José Hernández-Rodríguez

Large vessel involvement in biopsy-proven giant cell arteritis: prospective study in 40 newly diagnosed patients using CT angiography

Background Necroscopic and surgical studies have suggested that giant cell arteritis (GCA) may target the aorta and its main branches. Imaging techniques are able to detect large vessel vasculitis (LVV) non-invasively in patients, but the prevalence of LVV in GCA has not been clearly established. Objective To assess prospectively the prevalence, characteristics and topography of LVV in patients with newly diagnosed GCA and to determine the associated clinical and laboratory features. Methods CT angiography (CTA) was performed in 40 consecutive patients with newly diagnosed biopsy-proven GCA. Patients were treatment-naïve or had been treated with corticosteroids for <3 days. Vessel wall thickness and vessel diameter (dilation or stenoses) at four aortic segments (ascending aorta, aortic arch, descending thoracic and abdominal aorta) and at the main aortic branches were evaluated. Results LVV was detected in 27 patients (67.5%). The vessels involved were as follows: aorta (26 patients, 65%), brachiocephalic trunk (19 patients, 47.5%), carotid arteries (14 patients, 35%), subclavian arteries (17 patients, 42.5%), axillary arteries (7 patients, 17.5%), splanchnic arteries (9 patients, 22.5%), renal arteries (3 patients, 7.5%), iliac arteries (6 patients, 15%) and femoral arteries (11 patients, 30%). Dilation of the thoracic aorta was already present in 6 patients (15%). Cranial ischaemic events were significantly less frequent in patients with LVV (p=0.029). Treatment-naïve patients had a higher frequency of LVV (77% vs 29%, p=0.005). Conclusions CTA-defined LVV occurs in two-thirds of patients with GCA at the time of diagnosis and aortic dilation is already present in 15%. Previous corticosteroid treatment may decrease CTA-detected LVV.

Elevated Production of Interleukin-6 Is Associated With a Lower Incidence of Disease-Related Ischemic Events in Patients With Giant-Cell Arteritis. Angiogenic Activity of Interleukin-6 as a Potential Protective Mechanism

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)-1&bgr;, tumor necrosis factor-&agr; (TNF-&agr;), 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-1&bgr; or TNF-&agr;. 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.

Development of aortic aneurysm/dilatation during the followup of patients with giant cell arteritis: A cross‐sectional screening of fifty‐four prospectively followed patients

OBJECTIVE Giant cell arteritis (GCA) may involve the aorta. Retrospective studies have demonstrated a higher prevalence of aortic aneurysm among patients with GCA compared with the general population. We investigated the prevalence of aortic aneurysm in a cohort of patients with biopsy-proven GCA using a defined protocol and assessed whether persisting low-grade disease activity is associated with higher risk of developing aortic aneurysm. METHODS Fifty-four patients with GCA (14 men and 40 women) were cross-sectionally evaluated after a median followup of 5.4 years (range 4.0-10.5 years). The screening protocol included a chest radiograph, abdominal ultrasonography scan, and computed tomography scan when aortic aneurysm was suspected or changes with respect to the baseline chest radiograph were observed. Clinical and laboratory data, corticosteroid requirements, and relapses were prospectively recorded. RESULTS Twelve patients (22.2%) had significant aortic structural damage (aneurysm/dilatation), 5 of them candidates for surgical repair. Aortic aneurysm/dilatation was more frequent among men (50%) than women (12.5%; relative risk 3.5, 95% confidence interval 1.53-8.01, P = 0.007). At the time of screening, patients with aneurysm/dilatation had lower serum acute-phase reactants, lower relapse rate, and needed shorter periods to withdraw prednisone than patients without aortic structural damage. CONCLUSION There is a substantial risk of developing aortic aneurysm/dilatation among patients with GCA. Our data do not support that aneurysm formation mainly results from persistent detectable disease activity. Additional factors including characteristics of the initial injury or the target tissue may also determine susceptibility to aortic aneurysm/dilatation.

Cell adhesion molecules in the development of inflammatory infiltrates in giant cell arteritis: Inflammation-induced angiogenesis as the preferential site of leukocyte–endothelial cell interactions

OBJECTIVE To investigate the expression pattern of adhesion molecules involved in leukocyte-endothelial cell interactions in giant cell arteritis (GCA). METHODS Immunohistochemical analysis was performed on frozen temporal artery sections from 32 patients with biopsy-proven GCA and from 12 control patients with other diseases. Adhesion molecules identified were intercellular adhesion molecule 1 (ICAM-1), ICAM-2, ICAM-3, vascular cell adhesion molecule 1 (VCAM-1), platelet endothelial cell adhesion molecule 1 (PECAM-1), E-selectin, P-selectin, L-selectin, lymphocyte function-associated antigen 1 (LFA-1), very late activation antigen 4 (VLA-4), Mac-1 (CD18/CD11b), and gp 150,95 (CD18/CD11c). Clinical and biochemical parameters of inflammation in the patients, as well as the duration of previous corticosteroid treatment, were prospectively recorded. RESULTS Constitutive (PECAM-1, ICAM-1, ICAM-2, and P-selectin) and inducible (E-selectin and VCAM-1) endothelial adhesion molecules for leukocytes were mainly expressed by adventitial microvessels and neovessels within inflammatory infiltrates. Concurrent analysis of leukocyte receptors indicated a preferential use of VLA-4/VCAM-1 and LFA-1/ICAM-1 at the adventitia and Mac-1/ICAM-1 at the intima-media junction. The intensity of inducible endothelial adhesion molecule expression (E-selectin and VCAM-1) correlated with the intensity of the systemic inflammatory response. Previous corticosteroid treatment reduced, but did not completely abrogate, the expression of the inducible endothelial adhesion molecules E-selectin and VCAM-1. CONCLUSION Inflammation-induced angiogenesis is the main site of leukocyte-endothelial cell interactions leading to the development of inflammatory infiltrates in GCA. The distribution of leukocyte-endothelial cell ligand pairs suggests a heterogeneity in leukocyte-endothelial cell interactions used by different functional cell subsets at distinct areas of the temporal artery.

Tissue and Serum Angiogenic Activity Is Associated With Low Prevalence of Ischemic Complications in Patients With Giant-Cell Arteritis

Background—Vascular inflammatory lesions from patients with giant-cell arteritis show a remarkable amount of neovascularization, but its clinical implications have never been investigated. Methods and Results—To assess the clinical relevance of neovascularization in giant-cell arteritis, angiogenesis was measured in temporal artery sections from 31 patients with biopsy-proven giant-cell arteritis by staining endothelial cells with Ulex europaeus lectin. Angiogenesis was highly variable among these patients. Patients without ischemic complications had higher tissue angiogenesis scores than patients with ischemic events (5.69±0.6 versus 2.91±0.6, P =0.003). Angiogenesis was also more prominent in patients with a strong acute phase response (score: 5.31±0.6) compared with those with a weak systemic inflammatory reaction (2.30±0.44;P =0.0007). Serum angiogenic activity was studied in an additional series of 38 biopsy-proven patients. Sera from patients without ischemic events tended to be more active in stimulating human umbilical vein endothelial cell growth (optical density ×1000, 270±15 versus 192±14, P =0.065) and differentiation into capillary-like structures (107±5 versus 84±8 relative units, P =0.0058) than patients with ischemic complications. Sera from patients without ischemic events had more in vivo full angiogenic activity tested in the chick chorioallantoic membrane than sera from patients with ischemic complications. Conclusion—Inflammation-induced angiogenic activity may play a compensatory role for ischemia in patients with giant-cell arteritis.

Positron emission tomography assessment of large vessel inflammation in patients with newly diagnosed, biopsy-proven giant cell arteritis: a prospective, case–control study

Background Positron emission tomography (PET) scan is emerging as a promising imaging technique to detect large-vessel inflammation in giant cell arteritis (GCA). However, the lack of a standardised definition of arteritis based on 18fluorodeoxyglucose (FDG) uptake is an important limitation to the use of PET scan for diagnostic purposes. Objective To prospectively assess the intensity and distribution of FDG uptake at different vascular territories in patients with newly diagnosed GCA compared with controls. Methods 32 consecutive, biopsy-proven, GCA patients treated with glucocorticoids for ≤3 days were included. The control group consisted of 20 individuals, who underwent PET/CT for cancer staging. Maximal standardised uptake value (SUVm) was calculated at four aortic segments, supraaortic branches and iliac-femoral territory. Sensitivity and specificity was calculated by receiver–operator characteristic curves (ROC) analysis. Results Mean SUVm was significantly higher in patients than in controls in all vessels explored and correlated with acute-phase reactants and serum IL-6. Mean of the SUVm at all the vascular territories had an area under the curve (AUC) of 0.830, and a cut-off of 1.89 yielded a sensitivity of 80% and a specificity of 79% for GCA diagnosis. There were no significant differences in AUC among the vascular beds examined. Conclusions FDG uptake by large vessels has a substantial sensitivity and specificity for GCA diagnosis.

Treatment of Polymyalgia Rheumatica: A Systematic Review

BACKGROUND Polymyalgia rheumatica (PMR) treatment is based on low-dose glucocorticoids. Glucocorticoid-sparing agents have also been tested. Our objective was to systematically examine the peer-reviewed literature on PMR therapy, particularly the optimal glucocorticoid type, starting doses, and subsequent reduction regimens as well as glucocorticoid-sparing medications. METHODS We searched Cochrane Databases and MEDLINE (1957 through December 2008) for English-language articles on PMR treatment (randomized trials, prospective cohorts, case-control trials, and case series) that included 20 or more patients. All data on study design, PMR definition criteria, medical therapy, and disease outcomes were collected using a standardized protocol. RESULTS Thirty studies (13 randomized trials and 17 observational studies) were analyzed. No meta-analyses or systematic reviews were found. The PMR definition criteria, treatment protocols, and outcome measures differed widely among the trials. Starting prednisone doses higher than 10 mg/d were associated with fewer relapses and shorter therapy than were lower doses; starting prednisone doses of 15 mg/d or lower were associated with lower cumulative glucocorticoid doses than were higher starting prednisone doses; and starting prednisone doses higher than 15 mg/d were associated with more glucocorticoid-related adverse effects. Slow prednisone dose tapering (<1 mg/mo) was associated with fewer relapses and more frequent glucocorticoid treatment cessation than faster tapering regimens. Initial addition of oral or intramuscular methotrexate provided efficacy at doses of 10 mg/wk or higher. Infliximab was ineffective as initial cotreatment. CONCLUSIONS The scarcity of randomized trials and the high level of heterogeneity of studies on PMR therapy do not allow firm conclusions to be drawn. However, PMR remission seems to be achieved with prednisone treatment at a dose of 15 mg/d in most patients, and reductions below 10 mg/d should preferably follow a tapering rate of less than 1 mg/mo. Methotrexate seems to exert glucocorticoid-sparing properties.

Early recruitment of phagocytes contributes to the vascular inflammation of giant cell arteritis

Vascular inflammation in giant cell arteritis is generally described as a process involving dendritic cells, T‐lymphocytes, and effector tissue macrophages. Less is known about the contribution of phagocytes that are recruited early, such as monocytes and neutrophils. These cells express and secrete pro‐inflammatory S100 proteins which directly activate endothelial cells. In this study the expression of S100A8/S100A9 and S100A12, pro‐inflammatory proteins specific for early recruited phagocytes, was studied in biopsies from 36 patients with giant cell arteritis. In addition, serum concentrations of these proteins were analysed in serum samples from 42 patients and 35 healthy controls. The S100A8/S100A9 complex was found to be abundant in the adventitia and media in affected arteries. Besides neutrophils, cells expressing these proteins belonged to a pro‐inflammatory subtype of CD68‐positive monocytes. In contrast, S100A12 expression was restricted to neutrophils that were found around the vasa vasorum within the adventitial layer. Both S100A8/S100A9 and S100A12 serum concentrations were significantly higher in patients with giant cell arteritis than in healthy controls. In conclusion, recently recruited phagocytes expressing pro‐inflammatory S100 proteins take part in the vascular inflammation of giant cell arteritis. They may play important roles at the vasa vasorum of affected vessels, which represent sites of entry for recruited inflammatory cells. These data indicate that phagocytes within the adventitia and media contribute to the process of inflammation via release of the pro‐inflammatory S100 proteins S100A8, S100A9, and S100A12. Copyright

Small‐vessel vasculitis surrounding a spared temporal artery: Clinical and pathologic findings in a series of twenty‐eight patients

OBJECTIVE Occasionally, a temporal artery biopsy reveals small-vessel vasculitis (SVV) surrounding a spared temporal artery, the significance of which is unclear. We analyzed the final diagnosis in a series of patients with this condition and tried to identify histopathologic features with potential usefulness in predicting the ultimate diagnosis. METHODS We performed a clinical and histopathologic review of 28 patients in whom SVV surrounding a spared temporal artery was the first histologic finding that led to the diagnosis of vasculitis. For comparison purposes, we analyzed the pattern of small vessel involvement in 30 patients with biopsy-proven giant cell arteritis (GCA). RESULTS GCA was considered the most likely diagnosis in 12 patients, based on the absence of clinical evidence of additional organ involvement and normal findings on muscle biopsy and electrophysiologic study. Three patients had systemic necrotizing vasculitis (SNV), based on the demonstration of typical lesions on subsequent muscle, nerve, or kidney biopsy. After extensive evaluation, 4 patients remained unclassifiable. Nine patients were incompletely studied. Fibrinoid necrosis was significantly more frequent in patients with SNV (P = 0.0022), whereas involvement of vasa vasorum was more frequent in patients classified as having GCA (P = 0.022). No differences in the pattern of small vessel involvement were found in patients with SVV surrounding a spared temporal artery who were classified as having GCA compared with patients with biopsy-proven GCA. Granulocytes were observed at similar frequency in all conditions. CONCLUSION SVV may be the only abnormal feature in a temporal artery biopsy and the only histologic evidence of vasculitis. The diagnosis of GCA can be reasonably established in most of these patients when there is no apparent evidence of additional organ involvement. However, when fibrinoid necrosis is observed or the temporal artery vasa vasorum are not involved, SNV must be extensively excluded.

Diagnosis and classification of polyarteritis nodosa.

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis preferentially targeting medium-sized arteries and not associated with glomerulonephritis or small vessel involvement. Anti-neutrophil cytoplasmic antibodies are typically negative. PAN may be triggered by viral infections, particularly hepatitis B virus, but remains idiopathic in most cases. Clinical manifestations of PAN are multisystemic. Peripheral nerve and skin are the most frequently affected tissues. Involvement of the gastrointestinal tract, kidneys, heart, and central nervous system is associated with higher mortality. Laboratory abnormalities reveal a prominent acute phase response but are non-specific. Histologic confirmation of vasculitis in medium sized arteries is desirable and biopsies must be obtained from symptomatic organs if feasible. Skin or muscle and nerve are preferred because of higher diagnostic yield and safety. If biopsies are negative or cannot be obtained, visceral angiography, may reveal multiple micro-aneurysms supporting the diagnosis of PAN. Current treatment policy includes high-dose corticosteroids, which are combined with immunosuppressive agents when critical organ involvement or life-threatening complications occur. IV pulse cyclophosphamide in the remission induction phase, later switched to a safer immunosuppressant for remission maintenance is a frequently used therapeutic approach. A recent consensus algorithm for the classification of PAN has attempted to overcome some of the caveats of the 1990 American College of Rheumatology (ACR) classification criteria which have proven to be unsatisfactory, and has also confirmed the low prevalence of PAN compared to other systemic necrotizing vasculitides. European league against rheumatic diseases (EULAR)/ACR endorsed international cooperation to establish new diagnostic/classification criteria is currently under way.