REVIEW

Diagnostic Approach to the Complexity of

IgG4-Related Disease
John H. Stone, MD, MPH; Pilar Brito-Zern, MD, PhD; Xavier Bosch, MD, PhD;
and Manuel Ramos-Casals, MD, PhD

Abstract

IgG4-related disease (IgG4-RD) is a systemic disease characterized by the inltration of IgG4-bearing plasma
cells and, more importantly, distinctive histopathological features: storiform brosis, obliterative phlebitis, a
lymphoplasmacytic inltrate, and mild-to-moderate tissue eosinophilia. The diagnostic approach is com-
plex and relies on the coexistence of various clinical, laboratory, and histopathological ndings, none of
which is pathognomonic in and of itself. IgG4-related disease should be suspected in patients presenting
with unexplained enlargement or swelling of 1 or more organs or tissue organs. Four laboratory abnor-
malities often provide initial clues to the diagnosis of IgG4-RD: peripheral eosinophilia, hyper-
gammaglobulinemia, elevated serum IgE levels, and hypocomplementemia. Elevated serum IgG4 levels
provided critical information in identifying the rst cases of IgG4-RD, but recent studies have reported
substantial limitations to the measurement of serum IgG4 concentrations, precluding reliance on serum
IgG4 concentrations for diagnostic purposes. In contrast, new studies have suggested a promising role of
ow cytometry studies in the diagnosis and longitudinal management of IgG4-RD. Demonstration of the
classic histopathological features of IgG4-RD remains crucial to diagnosis in most cases, and biopsy proof is
preferred strongly by most disease experts before the initiation of treatment. Of note, the multiorgan nature
of IgG4-RD was rst established in 2003. This review intends to provide most recent knowledge about the
clinical, laboratory, radiological, and pathological characteristics of IgG4-RD that may guide the physician to
establish an early diagnosis. We searched PubMed and MEDLINE for relevant articles published between
January 1, 2000, and November 1, 2014, using the search terms IgG4 and IgG4-related.
2015 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2015;90(7):927-939

From the Harvard Medical

I
gG4-related disease (IgG4-RD) is a systemic parotid, and submandibular gland involve-
School, Boston, MA
broinammatory disease characterized by ment), and Ormond disease (retroperitoneal (J.H.S.); Department of
the inltration of IgG4-bearing plasma cells brosis). The epidemiology of this disease has Medicine, Division of
into affected organs and tissues. Many patients not been explored in detail, although nearly Rheumatology, Allergy,
and Immunology, Massa-
also have a marked elevation in the serum con- 80% of patients have been reported from Japan, chusetts General Hospital,
centrations of IgG4.1 This disease was rst with a mean age of approximately 60 years at Boston (J.H.S.); Josep Font
identied in the initial years of the 21st century diagnosis and with a male predominance.4 Laboratory of Autoim-
mune Diseases, CELLEX-
by Japanese investigators.2,3 It was recognized Although the clinical presentations are protean Institut dInvestigacions
initially in patients with sclerosing pancreatitisd and the natural history is variable, many organ Biomdiques August Pi i
now known as type 1 (IgG4-related) autoim- system manifestations of IgG4-RD can quickly Sunyer (IDIBAPS), Barce-
lona, Spain (P.B.-Z.,
mune pancreatitisdwho were found to have lead to the failure of vital organs such as M.R.-C.); and Department
the same histopathological features in extrap- pancreas, liver and biliary tree, kidneys, or aorta. of Autoimmune Diseases
ancreatic organs as in the pancreas, thus herald- Few data exist on the diagnostic approach (P.B.-Z., M.R.-C.) and
Department of Internal
ing a multiorgan disease. Since 2003, the disease to patients with suspected IgG4-RD. This re- Medicine (ICMiD) (X.B.),
has been reported in nearly every organ.4 view addresses current knowledge about the Hospital Clnic, University
The diagnosis of IgG4-RD now provides diagnosis of IgG4-RD, focusing on the clinical, of Barcelona, Spain.

context for various single organ syndromes
that once seemed highly disparate. Examples
of this are Riedel thyroiditis, Kttner tumor
(sclerosing sialadenitis of the submandibular
gland), Mikulicz disease (simultaneous lacrimal,
laboratory, radiological, and pathological fea-
tures that may facilitate an early diagnosis of
this complex disease. The authors searched
PubMed and MEDLINE for potentially rele-
vant articles published from January 1, 2000,

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ARTICLE HIGHLIGHTS
n First identied in the initial years of the 21st century as a unied
disorder, IgG4-related disease (IgG4-RD) is a multiorgan entity
that integrates numerous conditions formerly considered un-
related, single-organ diseases.
n Serum IgG4 levels were initially thought to be a key diagnostic
feature of IgG4-RD, but recent evidence has de-emphasized the
value of elevated serum IgG4 levels.
n The key to diagnosis is immunohistochemical demonstration of
tissue inltration by IgG4-bearing plasma cells and morpholog-
ical evidence of lymphoplasmacytic inltrates, storiform brosis,
and obliterative phlebitis.
n Although the heterogeneous clinical, laboratory, and histologi-
cal presentation affecting a wide range of organ systems means
that the diagnostic approach may be complex, IgG4-RD should
be clinically suspected in patients presenting with unexplained
enlargement or swelling of 1 or more organs or tissues.
n The more clinical, laboratory, imaging, and pathological red ags
the patient presents, the greater the likelihood of a diagnosis of
IgG4-RD.
n New research suggests a promising role of ow cytometry
analysis in the diagnosis and longitudinal management of IgG4-RD.
through November 1, 2014, using the search
terms IgG4 and IgG4-related. Searches were
boosted by examining references of identied
articles, and articles judged relevant were
selected for full-text review. We selected pub-
lications since 2000, because it was not until
2003 that the multiorgan nature of IgG4-RD
was unearthed.
CLINICAL SUSPICION
The signs and symptoms of IgG4-RD at presen-
tation are diverse and may be divided into gen-
eral and organ-specic signs and symptoms.
General Signs and Symptoms
IgG4-related disease usually presents sub-
acutely, and most patients do not appear at rst
to be severely ill (ie, constitutional symptoms
such as hectic fevers or other features suggest-
ing infection or sepsis are absent). Some pa-
tients lose a substantial amount of weight (eg,
10-25 lb); however, the period over which
the weight is lost is many months, and many
n n
928 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
weeks elapse before patients realize that they
are ill. Most reports have focused on describing
the organs involved and not on the signs and
symptoms that led ultimately to diagnosis.
Only 2 small series including a total of 53 pa-
tients with systemic IgG4-RD reported detailed
signs and symptoms at diagnosis.5,6 The main
general symptoms included asthenia in 14 pa-
tients (26%), weight loss in 11 (21%), and fever
in 4 (8%).
Organ-Specic 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,4 approximately 40% of the pa-
tients had single-organ involvementdusually
with a tumefactive lesiondat the time of their
description. In the 2 aforementioned small
series,5,6 organ-specic symptoms at diagnosis
included abdominal pain in 21 patients (40%),
sicca features in 8 (15%), respiratory symptoms
in 7 (13%), pruritus in 7 (13%), and diarrhea in
3 (6%). Sentinel signs, that is, ndings that on
further evaluation led directly to the diagnosis,
included salivary gland swelling in 22 patients
(42%), lymphadenopathy in 22 (42%), jaun-
dice in 12 (23%), lacrimal gland swelling in
14 (26%), hepatomegaly in 3 (6%), and spleno-
megaly in 2 (4%).
The presenting features of IgG4-RD vary
substantially according to the specic specialty
evaluating the patient rst. Gastroenterologists
are more likely to encounter patients with jaun-
dice, pruritus, and mild abdominal discomfort
resulting from autoimmune pancreatitis or
IgG4-related sclerosing cholangitis. Ophthal-
mologists are more likely to be referred patients
with lacrimal gland swelling or other orbital le-
sions. Nephrologists may be called to evaluate
patients with renal dysfunction caused by tubu-
lointerstitial nephritis or, rarely, nephrotic
range proteinuria associated with IgG4-related
membranous glomerulonephropathy (GN).
Although rheumatologists are perhaps most
likely to encounter patients with major salivary
gland enlargement because this disease feature
often raises the spectrum of Sjgren syndrome,
these specialists may also be consulted in the
setting of multiorgan disease.
Multiorgan disease is sometimes easier to
identify at diagnosis because patients appear
more ill, yet multiorgan disease can evolve
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COMPLEXITY OF IgG4-RELATED DISEASE

metachronously, adding 1 organ at a time, over

TABLE 1. Main Laboratory Abnormalities and Immunological Features Detailed
months or even years, thereby achieving a sub-
in the Main Series (n>10) of Patients With IgG4-Related Disease4,a
tle presentation.1 As mentioned earlier, involve-
Elevated C-reactive protein levels 33/182 (18)
ment of major organs may lead to organ failure.
Eosinophilia 74/219 (34)
Serum IgG levels (mg/dL)
LABORATORY ABNORMALITIES >1800 313/510 (61)
Mean of individual values (n192) 2589.17 (range, 611-9470)
Routine Tests Range of mean IgG values (26 studies) (mg/dL)
Routine laboratory tests such as complete <1800 4/26 (15)
blood cell counts and biochemical proles 1800-3600 20/26 (77)
often provide nonspecic indications of organ 3601-5000 2/26 (8)
involvement that require further investigation. Serum IgG4 levels (mg/dL)
In particular, abnormalities of liver function >135 1586/1883 (84)
Mean of individual values (n192) 769.42 (range, 15-4020)
tests that suggest biliary obstruction should
Range of mean IgG4 values (42 studies) (mg/dL)
focus diagnostic efforts on the pancreas and <135 1/42 (2)
biliary tree, whereas elevated serum creatinine 135-270 4/42 (10)
levels or proteinuria may signal renal disease. 271-540 8/42 (19)
Mild-to-moderate peripheral eosinophilia is 541-1080 24/42 (57)
found in 34% of patients (Table 1), but this >1080 5/44 (11)
Mean serum IgG4/total IgG ratio (%) 39.92 (range, 25-86)
nding is quite nonspecic and does not guide
Serum IgE levels >360 IU/mL 96/165 (58)
the physician to a specic organ that can be
Autoantibodies and complement
targeted for biopsy. Antinuclear antibodies 168/524 (32)
Elevated C-reactive protein levels were re- Rheumatoid factor 50/255 (20)
ported in 23% of cases.4 Even in the setting of Anti-Ro/SSA antibodies 14/249 (6)
multiorgan disease, elevation in serum C-reac- Anti-La/SSB antibodies 0/249 (0)
tive protein concentrations is, however, gener- Low complement levels 80/220 (36)
ally modest and is less pronounced than is a
Values are presented as n/N (%) or as otherwise indicated, with n number of cases with the
elevation in the erythrocyte sedimentation rate. feature, and N number of cases in which the feature was detailed.

Serum IgG4 Levels

Although most patients with IgG4-RD have
elevated serum IgG4 concentrations, the range
varies widely. A serum IgG4 level of greater
than 135 mg/dL (to convert to mmol/L,
multiply by 0.0259), the upper limit of normal
for many reference laboratories, was reported in
1586 of 1883 patients (84%) for whom such
data were detailed.4 The mean serum IgG4
level, reported individually in 349 cases, was
769 mg/dL, ranging between 15 and 4020
mg/dL (Table 1). Of the nearly 40 studies in
which the mean IgG4 level was reported,4
more than half reported a mean value that was
4 to 6 times higher than the upper limit of
normal. Only 5 studies reported a mean serum
IgG4 concentration more than 6 times the up-
per limit of normal, and only 4 had mean values
between 135 and 270 mg/dL (ie, a maximum of
2 times higher than the cutoff).4 Some studies
also measured the IgG4/total IgG ratio, which
is usually less than 5%. The mean ratio found
in these studies was 40%, ranging from 25%
to 86%.7,8
The frequency of serum IgG4 concentration
elevation in cohorts of patients with IgG4-RD
may be affected profoundly by the manner in
which potential patients of the cohort were
identied originally. Two studies from 1 major
referral center illustrate this point. When cases
were sought by querying the hospital laboratory
database about the number of patients with
abnormally high serum IgG4 concentration
measurements, the sensitivity of an elevated
serum IgG4 concentration for the diagnosis of
IgG4-RD was estimated to be 90%.9 However,
when histopathological proof of IgG4-RD was
the main criterion for cohort entry (ie, potential
patients entered the cohort through the pa-
thology department rather than through sero-
logical testing), just over half of the patients
with biopsy-proven disease were found to
have elevated serum IgG4 concentrations
before treatment.10
Several major points should be drawn from
contrasting studies from the same center. First,

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elevated serum IgG4 levels by themselves have a
low specicity (60%) and a low positive predic-
tive value (34%) for the diagnosis of IgG4-RD.9
Second, a large proportion of patients with
biopsy-proven, clinically validated IgG4-RD
have normal serum IgG4 levels, even before
beginning treatment.10 Therefore, reliance on
serum IgG4 concentration elevation for diag-
nosis is certain to lead to substantial underdiag-
nosis. Finally, in patients with elevated serum
IgG4 levels, the range of values is extremely
wide.4 Factors contributing to such IgG4
response variability remain poorly dened.
Nevertheless, although current diagnostic
criteria of IgG4-RD recommend the measure-
ment of serum IgG4 levels, most patients with
this disease may often be identied by high
serum IgG4 concentrations and can be diag-
nosed in combination with other components
such as imaging and histology.2,4 Therefore,
rigorous clinicopathologic correlation is
required to ensure that the disease is neither
overdiagnosed nor underdiagnosed on the
basis of serum IgG4 values.
Serum IgG4 concentration tends to correlate
with the number of organs involved: the greater
the number of organs affected, the higher the
serum concentration.9 In addition, elevated
serum IgG4 concentrations appear to identify a
subset of IgG4-RDs that are more inamma-
tory as compared with normal serum IgG4
levels. That is, patients with elevated serum
IgG4 concentrations denote a large subset of pa-
tients with IgG4-RD whose disease is character-
ized by more extensive organ involvement, high
inammatory markers, low complement levels,
and (possibly) greater refractoriness to treat-
ment as compared with patients with normal
IgG4 levels.11-14 In a study of patients with auto-
immune pancreatitis, Matsubayashi et al11 re-
ported a higher frequency of certain symptoms
(eg, jaundice) and number of extrahepatic
lesions together with a large size of pancreatic
lesions in patients with higher IgG4 levels.
A potential pitfall in serum-based diagnosis
is related to the technique used for measuring
IgG4 levels. Some nephelometry assays are sus-
ceptible to the prozone or hook effect, which
leads to spuriously low reports of the antigen
being measured (IgG4 in this case). This pro-
zone effect is more likely to occur when condi-
tions of large antigen excess exist. Falsely low
measurements of serum IgG4 concentrations
n n
930 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
were reported in 26% of patients in 1 study
because of the prozone effect.15 This error in
measurement can be circumvented by perform-
ing appropriate dilutions, which allow for the
reagent antibody to remain in excess of the an-
tigen of interest. Newer assays designed to
detect higher serum IgG4 concentrations have
the potential to prevent this problem in the
future.
Polyclonal Hypergammaglobulinemia
Hypergammaglobulinemia (total serum IgG
levels >1800 mg/dL) was reported in 313 of
510 cases (61%). The mean serum IgG level
detailed individually in 192 cases was 2589
mg/dL, ranging between 611 and 9470 mg/dL
(Table 1). Most studies reported a mean of
serum IgG levels between 1800 and 3600 mg/
dL.4 Although serum IgE levels were elevated
in 96 (58%) of 165 patients included in 10
studies,5,6,16-23 a recent study reported the pres-
ence of serum monoclonal bands in patients
with IgG4-RD due to the relatively restricted
migration of polyclonal IgG4, which may form
a characteristic focal band bridging the b and
g fraction in serum protein electrophoresis.24
Autoantibodies
No specic autoantibody has been described
consistently in patients with IgG4-RD, but the
nding of nonspecic antibodies common to
other immune-mediated conditions is common.
The prevalence of serum positive antinu-
clear antibody and rheumatoid factor in patients
with IgG4-RD, for example, is nearly 30% and
20%, respectively (Table 1). Most positive anti-
nuclear antibody and rheumatoid factor assays
are associated with low serum titers. Identica-
tion of more specic autoantibodies such as
anti-Ro/SSA, antiedouble stranded DNA, or
antieneutrophil cytoplasmic antibodies is high-
ly unusual, however, and should suggest the
presence of another condition, such as Sjgren
syndrome, systemic lupus erythematosus, or
granulomatosis with polyangiitis, respectively.
In contrast, hypocomplementemia was re-
ported in 115 of 281 patients (41%) in
whom the test was done.4 Hypocomplemente-
mia is a particularly common nding in pa-
tients with IgG4-related kidney disease
(IgG4-RKD). The precise mechanisms for this
association remain to be dened. Although,
in theory, IgG4 does not bind complement
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COMPLEXITY OF IgG4-RELATED DISEASE
effectively,25 immune complexes composed of
other immunoglobulin subclasses that bind
the complement more effectively (eg, IgG1
and IgG3) may account for this nding.
IMAGING STUDIES
Cross-sectional imaging studies using computed
tomography (CT) or magnetic resonance imaging
(MRI) play an important diagnostic role. Organ le-
sions of IgG4-RD frequently lead to the nding of
organ enlargement or frank pseudotumors on CT.
These same lesions usually generate low signal in-
tensity on T2-weighted MRI.26,27 Some studies
have suggested a potential diagnostic role of
18F-uorodeoxyglucose positron emission to-
mography/CT .28,29 A recent study identied a
more extensive disease using positron emission
tomography/CT in nearly 70% of cases in com-
parison with the standard evaluation (ie, physical
examination, ultrasonography, and CT).30 Posi-
tron emission tomography/CT may be more sen-
sitive than conventional imaging studies to detect
some specic organ involvements such as major
salivary glands, lymph nodes, or vascular involve-
ment but less sensitive for small-sized lesions or
brain and kidney involvement.31
Pancreatic and Biliary Tract Involvement
The pancreas is among the most commonly
affected organs in IgG4-RD. Abdominal CT often
shows pancreatic enlargement, more frequently
focal (56%) than diffuse (44%).11,32 Focal lesions
can easily be confused with malignant pancreatic
neoplasms. The morphology of the pancreas is
often described as sausage-shaped when the
enlargement is diffuse. Edema around the rim
of the organ leads to enhancement. Pancreatic
atrophydeither diffuse or distaldhas also
been reported.32,33 Uncommon radiological
ndings are those of acute pancreatitis (inam-
mation and edema), a normal-size gland with
diffusely decreased enhancement, and a normal
pancreatic appearance on imaging.32
Biliary strictures caused by the inammation
of the bile ducts are the key sign in imaging
studies of IgG4-related sclerosing cholangitis.
These have been classied according to their
cholangiographic location into 4 types: type 1,
stricture localized to the distal common bile
duct; type 2, stricture involving the intrahepatic
bile ducts; type 3, strictures involving both the
hilar and distal common bile ducts; and type
4, strictures of only hilar bile ducts.34 Type 1
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stricturesdthose localized to the distal common
bile ductdare the most common. Three studies
including 428 patients found that types I, II, III,
and IV patterns were present in 66%, 15%,
13%, and 11% of patients, respectively.35-37 A
recent study reported that although the presence
of continuous stricture in the bile ducts, gall-
bladder involvement, and single-wall common
bile duct thickness greater than 2.5 mm may
help differentiate IgG4-RD from other inamma-
tory biliary diseases, the location and length of
common bile duct stricture were less useful.38
Salivary Gland Involvement
Major salivary glands enlargement is a common
hallmark of IgG4-RD, with the submandibular
glands being more commonly affected than the
parotid glands. Some studies using ultrasound
studies to characterize glandular involvement
of IgG4-RD have revealed multiple hypoechoic
areas in enlarged glands as the foremost
nding.39 Asai et al40 reported 2 patterns in
submandibular glands, namely, localized
tumor-forming and diffuse focal involvement.
With regard to MRI studies, main reported
features are well-dened, iso/hypointense
T2-weighted MRI lesions, with homogeneous
enhancement without vascular occlusion or
compression signs.41
Ocular Involvement
Ocular CT imaging studies disclosed not only a
predominant involvement of lachrymal glands
(often bilateral) but also involvement of other
tissues including trigeminal nerve branches
(frontal, supraorbital, or infraorbital nerves),
extraocular muscles (orbital myositis), orbital
fat tissue, eyelids, and nasolacrimal duct or
bones comprising part of the orbit.42 Ocular
adnexal lesions exhibited well-dened mar-
gins, isoattenuation on precontrast CT studies,
T1-isointense and T2-hypointense MRI lesions
with a homogeneous internal architecture,
enhancement patterns, and bone remodeling
without destruction.43
Pulmonary Involvement
CT pulmonary lesions have been classied into
4 types: (1) thickening of bronchovascular
bundles and interlobular septa (20 cases); (2)
solid nodules resembling primary lung cancer
(19 cases); (3) interstitial involvement (3 cases);
and (4) round-shaped ground-glass opacities
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Retroperitoneal Involvement
TABLE 2. Main Pathological Features Detailed in the Main Series (n>10) of
Retroperitoneal brosis has been reported in 13%
Patients With IgG4-Related Disease4,a,b
of patients presenting systemic IgG4-RD.4 CT
Histopathological features
ndings have documented the primary locations
Lymphocytic inltration 509/511 (100)
of retroperitoneal masses as periaortic (83%) and
Fibrosis 238/305 (78)
Storiform brosis 56/76 (74)
peri-iliac (67%), even though pericaval, presacral,
Phlebitis 136/317 (43) retrovesicular, and perirectal locations also
Obliterative phlebitis 124/306 (41) occur.47 One third of patients have concomitant
Eosinophilia 130/257 (51) hydronephrosis, more commonly unilateral.
Follicular lymphoid formation 98/204 (48) Intra-abdominal, inguinal, and axillary lymph-
Germinal centers 31/59 (53) adenopathy is common in the setting of IgG4-
No. of IgG4 cells per HPF related retroperitoneal brosis. Furthermore,
Mean of individual values (n57) 117.6 (range, 1-396) aortitis is a common nding in imaging studies
Range of mean IgG4 cells per HPF (11 studies)
(periaortitis, aortic dilatation, and aneurysms).
10-30 1/11 (9)
31-50 2/11 (18)
51-100 1/11 (9) Central Nervous System Involvement
101-200 4/11 (36) Involvement of the central nervous system
>200 3/11 (27) has been reported infrequently. Hypertrophic
IgG4/total IgG cell ratio (%) pachymeningitis has been identied by localized
Mean of individual values (n139) 57.84 (range, 0-100)
or diffuse thickening of the cranial or spinal cord
Ratio used in 9 studies
>30% 6/9 (67) dura mater, with imaging studies commonly
>40% 2/9 (22) disclosing either linear dural thickening or a
>50% 1/9 (11) bulging mass.48 Destructive bone involvement
a
HPF high-power eld. has been reported in isolated cases, affecting
b
Values are presented as n/N (%) or as otherwise indicated, with n number of cases with the the bones of the orbit or the temporal, maxillary,
feature, and N number of cases in which the feature was detailed. or mastoid bones, and cranial nerves are often
involved in adjacent tumor masses. Involvement
of the hypophysis is rare. MRI studies typically
reveal enlargement of the anterior pituitary and
resembling bronchioloalveolar carcinoma (1
thickening of the pituitary stalk.
case).20,44 Pleural effusions are unusual and
seldom dominate the clinical picture, but pro-
nounced pleural thickening is not uncommon. HISTOPATHOLOGICAL APPROACH
Hilar and/or mediastinal lymphadenopathy ac- Histopathological analysis of specimens from the
companies most cases of pulmonary disease. organ involved remains the diagnostic corner-
stone of IgG4-RD. Needle biopsies are generally
Renal Involvement useful in excluding malignancies but often pro-
Intrarenal disease has been described in 13% of vide insufcient quantities of tissue to conrm a
patients who reported systemic involvement at diagnosis of IgG4-RD.49
presentation.4 CT imaging has revealed kidney
abnormalities in nearly 70% of patients with Morphological Data
IgG4-RKD.45 Most common ndings are The key morphological features of IgG4-RD are
multiple low-density lesions with T2 hypoin- dense lymphoplasmacytic inltrates, brosis
tensity, diffusion restriction, and a progressive with a storiform pattern, obliterative phlebitis,
enhancement pattern in more than half of the and (often) eosinophilic inltration.46 Table 2
cases, followed by diffuse renal swelling (typi- summarizes the prevalence of the chief histo-
cally bilateral) and diffuse thickening of the pathological features.4 Storiform brosis, eosin-
renal pelvis wall.45,46 Solitary nodules or cysts ophilic inltration, and obliterative phlebitis
have rarely been reported. Renal atrophy is were found in 78%, 51%, and 40% of cases,
infrequently found at diagnosis, but it has respectively. Condent pathological diagnosis
been reported in nearly half of the cases during requires the presence of at least 2 of these major
follow-up, even in those patients who appeared histological features and careful clinicopatho-
to respond well to glucocorticoid treatment.45 logic correlation. In contrast, the presence of
n n
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COMPLEXITY OF IgG4-RELATED DISEASE

TABLE 3. Differential Diagnosis in Patients With Suspected IgG4-Related Disease Associated With Elevated
Serum IgG4 Levels66-71
No. of No. of patients Percentage of
patients with serum IgG4 patients with IgG4
Disease tested levels >135 mg/dL levels >135 mg/dL
Sjgren syndrome 284 22 7.7
Pancreatic cancer 153 8 5.2
Systemic lupus erythematosus 122 17 13.9
Rheumatoid arthritis 83 12 14.5
Biliary tract cancer 64 4 6.2
Chronic pancreatitis 45 2 4.4
Systemic sclerosis 44 3 6.8
Liver cirrhosis 22 2 9.1
Chronic hepatitis 21 1 4.8
Castleman disease 16 7 43.7
Hypereosinophilic syndrome 16 2 12.5
Interstitial lung disease 12 4 33.3
Behet disease 10 1 10
Eosinophilic granulomatosis with polyangiitis 7 5 71.4
Asthma 7 1 14.3
Inammatory myopathies 6 1 16.7
Antiphospholipid syndrome 5 1 20
Mixed connective tissue disease 5 0 0
Microscopic polyangiitis 5 1 20
Healthy controls 77 1 1.3
SI conversion factor: To convert mg/dL values to mmol/L, multiply by 0.0259.

epithelioid cell granulomas, other features of
granulomatous inammation, and the nding
of a prominent neutrophil inltrate are all high-
ly atypical of IgG4-RD and must trigger consid-
eration of other diagnoses.49 IgG4-related
disease is analogous to sarcoidosis in 1 funda-
mental way: regardless of the organ involved,
the same histopathological features are found
throughout all involved organs.
Subtle variations in histopathological nd-
ings exist between some organs.49 As an
example, typical storiform brosis is rare in
lacrimal, parotid, and minor salivary glands
and in interstitial lung disease, whereas oblit-
erative phlebitis is reported more frequently
in the pancreas and submandibular glands
than in the parotid/lacrimal glands, lymph
nodes, or kidneys.49
Immunohistochemical Studies
Immunohistochemical studies with IgG4 and
IgG staining represent an important part of the
pathological diagnosis of IgG4-RD.1 Tissue inl-
tration by IgG4 plasma cells is a strong charac-
teristic of IgG4-RD, but does not constitute a sine
qua non nding for diagnosis because, as noted,
an impressively long list of other diagnoses can
be associated with tissue-inltrating IgG4
plasma cells.49 In addition, in some cases, there
is a paucity of inltrating IgG4 plasma cells
and the diagnosis is based on the morphologic
appearance.2,49
Semiquantitative analysis of IgG4 immuno-
staining helps distinguish IgG4-RD from other
conditions. Various cutoff values ranging from
more than 10 to more than 50 IgG4 plasma
cells per high-power eld (HPF) have been pro-
posed. The mean number of IgG4 cells per
HPF detailed in 57 cases was 118 (ranging
from 1 to 396).4 In 11 studies in which the
mean number of IgG4 plasma cells per HPF
was detailed, a mean value of more than 100
was found in more than half of the cases,
ranging from 13 to 229.20,21,42,47,50-56 Most pa-
tients in whom this feature was detailed had
more than10 IgG4 cells per HPF (498 of
538 [93%]) (Table 2). A critical point in inter-
preting the number of IgG4 plasma cell
counts within tissues is that the cutoff for
a positive number varies according to the

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TABLE 4. Differential Diagnosis in Patients With Suspected IgG4-Related
Disease Associated With Tissue Inltration by IgG4 Cells
Vasculitis
Eosinophilic granulomatous with polyangiitis (Churg-Strauss)
Granulomatosis with polyangiitis (Wegener)
Hypocomplementemic urticarial vasculitis
Hematological malignancy
Castleman disease
Extranodal marginal zone B-cell lymphoma
Follicular lymphoma
Angioimmunoblastic lymphoma
Solid-organ neoplasms
Pancreatic cancer
Lung cancer
Sarcoma
Infections
Pulmonary abscess
Epstein-Barr viruserelated lymphadenopathy
Aortitis caused by chronic Staphylococcus aureus infection
Digestive diseases
Inammatory bowel disease
Diverticulitis
Other systemic diseases
Rheumatoid arthritis (synovium and lymph nodes)
Histiocytosis (Rosai-Dorfman disease)
specic tissue. Guidelines have been suggested
in an international consensus report.49
Measurement of the IgG4 plasma cell/
total IgG plasma cell ratio may be useful, espe-
cially in cases in which brosis predominates. In
the 6 studies in which the ratio was detailed, 3
used a minimum ratio of 30%, 1 used 40%,
and 2 used 50%.6,8,44,57-59 The mean IgG4
plasma cell/total IgG plasma cell ratio per
HPF specied in 139 cases was 58%, ranging
from 0% to 100% (Table 2). A major example
of the utility of the IgG4 plasma cell/total
IgG plasma cell ratio is in retroperitoneal
brosis, a condition in which the brotic nature
of the disease is frequently so dominant at the
time of diagnosis that the lymphoplasmacytic
inltrate present early in this condition is sparse
by the time the patient comes to medical atten-
tion. Finding high numbers of IgG4 plasma
cells per HPF is unlikely in this setting. In
such cases, the IgG4 plasma cell/total IgG
plasma cell ratio can be useful in suggesting
the diagnosis. If there are only 10 plasma cells
per HPF but 90% of them are IgG4, the diag-
nosis of IgG4-related retroperitoneal brosis is
tenable if other pathological and clinical fea-
tures consistent with this diagnosis are present.
n n
934 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
Unusual Case of the Kidney
IgG4-related kidney disease represents an un-
usual exception to the pathology of IgG4-RD
in that at least 2 types of lesions are found in
this organ. Renal biopsy disclosed tubulointersti-
tial nephritis in 110 of 115 biopsy-proven cases
of IgG4-RKD (96%). Such cases of tubulointer-
stitial nephritis include all the classic histopatho-
logical features and immunostaining ndings
found in other organs affected by IgG4-RD,
namely, a lymphoplasmacytic inltrate, stori-
form brosis, common presence of moderate tis-
sue eosinophilia, and occasional presence of
obliterative phlebitis. However, biopsies also
disclosed concomitant glomerular lesions in
22% of cases in 1 study.4 Glomerular lesions
included various pathologies: membranous GN
(n7), Henoch-Schnlein GN/IgA nephropathy
(n4), focal and segmental endocapillary prolif-
erative GN (n2), membranoproliferative GN
(n1), mesangial proliferative GN (n1), and
other GN not otherwise specied (n3).45,60,61
Alexander et al62 recently reported 9 additional
patients with membranous GN. Membranous
GN secondary to IgG4-RD is a disorder distinct
from idiopathic membranous GN, which is char-
acterized by the deposition of immunoglobulin,
predominantly IgG4, along the glomerular-
basement membrane epithelial surface, and is
associated with antibodies directed against the
phospholipase A2 receptor.63
The presence of both tubulointerstitial
nephritis and various glomerular lesions in
patients with IgG4-RD strongly suggests the
possibility of different pathophysiological
mechanisms in these manifestations of renal
disease. Further investigation is required to
elucidate them.
FLOW CYTOMETRY
Blood plasmablast concentrations may be
superior to serum IgG4 concentrations for the
diagnosis of IgG4-RD and offer important possi-
bilities to follow disease activity in the longitudi-
nal evaluation of patients. Untreated patients with
IgG4-RD have a marked elevation in blood plas-
mablast concentrations.12,64 Plasmablasts can be
identied through ow cytometry analysis of pe-
ripheral blood, gating on cells that are CD19low
CD38CD20CD27.12 Of note, increased pla-
smablasts showing CD19CD38CD20CD27
cells in IgG4-RD are also expressed as CD19low
CD38CD20CD27 cells.12 Interestingly,
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COMPLEXITY OF IgG4-RELATED DISEASE

plasmablasts share some surface markers with

TABLE 5. Red Flags for the Diagnosis of IgG4-Related Disease
human regulatory B cells.64 In several pheno-
types of regulatory B cells, CD19CD24hi Epidemiological features
Middle-aged men
CD38hi B cells is one of them, including these
Patients from Southeast Asian countries
plasmablasts,65 which suggests that increased
Clinical ndings
plasmablasts may be regulatory B cells. Tumefactive lesion in 1 organs
Concentrations of IgG4 plasmablasts can Abdominal symptoms
also be determined by ow cytometry.12 Early Orbital swelling
studies of ow cytometry in IgG4-RD suggest Renal dysfunction
that circulating plasmablasts are highly elevated Salivary gland swelling
Lymph node enlargement
even in patients with normal serum IgG4 con- Laboratory abnormalities
centrations. In addition, elevation in plasma- Eosinophilia
blasts appears to decline sharply with therapy Elevated IgE levels
and rise again during disease ares. Therefore, Hypergammaglobulinemia
plasmablast counts are a potentially useful Monoclonal band
biomarker for diagnosis, for assessing the Hypocomplementemia
response to treatment, and for determining IgG4 levels >135 mg/dL
the appropriate time for retreatment. Addi- Imaging ndings
Solitary or multiple nodules/masses
tional studies of plasmablasts are required,
Enlarged organs
particularly prospective investigations that Homogeneous lesions with well-dened margins
focus on IgG4 plasmablasts, the relation of Enhancement/thickening patterns
these cells concentration to disease activity, T2-weighted hypointense lesions on magnetic resonance imaging
and the ability of increases in their concentra- Histopathological ndings
tions to predict disease relapses. Lymphocytic inltration
Storiform brosis
Obliterative phlebitis
DIFFERENTIAL DIAGNOSIS
Eosinophilic inltration
The rst diagnostic challenge is to differentiate Immunohistochemical ndings
whether the clinical picture owes to IgG4-RD IgG4 cells per high-power eld >10
or to malignancy, especially when the disease IgG4/total IgG cell ratio >40%
affects a single organ and is either diagnosed un- Flow cytometry ndings
expectedly in pathological specimens or identi- Increased circulating plasmablasts (CD19lowCD38CD20CD27)
ed incidentally on radiological studies. It is The more features of different subsets the patient presents, the greater the probability of a
essential to differentiate single-organ IgG4-RD diagnosis of IgG4-related disease.
from pancreatic cancer, cholangiocarcinoma,
lung adenocarcinoma, prostate cancer, and elevated numbers of IgG4 plasma cells in tis-
lymphoma. Similarly, multiorgan IgG4-RD sue (Table 4). Yet these conditions lack the
may mimic lymphoma or a metastatic cancer, characteristic histopathological features of
with manifestations of weight loss, other consti- IgG4-RD.49 For this reason, the presence of
tutional symptoms, and lymphadenopathy. the classic histopathological features is actually
Some laboratory abnormalities may help of greater utility than immunostaining studies
differentiate IgG4-RD from other systemic for IgG4 positivity in plasma cells. Clinicopath-
inltrative diseases, including eosinophilia, ologic correlation is essential to making a diag-
hypergammaglobulinemia, elevated serum IgE nosis of IgG4-RD, however, even in the
levels, hypocomplementemia, and, especially, presence of typical histopathological features.
elevated levels of IgG4. None of these features The clinician must answer this critical question:
is pathognomonic of IgG4-RD, however, and Do these pathological ndings make sense
even elevated IgG4 levels have been reported within the patients clinical context? Red ags
in a wide range of diseases (Table 3).14,66-70 for the diagnosis of IgG4-RD are shown in
In addition, limitations about its test character- Table 5.
istics preclude reliance on measurements of
serum IgG4 levels for the purpose of diagnosis. DIAGNOSTIC CRITERIA
With respect to inltration by IgG4 cells, The diagnostic approach is heterogeneous, and
multiple clinical entities can be associated with the rst proposed sets of criteria centered on

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 MAYO CLINIC PROCEEDINGS

Clinical suspicion

Laboratory Tumefactive lesion in Imaging

abnormalities >=1 organs findings

Eosinophilia Solitary or multiple nodules/masses

Elevated IgE levels Enlarged organs
Hypergammaglobulinemia T2-weighted hypointense lesions (MRI)
Hypocomplementemia Enhancement/thickening patterns

IgG4-specific studies

Serum IgG4 levels

Flow cytometry
Histopathological studies

>135 mg/dL
Increased circulating
(excluding other plasmablasts
diseases, see Table 3) Morphologic Immunohistochemical

Lymphocytic infiltration IgG4+ cells per HPF >10

Storiform fibrosis IgG4+/IgG+ cell ratio >40%
Obliterative phlebitis
Eosinophilic infiltration (excluding other diseases, see Table 4)

FIGURE. Diagnostic algorithm in IgG4-related disease: sequential diagnostic approach integrating clinical suspicion and IgG4-specic
diagnostic tests. HPF high-power eld; MRI magnetic resonance imaging.

specic organs rather than IgG4-RD as a whole.
The best examples of organ-specic criteria are
those created for IgG4-related pancreatitis, scle-
rosing cholangitis, kidney disease, and major
salivary gland disease. In 2012, Umehara et al71
proposed a set of criteria for the diagnosis of sys-
temic IgG4-RD designed to be used indepen-
dently of the predominant organ involvement
but exclusively focused on IgG4-related diag-
nostic tests (in particular elevated serum levels
and immunohistochemical studies). The sensi-
tivity and specicity of these criteria remain
untested.
We have found a wide heterogeneity of the
diagnostic criteria used in the main studies.4
Thus, a signicant percentage of studies did
not specify the criteria used, and a large per-
centage used organ-specic criteria, with only
15 using the Umehara criteria,71 including clin-
ical, serological, and histopathological criteria.
n n
936 Mayo Clin Proc.
In these studies, 82% of patients fullled all 3
of the Umehara criteria and were therefore clas-
sied as having denitive IgG4-RD, whereas
only 7% were classied as probable disease
(ie, fulllment only of clinical and serological
criteria).
CONCLUSION
IgG4-related disease is an increasingly recog-
nized systemic disease in adults, with a hetero-
geneous clinical, laboratory, and histological
presentation affecting a wide range of organ
systems. The diagnostic approach is complex
and should include not only IgG4-related tests
(serum levels of IgG4 and immunohistochem-
ical studies) but also an extensive evaluation
of the patients condition including epidemio-
logical, clinical, laboratory, imaging, and
typical pathological features; the more features
of different subsets the patient presents, the
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COMPLEXITY OF IgG4-RELATED DISEASE
greater the probability of a diagnosis of IgG4-
RD (Figure). Therefore, a compatible clinical
and laboratory picture together with elevated
serum IgG4 levels and a highly suggestive his-
topathological setting, including both classical
features and immunohistochemical studies,
should be considered the ideal scenario for a
solid diagnosis of IgG4-RD. This diagnostic
approach is common to other complex sys-
temic diseases such as sarcoidosis or adult
hemophagocytic syndrome (hemophagocytic
lymphohistiocytosis).72 Flow cytometry will
probably play an increasingly important role
in the future in diagnosing IgG4-RD.
Advances in the understanding of IgG4-RD
are likely to alter the optimal diagnostic approach
in the future. With respect to serum IgG4 levels,
which were identied as the key feature in
identifying the rst cases of IgG4-RD, recent
studies9,15 have reported some signicant limita-
tions of their measurement and clinical interpre-
tation, suggesting that the role of serum IgG4
levels in making the diagnosis should be de-
emphasized compared with the prominence it
has held in the initial years of the description of
IgG4-RD. Elevated IgG4 levels in other diseases
should be carefully evaluated to rule out poten-
tial misdiagnosis or even a possible coexistence
of 2 diseases. With regard to histopathological
studies and IgG4 tissue immunostaining,
abnormal results are the most reliable diagnostic
tools at this time, though they are not pathogno-
monic and may show signicant variations
depending on the organ whose biopsy was per-
formed, the time of disease evolution (early vs
advanced disease), or the therapies administered.
Experience is a key factor in interpreting the
pathological ndings in IgG4-RD.
This review illustrates the complex approach
to the diagnosis of IgG4-RD. The body of the
available evidence relies predominantly on a
small series of cases, with a high degree of hetero-
geneity, especially with respect to the lack of
a homogeneous organ-by-organ diagnostic
approach. Greater understanding of the etiopa-
thogenic mechanisms for the role of IgG4 in
organ damage, identication of new disease
markers with greatest sensitivity and specicity
rates, and, especially, active multidisciplinary
collaboration promoting a standardized set of
classication criteria, well-designed and interna-
tionally validated, which include the main
features that help differentiate IgG4-RD from
Mayo Clin Proc. n July 2015;90(7):927-939 n http://dx.doi.org/10.1016/j.mayocp.2015.03.020
www.mayoclinicproceedings.org
other diseases, will improve the diagnostic
approach of this emerging and as yet little-
known systemic disease.
Abbreviations and Acronyms: CT = computed tomogra-
phy; GN = glomerulonephropathy; HPF = high-power eld;
IgG4-RD = IgG4-related disease; IgG4-RKD = IgG4-related
kidney disease; MRI = magnetic resonance imaging
Grant Support: The work was supported by the Josep Font
Research Fellow Award, Hospital Clinic, Barcelona, Spain
(P.B.-Z.).
Correspondence: Address to John H. Stone, MD, MPH,
Rheumatology Unit, Massachusetts General Hospital, 55
Fruit Street/Yawkey 2, Boston, MA 02114 (jhstone@
partners.org).
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COMPLEXITY OF IgG4-RELATED DISEASE
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