Immune signatures in chronic inflammatory diseases: Focus on metabolism and IL-6

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases that may develop with aging. GCA is one of the most common forms of vasculitis affecting large- and medium-sized blood vessels in elderly patients. Histologically, inflamed arteries of patients with GCA show infiltration of CD4+ T-cells and macrophages, but the pathogenesis of GCA is not yet fully understood. In this thesis, we first explored macrophage heterogeneity and their varying functions in GCA pathogenesis. Next, we studied markers of cellular metabolism and reported their role in vascular imaging and assisting in the diagnosis and monitoring of disease activity. A negative association between glucose and lipid metabolism, and the risk of developing GCA has been reported in population-based registry and cohort studies. As the data on this relation were limited, we further studied the metabolic features and prevalence of comorbidities in treatment-naïve patients with GCA and PMR, and compared these data with those of the population-based Dutch Lifelines cohort. We demonstrated metabolic disturbances in treatment-naïve GCA patients, suggesting the potential of metabolic factors as biomarkers. Glucocorticoids (GCs) are the mainstay for GCA treatment. Prolonged GC treatment is associated with GC-related adverse events. Here, we unveiled an increase in comorbidities and an unhealthy metabolic profile with GC treatment, indicating the need for prednisone-sparing targeted treatment in patients with GCA. One of the proven GC-sparing drugs is Tocilizumab, a drug that blocks the IL-6 receptor. Unfortunately, Tocilizumab is only effective in half of the patients. Therefore, we analyzed downstream interleukin-6 (IL-6) signalling in GCA patients in order to identify patients who will benefit from treatment with tocilizumab from those who will not benefit. The discoveries in this thesis demonstrate the crucial involvement of metabolism and the IL-6 signalling pathway in the progression of GCA and introduce a new perspective for diagnostic tools and therapeutic strategies in GCA.