Systemic Lupus Erythematosus Pathology Research Articles

An abnormal increase in CD26(-)CD28(-) cytotoxic effector CD4 and CD8 T cell populations in patients with systemic lupus erythematosus.

CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, our group has previously shown that levels of circulating CD26+ T cells are decreased in patients with systemic lupus erythematosus (SLE), although the role of reduced CD26 T cell surface expression in SLE pathology remains to be elucidated. In the present study, we conducted CD26-based T cell subset analyses utilizing peripheral blood mononuclear cells from 57 SLE patients and 31 healthy adult volunteers. We show that the increase in CD26(-) T cell population reflects the abnormal expansion of CD26(-)CD28(-) cytotoxic subsets of both CD8 T cells and CD4 T cells in SLE patients. Single cell RNA sequencing analysis of the CD26(-)CD28(-) CD4 and CD8 T cell populations reveals unique characteristics with similarities to natural killer T cells. In addition, the level of CD26(-)CD28(-) T cells is increased in some active stage SLE patients with renal manifestation. Meanwhile, effect of prednisolone treatment on these populations varies from patient to patient, with levels of these cytotoxic effector populations still being elevated in some inactive stage SLE patients. Taken together, our data suggest that analysis of these populations in SLE may be a useful tool to classify this markedly heterogeneous condition.

Abstract P180: Female mice with systemic lupus erythematosus produce antibodies to mitochondrial antigens and have impaired renal mitochondrial function

Patients with autoimmune disorders like systemic lupus erythematosus (SLE) are at significant risk for renal and cardiovascular mortality. The pathology of SLE is driven by a loss of immune tolerance with the subsequent production of autoantibodies (IgG), and our laboratory previously demonstrated a mechanistic role for autoantibodies in autoimmune mediated hypertension. While anti-double stranded DNA (dsDNA) antibodies are pathognomonic for SLE, a breadth of autoantibodies may contribute to disease pathology. The goal of this study is to identify autoantibodies that may contribute to the renal and cardiovascular consequences associated with SLE. To accomplish this goal, an antigen array was performed (University of Texas Southwestern Genomics & Microarray Core Facility) using plasma samples collected from an established experimental mouse model of SLE (30 week old female NZBWF1, n=8) and healthy controls (30 week old female NZWLacJ, n=7). As anticipated, autoantibodies raised to nuclear antigens were prominently represented in the array and were significantly increased relative to control mice. This includes antibodies to dsDNA, ssRNA, chromatin, and histones (total) (p<0.02). In addition, SLE mice produce antibodies to mitochondrial antigens including cardiolipin and cytochrome C (p<0.02 vs control mice), critical components of the inner mitochondrial membrane and respiratory chain, respectively. In a separate study, renal mitochondrial function was tested using high resolution respirometry (Oroboros Instruments) in whole kidney homogenates from 30 week old female SLE (n=6) and control mice (n=5). Results show that coupled respiration, an estimation of oxidative phosphorylation, is significantly impaired at Complex I in kidneys from SLE mice compared to healthy controls (62±9 vs. 90±7 pmol/s/mg tissue, p<0.05). Uncoupled respiration, an estimation of maximal electron transport, is also reduced in the kidneys of female SLE mice compared to controls (157±23 vs. 212±14 pmol/s/mg tissue, p=0.07). These data provide insight for new mechanistic pathways to pursue in understanding the underlying mechanisms promoting cardiovascular risk factors like hypertension during SLE.

NADPH oxidase in B cells and macrophages protects against murine lupus by regulation of TLR7.

Loss of NADPH oxidase (NOX2) exacerbates systemic lupus erythematosus (SLE) in mice and humans, but the mechanisms underlying this effect remain unclear. To identify the cell lineages in which NOX2 deficiency drives SLE, we employed conditional KO and chimeric approaches to delete Cybb in several hematopoietic cell lineages of MRL.Faslpr SLE-prone mice. Deletion of Cybb in macrophages/monocytes exacerbated SLE nephritis, though not to the degree observed in the Cybb global KOs. Unexpectedly, the absence of Cybb in B cells resulted in profound glomerulonephritis and interstitial nephritis, rivaling that seen with global deletion. Furthermore, we identified that NOX2 is a key regulator of TLR7, a driver of SLE pathology, both globally and specifically in B cells. This is mediated in part through suppression of TLR7-mediated NF-κB signaling in B cells. Thus, NOX2's immunomodulatory effect in SLE is orchestrated not only by its function in the myeloid compartment, but through a pivotal role in B cells by selectively inhibiting TLR7 signaling.

#1843 Deletion of IL17-producing follicular helper T cells restrains the germinal center reaction in systemic lupus erythematosus

Abstract Background and Aims Systemic lupus erythematosus (SLE) is an autoimmune disorder in which autoantibody formation can lead to severe kidney pathology. Interleukin (IL)17-producing T cells have been suggested to play an important role in the pathogenesis of SLE, and IL-17 inhibition was shown to ameliorate SLE pathology in lupus-prone mice. Moreover, the frequency of circulating follicular helper T (Tfh) cells, a T cell subset that orchestrates the maturation of high-affinity antibodies in the germinal center of secondary lymphoid organs, is associated with disease activity in SLE. Increased frequencies of IL17-producing Tfh have been reported in SLE patients compared to controls, but their role in SLE pathogenesis is still unknown. Method By leveraging the B6.Sle1NZM2410/AegYaa strain, we generated lupus-prone mice in which IL17-producing Tfh cells could be either fate-mapped (SLE Tfh17-FM, Il17aCRERosaLoxSTOPLox-YFPSle1+/+Yaa+) or fate-mapped and selectively depleted by intraperitoneal diphtheria toxin (DT) administration (SLE Tfh17-DTR, Il17aCRERosaLoxSTOPLox-YFPCxcr5LoxSTOPLox-DTRSle1+/+Yaa+). Tfh17-FM and Tfh17-DTR mice (both Sle1−/−Yaa−) were used as controls. Results Tfh17 comprised approximately 0.4% of total splenic Tfh in SLE mice at 6 weeks of life, and DT administration caused potent and selective depletion of these cells in the SLE Tfh17-DTR strain (Fig. 1A). Early Tfh17 deletion from week 4 to week 9 did not modify the increased Tfh frequency observed at 20 weeks in SLE mice, but resulted in long-term reduction of splenic germinal center (GC) B cells and plasmacells (Fig. 1B-C). IL17 receptor A was overexpressed in non-GC B cells and plasmacells of SLE mice compared to controls, suggesting a possible increased susceptibility of these subsets to IL17 (Fig. 1D). SLE Tfh17-DTR mice treated with DT displayed a trend towards decreased anti-DNA levels compared to SLE Tfh17-FM (Fig. 1E), but both glomerular immunocomplex deposition and renal pathology were not significantly impacted (Fig. 1F-G). Conclusion The germinal center reaction is affected by selective depletion of IL17-producing Tfh cells in SLE mice, with reduced differentiation of GC B cells and plasmacells. The modest effect of Tfh17 depletion on autoantibody levels and lupus nephritis pathology suggests that other Tfh subsets may play a role in GC-derived autoantibody generation. In addition, extrafollicular sources may also contribute to autoantibody production in SLE.

Integration of multi-omics analysis reveals metabolic alterations of B lymphocytes in systemic lupus erythematosus

ObjectiveTo link changes in the B-cell transcriptome from systemic lupus erythematosus (SLE) patients with those in their macroenvironment, including cellular and fluidic components. MethodsAnalysis was performed on 363 patients and 508 controls, encompassing transcriptomics, metabolomics, and clinical data. B-cell and whole-blood transcriptomes were analysed using DESeq and GSEA. Plasma and urine metabolomics peak changes were quantified and annotated using Ceu Mass Mediator database. Common sources of variation were identified using MOFA integration analysis. ResultsCellular macroenvironment was enriched in cytokines, stress responses, lipidic synthesis/mobility pathways and nucleotide degradation. B cells shared these pathways, except nucleotide degradation diverted to nucleotide salvage pathway, and distinct glycosylation, LPA receptors and Schlafen proteins. ConclusionsB cells showed metabolic changes shared with their macroenvironment and unique changes directly or indirectly induced by IFN-α signalling. This study underscores the importance of understanding the interplay between B cells and their macroenvironment in SLE pathology.

Altered mitochondrial homeostasis in SLE neutrophils promotes aberrant NET release but blunts NETosis during infection.

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a lack of immune tolerance to nuclear antigens leading to systemic inflammation. Patients with SLE are more susceptible to bacterial infections, which is thought to be the result of immunosuppressants used to treat their disease. However, we showed that SLE neutrophils are impaired in their response to bacterial infection. While the unique cell death process resulting in the formation of neutrophil extracellular traps (NET; NETosis) has been attributed to antagonizing SLE pathology, we demonstrated that SLE neutrophils fail to undergo NETosis in response to the bacterial pathogens. Herein, we identified that production of lactate by phylogenetically distinct bacterial pathogens caused increased generation of mitochondrial superoxide and triggered NET release. In contrast, SLE neutrophils displayed an altered metabolic state that rendered them incapable of sensing bacterial lactate. As such, SLE neutrophils failed to undergo NETosis in response to the bacterial pathogen Staphylococcus aureus and underwent aberrant NET release upon stimulation with apoptotic debris. These results indicate that NET formation in response to bacteria may be distinct from pathways promoting heightened NETosis in SLE. Furthermore, deciphering the metabolic disruptions driving inappropriate NET formation in SLE may lead to clinically actionable biomarkers that limit accumulation of nuclear antigens and restores host defense.

Neuropsychological profiles comparison between Multiple Sclerosis patients and Multiple Sclerosis patients with overlapping features of systemic lupus erythematosus

AimMultiple sclerosis (MS) and Systemic Lupus Erythematosus (SLE) are autoimmune disorders that may lead to cognitive impairment. This study aimed to compare the neuropsychological profiles of patients with MS, and MS and coexisting SLE features. MethodsWe included a total of 90 participants, divided into 3 groups: 30 patients with clinically definite relapsing remitting MS, 30 with coexisting MS and incomplete SLE (overlap group) and 30 healthy controls (HC). All participants underwent neuropsychological assessment with the Montreal Cognitive Assessment (MoCA), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Selective Reminding Test (SRT). ResultsBoth groups scored lower on the MoCA compared to the HC (p < .001). The overlap group showed the lowest performance on the SDMT and PASAT compared to the other two groups (p < .01), while the MS group scored similarly to the HC in the PASAT (p > .05). Regarding the learning rate and long-term recall, the overlap group had lower scores compared to both the MS and HC (p < .001), but it outperformed both groups in the retention efficacy score (p < .001). The MS group did not differ significantly from the HC in these memory domains (p > .05). ConclusionThe overlap group exhibited a broader range of impairments, including slower processing speed, decreased working memory, reduced learning rate, and long-term retrieval deficits. Their retention ability remained intact. The coexistence of MS with SLE pathology had additive impacts on cognitive function.

CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus.

B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells populate the secondary lymphatic organs, where they undergo further maturation leading to the development of memory B cells as well as antibody-producing plasmablasts and plasma cells. Targeting B cells is an important strategy to treat autoimmune diseases such as SLE, in which B cell tolerance is disturbed and autoimmune B cells and autoantibodies emerge. This review discusses the functional aspects of antibody- and cell-based B cell-depleting therapy in SLE. It thereby particularly focuses on lessons learned from chimeric antigen receptor (CAR) T cell treatment on the role of B cells in SLE for understanding B cell pathology in SLE. CAR T cells model a deep B cell depletion and thereby allow understanding the role of aberrant B cell activation in the pathogenesis of SLE. Furthermore, the effects of B cell depletion on autoantibody production can be better described, ie, explaining the concept of different cellular sources of (auto-) antibodies in the form of short-lived plasmablasts and long-lived plasma cells, which differ in their susceptibility to B cell depletion and require different targeted therapeutic approaches. Finally, the safety of deep B cell depletion in autoimmune disease is discussed.

The Impact of Physical Therapy on Psychomotor Functions in a Patient with Systemic Lupus Erythematosus and Diabetes Mellitus

"The scientific and medical world is making permanent efforts to study, understand, and cure the complicated pathology of Systemic Lupus Erythematosus (SLE) – the disease with 100 faces, due to the diversity and complexity of the symptoms. SLE has a devastating impact on the patient’s life, causing multiple metabolic imbalances produced by both the disease itself and the necessary medication. This case report addresses the therapeutic aspects of SLE and diabetes mellitus, on a 47-year-old male with a sensitive multi-pathology and aggressive evolution, medication, and approaching psychomotor rehabilitation therapy, up to now, when SLE treatment has ended. Also, this case study report highlights the importance of flexibility in the psychomotor rehabilitation strategy, in the context of a large range of factors that influence its definition."

Managing Azathioprine-Induced Myelosuppression and Alopecia Totalis: Lessons from a SLE Patient

Introduction Azathioprine (AZA), an immunosuppressant and mercaptopurine analog, is used to manage rheumatological and immunological conditions. Although effective, AZA can cause myelosuppression, sometimes necessitating dose adjustments or discontinuation. While severe pancytopenia or alopecia is rare, these issues can arise. This report describes a case of severe myelosuppression and alopecia totalis following AZA treatment in a patient with systemic lupus erythematosus (SLE). Case Report A 27-year-old healthy female presented with an 8-month history of fever, cough with pleuritic chest pain, and hemoptysis. Clinical and biochemical evaluations diagnosed her with SLE and secondary pulmonary vasculitis. She was initially treated with systemic steroids, followed by AZA. AZA was started at 25 mg daily (0.8 mg/kg) and increased to 75 mg daily (2 mg/kg) over three months. After dose escalation, she developed increased hair loss, feverishness, and lethargy, prompting her admission to a medical facility. Examination revealed significant non-scarring alopecia, (Figure 1) but no clinical signs of an SLE flare. Laboratory tests showed pancytopenia: hemoglobin 8.4 g/dL, white blood cells 880/[Formula: see text]L, platelets 130K/[Formula: see text]L, and absolute neutrophil count 38/[Formula: see text]L. Inflammatory markers, complement levels, and septic screening were normal. AZA was discontinued, and she was treated for neutropenic sepsis with high-dose steroids and GM-CSF. Despite these measures, blood parameters did not improve as expected. After 25 days of treatment, hair loss ceased, and cytopenias began to recover. Bone marrow analysis was not performed during the acute phase. Upon discharge, her blood counts were WBC 6,130/[Formula: see text]L, hemoglobin 10.9 g/dL, and platelets 85K/[Formula: see text]L. Given her SLE and lung pathology, she continued immunosuppressive therapy but was switched from AZA to IV Rituximab. Six weeks later, her blood counts had improved (WBC 10K/[Formula: see text]L, hemoglobin 10.9 g/dL, platelets 289K/[Formula: see text]L), and hair regrowth was observed. (Figure 2) Conclusion This case underscores the need for clinicians to be vigilant for early signs of severe myelosuppression, such as alopecia, in patients receiving azathioprine. Awareness of these uncommon side effects is crucial for effective management.

Novel biomarker discovery through comprehensive proteomic analysis of lupus mouse serum

ObjectivesThe difficulty of monitoring organ-specific pathology in systemic lupus erythematosus (SLE) often complicates disease prognostication and treatment. Improved non-invasive biomarkers of active organ pathology, particularly lupus nephritis, would improve patient care. We sought to validate and apply a novel strategy to generate the first comprehensive serum proteome of a lupus mouse model and identify mechanism-linked lupus biomarker candidates for subsequent clinical investigation. MethodsSerum levels of 1308 diverse proteins were measured in eight adult female MRL/lpr lupus mice and eight control MRL/mpj mice. ELISA validation confirmed fold increases. Protein enrichment analysis provided biological relevance to findings. Individual protein levels were correlated with measures of lymphoproliferative, humoral, and renal disease. ResultsFour hundred and six proteins were increased in MRL/lpr serum, including proteins increased in human SLE such as VCAM-1, L-selectin, TNFRI/II, TWEAK, CXCL13, MCP-1, IP-10, IL-10, and TARC. Newly validated proteins included IL-6, IL-17, and MDC. Results of pathway enrichment analysis, which revealed enhancement of cytokine signaling and immune cell migration, reinforced the similarity of the MRL/lpr disease to human pathology. Fifty-two proteins positively correlated with at least one measure of lupus-like disease. TECK, TSLP, PDGFR-alpha, and MDC were identified as novel candidate biomarkers of renal disease. ConclusionsWe successfully validated a novel serum proteomic screening strategy in a spontaneous murine lupus model that highlighted potential new biomarkers. Importantly, we generated a comprehensive snapshot of the serum proteome which will enable identification of other candidates and serve as a reference for future mechanistic and therapeutic studies in lupus.

Identification and Characterization of CD8+ CD27+ CXCR3- T Cell Dysregulation and Progression-Associated Biomarkers in Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) etiopathogenesis highlights the contributions of overproduction of CD4+ T cells and loss of immune tolerance. However, the involvement of CD8+ T cells in SLE pathology and disease progression remains unclear. Here, the comprehensive immune cell dysregulation in total 263 clinical peripheral blood samples composed of active SLE (aSLE), remission SLE (rSLE) and healthy controls (HCs) is investigated via mass cytometry, flow cytometry and single-cell RNA sequencing. This is observed that CD8+ CD27+ CXCR3- T cells are increased in rSLE compare to aSLE. Meanwhile, the effector function of CD8+ CD27+ CXCR3- T cells are overactive in aSLE compare to HCs and rSLE, and are positively associated with clinical SLE activity. In addition, the response of peripheral blood mononuclear cells (PBMCs) is monitored to interleukin-2 stimulation in aSLE and rSLE to construct dynamic network biomarker (DNB) model. It is demonstrated that DNB score-related parameters can faithfully predict the remission of aSLE and the flares of rSLE. The abundance and functional dysregulation of CD8+ CD27+ CXCR3- T cells can be potential biomarkers for SLE prognosis and concomitant diagnosis. The DNB score with accurate prediction to SLE disease progression can provide clinical treatment suggestions especially for drug dosage determination.

Protein citrullination and NET formation do not contribute to the pathology of A20/TNFAIP3 mutant mice

A20 serves as a critical brake on NF-κB-dependent inflammation. In humans, polymorphisms in or near the TNFAIP3/A20 gene have been linked to various inflammatory disorders, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Experimental gene knockout studies in mice have confirmed A20 as a susceptibility gene for SLE and RA. Here, we examine the significance of protein citrullination and NET formation in the autoimmune pathology of A20 mutant mice because autoimmunity directed against citrullinated antigens released by neutrophil extracellular traps (NETs) is central to the pathogenesis of RA and SLE. Furthermore, genetic variants impairing the deubiquitinase (DUB) function of A20 have been shown to contribute to autoimmune susceptibility. Our findings demonstrate that genetic disruption of A20 DUB function in A20 C103R knockin mice does not result in autoimmune pathology. Moreover, we show that PAD4 deficiency, which abolishes protein citrullination and NET formation, does not prevent the development of autoimmunity in A20 deficient mice. Collectively, these findings provide experimental confirmation that PAD4-dependent protein citrullination and NET formation do not serve as pathogenic mechanisms in the development of RA and SLE pathology in mice with A20 mutations.

Epigenetics and treatment of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a disease associated with an impaired autoimmune response; the immune system attacks erroneously own tissues, which leads to inflammation, tissue damage and complement activation. The latter plays a pivotal role in SLE pathology, as complement level is suited as histological marker for disease diagnoses and management. Besides, environmentally factors have been highlighted and their significant contribution for individual genetic predisposition has been pointed out. Here complement factors, their activity and their ability to modify DNA with histone proteins are reviewed; known gene mutations involved in SLE, and new therapeutic approaches suggested for SLE are discussed and summarized, as well.

Identification and Clinical Correlation Analysis of IFI44 in Systemic Lupus Erythematosus Combined with Bioinformatics and Immune Infiltration Analysis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can cause systemic damage to multiple organs. This study aims to analyze the value and function of IFI44 in the diagnosis and pathology of SLE by bioinformatics and immune infiltration analysis. GSE49454 and GSE65391 of SLE were obtained from the GEO dataset, and R software was employed to identify DEGs and investigate their functions. The PPI network was utilized to identify hub genes associated with SLE. CIBERSORT was used to assess differences in immune cell infiltration in SLE patients and controls. ROC curve analysis was performed to evaluate the diagnostic value of IFI44 in SLE. The expression of IFI44 in PBMCs was detected by RT-qPCR, and the correlation between IFI44 expression and SLE-related clinical indicators was analyzed. A total of 65 DEGs were identified from the GSE49454 and GSE65391 databases. Through PPI analysis, IFI44 and RSAD2 were identified as significantly aberrantly expressed in SLE patients. SLE patients and controls showed a significant difference in the proportion of immune cell infiltration. IFI44 expression was positively correlated with activated DCs, monocytes, PCs, neutrophils, and activated memory CD4+T cells, while negatively correlated with M0 and CD8+T cells. The expression of IFI44 was significantly higher in SLE patients (P<0.01), especially in male patients (P=0.0376). ROC curve analysis demonstrated that IFI44 had a high diagnostic value for SLE. Correlation analysis indicated that IFI44 expression was correlated with levels of RBC, HGB, HCT, IgA, ESR, UPRO, C3, C4, and ENA in SLE patients. IFI44 may play a role in the pathogenesis of SLE by influencing the immune microenvironment of SLE patients, and thus has the potential to serve as a diagnostic marker and therapeutic target for SLE.

CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responses

Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity and mortality. Type I interferon (IFN) drives SLE pathology and plasmacytoid dendritic cells (pDCs) are potent producers of IFN; however, the specific effects of pDC depletion have not been demonstrated. We show CD123 was highly expressed on pDCs and the anti-CD123 antibody CSL362 potently depleted pDCs invitro. CSL362 pre-treatment abrogated the induction of IFNα and IFN-induced gene transcription following stimulation with SLE patient-derived serum or immune complexes. RNA transcripts induced in pDCs by exvivo stimulation with TLR ligands were reflected in gene expression profiles of SLE blood, and correlated with disease severity. TLR ligand-induced protein production by SLE patient peripheral mononuclear cells was abrogated by CSL362 pre-treatment including proteins over expressed in SLE patient serum. These findings implicate pDCs as key drivers in the cellular activation and production of soluble factors seen in SLE.

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

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

Splicing machinery is profoundly altered in systemic lupus erythematosus and antiphospholipid syndrome and directly linked to key clinical features

ObjectivesTo characterize the splicing machinery (SM) of leukocytes from primary antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome with lupus (APS + SLE) patients, and to assess its clinical involvement. MethodsMonocytes, lymphocytes and neutrophils from 80 patients (22 APS, 35 SLE and 23 APS + SLE) and 50 HD were purified, and 45 selected SM components were evaluated by qPCR-microfluidic array. Relationship with clinical features and underlying regulatory mechanisms were assessed. ResultsAPS, SLE and APS + SLE leukocytes displayed significant and specific alterations in SM-components (SMC), associated with clinical features [autoimmune profiles, disease activity, lupus nephritis (LN), and CV-risk markers]. A remarkable relationship among dysregulated SMC in monocytes and the presence of LN in SLE was highlighted, revealing a novel pathological mechanism, which was further explored. Immunohistology analysis of renal biopsies highlighted the pathological role of the myeloid compartment in LN. Transcriptomic analysis of monocytes from SLE-LN(+) vs SLE-LN(−) identified 271 genes differentially expressed, mainly involved in inflammation and IFN-signaling. Levels of IFN-related genes correlated with those of SMC in SLE-LN(+). These results were validated in two external SLE-LN(+) datasets of whole-blood and kidney biopsies. In vitro, SLE-LN(+)-serum promoted a concomitant dysregulation of both, the IFN signature and several SMC, further reversed by JAKinibs treatment. Interestingly, IFNs, key inflammatory cytokines in SLE pathology, also altered SMC. Lastly, the over/down-expression of selected SMC in SLE-monocytes reduced the release of inflammatory cytokines and their adhesion capacity. ConclusionOverall, we have identified, for the first time, a specific alteration of SMC in leukocytes from APS, SLE and APS + SLE patients that would be responsible for the development of distinctive clinical profiles.

P35 Lupus masquerading as Cholangiocarcinoma: One of the many faces of multifaceted lupus

Introduction/BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune condition which can present with a wide variety of clinical features. This variation can lead to delayed diagnosis or misdiagnosis. Gastroenetrological pathology in SLE is rare but primary autoimmune hepatitis, pancreatitis, lupus enteritis, cholestatic biliary disease and protein losing enteropathy have all been reported. We would like to share the first known presentation of SLE as cholangiocarcinoma.Description/MethodA 62-year-old, previously fit and well, gentleman presented with a 1 month history of painless jaundice, a palpable gallbladder (Courvoisier syndrome), dark urine, pale stool, generalised rash, pruritus, weight loss and anorexia. The presence of these red flag features raised concerns. Initial investigation with Endoscopic retrograde cholangiopancreatography (ERCP) revealed distal common bile duct (CBD) stricture which was further explored with computerised tomography of thorax, abdomen, pelvis and magnetic retrograde cholangiopancreatogram (MRCP) both raising the suspicion of a cholangiocarcinoma in the presence of constitutional symptoms. Several biopsies and brushings taken during multiple ERCP’s failed to identify clear mitotic cells, IgG 4 staining remained negative. Further investigation with Positron emission tomography – computerised tomography (PET-CT) showed significant FDG uptake around the upper part of the stent with final working diagnosis of Cholangiocarcinoma and a Whipple’s procedure was planned.In the interim, the patient developed swollen painful hands, scleritis and a yellow blistering rash. He was referred urgently onto the Rheumatology team after receiving the positive immunology results: ANA (1:1280), Anti double stranded DNA and Rheumatoid Factor (RF) along with hypocomplementemia (C3&C4).Discussion/ResultsSubsequent work up under rheumatology was done considering the possibilities of diagnosis of Systemic lupus erythematosus (SLE), Lupus related autoimmune hepatitis and reactive arthritis as a result of underlying malignancy. Patient’s immunology and other clinical features such as skin rash were strongly supportive of SLE as a primary diagnosis. He was initially treated with low dose prednisolone with dramatic improvement in arthritis and gradual improvement in liver function test. Following MDT discussions with the hepato-biliary team it was felt that lupus was the cause of the biliary stricture which settled well with steroid treatment. A final ERCP was arranged to remove the stent and take final brushings. Methotrexate was started at this point. His SLE remains well controlled on methotrexate and his liver function tests, including bilirubin, remain within the normal range. Patient has now been completely asymptomatic and is discharged from the care of hepatobiliary team with long term follow up for his SLE with rheumatology.Key learning points/ConclusionThis is extremely rare first presentation of SLE presenting with painless jaundice and biliary stricture which improved both biochemically and clinically with treatment of SLE. The key learning points included:Urgent review by rheumatology can facilitate timely diagnosis and preventable admissions/interventions such as major intraabdominal procedure in the form of whipple’s disease planned in our case.Cancer remains a major cause of mortality and morbidity in rheumatological conditions like SLE. Hence initial diagnosis can become extremely difficult if an overlap between these two happens.Treatment options can be limited initially and steroids remain the main stay of treatment till mitotic lesions have been ruled out and disease modifying agents can be used without any contraindications. But disease control for our conditions remains challenging in presence of cancers.

Real-world data on vitamin D supplementation and its impacts in systemic lupus erythematosus: Cross-sectional analysis of a lupus registry of nationwide institutions (LUNA).

BackgroundAlthough vitamin D concentration is reportedly associated with the pathogenesis and pathology of systemic lupus erythematosus (SLE), benefits of vitamin D supplementation in SLE patients have not been elucidated, to our knowledge. We investigated the clinical impacts of vitamin D supplementation in SLE.MethodsA cross-sectional analysis was performed using data from a lupus registry of nationwide institutions. We evaluated vitamin D supplementation status associated with disease-related Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) as a parameter of long-term disease activity control.ResultsOf the enrolled 870 patients (mean age: 45 years, mean disease duration: 153 months), 426 (49%) received vitamin D supplementation. Patients with vitamin D supplementation were younger (43.2 vs 47.5 years, P < 0.0001), received higher doses of prednisolone (7.6 vs 6.8 mg/day, P = 0.002), and showed higher estimated glomerular filtration rates (79.3 vs 75.3 mL/min/1.73m2, P = 0.02) than those without supplementation. Disease-related SDI (0.73 ± 1.12 vs 0.73 ± 1.10, P = 0.75), total SDI, and SLE Disease Activity Index (SLEDAI) did not significantly differ between patients receiving and not receiving vitamin D supplementation. Even after excluding 136 patients who were highly recommended vitamin D supplementation (with age ≥ 75 years, history of bone fracture or avascular necrosis, denosumab use, and end-stage renal failure), disease-related SDI, total SDI, and SLEDAI did not significantly differ between the two groups.ConclusionsEven with a possible Vitamin D deficiency and a high risk of bone fractures in SLE patients, only half of our cohort received its supplementation. The effect of vitamin D supplementation for disease activity control was not observed.