IgG4-related disease

IMMUNOGLOBULIN G4
RELATED DISEASE
1 MAY 2020
PAIRACH SUPSONGSERM, MD

OUTLINE
• Overview
• Introduction and Historical Details
• The IgG4 Molecule
• Epidemiology
• Pathological Features
• Pathophysiological Mechanisms
• Clinical Features
• Laboratory Abnormalities
• Imaging Features
• Diagnosis
• Differential Diagnosis
• Treatment
• Long-term Prognosis

OVERVIEW
• IgG4-related disease is the term used to refer to a
condition characterized by a lymphoplasmacytic
infiltrate, fibrosis and an increased number of IgG4+
cells present in tissue, in most cases, with an
elevated serum IgG4 level
• This disease frequently affects the pancreas, salivary
glands and lymph nodes, but can involve almost any
tissue
• Its etiology and the exact role of the different
inflammatory cells in the damage to the target organ
is still unclear
• As yet, there is no international consensus about
diagnostic criteria for the disease, but there are
important advances in its treatment and in the quest
to achieve remission
Oscar Ardila-Suarez, Andy Abril, José A. Gómez-Puerta. IgG4-related Disease: A Concise Review of the Current Literature. Reumatol Clin. 2017;13(3):160–166

INTRODUCTION AND HISTORICAL DETAILS
Year Historical Details
1892 Johann von Mikulicz-Radecki described a 42-year-
old patient, a farmer, without sicca symptoms, who
had “symmetrical edema of the lacrimal, parotid
and submandibular glands, with their massive
infiltration by mononuclear cells
1953 A possible clinical manifestation of Sjögren’s
syndrome
1960s Cases were reported of another condition referred
to as “chronic sclerosing pancreatitis”
1995 The concept of autoimmune pancreatitis was
proposed
2001 Elevated serum IgG4 levels were recorded in
patients with sclerosing pancreatitis

INTRODUCTION AND HISTORICAL DETAILS
Year Historical Details
2004 The documentation of elevated IgG4 concentrations
in patients with Mikulicz’ disease established it
definitely within the IgG4-RD spectrum
2010 The current nomenclature of IgG4-RD was proposed
2011 The current nomenclature was accepted during the
first international symposium
2012 The first international consensus on the pathological
findings that define it at the present time

Vinay S. Mahajan et al. IgG4-Related Disease. ARI. September 2013

THE IGG4 MOLECULE
• IgG4 is a unique antibody in both structure and function
• This molecule accounts for less than 5% of the total IgG in healthy persons and is the least abundant IgG
subclass
• In contrast to IgG1, IgG2, and IgG3, serum IgG4 concentrations among ostensibly healthy people vary by
a factor of more than 100 (normal range, 0.01 to 1.4 mg per milliliter), but IgG4 concentrations within
individual persons are generally stable
• Although the constant domains of IgG4 heavy chains share more than 95% homology with those of
other IgG subclasses, amino acid differences within the second constant domain lead to weak or
negligible binding of IgG4 to both C1q and Fcγ receptors
• IgG4 does not activate the classical complement pathway effectively and has been traditionally
considered to play only a limited role in immune activation
John H. Stone, Yoh Zen, Vikram Deshpande. IgG4-Related Disease. N Engl J Med 2012;366:539-51

THE IGG4 MOLECULE
• A unique characteristic of IgG4 is its half-antibody
exchange reaction, also referred to as fragment
antigen-binding (Fab)–arm exchange
• IgG4 easily forms disulfide bonds within the heavy
chains in its hinge region because the disulfide
bonds between the heavy chains of the IgG4
molecule are unstable
• In an IgG4 molecule without disulfide bonds
between the heavy chains, dissociations of the
noncovalent bonds permit the chains to separate
and recombine randomly, such that asymmetric
antibodies with two different antigen-combining
sites are formed
• The resulting bispecific (functionally monovalent)
IgG4 molecules are unable to crosslink antigens,
thereby losing the ability to form immune complexes

THE IGG4 MOLECULE
• IgG4 has rheumatoid factor activity and can bind the Fc portion of other IgG antibodies, particularly
other IgG4 molecules
• In contrast to classic rheumatoid factor, which binds by means of variable domains, this interaction
between IgG4 and IgG occurs between Fc constant domains
• The Fc interaction between IgG4 molecules is a potential transient intermediate of the Fab-arm
exchange reaction and may contribute to the molecule’s anti-inflammatory function

THE IGG4 MOLECULE
• Physiologic IgG4 responses can be induced by prolonged or repeated antigen exposures
• IgG4 production, like IgE production, is controlled primarily by type 2 helper T (Th2) cells
• Th2 cytokines such as interleukin-4 and interleukin-13 enhance the production of both IgG4 and IgE
• In contrast, interleukin-10, interleukin-12, and interleukin-21 shift the balance between IgG4 and IgE,
favoring IgG4

EPIDEMIOLOGY
P. Brito-Zerón et al. The clinical spectrum of IgG4-related disease. Autoimmunity Reviews 13 (2014) 1203–1210

EPIDEMIOLOGY
• Using these histological findings, it was
estimated that the prevalence of IgG4-RD in
Japan is 2.63–10.2 cases per 1000000 population
• An incidence of 336–1300 new cases each year
• The majority of patients are men (62 to 83%) and
older than 50 years of age
Histopathological Findings
1. The presence of a storiform pattern of sclerosis
2. A dense lymphoplasmacytic infiltrate
3. An increased proportion of IgG4-positive cells
with respect to IgG-positive cells according to
immunohistochemical evidence (The average of this
proportion is an IgG4+/IgG+ plasma cell ratio >40%,
but the criteria varies depending on the organ
affected)

PATHOLOGICAL FEATURES
• Histopathological analysis of biopsy specimens remains the cornerstone in the diagnosis of IgG4-related
disease
• Elevated concentrations of IgG4 in tissue and serum are helpful in diagnosing IgG4-related disease, but
neither one is a specific diagnostic marker
• Correlation with specific histopathological findings is essential, regardless of the serum IgG4
concentration, the number of IgG4-positive plasma cells in tissue, or the ratio of IgG4 to IgG in tissue
• Misdiagnoses of IgG4-related disease are increasingly common because of excessive emphasis on
moderate elevations of serum IgG4 concentration and overreliance on the finding of IgG4-positive
plasma cells in tissue

The Key Morphologic Features of IgG4-Related Disease
A dense lymphoplasmacytic infiltrate that is organized in a storiform
(i.e., matted and irregularly whorled) pattern
Obliterative phlebitis
A mild-to-moderate eosinophil infiltrate

Terumi Kamisawa, Yoh Zen, Shiv Pillai, John H Stone. IgG4-related disease. Lancet 2015; 385: 1460–71
Transection of the bile duct with IgG4-related
sclerosing cholangitis shows diff use wall thickening
A well circumscribed nodule is formed in the
pancreatic head of this patient with type 1
autoimmune pancreatitis

• In glandular organs, the infiltrate tends to aggregate around ductal structures
• The inflammatory lesion frequently forms a tumefactive mass that may destroy the involved organ
• Neutrophils are detected only rarely, in association with mucosal erosions or some pulmonary
manifestations of IgG4-related disease
• Granulomas are also distinctly unusual

• The inflammatory infiltrate is composed of an admixture of T and B lymphocytes
• Whereas B cells are typically organized in germinal centers, T cells are distributed diffusely throughout
the lesion
• All immunoglobulin subclasses may be represented within involved tissue, but IgG4 predominates
• The presence of IgG4-bearing plasma cells is required for a diagnosis of IgG4-related disease, but IgG4-
positive cells are found in a wide variety of inflammatory infiltrates, and the detection of substantial
numbers of IgG4-positive plasma cells is therefore not diagnostic of IgG4-related disease

• Semiquantitative analysis of IgG4 immunostaining helps to distinguish IgG4-related disease from other
conditions
• A variety of cutoff points, ranging from more than 10 to more than 50 IgG4-positive plasma cells per
high-power field, has been proposed
• The ratio of IgG4-bearing plasma cells to IgG-bearing plasma cells further assists in confirming the
diagnosis of IgG4-related disease: a ratio higher than 50% is very suggestive of the diagnosis
• IgG4-related disease is more difficult to diagnose in the late phase of organ involvement, when fewer
plasma cells are present and fibrosis may predominate in some tissues (e.g., the retroperitoneum)

• The closest histopathological mimickers of IgG4-related disease are lymphomas
• Clonality studies are necessary to rule out these cancers
• An early clue to the diagnosis of B-cell lymphoma is the presence of a predominantly B-cell infiltrate
• In contrast, the lymphoid inflammatory infiltrate in IgG4-related disease is composed primarily of T cells
• Tissues from patients with IgG4-related disease show diffuse infiltrates of IgG4-bearing plasma cells, in
contrast to the focal aggregates of IgG4-bearing cells that are detected in most other inflammatory
mimickers of this condition
• A diffuse plasma-cell infiltrate with more than 30 IgG4-positive cells per high power field and a ratio of
IgG4 to IgG that is higher than 50% provides compelling evidence of IgG4-related disease, particularly in
conjunction with the characteristic histopathological appearance

PATHOPHYSIOLOGICAL MECHANISMS
• Potential initiating mechanisms:
1. Genetic risk factors
2. Bacterial infection and molecular mimicry
3. Autoimmunity
• Specific disease pathways:
1. Th2 cells and regulatory immune reaction
2. Role of IgG4 antibodies

Pathophysiological Mechanisms:
Potential Initiating Mechanisms >
Genetic Risk Factors

Methods:
- HLA-A, -B, -C, -DR, and -DQ gene
typing and HLA-DRB1, -DQB1,
and -DPB1 allele typing were
performed by the PCR sequence-
specific primers method and the
restriction fragment length
polymorphism method,
respectively
- In 40 patients with autoimmune
pancreatitis, 43 patients with
chronic calcifying pancreatitis, and
201 healthy subjects

PATHOPHYSIOLOGICAL MECHANISMS:
POTENTIAL INITIATING MECHANISMS >
GENETIC RISK FACTORS
• DQβ1-57 without aspartic acid is associated with disease relapse in Korean populations
• Non-HLA genes in which single-nucleotide polymorphisms are involved in disease susceptibility or
recurrence encode proteins that include cytotoxic T-lymphocyte–associated antigen 4, tumor necrosis
factor α, and Fc receptor–like 3

BACTERIAL INFECTION AND MOLECULAR MIMICRY
• Substantial homology exists between human carbonic anhydrase II and the α-carbonic anhydrase of
Helicobacter pylori
• The homologous segments contain the binding motif of the HLA molecule DRB1*0405
• Homology also exists between the plasminogen-binding protein of H. pylori and the ubiquitin-protein
ligase E3 component n-recognin 2, which is expressed in pancreatic acinar cells
• Antibodies directed against these bacterial components could behave as autoantibodies by means of
molecular mimicry in genetically predisposed persons

AUTOIMMUNITY
• Autoimmunity is widely regarded as the initial immunologic stimulus for the Th2-cell immune response
that is associated with IgG4-related disease
• Serum IgG4 from patients with IgG4-related disease binds to the normal epithelia of the pancreatic
ducts, bile ducts, and salivary-gland ducts
• Potential autoantigens at these sites include carbonic anhydrases, lactoferrin, pancreatic secretory
trypsin inhibitor, and trypsinogens
• Antibodies directed against such antigens, some of which are expressed in various exocrine organs, may
be related to systemic manifestations of IgG4-related disease

SPECIFIC DISEASE PATHWAYS >
TH2 CELLS AND REGULATORY IMMUNE REACTION
• Th2-cell responses are predominantly activated at affected sites
• Tissue messenger RNA (mRNA) expression levels of Th2 cytokines, including interleukin-4, interleukin-5,
interleukin-10, and interleukin-13, are substantially higher than in classic autoimmune conditions
• PBMCs that are collected from patients and stimulated principally produce Th2-type cytokines,
indicating that the peripheral-blood T-cell phenotype is also shifted toward Th2 responses
• Eosinophilia and elevated serum IgE levels, both observed in approximately 40% of patients with IgG4-
related disease, are also mediated by Th2 cytokines

TH2 CELLS AND REGULATORY IMMUNE REACTION
• Another immunologic characteristic of IgG4- related disease is the activation of regulatory T (Treg) cells
• This marks an important contrast to classic autoimmune conditions, in which the function of Treg cells is
impaired
• The activation of Treg cells in IgG4-related disease is indicated by a higher expression level of the FOXP3
mRNA in tissue, as compared with the expression level in classic autoimmune and other conditions, as
well as larger infiltrates of CD4+CD25+ Treg cells at affected sites and increased numbers of CD4+CD25
high Treg cells in the blood
• TGF-β appears to be overexpressed in IgG4-related disease
• TGF-β may play a central role in the promotion of fibrosis in IgG4-related disease

ROLE OF IGG4 ANTIBODIES
• There are two possible explanations for the overabundance of IgG4 antibodies:
1. The antibodies may behave as tissue-destructive immunoglobulins
2. The excess of IgG4 may simply be an overexpression of these antibodies in response to an unknown
primary inflammatory stimulus
• The high percentage of IgG4 antibodies that have become bispecific immunoglobulins through the Fab-
arm exchange would render such antibodies unlikely to participate in a tissue-destructive immune
response
• It is possible that a high percentage of IgG4 antibodies retain monospecificity and hence retain their
potential to bind antigens and contribute to destructive inflammation

CLINICAL FEATURES
• General signs and symptoms
• Organ-specific signs and symptoms
John H. Stone, Pilar Brito-Zerón, Xavier Bosch, Manuel Ramos-Casals. DiagnosticApproach to the Complexity of IgG4-Related Disease. Mayo Clin Proc. 2015;90(7):927-939
Shigeyuki Kawa. ImmunoglobulinG4-related Disease: An Overview. JMA Journal 2018

CLINICAL FEATURES:
GENERAL SIGNS AND SYMPTOMS
• IgG4-related disease usually presents subacutely,
and most patients do not appear at first to be
severely ill
• Only 2 small series including a total of 53 patients
with systemic IgG4-RD reported detailed signs
and symptoms at diagnosis
• The main general symptoms included:
1. Asthenia in 14 patients (26%)
2. Weight loss in 11 (21%)
3. Fever in 4 (8%)
Mikael Ebbo et al. IgG4-Related Systemic Disease. Medicine January 2012.

CLINICAL FEATURES:
ORGAN-SPECIFIC SIGNS AND SYMPTOMS
• The classic feature of IgG4-RD is a tumefactive
lesion in 1 or more organs
• Of the 832 reported cases in which the number
of organs affected was detailed, approximately
40% of the patients had single-organ involvement
(Usually with a tumefactive lesion)
P. Brito-Zerón et al. The clinical spectrum of IgG4-related disease. Autoimmunity Reviews 13 (2014) 1203–1210

Mikael Ebbo et al. IgG4-Related Systemic Disease. Medicine January 2012.
Sentinel Signs No (%)
Salivary gland swelling 22 (42%)
Lymphadenopathy 22 (42%)
Jaundice 12 (23%)
Lacrimal gland swelling 14 (26%)
Hepatomegaly 3 (6%)
Splenomegaly 2 (4%)

CLINICAL FEATURES:
ORGAN-SPECIFIC SIGNS AND SYMPTOMS >
IGG4-RELATED PITUITARY AND STALK LESIONS
• IgG4-related pituitary and stalk lesions exhibit
the clinical findings of compressive optic
neuropathy, panhypopituitarism, pituitary
hypothyroidism, AI, and SIADH
• All of which require differentiation from primary
hypophysitis
Shigeyuki Kawa. Immunoglobulin G4-related Disease: An Overview. JMA Journal 2018

CLINICAL FEATURES:
IGG4-RELATED HYPERTROPHIC PACHYMENINGITIS
• Hypertrophic pachymeningitis is a rare
fibroinflammatory lesion that causes thickening
of the dura in the cranium and/or spinal canal
• Presents as radiculomyelopathy, headache, and
cranial nerve palsy
• This condition was considered to be a member of
multifocal idiopathic fibrosclerosis (MIF)

CLINICAL FEATURES:
IGG4-RELATED LACRIMAL AND SALIVARY GLAND LESIONS
• IgG4-related lacrimal and salivary gland lesions
constitute a representative of IgG4-RDs and
correspond to the existing diseases of Mikulicz’s
disease and Küttner tumor
• Characteristic clinical findings include
symmetrical swelling of the lacrimal and salivary
glands with milder exocrine dysfunction and
negative results for anti-SS-A/Ro and anti-SSB/La
autoantibodies, in contrast to those of Sjögren’s
syndrome

CLINICAL FEATURES:
IGG4-RELATED OPHTHALMIC DISEASE
• Patients with IgG4-related lacrimal gland lesions
sometimes develop complicating ocular adnexa
lesions, such as trigeminal nerve branch
enlargement, extraocular muscle enlargement
diffuse orbital fat lesions, orbital mass lesions,
eyelid lesions, and nasolacrimal duct lesions
• All of which might occur independently

CLINICAL FEATURES:
IGG4-RELATED THYROID DISEASE
• AIP and IgG4-RD are significantly associated with
hypothyroidism, which supports the existence of
IgG4-related thyroiditis
• Hashimoto’s thyroiditis is classified as either IgG4
or non-IgG4 thyroiditis based on immunostaining
profiles
• Riedel’s thyroiditis is a chronic fibrosing disorder
of an unknown etiology that is considered to be a
member of MIF

CLINICAL FEATURES:
IGG4-RELATED RESPIRATORY DISEASE
• IgG4-related respiratory disease includes the
imaging findings of intrathoracic lesions, such as
hilar/mediastinal lymphadenopathy, bronchial
wall/bronchovascular bundle thickening,
interlobular septal wall thickening, nodular
shadow, infiltrative shadow, pleural thickening,
and effusion

CLINICAL FEATURES:
AUTOIMMUNE PANCREATITIS
• AIP exhibits the typical clinical features of IgG4-RD:
elderly male preponderance, high serum IgG4 levels,
lymphoplasmacytic infiltration, obstructive phlebitis,
storiform fibrosis, IgG4-bearing plasma cell
infiltration, and a favorable response to
corticosteroid therapy
• Other hallmark AIP features include obstructive
jaundice and pancreatic swelling, which may mimic
pancreatic cancer
• Several autoantibodies are positive in IgG4-RD-
associated AIP, whereas other disease-specific ones,
such as anti-SSA/Ro, anti-SSB/La, and anti-
mitochondrial antibodies, are negative
• The imaging results of irregular narrowing of the
main pancreatic duct and capsule like rim are
specific and very useful for AIP diagnosis

CLINICAL FEATURES:
IGG4-RELATED SCLEROSING CHOLANGITIS
• IgG4-related sclerosing cholangitis is widely
distributed throughout the biliary system
• Lower bile duct lesions need differentiation from
pancreatic cancer and intra-hepatic or hilar
lesions of primary sclerosing cholangitis or biliary
malignancies

CLINICAL FEATURES:
IGG4-RELATED LIVER DISEASE
• IgG4-related liver disease includes some
histological changes
• Some lesions mimic those observed in
autoimmune hepatitis (AIH)

CLINICAL FEATURES:
IGG4-RELATED KIDNEY DISEASE
• IgG4-related kidney disease is characterized by
uriniferous tubules displaying tubulointerstitial
nephritis and sparse glomerular lesions with
membranous glomerulonephritis
• Most patients are diagnosed based on incidental
imaging abnormalities and have only mild urinary
dysfunction, whereas some develop acute or
progressive renal failure

CLINICAL FEATURES:
IGG4-RELATED RETROPERITONEAL FIBROSIS
• IgG4-related retroperitoneal fibrosis is disclosed
by the CT or MRI findings of soft tissue density or
masses around the aorta and ureter
• Peri-ureteral lesions sometimes cause symptoms
of lumbago or back pain due to hydronephrosis,
which may result in renal atrophy and failure

CLINICAL FEATURES:
IGG4-RELATED PERIAORTITIS/PERIARTERITIS
• IgG4-related arterial lesions are characterized by
arterial wall thickening mainly in the adventitia
that responds well to corticosteroid treatment
• Patients with prior luminal dilatation have shown
symptom exacerbation after therapy

CLINICAL FEATURES:
IGG4-RELATED PROSTATE DISEASE
• Patients with IgG4-RD sometimes display ameliorated prostatic symptoms after corticosteroid
treatment, suggesting the presence of IgG4-related prostate diseases
• Present as a symmetrically affected, nontender, swollen prostate in imaging analyses

John H. Stone, Pilar Brito-Zerón, Xavier Bosch, Manuel Ramos-Casals. Diagnostic Approach to the Complexity of IgG4-Related Disease. Mayo Clin Proc. 2015;90(7):927-939.
Serum IgG4 levels in normal subjects
generally range from less than 10 mg/dL to
140 mg/dL

IMAGING FEATURES
• The appearance in images varies considerably, particularly in the lung and kidney
• The imaging features are generally nonspecific and do not permit reliable distinctions between IgG4-
related disease and cancer
• In the pancreas, the presence of a peripancreatic halo and diffuse narrowing of the pancreatic duct
correspond, respectively, to a fibroinflammatory process extending into peripancreatic adipose tissue
and to non-occlusive periductal inflammation
• Arterial lesions are characterized on computed tomography by homogeneous wall thickening and
enhancement in the late phases after the administration of contrast material, corresponding to
sclerosing inflammation involving the adventitia

John H. Stone, Pilar Brito-Zerón, Xavier Bosch, Manuel Ramos-Casals. Diagnostic Approach to the Complexity of IgG4-Related Disease. Mayo Clin Proc. 2015;90(7):927-939.

TREATMENT
• Glucocorticoids
• Conventional steroid-sparing agents
• B-cell depletion

TREATMENT:
GLUCOCORTICOIDS
• These agents are the first-line, standard-of-care
approach for most patients
• Clinical improvement after the start of
glucocorticoid therapy is rapid
• A follow-up serological assessment should be
done about 2 weeks after treatment initiation
• Follow-up radiological assessment is also
appropriate for some types of organ
involvement, such as the pancreas, biliary tree,
lungs, and kidneys
• A poor response to glucocorticoids, however,
should raise the possibility of other diagnoses,
particularly cancer
Dose of Prednisolone Duration
1. 0.6–1 mg/kg, daily 2-4 weeks
2. Tapered by 5 mg every
1–2 weeks
6-18 weeks
3. 2.5-5 mg, daily
Discontinued entirely
after 2-3 months or
maintained about 3
years

TREATMENT:
GLUCOCORTICOIDS
• Both endocrine and exocrine pancreatic function can improve in autoimmune pancreatitis, and salivary
secretion in IgG4-related sialadenitis is more likely to improve after glucocorticoid therapy than is the
glandular function of Sjögren’s syndrome
• Retroperitoneal fibrosis, sclerosing mesenteritis, and fibrosing mediastinitis are less amenable to
therapy with glucocorticoids

TREATMENT:
CONVENTIONAL STEROID-SPARING AGENTS
• Drugs such as azathioprine, mycophenolate mofetil, and methotrexate, all used as means of achieving
additional immunosuppression and sparing patients the effects of long-term glucocorticoids
• None has been tested in prospective, controlled studies, and evidence for their efficacy beyond that
offered by concomitant glucocorticoid therapy is scarce

TREATMENT:
B-CELL DEPLETION
• Rituximab was used initially in patients who did not
respond to glucocorticoids, conventional steroid-sparing
agents, or both
• Under the assumption that B-cell depletion might
ameliorate the condition putatively mediated by high
serum concentrations of IgG4
• The plasma cells generating IgG4 in IgG4-related disease
are mainly of the short-lived type that naturally undergo
apoptosis within weeks, thus once these cells disappear as
programmed, they cannot be repleted after rituximab
administration because their precursors—CD20-positive B
cells—are not available
• IgG4-positive plasmablasts (positive for IgG4, CD38, CD37,
and CD19lo cells) seem to be a good biomarker for IgG4-
related disease and are probably superior to serum IgG4
concentrations for diagnosis and monitoring of disease
activity

LONG-TERM PROGNOSIS
• Recent studies have found that long-term disease affliction may instead transition to:
1. Transition to advanced-stage conditions exhibiting dysfunction
2. Complicating malignancy

LONG-TERM PROGNOSIS:
TRANSITION TO ADVANCED-STAGE CONDITIONS EXHIBITING
DYSFUNCTION
• AIP: chronic pancreatitis
• IgG4-related dacryoadenitis and sialadenitis:
exocrine dysfunction
• IgG4-RKD: renal atrophy
• IgG4-related periaortitis: luminal dilatation

LONG-TERM PROGNOSIS:
COMPLICATING MALIGNANCY
• A close association of IgG4-RD with malignancy in
the elderly has been reported that was
presumably due to persistent inflammatory
tissue damage or impaired immunosurveilance

IgG4-related disease

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