Supplement Article |
OP18. FACTORS INVOLVED IN THE PERSISTENCE OF INFLAMMATORY LESIONS IN GIANT CELL ARTERITIS (GCA)
Vasculitis Research Unit, Department of Internal Medicine, Hospital Clínic, University of Barcelona, IDIBAPS, Spain
Patients with GCA usually experience a dramatic relief of their cranial, polymyalgic and systemic symptoms with corticosteroid treatment. However, recurrences are frequent during steroid tapering and corticosteroid requirements are highly variable among individuals: while some patients easily enter sustained remission, others require remarkable cumulated corticosteroid doses with their ensuing adverse effects.
We and others have empirically observed that the intensity of the acute phase response is associated with different disease outcomes. Patients with a weak acute phase response have higher risk of developing disease-related ischemic events. These patients have weaker expression of pro-inflammatory cytokines in their lesions, lower concentrations of pro-inflammatory cytokines in their sera, weaker angiogenic response in their lesions, and lower expression of endothelial cell adhesion molecules for leukocytes. These patients achieve more rapidly a sustained remission, suffer from fewer relapses, and require lower cumulated corticosteroid doses. At the opposite edge of the spectrum, patients with a strong systemic inflammatory response have higher tissue production and circulating levels of pro-inflammatory cytokines, and prominent neovascularization in their lesions with strong expression of endothelial cell adhesion molecules. Although these patients have lower frequency of ischemic events, they suffer from a more refractory disease. These observations support the concept that, in some patients, GCA would easily evolve to a healing stage with higher risk of ischemic complications, perhaps facilitated by the scarring process itself, whereas other patients would develop a perpetuating disease with sustained inflammatory cascades with vascular regeneration and remodelling, leading to a more refractory and relapsing outcome.
Proinflammatory cytokines IL-1ß, TNF
and IL-6 may have an important role in contributing to these different outcomes. Their tissue expression correlates with the intensity of the acute phase reaction. In addition, TNF, and, IL-1ß, mRNA concentrations in lesions correlate with subsequent corticosteroid requirements. Based on their known biologic functions, pro-inflammatory cytokines may have important roles in perpetuating the inflammatory process by amplifying inflammatory cascades such as endothelial adhesion molecule expression, chemokine and cytokine production and by triggering the acute phase response leading to the general feeling of sickness in patients with GCA. Alternatively, these cytokines may be the downstream products of more relevant factors or may be co-ordinately regulated with other molecules with a more direct impact on the course of GCA.
Comparison of gene expression in vascular inflammatory lesions between easy responders and refractory patients may help to identify additional factors involved in persistence of inflammation in GCA. Using this approach we have identified CCL-2 (MCP-1) a powerful chemotactic factor for monocytes and Th1 lymphocytes, as a significant molecule associated with disease refractoriness.
Supported by SAF 02/03307 and 05/06250.