The International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS)--quality of life during the first 4 months after fracture.

UNLABELLED: The quality of life during the first 4 months after fracture was estimated in 2,808 fractured patients from 11 countries. Analysis showed that there were significant differences in the quality of life (QoL) loss between countries. Other factors such as QoL prior fracture and hospitalisation also had a significant impact on the QoL loss. INTRODUCTION: The International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS) was initiated in 2007 with the objective of estimating costs and quality of life related to fractures in several countries worldwide. The ICUROS is ongoing and enrols patients in 11 countries (Australia, Austria, Estonia, France, Italy, Lithuania, Mexico, Russia, Spain, UK and the USA). The objective of this paper is to outline the study design of ICUROS and present results regarding the QoL (measured using the EQ-5D) during the first 4 months after fracture based on the patients that have been thus far enrolled ICUROS. METHODS: ICUROS uses a prospective study design where data (costs and quality of life) are collected in four phases over 18 months after fracture. All countries use the same core case report forms. Quality of life was collected using the EQ-5D instrument and a time trade-off questionnaire. RESULTS: The total sample for the analysis was 2,808 patients (1,273 hip, 987 distal forearm and 548 vertebral fracture). For all fracture types and countries, the QoL was reduced significantly after fracture compared to pre-fracture QoL. A regression analysis showed that there were significant differences in the QoL loss between countries. Also, a higher level of QoL prior to the fracture significantly increased the QoL loss and patients who were hospitalised for their fracture also had a significantly higher loss compared to those who were not. CONCLUSIONS: The findings in this study indicate that there appear to be important variations in the QoL decrements related to fracture between countries.

Autologous progenitor cell implantation as a novel therapeutic intervention for ischaemic digits in systemic sclerosis.

OBJECTIVES: The effects of local stem cell implantation on clinical and functional characteristics of peripheral vascular disease were studied in two SSc patients with non-healing ischaemic ulcers. METHODS: The local injections of CD34(+) cells from peripheral blood (PB) after mobilization by G-CSF (Case 1) and bone marrow (BM) (Case 2) were used for ischaemic skin ulcers in hands, while mononuclear cells (MNCs) were implanted in lower extremities of the same patients. Ischaemic status was evaluated by measuring ulcer healing, Raynaud's condition score (RCS), visual analogue pain, RP and ulcer scales. To evaluate vasculoprotective action of the implanted cells, we studied weekly the changes in endothelial function, using measurement of flow-mediated brachial artery reactivity by high-resolution ultrasonography, circulating endothelial precursors (CD34(+)VEGFR2(+), CD133(+)VEGFR2(+) CEP) by FACS analysis, cutaneous blood flow (laser Doppler flowmetry), skin surface temperature (thermograph), peripheral arterial diameter and blood flow characteristics by Duplex ultrasonography. RESULTS: CD34(+) cells and MNCs both from BM and PB showed rapid and evident beneficial effect on vascular symptoms resulting in ulcer healing, remarkably decreased daily frequency and duration of RP attacks, RCS, visual analogue scale for RP, ulcers and pain. Physical function and disability measured with HAQ and SHAQ improved. Therapeutic efficacy of stem cell therapy was associated with restoration of endothelial function, augmentation of microcirculatory blood flow and significant increase in circulating CD133(+)VEGFR2(+) progenitors, known as cell effectors of angiogenesis. CONCLUSION: This first open-label pilot study demonstrates the feasibility and short-term safety of local CD34(+) cell therapy for SSc ischaemic complications.

Circulating endothelial progenitor cells in systemic sclerosis: relation to impaired angiogenesis and cardiovascular manifestations.

OBJECTIVE: Given the essential role of endothelial progenitor cells (EPCs) in endothelial repair and neovascularization, it is likely that insufficient angiogenesis seen in systemic sclerosis (SSc) is related to EPC alterations. The present study was aimed to analyze in SSc the number of circulating EPCs and their contribution into cardiovascular involvement. METHODS: EPC (CD34+VEGF-R2+ and CD133+VEGF-R2+) circulating levels were evaluated in 40 SSc patients and 24 controls by FACS; their correlations with peripheral vascular manifestations, heart involvement, Framingham risk score, carotid artery disease, endothelial function and morphological signs of microangiopathy were studied. RESULTS: Early stage SSc and high disease activity were accompanied by a rise in circulating EPC levels in association with increased membrane expression of Fas (CD95) that correlated positively with severity of peripheral vascular manifestations. EPC reduction with disease progression was linked with endothelial dysfunction and capillary loss, and showed a strong relation to the development of severe internal organ (predominantly cardiac) involvement and pulmonary hypertension. There was a tendency to decreased EPC levels in SSc pts with low HDL values, but no significant correlations were found between EPCs and Framingham risk factor score, carotid artery IMT and traditional cardiovascular risk factors. CONCLUSIONS: In early stage SSc mobilization of EPCs in response to tissue ischemia was preserved, but dropped with disease progression. EPC reduction may contribute to endothelial dysfunction and impaired angiogenesis, leading to the development of severe vascular life-threatening complications of SSc. Traditional cardiovascular risk factors and subclinical atherosclerosis did not influence EPC levels in SSc patients.

Cardiac troponin and beta-type myosin heavy chain concentrations in patients with polymyositis or dermatomyositis.

Cardiac troponin T (cTnT), cardiac troponin I (cTnI), myosin heavy chains (MHC), myoglobin, creatine kinase (CK), and creatine kinase isoenzyme MB (CKMB), were measured in blood samples from 39 polymyositis (PM) or dermatomyositis (DM) patients without clinical evidence for cardiac involvement to evaluate their clinical usefulness in this patient population. MHC, myoglobin, and CKMB were frequently elevated and correlated with each other and with disease severity. Undetectable cTnI in all but one patient indicated that MHC was released from skeletal muscle, thereby providing the first laboratory evidence of frequent slow-twitch muscle fibre-necrosis in patients with PM or DM. CKMB was elevated in 51%, cTnT in 41%, and cTnI in only 2.5% of patients. cTnI did not correlate with other markers or with disease severity scores. The close correlations found between cTnT and skeletal muscle damage markers and the relationship between cTnT with disease severity without clinical evidence for myocardial damage suggest a release of cTnT from skeletal muscle. The relationship of cTnT with disease severity indicates a possible role of the marker for risk stratification. However, the prognostic values of cardiac troponins and other muscle damage markers in PM/DM patients remain to be compared in prospective outcome trials.

The activated immune system and the renin-angiotensin-aldosterone system in congestive heart failure.

OBJECTS: The aim of the study was to investigate a possible relationship between plasma renin activity, angiotensin II, serum levels of angiotensin-converting enzyme, aldosterone and markers of immune activation in congestive heart failure (CHF). PATIENTS AND METHODS: Fifty-three patients (50 male, three female, mean age 46 +/- 16 years) with congestive heart failure were studied. Twenty-eight patients had I or II NYHA class of CHF and 25 patients had III or IV NYHA class (NYHA class, mean +/- SD: 2.3 +/- 0.9). Serum neopterin concentration and hormones were measured by commercial radioimmunoassays. Serum soluble receptors of tumour necrosis factor and interleukin-2 were determined by ELISA. RESULTS: All analytes significantly correlated with NYHA classes (P < 0.05). There existed correlations between neopterin and angiotensin-converting enzyme or aldosterone (rs = 0.35 and rs = 0.36, P < 0.05). The soluble tumour necrosis factor receptor concentrations correlated with plasma renin activity (rs = 0.38, P < 0.05). CONCLUSION: The result of our study suggest that there exists some relationship between the renin-angiotensin-aldosterone system and immune activation in severe congestive heart failure, however, the associations found are rather weak.

Anti-endothelial cell antibody, thrombomodulin, and von Willebrand factor in idiopathic inflammatory myopathies.

Sera from 19 patients with idiopathic inflammatory myopathy (IIM) were examined for the presence of anti-endothelial cell antibodies (AECA) by an immunoglobulin G-specific cellular enzyme-linked immunosorbent assay. The mean binding index of AECA was found to be 37.7% +/- 26.5% for the patients, compared with a mean of 7.2% +/- 2.7% for normal controls (P < 0.04). Levels of thrombomodulin, von Willebrand factor antigen, and serum creatine kinase were also shown to be augmented. Interestingly, positive correlations between AECA on the one hand and Raynaud's phenomenon and interstitial lung disease on the other were demonstrated. Given that the pathogenesis of IIM remains uncertain, these findings may be of importance.

Elevated serum levels of neopterin in adult patients with polymyositis/dermatomyositis.

We determined serum concentrations of neopterin, soluble tumour necrosis factor (55 kDa) receptor (sTNF-R) and soluble interleukin-2 receptor (sIL-2R) in plasma of 44 patients with polymyositis (PM)/dermatomyositis (DM), including 15 patients with primary PM, 13 patients with primary DM, and 16 patients with myositis and systemic sclerosis in overlap. Concentrations of neopterin, sTNF-R and sIL-2R were measured using commercially available immunoassays. Serum neopterin was increased in 35 of 44 PM/DM patients (80%), sTNF-R in 14 (32%) and sIL-2R in 18 (41%) patients, respectively. There were significant correlations between serum neopterin and sTNF-R, sIL-2R and erythrocyte sedimentation rate (all P < 0.001). Neopterin, as well as sTNF-R and sIL-2R, did not correlate with clinical (neuromuscular and activities of daily living scores) and laboratory (creatine kinase levels) manifestations of myositis. Increased serum levels of neopterin were associated with non-muscular manifestations of PM/DM. In conclusion, serum neopterin appears to be a useful laboratory marker for ongoing immune activation and global disease activity in PM/DM.

Serum concentrations of neopterin, soluble interleukin 2 receptor, and soluble tumor necrosis factor receptor in Wegener's granulomatosis.

OBJECTIVE: To investigate the possible relationship between serum levels of neopterin, soluble tumor necrosis factor-55 receptor (sTNF-55R), and soluble interleukin 2 receptor (sIL-2R) with disease activity in patients with Wegener's granulomatosis (WG). METHODS: Serum neopterin was measured by radioimmunoassay, sTNF-55R and sIL-2R were measured by ELISA in 26 patients with WG. RESULTS: Serum neopterin, sTNF-55R, and sIL-2R were significantly elevated in patients with generalized WG compared with healthy controls. Concentrations of the analytes correlated with disease activity indices in patients without infectious complications. The highest elevations of all 3 variables were observed in patients with intercurrent infections. CONCLUSION: The increased serum levels of neopterin, sTNF-55R, and sIL-2R suggest activation of cellular immunity in WG.

Antiendothelial cell antibodies: useful markers of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SS) encompasses a wide spectrum of clinical presentations. Antiendothelial cell antibodies (AECA) in patients with primary Raynaud's phenomenon (PRP), limited SS (lSSc), or diffuse SS (dSSc) may help to determine the long-term prognosis of the disease. METHODS: Twenty-seven normal controls, 13 patients with PRP, 36 with lSSc, and 31 with dSSc were included in the study. Sera were examined for the presence of AECA, using a cellular enzyme-linked immunosorbent assay (ELISA). Angiotensin-converting enzyme (ACE) activity, plasma von Willebrand factor antigen (vWfAg), and thrombomodulin (Tm) concentrations were also evaluated. The medical records of 50 of the lSSc and dSSc patients were reviewed and the organ system involvement noted. RESULTS: Antiendothelial cell antibodies were present in 3 patients with PRP, 16 patients with lSSc, and 26 patients with dSSc. These autoantibodies were mainly of the IgG isotype. There was no difference in ACE activity between patients and controls. In contrast, vWfAg and Tm concentrations were higher in patients with PRP relative to controls, and higher in patients with lSSc compared with those with PRP. The presence of AECA was associated with digital scars and ulcers (P < 0.004 and P < 0.003, respectively), severe RP (P < 0.01), grade 3 tortuosity of vessels (P < 0.0004), and lung involvement (P < 0.02). CONCLUSION: The significant trend for AECA to increase with disease severity across the three groups of patients studies suggests that the AECA test can identify subsets of SSc with differing prognoses.

Elastin degradation in systemic vasculitis.

The elastin peptide level (EP) and elastase-type activity (EA) were investigated in 89 patients with different types of systemic vasculitis (polyarteritis nodosa-14, non-specific aortoarteritis-33, temporal arteritis-23 and thromboangiitis obliterans-18) and compared to the controls: 31 patients with leg atherosclerosis and 12 aged subjects with no evident vascular pathology. EP and EA levels in patients with thromboangiitis obliterans were significantly lower as compared to leg atherosclerosis and the aged control group (p < 0.02 for EA, p < 0.05 for EP). The increase of EP predominated in giant-cell arteritis as compared to the other vasculitic groups (18/56 vs. 5/32, p < 0.05); EA in these patients was the lowest. The activation of elastin degradation after corticosteroid treatment was demonstrated by an increase of EP in temporal arteritis (p < 0.05) and of EA in thromboangiitis obliterans (p < 0.03). We suggest that the determination of the above parameters of elastin degradation may be helpful in the search for differences in mechanisms of vascular damage between atherosclerosis and inflammatory vascular diseases.

Role of beta 2-glycoprotein I in the antiphospholipid antibody binding to endothelial cells.

A group of anticardiolipin antibodies (aCL) require beta 2-glycoprotein I (beta 2GPI) to recognize their target, which might be located on endothelial cells (EC) and/or platelets. Following incubation with epithelial cells, 13 of 30 lupus sera retained EC-reactive antibodies of the IgG, IgA and IgM isotypes. Associated aCL and anti-phosphatidylethanolamine antibodies were partly absorbed on eC as well as EC. The former antibodies were more efficiently removed in the presence than in the absence of the latter. The presence of beta 2GPI in the affinity-purified aCL preparations may explain their binding to EC, as this cross-reaction was abrogated by the removal of the cofactor and restored by its re-introduction. Seventy four per cent of EC were faintly stained with polyclonal or monoclonal antibody directed to the cofactor. The beta 2GPI mediated aCL binding to EC membranes could this be influential in the development of thrombosis and/or thrombocytopenia in aCL-positive patients.

Serum neopterin concentrations in Wegener's granulomatosis correlate with vasculitis activity.

Raised serum neopterin concentrations were found in 13 of 27 patients (47%) with Wegener's granulomatosis. The neopterin concentrations significantly correlated with the Birmingham Vasculitis Activity Score as well as with the erythrocyte sedimentation rate and C-reactive protein. High serum neopterin levels were also associated with infectious complications. The finding of increased neopterin concentrations in patients with Wegener's granulomatosis supports the role of cell-mediated immunity and particularly of activated macrophages in the pathogenesis of the disease.

Serum soluble markers of immune activation and disease activity in systemic lupus erythematosus.

We investigated a possible association between markers of immune activation and disease activity in 52 patients with systemic lupus erythematosus (SLE). Serum concentrations of neopterin, beta-2-microglobulin, 55 kD-type soluble tumor necrosis factor receptor, soluble interleukin-2 receptor and soluble CD8 were compared to the Index of European Consensus Lupus Activity Measurement (ECLAM). All markers of immune activation, except sCD8, significantly correlated with ECLAM. Stepwise multiple linear regression analysis revealed erythrocyte sedimentation rate and neopterin to correlate best with ECLAM (multiple correlation coefficient = 0.74, P < 0.001). The study shows that serum neopterin concentrations are a useful independent index for disease activity in SLE. The finding of enhanced concentrations of various parameters of immune activation in patients confirm a role of the T cell and macrophage activation in the pathogenesis of SLE.

Serum-soluble receptors for tumor necrosis factor-alpha and interleukin-2, and neopterin in acute rheumatic fever.

Immune activation may play an important role in the pathogenesis of acute rheumatic fever (ARF). The objective of the present study was to investigate serum concentrations of various markers of immune activation in ARF patients. Sera of 32 patients with ARF were investigated, 20 of them in follow-up. Radioimmunoassay was used to quantify neopterin and ELISA for the measurement of 55-kDa-type soluble tumor necrosis factor receptor (sTNF-R) and soluble interleukin-2 receptor (sIL2-R). Markers of immune activation were found to be raised in 48% (sTNF-R), 28% (sIL2-R), and 78% (neopterin) of patients at the onset of ARF. There were significant correlations between the concentrations of neopterin and sTNF-R (rs = 0.60, P < 0.001) or sIL2-R (rs = 0.35, P < 0.05). Higher neopterin concentrations were found in patients with combined aortic and mitral insufficiency than in patients with mitral valve lesions alone (U = 2.67, P < 0.05) or without valve lesion (U = 2.36, P < 0.05). Increased concentrations of neopterin, sTNF-R, and sIL2-R demonstrate activation of the cellular immune system in patients with ARF. Higher serum neopterin concentrations are associated with development of combined aortic and mitral insufficiency during the first episode of ARF.

Anaphylatoxins in dilated cardiomyopathy.

OBJECTS: The aim of the study was to investigate the possible relationship between activation of complement system and thromboembolic complications in dilated cardiomyopathy (DCMP). METHODS: The plasma C3a and C5a concentrations were determined by radioimmunoassay measurement (Amersham International, UK) in 23 patients with DCMP, 9 with hypertrophic cardiomyopathy (HCMP) and 11 healthy volunteers. RESULTS: The mean C3a concentration was significantly higher in DCMP patients (572 +/- 55 ng ml-1) compared with hypertrophic cardiomyopathy (344 +/- 30 ng ml-1) and with healthy controls (294 +/- 43 ng ml-1) (P < 0.001). There were no significant correlations for C5a concentrations in this group. Mean C3a concentration in DCMP patients with thromboembolic complications (736 +/- 95 ng ml-1) was also significantly higher compared with DCMP patients without these complications (344 +/- 14 ng ml-1) (P < 0.001). CONCLUSIONS: We conclude that anaphylatoxins may play a role in the pathogenesis of thromboembolic complications.

Stimulated cellular immune system in patients with congestive heart failure.

In this cross-sectional study, we analysed serum concentrations of soluble markers of cellular immune activation, namely, interferon-gamma, neopterin (a product of activated macrophages), soluble interleukin-2 receptor, and soluble CD8, in 25 patients with congestive heart failure. Ten (40%) patients showed increased concentrations (i.e. above the reference ranges of healthy controls) of neopterin, 14 (56%) showed increased soluble interleukin-2 receptor, and 6 (24%) showed increased soluble CD8. Endogenous interferon-gamma was detectable in 10 patients (40%). In addition, we found significant correlations between neopterin and interferon-gamma (rs = 0.417, p < 0.05), and between neopterin and soluble CD8 concentrations (rs = 0.430, p < 0.05). All patients with increased soluble CD8 also had increased soluble interleukin-2 receptor. However, no significant correlations of soluble interleukin-2 receptor with soluble CD8 or any of the other quantities were observed. Increased concentrations of soluble interleukin-2 receptors, soluble CD8 and neopterin indicate that cellular immunity is stimulated in patients with congestive heart failure. Activated CD8-positive T-lymphocytes may represent the source of increased soluble CD8. Endogenous interferon-gamma, which is derived from activated T-cells, may induce neopterin release by monocytes/macrophages.

[Anti-endothelial cell antibodies in vasculitis in general, Sneddon's syndrome in particular]. / Anticorps anti-cellules endothéliales dans les vascularites en général, le syndrome de Sneddon en particulier.

Stringent conditions have been applied to set up an "enzyme-linked immunosorbent assay" to detect anti-endothelial cell autoantibodies. These predominated in Sneddon's syndrome.