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2009 Convegno Malattie Rare Vaglio [23 01]

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La patogenesi della fibrosi
retroperitoneale idiopatica

Published in: Health & Medicine
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2009 Convegno Malattie Rare Vaglio [23 01]

  1. 1. La patogenesi della fibrosi retroperitoneale idiopatica Augusto Vaglio Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione Università degli Studi di Parma
  2. 2. Fibrosi retroperitoneale: definizione “Retroperitoneal fibrosis is a disease that can occur at any age, with a peak incidence in patients 40 to 60 years of age. The characteristic finding is a periaortic fibrous mass that often surrounds the ureters, leading to ureteral obstruction. The pathogenesis of the disease remains unknown, although there is a high correlation with atherosclerotic disease of the aorta”. Gilkeson GS, Allen NB. Rheum Dis Clin North Am 1996
  3. 3. Fibrosi retroperitoneale: forme primitive e secondarie Idiopatica (75%) Secondaria (25%) • forma idiopatica “pura” • Farmaci (eg, ergotamina, metildopa) • Associata a malattie sistemiche • Neoplasie (eg, linfomi, sarcomi, autoimmuni (LES, artrite reumatoide) carcinomi del tratto GI, mammella, prostata) • Infezioni (eg, TB, actinomicosi) • Radioterapia • Chirurgia (eg, colectomia, isterectomia, linfoadenectomia) • Altre (eg, malattia di Erdheim-Chester, amiloidosi, traumi) Vaglio A, Palmisano A, Corradi D, et al. Rheum Dis Clin North Am 2007 Palmisano A, Vaglio A. Best Pract Res Clin Rheumatol in press
  4. 4. Fibrosi retroperitoneale idiopatica: aspetto TAC
  5. 5. Fibrosi retroperitoneale idiopatica e periaortite cronica Vaglio A, Salvarani C, Buzio C. Lancet 2006 Parums DV. Histopathology 1990
  6. 6. Periaortite cronica: ipotesi eziopatogenetiche L’ipotesi di Parums e Mitchinson La PC è secondaria all’aterosclerosi avanzata Reazione infiammatoria locale a ceroide ed LDL-ossidate? Anticorpi circolanti contro ceroide ed LDL-ox sono più frequenti nei pazienti che nei controlli (Arch Pathol Lab Med 1990) IgG sono riscontrate in prossimità del ceroide extracellulare (Atherosclerosis 1986) Macrofagi carichi di ceroide sono riscontrabili nei linfonodi loco-regionali (Atherosclerosis 1982) Vaglio A, Salvarani C, Buzio C. Lancet 2006
  7. 7. Periaortite cronica: ipotesi eziopatogenetiche Malattia infiammatoria localizzata a livello periaortico secondaria ad una reazione all’aterosclerosi avanzata vs Manifestazione di una malattia sistemica di origine autoimmune
  8. 8. Periaortite cronica: aspetti istopatologici Le principali alterazioni istopatologiche interessano sia la parete aortica che il circostante retroperitoneo e sono caratterizzate da un infiltrato infiammatorio cronico (linfociti, plasmacellule e macrofagi) e da marcata fibrosi. Parete aortica intima media avventizia Vaglio A, et al. Am J Med 2003
  9. 9. Periaortite cronica: aspetti istopatologici Retroperitoneo gentile concessione del Dr. D. Corradi, Università di Parma
  10. 10. Periaortite cronica: aspetti istopatologici Retroperitoneo Corradi D, et al. Kidney Int 2007
  11. 11. Periaortite cronica: aspetti istopatologici Infiltrato nodulare/perivascolare Infiltrato diffuso CD3 CD20 CD3 CD20 CD4 CD8 CD4 CD8 Corradi D, et al. Kidney Int 2007
  12. 12. Periaortite cronica: aspetti istopatologici vimentina actina muscolo-liscio Corradi D, et al. Kidney Int 2007
  13. 13. Periaortite cronica: aspetti istopatologici Collagene tipo I Corradi D, et al. Kidney Int 2007
  14. 14. Periaortite cronica: parametri laboratoristici Gli indici aspecifici di flogosi (VES, proteina C-reattiva, alfa-2 globuline) sono elevati nell’80-90% dei pazienti con periaortite cronica all’esordio di malattia Indici di ritenzione azotata Anemia (insufficienza renale, malattia infiammatoria cronica) (in alcuni casi) eosinofilia, leucocitosi, ipergammaglobulinemia Auto-anticorpi: ANA (fino al 50% dei casi); anti-tireoglobulina ed anti- tireoperossidasi (fino al 25-30%); anti-muscolo liscio; fattore reumatoide; ANCA
  15. 15. Periaortite cronica: associazione con patologie autoimmuni Glomerulonefriti ANCA+ Vaglio A, et al. J Intern Med 2002
  16. 16. Periaortite cronica: associazione con patologie autoimmuni Artriti infiammatorie Vaglio A, Palmisano A, Ferretti S, et al. Rheumatology (Oxford) 2008
  17. 17. Periaortite cronica: associazione con altre patologie autoimmuni Altre patologie autoimmuni Vaglio A, Salvarani C, Buzio C. Lancet 2006
  18. 18. Periaortite cronica: una vasculite dei grossi vasi? Ipotesi di un’aortite primitiva Infiammazione avventiziale con coinvolgimento dei vasa vasorum come primum movens della malattia Estensione nel retroperitoneo circostante e conseguente reazione fibrosante Estensione centripeta con assottigliamento della tonaca media, dilatazione aneurismatica e sviluppo di aterosclerosi Vaglio A, Salvarani C, Buzio C. Lancet 2006
  19. 19. Periaortite cronica: una vasculite dei grossi vasi? 18F-Fluorodeoxyglucose(FDG)- positron emission tomography (PET) Studio caso-controllo: 7 pazienti all’esordio di malattia e 14 controlli sottoposti a whole-body PET scan per sospetta neoplasia Tutti i pazienti (vs nessun controllo) mostravano uptake di FDG patologico a livello dell’aorta addominale. 3/7 (43%) pazienti vs 0% controlli (p= 0.03) mostravano anche un uptake patologico a livello dell’aorta toracica e di alcuni suoi rami maggiori Salvarani C, Pipitone N, Vaglio A, et al. Arthritis Rheum 2005
  20. 20. Periaortite cronica: una vasculite dei grossi vasi? B A Coinvolgimento dell’aorta toracica e dei suoi rami Coinvolgimento vasi toracici SI NO p value N. pazienti 14 27 n.s. Età, mediana (range)- anni 61 (43-75) 54 (32-82) n.s. Sesso F, n (%) 8 (57.1%) 6 (22.2%) 0.03 Tipo di CP (IRF/IAAA) 2/11 1/25 n.s. D VES, mediana (range)- mm/h 91 (51-112) 73 (47-100) n.s. PCR, median (range)- mg/L 28.5 (11.1-45) 27 (14,1-85,7) n.s. Positività ANA, n (%) 4/14 (28.6%) 6/21(28.6%) n.s. No. (tasso) di recidive 8 (57.1%) 7 (25.9%) 0.04 C senza interessamento E toracico p = 0.29 con interessamento toracico Vaglio A, et al. American College of F G Rheumatology Meeting 2008 (Abstract 634, S400)
  21. 21. Periaortite cronica: fattori immunogenetici Associazione con HLA-DRB1*03 Martorana D, Vaglio A, et al. Arthritis Rheum 2006
  22. 22. Periaortite cronica: anticorpi anti-fibroblasti (AFA) Gli AFA sono stati rilevati nel siero del 58% dei pazienti con sclerosi sistemica. In vitro, gli AFA inducono un fenotipo fibroblastico proadesivo e proinfiammatorio (Chizzolini C, et al. Arthritis Rheum ‘02) e stimolano i fibroblasti a produrre chemochine profibrotiche (CCL2, CXCL8, CXCL10) (Fineschi S, et al. Arthritis Rheum ‘08) AFA nella periaortite cronica 7/23 (30%) dei pazienti sono AFA-positivi Le IgG purificate sono attivamente internalizzate dai fibroblasti retroperitoneali, a differenza delle IgG dei pazienti AFA-negativi e dei soggetti normal. Paziente AFA-/controllo sano 5 min 15 min 30 min Paziente AFA+
  23. 23. Periaortite cronica: plasmacellule IgG4+ L’infiltrazione da parte di plasmacellule IgG4+ e/o elevati livelli di IgG4 sieriche caratterizzano patologie sclerosanti quali la pancreatite e la colangite sclerosante, la sialoadenite cronica, che in alcuni casi si associano alla periaortite cronica. Le biopsie retroperitoneali di PC mostrano nell’80-90% dei casi infiltrazione di plasmacellule IgG4+. Le biopsie di pareti aortiche in pazienti con IAAA mostrano anch’esse infiltrazione di plasmacellule IgG4+. Corradi D, et al. Kidney Int 2007; Sakata N, Am J Surg Pathol 2008 L’infiltrazione di plasmacellule IgG4+ nelle pancreato- colangiti sclerosanti è espressione di un milieu infiammatorio dominato da una risposta Th2, con aumentata espressione di IL4, IL5, IL10, IL13 e TGF-beta. Queste citochine possono stimolare la risposta autoanticorpale, la proliferazione e l’infiltrazione eosinofila e la reazione fibrosante. Zen Y, Hepatology 2007 Corradi D, et al. Kidney Int 2007
  24. 24. Periaortite cronica: evidenze di autoimmunità Vaglio A, et al. Autoimmun Rev 2006
  25. 25. Periaortite cronica: triggers infettivi • CMV (Yonemitsu Y, et al. Lab Invest 1996) • Chlamydia pneumoniae (Takemoto M, et al. Int J Cardiol 2005) • M. Tuberculosis (Molloy CB, et al. Rheumatology 2005; Greco P, et al. Clin Infect Dis 2005) Biopsia retroperitoneale Biopsia mediastinica Evoluzione TC delle lesioni retroperitoneale e mediastinica Greco P, Vaglio A, et al. Clin Infect Dis 2005
  26. 26. Periaortite cronica: fattori ambientali Uibu T, et al. Lancet 2004
  27. 27. Periaortite cronica: schema patogenetico aterosclerosi meccanismi fattori genetici autoimmuni (AFA) (HLA) periaortite infiltrazione cronica plasmacellulare IgG4+ fattori ambientali (fumo, asbesto) iperproduzione di citochine proinfiammatorie e profibrotiche triggers infettivi (virus, TB)
  28. 28. ringraziamenti Clinica Medica e Nefrologia, Università di Parma Urologia, Università di Parma Alessandra Palmisano Stefania Ferretti Lucio Manenti Pietro Cortellini Nicoletta Ronda Carlo Buzio Reumatologia, Ospedale di Reggio Emilia Genetica, Università di Parma Carlo Salvarani Davide Martorana Tauro Maria Neri Medicina Nucleare, Ospedale di Reggio Emilia Annibale Versari Anatomia Patologica, Università di Parma Domenico Corradi Immunologia, Università di Milano Roberta Maestri Elena Raschi Pier Luigi Meroni Radiologia, Università di Parma Rocco Cobelli Nefrologia, Policlinico, Milano Gabriella Moroni Radiologia, Istituto Figlie di S. Camillo, Cremona Francesco Ferrozzi

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