Sonja Dulic

University of Szeged

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Attila Balog

University of Szeged

MÁ

Miguel Á. González‐Gay

Universidad de Cantabria

Antonio López‐Berrio

Andalusian School of Public Health

R. Ortega Castro

Instituto Maimónides de Investigación Biomédica de Córdoba

Fátima Farinha

Institute of Biomedical Science

Rocío Aguilar‐Quesada

Andalusian School of Public Health

Rik Lories

KU Leuven

Mariana Brandão

Centro Hospitalar de Vila Nova de Gaia

Falk Hiepe

German Rheumatism Research Centre

Alain Saraux

Centre Hospitalier Régional Universitaire de Brest

Cooperative Institutions

Center for Rheumatology

Karolinska Institutet

Karolinska University Hospital

University of Szeged

Inserm

Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

Universidad de Granada

University of Milan

Andalusian Health Service

Centre Hospitalier Régional Universitaire de Brest

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Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

Kidney International Reports (2024)

Ioannis Parodis Julius Lindblom Daniel Toro‐Domínguez Lorenzo Beretta María Orietta Borghi

IntroductionCurrent therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options.MethodsWe analysed differentially expressed genes in peripheral blood from active LN (n=41) and active non-renal lupus (n=62) patients versus healthy controls (n=497) from the European PRECISESADS project (NTC02890121), and dysregulated gene modules in a discovery (n=26) and a replication (n=15) set of active LN cases.ResultsReplicated gene modules qualified for correlation analyses with serological markers, and regulatory network and druggability analysis. Unsupervised co-expression network analysis revealed 20 dysregulated gene modules and stratified the active LN population into three distinct subgroups. These subgroups were characterised by low, intermediate, and high interferon (IFN) signatures, with differential dysregulation of the "B cell" and "plasma cells/immunoglobulins" modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 inhibitors, programmed death-ligand 1 inhibitors, and irinotecan, while the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the "plasma cells/immunoglobulins" transcriptomic signature. In silico analysis demonstrated the low-IFN subgroup to benefit from calcineurin inhibition and the intermediate-IFN subgroup from B cell targeted therapies. High-IFN patients exhibited greater anticipated response to anifrolumab while daratumumab appeared beneficial for the intermediate-IFN and high-IFN subgroups.ConclusionIn summary, IFN upregulation and B and plasma cell gene dysregulation patterns revealed three LN patient subgroups, which may not necessarily represent distinct disease phenotypes but rather phases of the inflammatory processes during a renal flare, providing a conceptual framework for precision medicine in LN.

Nephritis

10.1016/j.ekir.2024.03.014

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Citations (5)

Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants

npj Genomic Medicine (2024)

Olivia Castellini-Pérez Elena Povedano Guillermo Barturen Manuel Martínez‐Bueno Andrii Iakovliev

Abstract The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls. Methylation quantitative trait loci analyses, cytokine and transcription factor activity - epigenetic associations and methylation-expression correlations were conducted. New drug targets were searched for based on differentially methylated genes. In a stratified approach, a total of 974 differential methylation CpG sites with dependency on molecular subtypes and autoantibody profiles were found. Mediation analyses suggested that SLE-associated SNPs in the HLA region exert their risk through DNA methylation changes. Novel genetic variants regulating DNAm in disease or in specific molecular contexts were identified. The epigenetic landscapes showed strong association with transcription factor activity and cytokine levels, conditioned by the molecular context. Epigenetic signals were enriched in known and novel drug targets for SLE. This study reveals possible genetic drivers and consequences of epigenetic variability on SLE heterogeneity and disentangles the DNAm mediation role on SLE genetic risk and novel disease-specific meQTLs. Finally, novel targets for drug development were discovered.

Epigenomics

Epigenome

Genetic Association

10.1038/s41525-024-00420-0

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Citations (1)

[Computerized tomography of the upper abdomen].

PubMed (1984)

R Bjelovuk M Jasović S Ledić Sonja Dulic

Upper abdomen

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Alterations of the thrombin generation profile in rheumatoid arthritis

Journal of Thrombosis and Thrombolysis (2015)

Anita Kern Attila Balog Sonja Dulic Eszter Barabás Mária Kiszelák

Thrombin Generation

Hematology

10.1007/s11239-015-1251-1

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Machine Learning for the Identification of a Common Signature for Anti–SSA/Ro 60 Antibody Expression Across Autoimmune Diseases

Arthritis & Rheumatology (2022)

Nathan Foulquier Christelle Le Dantec Éléonore Bettacchioli Christophe Jamin Marta E. Alarcón‐Riquelme

Anti-Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies, mainly associated with primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and undifferentiated connective tissue disease (UCTD). This study was undertaken to determine if there is a common signature for all patients expressing anti-Ro 60 autoantibodies regardless of their disease phenotype.

Identification

Extractable nuclear antigens

10.1002/art.42243

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Citations (15)

Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

medRxiv (Cold Spring Harbor Laboratory) (2020)

Guillermo Barturen Sepideh Babaei Francesc Català‐Moll Manuel Martínez‐Bueno Zuzanna Makowska

SUMMARY Background Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification. Methods With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time. Results Four clusters were identified. Three clusters were aberrant, representing ‘inflammatory’, ‘lymphoid’, and ‘interferon’ patterns each including all diagnoses and defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern and accumulated also healthy controls. An independent inception cohort showed that with time, the molecular clusters remain stable, showing that single aberrant molecular signatures characterize each individual patient. Conclusions Patients with SADs can be jointly stratified into three stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of therapy non-responsiveness marking a paradigm shift in the view of SADs.

10.1101/2020.02.21.20021618

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SAT0034 Analysis of the t-cell subset composition in ankylosing spondylitis patients with long-standing anti-tnf therapy

Annals of the Rheumatic Diseases (2017)

Sonja Dulic Zsófia Vásárhelyi Anna Bajnok Balázs Szalay Gergely Toldi

Background

Ankylosing spondylitis (AS) is a chronic, progressive, immune-mediated inflammatory disease, driven primarily by Th1 and Th17 cells. Anti-TNF therapies are successfully used in AS to achieve and maintain remission. However, their influence on the composition of the T-cell repertoire is not clear, and, in particular, the few published studies involve mostly patients with anti-TNF treatment of short duration.

Objectives

We aimed to characterize the changes in several T cell subsets after long-term anti-TNF treatment in AS patients.

Methods

Twenty-two AS patients on long-term anti-TNF therapy were evaluated (15 anti-TNF-responders and 7 non-responders). A wide range of cell subtypes were analysed with flow cytometry and compared with therapy-naïve and short-term data.

Results

Key findings include decreased proportions of naive CD4 and CD8 cells, increased frequencies of Th1 and Th17 cells and higher Th1/Th2 and Th17/Treg ratios in the long-term anti-TNF-treated patients (responders, non-responders and total), which was found to be significant not only when compared with healthy controls, but also with therapy-naive and short-term anti-TNF-treated AS patients. We have found several alterations within the various activated T-cell subsets – increase in CD4HLADR cells in responders, in CD8HLADR cells in the whole AS group and in responders, and in CD4CD25 cells in responders, and decrease in CD4CD69 cell percentages in long-term treated patients – becoming evident only after long-term anti-TNF-therapy.

Conclusions

This study provides a comprehensive assessment of the impact of anti-TNF therapy on the T cell repertoire in AS, and indicate that these therapies induce profound changes within T-cells. Changes in T cell phenotype seem to develop progressively during therapy, even in inactive disease, and reflect an ongoing effector T-cell differentiation and activation, and a normalization of Treg development.

Disclosure of Interest

None declared

Cell therapy

10.1136/annrheumdis-2017-eular.6335

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Citations (1)

Investigation of the adaptive immune response in immune-mediated diseases

Sonja Dulic

Adaptive response

10.14232/phd.10030

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Citations (0)

O31 Integrative analysis reveals a molecular stratification of systemic autoimmune diseases

Oral Presentations (2020)

Guillermo Barturen Sepideh Babaei Francesc Català‐Moll Manuel Martínez‐Bueno Zuzanna Makowska

Background

Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.

Methods

With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. An inception cohort prospectively followed for 6 and 14 months was studied to validate the results in early cases and analyze if cluster assignment was modified with time.

Results

Four clusters were identified

Three aberrant clusters were 'acute phase inflammatory', 'T cell immunity', and 'interferon', each including all diagnoses, were defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern, to which 74% of healthy controls clustered with patients. The inception cohort showed that most patients were either assigned always to the same cluster or moved from the healthy-like cluster to a single aberrant cluster resembling the relapsing-remitting dynamic of these diseases, showing that single aberrant molecular signatures characterize each individual patient.

Conclusions

Patients with SADs share molecular signatures and can be therefore stratified into three disease clusters differentiating each patient into a specific molecular disease pathway. Such assignment is stable with time. These results have important implications for understanding disease progression and therapy design marking a paradigm shift in our view of SADs.

Acknowledgment

This work has been supported through a grant from the Innovative Medicines Initiative Joint Undertaking No. 115565 and in-kind and in-cash contributions from the EFPIA partners. G.B. is supported by the Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry), through the Sara Borrell subprogram (CD18/00153). The authors would like to particularly express their gratitude to the patients, nurses and many others who helped directly or indirectly in the consecution of this study.

10.1136/lupus-2020-eurolupus.42

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[Chronic encapsulated intracerebral hematoma].

PubMed (1999)

Sonja Dulic

Radiological-morphologic features of chronic intracerebral hematomas are observed by computed tomography (CT) and magnetic resonance (MR), and in angiographic examination are particularly characterized by the absence of pathologic vascularization. The patient, aged 61, with confirmed diagnosis of encapsulated intracerebral hematoma, treated at the Clinic of Neurology and Clinic of Neurosurgery of the Military Medical Academy was presented. The patient was released after recovery, and was consequently followed up in an outpatient department by a neurosurgeon. Six-month follow-up demonstrated the regression of the clinical signs of the disease, as well as the alterations in CT and MR images in the same sense.

Intracerebral hematoma

Outpatient clinic

Neuroradiology

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Citations (3)