43 research outputs found
Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy.
No full textGiant 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
Corrigendum: Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy.
No full textGiant 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
Cross-phenotype analysis of Immunochip data identifies <i>KDM4C</i> as a relevant <i>locus</i> for the development of systemic vasculitis
No full textObjetiveSystemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis.MethodsImmunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu’s arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data.ResultsThe strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression.ConclusionsThrough a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.</jats:sec
Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy
No full textGiant 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
Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids
No full textOBJECTIVES: Giant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis. METHODS: We performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls. RESULTS: We identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63, as well as genes mediating the molecular response to GC, including FKBP5, ETS2, ZBTB16 and ADAMTS2. CONCLUSION: Our results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment
114. Effects of tocilizumab on ex-vivo peripheral blood mononuclear cells from patients with GCA
No full textBackground: Giant –cell arteritis (GCA) is a chronic granulomatous vasculitis affecting individuals aged ≥50 years. Glucocorticoids (GCs) are only effective therapy able to induce disease remission but most patients relapse when GC are tapered and suffer from GC-related toxicity. Interleukin-6 (IL-6) is a pleiotropic cytokine that may play a pivotal role in GCA pathogenesis since its transcripts are increased in vascular lesions and elevated serum levels have been reported in active GCA patients. Recently, blocking IL-6 receptor with tocilizumab (TCZ) has demonstrated effectiveness in reducing GCA flares and sparing GC. However, 40% of patients still relapse when GCs are discontinued, indicating heterogeneity in TCZ-response. Therefore, identifying predictors of response to TCZ is crucial. TCZ strongly reduces systemic symptoand acute-phase reactants but little is known about the effects of TCZ on vascular lesions or peripheral blood mononuclear cells (PBMCs). The aim of this study was to investigate transcriptomic changes induced by IL-6 and TCZ+IL6 on ex-vivo PBMCs from patients in clinical remission.
Methods: PBMCs were isolated from 17 patients in remission and 5 age and sex – matched controls using Lymphoprep™ density gradient. Fourteen patients were receiving prednisone (<5mg/day) and 4 patients were in sustained remission without prednisone. PBMCs were exposed to recombinant human (rh) IL-6 (IL6 group) (20 ng/ml) and combination of rhIL-6 and TCZ (20 µg/ml) (TCZ+IL6 group) and cultured for 24h. Total RNA was extracted from cells using TRIzol™ reagent. RNA (100ng/sample) was processed using nCounter Prep Station screening for 256 genes from Human Inflammation Nanostring panel. Barcode counts were processed with nSolver 4.0 Software. Normalized data were analysed using R Studio 4.0.3 and paired or unpaired Wilcoxon tests were applied.
Results: Total count of PBMCs was significantly lower in GCA compared to controls (1.26±0.43, 2.53±0.2 cell/ml, respectively; p<0.0001). At transcriptomic level, 64 transcripts were differentially expressed between controls and patients, even considered in clinical remission; 5 transcripts were increased and 59 were decreased in GCA. After stimulation with IL-6, 12 transcripts were increased and 34 decreased respect to baseline condition. A total of 113 transcripts were differentially expressed between IL-6 group and TCZ+IL6 group. After correction for multiple comparisons, 73 transcripts remained significant (FDR<0.05), of which 63 transcripts were increased with TCZ exposure. However, 8 transcripts that were increased with IL-6 stimulation, decreased their expression after exposure to TCZ: STAT3, HIF1A, CCL2, CCR1, BCL6, MYC, TLR2 and C3AR1; all of them being target genes of STAT3.
Conclusions: Patients with GCA in clinical remission still have transcriptomic differences with healthy controls. Tocilizumab reduces expression of STAT3 and 7 other transcripts downstream from STAT3, important for differentiation of naïve T helper cells to follicular T helper cells (BCL6), cell growth/apoptosis (MYC), monocyte trafficking and activation (CCL2, CR1), activation of IL-6 (TLR2) and hypoxia (HIF1A). Validation is in process. Studies in active, treatment-naïve patients are ongoing.
Disclosures: Marc Corbera- Bellalta, Farah Kamberovic, Roser Alba-Rovira, Marco A Alba, and Patricia Pérez-Galán have no disclosures to report. Georgina Espigol-Frigolé reports consulting for Janssen and Hoffmann-La Roche; meeting attendance suport from Boehringer Ingelheim. Sergio Prieto-Gonzalez reports lecturing for Roche; meeting attendance support from Italfarmo and CSL Behring. Maria C Cid reports a research grant from Kiniksa; consulting for Janssen, GSK, and Abbvie; educational grant from GSK and Vifor; meeting attendance support from Roche and Kiniksa. Funding received from EU Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement No. 813545), Spanish Ministry for Science and Innovation /AEI project No. PID2020-114909RB-I00, and the Vasculitis Foundation
Influence of the EULAR recommendations for the use of imaging in large vessel vasculitis in the diagnosis of giant cell arteritis: results of the ARTESER register
No full textObjective The main study objective was to determine how giant cell arteritis (GCA) is diagnosed in our clinical practice and whether the EULAR recommendations have influenced the diagnostic procedures used.Methods ARTEritis of the Rheumatology Spanish Society -Sociedad Española de Reumatología (ARTESER) is a multicentre observational retrospective study conducted in 26 hospitals with support from the Spanish Society of Rheumatology. All patients diagnosed with GCA between 1 June 2013 and 29 March 2019 were included. The gold standard for the diagnosis of GCA was the judgement of the physician in charge, according to clinical criteria, supported by data available from laboratory tests, imaging studies (ultrasound, positron emission tomography (PET) and MRI/CT angiography) and temporal artery biopsy (TAB) when available.Results We included 1675 patients with GCA (mean age±SD (76.9±8.1) years, 1178 women (70.3%)). Of these, 776 patients had a positive TAB (46.3%), 503 (30.0%) positive ultrasound, 245 positive PET (14.6%) and 64 positive MRI/CT angiography (3.8%). These percentages changed substantially over the study. From 2013 to 2019, the use of ultrasound in diagnosis grew from 25.8% to 52.9% and PET from 12.3% to 19.6%, while use of TAB decreased from 50.3% to 33.3%.Conclusions Biopsy was the most widely used diagnostic test for confirming GCA, but use of imaging as a diagnostic tool has grown in recent years. Following publication of the 2018 EULAR recommendations, ultrasound has displaced biopsy as the first-line diagnostic test; TAB was performed in a third and PET in a fifth of cases
Tocilizumab in Extracranial Giant-Cell Arteritis and Takayasu Arteritis: A Multicentric Observational Comparative Study
No full textTocilizumab (TCZ) has demonstrated potential efficacy in managing large-vessel (LV) vasculitis such as giant-cell arteritis (GCA) and Takayasu arteritis (TAK). Despite the shared characteristics between the LV-GCA phenotype and TAK, there are differences between both entities that may affect therapeutic responses to TCZ. We aim to assess and compare the effectiveness and safety of TCZ in patients with LV-GCA and TAK. Multicenter, observational study on 70 LV-GCA patients and 57 TAK patients treated with TCZ. Outcomes were assessed at baseline and at 1, 3, 6 and 12 months post-treatment initiation. The variables analyzed included the following: (a) the achievement of clinical remission and improvement in laboratory markers; (b) imaging-based disease activity; (c) a glucocorticoid (GC)-sparing effect; and (d) side events and a safety profile. At the treatment initiation, TAK patients were younger, exhibited longer disease duration, had received more prior biologics, and were on higher doses of prednisone compared to LV-GCA patients. While TAK patients showed a slower initial clinical response, remission rates at 12 months were comparable between groups (74.5% for LV-GCA vs. 76.9% for TAK). Both groups experienced rapid laboratory marker improvement and a significant GC-sparing effect. However, complete imaging resolution was observed in only 18.9% of LV-GCA patients and 21.1% of TAK patients. The safety profile was similar in both groups, with severe infections leading to TCZ discontinuation in four LV-GCA and three TAK patients. In clinical practice, TCZ demonstrates similar efficacy in promoting remission and reducing GC dependency in both LV-GCA and TAK patients. Nonetheless, discrepancies between clinical outcomes and imaging improvement highlight the need for further investigation into disease monitoring and management strategies
Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis
No full textObjective: Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis.
Methods: Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu’s arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data.
Results: The strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression.
Conclusions: Through a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions
Influence of the EULAR recommendations for the use of imaging in large vessel vasculitis in the diagnosis of giant cell arteritis: Rfesults of the ARTESER register
No full textObjective: The main study objective was to determine how giant cell arteritis (GCA) is diagnosed in our clinical practice and whether the EULAR recommendations have influenced the diagnostic procedures used. Methods: ARTEritis of the Rheumatology Spanish Society -Sociedad Española de Reumatología (ARTESER) is a multicentre observational retrospective study conducted in 26 hospitals with support from the Spanish Society of Rheumatology. All patients diagnosed with GCA between 1 June 2013 and 29 March 2019 were included. The gold standard for the diagnosis of GCA was the judgement of the physician in charge, according to clinical criteria, supported by data available from laboratory tests, imaging studies (ultrasound, positron emission tomography (PET) and MRI/CT angiography) and temporal artery biopsy (TAB) when available. Results: We included 1675 patients with GCA (mean age±SD (76.9±8.1) years, 1178 women (70.3%)). Of these, 776 patients had a positive TAB (46.3%), 503 (30.0%) positive ultrasound, 245 positive PET (14.6%) and 64 positive MRI/CT angiography (3.8%). These percentages changed substantially over the study. From 2013 to 2019, the use of ultrasound in diagnosis grew from 25.8% to 52.9% and PET from 12.3% to 19.6%, while use of TAB decreased from 50.3% to 33.3%. Conclusions: Biopsy was the most widely used diagnostic test for confirming GCA, but use of imaging as a diagnostic tool has grown in recent years. Following publication of the 2018 EULAR recommendations, ultrasound has displaced biopsy as the first-line diagnostic test; TAB was performed in a third and PET in a fifth of cases
