Rheumatoid Arthritis: Valentini G

Malesci D, Valentini G, La Montagna G. · No affiliation provided · Reumatismo. · Pubmed #17013432 links to  free full text

Abstract: Toward the end of the last century a better knowledge of cardiovascular (CV) risk factors and their associations led investigators to propose the existence of a unique pathophysiological condition called "metabolic" or "insulin resistance syndrome". Among all, insulin-resistance and compensatory hyperinsulinemia are considered its most important treatment targets. Different definitions have been provided by World Health Organization (WHO) and by The Third Report of The National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP III). In particular, abdominal obesity, hypertension, low HDL cholesterol and hyperglicemia are the most common items used for its definition. The presence of MetS is effective in predicting the future risk of diabetes and coronaropathies. The evidence of a higher CV risk rate among different rheumatic inflammatory diseases has recently been associated with high prevalence of MetS in some cases. Rheumatoid or psoriatic arthritis have the large series among arthritis, whereas systemic lupus erythematosus among connective tissue disorders. This review analyses all most important studies about the evidence of MetS in rheumatic patients and the main clinical and prognostic significance of this relation.

Ferraccioli GF, Valentini G, Valesini G, Bombardieri S. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #11791629 No free full text.

This publication has no abstract.

Visser K, Katchamart W, Loza E, Martinez-Lopez JA, Salliot C, Trudeau J, Bombardier C, Carmona L, van der Heijde D, Bijlsma JW, Boumpas DT, Canhao H, Edwards CJ, Hamuryudan V, Kvien TK, Leeb BF, Martín-Mola EM, Mielants H, Müller-Ladner U, Murphy G, Østergaard M, Pereira IA, Ramos-Remus C, Valentini G, Zochling J, Dougados M. · Leiden University Medical Center, Department of Rheumatology, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #19033291 links to  free full text

Abstract: OBJECTIVES: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. METHODS: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. CONCLUSIONS: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

Ferri C, Ferraccioli G, Ferrari D, Galeazzi M, Lapadula G, Montecucco C, Triolo G, Valentini G, Valesini G, Anonymous00027. · Rheumatic Disease Unit, University of Modena and Reggio Emilia, Modena/Reggio Emilia, Modena, Italy. · J Rheumatol. · Pubmed #18688917 No free full text.

Abstract: OBJECTIVE: The prevalence of concurrent rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection is probably underestimated because of the increasing spread of this virus worldwide, especially in developing countries. In these patients, anti-tumor necrosis factor-alpha (anti-TNF-alpha) therapy may aggravate hepatitis and increase viremia. We evaluated the safety of these treatments, which remain controversial. METHODS: Thirty-one HCV-positive patients (23 women, 8 men, mean age 59+/-13 yrs, mean disease duration 13+/-11.5 SD yrs) with active RA [Disease Activity Score 28 (DAS28)>3.2] unresponsive to conventional therapies were treated with TNF-alpha blockers (infliximab 11, etanercept 17, adalimumab 3) at standard dosages. Safety and efficacy were evaluated at the third month of treatment and at the patient's last observation. RESULTS: A significant clinical-serological improvement was recorded at the 3-month reevaluation. Mean values of patients assessment of general health on visual analog scale (range 0.100) decreased from 69+/-29 (SD) to 35+/-27 (p<0.0001), Ritchie index from 21.6+/-13.9 to 10.1+/-3.7 (p<0.0001), erythrocyte sedimentation rate from 36+/-25 to 28+/-22 mm/h (p=0.04), and DAS28 from 5.2+/-1.6 to 2.78+/-1.3 (p<0.0001); a DAS28<2.6 was recorded in 15/31 (48%) patients. At the last observation 19 patients (61%) continued TNF-alpha blockers, and the observed benefits persisted after 22+/-11 months of followup. Mean values of transaminases (ALT) and HCV viral load showed no significant variations; TNF-alpha blockers were discontinued in only one patient because of persistently elevated ALT not correlated to the variations of HCV viremia; this latter increased significantly (>or=2 log10) in 4 cases. CONCLUSION: Previous observations had suggested the safety of TNF-alpha blockers for treatment of RA in patients with concurrent HCV infection. Given the clinical-therapeutic implications, our results support the safety of TNF-alpha blockers in patients with HCV, provided there is close monitoring of clinical and virological data (mainly ALT and HCV viremia).

Marchesoni A, Govoni M, Valentini G, Valesini G, Salaffi F, Macchioni P, Alberighi OD, Ferraccioli G, Anonymous00350. · UOC Rheumatology Day Hospital, G. Pini Orthopaedic Institute, University of Milan, Milan, Italy. · J Rheumatol. · Pubmed #18050379 No free full text.

Abstract: OBJECTIVE: In 1999, the Italian Society of Rheumatology started a project to determine the prevalence and clinical characteristics of aggressive rheumatoid arthritis (ARA). METHODS: For 1 year, all patients with RA for > 5 years and referred to participating centers were entered in a registry and classified as having ARA if they fulfilled the following criteria: 10 swollen joints for at least 6 weeks, positive rheumatoid factor (RF), and at least one bone erosion (if disease duration of 2 years); (a) RF-positive and having 10 swollen joints or at least one newly eroded joint, or (b) if RF-negative, having 10 swollen joints and at least one newly eroded joint (if disease duration > 2 to < 5 years). RESULTS: The 94 participating centers enrolled 1218 patients with RA, 1130 of whom had enough data to be classified as ARA (29.0%) or non-ARA (71.0%). The frequency of ARA was 15% in the 2-year group and 63% in the > 2 to < 5-year group, but 35% of the patients in the 2-year group had erosions. Bone erosions were associated with disease duration, a Health Assessment Questionnaire value > 1.5, female sex, and RF positivity. Conditions other than RA were recorded in about 50% of the patients, and only 30% 40% were taking disease modifying antirheumatic drugs. CONCLUSION: In an Italian RA population, the GIARA (Gruppo Italiano Artrite Reumatoide Aggressiva) criteria for ARA were met by 15% of the patients with disease duration of 2 years, but erosions were seen in 35%. Upon referral, most of the RA patients were inadequately treated and had other conditions.

van der Heijde D, Klareskog L, Landewé R, Bruyn GA, Cantagrel A, Durez P, Herrero-Beaumont G, Molad Y, Codreanu C, Valentini G, Zahora R, Pedersen R, MacPeek D, Wajdula J, Fatenejad S. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #18050208 links to  free full text

Abstract: OBJECTIVE: The Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) is a 3-year, double-blind, multicenter study evaluating the efficacy and safety of etanercept, methotrexate, and the combination of etanercept plus methotrexate in patients with active rheumatoid arthritis (RA). The results after 1 and 2 years of the study have been previously reported. Here we provide the 3-year clinical and radiographic outcomes and safety of etanercept, methotrexate, and the combination in patients with RA. METHODS: In this randomized, double-blind, multicenter TEMPO study, 682 patients received etanercept 25 mg twice weekly, methotrexate < or =20 mg weekly, or the combination. Key efficacy assessments included the Disease Activity Score (DAS) and the DAS in 28 joints. RESULTS: Combination therapy resulted in significantly greater improvement in the DAS and in more patients with disease in remission than either monotherapy. This finding was confirmed by longitudinal analysis; patients receiving combination therapy were more than twice as likely to have disease in remission than those receiving either monotherapy. Independent predictors of remission included male sex, lower disease activity, lower level of joint destruction, and/or better physical function. Combination and etanercept therapy both resulted in significantly less radiographic progression than did methotrexate (P < 0.05). Etanercept and combination treatment were well tolerated, with no new safety findings. CONCLUSION: Etanercept plus methotrexate showed sustained efficacy through 3 years and remained more effective than either monotherapy, even after adjustment for patient withdrawal. Combination therapy for 3 years led to disease remission and inhibition of radiographic progression, 2 key goals for treatment of patients with RA.

La Montagna G, Cacciapuoti F, Buono R, Manzella D, Mennillo GA, Arciello A, Valentini G, Paolisso G. · Department of Clinical and Experimental Medicine and Surgery-Rheumatology Unit, Second University of Naples, Via Pansini, 5-80131 Naples, Italy. · Diab Vasc Dis Res. · Pubmed #17654447 links to  free full text

Abstract: The objective of this study was to investigate the relationship between insulin resistance (IR) and subclinical atherosclerosis in patients with rheumatoid arthritis (RA). Carotid artery intima media thickness (IMT), using ultrasound evaluation, and other clinical and laboratory variables were investigated in 45 RA outpatients and in 48 controls with soft tissue disorders. IR was assayed by homeostasis model assessment (HOMA2) and metabolic syndrome by National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) criteria. Insulin resistance, as defined by HOMA2-IR>1, was seen in 40 (88.9%) RA patients and in three (6.2%) controls (p<0.001). No significant difference was detected in the prevalence of metabolic syndrome. The median IMT was greater in RA patients (0.76 mm; interquartile range [IQR] 0.65, 0.85) than in the controls (0.66 mm; IQR 0.60, 0.72) (p<0.001). Dividing the RA patients according to the cut-off IMT value (0.72 mm), a difference was detected in both systolic (p=0.04) and diastolic blood pressure (p=0.02), disease activity score (DAS28) (p=0.008), HOMA2-IR (p<0.001) and cumulative oral steroid dose (p=0.001). Moreover, the frequency of cases with increased IMT was higher in glucocorticoid users than in non-users (21/23 vs. 9/22, respectively) (p<0.001). Spearman's rho correlation showed a significant positive relationship between IMT and HOMA2-IR (p<0.001). Multivariate stepwise analysis selected HOMA2-IR plus diastolic BP plus glucocorticoid exposure as the best predictive model for subclinical atherosclerosis (R2c=0.577, F=21, p<0.001). In conclusion, this study showed a significantly higher prevalence of IR in RA patients and pointed out a significant association between IR and subclinical atherosclerosis. This relationship may be driven primarily by exposure to steroid therapy.

Mancarella L, Bobbio-Pallavicini F, Ceccarelli F, Falappone PC, Ferrante A, Malesci D, Massara A, Nacci F, Secchi ME, Manganelli S, Salaffi F, Bambara ML, Bombardieri S, Cutolo M, Ferri C, Galeazzi M, Gerli R, Giacomelli R, Grassi W, Lapadula G, Cerinic MM, Montecucco C, Trotta F, Triolo G, Valentini G, Valesini G, Ferraccioli GF, Anonymous00012. · Division of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy. · J Rheumatol. · Pubmed #17611987 No free full text.

Abstract: OBJECTIVE: To assess the prevalence of good clinical response and remission in rheumatoid arthritis (RA) patients with longstanding disease treated with anti-tumor necrosis factor-alpha (TNF-alpha) drugs at outpatient clinics. METHODS: Retrospective national study of 14 academic tertiary referral rheumatology medical centers. RA patients with a Disease Activity Score (DAS28) > 3.2 were defined as having active disease and could start TNF-alpha blockers. All patients received one TNF-alpha blocker plus methotrexate (10-20 mg/wk). At the third month the patients were categorized as responders or nonresponders, based on improvement of at least 0.25 of the Health Assessment Questionnaire (HAQ). Those who had improved by at least 0.25 HAQ were analyzed for possible predictors of DAS28 remission at the sixth month. RESULTS: A total of 1257 patients started TNF-alpha blockers. Of these, 591 (46.7%) reached the sixth month with an improvement of HAQ of 0.25 at the third month. In the cohort of patients reaching HAQ of 0.25, DAS28 remission was seen in 24% of rheumatoid factor (RF)-positive and 36% of RF-negative patients (p = 0.03). Logistic regression analysis for predictors of remission identified age at baseline, HAQ < 1.63, and RF negativity as positive predictors of remission at 6 months along with sex (male). CONCLUSION: We show that only a minority of patients with longstanding RA achieve a good clinical response or remission at the outpatient community level. Predictors of remission identify characteristics commonly observed in subsets with less severe RA.

La Montagna G, Tirri R, Vitello R, Malesci D, Buono R, Mennillo G, Valentini G. · Unità di Reumatologia, Seconda Università degli Studi di Napoli, Italia. · Reumatismo. · Pubmed #17216014 links to  free full text

Abstract: OBJECTIVE: To evaluate the treatment duration with MTX monotherapy or in association with DMARDs or TNFalpha inhibitors and the incidence and typology of adverse events (AE) occurred in rheumatoid arthritis (RA) patients. METHODS: A retrospective large cohort study of RA outpatients, consecutively seen from January 2000 to June 2005 was performed. Study group were RA patients classified according to the 1984 ACR criteria for the classification of rheumatoid arthritis. The patients were divided in 3 groups according to the treatment regimen: MTX monotherapy, MTX in combination with DMARD or with anti TNFalpha agents. We analyzed 348 therapeutic cycles, 177 of whom using MTX monotherapy. RESULTS: The 224 RA patients accumulated 800 person-years of follow up. Follow up for each of the groups was: MTX monotherapy 479.4 person-years, MTX in combination with DMARDs 244.5, or with TNFalpha inhibitors, 75.7 person-years. From the Kaplan-Meier analysis, the probability of patients remaining on treatment 5 years was 58.5 after starting MTX. The incidence of any AE was 8.87 per 100 person-years. From all, 69 (97.2%) AE were no severe. Among those, more frequently were observed at gastrointestinal tract (31%), liver (19.7%), skin (15.5%). Incidence of severe AE (lung adenocarcinoma, 1 case; pancreatitis, 1 case) was 0.25 per 100 person-years, occurring in patients taking MTX monotherapy or MTX in combination with DMARDs, respectively. CONCLUSIONS: These data confirm that methotrexate is well tolerated in clinical practice in the medium-long term. Nevertheless, the occurrence of severe AE require an accurate vigilance for methotrexate toxicity.

Iannone F, Trotta F, Montecucco C, Monteccuco C, Giacomelli R, Galeazzi M, Matucci-Cerinic M, Ferri C, Cutolo M, Maria Bambara L, Triolo G, Ferraccioli G, Valentini G, Lapadula G, Anonymous00086. · Department of Internal Medicine and Public Medicine, Rheumatology Unit, University of Bari, Bari, Italy. · Ann Rheum Dis. · Pubmed #16837489 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy of switching to etanercept treatment in patients with rheumatoid arthritis who already responded to infliximab, but presented side effects. METHODS: Charts of 553 patients with rheumatoid arthritis were retrospectively reviewed to select patients who responded to the treatment with infliximab and switched to etanercept because of occurrence of adverse effects. Clinical data were gathered during 24 weeks of etanercept treatment and for the same period of infliximab treatment before infliximab was stopped. Disease Activity Score computed on 44 joints (DAS-44), erythrocyte sedimentation rate (ESR) 1st hour, Visual Analogue Scale (VAS) of pain, Health Assessment Questionnaire (HAQ), and C reactive protein (CRP) were assessed every 8 weeks. RESULTS: 37 patients were analysed. Adverse events to infliximab were mostly infusion reactions. No statistically significant difference between infliximab, before withdrawal, and etanercept, after 24 weeks, was detected in terms of DAS-44 (2.7 and 1.9, respectively), HAQ (0.75 and 0.75, respectively), ESR (21 and 14, respectively) and CRP (0.5 and 0.3, respectively). VAS pain decreased significantly after switching to etanercept treatment (40 and 24, respectively; p<0.05). CONCLUSIONS: Our study shows that etanercept maintains the clinical benefit achieved by infliximab, and suggests that a second tumour necrosis factor (TNF) alpha inhibitor can be the favourable treatment for rheumatoid arthritis when the first TNFalpha blocker has been withdrawn because of adverse events.

La Montagna G, Cuomo G, Chiarolanza I, Ruocco L, Valentini G. · Dipartimento di Internistica Clinica e Sperimentale F. Magrassi e A. Lanzara, Seconda Università degli Studi di Napoli, Sezione di Reumatologia. · Reumatismo. · Pubmed #16829988 links to  free full text

Abstract: OBJECTIVE. To investigate the Italian version of HAQ-DI (Health Assessment Questionnaire Disability Index) in systemic sclerosis (SSc). METHODS. 121 SSc patients, satisfying ACR criteria for the classification of this disease and consecutively admitted to a tertiary Unit, were invited to participate to the study. The Italian version of HAQ-DI, as validated in rheumatoid arthritis, was administered to each of them. The relationships between this parameter and the following disease aspects: disease subset, wide extent of skin sclerosis, joint contractures, myopathy, active digital ulcers, were investigated. RESULTS. HAQ-DI resulted to be 0.772+/-0.074 (mean+/-SE) Statistically significant differences in HAQ-DI scores were detected between patients with and respectively without wide extent of skin sclerosis (ie modified Rodnan skin score >14) (1.158+/-0.176 vs 0.652+/-0.076; P<0.001), joints contractures (0.839+/-0.076 vs 0.159+/-0.147; P<0.001), myopathy (1.875+/-0.184 vs 0.656+/-0.071; P<0.001), digital ulcers (1.047+/-0.135 vs 0.680+/-0.109; P=0.006). CONCLUSIONS. Our data support the validity of the Italian version of HAQ-DI in SSc.

Cuomo G, Molinaro G, La Montagna G, Migliaresi S, Valentini G. · Unità Operativa di Reumatologia, Seconda Università di Napoli, Napoli. · Reumatismo. · Pubmed #16639484 links to  free full text

Abstract: OBJECTIVE: To compare the SDAI values to DAS28 scores in RA patients undergoing different DMARD regimens. METHODS: The SDAI is an unweighted numerical sum of five outcome parameters: tender and swollen joint count (based on 28-joint assessment), patient and physician global assessment of disease activity (visual analogue scale: 0-10 cm) and level of C-reactive protein (mg/dl). 80 patients (F/M 68/12; age between 20-68 years, median 52) with active rheumatoid arthritis were prospectively enrolled in the study. The patients were randomly assigned to one of four groups according to the therapeutic regimens: group I: Methotrexate (MTX) 15 mg/weekly + salazopyrin 2 g/daily; group II: MTX 15 mg/weekly + infliximab 3 mg/Kg at time 0, 2, 4 and every 8 weeks; group III: MTX 15 mg/weekly + etanercept 25 mg/twice weekly; group IV: MTX 15 mg/weekly + adalimumab 40 mg/every other week. SDAI and DAS28 were determined at baseline and after 6 months in each patient. Mean changes in SDAI values were compared to those detected in DAS 28 at baseline and after 6 months. RESULTS: SDAI and DAS 28 were found to be significantly correlated at baseline. Moreover, changes in SDAI over time paralleled those in DAS, and were found to be significantly correlated. CONCLUSIONS: SDAI is a valid measure of response to treatment in RA patients undergoing different therapeutic regimens.

Malesci D, La Montagna G, Valentini G. · U.O. di Reumatologia, Seconda Università degli studi di Napoli Via Pansini, 5 - 80131 Napoli, Italia. · Reumatismo. · Pubmed #16380749 links to  free full text

Abstract: Joint involvement occurs in thirds of SSc patients during the course of the disease, but may be the onset manifestation. Arthralgias, stiffness and tendon sheath involvement constitute the most common clinical findings affecting all joints, but predominantly the fingers, wrists and ankles. The most common radiographic abnormalities in SSc patients are subcutaneous calcinosis and digital tuft resorptions, which are frequently observed at the hands. Juxtaarticular demineralisation, joint space narrowing and erosions also occur and are diagnostic challenges with rheumatoid arthritis. Flexion deformities and tendon friction rubs are more common in dcSSc; arthritis/arthralgias and radiographic abnormalities similarly affect patients from each subset. A recent classification of radiological patterns (inflammatory, degenerative, periarticular fibrotic) pointed out a greater prevalence of the fibrotic pattern at the hands and degenerative pattern at the feet.

Cigliano L, Spagnuolo MS, Cuomo G, Valentini G, Niglio A, Abrescia P. · Dipartimento di Fisiologia Generale ed Ambientale, Università di Napoli Federico II, via Mezzocannone 8, Napoli-80134, Italia. · Life Sci. · Pubmed #15848223 No free full text.

Abstract: Growing evidence suggests that atherogenesis is associated with inflammation or defective removal of cholesterol excess from peripheral cells. Apolipoprotein A-I [ApoA-I] activates the enzyme Lecithin-Cholesterol Acyl-Transferase to esterify cell cholesterol for transport to liver. Haptoglobin [Hpt] was previously found able to bind ApoA-I, and suggested to reduce the enzyme activation. The aim of this study was to demonstrate that enhanced levels of Hpt, as present during inflammation, are associated with low enzyme activity and increased thickness of the arterial wall. Enzyme activity and Hpt concentration were analysed in patients with rheumatoid arthritis having the same plasma levels of antioxidants (ascorbate, urate, alpha-tocopherol, retinol) or oxidation markers (nitrotyrosine, lipoperoxide) of healthy subjects. Cholesterol esterification, determined as ratio of cholesteryl esters with cholesterol in high-density lipoproteins, was lower in patients than in controls, and negatively correlated with the intima-media wall thickness of the common carotid. The ratio of Hpt with ApoA-I was negatively correlated with the enzyme activity, while positively correlated with intima-media wall thickness. The results suggest that high Hpt levels might severely impair the enzyme activity, thus contributing to cholesterol accumulation in vascular cells, and lesion formation in the endothelium.

Cuomo G, Di Micco P, Niglio A, La Montagna G, Valentini G. · Unità Operativa di Reumatologia, Seconda Università degli Studi di Napoli, 80131 Naples. · Reumatismo. · Pubmed #15643478 links to  free full text

Abstract: OBJECTIVES: To investigate the intima-media thickness of the common carotid arteries (IMT-CCA) in patients with Rheumatoid Arthritis (RA), and its relationships with classical atherosclerosis risk factors and disease features i.e. duration, activity and disability. METHODS: 48 RA patients (35 F, 13 M; age ed 26-69 years median 55; disease duration 1-18 years, median 8), and 22 controls (16 F, 6 M; age 28-66, median 50) matched for classical atherosclerosis risk factors, i.e. age, sex, smoking, blood pressure, body mass index, diabetes, familiarity, and for postmenopausal status, were studied. IMT and plaques were measured in the left and right common carotid arteries. Serum total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apoliporotein AI, apolipoprotein B, and rheumatoid factor were determined in patients and controls. The DAS28, the HAQ-DI and disease duration were considered as clinical parameters reflecting disease status. RESULTS: The IMT-CCA (mean +/- SD) was significantly greater in the 48 RA patients than in the 22 controls subjects (1.00+/-0.25 vs. 0.78+/-0.21; p=0.0007). In the 70 subjects investigated CCA-IMT resulted to be significantly correlated with diastolic blood pressure, body mass index, triglyceride and RA status. In the 48 RA patients no correlation was detected with either disease duration or activity or disability. CONCLUSION: our study confirms an increased IMT in RA patients without any clinically evident manifestation of cardiovascular disease. It supports the existence of subclinical atherosclerosis in RA.

Saso L, Valentini G, Casini ML, Grippa E, Gatto MT, Leone MG, Silvestrini B. · Department of Pharmacology of Natural Substances and General Physiology, University of Rome La Sapienza, Italy. · Arch Pharm Res. · Pubmed #11339635 No free full text.

Abstract: The activity of nonsteroidal antiinflammatory drugs (NSAIDs) in rheumatoid arthritis is not only due to the inhibition of the production of prostaglandins, which can even have beneficial immunosuppressive effects in chronic inflammatory processes. Since we speculated that these drugs could also act by protecting endogenous proteins against denaturation, we evaluated their effect on heat-induced denaturation human serum albumin (HSA) in comparison with several fatty acids which are known to be potent stabilizers of this protein. By the Mizushimas assay and a recently developed HPLC assay, we observed that NSAIDs were slightly less active [EC50 to approximately 10(-5)-10(-4) M] than FA and that the HPLC method was less sensitive but more selective than the turbidimetric assay, i.e. it was capable of distinguishing true antiaggregant agents like FA and NSAIDs from substances capable of inhibiting the precipitation of denatured protein aggregates. In conclusion, this survey could be useful for the development of more effective agents in protein condensation diseases like rheumatic disorders, cataract and Alzheimers disease.

Riccieri V, Spadaro A, Saso L, Valentini G, Taccari E, Silvestrini B. · Department of Medical Therapy, Rheumatology Unit, University of Rome La Sapienza, Italy. · Clin Exp Rheumatol. · Pubmed #11247326 No free full text.

Abstract: OBJECTIVE: [corrected] To assess the possible correlations between the immune activation of certain surface antigens at the lip salivary gland (LSG) level, and changes in glycosylation of serum proteins in primary Sjögren's syndrome (SS). METHODS: LSG biopsy samples were obtained from 22 SS patients (mean age 56.3 years; mean disease duration 70.8 months) and prepared for immunohistochemical analysis using murine monoclonal antibodies for interleukin-2 receptor (IL-2R) (CD25) and for the class II major histocompatibility antigen HLA-DR. The glycosylation of serum proteins was evaluated in all patients by an enzyme-linked lectin assay (ELLA) using concanavalin A (Con A). RESULTS: In LSG specimens the presence of IL-2R was observed at the infiltrating level, mainly periductally, in 13 (59%) cases and on the epithelial cells of 14 (64%) patients. In 13 out of 22 SS patients (59%) a marked positivity both of the infiltrates and of the epithelium was found for anti-HLA-DR monoclonal antibody. The degree of expression of different antigens on LSG samples was correlated with their histologic class according to Tarpley evaluation. The positivity for IL-2R and HLA-DR molecules on glandular tissues was correlated. A significant increase in the total Con A reactivity of serum proteins was found in those patients expressing IL-2R and HLA-DR antigens on LSG specimens. CONCLUSIONS: The co-expression of IL-2R and HLA-DR antigens on both the epithelium and infiltrates of LSG is consistent with a participation of these cells in the immune process of SS. Moreover, changes in the glycosylation of serum proteins seem to be related to the presence of these immunoactivation markers of the disease at the LSG level, suggesting that the control of protein glycosylation could be mediated by the same mechanisms involved in the tissue damage of SS.

Saso L, Valentini G, Riccieri V, Spadaro A, Zoppini A, Silvestrini B. · Department of Pharmacology of Natural Substances and General Physiology, University of Rome La Sapienza, Italy. · IUBMB Life. · Pubmed #10632566 No free full text.

Abstract: A strong increase of the affinity for concanavalin A (Con A) of serum alpha 2-macroglobulin, a non-acute-phase protein, was observed by lectin blotting in patients with Sjögren's syndrome (SS). On the contrary, the total Con A reactivity of serum proteins, measured by enzyme-linked lectin assay, was not augmented in SS, compared with normal donors, probably because positive changes of certain proteins were balanced by negative changes of others, as suggested by lectin blotting analysis. However, a significant increase of total Con A reactivity occurred in subjects with increased serum concentrations of soluble interleukin (IL)-2 receptor, compared with patients with normal concentrations of this marker of disease activity. On the other hand, the same parameter did not appear to be different in patients with normal or increased serum concentrations of IL-6, indicating that this cytokine was not probably responsible for the changes of glycosylation described here.

Saso L, Valentini G, Mattei E, Panzironi C, Casini ML, Grippa E, Silvestrini B. · Department of Pharmacology of Natural Substances and General Physiology, University of Rome La Sapienza, Italy. · Arch Pharm Res. · Pubmed #10549576 No free full text.

Abstract: The mechanism of action of fish oil (FO), currently used in different chronic inflammatory conditions such as rheumatoid arthritis (RA), is not completely understood, although it is thought that it could alter the metabolism of endogenous autacoids. In addition, we hypothesized that the known capability of fatty acids (FA) of stabilizing serum albumin and perhaps other proteins, may be of pharmacological relevance considering that it is shared by other anti-rheumatic agents (e.g. nonsteroidal antiinflammatory drugs). Thus, we studied the effect of oral administration of FO and corn oil (CO), a vegetable oil with a different composition, on the stability of rat serum proteins, evaluated by a classical in vitro method based on heat-induced protein denaturation. FO, and, to a lower extent, CO inhibited heat-induced denaturation of rat serum (RS): based on the inhibitory activity (EC50) of the major fatty acids against heat-induced denaturation of RS in vitro, it was possible to speculate that in vivo effects of palmitic acid (C16:0) and eicosapentaenoic acid (EPA, C20:5, n-3) may be more relevant than that of linolenic acid (C18:2). To better investigate this phenomenon, we extracted albumin from the serum of animals treated or not with FO with a one-step affinity chromatography technique, obtaining high purity rat serum albumin preparations (RSA-CTRL and RSA-FO), as judged by SDS-PAGE with Coomassie blue staining. When these RSA preparations were heated at 70 degrees C for 30 min, it was noted that RSA-FO was much more stable than RSA-CTRL, presumably due to higher number of long chain fatty acids (FA) such as palmitic acid or EPA. In conclusion, we provided evidences that oral administration of FO in the rat stabilizes serum albumin, due to an increase in the number of protein bound long chain fatty acids (e.g. palmitic acid and EPA). We speculate that the stabilization of serum albumin and perhaps other proteins could prevent changes of antigenicity due to protein denaturation and glycosylation, which may trigger pathological autoimmune responses, suggesting that this action may be involved in the mode of action of FO in RA and other chronic inflammatory diseases.

Saso L, Valentini G, Casini ML, Mattei E, Braghiroli L, Mazzanti G, Panzironi C, Grippa E, Silvestrini B. · Institute of Pharmacology and Pharmacognosy, University La Sapienza, Rome, Italy. · Jpn J Pharmacol. · Pubmed #10082322 links to  free full text

Abstract: Natural hydrophobic substances like bile salts (cholate, deoxycholate, chenodeoxycholate, lithocholate and their conjugates with glycine and taurine), fatty acids (caprylic, capric, lauric, myristic, palmitic, stearic, oleic, linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acid) were much more active (EC50 approximately 10(-4)-10(-5) M) than selected amino acids (EC50 > 10(-2) M) and inorganic salts (EC50 approximately 10(-1) M) in inhibiting heat-induced denaturation of human serum albumin in vitro. Fish oil, rich in n-3-polyunsaturated acids such as eicosapentaenoic acid and docosahexaenoic acid, administered p.o. (1 ml/kg) in the rat, protected ex vivo (after 2 hr) serum against heat-induced denaturation more than bendazac, a known antidenaturant drug. Thus, we speculated that the antidenaturant activity of fish oil may be partly (in addition to the known effect on endogenous eicosanoid composition) responsible for its beneficial effects in rheumatoid arthritis and other rheumatic conditions. In this connection, it is of note that the in vitro antidenaturant activity of fish oil fatty acids was higher than that of known antidenaturant drugs such as bendazac and bindarit and nonsteroidal anti-inflammatory drugs like phenylbutazone and indomethacin which could exert beneficial effects in chronic inflammatory conditions by stabilizing endogenous proteins.

La Montagna G, Valentini G. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #15789900 No free full text.

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