Rheumatoid Arthritis: Giacomelli R

Giacomelli R, Cipriani P, Matucci Cerinic M, Fulminis A, Barattelli G, Pingiotti E, Di Franco M, Trotta A, Perricone R, Zazzeroni F, Alesse E, Tonietti G. · Clinica Medica, University of L'Aquila, Italy. · Clin Exp Rheumatol. · Pubmed #12102473 No free full text.

Abstract: OBJECTIVE: To evaluate the ability of two different combination therapies with prednisone (PDN), methotrexate (MTX) and cyclosporine (CSA) to modulate both TNFalpha transcription and production in early rheumatoid arthritis (RA). METHODS: 24 patients with early RA received a step-down bridge therapy with MTX and PDN (group A). Twelve patients out of the 24 randomly received also CSA (group B). Blood samples and peripheral blood mononuclear cells (PBMC) were collected at different times. TNFalpha levels were measured both in sera and in PBMC supernatants. TNFalpha mRNA was assessed by use of RT-PCR. RESULTS: 10 patients in group A and 9 in group B improved. At baseline, RA patients serum TNFalpha levels were increased compared to controls (p < 0.001) and did not correlate with clinical and serological parameters. These levels decreased within the first month of therapy in both groups, the lower levels being observed in the sera of CSA treated patients. After 30 days of therapy, TNFalpha levels in group B supernatants were significantly lower than those observed in group A, both after 24 and 48 hours of PHA stimulation (p < 0.03 and p < 0.05 respectively). TNFalpha mRNA levels never differed between patients and controls, independently of both the clinical picture and the assigned therapy. CONCLUSION: The addition of CSA to a treatment regimen of PDN + MTX lowers TNFalpha production in vitro without decreasing TNFalpha mRNA expression. This effect could help to induce early immunosoppressive and therapeutic effects during RA.

Pingiotti E, Cipriani P, Marrelli A, Liakouli V, Fratini S, Penco M, Giacomelli R. · Department of Internal Medicine and Public Health, University of L'Aquila, Via Vetoio, Coppito, L'Aquila 67100, Italy. · Ann N Y Acad Sci. · Pubmed #17804530 No free full text.

Abstract: Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis. Fractalkine, a CX3C/chemokine (CX3CL1), mediates monocytes-macrophage infiltration in activated endothelium, suggesting its specific role in atherosclerosis-related inflammation. In this study, we evaluate the following in early RA patients: the expression of fractalkine receptor (CX3CR1) on CD4+/CD28- T cells, a subset involved in atherosclerotic infiltration; the correlation between this subset and validated markers of early atherosclerosis. CD4+ T cells were isolated by immunomagnetics beads in 50 early RA patients and 26 healthy controls (HC). After isolation, CD4+/CD28-/CX3CR1+ T lymphocytes were assessed by FACS analysis. Endothelial dysfunction was evaluated by both carotid intima-media thickness (IMT) and flow-mediated vasodilation (FMV). We observed: a higher expansion of CD4+/CD28- subset in RA patients when compared to HC (7.7%, 5.15-9.7 vs. 0.7%, 0.2-1.5, P < 0.01; respectively); this expansion directly correlated with increased IMT (0.91 mm, 0.5-1.3 vs. 0.7 mm, 0.2-1, P < 0.01; RA vs. C, respectively) and inversely correlated with FMV (3.5%, 1.7-7 vs. 9%, 3.5-11, P < 0.01; RA vs. C, respectively); the large majority of CD4+/CD28-, in RA, coexpressed CX3CR1 (93%, 67-99 vs. 30%, 10-48, P < 0.01; RA vs. C, respectively); this expansion significantly correlated with both the parameters of premature vascular damage and DAS 28. Our data suggest that CX3CL1/CX3CR1 axis might play a role in the induction and development of the endothelial dysfunction during RA.

Priori R, Medda E, Conti F, Cassarà EA, Sabbadini MG, Antonioli CM, Gerli R, Danieli MG, Giacomelli R, Pietrogrande M, Valesini G, Stazi MA. · Cattedra di Reumatologia, Dipartimento di Clinica e Terapia Medica, Università di Roma, Rome, Italy. · Clin Exp Rheumatol. · Pubmed #17631733 No free full text.

Abstract: OBJECTIVE: The aim of this study was to investigate potential risk factors for Sjögren's syndrome (SS) by means of a multi-centre case-control study, focusing in particular on familial and environmental risk factors. 140 female SS patients and 109 female controls with orthopaedic problems were consecutively enrolled in seven university hospitals in Italy. METHODS: Information regarding the patient's lifestyle, her medical, menstrual and pregnancy history, and any family history of autoimmune diseases (AD) was obtained through a detailed structured questionnaire. The odds ratio (OR) and 95% confidence interval (95%CI) were calculated using unconditional logistic regression, adjusting for age and family size. The probability of first-degree relatives developing an autoimmune disease was also investigated. RESULTS: A positive family history of AD was significantly associated with SS. Subjects with a first-degree relative (FDR) with AD showed a seven-fold increase in the risk for SS compared to controls (OR=7.4, 95%CI 2.8-20.1); the strength of this association increased with the number of relatives affected. Similarly, the FDR of SS patients had a higher risk of AD in comparison to subjects without FDR affected by SS. Women with one or more pregnancies had an increased risk of SS (OR=2.1, 95%CI 1.0-4.3). CONCLUSION: This study suggests that a family history of AD is associated with SS.

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.

Cinelli M, Guiducci S, Del Rosso A, Pignone A, Del Rosso M, Fibbi G, Serratì S, Gabrielli A, Giacomelli R, Piccardi N, Matucci Cerinic M. · Department of Medicine and Surgery, Division of Medicine and Rheumatology, AOUC, University of Florence, Italy. · Scand J Rheumatol. · Pubmed #17062432 No free full text.

Abstract: BACKGROUND: In rheumatoid arthritis (RA), hypertrophy of the synovial membrane generates a tumour-like pannus that invades the joint cavity and erodes cartilage and bone. Invasion of the extracellular matrix (ECM) is accompanied by angiogenesis, in which vascular endothelial growth factor (VEGF) and tissue inhibitors of metalloproteinases (TIMPs), produced by synoviocytes lining the pannus, have a primary role. Piascledine (PSD) is used in the treatment of osteoarthritis and has anti-inflammatory effects in vitro. OBJECTIVE: To study the effects of PSD on levels of VEGF and TIMP-1 and chemoinvasion in RA synoviocytes and healthy controls. METHODS: The effects of PSD 5, 10, and 20 microg/mL were evaluated, with/without interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNFalpha) 20 ng/mL, on synoviocytes. The levels of VEGF and TIMP-1 were assayed in the culture medium by enzyme-linked immunosorbent assay (ELISA). Chemoinvasion was measured by the Boyden chamber invasion assay. RESULTS: RA synoviocytes treated with PSD showed, compared to basal, lower levels of VEGF (41080+/-830 vs. 79210+/-920 pg/106 cells, p<0.001) and increased levels of TIMP-1 (23540+/-93.2 vs. 12860+/-42.9 ng/106 cells, p<0.001). PSD decreased dose-dependently IL-1beta and TNFalpha induced migration. CONCLUSIONS: In RA synoviocytes, and also to a lesser extent in control cells, PSD modulates VEGF and TIMP-1 and decreases chemoinvasion. PSD might have a role in the treatment of RA synovitis controlling invasiveness.

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.

Guiducci S, Del Rosso A, Cinelli M, Perfetto F, Livi R, Rossi A, Gabrielli A, Giacomelli R, Iori N, Fibbi G, Del Rosso M, Cerinic MM. · Division of Rheumatology, Department of Internal Medicine, University of Florence, Florence, Italy. · Arthritis Res Ther. · Pubmed #16277677 links to  free full text

Abstract: Extracellular fibrinolysis, controlled by the membrane-bound fibrinolytic system, is involved in cartilage damage and rheumatoid arthritis (RA) synovitis. Estrogen status and metabolism seem to be impaired in RA, and synoviocytes show receptors for estrogens. Our aims in this study were to evaluate in healthy and RA synoviocytes the effects of Raloxifene (RAL), a selective estrogen receptor modulator (SERM), on: proliferation; the components of the fibrinolytic system; and chemoinvasion. The effects of RAL were studied in vitro on synoviocytes from four RA patients and four controls. Proliferation was evaluated as cell number increase, and synoviocytes were treated with 0.5 microM and 1 microM RAL with and without urokinase-plasminogen activator (u-PA) and anti-u-PA/anti-u-PA receptor (u-PAR) antibodies. Fibrinolytic system components (u-PA, u-PAR and plasminogen activator inhibitor (PAI)-1) were assayed by ELISA with cells treated with 0.5 microM and 1 microM RAL for 48 h. u-PA activity was evaluated by zymography and a direct fibrinolytic assay. U-PAR/cell and its saturation were studied by radioiodination of u-PA and a u-PA binding assay. Chemoinvasion was measured using the Boyden chamber invasion assay. u-PA induced proliferation of RA synoviocytes was blocked by RAL (p < 0.05) and antagonized by antibodies alone. The inhibitory effect of RAL was not additive with u-PA/u-PAR antagonism. RA synoviocytes treated with RAL showed, compared to basal, higher levels of PAI-1 (10.75 +/- 0.26 versus 5.5 +/- 0.1 microg/10(6) cells, respectively; p < 0.01), lower levels of u-PA (1.04 +/- 0.05 versus 3.1 +/- 0.4 ng/10(6) cells, respectively; p < 0.001), and lower levels of u-PAR (11.28 +/- 0.22 versus 23.6 +/- 0.1 ng/10(6) cells, respectively; p < 0.001). RAL also significantly inhibited u-PA-induced migration. Similar effects were also shown, at least partially, in controls. RAL exerts anti-proliferative and anti-invasive effects on synoviocytes, mainly modulating u-PAR and, to a lesser extent, u-PA and PAI-1 levels, and inhibiting cell migration and proliferation.

Del Rosso A, Cinelli M, Guiducci S, Pignone A, Fibbi G, Margheri F, Gabrielli A, Giacomelli R, Coppini A, Del Rosso M, Matucci Cerinic M. · Department of Internal Medicine, Division of Rheumatology, University of Florence, Viale Pieraccini 18, 50139 Firenze, Italy. · Rheumatology (Oxford). · Pubmed #15998634 links to  free full text

Abstract: OBJECTIVE: Extracellular fibrinolysis, controlled by the cell-associated fibrinolytic system (urokinase plasminogen activator, uPA; uPA receptor, uPAR; plasminogen activator inhibitor type-1, PAI-1), is involved in cartilage damage generation and in rheumatoid arthritis (RA) synovitis. Since steroids reduce the rate of radiological progression of RA, we planned to evaluate in healthy and RA synoviocytes the effects of the steroid deflazacort on uPA, uPAR and PAI-1 expression, and subsequent phenotypic modifications in terms of uPA/uPAR-dependent invasion and proliferation. METHODS: uPA, uPAR and PAI-1 levels were studied by ELISA, RT-PCR (uPAR) and zymography (uPA) in synoviocytes from four RA patients and four healthy controls. Chemoinvasion was assessed by the Boyden chamber invasion assay, using Matrigel as the invasion substrate. Proliferation was evaluated by cell counting. Both invasion and proliferation were measured upon treatment with deflazacort 5 muM with or without parallel stimulation with uPA 500 ng/ml or in the presence of monoclonal anti-uPA and anti-uPAR antibodies. RESULTS: Invasion and proliferation of RA synoviocytes require a proper functional balance of the fibrinolytic system. Both deflazacort and monoclonal antibodies against uPA and uPAR reduced expression and activity of the system, thus inhibiting invasion and proliferation. In RA synoviocytes, deflazacort induced higher PAI-1 and lower uPA and uPAR levels, as well as a decrease in uPA enzymatic activity. The levels of uPAR mRNA were concomitantly reduced, as was uPA-induced chemoinvasion. All these effects were also shown in controls, though to a lesser extent. CONCLUSIONS: Deflazacort might control RA synovial proliferation and invasion by differential modulation of single members of the fibrinolytic system.

Giacomelli R, Matucci-Cerinic M, Bombardieri S. · Internal Medicine, University of L'Aquila, School of Medicine, Italy. · Ann Rheum Dis. · Pubmed #12429531 links to  free full text

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Giacomelli R, Passacantando A, Perricone R, Parzanese I, Rascente M, Minisola G, Tonietti G. · Clinica Medica, Department of Internal Medicine, University of L'Aquila, via Vetoio, 67100 L'Aquila, Italy. · Clin Exp Rheumatol. · Pubmed #11407087 No free full text.

Abstract: OBJECTIVE: To assess the percentage of T lymphocytes, bearing CD134, a member of the TNF receptor superfamily, primarily found on autoreactive CD4+ T cells in the peripheral blood (PB) and synovial fluid (SF) of rheumatoid arthritis (RA) patients. METHODS: The surface expression of CD134 on SF and PB mononuclear cells was performed by flow cytometry in 25 RA patients and correlated to the disease activity. RESULTS: CD134 expression on CD3+, CD4+, CD8+ and CD25+ cells was higher in SF than in PB of RA patients (P < 0.001). No differences were observed in the percentage of CD134+/CD4+ T lymphocytes in the PB of RA patients and controls. Patients with active RA had significantly higher percentage of CD3+/CD134+, CD4+/CD 134+, CD8+/CD134+ and CD25+/CD 134+ than those with inactive disease. CONCLUSION: These findings suggest that CD134+ T cells are involved in the immunopathological process of RA synovitis, maybe mirroring some other autoimmune disease in which autoreactive T cell infiltrating the target tissues largely coexpress CD134.

Gerli R, Bistoni O, Lunardi C, Giacomelli R, Tomassini C, Biagini P, Pitzalis C. · Department of Clinical and Experimental Medicine, Section of Internal Medicine and Oncological Sciences, Centre for the Study of Rheumatic Diseases, University of Perugia, Italy. · Rheumatology (Oxford). · Pubmed #10587561 links to  free full text

Abstract: OBJECTIVE: To evaluate whether serum levels of the soluble form of CD30 (sCD30) correlate with disease activity in early rheumatoid arthritis (RA) and may have prognostic value in predicting the response to disease-modifying anti-rheumatic drugs (DMARDs). METHODS: The levels of sCD30 and C-reactive protein (CRP) were measured in the serum of 14 untreated subjects with early RA, before and during treatment with hydroxychloroquine, for a follow-up period of 8 months. At the end of the study, patients were also evaluated for their response to DMARDs. RESULTS: An inverse correlation between sCD30 and CRP serum values was demonstrated at baseline, but not during the follow-up. Patients who responded to DMARD therapy had higher sCD30 basal levels than non-responders. CONCLUSIONS: The evaluation of sCD30 serum levels in early RA may reflect the attempt by CD30+ T cells to downmodulate inflammation and may be a useful marker to predict a good response to DMARDs.

Gerli R, Caligaris-Cappio F, Bistoni O, Bertero MT, Giacomelli R, Falini B. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #10410280 No free full text.

This publication has no abstract.