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

Concept

To provide tools to select the likely most effective therapy for each patient with giant cell arteritis (GCA) right from the time of diagnosis.

Facts and Figures

Project Lead
N Pipitone
Azienda Unità Sanitaria Locale
nicolo.pipitone@ausl.re.it
FOREUM research grant: € 600.000
2018–2023

Meet the Team

Project Lead

N Pipitone
Azienda Unità Sanitaria Locale
nicolo.pipitone@ausl.re.it
S Croci
Azienda Unità Sanitaria Locale
F Ciccia
Università della Campania Vanvitelli
R Alessandro
University of Palermo
S Fontana
University of Palermo
M Gonzalez-Gay
Hospital Universitario Marqués de Valdecilla
S Castaneda
Hospital La Princesa
J Martin
Institute of Parasitology and Biomedicine López-Neyra
P Liò
University of Cambridge
D Saadoun
Pitie-Salpetriere Hospital
D Conti
Associazione Malati Reumatici Emilia Romagna
J Baquero
Foro Español de Pacientes
V Romero
Liga Reumatologica Española
L Carmona
Instituto de Salud Musculoesquelética

Final results

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.

Lay Summary

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.

Publications

  • 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

Read more

  • 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

Read more

 

EULAR Abstracts

2020

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

Go to EULAR Abstract Archive

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

 

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