Impact of sex disparities on the clinical manifestations in patients with systemic lupus erythematosus

Boodhoo, Kamini Devi; Liu, Sijia; Zuo, Xiaoxia

doi:10.1097/md.0000000000004272

Cited by 63 publications

(57 citation statements)

References 49 publications

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“…no. reviews contributing termsReviews contributing terms‘Place’Place of residence5No-5No-5[10–14]‘Race’Race / ethnicity / culture / language3Yes →69No-9[11, 15–22]Occupation6No-6No-6[11], [13], [16], [23], [24], [25]‘Gender’Gender / sex1Yes →67No-7[16], [17], [18], [19], [26], [27], [28]Religion0Yes →11Yes →23[17, 29, 30]Education7No-7No-7[11, 13, 16, 24, 25, 31, 32]‘SES’Socio-economic status12No-12No-12[11], [13], [15], [23], [24], [25], [31], [32], [33], [34], [35], [36]Social capital0Yes →11Yes →45[17, 37–40]Other category not encompassed by PROGRESS-Plus6No-...…”

Section: Resultsmentioning

confidence: 99%

Development and validation of a search filter to identify equity-focused studies: reducing the number needed to screen

Prady

Uphoff

Power

et al. 2018

BMC Med Res Methodol

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BackgroundHealth inequalities, worse health associated with social and economic disadvantage, are reported by a minority of research articles. Locating these studies when conducting an equity-focused systematic review is challenging due to a deficit in standardised terminology, indexing, and lack of validated search filters. Current reporting guidelines recommend not applying filters, meaning that increased resources are needed at the screening stage.MethodsWe aimed to design and test search filters to locate studies that reported outcomes by a social determinant of health. We developed and expanded a ‘specific terms strategy’ using keywords and subject headings compiled from recent systematic reviews that applied an equity filter. A ‘non-specific strategy’ was compiled from phrases used to describe equity analyses that were reported in titles and abstracts, and related subject headings. Gold standard evaluation and validation sets were compiled. The filters were developed in MEDLINE, adapted for Embase and tested in both. We set a target of 0.90 sensitivity (95% CI; 0.84, 0.94) in retrieving 150 gold standard validation papers. We noted the reduction in the number needed to screen in a proposed equity-focused systematic review and the proportion of equity-focused reviews we assessed in the project that applied an equity filter to their search strategy.ResultsThe specific terms strategy filtered out 93-95% of all records, and retrieved a validation set of articles with a sensitivity of 0.84 in MEDLINE (0.77, 0.89), and 0.87 (0.81, 0.92) in Embase. When combined (Boolean ‘OR’) with the non-specific strategy sensitivity was 0.92 (0.86, 0.96) in MEDLINE (Embase 0.94; 0.89, 0.97). The number needed to screen was reduced by 77% by applying the specific terms strategy, and by 59.7% (MEDLINE) and 63.5% (Embase) by applying the combined strategy. Eighty-one per cent of systematic reviews filtered studies by equity.ConclusionsA combined approach of using specific and non-specific terms is recommended if systematic reviewers wish to filter studies for reporting outcomes by social determinants. Future research should concentrate on the indexing standardisation for equity studies and further development and testing of both specific and non-specific terms for accurate study retrieval.Electronic supplementary materialThe online version of this article (10.1186/s12874-018-0567-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Development and validation of a search filter to identify equity-focused studies: reducing the number needed to screen

Prady

Uphoff

Power

et al. 2018

BMC Med Res Methodol

View full text Add to dashboard Cite

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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%

P108 Exploring the molecular basis of gender bias in systemic lupus erythematosus (SLE)

Kosmara

Panousis

Banos

et al. 2018

Poster Presentations

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Background/objectivesSLE features a substantially greater frequency in females than in males (ratio ranging 7:1–15:1). By contrast, males tend to suffer from more severe disease.1–3 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.Materials and methodsWhole blood RNA was extracted from SLE patients and healthy individuals. Paired-end mRNA sequencing was performed using the Illumina HiSeq2000 platform. A list of DEGs in SLE males versus females were generated using 5% false discovery rate (FDR). To increase the specificity of our results, we generated a similar list of DEGs in healthy males versus females using a 50% and 90% FDR cut-off, and the two lists were intersected.ResultsWe studied 142 SLE patients with diverse levels of disease activity/severity (120 SLE females, 22 SLE males) compared to 58 matched healthy volunteers (48 healthy females, 10 healthy males). We identified 39 genes which were significantly differentially expressed in SLE males versus females. Notably, 6 of these genes were not differentially expressed in healthy males versus females at either 50 or 90% FDR, highlighting a potential role in disease sexual dimorphism. The proteins encoded by these genes are implicated in various biological processes such as transcriptional regulation and DNA damage repair (SMC1A), lipoprotein particles catabolism (APOE), glutathione biosynthesis and metabolism (OPLAH), correct composition of bone and cartilage matrix (ARSD), whereas 2 of these genes do not code for proteins (MTCO2 and FRG1B). Further validation of these genes is in progress.ConclusionsA gender-biased molecular signature specifically associated with SLE was unraveled. Further investigation of the molecular pathways which are associated with these genes will give us insights for the molecular basis of gender bias in SLE and lead to novel, more effective treatments tailored for male and female patients.References. Margery-Muir AA, et al. Gender balance in patients with systemic lupus erythematosus. Autoimmun Rev 2017;16(3):258–268.. Boodhoo KD, Liu S, Zuo X. Impact of sex disparities on the clinical manifestations in patients with systemic lupus erythematosus: A systematic review and meta-analysis. Medicine (Baltimore) 2016;95(29):e4272.. Gergianaki I, et al. Epidemiology and burden of systemic lupus erythematosus in a Southern European population: Data from the community-based lupus registry of Crete, Greece. Ann Rheum Dis 2017.

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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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Impact of sex disparities on the clinical manifestations in patients with systemic lupus erythematosus

Cited by 63 publications

References 49 publications

Development and validation of a search filter to identify equity-focused studies: reducing the number needed to screen

Development and validation of a search filter to identify equity-focused studies: reducing the number needed to screen

P108 Exploring the molecular basis of gender bias in systemic lupus erythematosus (SLE)

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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