OBJECTIVES: Active proliferative lupus nephritis (LN) is associated with elevated urinary neutrophil granule proteins such as proteinase 3 (PR3), implicating active cellular degranulation in LN. Yet, mature neutrophils are rarely observed in LN biopsies, raising the possibility of an unrecognized cellular source. We aimed to identify and characterize PR3-expressing myeloid cells in LN kidneys using a spatially resolved multi-omics approach. METHODS: Serial immunohistochemistry (10-plex) and spatial transcriptomics were employed to assess the distribution of PR3+ cells across renal tissue and characterize their cellular phenotype. RESULTS: PR3+ cells were abundant in LN kidney biopsies, but with marked inter-patient heterogeneity. These cells were predominantly localized to the tubulointerstitium and showed similar distribution in both proliferative and membranous LN. In contrast, intraglomerular PR3+ cells were enriched in proliferative LN and correlated with the NIH Activity Index. Phenotype analysis identified four subsets of PR3+ cells, consistent with a monocyte/neutrophil lineage. Most PR3+ cells lacked multilobate nuclei, distinguishing them from mature neutrophils, suggesting that these cells may be overlooked by conventional light microscopy. CONCLUSIONS: PR3+ myeloid cells are a prominent and heterogeneous population in lupus nephritis. While intraglomerular PR3+ cells were specific to proliferative LN and correlated with histologic activity, the widespread presence of PR3+ cells in the tubulointerstitium suggests broader involvement in renal inflammation than previously recognized. These findings reveal a potentially overlooked immune cell population that may contribute to renal injury in LN.
Objective This study aims to investigate the spatial transcriptomics of hypoxia and immune‐mediated damage within renal tissue in patients with lupus nephritis (LN) in comparison to healthy controls from kidney transplants. Methods Renal biopsies from patients with LN and transplant controls were imaged using multiplexed cyclic immunofluorescence to spatially quantify immune and endothelial cell markers. An independent LN cohort of patients underwent Visium spatial transcriptomics analysis. Hypoxia was modeled in cell lines and primary neutrophils using cobalt chloride, and urinary neutrophil cargo proteins were measured using an enzyme‐linked immunosorbent assay. Results LN glomeruli exhibited increased HIF‐1α–expressing CD68 + macrophages and CD66 + neutrophils along with diffuse perinuclear staining for myeloperoxidase (MPO), indicative of heightened NETosis and N2 reparative neutrophil presence. Spatial transcriptomic analysis confirmed the correlation between glomerular hypoxia and neutrophil extracellular trap (NET) formation. The renal pathology activity index was highly correlated with hypoxic neutrophil count, and these parameters correlated with glomerular endothelial rarefaction and reduced capillary lengths, junctions, and branching. Urinary neutrophil cargo and NET proteins (MPO and proteinase 3) were also elevated in active LN. Conclusion We posit that glomerular endothelial cell damage leads to hypoxia in LN, resulting in hypoxic, reparative myeloid cells and NETosis, whereas the latter has been linked to downstream inflammation and in situ trapping of antinuclear antibodies in LN. These glomerular events underpin high renal pathology activity and may pave the path toward irreversible damage in LN. Detection of neutrophil cargo in urine supports the potential for a liquid biopsy to monitor disease progression.
Objective Systemic lupus erythematosus (SLE) is a complex autoimmune disease driven by neutrophil dysregulation and neutrophil extracellular trap (NET) formation, with unmet therapeutic needs. This study aimed to investigate the therapeutic potential of protein kinase CK2 inhibitor CX‐4945 in SLE as well as to elucidate the underlying mechanisms. Methods CX‐4945 was administered to multiple murine models, including MRL/lpr mice, imiquimod (IMQ)‐induced lupus model, IMQ‐induced psoriasis model, and cecal ligation and puncture–induced sepsis model. Renal function, histopathological changes, immune complex deposition, NET formation, and inflammatory cytokine levels were evaluated. Results CX‐4945 significantly ameliorated renal damage in MRL/lpr and IMQ‐induced lupus models, as evidenced by reduced urinary albumin‐to‐creatinine ratio, glomerular abnormalities, immune complex/complement C3 deposition, and neutrophil infiltration. The neutrophils from patients with SLE exhibited elevated CK2α expression and enzyme activity. Mechanistically, CX‐4945 suppressed interferon‐stimulated genes and reactive oxygen species–related pathways, induced mitochondrial metabolic rewiring, inhibited JNK/p38 MAPK phosphorylation, and modified NET protein composition to abrogate macrophage proinflammatory responses. Conclusion CK2α is aberrantly up‐regulated in SLE neutrophils, and targeting CK2 with CX‐4945 exerts therapeutic effects in SLE. These findings identify CK2 as a novel therapeutic target for SLE and support the repurposing of CX‐4945 for treating neutrophil‐driven inflammatory and autoimmune diseases. image
Background Systemic lupus erythematosus (SLE) is characterized by the immune system producing autoantibodies that target the body’s own cells and tissues, leading to inflammation and tissue damage. Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in regulating immune cell trafficking, and its function relies on a gradient of sphingosine-1-phosphate (S1P). During inflammatory immune responses, the S1P gradient is altered, promoting lymphocyte migration to inflammatory sites. Consequently, S1PR1 has become a therapeutic target for inhibiting lymphocyte egress from lymphoid tissues in autoimmune and inflammatory diseases. However, knowledge of S1PR1 expression and function in B cell subsets and antibody-secreting cells (ASCs) in SLE remains limited. Methods Peripheral blood mononuclear cells (PBMCs) from forty-nine patients with SLE were enrolled to assess S1PR1 expression in B cell subsets and plasma cells. Significant differences in surface S1PR1 expression on activated naive (aNAV), Double Negative 2 (DN2) B cells and ASCs were further analyzed for correlations with disease activity, Lupus Nephritis (LN) involvement, inflammatory markers, S1P levels, and chemokine receptor expression. Results Intracellular S1PR1 expression was significantly increased across all B cell subsets, including naive (rNAV and aNAV), memory (SWM, USM, DN1, DN2), and ASCs. In contrast, surface S1PR1 expression differed markedly among subsets, with downregulation observed in aNAV and DN2 B cells and upregulation in ASCs. Further analysis revealed that surface S1PR1 downregulation on aNAV B cells was significantly associated with active disease status, SLEDAI-2 K scores, and LN involvement. Inflammatory markers (IL-6, IL-8, and C3c levels) showed no correlation with surface S1PR1 expression, whereas erythrocyte sedimentation rate (ESR) demonstrated a significant negative correlation. In addition, lupus aNAV and DN2 B cells exhibited reduced surface CXCR3 expression without correlation to S1PR1 expression, whereas other B cell
Abstract Objectives Antimalarial agents, particularly hydroxychloroquine, are fundamental in SLE management. While their renal benefits in lupus nephritis (LN) are recognized, their corresponding role in reducing extra-renal damage is less defined. This study examined the association between antimalarial use and extra-renal damage accrual in biopsy-confirmed LN. Methods This was a retrospective analysis of a prospectively followed cohort of patients with biopsy-confirmed LN enrolled in the University of Toronto Lupus Clinic (1970–2024). Extra-renal damage was defined as any increase (≥1) in the extra-renal SLICC/ACR Damage Index (SDI). Antimalarial use was analyzed as a time-dependent variable. Associations were assessed using multivariable Cox proportional hazards models. Results Among 352 patients, the median age was 34.1 years, 14.5% were male, and the median follow-up was 9.6 years [IQR 4.9–16.6]. Antimalarials were used by 47.7% at baseline, 58.5% during the first year, and 67.9% by year 5. Among 327 patients with complete SDI data, extra-renal damage occurred in 151 patients (46.2%) with a median time of 4.1 years [1.8–8.9]. In multivariable models, antimalarial use was independently protective against extra-renal damage accrual (HR 0.51, 95% CI 0.37–0.72). This protective effect remained significant across all baseline extra-renal SDI subgroups, including in patients with SDI=0 and those with SDI ≥1. Conclusions Extra-renal damage is common in patients with LN. In this population, antimalarial therapy was associated with a significant protective effect against extra-renal damage. These findings extend the benefits of antimalarials beyond renal protection and reinforce their essential role in reducing damage accrual in SLE patients with LN.
Lupus nephritis (LN) represents the most severe renal manifestation of systemic lupus erythematosus (SLE), contributing to significant morbidity. While current assessments focus on glomerular pathology, tubulointerstitial lesions may offer critical insights into disease progression and treatment response. This study develops a clinical prediction model integrating tubulointerstitial molecular signatures. We performed bioinformatics analysis using two independent tubulointerstitial gene expression datasets (GSE113342 and GSE200306), applying batch effect correction and principal component analysis (PCA) to identify differentially expressed genes (DEGs). A protein‒protein interaction (PPI) network isolated hub genes, and least absolute shrinkage and selection operator (LASSO) regression defined the novel "Nscore" parameter predictive of treatment response. The Nscore, incorporating seven key genes (EGR1, IL6R, TFRC, CCL19, IFI16, IFI35, and Fra1), showed a significant positive correlation with 24-h proteinuria and effectively distinguished complete-response (CR)/partial-response (PR) from non-response (NR). Immune deconvolution using the CIBERSORT algorithm revealed an increased abundance of T follicular helper (Tfh) cells and M1 macrophages in NR samples. A clinical nomogram integrating Nscore and sex demonstrated excellent discrimination. This model combines molecular biomarkers with clinical parameters to improve personalized therapeutic stratification, advancing treatment strategies beyond traditional glomerulocentric paradigms and identifying immune cell signatures as potential targets for immunomodulatory interventions.
Lupus nephritis (LN) represents the most severe and frequent complication of systemic lupus erythematosus (SLE), yet its treatment remains a significant unmet clinical need. Recent advances in immunometabolism have revealed that glucose metabolic reprogramming—including shifts in glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid (TCA) cycle—plays a central role in driving pathogenic immune cell activation in SLE. However, a critical gap persists in understanding how these metabolic alterations specifically operate within the renal microenvironment to promote immune cell infiltration and intrinsic kidney cell injury in LN. This review synthesizes current evidence on the molecular mechanisms linking glucose metabolism to immune dysfunction in innate immune cells including monocytes/macrophages, neutrophils and DCs and adaptive immune cells including T cells, B cells and renal resident cells. We further discuss therapeutic strategies targeting metabolic pathways, including repurposed drugs (metformin, hydroxychloroquine, rapamycin), preclinical small molecules (PKM2, PFKFB3, LDHA, GLUT1 inhibitors), and combination therapies with biologics. Safety considerations, particularly the sensitivity of regulatory T cells (Tregs) to glycolysis inhibition, underscore the need for dose optimization. Finally, we highlight future directions, including real-time metabolic imaging, personalized glycolysis scoring, and spatiotemporal metabolic epigenetic models, which hold promise for advancing precision medicine in LN.
Introduction Lupus nephritis (LN) represents one of the most frequent and severe manifestations of systemic lupus erythematosus (SLE), highlighting an urgent need for novel non-invasive approaches to improve its diagnosis and clinical monitoring. Objectives To characterize serum and urinary metabolomic profiles, together with urinary cytokine expression, in patients with lupus nephritis (LN) across the clinical spectrum from active disease, post-induction response, and sustained remission. Methods We enrolled 62 patients fulfilling the 2019 ACR/EULAR SLE criteria, divided into three groups: active LN (n=21), post-induction responders at 6 months (n=21), and sustained responders with ≥2 years of remission (n=20). Untargeted metabolomic profiling of serum and urine was performed using GC-MS, and urinary cytokines were measured by luminometry. Statistical analyses included Kruskal-Wallis tests and multinomial logistic regression. Results Median age was 36 years; 87% were female. Twelve serum metabolites and ten urinary metabolites differed significantly across groups. Active LN patients showed increased urinary threonate and elevated cytokines (15 out of 17 measured, including IL-10). Serum glycerol was significantly higher in post-induction responders compared to sustained responders, while urinary sucrose was lower in this group. Logistic regression identified urinary threonate as discriminative for active LN, whereas serum glycerol (OR 1.05, 95% CI 1.048–1.050) and urinary sucrose (OR 0.98, 95% CI 0.9802–0.981) differentiated post-induction from sustained response. Increased urinary IL-10 was strongly associated with active LN, while G-CSF discriminated post-induction from sustained responders. Discussion and conclusions The combined analysis of serum/urinary metabolomic profiles and urinary cytokines provides discriminatory power to differentiate active LN from remission states, supporting their potential role as non-invasive biomarkers for diagnosis and treatment monitoring.
To evaluate the prevalence, associated factors, and prognostic performance of NIH activity index–defined interstitial inflammation (NIH-TII) and interstitial fibrosis and tubular atrophy (IFTA) in lupus nephritis (LN). This retrospective cohort study analyzed 195 renal biopsy episodes from 135 LN patients. Tubulointerstitial lesions were graded according to histopathological severity. NIH-TII was assessed semiquantitatively using the interstitial inflammation component of the modified NIH activity index. Among 195 renal biopsies, class IV LN was most frequent (49.2%). Tubulointerstitial involvement was present in 74.3% of cases, with isolated NIH-TII in 14.4%, isolated IFTA in 15.9%, and both in 44.1%. Moderate-to-severe NIH-TII and IFTA were observed in 11.3% and 15.9% of biopsies, respectively. Patients with moderate-to-severe NIH-TII were older, had worse renal function, and more frequently exhibited moderate-to-severe IFTA. Moderate-to-severe IFTA was associated with older age, longer SLE duration, prior LN episodes, higher chronicity index, and impaired renal function, and was strongly associated with non-renal response and ESRD progression. In multivariable logistic regression, prior LN episodes (OR 8.4) and moderate-to-severe IFTA (OR 4.92) predicted non-renal response. In multivariable Cox regression, prior LN episodes (HR 8.55), moderate-to-severe IFTA (HR 8.93), and thrombotic microangiopathy (HR 12.99) predicted ESRD progression. Longitudinal analyses showed frequent progression of IFTA over time with increasing chronicity index. Moderate-to-severe IFTA was a strong predictor of renal non-response and ESRD progression. TII defined according to the NIH activity index, which does not include systematic assessment of tubulitis or total cortical inflammatory burden, was not independently associated with outcomes.
Background To evaluate the prognostic impact of tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy on renal function decline in patients with lupus nephritis. Methods This systematic review and meta-analysis followed PRISMA and Cochrane guidelines and was registered in PROSPERO (CRD420251045672). PubMed, Embase, Web of Science, and Cochrane were searched for studies evaluating the association between tubulointerstitial histopathologic lesions in lupus nephritis and renal outcomes. Risk ratios were pooled using random-effects models. Prespecified subgroup analyses were conducted according to follow-up duration, and sensitivity analyses included leave-one-out testing and restriction to studies defining ≥25% tubulointerstitial involvement. Meta-regression was performed to explore study-level sources of heterogeneity. Risk of bias was assessed using the Newcastle–Ottawa Scale. Analyses were performed in RStudio. Results Twenty-one retrospective studies encompassing 3607 adult patients with lupus nephritis were included. Tubulointerstitial inflammation (TII) was associated with an increased risk of renal function decline (RR 2.22; 95% CI 1.75–2.82), as was interstitial fibrosis/tubular atrophy (IFTA) (RR 3.44; 95% CI 2.70–4.38). No significant difference was observed between TII and IFTA regarding renal outcomes (RR 0.78; 95% CI 0.59–1.03). In subgroup analyses stratified by follow-up duration, the association between TII and renal decline was stronger in studies with longer follow-up (>5 years), whereas IFTA conferred a consistently elevated risk across follow-up strata. Sensitivity analyses, including leave-one-out testing, confirmed the robustness of findings. Funnel plot symmetry and Egger’s test ( p = 0.9074) indicated no evidence of publication bias. Study-level meta-regression suggested that the association between TII and renal decline varied according to the distribution of proliferative glomerular classes, while the association for IFTA was not significantly modified by glomerular pattern. Conclusion This meta-analysis found that both interstitial fibrosis/tubular atrophy (IFTA) and tubulointerstitial inflammation (TII)
Lupus nephritis (LN) remains a leading cause of morbidity and mortality in systemic lupus erythematosus (SLE). Although recent years have witnessed the approval of several targeted therapies, achieving long-term, drug-free remission remains challenging. This commentary evaluates the global landscape of interventional LN clinical trials from 2001 to 2026 to identify emerging trends and strategic gaps in drug development. We analyzed 200 interventional pharmacological trials retrieved from three major global registries: ClinicalTrials.gov, Chinadrugtrials.org, and ISRCTN. Trials were systematically categorized by study phase, geographic distribution, and therapeutic mechanism, with data synthesized to reflect the transition from non-specific immunosuppression to precision-targeted approaches. Our analysis indicates an accelerating trend in Phase II/III trials, with a notable geographic shift toward the Asia-Pacific region. We identify a diversification of therapeutic targets beyond B-cell depletion (e.g., obinutuzumab) to include complement inhibitors, intracellular signaling blockers (BTK and JAK inhibitors), and novel immune-reset strategies such as CAR-T therapy. Despite these innovations, complete renal response rates in pivotal trials often plateau at 40-50%, suggesting a persistent "ceiling effect". To break current therapeutic plateaus, future research must prioritize: (1) integrating pharmacogenomics (e.g., CYP3A5 and TPMT genotyping) for personalized drug selection; (2) developing steroid-fast-tapering or steroid-free induction protocols to minimize toxicity; and (3) validating real-time molecular biomarkers to replace lagging clinical indicators. This data-driven perspective provides a practical framework for refining trial designs and achieving precision medicine in LN.
Background: Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are complex autoimmune diseases with the potential to affect multiple organ systems and significantly impact quality of life. In the Middle East and North Africa (MENA), the burden of these conditions is amplified by a combination of genetic predisposition, environmental exposures, and socio-economic factors that shape both presentation and outcomes. High consanguinity rates, high ultraviolet exposure, infections, and lifestyle factors contribute to earlier onset and more aggressive disease, with lupus nephritis affecting up to 60% of patients. APS adds an additional layer of complexity through thrombotic events and pregnancy complications. Purpose: This review brings together current knowledge on the epidemiology, clinical patterns, and management challenges of SLE and APS across the region. Results: While individual country reports exist, the lack of large-scale registries limits our ability to fully define disease prevalence and outcomes. Delayed diagnosis, shortages of rheumatology specialists, and unequal access to advanced diagnostics and biologic therapies remain persistent barriers. In some low-resource or conflict-affected settings, even basic immunosuppressive medications are inconsistently available. The financial impact is substantial, driven by hospitalizations, medications, and loss of productivity, with many patients facing significant out-of-pocket costs. Recent advances, including biologics such as belimumab and anifrolumab, offer opportunities to improve outcomes but are not equitably accessible across the region. Conclusions: Moving forward, investment in healthcare infrastructure, training, and culturally appropriate patient education will be essential. Establishing regional registries, expanding research into genetic and environmental risk factors, and developing locally relevant management strategies are critical next steps. By addressing these gaps through coordinated action between policymakers, healthcare providers, researchers, and patient communities, it is possible to reduce the disparities in care and improve survival, function,
International guidelines recommend early combination of standard therapy with innovative agents in lupus nephritis (LN) to prevent kidney damage. Whether this accelerates renal response is unclear. We aimed to compare renal response trajectories, predictors and glucocorticoid (GC) burden in LN patients receiving early belimumab plus standard-of-care (SoC) vs SoC alone. Consecutive adult patients with biopsy-proven LN treated with belimumab plus SoC as initial therapy were enrolled from Italian lupus referral centres and compared with a historical SoC cohort (1990-2016). Data were collected at baseline and during follow-up. Propensity score matching based on baseline proteinuria, estimated glomerular filtration rate, standard initial treatment and histological class led to comparable groups. Complete renal response (CRR) was defined per 2019 EULAR/EDTA. Cox regression was used to assess predictors. Ninety-one belimumab patients were matched to 91 SoC patients. At 6 months, CRR was higher in the belimumab group (35.9% vs 16.5%, odds ratio [95% CI]: 2.81 [1.30, 6.29], P = 0.005), while response rates at 12 months were similar (P = 0.87). Time-to-CRR was shorter with belimumab (median [interquartile range] 5.64 [4.08, 7.80] vs 7.92 [5.28, 11.04] months, P < 0.01). At CRR, GC dose was lower in the belimumab group (5 [5-15] vs 15 [10-20] mg/day, P = 0.018). Independent predictors of earlier CRR were baseline proteinuria (hazard ratio per g/24 h increase [95% CI]: 0.89 [0.80, 0.98], P = 0.019) and belimumab use (1.70 [1.11, 2.62], P = 0.016). Early belimumab combination therapy accelerates CRR and reduces GC exposure. Achieving early CRR with lower GC is a key target to limit kidney and GC-related damage, supporting early belimumab integration in LN management.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominantly affects women of childbearing age. As the prevalence of SLE rises, and advances since the 1960s have substantially improved survival and quality of life, the number of women with SLE who become pregnant is steadily increasing. Although pregnancy is feasible for most patients with well-controlled SLE, pregnancy remains challenging for both women with SLE and clinicians because the risk of maternal complications and adverse fetal outcomes is higher than that in the general population. Moreover, the increased risk of pregnancy complications persists in subsequent pregnancies in women with SLE, whereas in healthy women this risk decreases owing to the development of maternal-fetal immune tolerance. During pregnancy and the postpartum period, women remain at risk of disease flares and other complications, particularly those with active disease at conception, a history of lupus nephritis, antiphospholipid syndrome or recent medication withdrawal. Important knowledge gaps persist regarding the mechanisms underlying these complications and the safety of treatment during conception, pregnancy and lactation. Preconception counselling, assessment of risk factors for adverse outcomes, pregnancy planning, timely medication adjustment and multidisciplinary management are essential to improve the maternal and fetal outcomes in women with SLE.
Systemic lupus erythematosus (SLE), a systemic autoimmune disease with heterogeneous severity, poses a challenge in classifying patients due to its dynamic phenotype. We therefore aimed to identify clinical clusters at diagnosis and at the last available visit to define subgroups with different disease trajectories. This retrospective study included 278 SLE patients fulfilling the 2019 EULAR/American College of Rheumatology classification criteria. Data were extracted from the patient's medical record, encompassing demographic, clinical and immunological features. Two hierarchical clustering analyses were performed: one at diagnosis and the other at the last available visit based on 23 clinical manifestations. We assessed the distribution of autoantibodies among clusters, and survival analyses compared prognosis using the Cox regression model. Three symptom clusters were identified at diagnosis and confirmed at the last available visit, with consistent clinical profiles. The largest, clusters 1/1', exhibited early articular (95.3%; p=0.0043) and mucocutaneous (58.7%; p=0.0031) symptoms with the best survival rate. Clusters 2/2' displayed the most severe phenotype, including renal involvement (62.2%; p<0.0001), positivity for anti-DNA (90.0%; p=0.0151) and anti-Sm (34.4%; p<0.0001) autoantibodies, and worse prognosis. Clusters 3/3' exhibited a high proportion of SLE patients fulfilling the definition of mixed connective tissue disease (MCTD) (50.0%; p<0.0001) with anti-U1-RNP 70 kDa autoantibodies (87.5%; p<0.0001). Clusters 1 and 2 remained stable during follow-up, cluster 2 even expanding over time, while over half of cluster 3 patients transitioned to a different subgroup. We identified a distinct MCTD phenotype within SLE patients, a severe SLE phenotype with poor prognosis, and a third group of SLE patients with lower visceral involvement. Clusters remained stable over time, providing insights into disease progression.
In patients with systemic lupus erythematosus (SLE), increased type I interferon signaling is associated with increased disease activity across organs, including in the kidney, which can cause lupus nephritis (LN). Anifrolumab, which abrogates type I interferon signaling, is an approved treatment for moderate to severe SLE. In a phase 2 trial in patients with LN (TULIP-LN; NCT02547922), promising clinical benefit was observed with an intensified regimen (IR) of intravenous anifrolumab (3× 900 mg Q4W, 300 mg thereafter) compared with the approved SLE dose (basic regimen [BR], 300 mg Q4W). Anifrolumab clearance was greater with higher levels of proteinuria; however, the quantitative relationship between proteinuria and anifrolumab exposure was not fully characterized. Here, we describe a mathematical model of time-varying anifrolumab pharmacokinetics, 24-hour urine protein-creatinine ratio (UPCR24), and investigational product discontinuation in patients with LN. The model evaluated both TULIP-LN anifrolumab dosing regimens (IR and BR) and revealed a temporal association between clearance and proteinuria in patients with LN, with each mg/mg UPCR reduction resulting in a 21% decrease in linear anifrolumab clearance. Our model indicated that an intensified regimen including 6 initial anifrolumab 900 mg doses provided adequate exposure and rapid UPCR24 reduction. Higher anifrolumab exposure and reduced UPCR24 were each associated with decreased risk of treatment discontinuation. These model results guided the selection of an optimized, longer intensified anifrolumab dosing regimen (6× 900 mg Q4W, 300 mg thereafter) for the ongoing phase 3 IRIS trial (NCT05138133).
Lupus Low Disease Activity State (LLDAS) and Definition of Remission in SLE (DORIS) are associated with improved outcomes in SLE; however, their value in lupus nephritis (LN) remains unexplored. We sought to evaluate their prognostic value on organ damage accrual, renal flares and chronic kidney disease in patients with LN. Multicentre retrospective cohort study of patients with biopsy-proven LN who achieved renal response. Enrolment date was the time of first renal response. Longitudinal data were analysed using Cox proportional hazards models. Modified LLDAS (mLLDAS) and DORIS (mDORIS) attainment and sustained durations were evaluated. 155 patients with 1703 visits were included. During a median follow-up of 3.5 years (IQR 4.5), 127 patients (81.9%) achieved mLLDAS and 92 (59.4%) achieved mDORIS. Both states demonstrated robust protective effects across all outcomes. For organ damage, mLLDAS attainment was associated with 85% risk reduction (adjusted HR (aHR 0.15, 95% CI 0.07 to 0.32), while mDORIS conferred a 79% reduction (aHR 0.21, 95% CI 0.08 to 0.55). Periods under mLLDAS were also associated with a 73% reduction in renal flare risk (aHR 0.27, 95% CI 0.14 to 0.51), with similar effects for mDORIS. Sustained achievement resulted in progressively greater protection, with the strongest effects seen for ≥24 consecutive months. Early attainment protected against damage accrual (aHR 0.31, 95% CI 0.16 to 0.61) and renal flares (aHR 0.51, 95% CI 0.29 to 1.00). Following renal response, achievement of mLLDAS and mDORIS is strongly associated with improved outcomes in LN patients. Earlier attainment and longer duration in these states confer progressively greater protection.
Belimumab, approved for systemic lupus erythematosus (SLE) and lupus nephritis (LN) treatment, is a B-cell-modulating monoclonal antibody that selectively inhibits B-lymphocyte stimulator (BLyS) and downregulates autoreactive B-cells. Comparing belimumab's results from BLISS-LN (phase 3, ClinicalTrials.gov Identifier: NCT01639339) with other LN trial outcomes pose challenges because, unlike other trials, BLISS-LN included patients with pure class V LN (membranous) and patients receiving cyclophosphamide as standard therapy (ST). This post hoc analysis of BLISS-LN investigated kidney outcomes in patients with proliferative (class III or IV) or proliferative plus membranous LN (class III or IV with/without class V) treated with mycophenolate mofetil (MMF)-based ST to more closely align with those of other phase 3 LN trials and current practice. Only patients with active class III or IV LN with/without class V who received MMF ST in BLISS-LN were included. Kidney responses (complete renal response [CRR]; primary efficacy renal response [PERR]), urine protein to creatinine ratio (uPCR) under 0.5 g/g responders, estimated glomerular filtration rate (eGFR) slope, and changes from baseline in uPCR, eGFR, and biomarkers were assessed up to Week 104. Safety outcomes were assessed through Week 104. The MMF subgroup comprised 271 patients (60.5% of overall BLISS-LN population; with 135 receiving belimumab; 136 receiving placebo). Baseline demographics and characteristics were balanced. CRR treatment differences between belimumab and placebo were higher in the MMF subgroup (14.9%) versus the overall BLISS-LN population (10.3%). Treatment differences were greater for PERR, uPCR under 0.5 responders and eGFR slope with belimumab versus placebo in the MMF subgroup, and versus the overall population. Other endpoints showed a similar trend. Safety outcomes were consistent with belimumab's known safety profile. Fewer serious adverse events were reported for belimumab vs placebo in
IgA nephropathy (IgAN) is a chronic kidney disease involving deposition of IgA-containing immune complexes in the glomerulus, causing glomerular inflammation and scarring. It is the most common immune-mediated glomerular disease worldwide, and affects an estimated 198 887 to 208 184 persons in the US. Up to 50% of patients with IgAN develop kidney failure within 10 years of diagnosis. IgAN typically presents with nephritic syndrome and usually occurs in younger adults, with a mean age at diagnosis of 34 to 45 years. Incidence is highest in East Asia. Approximately 60% of cases are detected incidentally with hematuria or proteinuria on urinalysis. Up to 30% of patients present with episodic visible hematuria, often concomitantly with an upper respiratory or gastrointestinal tract infection (synpharyngitic hematuria). Less common presentations include nephrotic syndrome (<5%) and rapidly progressive glomerulonephritis (<5%). When IgAN is suspected (due to hematuria, proteinuria, or reduced kidney function), initial workup should include quantification of proteinuria and assessment for other causes of nephritic syndrome (eg, lupus nephritis). Adults with suspected IgAN and proteinuria greater than or equal to 0.5 g per day should undergo kidney biopsy. The diagnosis of primary IgAN is based on presence of IgA-dominant immune deposits in the glomerular mesangium after excluding other causes of this histologic appearance, ie, IgA vasculitis, IgA-dominant infection-related glomerulonephritis, and secondary IgAN from diseases such as cirrhosis, inflammatory bowel disease, celiac disease, infection (eg, viral hepatitis), and autoimmune diseases (eg, axial spondyloarthritis). Based on the Kidney Disease: Improving Global Outcomes 2025 clinical practice guideline for the management of IgAN, treatment for patients with proteinuria greater than 0.5 g per day includes behavioral modifications (eg, dietary sodium <2 g/d, smoking cessation, weight control, exercise), antihypertensive medications for
BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by heterogeneous clinical manifestations and multi-organ involvement. Current understanding of SLE pathogenesis remains limited, particularly due to the cellular and molecular diversity of immune cells across tissues. Therefore, a comprehensive review synthesizing recent advances in applying single-cell technologies to SLE research is urgently needed to bridge this knowledge gap.TechnologySingle-cell RNA sequencing (scRNA-seq) provides high-resolution transcriptomic profiling at the single-cell level. This technology facilitates the identification of rare cell subsets, the characterization of cellular states, and the elucidation of disease-specific gene expression patterns. This technology has been applied to various SLE sample types, including peripheral blood, kidney, skin, and bone marrow.ResultsScRNA-seq has revealed distinct immune cell subpopulations and their functional alterations in SLE, including aberrant B- and T-cell subsets, dysregulated interferon-stimulated genes, and pathogenic low-density granulocytes. Crucially, by deconvoluting this cellular heterogeneity, these high-resolution insights bridge the gap between fundamental pathogenesis and clinical application, uncovering cell-specific pathways that can be harnessed as actionable therapeutic targets and prognostic biomarkers. Integration with spatial transcriptomics and machine learning further enhances research capabilities. These tools allow for mapping disease-specific immune niches and predicting clinical outcomes. Ultimately, these findings underscore the transformative potential of scRNA-seq in decoding SLE pathogenesis and guiding future targeted therapies.
Shared decision-making (SDM) is a process in which patients and clinicians work together to make health care decisions. Purposeful SDM (PSDM) is a problem-based approach that emphasizes the multifaceted nature of SDM in response to different settings and contexts. In this integrative review, we systematically identify rheumatology patient decision aids (PDAs) described in peer-reviewed published literature and assess how they support PSDM. Articles were identified through a search of Ovid MEDLINE, EMBASE, CINAHL, and PsycINFO from 1948 to 2023. This search was supplemented through contacting authors and scanning references. The research team analyzed and classified PDAs into 1 of 4 modes. In addition, research team members utilized the SUNDAE Checklist (Standards for UNiversal reporting of Patient Decision Aid Evaluation), a 26-item checklist to assess the quality of manuscripts evaluating PDAs. Forty-six records met the inclusion criteria. Among the 23 articles containing original data, there were 21 PDAs. The most common conditions represented included rheumatoid arthritis (n=8), osteoarthritis (n=7), and lupus nephritis (n=3). Fifteen addressed weighing treatment options (mode 1), while only 6 addressed intra- or interpersonal conflict (mode 2) and 2 addressed problem-solving (Mode 3). The mean number of SUNDAE checklist criteria satisfied was 21.5 (±4.3). There exist opportunities to develop and refine tools that (1) address PSDM modes beyond weighing treatment options, (2) cover a wider variety of rheumatologic conditions, and (3) more transparently report evaluation of PDA content, development, and delivery.