Objectives Fibromyalgia (FM) symptoms are a common comorbidity in systemic lupus erythematosus (SLE), contributing to increased pain, fatigue, and insomnia. These symptoms can significantly impair physical and cognitive function, making it harder to perform daily activities, exercise, and tasks requiring concentration. This study examines the effect of FM symptoms on function and explores how various treatment approaches can moderate these effects through a multicenter cross-sectional analysis of SLE patients from 7 Canadian clinics. Methods Data on disease burden metrics (FM symptoms, pain areas, disease activity, and irreversible damage), medication use (antimalarials, corticosteroids, immunosuppressants, biologics and narcotics), and sociodemographic factors were collected. Linear mixed-effects models evaluated the effect of FM symptoms and other disease burden variables on 5 functional outcomes: fatigue severity (FSS), cognitive dysfunction (PDQ), disability (WHODAS), depression (BDI), and work role functioning (WRF). Moderation models were used to assess if SLE treatments ameliorated the effect of these variables on function, while correcting for multiple testing. Results The models established that a higher number of reported fibromyalgia symptoms was the strongest predictor of functional impairment, being significantly associated with increased fatigue (β = 1.06, p < 0.001), cognitive dysfunction (β = 1.21, p < 0.001), and higher disability (β = 0.68, p < 0.001), and depression scores (β = 0.73, p < 0.001). Conversely, irreversible damage scores were uniquely linked to worsened work role functioning (β = −4.41, p = 0.020). Building on these models, moderation analyses revealed that certain treatments lowered the effect of the disease burden metrics on various function metrics (Figure 1). Immunosuppressants moderated the impact of organ damage on disability from β = 2.62 to β = 0.45 (p = 0.022) and perceived deficits from 2.28 to −0.84 (p = 0.041). Corticosteroids attenuated the association between FM symptoms and cognitive dysfunction falling from β = 1.42 to β = 0.14 in users (p = .024). Figure 1. Simple Slopes of Effects of Immunosuppressants and Corticosteroids Conclusion This study demonstrates that the reported number of fibromyalgia symptoms is the dominant factor driving functional burden across nearly all measured domains in SLE, surpassing the impact of disease activity. Most significantly, we provide evidence that certain SLE treatments act as functional shields: corticosteroids protecting cognition from FM effects and immunosuppressants mitigating disability linked to damage. These moderation effects strongly support tailoring treatment not only to disease activity but also to the patient’s functional risk profile, moving clinical practice closer to truly personalized medicine. Supported by a CIORA grant

OBJECTIVE:Hydroxychloroquine (HCQ) is the cornerstone of systemic lupus erythematosus (SLE) management with benefits extending beyond SLE control, including protection against atherosclerotic cardiovascular disease (ASCVD). Although HCQ blood levels reflect recent exposure and long-term intake reflects medication adherence, the impact of longitudinal changes in both measures on ASCVD risk over time remains unclear. We evaluated how HCQ blood levels and long-term intake patterns relate to estimated ASCVD risk at baseline and after one year. METHODS:In this prospective longitudinal study, 248 adults with SLE from the Wisconsin cohort (meeting 2019 American College of Rheumatology/EULAR criteria) taking HCQ and completing baseline and one-year follow-up visits were included. Long-term HCQ intake was estimated using the proportion of days covered (PDC), and whole-blood HCQ levels served as a marker of recent exposure. Ten-year ASCVD risk was calculated at both time points using the PREVENT calculator. Multivariable linear regression assessed associations between HCQ exposure patterns and ASCVD risk. Changes in exposure categories over one year were also evaluated. RESULTS:Patients with very low HCQ blood levels (<200 ng/mL) and low long-term intake (PDC <80%) had significantly higher ASCVD risk at baseline (+2.1%) with a mean predicted risk of 6.6%. Those who remained in or transitioned into these low-exposure categories over one year had the highest ASCVD risk at follow-up (5.7%). CONCLUSION:Maintaining low long-term HCQ intake and very low HCQ blood levels increased ASCVD risk in patients with SLE. Interventions promoting sustained adherence and therapeutic HCQ levels may enhance cardiovascular outcomes and reduce unnecessary preventive therapies.

OBJECTIVE:This study attempted to quantify the bias expected due to partly interval-censored (IC) outcomes in the estimated association between hydroxychloroquine (HCQ) taper/cessation and time to disease flare among individuals with systemic lupus erythematosus (SLE). METHODS:Using data-driven simulations, we estimated bias expected due to IC using real-world data from the Systemic Lupus International Collaborating Clinics inception cohort. The time-varying exposure of interest was a binary indicator of HCQ tapering/cessation. The composite outcome was lupus flare, defined as lupus hospitalizations or increases in disease activity or medication dose. The two latter components were IC, as they were recorded only at annual assessment, without a precise date. For the unknown IC event times, a "true" event time was randomly generated from a uniform distribution of the time between two assessments. Each simulated sample was analyzed separately imputing unknown event times (for IC outcomes) either at the midpoint or endpoint of the interval between the two adjacent yearly assessments. Results of multivariable Cox proportional hazards models, adjusted for demographics, drugs, and clinical variables, using either "true" or imputed IC event times were compared. RESULTS:The 1543 SLE patients were followed for a median of 42.2 months. During follow-up, 396 participants tapered/stopped HCQ and 1187 experienced a flare. The adjusted uncorrected hazard ratio was 1.51 (95% confidence interval: 1.30, 1.75) and 1.40 (95% confidence interval: 1.21, 1.62) for midpoint and endpoint imputations, respectively. Data-driven simulations showed that imputation of IC event times resulted in a small but systematic bias toward the null that was consistently larger for endpoint than for midpoint imputation. CONCLUSIONS:IC events induced bias toward the null in the estimated association between HCQ taper/cessation and lupus flares. Data-driven simulations are useful for quantitative bias analyses in complex situations, as they allow accounting for relevant characteristics of a particular real-world dataset.

Objectives Systemic lupus erythematosus (SLE) is characterized by unpredictable flares interspersed with periods of disease quiescence. Elevated interferon (IFN) levels increase the likelihood of flares, but the precise immunologic mechanisms by which this occurs are unclear. In mice, IFN exposure expands age-associated B cells (ABCs), a population enriched for autoreactive and ANA-secreting cells. In this study, we examined the role of IFN in the activation and differentiation of B-cell subsets in flaring and quiescent SLE patients. Methods A CyTOF panel was developed to quantify IFN-induced proteins (IIPs) across peripheral blood immune populations. A composite IIP score (mean expression of 6 IIPs) was generated for each cell population as a surrogate for IFN exposure. 15 healthy controls (HCs), 26 quiescent (clinical SLEDAI > 0 for 1 year with no increase in immunosuppressive treatment, ≤ 10 mg prednisone) and 42 recently flaring (<1 month, change in clinical SLEDAI-2K ≥ 1 requiring escalation of therapy) were analyzed. To assess the direct effects of IFN, naïve B cells from HCs were isolated and stimulated with IFNα, IFNβ, or IFNγ. Cells were cultured under conditions that either promoted or inhibited ABC differentiation, including IL-21, anti-CD40, Fab2, CpG, or IL-4. Results CyTOF identified 7 B cell subsets, all of which exhibited higher IIP levels and greater activation in flaring vs quiescent patients (Figure 1A). ABCs were more abundant in flaring patients, and their frequency correlated with the global IIP signature (Figure 1B,C). Expression of activation markers (CD86, TLR7, TLR9, HLA-DR, Ki67) was strongly associated with IIP score, but not disease status, indicating that IFN, rather than flare alone, drives B cell activation (Figure 1D). Importantly, the association between activation and IFN exposure was evident even within individual patients, where the top 10% of IFN-experienced B cells had significantly higher activation than the bottom 10%. In vitro, IFNα and IFNβ directly induced expression of activation markers within 18-24 hours. In isolated naïve B cells, all 3 IFNs increased ABC differentiation, even without canonical ABC-inducing signals (Figure 1E). Notably, IFN overcame IL-4-mediated suppression of ABC differentiation, in part by reducing IL-4Rα and inducing TLR7 expression. In SLE patients treated with the IFN-blocking therapy Anifrolumab, ABC frequency and IIP signatures decreased (Figure 1F). Figure 1. A) IIP score for HCs, quiescent, and flaring SLE patients in B cell subsets. Higher IIP scores were found in flaring versus quiescent, and SLE patients versus HCs. (Mann Whitney U test with BH correction for multiple tests) B) Frequency of B cell subsets displayed as the proportion of CD19+ B cells. Flaring patients had more ABCs than quiescent patients and HCs. (Mann Whitney U test with BH correction for multiple tests) C) Correlation between cellular abundance and IFN signature. The proportion of ABCs were correlated with IIP score as well as IFN-stimulated genes (ISGs). IIP score also correlated with the proportion of PBs. (Spearman correlation) D) Correlation of IIP score and markers of activation. The expression of activation markers correlated with IIP score for SLE patients. (Spearman correlation) E) ABC differentiation from purified naïve B cells. 5 days of incubation with IFNα, IFNβ, or IFNγ caused significantly more differentiation of ABCs, irrespective of the incubation conditions (+/− IL-21, IL-4, anti-CD40, CpG). Results are displayed as the fold change from the respective non-IFN conditions. (Student’s T test with Holm correction for multiple comparisons post Shapiro-Wilk test to assess for normality) F) The ABC profile of patients treated with Anifrolumab versus standard-of-care. Both the IIP score and proportion of ABCs were significantly reduced in Anifrolumab-treated patients. (Mann Whitney U test) In Anifrolumab-treated patients, the frequency of ABCs showed a trend to correlation with the IIP score. (Spearman correlation) Conclusion IFN exposure drives human B-cell activation and promotes differentiation of ABCs. Our results identify a mechanistic link between IFN signaling and pathogenic B-cell development, and support IFN blockade as a strategy to reduce pathogenic ABCs and prevent SLE flares.

Objectives Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease associated with a severe morbidity and mortality. Around 70% of SLE patients follow a relapse-remitting pattern of disease characterized by flares of disease activity, followed by prolonged periods of disease quiescence. Memory CD4+ T cell subsets have been shown to play an important role in driving the autoantibody production which causes flares in SLE, however the precise T cell changes that accompany flares are unknown. Methods CITE-seq and TCR-seq were performed to assess the transcriptomic profiles of CD4+ memory T cells in flaring and quiescent SLE patients. CD4+ memory T cells were isolated from PBMCs by negative selection using magnetic sorting, stained with oligo-conjugated antibodies against surface proteins for subset classification, and subsequently partitioned, barcoded, and sequenced. We examined samples from 15 distinct patients at 2 separate clinical visits spaced one year apart, yielding 30 samples. The longitudinal nature of our data allows us to inspect transcriptional changes both between and within patients. Results Integrated analysis of 30 samples identified 10 immune cell clusters (Figure 1A). At baseline, flaring patients (n=9) were significantly enriched for Tfh, Th2, Th17 cells, and a Treg subset, while quiescent patients (n=6) had increased Th1 cells. TCR repertoire analyses at baseline revealed a higher proportion of expanded clonotypes in flaring patients, which was not seen in quiescent patients. Interestingly, we also found that there was a higher proportion of expanded clonotypes at follow-up in various subsets of interest, particularly in flaring patients that later became quiescent, suggesting tissue egress and recirculation following resolution of inflammation. Clonal overlap among subsets was markedly greater in flaring patients, suggesting shared antigen specificity and differentiation from common progenitors. More specifically, we identified 2 functionally deviated/exhausted Treg subsets (ISGhi/ISGlo) (Figure 1B) and, at baseline, found notable clonal overlap between the ISGhi Treg subset and Th2/17 cells and between the ISGlo subset and Tfh/Tph cells in flaring patients, which was absent in quiescent patients (Figure 1C). This suggests that there are 2 distinct subsets of cells with shared antigen exposure and/or functional plasticity; one that is exposed to an IFN-rich environment in the tissue, and another that is more involved in T-B cell interactions within lymphoid compartments. Conclusion We found abnormal Treg subsets with features of exhaustion and functional deviation that shared antigen specificity with other T helper cells. Their increased prevalence during flares suggests that dysregulated immunoregulation may contribute to SLE pathogenesis.

OBJECTIVE:To determine if the levels of five urinary biomarkers (UBs), including cluster of differentiation 163 (CD163), monocyte chemoattractant protein-1 (MCP-1), adiponectin, soluble vascular cell adhesion molecule and platelet factor 4 (PF4), measured 24 months after a lupus nephritis (LN) flare are associated with adverse long-term outcomes. METHODS:We included patients with an LN flare who had a preflare estimated glomerular filtration rate (eGFR) ≥60 mL/min and stored urine 24±3 months after the flare. The following outcomes were then examined: (1) time to a subsequent LN flare and (2) time to 30% sustained decline in eGFR. UBs were measured by ELISA 24±3 months after the LN flare. The results were normalised to urine creatinine and expressed as pg per mmol of urine creatinine. RESULTS:69 patients with LN were included, the median (IQR) follow-up time after their 24-month urinary sample collection was 129 (97.5-150) months. 50 patients achieved a primary efficacy renal response 24 months after the LN flare. This subcohort of patients had significantly lower UB levels. In this subcohort, 27 (54%) experienced a subsequent LN flare with a median time to flare (IQR) of 3.5 (1.67-6.87) years, and 10 (20%) had a 30% decline in eGFR at a median time of 4.38 (3.73-5.33) years after their 24-month urinary sample collection. Elevated levels of MCP-1 (HR 1.40 (1.11-1.76), p=0.004) and CD163 (HR 1.14 (1.00-1.38), p=0.01) predicted a subsequent LN flare. While CD163 (HR 1.16 (1.02-1.32), p=0.02), MCP-1 (HR 1.33 (1.01-1.74), p=0.04), adiponectin (HR 2.67 (1.68-2.46), p<0.001) and PF4 (HR 1.14 (1.04-1.25), p=0.002) predicted a 30% decline in eGFR. CONCLUSION:UBs measured 24±3 months after an LN flare were associated with subsequent flares and a clinically meaningful decline in kidney function.

Since their discovery, glucocorticoids continue to be the most potent antiinflammatory medication available for the management of systemic lupus erythematosus (SLE). Glucocorticoids are often used in the context of recent flare, persistently active disease, and sometimes to maintain disease quiescence. Furthermore, glucocorticoids are considered the cornerstone agent utilized to treat several manifestations of SLE with different dosage ranges: low, moderate, high, and very high. Unfortunately, glucocorticoids also exhibit several adverse effects that could occur either in a short period and or after long exposure. In this chapter, we review the properties of glucocorticoids (antiinflammatory and immunosuppressive effects), their role in the management of SLE, their adverse events, and future directions regarding their use. We also reflect on the experience with glucocorticoids of Toronto Lupus Clinic, a prospective observational cohort study of 46 years duration.

O021 / #624 Topic:AS22 - SLE Heterogeneity ABSTRACT CONCURRENT SESSION 03: INNATE AND ADAPTIVE IMMUNITY IN SLE 22-05-2025 1:40 PM - 2:40 PM High levels of peripheral blood interferon (IFN)-induced gene (IIG) expression are a characteristic feature of SLE and associated with an increased risk of flare. However, how these global changes correlate with those in individual immune populations and act to promote flares remains unclear. To address this question, we examined the IFN-induced immune changes in SLE patients at a single-cell level. A 40-marker CyTOF panel was used to measure IFN-induced protein (IIP) levels in the peripheral blood immune populations of 15 healthy controls (HC), 26 quiescent (clinical SLEDAI-2K = 0 for 1 year), and 42 recently flaring (clinical SLEDAI-2K ≥ 1 requiring an escalation of therapy) SLE patients. Twenty-nine immune populations were identified (Figure 1A). The mean IIP levels in all populations strongly correlated with global IIG expression, and were higher in flaring than quiescent patients (Figure 1B,C). Despite this correlation, there was significant heterogeneity in IIP expression between and within the cell subsets of individual patients, with the highest median levels of IIP seen in monocytes, plasmablast/plasma cells, and activated double positive T cells. These differences paralleled the response of these populations to exogenous IFN in HC cells in vitro. Within each cell subset of individual patients, there was a variably broad distribution of IIP expression, sometimes with distinct peaks (Figure 1D). To assess the factors contributing to this heterogeneity, we performed an analysis of extremes comparing the top and bottom 10% of IIP expressing cells in each subject (Figure 2A). Although the top IIP expressing cell subset of most populations had elevated levels of activation markers, such as Ki67, CD86, TLR7, TLR9, and HLA-DR, these molecules were induced by IFN in vitro, suggesting that IFN plays a direct role in their upregulation in vivo (Figure 2B). Notably, increased levels of the trafficking markers were also seen in the high IIP expressing cell subset, but with the exception of β7 (an integrin implicated in homing and retention in the gut), were not induced by IFN in vitro. Furthermore, these trafficking molecules demonstrated distinct patterns of expression, suggesting that these cells had transited different tissues. Longitudinal analysis of IIP expression over time revealed relatively stable levels despite changes in disease activity, and although the levels of IIP in the different cell subsets tended to correlate with each other, only the levels within B cells were associated with sustained or recurrent disease activity 1 year later. Figure 1. A) UMAP of the individual cell types showing their differential abundance and relatedness, as well as the average of 6 IIPs In HCs, quiescent and flaring patients: 29 cell types were identified based on their expression of the markers in our panel. There is a gradient in expression of average IIP expression in most cell types from low to high in HCs, quiescent patients, and flaring patients. B) Correlation matrix in all cells: Correlation between IIP expression (shown on theyaxis) and IIG expression in individual cell populations (shown on thexaxis). R values are denoted by colour, and p values by the size of the dots. C) Immunologic differences in IIP expression in immuno cell populations comparing flaring and quiescent patients: Waterfall plot showing the differential levels of IIP scores between flaring and quiescent, with bars above the line indicating increased expression in SLE patients. 27/29 immune cell subsets have significantly higher IIP scores in flaring patients relative to quiescent. D) Heterogeneity in IIP expression levels within the cell subsets of individual patients and HCs: Patients were separated into IIG high and low groups based on the top and bottom 15% of IIG score. Regardless of IIG group, there was heterogeneity in the IIP signature on a single cell level that was found within patient cells. Myeloid cells had the most marked heterogeneity, followed by T cells and then B colls. Figure 2. A) Analysis of extremes. Comparing the top and bottom 10% of IIP expressing cells within the same HCs and patients from ex vivo samples, it was found that certain activation and trafficking markers are upregulated in the IIP high cells, some of which are directly induced by IFN. R values are denoted by colour, and p values by the size of the dots. B) Incubation with IFNα and IFNβ induces several of the cellular markers that are associated with increased IIP expression in-vitro. PBMCs from healthy controls were stimulated with the indicated IFNs for 18 or 24 hours in the presence of Golgi-Stop for the last 2 hours. Shown are fold increases relative to unstimulated control. Although the mean IIP expression in each immune population correlates strongly with the IFN signature, there is significant heterogeneity between and within the cell populations of each patient in IIP expression. This appears to result not only from variability in the cells capacity to respond to IFN, but also variable exposure to IFN as cells traffic through the body.

Background Kidney function is not routinely assessed during pregnancy. Several studies have proposed antepartum kidney function, particularly second trimester kidney function, as a potential predictor of adverse pregnancy outcomes. It has been previously established that patients with systemic lupus erythematosus are at increased risk for adverse pregnancy outcomes. The association between second trimester kidney function and adverse pregnancy outcomes has not been evaluated in diverse patient populations, particularly among patients with high obstetrical risk. Methods In this observational study of pregnant patients with lupus in North America and Europe from 1995 to 2017, we used second trimester creatinine and eGFR to model the log odds of preeclampsia, preterm birth, low birthweight, fetal loss, and a composite of those outcomes. We incorporated these measures into a regression setting using fractional polynomials, and we further examined discrete formulations of eGFR. Results Among 684 pregnancies in patients with lupus, the mean second trimester creatinine was 0.63 mg/dl +/- SD 0.26 and the median value 0.60 (interquartile range, 0.50-0.70). At least 1 in 3 patients in this combined cohort experienced an adverse outcome. Mixtures of U-shaped and linear relationships between continuous kidney function and the log odds of adverse pregnancy outcomes were observed. Stratifying the cohort by diagnosis of lupus nephritis (LN; active or in remission) or without diagnosis of nephritis, we found differences in the relationship between kidney function and adverse outcomes. Conclusions We observed high rates of adverse pregnancy outcomes in our diverse patient population comprised of pregnant patients with lupus with and without LN. We identified complex relationships between second trimester kidney function and adverse pregnancy outcomes that differed by the outcome and diagnosis of LN.

OBJECTIVES:Systemic lupus erythematosus (SLE) remains a deadly disease, yet our ability to predict adverse outcomes is poor. Mitochondria are organelles recognised by the immune system when released from cells, and antimitochondrial antibodies (AMA) can be detected in people with SLE. We assessed AMA as markers of nephritis, arterial vascular events (AVE), and other outcomes including mortality. METHODS:We studied sera and data from 1114 participants of the Systemic Lupus International Collaborating Clinics inception cohort. We measured antiwhole mitochondria (AwMA), antimitochondrial DNA (AmtDNA), and antimitochondrial RNA (AmtRNA) antibodies by direct Enzyme-Linked ImmunoSorbent Assays (ELISAs). Separate multivariable Cox proportional hazards regression models estimated associations of either baseline or most recent measures of AMA with the outcomes, adjusted for biological sex, age, medications, and other clinical factors. Interactions of AMA with biological sex were tested for each outcome. RESULTS:All AMA titres were elevated in SLE vs healthy individuals. Higher AMA levels were associated with a higher hazard of nephritis, with the strongest associations for most recent AmtDNA (adjusted hazard ratio [aHR] =1.61 for increase of 1 SD, 95% CI 1.43-1.82) and AmtRNA (aHR =1.59, 1.46-1.73). Higher baseline AwMA levels predicted early mortality (aHR =1.19, 1.02-1.40). Most recent AmtDNA (aHR =1.68, 1.28-2.19) was associated with higher mortality throughout the follow-up. For AVE, the impact of higher AmtRNA was stronger in females. CONCLUSIONS:Baseline and most recent assessments of AMA levels may help identify individuals at higher risk of severe outcomes in SLE, including mortality. Integrating AMA into precision medicine strategies will allow deeper exploration of lupus heterogeneity.

OBJECTIVE:SLE is a complex, heterogenous autoimmune disease. SLE researchers do not always collect the same data, making comparative studies difficult. We aimed to ascertain what variables SLE clinical researchers commonly collect for SLE research. Our ultimate goal is to generate a minimal core dataset for future SLE studies. METHODS:In 2020, we designed and distributed a questionnaire to members of the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) as well as additional active research centres in China. Our survey included 26 questions about the types of data that are routinely collected for research. Variables collected by ≥75% of participating respondents were used as a threshold for inclusion. RESULTS:18 of 36 invited respondents replied (8 from USA/Canada, 5 from China and 5 from Europe). Many key variables in the domains of sociodemographics, SLE specific, comorbidities, baseline haematology/biochemistry/immunology and treatment data were collected by ≥75% respondents including the 1997 American College of Rheumatology (ACR) Classification Criteria (83%), SLE Disease Activity Index-2000 (82%), current treatment (100%), drug name, dose, frequency and start date (75-100%) and complement C3/4 (94%). A range of other items was collected by 50-<75% of respondents including SLICC 2012 Criteria (67%), SLICC/ACR Damage Index (68%) and Short Form Health Survey-36 (53%). Less than 50% of respondents collect certain items including European Alliance of Associations for Rheumatology/ACR 2019 criteria (33%), British Isles Lupus Assessment Group scores (12%) and pneumococcal vaccine status (39%). CONCLUSIONS:The frequency with which an initial set of variables is collected in SLE cohorts globally was identified and can form the basis from which to develop a core minimum dataset for SLE. Further refinement and common definitions will be needed to finalise a minimal core dataset suitable for widespread use.

Systemic lupus erythematosus (SLE) has a significant and long-lasting impact on work outcomes, is a source of long-lasting work disability, and presents challenges with participation in activities of daily living. This study aimed to create a functional profile for patients with SLE. A functional profile is defined as activities of daily living and those related to work functioning (activities of daily living). A cross-sectional investigation was carried out across 6 Canadian facilities, comprising 6 academic institutions and 1 community-based facility. Clinical measurements were obtained, including the SLEDAI-2K and ACR/SLICC Damage Index (SDI) and patients’ medications. Patients completed the Work Role Functioning Questionnaire v2.0 (WRFQ), the World Health Organization—Disability (WHO-DAS) Assessment Schedule 2.0 (WHO-DAS), and the Beck Depression Inventory (BDI-II). Descriptive and inferential statistics were computed for the demographic, clinical, and functional outcomes. Univariate and multivariate regression analyses to study the association with WHO-DAS and WRF were performed. 404 patients were studied; mean age was 47.0±13.71 years and 91.8%% were female (64.7% White, 12.4% Black, 6.7% Chinese and 16.2% other races) with a mean SLE duration of 15.7 ±11.8 years. The total mean score for the WRFQ was 71.51.8±23.5. The WRFQ subscale mean scores were also reported for work scheduling demands (66.8±28.8), work output demands (71.1±25.6), physical demands (67.3±27.9), mental and social demands (74.4±22.8) and flexibility demands (75.0±24.7) (Figure 1). Comparison to the general working population). The WHO-DAS 2.0 total mean score was 25.1±9.71, representing approximately the 93.8th population percentile, meaning that only about 6.1% of the population scored higher (more disabled) than our sample. In the multivariate analysis, sex (Female), damage (SDI), prednisone dose, fatigue severity score, Work Role Functioning total scores, presence of fibromyalgia, Role Emotinal SF-36, depression and pain were associated with increased disability. Similarly, fatigue severity score, depression, and pain were associated with decreased WRF total scores. This Canadian study confirmed that patients with SLE suffers from high level of disability and functional decline and as measured by WHO-DAS and WRF. Several factors were associated with disability and functional decline including accrued damage, presence of fatigue and fibromyalgia, depression, pain and prednisone dose. Developing the initial functional profile of work disability will facilitate a multidisciplinary approach to enhance the care and management of work disabilities and related functional outcomes. Supported by a CIORA grant. Best Abstract on Quality Care Initiatives in Rheumatology Award

Economic analyses of SLE often include only direct healthcare costs. Indirect costs, particularly from lost productivity in unpaid labor, are often overlooked, especially relevant for a disease disproportionately affecting women. We assessed indirect costs due to lost productivity in both paid and unpaid labor, stratified by gender, in a national multicenter SLE cohort. Patients fulfilling ACR or SLICC SLE Classification Criteria completed a validated questionnaire on lost productivity. Total indirect costs included: 1) absenteeism (time lost from paid labor because of illness), 2) presenteeism (degree of productivity impairment in paid/unpaid labor), 3) opportunity costs (additional time patients would be working in paid/unpaid labor if not ill). Opportunity costs were calculated as the difference between the time patients worked versus an age, sex, and geographic-matched general population in paid and unpaid labor. Indirect costs from paid and unpaid labor were valued using age-and-sex-specific wages from Statistics Canada. The association of gender with annual indirect costs was assessed (adjusted for race/ethnicity, age, disease duration, and the SLICC/ACR Damage Index [SDI]) using random effects linear regression modeling. 1804 patients participated, 90.8% female, 66.9% white, mean age at diagnosis 33.7 (SD 13.9) years, mean SLE duration 14.7 (11.7) years, and mean SDI 1.3 (range 0-12.0). Patients were followed a mean of 4.9 (range 1.0-9.6) years with 48.9% employed (49.5% among females, 44.0% among males) at the initial and 37.0% (37.1% among females, 36.7% among males) at the final observation. Overall, total annual indirect costs were $36 405 (absenteeism: $829; presenteeism in paid labor: $4624; presenteeism in unpaid labor: $8922; opportunity costs in paid labor: $8512; opportunity costs in unpaid labor: $13 519). Among women, opportunity costs from unpaid labor were 38.8% ($14 175/$36 538) and from paid labor 21.3% ($7802/$36 538) of total indirect costs; among men, opportunity costs from unpaid labor were 19.3% ($6765/$35 064) and from paid labor 44.7% ($15 685/$35 064) of total indirect costs (Figure 1). Regression modeling showed that women incurred higher opportunity costs from unpaid labor (coefficient $7309, 95% CI $3514, $11 105), and lower opportunity costs from paid labor (coefficient −$8336, 95% CI −$12 524, −$4147). Figure 1a: Components of Annual Indirect Costs: Female Total: $36 538 (2023 Canadian Dollars) Figure 1b: Components of Annual Indirect Costs: Male Total: $35 064 (2023 Canadian Dollars) Indirect costs, particularly from unpaid labor, are substantial, especially in women, where they represent 38.8% of total indirect costs versus 19.3% in men. Hence, economic analyses weighing costs and benefits of novel/emerging therapies should incorporate costs resulting from lost productivity, particularly important for a disease that disproportionately affects women.

O052 / #245 Topic:AS24 - SLE-Treatment ABSTRACT CONCURRENT SESSION 09: SLE THERAPY – REVISITING OLD DRUGS AND UNLOCKING HIDDEN POTENTIAL OF NEW MEDICATIONS 24-05-2025 10:40 AM - 11:40 AM We previously evaluated hydroxychloroquine (HCQ) tapering/cessation and risk of systemic lupus erythematosus (SLE) flare in the SLICC Inception cohort. However, in our approach we did not account for potential bias due to interval-censored (IC) outcomes, where exact timing of events are unknown. Our objective was to address this, with alternative approaches to defining timing of IC events, including the Simulation Extrapolation (SIMEX) approach. We evaluated 1,543 members of the SLICC Inception cohort (January 1999 to January 2019). Adults (18+) with SLE were enrolled in this cohort within 15 months of diagnosis and followed annually with questionnaires and physician assessment. In our time-to-event analyses, time-zero was defined as cohort entry if a subject was taking HCQ at the time, or the first prescription of HCQ otherwise. HCQ tapering/cessation was defined as the first cessation or decreased dose of HCQ and modeled as a binary time-varying exposure. Multivariable proportional hazard regression assessed associations between HCQ tapering/cessation and time to SLE flare, controlling for demographics (age, sex, race/ethnicity, region, education), baseline medication (steroids, immunosuppressives, biologics), enrollment year, time between diagnosis and cohort entry, smoking status, end-stage renal disease, and body mass index. Lupus flare was defined as the earliest of: A. Increase (from prior score) of at least 4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), B. Increase/initiation of SLE therapy (prednisone, immunosuppressive, or biologic), or C. SLE-related hospitalization. Since exact date of increased SLEDAI-2K was unknown, these represented IC events. We compared alternative analyses, imputing the IC event time at either the end- or the mid-point of the interval between the previous clinic visit and the visit when the outcome was reported. In sensitivity analyses we used SIMEX, a more sophisticated method based on simulations that allowed us to assess how the HR of interest changes with increasing time interval between adjacent visits. By extrapolating observed trends between the original and simulated data, we could correct the bias estimated to be within the original data, due to IC events.[1] Out of the total 1,543 subjects, 398 (25.8%) decreased or stopped their HCQ at some point during their follow-up and 1,187 experienced a disease flare (76.9%). When IC event times were imputed at the end of the relevant time interval, the adjusted HR for flare related to HCQ decrease/cessation was 1.43 (95% confidence interval, CI 1.24-1.66). When IC event times were imputed at the mid-point, the point estimate for the adjusted HR was slightly higher (1.53, 95% CI1.32-1.78). SIMEX correction yielded an even higher point estimate for the adjusted HR (1.68, bootstrapped 95% CI 1.44-2.02). HCQ tapering/cessation was associated with greater flare risk regardless of how IC events were handled. Correcting imprecise timing of IC events tended to increase the strength of estimated associations, although confidence intervals overlapped. Limitations of these analyses include failure to account for disease status and/or other concomitant drug changes at tapering/cessation. Future analyses will address these issues (and stratify outcomes according to whether HCQ was tapered vs stopped).References:[1.] Abrahamowicz M. Biom J 2022;64(8):1467-85.

O048 / #626 Topic:AS15 - Lupus Nephritis-Clinical ABSTRACT CONCURRENT SESSION 08: RECENT ADVANCES IN LUPUS BIOMARKERS 23-05-2025 1:40 PM - 2:40 PM Lupus nephritis (LN) affects up to 50% of patients with lupus, of whom 40% will experience a subsequent renal flare, and up to 20% will progress to end-stage renal disease. Repeat kidney biopsies (KB) performed 2 years after the last LN flare have been shown to predict subsequent renal flares and renal dysfunction. In this study, we assessed whether 5 urinary biomarkers (UB), including CD163, MCP-1, Adiponectin, sVCAM-1 and PF4 measured 2 years after a LN flare, predict long-term renal outcomes. Patients who had a LN flare and stored urine 24±3 months after the LN flare were included in the study. The 5 UB levels were measured by ELISA 24±3 months after the LN flare. Examined renal outcomes: 1) Time to a subsequent LN flare (increase in proteinuria of at least 1000 mg/day if the baseline was <500 mg/day or doubling of proteinuria if the baseline was ≥500 mg/day, prompting a change in therapy) and 2) time to 30% decline in eGFR, after their 2-year urinary sample collection. 69 patients with LN were included. The median (IQR) follow-up time after their 2-year urinary sample collection was 129 (97.5-150) months. 50 patients achieved proteinuria of ≤700 mg at 2 years after the LN flare. This subcohort of patients had significantly lower UB levels 2 years after the LN flare compared to patients who persisted with proteinuria >700 mg (Figure 1). In this subcohort of patients, 27 (54%) experienced a subsequent LN flare with a median time to flare (IQR) of 3.5 (1.67-6.87) years, and 10 (20%) had a 30% decline in eGFR at a median time of 4.38 (3.73-5.33) years after their 2-year urinary sample collection. Elevated levels of MCP-1 (HR 1.13 (1.01-1.27), p=0.03) and CD163 (HR 1.48 (1.15-1.90), p=0.002) predicted a subsequent LN flare. While CD163 (HR 1.31 (1.10-1.57), p=0.002), Adiponectin (HR 1.53 (1.22-1.91), p=0.0002), sVCAM-1 (HR 1.11 (1.03-1.21), p=0.006), and PF4 (HR 1.14 (1.04-1.25), p=0.003) predicted a 30% decline in eGFR (Table 1). Figure 1. UB were significantly higher in patients who did not achieve an uPCR ≤700 mg (n=19) at 24±3 months after the LN flare as compared to those who did (n=50). Symbols represent the determination from a single individual, columns the median and the bars IQR. Table 1. Multivariable Cox Regression analysis. Predictors of adverse renal outcomes (Subcohort of patients who achieved a proteinuria of ≤700 mg at 24±3 months after the LN flare, N=50) UB measured 2 years after an LN flare predicted long-term renal outcomes.

Background: In-efficiencies associated with patient recruitment for Lupus trials can lead to prolonged trial durations, increased costs, and delays in bringing effective treatments to market. By applying Bayesian optimization methods in trial design, we are able to design response-adaptive trials that optimize patients' allocation to more promising arms. We retrospectively analyzed a failed phase 2 randomized control trial of a Lupus therapeutic agent. Objectives: Based on the potential features accounting for heterogeneity in response to treatment in this trial, we aim to use our interactive adaptive-trial AI simulation tool to simulate a clinical trial run on a highly responsive sub-population. Methods: To demonstrate the potential for increased efficiency leveraging the tool, and as part of a retrospective analysis of a failed phase 2 randomized control trial with 3 treatment arms and a standard of care control, we implemented our proprietary algorithms incorporating Bayesian optimization tools. In consideration of the uncertainty when predicting arm efficacy during trial design, we ran (i) a retrospective analysis of the failed phase 2 study, which revealed a multitude of factors, as potential predictors of response to treatment and (ii) a sensitivity analysis on two scenarios to ensure robustness of the adaptive design. Scenario 1: only one arm is efficacious; Scenario 2: two arms are efficacious. In both scenarios effectiveness was defined as a ~40% response rate and the control arm response rate was set at ~25% as seen in the original failed trial. Type 1 error (one sided) was set to α=0.05. Power was evaluated in the range of 75-90%. A response adaptive randomization with a single interim, set to occur after approximately 30% of subjects had reached the measured outcome ('adaptive design'), was simulated 100,000 times and compared to a fixed trial design. Validation was performed using multiple point sensitivity analyses. Results: At 85% power, the adaptive design as compared with the fixed design, was able to achieve potential reductions in sample size estimated at 17% and 15% for the two efficacious arms (291 vs 350 subjects, Figure 2) and one efficacious arm (370 vs 438 subjects) scenarios, respectively. Figure 1 presents a single simulation run of the adaptive design from the interactive adaptive-trial AI simulation tool. Two hundred and ninety-six subjects were recruited at a 1:1 allocation ratio prior to the interim analysis (of which at least 122 subjects reached the outcome measure), which after analysis that revealed two efficacious arms, diverted patients recruited post-interim mainly to those arms, enabling the trial to achieve significance with a smaller average total sample size (291 vs 350 subjects, as mentioned above). Conclusion: By implementing an innovative approach and using an interactive adaptive-trial AI simulation tool to simulate and visualize trial design, a potential reduction in sample size and increase in the proportion of Lupus patients allocated to efficacious treatment arms was achieved based on select features explaining heterogeneity in subsets of patients. Further evaluation of additional case studies is on-going. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Tahel Ilan Ber: None declared, Dan Goldstaub Merck-MSD, Teva, Oshri Machluf: None declared, Neta Shanwetter Levit: None declared, Roni Cohen: None declared, Yaron Racah: None declared, Elad Berkman: None declared, Raviv Pryluk: None declared, Murray B Urowitz PhaseV Trials Inc.