistent with a role of this antibody in activating complement and suggests the value of assaying anti-C1q in studies on therapies that can impact autoantibody levels.

PV233 / #350 Poster Topic:AS23 - SLE-Diagnosis, Manifestations, & Outcomes In SLE, early childhood trauma and adverse childhood experiences have been associated with chronic pain, fatigue, depression, self-reported flares and incident SLE. In this study we evaluated the frequency and impact of abusive and non-abusive trauma on quality of life in SLE. This study involved adult SLE patients (2012 SLICC or 2019 ACR/EULAR criteria) from August 2023 to April 2024. Patients completed the LupusPRO; FACIT-fatigue scale; PROMIS measures for pain intensity, pain interference, self-efficacy, and psychological stress; and the Trauma History Screen. Additional trauma questions regarding emotional abuse and pregnancy loss or abortion were added. Abusive trauma was defined as physical, sexual, and emotional trauma as an adult or child. Patients were divided into 3 groups: abusive trauma, non-abusive trauma, and no trauma. Differences across groups were analyzed by Fisher’s exact test or ANOVA. In this cohort of 262 SLE patients (92% female, mean age 44 years, mean disease duration 15 years, 60% self-reported Black), the vast majority experienced at least 1 traumatic event (85%) with almost half suffering abusive trauma. Trauma was more common among women, with abusive trauma occurring almost exclusively in women. Education attainment was similar across groups, however a greater number of patients with abusive trauma had an annual income less than $50,000. There was a progressive increase in fatigue, pain intensity, and pain interference across the 3 groups with the highest scores in those with abusive trauma (Table 1). More than half of patients with abusive trauma reported moderate to severe levels of fatigue, pain intensity and interference in social and daily activities. Likewise, patients with trauma reported significantly more psychological stress and lower self-efficacy for managing symptoms and medications than those without trauma. When evaluating the relationship of trauma across LupusPRO, patients with abusive trauma had lower scores for sleep, physical and emotional health, pain, fatigue, cognition, body image, effects from lupus medications indicating worse health-related quality of life in these domains (Figure 1). Finally, scores for coping, desires and goals, and support system were worse in patients with abusive trauma. Table 1. Influence of trauma on pain, fatigue, self-efficacy and stress Figure 1. Influence of trauma on LupusPRO health and non-health related quality of life Many patients with lupus have suffered trauma, including abusive trauma, throughout their lives and experience reduced quality of life across multiple health and non-health domains. Further, the data suggest that abusive trauma can impact the burden and severity of lupus symptoms as well the ability to manage symptoms and medications. Incorporating a trauma-informed approach to care may therefore be important in developing and delivering treatment to improve quality of life in SLE.

PV207 / #177 Poster Topic:AS23 - SLE-Diagnosis, Manifestations, & Outcomes Our prior qualitative work demonstrated there are at least 2 distinct subgroups of Type 2 SLE; one is related to active inflammation (Intermittent Type 2 SLE) and another can be present regardless of inflammation (Persistent Type 2 SLE). The objective of this study was to utilize longitudinal measures of Type 1 and Type 2 SLE activity to characterize these Type 2 SLE subgroups. SLE patients meeting SLICC or ACR criteria were enrolled in a university lupus registry. At each clinic visit, participants completed the Polysymptomatic Distress Scale (PSD), and rheumatologists completed disease activity measures, including the SLEDAI and Physician Global Assessments (PGA) for both Type 1 and Type 2 SLE activity. Patients seen between May 2023 and April 2024 were invited to participate in a substudy that included the FACIT-fatigue scale; PROMIS measures for pain intensity, pain interference, self-efficacy, and psychological stress; and the Trauma History Screen. Only patients who participated in the substudy and had ≥3 visits in the registry were included in the analysis. High Type 1 SLE activity was defined as clinical SLEDAI ≥4, SLEDAI ≥6, active lupus nephritis or PGA ≥1. High Type 2 SLE activity was defined as Type 2 PGA ≥1 or PSD ≥8. Patients who had high Type 1 SLE activity at <30% of visits and high Type 2 SLE activity at ≥50% of visits were classified as Persistent Type 2 SLE. Patients who had fluctuating Type 2 SLE activity were classified as Intermittent Type 2 SLE. Patients who never had high Type 2 SLE activity during follow-up (n=13) were excluded from the analysis. Differences in characteristics between the 2 groups were estimated by t-tests and Fisher’s exact tests. The analysis included 183 patients (mean age 45 years, 92% female, 60% Black); 26% of patients had Persistent Type 2 SLE. Demographics were similar between the 2 groups (Table 1). Patients with Persistent Type 2 SLE were more likely to have experienced abusive trauma. While patients with Intermittent Type 2 SLE had higher Type 1 SLE activity over time, approximately half of patients in each group had a history of lupus nephritis, and there were no differences between groups in historical use of prednisone, DMARDs, or biologics. Patients in the Persistent Type 2 SLE group were more likely to have been prescribed a Type 2 SLE medication and to have been prescribed more Type 2 SLE medications over time. By definition, patients with Persistent Type 2 SLE had higher PSD scores during follow-up, yet patients with Intermittent Type 2 SLE still had mild to moderate PSD scores, on average, during follow-up. There were similar self-efficacy scores for managing medications between groups, yet patients with Persistent Type 2 SLE had lower self-efficacy for managing symptoms; they also had worse scores for FACIT-fatigue, PROMIS pain intensity, and pain interference. Table 1. Cohort characteristics. One in 4 patients met our study definition for Persistent Type 2 SLE. Despite having taken on average 4 different medications to treat Type 2 SLE symptoms, patients with Persistent Type 2 SLE continued to have a high burden of pain, fatigue, depression, and brain fog, demonstrating a need for better treatment approaches. Several psychosocial stressors could predispose or perpetuate Persistent Type 2, and future work will evaluate these triggers to better understand the etiology and target solutions for these symptoms.

Background: HLA homozygosity of specific alleles at a single locus is associated with increased risk for autoimmunity and/or more severe clinical phenotypes. However, the contribution of the overall limitation of HLA diversity across multiple loci to autoimmunity risk remains to be determined. Methods: We conducted a proof-of-concept case-control study of 413 individuals (279 cases with pediatric-onset autoimmune rheumatic diseases, 134 matched controls) examining the "Limitation of HLA Diversity" (LoHLAD) across multiple loci as an allele-independent risk factor for autoimmunity. We examined the association of LoHLAD with pediatric-onset autoimmune rheumatic diseases at five HLA loci (A, B, DQB1, DRB1, DRB3/4/5). LoHLAD was defined as (1) homozygosity at any of the examined loci, and/or (2) the presence of a single allele or the complete lack of an allele at the HLA-DRB3/4/5 locus. Results: The frequency of LoHLAD at any locus was significantly higher in cases compared to controls (65.95% vs. 30.60%, OR 4.39 [2.82-6.84], p < 0.0001). Higher frequencies of LoHLAD in cases compared to controls were observed at both class I (19.35% vs. 10.45%, OR 2.06 [1.10-3.86], p = 0.031) and class II (54.48% vs. 20.15%, OR 4.74 [2.92-7.69], p < 0.0001) loci. Specifically, significant differences between cases and controls were observed at the B (OR 8.63 [1.14-65.55], p = 0.016), DQB1 (OR 3.34 [1.27-8.78], p = 0.016), and DRB3/4/5 (OR 4.64 [2.77-7.75], p < 0.0001) loci. Multiple logistic regression models confirmed the ability of LoHLAD to positively predict autoimmunity. Conclusions: LoHLAD is a significant allele-independent risk factor for pediatric-onset autoimmune rheumatic disease.

PT001 / #268 Topic: AS04 - Biomarkers POSTER TOUR 02: RECENT INSIGHTS ON THE PATHOGENESIS OF LUPUS NEPHRITIS 23-05-2025 10:00 AM - 10:40 AM Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by widespread tissue inflammation and damage in association with antinuclear antibody production. Emerging research suggests that disturbances in the microbiome (dysbiosis) can interact with the immune system to drive pathogenesis. Microbial cell-free DNA (mcfDNA) in plasma, analogous to human cell-free DNA, is thought to originate from microbial organisms undergoing cellular turnover. These microbial derived DNA fragments can transverse into the bloodstream and may be processed by circulating DNases. However, these degraded fragments may also be readily detected, identified, and quantified in plasma using advanced molecular and bioinformatics methodologies. The purpose of this pilot study was to explore a possible relationship between plasma mcfDNA and disease activity in patients with lupus. Plasma samples from patients with lupus were collected at 2 clinical centers. Patients were clustered into 3 groups: complete remission, remission with a positive anti-dsDNA titre, and active disease (SLEDAI greater > 6) with a positive anti-dsDNA titre. Specimens from a healthy cohort were derived from an independent collection center. Plasma was collected, processed, and stored in K2-EDTA tubes. Cell-free DNA was extracted from plasma via the Karius Discovery assay and sequenced at a depth of 400M paired-end reads per sample. A set of analytical filters was applied to control for contamination, separating biological signals from background. Differential abundance analysis, correlation analysis, and principal coordinate analysis were conducted to identify microbial signatures that discriminated between the healthy and lupus patient populations as well as the disease activity groupings. Identified features were incorporated into a gradient-boosted machine learning classifier to assess their predictive power. Our study included 54 patients with SLE (median age 37.5 years, 46% had a history of lupus nephritis, 85% female) and 36 healthy controls (median age 45 years, 61% female). Our analysis indicated specific elevated microbial species, estimated in molecules per microliter (MPM), with concordant findings observed across both clinical centers. The mcfDNA that were identified were associated with the oral (Streptococcus, Prevotella, Porphyromonas, and Veillonella species); gastro-intestinal (Bacteroides, Alcaligenes, Streptomyces, and Campylobacter species); and skin (Staphylococcus, Corynebacterium, and Acintobacter species) microbiomes (Figure 1). Principal coordinate analysis and preliminary machine learning classifiers suggested a possible partition between the healthy individuals and those with lupus (Figure 2). The analysis also indicated that a subset of the microbial signatures may differentiate between disease activity groupings. Figure 1. Figure 2. Our pilot study provides preliminary data suggesting an increase in mcfDNA concentration from signature microbial species that can distinguish patients with SLE from controls and differentiate between disease subgroups. Further studies, including longitudinal analyses of larger and more diverse patient cohorts, will be needed to determine the utility of plasma mcfDNA as a biomarker for disease activity and delineate mechanisms by which increased mcfDNA may arise and contribute to pathogenesis.

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SOURCE CITATION:Kingsbury SR, Tharmanathan P, Keding A, et al. Pain reduction with oral methotrexate in knee osteoarthritis: a randomized, placebo-controlled clinical trial. Ann Intern Med. 2024;177:1145-1156. 39074374.

ObjectiveSystemic lupus erythematosus (SLE) flares are associated with increased damage and decreased health-related quality of life. We hypothesized that there is discordance between physicians’ and patients’ views of SLE flare. In this study, we aimed to explore patient and physician descriptions of SLE flares.MethodsWe conducted a qualitative descriptive study using in-depth interviews with a purposeful sample of patients with SLE (who met 1997 American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria) and practicing rheumatologists. Interviews were audio-recorded, transcribed, and analyzed using applied thematic analysis.ResultsForty-two patient participants with SLE, representing a range of SLE activity, completed interviews. The majority described flare symptoms as joint pain, fatigue, and skin issues lasting several days. Few included objective signs or laboratory measures, when available, as features of flare. We interviewed 13 rheumatologists from 10 academic and 3 community settings. The majority defined flare as increased or worsening SLE disease activity, with slightly more than half requiring objective findings. Around half of the rheumatologists included fatigue, pain, or other patient-reported symptoms.ConclusionPatients and physicians described flare differently. Participants with SLE perceived flares as several days of fatigue, pain, and skin issues. Providers defined flares as periods of increased clinical SLE activity. Our findings suggest the current definition of flare may be insufficient to integrate both perceptions. Further study is needed to understand the pathophysiology of patient flares and the best way to incorporate patients’ perspectives into clinical assessments.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that primarily affects young women and causes a wide range of inflammatory manifestations. The hallmark of SLE is the production of antibodies to components of the cell nucleus (antinuclear antibodies [ANAs]). These antibodies can bind to DNA, RNA, and protein complexes with nucleic acids. Among ANAs, antibodies to DNA (anti-DNA) are markers for classification and disease activity, waxing and waning disease activity in many patients. In the blood, anti-DNA antibodies can bind to DNA to form immune complexes with two distinct roles in pathogenesis: (1) renal deposition to provoke nephritis and (2) stimulation of cytokine production following uptake into innate immune cells and interaction with internal nucleic acid sensors. These sensors are part of an internal host defense system in the cell cytoplasm that can respond to DNA from infecting organisms; during cell stress, DNA from nuclear and mitochondrial sources can also trigger these sensors. The formation of immune complexes requires a source of extracellular DNA in an immunologically accessible form. As shown in in vivo and in vitro systems, extracellular DNA can emerge from dead and dying cells in both a free and a particulate form. Neutrophils undergoing the process of NETosis can release DNA in mesh-like structures called neutrophil extracellular traps. In SLE, therefore, the combination of ANAs and immunologically active DNA can create new structures that can promote inflammation throughout the body as well as drive organ inflammation and damage.

Autoimmune and inflammatory diseases are highly complex, limiting treatment and the development of new therapies. Recent work has shown that cell-free DNA bound to biological microparticles is linked to systemic lupus erythematosus, a prototypic autoimmune disease. However, the heterogeneity and technical challenges associated with the study of biological particles have hindered a mechanistic understanding of their role. Our goal was to develop a well-controlled DNA-particle model system to understand how DNA-particle complexes affect cells. We first characterized the adsorption of DNA on the surface of polystyrene nanoparticles (200 nm and 2 µm) using transmission electron microscopy, dynamic light scattering, and colorimetric DNA concentration assays. We found that DNA adsorbed on the surface of nanoparticles was resistant to degradation by DNase 1. Macrophage cells incubated with the DNA-nanoparticle complexes had increased production of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). We probed two intracellular DNA sensing pathways, toll-like receptor 9 (TLR9) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), to determine how cells sense the DNA-nanoparticle complexes. We found that the cGAS-STING pathway is the primary route for the interaction between DNA-nanoparticles and macrophages. These studies provide a molecular and cellular-level understanding of DNA-nanoparticle-macrophage interactions. In addition, this work provides the mechanistic information necessary for future in vivo experiments to elucidate the role of DNA-particle interactions in autoimmune diseases, providing a unique experimental framework to develop novel therapeutic approaches.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterised by antibodies to DNA (anti-DNA) and other nuclear macromolecules. Anti-DNA antibodies are markers for classification and disease activity and promote pathogenesis by forming immune complexes that deposit in the tissue or stimulate cytokine production. Studies on the antibody response to DNA have focused primarily on a conformation of DNA known as B-DNA, the classic right-handed double helix. Among other conformations of DNA, Z-DNA is a left-handed helix with a zig-zag backbone; hence, the term Z-DNA. Z-DNA formation is favoured by certain base sequences, with the energetically unfavourable flip from B-DNA to Z-DNA dependent on conditions. Z-DNA differs from B-DNA in its immunogenicity in animal models. Furthermore, anti-Z-DNA antibodies, but not anti-B-DNA antibodies, can be present in otherwise healthy individuals. In SLE, antibodies to Z-DNA can occur in association with antibodies to B-DNA as a cross-reactive response, rising and falling together. While formed transiently in chromosomal DNA, Z-DNA is stably present in bacterial biofilms; biofilms can provide protection against antibiotics and other challenges including elements of host defence. The high GC content of certain bacterial DNA also favours Z-DNA formation as do DNA-binding proteins of bacterial or host origin. Together, these findings suggest that sources of Z-DNA can enhance the immunogenicity of DNA and, in SLE, stimulate the production of cross-reactive antibodies that bind both B-DNA and Z-DNA. As such, DNA can act as a molecular chameleon that, when stabilised in the Z-DNA conformation, can drive autoimmunity.

OBJECTIVE:The Type 1 and 2 systemic lupus erythematosus (SLE) Model was developed to encapsulate all signs and symptoms that patients with SLE experience. Our previous qualitative work demonstrated the model accurately reflects the lived experience of people living with SLE. The objective of this study was to present the Type 1 and 2 SLE Model to rheumatologists to understand how the model fits with their experiences treating patients with SLE. METHODS:We conducted a qualitative descriptive study using semistructured interviews with rheumatologists. Rheumatologists were asked about their general impression of the Type 1 and 2 SLE Model, how the model does or does not fit within their approach to treating patients with SLE, the utility of the model in clinical practice, and any suggested changes. Applied thematic analysis identified salient themes. RESULTS:We interviewed 13 rheumatologists. The majority of rheumatologists approved of the model and found it useful to guide therapy and clinical decision-making. Several rheumatologists thought the model was helpful for patient education to manage expectations about differences between Type 1 and Type 2 symptoms and treatments. A few rheumatologists expressed concern that the model could lead to an overdiagnosis of SLE. CONCLUSION:The Type 1 and 2 SLE Model was accepted by most rheumatologists interviewed and welcomed as a useful approach to identifying and treating symptoms in patients with SLE. Future studies will determine how implementing the Type 1 and 2 SLE Model affects patient understanding, the physician-patient relationship, and clinical outcomes.

Introduction Cell-bound complement activation products (CB-CAPs) in a multi-analyte assay with algorithm (MAP) is a valuable biomarker for the diagnosis of SLE. Erythrocyte-bound complement activation products have been associated with SLE disease activity. The clinical and serologic phenotype of longitudinal MAP positive patients has not been well described. Herein, we evaluated the relationship between longitudinal MAP results with clinical and laboratory variables. Methods This was a longitudinal study of adult SLE patients (2012 SLICC or 2019 ACR/EULAR criteria with a range of disease activity) with ≥2 routine lupus clinic visits from June 2020 to July 2022. Patients completed the polysymptomatic distress scale. The treating rheumatologist scored the PGA and SLEDAI scores at the time of the visit. Autoantibodies including ANA and anti-RNA-binding proteins were measured by ELISA. Anti-dsDNA was determined by immunofluorescence using the Crithidia luciliea assays. CB-CAPs were analyzed by flow cytometry. The multi-analyte assay panel (MAP) was determined using a 2-tier algorithm. Chi- square and ANOVA tests were used to analyze differences in demographic and disease history between persistently MAP positive, MAP negative, and patients with changing MAP positivity. Serologies and clinical variables at follow-up visits were compared using generalized linear models. Results In this longitudinal cohort of 113 patients with 175 follow-up visits (100% SLICC SLE, 90% female, 62% Black, mean age 45) 65% were consistently MAP positive, 20% were negative, and MAP positivity changed in 15%. Patients with persistent MAP positivity were younger and more often of Black race. There was no difference in MAP positivity based on SLE disease duration. Significantly more MAP positive patients met 2019 ACR/EULAR criteria and had higher total ACR/EULAR scores. Patients who remained MAP positive were more likely to have a history of acute cutaneous lupus but there was no difference in other historical manifestations of SLE between the three groups (table 1). When evaluating longitudinal associations, patients with persistent MAP positivity had higher total SLEDAI scores, but there was no difference in the clinical SLEDAI. Therapy was comparable across groups except for greater use of belimumab, rituximab, and cyclophosphamide in persistent MAP-positive patients. Patients who remained MAP positive reported higher rates of depression, but a similar amount of polysymptomatic distress and fatigue. A greater number of lupus-specific serologies were present in those with MAP positivity (table 2). Conclusion Identifying endotypes of SLE is important to advancing personalized medicine. In this longitudinal cohort of SLE with a full spectrum of disease active, MAP results were static in most patients. MAP resulted changed between visits in a subset of patients; although there was not a distinct clinical, demographic or laboratory phenotype in those patients. Patients with consistent MAP positivity reported more depression and had a greater burden of disease activity as measured by the ACR/EULAR score and greater use of biologic and cytotoxic therapy. Combining longitudinal MAP scores with traditional assessment of SLE assessments activity may provide useful prognostic information and allow identification of a higher risk cohort of patients. Larger longitudinal studies are on-going to evaluate the relationship between individual CB-CAPs and markers of disease activity.