Gender balance in patients with systemic lupus erythematosus

Margery-Muir, Audrey A; Bundell, Christine; Nelson, Delia J.; Groth, David; Wetherall, J. D.

doi:10.1016/j.autrev.2017.01.007

Cited by 58 publications

(49 citation statements)

References 114 publications

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“…Systemic lupus erythematosus (SLE) is a prototypic chronic multi-organ autoimmune disease characterized by immune complex deposition and vasculopathy, and therefore, can affect any organ and tissue of the human body. As a complex autoimmune disease (1), it is characterized by clinical heterogeneity, more common among women (2) and with an estimated prevalence of 20 to 150 cases per 100,000 population (3,4). The pathogenesis of SLE is not fully understood and believed to be a result of a complex interplay between genetic susceptibility (5) and environmental factors in subjects with primary dysregulation in both innate and adaptive immune system with dysregulation of type -1 interferon being a common denominator (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity, safety and tolerability of anti-pneumococcal vaccination in systemic lupus erythematosus patients: An evidence-informed and PRISMA compliant systematic review and meta-analysis

Adawi

Bragazzi

McGonagle

et al. 2019

Autoimmunity Reviews

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Section: Introductionmentioning

confidence: 99%

Immunogenicity, safety and tolerability of anti-pneumococcal vaccination in systemic lupus erythematosus patients: An evidence-informed and PRISMA compliant systematic review and meta-analysis

Adawi

Bragazzi

McGonagle

et al. 2019

Autoimmunity Reviews

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“…Since SLE develops late in the second year of life and autoantibodies appear several months after their birth, the MRL+/+ mice are an ideal model to study the role of PCE in inducing/exacerbating ADs. Female mice were chosen for this study due to higher susceptibility and prevalence of ADs in females (Danchenko et al, 2006; Frostegard et al, 2005; Margery-Muir et al, 2017; Wang et al, 2010, 2012b). Five-week old female MRL+/+ mice, purchased from The Jackson Laboratories (Bar Harber, ME), were housed in plastic cages on a bedding of wood chips at the University of Texas Medical Branch (UTMB) animal house facility maintained at ~ 22 °C, 50–60% relative humidity, and a 12h light/dark cycle.…”

Section: Methodsmentioning

confidence: 99%

Autoimmune potential of perchloroethylene: Role of lipid-derived aldehydes

Wang

Ansari

et al. 2017

Toxicology and Applied Pharmacology

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Tetrachloroethene (perchloroethylene, PCE), an ubiquitous environmental contaminant, has been implicated in inducing autoimmunity/autoimmune diseases (ADs), including systemic lupus erythematosus (SLE) and scleroderma in humans. However, experimental evidence suggesting the potential of PCE in mediating autoimmunity is lacking. This study was, therefore, undertaken to explore PCE’s potential in inducing/exacerbating an autoimmune response. Six-week old female MRL+/+ mice, in groups of 6 each, were treated with PCE (0.5 mg/ml) via drinking water for 12, 18 and 24 weeks and markers of autoimmunity and oxidative stress were evaluated. PCE exposure led to significant increases in serum anti-nuclear antibodies (ANA), anti-dsDNA and anti-scleroderma-70 (anti-Scl-70) antibodies at 18 weeks and, to a greater extent at 24 weeks, suggesting that PCE exposure exacerbated autoimmunity in our animal model. The increases in autoantibodies were associated with time-dependent increases in malondialdehyde (MDA)-protein adducts and their antibodies, as well as significantly decreased levels of antioxidants GSH and SOD. The splenocytes isolated from mice treated with PCE for 18 and 24 weeks showed greater Th17 cell proliferation and increased release of IL-17 in culture supernatants following stimulation with MDA-mouse serum albumin adducts, suggesting that MDA-modified proteins may act as an immunologic trigger by activating Th17 cells and contribute to PCE-mediated autoimmunity. Our studies thus provide an experimental evidence that PCE induces/exacerbates an autoimmune response and lipid-derived aldehydes (such as MDA) contribute to this response.

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“…By contrast, males tend to suffer from more severe disease. [1][2][3] Understanding the molecular basis of SLE variability and sexual dimorphism may advance our understanding of disease pathogenesis and assist the development of personalized treatments. We performed full transcriptome analysis (RNA-seq) to monitor for differentially expressed genes (DEGs) between male and female SLE patients that are not differentially expressed between male and female healthy subjects, thus identifying a gender-biased molecular signature specific for the disease.…”

Section: Exploring the Molecular Basis Of Gender Bias In Systemic Lupmentioning

confidence: 99%

“…Preclinical studies have shown the ability of synthetic vaccine particles containing rapamycin (SVP-R) to inhibit the formation of ADAs against pegsiticase, a pegylated uricase. 1 Here we report initial data on the safety, immunogenicity and activity of an ongoing Phase 2 study of SEL-212, a novel combination therapy consisting of pegsiticase and SVP-R. Objectives Evaluate the ability of monthly doses of SEL-212 to mitigate the immunogenicity of pegsiticase and enable sustained control of sUA in gout patients.…”

Section: Exploring the Molecular Basis Of Gender Bias In Systemic Lupmentioning

confidence: 99%

P109 Clinical development of a novel strategy to mitigate biologic immunogenicity: monthly dosing of a pegylated uricase with SVP-R enables sustained reduction of serum uric acid (SUA) levels by mitigating formation of anti-drug antibodies (ADAS)

Sands

Kivitz

DeHaan

et al. 2018

Poster Presentations

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IntroductionPegylated uricases are a promising but highly immunogenic therapy for severe gout. Preclinical studies have shown the ability of synthetic vaccine particles containing rapamycin (SVP-R) to inhibit the formation of ADAs against pegsiticase, a pegylated uricase.1 Here we report initial data on the safety, immunogenicity and activity of an ongoing Phase 2 study of SEL-212, a novel combination therapy consisting of pegsiticase and SVP-R.ObjectivesEvaluate the ability of monthly doses of SEL-212 to mitigate the immunogenicity of pegsiticase and enable sustained control of sUA in gout patients.MethodsPatients with symptomatic gout and elevated sUA (≥6 mg/dL) were treated with fixed doses of pegsiticase (0.2 mg/kg or 0.4 mg/kg) alone or co-administered with SVP-R (0.05, 0.08, or 0.1 mg/kg). SEL-212 was infused in 28 day cycles x3 doses followed by challenge with pegsiticase alone on 28 day cycles x2 doses. Safety, tolerability, sUA, and ADAs were monitoredResultsIn the SEL-212 Phase 1b study, 70% of patients administered 0.4 mg/kg pegsiticase with a mid-dose of 0.1 mg/kg SVP-R showed low or no ADA formation correlating with sustained low sUA levels for at least 30 days after a single dose, compared to 20% for patients treated with pegsiticase alone. In the ongoing Phase 2 study, the majority of patients receiving 0.1 mg/kg SVP-R administered with either 0.2 or 0.4 mg/kg pegsiticase also showed low or no ADAs and maintained low sUA levels after 3 monthly doses of SEL-212, indicating sustained activity with repeated doses of SEL-212. However after 2 subsequent doses of pegsiticase alone, a drop in activity was noted. These data suggest that either a higher dose of SVP-R or the addition of SVP-R at the 4th and 5th dose may be required to sustain activity through 5 months. Currently patients are being dosed with 0.15 mg/kg SVP-R, a dose level which enabled sustained control of sUA levels in all patients in Phase 1b. SEL-212 was generally well tolerated and associated with a low rate of gout flare rates compared to those treated with pegsiticase alone.ConclusionsSVP-R showed a dose-dependent reduction in ADAs and enabled sustained control of sUA with repeated dosing of SEL-212. SVP-R is a promising approach to prevent the formation of ADAs against immunogenic biologic therapies.Reference. Kishimoto TK, et al. Nature Nanotechnol2016;11:890–899.AcknowledgementsWe thank the patients that participated in these studies, the clinical study site investigators, and the entire SEL-212 project team.Disclosure of interestE. Sands Employee of: Selecta Biosciences, A. Kivitz: None declared, W. DeHaan Employee of: Selecta Biosciences, L. Johnston Employee of: Selecta Biosciences, T. Kishimoto Employee of: Selecta Biosciences

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Gender balance in patients with systemic lupus erythematosus

Cited by 58 publications

References 114 publications

Immunogenicity, safety and tolerability of anti-pneumococcal vaccination in systemic lupus erythematosus patients: An evidence-informed and PRISMA compliant systematic review and meta-analysis

Immunogenicity, safety and tolerability of anti-pneumococcal vaccination in systemic lupus erythematosus patients: An evidence-informed and PRISMA compliant systematic review and meta-analysis

Autoimmune potential of perchloroethylene: Role of lipid-derived aldehydes

P109 Clinical development of a novel strategy to mitigate biologic immunogenicity: monthly dosing of a pegylated uricase with SVP-R enables sustained reduction of serum uric acid (SUA) levels by mitigating formation of anti-drug antibodies (ADAS)

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