anti-dsDNA Antibody Titers Research Articles

Perinuclear anti-neutrophil cytoplasmic antibody in systemic lupus erythematosus indicates more severe condition

ObjectiveTo investigate the clinical significance of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) in patients with systemic lupus erythematosus (SLE). MethodsThis retrospective study included 120 SLE patients. All patients were divided into group p-ANCA+ and group p-ANCA−. Demographic characteristics, clinical symptoms, autoantibodies, laboratory tests and renal pathology were compared between these two groups. ResultsAmong 120 patients, 45 (37.5%) patients were p-ANCA+ and 75 (62.5%) patients were p-ANCA−. The occurrence of lupus nephritis was significantly higher in group p-ANCA+ (P = 0.046). For autoantibodies, the occurrences of anti-dsDNA, anti-nucleosome and anti-histone were significantly higher in group p-ANCA+ (P < 0.001, P = 0.004 and P = 0.006, respectively). Titers of anti-dsDNA antibody, erythrocyte sedimentation rate (ESR), serum beta-2-microglobulin (β2-MG) and systemic lupus erythematosus disease activity index (SLEDAI) were higher in group p-ANCA+ (P < 0.001, P = 0.021, P < 0.001 and P = 0.005, respectively), while albumin was significantly lower than p-ANCA− group (P = 0.012). There were no differences in the classification of lupus nephritis, activity index and chronicity index. p-ANCA correlated with lupus nephritis, anti-dsDNA antibody, anti-nucleosome antibody and anti-histone antibody, and also disease activity markers, such as titers of anti-dsDNA antibody, ESR, albumin, serum β2-MG and SLEDAI. ConclusionThe appearance of p-ANCA in SLE indicated high probability of lupus nephritis and more severe condition.

Factors affecting the Apgar score of offsprings born to mothers suffering from systemic lupus erythematosus.

To reveal which disease activity parameters affect low Apgar scores of newborns, which is considered as a predictive parameter for neurological development.We examined retrospectively the data from 42 newborns who were delivered from systemic lupus erythematosus (SLE) mothers from 2006 to 2019. We evaluated whether the disease activity parameters, such as the achievement ratio of lupus low disease activity state (LLDAS), SLE disease activities index (SLEDAI), complement level, titer of anti-double stranded DNA (anti-dsDNA) antibody, therapeutic agents were related with low Apgar scores of newborns.In 42 newborns, adverse pregnancy outcomes, especially preterm birth (16.7%), low birth weight (31.0%) light-for-date (11.9%) were associated with disease activity parameters or prednisolone dose. Apgar scores at 1 minute were related with unachieved LLDAS and the titer of anti-dsDNA antibody at first and third trimester, SLEDAI score and complement level at third trimester, mean prednisolone dose. Apgar scores at 5 minutes were also associated with the titer of anti-dsDNA antibodies at first and third trimester and mean prednisolone dose. Multivariate analysis showed only high titer of anti-dsDNA antibody was significantly associated with low Apgar score at both one minute and 5 minutes.In our retrospective study, high titer of anti-dsDNA antibodies at first and third trimester was a risk factor for low Apgar scores of newborns born to SLE mothers. We considered that high titer of anti-dsDNA antibody influenced on childrens neurological development, therefore, there is a need for long-term follow-up study of SLE offsprings.

Effects of AS2819899, a novel selective PI3Kδ inhibitor, in a NZB/W F1 mouse lupus-like nephritis model

Phosphoinositide 3-kinases generate lipid-based second messengers that control an array of intracellular signaling pathways. In particular, phosphoinositide 3-kinases delta (PI3Kδ) is expressed primarily in hematopoietic cells and plays an important role in B-cell development and function. B cells play a critical role in autoimmune diseases by producing autoantibodies. Studies have therefore increasingly focused on PI3Kδ as a therapeutic target for the treatment of inflammatory and autoimmune diseases. One such autoimmune disease is systemic lupus erythematosus (SLE). SLE is a chronic systemic autoimmune disease with repeated recurrence and remission, and autoantibodies play an important role in its pathogenesis. Here, we examined the pharmacological profile of the novel PI3Kδ selective inhibitor AS2819899 and investigated its therapeutic potential against SLE in a NZB/W F1 mouse lupus-like nephritis model, a widely-used SLE mouse model. AS2819899 prevented B and T cell activation in vitro, and inhibited antibody production in a T-cell independent de novo antibody production mouse model. In the spontaneous NZB/W F1 mouse model, AS2819899 treatment significantly reduced anti-dsDNA antibody titers and improved kidney dysfunction. Further, AS2819899 inhibited the memory recall reaction in a T-cell dependent antibody production mouse model, suggesting that AS2819899 can potentially maintain remission of SLE. Moreover, we identified a pharmacodynamics marker for AS2819899 that may be useful in clinical studies. These results indicate that AS2819899 may be an attractive therapeutic candidate for SLE, including the maintenance of remission.

Clinical and histological significance of urinary CD11c+ macrophages in lupus nephritis

BackgroundInfiltration of immune cells into the kidney is one of the key features of lupus nephritis (LN). The presence of immune cells in the urine may be used as a non-invasive biomarker of LN. Here, we aimed to analyze the clinicopathologic significance of urinary CD11c+ macrophages in patients with LN.MethodsThe numbers and proportions of CD11c+ macrophages in the urine samples of patients with LN at the time of kidney biopsy were examined using flow cytometry. We also examined the association between the levels of urinary CD11c+ macrophages and the clinical and pathologic features of patients with LN.ResultsCompared with patients without LN or those with non-proliferative LN, patients with proliferative LN had significantly higher numbers and proportions of urinary CD11c+ macrophages, which were strongly correlated with the serum anti-dsDNA antibody titer. The numbers and proportions of urinary CD11c+ macrophages were significantly associated with the values of chronicity indices such as tubular atrophy and interstitial fibrosis. No significant relationships were found between the levels of urinary CD11c+ macrophages and the activity scores, degree of proteinuria, or lupus disease activity. Urinary CD11c+ macrophages were more abundant in patients who did not achieve renal response to induction treatment with immunosuppressants than in those who achieved complete or partial response. The receiver operating characteristic (ROC) curve analysis showed that the number of urinary CD11c+ macrophages was the most powerful predictor of renal response at 6 months (ROC-AUC = 1.00, p = 0.0004).ConclusionThe urinary levels of CD11c+ macrophages were closely associated with the chronic pathologic changes of LN and renal response and may thus be used as a novel biomarker in LN.

Ezh2-mediated epigenetic modification is required for allogeneic T cell-induced lupus disease

BackgroundThe mechanisms involved in the pathogenesis of autoimmune disorders, including systemic lupus erythematosus (SLE), have not been fully elucidated. Some of these mechanisms involve epigenetic regulation of gene expression. The histone methyltransferase Ezh2 contributes to epigenetic regulation of gene expression, is highly expressed in germinal center (GC) B cells and follicular T helper (TFH) cells, and may be involved in lupus pathogenesis.MethodsThe murine bm12 model of lupus-like chronic graft versus host disease (cGVHD) was induced by intra-peritoneal injection of negatively isolated allogeneic CD4+ T cells. Lupus-like disease development was monitored by ELISA determination of serum anti-dsDNA and anti-chromatin antibody titers. Immune cell activation and Ezh2 expression were evaluated by flow cytometry and Western blotting.ResultsDecreased autoantibody production and GC formation are observed when Ezh2-deficient CD4+ T cells are used instead of wild-type (WT) to induce cGVHD and when mice that receive allogeneic WT donor T cells to induce cGVHD are treated with GSK503, an Ezh2-specific inhibitor. In the bm12 cGVHD model, WT donor T cells are normally fully activated 1 week after infusion into an allogeneic host, exhibit a TFH cell (PD-1hi/CXCR5hi) phenotype with upregulated Ezh2, and activate B cells to form germinal centers (GCs). In contrast, Ezh2-deficient donor T cells generate fewer TFH cells that fail to activate B cells or promote GC formation. Despite similar T-independent, LPS-induced B cell responses, OVA-immunized CD4.Ezh2-KO mice had a skewed low-affinity IgM phenotype in comparison to similarly treated WT mice. In addition, early after OVA immunization, more CD4+ T cells from B6.CD4.Ezh2-KO mice had a CD44lo/CD62Llo phenotype, which suggests arrested or delayed activation, than CD4+ T cells from ovalbumin-immunized B6.WT mice.ConclusionEzh2 gene deletion or pharmacological Ezh2 inhibition suppresses autoantibody production and GC formation in bm12 lupus-like cGVHD and decreases affinity maturation and isotype switching in response to immunization with a T cell-dependent antigen. Ezh2 inhibition may be useful for the treatment of lupus and other autoimmune disorders.

OP0006 ABNORMAL IRON METABOLISM AND MITOCHONDRIAL DYSFUNCTION: INVESTIGATING A NOVEL PATHOLOGICAL MECHANISM IN SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Iron is vital for numerous essential physiological processes including erythropoiesis and energy metabolism (as iron is found in the mitochondrial electron transport chain, the central site of ATP production). Iron homeostasis is tightly controlled by a number of regulators including; 1. Hepcidin, which prevents iron release from stores (under the influence of IL6 and IL1β); 2. Ferritin, an iron storage protein; 3. Lipocalin-2 (LCN2), which is released upon innate immune activation that induces iron sequestration; 4. Transferrin, which binds circulating iron and enables its transport to effector cell targets; 5. Haptoglobin, which binds free haemoglobin and assisting iron recycling; 6. Erythropoietin (EPO), which stimulates erythropoiesis as a result of hypoxia.Chronic inflammation may result in dysregulation of iron metabolism and in turn impair mitochondrial function yet little is known regarding how these processes change in systemic lupus erythematosus (SLE).Objectives:In this study, we investigated how dysregulation of iron metabolism may occur in SLE and subsequently sought to identify how a lack of iron may ultimately induce abnormal mitochondrial function.Methods:1. Investigating abnormal iron metabolism in SLE.Serum samples from patients with SLE (n=39) and healthy controls (HC, n=17) were assessed hepcidin, IL-1ß, IL-6, ferritin, LCN2, EPO, haptoglobin and transferrin levels by ELISA. Hierarchical cluster analysis of normalised data (converted to Z-scores) was performed using MeV software in order to characterise patient groups based upon iron metabolism profile. Anti-dsDNA antibody titres, complement C3 levels and SLEDAI-2K were excluded to limit the influence of these variables on cluster analysis. Results were presented as a heatmap.2. Studying mitochondrial function in iron deficiency and SLE. Peripheral blood mononuclear cells (PBMCs) from HCs and patients with SLE were analysed using Seahorse Respirometry, which measures mitochondrial oxygen consumption rate (a measure of energy metabolism dependent upon oxidative phosphorylation). To assess differences between health, iron deficiency and SLE 3 groups were assessed; 1. PBMCs derived from HCs; 2. PBMCs from patients with SLE; 3. Healthy PBMCs cultured in iron deficient condition, in which cells were treated with the potent iron chelator, Deferiprone.Results:Figure 1a demonstrates that four groups were identified following cluster analysis. In spite of excluding markers of disease activity, these groups showed significant differences in SLEDAI-2K (shown in Figure 1b). In summary, patients with more active disease (Groups C and D) showed higher levels of hepcidin (which prevents the release of iron from stores, under the influence of IL-1ß and IL-6) and reduced transferrin thus suggesting that iron is inefficiently transported when compared with those with less active disease (in Groups A and B).Figure 2a demonstrates that basal mitochondrial respiration is significantly reduced in PBMCs derived from healthy controls when grown in iron deficiency conditions (following treatment with Deferiprone and is lower still in those with SLE. Figure 2b shows that PBMCs from patients with SLE have reduced maximal mitochondrial respiration capacity that is comparable to the levels seen in iron deficient healthy PBMCs.Conclusion:Patients with SLE demonstrate abnormalities in iron metabolism that results in cellular iron deficiency as iron is not released from stores, nor adequately transported at the rate required to meet physiological demands. Furthermore, PBMCs derived from patients with SLE who impaired basal and maximal respiration that is comparable with healthy PBMCs treated potent iron chelation. This suggests that abnormal iron metabolism may in turn limit mitochondrial energy metabolism in SLE and represents a potential future therapeutic target.

Immunological characteristics and clinical significance of urinary CD11c+ macrophages in lupus nephritis

Abstract Kidney-infiltrating immune cells may be involved in the pathogenesis of lupus nephritis (LN). We aimed to analyse the immunological characteristics and clinicopathologic relevance of urinary CD11c+ macrophages in patients with LN. Compared with patients with no LN or non-proliferative LN, those with proliferative LN had significantly higher urinary levels of CD11c+ macrophages, which were strongly correlated with their anti-dsDNA antibody titer. Urinary CD11c+ macrophages expressed pro-inflammatory cytokines, such as interleukin (IL)-6 and IL-1β, and resembled infiltrated monocytes rather than tissue-resident macrophages in terms of surface marker expression. They showed high expression of the chemokine receptor CXCR3, whose cognate chemokine IP-10 was expressed by urinary tubular epithelial cells (TECs). When treated with sera from systemic lupus erythematosus patients, peripheral monocytes acquired the morphological and functional properties of urinary CD11c+ macrophages, which was blocked by DNase treatment. Finally, SLE sera treated monocytes induced fibronectin expression, apoptosis, and cell detachment in HK-2 cells via IL-6 production. Importantly, the number of urinary CD11c+ macrophages was significantly associated with chronicity indices, including tubular atrophy and interstitial fibrosis, and renal response in LN patients. CD11c+ macrophages may be involved in the pathogenesis of tubulointerstitial damage in LN.

Serum levels of soluble programmed cell death protein 1 and soluble programmed cell death protein ligand 2 are increased in systemic lupus erythematosus and associated with the disease activity.

Programmed cell death protein 1 (PD-1) pathway plays important roles in systemic lupus erythematosus (SLE). We aimed to elucidate the association of serum soluble PD-1 (sPD-1) and related molecules with SLE and to explore their usefulness as biomarkers. We retrospectively measured the serum levels of sPD-1, soluble PD-ligand 1 (sPD-L1), soluble PD-ligand 2 (sPD-L2) and interleukin (IL)-21 by ELISA in SLE patients, systemic sclerosis patients and healthy controls. Repeat sera samples were also obtained post treatment. The serum levels of sPD-1 and sPD-L2 in SLE patients with high disease activity were significantly higher than those in SLE patients with low disease activity, systemic sclerosis patients and healthy controls (n = 58, 15, 20 and 21, respectively; p < 0.001). However, the serum levels of sPD-L1 and IL-21 were not elevated in SLE patients. The serum levels of sPD-1 and sPD-L2 were higher among active SLE patients who tested positive for anti-dsDNA antibodies than in those who tested negative (p = 0.002 and <0.001, respectively). There were moderate correlations between the serum levels of sPD-1 and sPD-L2 and the SLE Disease Activity Index 2000 scores, the titres of anti-dsDNA antibodies and the serum levels of complements. Furthermore, the serum levels of sPD-1 and sPD-L2 decreased significantly in accordance with disease amelioration following treatment (p < 0.001). The present study demonstrated the association of serum sPD-1 and sPD-L2 with SLE and suggests their usefulness as disease activity biomarkers for SLE.

Angiotensin II receptor agonist antibodies are associated with microvascular damage in lupus nephritis.

Angiotensin II type 1 receptor agonist antibodies (AT1R-AAs) have been associated with hypertension, atherosclerosis and vascular inflammation in human diseases. The aim of the study was to evaluate the prevalence of AT1R-AAs in active lupus nephritis (LN) patients and their association with vascular damage. One hundred and seven active LN patients underwent a complete clinical examination, measurement of AT1R-AAs, ambulatory blood pressure monitoring, carotid intima-media thickness measurement and morphometric analysis of subintimal fibrosis and medial hyperplasia of the vessels in the kidney tissue. Plasma AT1R-AAs were positive in 58 (54.2%) patients. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, complement C3 and C4 levels and titers of anti-dsDNA antibodies were higher in the group with positive AT1R-AAs compared with those with negative AT1R-AAs. The AT1R-AA titers correlated with anti-dsDNA antibody titers and with complement C3 and C4 serum levels. In the kidney biopsy, the percentage of subintimal fibrosis and the area of medial hyperplasia were greater in the AT1R-AA-positive patients. No differences in arterial pressure, carotid intima-media thickness and response to therapy were detected. In conclusion, AT1R-AAs are prevalent in active LN patients and are associated with histologic features of microvascular damage.

The additive effects of hydroxychloroquine to maintenance therapy with standard of care in patients with systemic lupus erythematosus.

In this retrospective study, the effect of hydroxychloroquine (HCQ) added to maintenance therapy according to the standard of care (SoC) was evaluated for 1year in 101 patients with systemic lupus erythematosus (SLE). The primary endpoint was the SLE Disease Activity Index (SLEDAI). The secondary endpoints were the British Isles Lupus Assessment Group index, serum complement activity (CH50) levels, anti-double-stranded DNA (dsDNA) antibody titer, concomitant corticosteroid (CS) dose, and Systemic Lupus International Collaborating Clinics (SLICC) damage index. These variables were compared between the SoC+HCQ (n=42) and SoC (n=59) groups. The SLEDAI improved from 2 (0, 6) to 0 (0, 4) in the SoC+HCQ group (P = .038) but significantly deteriorated from 1 (0, 4) to 2 (0, 8) in the SoC group (P = .033). CH50, anti-dsDNA antibody titer, concomitant CS dose, and SLICC damage index did not significantly change. The increase in the SLEDAI and concomitant CS dose after 1year were all significantly greater in the SoC group, and the proportion of patients with SLEDAI flare was significantly lower in the SoC+HCQ group (SoC+HCQ: 4.76% vs SoC: 25.4%, P=.006). Univariate logistic regression analyses identified HCQ as a predictive factor for no SLEDAI flare (P=.003, odds ratio 6.81, 95% confidence interval 1.77-45.00). The use of HCQ effectively improved SLEDAI scores and was a predictive factor for the prevention of SLEDAI flare. Therefore, HCQ may be considered a potential mainstay of maintenance therapy.

Clinicopathologic characteristics and outcomes of lupus nephritis with positive antineutrophil cytoplasmic antibody

Aims The aim was to determine whether anti-neutrophil cytoplasmic antibody (ANCA)-positive serology in patients with lupus nephritis (LN) is associated with different clinicopathologic features and outcomes. Methods In our retrospective analysis, 283 patients were enrolled between 2013 and 2018. Thirty-six patients were ANCA-positive, and this group was compared with the remaining 247 patients who were confirmed as ANCA-negative at the time of biopsy. Results ANCA-positive LN patients exhibited higher anti-dsDNA antibody titers and serum creatinine levels and lower serum hemoglobin concentrations than ANCA-negative LN patients. On pathological evaluation, segmental endocapillary hypercellularity observed by light microscopy was significantly more common in the ANCA-positive group. This feature was not significantly different in the treatment group, but the response to treatment was significantly different, as was remission (76.1% vs 69.4%, p < 0.001), between the ANCA-negative and ANCA-positive groups. During follow-up, the times to renal replacement therapy (RRT) and death were significantly different between the two unmatched groups (chi-square test, p = 0.041). Multivariate Cox analysis revealed that neurological disorders, ANCA positivity, and the chronicity index (CI) remained independent risk factors for patient survival. Pulmonary infection was the main cause of death and was most often due to fungal infection. Conclusion ANCA-positive LN patients typically exhibited higher anti-dsDNA antibody titers, lower serum hemoglobin concentrations and worse renal function than ANCA-negative LN patients. Fungal infection was the main cause of death. We observed that ANCA positivity was an independent risk factor for patient survival.

Efficacy and safety of bortezomib in refractory lupus nephritis: a single-center experience.

Resistant lupus nephritis (LN) has been associated with the persistence of long-lived plasma cells. Preliminary studies identified bortezomib as a potential treatment option for patients with refractory LN. The aim of this study was to analyze the efficacy and safety of bortezomib in the treatment of severe refractory LN. This retrospective study included 12 female patients diagnosed for the first time with class IV or IV/V LN with acute or rapidly progressive kidney injury (n = 11) and/or severe nephrotic syndrome (n = 1) who showed resistance to induction therapy with cyclophosphamide, steroids, mycophenolate, and rituximab, and were treated with either intravenous or subcutaneous bortezomib plus intravenous dexamethasone. All patients with acute or rapidly progressive kidney injury showed a significant reduction in both biochemical and immunological activity after a mean of 6 (minimum 5, maximum 7) weekly cycles of bortezomib regimen, with a significant increase in C3 levels and a significant decrease of anti-ds DNA antibody titers, Systemic Lupus Erythematosus Disease Activity Index score, serum creatinine, and proteinuria. One patient (8.3%) achieved a complete response, and 10 patients (83.4%) achieved a partial response. During follow-up, all these patients maintained partial responses under treatment with mycophenolate and low-dose glucocorticoids. The patient with refractory nephrotic syndrome showed a partial response but relapsed 11 months after the end of bortezomib treatment and was resistant to treatment. A significant decrease in serum IgG levels after initiation of bortezomib treatment was observed in all patients, five of them (41.6%) showed hypogammaglobulinemia (<500 mg/dl), but no patient suffered from opportunistic infections; in only two patients (16.6%) hypogammaglobulinemia persisted at the end of follow-up. Two patients (16.6%) suffered from sensory neuropathy, which led to bortezomib treatment discontinuation. Bortezomib may be an effective option for refractory LN, but close monitoring must be performed for possible adverse events such as peripheral neuropathy and hypogammaglobulinemia.

PKN1 kinase-negative knock-in mice develop splenomegaly and leukopenia at advanced age without obvious autoimmune-like phenotypes

Protein kinase N1 (PKN1) knockout (KO) mice spontaneously form germinal centers (GCs) and develop an autoimmune-like disease with age. Here, we investigated the function of PKN1 kinase activity in vivo using aged mice deficient in kinase activity resulting from the introduction of a point mutation (T778A) in the activation loop of the enzyme. PKN1[T778A] mice reached adulthood without external abnormalities; however, the average spleen size and weight of aged PKN1[T778A] mice increased significantly compared to aged wild type (WT) mice. Histologic examination and Southern blot analyses of spleens showed extramedullary hematopoiesis and/or lymphomagenesis in some cases, although without significantly different incidences between PKN1[T778A] and WT mice. Additionally, flow cytometry revealed increased numbers in B220+, CD3+, Gr1+ and CD193+ leukocytes in the spleen of aged PKN1[T778A] mice, whereas the number of lymphocytes, neutrophils, eosinophils, and monocytes was reduced in the peripheral blood, suggesting an advanced impairment of leukocyte trafficking with age. Moreover, aged PKN1[T778A] mice showed no obvious GC formation nor autoimmune-like phenotypes, such as glomerulonephritis or increased anti-dsDNA antibody titer, in peripheral blood. Our results showing phenotypic differences between aged Pkn1-KO and PKN1[T778A] mice may provide insight into the importance of PKN1-specific kinase-independent functions in vivo.

Urinary podocyte microparticles are associated with disease activity and renal injury in systemic lupus erythematosus

BackgroundNew non-invasive biomarkers are demanded to identify renal damage in various autoimmune-associated kidney diseases. Glomerular podocyte damage mediated by systemic lupus erythematosus (SLE) plays an important role in the pathogenesis and progression of lupus nephritis (LN). This study evaluated whether the podocyte-derived microparticles (MPs) were novel biomarkers of clinical and histological features in SLE patients with LN.MethodsA cross-sectional study, including 34 SLE patients and 16 healthy controls, was designed. Urinary annexin V+ podocalyxin+ MPs of all participants were quantified by flow cytometry. The correlation of podocyte-derived MPs with clinical and histological parameters of SLE patients was analysed.ResultsThe number of annexin V+ podocalyxin+ MPs from urine samples were markly increased in patients with SLE. Furthermore, the level of urinary podocyte-derived MPs was positively correlated with the SLE Disease Activity Index (SLEDAI) score, anti-dsDNA antibody titre, erythrocyte sedimentation rate, and proteinuria. Conversely, it was negatively correlated with the level of complement C3 and serum albumin. The number of urinary podocyte-derived MPs was significantly increased in SLE patients with high activity indices. Receiver operating characteristic (ROC) curves were calculated to assess the power for podocyte-derived MP levels in differentiating between SLE patients with and without LN. Podocyte-derived MP levels were able to differentiate between SLE patients with mild disease activity, as well as those with moderate and above disease activity. SLE patients showed increased podocyte-derived MP excretion into the urine.ConclusionsThese findings suggest that the change in urinary podocyte-derived MP levels could be useful for evaluating and monitoring SLE disease activity.

Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation

RIP3 activation leads to activation of necroptosis and the NLRP3 inflammasome pathways. The activation of RIP3 in lupus nephritis (LN) has not been investigated. In this study, RIP3 and necroptosis pathway activations were demonstrated in podocytes in renal biopsies from patients with class IV LN and in the diseased kidneys from lupus-prone NZM2328 and MRL/lpr mice. RIP3 activation was accompanied with the activation of MLKL, the effector molecule of the necroptosis pathway, and activation of caspase-1, the effector of the NLRP3 inflammasome pathway. Podocyte activation of RIP3 was detected readily with the development of LN in NZM2328 mice, suggesting this activation may play a significant role in the pathogenesis of LN. GSK872, a RIP3 specific inhibitor, inhibited the development of LN in MRL/lpr mice with down-regulation of RIP3 activation in podocytes, decreased the splenic sizes and weights and anti-dsDNA antibody titers. IgG from pooled sera of diseased NZM2328 mice succumbing to LN induced both the necroptosis pathway and NLRP3 inflammasome activation in a podocyte cell line and this activation was specifically blocked by GSK872. These results indicate that the necroptosis pathway and the RIP3 dependent NLRP3 inflammasome pathway are activated in podocytes during LN. Inhibition of RIP3 kinase may be a novel therapeutic approach to treat LN and systemic lupus erythematosus (SLE).

Use of Intravenous Immunoglobulin Therapy at Unconventional Doses in Refractory Fulminant Systemic Lupus Erythematosus.

The use of human intravenous immunoglobulins (IVIg) in systemic lupus erythematosus (SLE) currently relies on evidence from small case series and is mainly regarded as an off-label strategy in cases that are refractory to conventional therapies or poorly controlled with high doses of corticosteroids. Standard dosage regimens typically entail the administration of a total amount of 2 g/kg of IVIg divided into five consecutive days in order to minimize the risk of severe adverse events. We herein describe the case of a 28-year-old woman with a known history of antiphospholipid syndrome (APS) who was admitted to our hospital following fulminant onset of SLE in spite of ongoing immunosuppressive therapy. Acute renal insufficiency with nephrotic-range proteinuria, central nervous system involvement, severe thrombocytopenia, malar rash, pancreatic injury and moderate-severe aortic valve steno-insufficiency were the most prominent clinical manifestations, along with high titres of anti-dsDNA antibodies. Pulses of methyl-prednisolone followed by high-dose corticosteroids proved ineffective. Strikingly, IVIg therapy delivered at unconventional doses (1.2 g/kg) due to the presence of multiple risk factors for adverse events resulted in a significant, comprehensive clinical improvement. Although large-scale randomized double-blind studies are needed, the use of IVIg might constitute a valuable therapeutic modality as a last-resort strategy in cases of fulminant SLE. The total dose of immunoglobulins should be dictated by the clinical response as well as the presence of pre-existing risk factors for adverse events.LEARNING POINTSThe use of immunoglobulins in the treatment of systemic lupus erythematosus is mainly based on small prospective studies and case series.Their use as a rescue strategy in cases of systemic lupus erythematosus that are refractory to conventional immunosuppressive therapy may be a valid therapeutic alternative in selected patients.The short-term clinical response and the presence of risk factors for adverse effects should dictate the overall dose of immunoglobulins administered to the patient.

Evaluating duration of response to treatment in systemic lupus erythematosus clinical trials

ObjectiveTo evaluate response duration and identify predictors of transitioning into and out of the response state in patients with SLE receiving standard of care (SoC) in 52-week clinical trials.MethodsA multistate...

Macrophage activation syndrome in adult systemic lupus erythematosus: report of seven adult cases from a single Italian rheumatology center.

The aim was to describe the macrophage activation syndrome (MAS), a life-threatening syndrome characterized by excessive immune activation that can be triggered by conditions affecting immune homeostasis, in a cohort of adult Italian patients with systemic lupus erythematosus (SLE). This was a monocentric retrospective evaluation. The utility of the H-score, developed to estimate the individual risk of having reactive MAS in adult patients, was assessed. Among 511 patients with SLE, 7 cases (1.4%) of MAS (all females) were identified and their medical records reviewed. In all cases, MAS was simultaneous to the onset of SLE. All patients had fever, lymphadenopathy, hematological involvement, and high titer of anti-dsDNA antibodies. Workup for infections and malignancies was negative. In all cases, the H-score was higher than the cut-off suggested for the classification of reactive MAS. All cases required hospital admission, and 2 patients were admitted to the intensive care unit. Most patients were treated successfully with high doses of corticosteroids and with immunosuppressive drugs, whereas the full therapeutic regimen developed for primary hemophagocytic lymphohistiocytosis HLH was used only in one case. No death from MAS was observed. MAS is a rare and severe disorder that complicated the onset of SLE in our cohort. The H-score may be useful in the classification of these patients.

Wpływ wybranych cytokin na uszkodzenie narządów w toczniu rumieniowatym układowym

ABSTRAKTToczeń rumieniowaty układowy (TRU) jest chorobą reumatyczną o nie w pełni poznanej patogenezie. W przebiegu tej choroby występuje dysfunkcja układu immunologicznego polegająca na wytwarzaniu autoprzeciwciał i odkładaniu się kompleksów immunologicznych, które przyczyniają się do uszkodzeń różnych narządów. Najczęściej zajęte narządy to: nerki, skóra, układ ruchu, narząd wzroku, układ oddechowy, układ sercowo-naczyniowy oraz nerwowy, zarówno ośrodkowy, jak i obwodowy. W ostatnich latach pojawiły się doniesienia dotyczące roli cytokin w patogenezie zajęcia różnych narządów. Jednakże do tej pory nie jest w pełni jasne, które cytokiny są odpowiedzialne za nasilenie, a które za zmniejszenie odpowiedzi zapalnej, co mogłoby pomóc w ustaleniu związku z obrazem klinicznym. W artykule zestawione zostały doniesienia dotyczące Interleukin (IL) 4, 7, 10, 18 oraz ich związku z zajęciem narządowym w przebiegu TRU. W przypadku IL-4 wskazuje się na ochronną rolę tej cytokiny poprzez zapobieganie rozwojowi odpowiedzi autoimmunologicznej, z kolei IL-7 przypisuje się udział w rozwoju autoreaktywnych klonów limfocytów T oraz rozwoju choroby. Natomiast IL-10, pomimo swojego ochronnego działania, występuje u chorych na TRU w znacznie wyższych stężeniach niż w populacji ogólnej i koreluje ze stopniem aktywności choroby wyrażonej za pomocą skali SLEDAI. Działanie prozapalne ma IL-18, co przyczynia się w konsekwencji do uszkodzenia tkanek i narządów. W surowicy chorych na TRU stwierdza się znacznie wyższe stężenie IL-18 niż w grupie kontrolnej, ponadto wykazano statystycznie istotną dodatnią korelację pomiędzy stężeniem IL-18 w surowicy chorych a stopniem aktywności choroby mierzonym za pomocą skali SLEDAI oraz mianem przeciwciał anty-dsDNA. Wzrastające stężenie IL-18 w surowicy chorych na TRU jest związane ze wzrostem ryzyka sercowo-naczyniowego. Dodatkowo IL-18 przypisuje się rolę w zajęciu nerek oraz skóry u chorych na TRU.

Multicenter double-blind randomized controlled trial to evaluate the effectiveness and safety of bortezomib as a treatment for refractory systemic lupus erythematosus

Objectives: The objective of this study is to evaluate the efficacy and safety of bortezomib for treating systemic lupus erythematosus (SLE), in patients whose disease activity could not be controlled.Methods: Fourteen SLE patients with persistent disease activity were selected, who required prednisolone doses of >10 mg/d despite concomitant immunosuppressive therapy. Patients were randomly administered either bortezomib or a placebo, eight times. The primary and secondary end-points were a change in anti-dsDNA antibody titer at week 24 and the SLE Responder Index (SRI), respectively.Results: In the bortezomib group, four out of eight patients discontinued the trial; three others failed to complete the minimum protocol treatment due to adverse reactions. The changes in anti-dsDNA antibody titers at week 24 were 4.24% and −1.96%, for the bortezomib and placebo groups, respectively, disconfirming bortezomib’s efficacy. In contrast, the corresponding SRI at week 12 was 75% and 40%.Conclusions: As bortezomib therapy for SLE is associated with many adverse reactions, treatment indications should be selected carefully, and protocols should aim to prevent these occurrences. Although the change in anti-dsDNA antibody titer did not support the efficacy of bortezomib as a treatment for SLE, high SRI in the treatment group suggests bortezomib may utilize mechanisms other than inhibition of anti-dsDNA antibody production.