Traditional cardiovascular risk factors in primary Sjögren's syndrome--role of dyslipidaemia.
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Atherosclerosis↗
Biomedical subjects
R Gerli
Publications and source records attributed to R Gerli.
The diagnostic utility of anti-cyclic citrullinated peptide antibodies, matrix metalloproteinase-3, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein in patients with erosive and non-erosive rheumatoid arthritis.
OBJECTIVE: To compare the diagnostic utility of laboratory variables, including matrix metalloproteinase-3 (MMP-3), anticyclic citrullinated peptide (CCP) antibodies, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in patients with erosive and non-erosive rheumatoid arthritis (RA). METHODS: We assembled a training set, consisting of 60 patients with RA, all fulfilling the revised criteria of the American College of Rheumatology. A commercial enzyme linked immunosorbent assay (ELISA) was used both to test for anti-CCP antibodies (second generation ELISA kit) and MMP; RF were detected by latex-enhanced immunonephelometric assay. CRP was measured by latex turbidimetric immunoassay. RESULTS: The levels of anti-CCP antibody titers and ESR were significantly higher in patients with erosive disease than those in non-erosive RA patients (p < 0.001 and 0.0341) respectively. Moreover, a higher frequency of elevated titers of anti-CCP antibodies was found in RA patients with erosions compared to patients with non-erosive RA (78.3% vs. 43.2% respectively). The ROC curves of anti-CCP passed closer to the upper left corner than those other markers and area under the curve (AUC) of anti-CCP was significantly larger than AUC of other markers (0.755 for anti-CCP, 0.660 for ESR, 0.611 for CRP, 0.577 for RF, and 0.484 for MMP-3 female). A positive predictive value was higher for anti-CCP antibodies in comparison to other markers. We did not find significant statistical correlation between anti-CCP antibody titers and inflammatory markers such as ESR or CRP. However, we confirmed the correlation of elevated titers of anti-CCP antibodies and RF in both groups of patients whereas the degree of correlation was more significant in non-erosive patients. CONCLUSION: The results of our study suggest that the presence of elevated anti-CCP antibody titers have better diagnostic performance than MMP-3, RF, CRP and ESR in patients with erosive RA.
Aged↗
Cardiovascular involvement in rheumatoid arthritis.
Cardiovascular (CV) disease morbidity and mortality are increased in patients with rheumatoid arthritis (RA) and much of the excess CV disease morbidity appears to be due to atherosclerosis. The pathogenesis of atherosclerosis (ATS) in RA is complex and there is increasing evidence that many factors including novel and traditional cardiovascular risk factors, RA treatments and the RA inflammatory disease process are involved in the development of CV disease in these patients. Of particular interest are the effects of chronic inflammation and immune dysregulation associated with RA. These have been shown to be associated with endothelial dysfunction, which is an early, potentially reversible, functional abnormality of the arterial wall. However, as several CV disease risk factors and drug prescribing are also influenced by RA disease severity it is very difficult to separate out the effects of the inflammatory disease burden on the cardiovascular system in RA.
Arthritis, Rheumatoid↗
Hyaluronan and sulphated hyaluronan micropatterns: effect of chemical and topographic cues on lymphatic endothelial cell alignment and proliferation.
While tissue engineered blood vessels have entered surgical practice, the construction of artificial lymphatic vessels has never been attempted due to the small dimensions and fragility of lymphatic vessels. A possible alternative would be to obtain a new growth of interrupted lymphatic vessels. We have previously reported that lymphatic endothelial cells align when cultured on striped micropatterns of hyaluronan (Hyal) and aminosilanized glass. We here report a comparative study in which lymphatic endothelial cells have been plated on micropatterns with stripes of different width and height obtained by the photoimmobilization of Hyal and its sulphated derivative (HyalS) on aminosilanized glass to verify whether their response correlated with surface-chemistry andlor topography. On Hyal micropatterns, cells adhered to aminosilanized glass, avoiding Hyal stripes and molding their shape in accordance to the micropattern topography. Stress fibers, integrins and focal adhesion kinase organized accordingly. HyalS micropatterns with the same topography were unable to guide cell response, cells randomly adhered to HyalS and glass stripes, and polarization was attained only by increasing stripe height. These data indicate that surface chemistry is the main cue responsible for lymphatic endothelial cell guidance. When surface chemistry of stripes promotes cell adhesion as well as that of the substrate, topographical parameters become prevalent. Micropatterns with defined chemical and topographical properties may contribute to the design of new platforms for controlled cell growth in tissue engineering of lymphatic vessels.
Actins↗
Contribution of MHC class I chain-related A (MICA) gene polymorphism to genetic susceptibility for systemic lupus erythematosus.
OBJECTIVE: To evaluate the contribution of the MHC class I chain-related A (MICA) gene polymorphism to the genetic risk of systemic lupus erythematosus (SLE). METHODS: HLA-DRB1-DQA1-DQB1 genotyping, MICA exon 5 microsatellite genotyping and HLA-B8 genotyping were performed in 48 Italian SLE patients and in 158 healthy control subjects. RESULTS: Of HLA class II haplotypes, only DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) was significantly more frequent among SLE patients than among healthy control subjects [odds ratio (OR) = 6.5, corrected P < 0.0026]. HLA-B8 was detected in 31% SLE patients and 13% healthy control subjects (OR = 3.0, P = 0.005). The allele-wise comparison between patients and controls showed that both MICA5 (OR = 2.5, corrected P < 0.0005) and MICA5.1 (OR = 2.4, corrected P < 0.0005) were positively and MICA9 (OR = 0.2, corrected P < 0.0005) was negatively associated with the disease. The MICA5/5.1 genotype was positively associated with SLE (OR = 28.9, corrected P < 0.0015) also in subjects negative for DR3-DQ2 (OR > 22.6, corrected P < 0.011). The simultaneous presence of DR3-DQ2 and MICA5.1 was detected in 15/48 (31%) SLE and in 10/158 (6%) healthy control subjects (OR = 6.7, corrected P < 0.011). The simultaneous combination of DR3-DQ2 and MICA5 was found in 10/48 (21%) SLE patients and in only 1/158 healthy control subjects (OR = 41.3, corrected P < 0.011). Logistic regression analysis showed the independent positive associations of MICA5 and MICA5.1 and negative association of MICA9 with the disease, and revealed that the interaction of the three major markers (DR3-DQ2, MICA5 and MICA5.1) was associated with increasing genetic risk, which was highest (OR > 30.3) in DR3-DQ2-positive subjects carrying the MICA5-5.1 genotype. CONCLUSIONS: Our study provides the first demonstration of the independent association of the MICA gene polymorphism with genetic risk of SLE.
Adult↗
Anti-beta 2 glycoprotein I antibodies in centenarians.
BACKGROUND: Non-organ-specific autoantibodies are present in centenarians without evidence of autoimmune diseases but conflicting or no data on anti-phospholipid and anti-phospholipid binding proteins were reported. OBJECTIVE: To investigate the presence and antigen specificity of anti-phospholipid and anti-phospholipid binding proteins in centenarians. METHODS: Seventy-seven centenarians, 70 adult controls, 65 unselected elderly subjects, and 38 old SENIEUR volunteers were investigated. Anti-cardiolipin, anti-human beta 2 glycoprotein I, and lupus anticoagulant were detected. Antigen specificity was assayed against plates coated with anionic, neutral and cationic phospholipids and beta 2 glycoprotein I-dependence was also evaluated. RESULTS: 54.3% of the centenarians were positive for IgG and 8.6% for IgM anti-beta 2 glycoprotein I antibodies, while only 20.7% centenarians were positive for anti-cardiolipin IgG and 2.59% for IgM; none resulted positive for lupus anticoagulant. Anti-cardiolipin positive sera cross-reacted with negatively charged phospholipids and displayed decreased binding to serum-free cardiolipin-coated plates that was restored by human beta 2 glycoprotein I or fetal calf serum. CONCLUSIONS: Centenarians display high reactivity against human beta 2 glycoprotein I but low binding to the bovine molecule in the anti-cardiolipin assay. In spite of the presence of antibodies comparable to those found in patients with the anti-phospholipid syndrome, no vascular events were reported suggesting the presence of unknown protective factors and/or the lack of triggering factors.
Aged↗
Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity.
BACKGROUND: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease. Endothelial dysfunction represents the earliest stage of atherosclerosis. OBJECTIVE: To evaluate the influence of chronic inflammatory state on endothelial function in patients with RA by measuring endothelial reactivity in young patients with RA with low disease activity and without traditional cardiovascular risk factors. METHODS: Brachial flow mediated vasodilatation (FMV), assessed by non-invasive ultrasound, was evaluated in 32 young to middle aged patients with RA (age </=59 years), with DAS28 </=3.2 and without overt cardiovascular disease, and in 28 age and sex matched controls. RESULTS: Mean (SD) FMV was significantly lower in patients than in controls (3.2 (1.3)% v 5.7 (2.0)%; p<0.001), inversely related to low density lipoprotein cholesterol (r = -0.45, p<0.05) and C reactive protein (CRP), expressed as the value at the moment of ultrasound evaluation (r = -0.44, p<0.05), as the average of CRP levels evaluated at different times during the disease (r = -0.47, p<0.05), or as the average of >/=4 determinations multiplied by the disease duration (r = -0.40, p<0.05). In a multivariate regression model, a lower brachial flow mediated vasodilatation was independently predicted by low density lipoprotein cholesterol (beta = -0.40, p<0.05), average CRP levels multiplied by the disease duration (beta = -0.44, p<0.05), and brachial artery diameter (beta = -0.28, p<0.05). CONCLUSIONS: Young to middle aged patients with RA with low disease activity, free from cardiovascular risk factors and overt cardiovascular disease, have an altered endothelial reactivity that seems to be primarily related to the disease associated chronic inflammatory condition.
Adult↗
Micropatterned hyaluronan surfaces promote lymphatic endothelial cell alignment and orient their growth.
The implant of a biocompatible device capable of guiding lymphatic vessel regeneration in patients who underwent removal of lymph nodes might contribute to restoring an efficient lymphatic drainage and help to prevent the occurrence of lymphedema. The aim of this study was to evaluate whether a microstructured surface could provide a guidance for the growth of cultured lymphatic endothelial cells. The presence of microstructures on a surface permits the control of cell adhesion, migration, proliferation, and differentiation. We report here that lymphatic endothelial cells align on microstructures of alternating hyaluronan and aminosylanized glass stripes obtained by photoimmobilization. Cells consistently spread and proliferate only on aminosylanized glass. They orient parallel to the longitudinal axis of the stripe. A pattern of alternating stripes of aminosylanized glass uniformly covered by elongated cells and of hyaluronan devoid of cells eventuallyforms. The presence of alpha(v)-integrins along cell borders of cells in search of contact with each other and at the leading edge of migrating cells, sites where new focal adhesions are presumably formed, indicates that integrin-mediated adhesion to the substrate guides cell migration along the microstructure. Micropatterned surfaces of hyaluronan thus proved to adequately orient the growth of cells allowing the regeneration of lymphatic endothelium in the desired direction.
Animals↗
The pattern of fibrillin deposition correlates with microfibril-associated glycoprotein 1 (MAGP-1) expression in cultured blood and lymphatic endothelial cells.
Fibrillins constitute the major structural components of 10-12nm microfibrils of the extracellular matrix of several elastic and non elastic tissues and of initial lymphatic vessel anchoring filaments. Microfibril-Associated Glycoprotein-1 (MAGP-1) binds fibrillin to tropoelastin during elastogenesis. We recently reported that cultured blood endothelial cells deposit fibrillin in a honeycomb pattern, whereas lymphatic endothelial cells form an irregular web. The aim of this immunohistochemical study was to verify whether the deposition pattern of fibrillin is related to the expression of MAGP-1 in confluent and postconfluent cultures of bovine aortic (AEC), pulmonary artery (PAEC) and lymphatic endothelial cells (LEC). In AEC and PAEC, MAGP-1 and fibrillin co-localized and their deposition increased with time in culture. In AEC, both proteins formed a honeycomb pattern. In LEC, MAGP-1 deposition was still negligible when fibrillin formed an irregular web covering the entire surface. PAEC, which in vivo are exposed to physiological conditions intermediate between AEC and LEC, had an intermediate pattern of deposition of fibrillin and MAGP-1. Assuming that early elastogenesis is an intrinsic functional need for the aorta, but not for the thoracic duct, we propose that delayed appearance of MAGP-1 in LEC may correlate with their irregular fibrillin deposition. Different fibrillin scaffolds could in turn account for the specificity of elastic fibers in compliance with the specific functional requirements of the tissue.
Animals↗
A comparison of the therapeutic efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis.
OBJECTIVE: To evaluate and compare the efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis of the knee or hip. METHODS: In this 6-week double-blind, active comparator controlled, parallel-group study eligible osteoarthritis patients were randomised to receive either etoricoxib 60 mg once daily (n = 256) or diclofenac 50 mg three times daily (n = 260). The primary study endpoint was the Western Ontario McMaster osteoarthritis index (WOMAC) pain subscale. Other endpoints included were the WOMAC stiffness and physical function subscales, and the Patient's Global Assessment of Response to Therapy (PGART) questionnaire. Early efficacy was evaluated using WOMAC first question (pain walking on a flat surface) and PGART 4 h after the morning dose of each drug on days 1 and 2. Rescue medication (paracetamol) used was also recorded. The study was designed to show comparable efficacy between etoricoxib 60 mg once daily and diclofenac 50 mg three times daily with respect to the primary endpoint and was conducted outside the United States at 67 centres in 29 countries. RESULTS: Etoricoxib (60 mg once daily) was comparable in efficacy to diclofenac (150 mg daily) on all the above parameters. The one exception was in the assessment of early efficacy where etoricoxib demonstrated significantly greater benefit within 4 h of taking the first dose on the first day of therapy (p = 0.007) as evaluated by the percentage of patients with good or excellent (PGART) responses. The treatment effects of both drugs were similar by the time day 2 was reached and were sustained throughout the 6 weeks of therapy. Both treatments were generally well tolerated. CONCLUSIONS: Etoricoxib is clinically effective in the therapy of osteoarthritis providing a magnitude of effect comparable to that of the maximum recommended daily dose of diclofenac. The onset of clinical benefit with etoricoxib on day one is more rapid than that of diclofenac. Both drugs were generally well tolerated.
Adult↗
Familial autoimmunity as a risk factor for systemic lupus erythematosus and vice versa: a case-control study.
The objective of this multicentric case-control study was to investigate if a history of autoimmune disease (AD) in first-degree relatives (FDR) is a risk factor for systemic lupus erythematosus (SLE) and to evaluate the risk of AD among FDR of SLE patients. Cases were Italian SLE patients consecutively enrolled. Controls were orthopaedic inpatients without any autoimmune diseases. The strength of the association between family history of AD and SLE was measured as an odds ratio (OR) calculated from the coefficient of an unconditional regression model. To calculate the risk of AD among FDR of SLE patients, the extended generalized estimating equation technique was used. In total, 154 SLE cases and 140 controls were enrolled. A family history of AD was reported by 22.7% of SLE patients and by 5.7% of the controls. The risk of SLE increased with the number of FDR with AD (one FDR affected, OR = 4.1; two or more, OR = 11.3). The probability of having AD was higher among FDR of SLE cases in comparison to FDR of controls (RR = 4.6; 95%CI 1.9-11.1). A female SLE patient conferred an increased risk of AD to her FDR; this risk is doubled in females (OR 10.3; 95% CI 3.1-34.4).
Adult↗
In vivo activated T cells in rheumatoid synovitis. Analysis of Th1- and Th2-type cytokine production at clonal level in different stages of disease.
T-cell cytokines play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). Their detection in the joint, however, is impaired by the complex network present in the synovium. Although many synovial T cells show signs of previous activation, only a few express interleukin (IL)-2 receptor, marker of recent activation. The aim of this study was to analyse the cytokine production by in vivo activated (IL-2R +) T cells from RA at different stages of the disease. For this purpose, T cells were isolated from peripheral blood and synovial fluid of four patients with active RA, two at the onset of the disease, one in the early phase during treatment, one in long-lasting chronic phase. One patient was studied at the onset of the disease and 52 months later. Cells were initially expanded with a low dose of IL-2, cloned and analysed for cytokine production. The results showed a strong predominance of T helper (Th) 1 clones in the blood and a slight prevalence of Th0 clones in the joint of all the four patients. Interferon-gamma and IL-2 production was higher in the long-lasting RA, whereas IL-4 synthesis was prevalent in early RA. Enrichment in IL-10-producing clones was present only in the joint of the untreated patients. The longitudinal study confirmed the differences in cytokine production between early and late phases of disease. These data confirm that RA is mainly a Th1-driven condition. However, in vivo activated synovial T cells produce also Th2-type anti-inflammatory cytokines, such as IL-4 and IL-10. The synthesis of both cytokines is a feature of the very early phase of RA, although the selective recruitment of IL-10-producing T cells is quickly lost.
Adult↗
Unmasking the anti-inflammatory cytokine response in rheumatoid synovitis.
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Arthritis, Rheumatoid↗
Clinical and serological associations of ribosomal P autoantibodies in systemic lupus erythematosus: prospective evaluation in a large cohort of Italian patients.
OBJECTIVE: To verify the association of ribosomal anti-P antibodies (anti-P), as detected by a sensitive ELISA, with serological findings and clinical manifestations, including neuropsychiatric involvement evaluated according to the American College of Rheumatology (ACR) nomenclature, in a large cohort of patients with systemic lupus erythematosus (SLE). METHODS: Anti-P were evaluated in the serum of 149 consecutive Italian SLE patients by an ELISA using a multiple antigen peptide carrying four copies of a common P0, P1 and P2 epitope. A complete laboratory evaluation and clinical examination were performed in each patient. In addition, all patients underwent an accurate neuropsychiatric and neuropsychological assessment performed by trained specialists according to the 1999 ACR suggestions. RESULTS: Serum anti-P were detected in 18/149 patients (12.1%). The anti-P prevalence was similar (11.7%) when the analysis was performed in a larger series of sera including 82 additional SLE patients, who were not included in the clinical study. The age of anti-P-positive patients at disease onset was less than 33 yr and, in comparison with the anti-P-negative patients, these patients showed more active disease activity and a higher prevalence of photosensitivity and malar and discoid rash. A strong association between IgG anticardiolipin antibodies and anti-P was also found. However, anti-P were associated with neither neuropsychiatric syndromes nor cognitive impairment. CONCLUSION: This study does not seem to confirm the described association of anti-P with SLE neuropsychiatric manifestations. However, it supports the anti-P association with different skin manifestations as well as the presence of anticardiolipin in a subset of patients with SLE characterized by early disease onset.
Adolescent↗
Salicylates inhibit T cell adhesion on endothelium under nonstatic conditions: induction of L-selectin shedding by a tyrosine kinase-dependent mechanism.
Salicylates inhibit T cell adhesion to and transmigration through endothelium by preventing integrin activation induced by contact with endothelial cells. In the present study the effects of aspirin and sodium salicylate on the first steps of T cell adhesion have been analyzed in a nonstatic in vitro system. Salicylates partially reduced adhesion to activated endothelium and, in parallel, L-selectin expression on resting T cells by inducing shedding of the molecule without affecting its mRNA transcript. The role of L-selectin down-regulation in reducing T cell adhesion in this system was supported by the fact that aspirin inhibited T cell adhesion also on plastic-immobilized L-selectin ligand or when alpha(4) integrin-mediated adhesion to endothelium was blocked by specific mAbs. In addition, preincubation of T cells with inhibitors of L-selectin shedding prevented both functional and phenotypic inhibitory effects of salicylates. The decrease in T cell adhesion and L-selectin expression seems to be dependent on intracellular calcium increase and tyrosine kinase activation, because these effects could be reversed by preincubating salicylate-treated T cells with EGTA, genistein, or tyrphostin. Finally, the infusion of aspirin into healthy volunteers induced down-regulation of L-selectin on circulating T cells. These results suggest that salicylates interfere not only with integrin activation, but also with the L-selectin-mediated first steps of T cell binding to endothelium.
Aspirin↗
Role of CD30+ T cells in rheumatoid arthritis: a counter-regulatory paradigm for Th1-driven diseases.
CD30 has been proposed to identify Th0/2-type clones. However, the in vivo relevance of this finding is still a matter of debate, as high serum levels of soluble CD30 have been found in both Th1- and Th2- dominated disorders. Among these, rheumatoid arthritis represents a condition where the Th1 predominance is combined with the presence of CD30(+) T-cell activity, particularly in specific stages of the disease. This article discusses the hypothesis that CD30(+) T cells might play a counter-regulatory role at sites of inflammation in Th1-mediated conditions, such as rheumatoid arthritis.
Animals↗
Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians.
Several lines of evidence point to a profound remodelling of the cytokine network in healthy elderly subjects, with decreased type-1 cytokine production (IL 2) and a shift to type 0 and 2. We have also observed an increase of proinflammatory cytokines (IL-1, IL-6, TNF-alpha) in vitro, and an increase of circulating stem cell factor in vivo. In this setting, we studied changes of chemokines (MCP-1 and RANTES) with aging, as well as other molecules, namely, sTNF-RI and sTNF-RII, and the soluble form of the CD30 molecule (sCD30), involved in the pro- and antiinflammatory cytokine balance. The subjects enrolled in the study belonged to three different selected healthy groups of young, aged and centenarians. The presence of rheumatoid factor (RF) and antinuclear antibodies (ANA) was simultaneously assessed. The results show that MCP-1 serum levels were higher in the healthy aged and lowest in the young, while RANTES increased exclusively in centenarians. Only centenarians had autoantibodies (ANA and RF). sTNF-RI and sTNF-RII were significantly elevated in healthy old subjects compared to the young, and even higher in selected centenarians compared to the other age groups. sCD30 serum levels were significantly raised in centenarians compared to the young, despite absence of circulating CD30+ cells in the peripheral blood of the whole study population. No relationship among serum values of these different members of the TNF-R family was found, despite a strong correlation for sTNF-RI and sTNF-RII in all groups. We hypothesize that the increased chemokine levels in aged people, and raised sCD30 levels in centenarians, may reflect a general shift towards type 0/2 cytokines in normal aging, which may be responsible, at least in part, for the appearance of circulating autoantibodies without definite clinical consequences at advanced age.
Adult↗
CD30+ T cells in rheumatoid synovitis: mechanisms of recruitment and functional role.
High serum levels of soluble CD30 (sCD30) have been reported to better predict the response to second line therapy in rheumatoid arthritis (RA). It is believed that sCD30 is released by CD30+ T cells present in the RA synovium. However, both the mechanism of recruitment to the joint and the functional role of this T cell subset in the pathogenesis of the disease remain unknown. This study confirmed higher levels of sCD30 in the serum and synovial fluid (SF) of RA patients compared with normal controls. However, analysis of mRNA and cell surface CD30 expression showed that CD30+ T cells are detectable in the SF, but not in the synovial membrane. In contrast, T cells expressing the CD30 transcript, but not the surface molecule, were found in the peripheral blood of both RA and normal controls. CD30 surface expression was up-regulated by adhesion and migration through endothelium in vitro and in a delayed-type hypersensitivity model in vivo. Although the great majority of fresh or cloned CD30+ T cells from SF produced both IFN-gamma and IL-4, CD30 expression strictly correlated with IL-4 synthesis in synovial T cell clones. In addition, CD30+ T cell clones also produced high amounts of the anti-inflammatory cytokine IL-10. On this basis, we would like to propose that synovial CD30+ cells may play a role in the control of the inflammatory response. Serum sCD30 may reflect such cell activity and, therefore, explain the previously demonstrated correlation between high sCD30 serum levels and positive response to therapy.
Adult↗