Analysis of the common genetic component of large-vessel vasculitides through a meta- Immunochip strategy

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P?=?7.54E-07; ORGCA?=?1.19, ORTAK?=?1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA?=?5.52E-04, ORGCA?=?1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus

A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

Lupus nephritis is characterized by unique DNA methylation changes in naïve CD4+ T cells

Objective. To characterize DNA methylation changes in naïve CD4+ T cells in lupus patients with renal involvement. Methods. Genome-wide DNA methylation changes in naïve CD4+ T cells were identified and compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients, and 56 age-, sex-, and ethnicity-matched healthy controls were studied. Results. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement. The tyrosine kinase gene TNK2 involved in cell trafficking and tissue invasion, and the phosphatase gene DUSP5 which dephosphorylates and inhibits ERK signaling pathway, are among the most hypomethylated. Renal involvement is characterized by more robust demethylation in interferon-regulated genes in lupus patients. The type-I interferon master regulator IRF7 is only hypomethylated with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, ISG15, ISG20, ITGAX, and PARP12 (p=1.78X10-6). Among the CG sites only hypomethylated with renal involvement, CG10152449 in CHST12 has a sensitivity of 85.7% and a specificity of 64.3% for detecting renal involvement in lupus patients (p=0.0029). Conclusions. We identified novel differentially methylated targets in the presence of renal involvement in lupus. These identified targets will help to better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvements in lupus

Efficacy and safety of belimumab in patients of black race with systemic lupus erythematosus: Results from the embrace study

Background Black patients have an increased prevalence and severity of systemic lupus erythematosus (SLE), alongside higher mortality rates. The efficacy and safety of intravenous (IV) belimumab has been demonstrated in several Phase 2/3 studies; however, the small number of black patients within these trials, and the conflicting results, have limited conclusions regarding efficacy in this population. The objective of this study was to specifically assess the efficacy and safety of IV belimumab plus standard of care (SoC) in black patients with active, auto antibody-positive SLE. Methods EMBRACE (NCT01632241) is a randomized, multicenter, double-blind, placebo-controlled trial in patients of self identified black race, aged 18 years, with active SLE at screening. Patients were randomized (2:1) to monthly belimumab 10 mg/kg IV or placebo, plus SoC. The primary endpoint was the SLE Responder Index (SRI) response rate with modified SLEDAI-2K (S2K) scoring for proteinuria at Week 52 (SRI-S2K response required a 4 point reduction in the SELENA-SLEDAI (SS)-S2K, no worsening [increase of \u3c0.3] in Physician\u27s Global Assessment (PGA), and no new BILAG A or 2 new B organ domain scores). Key secondary endpoints included SRI response rate with SS scoring of proteinuria at Week 52, time to first severe SFI flare, and reductions in prednisone dose by 25% to 7.5 mg/day during Weeks 4052. Subgroup analyses of the primary endpoint were also conducted. Step-down sequential testing was utilized to control the overall type 1 error rate (2-sided, alpha=0.05). Safety was assessed by monitoring adverse events (AEs). Results The mITT population comprised 448 patients; 96.9% were female and mean (SD) age was 38.8 (11.42) years. Although the study did not achieve the primary endpoint, numerical trends were observed in favor of belimumab, and significant improvements were observed in subgroups with characteristics of high disease activity (HDA; table). Study withdrawals were similar between groups (belimumab 22.4%; placebo 24.2%) and AEs were the primary reason for withdrawals (belimumab 5.4%; placebo 6.7%). The percentage of patients who experienced an AE (belimumab 83.7%; placebo 87.3%) or serious AE (belimumab 10.9%; placebo 18.8%) was similar between groups. Two deaths occurred within the belimumab group (0.6%; pneumonia and meningitis); neither were established as directly related to belimumab. Conclusions Whilst the primary endpoint of this study in black patients with SLE was not achieved, improvements in favor of belimumab were observed, with significant benefits in patients with HDA. The safety profile was acceptable and consistent with previous studies. (Table Presented)

CD4+CD28+KIR+CD11ahi T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients

OBJECTIVE: The goal of this study was to comprehensively characterize CD4+CD28+ T cells overexpressing CD11a and KIR genes, and examine the relationship between this T cell subset, genetic risk, and disease activity in lupus. METHODS: The size of the CD4+CD28+KIR+CD11ahi T cell subset was determined by flow cytometry, and total genetic risk for lupus was calculated in 105 female patients using 43 confirmed genetic susceptibility loci. Primary CD4+CD28+KIR+CD11ahi T cells were isolated from lupus patients or were induced from healthy individuals using 5-azacytidine. Genome-wide DNA methylation was analyzed using an array-based approach, and the transcriptome was assessed by RNA sequencing. Transcripts in the CDR3 region were used to assess the TCR repertoire. Chromatin accessibility was determined using ATAC-seq. RESULTS: A total of 31,019 differentially methylated sites were identified in induced KIR+CD11ahi T cells with \u3e99% being hypomethylated. RNA sequencing revealed a clear pro-inflammatory transcriptional profile. TCR repertoire analysis suggests less clonotype diversity in KIR+CD11ahi compared to autologous KIR-CD11alow T cells. Similarly, primary KIR+CD11ahi T cells isolated from lupus patients were hypomethylated and characterized by a pro-inflammatory chromatin structure. We show that the genetic risk for lupus was significantly higher in African-American compared to European-American lupus patients. The demethylated CD4+CD28+KIR+CD11ahi T cell subset size was a better predictor of disease activity in young (age ≤ 40) European-American patients independent of genetic risk. CONCLUSION: CD4+CD28+KIR+CD11ahi T cells are demethylated and characterized by pro-inflammatory epigenetic and transcriptional profiles in lupus. Eliminating these cells or blocking their pro-inflammatory characteristics might present a novel therapeutic approach for lupus

Mortality and adverse events of special interest with intravenous belimumab for adults with active, autoantibody-positive systemic lupus erythematosus (BASE): a multicentre, double-blind, randomised, placebo-controlled, phase 4 trial

Background: Belimumab is approved for the treatment of active systemic lupus erythematosus (SLE). Although clinical trials showed a favourable benefit–risk profile, numerical differences in the incidence of mortality and adverse events of special interest (AESIs) have been reported. We assessed the frequency of these events in patients with SLE receiving belimumab or placebo plus standard therapy. Methods: BASE was a double-blind, randomised, placebo-controlled, phase 4 trial done in 33 countries. Adults with active SLE were randomly assigned (1:1) to receive intravenous belimumab (10 mg/kg) or placebo, plus standard therapy, for 48 weeks. The primary endpoints were incidences of all-cause mortality and AESIs during the on-treatment period (first-to-last study drug dose + 28 days). Safety analyses were done in the as-treated population (patients grouped by actual treatment received \u3e50% of the time). This study was registered with ClinicalTrials.gov (NCT01705977). Findings: Between Nov 27, 2012, and July 28, 2017, we randomly assigned 4018 patients. The as-treated population included 2002 patients in the belimumab group versus 2001 in the placebo group. Ten (0·50%) patients in the belimumab group died versus eight (0·40%) in the placebo group (difference 0·10%, 95% CI −0·31 to 0·51). Incidences were similar in the belimumab and placebo groups for serious infections (75 [3·75%] of 2002 vs 82 [4·10%] of 2001; difference −0·35%, 95% CI −1·55 to 0·85), opportunistic infections and other infections of interest (36 [1·80%] vs 50 [2·50%]; −0·70%, −1·60 to 0·20), non-melanoma skin cancers (4 [0·20%] vs 3 [0·15%]; 0·05%, −0·21 to 0·31) and other malignancies (5 [0·25%] vs 5 [0·25%]; 0·00%, −0·31 to 0·31). A higher proportion of patients in the belimumab group than in the placebo group had infusion and hypersensitivity reactions (8 [0·40%] vs 2 [0·10%]; 0·30%, −0·01 to 0·61), serious depression (7 [0·35%] vs 1 [0·05%]; 0·30%, 0·02 to 0·58), treatment-emergent suicidality (28 [1·42%] of 1972 patients vs 23 [1·16%] of 1986; 0·26%, −0·44 to 0·96), and sponsor-adjudicated serious suicide or self-injury (15 [0·75%] of 1972 patients vs 5 [0·25%] of 1986; post hoc difference 0·50%, 0·06 to 0·94). Interpretation: In line with previously published data, incidences of all-cause mortality and AESIs were similar in patients given belimumab and placebo, except for serious infusion or hypersensitivity reactions, serious depression, treatment-emergent suicidality, and sponsor-adjudicated serious suicide or self-injury events. Funding: GSK

Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans.

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146461/1/art40541_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146461/2/art40541.pd