Rheumatoid Arthritis: Tomietto P

Ferraccioli GF, Tomietto P, De Santis M. · Division of Rheumatology, Department of Internal Medicine and Geriatrics, Catholic University of the Sacred Heart, Complesso Integrato Columbus Via Moscati 31, 00168 Rome, Italy. · Ann N Y Acad Sci. · Pubmed #16127006 No free full text.

Abstract: T cells exert a fundamental role in different autoimmune chronic inflammatory diseases. The low-affinity autoreactive T cell clones provide the first amplification loop after the antigen (AgX) presentation, and if not counterregulated by the T regulatory cells (Treg), they maintain the inflammation and predispose to organ damage. Interrupting the T cell amplification loop through calcineurin antagonists leads to maintenance of the whole process under the autoimmune threshold.

Fabris M, Tolusso B, Gremese E, Tomietto P, Ferraccioli G. · Cattedra di Reumatologia, DPMSC, Università degli Studi di Udine. · Reumatismo. · Pubmed #15309217 links to  free full text

Abstract: OBJECTIVE: Given the role of TNF-alpha in Rheumatoid Arthritis (RA) we decided to define the characteristics of the TNF-alpha synthesis by peripheral blood mononuclear cells (PBMNCs) obtained from active-aggressive RA patients giving a particular attention to the modulation of the expression of two fundamental proteins in TNF-alpha mRNA stability regulation, Tristetraprolin (TTP) and HuR. METHODS: 11 RA patients with active disease were enrolled in the study before their entry in 2 double blind protocols: Infliximab versus MTX and Etanercept versus MTX. 9 healthy blood donors were taken as controls. PBMNCs obtained by Ficoll centrifugation and plastic adherence were stimulated with lipopolysaccharide (LPS) and TNF-alpha was measured in the supernatant during 8 hours by ELISA. At each time point the cells were harvested and analysed for TNF-alpha, TTP and HuR mRNA expression by semi-quantitative PCR. RESULTS: MNCs TNF-alpha secretion after LPS stimulation did not differ significantly between RA and control subjects, even if a tendency towards a more prompt response was observed in the patients. More importantly only the DMARDs responsive patients (DAS < 3.7 at the 6th month, with a minimal reduction of 1.2 points) disclosed precociously (at the first month) a significant change in the profile of TNF-alpha secretion and maintained it until the 6th month. The "normalization" of the synthetic behaviour was accompanied by the resetting in the regulation of the expression of the TTP, that appeared significantly different in the patients before and after therapy. CONCLUSIONS: Independently from the type of therapy, responsive patients demonstrate a rapid change in the cellular biology at the systemic level that might drive the resolution of the inflammatory process at the synovial level.

Ferraccioli GF, Gremese E, Tomietto P, Favret G, Damato R, Di Poi E. · Division of Rheumatology, Department of Internal Medicine, School of Medicine, DPMSC, University of Udine, 33100 Udine, Italy. · Rheumatology (Oxford). · Pubmed #12154206 links to  free full text

Abstract: OBJECTIVE: To evaluate two monotherapies followed by step-up combination therapy with two or three complementary drugs in active rheumatoid arthritis (RA) in comparison with sulphasalazine (SSZ) alone. METHODS: One hundred and twenty-six consecutive patients with early active RA were enrolled in this open controlled clinical trial. The primary end-point was 50% improvement according to the ACR criteria (ACR50) at 6, 12 or 18 months. The secondary end-points were a full response (Magnusson criteria) and/or remission (ACR criteria) at 3 yr. Methotrexate (MTX) (group 1), cyclosporin A (CsA) (group 2) or SSZ (group 3) was used first. After 6 months, a combination of two drugs (CsA and MTX) was employed in groups 1 and 2. SSZ was added after 12 months if improvement was less than ACR50 with the combination. Group 3 continued with SSZ alone. RESULTS: After 6 months, 57% of patients in group 1, 31% of group 2 (MTX vs CsA, P=0.002) and 33% of group 3 (MTX vs SSZ, P=0.01) had reached ACR50 improvement according to intention-to-treat analysis. At month 12 after starting a drug combination, 67% of group 1 and 76% of group 2 had reached ACR50 compared with 24% of group 3. At the 18-month follow-up, 90% of group 1 and 88% of group 2 but only 24% of group 3 had reached ACR50. After 18 months, 62% of group 1, 60% of group 2 and 48% of group 3 showed side-effects and three, five and eight patients in the three groups respectively had dropped out of the study. At the 3-yr follow-up, 9% of the patients in groups 1 and 2 and 7% of group 3 were in remission according to the ACR criteria; according to the Magnusson criteria, 40% showed a full response in groups 1 and 2 but only 21% did so in group 3. CONCLUSION: MTX appears to be the fastest-acting agent. A step-up approach with MTX plus CsA plus SSZ led to a 50% improvement according to the ACR criteria in most patients. After 3 yr, 40% of patients receiving combination therapy and 21% of patients receiving monotherapy showed a full response, while 9 and 7% respectively attained remission.

Tomietto P, Annese V, D'agostini S, Venturini P, La Torre G, De Vita S, Ferraccioli GF. · University of Udine, Udine, Italy. · Arthritis Rheum. · Pubmed #18050188 links to  free full text

Abstract: OBJECTIVE: To determine factors affecting the severity of cognitive impairment in systemic lupus erythematosus (SLE) and to analyze its anatomic location. METHODS: Fifteen cognitive functions grouped into 8 domains were evaluated in 52 patients with SLE and 20 with rheumatoid arthritis. Patients were classified according to severity of impairment as normal, mild, or moderate/severe. Multivariate analysis was performed to identify the main factors affecting severity of cognitive deficits. The most likely anatomic site of damage according to neuropsychological performance was compared with the lesion's location on magnetic resonance imaging (MRI). RESULTS: In SLE patients, a stepwise regression analysis showed that the number of impaired functions (dependent variable) was associated with antiphospholipid antibody positivity (aPL+; P = 0.04), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI; P = 0.001), hypertension (P = 0.032), and was inversely related to educational level (P = 0.021). Including MRI, the number of impaired functions was associated with severity of MRI (P < 0.001), the SDI (P = 0.013), and the presence of Raynaud's phenomenon (P = 0.04). The contemporary presence of aPL+ and Raynaud's phenomenon resulted in a higher probability to develop moderate/severe cognitive deficits (P = 0.015). Two logistic multiple regression analyses identified hypertension (P < 0.05), the SDI (P < 0.01), and moderate/severe MRI findings as main predictors of moderate/severe impairment (dependent variable). The damage site hypothesized through neuropsychological testing corresponded with MRI findings in 71.7% of SLE patients K = 0.42, P = 0.005). CONCLUSION: Hypertension, aPL+, accumulated damage, and MRI lesions are the main factors affecting severity of cognitive impairment in SLE. The hypothesized sites of central nervous system involvement according to neuropsychological testing correlated with MRI findings in most patients.

Annese V, Tomietto P, Venturini P, D'Agostini S, Ferraccioli G. · Cattedra di Reumatologia, Università Cattolica di Roma · Reumatismo. · Pubmed #16639488 links to  free full text

Abstract: OBJECTIVES: To determine the role of antiphospholipid antibodies (aPL) and of Raynaud's phenomenon (RP) in the development of migraine in patients with systemic lupus erythematosus (SLE). METHODS: 50 unselected SLE patients and 20 rheumatoid arthritis (RA) controls underwent an interview to define the presence of migraine according to the guidelines of the International Headache Society (1988). Serological tests for aPL were performed in all patients. SLE patients were divided according to positivity for RP and/or aPL into 4 subsets: R-/aPL-, R-/aPL+, R+/aPL- and R+/aPL+. Data were analysed using Fisher's exact test, Chi-square test and U Mann-Whitney test. RESULTS: SLE and RA patients were similar for demographic and clinical features; aPL positivity was found in a greater proportion of SLE patients versus RA controls (68% vs 25%, p=0.0036). 31 of the 50 lupic patients (62%) and 7 of the 20 RA controls (35%) suffered from migraine (OR=3, CI:1-8.9). Among SLE and RA patients, migraine was associated with aPL positivity (p=0.027 and p=0.019). Analysing the combined effect of aPL and RP on migraine, in R+/aPL+ patients we detected an higher frequency of migraine (85.7%) with respect to the patients negative for these two features (27%, p=0.0051, OR=16, CI:2.2-118) and to the patients positive only for aPL (65%, p=0.0031, OR=6.2, CI:1.2-32). CONCLUSIONS: Migraine in SLE and RA associates with aPL positivity. The simultaneous presence of RP increases by 2,5 times the probability of having migraine, suggesting that cerebral vasospasm might be more common in patients with peripheral vasospasm, given the presence of aPL.

Fabris M, Tolusso B, Di Poi E, Tomietto P, Sacco S, Gremese E, Ferraccioli G. · Department of Rheumatology, Universita' Cattolica del Sacro Cuore School of Medicine, Rome, Italy. · J Rheumatol. · Pubmed #15940758 No free full text.

Abstract: OBJECTIVE: To analyze tumor necrosis factor-alpha (TNF-alpha) synthesis by mononuclear cells stimulated with lipopolysaccharide (LPS) in patients with rheumatoid arthritis (RA). METHODS: TNF-alpha molecular expression and extracellular release were assessed in the peripheral blood mononuclear cells (PBMC) of 27 RA patients and 16 healthy blood donor controls during 8 hours of LPS stimulation. We also analyzed the mRNA expression of tristetraprolin (TTP), the major TNF-alpha mRNA destabilizing factor. TNF receptor p75 (TNFR 2) plasma concentrations were also tested in all patients. RESULTS: Controls and patients demonstrated a comparable wide range of TNF-alpha release capability, but patients achieved the peak value of protein release more quickly. Defining the median TNF-alpha release in controls as the cutoff value to distinguish high and low LPS-induced TNF-alpha-releasing phenotypes, patients with early RA (disease duration < 1 yr) belonged mainly to the low TNF-alpha producer subgroup, whereas patients with long-standing RA (> 1 yr) were prevalently high TNF-alpha producers. TTP molecular expression was higher in patients with shorter, than in patients with longer, disease duration. The profile of TNF-alpha release in patients with early RA changed significantly when retested after 6 months of therapy, while patients with long-standing disease maintained the same behavior as at baseline. Finally, a baseline low TNF-alpha-producer phenotype predisposed to a better responsiveness to disease modifying antirheumatic drugs. CONCLUSION: The LPS-induced TNF-alpha-releasing phenotype differs between cells obtained from RA patients with different disease durations and seems to influence the therapeutic outcome.

Tolusso B, Sacco S, Gremese E, La Torre G, Tomietto P, Ferraccioli GF. · Division of Rheumatology, UCSC, Catholic University of Rome, Rome, Italy. · Hum Immunol. · Pubmed #15603867 No free full text.

Abstract: OBJECTIVE: To assess the relationship between tumor necrosis factor receptor II (TNF-RII) gene polymorphisms and sTNFRII plasma levels in healthy blood donors (HBDs) and in rheumatoid arthritis (RA) patients. 113 HBDs and 49 RA patients were genotyped for the T/G polymorphism in exon 6 of the TNF-RII gene. In the same cases, sTNF-RII plasma levels were determined by an enzyme-linked immunosorbent assay (ELISA) procedure. sTNF-RII levels were higher in RA patients than in HBDs (p < 0.0001). No difference in sTNF-RII levels arose between RA patients on low oral doses of glucocorticoids versus those not taking glucocorticoids. In healthy controls, we observed lower levels of the sTNF-RII in carriers of the TT genotype compared to TG/GG genotype (p = 0.04). In RA there was the same behaviour between TT and TG/GG carriers, even though the difference was not statistically significant. When analyzing the correlation between sTNF-RII plasma levels and disease activity parameters, significant correlations were seen with disease activity score (r = 0.40, p = 0.01), swollen joint count (r = 0.38, p = 0.01), and tender joint count (r = 0.42, p = 0.01), but not with erythrocyte sedimentation rate (r = 0.22, p = ns) nor with C-reactive protein (r = 0.14, p = NS). The correlation remained significant only in the RA subgroup carrying the TT genotype. Healthy donors carrying the TT genotype showed lower sTNF-RII plasma levels than carriers of the TG/GG genotypes, while in RA patients we observed only a trend.

Tolusso B, Fabris M, Di Poi E, Assaloni R, Tomietto P, Ferraccioli GF. · No affiliation provided · Ann Rheum Dis. · Pubmed #12594130 links to  free full text

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