IgG4-related disease

IgG4 – Related Disease
Suda Sibunruang, M.D.

Outline
• Introduction
• Historical context
• Pathogenesis
• Epidemiology
• Clinical manifestations and laboratory
findings
• Treatment and prognosis

Yamamoto M. et. al. Nat Rev Rheumatol 2014;10:148–59
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD)
• Immune - mediated
fibroinflammatory
condition
• Can affect almost any
organ
• Now being recognized
with increasing frequency

www.rheumatologynetwork.com ,access May 25, 2015
IgG4-RD is characterized by…
Often but not always - elevate serum levels of IgG4
Cause progressive fibrosis and organ damage

Picture from www.mbl.co.jp , access May 25, 2015
Unifies many diverse conditions, previously thought
to be unrelated to each other, as a part of
IgG4- RD spectrum

• Early intervention using glucocorticoids can improve
IgG4-related organ dysfunction
• However, patients often relapse when doses
of these agents are tapered
• Disease has also been associated with an increased
incidence of certain malignancies

Okazaki K. et. al. Autoimmunity Reviews 2014;451–8

Himi T. et. al. Auris Nasus Larynx 2012;39: 9–17
Mikulicz-Radecki (1850 - 1905)
Illustration of the first reported case of Mikulicz’s disease (MD).
42-year-old male developed bilateral, painless swelling of lacrimal, parotid,
and submandibular glands.

Immunohistochemistry for IgG4 in salivary glands
Abundant IgG4-postive cells
infiltrate around acinar and ductal cells
No infiltrating IgG4-positive cells
Mikulicz’s disease Sjogren’s syndrome

Hamano H. et. al. N Engl J Med 2001;344:732-8
Background
• Most patients with chronic pancreatitis have a long history of alcohol
abuse. Alcohol-induced chronic pancreatitis is characterized by recurrent attacks
of abdominal pain, irregular dilatation of pancreatic duct with stone formation,
atrophy of pancreatic parenchyma, and pancreatic exocrine and endocrine
insufficiency.
• A unique form of chronic pancreatitis characterized by infrequent attacks of
abdominal pain, irregular narrowing of main pancreatic duct, lymphoplasmacytic
inflammation of pancreas, and hypergammaglobulinemia and that responds to
glucocorticoid.
• Preliminary studies suggested that serum IgG4 concentrations are elevated
in this disease but not in other diseases of pancreas or biliary tract.
Methods
• Measured serum IgG4 concentrations using single radial immunodiffusion &
ELISA in 20 patients with sclerosing pancreatitis, 20 normal subjects, and
154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary
cirrhosis, primary sclerosing cholangitis, or Sjogren’s syndrome.

CT shows diffuse swelling of pancreas with
late phase enhancement and low-density rim
Endoscopic pancreatography shows diffusely irregular
narrowing of main pancreatic duct
Endoscopic chorangiography shows beaded
like and long stenotic biliary duct similar to
primary sclerosing cholangitis

Hamano H. et. al. N Engl J Med 2001;344:732-8

Thus a relationship between AIP and IgG4 became apparent

IgG4-related pancreatitis is defined as type 1 AIP
(lymphoplasmacytic sclerosing
Pancreatitis)
(idiopathic ductcentric
pancreatitis )
(granulocytic epithelial
Lesions)

Mahajan VS. et. al. Annu Rev Pathol Mech Dis 2014;9:315–47

Umehara H. et. al. Mod Rheumatol 2012;22:21–30
Comprehensive diagnostic criteria for IgG4-related disease, 2011

Umehara H. et. al. International Immunology 2014;26:585–95

IgG4 antibodies are unusual in many respects
Torre DE. et. al. Clin Exp Immunol 2015 [Epub ahead of print]

Stone JH. et. al. N Engl J Med 2012;366:539-51

IgG4 antibodies are unusual in many respects
A single amino acid difference in hinge region
(a serine in lieu of proline found in IgG1)
causes inefficient formation of disulfide bridges
between heavy chains of molecule

Fc-dependent interactions
Prevent immune-complex-mediated and
Fc-receptor-mediated immune responses
Fc of IgG4 can also interact with
various Fc receptors and complement
proteins, but has minimal capacity to
activate them to induce signalling;
thus, these antibodies might
antagonize proinflammatory
responses mediated by other antibody
classes via competitive interaction

Properties of IgG4 antibodies
• Is often considered to function as an anti-inflammatory antibody
• Failure to bind efficiently to low-affinity FcRs and C1q renders them inefficient in
- Phagocyte activation
- Antibody-dependent cellular cytotoxicity
- Complement-mediated damage
• IgG4 antibodies can bind to FcγRI, the high-affinity receptor for IgG Fc, but less
efficiently than IgG1 and IgG3

Pathogenesis
• Remains unclear
• Whether IgG4 antibodies are pathogenic in
IgG4-RD or are produced in excess in response
to inflammatory stimuli due to their anti-
inflammatory properties, remains unclear

PAMPs and DAMPs are recognized by
TLRs and NOD2 in monocytes and
basophils initiating signalling
that leads to production of BAFF,
which promotes Ig class-switching
and results in production of IgG4
BAFF, B-cell-activating factor
(also known as, TNF ligand superfamily
member 13B, or B-lymphocyte stimulator
[BLyS])

PAMPs and DAMPs are recognized by
TLRs and NOD2 in monocytes and
basophils initiating signalling
that leads to production of BAFF,
which promotes Ig class-switching
and results in production of IgG4

Activated basophils produce IL-13,
and support TH2-cell-dominant
inflammation.
TH2 cells secrete IL-4 and IL-5,
which promote TH2 cell
self-propagation via differentiation of
naive T cells and activation of
eosinophils, respectively.

Excess immunoreaction of
TH2 cells leads to recruitment of
TREG cells, which secrete high levels
of IL-10,inducing further
class-switching to IgG4,
and TGF-β, driving severe fibrosis

IL-6 and IL-21 promotes differentiation
of naive T cells to TFH cells, leading to
formation of ectopic germinal centres,
plasmacyte development and
active antibody production.

Potential triggers
Signals from innate immune system
may determine state of T helper cell
polarization
When inflammation turns chronic,
Treg cells may also be induced
to dampen it
Activated T helper cells and Treg cells
may produce an inflammatory cytokine
Class-switching of autoreactive B cells to
IgG4 and IgE and induce the differentiation
and expansion of IgG4+ plasma cells

IL-5, IL-13, and TGF-β could lead to
recruitment of eosinophils and
activation of fibroblasts
Cytokine milieu may also generate
profibrotic, alternatively activated
macrophages that produce additional
fibrogenic cytokines
Some IgG4 and some IgE antibodies,
may be cross-reactive to self-antigen
B cells that recognize self-antigen are
capable of efficient antigen presentation of
cognate self-antigens to autoreactive T cells,
thereby setting up a vicious cycle

Pathogenic model for IgG4-Related Disease
(1). Dendritic and naive/memory B cells might present
antigens to CD4+T lymphocytes triggering their
activation
(2). Local signals from innate immune system
might determine T helper cell polarization and
differentiation into effector or memory T cells
Activated naive B cells migrate to germinal centre
Where they undergo somatic hypermutation and
affinity maturation, and differentiate into memory
B cells or plasmablasts
(3). IgG4/IgE class switch probably occurs under
influence of cytokines produced by activated CD4+
Th2 or T regulatory cells.
Effector CD4+ T cells migrate to inflamed tissues
where they are thought to drive fibroinflammatory
process by producting a variety of pro-fibrotic
cytokines (such as IL-4, IL-10, IL-13, TGF-β),
and by inducing M2 macrophages differentiation
and eosinophils activation
(4). IgG4 antibodies might have an antinflammatory
role but, together with IgE, they might also facilitate
antigen capture by innate immune cells through
Fc receptor binding, and presentation to T cells.
In theory, IgG4+ plasma cells in the tissue might also
have a pro-fibrotic role through the production of IL-6

Pathogenic model for IgG4-Related Disease
• Rituximab might eliminate both short-lived
plasma cells and a major B cell type required
for antigen presentation to T cells.
• This in turn leads to loss of activated T cells
and profibrotic cytokines, and to
a reduction in fibroblasts activation.
• Disease relapse corresponds to a new
plasmablasts expansion. Whether re-emerging
plasmablasts observed at disease relapse
differentiate de novo from naive B cells or
from CD20- memory B cells that survive
rituximab therapy is not known

Mattoo H. et. al. J Allergy Clin Immunol 2014;134:679-87

Susceptibility genes
Familial cases are rare
• HLA-DRB1*0405 (P = 2.9 × 10–6; OR 4.97)
• HLA-DQB1*0401 (P = 2.0 × 10–6; OR 5.12)
associated with type 1 AIP in Japanese
• HLA-DRB1*0701 (P = 0.033; OR 2.519)
• DQB1*0202 (P = 0.023; OR 2.68)
associated with type 1 AIP in Korean

Micro-organisms (1)
• Might be a triggering factor for the immune,
and potentially autoimmune responses
• Helicobacter pylori plasminogen-binding
protein (PBP) has been a focus of attention
because antibodies targeting this protein were
detected in patients with AIP
• PBP shares amino acid sequence homology
with human E3 ubiquitin-protein ligase UBR2,
which is expressed in pancreatic acini

Micro-organisms (2)
• However, PBP is not specific to H. pylori, and is
expressed by other enterobacteria
• Furthermore, study that identified anti- PBP
antibodies in AIP only included patients with
type 2 AIP
• Therefore, whether a relationship exists
between PBP and IgG4-RD remains to be
determined

Autoantibodies
• Hypergammaglobulinaemia and certain autoantibodies
are often detected
• In patients with IgG4-related dacryoadenitis and
sialadenitis, ANA (titres ≥160:1) were detected in
15.7%, whereas RF was detected in 20.0%
• Anti-carbonic anhydrase II antibodies, anti-lactoferrin
antibodies, and anti-pancreatic secretory trypsin
inhibitor antibodies have been reported in patients
with type 1 AIP
• However, these autoantibodies are neither associated
with disease activity nor related to clinical features

Epidemiology (1)
• Remains poorly described, partly because of
substantial challenges in recognition and
diagnosis
• Most cases have been reported in Asia, but case
reports from Europe and USA are now increasing
• Incidence throughout Japan was estimated to be
0.28–1.08/100,000, with 336–1,300 patients
newly diagnosed per year
• Approximately 6,700–26,000 patients who
developed IgG4-RD over the past 20 years

Epidemiology (2)
• Incidence of IgG4-RD through a network of
Japanese researchers in an AIP study; they
reported that 8,000 patients throughout Japan
had IgG4-RD, including around 4,300 patients
with IgG4-related dacryoadenitis and
sialadenitis and 2,700 patients with type 1 AIP

65-year-old man with persistent swelling of both upper eyelids
for 6 months before consulting ENT…
Refer to rheumatologist on suspicion of Sjogren’s syndrome
No sicca symptoms / ANA- negative / anti-SSA- negative
Serum IgG4 786 mg/dl; (normal levels are <105 mg/dl)

Clinical signs & Lab finding (1)
• Typical patient is a middle aged to
elderly male
• Overall male-to-female ratio in most organ
systems is 3.5 : 1
• Some variability exists in sex distribution
from organ to organ
• Head and neck, male to- female ratio is closer
to 1 : 1

• Swollen but painless organs
• Rarely present with general symptoms such as
fever and malaise
• Almost all cases present with elevated serum
levels of IgG4 (≥135 mg/dl)

• Hypocomplementaemia and elevated levels of
circulating immune complexes are often
detected in patients with multiple organ
dysfunction, particularly with renal
involvement

Organ involvement
Involvement of nearly every anatomic site has
been reported, but most commonly affected;
• Pancreas
• Biliary tract
• Major salivary glands (submandibular, parotid)
• Lacrimal glands
• Retroperitoneum
• Lymph nodes
Khosroshahi A. et. al. Arthritis Rheumatol 2015 [Epub ahead of print] access May 3, 2015

Lacrimal & Salivary glands
• Changes in facial appearance, such as
continuous and painless swelling of the upper
eyelids, and parotid and submandibular
portions
Bilateral enlargement of
parotid and submandibular glands

Orbital & periorbital
• In addition to dacryoadenitis, inflammation of orbital region
can manifest as ocular myositis, perineuritis of optic nerve
and trigeminal nerves, and orbital inflammatory
pseudotumour
Proptosis

Sogabe, Y. et al. Jpn J Ophthalmol 2012;56:511–4
Infraorbital nerve enlargement (IONE)

Thyroid gland
Certain forms of thyroiditis are on spectrum of
IgG4-RD
• A substantial portion of cases of Riedel
thyroiditis
• Fibrous variant of Hashimoto thyroiditis
IgG4-related thyroiditis is often associated with
massive enlargement of thyroid due to
lymphocytic infiltration

IgG4-related thyroid disease
Thyroid gland has a hard, woody feel

Pituitary gland & dura mater
CNS involvement; generally does not affect brain parenchyma
• Hypophysitis (pituitary gland)
Anterior hypophysitis; headache, visual field deficit
and lactation, etc.
Posterior hypophysitis is often associated with
diabetes insipidus
Clinical manifestations depend on which hormonal axis is interrupted
• Pachymeningitis (dura mater)
Involve either intracranial meninges or intraspinal meninges
Chronic headache and cranial neuropathy

Lung and respiratory tract
Pulmonary involvement:
Bronchial
• asthma-like symptoms, with CT imaging
revealing thickened bronchial and bronchiolar
walls
Alveolar
• asymptomatic, but CT imaging detects various
patterns of inflammation suggestive of
interstitial or organizing pneumonia

IgG4-RD has a predilection for bronchovascular bundle regions

Pancreas & bile duct
• Upper abdominal discomfort and obstructive jaundice
• Sometimes present with diarrhea and impaired glucose
tolerance due to reductions in exocrine and endocrine
functions of pancreas
Kamisawa T. et. al. Lancet 2015;385:1460-71
Diffuse wall thickening of bile duct
Nodule is formed in pancreatic head

Kidney
• Mainly manifests as tubulointerstitial nephritis (TIN),
whereas IgG4-related glomerulonephritis is rare

Retroperitoneal cavity
• Retroperitoneal fibrosis can be drug-induced,
malignancy-related or idiopathic
• A proportion of cases of idiopathic
retroperitoneal fibrosis (Ormond’s disease)
are considered to represent IgG4-RD
• Main affected sites are regions around
thoracic and lumbar spine, abdominal aorta
and branching arteries, and ureters

Retroperitoneal cavity
• A major insight has been the link established
between IgG4-RD and vascular inflammation
leading to aneurysms in both abdominal and
thoracic aortas
Large mass in pelvis,
near bladder, encompassing
and compressing left ureter

Chiba K. et. al. Intern Med 2013;52:1545-51

Prostate gland
• Symptoms of benign prostatic hyperplasia

Lymph nodes
• Either generalized or localized adjacent to a
specific affected organ
• Generally 1–3 cm in diameter and are non tender
• Although lymphadenopathy is often a prominent
clinical feature, establishing diagnosis through
lymph node biopsy is generally difficult because it
is unusual for lymph nodes to undergo degree of
fibrosis observed in other organs

Skin
• Small number of patients with cutaneous
disease associated with IgG4-RD
• Typical lesions are erythematous, flesh-
colored papules with a predilection for head
and cheeks

Lowe GC. et. al. International Journal of Dermatology 2015;54:377–82
Bilateral lymphadenopathy and an erythematous eruption
on chest, and a papular lichenoid eruption on lower extremity

Investigations
• Radiologic studies
• Serum IgG4 level
• Histopathology

Radiologic studies
• Indeed, diagnosis is often suggested by
incidental radiologic findings on studies
performed for reasons related or unrelated to
IgG4-RD
• Selection of imaging modality appropriate to
assessment of IgG4-RD is based on organ
under evaluation, local radiology expertise,
and availability, as well as considerations such
as radiation exposure and cost

Radiologic studies
• Enhanced CT and F-fluorodeoxyglucose
positron emission tomography (FDG-PET) are
useful tools for diagnosis and examination of
complications
• CT images reveal organ enlargement
• FDG-PET detects severe inflammation

Serum IgG4
• Remain important in evaluation and
longitudinal assessments, but elevated levels
are neither necessary nor sufficient for
diagnosis of IgG4-RD
• 3 - 30% of patients have normal serum IgG4
level
• Elevated IgG4 concentrations have been
observed in a variety of other conditions

Su Y. et. al. PLoS One 2015;10:e0126582
Serum IgG4 levels in various disorders

Tabata T. et. al. Intern Med 2011;50: 69-75

Serum IgG4
• However, degree of serum IgG4 elevation
correlates with number of organs involved:
the greater the extent of disease,
the higher the likelihood of an elevated
serum IgG4

Mattoo H. et. al. J Allergy Clin Immunol 2014;134:679-87
• Recent study indicates that IgG4-RD
patients have substantial elevations of
circulating plasmablasts
• Plasmablast levels correlate with disease
activity
• Additional studies of circulating plasmablasts
and IgG4+ plasmablasts as
biomarkers are required

IgG4-related aortitis shows virtually entire wall of aorta.
Although the media (inner layer, asterisk) is relatively unaffected,
a dense lymphoplasmacytic infiltrate is present on adventitial aspect
(outer layer) of aorta, and a vein obliterated by inflammation
is indicative of obliterative phlebitis (arrow)

Obliterative phlebitis
Obliteration of venous channels by extensive
lymphoplasmacytic cell infiltration

Immunostaining for IgG4 shows many
IgG4-positive plasma cells

Storiform fibrosis

Pattern is often likened to a cartwheel, with the bands
of fibrosis (arrowheads) emanating from the center
(asterisk) representing the spokes of the wheel

Histopathology
• Presence of significant IgG4+ plasma cell
infiltrates in biopsy specimens is not specific for
IgG4-RD
• Common mimickers of IgG4-RD, including
malignancy, granulomatosis with polyangiitis,
eosinophilic granulomatosis with polyangiitis, and
multicentric Castleman’s disease
• Findings of storiform fibrosis and obliterative
phlebitis heighten diagnostic specificity, but
clinicopathologic correlation is always essential

Histopathology
• Needle biopsies are usually insufficient for
diagnosis of IgG4-RD
• Storiform fibrosis might not be detected;
hence, use of en-bloc biopsy is recommended
• However, needle biopsy generally use to
exclude malignancy with some confidence

Deshpande V. et. al. Mod Pathol 2012;25:1181-92

Organ-specific diagnostic criteria can be applied
when biopsies are difficult to obtain

Organ-specific diagnostic criteria have been developed in various populations,
but none of these criteria have been validated for use in racial or ethnic groups
other than the ones in which they were formulated

Major aim of treatment
• Prevention of fibrosis and its potentially
destructive impact on organs

Treatment
• Not all manifestations of IgG4-RD require
immediate treatment
• “Watchful waiting” may be appropriate, for
example, in patients with asymptomatic
lymphadenopathy or mild submandibular
gland enlargement

Treatment
• Spontaneous remissions or temporary remissions
without treatment have been reported, but
follow-up in such cases was short and a relapsing-
remitting pattern with progressive organ injury
has been well-described
• Further, metachronous nature of IgG4-RD
suggests that although disease may appear to
improve at least temporarily in one organ, it may
re-emerge months or years later at a different
site

Treatment
• Treatment leads to faster and more complete
remission with fewer long-term complications
of IgG4-RD than does waiting to treat
• Treatment is therefore justified in most cases
in which laboratory evidence or radiology
studies suggest organ dysfunction

Treatment
Multiple approaches have been reported,
• Systemic glucocorticoid
• “Steroid-sparing” immunosuppressive drugs
• Biologic agents
• Surgical resection of affected tissues
But no randomized clinical trials or formal
treatment guidelines exist

Kamisawa T. et. al. J Gastroenterol 2014;49:961–70
Regimen of oral steroid therapy for AIP
Enlarged organs generally improve rapidly after initiation of prednisolone,
and gland secretions gradually increase with treatment.
Indeed, reversal of gland dysfunction has been shown

Maintenance therapy
In an effort to minimize morbidity, those with organ-
threatening IgG4-RD manifestations and patients at
elevated risk of relapse likely benefit from maintenance
therapy
Higher risk for recurrence following remission induction
• Multi-organ disease
• Significantly elevated serum IgG4 concentrations
• Involvement of proximal bile ducts
• History of disease relapse
Optimal duration of maintenance therapy has not been
studied

Maintenance therapy
• Relapses in IgG4-RD patients are common,
even with the use of glucocorticoid
maintenance therapy

Hart PA, et al. Gut 2013;62:1607–15
Addition of a steroid-sparing agent is appropriate when
patients are not able to taper glucocorticoids because of persistently active
disease. In certain circumstances, providers may consider adding steroid-sparing
agents during induction therapy with plans to continue the agent as maintenance
therapy

Rituximab, an anti-CD20 antibody, promotes depletion of B cells
T helper cells and Tregs may act as critical mediators of fibrosis by secreting IFN-γ, IL-4, IL-13, and TGF-β.
These cytokines induce recruitment and activation of fibroblasts and macrophages.
T follicular helper cells (as well as Th2 cells and Tregs) may secrete IL-4 and IL-10, thereby promoting class-switching
to IgG4 and differentiation of B cells into IgG4+ plasma cells. Activated state of T cells may be maintained by
antigenic peptides presented in the context of class II MHC molecules by autoreactive B cells, and perhaps by activated
macrophages, dendritic cells, and eosinophils in an IgG4- and FcγRI-dependent manner

Rituximab-mediated B cell depletion results in loss of short-lived plasma cells
by depleting their CD20+ precursors.
This leads, in turn, to a rapid decline in serum IgG4 levels.
B cell depletion may eliminate a major cell type required for antigen presentation to T
cells, leading to loss of activated T cells and profibrotic cytokines and a reduction in
inflammatory cellular infiltrate.

IgG4-RD Responder Index (RI)
• Quantitative means of assessing overall
disease response to treatment

Carruthers MN. et. al. International journal of rheumatology 2012;259408
Number can be compared
between visits to assess
disease activity over time
as well as being used for
a clinical trial endpoint

Highly Fibrotic Lesions
• Long-standing, highly fibrotic lesions may
respond poorly if at all to currently available
pharmacologic agents
• In such patients, risk-benefit balance may not
favor repeated courses of treatment
• Surgical debulking is an option, but suitability
of surgical interventions is governed by
anatomic regions and adjacent structures
involved

Prognosis
• Although initial prognosis of patients with
IgG4-RD is generally good, relapse ratio after
tapering or discontinuing steroids is very high
• Around half of patients treated for IgG4-
related dacryoadenitis and sialadenitis who
relapse present with new lesions in different
organs during both short-term and long-term
(>10 years) follow-up

Inoue D. et. al. Medicine (Baltimore) 2015;94:e680
Incidence rate of cancers within 3 years of
diagnosis of IgG4-RD was higher than
in rate observed for general population
(383 versus 100)
Several reports have described
complication of pancreatic cancer during
follow-up of patients with type 1 AIP
However, malignancies observed
in patients were all different,
and no characteristic correlated
with development of cancer
Although cause of this association
therefore remains unclear

International Consensus Guidance Statement
on the Management and Treatment of IgG4-Related Disease
Second International Symposium on IgG4-Related Disease, February, 2014
International panel of forty-two experts develop recommendations for
management of IgG4-RD in order to provide guidance to clinicians

Patient Evaluation
• Most accurate assessment of IgG4-RD is
based on a full clinical history, physical
examination, selected laboratory
investigations, and appropriate radiology
studies (96% agreement)
Clinicopathologic correlation is required
to make correct diagnosis

Tissue Confirmation Prior to
Treatment
• Diagnostic confirmation by biopsy is strongly
recommended for exclusion of malignancies
and other IgG4-RD mimics
(94% agreement)

Indications for Therapy
• All patients with symptomatic, active IgG4-
RD require treatment, some urgently.
A subset of patients with asymptomatic
IgG4-RD also requires treatment
(87% agreement)

Remission Induction With
Glucocorticoids
• Glucocorticoids are the first-line agent for
remission induction in all patients with
active, untreated IgG4-RD unless
contraindications to such treatment are
present
(94% agreement)

Use of Steroid-Sparing Agents
• Some but not all patients require
combination of glucocorticoids and a steroid-
sparing immunosuppressive agent from the
start of treatment
• This is because glucocorticoid monotherapy
will ultimately fail to control disease and
long-term glucocorticoid toxicities pose a
high risk to patients
(46% agreement)

Use of Maintenance Therapy
Following Remission Induction
• Following a successful course of induction
therapy, certain patients benefit from
maintenance therapy
(94% agreement)

Managing Disease Relapse
• Re-treatment with glucocorticoids is
indicated in patients who relapse off of
treatment following successful remission
induction
• Following relapse, introduction of a steroid-
sparing agent for continuation in remission
maintenance period should be considered
(81% agreement)

Take home message (1)
• IgG4-RD represents a chronic inflammatory
disorder characterized by various systemic
organ dysfunctions
• Disease is associated with elevated serum
levels of IgG4 and specific histopathological
features, including abundant IgG4+ plasmacyte
infiltration, storiform fibrosis and obliterative
phlebitis

• Associated with a predominantly type 2
T-helper-cell cytokine profile, and infiltration
of regulatory T cells
• Examination for systemic organ failure and
screening for underlying malignancies is
important during the diagnosis and follow-up
of IgG4-related disease

• Glucocorticoids are effective in the treatment
of IgG4-related disease, but the rate of relapse
after tapering or discontinuing
glucocorticosteroids is high

IgG4-related disease

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