IgG4 Syndrome - rheumatology.gr · IgG4 Syndrome Γ.Ε ... Pathophysiology Is it an autoimmune ......

27
IgG4 Syndrome Γ.Ε. Φραγκούλης, MD Μέτσοβο, Ιανουάριος 2010 Παθολογική Φυσιολογία Ιατρική Σχολή Εθνικό & Καποδιστριακό Πανεπιστήμιο Αθηνών

Transcript of IgG4 Syndrome - rheumatology.gr · IgG4 Syndrome Γ.Ε ... Pathophysiology Is it an autoimmune ......

IgG4 Syndrome

Γ.Ε. Φραγκούλης, MD

Μέτσοβο, Ιανουάριος 2010Παθολογική Φυσιολογία

Ιατρική Σχολή

Εθνικό & Καποδιστριακό Πανεπιστήμιο

Αθηνών

Outline

Definitions

Pathophysiology

Clinical manifestations

Treatment

Conclusions

Definitions

Firstly described: 2001 in a patient with autoimmune pancreatitis

Other names “IgG4-related systemic sclerosing disease”

“IgG4-related autoimmune disease”

“IgG4-related systemic disease”

“IgG4-positive multiorgan lymphoproliferative

syndrome”

N Engl J Med. 2001 Mar

Definitions

Tissue

Infiltrates by IgG4 (+) plasmatocytes

Fibrosis

Serum

IgG4

> 135 or 140 mg/dl

Not disease activity marker

Response to Glucocorticosteroids

Not always high

Pathophysiology

Is it an autoimmune

condition ? Correlation with

HLA DRB1*0405

HLA DQB1*0401

Immuner-complexes

deposition in tissues

Possible autoantigens

Allergic reaction?

Τh2 cytokines

From PBMCs

In tissues

IgE

Allergies

Ota et al, Immunogenetics 2007Zen et al. Hepatology 2007Bateman et al Histopathology 2009

Pathophysiology

Potential autoantigens Antibodies against

Lactoferin (73% of AIP patients)

CA I, II and IV (50%)

Pancreatic Secretory Trypsin Inhibitor (35%)

Plasminogen binding protein of H. pylori (90%)

Their role is debatable…

Pathophysiology

Role of T regulatory cells (Tregs) In tissues and in peripheral blood

IL-10 and TGF-b αριθμός Tregs

IgG4 antibodies Τh2 cytokines, Tregs, IL-10

Differentiation of B lymphocytes into IgG4 plasmatocytes IgG4 antibodies in other diseases

multicentric Castleman’s disease idiopathic plasmacytic lympadenopathy, Wegener’s granulomatosis, Pemphigus vulgaris Pemphigus foliaceus

Jeannin et al. Blood 1998

Clinical manifestations

Pancreatitis

Sclerosing Cholangitis

Sclerosing Sialadenitis

Tubulointerstitial nephritis

Riedel or Hashimoto’s

thyroiditis (?)

Lymphadenopathy

Retroperitoneal fibrosis

Hypophisitis

Mastitis

Prostatitis

Lung involvement

Skin involvement

Autoimmune pancreatitis

The most common clinical manifestation Usually accompanied with extrapancreatic manifestations US/CT

Diffuse or segmental enlargement of pancreas (sausage like appearance)

Hypoechogenic with hyperehcogenic spots Pseudocysts and calcifications are rare

ERCP Usually diffuse narrowing of pancreatic duct

Kamisawa et al. Am. J. Gastroenterol, 2001

Zhang et al. Mod Pathol, 2007

Autoimmune Pancreatitis

At least 10 IgG4+ plasma cells per high-power field within areas of lymphoplasmacytic infiltrate

Diffusely enlarged pancreas with delayed and ‘rim’ enhancement

Irregular pancreatic duct Increased serum IgG4 concentration Unexplained pancreatic disease after a full clinical work-

up, including exclusion of cancer Raised serum IgG4 concentration and/or extrapancreatic

organ involvement with increased numbers of tissue IgG4+ plasma cells

Resolution of marked improvement in disease with steroid therapy

Chari. J. Gastroenterol, 2007

Autoimmune Pancreatitis

Features Lymphoplasmacytic autoimmune pancreatitis (LPP)

Idiopathic duct centric chronic pancreatitis (ICP)

Gender Male No gender predominance

Association with IBD No Yes

Characteristic Infiltrates

IgG4 plasmatocytes Granulocytes

Epithelium Intact Infiltrated

Obliterative phlebitis Yes No

Sato et al. Pathology International, 2010

Autoimmune Pancreatitis

Differential diagnosis from pancreatic cancer

infiltrates by IgG4 (+) plasmatocytes

serum levels of IgG4

Not definite criterion

No upstream dilatation

Ghazale et al. Am J Gastroenterol, 2007

Sclerosing cholangitis

Cholangiography Lower bile duct stenosis

Intraductal US Wall thickening of bile

ducts

Histology Lymphoplasmacytic

infiltration (>PSC) IgG4 infiltrates

Fibrosis (<PSC)

Takuma et al. Curr opin in Rheum, 2011

Sclerosing cholangitis

Features Primary Sclerosing Cholangitis (PSC)

Cholangitis associated with IgG4 (CAI)

Association with IBD Yes Weak

Association with cholangiocarcinoma

Yes No

Response to glucocorticosteroids

No Yes

Pancreatic abnormalities Rare Frequent

Inflitration by IgG4 plasmatocytes

Rare Frequent

P-ANCA Frequent Rare

Raised IgG4 levels Rare (10%) Frequent

Bjornsson et al. Hepatology, 2007

Salivary Gland Enlargement

Similarities with SS Dry eyes, dry mouth Arhtralgias Low complement levels Antinuclear autoantibodies

Differences with SS total IgG, IgG2, IgG4

and IgE IgG1, IgG3, IgA and IgM No anti-Ro and/or anti-La IgG4 (+) plasmatocytes in

the salivary glands

Misdiagnosed as SS

Masaki et al. Ann Rheum Dis, 2009Fragoulis, Moutsopoulos, J Rheum 2010

Mickuliz’s DiseaseKuttner’s tumor

Salivary Gland Enlargement

Histological Differences with SS Large lymphoid follicles Germinal centers Obliterative plebitis Interlobular fibrosis

Geyer et al. Curr Opin Rheum, 2011

Lymphadenopathy

Lymph nodes Regional or distal Size: 1-5 cm (usually 2cm) 3 histological types have been recognized but all of

them> 60% of infiltrating plasma cells are IgG4 (+) in the majority eosinophilic infiltration

In these patients ESR, IgG, IgE and IL-2r IL-6, CRP No B symptoms

Sato et al. Mod Pathol, 2009

Lymphomas

Only few NHLs have been described till nowMost of them

MALT type Various organs (not necessarily in that infiltrated by

IgG4 (+) plasmatocytes One case of IgG4 producing MZ lymphoma in the

lymph node

Takahashi et al. Pancreas, 2009

Tubulointerstitial nephritis

Few cases of renal involvement Tubulointerstitial nephritis

(mainly) Some cases of IgG4-

related nodular lesions DD from renal cell

carcinoma

Murashima et al. Am J Kidney Dis, 2007

Skin

Erythematous papules or plaques Face/head/scalp SC lymphoplasmacytic infiltrate

IgG4 Eosinophils Histiocytes

Follicle formation Stromal fibrosis

Cheuk et al. Am J Surg Pathol 2009

Hashimoto’s Thyroiditis

In a large scale study 27% of Hashimoto thyroiditis

patients identified as IgG4 thyroiditis based on > 20 IgG4 plasmatocytes / HPF IgG4/IgG ratio > 30% Higher grades of lymphoplasmacytic

proliferation Stromal fibrosis Follicular cells degeneration High IgG4 serum levels

IgG4 thyroiditis Higher titers of anti-TPO & anti-TG

compared to non-IgG4 thyroiditis Diffuse low echogenicity

Li et al. Curr Opin in Rheum, 2011

Riedel thyroiditis

Riedel thyroiditis

Few cases have been described

Difficult differential diagnosis from fibrous variant of

Hashimoto’s thyroiditis

IgG4 related inflammatory abdominal aneurysm

IgG4 IAAA 50% of total IAAA 5% of total AAAs

Characteristics Similar clinicopathological with IgG4 disease (allergies, IgE,

IgG4 levels etc) Less rupture than non IgG4 No difference in diameter or location Histological

Eosinohpils Obliterative phlebitis Perineural infiltration Lyphoid follicle formation IgG4 plasmatocytes

Kamisawa et al. Curr Opin in Rheum, 2011

Thoracic aortic aneurysms and other atreries

Some cases and only few studies

9% of nonifectious aoritis may be IgG4 related

Mesenteric and right coronary arteries has been

found to be involved

Matsumoto et al Hum Pathol, 2008

Treatment

GC: 30-40 mg qd for 4w tapering by 5mg every 1-2 w for 1-2 mo 2.5-5mg qd for 3y

IgG4 levelsnormalization of liver function tests resolution of the strictures

less effective in the later stages fibrosis & atrophy

some cases improve without any treatment while others relapse after tapering the GCs

32% after 6mo, 56% after 12mo, 96% after 3yRetreat with high GCs.

Erkelens et al. Lancet, 1999Ghazale et al. Curr. Gastroenterol Repr, 2008

Treatment

AZA: 2-2.5mg/kg/day

MMF: 750mg twice daily

In GC refractory cases

RTX only small studies have been published

Ghazale et al. Gastroenterolgy, 2008

Ghazale et al Gut, 2007

Conclusions

Is it an autoimmune disorder ?

Is this a real entity or disease subgroups ?

Genetic make-up?

Prevalence among racial or ethnic groups?