The synovial and blood monocyte DNA methylomes mirror prognosis, evolution, and treatment in early arthritis

Calle-Fabregat, Carlos de la; Rodríguez-Ubreva, Javier; Ciudad, Laura; Ramírez, Julio; Celis, Raquel; Azuaga, Ana Belén; Cuervo, Andrea; Graell, Eduard; Pérez-García, Carolina; Díaz-Torné, Cèsar; Salvador, Georgina; Gómez-Puerta, José A.; Haro, Isabel; Sanmartí, Raimón; Cañete, Juan D.; Ballestar, Esteban

doi:10.1172/jci.insight.158783

Cited by 12 publications

(7 citation statements)

References 54 publications

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“…Further work is needed to support this, namely (1) longitudinal measurements to determine whether the observed methylation changes (and gene expression of correlated transcripts) are sustained over time where the IGS/IFN-α levels are not and (2) ex vivo confirmation of the propensity for IFN-α to induce relevant epigenetic changes in relevant cell populations. Indeed, although we have focused on T and B lymphocytes in view of their known relevance to RA pathophysiology, these effects are likely to extend to other cell subsets 40 41…”

Section: Discussionmentioning

confidence: 99%

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

et al. 2022

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ObjectivesAn interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action.MethodsIn a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes.ResultsWe reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α).ConclusionsOur data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.

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Section: Discussionmentioning

confidence: 99%

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

et al. 2022

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“…Since altered DNA methylation modifications are detected in diverse B-cell subsets, the associations between epigenetic modifications and disease status deserve further investigation. Synovial and blood monocytes of undifferentiated arthritis patients show marked alterations in methylation profiles compared with those from healthy donors [ 15 ]. DNA methylation-based biomarkers are closely associated with prognosis, disease activity, and treatment efficacy in patients with early inflammatory arthritis, suggesting that the DNA methylation signatures of many immune subsets could serve as important biomarkers for personalized clinical management of autoimmune disease patients [ 15 , 16 ].…”

Section: Epigenetic Biomarkers and Therapies For Autoimmune Diseasesmentioning

confidence: 99%

“…Genome-wide epigenomic analysis has identified significant alterations in the epigenetic profiles of B cells from patients with autoimmune diseases [ 14 ]. Recent studies have revealed that epigenetic signatures, including DNA methylation profiles, may serve as useful biomarkers that can reflect disease prognosis, severity, and responses to therapies [ 15 , 16 ]. Moreover, clinical investigations and animal studies suggest that targeting epigenetic modifiers could be a novel effective therapeutic strategy [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

et al. 2022

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B cells play a pivotal role in the pathogenesis of autoimmune diseases. Although previous studies have shown many genetic polymorphisms associated with B-cell activation in patients with various autoimmune disorders, progress in epigenetic research has revealed new mechanisms leading to B-cell hyperactivation. Epigenetic mechanisms, including those involving histone modifications, DNA methylation, and noncoding RNAs, regulate B-cell responses, and their dysregulation can contribute to the pathogenesis of autoimmune diseases. Patients with autoimmune diseases show epigenetic alterations that lead to the initiation and perpetuation of autoimmune inflammation. Moreover, many clinical and animal model studies have shown the promising potential of epigenetic therapies for patients. In this review, we present an up-to-date overview of epigenetic mechanisms with a focus on their roles in regulating functional B-cell subsets. Furthermore, we discuss epigenetic dysregulation in B cells and highlight its contribution to the development of autoimmune diseases. Based on clinical and preclinical evidence, we discuss novel epigenetic biomarkers and therapies for patients with autoimmune disorders.

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“…Interestingly, besides aiding in the classification of patients at the time of diagnosis, DNAm profiles have been proposed as a prognostic biomarker in early undifferentiated stages of arthritis (UA) to anticipate the progression into differentiated forms of the disease. [ 32 , 33 ]…”

Section: Introductionmentioning

confidence: 99%

“…However, autoimmune rheumatic diseases are usually characterized by a complex pathogenesis, which makes it difficult to find robust biomarkers to monitor disease activity. Different studies have found an association between DNAm signatures and disease activity in RA, [ 25 ] UA, [ 33 ] and SLE, [ 34 ] suggesting the possibility of generating activity biomarkers for these diseases.…”

Section: Introductionmentioning

confidence: 99%

Designing studies for epigenetic biomarker development in autoimmune rheumatic diseases

Calle-Fabregat

Rodríguez-Ubreva

Cañete

et al. 2022

Rheumatology and Immunology Research

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In just a few years, the number of epigenetic studies in autoimmune rheumatic and inflammatory diseases has greatly increased. This is in part due to the need of identifying additional determinants to genetics to explain the pathogenesis and development of these disorders. In this regard, epigenetics provides potential mechanisms that determine gene function, are linked to environmental factors, and could explain a wide range of phenotypic variability among patients with these diseases. Despite the high interest and number of studies describing epigenetic alterations under these conditions and exploring their relationship to various clinical aspects, few of the proposed biomarkers have yet reached clinical practice. The potential of epigenetic markers is high, as these alterations link measurable features with a number of biological traits. In the present article, we present published studies in the field, discuss some frequent limitations in the existing research, and propose a number of considerations that should be taken into account by those starting new projects in the field, with an aim to generate biomarkers that could make it into the clinics.

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The synovial and blood monocyte DNA methylomes mirror prognosis, evolution, and treatment in early arthritis

Cited by 12 publications

References 54 publications

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

Designing studies for epigenetic biomarker development in autoimmune rheumatic diseases

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