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Malattia da IgG4 - siaaic- · PDF file Malattia da IgG4 Riccardo Capecchi Immunologia Clinica e Allergologia Dipartimento di Medicina Clinica e Sperimentale Università di Pisa. Universita’

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  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Malattia da IgG4 Riccardo Capecchi

    Immunologia Clinica e Allergologia Dipartimento di Medicina Clinica e Sperimentale

    Università di Pisa

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    IgG4-Related Disease (IgG4-RD)

    • IgG4-RD is an immunomediated fibroinflammatory condition characterized by:

    • Lymphoplasmacytic infiltration • IgG4+ plasma cells in lesions • Storiform fibrosis (spindle cells having elongated nuclei radiating from a

    center) • Obliterative phlebitis • Mild to moderate eosinophilia • High serum IgG4 concentration (very often, not always)

    J Stone et al, N Engl J Med 2012 Kamisawa et al, Lancet 2015 Kanno et al, Pancreas, 2012

    Prevalence: 2-3 cases/100.000 (male, 50-80 years)

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    IgG4-RD: Pathogenesis

    Mahajan V S et al, Annu. Rev. Pathol. Mech. Dis. 2014

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Brito-Zerón et al, Autoimmunity Reviews 2014

    IgG4-RD: organs involvement

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    J Stone et al, N Engl J Med 2012

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    IgG4-RD: Diagnosis

    Okazaki et al, Int J Rheumatol 2012

    • it is important to differentiate IgG4-RD from malignant tumors of each organ (e.g. cancer, lymphoma) and similar diseases (e.g. Sjögren's syndrome, primary sclerosing cholangitis, Castleman's disease, secondary retroperitoneal fibrosis, Wegener's granulomatosis, sarcoidosis, Churg–Strauss syndrome)

    • Even when patients cannot be diagnosed using the CCD criteria, they may be diagnosed using organ specific diagnostic criteria for IgG4RD (es AIP or Mikulicz)

    Okazaki et al, Autoimmun Rev 2014

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    IgG4-RD: Laboratory  Markers of inflammation (CRP and ESR) (20%)

     Increase of IgG4 (60%)

     Eosinophilia (30%)

     Increase of IgE (30%)

     Increase of circulating CD19+CD20-CD27+CD38+

    cells (plasmablasts)

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    IgG4-RD: histology

    Altamente probabile: 2/3 criteri

     Infiltrato linfoplasmocitoide denso

     Fibrosi storiforme  Flebite obliterante

    10-200 IgG4+ cells /campo

    Rapporto IgG4/IgG >40% (>50% nell’aorta)

    Deshpande et al, Consensus statement, Modern Pathol 2012

    IHC analysis

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Therapy Most clinical manifestations of IgG4-related disease respond quickly to glucocorticoids. These agents are the first-line, standard-of-care approach for most patients. However, relapses are common.

    Glucocorticoids • Starting prednisolone dose 0,6 – 1 mg/kg daily. After 2-4 weeks, the dose is tapered by 5

    mg every 1-2 weeks according to clinical response

    • Clinical improvement is rapid (after 2 weeks make a serological assessment)

    • A poor response to GCS raise the possibility of other diagnoses (es cancer)

    Khosroshahi A et al, Arthritis & Rheumatology 2015

    Steroid-sparing agents • Some experiences with azathioprine, mycophenolate mofetil and methotrexate as means

    of sparing patients the effects of long-term glucocorticoids Rituximab

    • B-cell depletion induced by anti-CD20 targets the subset of plasma cells that produce IgG4 • Good response to therapy and some results on fibrosis. Relapses are still common

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Dipartimento di Medicina Interna

    Aim of the Study

    To investigate mediators regulating fibrotic and

    angiogenic processes in IgG4- RD patients

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Patients and Methods We recruited at the Clinical Immunology and Rheumatology Units

    • 13 patients fulfilling the criteria for the diagnosis of IgG4RD

    • 11 normal subjects (NHS)

     Pro-fibrotic and pro- and anti-angiogenic mediators were quantified in the sera of patient and control groups by ELISA at enrollment.

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Fibrosis in IgG4-RD (1) Transforming growth factor (TGF)-beta1

     TGF-beta1: the main pro- fibrotic mediator.

     Relevant in the differentiation of fibroblasts into myofibroblasts (key cells in fibrosis).

    Detlefsen et al, Am J Surg Pathol 2008

    Takeuchi et al, Modern Pathology 2014

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Dipartimento di Medicina Interna

    Fibrosis in IgG4-RD (2) Stromal Cell Derived Factor (SDF)-1

     SDF-1 is a CXCL12 chemokine ubiquitously expressed in many tissues and cell types.

     It is chemotactic for mesenchymal stem cells and EPCs

     It is relevant in fibrosis and angiogenesis (neoplastic diseases).

     SDF-1 is important in the recruitment of B cells.

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Anti Pro Anti Pro VEGF FGF-2 Angiopoietins HGF

    Angiostatin Endostatin

    Angiogenesis: from Physiology to Pathology

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Dipartimento di Medicina Interna

    Angiogenesis in IgG4-RD (1)

    Vascular Endothelial Growth factor (VEGF)

     VEGF is the main pro- angiogenic mediator

     It stimulates endothelial cells by acting on VEGFR2

     It is increased in inflammatory diseases, fibrosis and neoplastic diseases.

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Dipartimento di Medicina Interna

    Angiogenesis in IgG4-RD (2)

    Endostatin (ES)  ES is the main endogenous inhibitor of VEGF

     It is produced by the cleavage of C-terminal collagen XVIII

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Conclusions o Levels of SDF-1 and ES (but not VEGF) are

    increased in IgG4-RD sera

    o The role of collagen degradation vs VEGF

    inhibition in the production of ES should be explored

    o Prospective studies should be planned to evaluate the role of SDF-1 and ES as biomarkers of disease activity or response to therapy

  • Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

    Dipartimento di Medicina Interna

    Slide 1 IgG4-Related Disease (IgG4-RD) Slide 3 Slide 4 Slide 5 Slide 6 Slide 7 Slide 8 Slide 9 Slide 10 Slide 11 Patients and Methods Slide 13 Slide 14 Slide 15 Slide 16 Slide 17 Slide 18 Slide 19