Risk Of Lupus Nephritis Research Articles

CD11b suppresses TLR7-driven inflammatory signaling to protect against lupus nephritis.

Lupus Nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) that affects kidney function. Here, we investigated the role of CD11b, a protein encoded by the ITGAM gene, in the development of LN and its functional activation as a therapeutic strategy. Genetic coding variants of ITGAM significantly increase the risk for SLE and LN by producing a less active CD11b and leading to elevated levels of type I interferon (IFN I). However, a molecular mechanism for how these variants increase LN risk has been unclear. Here, we determined that these variants also significantly associate with elevations in soluble urokinase plasminogen activator receptor (suPAR), a known biomarker linked to kidney disease, suggesting a novel molecular connection. Pharmacologic activation of CD11b with a novel, clinical-stage agonist ONT01 significantly suppressed suPAR production in myeloid cells and reduced systemic inflammation and kidney damage in multiple experimental models of LN. Importantly, delaying treatment with ONT01 until after disease onset also significantly reduced serum suPAR and inflammatory cytokines, and decreased immune complex deposition in the glomerulus, glomerulonephritis and albuminuria, suggesting that CD11b activation is therapeutic for LN. Genetic activation of CD11b via a gain-of-function CD11b mutation also showed complete protection from LN, whereas genetic deletion of CD11b worsened the disease in mice, providing further evidence of the role of CD11b activation in regulating LN. Finally, transfer of human LN PBMCs generated human LN like disease in mice that was significantly reduced by ONT01. Together, these data provide strong evidence that ONT01 mediated CD11b activation can therapeutically modulate TLR7-driven inflammation and protect against LN. These findings support clinical development of CD11b agonists as novel therapeutics for treating lupus nephritis in human patients.

Early human migration determines the risk of being attacked by wolves: ethnic gene diversity on the development of systemic lupus erythematosus.

The prevalence of systemic lupus erythematosus (SLE) varies significantly based on ethnicity rather than geographic distribution; thus, the prevalence is higher in Asian, Hispanic, and Black African populations than in European populations. The risk of developing lupus nephritis (LN) is the highest among Asian populations. Therefore, we hypothesize that human genetic diversity between races has occurred through the early human migration and human genetic adaptation to various environments, with a particular focus on pathogens. Additionally, we compile the currently available evidence on the ethnic gene diversity of SLE and how it relates to disease severity. The human leukocyte antigen (HLA) locus is well established as associated with susceptibility to SLE; specific allele distributions have been observed across diverse populations. Notably, specific amino acid residues within these HLA loci demonstrate significant associations with SLE risk. The non-HLA genetic loci associated with SLE risk also varies across diverse ancestries, implicating distinct immunological pathways, such as the type-I interferon and janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways in Asians, the type-II interferon signaling pathway in Europeans, and B cell activation pathway in Africans. Furthermore, assessing individual genetic susceptibility using genetic risk scores (GRS) for SLE helps to reveal the diverse prevalence, age of onset, and clinical phenotypes across different ethnicities. A higher GRS increases the risk of LN and the severity of SLE. Therefore, understanding ethnic gene diversity is crucial for elucidating disease mechanisms and SLE severity, which could enable the development of novel drugs specific to each race.

Metformin in Systemic Lupus Erythematosus: Investigating Cardiovascular Impact and Nephroprotective Effects in Lupus Nephritis.

Systemic lupus erythematosus (SLE) is characterized by widespread organ inflammation. Metformin, commonly used for diabetes mellitus type 2, has been explored for its anti-inflammatory potential in SLE. This study investigates the association of metformin use on renal and cardiovascular outcomes in patients with SLE. This is a retrospective study. We used the multicenter research network (TriNetX) database from 88 health care organizations globally. Patients with SLE aged 18 and above, admitted between January 1, 2014, and April 21, 2024, were included. Propensity score matching compared patients with SLE on metformin with those not on metformin, considering demographics, laboratory results, comorbidities, and baseline medication use. The study assessed outcomes, including lupus nephritis (LN), chronic kidney disease (CKD), and major adverse cardiovascular events (MACEs) at one and five years after SLE diagnosis. We identified 9,178 patients with SLE on metformin and 78,983 patients with SLE not on metformin. After propensity score matching, patients with SLE on metformin had higher levels of hemoglobin A1C, whereas patients not on metformin had higher levels of urea nitrogen. When comparing both groups, the risk of developing LN (risk ratio [RR] = 1.70 [1.17-2.41]; P = 0.004), CKD (RR = 1.27 [1.07-1.52]; P = 0.007), and MACEs (RR = 1.21 [1.00-1.46]; P = 0.04) was significantly higher among patients not on metformin at one year after SLE diagnosis. After five years, the risk of LN and CKD was also higher in patients with SLE not on metformin. MACE risk was no longer significant after five years of diagnosis between both groups. Patients with SLE not on metformin have a higher risk of developing LN, CKD, and MACEs compared with patients treated with metformin. Metformin's anti-inflammatory potential offers promise as a complementary therapy for SLE. Nonetheless, further research and clinical trials are needed to clarify its mechanisms, optimal dosage, and long-term effects.

Development and validation of a prognostic nomogram for the renal relapse of lupus nephritis

ObjectivesThis study aims to assess the risk of relapse after complete remission (CR) and partial remission (PR), and to develop a prognostic nomogram predicting the probability in lupus nephritis (LN) patients. MethodsData from patients with LN who had been in remission were collected as a training cohort. The prognostic factors were analyzed using the univariable and multivariable Cox model for the training group. A nomogram was then developed using significant predictors in multivariable analysis. Both discrimination and calibration were assessed by bootstrapping with 100 resamples. ResultsA total of 247 participants were enrolled, including 108 in the relapse group and 139 in the no relapse group. In multivariate Cox analysis, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), erythrocyte sedimentation rate (ESR), complement 1q (C1q), and antiphospholipid (aPL), anti-Sm antibody were found to be significant for predicting relapse rates. The prognostic nomogram including the aforementioned factors effectively predicted 1- and 3-year probability of flare-free. Moreover, a favorable consistency between the predicted and actual survival probabilities was demonstrated using calibration curves. ConclusionsHigh SLEDAI, ESR, and positive aPL, anti-Sm antibody are potential risk factors for LN flare, while high C1q can reduce its recurrence. The visualized model we established can help predict the relapse risk of LN and aid clinical decision-making for individual patients.

Development and validation of a prognostic nomogram for the renal relapse of lupus nephritis

ObjectivesThis study aims to assess the risk of relapse after complete remission (CR) and partial remission (PR), and to develop a prognostic nomogram predicting the probability in lupus nephritis (LN) patients. MethodsData from patients with LN who had been in remission were collected as a training cohort. The prognostic factors were analyzed using the univariable and multivariable Cox model for the training group. A nomogram was then developed using significant predictors in multivariable analysis. Both discrimination and calibration were assessed by bootstrapping with 100 resamples. ResultsA total of 247 participants were enrolled, including 108 in the relapse group and 139 in the no relapse group. In multivariate Cox analysis, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), erythrocyte sedimentation rate (ESR), complement 1q (C1q), and antiphospholipid (aPL), anti-Sm antibody were found to be significant for predicting relapse rates. The prognostic nomogram including the aforementioned factors effectively predicted 1- and 3-year probability of flare-free. Moreover, a favorable consistency between the predicted and actual survival probabilities was demonstrated using calibration curves. ConclusionsHigh SLEDAI, ESR, and positive aPL, anti-Sm antibody are potential risk factors for LN flare, while high C1q can reduce its recurrence. The visualized model we established can help predict the relapse risk of LN and aid clinical decision-making for individual patients.

Risk and Factors associated with disease manifestations in systemic lupus erythematosus - lupus nephritis (RIFLE-LN): a ten-year risk prediction strategy derived from a cohort of 1652 patients.

Lupus nephritis (LN) remains one of the most severe manifestations in patients with systemic lupus erythematosus (SLE). Onset and overall LN risk among SLE patients remains considerably difficult to predict. Utilizing a territory-wide longitudinal cohort of over 10 years serial follow-up data, we developed and validated a risk stratification strategy to predict LN risk among Chinese SLE patients - Risk and Factors associated with disease manifestations in systemic Lupus Erythematosus - Lupus Nephritis (RIFLE-LN). Demographic and longitudinal data including autoantibody profiles, clinical manifestations, major organ involvement, LN biopsy results and outcomes were documented. Association analysis was performed to identify factors associated with LN. Regression modelling was used to develop a prediction model for 10-year risk of LN and thereafter validated. A total of 1652 patients were recruited: 1382 patients were assigned for training and validation of the RIFLE-LN model; while 270 were assigned for testing. The median follow-up duration was 21 years. In the training and validation cohort, 845 (61%) of SLE patients developed LN. Cox regression and log rank test showed significant positive association between male sex, age of SLE onset and anti-dsDNA positivity. These factors were thereafter used to develop RIFLE-LN. The algorithm was tested in 270 independent patients and showed good performance (AUC = 0·70). By using male sex, anti-dsDNA positivity, age of SLE onset and SLE duration; RIFLE-LN can predict LN among Chinese SLE patients with good performance. We advocate its potential utility in guiding clinical management and disease monitoring. Further validation studies in independent cohorts are required.

Association of C-reactive protein and complement factor H gene polymorphisms with risk of lupus nephritis in Chinese population.

Complement overactivation is a major driver of lupus nephritis (LN). Impaired interactions of C-reactive protein (CRP) with complement factor H (CFH) have been shown as a pathogenic mechanism that contributes to the overactivation of complement in LN. However, genetic variations of neither CRP nor CFH show consistent influences on the risk of LN. To examine whether genetic variations of CRP and CFH in combination can improve the risk stratification in Chinese population. We genotyped six CRP single nucleotide polymorphisms (SNPs) (rs1205, rs3093062, rs2794521, rs1800947, rs3093077, and rs1130864) and three CFH SNPs (rs482934, rs1061170, and rs1061147) in 270 LN patients and 303 healthy subjects. No linkage was found among CRP and CFH SNPs, indicating lack of genetic interactions between the two genes. Moreover, CRP and CFH SNPs, neither individually nor in combination, are associated with the risk or clinical manifestations of LN. Given the unambiguous pathogenic roles of the two genes. These findings suggest that the biological effects of most genetic variations of CRP and CFH on their expressions or activities are not sufficient to influence the disease course of LN.

Genetics of longitudinal kidney function in children and adults with systemic lupus erythematosus.

Genome-wide association studies (GWAS) have identified loci associated with estimated glomerular filtration rate (eGFR). Few LN risk loci have been identified to date. We tested the association of SLE and eGFR polygenic risk scores (PRS) with repeated eGFR measures from children and adults with SLE. Patients from two tertiary care lupus clinics that met ≥4 ACR and/or SLICC criteria for SLE were genotyped on the Illumina MEGA or Omni1-Quad arrays. PRSs were calculated for SLE and eGFR, using published weighted GWA-significant alleles. eGFR was calculated using the CKD-EPI and Schwartz equations. We tested the effect of eGFR- and SLE-PRSs on eGFR mean and variance, adjusting for age at diagnosis, sex, ancestry, follow-up time, and clinical event flags. We included 1158 SLE patients (37% biopsy-confirmed LN) with 36 733 eGFR measures over a median of 7.6 years (IQR: 3.9-15.3). LN was associated with lower within-person mean eGFR [LN: 93.8 (s.d. 26.4) vs non-LN: 101.6 (s.d. 17.7) mL/min per 1.73 m2; P < 0.0001] and higher variance [LN median: 157.0 (IQR: 89.5, 268.9) vs non-LN median: 84.9 (IQR: 46.9, 138.2) (mL/min per 1.73 m2)2; P < 0.0001]. Increasing SLE-PRSs were associated with lower mean eGFR and greater variance, while increasing eGFR-PRS was associated with increased eGFR mean and variance. We observed significant associations between SLE and eGFR PRSs and repeated eGFR measurements, in a large cohort of children and adults with SLE. Longitudinal eGFR may serve as a powerful alternative outcome to LN categories for discovery of LN risk loci.

Role of crescents for lupus nephritis in clinical, pathological and prognosis: a single-center retrospective cohort study

BackgroundReferring to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2018 pathological classification, we aim to reveal the significance of cellular/fibrocellular crescents in lupus nephritis (LN) patients.MethodsPatients with LN proven by renal biopsy at the First Affiliated Hospital of Wenzhou Medical University from December 2001 to November 2017 were identified, and eligible cases were divided into two groups according to the presence or absence of cellular/fibrocellular crescents in renal biopsy tissues.ResultsA total of 401 LN patients were identified from our follow-up database, and 296 eligible LN patients were enrolled in the study. Of these patients, 146 patients in the group without cellular/fibrocellular crescents (non-crescent group) and 150 patients in the group with cellular/fibrocellular crescents (Crescent group). The median follow-up time of patients was 47 months, and a total of 54 patients progressed to the composite endpoint. Crescent group had higher serum creatinine, lower serum albumin, higher systemic lupus erythematosus (SLE) disease activity index, and higher activity index of renal tissue. The interaction between cellular/fibrocellular crescents and proteinuria at baseline was associated with the prognostic risk of LN (P = 0.006). In the group with proteinuria < 3.5 g/24 h, the prognosis of crescent group was significantly worse than of non-crescent group (P < 0.001), while in the group with proteinuria ≥ 3.5 g/24 h, there was no significant relationship between crescents and prognosis (p = 0.452). By multivariable Cox hazard analysis, positive anti-dsDNA, chronic index of renal biopsy tissue, cellular/fibrocellular crescents and its interaction with 24 h proteinuria were independent risk factors for poor prognosis of LN.ConclusionsLN patients with cellular/fibrocellular crescents had more severe and active disease features, and cellular/fibrocellular crescents is a risk factor for poor prognosis of LN. There was an interaction between cellular/fibrocellular crescents and proteinuria in predicting poor prognosis, and among patients with low levels of proteinuria at the time of renal biopsy, those with crescents had a worse long-term prognosis than those without crescents.

Peripheral CD4 +CD8 + double positive T cells: A potential marker to evaluate renal impairment susceptibility during systemic lupus erythematosus.

Lupus nephritis (LN) has a high incidence in systemic lupus erythematosus (SLE) patients, but there is a lack of sensitive predictive markers. The purpose of the study was to investigate the association between the CD4 +CD8 + double positive T (DPT) lymphocytes and LN. The study included patients with SLE without renal impairment (SLE-NRI), LN, nephritic syndrome (NS), or nephritis. Peripheral blood lymphocyte subsets were analyzed by flow cytometry. Biochemical measurements were performed with peripheral blood in accordance with the recommendations proposed by the National Center for Clinical Laboratories. The proportions of DPT cells in the LN group were significantly higher than that in the SLE-NRI group ( t=4.012, P<0.001), NS group ( t=3.240, P=0.001), and nephritis group ( t=2.57, P=0.011). In the LN group, the risk of renal impairment increased significantly in a DPT cells proportion-dependent manner. The risk of LN was 5.136 times (95% confidence interval, 2.115-12.473) higher in cases with a high proportion of DPT cells than those whose proportion of DPT cells within the normal range. These findings indicated that the proportion of DPT cells could be a potential marker to evaluate LN susceptibility, and the interference of NS and nephritis could be effectively excluded when assessing the risk of renal impairment during SLE with DPT cell proportion.

Immunogenetic Profiling of SLE and LN among Jordanian Patients.

Systemic Lupus Erythematosus (SLE) is a prolonged inflammatory autoimmune disease, which is characterized by a high titer of serological autoantibodies. Interactions between environmental and genetic factors play a crucial role in the pathogenesis of SLE. Human Leukocyte Antigen (HLA) genes, namely HLA-class II genes, are one of the main candidate genes that increase susceptibility to SLE. The aim of this study was to investigate, for the first time, the association of HLA-DRB1 and HLA-DQB1 genes among Jordanian patients diagnosed with SLE and Lupus Nephritis (LN) using the Polymerase Chain Reaction-Sequence-Specific Primer (PCR-SSP) technique. This study showed that SLE is positively associated with DRB1*0301, DRB1*1101, DRB1*1102 and HLA-DQB1*0601. Furthermore, HLA-DRB1*0301, DRB1*1101, HLA-DRB1*1501 and HLA-DQB1*0601 were found to be linked to SLE patients with LN. In addition, haplotypes HLA-DRB1*0301/DQB1*0201 and HLA-DRB1*1501/DQB1*0601 were found to be linked to SLE and LN. Our findings may serve as possible predictive markers for early screening for LN risk in SLE patients. In light of these results, the role of HLA gene polymorphisms may help in understanding the clinical course, prognosis of the disease and developing better treatment strategies for SLE patients. In addition, it may help in early diagnosis, prevention, intervention and management of the disease.

Low serum uromodulin levels and their association with lupus flares.

BackgroundOnly two previous studies in systemic lupus erythematosus (SLE) patients have identified that the blood concentrations of uromodulin are lower in nephritis. However, none of them had evaluated whether a low serum uromodulin adjusted by the glomerular filtration rate (sUromod/eGFR index) contributed to identify patients in risk of lupus nephritis (LN) using multivariable models.AimTherefore, this study aimed two objectives to evaluate the association between low serum uromodulin levels and low sUromod adjusted by eGFR with renal flares in SLE excluding effects of potential confounders in multivariable analyses; and to identify the value of low sUmod and low sUmod/eGFR index as a potential diagnostic marker of LN.Patients and methodsDesign: Cross-sectional study. SLE patients (n = 114) were investigated for lupus flare with renal SLEDAI. Two groups: a) SLE with renal flare (renal-SLEDAI≥4, n = 41) and b) SLE non-renal flare (renal SLEDAI<4, n = 73). SLE patients were evaluated by other indices including a global disease activity index (SLEDAI) and SLICC renal disease activity score. Serum uromodulin levels (ng/mL) were quantified by ELISA. Serum uromodulin was adjusted by eGFR (sUromod/eGFR index). Cutt-offs of low sUromodulin and low sUromod/eGFR index were computed, ROC curves were performed and values of diagnostic tests were obtained. Multivariable logistic regression models were performed to identify if low sUromod/eGFR index is associated to renal flares.ResultsLow serum uromodulin and low sUromod/eGFR index correlated to high scores of renal-SLEDAI, SLICC-renal and proteinuria. SLE patients with a renal flare had lower uromodulin levels compared to SLE patients without renal flare (p = 0.004). After adjusting by potential confounders, the low sUromod/eGFR index (<0.80 ng/mL) increased the risk of a renal flare (OR, 2.91; 95%CI, 1.21 to 6.98; p = 0.02).ConclusionsWe propose the low sUromod/eGFR index as a potential new marker of renal disease activity in SLE.

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

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. 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. 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. 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.

High mobility group box protein 1 (HMGB1) serum and urinary levels and gene polymorphism in Egyptian patients with systemic lupus erythematosus: A possible relation to lupus nephritis.

The aim of this study was to evaluate the effects of the high mobility group box protein 1 (HMGB1) serum and urinary levels and gene polymorphisms on systemic lupus erythematosus (SLE) development and investigate their link to lupus nephritis (LN). We enrolled 120 Egyptian SLE patients and 120 healthy controls. Thorough medical and clinical evaluation were carried out, and SLE disease activity index (SLEDAI) was assessed. Lupus patients were divided into two groups according to the presence of LN. Measurement of HMGB1 serum and urinary levels was done using ELISA and genotyping for HMGB1 (rs1045411) was performed. There were statistically significantly higher HMGB1 serum and urinary levels in SLE patients (p < 0.001). There was a marginally significant association between lupus and alleles (p = 0.059, φ = -0.086). 'C' allele was marginally significant risk allele for SLE. After classifying SLE patients based on the presence or absence of LN, there was no significant difference as regard sex (p = 0.387), age (p = 0.208) and disease duration (p = 0.094).However, there was a significant difference between the 2 groups in regard to the frequency of musculoskeletal manifestations (p = 0.035), SLEDAI score (p < 0.001), both serum (p < 0.001) and urinary HMGB1 levels (p < 0.001) in addition to the frequency of HMGB1 genotypes (p = 0.003). Lupus patients with C/T-T/T HMGB1 genotypes had 3.5-times higher odds to exhibit LN. Serum and urine HMGB1 measurements are helpful in the diagnosis of SLE and the prediction of LN. There is a link between HMGB1 gene variations and the risk of SLE, with evidence that the C/T-T/T HMGB1 genotype is linked to a significantly greater risk of LN in the Egyptian population.

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.

OA10 Survival analysis of 496 patients with systemic lupus erythematosus with up to 40 years follow-up shows improved survival in patients diagnosed in more recent time-periods

Abstract Background/Aims Patients with systemic lupus erythematosus (SLE) have increased mortality compared to age- and sex-matched controls. Lupus nephritis (LN) is a severe manifestation of SLE and an important cause of death. Our objective was to carry out a retrospective survival analysis to investigate factors that could influence risk of mortality and LN in a large multi-ethnic cohort of patients with SLE. Methods By careful review of medical records, we identified 496 patients with SLE for whom we had complete information regarding period of observation and occurrence of death and nephritis. Patients were stratified into groups according to sex, ethnicity (Caucasian, African/Caribbean, South Asian, East Asian, Other), age at start of follow-up (above and below median) and time-period of diagnosis (1978-89, 1990-99, 2000-5, 2006-11). Kaplan-Meier analysis was used to investigate differences between the groups in survival and LN. Results Overall, there were 454 women and 42 men. 91 patients died and 165 developed LN. Mean follow-up was 15.8 ± 8.75 years with a maximum of 40 years. Median age at start of follow-up was 28.0 ± 12.13 years. Results are shown in Table 1 There were no differences between men and women in mortality or LN. Caucasian patients were significantly less likely to develop LN (P &amp;lt; 0.0001) than other groups but there was no mortality difference between ethnic groups. Patients diagnosed below age 28 were more likely to develop LN (P &amp;lt; 0.0001) but less likely to die (P = 0.0039) than those diagnosed above age 28. Patients diagnosed between 2006 and 2011 were significantly less likely to die than those diagnosed between 1978 and1989 by Cox proportional hazards analysis of survival curves. (P = 0.019) Conclusion In this long-term survival analysis of 496 patients, non-Caucasian patients and those diagnosed below the age of 28 years were more likely to develop LN. The latter group were less likely to die than those diagnosed at older ages. Survival curves for groups of patients diagnosed in successive time periods suggested improved survival over time. Disclosure W. Luo: None. F. Farinha: None. D.A. Isenberg: None. A. Rahman: None.

Toll-like receptor 5 and Toll-like receptor 9 single nucleotide polymorphisms and risk of systemic lupus erythematosus and nephritis in Egyptian patients

BackgroundToll-like (TLRs) play a crucial role in both adaptive and innate immunity. The aim of the present study was to assess the association of TLR5-rs5744168, TLR9-rs187084, and TLR9-rs352140 single nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) and lupus nephritis (LN) in Egyptian patients.ResultsThe C allele and homozygous CC genotype of the TLR9-rs352140 in co-dominant and recessive models were more prevalent in SLE patients than controls (P = 0.047, P = 0.017, and P = 0.005 respectively). In contrast, allelic and genotyping distribution of TLR5-rs5744168 and TLR9-rs187084 SNPs showed no association with the risk of SLE. The T allele of the TLR5-rs5744168 was more prevalent in LN patients than controls (P = 0.021). The homozygous TT genotype of TLR5-rs5744168 SNP was more prevalent in LN patients in the co-dominant and the recessive models than controls (P = 0.036 and P = 0.011 respectively). The C allele of the TLR9-rs352140 was more prevalent in LN patients than controls (P = 0.015). The homozygous CC genotype of the TLR9-rs352140 SNP was more prevalent in LN than controls in co-dominant and recessive models (P = 0.002 and P < 0.001). In the recessive model of the TLR5-rs5744168 SNP, the TT genotype was found in 3.2% of the SLE patients while none of the SLE patients without LN or controls had TT genotype (P = 0.036). Also, in the recessive model of the TLR9-rs352140 SNP, the CC genotype was significantly more frequent in SLE patients with LN than without LN (44.4% vs 29.9%, P = 0.045).ConclusionOur results support the potential role of TLR5-rs5744168 SNP and TLR9-rs3532140 SNP not only in increasing the risk for development of SLE, but also in increasing the risk of LN in SLE patients among the Egyptian population.

The relationship between the modified National Institute of Health activity and chronicity scoring system, and the long-term prognosis for lupus nephritis: A retrospective single-center study

The revision of International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification guidelines for lupus nephritis (LN) was suggested by a working group, who recommended a modified National Institute of Health (NIH) activity and chronicity scoring system to evaluate active and chronic LN lesions. However, whether this approach was useful for estimating long-term prognosis for LN patients is unclear. We conducted a retrospective cohort study in Japanese subjects with biopsy-proven LN, between 1977 and 2018. Pathologic lesions were evaluated based on ISN/RPS 2003 classifications and the modified NIH scoring system. Patients were grouped by activity index (low, 0-5; moderate, 6-11; high, 12-24), and chronicity index (low, 0-2; moderate, 3-5; high, 6-12). The primary outcome was a composite of end-stage kidney disease (ESKD) or all-cause death, and the secondary outcome was ESKD alone. Sixty-six subjects with a median age of 31 years were included. During median follow-up (11.5 years), 15 patients reached the primary outcome: 10 had ESKD, four had died, and one had ESKD and died. Kaplan-Meier analysis showed that the cumulative primary outcome incidence increased with a higher chronicity index (log-rank trend p < 0.001). From multivariable survival analysis, moderate (hazard ratio [HR] 6.17, 95% confidence interval [CI] 1.14 to 33.20; p = 0.034) and high chronicity indices (HR 20.20, 95% CI 1.13 to 359.82; p = 0.041) were risk factors for the primary outcome. Moderate and high chronicity indices were associated with an increased ESKD risk for LN.

Principles of pediatric lupus nephritis in a prospective contemporary multi-center cohort.

Lupus nephritis (LN) is a life-threatening manifestation of systemic lupus erythematosus (SLE) and is more common in children than adults. The epidemiology and management of childhood-onset SLE (cSLE) have changed over time, prompting the need to reassess expected outcomes. The purpose of this study is to use the Childhood Arthritis and Rheumatology Research Alliance (CARRA) prospective registry to validate historical principles of LN in a contemporary, real-world cohort. After an extensive literature review, six principles of LN in cSLE were identified. The CARRA registry was queried to evaluate these principles in determining the rate of LN in cSLE, median time from cSLE diagnosis to LN, short-term renal outcomes, and frequency of rituximab as an induction therapy. Of the 677 cSLE patients in the CARRA registry, 32% had documented LN. Decline in kidney function was more common in Black cSLE patients than non-Black patients (p = 0.04). Black race was associated with worse short-term renal outcomes. In short-term follow up, most children with LN had unchanged or improved kidney function, and end stage kidney disease (ESKD) was rare. Ongoing follow-up of cSLE patients in the CARRA registry will be necessary to evaluate long-term outcomes to inform risk, management, and prognosis of LN in cSLE.

Interferon Lambda 3/4 (IFNλ3/4) rs12979860 Polymorphisms Is Not Associated With Susceptibility to Systemic Lupus Erythematosus, Although It Regulates OASL Expression in Patients With SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex etiology. Various genetic factors are associated with susceptibility to developing SLE and contribute to its onset and progression. Different single-nucleotide polymorphisms (SNPs) have been associated with SLE in several populations. The rs12979860 SNP in interferon lambda 3/4 (IFNλ3/4) is significantly associated with SLE susceptibility in patients negative for nephritis in Taiwanese people, and interferon-stimulated genes (ISGs) are differentially expressed in normal liver by the rs12979860 genotype. This study aimed to investigate whether rs12979860 is associated with the presence of SLE and lupus nephritis in Mexican individuals as well as with the expression of several ISGs in SLE patients. In total, 439 SLE patients and 358 healthy donors were genotyped for rs12979860 using real-time PCR, and allelic discrimination plots were constructed. Additionally, peripheral blood mononuclear cells (PBMCs) were isolated from the venous blood of SLE patients by centrifugation (n = 78). The mRNA levels of 2′-5′-oligoadenylate synthetase like (OASL), myxovirus resistance 1 (MX1), 2′5′-oligoadenylate synthetase 1 (OAS1), interferon-stimulated gene 15 (ISG15) and lymphocyte antigen 6 complex, locus E (LY6E) were determined using real-time PCR. The distributions of rs12979860 genotypes and allele frequencies were compared between SLE patients and healthy donors; case-control analysis revealed that rs12979860 was not associated with SLE susceptibility (OR 1.18, 95% CI 0.97–1.45, p = 0.08) or with the risk for lupus nephritis (OR 0.913, 95% CI 0.590–1.411, p = 0.682). However, OASL expression levels in PBMCs were significantly different between rs12979860 genotypes in SLE patients: median OASL mRNA levels were significantly higher in patients carrying the CC genotype (197.10, IQR 71.10–411.17) than in those with CT/TT genotypes (173.75, IQR 58.80–278.75, p = 0.016). Our results suggest that the SNP rs12979860 does not play a relevant role in susceptibility to SLE in Mexican individuals. However, IFNλ3/4 genotypes appear to be associated with OASL expression in PBMCs from patients with SLE.