OP0014 TRANSCRIPTS EXPRESSED IN TEMPORAL ARTERY BIOPSIES ASSOCIATED WITH RESPONSE TO THERAPY IN PATIENTS WITH GIANT CELL ARTERITIS
Authors: S. Croci, A. Rossi, V. Manicardi, M. Bonacini, F. Torricelli, C. Ascione, A. Ciarrocchi, M. Á. González-Gay, S. Castañeda, G. Guggino, D. Saadoun, P. Lio, S. Fontana, J. Martin, A. Cavazza, A. Zerbini, F. Muratore, N. Pipitone, C. Salvarani
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Giant cell arteritis (GCA) is the most common inflammatory disease of medium- and large-sized arteries in people older than 50 years of age. Diagnosis derives from the integration of clinical signs, laboratory data, large-vessel imaging and temporal artery biopsies (TABs) showing infiltrating immune cells. Glucocorticoids (GCs) are the cornerstone of the treatment of GCA, however about one third of patients develop flares during GC tapering or after GC suspension. Tocilizumab (TCZ, a monoclonal anti-interleukin-6 receptor antibody) in association with GCs is an additional effective therapeutic option, but some patients still develop flares. Currently, it is not known how to predict patients' response to therapy. We hypothesized that molecular features in inflamed TABs might determine patients' therapeutic outcome and thus help to distinguish at diagnosis responders from non-responders. <h3>Objectives:</h3> To identify transcripts in TABs from patients with GCA whose levels are associated with patients' response to therapy. <h3>Methods:</h3> Patients with new-onset GCA with transmural inflammation in TABs, taking GCs for a maximum of 14 days at the time of TABs were included. A prospective cohort (n=40) and a retrospective cohort (n=36) of patients were used. Thirty-five patients of the prospective cohort received a 26-week GCs taper regimen [1], while five patients received a 26-week GCs taper regimen + 162 mg of subcutaneous TCZ every week followed by maximum 26 weeks of TCZ monotherapy. All the patients of the retrospective cohort received GCs with a tapering based on clinical practice. Patients were classified in responders (absence of disease flares) and non-responders (development of flares during therapy or follow-up). Flares were defined as recurrence of symptoms attributable to active GCA with or without elevation of erythrocyte sedimentation rate and/or C-reactive protein, with the need for an increase in GCs dose and/or change in therapy. Patients of the prospective cohort were followed for 1-year while patients of the retrospective cohort were followed for 2-years to have similar follow-up periods after GC discontinuation in the two cohorts. RNA was extracted from snap-frozen TABs performed at diagnosis. 100 ng RNA were processed with the Illumina stranded total RNA prep ligation with ribo-zero plus. Samples were uniquely indexed, pooled and sequenced on NovaSeq 6000 system. Sequences were aligned to the human reference transcriptome. Raw data were checked for quality with MultiQC. Expression matrix was filtered on protein coding genes and differentially expressed genes were identified with DESeq2. Gene set enrichment analysis was performed with Enrichr and protein–protein interactions predicted with STRING. <h3>Results:</h3> 55% of the patients of the prospective cohort developed flares while 45% of the patients were classified as responders to therapy. Patients of the retrospective cohort were half responders and half non-responders to therapy. The transcriptome from patients' TABs was analysed by RNA-sequencing. After quality control, 11 samples resulted of low quality and were excluded. Differential gene expression analysis was thus performed on 29 TABs from patients who effectively responded to therapy versus 36 TABs from patients who developed flares. 24 genes resulted differentially expressed between the two groups, with fold changes &gt; 2 or &lt; -2 and adjusted p-values &lt; 0.1 (23 genes with higher expression and one gene with lower expression in responders). 97 genes resulted differentially expressed with fold changes &gt; 2 or &lt; -2 and unadjusted p-values &lt; 0.01 (86 genes with higher expression and 11 genes with lower expression in responders). Gene set enrichment analysis revealed the overexpression of genes associated with striated muscle functions and the lower expression of genes associated with G-protein coupled receptors. Many of the overexpressed genes encoded proteins with predicted interactions in striated muscle. <h3>Conclusion:</h3> Our study identified potential genes associated with response to therapy in TABs from patients with GCA, that are currently being validated. <h3>REFERENCES:</h3> [1] Muratore F Semin Arthritis Rheum. 2024;64:152351. <h3>Acknowledgements:</h3> Foundation for Research in Rheumatology (FOREUM) for funding the project (https://www.foreum.org/projects.cfm?projectid=142). <h3>Disclosure of Interests:</h3> <b>None declared.</b>