Faculty Bibliography

BACKGROUND:Interstitial fibrosis in lupus nephritis (LN) is often infiltrated by immune cells but typically regarded as non-specific 'scar reaction'. This study aimed to investigate the relationship between inflammatory fibrosis and kidney disease progression in LN. METHODS:Interstitial fibrosis and tubular atrophy (IFTA) were scored in 124 LN kidney biopsies. Inflammation in areas of IFTA (i-IFTA) was graded 0-3 according to the Banff Classification of Allograft Pathology. Significant glomerular filtration rate (GFR) loss was defined as a decline of >15 mL/min at 3 years from biopsy. Immune cell phenotype was defined by serial immunohistochemistry (13-plex). RESULTS:IFTA was observed in 88/124 (71%) biopsies, and i-IFTA was identified in 76/88 (86%) cases. The distribution of i-IFTA grades was heterogeneous across all IFTA grades. In patients with moderate-to-severe IFTA (>25%), the degree of i-IFTA was associated with a higher risk of significant GFR loss: 0/1 (0%), 0/3 (%), 3/4 (75%) and 7/9 (78%) for i-IFTA grades 0, 1, 2 and 3, respectively (p=0.015). Multiplexed histology revealed that i-IFTA was mostly composed of CD163+ macrophages and CD4 T cells, followed by CD8 T cells and granulocytes. CONCLUSION/CONCLUSIONS:I-IFTA is frequently observed in LN and is dominated by macrophages and T cells. For patients with baseline IFTA >25%, the degree of i-IFTA emerged as a predictor of GFR loss. These data support the routine scoring of i-IFTA in LN due to its prognostic implications and nominate i-IFTA as a potential therapeutic target.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with an increased risk of vascular dysfunction and cardiovascular disease. We validate our previously developed Systemic Lupus Erythematosus Activity Platelet-Gene Expression Signature (SLAP-GES) score and investigate its relationship with platelet activity and vascular health. SLAP-GES was associated with the SLE Disease Activity Index (Padj < 0.001) and consistent over time (r = 0.76; P = 9 × 10^-5). Moreover, SLAP-GES was associated increased platelet aggregation in response to submaximal epinephrine (P = 0.084), leukocyte platelet aggregates (P = 0.014), and neutrophil platelet aggregates (P = 0.043). SLAP-GES was also associated with impaired glycocalyx (P = 0.011) and brachial artery flow-mediated dilation (P = 0.045). Altogether, SLAP-GES is associated with SLE disease activity, platelet activity, and impaired vascular health.

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/CONCLUSIONS: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/CONCLUSIONS: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.

Monocytes and macrophages in patients with lupus nephritis exhibit altered behavior compared with healthy kidneys. How to optimally use mouse models to develop treatments targeting these cells is poorly understood. This study compared intrarenal myeloid cells in four mouse models and 155 lupus nephritis patients using single-cell profiling, spatial transcriptomics, and functional studies. Across mouse models, monocyte and macrophage subsets consistently expanded or contracted in disease. A subset of murine classical monocytes expanded in disease; these cells expressed Cd9, Spp1, Ctsd, Cd63, Apoe, and Trem2, genes associated with tissue injury in other organs that play roles in inflammation, lipid metabolism, and tissue repair. Resident macrophages expressed similar genes in clinical disease. In humans, we identified analogous disease-associated monocytes and macrophages that were associated with kidney histological subtypes and disease progression, sharing gene expression and localizing to similar kidney microenvironments as in mice. This cross-species analysis supports the use of mouse functional studies for understanding human lupus nephritis.

OBJECTIVES/OBJECTIVE:Novel biologic agents targeting the neonatal Fc receptor (FcRn) offer a promising strategy to prevent cardiac neonatal lupus (cardiac-NL) in pregnant patients with high-titre anti-SSA/Ro52 kD or 60 kD autoantibodies via dual effects: reducing serum immunoglobin G (IgG) levels and inhibiting placental transfer. This study was initiated to assess the feasibility of FcRn blockade as prophylactic therapy for recurrent cardiac-NL. METHODS:A 34-year-old pregnant patient with systemic lupus erythematosus and 3 prior consecutive pregnancies complicated by neonatal lupus (1 cutaneous, 1 fatal cardiac-NL at 20 weeks, 1 cardiac-NL delivered at 32 weeks and neonatal cutaneous NL), each despite hydroxychloroquine 400 mg daily, was treated with weekly subcutaneous infusions of 560 mg rozanolixizumab (humanised IgG4 monoclonal antibody against FcRn) from gestational weeks 14 to 28 (to cover the vulnerable period of fetal cardiac injury) through a compassionate use designation. The patient performed home fetal heart rhythm monitoring thrice daily with weekly echocardiograms. RESULTS:Maternal anti-SSA/Ro52 kD and 60 kD autoantibodies, total IgG, and subclasses IgG1, 2, 3 decreased by about 65% at gestational week 22, with a return to near baseline levels by week 34. The pregnancy was uncomplicated, resulting in a spontaneous vaginal delivery of a healthy neonate at 37 weeks. At delivery, cord blood and maternal IgG levels were normal, obviating the need for rescue intravenous immune globulin. The neonate had a normal echocardiogram and electrocardiogram but developed a rash consistent with neonatal lupus at 5 weeks of life. There were no serious adverse events. CONCLUSIONS:The successful application of FcRn blockade to prevent recurrent cardiac-NL sets a precedent for a multicentre study.

OBJECTIVE:Lupus nephritis (LN) management remains challenging, and novel noninvasive biomarkers are needed. This study quantified serum soluble mediators in the Accelerating Medicines Partnership (AMP) LN cohort to identify biomarkers of histological features and treatment response. METHODS:SLE patients (n=268) undergoing clinically indicated kidney biopsies (urine protein/creatinine ratio [UPCR] > 0.5) were recruited through the AMP RA/SLE network. Serum was collected at biopsy and 3-, 6-, and 12-months post-biopsy, alongside samples from 22 healthy controls. Concentrations of 66 immune mediators were quantified using xMAP multiplex assays, and TNF-α converting enzyme (TACE) measured by ELISA. Seven mediators with >95% values below detection limits were excluded from analyses. Bootstrapped LASSO regression identified proliferative LN (class III/IV+V) predictors from baseline mediators. Associations with 12-month treatment response (complete/partial vs. no response) were tested using 3-month changes in LASSO-selected mediators and UPCR via logistic regression. Molecular clustering of mediator profiles was performed to identify LN subgroups. RESULTS:Proliferative LN patients (class [III or IV] + V; n=160) displayed a distinct mediator profile compared to non-proliferative LN (class I/II/V; n=96). LASSO regression identified 20 mediators predictive of proliferative LN (AUC, 0.82; 95% CI, 0.81-0.91), including elevated syndecan-1, TNFRI, TNFRII, and VCAM-1, as well as decreased CCL3/MIP-1α, CD40L, and IL-5 levels. Among proliferative LN patients, 3-month reductions in syndecan-1 and VCAM-1, mediators associated with intrarenal LN activity and/or chronicity, predicted 12-month treatment response. A model incorporating these reductions and a decline in UPCR predicted treatment response in proliferative LN (0.90; 95% CI, 0.82-0.98). Molecular clustering revealed 4 distinct LN subgroups with unique soluble mediator signatures and clinical features, not captured by histology alone. CONCLUSION/CONCLUSIONS:Serum soluble mediators, particularly syndecan-1 and VCAM-1, reflect LN histological activity and early decreases predict treatment response, supporting their potential utility as noninvasive longitudinal biomarkers. The substantial heterogeneity within LN highlights the potential for biomarker-guided reclassification to advance precision medicine approaches.

OBJECTIVE:The objective is to provide evidence-based and expert guidance for the screening, treatment, and management of lupus nephritis. METHODS:The Core Team developed clinical questions for screening, treatment, and management of lupus nephritis using the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were completed for each PICO question, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the quality of evidence and to formulate recommendations. The Voting Panel achieved a consensus ≥70% on the direction (for or against) and strength (strong or conditional) of each recommendation. RESULTS:We present 28 graded recommendations (7 strong, 21 conditional) and 13 ungraded, consensus-based good practice statements for the screening and management of lupus nephritis. Our recommendations focus on the unifying principle that lupus nephritis therapy is continuous and ongoing, rather than consisting of discrete induction/initial and maintenance/subsequent therapies. Therapy should include pulse glucocorticoids followed by oral glucocorticoid taper and two additional immunosuppressive agents for 3-5 years for those achieving complete renal response. CONCLUSION/CONCLUSIONS:This guideline provides direction for clinicians regarding screening and treatment decisions for management of lupus nephritis. 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 individual patient.

The accepted version of this article was posted prematurely on March 24, 2025. The final version of record will be made fully available at a later date.

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation and identify correlates of renal parameters. Unbiased analysis identified three immunologically distinct groups of patients that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells showed more active disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive but with chronic renal injuries. The major immunologic axes of variation could be distilled down to five simple cytometric parameters that recapitulate several clinical associations, highlighting the potential for blood immunoprofiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.