non-LN Patients Research Articles

Clinical Features and Survival Analysis of Lupus Nephritis among Patients with Systemic Lupus Erythematosus: A Three-Decade-Long Retrospective Cohort Study.

Background/Objectives: Lupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus (SLE). The aim of our retrospective cohort study was to compare the clinical characteristics, therapy, survival, causes of death, and prognostic factors of LN and non-LN lupus patients. Moreover, we compared a wide spectrum of clinical data of LN patients diagnosed before and since 2005 to determine any changes in disease course and outcomes. Methods: We assessed the clinical and laboratory data of 384 SLE patients, out of whom, 127 patients were diagnosed with LN between 1990 and 2020. Results: Based on our observations, discoid LE, subacute cutaneous LE, antiphospholipid syndrome, Sjögren's syndrome, and rheumatoid arthritis were more common in non-LN patients, while anemia and anti-RNP positivity were more frequent in LN patients. Development of LN did not affect survival rates; male sex and presence of APS were negative prognostic parameters in the non-LN group while achieving remission was a positive prognostic factor in both groups. Death caused by sepsis was more prevalent in the LN group. Serositis and neurological manifestations occurred less frequently in LN patients diagnosed after 2005. The use of mycophenolate mofetil became more common, and the cumulative corticosteroid dose decreased. The SLICC Damage Index score also decreased. Conclusions: Our study demonstrated that the disease course has changed in recent years, and the main therapeutic goal in both SLE and lupus nephritis should be to achieve remission because this significantly improves long-term prognosis and patient survival.

Comparison of Clinical and Laboratory Characteristics in Lupus Nephritis vs. Non-Lupus Nephritis Patients-A Comprehensive Retrospective Analysis Based on 921 Patients.

Background: Lupus nephritis (LN) is an inflammation of the kidneys that is related to systemic lupus erythematosus (SLE). This study aimed to evaluate the differences in clinical and laboratory characteristics between LN and non-LN SLE patients. Methods: We conducted a retrospective analysis of medical records collected from SLE patients treated at the University Hospital in Kraków, Poland, from 2012 to 2022. All patients met the 2019 European League Against Rheumatism and the American College of Rheumatology (EULAR/ACR) criteria for SLE. Results: Among 921 SLE patients, LN was documented in 331 (35.94%). LN patients were younger at SLE diagnosis (29 vs. 37 years; p < 0.001) and had a male proportion that was 2.09 times higher than the non-LN group (16.62% vs. 7.97%; p < 0.001). They were more often diagnosed with serositis and hematological or neurological involvement (p < 0.001 for all). Hypertension and hypercholesterolemia occurred more frequently in these patients (p < 0.001 for both). LN patients exhibited a higher frequency of anti-dsDNA, anti-histone, and anti-nucleosome antibodies (p < 0.001 for all). Conversely, the non-LN group had a 1.24-fold (95% CI: 1.03-1.50; p = 0.021) increase in the odds ratio of having positive anti-cardiolipin IgM antibody results. LN patients were more frequently treated with immunosuppressants. The risk factors for experiencing at least three LN flares included female sex, younger age at the onset of LN or SLE, LN occurring later than SLE onset, the presence of anti-nucleosome or anti-dsDNA antibodies, and certain SLE manifestations such as myalgia, arthritis, proteinuria > 3.5 g/day, and pathological urinary casts in the urine sediment. Conclusions: LN patients differ from non-LN patients in the age of SLE diagnosis, treatment modalities, and autoantibody profile and have more frequent, severe manifestations of SLE. However, we still need more prospective studies to understand the diversity of LN and its progression in SLE patients.

Clinical and laboratory characteristics of early-onset and delayed-onset lupus nephritis patients: A single-center retrospective study

BackgroundLupus nephritis (LN) manifests systemic lupus erythematosus (SLE) and is characterized by various clinical and laboratory features. This study aimed to comprehensively evaluate the characteristics of LN patients according to the time of LN diagnosis: early-onset (LN diagnosed within one year from SLE diagnosis) vs. delayed-onset (LN diagnosed more than one year after SLE diagnosis).MethodsWe conducted a retrospective analysis of medical records from all SLE patients treated at the University Hospital in Kraków, Poland, from 2012 to 2022. We collected data on demographic, clinical, and laboratory characteristics, including histological findings, treatment modalities, and disease outcomes. Statistical analyses were performed to identify factors impacting LN development and prognosis.ResultsAmong 331 LN patients, early-onset was diagnosed in 207 (62.54%) and delayed-onset was documented in 122 cases (36.86%). In 2 (0.6%) LN cases, the time of first kidney manifestation in the SLE course was unknown. Delayed-onset LN had a higher female-to-male ratio and younger age at SLE diagnosis. This group was associated with more severe clinical manifestations. In turn, studied subgroups did not differ in internist comorbidities, kidney histopathology, and family history regarding autoimmune diseases. Delayed-onset LN exhibited a higher frequency of anti-dsDNA, anti-Smith, anti-Ro, anti-RNP, and anti-cardiolipin IgG autoantibodies. During a 14-year follow-up period, 16 patients died. Mortality rate and causes of death were comparable in both analyzed subgroups.ConclusionsMore severe clinical manifestations in delayed-onset LN prompt strict monitoring of non-LN SLE patients to diagnose and treat kidney involvement early. Also, recognizing the higher frequency of autoantibodies such as anti-dsDNA or anti-Smith in delayed-onset LN underscores the potential value of autoantibody profiling as a diagnostic and prognostic tool.

Granulin in renal tubular epithelia is associated with interstitial inflammation and activates the TLR9-IFN-α pathway in lupus nephritis.

This study aimed to investigate the possible role of granulin (GRN) in activating the TLR9-IFN-α pathway in renal tubular epithelial cells (RTECs) and explore clues that RTECs regulate the micro-environment of inflammatory response in lupus nephritis (LN). Renal sections from 57 LN patients and 30 non-LN patients were sampled for histological study, and GRN overexpression RTECs were applied for cytological study. In the histological study, GRN is highly expressed in LN RTECs with tubulointerstitial inflammation (TII) and well co-localized with TLR9. ROC analysis suggested a potential relationship between GRN expression in RTECs and therapeutic response. Moreover, IFN-α also highly expressed in LN RTECs with TII, and the intensity of IFN-α is positively correlated with the co-localization intensity of GRN and TLR9. In the cytological study, LN serum, especially serum from LN with TII, activates the expression of TLR9 in RTECs, and GRN engages the interaction of TLR9 to activate the expression of IFN-α in RTECs. While TLR9 inhibitors can suppress the expression of IFN-α in RTECs, the degree of inhibition is dose-dependent. The expression of GRN in RTECs is associated with interstitial inflammation and therapeutic response. GRN may mediate the activation of the TLR9-IFN-α pathway in RTECs and involve in the micro-environment of inflammatory response in LN.

Population-wide long-term study of incidence, renal failure, and mortality rates for lupus nephritis.

Given limited regional data, we investigate the state-wide epidemiology, renal and patient outcomes for lupus nephritis (LN) in Western Australia (WA). Patients hospitalized with incident SLE (≥2 diagnostic codes in the state-wide WA Health Hospital Morbidity Data Collection) in the period 1985-2015 were included (n = 1480). LN was defined by the presence of glomerulonephritis and/or raised serum creatinine. Trends over three study decades for annual incidence rate (AIR)/100.000 population, mortality (MR), and end-stage renal disease (ESRD) rates/100 person years were analyzed by least square regression and compared with a matched control group (n = 12 840). Clinical evidence of LN developed in 366 SLE patients (25.9%) after a median disease duration of 10 months (IQR 0-101) with renal biopsy performed in 308 (84.2%). The AIR for LN (0.63/100.000) did not change significantly over time (R2 = .11, p = .85), while point prevalence reached 11.9/100.000 in 2015. ESRD developed in 14.1% (n = 54) of LN patients vs. 0.2% in non-LN SLE patients and 0.05% in controls (all p ≤ 0.01). ESRD rates increased over time in LN patients (0.4 to 0.7, R2 = .52, p = .26). The odds ratio for death was 8.81 (CI 3.78-22.9) for LN and 6.62 (CI 2.76-17.9) for non-LN SLE patients compared to controls and MR for LN patients increased over time (1.3 to 2.2, R2 = .84, p = .26). The incidence rate of LN in WA remained unchanged over 30 years. A lack of improvement in renal failure and mortality rates illustrates the pressing need for better long-term treatment options and/or strategies in LN.

Urinary aberrations in systemic lupus erythematosus not always indicative of lupus nephritis: a cross-sectional cohort study

IntroductionKidney biopsy is the reference tool for diagnosing and guiding treatment strategies in inflammatory renal diseases, such as lupus nephritis (LN).We investigated the histopathological findings in first-time kidney biopsies from a large cohort of SLE patients. We focused on the occurrence and type of histopathological findings other than LN, and fulfillment of renal criteria in established SLE classification systems were analyzed.MethodsWe retrospectively included SLE patients (n = 139) who underwent a first kidney biopsy between 1995 and 2021, upon clinical suspicion of renal involvement. Based on histology, two groups were defined, LN and non-LN, for which clinical and laboratory features were compared.ResultsFindings consistent with LN according to ISN/RPS classification system were present in 123/139 patients (88.5%) and findings not consistent with LN were present in 16 /139 (11.5%).Non-LN patients were older at SLE diagnosis compared to LN patients (M, years 38.0 vs. 30.1, p=0.013) and had longer disease duration (M, years 11.9 vs 0.5) (p=0.027).Among non-LN patients 85.7% met the SLICC criteria item for renal SLE, seen in 94.7% in the LN group (ns). For the ACR/EULAR criteria, 66.7% of the non-LN group fulfilled the criteria compared to 74.8% in LN patients (ns). Proteinuria below the criteria cut-off level (< 0.5 g/24 h) was seen in 20% of patients with class III/IV LN.ConclusionOur data confirm the importance of kidney biopsy for ruling out the presence of renal pathology other than LN. Patients with low-grade proteinuria may exhibit severe types of LN, which reinforces the need for early biopsies to detect LN.Key Points• Our findings show that histopathology changes other than lupus nephritis may occur in a significant number of patients with clinical and laboratory signs of novel kidney involvement.• Low-grade proteinuria does not exclude findings of active lupus nephritis that require the start of immunosuppressive therapy.• The study stresses the importance of performing kidney biopsies also in the presence of low-grade proteinuria or when signs of kidney function abnormalities occur.• This is crucial as early detection and prompt initiation of therapy may improve outcomes in lupus nephritis.

The Value of Lipocalin-2 in Patients with Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune multisystem disease predominantly affecting women in the childbearing period. The majority of the pathology in SLE is related to deposits of immune complexes in various organs, which trigger complement and other mediators of inflammation. SLE is characterized by a very large spectrum of clinical manifestations accompanied by prototypic abnormalities of the immune system. Methods: This study was conducted on thirty SLE patients who were diagnosed according to the American College of Rheumatology (ACR) revised criteria. The patient was selected from the outpatient clinic of Rheumatology and Rehabilitation of Ain Shams University Hospital. Fifteen subjects, matched for age and sex, were included in the study and served as a control group. Comparison of quantitative variables between the study groups was done using the Kruskal Wallis analysis of variance (ANOVA) test with Mann Whitney U test for independent samples as posthoc multiple 2-group comparisons. A probability value (p-value) less than 0.05 was considered statistically significant. All statistical calculations were done using computer programs Microsoft Excel 2007 (Microsoft Corporation, NY, USA) and SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) version 15 for Microsoft Windows. Results and Discussion: Our results come in agreement with the study done by Farzaneh and his colleagues in 2013, who studied fifty-two lupus patients; urinary lipocalin-2 levels in LN patients were significantly higher than those in non-LN patients. Also, our results were in accordance with the study done by Hammad, who studied 33 children with active SLE (22 with and 11 without LN) and compared them with 15 matched controls. Levels of urinary NGAL were higher in patients with LN than those without LN. These findings come in consistent with previous work done by Youssef and his co-worker in 2015, who studied 44 SLE patients and divided them into two groups, group I (twenty-two patients with LN) and group II (twenty-two patients without LN), the urinary lipocalin-2 had the highest mean levels in LN patients (group I) compared to group II and controls with a statistically significant difference. Also, between SLE patients without nephritis (group II) and controls. Conclusions: In this study, urinary lipocalin-2 was significantly higher in the SLE patients compared to the control group, and the lupus nephritis patients, when compared to the patients with SLE without nephritis,showed significantly higher levels of urinary lipocalin-2. The significant association of the urinary lipocalin-2 with the renal SLEDAI shows that urinary lipocalin-2 can be an early biomarker to diagnose patients with lupus nephritis and to detect renal disease activity.

Plasma soluble tumor necrosis factor receptor I as a biomarker of lupus nephritis and disease activity in systemic lupus erythematosus patients

Objectives The goal of our study was to evaluate the potential role of sTNF-RI as a biomarker of renal involvement in SLE patients and active SLE. Methods The study sample consisted of two cohorts. The discovery cohort included 16 SLE patients without renal involvement (non-LN), 60 lupus nephritis (LN) patients and 21 healthy controls (HCs) and the replication cohort included 18 SLE non-LN patients, 116 LN patients and 36 HCs. Results The sTNF-RI levels differed significantly in the discovery cohort. The plasma sTNF-RI levels were higher in LN patients than in non-LN patients (p = .009) and HCs (p = 4 × 10−6). Plasma sTNF-RI levels were significantly higher in non-LN patients than in HCs (p = .03). The finding was confirmed in independent replication cohort (LNs vs. non-LN, p = 4.053 × 10−7; LNs vs. HCs, p = 2.395 × 10−18; non-LN vs. HCs, p = 2.51 × 10−4). The plasma sTNF-RI levels were associated with disease activity, renal function in SLE patients and urine protein in LN patients. The multivariate analysis revealed that high sTNF-RI was an independent risk factor for renal involvement. The multivariate logistic regression results suggested that high TNF-RI, high systolic blood pressure, high serum creatinine, low C4 and positive anti-dsDNA were independent risks of active SLE patients. A nomogram was constructed based on the results of multivariate logistic regression analysis and it was practical in predicting the risk of the active SLE patients. Immunohistochemistry suggested that the expression of TNF-RI in the kidney was increased. Conclusions Plasma sTNF-RI might be a good biomarker of renal involvement and disease activity in SLE patients.

Serological, fragmentomic, and epigenetic characteristics of cell-free DNA in patients with lupus nephritis.

The biological characteristics of plasma circulating cell-free DNA (cfDNA) are related to the pathogenesis of lupus nephritis (LN). The aim of this study was to explore the biological characteristics of cfDNA in patients with LN in terms of serology, fragment omics, and epigenetics, and to discuss the possibility of liquid biopsy for cfDNA as an alternative to conventional tissue biopsy. cfDNA was extracted from plasma samples of 127 patients with systemic lupus erythematosus (64 with LN, 63 without LN). The cfDNA concentration was determined using the Qubit method. Next-generation sequencing cfDNA methylation profiling was performed for three LN patients and six non-LN patients. The methylation panel was designed based on data from The Cancer Genome Atlas cohort. The fragmentation index, motif score, and DELFI score were calculated to explore the fragmentation profile of cfDNA in patients with LN. Statistical and machine learning methods were used to select features to calculate the methylation scores of the samples. Patients with LN had significantly lower cfDNA concentrations (P = 0.0347) than those without LN. This may be associated with the presence of anti-double-stranded DNA antibodies (r = -0.4189; P = 0.0296). The mean DELFI score (proportion of short fragments of cfDNA) in patients with LN was significantly higher than that in patients without LN (P = 0.0238). Based on the pan-cancer data, 73, 66, 8, and 10 features were selected and used to calculate the methylation scores. The mean methylation scores of these features in patients with LN differed significantly from those in patients without LN (P = 0.0238). The specificity of cfDNA in patients with LN was identified using serological, fragmentomic, and epigenetic analyses. The findings may have implications for the development of new molecular markers of LN.

Serum cystatin C and βeta-2 microglobulin as potential biomarkers in children with lupus nephritis.

In this study, we aimed to assess serum levels of Cystatin C (Cys C) and beta-2 microglobulin (β2M) in juvenile systemic lupus erythematosus (JSLE) patients and to investigate their role as potential biomarkers of lupus nephritis (LN) and overall disease activity. Between December 2018 and November 2019, a total of 40 patients with JSLE (11 males, 29 females; mean age: 12.6±2.5 years; range, 7.5 to 16 years) and 40 age- and sex-matched controls (10 males, 30 females; mean age: 12.3±2.4 years; range, 7 to 16 years) were included in this study. Serum (s) Cys C and β2M levels were compared between the groups. The SLE Disease Activity Index (SLEDAI-2K), the renal SLEDAI (rSLEDAI), and the Renal Damage Index were used. JSLE patients had significantly elevated mean sCyc C and sβ2M levels (1.4±0.8 mg/mL and 2.8±0.9 mg/mL, respectively) compared to the controls (0.6±0.1 mg/mL and 2.0±0.2 mg/mL, respectively; p<0.00). The mean sCys C and sβ2M levels were significantly higher in the LN group, compared to non-LN patients (1.8±0.7 mg/mL and 3.1±1.0 mg/mL, respectively vs. 0.8±0.3 mg/mL and 2.4±0.6 mg/mL, respectively; p=0.002 and p=0.02, respectively). The sCys C levels had significant positive correlations with erythrocyte sedimentation rate (r=0.3, p=0.05), serum creatinine (r=0.41, p= 0.007), 24-h urinary protein (r=0.58, p<0.001), anti-double stranded deoxyribonucleic acid antibodies titers (r=0.55, p=0.002), extra-renal SLEDAI scores (r=0.36, p=0.04), rSLEDAI (r=0.46, p=0.002), and renal class (r=0.7, p=0.0001). Serum β2M levels were significantly negatively correlated with complement 4 levels (r=-0.31, p=0.04) and significantly positively correlated with extra-renal SLEDAI scores (r=0.3, p=0.05). These findings confirm that sCys C and sβ2M levels are increased in JSLE patients in association with the overall active disease. However, sCys C level may act as a promising non-invasive biomarker for predicting kidney disease activity and biopsy classes in children with JSLE.

Absolute quantification and characterization of oxylipins in lupus nephritis and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multi-organ inflammation and defect, which is linked to many molecule mediators. Oxylipins as a class of lipid mediator have not been broadly investigated in SLE. Here, we applied targeted mass spectrometry analysis to screen the alteration of oxylipins in serum of 98 SLE patients and 106 healthy controls. The correlation of oxylipins to lupus nephritis (LN) and SLE disease activity, and the biomarkers for SLE classification, were analyzed. Among 128 oxylipins analyzed, 92 were absolutely quantified and 26 were significantly changed. They were mainly generated from the metabolism of several polyunsaturated fatty acids, including arachidonic acid (AA), linoleic acid (LA), docosahexanoic acid (DHA), eicosapentanoic acid (EPA) and dihomo-γ-linolenic acid (DGLA). Several oxylipins, especially those produced from AA, showed different abundance between patients with and without lupus nephritis (LN). The DGLA metabolic activity and DGLA generated PGE1, were significantly associated with SLE disease activity. Random forest-based machine learning identified a 5-oxylipin combination as potential biomarker for SLE classification with high accuracy. Seven individual oxylipin biomarkers were also identified with good performance in distinguishing SLE patients from healthy controls (individual AUC > 0.7). Interestingly, the biomarkers for differentiating SLE patients from healthy controls are distinct from the oxylipins differentially expressed in LN patients vs. non-LN patients. This study provides possibilities for the understanding of SLE characteristics and the development of new tools for SLE classification.

SLE stratification based on BAFF and IFN-I bioactivity for biologics and implications of BAFF produced by glomeruli in lupus nephritis.

B-cell activating factor (BAFF) is implicated in SLE pathogenesis. Blocking BAFF signalling has contributed to reducing glucocorticoid dosage and preventing organ damage. However, clinical characteristics of patients who may benefit from this therapy are not yet fully elucidated. Therefore, we identified patients with high BAFF-bioactivity to investigate their clinical characteristics and BAFF-producing cells. We established the reporter cell for BAFF and investigated the clinical characteristics of SLE patients with high BAFF-bioactivity. We identified BAFF-expressing kidney cells using publicly available scRNA-seq data and immunohistological analysis. SLE patients were stratified based on the bioactivity of BAFF and type-I IFN (IFN-I) to identify associated characteristic clinical manifestations. SLE patients, especially patients with LN, had significantly higher serum BAFF-bioactivity than healthy controls (HC) and non-LN patients. Additionally, single-cell-RNA-seq data and immunohistological analysis of kidney samples from LN patients revealed that BAFF is expressed in glomerular macrophages and mesangial cells. Notably, BAFF bioactivity was elevated in the urine of LN patients compared with that of non-LN patients, while no IFN-I bioactivity was detected in the urine. Furthermore, SLE stratification based on bioactivities of serum BAFF and IFN-I revealed the clinical characteristics of patients: high BAFF represented patients with LN and high IFN-I represented patients with blood and skin manifestations. Monitoring urinary BAFF-bioactivity may be valuable in diagnosing LN. Furthermore, stratification based on serum BAFF and IFN-I bioactivities may allow the identification of appropriate patients for biologics targeting BAFF and IFN-I.

Anxiety and depression prevalence and their risk factors in lupus nephritis patients: A case-control study.

IntroductionAnxiety and depression exhibit a high prevalence in systemic lupus erythematosus (SLE) patients, while this issue is seldom explored in lupus nephritis (LN). Hence, the current study aimed to investigate the prevalence of anxiety and depression, and the risk factors for these mental disorders in LN patients.MethodsFifty LN patients, 50 non‐LN SLE patients, and 50 health control (HCs) were enrolled. The Hospital Anxiety and Depression Scale (HADS) for anxiety (HADS‐A) score and HADS for depression (HADS‐D) score were evaluated.ResultsHADS‐A score was highest in LN patients (median 7.0, interquartile range [IQR]: 6.0–10.0), followed by non‐LN SLE patients (median 6.0, IQR: 5.0–8.0), and lowest in HCs (median 5.0, IQR: 3.0–7.0) (p < .001). Besides, the anxiety rate was most frequent in LN patients (38.0%), followed by non‐LN SLE patients (28.0%), least common in HCs (12.0%) (p = .011). HADS‐D score was highest in LN patients (median 7.5, IQR: 6.0–11.0), followed by non‐LN SLE patients (median 6.0, IQR: 5.0–8.3), and lowest in HCs (median 4.0, IQR: 2.0–6.3) (p < .001). Similarly, the depression rate was most prevalent in LN patients (50.0%), subsequently the non‐LN SLE patients (30.0%), and rarest in HCs (10.0%) (p < .001). Furthermore, in LN patients, age (p = .009), LN activity index (p = .020), alopecia (p = .023), 24 h proteinuria (p = .044), and C‐reactive protein (p = .049) were independently correlated with higher anxiety risk; meanwhile, age (p = .001) and LN activity index (p = .009) were independently correlated with higher depression risk.ConclusionAnxiety and depression are highly prevalent, which link to aging, alopecia, inflammation, and severe renal involvement in LN patients.

MALT1 serves as a biomarker for estimating disease risk of lupus nephritis: a prospective case-control study.

BackgroundMucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) regulates immune/inflammation response and kidney injury, indicating that it might participate in the lupus nephritis (LN) pathology. The present study sought to investigate the utility of MALT1 serving as an indicator of severity and inflammation biomarker in LN.MethodsIn total, 30 LN patients and 30 non-LN systemic lupus erythematosus (SLE) patients were recruited, and blood MALT1 expression was detected using reverse transcription-quantitative polymerase. Besides, the SLE disease activity index was calculated for all subjects to assess disease activity.ResultsMALT1 was more increased in LN patients than non-LN SLE patients {2.26 [interquartile range (IQR): 1.38–3.54] vs. 1.04 (IQR, 0.60–1.62); P<0.001}. Additionally, the multivariate logistic regression model analysis indicated that higher MALT1 [odds ratio (OR): 3.097, 95% CI: 1.292–7.425, P=0.011] and higher serum creatinine (Scr) (OR: 1.055, 95% CI: 1.012–1.099, P=0.011) were independently related to an elevated risk of LN. The MALT1 and Scr-based nomogram exhibited a good value in estimating LN risk with an area under the curve (AUC) of 0.873 (95%CI: 0.787–0.960). MALT1 was highest in LN patients with class IV (accompanied by V or not), followed by class V and class III (accompanied by V or not) patients, and lowest in class II patients (P=0.046). MALT1 was positively linked to the LN activity index (rs=0.370, P=0.044); however, while it was positively associated with the LN chronicity index, the level did not reach statistical significance (rs=0.341, P=0.066). MALT1 was positively linked to 24 h proteinuria (rs=0.473, P=0.008), Scr (rs=0.378, P=0.039), and C-reactive protein (CRP) (rs=0.410, P=0.025) in LN patients.ConclusionsMALT1 might serve as a useful biomarker for estimating the disease risk in LN patients; however, future large-sample size studies need to be conducted to validate our findings.

Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis

ObjectivesPatients with lupus nephritis (LN) are in urgent need for early diagnosis and therapeutic interventions targeting aberrant molecular pathways enriched in affected kidneys.MethodsWe used mRNA-sequencing in effector (spleen) and target...

Identification and Validation of a Urinary Biomarker Panel to Accurately Diagnose and Predict Response to Therapy in Lupus Nephritis.

BackgroundWe have previously shown that 15 urinary biomarkers (of 129 tested by Luminex), discriminate between active Lupus Nephritis (ALN) and non-LN patients. The aim of this study was to evaluate the ability of these 15 previously-identified urinary biomarkers to predict treatment responses to conventional therapy, and for the most predictive of these biomarkers to validate their utility to identify ALN patients in an independent prospectively-acquired lupus cohort.MethodsOur study had a 3-stage approach. In stage 1, we used Luminex to examine whether our previously identified urinary biomarkers at the time of the renal flare ( ± 3 months) or 12 ± 3 months after treatment of biopsy-proven ALN could predict treatment responses. In stage 2, a larger prospectively-acquired cross-sectional cohort was used to further validate the utility of the most predictive urinary biomarkers (identified in stage 1) to detect ALN patients. In this 2nd stage, cut-offs with the best operating characteristics to detect ALN patients were produced for each biomarker and different combinations and/or numbers of elevated biomarkers needed to accurately identify ALN patients were analyzed. In stage 3, we aimed to further corroborate the sensitivity of the cut-offs created in stage 2 to detect ALN patients in a biopsy-proven ALN cohort who had a urine sample collection within 3 months of their biopsy.ResultsTwenty-one patients were included in stage 1. Twelve (57.1%), 4 (19.1%), and 5 (23.8%) patients had a complete (CR), partial (PR) and no (NR) remission at 24 ± 3 months, respectively. The percentage decrease following 12 ± 3 months of treatment for Adiponectin, MCP-1, sVCAM-1, PF4, IL-15 and vWF was significantly higher in patients with CR in comparison to those with PR/NR. In stage 2, a total of 247 SLE patients were included, of which 24 (9.7%) had ALN, 79 (31.9%) had LN in remission (RLN) and 144 (58.3%) were non-LN (NLN) patients. Based on the combinations of biomarkers with the best operating characteristics we propose “rule out” and “rule in” ALN criteria. In stage 3, 53 biopsy-proven ALN patients were included, 35 with proliferative LN and 18 with non-proliferative ALN, demonstrating that our “rule in ALN” criteria operate better in detecting active proliferative than non-proliferative classes.ConclusionsOur results provide further evidence to support the role of Adiponectin, MCP-1, sVCAM-1 and PF4 in the detection of proliferative ALN cases. We further show the clinical utility of measuring multiple rather than a single biomarker and we propose novel “rule in” and “rule out” criteria for the detection of proliferative ALN with excellent operating characteristics.

Cytokines and autoantibodies profile during systemic lupus erythematosus and psoriasis diseases in Egypt

ObjectiveCytokine, a small secreted protein, is secreted from one cell types to exert a particular effect on other cell types and/or on itself. Cytokines are characterized by their redundancy in the function; they are secreted in a cascade and can work synergistically and/or antagonistically. Cytokines have an important role in thepathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE) and psoriasis (PS).Due to their crucial roles in the immune cells’ development, differentiation and regulation; any dysregulation in their production and/or action can lead to the development of autoimmune diseases.The study population was composed of healthy control volunteers, SLE patients that were diagnosed as lupus nephritis (LN) patients or non-LN patients with developed atherosclerosis (As), and psoriasis patients that were diagnosed as psoriasis patients without arthritis (Ps) or psoriatic arthritis patients (PsA). MethodsThe current study aimed to measure and compare the levels of T helper (h)1, Th2 and Th17 cytokines (IFN-γ, TNF-α, IL-17, -1β, -12, -10, -4, -2, -23, -18, -34 and -6) among Egyptian SLE and Ps patients. In addition, the pathway and type of Th cells involved in autoimmune-mediated tissue injury was examined. Detection of autoantibodies (ANA, anti-dsDNA, anti-sm, anti-histone, anti-ribosomal, APLA and anti-Ro/SSA) was performed to find if there is a relation between disease development and their presence. ResultsDetection of autoantibodies and complement proteins were beneficial in the diagnosis of SLE and psoriasis. ANA and anti-dsDNA autoantibodies were a good marker for the diagnosis of SLE and monitoring disease activity; however, other autoantibodies like APLA, anti-sm, anti-histone and anti-ribosomal can be used to indicate the disease activity. ConclusionsCytokines can be used to determine the disease activity and autoimmune-mediated tissue injured in both SLE and psoriasis. Where, IL-17 recorded the highest level in LN and PsA patients; while the highest levels of IL-34, -23 and -6 were recorded in PsA patients and IL-1β was a characteristic cytokine in As patients.

Associations of lymphocyte subpopulations with clinical phenotypes and long-term outcomes in juvenile-onset systemic lupus erythematosus.

Juvenile-onset systemic lupus erythematosus (JSLE) is a complex and heterogeneous immune-mediated disease. Cellular components have crucial roles in disease phenotypes and outcomes. We aimed to determine the associations of lymphocyte subsets with clinical manifestations and long-term outcomes in JSLE patients. A cohort of 60 JSLE patients provided blood samples during active disease, of whom 34 provided further samples during inactive disease. In a longitudinal study, blood samples were obtained from 49 of the JSLE patients at 0, 3, and 6 months. The healthy control (HC) group consisted of 42 age-matched children. Lymphocyte subsets were analyzed by flow cytometry. The percentages of CD4+ T, γδ T, and NK cells were significantly decreased in JSLE patients compared with HC, while the percentages of CD8+ T, NKT, and CD19+ B cells were significantly increased. The percentage of regulatory T cells (Tregs) was significantly lower in JSLE patients with lupus nephritis (LN) than in non-LN JSLE patients and HC. The patients were stratified into high and low groups by the median frequency of each lymphocyte subset. The γδ T cells high group and NK cells high group were significantly related to mucosal ulcer. The CD4+ T cells high group was significantly associated with arthritis, and the NKT cells high group was substantially linked with autoimmune hemolytic anemia. The CD8+ T cells low group was mainly related to vasculitis, and the Tregs low group was significantly associated with LN. The percentage of Tregs was significantly increased at 6 months of follow-up, and the LN JSLE group had a lower Treg percentage than the non-LN JSLE group. Predictors of remission on therapy were high Tregs, high absolute lymphocyte count, direct Coombs test positivity, and LN absence at enrollment. JSLE patients exhibited altered lymphocyte subsets, which were strongly associated with clinical phenotypes and long-term outcomes.

Anti-DFS70 Antibodies Are Associated With Proliferative Lupus Nephritis and Renal Pathological Activity.

ObjectiveThe significance of anti-dense fine speckles 70 (DFS70) antibodies in systemic lupus erythematosus (SLE) is still unclear, especially in lupus nephritis (LN) patients. We investigated the prevalence, clinical and pathological relevance of anti-DFS70 antibodies in LN patients.MethodsAnti-DFS70 antibodies were measured using enzyme-linked immunosorbent assays in 377 biopsy-proven LN patients, 268 non-LN SLE patients, 232 chronic kidney disease (CKD) patients, and 78 healthy individuals (HI). Demographic, clinical, and pathological parameters were compared between LN patients with and without anti-DFS70 antibodies. Stepwise multivariable logistic regression was performed to identify covariates associated with anti-DFS70 antibodies.ResultsThe prevalence of anti-DFS70 antibodies in LN (19.6%) was comparable to non-LN SLE patients (19.8%, P=0.9630), but was significantly higher than CKD patients (13.4%, P=0.0468) and HI (9.0%, P=0.0252). Using multivariable logistic regression analysis, the titer of anti-double-stranded DNA (dsDNA) antibodies (adjusted odds ratio=1.002, 95% confidence interval 1.001-1.003, P=0.004) was associated with positive anti-DFS70 antibodies in LN patients. In addition, anti-DFS70 antibodies were more prevalent in proliferative LN (22.0%, 68/309) compared to membrane LN patients (10.2%, 6/59, P=0.0376). Furthermore, LN patients with positive anti-DFS70 antibodies had significantly higher activity index (AI) compared to patients who were negative (8.0 vs 6.0, P=0.0131). However, the chronicity index was similar between the groups (3.0 vs 3.0, P=0.8412).ConclusionAnti-DFS70 antibodies were not associated with LN development in SLE patients but were associated with anti-dsDNA antibodies, proliferative LN, and renal AI. This suggests their potential to serve as a non-histological biomarker for LN subclass and activity status.

The role of Dickkopf-1 as a biomarker in systemic lupus erythematosus and active lupus nephritis

BackgroundSystemic lupus erythematosus (SLE) is a chronic disease which is mainly attributed to autoantibodies, cytokines, and immune complex deposition. Studies have demonstrated that cytokines and autoantibodies were strongly associated with renal diseases and can be used for the prediction of patients with lupus nephritis (LN). However, antibodies to dsDNA and the reduction of complements were also detected in non-LN patients as well as clinically non-active SLE patients. The current study was performed to detect the role of serum DKK-1 as a biomarker for the identification of SLE patients and patients with LN and its relation to disease activity and severity. The study was conducted on fifty clinically diagnosed SLE patients who were diagnosed according to Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, in addition to thirty healthy control volunteers matched for age and sex. Assessment of SLE disease activity was done using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Assessment of SLE disease severity was done using the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) damage index. Serum levels of DKK-1 were measured for all participants by ELISA using commercially available kits.ResultsDKK-1 serum levels were significantly higher among active lupus nephritis cases as compared with SLE cases with no LN and with healthy controls (9197.60 μg/uL ± 2939.2 μg/uL vs. 6405.15 μg/uL ± 2018.91 μg/uL vs. 2790.33 μg/uL ± 833.49 μg/uL) respectively (p-values < 0.001). DKK-1 concentration was significantly higher among SLE patients with positive as compared with negative anti-double-stranded DNA (dsDNA) antibodies (p-value < 0.001). According to receiver operating characteristic (ROC) curve analysis, serum DKK-1 level diagnosed the SLE at a statistically significant level with a 98% sensitivity and 70% specificity and serum DKK-1 level also diagnosed active lupus nephritis at a 90% sensitivity and 63% specificity.ConclusionDKK-1 could diagnose SLE and lupus nephritis with high sensitivity and specificity. Serum DKK-1 is a reliable biomarker for the identification of SLE and patients with LN and could be used as a key molecule for the diagnosis of SLE and as a prognostic indicator of LN.