Rheumatoid Arthritis: Gremese E

Gremese E, Ferraccioli GF. · Division of Rheumatology, Catholic University of the Sacred Heart, School of Medicine, CIC-Via Moscati 31, 00168 Rome, Italy. · Clin Exp Rheumatol. · Pubmed #15552522 No free full text.

Abstract: Combination therapy has emerged as a crucial therapeutic tool to control aggressive rheumatoid arthritis (RA). Cyclosporine (CsA) when combined with methotrexate (MTX) has shown substantial benefit in clinical practice. The primary benefit is its positive effect in the control of joint-bone erosions. The most feared adverse effect is the development of nephrotoxicity, which may be in part hemodynamic and in part structural, i.e. fibrotic. Careful monitoring of concomitant drugs, hypertension and through blood levels should allow the patient to maintain normal renal function. The successful employment of CsA in lupus nephritis clearly supports this statement.

Ferraccioli G, Gremese E. · Division of Rheumatology, DPMSC, School of Medicine, University of Udine, Udine 33100, Italy. · Autoimmun Rev. · Pubmed #15246021 No free full text.

Abstract: Rheumatoid arthritis is a disease at high cardiovascular risk. It has recently been shown that RA patients with more than 10 years disease duration present a risk of myocardial infarction more than three times higher than osteoarthritis controls. The major determinant is thought to be the chronic inflammatory process, driven by some key cytokines among which TNF alpha is thought to play the leading role in the majority of the patients. TNFalpha, therefore, once blocked by specific inhibitors like TNF alpha blockers (Infliximab, Etanercept) should profoundly decrease the cardiovascular risk. However, TNF blockers induce the appearance of autoimmunity though in a small minority of the patients. This autoimmunity is thought to be due to the poor clearance of apoptotic bodies once the systemic inflammation (CRP, SAP) is controlled by the specific blockers, and to the lack of control of some B cell populations producing autoantibodies to specific autoantigens. Among the autoantibodies arising during TNF blockade, anticardiolipin appear to be the most crucial with respect to the cardiovascular risk. The appearance of anticardiolipins at clinically significant levels appears to be driven by two possible mechanisms, one due to common infections of the urinary or upper airways tract during blockade of soluble TNF alpha, the other due to the escape of some autoreactive B cells during blockade of soluble and membranous TNF alpha. Since both autoantibodies related to infections as well as the high levels unrelated to infections, can be well controlled by appropriate therapies, clinicians should pay attention to the biological phenomenon before it becomes a clinical problem.

De Vita S, De Marchi G, Sacco S, Gremese E, Fabris M, Ferraccioli G. · Division of Rheumatology, DPMSC, University of Udine, Italy. · Blood Cells Mol Dis. · Pubmed #11778660 No free full text.

Abstract: A classification of nonmalignant lymphoproliferation in Sjögren's syndrome is presented, based on the results of international meetings regarding Sjögren's syndrome-associated lymphomagenesis and on our results of a clinico-pathologic and molecular study and long-term follow-up in well-characterized patients. Sjögren's syndrome pathobiology has similarities to hepatitis C virus-related B-cell lymphoproliferation. Antigen stimulation with the preferential expansion of rheumatoid factor-positive clones and specific immunoglobulin gene expression and recombination represent key biologic events in lymphoproliferation. This classification is based on the coupling of molecular and histological studies and may result in more selective treatment approaches.

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, Assaloni R, Di Poi E, Gremese E, De Marchi G, Fabris M. · Division of Rheumatology, Dipartimento Patologia Medicina Sperimentale e Clinica, School of Medicine, University of Udine, Italy. · Rheumatology (Oxford). · Pubmed #12364628 links to  free full text

Abstract: OBJECTIVE: To assess the possible clinical and biological rescue of rheumatoid arthritis (RA) in 16 patients who were still active despite intensive combination therapy after receiving infliximab following the Anti-Tumour necrosis factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) schedule. METHODS: Sixteen patients who were still active despite combination therapy with optimal doses of methotrexate (MTX 15-17.5 mg/week) and cyclosporin A (CsA 2.5-3.5 mg/day) received infliximab. Ten received their combination plus infliximab (Combi), and six received infliximab plus MTX alone (Mono). The follow-up was carried out for 30 weeks in all patients and for 46 weeks in eight. Efficacy and safety were examined. RESULTS: At entry, the mean disease activity score (DAS) was 5.6 (all patients had a DAS >3.7). After therapy, eight of 10 patients in Combi and four out of six in Mono showed an improvement of >50% in the initial swollen joint count, yet only one patient reached 50% improvement in the initial DAS after 30 weeks, and one patient had a DAS <2.4 (low disease activity). Of the eight patients who reached 46 weeks of follow-up, three showed an improvement in DAS of 50% and two had a DAS <2.4. When considering the change over time, the difference between DAS at entry and at week 30 was statistically significant only in patients receiving MTX plus CsA, while it was not significant in those receiving MTX only. Two patients developed recurrent febrile upper respiratory infections in the Combi therapy group, while two had a single febrile infection in the MTX alone group. Two patients became strongly anti-cardiolipin positive (IgM >40 MPL) and one developed a coronary syndrome. CONCLUSION: Infliximab can be added incrementally to MTX plus CsA, with favourable results in terms of efficacy and safety over time in severe rapidly aggressive and progressive RA. Finally, minor evidence emerged for a stronger efficacy of the Combi treatment compared with Mono.

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.

Tolusso B, De Santis M, Bosello S, Gremese E, Gobessi S, Cuoghi I, Totaro MC, Bigotti G, Rumi C, Efremov DG, Ferraccioli G. · Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy. · Clin Immunol. · Pubmed #19136305 No free full text.

Abstract: B cells have acquired an important role in the pathogenesis of rheumatoid arthritis (RA) since B cell depletion allowed to rescue patients poorly responders to TNFalpha blockers. This study focused on the involvement of ZAP-70 as a bio-marker of B cells immune activation in RA. ZAP-70 expression in synovial fluid (SF) B cells obtained from RA patients was increased compared to SF B cells of osteoarthritis (OA) patients. Moreover we found that ZAP-70 positive/CD38 positive and ZAP-70 positive/CD5 positive B cells were enriched in SF. The analysis of B cell apoptosis in vitro showed that the percentage of ZAP-70 negative B cells spontaneously undergoing apoptosis was significantly higher than ZAP-70 positive B cells. The ZAP-70 positive B cell ratio (SF/peripheral blood (PB)) showed a positive correlation with SF autoantibody levels and with local levels of BAFF and IL6. ZAP-70 positive B cells seem to define a subset characterized by increased survival and high relationship with local inflammation and autoimmunity.

Tolusso B, Frezza D, Mattioli C, Fedele AL, Bosello S, Faustini F, Peluso G, Giambra V, Pietrapertosa D, Morelli A, Gremese E, De Santis M, Ferraccioli GF. · Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy. · Ann Rheum Dis. · Pubmed #18952640 links to  free full text

Abstract: OBJECTIVE: To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker for rheumatoid arthritis (RA) and to define the possible association with autoantibody positivity and clinical outcome. METHODS: Genomic DNA was obtained from two cohorts of patients with RA (100 with early RA (ERA) and 114 with longstanding RA (LSRA)) and from 248 gender-matched controls from the same geographical area. Clinical and immunological characteristics were recorded for all the patients. RESULTS: The percentage of the 2/2 genotype was higher in patients with ERA (27.0%), and in patients with LSRA (34.2%), than in controls (14.9%) (ERA: OR = 2.11 (95% CI 1.20 to 3.70) vs controls; LSRA: OR = 2.96 (95% CI 1.76 to 5.00) vs controls). A lower representation of allele *3 was present in patients with ERA (2.0%) than in controls (6.0%; OR = 0.32 (95% CI 0.11 to 0.91)). No significant associations were found between polymorphisms and autoantibodies positivity. CONCLUSION: The HS1,2A allele *2 associates with early and longstanding RA.

Tolusso B, Pietrapertosa D, Morelli A, De Santis M, Gremese E, Farina G, Carniello SG, Del Frate M, Ferraccioli G. · UCSC-Catholic University of Rome, Division of Rheumatology, 00168 Rome, Italy. · Pharmacogenomics. · Pubmed #16886894 No free full text.

Abstract: OBJECTIVES: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibility to, and severity of, rheumatoid arthritis (RA) patients, comparing them with the genotype distribution in healthy controls. Also, to assess the influence of IL1-B and IL1RN gene polymorphism on IL-1beta/IL-1Ra plasma levels and response to therapy. PATIENTS AND METHODS: We tested the allelic distribution of IL-1B (-511 and +3953) and IL-1RN (variable number of tandem repeats) gene polymorphism in 126 RA patients and 178 healthy blood donors (HBDs). The patients were categorized into two subgroups in relation to the response to methotrexate (MTX) therapy. Group A included 70 RA patients in stable partial remission after 6 months of MTX treatment (MTX-R). Group B included 56 RA patients with active disease despite MTX therapy. This group received antitumor necrosis factor (TNF) biological drugs and were defined MTX-nonresponders (MTX-NR). RESULTS: None of the two IL-1B (-511 and +3953) gene polymorphisms were significantly different in frequency between RA patients and healthy controls. We observed an increased frequency of the rare allele IL1RN*3 in RA patients with active disease, not responding to MTX therapy (MTX-NR) (4.5%) vs MTX-R (3.6%) and healthy controls (0.8%). Interestingly, RA patients whose genotypes included the IL1RN*long allele (haplotype long-C-T) showed the worse response to MTX. HBDs harboring the IL1RN*2/2 genotype showed significantly lower levels of plasma IL1-Ra, but comparable levels of IL-1beta with regard to subjects with the presence of the IL1RN* long allele. Furthermore, the presence of the TT IL-1B +3953 genotype was associated with lower plasma levels of IL1-Ra, both in HBDs and in RA patients. Carriers of the IL1RN*2 allele responded better to infliximab therapy. CONCLUSIONS: The results of this study provide evidence of an association between the IL1RN*long allele and RA, the strongest association being observed in RA patients with an aggressive disease resistant to MTX treatment.

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.

Ferraccioli GF, Gremese E. · Division of Rheumatology, Post-Graduate School of Rheumatology, Catholic University School of Medicine, Rome, Italy. · Ann Rheum Dis. · Pubmed #15028556 links to  free full text

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Baraldo M, Ferraccioli G, Pea F, Gremese E, Furlanut M. · Chair of Pharmacology, DPMSC, School of Medicine, University of Udine, Italy. · Pharmacol Res. · Pubmed #10660945 No free full text.

Abstract: To evaluate the effects of a 6-month methotrexate (MTX) treatment period on cyclosporine A (CsA) pharmacokinetics were subsequently added in patients with rheumatoid arthritis (RA) in comparison with patients treated with CsA only, CsA was administered to 30 subjects with RA (group A) treated with MTX (10 mg week-1 i.m.) for 6 months and to 30 patients (group B) who received no MTX treatment. The mean doses +/- SD of CsA used in groups A and B were 3.2 +/- 0.5 and 3.3 +/- 0.4 mg kg-1, respectively. CsA levels were determined in whole blood by means of a fluorescence polarization immunoassay (FPIA) method with a specific monoclonal antibody. The following pharmacokinetics parameters were calculated: area under the curve from 0 to 24 h (AUC0-24), half-life of the elimination phase (T1/2 beta), total body clearance CL.F-1; V.F-1 and apparent volume of distribution (Vd beta). The mean blood concentrations and the pharmacokinetic parameters calculated in group A did not present significant statistical differences in comparison to group B. In conclusion, a 6-month MTX therapy does not produce liver function modifications to such an extent as to modify the pharmacokinetics of CsA subsequently added. Therefore, from a clinical pharmacological point of view, an MTX-CsA cotreatment appears feasible.