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Autoimmune pancreatitis :

The story as a whole not through a

hole
BY
PROF DR

Abdel Rahman Abdel Hai Mokhtar

Internal Meicine @ Mansoura University
2017

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 As early as 1961, Sarles et al described a
form of idiopathic chronic pancreatitis
with obstructive jaundice and hyper
gammaglobulinaemia, with the suspicion
that there was an underlying autoimmune
process.

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 Considering
these
observations,
led to the
term AIP.

2011-International
2011-International IgG4-
IgG4- related
related diseases
diseases symposium
symposium held
held in
in
Boston
Boston the
the term
term IgG4-related
IgG4-related disease
disease
(IgG4-RD)
(IgG4-RD) was
was proposed
proposed

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 IgG4-Related Disease

 IgG4-associated sclerosing or systemic

disease (ISD) is a recently established
umbrella term for a range of organ
abnormalities that are all associated
with elevated IgG4 serum levels and/or
IgG4-positive plasma cell infiltrates in
different tissues.
Kamisawa T, Takuma K, Egawa N et al.,2010

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Many medical conditions that have long been viewed as conditions confined to
single organs ,names embedded in the medical literature for more than a century in
some cases — may now be replaced by designations that describe a key pathological
feature and perhaps provide more insight into the pathophysiology

Autoimmune pancreatitis

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And the list
is still
growing

n ?
o
m
o m
i sc
a t
h
W

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 What is common?

Clinically Serologically Pathologically

 Male
 Asian  Serum globin more  Fibrosis
 Age _ 50  Serum IgE more  Lymphoplasmcytosis
 Tumor  Serum IgG more  No granuloma
 Allergy
Outcome Good Response To Steroids
Legal Debates in IgG4 related
diseases

 IgG4 what’s wrong ?

 Autoimmune/ allergic/ infective disease?

 why multifocal fibro-inflammation?

 IgG4


what is wrong ?
 Immunoglobulins (Ig) are divided in isotypes: nine in
humans (IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, IgE)
Each isotype displays distinct structural
and effector properties
 Fragment, antigen binding

Antibodies of the IgG class exert two major effector

functions: activation of complement and
opsonisation (i.e. the induction of phagocytosis).

These functions, mediated via the (constant) Fc

fragment are induced as a result of interaction of the
antibody with its antigen via the (variable) Fab moiety
Fragment, antigen binding.

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IgG4
(Fragment, antigen binding)
Most IgG subclasses are symmetric and contain two
identical antigen-binding sites.
These antibodies are therefore monospecific (i.e. can bind
to one particular epitope).
once they are secreted
they engage in a unique
process called :
Fab-arm exchange
so they become bispecific
(Van der Neut Kolfschoten et al,
2007).
Fab-arm exchange

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 The Unique IgG4

All the 3 criteria confers anti-inflammatory properties

Yamamoto, M. et al. (2013) Mechanisms and assessment of IgG4-related disease:

lessons for the rheumatologist
Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.183
 The Unique IgG4

Antibody-dependent cell-mediated cytotoxicity

(ADCC)

Complement-dependent cytotoxicity (CDC)

The existence of the IgG4 subclass,

its up-regulation by anti-inflammatory
factors and its own anti-inflammatory
characteristics may help the immune
system to dampen inappropriate
inflammatory reactions.

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2009 Blackwell Publishing Ltd, Clinical & Experimental Allergy, 39 : 469–477
Whether IgG4 has a direct role in the pathogenesis of IgG4RD is
still unclear, and the finding of high IgG4 levels could be an
epiphenomenon.?

The purported tendency of IgG4 antibodies to fulfill anti inflammatory

functions and the fact that disease-specific IgG4 auto antibodies have not
been identified in IgG4-related disease suggest that they are a response to
an inflammatory stimulus.

A major gap in the understanding of

IgG4-related disease pertains to the
extent of Fab-arm exchange in patients
with this condition. ?????

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 IgG4-related disease
Autoimmune ?/ allergic?/ infective disease?
At present,
it is not clear whether IgG4-RD is caused by abnormal
acquired immunity like autoimmune diseases, and whether
the enhanced production of IgG4 antibody is a true cause of
IgG4-RD or an epiphenomenon associated with inflammatory
reactions.

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 Potential Triggers
 Specific Disease Pathways
 Cellular response
 Potential Triggers
 Male (60-80%)
 Asian
 >50 years
H. Pylori has been
 HLA DRB1*0405 (Japanese) linked to AIP
 HLA DQβ1-57 (Korean) (molecular mimicry)

N Engl J Med 2012;366:539-51

Auto-antibodies directed against
antigens expressed
in various exocrine organs
Th2-cell responses are Eosinophilia & high
predominantly activated serum IgE levels, both
at affected sites in
contrast to classic
Specific Disease Pathways observed in
approximately 40% of
autoimmune conditions patients with
IgG4-related disease,
are also mediated by
Th2
Cytokines mimicking
allergic disease.

In addition to IL-
10,
which can be
produced by Treg
cells as well as
Th2 lymphocytes,

(TGF-β) appears to
be over expressed
in IgG4-related
disease.

TGF-β may play a

central role in the
promotion of
Another immunologic characteristic of IgG4-RD fibrosis in IgG4-
is the activation of regulatory T (Treg) cells. related disease
This is an important contrast to classic
autoimmune conditions, in which the function of
Treg cells is impaired. N Engl J Med 2012;366:539-51
 Cellular response

Plasma cells
(IgG4 +ve)
T cells more

V/S
Malignancy:
B cell
Lymphoma Tumefactive It is unclear whether these organ
enlargement of dysfucntion are due to immune
organs or sites complex–mediated tissue damage or
are a bystander phenomenon

So, not all IgG4 looses specificity

IgG4 related diseases

A new
entity

New understanding of
an existing disease

Multiple diseases under pathologic umbrella

The histopathologic features of this disease bear striking
similarities across organs, regardless of the site of involvement.
So, what ever your
subspecialty you
should be aware ,
and should keep a
high index of
suspicion.

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Message to the Clinicians

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 Message to the Clinician
 Diagnostic Challenge ?
 Clinical presentation
 When to suspect ?
 When not to suspect ?
 Cardinal diagnostic feature.
 Therapeutic approach

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 Diagnostic Challenge ?

Closely1mimics other well known disease.

So , needs high index of suspicion.

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Rare compared to the disease it mimics 2-3% of those suspected to have
pancreatic cancer.

No single diagnostic test is sensitive and specific enough for autoimmune

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pancreatitis; rather, all the criteria have to be evaluated together combined
with the clinical response to treatment.

Price of misdiagnosis is heavy:

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AIP mistaken for cancer …..major surgery.
Cancer mistaken for autoimmune pancreatitis…delay in surgery.
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 A classical picture is

Obstructive jaundice, often painless or with mild epigastric pain.

A new onset diabetes or symptoms of pancreatic insufficiency and weight loss

may occur.

A rarer presentation is acute pancreatitis and its sequelae .

A characteristic feature of type 1 AIP is extra pancreatic other organ

involvement.

Fluctuating symptoms and /or signs with or without (spontaneous ) steroids.

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 When To Suspect ????
The possibility of IgG4-RD should be considered in patients with one of
the characteristic patterns of organ or tissue involvement.

Patients at high risk for having IgG4-RD are those with any of the
following:
 Pancreatitis of unknown origin
 Sclerosing cholangitis
 Bilateral salivary and/or lacrimal gland enlargement
 Retroperitoneal fibrosis
 Orbital pseudotumor or proptosis

The likelihood of IgG4-RD for patients presenting with at least one of

these conditions is significantly increased if high serum levels of IgG4,
allergic symptoms, and/or other fibrotic processes are also present.

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When To Suspect ????

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 When not to suspect ??

Features of ●

●
Narcotic requiring pain.
Marked anorexia & cachexia.
Cancer ●
Dilated pancreatic duct /pancreatic atrophy.

Recurrent
pancreatitis ●
Very uncommon in
without biliary AIP.
involvement
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CARDINAL DIAGNOSTIC FEATURES :

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AIP can be diagnosed when patient has
 Diagnostic histology:
(LPSP= lymphoplasmacytic sclerosing pancreatitis)

post resection or core biopsy.

 Typical imaging + serology , OOI ( other
organ involvement ) or compatible
histology.
 Atypical imaging + serology/OOI/compatible
histology + response to steroid.

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 Circulating plasmablasts as Potential Biomarkers
 studies of circulating plasmablasts confirm that these
cells are elevated to dramatically high levels in patients
with active IgG4-RD, even in patients with normal serum
IgG4 concentrations.
 Plasmablast counts therefore are a potentially useful
biomarker for diagnosis, assessing response to
treatment, and determining the appropriate time for
retreatment.
 Additional studies of plasmablasts are required,
particularly prospective investigations that focus on
IgG4+ plasmablasts, the response of these cells to
treatment, and their ability to predict disease relapses.

www.uptodate.com ©2015 UpToDate ®

Therapeutic approach

Algorithm informing treatment decisions in patients

with IgG4-related disease

Yamamoto, M. et al. (2013) Mechanisms and assessment of IgG4-related disease:

lessons for the rheumatologist
Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.183

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To Conclude :
 IgG4 – related disease is a relatively
newly recognized multifaceted
syndrome .
 Awareness of this condition and
accumulation of more cases worldwide
seems necessary.
 It should be in the differential
diagnosis especially in multisystem
disease presentation.
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Thank You

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