Pathogenesis of giant cell arteritis

GCA is an immune-mediated chronic inflammatory disease of large vessels. The pathogenesis of GCA is poorly understood. The epidemiology of GCA strongly indicates that genetic background, ageing and gender undoubtedly play a role. Various polymorphisms have been associated with increased risk of GCA but the strongest association appears to be with variants in the class II major histocompatibility complex reinforcing the concept that GCA is an antigen-driven disease [1]. However, the nature of the triggering agent(s) has not been identified. Activated dendritic cells are present in lesions and are thought to play an important role in T-cell activation [2, 3]. GCA is characterized by a prominent Th1-mediated immune response with vigorous expression of IFNγ and IFNγ- induced products in lesions in accordance with the granulomatous nature of lesions [2, 3]. In recent years it has become apparent that a Th17-mediated immune response also contributes to GCA and that patient with prominent Th17 response respond better to glucocorticoid treatment [4, 5]. Amplification cascades following these inititating events are seminal in the development and perpetuation of GCA lesions. IFNγ is a potent activator of macrophages which maintain inflammatory cascades and participate in vascular injury. Macrophages produce pro-inflammatory cytokines IL-1, TNFα and IL-6 among many others which correlate with the intensity of the systemic inflammatory response, typical of the disease [6]. Tissue expression and serum concentrations of TNFa and IL-6 correlate with disease persistence [6]. Chemokines, endothelial adhesion molecules and colony-stimulating factors are also produced in lesions and reinforce inflammatory loops by recruiting and expanding the half-life of additional inflammatory cells [6, 7]. Angiogenic factors are produced in lesions and promote neovascularization providing new entries for infiltrating leucocytes [8]. Activated macrophages produce reactive oxygen species which contribute to oxidative damage and vessel wall injury [9]. Matrix metalloprotease (MMP-9 and MMP-2) expression, activation and proteolytic activity have been detected in lesions and, given their elastinolytic activity, are probably contributing to disruption of elastic fibres and abnormal vascular remodelling [10]. Currently the treatment of GCA mainly relies on glucocorticoids with induce a rapid relief of symptoms but are unable to induce sustained remission in 60–70% of patients. Understanding the pathogenic mechanisms leading to GCA may lead to the identification of better therapeutic agents. The association between increased expression of TNFα and persistent disease activity provided support to the performance of clinical trials blocking TNF with infliximab, etanercept or adalimumab which, unfortunately, have proved insufficient to abrogate disease activity and maintain remission, presumably due to redundancy in inflammatory pathways [11, 12]. Currently, blocking the IL-6 receptor with tocilizumab is being tested in an international multicentre trial. IL-6 is a multifunctional cytokine involved not only in inducing the acute phase response and ensuing systemic symptoms but also in maintaining the Th17 pathway. Interfering with CD28-mediated T-cell co-stimulation with abatacept, presumably during antigen presentation, is also currently being tested in a multicentre trial. Growth factors produced by activated macrophages or by injured vascular smooth muscle cells drive a vascular remodelling programme leading to myofibroblast differentiation of smooth muscle cells, migration towards the intimal layer and deposition of extra cellular matrix proteins. This leads to intimal hyperplasia and vessel occlusion, source of the ischaemic complications of GCA patients. Several factors including PDGFs, TGFβ and endothelin-1, may contribute to myofibroblast activation and production of matrix, eventually leading to vascular occlusion [13, 14]. Their expression in lesions is not down-regulated by glucocorticoids suggesting that mechanisms of vessel occlusion may require a specific approach in large-vessel vasculitis [15, 16].