Malattia da IgG4 Riccardo Capecchi Immunologia Clinica e - - PowerPoint PPT Presentation

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

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Brito-Zerón et al, Autoimmunity Reviews 2014

IgG4-RD: organs involvement

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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 difgerentiate 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 fjbrosis, Wegener's granulomatosis, sarcoidosis, Churg–Strauss syndrome)

• Even when patients cannot be diagnosed using the CCD criteria, they may be diagnosed

using organ specifjc diagnostic criteria for IgG4RD (es AIP or Mikulicz)

Okazaki et al, Autoimmun Rev 2014

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IgG4-RD: Laboratory

 Markers of infmammation (CRP and ESR) (20%)  Increase of IgG4 (60%)  Eosinophilia (30%)  Increase of IgE (30%)  Increase of circulating CD19+CD20-CD27+CD38+

cells (plasmablasts)

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IgG4-RD: histology

Altamente probabile: 2/3 criteri

 Infjltrato

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

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Therapy

Most clinical manifestations of IgG4-related disease respond quickly to glucocorticoids. These agents are the fjrst-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
• f sparing patients the efgects 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 fjbrosis. Relapses are still common

Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

Dipartimento di Medicina Interna

Aim of the Study T

• investigate mediators

regulating fjbrotic 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 fulfjlling the criteria for the diagnosis of IgG4RD
• 11 normal subjects (NHS)
• Pro-fjbrotic and pro- and anti-angiogenic mediators were

quantifjed in the sera of patient and control groups by ELISA at enrollment.

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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.

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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

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

increased in IgG4-RD sera

• The role of collagen degradation vs VEGF

inhibition in the production of ES should be explored

• 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