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Favero, Marta (2010) Synovial inflammation and associated intra-articular pathology in a cohort of patients undergoing anterior cruciate ligament reconstruction for traumatic rupture. [Tesi di dottorato]

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Abstract (inglese)

Purpose:
Previous epidemiologic studies have established that there is a strong relationship between anterior cruciate ligament (ACL) disruption and the risk for subsequent development of osteoarthritis (OA). Though not normally considered a classical inflammatory arthropathy, OA is often associated with low-grade synovitis. In patients with OA, synovial inflammation is one factor associated with risk of progression of structural joint deterioration and symptoms. The aims of the study were to characterize the histopathological features and chemokine profile of the synovium in patients undergoing ACL reconstruction after traumatic ACL rupture and to determine the relationship between the synovial characteristics and meniscal and/or cartilage abnormalities.

Materials and Methods:
The study was conducted in the context of the ACL registry at the Hospital for Special Surgery (HSS), New York, USA, which maintains extensive records of preclinical, intraoperative and post-operative data for 1200 patients who have undergone ACL reconstruction for traumatic ACL rupture. Synovial biopsies were collected from 40 patients during arthroscopic surgery and processed for histology and RNA extraction. Synovial features of inflammation and degeneration were assessed using a combination histological synovial scoring system developed at HSS in which the following six features were graded: perivascular mononuclear cell infiltration, detritus, mucoid change, fibrosis, increased vascularity and hyperplasia of the synovial lining layer, leading to a total combined maximal score of 15. The following clinical data were also collected: age, sex, body mass index (BMI), date of injury, time to surgery and the intraoperative presence or absence of meniscal and/or cartilage abnormalities. Total RNA extracts were prepared from the suprapatellar synovial samples and the levels of mRNA for four chemokines (IL-8, CCL19, CCL21, and CCL5) and one chemokine receptor (CCR7), shown previously to be associated with synovial inflammation in patients undergoing meniscectomy by microarray pathway analysis (C Scanzello, Arthritis Rheum 2011) [1], were measured by real-time qPCR.

Results:
Of the 40 patients undergoing synovial biopsy and analysis, 19 were female and 21 male, with median ages of 20 and 36, respectively. 85% of the patients exhibited histological evidence of synovial inflammation or degeneration in the suprapatellar area: 44.1% of patients scored 1 or 2, 44.1% scored 3 or 4, 5.8% scored 5 or 6, and 5.8% scored 7 or 8. Arthroscopically, meniscal abnormalities (mostly tears) were observed in 19/40 patients (47%), and cartilage defects were observed in 16/40 patients (40%). No association was observed between the body mass index (BMI), date of injury, time to surgery, and frequency of cartilage defects or meniscal pathology. The patients were divided in two groups based on age: 19 of patients older than 30 years and 21 patients younger than 30 years. Meniscal tears were associated with synovial inflammation in patients older than 30 years. We selected 16 synovial suprapatellar biopsies from patients > 30 years for qPCR analysis, 8 from patients without synovial inflammation (grade 0-2) and 8 with synovial inflammation (grade 3-8). The levels of CCL5 and CCL19 mRNA were significantly upregulated in biopsy specimens exhibiting inflammation with associated fold-changes of 2.7 (P=0.0426) and 4.7 (P=0.0289), respectively.

Conclusions:
In our study, we observed a high percentage of low-grade synovitis (85%), meniscal tear (47%), and/or cartilage defects (40%) in patients undergoing ACL reconstruction for traumatic ACL rupture. In a cohort of patients > 30-years-old, the presence of synovitis correlated with evidence of a meniscal tear, suggesting a relationship between these two pathologic processes. Preliminary analysis of mRNA expression patterns in this group of patients confirmed the upregulation of CCL5 and CCL19. This is in agreement with previously published data [1]. These two chemokines may play an important contributory role in the pathophysiology of OA particularly in those patients having synovial inflammation

Abstract (italiano)

Scopo dello studio:
I dati riportati in lettura evidenziano una stretta correlazione tra la rottura del legamento crociato anteriore (LCA) e il rischio di sviluppare osteoartrosi (OA). Benché non sia considerata una classica artropatia infiammatoria, l’OA è spesso associata alla presenza di sinovite di basso grado. Nei pazienti affetti da OA, l’infiammazione sinoviale viene considerata un fattore di rischio correlato con l’attività di malattia e con la progressione del danno articolare. Lo scopo dello studio consiste nel caratterizzare la sinovite dei pazienti sottoposti a ricostruzione del LCA post rottura traumatica e nell’identificare la correlazione tra la presenza d’infiammazione sinoviale e la coesistenza di lesioni meniscali e cartilaginee.

Materiali e Metodi:
Lo studio è stato condotto presso l’Hospital for Special Surgery (HSS) di New York, USA, utilizzando il registro per il LCA, che raccoglie i dati clinici, preoperatori ed intraoperatori, di 1200 pazienti sottoposti a ricostruzione del LCA in seguito a rottura traumatica. Su 40 pazienti sono state eseguite biopsie sinoviali in corso di artroscopia ed i campioni raccolti sono stati sottoposti ad istologia e ad estrazione di RNA. La presenza d’infiammazione sinoviale è stata valutata mediante l’utilizzo di uno score istologico composito messo a punto all’HSS. Tale score prende in considerazione la presenza dei seguenti parametri istologici per un punteggio complessivo massimo di 15: infiltrazione perivascolare di cellule mononucleate, detriti, cambiamenti mucoidi, fibrosi, incremento della vascolarizzazione ed iperplasia della membrana sinoviale. Sono stati inoltre raccolti i seguenti dati clinici: età, sesso, indice di massa corporea (BMI), data del trauma, data dell’intervento chirurgico e riscontro intraoperatorio di lesioni meniscali e/o cartilaginee. I livelli di mRNA di 4 chemochine (IL-8, CCL19, CCL21, and CCL5) e di un recettore per le chemochine (CCR7) sono stati misurati sulla sinovia sovrapatellare, tramite real time qPCR. Tali chemochine sono risultate precedentemente associate all’infiammazione sinoviale nei pazienti sottoposti a meniscectomia in uno studio condotto tramite microarray analisi (C Scanzello, Arthritis Rheum 2011) [1].

Risultati:
Dei 40 pazienti sottoposti a biopsia sinoviale, 19 sono femmine e 21 maschi, con un’età mediana rispettivamente di 20 e 36 anni. L’85% dei pazienti analizzati presenta segni istologici d’infiammazione sinoviale a livello sovrapatellare: il 44.1% dei pazienti ha uno score tra 1 e 2, il 44.1% uno score tra 3 e 4, il 5.8% score tra 5 e 6, e il 5.8% uno score tra 7 e 8. Durante l’artroscopia si sono riscontrate lesioni meniscali in19/40 pazienti (47%) e cartilaginee in 16/40 pazienti (40%). Non si sono identificate correlazioni tra grado d’infiammazione sinoviale e BMI, data del trauma, data dell’intervento e frequenza delle lesioni meniscali e cartilaginee. A seconda dell’età si è suddiviso i pazienti in due gruppi: 19 pazienti hanno un’età superiore a 30 anni e 21 un’età inferiore ai 30 anni. La presenza di lesioni meniscali è associata all’infiammazione sinoviale nei pazienti con età > 30 anni. Tra le biopsie sinoviali sovrapatellari eseguite su pazienti con età > 30 anni, se ne sono selezionate 16 da sottoporre a qPCR analisi: 8 biopsie provenienti da pazienti senza segni d’infiammazione sinoviale (grado 0-2) e 8 provenienti da pazienti con infiammazione sinoviale (grado 3-8). I livelli di mRNA di CCL5 e CCL19 risultano significativamente più elevati nei pazienti con infiammazione sinoviale di 2.7 (p = 0.0426) e di 4.7 volte (p =0.0289) rispettivamente.

Conclusioni:
Nel nostro studio, i pazienti sottoposti a ricostruzione del LCA per rottura traumatica presentano un’alta percentuale di sinovite di basso grado (85%), lesioni meniscali (47%) e difetti cartilaginei (40%). Nel gruppo di pazienti con età > 30 anni, la presenza di sinovite si correla con il riscontro di lesioni meniscali suggerendo una possibile relazione tra i due processi patologici. L’analisi dell’espressione dell’mRNA in questo gruppo di pazienti, ha confermato un incremento di CCL5 and CCL19, in accordo con quanto riportato in letteratura [1]. Queste due chemochine potrebbero avere un ruolo chiave nella patofisiologia dell’OA, in particolar modo nei pazienti con infiammazione sinoviale

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Tipo di EPrint:Tesi di dottorato
Relatore:Schiavon, Franco
Dottorato (corsi e scuole):Ciclo 24 > Scuole 24 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE REUMATOLOGICHE
Data di deposito della tesi:31 Gennaio 2012
Anno di Pubblicazione:31 Gennaio 2010
Parole chiave (italiano / inglese):sinovite, osteoartrosi, legamento crociato anteriore/ synovitis, osteoarthritis, anterior cruciate ligament
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/16 Reumatologia
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Medicina Clinica e Sperimentale
Codice ID:4733
Depositato il:21 Nov 2012 12:22
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