Quiescent Systemic Lupus Erythematosus Research Articles

Active but not quiescent lupus nephritis during pregnancy is associated with a higher rate of adverse obstetric outcomes: Analysis of a prospective cohort.

To compare the maternal-fetal/neonatal outcome in patients with systemic lupus erythematosus (SLE) with and without lupus nephritis (LN) in remission or with active disease. A prospective cohort of pregnant patients with SLE (ACR 1997 criteria) was studied from January 2009 to December 2021. Demographic, clinical, biochemical, and immunological variables as well as the usual maternal-fetal/neonatal complications were recorded. We compared four groups according to the status of SLE during pregnancy: patients with quiescent SLE without lupus nephritis, patients with active SLE without lupus nephritis, patients with quiescent lupus nephritis, and patients with active lupus nephritis. Statistical analysis included descriptive statistics, bivariate analysis, and Cox regression analysis. A total of 439 pregnancies were studied, with a median age of 28 ± 6, SLE duration of 60 months (interquartile range 36-120). A higher frequency of maternal and fetal/neonatal complications was observed in patients with active SLE with or without lupus nephritis. Multivariate analysis showed that active LN was a risk factor for gestational hypertension (hazard ratios [HR] 1.95; 95% confidence intervals [CI]: 1.01-6.39), premature rupture of membranes (HR 3.56; 95% CI: 1.79-16.05) and more frequent cesarean section (HR 1.82; 95% CI: 1.13-2.94). LN is associated with a higher frequency of maternal complications, especially in those patients with active disease during pregnancy, and those maternal complications had an impact on poor fetal/neonatal outcomes. Strict control and timely care of LN could improve the obstetric prognosis.

Different Immunologic Profiles Are Associated With Distinct Clinical Phenotypes in Longitudinally Observed Patients With Systemic Lupus Erythematosus.

The aim of this study was to determine the immunologic profile associated with disease flares in patients with systemic lupus erythematosus (SLE) and to investigate the clinical significance of any differences observed between patients during and following a flare. Multiparameter flow cytometry was used to examine 47 immune populations within the peripheral blood of 16 healthy controls, 25 patients with clinically quiescent SLE, and 46 patients with SLE experiencing a flare at baseline and at 6- and 12-month follow-up visits. Unsupervised clustering was used to identify patients with similar immune profiles and to track changes over time. Parametric or nonparametric statistics were used when appropriate to assess the association of cellular phenotypes with clinical and laboratory parameters. Five clusters of patients were identified that variably contained patients with active and quiescent SLE, and that had distinct clinical phenotypes. Patients characterized by increased T peripheral helper, activated B, and age-associated B cells were the most likely to be flaring at baseline, as well as the most likely to remain active or flare over the subsequent year if they acquired or retained this phenotype at follow-up. In contrast, patients who had increased T helper (Th) cells in the absence of B cell changes, or who had increased Th1 cells and innate immune populations, mostly developed quiescent SLE on follow-up. A significant proportion of patients with SLE had depletion of many immune populations at flare and only showed increases in these populations post-flare. Cellular phenotyping of patients with SLE reveals several distinct immunologic profiles that may help to stratify patients with regard to prognosis and treatment.

Histone-Specific CD4+ T Cell Plasticity in Active and Quiescent Systemic Lupus Erythematosus.

The aim of this study was to assess whether circulating histone-specific T cells represent tools for precision medicine in systemic lupus erythematosus (SLE). Seroprevalence of autoantibodies and HLA-DR beta (DRB) 1 profile were assessed among 185 patients with SLE and combined with bioinformatics and literature evidence to identify HLA-peptide autoepitope couples for ex vivo detection of antigen-specific T cells through flow cytometry. T cell differentiation and polarization was investigated in patients with SLE, patients with Takayasu arteritis, and healthy controls carrying HLA-DRB1*03:01 and/or HLA-DRB1*11:01. SLE Disease Activity Index 2000 and Lupus Low Disease Activity State were used to estimate disease activity and remission. Histone-specific CD4+ T cells were selectively detected in patients with SLE. Among patients with a history of anti-DNA antibodies, 77% had detectable histone-specific T cells, whereas 50% had lymphocytes releasing cytokines or upregulating activation markers after in vitro challenge with histone peptide antigens. Histone-specific regulatory and effector T helper (Th) 1-, Th2-, and atypical Th1/Th17 (Th1*)-polarized cells were significantly more abundant in patients with SLE with quiescent disease. In contrast, total Th1-, Th2-, and Th1*-polarized and regulatory T cells were similarly represented between patients and controls or patients with SLE with active versus quiescent disease. Histone-specific effector memory T cells accumulated in the blood of patients with quiescent SLE, whereas total effector memory T cell counts did not change. Immunosuppressants were associated with expanded CD4+ histone-specific naive T (TN) and terminally differentiated T cells. Histone-specific T cells are selectively detected in patients with SLE, and their concentration in the blood varies with disease activity, suggesting that they represent innovative tools for patient stratification and therapy.

Biomarkers of Oxidative Stress in Systemic Lupus Erythematosus Patients with Active Nephritis.

Oxidative stress plays an important role in systemic lupus erythematosus (SLE) and especially in lupus nephritis (LN). The aim of this study was to compare redox-related biomarkers between patients with active LN, quiescent SLE (Q-SLE) and healthy controls (HC) and to explore their association with clinical characteristics such as disease activity in patients. We investigated levels of plasma free thiols (R-SH, sulfhydryl groups), levels of soluble receptor for advanced glycation end products (sRAGE) and levels of malondialdehyde (MDA) in SLE patients with active LN (n = 23), patients with quiescent SLE (n = 47) and HC (n = 23). Data of LN patients who previously participated in Dutch lupus nephritis studies and longitudinal samples up to 36 months were analyzed. Thiol levels were lower in active LN at baseline and Q-SLE patients compared to HC. In generalized estimating equation (GEE) modelling, free thiol levels were negatively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) over time (p < 0.001). sRAGE and MDA were positively correlated with the SLEDAI over time (p = 0.035 and p = 0.016, respectively). These results indicate that oxidative stress levels in LN patients are increased compared to HC and associated with SLE disease activity. Therefore, interventional therapy to restore redox homeostasis may be useful as an adjunctive therapy in the treatment of oxidative damage in SLE.

Soluble Receptor Level of Advanced Glycation (sRAGE) Products in Serum in Patients with Systemic Lupus Erythematosus:

Objectives: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by antibody formation against nuclear autoantigens. A receptor for Advanced Glycation (RAGE) is produced by many immune system cells, such as neutrophils, macrophages, and T cells, and interacts with many classes of ligands. In light of these results, the level of sRAGE, the soluble form of RAGE, may be associated with disease activity. In light of this information, we aimed to evaluate whether there is a relationship between plasma sRAGE levels and SLE. Materials and Methods: Eighteen patients diagnosed with SLE (M/F: 1/17) and twenty-one patients without any disease diagnosis (M/F: 2/19) were included as the control group. In these patients, plasma sRAGE level was measured by ELIZA method using an ELIZA (enzyme-linked immunosorbent assay) kit (BioVendor Research and Diagnostic Products). The data obtained were compared between the groups. Results: The mean plasma sRAGE level was lower in patients with SLE than in healthy control patients but not statistically significant (p=0.966). Our study found a positive correlation between SLEDAI and sRAGE levels in patients with SLE (r=0.628, p=0.005). Although no significant correlation was found between patients with SLE, sRAGE levels were positively correlated between fourteen patients classified as active SLE and the control group. Conclusions: In our study, we found that plasma sRAGE levels in patients with SLE were lower than in healthy controls, but plasma sRAGE levels in patients with active SLE were higher than plasma sRAGE levels in patients with inactive SLE. We hypothesized that reduced sRAGE levels in patients with SLE could be explained by the depletion of this soluble receptor. Our study differed from another similar study showing that blood sRAGE levels were higher in patients with SLE than in healthy controls. Blood sRAGE levels were significantly increased during active disease compared with patients with quiescent SLE.

Why lupus patients discontinue antimalarials in real life: A 50 years-experience from a reference centre.

Because of the efficacy and good safety profile of antimalarials in systemic lupus erythematosus (SLE), hydroxychloroquine (HCQ) is currently recommended in all SLE patients. However, patients' compliance was reported as suboptimal. This study aims to elucidate the reasons for discontinuing antimalarials in a large series of SLE patients followed in a single centre during the last 50years. Among all patients diagnosed between 1968 and 2017 at our reference centre, retrospective data were obtained from electronic medical records of SLE patients consecutively visited during 2015-2017 and controlled for at least 1year. Demographic, clinical, laboratory and therapeutic data at disease onset and during the follow-up in the whole cohort and differences between SLE patients discontinuing and continuing on antimalarials were analysed. Five-hundred thirty-nine patients followed during a median of 19years were analysed. Median age at disease diagnosis was 29years and 91.8% were women. Antimalarials were initiated by 521 (96.7%) patients and 18 (3.3%) cases did not start them mainly because of a quiescent or life-threatening SLE disease. In the 129 (24.7%) patients starting antimalarials with subsequent discontinuation, median treatment duration was 8.4 years. The main reason leading to treatment cessation was drug toxicity in 97 (18.6%) patients, of which macular toxicity was the most frequent adverse effect (n = 80; 15.3%). Treatment was stopped because of patient's preference in 13 (2.5%) cases. The factors independently associated with antimalarial discontinuation were age at the end of follow-up (OR 1.130, 95% CI 1.005-1.269, p = 0.040), duration on antimalarials (OR 0.872, 95% CI 0.841-0.903, p < 0.001), presence of hepatitis C virus infection (HCV) (OR 13.948, 95% CI 1.321-147.324, p = 0.028) and anti-β2-glycoprotein 1 antibodies (OR 2.275, 95% CI 1.146-4.517, p = 0.019). In our 50 years-experience, almost all SLE patients underwent antimalarials. These drugs are usually stopped because of adverse effects, particularly macular toxicity. After a long-term follow-up, patients' compliance to antimalarials was considerably high in our SLE patients.

Outcomes following antimalarial withdrawal in patients with quiescent systemic lupus erythematosus

ObjectiveAntimalarial medications (AMs) are central to the management of SLE. We investigated the rate of flare in lupus patients who withdrew AM after achieving clinical remission for at least one year, compared to those who continued therapy and compared flare rates in cases who tapered AM versus abruptly withdrew. MethodsCases achieved clinical remission for at least one year then ceased their AM. Index date was defined as the date of complete AM cessation. Controls achieved clinical remission for at least one year and continued AM. Controls were matched according to the duration of AM before remission and the duration of therapy from remission date to case index date. All patients had ≥ 2 years of follow up. ResultsOf 1573 patients on AM, 165 achieved a one-year remission and then ceased their AM. 96 had adequate follow-up, 88 were successfully matched to one control and 85 to 2 controls for a total of 173 controls. Flare occurred in 61.4% of cases and 45.1% of controls (p = 0.002). 52.3% patients who withdrew AM later restarted it due to disease flare. 88% recaptured control or improved, while 12% did not. Patients who tapered had significantly fewer flares (45.9% vs. 72.6%; p = 0.01). ConclusionAMs aid in preventing disease flare even in patients who have achieved prolonged clinical remission. Tapering AM results in lower flare rates. Hence, except in the setting of toxicity, cessation of antimalarial therapy in patients with prolonged disease quiescence is feasible using a slow taper.

Treatments and outcomes in Chinese patients with serologically active clinically quiescent systemic lupus erythematosus: a retrospective observational study

ObjectiveTo clarify the frequency and outcome of patients with systemic lupus erythematosus (SLE) who achieved the clinical state as serologically active clinically quiescent (SACQ) and to identify factors associated with the flare of disease.MethodsClinical data of patients diagnosed as SLE and followed in Peking University First Hospital from 2009 to 2015 were retrospectively reviewed. Six hundred eighty-two patients who were followed up for more than 6 months were analyzed. SACQ was defined as an at least a 6-month period with persistent serologic activity and without clinical activity and daily dose of prednisone or equivalent were less than 7.5 mg. Serologically quiescent clinically quiescent (SQCQ) patients served as control groups. Data including demographics, initial symptoms, duration to SACQ, treatments before and after SACQ, and characteristics of the patients suffered from flare were analyzed.ResultsAmong the 682 patients, 170 patients were SACQ (24.9%) and 187 patients were SQCQ. SQCQ patients (38.61 ± 15.08 years old) were older at baseline than SACQ patients (38.61 ± 15.08 years vs. 32.09 ± 14.35 years, p < 0.001). Of 170 SACQ patients, 32.9% experienced flare that was significantly higher than 15.5% of SQCQ patients (29/187). Corticosteroids (OR 1.323, 95% CI 1.129 to 1.550; p = 0.001) was an independent risk factor for flare, while antimalarials (OR 0.045, 95% CI 0.004 to 0.474; p = 0.010) and immunosuppressants (OR 0.332, 95% CI 0.156 to 0.706; p = 0.004) were protective factors in SACQ patients; however, only antimalarials was protective factors in SQCQ patients (OR 0.028, 95% CI 0.001 to 0.743; p = 0.033).ConclusionAbout one third of SLE patients with SACQ experience flare, significantly more frequent than that of patients with SQCQ. Thus, approach to prevent flare in SACQ patient is required. Maintenance therapy of hydroxychloroquine and immunosuppressant agents may be protective and beneficial treatment strategy in these patients.

Gradual Glucocorticosteroid Withdrawal Is Safe in Clinically Quiescent Systemic Lupus Erythematosus.

ObjectivesPatients with systemic lupus erythematosus (SLE) are usually treated with glucocorticosteroids even during periods of clinically quiescent disease. A recent study showed that abrupt glucocorticoid withdrawal was associated with an increased likelihood of flare in the next 12 months. The aim of the present study was to assess clinical flare rates and damage accrual in patients who tapered glucocorticosteroids gradually.MethodsPatients from the Toronto Lupus Clinic with 2 consecutive years of clinically quiescent disease were retrieved from the database. Individuals who maintained a low prednisone dose (5 mg/day) comprised the maintenance group, whereas patients who gradually tapered prednisone within these two years comprised the withdrawal group. All individuals were followed for 2 years after prednisone discontinuation or the corresponding date for the maintenance group. Propensity score matching was implemented to adjust for certain baseline differences. Outcomes included clinical flares and damage accrual.ResultsOf 270 eligible patients, 204 were matched (102 in each group). Flare rate (any increase in clinical SLE Disease Activity Index 2000) was lower in the withdrawal group both at 12 (17.6% versus 29.4%; P = 0.023) and 24 months (33.3% versus 50%; P = 0.01). Moderate to severe flares (requiring systemic treatment escalation) were not different at 12 months (10.8% versus 13.7%; P = 0.467) but were less frequent at 24 months (14.7% versus 27.5%; P = 0.024). Damage accrual was less frequent in the withdrawal group (6.9% versus 17.6%; P = 0.022). No predictors for clinical flares were identified.ConclusionGradual glucocorticoid withdrawal is safe in clinically quiescent SLE and is associated with fewer clinical flares and less damage accrual at 24 months.

Maternal and Fetal Outcomes in Systemic Lupus Erythematosus Pregnancies

To describe the maternal and fetal outcomes in systemic lupus erythematosus (SLE) pregnancies followed-up in a single tertiary referral centre. We performed a retrospective cohort study of 75 SLE pregnancies who were followed up in Singapore General Hospital over a 16-year period from 2000 to 2016. Adverse fetal and maternal outcomes including preterm delivery, miscarriages, fetal growth restriction, congenital heart block, neonatal lupus, pre-eclampsia and SLE flares were obtained from the medical records. The mean age at conception was 32 years old (SD 3.8). The mean SLE disease duration was 5.9 years (SD 5.2). The majority (88%) had quiescent SLE disease activity at baseline. Most pregnancies resulted in a live birth (74.7%). The mean gestational age at birth was 37.4 weeks (SD 3.4). Adverse fetal outcomes occurred in 53.3%. Preterm delivery (33.9%), miscarriages (20%) and fetal growth restriction (17.3%) were the most frequent adverse fetal outcomes. There was 1 neonatal death and SLE flares occurred in a third (33%). In the subgroup of SLE pregnancies with antiphospholipid syndrome, there were higher SLE flare rates (40%) and adverse fetal outcomes occurred in 8 pregnancies (80%). There were no predictive factors identified for all adverse fetal and maternal outcomes. In the subgroup analysis of preterm delivery, anti-Ro (SS-A) antibody positivity and hydroxychloroquine treatment were associated with a lower risk of preterm delivery. Although the majority had quiescent SLE disease activity at baseline, SLE pregnancies were associated with high rates of adverse fetal and maternal outcomes.

Discontinuation of hydroxychloroquine in older patients with systemic lupus erythematosus: a multicenter retrospective study

BackgroundAlthough hydroxychloroquine (HCQ) is a mainstay of treatment for patients with systemic lupus erythematosus (SLE), ocular toxicity can result from accumulated exposure. As the longevity of patients with SLE improves, data are needed to balance the risk of ocular toxicity and the risk of disease flare, especially in older patients with quiescent disease. Accordingly, this study was initiated to examine the safety of HCQ withdrawal in older SLE patients.MethodsData were obtained by retrospective chart review at three major lupus centers in New York City. Twenty-six patients who discontinued HCQ and thirty-two patients on HCQ matched for gender, race/ethnicity, and age were included in this study. The primary outcome was the occurrence of a lupus flare classified by the revised version of the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare composite index, within 1 year of HCQ withdrawal or matched time of continuation.ResultsFive patients (19.2%) in the HCQ withdrawal group compared to five (15.6%) in the HCQ continuation group experienced a flare of any severity (odds ratio [OR] = 1.28; 95% CI 0.31, 5.30; p = 0.73). There were no severe flares in either group. The results were similar after adjusting for length of SLE, number of American College of Rheumatology criteria, low complement levels, and SELENA-SLEDAI score, and in a propensity score analysis (OR = 1.18; 95% CI 0.23, 6.16; p = 0.84). The analysis of time to any flare revealed a non-significant earlier time to flare in the HCQ withdrawal group (log-rank p = 0.67). Most flares were in the cutaneous and musculoskeletal systems, but one patient in the continuation group developed pericarditis. The most common reason for HCQ withdrawal was retinal toxicity (42.3%), followed by patient’s preference (34.6%), other confirmed or suspected adverse effects (15.4%), ophthalmologist recommendation for macular degeneration (3.8%), and rheumatologist recommendation for quiescent SLE (3.8%).ConclusionsIn this retrospective study of older stable patients with SLE on long-term HCQ, withdrawal did not significantly increase the risk of flares.

Activity Disease in SLE Patients Affected IFN-γ in the IGRA Results.

PurposeHighly active systemic lupus erythematosus (SLE) causes a high risk of tuberculosis (TB) infection in SLE patients in Indonesia, a country in which the disease, especially extrapulmonary TB, is endemic. Interferon (IFN)-γ releasing assay (IGRA) can detect latent or previous TB infection. This study sought to determine latent TB infection and levels of IFN-γ, a key player in various inflammation and autoimmune disease, in patients with SLE and relate findings to disease activity.Patients and MethodsThis experimental study included 79 female subjects distributed into three groups of active SLE, quiescent SLE and healthy controls. We used SLE Disease Activity Index–2000 (SLEDAI-2K) scores to stratify the subjects. Each group underwent IGRA testing using the QuantiFERON-TB Gold Plus kit.ResultsWe recruited 59 female patients with SLE. The patients had a median age and disease duration 30 and 5 years, respectively. Statistical analysis using the Kruskal–Wallis test showed that active condition, high SLEDAI-2K score and immunosuppressive therapies affect IGRA results. Specifically, healthy controls (n=20) were most likely to have negative IGRA results (67.09%), whilst 27.27% of active cases (n=33) and 3.85% of quiescent cases (n=26) had indeterminate results (p=0.02). The number of immunosuppressant therapies was significantly negatively correlated with IFN-γ (p=0.004). No difference in IFN-γ concentration was detected amongst the active and other groups (p>0.05).ConclusionHigh-activity SLE and immunosuppressive therapies cause dysregulation of the immune response, which, in turn, influences IGRA results. Thus, additional testing is necessary to detect TB infection in patients with SLE.

Serum GlycA Level is Elevated in Active Systemic Lupus Erythematosus and Correlates to Disease Activity and Lupus Nephritis Severity.

Objective: Reliable non-invasive biomarkers are needed to assess disease activity and prognosis in patients with systemic lupus erythematosus (SLE). Glycoprotein acetylation (GlycA), a novel biomarker for chronic inflammation, has been reported to be increased in several inflammatory diseases. We investigated the relevance of serum GlycA in SLE patients exhibiting various levels of activity and severity, especially with regards to renal involvement. Methods: Serum GlycA was measured by nuclear magnetic resonance spectroscopy in samples from well characterized SLE patients and from both healthy controls and patients with other kidney diseases (KD). Disease activity was evaluated using the Systemic Lupus Erythematosus Activity Index 2000 (SLEDAI-2K). Renal severity was assessed by kidney biopsy. Results: Serum GlycA was elevated in active (n = 105) compared to quiescent SLE patients (n = 39, p < 10−6), healthy controls (n = 20, p = 0.009) and KD controls (n = 21, p = 0.04), despite a more severely altered renal function in the latter. GlycA level was correlated to disease activity (SLEDAI-2K, ρ = 0.37, p < 10−4), C-reactive protein, neutrophil count, triglyceride levels, proteinuria and inversely to serum albumin. In patients with biopsy-proven lupus nephritis (LN), GlycA levels were higher in proliferative (n = 26) than non-proliferative LN (n = 10) in univariate analysis (p = 0.04), and was shown to predict proliferative LN independently of renal parameters, immunological activity, neutrophil count and daily corticosteroid dosage by multivariate analysis (p < 5 × 10−3 for all models). In LN patients with repeated longitudinal GlycA measurement (n = 11), GlycA varied over time and seemed to peak at the time of the flare. Conclusions: GlycA, as a summary measure for different inflammatory processes, could be a valuable biomarker of disease activity in patients with SLE, and a non-invasive biomarker of pathological severity in the context of LN.

Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder and systemic autoimmune diseases overlap syndrome: a single-center experience

To describe the clinical and radiological characteristics and outcomes of patients with aquaporin-4-immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD) coexisting with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) in a single center. We included patients with diagnosis of NMOSD and a concomitant diagnosis of SLE or pSS. Demographic, clinical, serological and imaging characteristics were retrieved from clinical charts. Twelve patients were included, of whom 11 (91.7%) were women. Seven (58.3%) had SLE and five (41.7%) pSS. In five (41.7%) patients NMOSD followed SLE/pSS onset, four (33.3%) patients had a simultaneous presentation, and in three (25%) NMOSD preceded pSS onset. The mean age at first neurological event was 39 years. Eleven patients (91.7%) experienced acute transverse myelitis/longitudinally extensive transverse myelitis, five (41.7%) optic neuritis, three (25%) a cerebral syndrome and two (16.7%) each area postrema syndrome, acute brainstem syndrome and cerebellar syndrome. Eleven (91.7%) patients went into either total or partial NMOSD remission at median follow-up of 89.5 months. AQP4-IgG seropositive NMOSD arose in the context of quiescent SLE and pSS with extraglandular features. As NMOSD coexisting with SLE/pSS is rare, collaborative multicenter studies are needed to clarify the natural history and outcomes of this overlap syndrome.

Dysregulated interferon-γ and interleukin-2 synthesis in peripheral blood T cells in quiescent systemic lupus erythematosus is dependent on the affected T-cell receptor ζ chain expression.

Dysregulated interferon-γ and interleukin-2 synthesis in peripheral blood T cells in quiescent systemic lupus erythematosus is dependent on the affected T-cell receptor ζ chain expression.

Trib1 Is Overexpressed in Systemic Lupus Erythematosus, While It Regulates Immunoglobulin Production in Murine B Cells.

Systemic lupus erythematosus (SLE) is a severe and heterogeneous autoimmune disease with a complex genetic etiology, characterized by the production of various pathogenic autoantibodies, which participate in end-organ damages. The majority of human SLE occurs in adults as a polygenic disease, and clinical flares interspersed with silent phases of various lengths characterize the usual evolution of the disease in time. Trying to understand the mechanism of the different phenotypic traits of the disease, and considering the central role of B cells in SLE, we previously performed a detailed wide analysis of gene expression variation in B cells from quiescent SLE patients. This analysis pointed out an overexpression of TRIB1. TRIB1 is a pseudokinase that has been implicated in the development of leukemia and also metabolic disorders. It is hypothesized that Trib1 plays an adapter or scaffold function in signaling pathways, notably in MAPK pathways. Therefore, we planned to understand the functional significance of TRIB1 overexpression in B cells in SLE. We produced a new knock-in model with B-cell-specific overexpression of Trib1. We showed that overexpression of Trib1 specifically in B cells does not impact B cell development nor induce any development of SLE symptoms in the mice. By contrast, Trib1 has a negative regulatory function on the production of immunoglobulins, notably IgG1, but also on the production of autoantibodies in an induced model. We observed a decrease of Erk activation in BCR-stimulated Trib1 overexpressing B cells. Finally, we searched for Trib1 partners in B cells by proteomic analysis in order to explore the regulatory function of Trib1 in B cells. Interestingly, we find an interaction between Trib1 and CD72, a negative regulator of B cells whose deficiency in mice leads to the development of autoimmunity. In conclusion, the overexpression of Trib1 could be one of the molecular pathways implicated in the negative regulation of B cells during SLE.

Upregulation of CD16- monocyte subsets in systemic lupus erythematous patients.

Monocytes are an important component in the innate immune system. However, studies to date have failed to conclude whether their levels are altered in patients with systemic lupus erythematosus (SLE). We applied the cytodiff counting method and comprehensively measured the circulating levels of distinct white blood cell (WBC) subsets, including CD16+, CD16-, and total monocytes, in 61 SLE patients as well as in 203 age-matched healthy controls (HCs). The absolute number of CD16- monocytes, total monocytes, immature granulocytes, mature neutrophils, total neutrophils, and T cell blasts was significantly higher, that of non-cytotoxic T lymphocytes, cytotoxic T+NK lymphocytes, T+NK lymphocytes, total lymphocytes, basophils, and eosinophils significantly lower (all p<0.05), but that of CD16+ monocytes, B lymphocytes, B cell blasts, non-B and non-T cell blasts, and total blasts was not statistically different in SLE patients, as compared to HC. Specifically, among all subsets examined, the percentage of CD16- monocytes and total monocytes was the only one that could discriminate active SLE from quiescent SLE (p=0.033 and 0.026, respectively). SLE patients with lupus nephritis were also associated with higher levels of circulating CD16- monocytes and total monocytes, in comparison with that of controls (both p<0.0001). This study suggests the significance of distinct WBC subsets, particularly the differential regulations of monocyte subsets, in the pathogenesis and development of SLE.

Secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma: a case report

BackgroundHemophagocytic lymphohistiocytosis is a disease process characterized by unregulated hyperactivation of the immune system associated with multiorgan involvement and high mortality rates. Early recognition is crucial and a recently validated diagnostic schema, the H-Score, may facilitate diagnosis particularly in secondary hemophagocytic lymphohistiocytosis cases. We present a patient with secondary hemophagocytic lymphohistiocytosis in association with metastatic renal cell carcinoma in whom high-dose steroid therapy induced a remarkable response.Case presentationA 35-year-old Vietnamese man with quiescent systemic lupus erythematosus was diagnosed 5 months prior to admission with left-sided renal cell carcinoma metastatic to the pancreas and spine. Ten days prior to admission, a febrile illness (temperatures to 39 °C) associated with flu-like symptoms unresponsive to levofloxacin developed. He took only two doses of pazopanib prior to admission. High fevers unresponsive to antimicrobial therapy, cytopenias, disseminated intravascular coagulation, and progressive multiorgan failure led to intubation and intensive care unit stay. Extensive infectious disease workup showed only negative results, but elevation of interleukin-2 receptor, exceedingly high ferritin levels and other features earned an H-Score of 302, consistent with >99% diagnostic probability for secondary hemophagocytic lymphohistiocytosis. High-dose steroid therapy produced a rapid clinical and biochemical response.ConclusionsHemophagocytic lymphohistiocytosis is a life-threatening disorder which is likely to be under-recognized. Increased awareness of this disease entity and its diagnosis is crucial toward early recognition and treatment. To our knowledge, our patient is only the second reported with secondary hemophagocytic lymphohistiocytosis occurring in the setting of renal cell carcinoma.

Defective DNA repair and chromatin organization in patients with quiescent systemic lupus erythematosus.

BackgroundExcessive autoantibody production characterizing systemic lupus erythematosus (SLE) occurs irrespective of the disease’s clinical status and is linked to increased lymphocyte apoptosis. Herein, we tested the hypothesis that defective DNA damage repair contributes to increased apoptosis in SLE.MethodsWe evaluated nucleotide excision repair at the N-ras locus, DNA double-strand breaks repair and apoptosis rates in peripheral blood mononuclear cells from anti-dsDNA autoantibody-positive patients (six with quiescent disease and six with proliferative nephritis) and matched healthy controls following ex vivo treatment with melphalan. Chromatin organization and expression levels of DNA repair- and apoptosis-associated genes were also studied in quiescent SLE.ResultsDefective nucleotide excision repair and DNA double-strand breaks repair were found in SLE, with lupus nephritis patients showing higher DNA damage levels than those with quiescent disease. Melphalan-induced apoptosis rates were higher in SLE than control cells and correlated inversely with DNA repair efficiency. Chromatin at the N-ras locus was more condensed in SLE than controls, while treatment with the histone deacetylase inhibitor vorinostat resulted in hyperacetylation of histone H4, chromatin decondensation, amelioration of DNA repair efficiency and decreased apoptosis. Accordingly, genes involved in DNA damage repair and signaling pathways, such as DDB1, ERCC2, XPA, XPC, MRE11A, RAD50, PARP1, MLH1, MLH3, and ATM were significantly underexpressed in SLE versus controls, whereas PPP1R15A, BARD1 and BBC3 genes implicated in apoptosis were significantly overexpressed.ConclusionsEpigenetically regulated functional abnormalities of DNA repair machinery occur in SLE, regardless of clinical disease activity, and may promote lymphocyte apoptosis. Approaches to correct these abnormalities may be of therapeutic value in SLE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1081-3) contains supplementary material, which is available to authorized users.

Can pregnancy induce relapse in systemic lupus erythematosus (SLE)?

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which mostly affects women of reproductive age. We evaluated the impact of pregnancy on maternal/fetal health, the pattern of organ involvements and the fare-up risk. Methods: In a retrospective study we studied the thirty-year medical records of patients between 1976-2005. Maternal, neonatal and infantile health data was retrieved. Incidence of flare-ups, pattern of organ involvements and the outcome of pregnancy was analyzed. Results: We studied 155 pregnancies in 129 SLE patients. Mean age of patients was 27.0 ± 5.5 years (range, 16-44). Thirty one cases (20.2%) experienced flares in the course of pregnancy. During pregnancy, SLE disease activity index (SLEDAI) score increased in 92 (59.3%) patients (median increase = 6 scores). On the other hand, 38 cases (24.5%) SLEDAI score remained unaltered and in 25 cases (16.1%) SLEDAI score decreased (median decrease = 1). Mean SLEDAI during pregnancy were significantly higher than preconceptional scores (P-value = 0.002).Term delivery was more common in quiescent SLE (54.2% vs. 34.6%, P-value = 0.04). Number of therapeutic abortions was higher in active SLE (38.5% vs. 10.2% P-value = 0.003). Conclusion: In this study increased SLEDAI and flare-up episodes were observed during pregnancy. However the majority of cases did not face major fetal or maternal complications.