Elevated production of serum B-cell-attracting chemokine-1 (BCA-1/CXCL13) is correlated with childhood-onset lupus disease activity, severity, and renal involvement

This chapter looks at the epidemiology of lupus—this disease is more common than is generally recognized and occurs most frequently in women. There is a significantly higher risk of developing lupus in people of African, Hispanic, and Asian (especially Chinese) descent, with increased incidence and prevalence in some other ethnic minority races. They appear to develop a more severe phenotype, often with renal involvement and at an earlier age than white people of North European descent. Although deaths due to lupus are now less common in North American and European countries, deaths due to renal lupus remain a significant problem in the ethnic minorities. Management should target reducing factors that increase the risk of lupus disease activity, damage, and mortality. Raising awareness of lupus, leading to early diagnosis and institution of appropriate therapy to reduce disease activity, will reduce chronic damage and the associated risk of subsequent premature death.

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II-08 Complement receptors 1 and 2 on B cell subsets are negatively associated with lupus disease activity

10.1136/lupus-2018-lsm.107 ◽

2018 ◽

Author(s):

Shoshana Rosenthal ◽

Dominik Reinhold ◽

Kenneth L Jones ◽

Weiming Zhang ◽

Duane Pearson ◽

...

Keyword(s):

Disease Activity ◽

B Cell ◽

Complement Receptors ◽

Negatively Associated ◽

B Cell Subsets ◽

Lupus Disease Activity

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OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2955 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 4-5

Author(s):

A. Aue ◽

F. Szelinski ◽

S. Weißenberg ◽

A. Wiedemann ◽

T. Rose ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

Autoimmune Diseases ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Type I ◽

Type I Ifn ◽

Systemic Lupus ◽

B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

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The expansion of activated naive DNA autoreactive B cells and its association with disease activity in systemic lupus erythematosus patients

Arthritis Research & Therapy ◽

10.1186/s13075-021-02557-0 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Kittikorn Wangriatisak ◽

Chokchai Thanadetsuntorn ◽

Thamonwan Krittayapoositpot ◽

Chaniya Leepiyasakulchai ◽

Thanitta Suangtamai ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Autoreactive B Cells ◽

Dsdna Antibody ◽

Cell Subpopulations ◽

B Cell Subsets

Abstract Background Autoreactive B cells are well recognized as key participants in the pathogenesis of systemic lupus erythematosus (SLE). However, elucidating the particular subset of B cells in producing anti-dsDNA antibodies is limited due to their B cell heterogeneity. This study aimed to identify peripheral B cell subpopulations that display autoreactivity to DNA and contribute to lupus pathogenesis. Methods Flow cytometry was used to detect total B cell subsets (n = 20) and DNA autoreactive B cells (n = 15) in SLE patients’ peripheral blood. Clinical disease activities were assessed in SLE patients using modified SLEDAI-2 K and used for correlation analyses with expanded B cell subsets and DNA autoreactive B cells. Results The increases of circulating double negative 2 (DN2) and activated naïve (aNAV) B cells were significantly observed in SLE patients. Expanded B cell subsets and DNA autoreactive B cells represented a high proportion of aNAV B cells with overexpression of CD69 and CD86. The frequencies of aNAV B cells in total B cell populations were significantly correlated with modified SLEDAI-2 K scores. Further analysis showed that expansion of aNAV DNA autoreactive B cells was more related to disease activity and serum anti-dsDNA antibody levels than to total aNAV B cells. Conclusion Our study demonstrated an expansion of aNAV B cells in SLE patients. The association between the frequency of aNAV B cells and disease activity patients suggested that these expanded B cells may play a role in SLE pathogenesis.

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POS0685 MYCOPHENOLATE MOFETIL IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS: FIVE-YEARS DRUG SURVIVAL IN RENAL AND NON-RENAL INVOLVEMENT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.925 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 588.2-588

Author(s):

G. Olivieri ◽

F. Ceccarelli ◽

F. Natalucci ◽

F. R. Spinelli ◽

C. Alessandri ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Mycophenolate Mofetil ◽

Disease Activity ◽

Lupus Erythematosus ◽

Treatment Duration ◽

Retention Rate ◽

Renal Involvement ◽

Joint Involvement ◽

Systemic Lupus ◽

Median Treatment

Background:The updated EULAR recommendations for the management of systemic lupus erythematosus (SLE) underline the use of Mycophenolate Mofetil (MMF) in the treatment of different disease related manifestations (1). Several randomized controlled trials have demonstrated the efficacy of MMF in lupus nephritis (LN) patients but only case series and open-labelled trials have analyzed the use of this drug in other than LN features. Moreover, no data are available about the MMF retention rate in a real-life setting.Objectives:The present study aims at evaluating the 5-years drug retention rate (DRR) of MMF in a large monocentric SLE cohort. Secondly, we investigated the influence of MMF in disease activity changes and chronic damage progression.Methods:We performed a longitudinal study including all the SLE patients (ACR 1997 criteria) starting MMF treatment in our Lupus Clinic. Data about indications, mean dosage, duration of treatment and reasons for drug withdrawal were registered. The DRR was estimated using the Kaplan–Meier method. Disease activity and chronic damage were assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and SLICC Damage Index (SDI), respectively.Results:The present analysis included 162 SLE patients (M/F 22/140, median age at the disease diagnosis 25.5 years, IQR 13). At the beginning of MMF treatment, we registered a median age of 34 months (IQR 21) and a median disease duration of 72 months (IQR 123). The most frequent indications for prescribing MMF were LN (101 patients, 62.3%) and musculoskeletal manifestations (39, 24.1%), followed by neuropsychiatric involvement (10, 6.2%), and others disease related manifestations (12, 7.4%; in particular skin involvement, hematological features, myositis, vasculitis). MMF was administered at a mean daily dosage of 2.1±0.6 grams; no differences in dosage were found between the different indications (p=ns).At the longitudinal analysis, we registered a median treatment duration of 30 months (IQR 55). Figure 1 reported data about DRR: in particular, at 60 months follow-up we observed a DRR of 61.1% for LN patients, which was similar to that registered for patients without renal involvement (NLN) (60.5%; p=ns). Interestingly, the DRR at 60 months was higher in the subgroup of patients treated for joint involvement (75.4%), even without reaching a statistically significant difference. During the observation period, 92 patients (59.2%) discontinued MMF (median treatment duration at discontinuation 25 months, IQR 35). Interestingly, the main cause of withdrawal was the achievement of persistent remission, observed in 20 patients (21.7%), followed by loss of efficacy (19 patients, 20.5%), drug intolerance and pregnancy planning (17 patients for both reasons, 18,4%). Furthermore, our analysis confirmed MMF efficacy, as demonstrated by the significant reduction in SLEDAI-2k values after 4, 12 and 24 months of treatment (p< 0.0001 for all the time-points in comparison with baseline). In addition, MMF resulted able to control chronic damage progression, as demonstrated by the lack of significant increase in SDI values (baseline: 0.6, IQR 1; last observation: 0.93, IQR 1; p=ns).Conclusion:The evaluation of a large SLE cohort demonstrated a good retention rate for MMF. In particular, our results demonstrated that MMF is also a safe and effective drug for SLE manifestation other than LN, in particular for joint involvement. Moreover, it is able to control disease activity and to prevent the progression of chronic damage.References:[1]Fanouriakis A et al. Ann Rheum Dis. 2019 Jun;78(6):736-745.Disclosure of Interests:None declared

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OP0045 NLRP12 INVOLVES IN THE LUPUS WITH POSITIVE INTERFERON SIGNATURE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.4215 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 23.2-24

Author(s):

Y. P. Tsao ◽

F. Y. Tseng ◽

C. W. Chao ◽

M. H. Chen ◽

S. T. Chen

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Animal Models ◽

Nucleic Acids ◽

Disease Activity ◽

Interferon Signature ◽

Healthy Donors ◽

Healthy Control ◽

Lupus Disease Activity

Background:Systemic lupus erythematous (SLE) is a systemic autoimmune disease with diverse etiological factors. It was recognized that interferon (IFN) signature involved in the progress of SLE. NLRP12 (NOD-like receptor family (NLR) pyrin domain containing 12) is a pyrin containing NLR protein that we had linked its new biological function to the cross-regulation of Toll like receptor (TLRs) and Rig-I like receptor (RIG-I) pathways. NLPR12 acts as an innate immune check-point in regulating type I IFNs expression during TLRs and RIG-I activation. The importance of NLRP12 in lupus disease activity remained to be elucidated.Objectives:To clarify the role of NLRP12 in regulating the interferon signature.Methods:Peripheral blood mononuclear cells (PBMCs) were collected from SLE patients and healthy donors for analysis of NLRP12 and IFN-α gene expression by RT-QPCR. PBMCs were applied for Chromatin immuneprecipitation (ChIP) assay and electrical mobility shift assay (EMSA) to determine the putative transcription factor that regulates NLRP12 expression. An involvement of epigenetic regulation of NLRP12 expression in SLE patients was also analyzed. Bone marrow derived dendritic cells (BMDCs) were collected from wild type mouse and Nlrp12 knocked-out mice. Another CD14+ monocytes were isolated from 10 cases of lupus patients and 8 cases of healthy control, following by stimulating different type of nucleic acids, and IFN-α and IL-6 were measured with ELISA assay. CD14+ monocytes in lupus patients were also pre-treated with IFNAR2 antibody for further nucleic acid stimulation. Two mice models were applied for evaluation the role of Nlrp12: intraperitoneal injection of TMPD (2,6,10,14-tetramethylpentadecane, or pristane) in C57BL/6 mice and Faslpr mice. Both models were conducted with and without Nlrp12 knockout.Results:NLRP12 expression was significantly lower in PBMC isolated from SLE patients compared to healthy donors. The inverse correlation was observed in NLRP12 and IFNA gene expression as well as NLRP12 expression and amount of double-stranded DNA autoantibody in SLE patients. NLRP12 expression showed negative correlations with IFN-α treatment, as well as herpes simplex virus-1 (HSV-1) infection. Results from ChIP and EMSA analysis indicated a potential transcription factor 1 (TF-1) regulating NLRP12 promoter activity. TF-1 lead to transcriptional suppression of NLRP12 in SLE PBMC, and it was gradually induced after IFN treatment. Recruitment of TF-1 to NLRP12 promoter in SLE PBMC compared to the healthy PBMC was detected, and increased when treating with IFN. Human CD14+ monocytes collected from lupus and healthy control stimulating with different type of nucleic acids revealing significant increasing level of IFN-α and IL-6 in lupus patients. Among animal models, both pristine induced mice and Faslpr mice revealed increasing autoantibodies production and severity of glomerulonephritis in Nlrp12-/- group in comparison with Nlrp12+/+ ones, indicating the role of NLRP12 in maintaining positive interferon signature as well as disease activity.Conclusion:Expression level of NLRP1.2 has been demonstrated to be a biomarker of disease activity in SLE patients. The NLRP12 was involved in the interferon signature, which was also negatively regulated by TF-1. Both clinical samples and animal models revealed NLRP12 in maintaining the positive interferon signature, indicating the possible role of exacerbating factor for lupus disease activity.Disclosure of Interests:None declared

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Disease activity index is associated with subclinical atherosclerosis in childhood-onset systemic lupus erythematosus

Pediatric Rheumatology ◽

10.1186/s12969-021-00513-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Priscila B. S. Medeiros ◽

Roberta G. Salomão ◽

Sara R. Teixeira ◽

Diane M. Rassi ◽

Luciana Rodrigues ◽

...

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Activity Index ◽

Subclinical Atherosclerosis ◽

Disease Activity Index ◽

Uncontrolled Hypertension ◽

Childhood Onset ◽

Systemic Lupus

Abstract Background Systemic lupus erythematosus (SLE) is an independent risk factor for cardiovascular events. The present study determined the prevalence of subclinical atherosclerosis in childhood-onset SLE using the carotid intima-media thickness (CIMT) measurement and investigated associations between traditional and nontraditional risk factors for atherosclerosis, such as medications, SLE Disease Activity Index - SLEDAI-2 K and SLICC-ACR damage index and CIMT. Methods Cross-sectional prospective study between 2017 and 2018. CIMT was assessed by ultrasonography. Data were collected by chart review, nutritional evaluation and laboratory tests and analyzed by Fisher, Wilcoxon-Mann-Whitney tests, multiple linear and log binomial regression. Results Twenty-eight patients (mean age 13.9 years, SD 3) were enrolled. The prevalence of subclinical atherosclerosis was 32% (95% CI 14.8, 49.4). The mean CIMT was 0.43 ± 0.035 mm. The most common traditional risk factors observed were dyslipidemia (82.1%), uncontrolled hypertension (14.2%), obesity (14.3%), and poor diet (78.6%). Uncontrolled hypertension (p = 0.04), proteinuria (p = 0.02), estimated glomerular filtration rate < 75 ml /min/1.73 m2 (p = 0.02) and SLEDAI-2 K > 5 (P = 0.04) were associated with subclinical atherosclerosis. SLEDAI-2 K > 5 maintained association with CIMT after adjusting for control variables. Conclusion Subclinical atherosclerosis is frequently observed in cSLE, mainly in patients with moderate to severe disease activity.

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FRI0182 RISK FACTORS ASSOCIATED WITH RENAL INVOLVEMENT IN PRIMARY SJÖGREN’S SYNDROME: DATA FROM THE SPANISH SJÖGRENSER COHORT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5149 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 674.3-675

Author(s):

J. Narváez ◽

C. Sánchez-Piedra ◽

M. Fernandez Castro ◽

V. Martinez Taboada ◽

A. Olive ◽

...

Keyword(s):

Risk Factors ◽

Renal Disease ◽

Disease Activity ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Renal Involvement ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Primary Sjögren’S Syndrome ◽

Sjögren‘S Syndrome

Objectives:To investigate the prevalence, risk factors, and effects of primary renal disease on morbidity and mortality in patients with primary Sjögren’s syndrome (pSS).Methods:All patients in the SJÖGRENSER (registry of adult SSp patients of the Spanish Society of Rheumatology, cross-sectional phase) cohort were retrospectively investigated for the presence of clinically significant renal involvement directly related to pSS activity.Results:Of the 437 patients investigated, 39 (9%) presented overt renal involvement during follow-up. Severe renal disease necessitating kidney biopsy was relatively rare (23%).Renal involvement may complicate pSS at any time during the disease course and is associated with severe disease (indicated by higher scores of involvement, activity, and damage), systemic multiorgan involvement, and a higher frequency of lymphoma. Multivariate analysis showed that older age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00–1.07), higher European League Against Rheumatism Sjogren’s Syndrome Disease Activity Index scores (OR 1.1, CI 1.03–1.18), serum anti-La/SSB positivity (OR 6.44, CI 1.36–30.37), and non-vasculitic cutaneous involvement (OR 8.64, 1.33–55.90) were independently associated with this complication.Chronic renal failure developed in 23 of 39 patients (59%); only 1 of them progressed to end-stage renal disease necessitating renal replacement therapy. Patients with renal disease showed higher Sjögren’s syndrome disease damage index scores (SSDDI), higher rates of hospitalization due to disease activity and higher rates of clinically relevant comorbidities.Conclusion:Renal involvement is an uncommon complication in pSS that was observed in 9% of patients. Although categorized as a non-negligible comorbidity, this condition shows a favorable prognosis.Disclosure of Interests:None declared

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Proteinuria Indicates Decreased Normal Glomeruli in ANCA-Associated Glomerulonephritis Independent of Systemic Disease Activity

Journal of Clinical Medicine ◽

10.3390/jcm10071538 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1538

Author(s):

Désirée Tampe ◽

Peter Korsten ◽

Philipp Ströbel ◽

Samy Hakroush ◽

Björn Tampe

Keyword(s):

Disease Activity ◽

Systemic Disease ◽

Renal Involvement ◽

Kidney Injury ◽

Antineutrophil Cytoplasmic Antibody ◽

Clinicopathological Characteristics ◽

Renal Outcome ◽

Study Results ◽

Renal Biopsies ◽

Stage Renal Disease

Background: Renal involvement is a common and severe complication of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), potentially resulting in a pauci-immune necrotizing and crescentic ANCA glomerulonephritis (GN) with acute kidney injury (AKI), end-stage renal disease (ESRD) or death. There is recent evidence that the degree of proteinuria at diagnosis is associated with long-term renal outcome in ANCA GN. Therefore, we here aimed to systematically describe the association between proteinuria and clinicopathological characteristics in 53 renal biopsies with ANCA GN and corresponding urinary samples at admission. Methods: A total number of 53 urinary samples at admission and corresponding renal biopsies with confirmed renal involvement of AAV were retrospectively included from 2015 to 2021 in a single-center study. Results: Proteinuria correlated with myeloperoxidase (MPO) subtype, diagnosis of microscopic polyangiitis (MPA) and severe deterioration of kidney function. Proteinuria was most prominent in sclerotic class ANCA GN and ANCA renal risk score (ARRS) high risk attributed to nonselective proteinuria, including both glomerular and tubular proteinuria. Finally, there was no association between proteinuria and systemic disease activity, suggesting that proteinuria reflected specific renal involvement in AAV rather that systemic disease activity. Conclusions: In conclusion, proteinuria correlated with distinct clinicopathological characteristics in ANCA GN, mostly attributed to a reduced fraction of normal glomeruli. Furthermore, proteinuria in ANCA GN reflected specific renal involvement in AAV rather than systemic disease activity. Therefore, urinary findings could further improve our understanding of mechanisms promoting kidney injury and progression of ANCA GN.

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