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Universita’ di Pisa - Facolta’ di Medicina e Chirurgia

Malattia da IgG4Riccardo Capecchi

Immunologia Clinica e AllergologiaDipartimento di Medicina Clinica e Sperimentale

Università di Pisa


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)


IgG4-RD: Pathogenesis

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


Brito-Zerón et al, Autoimmunity Reviews 2014

IgG4-RD: organs involvement


J Stone et al, N Engl J Med 2012


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


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)


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


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


Dipartimento di Medicina Interna

Aim of the Study

To investigate mediators regulating fibrotic and

angiogenic processes in IgG4-RD patients


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.


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



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.


Anti Pro Anti ProVEGFFGF-2AngiopoietinsHGF

AngiostatinEndostatin

Angiogenesis: from Physiology to Pathology



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.



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


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



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