Frontiers in lupus最新文献

{"title":"Insights into future management of lupus nephritis","authors":"A. Askanase, M. Dall'Era, S. Almaani","doi":"10.3389/flupu.2024.1334932","DOIUrl":"https://doi.org/10.3389/flupu.2024.1334932","url":null,"abstract":"Lupus nephritis (LN) is a common and serious manifestation of systemic lupus erythematosus and is a major cause of mortality and morbidity. The current standard-of-care treatment for LN include conventional immunosuppressive treatments such as mycophenolate mofetil, cyclophosphamide, or azathioprine, combined with glucocorticoids. However, this treatment approach has several unmet needs, such as achieving only modest remission rates, potential toxicities, and prolonged cumulative steroid exposure, resulting in suboptimal patient outcomes. The LN treatment landscape is evolving rapidly to meet these unmet needs, with belimumab and voclosporin being the first drugs approved specifically for treatment of LN in 2020 and 2021, respectively. Here, we review the likely roles in LN therapy for several targeted therapies, including select therapies under investigation, and interventions in early development such as therapies targeting B cells (obinutuzumab, atacicept, ianalumab, and CD19 chimeric antigen T-cell therapy), inflammatory cytokines (secukinumab and anifrolumab), and the immunoproteasome (zetomipzomib); we also review treatment strategies designed to minimize steroid exposure. Treatments in development have demonstrated encouraging short- and long-term efficacy and steroid-sparing potential, potentially paving the way for improved treatment regimens and patient outcomes in LN.","PeriodicalId":94014,"journal":{"name":"Frontiers in lupus","volume":"33 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139798393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteonecrosis is associated with APOL1 variants in African Americans with systemic lupus erythematosus","authors":"Kevin Yip, Meredith Akerman, Ruth Fernandez Ruiz, Nicole Leung, Huda Algasas, Yingzhi Qian, Jill P. Buyon, Jasmin Divers, Peter Izmirly, Michael Belmont, Ashira D. Blazer","doi":"10.3389/flupu.2023.1219277","DOIUrl":"https://doi.org/10.3389/flupu.2023.1219277","url":null,"abstract":"Background/purpose African Americans (AA) with systemic lupus erythematosus (SLE) are at higher risk for both kidney disease and Osteonecrosis (ON). Two Apolipoprotein L1 (APOL1) risk variants (RV), G1 and G2, have been associated with chronic kidney disease (CKD), hypertension, and microvascular disease in AAs, which are independent risk factors for ON. Accordingly, we investigated the association between carriers of the APOL1 risk variants and the prevalence of ON in AA SLE patients. Methods A cohort of 121 adult participants of self-reported AA ancestry and meeting at least four of the American College of Rheumatology (ACR) revised criteria for SLE were recruited from a high volume urban SLE clinical site. PCR/sequencing was used to stratify participants by APOL1 genotype. Medical records, including clinical notes and imaging reports, were retrospectively reviewed for documentation of ON. Association between the number of APOL1 risk variants with time to first ON was tested. Results In our cohort, 18 individuals developed ON; across the APOL1 genotype groups, 2/37 0RV, 11/59 1RV, and 5/15 2RV participants were affected. The mean time to ON was 27 years, 22 years, and 18 years in 0RV, 1RV, and 2RV carriers, respectively. An adjusted Cox regression model showed that carrying the APOL1 risk variants associated with shorter ON free survival with hazard ratios (HR) of 3.1 (95% CI: 1.6–6.2) and 9.6 (95% CI 2.4–37.8) for 1RV and 2RV carriers, respectively. 2RV carriers more often exhibited multiple and bilateral joint sites affected by ON. Disease duration was longer in ON-affected participants at 20.5 years compared to 9.0 years in those unaffected ( p < 0.001). In individuals who had received glucocorticoids, median cumulative prednisone equivalent dose was higher in ON-affected participants, though this did not reach statistical significance (18.7 g vs. 9.0 g; p -value = 0.3). Conclusion Our analysis suggests a higher risk of osteonecrosis among African American SLE patients who carry the APOL1 risk variants. In addition, disease duration increased the rate of ON. Given the high frequency of the APOL1 risk variants in African Americans, APOL1 high-risk genotype carriers may represent an ON-vulnerable subgroup within the AA population. Further work is necessary to uncover the mechanism of this association.","PeriodicalId":94014,"journal":{"name":"Frontiers in lupus","volume":"49 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135095382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased carotid intima–media thickening and antioxidized low-density lipoprotein in an anti-Ro60 SLE autoantibody subset","authors":"Biji T. Kurien, James Fesmire, Swapan K. Nath, R. Hal Scofield","doi":"10.3389/flupu.2023.1197309","DOIUrl":"https://doi.org/10.3389/flupu.2023.1197309","url":null,"abstract":"Objective Premature atherosclerosis is associated with systemic lupus erythematosus (SLE). We have previously shown an association of anti-Ro60/La/Ro52 with antioxidized low-density lipoprotein (LDL) in SLE. Here, we hypothesized that carotid intima–media thickening (CIMT) would be associated with antioxidized LDL (anti-oxLDL)/antilipoprotein lipase (ALPL) in a specific SLE autoantibody subset (anti-Ro60 positive, anti-RNP positive, anti-SmRNP positive, or extractable nuclear antigen antibody negative). Methods We carried out a case-control study (one time-point testing) of CIMT, ALPL, anti-oxLDL, anti-low density lipoprotein (ALDL), and anti-LDL in 114 SLE patients and 117 age/sex-matched controls. The levels of total cholesterol, LDL, high-density lipoprotein (HDL), triglycerides, and HDL-Trig were also measured. A student's t -test was used for statistical analysis. Results Interestingly, the level of CIMT was highest in the SLE subset with anti-Ro60 (23/114). CIMT and anti-oxLDL were statistically significantly elevated in the anti-Ro60 SLE subset (1.3 ± 1.66, p < 0.01; 0.26 ± 0.16, p < 0.002, respectively) compared with controls (0.54 ± 1.26; 0.165 ± 0.13, respectively), but not anti-LPL/anti-LDL. CIMT was significantly elevated (0.9 ± 1.71; p < 0.05) in the SLE subset without antiextractable nuclear antigen (ENA) (63/114) compared with controls. The other antibodies in this subset were not statistically different from other SLE subsets or controls. Only antioxLDL was significantly elevated (0.29 ± 0.27; p < 0.005) in the SLE subset with anti-RNP (14/114) compared with controls, while none were elevated in the anti-SmRNP subset (6/114). We did not find any significant differences in lipids between the various SLE subsets. Conclusion CIMT segregates in anti-Ro and ENA negative groups either with or without anti-oxLDL. It will be clinically important if cardiovascular events are augmented in the SLE anti-Ro subset having elevated antioxidized LDL antibodies.","PeriodicalId":94014,"journal":{"name":"Frontiers in lupus","volume":"93 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135719045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Undifferentiated connective tissue disease with an incidental photo-provocation: a case report","authors":"David Roofeh, J. Michelle Kahlenberg","doi":"10.3389/flupu.2023.1223001","DOIUrl":"https://doi.org/10.3389/flupu.2023.1223001","url":null,"abstract":"A female patient with undifferentiated connective tissue disease and no documented history of photosensitivity fastidiously adhered to the rheumatologist's recommendation to avoid UV light exposure. Due to unexpected UV exposure, she developed multiple erythematous/violaceous macules, concerning a cutaneous lupus erythematosus reaction with a chilblain-like appearance. This study highlighted the importance of screening for unintentional photo-provocation in those who are suspected of having or being at risk for developing systemic lupus erythematosus.","PeriodicalId":94014,"journal":{"name":"Frontiers in lupus","volume":"135 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135885295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lupus-associated NCF2 variant p.R395W in the NADPH oxidase 2 complex results in a reduced production of reactive oxygen species by myeloid cells","authors":"Zhimin Song, Dae-Goon Yoo, Rachel A. Idol, E. Barbu, C. Jacob, M. Dinauer","doi":"10.3389/flupu.2023.1186641","DOIUrl":"https://doi.org/10.3389/flupu.2023.1186641","url":null,"abstract":"The leukocyte NADPH oxidase 2 (NOX2) generates superoxide, and derivative reactive oxygen species play important roles in both host defense and immunoregulation. The rs13306575 genetic variant, resulting in an Arginine395→Tryptophan (R395W) substitution in the NOX2 NCF2 subunit, is associated with an increased risk of lupus in patients of Hispanic-American or of Korean ancestry. Arginine395 resides within the NCF2 PB1 domain and participates in a constitutive high-affinity interaction with the NOX2 NCF4 subunit to stabilize their expression. However, whether this variant impacts NCF2 function and NOX2 activity is unknown. To answer this question, mice expressing NCF2-R395W were generated using CRISPR/Cas9. NCF2 and NCF4 expression were reduced by twofold in neutrophils, macrophages, and dendritic cells homozygous for NCF2-R395W. Moreover, following stimulation with soluble or particulate stimuli, reactive oxygen species production at the plasma membrane and within cells was reduced in all three myeloid lineages expressing NCF2-R395W. Additional studies on Ncf2+/− mice, which have a reduced expression of wild-type NCF2 but not of NCF4, suggest that the reduced expression of both NCF2 and NCF4 contributes to the diminished NOX2 activity in NCF2-R395 mice. These results establish that the lupus-associated rs13306575 p.R395W allele is a functional hypomorph. The findings add to growing evidence implicating deficient NOX2 activity in the pathogenesis of lupus.","PeriodicalId":94014,"journal":{"name":"Frontiers in lupus","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86505500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of race and ethnicity on family participation in systemic lupus erythematosus genetic studies","authors":"R. Scofield, Rohan Sharma, T. Aberle, C. Cooney, J. Kelly, J. Harley, A. Rasmussen","doi":"10.3389/flupu.2023.1100534","DOIUrl":"https://doi.org/10.3389/flupu.2023.1100534","url":null,"abstract":"Objective Systemic lupus erythematosus (SLE) has a higher prevalence and is more severe in African Americans and Hispanics than in non-Hispanic Whites. To understand the shared and unique genetic risk factors of these populations, an adequate representation of African Americans and Hispanics in clinical and genetic research is indispensable while challenging. The goal of this study was to identify differences in research participation of families of different racial and ethnic backgrounds and the potential causes for the disparities. Methods Families were screened for eligibility to the Lupus Family Registry and Repository (LFRR) after self-referral or physician referral. We recorded the sociodemographic characteristics, self-identified race and ethnicity, ACR-SLE criteria, and the reasons given for not completing study participation for all families. Results A total of 1,472 families (950 non-Hispanic White, 405 African American, and 117 Hispanic) were screened but only 366 completed study participation (25%). Participation rates and reasons for non-participation varied between racial and ethnic groups. The main reason for African American families to not participate was that subjects critical to the family structure declined participation (OR = 1.6, p = 0.0001), while for White families, the main cause was that purported SLE patients did not meet ACR SLE criteria (OR = 1.81, p < 0.00002). Hispanics were the most likely to complete participation (OR = 4.25, p < 0.0001). Conclusions Successful recruitment of patients, families, and specific demographic groups is critical for the study of genetically complex diseases, such as SLE. There are significant disparities in SLE family recruitment across groups of people, likely due to their richly different cultures and environments.","PeriodicalId":94014,"journal":{"name":"Frontiers in lupus","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81235531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Non-Coding Variant in <i>SLC15A4</i> Modulates Enhancer Activity and Lysosomal Deacidification Linked to Lupus Susceptibility.","authors":"Manish Kumar Singh, Guru Prashad Maiti, HariKrishna Reddy-Rallabandi, Mehdi Fazel-Najafabadi, Loren L Looger, Swapan K Nath","doi":"10.3389/flupu.2023.1244670","DOIUrl":"10.3389/flupu.2023.1244670","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic basis. Despite the identification of several single nucleotide polymorphisms (SNPs) near the <i>SLC15A4</i> gene that are significantly associated with SLE across multiple populations, specific causal SNP(s) and molecular mechanisms responsible for disease susceptibility are unknown. To address this gap, we employed bioinformatics, expression quantitative trait loci (eQTLs), and 3D chromatin interaction analysis to nominate a likely functional variant, rs35907548, in an active intronic enhancer of <i>SLC15A4</i>. Through luciferase reporter assays followed by chromatin immunoprecipitation (ChIP)-qPCR, we observed significant allele-specific enhancer effects of rs35907548 in diverse cell lines. The rs35907548 risk allele T is associated with increased regulatory activity and target gene expression, as shown by eQTLs and chromosome conformation capture (3C)-qPCR. The latter revealed long-range chromatin interactions between the rs35907548 enhancer and the promoters of <i>SLC15A4, GLTLD1</i>, and an uncharacterized lncRNA. The enhancer-promoter interactions and expression effects were validated by CRISPR/Cas9 knock-out (KO) of the locus in HL60 promyeloblast cells. KO cells also displayed dramatically dysregulated endolysosomal pH regulation. Together, our data show that the rs35907548 risk allele affects multiple aspects of cellular physiology and may directly contribute to SLE.</p>","PeriodicalId":94014,"journal":{"name":"Frontiers in lupus","volume":"1 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10843804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling of horizontal pleiotropy identifies possible causal gene expression in systemic lupus erythematosus.","authors":"Iouri Chepelev, Isaac T W Harley, John B Harley","doi":"10.3389/flupu.2023.1234578","DOIUrl":"10.3389/flupu.2023.1234578","url":null,"abstract":"<p><strong>Background: </strong>Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with complex causes involving genetic and environmental factors. While genome-wide association studies (GWASs) have identified genetic loci associated with SLE, the functional genomic elements responsible for disease development remain largely unknown. Mendelian Randomization (MR) is an instrumental variable approach to causal inference based on data from observational studies, where genetic variants are employed as instrumental variables (IVs).</p><p><strong>Methods: </strong>This study utilized a two-step strategy to identify causal genes for SLE. In the first step, the classical MR method was employed, assuming the absence of horizontal pleiotropy, to estimate the causal effect of gene expression on SLE. In the second step, advanced probabilistic MR methods (PMR-Egger, MRAID, and MR-MtRobin) were applied to the genes identified in the first step, considering horizontal pleiotropy, to filter out false positives. PMR-Egger and MRAID analyses utilized whole blood expression quantitative trait loci (eQTL) and SLE GWAS summary data, while MR-MtRobin analysis used an independent eQTL dataset from multiple immune cell types along with the same SLE GWAS data.</p><p><strong>Results: </strong>The initial MR analysis identified 142 genes, including 43 outside of chromosome 6. Subsequently, applying the advanced MR methods reduced the number of genes with significant causal effects on SLE to 66. PMR-Egger, MRAID, and MR-MtRobin, respectively, identified 13, 7, and 16 non-chromosome 6 genes with significant causal effects. All methods identified expression of <i>PHRF1</i> gene as causal for SLE. A comprehensive literature review was conducted to enhance understanding of the functional roles and mechanisms of the identified genes in SLE development.</p><p><strong>Conclusions: </strong>The findings from the three MR methods exhibited overlapping genes with causal effects on SLE, demonstrating consistent results. However, each method also uncovered unique genes due to different modelling assumptions and technical factors, highlighting the complementary nature of the approaches. Importantly, MRAID demonstrated a reduced percentage of causal genes from the Major Histocompatibility complex (MHC) region on chromosome 6, indicating its potential in minimizing false positive findings. This study contributes to unraveling the mechanisms underlying SLE by employing advanced probabilistic MR methods to identify causal genes, thereby enhancing our understanding of SLE pathogenesis.</p>","PeriodicalId":94014,"journal":{"name":"Frontiers in lupus","volume":"1 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10554754/pdf/nihms-1930920.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41109237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}