Giant cell arteritis: diagnostic tools, treatment targets, and pathogenic pathways
|Title:||Giant cell arteritis: diagnostic tools, treatment targets, and pathogenic pathways||Authors:||Conway, Richard||Advisor:||Molloy, Eamonn S
|Permanent link:||http://hdl.handle.net/10197/9091||Date:||2017||Abstract:||Giant cell arteritis (GCA) is the most common form of systemic vasculitis. Up to 25% of patients develop cranial ischaemic complications (CIC). The diagnosis of GCA is clinical, assisted by supportive investigations. Glucocorticoids are the mainstay of treatment; high doses and prolonged courses mean that adverse events, such as fracture and infection, are common, occurring in up to 95% of patients. The current model of GCA pathogenesis implicates dual T-helper lymphocyte pathways with TH1 cells primarily responsible for ischaemic events and TH17 cells for systemic and polymyalgic features. We evaluated the performance of temporal artery (TA) ultrasound (US) for the diagnosis of GCA in a prospective real-world setting, demonstrating a sensitivity of 52% and specificity of 72%. A strategy of TA US followed by a TA biopsy (TAB) only in the case of a negative US was as effective as performing both procedures in all patients, with a sensitivity of 79% and specificity of 72%. The only significant predictor of a positive TA US in our study was male sex, with an odds ratio of 5.5. We investigated the pathogenic role of IL-12 and IL-23 in GCA. IL-12p35 and IL-23p19 were assessed by immunohistochemistry in inflammatory cells in TABs. IL-12p35 was increased in those with CICs and those with large vessel vasculitis on imaging, while IL-23p19 was increased in those with two or more relapses. Using our ex vivo culture models we stimulated PBMCs, TA explants, and myofibroblast outgrowths with IL-12 and IL-23. Both IL-12 and IL-23 stimulation independently increased IL-6 and IL-22 secretion in cultured PBMCs. IL-12 stimulation also increased IFN-γ secretion and decreased IL-8 secretion, while IL-23 stimulation increased IL-17A and IL-17F secretion. In our TA explant culture model, IL-23 stimulation increased IL-6 and IL-8 secretion. In the myofibroblast outgrowth culture model IL-12 and IL-23 stimulation increased the quantity of myofibroblast outgrowths from TABs, evidence of increased migration and invasion. Taken together these results suggest key roles for IL-12 and IL-23 in the inflammatory and proliferative pathways involved in GCA pathogenesis. Finally, we performed a prospective trial of ustekinumab in 25 patients with refractory GCA. No patient experienced a relapse of GCA while receiving ustekinumab. There were significant decreases in median prednisolone dose, BVAS, and acute phase reactants. 25% of patients successfully stopped glucocorticoids. We saw no new adverse events. These findings suggest that ustekinumab may have efficacy in GCA and warrants further evaluation in a randomised controlled trial.||Type of material:||Doctoral Thesis||Publisher:||University College Dublin. School of Medicine||Qualification Name:||Ph.D.||Copyright (published version):||2017 the author||Keywords:||Giant cell arteritis; Interleukin 12; Interleukin 23; Ultrasound; Ustekinumab; Vasculitis||Other versions:||http://dissertations.umi.com/ucd:10181||Language:||en||Status of Item:||Peer reviewed|
|Appears in Collections:||Medicine Theses|
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