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Expert Rev Clin Immunol. Author manuscript; available in PMC 2018 April 12.
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Published in final edited form as:

Expert Rev Clin Immunol. 2017 September ; 13(9): 867–875. doi:10.1080/1744666X.2017.1354698.

Diagnostic and treatment workup for IgG4-related disease

Mary Abraham and
Emory University School of Medicine, 1365 Clifton Rd, 3rd floor, Atlanta, GA 30322

Arezou Khosroshahi
Assistant Professor of Medicine, Emory University School of Medicine, 1365 Clifton Rd, 3rd floor,
Atlanta, GA 30322
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Abstract
Introduction—IgG4-Related Disease is a newly recognized condition which is increasingly
diagnosed by practitioners due to improvement in clinical awareness. Men and women have been
found to be affected by this disease in various organs, more commonly with involvement of the
salivary and lacrimal glands as well as pancreas and liver.

Areas Covered—The diagnosis and management of this condition remain challenging as

biomarkers and therapies are being investigated. Hallmark features on histology are still the gold
standard for confirmation of diagnosis, whereas serum IgG4 level has been shown to be neither
necessary nor sufficient for the diagnosis. Glucocorticoids remain the most effective initial
management for this condition while there are limited clinical trials on the effectiveness of
maintenance therapy.
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Expert Commentary—This review serves as an update on approaches for diagnosis and

management of IgG4-RD. Most of the known data in this field comes from retrospective cohort
studies and expert consensus guidelines but new ongoing prospective studies, clinical trials and
better understanding of the pathogenesis of this condition are promising.

Keywords
IgG4-RD; IgG4; Diagnosis and Management; plasmablasts; rituximab; glucocorticoids;
autoimmune

1- INTRODUCTION
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IgG4 related disease (IgG4-RD) is a systemic immune-mediated fibro-inflammatory

condition often involving several organ systems at the time of diagnosis or over time. The
concept of IgG4-RD emerged from an entity called autoimmune pancreatitis (AIP) only a
decade ago when Dr Kamisawa, a Japanese gastroenterologist, observed identical
pathological findings in other affected organs in patients with AIP(1). This disease is now

Correspondence to: Arezou Khosroshahi.

Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies,
honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
 Abraham and Khosroshahi Page 2

well known to affect almost any organ, with the most common reported in the pancreatic and
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biliary systems as well as salivary/lacrimal glands (2). The diagnosis is not often
straightforward, as clinical involvement of organs may occur in a chronological or
metachronous fashion. The disease is defined by mass forming lesions containing abundance
of IgG4 producing plasma cells, lymphocytes and fibrosis, mimicking malignancy. IgG4-RD
is responsive to glucocorticoid treatment, and timely identification of the disease can prevent
significant complications and organ damage. A series of previously idiopathic fibrosing
disorders such as idiopathic retroperitoneal fibrosis named as Ormond’s disease, Riedel’s
thyroiditis, sclerosing mesenteritis and Mikulicz disease among others have now been
recognized as part of IgG4-RD spectrum. IgG4 related diseases are commonly misdiagnosed
partly because of lack of familiarity of the clinicians and partly due to lack of a reliable
biomarker for this condition. Often elevated serum IgG4 concentration (3) is considered as a
biomarker to make the diagnosis and differentiate this condition from its mimickers (4)
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listed in Table 1 which can be misleading. The clinicohistopathological confirmation of

IgG4-RD, yet remains the main approach for the diagnosis of this protean condition.

The epidemiology of IgG4-RD has not been fully determined due to the rarity of the
diagnosis as well as misdiagnosis. A study from Japan in 2009 (5) revealed a prevalence of
8000 in their population, with males predominantly affected more than females, and an
average age of onset of 58.8 years with peak age of onset between 61 and 70 years. Cohorts
from Western countries have confirmed similar age and sex distributions but the true
estimates of incidence and prevalence of this condition remain unclear in the United States
and other countries, contributing to the difficulty in identifying those at risk of the disorder
(6). Although this condition most commonly affects elderly men, its head and neck
involvement seems to be equal between the two genders(7). IgG4-RD is typically reported to
occur in elder adults mostly, however there have been case reports showing children,
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predominantly females, are also affected (8).

2- CLINICAL PRESENTATION
Patients usually present with subacute formation of a mass lesion in an organ. The disease
itself does not cause constitutional symptoms or pain. Most often, patients’ complaints that
bring them to their physicians are due to cosmetic concerns because of salivary or lacrimal
gland involvement, obstructive symptoms due to mechanical compression of the mass like
obstructive jaundice in cases of pancreatitis and cholangitis, or obstructive uropathy due to
retroperitoneal fibrosis.

The frequency of reported organ involvement and presenting manifestation of IgG4-RD

varies significantly according to the subspecialty evaluating the patients. Most
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gastroenterologist see autoimmune pancreatitis followed by cholangitis as the most common

presentation of the disease, while rheumatologists may see more involvement of the salivary
and lacrimal glands.

60% of patients with IgG4-RD have more than one single organ involvement at the time of
diagnosis. A thorough history and physical exam can reveal other asymptomatic organ
involvement. As a common example, many patients with obstructive jaundice due to

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autoimmune pancreatitis are found to have bilateral submandibular gland involvement which
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could guide the clinician to have high suspicion for IgG4-RD and spare the patient from
invasive pancreatectomy due to concern for cancer. Many other organ involvements are
asymptomatic and can only be found by comprehensive imaging of the chest and abdomen.

Lymphadenopathy has been reported between 25–60% in different cohorts of patients with
IgG4-RD (6, 7) making lymphoproliferative disorders one of the big mimickers of IgG4-RD.
Tissue biopsy of the lymph node is not diagnostic for IgG4-RD as the characteristic fibrosis
of IgG4-RD does not happen in this tissue and other histologic features including IgG4
lymphoplasmacytic infiltrates are non-specific findings in lymph nodes. Based on the
histological diversity, 5 different subtypes of IgG4-related lymphadenopathy have been
proposed (9, 10) but none of the variants have the specific characteristics for the diagnosis of
IgG4-RD. However, lymph node biopsy to exclude malignancy, specifically lymphoma, is
necessary.
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Approximately 30–40% of patients with IgG4-RD have history of allergies including

asthma, eczema, seasonal or food allergy(11). More investigation is needed to clarify if this
history plays any significant role in the pathogenesis of this condition.

3- PATHOGENESIS
Pathogenesis of IgG4-RD is not fully understood. Over the past few years, a few models of
disease mechanism have been suggested. The abundance of plasma cells in the tissue and
increased level of IgG4 produced by antibody producing cells suggested a major role for B
cell and plasma cells. This role has been demonstrated by significant improvement of
patients with IgG4-RD after B cell depletion. Recent studies are suggesting that
dysregulated follicular helper T cells and CD4+ cytotoxic T cells may orchestrate IgG4-RD
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pathogenesis both by secreting profibrotic cytokines and by inducing IgG4 class switch,
plasma blast expansion and production of autoantibodies (12) (13) (14) (15). The role of
innate immunity also has been studied showing promotion of IgG4 production by innate
immune cells, such as plasmacytoid dendritic cells and monocytes isolated from patients
with IgG4-RD (16). The role of IgG4 molecule in pathogenesis of IgG4-RD has not been
proven. In general, IgG4 antibody is considered a non-inflammatory antibody and
traditionally dampens the activation of immune system. There are only a few specific
conditions in which IgG4 antibody plays a pathogenic role such as in pemphigus vulgaris
and thrombotic thrombocytopenic purpura. In IgG4-RD, the correlation between serum IgG4
and disease severity and observation of IgG4 immune complexes in IgG4-related
tubulointerstitial nephritis may suggest a pathogenic role for this antibody but needs to be
confirmed with further investigation
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4- DIAGNOSIS
Clinical history and thorough physical examination, coupled with lab testing, imaging and
most importantly histopathological examination remain the most accurate method to
diagnose IgG4-RD. It is imperative to obtain histopathologic confirmation of IgG4-RD
especially in tumefactive lesions where malignancy must be excluded. IgG4-RD should be

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considered when mass lesions present in typical organs including pancreas, salivary and
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lacrimal glands, lungs, liver, kidney and retroperitoneum. Rigorous exclusion of IgG4-RD
mimickers is the first and foremost important responsibility of clinicians. Although this
disease has been under recognized, it is necessary to consider the diagnosis while evaluating
patients with clinical findings suspicious of this condition. We can not emphasize enough the
importance of a vigorous work up to ensure malignancy or infection is not the underlying
cause of fibro inflammatory organ involvement.

Several conditions previously described as idiopathic fibrosing diseases are now considered
part of IgG4-RD. Table 2 summarizes a list of such conditions previously known as separate
entities which can now be categorized as different manifestations of IgG4-RD (17–21).

Although several diagnostic criteria for IgG4-RD, AIP, and IgG4-related kidney disease
have been proposed (22–24), clinicopathological correlation for the diagnosis can not be
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substituted by any diagnostic criteria for clinical purposes.

1. Laboratory
Elevated serum IgG4 levels were initially pivotal to the diagnosis of IgG4-RD but it has
been found that it is neither necessary nor sufficient for the diagnosis. Studies have shown
elevated IgG4 levels do not confirm and low IgG4 serum levels do not rule out IgG4-RD.
Great mimickers of IgG4-RD including pancreatic adenocarcinoma, lymphoma, and ANCA
associated vasculitis can present with elevated serum IgG4 levels while biopsy confirmed
IgG4-RD patients can have normal IgG4 concentrations. A meta-analysis of predominantly
Caucasian and Asian patients did not reveal a specific cut off value for serum IgG4 level to
diagnose IgG4-RD, but did find significantly high pooled sensitivity and specificity for
serum IgG4 level testing (25). However, another study has shown specificity and positive
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predictive value of elevated serum IgG4 concentrations to be 60% and 34% respectively
(26). Typically, an elevated serum IgG4 concentration in the right clinical setting with
typical organ involvement of IgG4-RD can favor or heighten clinical suspicion of IgG4-RD.
It is important to emphasize elevated IgG4 levels can be found in other diseases, especially
other autoimmune conditions, asthma, allergies, plasma cell dyscrasia, multicentric
castleman disease and other malignancies. Patients with more than 2 organ involvement of
IgG4-RD, usually have higher serum IgG4 concentrations and it is unlikely to have normal
serum IgG4 with multiple organ involvement. On another note, the higher serum IgG4 has
higher likelihood of representing IgG4-RD. There are only a few conditions that can cause
serum IgG4 concentrations > 5 times upper limit of normal. Increased ratios of IgG4 to total
IgG (>10%) is also a helpful finding and can increase diagnostic specificity, especially when
IgG4 concentrations are only slightly raised (27).
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Monitoring of serum IgG4 concentrations in assessment of disease activity seems useful in

some patients, but cannot be considered as the only determinant of disease activity and
prompt treatment. The serum IgG4 concentration decreases rapidly after treatment with
glucocorticoid or B cell depletion in most patients, but many patients do not achieve normal
levels while in clinical remission. Disease relapses also can occur in 10% of patients with
low serum IgG4 (28). In a prospective trial of rituximab in IgG4-RD, higher baseline
elevations in serum IgG4, IgE and blood eosinophil concentrations predicted greater risk of

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IgG4-RD relapse as well as shorter time to relapse (29), arguing for the measurement of
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these values prior to treatment.

When interpreting low serum IgG4 levels, one must rule out the effects of prozone
phenomenon in the immunoassay, a condition in which excess antigen competes for binding
sites on the antibody, and thereby causes immune complexes to resolubilize and reduce the
signal detected. It is important to recognize this phenomenon as many clinicians rely on an
elevated serum IgG4 level for diagnosis and often miss patients who actually have IgG4-RD
due to inaccurately low serum IgG4 level. (30). Egner et al found that 4 years after the initial
report of prozone phenomenon in IgG4 assay, this error still occurs in 41% of the high serum
IgG4 measurements causing spurious reading in their cohort at UK (31). It is highly
encouraged to dilute the test sample to allow the antibody concentration to remain in excess
of the antigen concentration and check for prozoning in the initial sample. This simple check
will enable the identification of elevated serum concentrations of IgG4 that may otherwise
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be missed.

The identification of high numbers of plasmablasts within blood by flow cytometry has been
suggested to be a more sensitive biomarker than serum IgG4 concentrations for disease
activity in IgG4-RD. Plasmablasts are usually found elevated in active IgG4-RD, even in
those with normal serum IgG4 concentrations, and has been shown to decrease when
compared to controls after treatment with rituximab (32). Measurement of plasmablasts is
done by flow cytometry on fresh blood samples and is not easy to perform regularly other
than in research settings.

Doorenspleet et al (33) have recently shown a significant role for measurement of dominant
IgG4 B cell receptor clones as a biomarker for IgG4 related cholangitis. Their initial study
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showed abundance of these specific clones measured by next generation sequencing in both
peripheral blood and tissue of the patients with IgG4 related cholangitis (34). They
developed a more affordable and practical technique of quantitative polymerase chain
reaction (qPCR) to measure the ratio of IgG4/IgG RNA of the same B cell receptors and
found sensitivity of 94% and specificity of 99% for diagnosis of IgG4-related cholangitis.
Serum IgG4 concentration’s sensitivity and specificity were calculated in the same study and
were 86% and 73% respectively (33). Measurement of IgG4/IgG RNA ratio by qPCR can be
a promising biomarker for the disease but will need further validation in other cohorts.

Hypocomplementemia has been found among active IgG4-RD patients with systemic
disease specifically with renal involvement (35). However, traditionally IgG4 molecule is
not thought to bind complement well and the low complements associated with renal disease
in these patients may be due to the associated higher concentrations of other IgG subclasses,
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such as IgG1(36) (37). Research on anti-hinge antibodies found in patients with RA, may
help elucidate the role of complement activation in IgG4-RD ((38).

IgE levels and peripheral eosinophilia have been other common features in IgG4-RD as are
positive anti-nuclear antibody and rheumatoid factor at low titers (35, 39). C-reactive protein
and erythrocyte sedimentation rate are nonspecific markers of inflammation and are not
typically elevated due to IgG4-RD unless associated with another type of inflammation at

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the time of diagnosis like in cases of aortitis or cholangitis. (35) There has been significant
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debate between investigators if elevated CRP is more suggestive of multi-centric castleman

disease rather than IgG4-RD. At this point, we conclude that if there is significant elevation
of CRP, the clinician should consider other diagnoses including multicentric castlman
disease and use their insightful interpretation of this laboratory finding in correlation with
other clinicopathological features to make the diagnosis. A list of most common laboratory
findings associated with IgG4-RD is summarized in Table 3.

2. Imaging
Often patients with IgG4-RD present with tumor like lesions and have already undergone
either a computed tomography (CT) or magnetic resonance imaging (MRI) of the area
affected by the disease to further characterize the disease.

Most cohorts report 56–60% of patients with IgG4-RD have multiple organ involvement at
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the time of diagnosis (40). However, many patients have clinical findings of one organ
involvement at the time of diagnosis by history and physical exam, making the discovery of
other organ involvement only possible by imaging studies.

As most symptoms of IgG4-RD are due to mass effect or damage to the organ due to
fibroinflammatory infiltration, it is fair to say many patients may have evidence of other
organ involvement on the cross -sectional imaging while being asymptomatic. Thus,
performing a thorough imaging of chest and abdomen is necessary for assessment of disease
activity at the time of the diagnosis. There have been much discussions among IgG4-RD
investigators regarding the specific type of imaging and which modality is the best to
evaluate the disease activity. 18-Fluorodeoxyglucose positron emission tomography (FDG
PET/CT) has shown effective diagnostic utility in IgG4-RD due to its ability to identify
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active inflammatory lesions, enabling a delineation of disease extent (41). Most investigators
find FDG PET/CT imaging a difficult and expensive test to perform at the diagnosis of each
patient and for monitoring of disease activity. It may be best to conclude that IgG4-RD
patients will require a whole body imaging assessment but leave it to the discretion of the
clinician to choose between computed tomography with contrast, magnetic resonance
imaging or PET/CT. There are certain imaging findings which in the right context would
make the clinician more confident to make the diagnosis of IgG4-RD. The characteristic
imaging patterns that are strong indicators of IgG4-RD (41, 42) are listed in Table 4.

Additionally, there have been suggestions for a role for gallium SPECT/CT in the diagnosis
of IgG4-RD and its treatment response (43). As this test is cheaper and more readily
available than FDG PET CT scan, if studies confirm that it offers similar diagnostic efficacy,
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it would be a better option (44). There are also thoughts that gallium SPECT/CT may be
superior to PET/CT for IgG4-RD in the kidneys because it allows differentiation of renal
involvement and perirenal pseudotumor (45).

3. Histopathology
Histopathologic assessment of the affected organs remains the gold standard for the
diagnosis of IgG4-RD. In most cases the biopsy is the best way to exclude the mimickers of
IgG4-RD including malignancy or infection. Needle biopsies may provide sufficient tissue

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to exclude the mimickers but not enough evidence to evaluate for the characteristic histology
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for IgG4-RD. Pathological findings of dense lymphoplasmacytic infiltration, storiform

fibrosis (an irregularly cartwheel like fibrotic pattern), and obliterative phlebitis are three
hallmarks ofIgG4-RD in the tissue [Figure 1A] (46). According to the consensus statement
on the pathology of IgG4-RD, two out of the three histological findings are needed for IgG4-
RD diagnosis (47). Findings of tissue eosinophilia and presence of germinal centers in the
affected organs are common on biopsy specimens and can strengthen suspicion for this
disease. On the other hand, presence of granuloma, prominent neutrophilic infiltration and
necrosis are findings that would exclude the diagnosis of IgG4-RD and increase the
suspicion for infections, sarcoidosis or other autoimmune process like granulomatosis with
polyangiitis (GPA). For pathological diagnosis of IgG4-RD, in addition to the above
histology, presence of IgG4 + plasma cells infiltrating the tissue is necessary [Figure 1B].
There has been controversy in the agreement for the required number of IgG4 plasma cells
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and it can vary in different organs. The consensus pathology statement considers at least >
10 in some organs including pancreas and >50 in most organs and a ratio of IgG4+ to IgG+
plasma cells of > 40% (47). This rate is associated with sensitivity of 94.4% and a specificity
of 85.7% (48).

However, IgG4 + plasma cell infiltration has been frequently seen in mimickers of IgG4-RD
and therefore, without the above mentioned histological findings, should not be diagnostic
for the disease. Relying solely on the number of IgG4 +plasma cells may misdiagnose cases
of pancreatic cancer, castleman disease, GPA, sarcoidosis, infections and lymphomas.
Although pathology is the key in the diagnosis, similar pathologic findings in certain tissue
in the absence of typical organ involvement may be considered nonspecific. Skin, lymph
node, thyroid and nasosinus cavities are among the sites that can show IgG4+ plasma cells in
the setting of fibro inflammation without specificity.
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Also, it is important to highlight that a negative or inconclusive biopsy result should not rule
out IgG4-RD due to inherent sampling variability present in needle biopsies and sometimes
fibrotic phase of the disease which lacks inflammation and IgG4+ cells.

4- TREATMENT & MANAGEMENT

As there has been no randomized controlled study on the treatment of IgG4-RD, the best
evidence-based optimal treatment of this disorder is still unknown. Several observational
studies have reported the effectiveness of certain medications in inducing remission and
maintaining lower relapse rates which are discussed here further. The choice of using certain
medication for treatment of IgG4-RD varies in different countries, among specialties and
different organ involvements (49).
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1. Glucocorticoid treatment
Glucocorticoids are cornerstone therapy for this condition. There has been report of 97–
100% response to glucocorticoid therapy in this disease (37). Response to glucocorticoids
has become part of the diagnostic criteria for diagnosis of AIP (23). In most studies,
glucocorticoids are used as the initial therapy for induction of IgG4-RD and many clinicians
use low dose 5–7.5 mg of prednisone equivalent for maintenance therapy. Despite short

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follow ups, between 40–76% of patient who had successful treatment with glucocorticoids
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will relapse in the same organ or another, requiring several induction treatments and long
tapers (50). Patients with IgG4-RD are usually older and have a high tendency to develop
diabetes due to pancreas injury and are subject to significant complications of steroid
therapy including challenges with sugar control, cataract, osteoporosis and increased
cardiovascular disease. The international consensus guidelines on the management of IgG4-
RD recommends 2–4 weeks of induction therapy with prednisone equivalent of 0.6 mg/kg or
30 mg/day. The glucocorticoid dose can be tapered over 8–12 weeks (4). During tapering,
IgG4-RD has been known to relapse frequently (51). The relapse episodes are treated with
the same induction regimen and many clinicians decide to start patients on steroid sparing
regimen after the first relapse. Some clinicians may keep the patients on long courses of low
dose steroid as maintenance therapy.

2. Steroid Sparing Strategies

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Due to the paucity of evidence on steroid-sparing agents in IgG4-RD and lack of any
prospective controlled trials, it has been difficult for clinicians to choose one treatment
strategy over others. According to a recent meta-analysis(49), azathioprine was used in 85%
of cases, with the next common being mycophenolate mofetil, methotrexate, tacrolimus,
leuflenomide and cyclophosphamide. Many patients have been reported to relapse on low
doses of azathioprine (50 mg po daily) or mycophenolate (1 g po daily). It has been reported
that the disease has been controlled by increasing the dose but upon evaluation of the series’
most of the responses were achieved in combination with glucocorticoids making it difficult
to assess their efficacy (49). There have been no studies comparing the efficacy of these
conventional steroid sparing agents. The choice of immunosuppressive agent is heavily
influenced by specific organ involvement and the specialty of the clinician taking care of the
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patient. Most studies on AIP have used azathioprine as steroid sparing agent of choice as it
is most common immunosuppressive agent used by gastroenterologists.

3. Biologics
Rituximab has shown promise in treating patients with IgG4-RD in multiple case series (52)
and a prospective open label study of 30 patients which showed 97% response rate with
significant reduction in patient’s baseline IgG4-RD responder index (IgG4-RD RI). The
primary outcome of this trial was defined as decline in IgG4-RD RI >2, no disease flare
before month 6th and off any glucocorticoid between months 2 and 6 was achieved in 77%
of the patients. Similar results were observed by other investigators conforming a significant
role of B cell depletion in this condition (53). In clinical practice rituximab is usually
considered the first steroid sparing agent after a relapse in countries that the medication is
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available (54).

Bortezomib, a proteasome inhibitor previously used to treat multiple myeloma, was reported
in a patient with IgG4-RD refractory to steroids and surgical treatment, with clinical
improvement in orbital pseudotumor and pulmonary infiltration (55). However, it is
important to note bortezomib was used in combination with cyclophosphamide and therefore
is unclear if bortezomib is truly clinically effective. Yamamota et al described the
effectiveness of abatacept in a rituximab refractory IgG4-RD patient, suggesting a more

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important role for T cells in the pathogenesis of IgG4-RD. The patient in this study had
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complete depletion of CD 19+ cells and still had a relapse (56). Although the mechanism in
which abatacept helped maintain relapse-free period in this IgG4-RD patient is unknown,
the author surmises a role for follicular helper T cells as well as a role in which abatacept
makes dendritic cells and macrophages secrete indoleamine 2,3-deoxygenase, which can
inhibit the proliferation of T cells (57, 58).

Infliximab, a monoclonal antibody against tumor necrosis factor alpha, was recently
proposed for use in the treatment of IgG4-related orbital disease refractory to corticosteroid
treatment. This biologic is known to be beneficial in severe orbital inflammation refractory
to conventional immunosuppressive treatment and is suggested to have beneficial effects in
IgG4-related orbital diseases through interference of IgG4 production in activated plasma
cells and mediation by Th2 lymphocytes (59).
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4. Radiation
Radiation has traditionally been a useful treatment for orbital pseudotumors. Since the
understanding of IgG4-RD and its significant response to glucocorticoids and B cell
depletion, clinicians try to spare patients from radiation therapy but there still exist cases
who are intolerant to steroids and radiation therapy may be beneficial. One recent case series
of IgG4-related ocular adnexal disease reported clinical improvement and ability to taper
steroids with minimal complications (60).

5. Stents
IgG4-RD is a fibroinflammatory condition. Delay in prompt treatment, may lead to
significant fibrosis and damage which will be refractory to glucocorticoid and other
immunosuppressive treatment. The fibrotic tissue or mass can cause mechanical obstruction
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and dysfunction of the organ which can be relieved mechanically. In the setting of
obstructive jaundice secondary to IgG4 related cholangitis, there is a role for relieving
obstruction or biliary strictures through endoscopic placement of metal or plastic stents.
(61). Similarly, in IgG4-RD retroperitoneal fibrosis, several case reports have shown the
benefit of ureteral stenting when significant ureteral obstruction is present (62, 63).
Sometimes these measures are used for temporary relief in the acute presentation until the
medical treatment start working. In some cases, it may be the patient’s only option because
of end stage disease.

5- PROGNOSIS
As there have been limited studies on IgG4-RD, the natural course of IgG4-RD remains
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incompletely defined. Case reports and case series indicate some patients improve
temporarily without treatment, but many experience a recurrence of their disease in the same
or another organ and may have chronic progressive disease (64). It is important to evaluate
for multiorgan involvement in patients who present with single organ disease because lack of
prompt treatment of certain organs can cause irreversible damage. In those without any
treatment, cirrhosis and portal hypertension, retroperitoneal fibrosis, complications from

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aortic aneurysms, biliary obstruction and diabetes mellitus are all causes of significant
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morbidity and mortality. Further studies are needed to delineate long term prognosis.

There have been few recent studies, suggesting an increased risk of cancer in patients with
IgG4-RD compared to general population. Yamamto et al and Hugget el all reported an
10.4% and 11% rate of malignancy in their IgG4-RD cohort over a 3-year period with
estimated risk of approximately 3 times higher than general population (65). Study by Asano
et al (66) even showed more striking results with rate of 22% over a mean follow up of 6
years. The older age of these patients in the IgG4-RD cohorts and the frequent cross
sectional imaging for monitoring their disease activity could be important bias in these
studies. More detailed investigations are required to evaluate the true relationship between
IgG4-RD and malignancy.

6- CONCLUSION
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Tissue biopsy remains the gold standard for the diagnosis but vigorous clinicopathological
correlation is the mainstay for confirming IgG4-RD [Figure 2]. Awareness of clinicians
about this condition will increase their consideration and rate of prompt diagnosis which is
essential to prevent damage in critical organs. The lack of reliable biomarker for this
condition has been an important hurdle for diagnosis. Advances in understanding its
pathogenesis, especially in the role of plasmablasts as well as the interaction between T cells
and B cells has led to exciting and promising ideas which may lead to new biomarker and
novel therapeutic options. It is still unknown which steroid-sparing medications would be
beneficial in IgG4-RD due to lack of randomized controlled trials. However, with increased
awareness and international collaborations, the field will move forward to conduct new
clinical trials to show efficacy of medications for maintenance therapy in IgG4-RD.
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Expert Commentary
IgG4-RD tend to present as tumerous lesions mimicking malignancy, infectious disorders or
inflammatory conditions like GPA (Wegener’s). Most patients undergo invasive procedures
for resection or biopsy of the affected organ to exclude other conditions. Unfortunately, most
of those patients get dismissed by the clinicians given the good news that their disease was
not malignancy. Many of them have recurrence of the condition in other organs after a few
months or years and return to the medical system for further burdensome and expensive
work ups or present with dysfunction of the organ due to progression of fibrosis which can
cause irreversible damage like cirrhosis, renal failure and loss of vision.

IgG4-RD is an under recognized condition but not a rare disease.

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The most basic determination of the population burden of IgG4-RD is the estimate of its
incidence and prevalence. These estimates do not exist for IgG4-RD because the diagnosis is
so new. There have been only a few studies pertaining to the epidemiology of the disease
from Japan, mostly focused on autoimmune pancreatitis. Understanding the true
epidemiology of IgG4-RD has been hampered by insufficient awareness of this newly
recognized condition. Definitive diagnosis generally requires a biopsy, insightful
interpretation of the pathology by an expert pathologist who considers the disease, and

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rigorous clinicopathological correlation with patient’s history, radiology imaging and

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laboratory findings. Initiation of these protocols takes time and building of awareness to
facilitate proper diagnosis is essential. On the other hand, identification of a reliable
biomarker would facilitate such an effort to identify more patients based on the suggestive
laboratory test. Since the initial recognition of this condition and even up to now in Japan,
the elevation of serum IgG4 concentration and increased numbers of IgG4-positive plasma
cells in tissue have been regarded as diagnostic hallmarks. However, there exists significant
variability in the reported frequency of elevated serum IgG4 in the published series from
44%–100%. Recently, investigators in the West have been disregarding serum IgG4 as a
diagnostic factor for the condition because of lack of accuracy in the assay and values.

Nonetheless, elevation of serum IgG4 is highly suggestive of IgG4-RD particularly in a

patient with characteristic organ involvement such as an orbital tumerfactive lesion. An
elevation greater than 2 fold of upper limit of normal (normal: 140 mg/dl) has a specificity
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of 99% for IgG4-RD and is rarely observed in other conditions. Moreover, in the majority of
patients’ serum IgG4 concentrations correlate approximately with disease activity. Elevation
of the serum IgG4 in many patients with multiple organ involvement is dramatic,
occasionally reaching 30 to 40 times the upper limit of normal.

There is no one test or clinical feature that serves as a definitive marker for the disease. Lack
of a reliable biomarker has caused difficulty in making diagnosis even when a clinician is
aware of this condition. Diagnostic delays in the setting of IgG4-RD can lead to cirrhosis,
pancreatic failure, aneurysms of the thoracic or abdominal aorta, advanced renal
dysfunction, and many other complications. The failure of serum IgG4 assays to identify
potential IgG4-RD patients accurately may also lead to additional morbidity and costs from
unnecessary diagnostic procedures. For this reason, better understanding of the current
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diagnostic tests and correlation of clinicopathological findings summarized in this review

can help the diagnosis and disease activity monitoring of this condition.

One of the most characteristic features of this condition is its responsiveness to steroid
treatment. The response is usually striking and has been part of some of the classification
criteria for diagnosis of IgG4-RD. Although patients with IgG4-RD have complete
remission after a short period of treatment with glucocorticoid, there is a crucial need for an
effective steroid sparing agent for their maintenance therapy. Glucocorticoid side effects are
well known and more pronounced in this patient population as they are usually older and
some have already developed diabetes due to pancreatic insufficiency. In this review, we
have summarized the available treatment strategies which are vastly used by IgG4-RD
experts for treatment of patients with this condition.
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5-year view
This condition has received an official recognition by medical society in the past decade.
Lots have been achieved in its clinical description and responsiveness to treatment. Many
ongoing investigations in understanding the mechanism of the disease will be guiding the
path in the next five years to identify reliable biomarkers for diagnosing the disease and to
approach its management.

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 Abraham and Khosroshahi Page 12

Acknowledgments
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Funding

This manuscript was funded by the National Institutes of Health, National Center for Advancing Translational
Sciences (KL2TR000455 and UL1TR000454)

References
*= of interest; **= of considerable interest

1. Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J

Gastroenterol. 2006; 41(7):613–25. [PubMed: 16932997]
2***. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012; 366(6):539–51. A
thoughtful review of clinical and pathological aspects of IgG4-RD. [PubMed: 22316447]
3. Culver EL, Sadler R, Simpson D, Cargill T, Makuch M, Bateman AC, et al. Elevated Serum IgG4
Levels in Diagnosis, Treatment Response, Organ Involvement, and Relapse in a Prospective IgG4-
Author Manuscript

Related Disease UK Cohort. Am J Gastroenterol. 2016; 111(5):733–43. [PubMed: 27091321]

4***. Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, et al.
International Consensus Guidance Statement on the Management and Treatment of IgG4-Related
Disease. Arthritis Rheumatol. 2015; 67(7):1688–99. An important international consesnsus
statement of the IgG4-RD experts on management of patients with systemic IgG4-RD. [PubMed:
25809420]
5. Uchida K, Masamune A, Shimosegawa T, Okazaki K. Prevalence of IgG4-Related Disease in Japan
Based on Nationwide Survey in 2009. Int J Rheumatol. 2012; 2012:358371. [PubMed: 22899936]
6. Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, et al. IgG4-Related
Disease: Clinical and Laboratory Features in One Hundred Twenty-Five Patients. Arthritis
Rheumatol. 2015; 67(9):2466–75. [PubMed: 25988916]
7. Zen Y, Nakanuma Y. IgG4-Related Disease: A Cross-sectional Study of 114 Cases. The American
Journal of Surgical Pathology. 2010; 34(12):1812–9. [PubMed: 21107087]
8. Karim F, Loeffen J, Bramer W, Westenberg L, Verdijk R, van Hagen M, et al. IgG4-related disease:
Author Manuscript

a systematic review of this unrecognized disease in pediatrics. Pediatr Rheumatol Online J. 2016;
14(1):18. [PubMed: 27012661]
9. Sato Y, Yoshino T. IgG4-Related Lymphadenopathy. Int J Rheumatol. 2012; 2012:572539.
[PubMed: 22719769]
10. Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK. Lymphadenopathy of IgG4-related
sclerosing disease. Am J Surg Pathol. 2008; 32(5):671–81. [PubMed: 18344866]
11. Della Torre E, Mattoo H, Mahajan VS, Carruthers M, Pillai S, Stone JH. Prevalence of atopy,
eosinophilia, and IgE elevation in IgG4-related disease. Allergy. 2014; 69(2):269–72. [PubMed:
24266692]
12. Akiyama M, Yasuoka H, Yamaoka K, Suzuki K, Kaneko Y, Kondo H, et al. Enhanced IgG4
production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the
pathogenesis of IgG4-related disease. Arthritis Res Ther. 2016; 18:167. [PubMed: 27411315]
13. Ohno K, Sato Y, Ohshima K-i, Takata K, Miyata-Takata T, Takeuchi M, et al. A subset of ocular
adnexal marginal zone lymphomas may arise in association with IgG4-related disease. Scientific
Reports. 2015; 5:13539. [PubMed: 26311608]
Author Manuscript

14. Stone JH. IgG4-related disease: pathophysiologic insights drive emerging treatment approaches.
Clin Exp Rheumatol. 2016; 34(4 Suppl 98):66–8. [PubMed: 27586808]
15**. Della-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp
Immunol. 2015; 181(2):191–206. A thourough and detailed review of immunologic aspects of
the IgG4-RD with well illustrated model for mechanism of the disease. [PubMed: 25865251]
16. Watanabe T, Yamashita K, Kudo M. IgG4-Related Disease and Innate Immunity. Curr Top
Microbiol Immunol. 2017; 401:115–28. [PubMed: 27744509]

Expert Rev Clin Immunol. Author manuscript; available in PMC 2018 April 12.
 Abraham and Khosroshahi Page 13

17. Beltrame RC, Friderichs M, Fior BR, Schaefer PG, Thome GG, Silva DR, et al. Acute
tubulointerstitial nephritis with severe renal impairment associated with multisystem IgG4-related
Author Manuscript

disease. J Bras Nefrol. 2016; 38(3):374–8. [PubMed: 27737399]

18. Bennett AE, Fenske NA, Rodriguez-Waitkus P, Messina JL. IgG4-related skin disease may have
distinct systemic manifestations: a systematic review. Int J Dermatol. 2016; 55(11):1184–95.
[PubMed: 27419384]
19. Babur Guler G, Canturk E, Guler E, Oran G, Demir GG, Akcevin A, et al. IgG4-related aortitis
mimicking intramural hematoma. Anatol J Cardiol. 2016; 16(9):728–9. [PubMed: 27609436]
20. Abe A, Manabe T, Takizawa N, Ueki T, Yamada D, Nagayoshi K, et al. IgG4-related sclerosing
mesenteritis causing bowel obstruction: a case report. Surg Case Rep. 2016; 2(1):120. [PubMed:
27797069]
21. Acevedo Ribo M, Ahijado Hormigos FJ, Diaz F, Romero Molina M, Fernandez Rojo MA, Garcia
Rubiales MA, et al. IgG4-related disease and idiopathic membranous nephropathy: “The clothes
do not make the man”. Clin Nephrol. 2016; 86(12):345–8. [PubMed: 27737530]
22. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Comprehensive
diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012; 22(1):21–30.
Author Manuscript

[PubMed: 22218969]
23. Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, et al.
International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the
International Association of Pancreatology. Pancreas. 2011; 40(3):352–8. [PubMed: 21412117]
24. Kawano M, Saeki T, Nakashima H, Nishi S, Yamaguchi Y, Hisano S, et al. Proposal for diagnostic
criteria for IgG4-related kidney disease. Clin Exp Nephrol. 2011; 15(5):615–26. [PubMed:
21898030]
25. Xu WL, Ling YC, Wang ZK, Deng F. Diagnostic performance of serum IgG4 level for IgG4-
related disease: a meta-analysis. Sci Rep. 2016; 6:32035. [PubMed: 27558881]
26. Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of
serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis. 2015; 74(1):14–8. [PubMed:
24651618]
27. Boonstra K, Culver EL, de Buy Wenniger LM, van Heerde MJ, van Erpecum KJ, Poen AC, et al.
Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-
associated cholangitis from primary sclerosing cholangitis. Hepatology. 2014; 59(5):1954–63.
Author Manuscript

[PubMed: 24375491]
28. Kamisawa T, Shimosegawa T, Okazaki K, Nishino T, Watanabe H, Kanno A, et al. Standard steroid
treatment for autoimmune pancreatitis. Gut. 2009; 58(11):1504–7. [PubMed: 19398440]
29. Wallace ZS, Mattoo H, Mahajan VS, Kulikova M, Lu L, Deshpande V, et al. Predictors of disease
relapse in IgG4-related disease following rituximab. Rheumatology (Oxford). 2016; 55(6):1000–8.
[PubMed: 26888853]
30. Khosroshahi A, Cheryk LA, Carruthers MN, Edwards JA, Bloch DB, Stone JH. Brief Report:
spuriously low serum IgG4 concentrations caused by the prozone phenomenon in patients with
IgG4-related disease. Arthritis Rheumatol. 2014; 66(1):213–7. [PubMed: 24431286]
31. Egner W, Swallow K, Lock RJ, Patel D. Falsely low immunoglobulin (Ig)G4 in routine analysis:
how not to miss IgG4 disease. Clin Exp Immunol. 2016; 186(1):57–63. [PubMed: 27125474]
32. Wallace ZS, Mattoo H, Carruthers M, Mahajan VS, Della Torre E, Lee H, et al. Plasmablasts as a
biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis.
2015; 74(1):190–5. [PubMed: 24817416]
Author Manuscript

33. Doorenspleet ME, Hubers LM, Culver EL, Maillette de Buy Wenniger LJ, Klarenbeek PL,
Chapman RW, et al. Immunoglobulin G4(+) B-cell receptor clones distinguish immunoglobulin G
4-related disease from primary sclerosing cholangitis and biliary/pancreatic malignancies.
Hepatology. 2016; 64(2):501–7. [PubMed: 27015613]
34. Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, Verheij J, Baas F, Elferink RP, et
al. Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell
receptor repertoire in immunoglobulin G4 associated cholangitis. Hepatology. 2013; 57(6):2390–8.
[PubMed: 23300096]

Expert Rev Clin Immunol. Author manuscript; available in PMC 2018 April 12.
 Abraham and Khosroshahi Page 14

35. Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, et al. IgG4-Related
Disease: Baseline clinical and laboratory features in 125 patients with biopsy-proven disease.
Author Manuscript

Arthritis & rheumatology (Hoboken, NJ). 2015; 67(9):2466–75.

36. Kawa, S. The Immunobiology of Immunoglobulin G4 and Complement Activation Pathways in
IgG4-Related Disease. Berlin, Heidelberg: Springer Berlin Heidelberg; p. 1-13.
37. Muraki T, Hamano H, Ochi Y, Komatsu K, Komiyama Y, Arakura N, et al. Autoimmune
pancreatitis and complement activation system. Pancreas. 2006; 32(1):16–21. [PubMed:
16340739]
38. van de Stadt LA, de Vrieze H, Derksen NIL, Brouwer M, Wouters D, van Schaardenburg D, et al.
Antibodies to IgG4 Hinge Can Be Found in Rheumatoid Arthritis Patients During All Stages of
Disease and May Exacerbate Chronic Antibody-Mediated Inflammation. Arthritis &
Rheumatology. 2014; 66(5):1133–40. [PubMed: 24782178]
39. Kiyama K, Yoshifuji H, Kandou T, Hosono Y, Kitagori K, Nakashima R, et al. Screening for IgG4-
type anti-nuclear antibodies in IgG4-related disease. BMC Musculoskelet Disord. 2015; 16:129.
[PubMed: 26018403]
40. Inoue D, Yoshida K, Yoneda N, Ozaki K, Matsubara T, Nagai K, et al. IgG4-related disease:
Author Manuscript

dataset of 235 consecutive patients. Medicine (Baltimore). 2015; 94(15):e680. [PubMed:

25881845]
41. Zhang J, Chen H, Ma Y, Xiao Y, Niu N, Lin W, et al. Characterizing IgG4-related disease with
(18)F-FDG PET/CT: a prospective cohort study. European Journal of Nuclear Medicine and
Molecular Imaging. 2014; 41(8):1624–34. [PubMed: 24764034]
42. Inoue D, Zen Y, Abo H, Gabata T, Demachi H, Yoshikawa J, et al. Immunoglobulin G4-related
periaortitis and periarteritis: CT findings in 17 patients. Radiology. 2011; 261(2):625–33.
[PubMed: 21803920]
43. Chuang TL, Hsu BB, Chi CL, Wang YF. Gallium SPECT/CT in evaluation of IgG4-related
disease: A case report and literature review. Medicine (Baltimore). 2016; 95(37):e4865. [PubMed:
27631251]
44. Ishii S, Shishido F, Miyajima M, Sakuma K, Shigihara T, Kikuchi K. Whole-Body Gallium-67
Scintigraphic Findings in IgG4-Related Disease. Clinical Nuclear Medicine. 2011; 36(7)
45. Aoki A, Sato K, Itabashi M, Takei T, Yoshida T, Arai J, et al. A case of Mikulicz’s disease
complicated with severe interstitial nephritis associated with IgG4. Clinical and Experimental
Author Manuscript

Nephrology. 2009; 13(4):367. [PubMed: 19142575]

46. Ghably JG, Borthwick T, O’Neil TJ, Youngberg GA, Datta AA, Krishnaswamy G. IgG4-related
disease: a primer on diagnosis and management. Ann Allergy Asthma Immunol. 2015; 114(6):
447–54. [PubMed: 26021892]
47. Bateman AC, Culver EL. IgG4-related disease – experience of 100 consecutive cases from a
specialist centre. Histopathology. 2016 n/a-n/a.
48. Masaki Y, Kurose N, Yamamoto M, Takahashi H, Saeki T, Azumi A, et al. Cutoff Values of Serum
IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related
Disease. International Journal of Rheumatology. 2012; 2012:580814. [PubMed: 22654917]
49. Brito-Zeron P, Kostov B, Bosch X, Acar-Denizli N, Ramos-Casals M, Stone JH. Therapeutic
approach to IgG4-related disease: A systematic review. Medicine (Baltimore). 2016; 95(26):e4002.
[PubMed: 27368010]
50. Sah RP, Chari ST. Recent developments in steroid-responsive pancreatitides (autoimmune
pancreatitis). Curr Opin Gastroenterol. 2015; 31(5):387–94. [PubMed: 26154429]
Author Manuscript

51***. Hart PA, Topazian MD, Witzig TE, Clain JE, Gleeson FC, Klebig RR, et al. Treatment of
relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic
experience. Gut. 2013; 62(11):1607–15. A thougtful description of experince with treatment of
relapses and maintenance of remission in IgG4-RD using different steroid-sparing agents.
[PubMed: 22936672]
52. Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of
serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis
Rheum. 2010; 62(6):1755–62. [PubMed: 20191576]

Expert Rev Clin Immunol. Author manuscript; available in PMC 2018 April 12.
 Abraham and Khosroshahi Page 15

53. Yamamoto M, Awakawa T, Takahashi H. Is rituximab effective for IgG4-related disease in the long
term? Experience of cases treated with rituximab for 4 years. Ann Rheum Dis. 2015; 74(8):e46.
Author Manuscript

[PubMed: 25862615]
54**. Carruthers MN, Topazian MD, Khosroshahi A, Witzig TE, Wallace ZS, Hart PA, et al.
Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis. 2015; 74(6):
1171–7. A two center prospective open label study of B cell depletion for treatment of IgG4-RD.
[PubMed: 25667206]
55. Khan ML, Colby TV, Viggiano RW, Fonseca R. Treatment With Bortezomib of a Patient Having
Hyper IgG4 Disease. Clinical Lymphoma, Myeloma and Leukemia. 10(3):217–9.
56. Yamamoto M, Takahashi H, Takano K, Shimizu Y, Sakurai N, Suzuki C, et al. Efficacy of
abatacept for IgG4-related disease over 8 months. Ann Rheum Dis. 2016; 75(8):1576–8. [PubMed:
27147710]
57. Yamamoto M, Takahashi H, Takano K, Himi T, Nakase H. Response to: ‘Could abatacept directly
target expanded plasmablasts in IgG4-related disease?’ by Alegria et al. Ann Rheum Dis. 2016;
75(11):e74. [PubMed: 27651399]
58. Davis PM, Nadler SG, Stetsko DK, Suchard SJ. Abatacept modulates human dendritic cell-
Author Manuscript

stimulated T-cell proliferation and effector function independent of IDO induction. Clin Immunol.
2008; 126(1):38–47. [PubMed: 17945538]
59. Balaskas K, de Leval L, La Corte R, Zografos L, Guex-Crosier Y. Infliximab Therapy for a Severe
Case of IgG4-related Ocular Adnexal Disorder Recalcitrant to Corticosteroid Treatment. Ocular
Immunology and Inflammation. 2012; 20(6):478–80. [PubMed: 22946470]
60. Lin YH, Yen SH, Tsai CC, Kao SC, Lee FL. Adjunctive Orbital Radiotherapy for Ocular Adnexal
IgG4-related Disease: Preliminary Experience in Patients Refractory or Intolerant to Corticosteroid
Therapy. Ocul Immunol Inflamm. 2015; 23(2):162–7. [PubMed: 25010381]
61. Mahajan A, Ho H, Sauer B, Phillips MS, Shami VM, Ellen K, et al. Temporary placement of fully
covered self-expandable metal stents in benign biliary strictures: midterm evaluation (with video).
Gastrointest Endosc. 2009; 70(2):303–9. [PubMed: 19523620]
62. Maeta S, Munemura C, Ishida C, Fukui T, Murawaki Y. Case report; Acute renal failure due to
IgG4-related retroperitoneal fibrosis. Nihon Naika Gakkai Zasshi. 2012; 101(4):1079–81.
[PubMed: 22730738]
63. Hart PA, Moyer AM, Yi ES, Hogan MC, Pearson RK, Chari ST. IgG4–related paratesticular
Author Manuscript

pseudotumor in a patient with autoimmune pancreatitis and retroperitoneal fibrosis: an

extrapancreatic manifestation of IgG4–related disease. Human Pathology. 43(11):2084–7.
64. Khosroshahi A, Stone JH. Treatment approaches to IgG4-related systemic disease. Curr Opin
Rheumatol. 2011; 23(1):67–71. [PubMed: 21124087]
65. Huggett MT, Culver EL, Kumar M, Hurst JM, Rodriguez-Justo M, Chapman MH, et al. Type 1
autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic
organ failure, malignancy, and mortality in a prospective UK cohort. Am J Gastroenterol. 2014;
109(10):1675–83. [PubMed: 25155229]
66. Asano J, Watanabe T, Oguchi T, Kanai K, Maruyama M, Ito T, et al. Association Between
Immunoglobulin G4-related Disease and Malignancy within 12 Years after Diagnosis: An Analysis
after Longterm Followup. J Rheumatol. 2015; 42(11):2135–42. [PubMed: 26472416]
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KEY ISSUES
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• The true US prevalence of IgG4-RD is unknown, but is thought to affect

males more than females and have an age of onset between 50–70 years old

• Organs can be metachronously affected often leading to clinical and

diagnostic confusion

• Elevated IgG4 serum level is neither necessary nor sufficient to diagnose

IgG4-RD and in cases of low IgG4 serum level with high clinical suspicion
for the disorder, one must check for the presence of prozone effect

• Measuring circulating plasmablasts or IgG4/IgG RNA ratio may be superior

biomarkers in active IgG4-RD than measuring serum IgG4 level

• Clinicohistopathological findings remain the diagnostic gold standard for this

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disorder

• Glucocorticoids remain the best initial therapy although disease relapse is

common

• Rituximab has shown benefit as steroid sparing treatment of this disease

• Other steroid soaring agents such as methotrexate, azathioprine,

mycophenolate mofetil have been used for maintenance therapy with
unknown efficacy

• Surgical resection and placement of stents can be used if medical treatment

not useful
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Figure 1. Pathology of a lacrimal gland in a patient with multi systemic IgG4-RD

A: High power field view shows significant lymphoplasmacytic infiltration of the gland with
fibrosis (Hematoxylin and Eosin staining)
B: IgG4 immunohistochemical staining of the gland shows marked infiltration of the gland
by IgG4 + plasma cells
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Figure 2. Summary of key elements in diagnosis of IgG4-RD

*Gold Standard and still necessary for diagnosis
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Table 1

Mimickers of IgG4-RD
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Autoimmune Malignancy Other

Antineutrophil cytoplasmic antibody- Adenocarcinoma and Squamous Cell Castleman’s Disease
associated vasculitis Carcinoma

Granulomatosis with Polyangitis Extranodal Marginal Zone lymphoma Cutaneous Plasmacytosis

Eosinophilic Granulomatosis with Inflammatory myofibroblastic tumor Erdheim-Chester Disease

Polyangitis

Microscopic Polyangitis Lymphoplasmocytic Lymphoma Inflammatory Bowel Disease

Sarcoidosis Lymphoproliferative Disease Perforating Collagenosis

Sjogren’s Disease Follicular Lymphoma Primary Sclerosing Cholangitis

Rhinosinusitis

Rosai-Dorfman Disease

Splenic Sclerosing Angiomatoid Nodular

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transformation

Xanthogranuloma
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Table 2

Conditions previously known as separate entities now mostly recognized as part of IgG4-RD
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Mikulicz’s disease

Kuttner’s tumor

Eosinophilic angiocentric fibrosis

Riedel’s thyroiditis

Idiopathic cervical fibrosis

Pulmonary inflammatory pseudotumor

Chronic sclerosing aortitis

Preaortitis and periarteritis

Autoimmune pancreatitis

Sclerosing cholangitis

Idiopathic tubulointerstitial nephritis

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Retroperitoneal fibrosis

Sclerosing mesenteritis

Inflammatory aortic aneurysm

Multifocal fibrosclerosis
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Table 3

Most common laboratory findings associated with IgG4-RD

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Labs associated with IgG4-RD

IgG4 level > 135

Elevated IgG4: IgG ratio >10%

Peripheral eosinophils

CRP normal

ESR normal

ANA low titer positive

Elevated IgE levels

Hypocomplementemia

Increased number of circulating plasmablasts by flow cytometry

qPCR of IgG4/IgG RNA

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Table 4

Imaging findings strongly suggestive of IgG4-RD

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Imaging patterns strongly suggestive of IgG4-RD

Symmetric bilateral enlargement of salivary glands with even distribution of 18F-FDG uptake without signs of infection

Enlargement of lacrimal glands

Involvement of trigeminal nerve branches
Orbital myositis
Orbital adnexal soft tissue

Bronchovascular and septal thickening in the lungs

Pleural or parenchymal nodules

Diffusely enlarged pancreas with loss of lobulation with or without pancreaticobiliary duct narrowing
Enhancement around the pancreatic rim
Pancreatic atrophy due to damage

Patchy or diffuse thickness of aorta wall and soft tissue around the abdominal aorta

Patchy retroperitoneal lesion with moderate to intense 18F-FDG uptake

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Bilateral renal cortex low density areas

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