A distinct profile of six soluble adhesion molecules (ICAM-1, ICAM-3, VCAM-1, E-selectin, L-selectin and P-selectin) in rheumatoid arthritis

Soluble forms of ICAM-1, VCAM-1, E-selectin, L-selectin, P-selectin and, more recently, ICAM-3 are known to exist in human serum and have elevated levels in numerous diseases. Previous studies have demonstrated that in rheumatoid arthritis (RA) the levels of circulating sICAM-1 and sE-selectin are elevated relative to healthy controls. We have compared the serum profiles of these six soluble adhesion molecules in patients with RA (n = 22) to those seen in healthy controls (n = 10) using sandwich ELISA. In the patients, there were significant elevations of serum sICAM-1 (P < 0.0001), sICAM-3 (P = 0.0327), sVCAM-1 (P = 0.0025), sL-selectin (P = 0.0194) and sP-selectin (P = 0.0025), but not E-selectin (P = 0.0672). However, only sP- selectin was found to correlate with disease activity in the patients (r = 0.461, P < 0.05). Thus, there is a distinct profile of soluble adhesion molecules in RA of which only sP-selectin correlates with disease activity.      

Soluble adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and vascular endothelial growth factor (VEGF) in patients with distinct variants of rheumatoid synovitis

BACKGROUND: Cell adhesion molecules and endothelial growth factors have an important role in the infiltrating of rheumatoid synovium with mononuclear cells, leading to the initiation and progression of the disease. OBJECTIVE: To investigate whether the serum profile of soluble adhesion molecules and of vascular endothelial growth factor (VEGF) is associated with the histological appearance of rheumatoid arthritis (RA). METHODS: Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), and VEGF were assessed by enzyme linked immunosorbent assay (ELISA) in 40 patients with RA and 32 patients with osteoarthritis (OA). RESULTS: Histological analysis of synovium specimens distinguished two types of rheumatoid synovitis. Twenty four RA samples presented diffuse infiltrates of mononuclear cells without any further microanatomical organisation, whereas in the remaining 16 samples lymphocytic follicles with germinal centre-like structures were identified. In comparison with patients with OA, constituting a control group, higher serum concentrations of sICAM-1 (p<0.001), sVCAM-1 (p<0.001), sE-selectin (p<0.01), and VEGF (p<0.001) were detected in patients with RA. Raised concentrations of sICAM-1, sVCAM-1, and VEGF dominated in the serum of patients with RA with follicular synovitis compared with those with diffuse synovitis (p<0.01 for all comparisons). The serum concentrations of sICAM-1, sVCAM-1, and VEGF correlated with markers of disease activity such as the erythrocyte sedimentation rate and C reactive protein levels. Furthermore, the clinical data analysed in our study indicated that patients with RA with follicular synovitis tend to have more severe disease. CONCLUSIONS: The distinct histological appearances of rheumatoid synovitis associated with different serum profiles of sICAM-1, sVCAM-1, and VEGF reflect varied clinical activity of the disease and confirm RA heterogeneity. Patients with different histological forms of synovitis may respond differently to the treatment regimens.     

Altered levels of soluble adhesion molecules in patients with rheumatoid arthritis complicated by peripheral neuropathy

OBJECTIVE: To assess levels of 2 circulating soluble adhesion molecules, vascular cellular adhesion molecule (sVCAM) and E-selectin, in patients with rheumatoid arthritis (RA) complicated by peripheral neuropathy compared to RA patients with no neurological complications and healthy controls. METHODS: In total, 25 RA patients with peripheral neuropathy (detected by clinical examination and confirmed by electromyography and nerve conduction studies), 40 RA patients without peripheral neuropathy, and 25 controls were studied. Clinical and laboratory assessments of disease activity were carried out and levels of sVCAM-1 and E-selectin were measured by ELISA in each of the 3 groups. RESULTS: Levels of sVCAM-1 and sE-selectin were higher (p < 0.001) in RA patients with peripheral neuropathy than in patients without neuropathy and controls. Levels of sE-selectin and sVCAM-1 correlated positively with disease activity variables. Correlation was independent of age and sex. CONCLUSION: Peripheral neuropathy in patients with RA is associated with increased endothelial cell activation evidenced by elevated serum levels of sVCAM-1 and sE-selectin in this group of patients.     

A study on soluble intercellular adhesion molecule-1 and selenium in patients with rheumatoid arthritis complicated by vasculitis

Clinical manifestations of vasculitis, as a complication of rheumatoid arthritis (RA), can be postulated as a consequence of immune response abnormalities and endothelial cell dysfunction. In this study we searched for the relationship between the extent of vascular involvement and either serum sICAM-1 or selenium concentrations. We also explored the possible interaction of serum selenium with sICAM-1 to provide a greater understanding of their role in rheumatoid vasculitis (RV). For the study, we measured the serum titers of sICAM-1 using an ELISA assay and the serum selenium concentrations using the ETAAS method in 37 women suffering from RA and 18 normal women serving as controls. All the RA patients were evaluated by extensive clinical, laboratory and capillaroscopic studies. In all patients with extra-articular manifestations, severe or moderate changes in nailfold capillaroscopy were found. Serum sICAM-1 titers in RA patients with mild vasculitis on nailfold capillaroscopy did not differ significantly from those of the healthy subjects, whereas a higher sICAM-1 level seemed to reflect the more intensive vascular changes in capillaroscopy. These data suggest that sICAM-1 serum levels may reflect the extent of the microvascular involvement in RA patients. Compared with controls, all the RA patients had markedly lower serum selenium concentrations, irrespective of the degree of the capillaroscopic vascular changes. A significant inverse correlation between sICAM-1 and selenium was found in the controls (r = –0.54; P<0.02). By contrast, no correlation was noted in RA patients (r=0.10, P not significant). This suggests that the sICAM-1 shedding in RV does not appear to be influenced by selenium, presumably owing to its low serum concentration.Abbreviations CRP Serum C-reactive protein - DAS Disease activity score - ESR Erythrocyte sedimentation rate - GSH-Px Glutathione peroxidase - NSAIDs Non-steroidal anti-inflammatory drugs - RA Rheumatoid arthritis - RV Rheumatoid vasculitis - TR Thioredoxin reductase     

Inflammatory cytokines,endothelial markers and adhesion molecules in rheumatoid arthritis: effect of intensive anti-inflammatory treatment

Tumour necrosis factor alpha (TNF-α) and interlekin-6 (IL-6) are key inflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA), a disease also associated with endothelial perturbation and increased serum levels of adhesion molecules. As relationships between these processes and molecules are unclear, we tested the hypotheses (a) that TNF-α and IL-6 are linked to endothelial activation/damage and levels of soluble adhesion molecules, and (b) that intensive anti-inflammatory treatment improves levels of these indices. We recruited 66 patients with RA, 48 community controls (CC), and 25 disease controls (DC). Plasma TNF-α and IL-6 were compared to markers of vascular biology (vWF, sE-sel), soluble adhesion molecules (sICAM, sVCAM) and routine inflammatory markers (CRP and ESR). Blood was obtained at baseline and at 1 week and again 4 weeks after anti-inflammatory treatment in a subgroup of 29 patients with RA. With the exception of sE-selectin, RA patients had increased levels of all plasma markers compared to the HCs, whilst levels in the DCs were largely intermediate between RA and the CCs. Within the RA group, sEsel correlated with both CRP and ESR whilst TNF-α correlated with sVCAM (all r > 0.32, P < 0.01). After 1 week of combined anti-inflammatory therapy, only CRP, ESR, sEsel and sVCAM were significantly reduced (all P < 0.05). In RA, endothelial activation (as sEsel) correlates with classical markers of inflammation and is reduced by intensive anti-inflammatory medications.     

康复运动对心衰患者血浆可溶性粘附分子水平的影响

目的:通过观察充血性心力衰竭(CHF)患者运动训练前、后血浆可溶性细胞间粘附分子-1(sICAM-1)、血管细胞粘附分子-1(sVCAM-1)和E-选择素(sE-selectin)水平的变化,探讨其临床意义。方法:用ELISA法检测23例CHF患者6 min步行运动试验前、后血浆sICAM-1、sVCAM-1、sE-selectin水平,并以20例健康体检者作为对照,18例患者运动训练一个月后进行了随访。结果:CHF患者基础状态血浆sICAM-1、sVCAM-1和sE-selectin水平显著高于对照组(P<0.05-<0.01),且sICAM-1、sVCAM-1水平与心功能密切相关(P<0.05);运动后即刻sICAM-1、sVCAM-1水平较运动前升高(P<0.05),而sE-selectin水平运动前、后无显著性差异;康复训练一月后,无论基础状态还是运动后,sICAM-1、sVCAM-1水平较前次实验明显降低(P<0.05),而sE-selectin水平无显著性变化。结论:CHF患者血浆可溶性粘附分子水平较正常升高,6 min步行运动试验升高CHF患者血浆sICAM-1、sVCAM-1水平,接近日常生活活动强度的运动训练可降低该二者水平。     

Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with Type 1 diabetes mellitus with microalbuminuria and overt nephropathy.

AIMS: Elevated urinary albumin excretion is associated with macrovascular atherosclerotic complications in Type 1 diabetes mellitus. Adhesion molecules mediate leucocyte adhesion to the endothelium early in the atherosclerotic process. The present study tests the hypothesis that microalbuminuria and diabetic nephropathy are associated with elevated plasma concentrations of soluble vascular adhesion molecule (sVCAM)-1, soluble intercellular adhesion molecule (sICAM)-1, and soluble E-selectin (sE-selectin) aiming to illustrate factors of potential pathogenetic relevance for the excess cardiovascular disease in diabetic patients with renal complications. METHODS: Soluble adhesion molecule concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in healthy controls (n = 16) and in 59 Type 1 diabetic patients: group 1-patients with normoalbuminuria (n = 16); group 2-patients with microalbuminuria (n = 15); group 3-patients with macroalbuminuria and normal serum creatinine (n = 15), group 4-patients with macroalbuminuria and moderately elevated serum creatinine (n = 13). RESULTS: Plasma concentrations of sVCAM-1 and sICAM-1 were similar in healthy controls and normoalbuminuric Type 1 diabetic patients, but the concentrations were increased by the presence of microalbuminuria and overt nephropathy (P < 0.001 and P < 0.0001, ANOVA). Concentrations of sE-selectin did not differ between diabetic patients and controls. CONCLUSIONS: Plasma concentration of sICAM-1 is elevated in Type 1 diabetic patients with microalbuminuria and the concentrations of sICAM-1 as well as sVCAM-1 are elevated in patients with macroalbuminuria and normal s-creatinine. The elevated plasma concentrations of these soluble adhesion molecule concentrations in patients with renal complication can be of pathogenetic importance for the development of atherosclerosis and plasma soluble adhesion molecule concentrations may provide additional information on cardiovascular risk.     

The incidence and characteristics of silent cerebral infarction in elderly diabetic patients: association with serum-soluble adhesion molecules

Summary The purpose of this study was to investigate the relationship between complications arising from silent cerebral infarction (SCI) and changes in the levels of serum-soluble adhesion molecules in 82 elderly diabetic patients aged 60 years and older. SCI was found in 43 % of the 82 patients, with incidence increasing in relation to age. The prevalence of SCI was higher in subjects with hypertension, poor metabolic control and increased fibrinolysis. The levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and E-selectin (sE-selectin) were higher in diabetic patients than in non-diabetic subjects (p < 0.05, p < 0.001, and p < 0.05, respectively). Also, sICAM-1 and sVCAM-1 were found at increased levels in diabetic patients with SCI compared to those without SCI (p < 0.01 and p < 0.05, respectively). In particular, the level of sICAM-1 was increased in patients with SCI due to perforating arterial occlusion, while the level of sVCAM-1 was increased in patients with SCI due to cortical arterial occlusion. However, no significant difference was found in sE-selectin levels. Overall average of the intima and media thickness (IMT) of the common carotid arteries increased with age. IMT proved to be greater in patients with SCI than in patients without SCI (p < 0.05), and showed a weak but significant positive correlation with sVCAM-1, while no correlation was found with either sICAM-1 or sE-selectin levels. In conclusion, measurement of serum adhesion molecules may be useful for diagnosing the early stages of brain damage and for prophylactic treatment which may prevent the onset or progression of SCI. [Diabetologia (1998) 41: 911–917] Received: 15 December 1997 and in revised form: 3 March 1998     

High serum concentrations of soluble E-selectin in patients with impaired glucose tolerance with hyperinsulinemia

High serum concentrations of soluble adhesion molecules are present in diabetics, but whether similar levels are present in patients with impaired glucose tolerance (IGT) is unclear. We measured serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and sE-selectin in 128 nondiabetic Japanese subjects. The concentrations of sICAM-1, sVCAM-1, and sE-selectin in IGT patients (n=47) were not different from those in subjects with normal glucose tolerance (NGT; n=81). IGT patients were subdivided into two groups by the results of 75 g OGTT, those with low- (hypoinsulinemia; n=23) or high-insulin (hyperinsulinemia; n=24). The levels of sICAM-1 and sVCAM-1 were not different among NGT and IGT with high-insulin or with low-insulin. However, sE-selectin concentrations were significantly higher in IGT patients with high-insulin than in NGT and IGT with low-insulin (61.1+/-3.4, 47.1+/-1.8 and 43.7+/-3.9 ng/ml, respectively, P<0.001). Adjustment for age and gender did not influence the results. Serum sE-selectin concentrations correlated significantly with the area under the curve of insulin (AUC(insulin)), AUC(glucose), diastolic blood pressure, and triglyceride levels (r=0.35, 0.26, 0.18 and 0.21, respectively), and negatively with HDL-cholesterol levels (r=-0.20). Multiple regression analysis showed that AUC(insulin) was the only independent factor that correlated with sE-selectin levels (P<0.001). Our results indicate that hyperinsulinemia/insulin resistance may be responsible for the elevation of sE-selectin levels.     

Soluble Intercellular Adhesion Molecule-1 and E-selectin in Patients with Asthma Exacerbation

Soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sE-selectin) are important factors in immunological processes of inflammatory cell buildup in target tissues. Studies have suggested that these molecules could be important markers of inflammatory diseases. This study was undertaken to assess the levels of sICAM-1 and sE-selectin during an acute attack of asthma in adults and children and to establish normal values (95th percentile) in healthy control subjects. We analyzed serum levels of ICAM-1 and E-selectin in 120 children and adults obtained during an acute attack of asthma: 40 with severe and 80 with moderately severe attack, and 50 healthy subjects as controls by ELISA (enzyme linked immunosorbent assay). sICAM-1 from patients with asthma was significantly higher than healthy controls (P < 0.001) but not for sE-selectin (P = 0.778). Significant differences were observed in moderately severe attack versus controls and severe attack of asthma for sICAM-1. With 95th percentile levels as cutoff for normal values (sICAM-1 = 585.08 ng/ml, sE-selectin = 160.87 ng/ml), it was observed that 88.3% of subjects (sICAM-1) and 98.5% of subjects (sE-selectin) with an acute attack of asthma had levels within the normal range. Although mean serum levels of sICAM-1 are higher in asthmatics than normal controls, it may be necessary to establish individual baseline values for serial estimation to evaluate their clinical relevance.     

Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement

Systemic sclerosis (SSc) is a chronic, multisystemic, autoimmune disease characterised by vascular changes and varying degrees of fibrosis of the skin and visceral organs. Organ systemic involvement in SSc is associated with an altered function of endothelial cells, perivascular infiltrating mononuclear cells and interstitial fibrosis. To evaluate the relationship between systemic manifestations and immunological markers of endothelial cell activation, serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were determined by an enzyme-linked immunosorbent assay in 31 SSc patients and in 30 healthy controls. In comparison with the control group, higher serum concentrations of sVCAM-1, sE-selectin, VEGF and ET-1 were detected in SSc patients (in all cases p<0.001). Elevated concentrations of sVCAM-1 (p<0.05), sE-selectin (p<0.05), VEGF (p<0.05) and ET-1 (p<0.01) dominated in the serum of SSc patients with organ systemic involvement compared to those without systemic manifestation of the disease. These results suggest that the serum levels of sVCAM-1, sE-selectin, VEGF and ET-1 may reflect the extent of internal organ involvement in SSc patients and point to a pathogenic role of these molecules in systemic manifestation of the disease.     

Oral fat load effects on inflammation and endothelial stress markers in healthy subjects

The aim was to study the effect of a standardized oral fat load (OFL) on different inflammatory parameters in a large sample of adult healthy subjects (n = 286) of both sexes. The fat load was given between 08:00 and 09:00 h after a 12-h fast. Blood samples were drawn before and 3, 6, 9, and 12 h after the OFL. All patients underwent a measurement of body mass index (BMI), blood glucose (BG), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and tumor necrosis factor-α (TNF-α). Fasting plasma glucose (FPG) increase was +3.26% at 3 h, +4.35% at 6 h, +1.09% at 9 h while FPG decrease was −1.09% at 12 h. High-density lipoprotein cholesterol increase was +2.08% at 3 h, and at 12 h during OFL study; a significant HDL-C decrease was present in subjects after 6 h (−4.17%; P < 0.05 vs 0). A significant Tg change was observed after 6 h (+70.37%; P < 0.01 vs 0) and 9 h (+58.33%; P < 0.05 vs 0) respectively, and the increase was +22.22% at 3 h and +18.52% at 12 h. Total cholesterol increase was +0.52% after 3 h, +1.04% after 6 h, while after 12 h the decrease was −0.52%. Low-density lipoprotein cholesterol increase was +1.64% after 6 h with a decrease of −0.82% at 9 and 12 h. A significant sICAM-1, hsCRP, and sE-selectin variation was observed after 6 and 9 h, while a significant sVCAM-1 change occurred after 3, 6, and 9 h. Soluble ICAM-1 increase was +20.58% at 3 h, +34.10% at 6 h (P < 0.05 vs 0) +25.94% at 9 h (P < 0.01 vs 0), and +19.14% at 12 h; sVCAM-1 increase was +13.97% (P < 0.05 vs 0) at 3 h, +18.55% at 6 h (P < 0.01 vs 0), +12.02% at 9 h (P < 0.05 vs 0), and +8.70% at 12 h. High-sensitivity CRP increase was +36.36% at 3 h, +90.91% at 6 h (P < 0.01 vs 0), +63.64% at 9 h (P < 0.05 vs 0), and +36.36% at 12 h. Soluble E-selectin increase was +27.11% at 3 h, +51.90% at 6 h (P < 0.05 vs 0), +45.19% at 9 h (P < 0.01 vs 0), and +20.12% at 12 h. Interleukin-6 increase was +61.11% at 3 h (P < 0.05 vs 0), +83.33% at 6 h (P < 0.001 vs 0), +55.56% at 9 h (P < 0.01 vs 0), and +22.22% at 12 h. Tumor necrosis factor-α increase was +42.86% at 3 h (P < 0.05 vs 0), +71.43% at 6 h (P < 0.01 vs 0), (+50.00% at 9 h (P < 0.05 vs 0), and +28.57% at 12 h. We observed that the OFL induces a complex and massive systemic inflammatory response that includes IL-6, TNF-α, hsCRP, and cell adhesion molecules, even before Tg significantly rises.     

Prospective study of autonomic neuropathy as a predictor of mortality in patients with diabetes

To investigate the relationships between serum concentrations of soluble adhesion molecules and hyperglycemia, insulin resistance, or other conventional risk factors in type 2 diabetes, we measured soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), insulin sensitivity, and conventional risk factors in 150 Japanese type 2 diabetic patients without apparent diabetic macroangiopathy. High serum concentrations of sVCAM-1 and sE-selectin were observed in patients with type 2 diabetes. Serum concentrations of soluble adhesion molecules were not significantly influenced by sex, hypertension, dyslipidemia, or microangiopathy. Spearman correlation showed that sVCAM-1 concentrations correlated significantly with fasting plasma glucose (FPG), fasting C-peptide, and insulin sensitivity [K index of the insulin tolerance test (K(ITT))] (rho=0.19,0.23, and -0.23, respectively). Soluble E-selectin concentrations correlated significantly with body mass index (BMI), FPG, fasting C-peptide, insulin sensitivity, and triglyceride (rho=0.33,0.42,0.26,-0.48, and 0.29, respectively). Multiple regression analysis showed that FPG, fasting C-peptide, and total cholesterol were independent factors that correlated with sVCAM-1 levels. BMI, FPG, and insulin sensitivity were independent factors that correlated with sE-selectin levels. Serum concentrations of sE-selectin significantly increased associated with clustering of conventional risk factors those obesity, hypertension, dyslipidemia, and current smoking (P<0.01). Thus, sVCAM-1 and sE-selectin levels are related to both hyperglycemia and insulin resistance. Soluble E-selectin levels may be related to obesity, hyperglycemia, and insulin resistance and may reflect the presence of a multiple risk factor clustering syndrome.     

Severe malaria in Cameroonian children: correlation between plasma levels of three soluble inducible adhesion molecules and TNF-alpha

Plasma levels of three soluble inducible adhesion molecules, namely: intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and endothelial leucocyte adhesion molecule-1 (sELAM-1) or sE-selectin and the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-alpha) were measured in well-defined clinical groups of children with severe and uncomplicated malaria. The goal of the study was to investigate the role of these molecules in immunopathogenic processes associated with severe malaria in Cameroonian children. Results showed significantly increased plasma concentrations of sICAM-1, sVCAM-1 and sE-selectin in children with severe malaria compared to those with uncomplicated malaria and healthy children (P<0.001). TNF-alpha levels increased significantly in children with severe malaria, approximately 2-folds compared to those with uncomplicated malaria and about 3-folds compared to healthy children (P<0.001). More importantly, levels of TNF-alpha strongly correlated with those of the three adhesion molecules and were significantly associated with increased risk of death (P=0.03). In addition, children who died from severe malaria showed higher mean levels of all measured factors compared to those who recovered, with significant differences observed with sICAM-1 (P<0.001) and sE-selectin (P=0.002). Furthermore, children with severe malarial anemia relative to those without, showed significantly elevated levels of the three soluble molecules; and sICAM-1 was significantly associated with increased risk of severe anemia. Taken together, these results confirm the role of TNF-alpha and the three adhesion molecules in pathogenic processes associated with severe malaria in children, and suggest an association between sICAM-1 and severe malarial anemia.     

Circulating soluble adhesion molecules in patients with systemic sclerosis: correlation between circulating soluble vascular cell adhesion molecule-1 (sVCAM-1) and impaired left ventricular diastolic function

The objective of this paper is to investigate the relation between circulating soluble adhesion molecules and cardiac involvement, as assessed by echocardiography in patients with systemic sclerosis (SSc). Nineteen patients with SSc were submitted for assessment of serum levels of circulating soluble intercellular adhesion molecules (sICAM-1), and soluble vascular cell adhesion molecules-1 (sVCAM-1), and echocardiography. Abnormal left ventricular filling patterns (↓E/A ratio) were detected in ten patients (52.6%) with significant negative correlation with sVCAM-1 (r=−0.484, P < 0.05). It was also significantly correlated with age (r=−0.791, P < 0.01), age of onset (r=−0.468, P < 0.05), degree of dyspnea (r=−0.687, P < 0.01), and erythrocyte sedimentation rate (ESR) (r=−0.489, P < 0.05). Our findings suggest an important role for sVCAM-1 as a marker of disease severity and impaired left ventricular filling pattern in SSc. Received: 30 December 1999 / Accepted: 13 July 2000     

Markers of low-grade inflammation and soluble cell adhesion molecules in Chinese patients with coronary artery disease

BACKGROUND: Inflammation plays an important role in atherosclerosis. Markers of low-grade chronic inflammation, such as C-reactive protein (CRP) and soluble cell adhesion molecules (sCAMs), have been associated with coronary artery disease (CAD). OBJECTIVE: To evaluate the significance of inflammatory markers as novel risk factors for CAD in the Chinese population. METHODS: High-sensitivity CRP (hs-CRP); sCAMs, including vascular cell adhesion molecule-1 (sVCAM-1), intercellular cell adhesion molecule-1 (sICAM-1), P-selectin (sP-selectin) and E-selectin (sE-selectin); and white blood cell (WBC) count were measured in 170 angiographically defined CAD patients (70% or greater stenosis affecting at least one vessel) and 177 healthy control subjects in the Chinese population in Singapore. RESULTS: The levels of hs-CRP, sVCAM-1 and sP-selectin, and the WBC count were higher in CAD patients than in control subjects (P<0.001, P<0.05, P<0.05 and P<0.001, respectively). There were no significant differences in the levels of sICAM-1 and sE-selectin between the two groups. Patients with unstable angina or myocardial infarction had higher levels of hs-CRP, and higher WBC and monocyte counts than those with stable angina or atypical chest pain (all P<0.05). The level of sP-selectin in patients with multivessel disease was higher than in those with single-vessel disease (P<0.05). Overall, the levels of hs-CRP and sCAMs showed a significant correlation with the lipid profile and the WBC count. CONCLUSIONS: The present study suggests that inflammatory markers, including hs-CRP and WBC count, together with sP-selectin and sVCAM-1, could serve as markers of atherogenesis in Chinese patients with CAD, with potential diagnostic and therapeutic implications.     

Soluble adhesion molecules are not involved in the development of retinopathy in type 2 diabetic patients

Abstract. Raised serum levels of adhesion molecules are believed to reflect endothelial activation and may contribute to the development of diabetic vascular complications. The aim of this study was to clarify the association between soluble adhesion molecules levels and retinopathy in type 2 diabetic patients. Levels of soluble Eselectin, ICAM-1 and VCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) in 47 type 2 diabetic patients classified in two subgroups according to the presence (n=34) or absence (n=13) of retinopathy as determined by fundus ophthalmoscopy; 22 control subjects were also studied. Soluble E-selectin levels were significantly elevated in both diabetic subgroups compared to control subjects (p<0.01), while no significant difference was found in sICAM-1 and sVCAM-1 levels. However, sE-selectin, sICAM-1 and sVCAM-1 levels were comparable in diabetic subgroups. The progression of retinopathy was not associated with an increase in soluble adhesion molecules levels. Stepwise multiple regression analysis revealed that only diabetes duration and microalbuminuria were independent determinants of retinopathy (p<0.01). Our results confirm the contribution of endothelial activation in the development of diabetic complications as indicated by increased levels of soluble adhesion molecules. However, a direct implication of adhesion molecules in the pathogenesis or progression of type 2 diabetic retinopathy cannot be supported.     

Increased soluble intercellular adhesion molecule-1, breast cancer and the acute phase response.

Abnormal levels of soluble intercellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP) and von Willebrand factor (vWf) are commonly found in breast and other cancers. However, the relationship between these molecules is unclear as raised sICAM-1 and vWf may simply reflect an acute phase response. We tested the hypothesis that raised sICAM-1 and vWf are related to the acute phase response by measuring both markers by enzyme-linked immunosorbent assay, and CRP by dry chemistry, in 40 women with breast cancer (cases) and 40 age-matched controls. All three markers were raised in the cases compared with the controls [sICAM-1 (mean +/- SD), 281 +/- 70 versus 230 +/- 40 ng/ml; vWf (mean +/- SD), 139 +/- 33 versus 106 +/- 16 IU/dl; CRP (median), 7 (interquartile range, 5-11) versus 5 (4-6) mg/dl; all P < 0.01]. However, sICAM-1 correlated strongly with CRP (r = 0.67, P < 0.001) in the cases but there was no significant relationship between vWf and CRP (r = -0.15, P = 0.351). There were no significant correlations in the controls. We conclude that raised sICAM-1 in breast cancer, like the acute phase response, reflects inflammation, and that raised vWf seems likely to be independent of the acute phase response.     

Circulating adhesion molecules in sera of asthmatic children

Infiltration of cells into the lung in asthma is regulated by several expressions of cell adhesion molecules (CAMs) on cells present in the airways, and may play a role in the pathogenesis of bronchial asthma. We sought to evaluate the role of serum concentrations of the soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in the control of disease activity in acute asthma. Circulating levels of sICAM-1, sVCAM-1, and sE-selectin in sera from 15 normal control subjects and from 20 allergic asthmatic children with acute exacerbations who had returned to stable condition were determined by using commercially available enzyme-linked immunosorbent assay kits. The mean concentration of serum sICAM-1 levels was significantly higher during an acute exacerbation of asthmatic children than in those with stable asthma (19.41 +/- 10.65 ng/mL vs. 13.46 +/- 5.44 ng/mL; P < 0.001) or in control subjects (9.83 +/- 2.02 ng/mL; P < 0.001). For sVCAM-1 and sE-selectin, the mean serum concentration of sVCAM-1 was slightly higher in children during an acute exacerbation asthma than when stable. However, the differences did not reach statistical significance. The mean serum concentrations of sVCAM-1 and sE-selectin in acute asthma or stable asthma were significantly higher than in control subjects. This study provides further evidence that serum concentrations of sICAM-1, sVCAM-1, and sE-selectin are increased in acute asthma. These findings further confirm that leukocyte endothelial adhesion plays a role in inflammatory airway disease.     

Association of HLA–C3 and smoking with vasculitis in patients with rheumatoid arthritis

Objective

To compare HLA–C genotypes and smoking habits in patients with vasculitis or other severe extraarticular manifestations of rheumatoid arthritis (ExRA) with those in RA patients without extraarticular disease.

Methods

Patients were recruited from a large research database of patients with RA at the Mayo Clinic, from 2 Swedish cohorts of prevalent RA cases, and from a regional Swedish early RA cohort. Patients with severe ExRA (n = 159) and control patients with RA but no history of ExRA (non‐ExRA controls) (n = 178) were matched for duration of RA and for clinical center. Data on smoking at RA onset, rheumatoid factor (RF) status, and antinuclear antibodies (ANAs) were extracted from the medical records. Polymerase chain reaction–based HLA–C genotyping was performed using a sequence‐specific primer kit.

Results

The distribution of HLA–C alleles was significantly different between patients with RA‐associated vasculitis and non‐ExRA controls (P = 0.014). This was mainly due to a positive association of the HLA–C3 allele with vasculitis (allele frequency 0.411 in vasculitis patients versus 0.199 in non‐ExRA controls; P < 0.001) and a decreased frequency of HLA–C7 (0.122 and 0.243, respectively; P = 0.018). The association between HLA–C3 and vasculitis was not due to linkage disequilibrium with HLA–DRB1. Smoking (P = 0.001), RF positivity (P < 0.0001), and presence of ANAs (P < 0.0001) were all associated with ExRA. HLA–C3 and smoking were both significant predictors of vasculitis in a multivariate model.

Conclusion

Vasculitis in RA is associated with HLA–C3. Smoking is an independent predictor of vasculitis and other types of severe ExRA. Our results suggest that these variables are among the genetic and environmental factors that contribute significantly to the pathomechanisms of systemic RA.