Duarte‐García, Alí

Objective Antiphospholipid syndrome (APS) is a thromboinflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody (aPL)–positive patients using whole‐blood transcriptomics. Methods Whole‐blood RNA sequencing was performed on 174 aPL‐positive patients, including those with primary APS (n = 102), secondary APS (n = 29), and aPL positivity without classifiable APS (n = 43). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes. Results Four transcriptionally distinct clusters were identified. At one end of the spectrum, cluster 1 showed up‐regulation of ribosomal and metabolic pathways and down‐regulation of mechanistic target of rapamycin (mTOR), NETosis, and Hippo/interleukin‐6 (IL‐6) signaling. In contrast, cluster 4 exhibited the opposite pattern, with strong up‐regulation of mTOR, NETosis, and Hippo/IL‐6 signaling. Cluster 2 demonstrated modest enrichment in messenger RNA processing and amino acid metabolism, and cluster 3 showed biosynthetic suppression with mild Hippo/IL‐6 activation. Clinically, cluster 4 stood out with higher IgG anticardiolipin and anti–β 2 ‐glycoprotein I positivity, elevated neutrophil counts, and increased urine protein‐to‐creatinine ratios. Immune deconvolution revealed distinct cell type profiles: cluster 1 was lymphoid predominant; cluster 2 had a balanced composition; cluster 3 was enriched in Treg cells, natural killer cells, macrophages, mast cells, and memory B cells; and cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features, including white matter lesions, seizures, and cardiac valve disease. Conclusion This study reveals four endotypes of aPL‐positive patients, a step toward personalized medicine for APS through pathway‐informed stratification and therapy.

Objective Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological diagnosis that can be associated with SLE. The clinical presentation, risk factors and outcomes of PRES in patients with SLE remain insufficiently described. Methods We conducted a multicentre cohort study at the Mayo Clinic and performed a systematic literature review (SLR) of patients with incident PRES and SLE. We described the clinical features, treatments and outcomes. Across both the cohort study and SLR, we assessed neurological sequelae, recurrence and survival. Within the cohort study, we examined PRES risk factors and discontinuation of antiseizure medications (ASMs). We used logistic regression to evaluate factors associated with neurological sequelae and Cox regression to assess predictors of recurrence. Kaplan-Meier methods estimated the rates of recurrence, survival and ASMs discontinuation. Results 550 cases (53 from the cohort study) were included, of whom 92% were female. Across both cohort and SLR, the most common symptom was seizure, occurring in 80%. PRES was the first manifestation of SLE in 13% of cases. In the adjusted analysis, older age was associated with neurological sequelae (OR 1.63 per 10-year increase; 95% CI 1.12 to 2.39). After 5 years of follow-up, 11.5% (95% CI 2.3 to 19.9%) of patients had a recurrent PRES episode. 30-day and 180-day survival following PRES was observed in 96.3% (95% CI 93.5 to 99.1%) and 93.7% (95% CI 89.8 to 97.7%) patients, respectively. In the Mayo Clinic cohort, 81% of PRES cases were attributed to hypertension in the context of lupus nephritis (LN), and by the fifth year of follow-up, 78.1% (95% CI 58.7 to 88.4%) of patients had discontinued ASMs. Conclusions In this cohort, most of the incident PRES episodes were preceded by hypertension and occurred in patients with LN. Although short-term and long-term prognoses are favourable, older patients more frequently experienced neurological sequelae.

Abstract Objectives Patient education is increasingly acknowledged as an important aspect of the management of systemic lupus erythematosus (SLE). The aim of the study was to develop the SLE Knowledge Assessment score (SLAKE), a digital multilingual self-assessment tool designed to quantify essential SLE knowledge. Methods International healthcare professionals (HCPs) and patient representatives engaged in a multi-step process to: identify essential SLE knowledge domains, select key domains via rating, and generate an item bank of 394 questions across 11 domains, which was then adapted into 19 languages. For validation, participants completed 44 questions (including 33 randomly selected), with scores calculated for total knowledge and the 11 specific domains. Statistical analyses examined associations between scores and demographic, clinical, and educational variables. Results SLAKE was used by 1182 SLE participants (1120 [94.8%] women, median age: 45 years [IQR: 35–54 years]), with a median SLE duration of 10 years (IQR: 4–20 years). The median SLAKE score was 37 (IQR: 34–40) of a maximum of 44 points while the median score across the 11 SLAKE domains ranged between 3 and 4 over a maximum of 4 points. There was a significant positive association between SLAKE score and SLE duration (p= 0.006), previous participation to a patient education course or a patient training for lupus (p< 0.0001) and the education level (p< 0.0001) but not with age (p= 0.48) or gender (p= 0.39). Conclusion SLAKE is a valid, multilingual, digital self-assessment tool that effectively measures essential SLE knowledge. Its randomized question bank and domain-specific scoring enable targeted education, ultimately supporting better disease management.

Abstract Background Antiphospholipid syndrome (APS) is diagnosed when vascular thrombosis or pregnancy morbidity occurs in the presence of persistent antiphospholipid antibodies (aPL). Although IgM-isotype antibodies are part of the laboratory criteria, their clinical value remains uncertain. We evaluated real-world aPL testing patterns to quantify the prevalence of isolated IgM positivity. Methods We analyzed aPL testing data across the Mayo Clinic sites between January 2006 and July 2025, lined up with the publication of the revised Sapporo (Sydney) classification criteria. For each patient, we identified the first time in which any aPL test was performed. We assessed available results for Lupus anticoagulant (LA), anticardiolipin (aCL) isotypes IgG and IgM, and anti–beta 2 glycoprotein (B2GP1) isotypes IgG and IgM. Positivity rates were calculated for each marker, and a subgroup of patients who had results for all three test categories at the initial workup was identified. In this cohort, we assessed the distribution of single, double, and triple positivity. We also quantified the number and percentage of patients who were positive only for IgM isotypes (aCL or B2GP1), with negative LA and IgG at initial testing. Antibodies were considered positive based on international criteria and internal standards. aCL and B2GP1 were positive if ≥40 units. LA positivity followed ISTH SSC guidelines, requiring demonstration of a phospholipid-dependent inhibitor in the following assays: screening, mixing, and confirmatory steps in DRVVT or aPTT-based platelet neutralization procedure (PNP), Staclot LA delta and HEX LA delta assays. Criteria for a positive result was as follows: DRVVT: prolonged screen and inhibited mix with screen/confirm ratio >1.2; Staclot LA delta: >7 seconds; PNP: shortening of the APTT clotting time with PNP by ≥5 seconds before 2023 and ≥2 seconds thereafter; HEX LA delta >13 seconds. Results A total of 99,814 unique patients underwent testing for at least one aPL marker. The most frequently tested was LA (n = 75,085), with a positivity rate of 10.29% (7,730/75,085). Among antibody isotypes, positivity rates were 1.2% (846/69,539) for aCL IgG, 1.7% (1,198/69,640) for aCL IgM, 1.9% (732/37,791) for B2GP1 IgG, and 2.0% (762/37,601) for B2GP1 IgM. Among the 30,274 patients who underwent simultaneous testing for LA, aCL IgG/IgM, and B2GP1 IgG/IgM, 1.3% (n = 407) were triple-positive, 1.4% (n = 427) were double-positive, and 9.9% (n = 3,009) had a single positive marker. The remaining 87.3% (n = 26,431) tested negative for all three. Of the 3,009 patients with only one positive marker, 9.8% (n = 296) were positive exclusively for aCL IgM, and 7.4% (n = 224) were positive exclusively for B2GP1 IgM. Among all fully tested patients, 2.2% (668/30,274) were positive for only IgM isotypes (either aCL or B2GP1) in the absence of IgG and LA positivity. Specifically, 0.9% (n = 296) were exclusively positive for aCL IgM and 0.7% (n = 224) for B2GP1 IgM. Additionally, 0.5% (n = 148) were simultaneously positive for both aCL IgM and B2GP1 IgM, without associated IgG or LA markers. Had only IgG and LA been assayed, 17.4 % (668/3843) of initially positive patients—and one-third of those classified as triple-positive—would have been missed. Conclusion Within this large-scale analysis of real-world APS test ordering practice, less than one-third of orders included a comprehensive characterization. Isolated IgM positivity, defined as aCL or B2GP1 IgM in the absence of IgG and LA, was infrequent yet represents a sizable proportion of initial positive aPL testing. How these results impact APS diagnosis and management of APS requires further study.

Objective To assess the impact of renal replacement therapy in people with lupus nephritis (LN)–associated end‐stage kidney disease (ESKD) and support the development of the 2024 American College of Rheumatology LN treatment guidelines. Methods We conducted a systematic literature review and meta‐analysis to address three Population, Intervention, Comparison, and Outcome (PICO) questions related to renal replacement therapy for ESKD due to LN, including comparisons of kidney transplant versus dialysis, hemodialysis versus peritoneal dialysis, and preemptive kidney transplant versus no preemptive kidney transplant. Outcomes of interest included mortality, cardiovascular (CV) events, infections, lupus flares, disease‐related damage, graft failure, and quality of life. We conducted a meta‐analysis and analyzed hazard ratios for time‐to‐event analyses and risk ratios for dichotomous outcomes, as well as absolute risk estimates. Results Sixteen comparative observational studies addressed at least one of the three PICO questions. Kidney transplant was found to reduce the risks of all‐cause mortality, CV mortality, infection‐related mortality, and CV events compared with dialysis (high certainty). Dialysis modality (peritoneal vs hemodialysis) was not associated with mortality (high certainty) or with other outcomes of infection, CV complications, and systemic lupus erythematosus flares (low certainty). Preemptive kidney transplant was associated with lower risks of graft failure and mortality (low certainty). Conclusion This systematic review identified improved outcomes with kidney transplant versus dialysis for people with LN‐associated ESKD and potential benefits of preemptive kidney transplant. This evidence supports the use of kidney transplant as a preferred renal replacement therapy for people with LN‐ESKD.

Objective To provide evidence‐based and expert guidance for the treatment and management of non‐renal systemic lupus erythematosus (SLE); treatment and management of lupus nephritis are addressed in a separate guideline. Methods Clinical questions for treatment and management of SLE were developed in the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were developed for each PICO question, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess evidence quality and formulate recommendations. The Voting Panel achieved a consensus of ≥70% agreement on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present recommendations and ungraded, consensus‐based good practice statements for the treatment and management of SLE that are applicable to pediatric and adult patients. Recommendations emphasize uniform treatment with hydroxychloroquine, limiting duration of glucocorticoid use, and early introduction of conventional and/or biologic immunosuppressive therapies to achieve and maintain control of SLE inflammation (remission or a low level of disease activity), reduce SLE‐related morbidity and mortality, and minimize medication‐related toxicities. Conclusion This guideline presents direction regarding treatment and management of SLE and provides a foundation for well‐informed, shared clinician–patient decision‐making. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each person with SLE.

Objective To provide evidence‐based and expert guidance for the treatment and management of non‐renal systemic lupus erythematosus (SLE); treatment and management of lupus nephritis are addressed in a separate guideline. Methods Clinical questions for treatment and management of SLE were developed in the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were developed for each PICO question, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess evidence quality and formulate recommendations. The Voting Panel achieved a consensus of ≥70% agreement on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present recommendations and ungraded, consensus‐based good practice statements for the treatment and management of SLE that are applicable to pediatric and adult patients. Recommendations emphasize uniform treatment with hydroxychloroquine, limiting duration of glucocorticoid use, and early introduction of conventional and/or biologic immunosuppressive therapies to achieve and maintain control of SLE inflammation (remission or a low level of disease activity), reduce SLE‐related morbidity and mortality, and minimize medication‐related toxicities. Conclusion This guideline presents direction regarding treatment and management of SLE and provides a foundation for well‐informed, shared clinician–patient decision‐making. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each person with SLE.

Objective A patient‐centered approach for chronic disease management, including systemic lupus erythematosus (SLE), aligns treatment with patients’ values and preferences, leading to improved outcomes. This paper summarizes how patient experiences, perspectives, and priorities informed the American College of Rheumatology (ACR) 2024 Lupus Nephritis (LN) and 2025 SLE screening, treatment guidelines. Methods We completed a cross‐sectional qualitative study using content analysis of two Patient Panel meetings for the ACR LN and SLE guidelines. Key themes were presented by Patient Panel representatives during Voting Panel Meetings along with evidence for each recommendation, to ensure comprehensive discussions and align treatment recommendations with patients’ priorities and values. Results Nineteen people (90% women) with diagnoses of SLE and/or LN participated in the Patient Panels and 17 consented to use their feedback for analysis. Thematic analysis of their discussions revealed nine patient‐reported key themes in three domains: (1) treatment and monitoring of LN and SLE: medication side effects, daily function, treatment goals, and monitoring and screening; (2) clinical communication: strategies to optimize communication and provider and structural impediments to effective communication; and (3) improving transparency and information sharing: clinical trial participation, and medical costs and insurance coverage. These themes were actively incorporated into discussions during the Voting Panels for the ACR LN and SLE guidelines. Conclusion This work supported the integration of patient experiences in the clinical practice guideline development process and aligned recommendations with real‐world patient experiences and priorities, thereby enhancing the clinical applicability of the ACR LN and SLE guidelines. image

BACKGROUND: Whereas antiphospholipid syndrome (APS) is best known for increasing the risk of macrovascular thrombosis, APS vasculopathy is characterized by the abnormal proliferation of endothelial and smooth muscle cells, leading to occlusion of small blood vessels in the skin, kidneys, and heart, among other organs. The underlying mechanisms remain unclear, and targeted treatment options for patients with APS are lacking. METHODS: To identify and analyze APS microvascular endothelial cells (MVECs), skin biopsies of patients with APS complicated by livedo racemosa were characterized using single-cell RNA sequencing. CCN1 (cellular communication network factor 1) and CCN2 were identified in skin and kidney biopsies by immunofluorescence microscopy and in plasma by ELISA. Healthy dermal MVECs were cultured with APS patient–derived serum or immunoglobulin G (IgG), and relevant signaling pathways were characterized using quantitative PCR, immunoblotting, and immunofluorescence microscopy. The proliferation and migration of vascular smooth muscle cells were determined after exposure to conditioned medium from APS IgG–stimulated MVECs. A mouse model of APS IgG–accelerated neointima formation was developed. Anti-CCN2 monoclonal antibodies were tested in vascular smooth muscle cell functional assays and the mouse model. RESULTS: Increased endothelial cell expression of CCN1 and CCN2 was identified by single-cell RNA sequencing and further confirmed in APS skin by microscopy as well as in APS plasma by ELISA. Exposure of healthy MVECs to patient IgG triggered the upregulation of CCN1 and CCN2 via Toll-like receptor 4– and YAP1 (yes-associated protein 1)–mediated signaling. CCN2, originating from APS IgG–stimulated MVECs led to the proliferation and migration of vascular smooth muscle cells, phenotypes that were inhibited by an anti-CCN2 antibody or depletion of EGFR (epidermal growth factor receptor). We further observed increased expression of CCN2, along with evidence of YAP1 nuclear translocation, in kidney vessels of APS nephropathy biopsies. Finally, CCN2 inhibition with an anti-CCN2 monoclonal antibody significantly reduced neointima thickening and cell proliferation in a mouse model of APS IgG–accelerated neointima formation. CONCLUSIONS: This study revealed activation of YAP1-mediated signaling in APS dermal microvessels and demonstrated that the YAP1 target CCN2 plays a role in facilitating pro-proliferative communication between MVECs and vascular smooth muscle cells. These findings offer insights into the cellular and molecular mechanisms underlying APS vasculopathy, providing potential therapeutic targets for patients.