Background & ObjectivePresence of lupus nephritis is associated with a shorter time to death in systemic lupus erythematosus. The aim of this study was to determine the frequency of peritubular capillaritis (ptc) and its relationship with both active and chronic lesions in lupus nephritis.Material-MethodsSpecimens from 57 patients were re-evaluated. The degree of inflammation within the peritubular capillaries in each biopsy was assessed according to the Banff classification, and ptc scoring was performed. Additionally, patients were grouped based on high/low activity and chronicity index scores.ResultsForty-five (78.9%) of the patients were female, with a mean age of 27.43 years. Ptc was identified in 45 (78.9%) patients, with ptc scores of 1, 2, and 3 observed in 20 (35.08%), 20 (35.08%), and 5 (8.7%) patients, respectively. Severe ptc (scores 2 or 3) was more commonly detected in patients with elevated serum creatinine (>1.20 mg/dL) compared to those with normal creatinine levels (92.3% vs 29.5%, p < 0.001). The severity of ptc was higher in Class 4 patients than in Class 3 patients (68.2% vs 21.7%, p = 0.005). The rate of high ptc scores was greater in patients with an activity index of 6 or above compared to those with an activity index below 6 (62.5% vs 30.3%, p = 0.032). No significant correlation was found between the chronicity index and ptc.ConclusionsThe findings of this study suggest that ptc is a frequently observed pathological feature in patients with lupus nephritis. Furthermore, the severity of ptc appears to be positively associated with elevated serum creatinine levels, and higher ptc scores are more commonly detected in cases with a high activity index.

Lupus nephritis (LN) can occur as an isolated component of disease activity or be accompanied by diverse extrarenal manifestations. Whether isolated renal disease is sufficient to decrease health-related quality of life (HRQOL) remains unknown. This study compared Patient-Reported Outcomes Measurement Information System 29-Item (PROMIS-29) scores in LN patients with isolated renal disease to those with extrarenal symptoms to evaluate the burden of LN on HRQOL and inform future LN clinical trials incorporating HRQOL outcomes.

A total of 181 LN patients consecutively enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership completed PROMIS-29 questionnaires at the time of a clinically indicated renal biopsy. Raw PROMIS-29 scores were converted to standardized T scores.

Seventy-five (41%) patients had extrarenal disease (mean age 34, 85% female) and 106 (59%) had isolated renal (mean age 36, 82% female). Rash (45%), arthritis (40%) and alopecia (40%) were the most common extrarenal manifestations. Compared with isolated renal, patients with extrarenal disease reported significantly worse pain interference, ability to participate in social roles, physical function, and fatigue. Patients with extrarenal disease had PROMIS-29 scores that significantly differed from the general population by >0.5 SD of the reference mean in pain interference, physical function, and fatigue. Arthritis was most strongly associated with worse scores in these three domains.

Most patients had isolated renal disease and extrarenal manifestations associated with worse HRQOL. These data highlight the importance of comprehensive disease management strategies that address both renal and extrarenal manifestations to improve overall patient outcomes.

We performed a scoping review of randomised clinical trials (RCTs) assessing pharmacological therapies for the initial management of lupus nephritis (LN), focusing on study design, included populations and outcome definitions, to assess the generalisability of their results and identify gaps in the evidence.

RCTs evaluating pharmacological interventions for the initial therapy of LN published between 2000 and 2024 were evaluated. Extracted variables included study design, selection criteria, outcome definitions, populations recruited and clinical characteristics of participants. Each study arm was included as intervention and segregated into guideline-recommended regimens (cyclophosphamide (CYC), mycophenolic acid analogues (MPAAs), calcineurin inhibitors and belimumab) or other regimens. Data were analysed by descriptive statistics, and Fragility Index (FI) was estimated to assess robustness of studies.

We included 124 intervention arms within 61 RCT, involving 7058 participants. Seventy-nine arms (63.7%) corresponded to guideline-recommended therapies: 33 (26.6%) MPAA, 28 (22.6%) NIH-CYC and 7 (5.6%) triple-drug therapies. While 100% of triple-drug therapies RCT were multinational, only 7.1% of NIH-CYC and 0% of tacrolimus RCTs were conducted in more than one country. Only 9 (14.8%) had follow-up ≥24 months. Ten (16.4%) RCTs exclusively included participants with severe or refractory LN. Only 29 (47.5%) reported serious adverse events, and few described patient-reported outcomes. Black and other race participants were under-represented, as well as participants from Middle East, North Africa, and the sub-Saharan African region. Response was variably defined and assessed at different intervals. Robustness of RCTs evaluating double-drug guideline-recommended therapies were mostly low, with FI ranging from 1 to 3.

Considering new recommendations for the management of LN, we call for broader inclusion of under-represented populations and homogenisation of study design. This study provides the rationale for evaluating unexplored treatment comparisons and conducting research on newer interventions in clinical settings where evidence is currently lacking.

A 14-year-old patient presents with hematuria and proteinuria. Clinical evaluation reveals a positive anti-nuclear antibody titer, positive anti-double stranded DNA antibody and hypocomplementemia. Systemic lupus erythematosus (SLE) is diagnosed based on the 2019 EULAR/ACR (European League Against Rheumatism/American College of Rheumatology) classification criteria (Aringer et al. Arthritis Rheumatol 71:1400-1412, 2019). A kidney biopsy is performed that confirms the presence of immune complex glomerulonephritis, ISN-RPS (International Society of Nephrology/Renal Pathology Society) class IV (Bajema et al. Kidney Int 93:789-796, 2018). According to the latest clinical practice guidelines (Rovin et al. Kidney Int 100:753-779, 2021; Fanouriakis et al. Ann Rheum Dis 83:15-29, 2023), there are alternatives to treating this patient with cyclophosphamide. But what if this patient also presented with oliguria and volume overload requiring intensive care and dialysis? What if this patient also presented with altered mental status and seizures, and was diagnosed with neuropsychiatric lupus? What if this patient was also diagnosed with a pulmonary hemorrhage and respiratory failure? The clinical practice guidelines do not address these scenarios that are not uncommon in patients with SLE. Moreover, in some countries worldwide, patients do not have the privilege of access to biologics or more expensive alternatives. The purpose of this review is to evaluate the contemporary options for initial treatment of nephritis in patients with SLE.

Reportedly, patients with LN and low-level proteinuria have favourable short-term renal outcomes. We aimed to clarify the long-term renal outcomes and overall survival of these patients, and the significance of renal biopsy in the early phase with low-level proteinuria.

We included 144 Japanese patients with biopsy-proven LN from 10 hospitals. Low-level proteinuria was defined by a urine protein:creatinine ratio (UPCR) of ≤1 g/gCr based on previous reports. The outcomes were end-stage renal disease (ESRD) and death.

Compared with patients with high-level proteinuria (UPCR >1 g/gCr), those with low-level proteinuria [n = 67 (46.5%)] had significantly improved renal function at the time of renal biopsy, and low activity index and chronicity index while the frequency of class III/IV was similar (79.1% vs 84.4%, P = 0.409). In patients with low-level proteinuria, CYC usage was less, and the incidences of ESRD (3.0% vs 13.0%, P = 0.036) and death (3.0% vs 16.9%, P = 0.006) during the total observation period (median, 72 months) were low. Kaplan-Meier analysis showed significant differences in the incidence of ESRD and death between the groups. Multivariate Cox regression analysis revealed that the significant risk factors for ESRD were high chronicity index and hypertension, whereas those for death were increased age and high-level proteinuria.

Patients with LN and low-level proteinuria had favourable long-term renal and life outcomes. As these patients have substantial active pathological lesions, renal biopsy in the early phase with low-level proteinuria could enable early diagnosis and treatment and thus improve prognosis.

Autoantibodies are a hallmark of lupus nephritis (LN), but their association with LN classes and treatment response are not adequately known. In this study, we quantified circulating autoantibodies in the Accelerating Medicines Partnership LN longitudinal cohort to identify serological biomarkers of LN histologic classification and treatment response and how these biomarkers change over time based on treatment response.

Peripheral blood samples were collected from 279 patients with systemic lupus erythematosus undergoing diagnostic kidney biopsy based on proteinuria. Of these, 268 were diagnosed with LN. Thirteen autoantibody specificities were measured by bead-based assays (Bio-Rad Bioplex 2200) and anti-C1q by enzyme-linked immunosorbent assay at the time of biopsy (baseline) and at 3, 6, and 12 months after biopsy. Clinical response was determined at 12 months.

Proliferative LN (International Society of Nephrology/Renal Pathology Society class III/IV±V, n = 160) was associated with higher concentrations of anti-C1q, anti-chromatin, anti-double-stranded DNA (dsDNA), and anti-ribosomal P autoantibodies compared to nonproliferative LN (classes I/II/V/VI, n = 108). Anti-C1q and-dsDNA were independently associated with proliferative LN. In proliferative LN, higher baseline anti-C1q levels predicted complete response (area under the curve [AUC] 0.72; P = 0.002) better than baseline proteinuria (AUC 0.59; P = 0.21). Furthermore, all autoantibody levels except for anti-La/SSB decreased over 12 months in patients with proliferative, but not membranous, LN with a complete response.

Baseline levels of anti-C1q and anti-dsDNA may serve as noninvasive biomarkers of proliferative LN, and anti-C1q may predict complete response at the time of kidney biopsy. In addition, tracking autoantibodies over time may provide further insights into treatment response and pathogenic mechanisms in patients with proliferative LN.

Epitope spreading is a critical mechanism driving the progression of autoimmune glomerulonephritis. This phenomenon, where immune responses broaden from a single epitope to encompass additional targets, contributes to the complexity and severity of diseases such as membranous nephropathy (MN), lupus nephritis (LN), and ANCA-associated vasculitis (AAV). In MN, intramolecular spreading within the phospholipase A2 receptor correlates with a worse prognosis, while LN exemplifies both intra- and intermolecular spreading, exacerbating renal involvement. Similarly, ANCA reactivity in AAV highlights the destructive potential of epitope diversification. Understanding these immunological cascades reveals therapeutic opportunities-targeting early epitope spreading could curb disease progression. Despite promising insights, the clinical utility of epitope spreading as a prognostic tool remains debated. This review provides a complete overview of the current evidence, exploring the dual-edged nature of epitope spreading, the intricate immune mechanisms behind it, and its therapeutic implications. By elucidating these dynamics, we aim to pave the way for more precise, targeted interventions in autoimmune glomerular diseases.

Lupus nephritis (LN) is a serious kidney complication associated with systemic lupus erythematosus (SLE), marked by the immune system's misdirected attack on kidney tissues, resulting in inflammation and compromised filtration. This condition has the potential to progress to end-stage renal disease in about 20% of patients within a decade of diagnosis. Lupus nephritis is more prevalent in females, highlighting the urgent need for effective treatment strategies. This systematic review consolidates findings from 16 research articles that explore various therapeutic options for LN. Key themes include the intricate pathogenesis involving immune complex deposition and the advancing treatment landscape, which encompasses both traditional immunosuppressants such as mycophenolate mofetil (MMF) and cyclophosphamide and newer biologics like belimumab and voclosporin. The review examines the efficacy and safety profiles of these treatments, underscoring the importance of personalized treatment plans based on disease severity and patient-specific factors. While newer therapies show promise for improving renal outcomes, the potential for adverse effects remains a significant concern. A thorough review was conducted to evaluate current research on lupus nephritis, focusing on treatment advancements. Two independent reviewers searched PubMed using targeted terms and MeSH categories, emphasizing studies published since 1990 identified 7898 articles from that, 16 articles met the criteria for inclusion in the study. The evaluation of bias risk was performed according to established protocols. This systematic approach provided a comprehensive analysis of recent developments in lupus nephritis therapy.

Our objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN).

We performed a systematic review and meta-analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy-proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta-analysis of proportions, meta-regression, and subgroup meta-analysis were performed at 6 and 12 months for all outcomes.

Fifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3-31.5), 3.2% (95% CI 2.4-4.0), and 0.2% (95% CI 0.0-0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9-52.3), 12.1% (95% CI 9.3-14.9), and 2.7% (95% CI 0.0-5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose-response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria.

A higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

Lupus nephritis (LN) is the most common major organ manifestation of the autoimmune disease SLE (lupus), with 10% of those afflicted progressing to ESKD. The kidney in LN is characterized by a significant immune infiltrate and proinflammatory cytokine milieu that affects intrinsic renal cells and is, in part, responsible for the tissue damage observed in LN. It is now increasingly appreciated that LN is not due to unidirectional immune cell activation with subsequent kidney damage. Rather, the kidney microenvironment influences the recruitment, survival, differentiation, and activation of immune cells, which, in turn, modify kidney cell function. This review covers how the biochemical environment of the kidney ( i.e ., low oxygen tension and hypertonicity) and unique kidney cell types affect the intrarenal immune cells in LN. The pathways used by intrinsic renal cells to interact with immune cells, such as antigen presentation and cytokine production, are discussed in detail. An understanding of these mechanisms can lead to the design of more kidney-targeted treatments and the avoidance of systemic immunosuppressive effects and may represent the next frontier of LN therapies.

This review will provide updates in the outcomes in the common rheumatologic diseases with kidney involvement. Covered are also advances in therapeutics for the use of pediatric rheumatologic diseases with kidney involvement, as well as the potential kidney complications from other rheumatologic diseases and their medications.

Two of the more common rheumatologic diseases with kidney involvement, lupus and vasculitis, continue to show inadequate response to initial therapy of renal disease and practice continues to be driven by results of adult studies.

There is a continued need for pediatric specific studies in rheumatologic diseases with kidney involvement as outcomes continue to be inadequate. Despite recently approved treatments for adults with rheumatic diseases and kidney involvement, therapeutic options in pediatrics remain limited, contributing to the overall morbidity and mortality.

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, has greater severity in children versus adults. Belimumab is approved for systemic lupus erythematosus treatment in patients aged ≥ 5 years, and for active LN in adults in the European Union, China, Japan and Latin America, and patients aged ≥ 5 years in the USA. Low prevalence of paediatric active LN makes conducting a clinical study within a reasonable period unfeasible. We describe a model-based extrapolation of belimumab efficacy and pharmacokinetics from adults to children with LN to support US Food and Drug Administration approval of intravenous belimumab 10 mg/kg (administered every 4 weeks after the loading dose) in children (aged 5-17 years) with active LN.

This concept assumed that disease progression, response to belimumab, exposure-response, and the target belimumab exposure for efficacy are similar across adult and paediatric systemic lupus erythematosus and LN, evaluated against the published literature for paediatric LN and belimumab systemic lupus erythematosus and LN clinical trial data in adults and children. A two-compartmental population pharmacokinetic model, previously developed for adults with LN, was used to extrapolate belimumab pharmacokinetics to children with LN.

The model captured the dependence of time-varying proteinuria on belimumab clearance, and therefore exposure. Sufficient target exposures for efficacy were achieved in children with active LN. A small proportion of children aged 5-11 years are predicted to have exposures below adult levels but no impact to efficacy is expected.

Our model demonstrated that intravenous belimumab 10 mg/kg every 4 weeks is appropriate for children aged 5-17 years with active LN.

Previous studies comparing the efficacy and safety of different treatment regimens for lupus nephritis are scarce. Moreover, confounding factors such as the duration of follow-up were hardly adjusted in those studies, potentially compromising the results and their extents to clinical settings.

To rigorously investigate the efficacy and safety of biologics in patients with lupus nephritis using Bayesian network meta-regression analyses that adjust for the follow-up period, in order to provide more robust evidence for clinicians.

Databases comprising PubMed, Embase, MedlinePlus, Cochrane Library, Google Scholars, and Scopus were retrieved for eligible articles from inception to February 29, 2024. The primary endpoint was the complete response rate, the secondary endpoint was the partial response rate, the tertiary endpoints were the adverse events, and infection-related adverse events. Napierian Logarithm of hazard ratio (lnHR) and the standard error of lnHR (selnHR) were generated for dichotomous variants by STATA 18.0 MP and then put into Rstudio 4.3.2 to conduct Bayesian network meta-analysis as well as network meta-regression analysis to yield hazard ratio (HR) as pairwise effect size.

Ten studies involving 2138 patients and 11 treatment regimens were ultimately included. In the original analysis, for the primary endpoint, compared to the control group, obinutuzumab (22.6 months), abatacept-30mg (20.5 months), abatacept-10mg (17.8 months), and belimumab (23.3 months) demonstrated significant superiority (HR ranged from 1.6 to 2.5), more ever, their significance regarding relative efficacy was correlated with follow up period, namely "time window" (shown in parentheses above). For the secondary endpoint, compared to the control group, obinutuzumab and abatacept-30mg showed conspicuous preponderance (HR ranged from 1.6 to 2.4), "time window" was also detected in abatacept-30mg (20.5 months), whereas obinutuzumab remained consistently obviously effective regardless of the follow-up period (shown in parentheses above). For the tertiary endpoint, there were no differences among active regimens and control.

Considering the efficacy and safety and "time window" phenomenon, we recommend obinutuzumab as the preferred treatment for LN. Certainly, more rigorous head-to-head clinical trials are warranted to validate those findings.

Systemic Lupus Erythematosus (SLE) and lupus nephritis treatment is still based on non-specific immune suppression despite the first biological therapy for the disease having been approved more than a decade ago. Intense basic and translational research has uncovered a multitude of pathways that are actively being evaluated as treatment targets in SLE and lupus nephritis, with two new medications receiving FDA approval in the last 3 years. Herein we provide an overview of targeted therapies for SLE including medications targeting the B lymphocyte compartment, intracellular signaling, co-stimulation, and finally the interferons and other cytokines.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and is one of the leading causes of morbidity and mortality in patients with SLE. It is estimated that up to 60% of individuals with SLE will develop LN, which can manifest at any stage of a patient's life; however, it commonly emerges early in the course of SLE and tends to exhibit a more aggressive phenotype in men compared to women. Black and Hispanic patients are more likely to progress to kidney failure than white patients. LN is characterized by kidney inflammation and chronic parenchymal damage, leading to impaired kidney function and potential progression to kidney failure. This article provides a comprehensive overview of the epidemiology, pathogenesis, clinical presentation, diagnosis, and management of LN, highlighting the importance of early recognition and treatment of LN to prevent progressive, irreversible kidney damage and improve patient outcomes. Additionally, the article discusses current and emerging therapies for LN, including traditional immunosuppressive agents, biological agents, and novel therapies targeting specific pathways involved in LN pathogenesis, to provide a practical guide for clinicians in properly diagnosing LN and determining a patient-centered treatment plan.

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 pathologic 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 in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN 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 at baseline showed more severe 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 primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.

Lupus nephritis is an important manifestation of systemic lupus erythematosus, which leads to chronic kidney disease, kidney failure, and can result in mortality. About 35%-60% of children with systemic lupus erythematosus develop kidney involvement. Over the past few decades, the outcome of patients with lupus nephritis has improved significantly with advances in immunosuppressive therapies and clinical management. Nonetheless, there is a paucity of high-level evidence to guide the management of childhood-onset lupus nephritis, because of the relatively small number of patients at each centre and also because children and adolescents are often excluded from clinical trials. Children and adults differ in more ways than just size, and there are remarkable differences between childhood- and adult-onset lupus nephritis in terms of disease severity, treatment efficacy, tolerance to medications and most importantly, psychosocial perspective. In this article, we review the 'art and science' of managing childhood-onset lupus nephritis, which has evolved in recent years, and highlight special considerations in this specific patient population.

We compared clinical characteristics and renal response in patients with childhood-onset proliferative lupus nephritis (LN) treated with the EuroLupus versus National Institutes of Health (NIH) cyclophosphamide (CYC) regimen.

A retrospective cohort study was conducted at 11 pediatric centers in North America that reported using both CYC regimens. Data were extracted from the electronic medical record at baseline and 3, 6, and 12 months after treatment initiation with CYC. To evaluate the adjusted association between CYC regimen (EuroLupus vs NIH) and renal response over time, generalized estimating equations with a logit link were used. An interaction between time and CYC regimen was included, and a contrast between CYC regimens at 12 months was used to evaluate the primary outcome.

One hundred forty-five patients (58 EuroLupus, 87 NIH) were included. EuroLupus patients were on average older at the start of current CYC therapy, had longer disease duration, and more commonly had relapsed or refractory LN compared with the NIH group. After multivariable adjustment, there was no significant association between CYC regimen and achieving complete renal response at 12 months (odds ratio [OR] of response for the EuroLupus regimen, reference NIH regimen: 0.76; 95% confidence interval [CI] 0.29-1.98). There was also no significant association between CYC regimen and achieving at least a partial renal response at 12 months (OR 1.35, 95% CI 0.57-3.19).

Our study failed to demonstrate a benefit of the NIH regimen over the EuroLupus CYC regimen in childhood-onset proliferative LN. However, future prospective outcome studies are needed.

Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis.

Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (n = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR < 0.5; (2) normal serum creatinine (≤ 1.3 mg/dL) or, if abnormal, ≤ 125% of baseline; and (3) prednisone ≤ 10 mg/day. Partial response (PR) required the following: (1) > 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day.

Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (ORadj = 3.71 [95%CI = 1.34-10.24]; p = 0.012), > 25% decrease in UPCR from baseline to week 12 (ORadj = 2.61 [95%CI = 1.07-6.41]; p = 0.036), lower chronicity index (ORadj = 1.33 per unit decrease [95%CI = 1.10-1.62]; p = 0.003), and positive anti-dsDNA antibody (ORadj = 2.61 [95%CI = 0.93-7.33]; p = 0.069).

CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, poses a substantial risk of progression to end-stage renal disease, with increased mortality. Conventional therapy for LN relies on broad-spectrum immunosuppressants such as glucocorticoids, mycophenolate mofetil, and calcineurin inhibitors. Although therapeutic regimens have evolved over the years, they have inherent limitations, including non-specific targeting, substantial adverse effects, high relapse rates, and prolonged maintenance and remission courses. These drawbacks underscore the need for targeted therapeutic strategies for LN. Recent advancements in our understanding of LN pathogenesis have led to the identification of novel therapeutic targets and the emergence of biological agents and small-molecule inhibitors with improved specificity and reduced toxicity. This review provides an overview of the current evidence on targeted therapies for LN, elucidates the biological mechanisms of responses and failure, highlights the challenges ahead, and outlines strategies for subsequent clinical trials and integrated immunomodulatory approaches.

Podocyte injury can disrupt the glomerular filtration barrier (GFB), leading to podocytopathies that emphasize podocytes as the glomerulus's key organizer. The coordinated cytoskeleton is essential for supporting the elegant structure and complete functions of podocytes. Therefore, cytoskeleton rearrangement is closely related to the pathogenesis of podocytopathies. In podocytopathies, the rearrangement of the cytoskeleton refers to significant alterations in a string of slit diaphragm (SD) and focal adhesion proteins such as the signaling node nephrin, calcium influx via transient receptor potential channel 6 (TRPC6), and regulation of the Rho family, eventually leading to the disorganization of the original cytoskeletal architecture. Thus, it is imperative to focus on these proteins and signaling pathways to probe the cytoskeleton rearrangement in podocytopathies. In this review, we describe podocytopathies and the podocyte cytoskeleton, then discuss the molecular mechanisms involved in cytoskeleton rearrangement in podocytopathies and summarize the effects of currently existing drugs on regulating the podocyte cytoskeleton.

Due to the suboptimal therapeutic efficacy and potential adverse effects associated with traditional immunosuppressive medications, there has been an increasing emphasis on the development and utilization of immunotherapies. This paper aims to provide clinicians with valuable insights for selecting appropriate therapeutic approaches and contribute to the development of novel immunotherapeutic drugs.

This paper categorizes the immunotherapeutic drugs that are used for the treatment of immune-mediated glomerular diseases into three groups: immunotherapies targeting antigen-presenting cells (anti-CD80), immunotherapies targeting T/B cells (anti-CD20, anti-CD22, BAFF and APRIL inhibitors, CD40-CD40L inhibitors, proteasome inhibitors, Syk inhibitors, and Btk inhibitors), and immunotherapies targeting the complement system (C5 inhibitors, C5a/C5aR inhibitors, C3 inhibitors, MASP2 inhibitors, factor B inhibitors, and factor D inhibitors). The article then provides a comprehensive overview of advances related to these immunotherapeutic drugs in clinical research.

Certain immunotherapeutic drugs, such as rituximab, belimumab, and eculizumab, have exhibited notable efficacy in treating specific immune-mediated glomerular diseases, thereby providing novel therapeutic approaches for patients. Nonetheless, the efficacy of numerous immunotherapeutic drugs remains to be substantiated.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is one of the most common manifestations of severe organ damage in SLE, and also an important cause of disability and death. Its pathogenesis is associated with immune abnormalities such as immune cells, cytokines, and immune complex deposition. Traditional immunosuppressive therapy has been unable to meet the treatment needs of patients while bringing them toxic effects. In recent years, targeted therapies have emerged, and several novel biologics have gradually entered people's sight. This review will briefly introduce the pathogenesis of LN and the mechanism of biological targets, and summarize and analyze the clinical trials of new biologics for treating LN. Although not all biologics show positive results in clinical trials, the experience learned from these trials can help researchers adjust and plan future trial programs to seek better treatment methods.

Lupus nephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Responsiveness to treatment is crucial to avoid chronic kidney disease. New molecules have been developed in recent years to improve renal survival rates. Biological therapies as coadjutant to conventional induction treatment have been tested in randomized clinical trials with heterogeneous results. Like many others biologic therapies, Abatacept has not shown a clear benefit in the context of clinical trials. We present two cases of lupus nephritis patients in whom addition of abatacept resulted in complete remission of the renal disease. The first case described a 49-year-old male with class IV lupus nephritis with nephrotic range proteinuria and high immunological activity refractory to conventional treatment with cyclophosphamide and corticosteroids and multitarget therapy with tacrolimus, mycophenolate mofetil and prednisone. Several biological therapies (rituximab, belimumab and tocilizumab) were unsuccessfully tried, so that abatacept was added to his background multitarget therapy showing complete clinical response. The second case described a 52-year-old female with class IV lupus nephritis treated initially with conventional treatment with partial response. In successive renal flares with nephrotic proteinuria, she showed intolerance to rituximab and refractoriness to voclosporin. Finally, abatacept was added to her background therapy with MMF and PDN showing complete and maintained remission of the disease. In no case the use of abatacept was associated with serious adverse events. Based on our experience, abatacept should be considered as a safe rescue therapy in patients with refractory lupus nephritis and proteinuria with nephrotic range. In addition to this case, we reviewed the use of abatacept in lupus nephritis in the literature.

To compare the clinical effectiveness and safety of novel biologics for the treatment of lupus nephritis based on a reticulated meta-analysis approach. Registered clinical trials in 4 major databases (PubMed, Embase, Web of Science, The Cochrane Register of Clinical Trials) and ClinicalTrials.gov were systematically searched with a search time frame of build to June 2022. And we screened registered randomized controlled clinical trials of biologics for the treatment of lupus nephritis according to the protocol's nadir criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 and Review Manager 5.3 software to compare and rank differences in effectiveness and safety between the biologics. A total of 10 registered randomized controlled clinical trials involving 2148 subjects were included in this study. The interventions were ranked from best to worst in terms of the primary outcome indicator of effectiveness, renal complete remission: belimumab > anifrolumab (900 + 300) mg > obinutuzumab > ocrelizumab 400 mg > abatacept 30/10 mg/kg > belimumab + rituximab > abatacept 10/10 mg/kg > abatacept (30/10 + 10/10) mg/kg > placeo > ocrelizumab 1000 mg > rituximab > anifrolumab 300 mg, belimumab was superior to placebo [OR = 1.75, 95% CI (1.13, 2.70)] and anifrolumab 300 mg [OR = 3.27, 95% CI (1.05, 10.14)], anifrolumab (900 + 300) mg was superior to anifrolumab 300 mg [OR = 3.56, 95% CI (1.30, 9.76)], and all were statistically significant. The ranking of each intervention in terms of overall renal remission for secondary outcome indicators from best to worst was: obinutuzumab > belimumab + rituximab > anifrolumab (900 + 300) mg > ocrelizumab 1000 mg > ocrelizumab 400 mg > belimumab > rituximab 1000 mg > abatacept 30/10 mg/kg > abatacept (30/10 + 10/10) mg/kg > placeo > abatacept 10/10 mg/kg > anifrolumab 300 mg, obinutuzumab was superior to placebo [OR = 2.27, 95% CI (1.11, 4.67)] and belimumab was also superior to placebo [OR = 1.56, 95% CI (1.07, 2.27)], and all were statistically significant. In terms of safety, with a focus on serious adverse events and serious infections, the results were: Serious adverse events at 1 year of monitoring occurred better with ocrelizumab 1000 mg than ocrelizumab 400 mg [OR = 0.51, 95% CI (0.29, 0.89)] and were statistically different; serious adverse events at 2 years of monitoring infection adverse events occurred better with obinutuzumab than with abatacept (30/10 + 10/10) mg/kg [OR = 0.24, 95% CI (0.07, 0.81)] and were statistically different. The safety of the new biologics in combination with conventional standard therapies is generally good, but it is belimumab and obinutuzumab that are most effective in achieving complete and overall remission in the kidney. This study protocol has been registered with PROSPERO, with a registration number of CRD42021262498.

Childhood-onset systemic lupus erythematosus is an inflammatory and autoimmune condition characterized by heterogeneous multisystem involvement and a chronic course with unpredictable flares. Kidney involvement, commonly called lupus nephritis, mainly presents with immune complex-mediated glomerulonephritis and is more frequent and severe in adults. Despite a considerable improvement in long-term renal prognosis, children and adolescents with lupus nephritis still experience significant morbidity and mortality. Moreover, current literature often lacks pediatric-specific data, leading clinicians to rely exclusively on adult therapeutic approaches. This review aims to describe pediatric lupus nephritis and provide an overview of the novel perspectives on the pathogenetic mechanisms, histopathological classification, therapeutic approach, novel biomarkers, and follow-up targets in children and adolescents with lupus nephritis.

To determine the safety and efficacy of biological agents used in the treatment of systemic lupus erythematosus (SLE) in adults.

Systematic review and meta-analysis following PRISMA guidelines.

MEDLINE (through Pubmed), EMBASE, Cochrane library, Clinicaltrials.gov, Australianclinicaltrials.gov.au, ANZCTR.org.au and WHO International Clinical Trials Registry Platform for studies published from 20 May 2021 and 15 years prior. A grey literature search was performed and completed on 31 May 2021.

Phase II, III or quasi randomised controlled trials, studies with only cerebral or cutaneous lupus were excluded.

Two authors independently screened studies for eligibility, extracted, reviewed data for accuracy, and used the Cochrane tool to assess risk of bias.

Forty-four studies were identified, consisting of 15 groups of drugs and 25 different biological agents, totalling 16,889 patients. The main outcomes assessed included Systemic Lupus Erythematosus Responder Index (SRI), BILAG-Based Composite Lupus Assessment (BICLA) and combined combined/partial renal remission (CRR/PRR). Four groups of biologics were found to improve outcomes. Anti-interferons: Anifrolumab increased BICLA response and SRI 5 to 8, decreased prednisone dosages, with increased herpes zoster infections, but fewer serious adverse events. Sifalimumab improved SRI but also increased herpes zoster infections. Anti BAFF/BLyS and/or APRIL: Belimumab consistently improved SRI 4, decreased prednisone dosages, increased combined CRR/PRR, and had no adverse safety outcomes. Tabalumab increased SRI 5 at 52 weeks with no steroid sparing effect but was associated with increased infusion related adverse events. Telitacicept improved SRI 4 at 52 weeks, with no increased adverse events, though data was rather sparse. Anti CD-20 monoclonal antibody, Obinutuzumab increased combined CRR/PRR at 1 and 2 years. Anti IL12/23 monoclonal antibody, Ustekinumab, increased SRI 4 to 6, but not BICLA at 24 weeks, with no concerning safety outcomes.

Multiple biologic agents are shown in high quality studies to have a significant therapeutic impact on outcomes in SLE.

Whereas genetic susceptibility for systemic lupus erythematosus (SLE) has been well explored, the triggers for clinical disease flares remain elusive. To investigate relationships between microbiota community resilience and disease activity, we performed the first longitudinal analyses of lupus gut-microbiota communities.

In an observational study, taxononomic analyses, including multivariate analysis of ß-diversity, assessed time-dependent alterations in faecal communities from patients and healthy controls. From gut blooms, strains were isolated, with genomes and associated glycans analysed.

Multivariate analyses documented that, unlike healthy controls, significant temporal community-wide ecological microbiota instability was common in SLE patients, and transient intestinal growth spikes of several pathogenic species were documented. Expansions of only the anaerobic commensal, Ruminococcus (blautia) gnavus (RG) occurred at times of high-disease activity, and were detected in almost half of patients during lupus nephritis (LN) disease flares. Whole genome sequence analysis of RG strains isolated during these flares documented 34 genes postulated to aid adaptation and expansion within a host with an inflammatory condition. Yet, the most specific feature of strains found during lupus flares was the common expression of a novel type of cell membrane-associated lipoglycan. These lipoglycans share conserved structural features documented by mass spectroscopy, and highly immunogenic repetitive antigenic-determinants, recognised by high-level serum IgG2 antibodies, that spontaneously arose, concurrent with RG blooms and lupus flares.

Our findings rationalise how blooms of the RG pathobiont may be common drivers of clinical flares of often remitting-relapsing lupus disease, and highlight the potential pathogenic properties of specific strains isolated from active LN patients.

Management of lupus nephritis has evolved considerably over the past years. Here, we provide a comprehensive review of clinical trials that form the basis for the Kidney Disease: Improving Global Outcomes and EULAR/ERA-EDTA updated guidelines and present day trials that will change the landscape of lupus nephritis therapy in years to come. In addition, we highlight the issues related to cost of therapy, resistant disease, and downstream adverse effects of specific therapies.

Lupus nephritis is a severe, organ-threatening manifestation of systemic lupus erythematosus. The current standard of care in the treatment of lupus nephritis is limited to broad-spectrum immunosuppressants, which have significant concerns of short- and long-term toxicity. With traditional approaches, kidney survival and patient outcomes have remained suboptimal. Robust research in the therapeutics of lupus nephritis has resulted in development of many novel drugs targeting specific inflammatory response pathways. Some newer agents have shown a definitive signal of benefit when added to standard of care. With the advent of precision medicine in nephrology, lupus nephritis treatment may undergo a shift toward incorporating approaches using these newer drugs and individualizing care of our patients. This review highlights major advances in management of lupus nephritis over the last 25 years and explores the ongoing trials of emerging therapies in lupus nephritis.

Lupus nephritis (LN) is a frequent and serious complication of systemic lupus erythematosus (SLE), impairing patients' quality of life and significantly increasing mortality. Despite optimizing the use of conventional immunosuppressants and other biological drugs, its management remains unsatisfactory. This is mainly due to the heterogeneity of SLE, but also to insufficiently effective treatment regimens and clinical trial limitations (strict criteria, low number of patients included, and side effects). Most clinical trials of new biological therapies have failed to meet their primary endpoints in both general SLE and LN, with only two biological drugs (belimumab and anifrolumab) being approved by the Food and Drug Administration (FDA) for the treatment of SLE. Recently, several Phase II randomized controlled trials have evaluated the efficacy and safety of new biologics in LN, and some of them have demonstrated an improvement in clinical and laboratory measures. Multi-target therapies are also being successfully developed and encourage a belief that there will be an improvement in LN outcomes.

I have been a scientific grasshopper throughout my career, moving from question to question within the domain of lupus. This has proven to be immensely gratifying. Scientific exploration is endlessly fascinating, and succeeding in studies you care about with colleagues and trainees leads to strong and lasting bonds. Science isn't easy; being a woman in science presents challenges, but the drive to understand a disease remains strong.

Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and Sjögren's syndrome (SS) are heterogeneous autoimmune diseases. Severe manifestations and refractory/intolerance to conventional immunosuppressants demand other options, namely biological drugs, and small molecules. We aimed to define evidence and practice-based guidance for the off-label use of biologics in SLE, APS, and SS. Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice in autoimmune disease management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2021. Preliminary recommendations were drafted by working groups for each disease. A revision meeting with all experts anticipated the consensus meeting held in June 2021. All experts voted (agree, disagree, neither agree nor disagree) during two rounds, and recommendations with at least 75% agreement were approved. A total of 32 final recommendations (20 for SLE treatment, 5 for APS, and 7 for SS) were approved by the experts. These recommendations consider organ involvement, manifestations, severity, and response to previous treatments. In these three autoimmune diseases, most recommendations refer to rituximab, which aligns with the higher number of studies and clinical experience with this biological agent. Belimumab sequential treatment after rituximab may also be used in severe cases of SLE and SS. Second-line therapy with baricitinib, bortezomib, eculizumab, secukinumab, or tocilizumab can be considered in SLE-specific manifestations. These evidence and practice-based recommendations may support treatment decision and, ultimately, improve the outcome of patients living with SLE, APS, or SS.

Childhood-onset systemic lupus erythematosus (SLE) is characterized by increased rates of kidney involvement, termed lupus nephritis. Despite the significant morbidity and mortality associated with this disease, lupus nephritis trials have been plagued by repeated failures to meet clinical endpoints. However, improvements in trial design and the development of targeted approaches have begun to yield promising results, including two new FDA-approved lupus nephritis treatments since 2020. These include belimumab, a monoclonal antibody targeting the B cell survival cytokine BAFF (B cell activating factor), and voclosporin, a cyclosporin analog with improved pharmacokinetic characteristics. In this review, we will summarize the data supporting regulatory approval for these agents in lupus nephritis and highlight ongoing clinical trials targeting the diverse immunologic drivers of renal inflammation in SLE. While pediatric patients remain underrepresented in lupus clinical trials, given the increased severity of childhood-onset SLE and need for long-term protection from kidney damage, we anticipate the need for off-label use of these targeted therapies in the pediatric population. Future studies are needed to define optimal patient selection, drug combinations, and treatment duration in pediatric lupus nephritis.

The stimulator of interferon genes (STING) is a critical protein in the activation of the immune system in response to DNA. It can participate the inflammatory response process by modulating the inflammation-preferred translation program through the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway or by inducing the secretion of type I interferons (IFNs) and a variety of proinflammatory factors through the recruitment of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) or the regulation of the nuclear factor kappa-B (NF-κB) pathway. Based on the structure, location, function, genotype, and regulatory mechanism of STING, this review summarizes the potential value of STING inhibitors in the prevention and treatment of infectious diseases, psoriasis, systemic lupus erythematosus, non-alcoholic fatty liver disease, and other inflammatory and autoimmune diseases.

The aim of this study was to examine the effect and safety of biological agents for lupus nephritis (LN).

PubMed, EMBASE, and the Cochrane Library databases were searched from their inception up to November 2021. The outcomes were overall response, complete remission, proteinuria, renal activity index, and adverse events (AEs). Only randomized controlled trials (RCTs) were included.

Nine RCTs (1645 patients) were included. The RCTs evaluated abatacept (n = 2), belimumab (n = 1), obinutuzumab (n = 1), atacicept (n = 1), IL-2 (n = 1), ocrelizumab (n = 1), and rituximab (n = 2). The use of biological agents was associated with higher likelihoods of achieving an overall response (relative risk [RR], 1.26; 95% confidence interval [CI], 1.15-1.39; p < 0.001; I2 = 14.3%; pQ = 0.301) and a complete response (RR, 1.33; 95% CI, 1.16-1.54; p < 0.001; I2 = 41.8%; pQ = 0.056). The use of biological agents was not associated with improvements in the urinary protein-to-creatinine ratio (weighted mean difference, 3.83; 95% CI, -3.71 to 11.38; p = 0.319; I2 = 99.4%; pQ < 0.001). The use of biological agents in patients with LN was also not associated with an increased risk of any AEs (RR, 1.01; 95% CI, 0.98-1.04; p = 0.519; I2 = 0.0%; pQ = 0.533), serious AEs (RR, 0.95; 95% CI, 0.82-1.09; p = 0.457; I2 = 0.0%; pQ = 0.667), grade >3 AEs (RR, 0.91; 95% CI, 0.67-1.22; p = 0.522; I2 = 0.0%; pQ = 0.977), infections (RR, 1.09; 95% CI, 0.99-1.20; p = 0.084; I2 = 0.0%; pQ = 0.430), and deaths (RR, 0.67; 95% CI, 0.36-1.24; p = 0.200; I2 = 0.0%; pQ = 0.439). The meta-regression analysis showed that follow-up duration and the sample size did not influence the complete response rate, whereas publications in 2012 to 2014 influence the rate compared with 2015 to 2020.

Biological agents seem to be effective and safe for managing patients with LN.

Despite available therapies, persistently active and corticosteroid-dependent Systemic Lupus Erythematosus (SLE) represent a significant therapeutic challenge. The purpose of this systematic review was to provide an updated view of targeted therapies currently in clinical development in SLE, with a special focus on the most promising ones.

We performed a systematic review of targeted therapies in clinical development in SLE in clinicaltrials.gov (search date: 28th of August 2022). Targeted therapies (defined as drugs specifically designed to block certain molecules, receptors, or pathways involved in the development of SLE) were extracted. For each investigational drug, we considered only the study at the most advanced stage of clinical development.

The systematic review yielded a total of 92 targeted therapies (58 biological DMARDs [bDMARDs] and 34 targeted synthetic [ts]DMARDs) assessed in a total of 203 clinical trials. The candidate drugs reached phase I (n=20), Ia/IIb (n=6), phase II (n=51), phase II/III (n=1), phase III (n=13) and phase IV (n=1). These trials were reported as recruiting (n=31), active but not recruiting (n=8), not yet recruiting (n=4), enrolling by invitation (n=2), completed (n=31), prematurely terminated (n=12) and withdrawn in 1 (status unknown in 3). The main investigational drugs for SLE target inflammatory cytokines, chemokines or their receptors (n=19), intracellular signaling pathways (n=18), B cells (n=14) or plasma cells (n=7),T/B cells co-stimulation molecules (n=10), complement molecules (n=5),T lymphocytes (n=2), plasmacytoid dendritic cells (n=2), as well as various other immune targets (n=15).

The pipeline of investigational drugs in SLE is highly diversified and will hopefully enable more optimal Treat-To-Target with the goal of disease modification. Companion biomarkers will be needed to better characterized SLE heterogeneity and optimize treatment selection at the individual-patient level.

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that can result in substantial morbidity and mortality. Diagnosis and treatment of SLE are clinical challenges. Patient presentation and response to therapy are heterogeneous because of the complex immune dysregulation that results in SLE disease pathogenesis. An intricate interplay between genetic risk and skewing of adaptive and innate immune system responses leads to overproduction of type I interferons and other cytokines, complement activation, immune-complex deposition, and ultimately inflammation and tissue damage. Here, we review the classification criteria as well as standard and emerging diagnostic tools available to identify patients with SLE. We then focus on medical management, including novel therapeutics, nonpharmacologic interventions, and comorbidity management.

To date, no studies have described randomized controlled trials (RCTs) evaluating the effectiveness and safety of various biological agents used in induction therapy for lupus nephritis.

We designed this study to assess the relative efficacy and safety of some of these biological agents in patients with lupus nephritis.

We collected data from RCTs that examined the efficacy and safety of any biological agents for lupus nephritis and then used these data to complete a Bayesian network meta-analysis to combine the direct and indirect evidence from these studies.

We identified nine RCTs evaluating rituximab, abatacept, belimumab, anifrolumab, obinutuzumab, ocrelizumab, and low-dose interleukin-2 (IL-2) across 1,480 patients. Low-dose IL-2, obinutuzumab, rituximab, and belimumab achieved complete remission in a significant proportion of respondents when compared with that in the control. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that low-dose IL-2 had the highest probability of achieving complete remission, followed by obinutuzumab, rituximab, belimumab, anifrolumab, abatacept, ocrelizumab, and the control. The risk of serious adverse events (SAE) tended to be lower for low-dose IL-2, rituximab, belimumab, and obinutuzumab than for the control. SUCRA-based ranking indicated that IL-2 had the highest probability of being safe, followed by rituximab, belimumab, obinutuzumab, control, anifrolumab, abatacept, and ocrelizumab.

Low-dose IL-2 was the most effective induction treatment for patients with lupus nephritis and had the lowest potential for SAE. Higher complete remission rates and a more favorable safety profile suggest that low-dose IL-2, obinutuzumab, rituximab, and belimumab may be superior to the current control as treatments for lupus nephritis.