GCA patients with a strong systemic inflammatory response, who have been previously shown to be more resistant to corticosteroid therapy, have elevated tissue expression of proinflammatory cytokines IL-1beta, TNFalpha and IL-6. High production of TNFalpha is associated with longer corticosteroid requirements.

Background— Patients with giant-cell arteritis (GCA) who develop a strong acute-phase response are at low risk of disease-related ischemic events. Methods and Results— To assess the potential protective role of proinflammatory cytokines in the development of ischemic events in GCA, we measured tissue expression (66 individuals) and/or circulating levels (80 individuals) of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6 in patients with biopsy-proven GCA. Tissue expression was determined by quantitative real-time polymerase chain reaction and immunohistochemistry. Circulating cytokines were determined by enzyme-linked immunoassay. We found that patients with disease-related ischemic events had lower IL-6 mRNA levels (5.9±2.1 versus 27.6±7.8 relative units, P =0.013), lower IL-6 immunohistochemical expression scores (1.5±0.9 versus 2.7±1, P =0.001), and lower circulating levels of IL-6 (13.6±2.1 versus 24±2.4 pg/mL, P =0.002) than patients without ischemic complications. No significant differences were found for either IL-1β or TNF-α. We subsequently investigated direct effects of IL-6 on vessel wall components. We found that IL-6 stimulates endothelial cell proliferation and differentiation into capillary-like structures and induces full angiogenic activity in both ex vivo (aortic ring) and in vivo (chick chorioallantoic membrane) assays. Conclusions— GCA patients with ischemic complications have lower tissue expression and circulating levels of IL-6 than patients with no ischemic events. IL-6 has relevant direct effects on vascular wall components that might be protective: IL-6 activates a functional program related to angiogenesis that may compensate for ischemia in patients with GCA.

JOSÉ HERNÁ NDEZ-RODRÍGUEZ, ANA GARCÍA-MARTÍNEZ, JORDI CASADEMONT, XAVIER FILELLA, MARÍA-JOSÉ ESTEBAN, ALFONSO LÓ PEZ-SOTO, JOAQUIM FERNÁ NDEZ-SOLÀ , Á LVARO URBANO-MÁ RQUEZ, JOSEP M. GRAU, AND MARIA C. CIDObjective. To assess whether the intensity of the initial systemic inflammatory response is able to predict response to therapy in patients with giant cell arteritis (GCA). Methods. Retrospective review of 75 patients (49 women and 26 men) with biopsy-proven GCA who had regular followup and were treated according to uniform criteria. Four parameters were used to evaluate the baseline inflammatory response at diagnosis: fever, weight loss, erythrocyte sedimentation rate > 85 mm/hour, and hemoglobin < 110 gm/liter. Patients were considered to have a weak inflammatory response if they had 2 or fewer inflammatory parameters (group 1) and a strong inflammatory response if 3 or 4 parameters were present (group 2). Time required to achieve a maintenance dose of less than 10 mg prednisone/day was recorded and analyzed by the Kaplan-Meier survival analysis method. Tumor necrosis factor ␣ (TNF␣) and interleukin 6 (IL-6) serum levels were also determined in 62 patients and 15 controls. Results. Forty patients had a weak (group 1) and 35 had a strong (group 2) initial inflammatory response. Patients in group 2 had significantly higher levels of circulating TNF␣ (31.9 ؎ 16.8 versus 22.3 ؎ 9 pg/ml; P ‫؍‬ 0.01) and IL-6 (28.2 ؎ 17.4 versus 16.6 ؎ 13 pg/ml; P ‫؍‬ 0.004) than patients in group 1. In group 1, 50% of patients required a median of 40 weeks (95% CI 37-43) to reach a maintenance dose of <10 mg, whereas in group 2 a median of 62 weeks (95% CI 42-82) was necessary (P ‫؍‬ 0.0062). Patients in group 2 experienced more flares than patients in group 1 (P ‫؍‬ 0.01) and received higher cumulative steroid doses (8.974 ؎ 3.939 gm versus 6.893 ؎ 3.075 gm; P ‫؍‬ 0.01). Conclusion. GCA patients with a strong initial systemic inflammatory reaction have more elevated circulating levels of IL-6 and TNF␣, have higher and more prolonged corticosteroid requirements, and experience more disease flares during corticosteroid therapy than patients with a weak systemic acute phase response.