OBJECTIVE:Using a hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust the HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring. METHODS:This observational study included patients (N = 2,010) across the Systemic Lupus International Collaborating Clinics, Wisconsin, international, and French studies who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified an HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for the Systemic Lupus Erythematosus Disease Activity Index 2000 [score ≥6]). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels. RESULTS:Among 1,842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ-related toxicity. Odds of toxicity were 2.1-fold higher with blood levels ≥1,150 ng/mL and 1.7-fold higher with the cumulative HCQ dose per 1,000-g increase. Blood levels ≥1,150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3-fold higher odds of having supratherapeutic levels (≥1,150 ng/mL). CONCLUSION:The therapeutic reference range for HCQ blood level monitoring is 750 to <1,150 ng/mL. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.

Genome-wide association studies have identified genetic polymorphisms at 11p15 associated with Systemic Lupus Erythematosus (lupus). Statistical fine mapping prioritizes a highly prevalent coding haplotype within the IRF7 gene. Analysis of ancient DNA confirms that this haplotype has persisted at high frequencies in the global population for millennia. The IRF7 risk haplotype is sufficient to increase nuclear localization of IRF7 and transcriptional activity downstream of pattern recognition receptor pathways. This risk haplotype increases IRF7 DNA binding strength and alters IRF7 DNA sequence specificity, resulting in genotype-dependent increases in IFN-α production in numerous biological systems, including monocytes and airway epithelial cells. CRISPR engineering of a homologous risk variant in mouse Irf7 results in both enhanced innate control of virus infection and increased autoantibody titers in a model of autoimmunity. Altogether, we establish a persistent and prominent genetic IRF7 haplotype that amplifies IRF7 activity in a manner that has immunological risks and benefits. HIGHLIGHTS:Genetic analysis using modern and evolutionary datasets identifies a persistent and highly prevalent lupus-associated coding haplotype in IRF7 at 11p15 The IRF7 lupus risk haplotype increases IFN-α production by monocytes and airway epithelial cells The IRF7 lupus risk haplotype increases IRF7 DNA binding strength and alters DNA sequence specificity A homologous lupus risk variant in mouse Irf7 enhances control of vesicular stomatitis virus and exacerbates autoantibody production.

OBJECTIVES:Our objective was to describe the social networks of Black individuals with rheumatic and musculoskeletal conditions and understand the clustering of health-related behaviors to inform future community-based, peer-led interventions. METHODS:We used an adapted Personal Network Survey for Clinical Research (PERSNET) to map the personal social networks of Black individuals with rheumatic conditions in Boston and Chicago. We used egocentric network analyses to quantify network composition, and descriptive statistics and Welch's two-sample t-tests to assess network characteristics and behavioral concordance between participants and their network members. RESULTS:We mapped the social networks of 40 individuals with rheumatic conditions in Boston and Chicago. All participants self-identified as Black, with 6 indicating Hispanic or Latino ethnicity. One participant self-identified as male. Networks had a median size of 10, with 54% of all possible ties present and an average of 5 structurally distinct connections within each network. Boston networks had a larger proportion of kin (71%) compared to those in Chicago (40%). There was greater diversity in sex and education within Boston networks. Chicago networks displayed morelanced strong and weak ties and higher prevalence of health problems within networks. Smoking and drinking behaviors clustered within networks across both sites, which may reflect patterns of behavioral homophily or social influence. CONCLUSIONS:Differences in network density, constraint, and diversity highlight structural and relational patterns that may influence how health behaviors develop. They also reveal network configurations that position individuals to act as bridges, introducing new information and behaviors into communities where medical mistrust and systemic inequities undermine health messaging.

Systemic lupus erythematosus (SLE) guidelines predominantly focus on common major organ involvement. An international taskforce from three SLE expert groups (European Reference Network on Connective Tissue and Musculoskeletal Diseases, Systemic Lupus International Collaborating Clinics, and the European Lupus Society) previously developed consensus therapeutic strategies for 24 rare SLE manifestations. Here, 77 participants contributed to the development of consensus therapeutic strategies for 22 additional rare SLE manifestations, including diffuse pulmonary haemorrhage, rare cutaneous manifestations (bullous lupus, chilblain lupus, lupus tumidus, erythema multiforme, and toxic epidermal necrolysis-like lupus erythematosus), renal manifestations (interstitial nephritis and lupus podocytopathy), rare neurological manifestations (chorea, small fibre neuropathy, catatonia, and intracranial hypertension), rare gastrointestinal manifestations (protein-losing enteropathy, lupus hepatitis, intestinal pseudo-obstruction, and peritonitis), musculoskeletal manifestations (myositis and Jaccoud's arthropathy), and other rare manifestations such as uveitis, angioedema due to anti-C1 esterase inhibitor antibodies, interstitial cystitis, and lupus mastitis. These expert-based therapeutic strategies provide a framework for guiding therapeutic decisions where evidence-based recommendations might be insufficient.

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.

Infertility presents a profound physical, emotional, and financial burden, particularly for rheumatology patients who often face substantial barriers to family building. The 2024 Alabama Supreme Court ruling in LePage v. Center for Reproductive Medicine equating embryo destruction with wrongful death introduced new legal uncertainties, sparking concerns about access to in vitro fertilization (IVF) and reproductive health services across the United States. Although Alabama's subsequent legislative action granted temporary protections for fertility providers, the broader implications of embryo personhood laws remain unresolved. For patients with rheumatic diseases, timely access to assisted reproductive technology (ART) is essential. However, barriers such as limited ART awareness, concerns about safety and success, social and religious stigma, and financial and legal restrictions disproportionately impact this population. The consequences of restrictive policies extend beyond females, affecting men and same‐sex couples who rely on IVF to expand their families. Infertility is a recognized medical condition, and restricting ART access is medically and ethically indefensible. As physicians, researchers, and advocates, we must actively oppose legal decisions and policies that limit ART availability, including insurance restrictions, discriminatory practices, and embryo personhood legislation. Protecting and expanding ART access is critical—not only for rheumatology patients but for the one in eight couples and one in four physicians affected by infertility. Ensuring equitable, evidence‐based reproductive care is imperative to safeguarding the right to family building for all.

OBJECTIVE:A data-driven and expert/patient consensus-based project to develop a revised Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) is under way supported by SLICC, ACR, and the Lupus Foundation of America. Our objective is to report the item generation and reduction phase results for a revised SDI. METHODS:Item generation included a literature review by literature review groups and a Delphi exercise of international systemic lupus erythematosus experts and patients. Item reduction involved Delphi rounds in which items with a median appropriateness score of ≤4 of 9 were excluded. A 14-member item reduction committee assessed remaining items and removed those that did not reflect the damage construct, were rare, or were not feasible to assess. The clinical domain groups then refined the remaining items and their definitions. RESULTS:The Delphi panel included 146 individuals from 35 countries. The Delphi exercise nominated 2,256 items, and the literature review identified 117 items. After removing redundancies, 226 candidate items remained. Subsequent Delphi rounds, followed by review by the item reduction committee and clinical domain groups, resulted in 39 items across 13 domains. Eleven items from the original SDI, including proteinuria and cranial neuropathy, were removed and several new items were proposed, including growth failure/reduced final height and adrenal insufficiency. Severity-based subitems are proposed for 17 items (43.6%). CONCLUSION:This data-driven and expert/patient consensus-based process has proposed 39 candidate items, some with subitems, and definitions for a revised SDI. Weighting of items and subitems is underway to develop a clinical scoring system.

Autoantibodies against phosphatidylethanolamine (PE), a major phospholipid in cell membranes, are associated with symptoms of thrombosis and obstetric complications. A growing body of evidence indicates the involvement of a cofactor for the reactivity of anti-PE (aPE) antibodies. The goals of this study were to identify the putative cofactor and investigate the pathogenic roles of aPE antibodies. Existing ELISA-based assays for detecting aPE antibodies showed that the bovine plasma is a known source of cofactor for the manifestation of reactivity by aPE antibodies. We used affinity pull-down and serial fractionation to purify the cofactor from bovine plasma and identified it as the C4b-binding protein (C4BP), which is a conserved inhibitor in the complement cascade. The human C4BP was subsequently shown to bind PE membrane with specificity and is targeted by aPE antibodies which led to elevated complement activation. Similarly, murine aPE antibodies bind C4BP, hindering its inhibitory function, causing heightened complement activation in vitro and in vivo in a mouse model of renal ischemia and reperfusion, which was antagonized by the coadministration of an anti-C5 antibody. Collectively, the present data identified C4BP with PE-binding specificity and as an antigenic target for aPE antibodies, which cause complement activation. These findings shed light on the pathogenic mechanism of aPE antibodies with implications in diagnosis and therapeutic treatment.

O011 / #377 Topic:AS19 - Patient-Reported Outcome Measures ABSTRACT CONCURRENT SESSION 01: FINDINGS FROM LUPUS CLINICAL TRIALS 22-05-2025 1:40 PM - 2:40 PM Systemic lupus erythematosus (SLE) imposes significant disease burden and diminishes health-related quality of life (HRQOL); improvement of HRQOL is therefore a key treatment goal in SLE.[1,2] Dapirolizumab pegol (DZP) is a novel, polyethylene glycol (PEG)-conjugated antigen-binding (Fab’) fragment, lacking an Fc domain, that inhibits CD40L signaling. In the phase 3 PHOENYCS GO trial (NCT04294667) in patients with SLE, DZP improved disease activity measured by clinician-reported outcomes at Week 48 vs placebo (PBO), and was generally well tolerated.[3] Here, we report the impact of DZP on HRQOL as measured by LupusQoL completed by patients in the PHOENYCS GO trial. PHOENYCS GO was a 48-week, randomized, double-blind, PBO-controlled trial. Patients aged ≥ 16 years with moderate-to-severe, active SLE characterized by persistently active or frequently flaring/relapsing-remitting disease activity despite stable standard of care (SOC) medication (antimalarials, corticosteroids, and/or immunosuppressants) were included. Patients were randomized 2:1 to intravenous DZP 24 mg/kg plus SOC medication (DZP+SOC) or PBO+SOC every 4 weeks. HRQOL outcomes were measured using LupusQoL, a patient-reported outcome based on responses on a 5-point Likert scale to 34 items across 8 HRQOL domains.[1] Each domain score ranges from 0 to 100; higher scores indicate better HRQOL. The least square (LS) mean change from baseline in LupusQoL domain scores at Weeks 12, 24, 36, and 48 are reported. The LS mean, difference for DZP+SOC vs PBO+SOC, and 95% CIs were computed using a mixed model for repeated measurements (MMRM). Analyses were performed on the full analysis set. Overall, 97.6% (203/208) of patients receiving DZP+SOC and 95.3% (102/107) of patients receiving PBO+SOC had LupusQoL responses available at any visit. Baseline LupusQoL scores were comparable between the treatment groups (Table). Patients receiving DZP+SOC demonstrated consistently greater improvements from baseline over time in LupusQoL scores across all domains compared with PBO+SOC (Figure). Patients receiving DZP+SOC reported greater improvements in the ‘Fatigue’ and ‘Burden to others’ domains at all assessed visits compared with those receiving PBO+SOC, as of Week 12 (all p < 0.05; nominal). Additionally, greater improvements were reported for patients receiving DZP+SOC compared with PBO+SOC in the ‘Physical health’ and ‘Planning’ domains at Weeks 24, 36, and 48, in the ‘Pain’ and ‘Emotional health’ domains at Weeks 36 and 48, in the ‘Intimate relationships’ domain at Weeks 24 and 36, and in the ‘Body image’ domain at Week 48 (each p < 0.05; nominal). Table. Baseline LupusQoL domain scores Figure. LS mean change from baseline in LupusQoL domain scores by visit (MMRM) Improvements in HRQOL were greater in patients treated with DZP+SOC vs PBO+SOC across all LupusQoL domains, starting at the earliest timepoint (Week 12) for some domains. These data, along with the previously reported significant improvements in overall disease activity,[3] support the potential of DZP as a valuable treatment option in SLE to improve HRQOL.References:[1.] McElhone K. Arthritis Care Res 2007;57:972-9. [2.] Fanouriakis A. Ann Rheum Dis 2019;78:736-45. [3.] Clowse M. Arthritis Rheumatol 2024;76 (suppl 9).Acknowledgments:This study was funded by UCB and Biogen. Medical writing support provided by Costello Medical and funded by UCB and Biogen.

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:The objective of this study was to examine the clinical outcomes during the implementation of a self-administered patient decision-aid (PtDA) for lupus. METHODS:We provided an effective computerized lupus PtDA in 15 rheumatology outpatient clinics 2019-2024 (including the COVID pandemic). We undertook Organizational Readiness to Implement Change Surveys (ORICs) and Team Learning and Psychological Safety Surveys (TLPSSs) at baseline. The primary study outcome objective measure, percent penetration/reach, was defined as the number of patients who viewed the lupus PtDA at the end of the study, divided by the total number of eligible patients (times 100). We used validated clinical personnel surveys to examine the perceived lupus PtDA appropriateness, acceptability, feasibility, success, and permanence, at 4 months, 12 months and 24 months post-PtDA implementation. RESULTS:Among the sites, the clinical personnels' (n = 184) baseline ORIC commitment and efficacy scores (a 0-5 scale, higher = better) ranged from 3.5 to 4.2, and 3.4 to 4.4, respectively; the TLPSS scores (a 0-7 scale, higher = better) were 3.9-5.5 for internal learning, 3.7-5.6 for external learning, and 4.3-5.5 for psychological safety. The penetration (primary outcome) among 15 geographically diverse US rheumatology clinics ranged from 3% to 44%. We found that the total number of providers in the clinic was positively associated with higher penetration. Clinical personnel-perceived lupus PtDA outcomes were optimal at 4 months (all scale scores ranged from 1 to 5, higher = better): (i) appropriateness, 3.43 (s.d. 0.86); (ii) acceptability, 3.53 (s.d. 0.83); (iii) feasibility, 3.44 (s.d. 0.71); (iv) success, 3.41 (s.d. 0.73); and (v) permanence, 3.22 (s.d. 0.74). CONCLUSION:We implemented a lupus PtDA with varied success rates during the COVID pandemic; more providers were associated with higher clinic penetration. Clinical personnel perceived high lupus PtDA appropriateness, acceptability, feasibility, success, and permanence that persisted up to 24 months. TRIAL REGISTRATION:ClinicalTrials.gov, http://clinicaltrials.gov, NCT03735238.

The Systemic Lupus International Collaborating Clinics (SLICC) is an international research group dedicated to promoting collaboration among scientific investigators in the study of systemic lupus erythematosus (SLE). Currently, most SLICC members are based in North America and Europe, with limited representation from other regions. SLICC recognises the importance of expanding its global collaborations and representation to ensure that its research accurately reflects the global burden of SLE and provides equal benefit to all patients with SLE worldwide. Given that SLICC currently lacks representation from the African continent, an opportunity was identified to convene a meeting bringing together lupus physicians with experience providing clinical care and conducting lupus research in Africa, along with members of the SLICC group. The purpose of the meeting was to share information regarding SLE in Africa, to discuss recent innovations and current challenges in the region and to explore future collaborations between SLICC members and colleagues in Africa in the areas of SLE clinical care, research and education. This meeting report highlights information presented during the seminar as well as a discussion of next steps moving forward.

Existing guidelines for systemic lupus erythematosus (SLE) predominantly focus on common and major organ involvements. An international taskforce involving experts from three SLE expert groups (ie, the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases, the Systemic Lupus Erythematosus International Collaborating Clinics group, and the European Lupus Society) was established. A total of 119 participants contributed to the development of consensus therapeutic strategies for 24 rare SLE manifestations, using a multistep process. For SLE enteritis and pancreatitis, experts recommended hydroxychloroquine, glucocorticoids, and cyclophosphamide or mycophenolate mofetil. Rare lung conditions such as pneumonitis were also managed with cyclophosphamide if severe or with mycophenolate mofetil if not severe. SLE for myocarditis with hydroxychloroquine, glucocorticoids, and cyclophosphamide or mycophenolate mofetil, are recommended based on severity. For CNS manifestations, hydroxychloroquine, glucocorticoids, and cyclophosphamide or mycophenolate mofetil were common choices for treatment. For rare skin manifestations, the preferred strategy was a combination of hydroxychloroquine and glucocorticoids with anifrolumab or mycophenolate mofetil. This expert-based consensus provides a valuable framework for guiding therapeutic decisions where the available recommendations might be insufficient or inapplicable.

OBJECTIVES:Childhood-onset systemic lupus erythematosus (cSLE), representing 15%-20% of individuals with SLE, has been difficult to study globally due to differences between registries. This initiative, supported by Childhood Arthritis Rheumatology Research Alliance (CARRA) and Paediatric Rheumatology European Society (PReS), aims to create Core and Expanded cSLE Datasets to standardise and enhance research worldwide. METHODS:21 international cSLE experts and 4 patients participated in a Delphi process (questionnaires, 2 topic-specific focus groups and 3 virtual consensus meetings) to create 2 standardised cSLE datasets. The Core cSLE Dataset was designed to include data essential to meaningful clinical research across many settings. The Expanded cSLE Dataset was designed for centres able to consistently collect data to address broader research questions. Final data items for the Core and Expanded datasets were determined by consensus defined as >80% agreement) using an adapted nominal group technique and voting. RESULTS:The resulting Core cSLE Dataset contains 46 items, including demographics, clinical features, laboratory results, medications and significant adverse events. The Expanded cSLE Dataset adds 26 additional items and includes patient-reported outcomes. Consensus was also achieved regarding the frequency and time points for data collection: baseline, quarterly follow-up visits, annually and flare visits. CONCLUSION:Standardised Core and Expanded cSLE Datasets for registry-based international cSLE research were defined through the consensus of global experts and patient/caregiver representatives, endorsed by CARRA and PReS. These datasets incorporate disease-specific and patient-specific features, optimised for diverse settings to facilitate international collaborative research for children and adolescents with SLE worldwide.