von Willebrand factor and vascular injury in rheumatoid arthritis.
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Biomedical subjects
Publications and source records attributed to B Seriolo.
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INTRODUCTION: The aim of the present study was to demonstrate, by nailfold videocapillaroscopy (NVC), the existence of diagnostic and follow-up parameters of microvascular damage in systemic sclerosis (SS) (grouped in the "early", "active" and "late" NVC patterns). The presence of the different subsets of skin involvement (limSS and difSS), as well as the role of some specific serum autoantibodies in the expression of the NVC parameters were investigated. METHODS: 245 consecutive SS patients were recruited and clinical data assessed. Antinuclear (ANA), antitopoisomerase I (Scl70) and anticentromere (ACA) antibodies were investigated in all patients. RESULTS: Giant capillaries and hemorrhages were confirmed to be the earliest NVC finding in SS (diagnostic parameters). The loss of capillaries, along with ramified capillaries and vascular architectural disorganization were validated as parameters of progression of SS microangiopathy. Really, both Raynaud's phenomenon (RP) and SS duration were detected longer in patients with the "late" than in those with the "active" or the "early" NVC pattern. Patients affected by limSS were found to have shorter disease duration, as well as showed more frequently the "early" or the "active" NVC patterns. Conversely, patients affected by the difSS showed longer disease duration and mostly the presence of the "active" or "late" NVC pattern. The Scl70 positivity was lower in the patients showing the "early" than in those with the "active" and the "late" NVC patterns, whereas no significant correlation was found between the Scl70 presence and both RP and SS duration. The ACA positivity was higher in patients showing the "early" NVC pattern, as well as in patients with longer disease duration. CONCLUSIONS: This study confirms that the identification of distinct NVC patterns may be useful to evaluate the severity and the stage of the SS microvascular damage. The presence of the Scl70 antibodies seems related to a more rapid progression of the SS microangiopathy. On the contrary, the presence of the ACA seems to be related to a slower progression of the SS microvascular damage. The SS peripheral microangiopathy is similar as in patients with limSS, as in those affected by difSS.
UNLABELLED: Secondary osteoporosis (OP) is a well-recognized complication of rheumatoid arthritis (RA). Treatment with TNF-alpha blockers, might influence bone metabolism and prevent structural bone damage in RA, in particular at the periarticular regions. OBJECTIVE: To assess the influence of anti-TNF-alpha therapy, on bone metabolism in RA patients. 36 RA patients were treated with stable therapy of prednisone (7.5 mg/day) and methotrexate (MTX=10 mg/week). Nine of these RA patients further received etanercept (25 mg, twice/weekly) and eleven infliximab (3mg/kg on 0, 2, 6, and every 8 weeks thereafter). A control group included 16 RA patients only with stable therapy (some dosage of prednisone and MTX). Quantitative Ultrasound (QUS) bone densitometry was obtained at the metaphyses of the proximal phalanges of both hands with a DBM Sonic 1200 QUS device (IGEA, Carpi, Italy). Bone mineral density (BMD) of the hip and lumbar spine were performed with a densitometer ( Lunar Prodigy, GE, USA) at baseline and after 12 months. Soluble bone turnover markers [osteocalcin (OC), bone alkaline phospatase (ALP) deoxypyridinoline/creatinine ratio (Dpd/Cr) and cross-linked N-telopeptide of type I collagen / creatinine ratio (NTx/Cr)] were measured using ELISA tests. RESULTS: AD-SoS values were found increased by +4.55% after 12 months of treatment in the RA patients treated with anti-TNF-alpha therapy. On the contrary, the Ad-SoS levels decreased by -4.48% during the same period in the control RA group. BMD increased by +3.64% at lumbar spine and +2.90% at the hip (both p<0.001) in TNF-alpha blockers-treated patients and decreased by -2.89% and -3.10% (both p<0.001, respectively at lumbar spine and at the hip) in RA patients without anti-TNF-alpha therapy. In RA patients treated with TNF-alpha blockers, OC and bone ALP levels were found significantly increased (p<0.01) and Dpd/Cr or NTx/Cr levels were found significantly decreased (p<0.01) at 12 months when compared to baseline values. CONCLUSION: During 12 months of treatment of RA patients with TNF-alpha blockers, bone formation seems increased while bone resorption seems decreased. The reduced rate of OP seems supported by the same mechanisms involved in the decreased bone joint resorption during anti-TNF-alpha therapy (i.e. increase of osteoblastic activity and decrease osteoclastic activity).
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OBJECTIVE: To investigate the possible relationships between plasma homocysteine levels and thrombotic events in a select population of rheumatoid arthritis (RA) patients with or without antiphospholipid (aPL) antibody positivity. METHODS: 168 female RA patients attending the Extra-articular Involvement RA Clinic of University of Genova and 72 female subjects matched for age and vascular diseases as controls were included in the study. 30 of the RA patients showed aPL antibody positivity and 138 aPL antibody negativity on the basis of the concomitant presence or absence of high concentrations of anticardiolipin (aCL) antibodies or the presence of lupus anticoagulant (LA). All subjects were evaluated for plasma homocysteine concentrations and for the occurrence of thrombotic events. RESULTS: Twenty-five RA patients and 5 controls reported a history of thrombotic events. Eleven and 5 of RA patients were found to have been previously affected by venous or arterial thrombosis, respectively. Plasma levels of homocysteine in aPL antibody positive patients with thrombosis were found to be significantly higher than in aPL antibody positive RA patients without thrombosis (p < 0.001). When RA patients with thromboses were analyzed, a significant increase of plasma homocysteine levels was found in aPL antibody-positive RA patients versus aPL antibody-negative RA patients (p < 0.04) and versus related controls (p < 0.003). CONCLUSIONS: The association observed between aPL antibody positivity and high levels of plasma homocysteine in RA patients may represent a possible risk factor for thrombotic events. Therefore, it is suggested that hyperhomocysteinemia might be involved in the vascular-related mortality observed in RA patients with a history of thrombosis.
Microvascular involvements represent one of the first step in many autoimmune diseases such as scleroderma (SSc) or antiphospholipid syndrome. Early in the disease, the peripheral microangiopathy may be well recognised and studied by nailfold videocapillaroscopy (NVC), a noninvasive and safe technique, that is reported to have both diagnostic and prognostic value, especially in the presence of Raynaud's phenomenon (RP). The classification of defined major NVC patterns in SSc might be useful in assessing the appearance and progression of the sclerodermic microangiopathy. In addition, the NVC changes might represent a morphological reproduction of the evolution of the SSc. The early appearance of giant capillaries and haemorrhages (Early pattern) is of great relevance for the early diagnosis of the SSc. Therefore, these alterations are more evident in the active phase of the disease (Active pattern). Conversely, the NVC observation of loss of capillaries, vascular architectural disorganisation and the presence of ramified/bushy capillaries (Late pattern) represents the clearest aspect of advanced SSc microvascular damages. Interesting, correlations between the NVC and clinical aspects of SSc, as well as the effects of therapeutical interventions have been observed.
Methotrexate (MTX) is a folic acid analogue with antiproliferative and antiinflammatory effects. In the past several years, MTX has become the most commonly used agent in patients with severe, destructive psoriatic arthritis (PsA), with positive clinical results. Liver changes and serum enzyme level increases do not seem to be a major problem in PSA patients treated with MTX. In addition, PSA patients treated with low-dose MTX were not associated with pulmonary fibrosis as evaluated by means of sensitive imaging techniques and pulmonary function tests. The concomitant use of folic acid reduces both the frequency of serum liver enzyme level increases but also the efficacy of MTX by competing with the folate receptors.
Sex hormones appear to play an important role as modulators of autoimmune disease onset/perpetuation. Steroid hormones are implicated in the immune response, with estrogens as enhancers at least of humoral immunity, and androgens and progesterone (and glucocorticoids) as natural immune suppressors. Serum levels of estrogens have been found to be normal in rheumatoid arthritis (RA) patients. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female RA patients as compared to controls, which is most probably due to an increase in local aromatase activity. Thus, available steroid pre-hormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e. TNF alpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular 16 alpha-hydroxyestrone, showing a mitogenic stimulating role. Indeed, recent studies by us indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase in markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on the immune/inflammatory response is exerted by activating the NFkB complex. In conclusion, locally increased estrogens may exert activating effects on synovial cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in RA.
OBJECTIVE: This multicentre, randomized, double-blind, placebo-controlled parallel-group study was undertaken to investigate the efficacy, safety and tolerability of lumiracoxib (Prexige), a cyclooxygenase-2 selective inhibitor, in patients with primary osteoarthritis (OA) of the hand. METHODS: The study randomized 594 patients aged > or = 18 years with symptomatic OA of the hand. Patients underwent a 3 to 7-day washout for previous nonsteroidal anti-inflammatory drugs and those with pain intensity > or = 40 mm on a 100 mm Visual Analogue Scale (VAS) in the target hand during the 24 hours prior to baseline and an increase in pain intensity of either > or = 20% or > or = 10 mm VAS since screening (whichever was greater) were randomized to lumiracoxib 200 mg once daily (od) (n=205), lumiracoxib 400 mg od (n=193) or placebo (n=196). The primary efficacy variable was overall OA pain intensity (VAS mm) in the target hand after 4 weeks of treatment. Safety and tolerability assessments were performed. RESULTS: After 4 weeks of treatment, overall OA pain intensity in the target hand was significantly lower for patients treated with lumiracoxib compared with patients treated with placebo (both doses p<0.001). There was no significant difference between lumiracoxib doses in terms of the reduction in overall OA pain intensity. Lumiracoxib was well tolerated. The incidence of adverse events was similar for active treatment groups and placebo. CONCLUSIONS: Lumiracoxib 200 and 400 mg od were effective and well tolerated treatments for OA of the hand. Lumiracoxib significantly improved overall OA pain intensity in the target hand versus placebo, with a tolerability profile similar to placebo.
Metalloproteinases (e.g. collagenase, elastase, stromelysin) are present in large amount in synovial fluid (SF) during rheumatoid arthritis (RA) and are actively involved in articular tissue damage. alpha 2-Macroglobulin (alpha 2M) functions as a "molecular trap" for proteinases and is considered the major inhibitor of metalloproteinases. We found increased concentrations of alpha 2M in SF of RA patients, significantly related to acute phase reactants, local inflammatory parameters and joint damage. The alpha 2M ratio between, RA SF and control SF, was found higher than between RA serum and control serum, indicating a selective localization and activity of alpha 2M in inflamed joint. The relationship between alpha 2M and the inflammatory parameters, including IL-6, is discussed.
BACKGROUND: Greater intake of vitamin D has been associated with a lower risk of rheumatoid arthritis (RA) and low serum vitamin D together with higher prevalence of RA seem common among North European people when compared to Southern Europe. OBJECTIVES: To evaluate serum 25-hydroxyvitamin D [25(OH)D] levels in female RA patients from North (Estonia) and South (Italy) Europe and to correlate them with the disease activity score (DAS28) during winter and summer. METHODS: Fifty-four RA Italian patients (IP) and 64 RA Estonian patients (EP) were evaluated for serum 25(OH)D levels in winter and summer time, as well as for DAS28 score. Normal female controls (C) were 35 (IC) and 30 (EC) age-matched subjects, respectively. 25(OH)D concentrations were measured by a competitive radioimmunoassay. Statistical analysis was performed by "r" Pearson correlation, "t" Student with Bonferroni correction and by repeated ANOVA measures (summer and winter) with two factors (country and clinical status). RESULTS: 25(OH)D levels were found significantly higher in IP versus EP (p = 0.0116) both in winter and in summer time. Differences were observed also in controls. The variations (increase) of 25(OH)D levels between winter and summer were found significant (p = 0.0005) in both IP and EP. Differences were observed also in controls. No significant differences were found concerning 25(OH)D levels between RA patients and their controls in either country. Interestingly, a significant negative correlation between 25(OH)D and DAS28, was found in summer only in IP (r =-0.57, p < 0.0001) and in winter in EP (r =-0.40, p < 0.05). CONCLUSION: Significantly lower 25(OH)D serum levels were observed in RA patients from North versus South Europe with a circannual rhythm in winter and summer time. In addition, 25(OH)D values showed a significant correlation (negative) with RA clinical status (DAS28) in both North and South European RA patients, suggesting possible effects of vitamin D among other factors on disease activity.
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Estrogens appear to play a central role in the immune response and immune-mediated diseases. Recent studies have shown the presence of estrogen receptors on the cells involved in the immune response, namely thymocytes, macrophages and endothelial cells. Particular attention has been focused on the dose-dependent influence of estrogen on the immune response, which appears to be related to the clinical symptoms of autoimmunity (i.e. the effects of pregnancy or oral contraceptive pills). The influence of estrogens on cytokine production by target cells, through interference with their transcriptional activity, has also been the focus of various studies. The effect of estrogens on the expression of the protooncogenes and oncosuppressor genes involved in programmed cell death (apoptosis) might also be relevant to human autoimmunity, in particular the uncontrolled synovial lining cell hyperplasia associated with rheumatoid arthritis and the prolonged T-cell survival in systemic lupus erythematosus. Estrogen-induced immunomodulation is a subject of growing interest and stimulating research.
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Macrophage-like synoviocytes originate in the bone marrow, like other mononuclear phagocytes, and are constantly replaced via the circulation. In rheumatoid synovium sections, 80-100% of the synovial lining cells are macrophage-like cells functioning as antigen processing- and antigen-presenting cells to T lymphocytes. Monocyte and lymphocyte traffic into the rheumatoid arthritis (RA) synovium is mediated by adhesion molecules such as endothelial-leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecules-1 and -2 (ICAM-1 and ICAM-2), as well as monocyte chemotactic protein 1 (MCP-1) and beta 2 integrins (CD11 a,b,c/CD18). Macrophage-like cells in the RA synovium are highly activated based on their morphology, surface class II HLA antigen expression, and synthesis of cytokines such as interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage CSF, and transforming growth-factor beta (TGF-beta). Evidence for type 1 (higher affinity) and type 2 (lower affinity) androgen (ARs) and estrogen receptors (ERs) on macrophage-like synoviocytes in either male or female synovial samples from both RA patients and controls has been reported. In particular, ERs have also been found on CD8+CD29+ CD45R0+ T lymphocytes (memory), infiltrating rheumatoid synovial tissues. Sex hormones have been found to influence macrophage activity in experimental and clinical conditions such as RA. Generally estrogens have immunostimulatory effects, whereas androgens are immuno-suppressive.(ABSTRACT TRUNCATED AT 250 WORDS)