Treatment with tocilizumab decrases CXCL13 expression in cultured temporal arteries from patients with Giant Cell Arteritis (GCA)

2018 edition

Nekane Terrades Garcia

BACKGROUND IL-6 has been considered a biomarker of disease activity in GCA and a potential therapeutic target. However, the functional role of IL-6 in GCA has not been explored. IL-6 has important roles in B cell homeostasis and Th17 differentiation as well as in driving the acuteÔÇôphase response which underlines systemic symptoms in GCA. Blocking IL-6 receptor with tocilizumab (TCZ) has shown efficacy in maintaining remission in two recently published randomized clinical trials.┬á We hypothesized that TCZ may disturb B cell homeostasis and interfere with tertiary lymphoid organ (TLO) formation.

PURPOSE  To explore TLO formation in GCA arteries and to investigate the impact of IL-6R blockade with TCZ on TLO markers in ex-vivo cultured arteries from patients with GCA.

METHODS Formation of TLO was explored in temporal artery biopsies from patients with GCA by immunofluorescence using CD20 (B cell marker) and CD21 (follicular dendritic cell marker). Expression of TLO markers CXCL13, LTα and LTβ was assessed by quantitative real-time PCR in temporal artery biopsies from 13 patients with GCA and 13 control individuals. To investigate the effect of TCZ, temporal arteries from 13 GCA patients and 8 controls were cultured on 3D matrix (Matrigel) with or without TCZ (purchased from Roche) at 10mg/ml or IgG isotype control at the same concentration. After 5-day culture, expression of CXCL13, LTα and LTβ was assessed by quantitative RT-PCR. Other pro-inflammatory  (IL-1b) survival ( BCL-6, BAFF)  or remodeling (TGFb) molecules relevant to GCA pathogenesis were also assessed.

RESULTS B cell clusters intermingled with follicular dendritic cells were identified in temporal artery biopsies from patients with GCA, particularly in the adventitial layer. mRNA expression of CXCL13 (16.93 vs 7.10 relative units, p=0.001),  LTα (16,82 vs 6.18, p=0.0001) and LTβ (16.75 vs 9.54, p=0.014) was significantly higher in temporal arteries from GCA patients compared to healthy controls. After 5-day culture, TCZ selectively induced a significantly decrease in CXCL13 mRNA expression in cultured arteries (p=0.023). No significant changes in LTα ,  LTβ, IL-1β, BCL-6, BAFF or TGFβ expression were observed upon TCZ treatment.

CONCLUSIONS Treatment with TCZ elicits a significant and selective reduction of CXCL13 expression in temporal artery lesions from patients with GCA. Disruption of B cell homeostasis may partially account for the therapeutic effects of TCZ in patients with GCA.