sciENcE oF MEdiciNE

IgG-4 Related Disease: An Introduction

by Orwah M. Al-Khalili, MD & Alan R. Erickson, MD

Glucocorticoids remain the Abstract Immunohistochemical examinations of

main initial therapy agents IgG4-related disease (IgG- AIP tissues revealed severe infiltration
with expected good and RD) describes a group of with IgG4-positive plasma cells that
quick response. fibroinflammatory diseases further enlightened the existence of
that affect a variety of tissues an IgG4-RD with a possible systemic
resulting in tumor-like effect and/ process.3 In the years to follow, several
or organ dysfunction. Clinical previously described syndromes
presentation varies according were linked to IgG4 infiltration and
to the tissue(s) involved, and now they are labeled as IgG4-RD
diagnosis relies on tissue affecting different tissues or organs.
findings of dense infiltration These syndromes include Mikulicz
of IgG4-positive plasma cells disease4, chronic sclerosing sialadenitis
and a characteristic storiform (Kuttner’s tumor)5, Riedels’
fibrosis. Treatment is mainly with thyroiditis6, mediastinal fibrosis,
glucocorticoids, while multiple retroperitoneal fibrosis (Ormond’s
immunosuppressive medications disease), periaortitis, idiopathic
can be used as adjuvant agents. hypocomplementic tubulointerstitial
Rituximab has showed promising nephritis, multifocal fibrosclerosis, and
results, but further studies are inflammatory pseudotumor.1
needed.
Epidemiology
Introduction The incidence of IGG4-RD
IgG 4 related disease (IgG4-RD) remains unknown. This is due to
is a systemic fibroinflammatory disease challenges in making the diagnosis
characterized by dense infiltration as the disease is often unrecognized
of IgG4-positive plasma cells in the or misdiagnosed. A cohort of 125
affected tissue(s) with or without biopsy proven IgG4-RD showed a
elevated plasma levels of IgG4.1 The mean age of 55 years old at diagnosis
inflammatory infiltration along with (50 years old at onset of symptoms);
a characteristic storiform fibrosis 78% were white and 61% were males.
can lead to the development of Head and neck tissues were the most
chronic damage and/or tumefactive affected sites.7 Mayo Clinic reported
lesions1 that may affect any organ. 166 patients with IgG-RD; the median
Orwah M. Al-Khalili, MD, (above), is In 2001, Hamano and colleagues age of onset was 61 years old and the
a rheumatology Fellow, University of published a study that showed
Nebraska Medical center, omaha, Neb.
male to female ratio was 3:1; 80 %
alan r. Erickson, Md, is an associate the association between elevated of patients were white. In the Mayo
professor of internal Medicine and plasma IgG4 levels and sclerosing Clinic report; hepatobiliary IgG4-RD
rheumatology, University of Nebraska
Medical center, omaha, Neb. pancreatitis 2, which is now called type was the most common entity.8 One
Contact: [email protected] 1 autoimmune pancreatitis (AIP). study from Japan reported 114 of

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cases with a similar male to female ratio of 3:1. The higher IgG4-RD. IL-10 causes increased production of IgG4
incidence of the disease in males persisted regardless of and can lead to fibrosis by increasing the expression of
the tissue affected with the only exception of IgG4-RD in Transforming Growth Factor- beta (TGF-β), which is a
the head and neck (sialadenitis or dacryoadenitis) where fibrogenic cytokine.12 A recent study showed that CD4+
the male to female distribution was equal. In this cohort effector/memory T cells with a cytolytic phenotype were
the average age at diagnosis was 64 years old.9 The disease expanded in IgG4-RD patients. These CD4+ cytotoxic
seems to be less common in the pediatrics population. lymphocytes (CD4+ CTLs) might play a major role in
A systematic review found 22 cases of IgG4-RD in the pathogenesis of the disease. Plasmablasts, which are
children with a median age of 13 years old (age range increased in IGG4-RD, are thought to be responsible for
was 22 months to 17 years); 64% were females in the reactivation of the CD4+CTLs and induce them to
contrast to the male predominance in the adult disease. make fibrosing-inducing cytokines including IL-1β and
In the pediatric population ophthalmic IgG4-RD was TGF-β1.14
the most common entity and it was seen in 44% of the
cases.10 Clinical Presentation
The symptoms of IgG4-RD vary considerably
Pathogenesis depending on the organ(s) or tissues involved. The
Most studies on the pathogenesis and the genetic most common presentation is a mass lesion or
associations of IgG4-RD were conducted in Asian organ enlargement. The most commonly affected
populations with AIP. Both human leukocyte antigen organs are salivary and lacrimal glands, pancreas and
(HLA), and non-HLA genes were associated with IgG4- biliary tract, and the kidneys; but any organ could be
RD. A study from Japan reported that the frequencies involved and multiorgan disease can be also seen.15
of HLA serotypes DRB1_0405 and DQB1_0401 were The inflammatory infiltration and fibrosis can result
significantly higher in patients with AIP than in healthy in tissue or organ dysfunction in addition to tumor-
like effects that can cause obstruction or compression
individuals and in patients with chronic calcifying
complications.16 Among the clinical features observed
pancreatitis not related to AIP. In addition, single are exophthalmos including orbital pseudotumor,
nucleotide polymorphisms (SNPs) in non-HLA genes salivary gland enlargement, pancreatic failure, lymph
were linked to AIP. Those genes include Cytotoxic node enlargement, retroperitoneal fibrosis, kidney
T-Lymphocyte Antigen-4 (CTLA-4) and Tumor necrosis disease with proteinuria and subsequent renal failure,
factor (TNF)- alpha promoter genes. The frequency and aortitis-related aortic aneurysm.17 A number of
of CTLA-4_ 49A and TNF- alpha promoter _863 cases will present as an incidental finding on imaging.
haplotypes were higher in Chinese AIP patients than Presentation is usually subacute, and some patients
in healthy individuals. A Japanese study found that the might have more than one organ affected at the
CTLA-4_49A haplotype is associated with a higher risk same time or years after the initial diagnosis. Many
of disease relapse. Another study reported an association patients have an existing allergic condition. Peripheral
between AIP and Fc receptor-like 3 (FCRL3) _110A/A eosinophilia is not uncommon while fever is rare.1
genotype.11
While impaired function or a decreased number Diagnosis
of regulatory T cells (Treg cells) is believed to be an The diagnosis of IgG4-RD can be challenging
important step in the development of autoimmune and the approach to diagnosis will depend on the site
disorders11, Treg cells seem to play an important role affected. A thorough process should always be followed
in the pathogenesis of IgG4-RD. The expression of to rule out the different diseases that can mimic
Th2 cytokines (IL-4, IL-5, and IL-13) and regulatory IgG4-RD. These diseases include a broad spectrum of
cytokines (IL-10 and TGF-β) was up-regulated in the conditions including malignancy, lymphoproliferative
affected tissues of type 1 AIP12, and in IgG4-related disorders, Antineutrophil cytoplasmic antibodies
tubulointerstitial nephritis.11 Similar findings were (ANCA)-associated vasculitis, sarcoidosis, Sjogren’s
reported in Mickulicz disease.13 The overproduction of syndrome, Castleman’s disease and others.16, 17
IL-4, IL-5, and IL-13 can explain the higher frequency It is important to remember that elevated plasma
of peripheral eosinophilia and IgE levels in patients with IgG4 levels are neither specific nor sensitive for IgG4-

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The assessment
should start with complete
history and physical
examination. Then when
the disease is suspected
lab testing and appropriate
radiology evaluation
will depend on the site
involved. Plasma IgG4
levels should be obtained
in all patients. Most cases
of renal IgG4-RD will
have low complements17,
which often correlates
with disease activity17,
thus complement levels
should be obtained
when renal IgG4-RD is
RD. Normal IgG4 can be seen in nearly one-fourth of suspected. Circulating plasmablasts measurement, if
the cases9, and using a cutoff level for IgG4 of 135 mg/ available, can be helpful especially if the serum IgG4
dl has a positive predictive value for IGG4-RD of only level is normal. Selection of the imaging modality
34%.18 While tissue biopsy is very helpful in ruling out in the assessment of IgG4-RD will depend on the
cancer and other possible disease processes, IgG4+ organ under evaluation, local radiology expertise, and
cellular staining on biopsy alone is not sufficient to availability. Computed tomography (CT), CT with
make a definite diagnosis of IgG4-RD as the presence of positron emission tomography (CT-PET), magnetic
IGG4+ plasma cells in the tissue can be seen in other resonance imaging (MRI), magnetic resonance
diseases including malignancy. In addition, certain sites
cholangiopancreatography (MRCP), Endoscopic
affected by IgG4-RD, like the retroperitoneum, orbital
retrograde cholangiopancreatography (ERCP), and
cavity and pancreas, are very difficult to biopsy.1,16,17
Elevated numbers of circulating plasmablasts can be seen endoscopic ultrasound (EUS) are modalities that
in a variety of inflammatory conditions but a significant are commonly used to evaluate IgG4-RD.17 Biopsy
elevation (>2,000 cells/ml) was observed in IgG4- remains the cornerstone step in evaluation. As noted,
RD and may serve as a marker for both diagnosis and the presence of high level of IgG4+ plasma cells
measurement of disease activity. Plasmablasts elevation (> 10/HPF or IgG4+/IgG4>40%) is typical but
in IgG4-RD was seen even in patients who had normal not diagnostic.9 Findings of storiform fibrosis and
IgG4 levels.19 However, the testing of plasmablasts obliterative phlebitis increase the specificity of the
might not be readily available in all clinical settings and diagnosis.16.17 Diagnosing biliary or pancreatic IgG4-
more studies are needed to advise a universal use of this RD is even more challenging due to difficulties in
test.17 Comprehensive diagnostic criteria for IgG4-RD obtaining adequate tissue samples. The characteristic
and organ-specific IgG4-RD (like AIP and IgG4-related imaging findings and serologic testing become the
kidney disease) exist and they take in consideration the
main diagnostic criteria. Fine needle aspiration of the
clinical, serological, radiographic and histopathologic
pancreas and brush cytology of the biliary system,
al manifestations.16 However, some of the proposed
criteria had low sensitivity (as low as 70%).16 Also, a however, remain important to rule out malignancy.16, 17
major caveat was the ability to make IgG4-RD diagnosis The diagnosis is made by clinical correlation of
without obtaining a biopsy, which can be problematic.17 the laboratory, imaging and histopathologic findings in
The use of these criteria should not replace the need for absence of malignancy or other disease processes that
obtaining a biopsy from the suspected lesion. could explain the presentation (Figure 1).

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Treatment maintenance therapy, however. Maintenance with small

Some patients with asymptomatic IgG4-RD can dose of glucocorticoids is the most practiced approach
be watched without treatment, e.g. asymptomatic in Japan for AIP.17 A steroid sparing agent and Rituximab
lymphadenopathy or mild submandibular gland for maintenance can also be used. Disease relapse or
enlargement.17 However, most patients will require flares should be managed with glucocorticoids and if the
initiation of therapy. Special attention should be made patient is not already on another immunosuppressive
to active IgG4-RD in the pancreas, biliary tree, aorta, then starting an agent should be strongly considered.17
mediastinum, kidneys, retroperitoneum and mesentery
as in those cases starting therapy in an urgent fashion References
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related disease: lessons from 10 consecutive patients. Medicine 2012;91: 57-66
induction is recommended for patients with higher risk
of organ dysfunction or high risk of relapse. There is Disclosure
no consensus on the optimal regimen or duration for None reported. MM

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