Pos0722 effects on soluble immune checkpoints induced by tocilizumab monotherapy after ultra-short-term glucocorticoids in large vessel – giant cell arteritis patients

Background The most affected vessels in Giant cell arteritis (GCA) are the temporary arteries, but in some patients extracranial large vessels are also involved (LV-GCA). Tocilizumab (TCZ), a monoclonal anti-interleukin-6 receptor1 antibody, has been approved as glucocorticoid (GC) sparing agent in patients with GCA. Recently, new therapeutic protocols that combine rapid GC tapering and TCZ are emerging, but their effects on circulating immune cells and mediators are scarcely known [1]. Another clinical need in LV-GCA management is the lack of a gold standard to define disease state. The role of immune checkpoint molecules is tuning the activation of the immune system. They are expressed on the surface of immune cells, but also soluble forms exist. Active GCA patients showed a reduction of CD4+ T cells expressing PD1 and VISTA in comparison to controls [2,3]. We hypothesize that soluble immune checkpoints are modulated by the TCZ and GC combined treatment and that they are biomarkers able to differentiate active from inactive LV-GCA patients. Objectives: 1) To evaluate the effects of TCZ monotherapy after ultra-short-term GC treatments on soluble immune checkpoints. 2) To identify plasma biomarkers able to discriminate between LV-GCA patients in the active phase from those in remission. Methods We included 16 patients with active LV-GCA enrolled in the single-arm open-label clinical trial (NCT05394909) performed at AUSL-IRCCS at Reggio Emilia. Inclusion criteria: PET/CT with FDG uptake ≥2 in at least one vascular district and at least one among ESR >40 mm/h (or CRP >10 mg/L); cranial or systemic manifestations of GCA or polymyalgia rheumatica. Exclusion criteria: more than 10 mg/day of prednisone for more than 10 consecutive days in the previous 3 months. Remission was defined by all the following: absence of any clinical signs and symptoms directly attributable to GCA; normalization of CRP and ESR values; absence of new/worsened vascular damage at CT; vascular FDG uptake <2 in all vascular districts at PET/CT or overall PET image interpretation of non-active vasculitis. All patients received 500 mg per day of methylprednisolone intravenously for three consecutive days and weekly subcutaneous TCZ injections from day 3 until week 52. Plasma samples were collected at baseline before treatment and after GC injections. For 10 patients plasma samples were also collected at week 52. Laboratory data were collected at the same time points. Concentrations of CD137L, CD137, CD27, CTLA4, CD80, CD40, CD40L, GITR, GITRL, ICOSL, IDO, LAG3, MICA, MICB, PD1, PDL1, PDL2, PTX3, TIM3 and VISTA were evaluated in plasma samples by a multiplex bead-based assay with the MAGPIX instrument. Wilcoxon test was used for comparison between groups, Spearman test was used for correlation analysis. P < 0.05 was considered statistically significant. Results Soluble CD137L, CTLA4, CD40, CD40L, GITR, IDO, PD1 and PDL1 were not detected in almost all of the samples irrespective of treatment and disease phase. Intravenous injections of GC determined a significant reduction of soluble CD137, CD80, GITRL, ICOSL, LAG3, MICA, and MICB and an increase of PTX3 and VISTA levels. After 52 weeks of TCZ as monotherapy, an increase in plasmatic ICOSL and a reduction in LAG3, PTX3, and VISTA were observed compared to baseline. At 52 weeks, 7 patients were classified in remission phase of the disease and 3 patients were active. Changes in immune checkpoint levels occurred irrespective to disease phase. Levels of soluble immune checkpoints did not correlate with ESR and CRP concentrations, markers currently used in clinical practice to evaluate systemic inflammation. Conclusion Ultra-short-term GC treatments and TCZ monotherapy modulate the levels of soluble immune checkpoints. The evaluation of the investigated panel of immune checkpoints did not allow to discriminate between LV-GCA patients in different disease phases. References [1]Gloor AD. Rheumatol 2019 [2]Hid CR. Front Immunol 2019 [3]Zhang H. Proc Natl Acad Sci 2017 [4]Hellmich B. Ann Rheum Dis 2019 Acknowledgements Azienda Unità Sanitaria Locale (AUSL)-IRCCS, Reggio Emilia, Italy: “Bando per la valorizzazione della Ricerca Istituzionale 2021.” Disclosure of Interests None Declared.