Pos0265 serum proteomics in giant cell arteritis in response to a three-day pulse of glucocorticoid followed by tocilizumab monotherapy (the gusto trial)

BackgroundMeasuring disease activity in Giant Cell Arteritis (GCA) remains a challenge, particularly, if Tocilizumab (TCZ) is prescribed which blunts the acute phase response. A proteome analysis may not only serve to identify biomarkers, but also to shed light on pathophysiology. The sequential administration of Glucocorticoids (GC) and TCZ as done in the GUSTO study (GCA treatment with ultra-short GC and TCZ) provides a unique opportunity to dissect the effects of GC and TCZ.ObjectivesTo investigate the effects of pulse GC-treatment and of ensuing long-term TCZ monotherapy on serum proteins in GCA; to compare the serological findings with clinical response; to search for proteins which are not under control of IL-6 and may be suitable as biomarkers of disease activity.MethodsEighteen patients with newly diagnosed GCA received 500 mg methylprednisolone intravenously for 3 consecutive days (NCT03745586). Thereafter, GC treatment was discontinued and a single dose of TCZ (8 mg/kg body-weight) was administered intravenously, followed by weekly subcutaneous TCZ injections (162 mg) from day 10 until week 52. Serum samples were collected prior to treatment (day 0), at day 3 (after GC treatment), day 10 and at weeks 4, 24, and 52 (Lancet Rheumatology, https://doi.org/10.1016/S2665-9913(21)00152-1). Sera of patients were analyzed on Olink Explore 1536, capturing over 1400 proteins. Protein wise t-tests (threshold, adjusted p-value < 0.05) with adjustment for multiple testing (Benjamini-Hochberg) were performed to identify differentially expressed proteins (DEPs) between day 0 vs day 3 (referred to as GC treatment) and day 0 vs week 52 (referred to as TCZ treatment, remission). DEPs were grouped in pathways identified in the KEGG database.ResultsSuccessful treatment resulted in the upregulation of 254 proteins and the downregulation of 245 proteins from day 0 to week 52. Protein levels did not change between week 24 and 52 during established full remission.In response to GC pulse therapy the ten most significant DEPs included ANGPTL7, AREG, IL1RL1, MATN3, MMP3, SPARCL1 (upregulated) and IL12A, IL12B, KLK10, SIGLEC6 (downregulated). Conversely, under treatment with TCZ, SIGLEC6 was continuously up- and MMP3 and AREG were continuously down-regulated from day 3 to week 4.KEGG pathways of interest in GCA (day 0 vs day 3 and day 0 vs week 52, respectively) included: cytokine-cytokine receptor interaction, the PI3K-AKT, JAK-STAT, IL17, TNF, NF-kappa B, Toll-like receptor and MAPK signaling pathways. Figure 1 displays the top 5 KEGG pathways enriched in TCZ-treated GCA patients in remission.Figure 1.Network plot of the top 5 KEGG pathways from day 0 vs week 52. Size in the figure legend refers to the number of proteins in each pathway. Estimate in the figure legend indicates the log2 fold change from day 0 vs week 52.ConclusionOne third of the measured proteins covering a wide spectrum of pathways changed in response to pulse GC-treatment followed by TCZ monotherapy. Several proteins were inversely induced by GC or TCZ. Osteopontin, CSF1 and CCL18 as markers of macrophage activation should be explored as biomarkers of disease activity in TCZ-treated GCA-patients.AcknowledgementsThe study was funded in 50% by the Research Funds of the Department of Rheumatology, Immunology and Allergology, University Hospital and University of Bern, Bern, Switzerland, and 50% by F Hoffmann-La Roche.Disclosure of InterestsLisa Christ Shareholder of: Gilead Sciences and F. Hoffmann-La Roche Ltd, Consultant of: Bristol-Myers Squibb, Novartis, and Sanofi, Grant/research support from: Gilead Sciences, F. Hoffmann-La Roche Ltd, and Pfizer, Andrea Gloor: None declared, Florian Kollert Shareholder of: Roche, Consultant of: BMS, Actelion, Boehringer-Ingelheim, Pfizer, Grant/research support from: Roche, Gilead, Pfizer, Employee of: Roche, Stephan Reichenbach: None declared, Peter Villiger Speakers bureau: Roche, MSD, AbbVie, Pfizer, Novartis, Grünenthal, Amgen, Sanofi, Chugai, BMS, and Gilead, Consultant of: Advisory fees from Roche, MSD, AbbVie, Pfizer, Novartis, Grünenthal, Amgen, Sanofi, Chugai, BMS, and Gilead, Grant/research support from: Research support from Roche, MSD, AbbVie, and Pfizer