malattia da igg4 - siaaic-toscoemiliana.org · malattia da igg4 riccardo capecchi immunologia...
TRANSCRIPT
-
Universita’ di Pisa - Facolta’ di Medicina e Chirurgia
Malattia da IgG4Riccardo Capecchi
Immunologia Clinica e AllergologiaDipartimento 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 2012Kamisawa et al, Lancet 2015Kanno 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
TherapyMost 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 glucocorticoidsRituximab
• 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 ProVEGFFGF-2AngiopoietinsHGF
AngiostatinEndostatin
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
Conclusionso 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 1IgG4-Related Disease (IgG4-RD)Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Patients and MethodsSlide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19