START – Molecular stratification of patients with giant cell arteritis to tailor glucocorticoid and tocilizumab therapy

We applied multi-omics technologies in inflamed temporal artery biopsies (TABs) from patients with Giant Cell Arteritis (GCA) (n=77) and normal TABs from patients without GCA (n=15). The analysis of the transcriptome, proteome and DNA methylation respectively on RNA, proteins and DNA extracted in parallel from the same tissue provides the unprecedented opportunity to perform multi-omics integration.
Inflamed TABs from patients with GCA revealed distinct molecular signatures compared to normal TABs from control patients. We identified set of genes, miRNAs, proteins expressed at higher or lower levels in inflamed versus normal TABs and CpGs differentially methylated. These results increase the knowledge on GCA pathogenesis and provide possible novel therapeutic targets for GCA. The comparison of molecular portraits between patients (I) with and without different clinical symptoms; (II) with and without flares revealed few biomarkers for patients stratification, suggesting that the investigated clinical characteristics may not derive from specific alterations in TABs.

The proposed research aimed to develop and validate biological markers which can be measured at diagnosis in samples from patients with Giant Cell Arteritis (GCA) to select the likely most effective individual therapy. GCA is a common inflammatory disease of the arteries (vasculitis), typically occurring after 50 years of age. The mainstay of therapy are glucocorticoids, but around one third of patients develop flares during therapy or after therapy discontinuation. Therefore, the discovery of new targets for additional therapies is a clinical need. Patients with GCA show clinical heterogeneity. Increasing the knowledge on the bases of clinical heterogeneity will allow to improve precision medicine for this disease. To confirm the diagnosis, patients are subjected to temporal artery biopsies (TABs), which gives the opportunity to study the tissues affected by inflammation. We hypothesized that molecular characteristics in TABs can determine the response to therapies of patients and their clinical manifestations.
We thus performed different kinds of high-throughput molecular analyses on TABs from 77 patients showing different clinical manifestations and different response to therapies. Specifically, we analysed all RNA transcripts, proteins and epigenetic modifications (DNA methylations). We identified several biomarkers which distinguished inflamed arteries from patients with GCA and normal arteries from control patients without GCA. This increased the knowledge on disease pathogenesis and provided novel targets which could be evaluated to develop novel therapies. Few biomarkers resulted associated with the clinical heterogeneity / differences among patients. They will be subjected to validation analyses to verify their potential clinical utility.

• Francesco Ciccia, Federica Macaluso, Daniele Mauro, Giovanni Francesco Nicoletti, Stefania Croci, Carlo Salvarani. New insights into the pathogenesis of giant cell arteritis: are they relevant for precision medicine? The Lancet Rheumatology 2021 Vol. 3, No. 12e874–e885. DOI: https://doi.org/10.1016/S2665-9913(21)00253-8
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• Ramon Viñas, Chaitanya K. Joshi, Dobrik Georgiev, Bianca Dumitrascu, Eric R. Gamazon, Pietro Liò. Hypergraph factorisation for multi-tissue gene expression imputation, in press on Nature Machine Intelligence 2023 Emma Ambags, Giulia Capitoli, Marco Nobile, Pietro Liò. Assisting clinical practice with fuzzy probabilistic decision trees, submitted to Expert Systems in May 2023
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EULAR Abstracts

2020

• SAT0338: Contrast-enhanced ultrasonography in the evaluation of myositis
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2023

• EULAR 2023 abstract presented as Poster Tour: POS0094 INSIGHT INTO GIANT CELL ARTERITIS PATHOGENESIS BY NANOSTRING NCOUNTER GENE EXPRESSION PROFILING IN TEMPORAL ARTERY BIOPSIES. DOI: 10.1136/annrheumdis-2023-eular.2316
• EULAR 2023 abstract presented as Poster: POS0728 EFFECTIVENESS AND SAFETY OF A 26 WEEK TAPER REGIMEN OF GLUCOCORTICOID IN NEWLY-DIAGNOSED GCA PATIENTS: A REAL LIFE EXPERIENCE. DOI: 10.1136/annrheumdis-2023-eular.5833