SP0002 Pathogenic Mechanisms in Giant-Cell Arteritis
Authors: M.C. Cid
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> Giant-cell arteritis (GCA) is a chronic inflammatory disease of large vessels. The epidemiology of GCA suggests that genetic background play a role in pathogenesis. Several polymorphisms have been associated with increased susceptibility to GCA but the strongest association has been found with MHC class II variants, supporting the concept that GCA is an antigen-driven disease [1]. However, the nature of the triggering antigen(s) has not been elucidated. Activated dendritic cells are present in lesions and are considered to play an important role in T-cell activation [2,3]. GCA is characterized by a marked Th1-mediated immune response with strong expression of IFNγ and IFNγ-induced molecules [2,3]. Th17 immune response also contributes to GCA and patients with prominent IL-17 expression respond better to glucocorticoid treatment [4,5]. Amplification cascades following initial events are crucial in the development and maintenance of GCA lesions. IFNγ is a potent activator of macrophages which produce pro-inflammatory cytokines IL-1, TNFα and IL-6, among others. Tissue expression and serum concentrations of TNFα and IL-6 are associated with persistent/relapsing disease [6]. Chemokines and adhesion molecules are also expressed in lesions and amplify inflammatory loops [6,7]. Angiogenic factors promote neovascularization, providing new entries for infiltrating leukocytes [8]. These mechanisms are though to contribute to he amplifiction and maintenance of inflammatory lesions. 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 are probably contributing to disruption of elastic fibres and abnormal vascular remodelling [10]. Currently, GCA treatment relies on glucocorticoids which induce a dramatic improvement of symptoms but are unable to achieve sustained remission in 60-70% of patients. Understanding the pathogenic mechanisms involved in GCA may lead to the discovery of better therapeutic agents. The association between increased expression of TNFα and persistent disease activity led to the performance of clinical trials blocking TNF with various agents which, unfortunately, have not been able to maintain remission, probably due to redundancy in cytokine pathways [11]. Currently, blocking IL-6 receptor with tocilizumab or interfering with CD28-mediated T-cell co-stimulation with abatacept, are being tested in multi-centre clinical trials. IL-6 is a multifunctional cytokine involved not only in inducing the acute phase response and related symptoms but also in maintaining the activation of the Th17 pathway. Growth factors produced by activated macrophages or by injured vascular smooth muscle cells induce myofibroblast differentiation, migration and production of matrix proteins, leading to intimal hyperplasia and vessel occlusion, source of the ischemic complications in GCA. PDGFs, TGFβ and endothelin-1, may contribute to myofibroblast activation [12,13]. Their expression in lesions is not down-regulated by glucocorticoids suggesting that mechanisms of vessel occlusion may require a specific approach [14,15]. <h3>References</h3> Carmona FD et al. Rheumatology (Oxford). 2014;53:6-18. Cid MC et al. Arthritis Rheum. 1989;32:884-93. Weyand CM, Goronzy JJ. Nat Rev Rheumatol. 2013;9:731-40. Espígol-Frigolé G et al. Ann Rheum Dis 2013;72:1481-7. Terrier B et al. Arthritis Rheum 2012;64:2001-11. Hernández-Rodríguez J, et al. Rheumatology 2004;43:294-301. Cid MC et al. Rheumatology 2006;45:1356-63. Cid MC et al. Circulation. 2002;106:1664-71. Rittner HLet al. Circ Res 1999;84:1050-8. Segarra M et al. Ann Rheum Dis. 2007;66:1429-35. Hoffman GS et al. Ann Intern Med. 2007;146:621-30. Lozano E et al. Ann Rheum Dis. 2010;69:434-42. Lozano E et al. Ann Rheum Dis. 2008; 67:1581-8. Visvanathan et al. Rheumatology 2011;50:2061-70. Corbera-Bellalta et al. Ann Rheum Dis 2014;73:616-23 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6228