THU0250 URINE AND SERUM S100 PROTEINS ASSOCIATE WITH LUPUS NEPHRITIS AND RESPONSE TO TREATMENT

Background:Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease. Approximately 30% of SLE patients develop lupus nephritis (LN) that affects treatment and prognosis. Easily accessible biomarkers do not exist to reliably predict renal disease1. Recently, calcium-binding S100 proteins have been suggested as biomarkers in systemic inflammatory conditions, including SLE2,3.Objectives:The MASTERPLANS Consortium aims to identify indicators of treatment responses in SLE. This study tested the applicability of S100 proteins in serum and urine as biomarkers for disease activity and response to treatment with rituximab in LN.Methods:S100A8/A9 and S100A12 proteins were quantified in the serum and urine of 243 SLE patients from the BILAG-BR study and 48 matched controls using MSD technology to determine whether they perform as biomarkers for active LN (n=85 SLE patients) and/or may be used to predict response to treatment with rituximab. Renal disease activity and response to treatment was based on BILAG-BR scores and changes in response to treatment4,5.Results:Serum S100A12 (p<0.001), and serum and urine S100A8/A9 (p<0.001) are elevated in SLE patients. While serum and urine S100 levels do not correlate with global SLE disease activity (SLEDAI), levels in urine and urine/serum ratios are elevated in SLE patients with active LN (S100A8/A9: urine p>0.005, urine/serum p<0.05; S100A12: urine p<0.05, serum/urine p<0.005). S100 proteins perform better as biomarkers for active LN involvement in SLE patients positive for anti-dsDNA antibodies. Lastly, binary logistic regression and AUC analysis suggests the combination of serum S100A8/A9 and S100A12 to predict response to RTX treatment in LN after 6 months.Conclusion:Findings from this study show promise for clinical application of S100 proteins to predict active renal disease in SLE and response to treatment with rituximab. Significantly overlapping values between groups currently prohibit the definition of cut-off values and prospective studies are required to validate findings.References:[1]Reppe Moe SE,et al. Assessing the relative impact of lupus nephritis on mortality in a population-based systemic lupus erythematosus cohort.Lupus. 2019;28(7):818-825.[2]Austermann J,et al. S100 proteins in rheumatic diseases.Nat Rev Rheumatol. 2018;14(9):528-541.[3]Tydén H,et al. Pro-inflammatory S100 proteins are associated with glomerulonephritis and anti-dsDNA antibodies in systemic lupus erythematosus.Lupus. 2017;26(2):139-149.[4]Yee CS,et al. Numerical scoring for the BILAG-2004 index.Rheumatology.2010; 49(9):1665-1669.[5]McCarthyet al. Short-term efficacy and safety of rituximab therapy in refractory systemic lupus erythematosus: Results from the british isles lupus assessment group biologics register.Rheumatol. 2018;57(3):470-479.Acknowledgments:Clinical information and serum/urine samples from SLE patients were provided by BILAG-BR centres.Disclosure of Interests:Jennifer Davies: None declared, Angela Midgley: None declared, Sean Donohue: None declared, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GSK, and UCB, Consultant of: Eli Lilly, AstraZeneca, UCB, Iltoo, and Merck Serono, Speakers bureau: UCB, Michael Beresford: None declared, Christian Hedrich Grant/research support from: Research grant support from Novartis (Molecular pathophysiology of psoriasis)., Speakers bureau: Speaker honoraria from Roche (pathophysiology of polyarticular JIA and systemic JIA); involved in advisory boards for Novartis (systemic JIA and IL-1 mediated diseases).

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Soluble TNF-R1, VEGF and other cytokines as markers of disease activity in systemic lupus erythematosus and lupus nephritis

Lupus ◽

10.1177/0961203319845487 ◽

2019 ◽

Vol 28 (6) ◽

pp. 713-721 ◽

Cited By ~ 4

Author(s):

Z Adhya ◽

M El Anbari ◽

S Anwar ◽

A Mortimer ◽

N Marr ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Disease Activity ◽

Lupus Erythematosus ◽

Response To Therapy ◽

Complement C3 ◽

Systemic Lupus ◽

Multiplex Bead ◽

Urine Markers ◽

Serum And Urine

Background Current non-invasive methods of assessing disease activity in systemic lupus erythematosus (SLE) are of limited sensitivity and specificity. Testing includes acute phase markers, autoantibodies and complement levels. Although measurements of dsDNA antibodies and complement C3/C4 levels are routine, they remain of limited value. Improved blood and urine markers may help in early detection of flare, distinction between flare and chronic damage, and monitoring response to therapy. Methods A total of 87 patients with SLE were tested for the following cytokines in serum and urine: monocyte chemoattractant protein 1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), soluble tumour necrosis factor receptor 1 (sTNF-R1), interferon-inducible protein 10 (IP-10), monocyte inhibitory protein 1α (MIP-1α) and vascular endothelial growth factor (VEGF). Patients attending the Lupus Unit at St Thomas’ Hospital, London, UK were divided into active lupus nephritis (LN), inactive LN and non-renal SLE groups based on their renal pathology and SLE disease activity index (SLEDAI). Cytokine testing was performed using the FIDIS multiplex bead assay. Results The mean level of serum sTNF-R1 was higher in the active LN group compared with both inactive LN and non-renal SLE groups ( p < 0.001). For urine measurements there were significant differences between active LN and non-renal SLE for VEGF ( p = 0.016), after statistical correction for multiple testing. Both urinary and serum sTNF-R1 and IP-10 levels correlated with SLEDAI scores ( p < 0.001), while serum VEGF correlated weakly with SLEDAI ( p = 0.025). The optimum combination for differentiating active from inactive LN patients was serum VEGF, sTNF-R1, MCP-1 and glomerular filtration rate plus urinary sTNF-R1 and protein-creatinine ratio. Conclusion These results indicate that for active LN, sTNF-R1 could be a useful serum cytokine marker, with potential for VEGF in the urine. This study has confirmed the ability of the multiplex bead technique to detect cytokines in a good analytical range, including very low and high levels, in both serum and urine. Combining serum and urine markers provided additional sensitivity in distinguishing active from inactive LN.

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Effect of Autoantibodies to Erythropoietin Receptor in Systemic Lupus Erythematosus with Biopsy-proven Lupus Nephritis

The Journal of Rheumatology ◽

10.3899/jrheum.151430 ◽

2016 ◽

Vol 43 (7) ◽

pp. 1328-1334 ◽

Cited By ~ 6

Author(s):

Akinori Hara ◽

Kengo Furuichi ◽

Junya Yamahana ◽

Haruka Yasuda ◽

Yasunori Iwata ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Disease Activity ◽

Lupus Erythematosus ◽

Significant Risk ◽

Serum Levels ◽

Erythropoietin Receptor ◽

Response To Treatment ◽

Systemic Lupus ◽

Renal Response

Objective.We examined the clinical significance of autoantibodies to the erythropoietin receptor (EPOR) in patients with systemic lupus erythematosus (SLE) who had biopsy-proven lupus nephritis (LN).Methods.Forty-six Japanese patients with SLE with LN who had undergone renal biopsy during 1993–2014 were enrolled in this study and followed for a mean of 83 months. Sera from those patients were screened for anti-EPOR antibodies using ELISA.Results.Anti-EPOR antibodies were detected in 18 (39%) of the 46 patients with SLE with anemia. Anti-EPOR antibodies were associated with low hemoglobin concentrations and reticulocytopenia. In addition, anti-EPOR antibodies were positively correlated with SLE disease activity, even though serum levels of the complement factors 3 and 4 did not differ between the 2 groups. In patients with International Society of Nephrology/Renal Pathology Society 2003 class IV LN, anti-EPOR antibodies were associated with active lesions including cellular crescents in glomeruli. Decrease in renal function was more frequently observed in patients without complete or partial renal response than in patients with it, and serum levels of the antibodies as well as renal response to treatment were significant risk factors for progression of renal dysfunction.Conclusion.The present study suggests that anti-EPOR antibodies might be involved in overall disease activity and active renal lesions, as well as in the impaired erythropoiesis in patients with SLE with LN. Further, the levels of anti-EPOR antibodies may be an additional predictor for renal injury.

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Urine and serum S100A8/A9 and S100A12 associate with active lupus nephritis and may predict response to rituximab treatment

RMD Open ◽

10.1136/rmdopen-2020-001257 ◽

2020 ◽

Vol 6 (2) ◽

pp. e001257

Author(s):

Jennifer C Davies ◽

Angela Midgley ◽

Emil Carlsson ◽

Sean Donohue ◽

Ian N Bruce ◽

...

Keyword(s):

Lupus Nephritis ◽

Renal Disease ◽

Disease Activity ◽

Calcium Binding ◽

Therapeutic Potential ◽

Activity Index ◽

S100 Proteins ◽

Response To Treatment ◽

Inflammatory Disorder ◽

Serum And Urine

BackgroundApproximately 30% of patients with the systemic autoimmune/inflammatory disorder systemic lupus erythematosus (SLE) develop lupus nephritis (LN) that affects treatment and prognosis. Easily accessible biomarkers do not exist to reliably predict renal disease. The Maximizing SLE Therapeutic Potential by Application of Novel and Systemic Approaches and the Engineering Consortium aims to identify indicators of treatment responses in SLE. This study tested the applicability of calcium-binding S100 proteins in serum and urine as biomarkers for disease activity and response to treatment with rituximab (RTX) in LN.MethodsS100A8/A9 and S100A12 proteins were quantified in the serum and urine of 243 patients with SLE from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR) study and 48 controls matched for age using Meso Scale Discovery’s technology to determine whether they perform as biomarkers for active LN and/or may be used to predict response to treatment with RTX. Renal disease activity and response to treatment was based on BILAG-BR scores and changes in response to treatment.ResultsSerum S100A12 (p<0.001), and serum and urine S100A8/A9 (p<0.001) levels are elevated in patients with SLE. While serum and urine S100 levels do not correlate with global disease activity (SLE Disease Activity Index), levels in urine and urine/serum ratios are elevated in patients with active LN. S100 proteins perform better as biomarkers for active LN involvement in patients with SLE who tested positive for anti-double-stranded DNA antibodies. Binary logistic regression and area under the curve analyses suggest the combination of serum S100A8/A9 and S100A12 can predict response to RTX treatment in LN after 6 months.ConclusionsFindings from this study show promise for clinical application of S100 proteins to predict active renal disease in SLE and response to treatment with RTX.

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Serum uric acid as a predictor for nephritis in Egyptian patients with systemic lupus erythematosus

Lupus ◽

10.1177/0961203320979042 ◽

2020 ◽

pp. 096120332097904

Author(s):

Eman Ahmed Hafez ◽

Sameh Abd El-mottleb Hassan ◽

Mohammed Abdel Monem Teama ◽

Fatma Mohammed Badr

Keyword(s):

Systemic Lupus Erythematosus ◽

Renal Function ◽

Uric Acid ◽

Lupus Nephritis ◽

Serum Creatinine ◽

Disease Activity ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Group 2 ◽

Group 1

Objective Lupus nephritis (LN) is closely associated with hyperuricemia, and uric acid is considered a risk factor for renal involvement in systemic lupus erythematosus (SLE). This study aimed to examine the association between serum uric acid (SUA) level and LN development and progression in SLE patients with normal renal function. Methods A total of 60 SLE patients with normal renal function from Ain Shams University Hospital were selected and assigned to group 1 (30 patients with LN) and group 2 (30 patients without LN). All patients were subjected to history taking, clinical examination, disease activity assessment based on SLE disease activity index (SLEDAI) and renal SLEDAI (SLEDAI-R) scores, and laboratory investigations, including as SUA, complete blood count, blood urea nitrogen (BUN), serum creatinine, creatinine clearance, urine analysis, protein/creatinine ratio, 24-h urinary protein excretion, Antinuclear antibodies (ANA), anti-dsDNA antibody, and serum complement (C3, C4). Results Disease duration, SLEDAI score, and SUA level were higher in group 1 than in group 2 (p < 0.001). SUA level was positively correlated with SLEDAI and SLEDAI-R scores, proteinuria, urinary casts, renal biopsy class, disease activity and chronicity indices, BUN level, and serum creatinine level but was negatively correlated with creatinine clearance (p < 0.05). SUA was a predictor of LN development in SLE patients (sensitivity, 83.3%; specificity, 70%). Conclusion SUA is associated with the development of lupus nephritis in patients with normal kidney function also SUA in-dependently correlated with disease activity and chronicity in LN.

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Longterm Outcomes and Damage Accrual in Patients with Childhood Systemic Lupus Erythematosus with Psychosis and Severe Cognitive Dysfunction

The Journal of Rheumatology ◽

10.3899/jrheum.121096 ◽

2013 ◽

Vol 40 (4) ◽

pp. 513-519 ◽

Cited By ~ 20

Author(s):

Lily Siok Hoon Lim ◽

Arlette Lefebvre ◽

Susanne Benseler ◽

Earl D. Silverman

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Cognitive Dysfunction ◽

Lupus Erythematosus ◽

Clinical Course ◽

Immunosuppressive Treatment ◽

Damage Index ◽

Response To Treatment ◽

Systemic Lupus ◽

Damage Accrual

Objective.(1) To describe the clinical course and response to treatment; and (2) to evaluate and compare damage accrual of distinct phenotypic subgroups of patients with clinically important psychiatric illness of pediatric systemic lupus erythematosus (pSLE).Methods.A single-center cohort study of patients with pSLE followed at a pediatric lupus clinic from 1985 to July 2009. Clinical course and response to treatment were studied. Remission was defined by absence of psychiatric/cognitive symptoms while receiving minimal doses of prednisone. Disease activity and damage were measured using SLE Disease Activity Index and SLE Damage Index.Results.Fifty-three children were included: 40 with psychosis and cognitive dysfunction (PSYC group) and 13 with isolated cognitive dysfunction (COG group). All received immunosuppressive treatment. Eighteen of 32 treated with azathioprine required a change to cyclophosphamide for poor response but none on cyclophosphamide required a change. The median times to remission were 72 weeks (PSYC) and 70 weeks (COG). Eight patients (7 PSYC, 1 COG) experienced flare following response/remission. New damage was noted in 50% of children at a median of 11 months: 57% of PSYC group, 31% of COG group. Persistent cognitive dysfunction was seen in 16% of PSYC patients and 15% of COG patients.Conclusion.Most patients responded to immunosuppressive treatment, although median time to remission was > 1 year. Roughly half the patients acquired a new damage item, most of which did not interfere with functional abilities. Fewer than 20% of patients developed neuropsychiatric damage. Both phenotypes of psychiatric pSLE responded equally well to current treatment.

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Clinical and immunological characteristics of 150 systemic lupus erythematosus patients in Jamaica: a comparative analysis

Lupus ◽

10.1177/0961203317707828 ◽

2017 ◽

Vol 26 (13) ◽

pp. 1448-1456 ◽

Cited By ~ 4

Author(s):

K C Maloney ◽

T S Ferguson ◽

H D Stewart ◽

A A Myers ◽

K De Ceulaer

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Disease Activity ◽

Renal Biopsy ◽

Diagnostic Criteria ◽

Lupus Erythematosus ◽

Antinuclear Antibodies ◽

Damage Index ◽

Systemic Lupus ◽

Dsdna Antibodies

Background Epidemiological studies in systemic lupus erythematosus have been reported in the literature in many countries and ethnic groups. Although systemic lupus erythematosus in Jamaica has been described in the past, there has not been a detailed evaluation of systemic lupus erythematosus patients in urban Jamaica, a largely Afro-Caribbean population. The goal of this study was to describe the clinical features, particularly disease activity, damage index and immunological features, of 150 systemic lupus erythematosus subjects. Methods 150 adult patients (≥18 years) followed in rheumatology clinic at a tertiary rheumatology hospital centre (one of two of the major public referral centres in Jamaica) and the private rheumatology offices in urban Jamaica who fulfilled Systemic Lupus International Collaborating Clinics (SLICC) criteria were included. Data were collected by detailed clinical interview and examination and laboratory investigations. Hence demographics, SLICC criteria, immunological profile, systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) and SLICC/American College of Rheumatology (ACR) damage index (SDI) were documented. Results Of the 150 patients, 145 (96.7%) were female and five (3.3%) were male. The mean age at systemic lupus erythematosus onset was 33.2 ± 10.9. Mean disease duration was 11.3 ± 8.6 years. The most prevalent clinical SLICC criteria were musculoskeletal, with 141 (94%) of subjects experiencing arthralgia/arthritis, followed by mucocutaneous manifestations of alopecia 103 (68.7%) and malar rash 46 (30.7%), discoid rash 45 (30%) and photosensitivity 40 (26.7%). Lupus nephritis (biopsy proven) occurred in 42 (28%) subjects and 25 (16.7%) met SLICC diagnostic criteria with only positive antinuclear antibodies/dsDNA antibodies and lupus nephritis on renal biopsy. The most common laboratory SLICC criteria were positive antinuclear antibodies 136 (90.7%) followed by anti-dsDNA antibodies 95 (63.3%) and low complement (C3) levels 38 (25.3%). Twenty-seven (18%) met SLICC diagnostic criteria with only positive antinuclear antibodies/anti-dsDNA antibodies and lupus nephritis on renal biopsy. Mean SLEDAI score was 6.9 ± 5.1 with a range of 0–32. Organ damage occurred in 129 (86%) patients; mean SDI was 2.4 ± 1.8, with a range of 0–9. Conclusion These results are similar to the clinical manifestations reported in other Afro-Caribbean populations; however, distinct differences exist with respect to organ involvement and damage, particularly with respect to renal involvement, which appears to be reduced in our participants.

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Analysis of disease activity and response to treatment in a large Spanish cohort of patients with systemic lupus erythematosus

Lupus ◽

10.1177/0961203314563818 ◽

2014 ◽

Vol 24 (7) ◽

pp. 720-729 ◽

Cited By ~ 13

Author(s):

J M Pego-Reigosa ◽

Í Rúa-Figueroa ◽

F J López-Longo ◽

M Galindo-Izquierdo ◽

J Calvo-Alén ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Response To Treatment ◽

Systemic Lupus ◽

Spanish Cohort

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The association between serum prolactin levels and interleukin-6 and systemic lupus erythematosus activity

Reumatismo ◽

10.4081/reumatismo.2018.1075 ◽

2018 ◽

Vol 70 (4) ◽

pp. 241-250 ◽

Cited By ~ 4

Author(s):

W.A. Wan Asyraf ◽

M.S. Mohd Shahrir ◽

W. Asrul ◽

A.W. Norasyikin ◽

O. Hanita ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Disease Activity ◽

Lupus Erythematosus ◽

Prolactin Level ◽

Serum Prolactin ◽

Systemic Lupus ◽

Serum Prolactin Level ◽

Active Lupus Nephritis ◽

Active Lupus

Based on the recent evidence of association between hyperprolactinemia and systemic lupus erythematosus disease activity (SLEDAI), a study was conducted to analyze the association of hyperprolactinemia with lupus nephritis disease activity. In this cross-sectional study, the analysis was conducted on SLE patients who visited the University Kebangsaan Malaysia Medical Centre (UKMMC) Nephrology Clinic from August 2015 till February 2016. The disease activity was measured using the SLEDAI score, with more than 4 indicating active lupus nephritis. Basal resting prolactin level was analyzed in 43 patients with lupus nephritis, in 27.9% of them had raised serum prolactin. The median of serum prolactin level at 0 minutes was 19.91 ng/mL (IQR: 15.95-22.65 ng/ mL) for active lupus nephritis, which was significantly higher compared to the median of serum prolactin level of 14.34 ng/mL (IQR: 11.09-18.70 ng/mL) for patients in remission (p=0.014). The serum prolactin level positively correlated with SLEDAI (rhos: 0.449, p=0.003) and the UPCI level in lupus nephritis patients (rhos: 0.241, p=0.032). The results were reproduced when the serum prolactin was repeated after 30 minutes. However, the serum prolactin levels at 0 minutes were higher than those taken after 30 minutes (p=0.001). An assessment of serum IL-6 levels found that the active lupus nephritis patients had a higher median level of 65.91 pg/ mL (IQR: 21.96-146.14 pg/mL) compared to the in-remission level of 15.84 pg/mL (IQR: 8.38-92.84 pg/mL), (p=0.039). Further correlation analysis revealed that there was no statistical correlation between the interleukin (IL)-6 levels with serum prolactin, SLEDAI and other lupus nephritis parameters. An ROC curve analysis of serum prolactin at 0 minutes and serum prolactin after 30 minutes and IL-6 levels for prediction of SLE disease activity provided the cutoff value of serum prolactin at 0 minutes, which was 14.63 ng/mL with a sensitivity of 91.7% and specificity of 58.1% and AUC of 0.74 (p=0.015). This study concurred with the previous findings that stated that hyperprolactinemia is prevalent in SLE patients and correlated with clinical disease activity and UPCI level. The baseline of the fasting serum prolactin level was found to be a sensitive biomarker for the evaluation of lupus nephritis disease activity.

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Serum GlycA level is a candidate biomarker for disease activity in systemic lupus erythematosus and for proliferative status of lupus nephritis, independent of renal function impairment.

10.1101/493809 ◽

2018 ◽

Author(s):

Tim Dierckx ◽

Sylvie Goletti ◽

Laurent Chiche ◽

Laurent Daniel ◽

Bernard Lauwerys ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Logistic Regression ◽

Renal Function ◽

Lupus Nephritis ◽

Serum Albumin ◽

Disease Activity ◽

Lupus Erythematosus ◽

Regression Models ◽

Systemic Lupus ◽

Logistic Regression Models

Objective: Glycoprotein acetylation (GlycA) is a novel biomarker for chronic inflammation, associated to cardiovascular risk. Serum GlycA levels are increased in several inflammatory diseases, including systemic lupus erythematosus (SLE). We investigated the relevance of serum GlycA measurement in SLE and lupus nephritis (LN). Methods: GlycA was measured by NMR in 194 serum samples from patients and controls. Comparisons were performed between groups. Clinical and biological parameters were tested for correlation with GlycA levels. The predictive value of GlycA to differentiate proliferative from non-proliferative LN was determined using logistic regression models. Results: GlycA was correlated to C-reactive protein (CRP), neutrophil count, proteinuria and the SLE disease activity index (SLEDAI), and inversely with serum albumin. GlycA was higher in active (n=105) than in quiescent (n=39) SLE patients, in healthy controls (n=29), and in patients with non-lupus nephritis (n=21), despite a more altered renal function in the latter. In patients with biopsy-proven active LN, GlycA was higher in proliferative (n=32) than non-proliferative (n=11) LN, independent of renal function and proteinuria level. Logistic regression models showed that, in univariate models, GlycA outperforms traditional biomarkers. A bivariate model using GlycA and BMI better predicted the proliferative status of LN than a model comprising CRP, renal function (eGFR), serum albumin, proteinuria, C3 consumption and the presence of anti-dsDNA antibodies. Conclusion: Serum GlycA is elevated in SLE, and correlates with disease activity and LN. Serum GlycA, which summarizes different inflammatory processes, could be a valuable biomarker to discriminate proliferative from non-proliferative LN and should be tested in large, prospective cohorts.

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