Tubular biomarkers and histology in lupus nephritis.

INTRODUCTION: The relevance of tubulo-interstitial involvement for kidney prognosis has recently been emphasized, but validated biomarkers for predicting histology are still lacking. The aim of our study was to evaluate different serum and urinary markers of tubular damage in patients with lupus nephritis (LN) and to correlate them with kidney histopathology. METHODS: A single-center retrospective study was conducted from January 2016 to December 2021. Serum and urine samples were collected on the same day of kidney biopsy and correlated with histologic data from a cohort of 15 LN patients. We analyzed the following urinary markers, adjusted for urine creatinine: beta 2-microglobulin, alpha 1-microglobulin, NGAL, uKIM-1, MCP-1, uDKK-3, and uUMOD. The serum markers sKIM-1 and sUMOD were also analyzed. RESULTS: A positive and strong correlation was observed between the degree of interstitial fibrosis (rho = 0.785, p = .001) and tubular atrophy (rho = 0.781, p = .001) and the levels of uDKK3. uUMOD also showed an inverse and moderate correlation with interstitial fibrosis (rho = -0.562, p = .037) and tubular atrophy (rho = -0.694, p = .006). Patients with >10% cortical interstitial inflammation had higher levels of uKIM-1 [4.9 (3.9, 5.5) vs. 0.8 (0.6, 1.5) mcg/mg, p = .001], MCP-1 [3.8 (2. 3, 4.2) vs. 0.7 (0.3, 1.2) mcg/mg, p = .001], sKIM-1 [9.2 (5.9, 32.7) vs. 1.4 (0, 3.5) pg/mL, p = .001], and lower sUMOD [8.7 (0, 39.7) vs. 46.1 (35.7, 53) ng/mL, p = .028]. CONCLUSION: The use of specific urinary and serum biomarkers of tubular dysfunction or injury may help to predict certain histologic parameters in LN patients.

Longitudinal assessment of urinary ALCAM, HPX, and PRDX6 in Korean patients with systemic lupus erythematosus: implications for disease activity monitoring and treatment response.

Introduction: This study aimed to demonstrate the potential of activated leukocyte cell adhesion molecule (ALCAM), hemopexin (HPX), and peroxiredoxin 6 (PRDX6) as urine biomarkers for systemic lupus erythematosus (SLE). Methods: Urine samples were collected from 138 Korean patients with SLE from the Ajou Lupus Cohort and 39 healthy controls (HC). The concentrations of urine biomarkers were analyzed using enzyme-linked immunosorbent assay kits specific for ALCAM, HPX, and PRDX6, respectively. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic utility, and Pearson's correlation analysis was conducted to assess the relationships between the disease activity and urine biomarkers. Results: Patients with SLE and patients with lupus nephritis (LN) showed significantly elevated ALCAM, HPX, and PRDX6 levels compared with HCs. ALCAM, HPX, and PRDX6 showed significant diagnostic values, especially for lupus nephritis (LN), with areas under the receiver operating characteristic curve for LN was 0.850 for ALCAM (95% CI, 0.778-0.921), 0.781 for HPX (95% CI, 0.695-0.867), and 0.714 for PRDX6 (95% CI, 0.617-0.812). Correlation analysis revealed that all proteins were significantly associated with anti-double stranded DNA antibody (ALCAM, r = 0.350, p < 0.001; HPX, r = 0.346, p < 0.001; PRDX6, r = 0.191, p = 0.026) and SLEDAI (ALCAM, r = 0.526, p < 0.001; HPX, r = 0.479, p < 0.001; PRDX6, r = 0.262, p = 0.002). Results from the follow-up of the three biomarker levels in these patients revealed a significant decrease, showing a positive correlation with changes in SLEDAI-2k scores (ALCAM, r = 0.502, p < 0.001; HPX, r = 0.475, p < 0.001; PRDX6, r = 0.245, p = 0.026), indicating their potential as indicators for tracking disease activity. Discussions: Urinary ALCAM, HPX, and PRDX6 levels have diagnostic value and reflect disease activity in Korean patients with SLE, emphasizing their potential for non-invasive monitoring and treatment response evaluation.

Urinary metabolomic profiling of a cohort of Colombian patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune and multisystem disease with a high public health impact. Lupus nephritis (LN), commonly known as renal involvement in SLE, is associated with a poorer prognosis and increased rates of morbidity and mortality in patients with SLE. Identifying new urinary biomarkers that can be used for LN prognosis or diagnosis is essential and is part of current active research. In this study, we applied an untargeted metabolomics approach involving liquid and gas chromatography coupled with mass spectrometry to urine samples collected from 17 individuals with SLE and no kidney damage, 23 individuals with LN, and 10 clinically healthy controls (HCs) to identify differential metabolic profiles for SLE and LN. The data analysis revealed a differentially abundant metabolite expression profile for each study group, and those metabolites may act as potential differential biomarkers of SLE and LN. The differential metabolic pathways found between the LN and SLE patients with no kidney involvement included primary bile acid biosynthesis, branched-chain amino acid synthesis and degradation, pantothenate and coenzyme A biosynthesis, lysine degradation, and tryptophan metabolism. Receiver operating characteristic curve analysis revealed that monopalmitin, glycolic acid, and glutamic acid allowed for the differentiation of individuals with SLE and no kidney involvement and individuals with LN considering high confidence levels. While the results offer promise, it is important to recognize the significant influence of medications and other external factors on metabolomics studies. This impact has the potential to obscure differences in metabolic profiles, presenting a considerable challenge in the identification of disease biomarkers. Therefore, experimental validation should be conducted with a larger sample size to explore the diagnostic potential of the metabolites found as well as to examine how treatment and disease activity influence the identified chemical compounds. This will be crucial for refining the accuracy and effectiveness of using urine metabolomics for diagnosing and monitoring lupus and lupus nephritis.

Assessment of Interleukin 17 in Egyptian Systemic Lupus Erythematosus Patients as a Biomarker in Disease Activity.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic idiopathic systemic autoimmune disorder with dysregulation of adaptive and innate immune systems. Interleukin (IL)-17 is the prototypical pro-inflammatory cytokine of T helper 17 (Th17) cells. Therefore, it contributes to the pathogenesis of human SLE. AIM: The aim of the research paper was the evaluation of IL-17 level as a biomarker in the SLE cohort and its relation to disease activity and analysis of IL-17 concentration in patients with lupus nephritis and non-lupus nephritis. METHODS: The research enrolled 45 SLE patients according to Systemic Lupus International Collaborating Clinics Classification Criteria (SLICC), and age and sex-matched. The patients underwent full history, clinical examination, laboratory investigation, and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) calculation. RESULTS: The mean age ± SD of the participants equaled 32 ± 11 years, and serum IL-17 in SLE cases was statistically significantly high (p < 0.001). No statistically significant correlations were reported between disease activity according to SLEDAI and IL-17. In addition, a statistically significant positive correlation was reported between IL-17 and ESR, and a high statistically significant negative correlation was reported between IL-17 and C3 and C4 (P < 0.001). A statistically significant positive correlation was reported between IL-17 and 24-hour urinary proteins with a Pvalue of 0.01. CONCLUSION: SLE cases demonstrated higher levels of serum IL-17, contributing to SLE pathogenesis. However, no statistically significant difference was reported between IL-17 and Lupus nephritis. IL-17 and SLE activity (SLEDAI) did not correlate. A statistically significant positive relation was reported between IL-17 and 24-hour urinary proteins. Additionally, a high statistically significant negative correlation was reported between IL-17 and C3 and C4.

Rationale and design of the Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study.

INTRODUCTION: Disease subtyping and monitoring are essential for the management of nephrotic syndrome (NS). Although various biomarkers for NS have been reported, their clinical efficacy has not been comprehensively validated in adult Japanese patients. METHODS: The Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study is a nationwide, multicenter, and prospective cohort study in Japan, enrolling adult (≥18 years) patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), and lupus nephritis (LN). Baseline clinical information and plasma and urine samples will be collected at the time of immunosuppressive therapy initiation or biopsy. Follow-up data and plasma and urine samples will be collected longitudinally based on the designated protocols. Candidate biomarkers will be measured: CD80, cytotoxic T-lymphocyte antigen 4, and soluble urokinase plasminogen activator receptor for MCD and FSGS; anti-phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A antibodies for MN; fragment Ba, C3a, factor I, and properdin for MPGN/C3G; and CD11b, CD16b, and CD163 for LN. Outcomes include complete and partial remission, relapse of proteinuria, a 30% reduction in estimated glomerular filtration rate (eGFR), eGFR decline, and initiation of renal replacement therapy. The diagnostic accuracy and predictive ability for clinical outcomes will be assessed for each biomarker. RESULTS: From April 2019 to April 2023, 365 patients were enrolled: 145, 21, 138, 10, and 51 cases of MCD, FSGS, MN, MPGN/C3G, and LN, respectively. CONCLUSION: This study will provide valuable insights into biomarkers for NS and serve as a biorepository for future studies.

Analytical validation of urine ALCAM ELISA as a test for lupus nephritis.

OBJECTIVES: Urinary activated leukocyte cell adhesion molecule (uALCAM) is emerging as an outstanding biomarker for active lupus nephritis (ALN). This study aims to evaluate the analytic performance of the human ALCAM ELISA as an assay method to quantify uALCAM in patients with lupus nephritis. METHODS: A commercially available human ALCAM ELISA kit was validated for its analytical performance as per Clinical & Laboratory Standards Institute guidelines. RESULTS: Assaying 30 sets of serial dilutions of ALCAM exhibited an average CV of 10% and 97%-105% recovery. The assay also exhibited overall acceptable imprecision (CV < 20%) in day-to-day, site-to-site, and lot-to-lot reproducibility. The assay exhibited a reportable range from 4018 pg/ml down to 62 pg/ml with an r2 of 0.999 in urine, with a limit of detection of 16-45 pg/ml. Most tested chemicals did not interfere with the assay, and no diurnal variations were observed in uALCAM levels. uALCAM was stable for at least 3 months at -20°C or -80°C. CONCLUSION: This analytic-validated uALCAM ELISA may provide physicians with an accurate and reliable tool for use in early detection of renal involvement in lupus, routine outpatient monitoring of disease activity, and long-term prognostication.

[The expression of autophagy-related proteins in peripheral blood mononuclear cells of patients with lupus nephritis is upregulated and related to kidney damage].

Objective To identify the relationship between nephritis activity, autophagy and inflammation in patients with SLE. Methods Western blot analysis was used to detect the expression of microtubule-associated protein 1 light chain 3 (LC3) and P62 in peripheral blood mononuclear cells (PBMCs) of SLE patients with lupus nephritis and non-lupus nephritis patients. Tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) in the serum of SLE patients were determined by ELISA. The correlation between LC3II/LC3I ratio and SLE disease activity score (SLEDAI), urinary protein, TNF-α and IFN-γ levels was analyzed by Pearson method. Results The expression of LC3 was increased and P62 was decreased in SLE patients. TNF-α and IFN-γ were increased in the serum of SLE patients. LC3II/LC3I ratio was positively correlated with SLEDAI (r=0.4560), 24 hour urine protein (r=0.3753), IFN-γ (r=0.5685), but had no correlation with TNF-α (r=0.04 683). Conclusion Autophagy is found in PBMCs of SLE, and the autophagy is correlated with renal damage and inflammation in patients with lupus nephritis.

Increased Immunoglobulin Gamma-3 Chain C in the Serum, Saliva, and Urine of Patients with Systemic Lupus Erythematosus.

Immunoglobulin gamma-3 chain C (IGHG3) levels have been detected in the blood and tissue of patients with systemic lupus erythematosus (SLE). This study aims to assess its clinical value by measuring and comparing levels of IGHG3 in different body fluids in patients with SLE. The levels of IGHG3 in saliva, serum, and urine from 181 patients with SLE and 99 healthy controls were measured and analyzed. In patients with SLE and healthy controls, salivary IGHG3 levels were 3078.9 ± 2473.8 and 1413.6 ± 1075.3 ng/mL, serum IGHG3 levels were 478.1 ± 160.9 and 364.4 ± 97.9 µg/mL, and urine IGHG3 levels were 64.0 ± 74.5 and 27.1 ± 16.2 ng/mL, respectively (all p < 0.001). Salivary IGHG3 was correlated with ESR (correlation coefficient [r], 0.173; p = 0.024). Serum IGHG3 was correlated with leukocyte count (r, -0.219; p = 0.003), lymphocyte count (r, 0.22; p = 0.03), anti-dsDNA antibody positivity (r, 0.22; p = 0.003), and C3 levels (r, -0.23; p = 0.002). Urinary IGHG3 was correlated with hemoglobin level (r, -0.183; p = 0.021), ESR (r, 0.204; p = 0.01), anti-dsDNA antibody positivity (r, 0.262; p = 0.001), C3 levels (r, -0.202; p = 0.011), and SLE disease activity index (r, 0.332; p = 0.01). Urinary IGHG3 was higher in patients with nephritis than in those without (119.5 ± 110.0 vs. 49.8 ± 54.4 ng/mL; p < 0.01). IGHG3 was increased in the saliva, serum, and urine of patients with SLE. While salivary IGHG3 was not identified to be specific to SLE disease activity, serum IGHG3 showed correlations with clinical characteristics. Urinary IGHG3 levels were associated with disease activity and renal involvement in SLE.

Analysis of the ratio of urinary beta-2-microglobulin to total protein concentration in children with isolated tubulointerstitial disease.

BACKGROUND: Proteinuria is broadly classified into glomerular and tubular proteinuria. Urinary beta-2-microglobulin (ß2-MG) is known as a marker for detecting tubulointerstitial diseases. However, tubulointerstitial damage can also lead to an increase in urinary ß2-MG level in some patients with glomerular diseases. This study aimed to determine the ratio of urinary ß2-MG to total protein (TP) concentration in patients with both isolated tubulointerstitial and glomerular disease. METHODS: This multicenter, retrospective study included children with Dent disease or lupus nephritis in five facilities. Their urinary ß2-MG levels were > 1000 µg/L. Urinary ß2-MG and TP concentrations were obtained, and the ratio of urinary ß2-MG to TP concentration (µg/mg) was calculated. The Mann-Whitney U test was performed to compare this ratio between these children. The optimal cutoff value of the ratio for considering the presence of glomerular disease was obtained from the receiver operating characteristic (ROC) curve. RESULTS: We obtained information on 23 children with Dent disease and 14 children with lupus nephritis. The median ratios of urinary ß2-MG to TP concentrations in children with Dent disease and lupus nephritis were 84.85 and 1.59, respectively. The ROC curve yielded the optimal cutoff value of this ratio for distinguishing between these diseases, and the cutoff value was found to be 22.3. CONCLUSION: In children with tubulointerstitial diseases, the urinary ß2-MG concentration may be approximately 8.5% of the TP concentration. The possibility of presenting with glomerular disease should be considered in patients with a ratio of urinary ß2-MG to TP concentration of < 22.3 (µg/mg).

Candidate MicroRNA Biomarkers in Lupus Nephritis: A Meta-analysis of Profiling Studies in Kidney, Blood and Urine Samples.

CONTEXT: Lupus nephritis (LN) is a kidney disease caused by systemic lupus erythematosus in which kidneys are attacked by the immune system. So far, various investigations have reported altered miRNA expression profiles in LN patients and different miRNAs have been introduced as biomarkers and/or therapeutic targets in LN. The aim of this study was to introduce a consensus panel of potential miRNA biomarkers by performing a meta-analysis of miRNA profiles in the LN patients. MATERIALS AND METHODS: A comprehensive literature review approach was performed to find LN-related miRNA expression profiles in renal tissues, blood, and urine samples. After selecting the eligible studies and performing the data extraction, meta-analysis was done based on the vote-counting rank strategy as well as meta-analysis of p-values. The meta-miRNAs and their related genes were subjected to functional enrichment analyses and network construction. RESULTS: The results of the meta-analysis of 41 studies were three lists of consensus miRNAs with altered expression profiles in the various tissue samples of LN patients (meta-analysis of p-values < 0.05). Of the 13 studies on kidney tissue, the meta-miRNAs were let-7a, miR-198, let-7e, miR-145, and miR-26a. In addition, meta-miRNAs of miR-199a, miR-21, miR-423, miR-1260b, miR-589, miR-150, miR-155, miR-146a, and miR-183 from 21 studies on blood samples, and miR-146a, miR-204, miR-30c, miR-3201, and miR-1273e from 11 studies on urine samples can be considered as non-invasive biomarker panels for LN. Functional enrichment analysis on the meta-miRNA lists confirmed the involvement of their target genes in nephropathy-related signaling pathways. CONCLUSION: Using a meta-analytical approach, our study proposes three meta-miRNA panels that could be the target of further research to assess their potential as therapeutic targets/biomarkers in LN disease.

The expression of autophagy-related proteins in peripheral blood mononuclear cells of patients with lupus nephritis is upregulated and related to kidney damage / 细胞与分子免疫学杂志

Objective To identify the relationship between nephritis activity, autophagy and inflammation in patients with SLE. Methods Western blot analysis was used to detect the expression of microtubule-associated protein 1 light chain 3 (LC3) and P62 in peripheral blood mononuclear cells (PBMCs) of SLE patients with lupus nephritis and non-lupus nephritis patients. Tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) in the serum of SLE patients were determined by ELISA. The correlation between LC3II/LC3I ratio and SLE disease activity score (SLEDAI), urinary protein, TNF-α and IFN-γ levels was analyzed by Pearson method. Results The expression of LC3 was increased and P62 was decreased in SLE patients. TNF-α and IFN-γ were increased in the serum of SLE patients. LC3II/LC3I ratio was positively correlated with SLEDAI (r=0.4560), 24 hour urine protein (r=0.3753), IFN-γ (r=0.5685), but had no correlation with TNF-α (r=0.04 683). Conclusion Autophagy is found in PBMCs of SLE, and the autophagy is correlated with renal damage and inflammation in patients with lupus nephritis.

Relationship between Blood Lipid Profiles and Risk of Lupus Nephritis in Children.

Objective: Systemic lupus erythematosus (SLE) is a relatively common rheumatic disease in children. The characteristics of blood lipid metabolism in children with LN are little reported. This study aimed to explore the relationship between blood lipid profiles and the risk of lupus nephritis (LN) in children. Methods: A total of 134 children with newly diagnosed SLE were divided into LN and non-LN groups according to pathological renal biopsy results. Clinical manifestations and blood lipid profiles were analyzed and compared between the two groups, and the relationships between blood lipid profiles and risk of LN were evaluated. Results: The positivity rate of an anti-dsDNA antibody and an SLE disease activity index (SLEDAI) were significantly increased, and C3 and C4 levels were significantly reduced in the LN compared with the non-LN group. The overall incidence of dyslipidemia was 79.9%, with a significantly high incidence in the LN group compared with the non-LN group. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and very LDLC (VLDL-C) were all higher in the LN group than those in the non-LN group. However, there was no significant difference in high-density lipoprotein cholesterol (HDL-C) between the two groups. The blood lipid levels were positively correlated with 24-hour urine protein quantification, urea, creatinine, uric acid, urinary IgG, urinary microalbumin, urinary transferrin, urinary α1 microglobulin, and urinary N-acetyl glucosidase, respectively. Receiver-operating characteristic curves showed that combined detection of TC, TG, LDL-C, and VLDL-C had higher discrimination capacity than that in individual measures. Additionally, increased TC was independently associated with the occurrence of LN. Conclusions: Children with LN have significant dyslipidemia. High levels of TC, TG, LDL-C, and VLDL-C are closely related to the occurrence of pLN. Clinical attention should be paid to monitoring and managing blood lipid profiles in children with LN.

Sysmex UN2000 detection of protein/creatinine ratio and of renal tubular epithelial cells can be used for screening lupus nephritis.

OBJECTIVES: This study is aimed to evaluate if automated urine sediment analysis UN2000 can be used to screen lupus nephritis. METHODS: UN2000 was used to examine 160 urine samples from patients with systemic lupus erythematosus and 124 urine samples from Lupus nephritis. The result of protein/creatinine ratio(P/C) and renal tubular epithelial cells (RTEC) were evaluated. With biochemical analysis and microscopic examination as the gold standard, the Kappa consistency test was used to analyze the accuracy of P/C and RTEC. Analysis was to evaluate the accuracy of P/C single item or RTEC single item and both screening lupusnephritis. RESULTS: The consistency of P/C and the gold standard, and that of RTEC and the gold standard are respectively strong and good (0.858 vs. 0.673). The specificity, positive predictive value, and coincidence were the highest when P/C ≥ 2 + was set as the only screening standard for lupus nephritis. When the standard was selected between P/C ≥ 2 + or RTEC > 2.8 cells/µl, the sensitivity and negative predictive value were the highest. CONCLUSION: UN 2000 can be used to screen lupus nephritis by detecting P/C and RTEC.

Urine inter-alpha-trypsin inhibitor family-related proteins may serve as biomarkers for disease activity of lupus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease involving multiple tissues. Inter-Alpha-Trypsin Inhibitor (ITI) family proteins have a role in maintaining tissue homeostasis, but their possible clinical significance in the SLE patients has not been reported. The aim of this study was to analyze and verify the expression of ITI-related proteins in the urine of SLE patients, further explore the features of these proteins in disease activity. METHODS: Based on label-free proteomics technology and bioinformatics technology, we analyzed the expression of ITI family-related proteins in the urine of lupus. Subsequently, Western-blot and targeted proteomics were used to qualitatively and quantitatively verify the expression of these proteins, respectively. RESULTS: A total of seven ITI family-related proteins were screened and identified; and six of these proteins were differentially expressed in the urine of SLE patients. Further quantitative analysis showed that the expressions of ITIH2, ECM1, and ITIH5 in urine between active SLE group and stable SLE group were consistent with the preliminary screening results. The expression of ITIH2 and ECM1 in the renal damage group were also consistent with the screening results. Moreover, ITIH2 and ECM1 have a good correlation with disease activity and have a certain correlation with renal damage. CONCLUSIONS: In this exploratory study, we evaluated the expression of ITI family-related proteins in the urine of SLE and found that urine ITIH2 and ECM1 were closely related to SLE activity, especially kidney damage, providing an experimental basis for further exploration of the potential roles in monitoring lupus and lupus nephritis activity.

Assessment of the Role of Urinary Heparanase in Lupus Nephritis Patients and Its Correlation with Disease Activity.

Assessing the activity of lupus nephritis (LN) with novel biomarkers is a promising noninvasive diagnostic tool for managing systemic lupus erythematosus (SLE). We assessed the ability of urinary heparanase to identify LN and its relation to the disease's activity. This crosssectional study had 90 subjects: 70 patients with SLE and 20 healthy controls. A full medical history, clinical examination, and routine investigations were carried out for the patients and controls. Immunological assays and assessments of the disease's activity with the SLE Disease Activity Index (SLEDAI) and the renal SLEDAI (r-SLEDAI) were carried out for LN groups. Urinary heparanase levels were measured using an enzyme-linked immunosorbent assay for all subjects. Of our patients, 20 had active LN, 17 had nonactive LN, 18 had active lupus without renal involvement, and 15 had nonactive lupus without renal involvement. The level of urinary heparanase was significantly higher in the LN groups than in the non-LN groups and the controls and was significantly higher in those with active LN than in those with nonactive LN. There were significant positive correlations between urinary heparanase and 24-h urinary protein, total SLEDAI, and r-SLEDAI, and significant negative correlations between urinary heparanase and Complements 3 and 4. Urinary heparanase predicted the activity of LN with a sensitivity of 80% and a specificity of 91.43%. Urinary heparanase levels were higher in patients with active LN and correlated with the markers of disease activity, indicating that it can serve as a useful new biomarker for the activity of LN.

Clinical Experience of Proteasome Inhibitor Bortezomib Regarding Efficacy and Safety in Severe Systemic Lupus Erythematosus: A Nationwide Study.

As treatment options in advanced systematic lupus erythematosus (SLE) are limited, there is an urgent need for new and effective therapeutic alternatives for selected cases with severe disease. Bortezomib (BTZ) is a specific, reversible, inhibitor of the 20S subunit of the proteasome. Herein, we report clinical experience regarding efficacy and safety from all patients receiving BTZ as therapy for SLE in Sweden during the years 2014-2020. 8 females and 4 males were included with a mean disease duration at BTZ initiation of 8.8 years (range 0.7-20 years). Renal involvement was the main target for BTZ. Reduction of global disease activity was recorded by decreasing SLEDAI-2K scores over time and remained significantly reduced at the 6-month (p=0.007) and the 12-month (p=0.008) follow-up visits. From BTZ initiation, complement protein 3 (C3) levels increased significantly after the 2nd treatment cycle (p=0.05), the 6-month (p=0.03) and the 12-month (p=0.04) follow-up visits. The urine albumin/creatinine ratio declined over time and reached significance at the 6-month (p=0.008) and the 12-month follow-up visits (p=0.004). Seroconversion of anti-dsDNA (27%), anti-C1q (50%) and anti-Sm (67%) was observed. 6 of 12 patients experienced at least one side-effect during follow-up, whereof the most common adverse events were infections. Safety parameters (C-reactive protein, blood cell counts) mainly remained stable over time. To conclude, we report favorable therapeutic effects of BTZ used in combination with corticosteroids in a majority of patients with severe SLE manifestations irresponsive to conventional immunosuppressive agents. Reduction of proteinuria was observed over time as well as seroconversion of some autoantibody specificities. In most patients, tolerance was acceptable but mild adverse events was not uncommon. Special attention should be paid to infections and hypogammaglobinemia.

Prognostic and Diagnostic Values of Novel Serum and Urine Biomarkers in Lupus Nephritis: A Systematic Review.

INTRODUCTION: While renal biopsy remains the gold standard for diagnosing lupus nephritis (LN), the prognostic and diagnostic role of non-invasive biomarkers for LN is currently debated. METHODS: Available studies published in last 5 years (2015-2020) assessing the diagnostic and prognostic value of urinary and/or serological biomarkers in subjects with LN were analyzed in this systematic review. RESULTS: Eighty-five studies were included (comprehending 13,496 patients with systemic lupus erythematosus [SLE], 8,872 LN, 487 pediatric LN, 3,977 SLE but no LN, 160 pediatric SLE but no LN and 7,679 controls). Most of the studies were cross-sectional (62; 73%), while 14 (17%) were prospective. In sixty studies (71%), the diagnosis of LN was biopsy-confirmed. Forty-four out of 85 (52%) investigated only serological biomarkers, 29 studies (34%) tested their population only with urinary biomarkers, and 12 (14%) investigated the presence of both. Outcome measures to assess the clinical utility of the analyzed biomarkers were heterogeneous, including up to 21 different activity scores, with the SLEDAI (in 60%) being the most used. Despite some heterogeneity, promising results have been shown for biomarkers such as urinary monocyte chemoattractant protein, urinary adiponectin, and urinary vascular cell adhesion protein 1. DISCUSSION/CONCLUSION: While serum and urine biomarkers have the potential to improve diagnostic and prognostic pathways in patients with LN, the vast heterogeneity across studies severely limits their applicability in current clinical practice. With the kidney biopsy still representing the gold standard, future efforts should focus on harmonizing study inclusion criteria and outcomes, particularly in clinical trials, in order to improve comparability and facilitate the implementations of available biomarkers into the daily practice.

Differences in rituximab use between pediatric rheumatologists and nephrologists for the treatment of refractory lupus nephritis and renal flare in childhood-onset SLE.

BACKGROUND: Consensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare. METHODS: Members of Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the American Society for Pediatric Nephrology (ASPN) were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: (1) refractory disease after induction treatment with corticosteroid and cyclophosphamide (CYC) and (2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included CYC, mycophenolate mofetil (MMF), rituximab (RTX), and others, alone or in combination. RESULTS: Seventy-six respondents from ASPN and foty-one respondents from CARRA represented approximately 15 % of the eligible members from each organization. Treatment choices between nephrologists and rheumatologists were highly variable and received greater than 50 % agreement for an individual treatment choice in only the following 2 of 6 follow up scenarios: 59 % of nephrologists, but only 38 % of rheumatologists, chose increasing dose of MMF in the case of LN refractory to induction therapy with proteinuria, hematuria, and improved serum creatinine. In a follow up scenario showing severe renal flare after achieving remission with induction therapy, 58 % of rheumatologists chose CYC and RTX combination therapy, whereas the top choice for nephrologists (43 %) was CYC alone. Rheumatologists in comparison to nephrologists chose more therapy options that contained RTX in all follow up scenarios except one (p < 0.05). CONCLUSIONS: Therapy choices for pediatric rheumatologists and nephrologists in the treatment of refractory LN or LN flare were highly variable with rheumatologists more often choosing rituximab. Further investigation is necessary to delineate the reasons behind this finding. This study highlights the importance of collaborative efforts in developing consensus treatment plans for pediatric LN.