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INIZIO_TESTO_DA_INDICIZZARE

RESEARCH PROGRAM

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Keywords
REUMATOLOGY; RHEUMATOID ARTHRITIS; AUTOANTIBODIES; RHEUMATOID FACTORS; ANTI-CCP; COMP; GENES; HLA; APOPTOSIS

STUDIES ON GENETIC AND IMMUNOLOGIC FACTORS MODULATING THE TISSUE DAMAGE AND THE CLINICAL COURSE IN RHEUMATOID ARTHRITIS PATIENTS.

Università degli Studi di Roma "La Sapienza"
Abstract
Rheumatoid arthritis (RA) is a systemic, immunologically mediated disease that results in inflammation of multiple joints, often leading to irreversible joint damage, deformity, and disability.
The disease may have various outcome: self-limiting, persistent nonerosive, and persistent erosive arthritis; the need for prognostic markers able to predict the evolution of the disease is largely noticed.
Such a need is even more heavy because new drugs very active are now available and the efficacy of these drugs is linked to high cost and risk of severe side effects.
The aim of this research project is to study the prevalence of a few genetic markers in Italian RA patients, their putative correlation with serological markers and to evaluate if they may represents markers of evolution of the disease, or of outcome of the therapy.
More than 500 RA patients represent the study population; they have been previously included in a register of subject treated with anti-TNF biological product (Progetto ANTARES) and attend the Division of Rheumatology of three University Hospital ( Roma, Siena and Padova).
Sequence variations in the genes HLA-DR –DQ; PTPN22; PAD2 e PAD4; OPN; CASP3 e CASP8 will be tested. In the patients sera anti-CCP, Rheumatoid Factors and COMP will be evaluated.
The Caspase 8 and 3 and PAD 2 and 4 enzyme will be evaluated as protein and specific mRNA espression because the correlation between apoptotis, citrullination >>>

Principal Investigator
Guido VALESINI Università degli Studi di ROMA "La Sapienza"
Research Objectives
The present study has two aims:
1) The main goal is the identification of genes involved in the different RA clinical (including response to therapy) and immunological phenotypes. To this purpose RA patients will be typed for different sequence variations in the gene listed below. The frequency of the different sequence variations will be compared in RA patients divided on the basis of the clinical and immunological phenotypes described in the project of the clinical Units and characterized by the clinical centers participating to this project .
2) Moreover we will test the association of the selected polymorphisms with RA susceptibility which to date has not been analysed in the Italian population. A case-control association study will be performed.
For both aims, the influence of each genetic variation will be analysed separately and in combination with the other genetic and phenotypic RA features in order to test the interactions of the different factors.

Timescale
24 months
National and international background
Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease, characterized by macrophage and linfomonocytic infiltrates, abnormal angiogenesis and synovial hyperplasia. At an early stage of the disease a major synovial inflammatory response may be observed; afterwards, as the chronic phase begins, the markedly hyperplastic synovial tissue and the anomalous activation of the bone metabolic cells provoke erosions in the subchondral bone causing joint destruction and ultimately ankylosis. There are no specific causes known to determine the disease, but the new immunologic developments have spread light on broad pathogenetic aspects.

If a patient presenting an aggressive and self-limiting RA fails to respond to conventional treatment taken as monotherapy or in combination, then there is a high probability of developing joint damage, invalidity and concomitant disorders that may directly or indirectly related to chronic inflammation, such as cardiovascular diseases.

Currently new drugs capable of controlling chronic inflammation, the so-called biological agents, are available: among these, the anti TNF sequestrants are the most studied.
In the context of a project promoted by Ministero della Salute (ANTARES Study), several rheumatological clinical centres, also involving the three institutes participating at this research program, have created a database containing the clinical parameters of the patients and the data related >>>