A pathogenic gut lipoglycan drives systemic thromboinflammation in lupus nephritis.

Imbalances in the gut microbiome have been linked to increased intestinal permeability and disease flares in systemic lupus erythematosus (SLE). Our study revealed that patients with flares of lupus nephritis (LN) and intestinal expansions of the anaerobic commensal, Ruminococcus gnavus (RG), displayed whole blood transcriptome profiles indicative of platelet, neutrophil, and myeloid cell activation, a profile reminiscent of sepsis. Serum analysis confirmed elevated serum levels of Platelet Factor 4 and neutrophil extracellular traps, which significantly correlated with levels of IgG-antibody to a novel lipoglycan (LG) produced by pathogenic RG strains, which was also documented in an independent LN cohort. To test for causality, in vivo mouse models further demonstrated that gut colonization with LG-producing RG strains, as well as a single intraperitoneal challenge with an LG preparation, caused platelet activation and megakaryocytosis in bone marrow and spleen. Mice colonized with RG strains that produce LG developed cellular infiltration of the kidneys by neutrophils and monocytes. Hence, RG expansions during renal flares may identify a specific LN flare endotype driven by thromboinflammatory mechanisms. Antibodies that arise from immune exposure to the RG lipoglycan may serve as a surrogate biomarker, helping to elucidate the impact of the relationship between gut microbiota communities and clinical outcomes in patients afflicted by LN. [208]

BackgroundSLE is an inflammatory condition associated with hyperactivation of the immune system, with mounting evidence that imbalances in the gut microbiota communities are common. These imbalances can range from subtle...

The Use of Serological Tests in the Care of Patients with Lupus Nephritis.

ObjectiveWhereas genetic susceptibility for Systemic Lupus Erythematosus (SLE) has been well explored, the triggers for clinical disease flares remain elusive. To investigate relationships between microbiota community resilience and disease activity,...

Background Systemic lupus erythematous (SLE) is a multi-system autoimmune disease which has a relapsing and remitting course. Patients with lupus nephritis (LN) are at risk of relapse and hence long term follow up and disease monitoring are of particular importance. Anti-C1q antibodies (C1Q Ab) are observed in 30-60% of patients with SLE. It has been postulated that the presence of C1Q Ab can predict a flare of LN. Here we undertook a prospective follow up of patients after having a C1Q Ab measurement to determine whether the result predicted a flare of LN. Methods SLE patients attending an Inner-City Lupus Center, were involved in the study. All fulfilled the 2012 SLICC criteria for SLE. A point-in-time measurement of C1Q Ab was made using an ELISA kit (Orgentec Diagnostika GmbH). A positive test defined by the manufacturer is a level above 10 U/ml. Medical records of patients were reviewed over the following 1 year to identify LN flares. A renal flare was defined as a doubling of the protein creatinine ratio with a subsequent decision to escalate immunosuppressive therapy. Chi Squared tests were used to assess statistical significance. 9 patients who were being treated for a flare of LN at the time of C1Q Ab were excluded from the analysis. Results 116 lupus patients were included in the study. Of those, 52 had biopsy proven LN (45%). Positive C1Q ab was more common in patients with a history of biopsy proven LN (n = 17, 32.7%) compared to those with non-renal SLE (n = 10, 15.6%),(p = 0.03). Renal flares tended to be more common in C1q ab positive LN patients (n = 4, 26.7%) compared to those without C1q ab (n = 2, 7.14%). (p = 0.782). Of the 64 patients with non-renal SLE, 1 (10%) C1Q Ab positive patient subsequently developed LN compared with 1 (1.85%) C1Q Ab negative patient (p = 0.173).There was no correlation between the level of C1Q Ab and the rate of LN flares. Having a positive dsDNA antibody level at the time of sampling also did not appear to predict a flare. Conclusion C1Q Ab has a known correlation with LN, however its ability to predict flares has been less well characterised. Our prospective analysis shows that although the C1Q Ab positive patients were more likely to have a flare of LN in the following year, there was not a statistically significant difference between the C1Q Ab positive and negative groups. In addition, only a relatively small proportion of C1Q Ab positive patients went on to have a flare (20%). Our data therefore does not support the use of C1Q Ab as a predicting factor for a subsequent flare of LN. Disclosures S. Bahal None. D. Pyne None. R. Rajakariar None. M. Lewis None. A. Pakozdi None. A. Cove-Smith None.

BackgroundSystemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with a plethora of manifestations potentially affecting every organ system. Lupus nephritis (LN) is recognized as one of the most common...

Background and Aims In lupus nephritis (LN), therapeutic schemas for remission induction are well known but data about duration of maintenance treatment are limited. There is no agreement between clinical practice guidelines about duration and withdrawal of therapy, and literature regarding this topic is scarce. Recently, a RCT has observed that immunosuppression discontinuation after 2‒3 years was related to LN relapse when compared with immunosuppression maintenance. However, immunosuppressive agents are related to severe adverse events and toxicity. We conducted this study with the aim to evaluate the incidence of LN relapse in a cohort of patients with discontinuation of immunosuppressive treatment after a first LN flare. We also aimed to determine factors associated to the presence of renal relapse in this population. Method Multicenter retrospective observational study including patients with biopsy proven LN who have received immunosuppressive treatment that was subsequently discontinued. Patients on prednisone at doses lower than 5 mg per day were allowed to be included. Patients were diagnosed between 1990 and 2018. The study was conducted in Spain. Relapse was defined according to Malvar et al criteria. Results 113 patients were included, mean age was 34.11 ±14.56 years-old and 85.8% were women. Serum creatinine at the time of LN diagnosis was 1.09±0.63 mg/dL, and proteinuria 3.16±2.53g/24h, ANA were positive in 85.84%, and anti-DNA Abs in 69.91%. Serum C3 and C4 levels were 72.51±44.06 and 13.04±11.27 respectively. 55.75% presented with class IV LN, 12.39% with class III or V LN, and 8.85% with class II. Mixed forms were less frequent. In a follow up period of 172.53±162.95 months, 17.7% (n = 20) presented a renal flare after immunosuppressive drugs withdrawal. Time from LN to relapse was 89.05±39.87 months, and time from immunosuppression discontinuation to relapse was 37.75±32.13 months. There were no differences in baseline characteristics between patients who relapsed and patients who did not, neither in histologic characteristics at the time of LN diagnostic biopsy except for glomerulosclerosis, that was less frequent in the relapse group (20% vs 34.41%, p = 0.0435). However, a tendency to a shorter time under immunosuppression in patients who relapsed was observed (73.55±79.06 vs 110.79±206.87 months). Data about treatment withdrawal in each group are summarized in Figure 1. Interestingly, there were no differences between both groups in steroids withdrawal (75% vs 78.49%,p = 0.7327) and hydroxychloroquine withdrawal (33.33% vs 21.74%, p = 0.3393). At the time of immunosuppression discontinuation, patients who relapsed presented lower serum C3 and C4 levels (78.79±24.89 vs 112.26±35.52, p = 0.0080 and 13.82±6.07 vs 23.09±12.56, p = 0.0333), but there were no differences in terms of renal function at this moment. At the end of follow up, patients who relapsed presented more albuminuria (227.87±259.79 vs 78.65±24.77, p = 0.0289) but creatinine levels were similar in both groups (0.84±0.30 vs 0.84±0.30, 0.5105). Only one patient died and two patients required renal replacement therapy, all in the no relapse group. Conclusion In a cohort of 113 patients with biopsy proven LN who were treated con immunosuppression and subsequently discontinued, 17.7% presented renal relapse at a mean time of 37 months after withdrawal. There was a tendency to a short time on immunosuppressive regimens in patients who relapsed. Also, lower serum C3 and C4 levels at the time of immunosuppression withdrawal were associated to renal relapse. At the end of a follow up of 14 years, patients who relapsed those who did not showed a similar maintained renal function but those who relapsed presented lower albuminuria.

THU0251 Different responses to induction therapy in two onset categories of lupus nephritis

Background and aimsThe aim of this study was to review renal flare frequency, to identify potential risk factors for relapses, to assess the value of serological tests during flares and...

ObjectivesTo study maternal and foetal outcomes in two consecutive pregnancies in women with renal and non-renal systemic lupus erythematosus (SLE) in relation to disease flares, preeclampsia and obstetric outcomes.Material and...

BackgroundPatients with lupus nephritis (LN) are at risk of relapse and hence long term disease monitoring is required. Here we undertook a prospective follow up of patients after having Anti-C1q...

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear components. Lupus nephritis (LN) is the major cause of morbidity and mortality in patients with SLE. Central to the pathogenesis of SLE is the accumulation of cellular waste, especially apoptotic microparticles (MPs), which stimulates diverse immune reactions including the formation of neutrophil extracellular traps (NETs). In this study, we investigated the content of MPs from SLE patients with and without (active) LN, their capacity to stimulate NET release, and assessed the molecular mechanisms underlying MP-induced NETosis. MPs from SLE patients with biopsy-proven active LN, remissive LN, without LN, and healthy controls were characterized by flow cytometry. Isolated neutrophils were exposed to MPs derived from either patient plasma or apoptotic human umbilical vein endothelial cells, and NET release was quantified by immunofluorescence imaging, spectrofluorometry or an in-house developed NET ELISA. MPs from SLE patients with active LN contain higher levels of acetylated chromatin compared to MPs from those with remissive LN, without LN, or healthy controls. MPs enriched in hyperacetylated chromatin are more potent in inducing NETosis when compared to MPs containing moderate acetylated chromatin. The release of NETs in response to MPs occurs rapidly in a concentration-dependent manner and proceeds independent from the formation of reactive oxygen species (ROS). Our data suggest that MPs containing acetylated chromatin drive ROS-independent NET release in SLE patients with active LN, which may lead to the glomerular deposition of NETs and subsequent NET-driven LN.

The role of urinary neutrophil gelatinase-associated lipocalin in lupus nephritis

AB0613 Predictive Role of Low Vitamin D Levels in Lupus Nephritis Flare

BackgroundTo investigate non-histologic factors that can discriminate proliferative lupus nephritis (LN) from membranous LN in patients with systemic lupus erythematosus with renal manifestations.MethodsPatients with biopsy-proven proliferative LN (class III ± V and class IV ± V) and membranous LN (class V) were included. Non-histologic factors were compared between the two groups. A logistic regression analysis was performed to identify the factors associated with proliferative LN. To assess the accuracy of these factors in discriminating between proliferative LN and membranous LN, we performed a receiver-operating characteristic analysis.ResultsOf the total 168 patients with biopsy-proven LN, 150 patients (89.3%) had proliferative LN, and 18 patients (10.7%) had membranous LN. In the multivariable logistic regression analysis, positive anti-double-stranded DNA (anti-dsDNA) antibody (adjusted OR = 11.200, 95% CI = 2.202–56.957, p = 0.004) was associated with proliferative LN, while positive anti-U1RNP antibody (adjusted OR = 0.176, 95% CI = 0.040–0.769, p = 0.021) and higher glomerular filtration rate (GFR) (adjusted OR = 0.973, 95% CI = 0.951–0.994, p = 0.013) were inversely associated with proliferative LN. Among these covariates, the anti-dsDNA antibody (area under the curve = 0.806, 95% CI = 0.695–0.916) had the highest accuracy in discriminating between proliferative LN and membranous LN.ConclusionThe positivity of anti-dsDNA antibody was associated with proliferative LN, while the positivity of anti-U1RNP antibody and GFR were inversely associated with proliferative LN. The anti-dsDNA antibody had a good accuracy in discriminating proliferative LN from membranous LN.