TBA (17A162)

IL-12 and IL-23 are Key Pathogenic Players in GCA


Richard Conway, Lorraine O’Neill, Phil Gallagher, Geraldine M McCarthy, Conor C Murphy, Douglas J Veale, Ursula Fearon, Eamonn S Molloy


Centre for Arthritis and Rheumatic Diseases, St Vincent’s University Hospital; Department of Rheumatology, Mater Misericordiae University Hospital; Department of Ophthalmology, Royal College of Surgeons of Ireland; Department of Molecular Rheumatology, Trinity College Dublin


Giant cell arteritis (GCA) is the most common form of systemic vasculitis; the pathogenesis is unclear. Current evidence suggests both TH1 and TH17 pathways are important but the proximal initiators and effector cytokines are unknown. IL-12 and IL-23 secreted by dendritic cells are hypothesised as stimulators of these pathways. We have previously evaluated IL-12/23 blockade with ustekinumab in 25 patients with refractory GCA in a prospective clinical trial; ustekinumab decreased median prednisolone dose (15 vs 5mg, p<0.001), ESR (29 vs 18, p=0.045), and CRP (13 vs 6, p=0.006) (ISR 2016, Ann Rheum Dis. 2016;75:1578-9).


To assess the role of IL-12 and IL-23 in GCA pathogenesis.


IL-12 and IL-23 were quantified by immunohistochemistry in temporal artery (TA) biopsies. TA explant, peripheral blood mononuclear cell (PBMC), and myofibroblast outgrowth culture models were established from patients with GCA and disease controls. PBMCs and TA explants were cultured for 24 hours in the presence or absence of IL-23 (10ng/ml) or IL-12 (50ng/ml). Gene expression was quantified by Real-time PCR and cytokine secretion by ELISA. Myofibroblast outgrowths were assessed following 28 days culture and quantified by counting the number of outgrowths/high-power field.


Immunohistochemistry (n=33) demonstrated IL-12p35 and IL-23p19 in inflammatory cells in positive TA biopsies, they were not detected in negative biopsies. IL-12p35 was increased in those with cranial ischaemic complications (p=0.026) and in large vessel vasculitis (p=0.006), IL-23p19 was increased in those with two or more relapses (p=0.007). In cultured PBMCs, IL-12 stimulation increased IL-6 (n=17, p=0.009), IL-22 (n=16, p=0.003), and IFN-γ (n=14, p=0.0001) and decreased IL-8 (n=15, p=0.0006) secretion, while IL-23 stimulation increased IL-6 (n=40, p=0.029), IL-22 (n=16, p=0.001), IL-17A (n=16, p=0.0003) and IL-17F (n=9, p=0.012) secretion. In TA explants, IL-23 stimulation increased gene expression of IL-8 (n=13, p=0.0001) and CCL-20 (n=9, 0.027) and protein expression of IL-6 (n=61, p=0.002) and IL-8 (n=60, p=0.004), IL-12 stimulation (n=14) had no effect; however, IFN-γ and IL-17A were not detectable. IL-12 (n=20, p=0.0005) and IL-23 (n=33, p<0.0001) stimulation increased the quantity of myofibroblast outgrowths from TA biopsies. In all experiments there were no significant differences between biopsy positive and biopsy negative GCA patients.


IL-12 and IL-23 promote expression of key cytokines from PBMCs and TAs and myofibroblast proliferation in TAs from GCA patients. Our results were consistent in biopsy positive and negative GCA, suggesting that IL-12 and IL-23 play proximal roles in inducing these pathways. This data suggests that IL12/IL23 play central and distinct roles in stimulating inflammatory and proliferative pathways in GCA and supports the rationale for IL12/IL23 blockade in GCA.