The Utility of Serum IgG4 Concentrations as a Biomarker.

Abstract

IgG4-related disease is a new disease entity involving IgG4 in its clinical presentation and having 6 characteristic features: (1) systemic involvement; (2) solitary or multiple lesions showing diffuse or localized swelling, masses, nodules, and/or wall thickening on imaging; (3) high serum IgG4 concentration >135 mg/dL; (4) abundant infiltration of lymphoplasmacytes and IgG4-bearing plasma cells; (5) a positive response to corticosteroid therapy; and (6) complications of other IgG4-related diseases. To date, most IgG4-related diseases have been recognized as extrapancreatic lesions of autoimmune pancreatitis. This paper will discuss the utility of IgG4 as a biomarker of IgG4-related diseases, including in the diagnosis of autoimmune pancreatitis and its differentiation from pancreatic cancer, in the prediction of relapse, in the long-term follow-up of patients with autoimmune pancreatitis and normal or elevated IgG4 concentrations, and in patients with autoimmune pancreatitis and extrapancreatic lesions, as well as the role of IgG4 in the pathogenesis of IgG4-related disease.

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Hindawi Publishing Corporation
International Journal of Rheumatology
Volume 2012, Article ID 198314, 4 pages
doi:10.1155/2012/198314
Review Article
TheUtility of SerumIgG4 Concentrationsas a Biomarker
Shigeyuki Kawa,1TetsuyaIto,2TakayukiWatanabe,2MasahiroMaruyama,2
HideakiHamano,3Masafumi Maruyama,2Takashi Muraki,2andNorikazu Arakura2
1Center for Health, Safety, and Environmental Management, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan
2Department of Gastroenterology, School of Medicine Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan
3Department of Medical Information, School of Medicine Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan
Correspondence should be addressed to Shigeyuki Kawa, skawapc@shinshu-u.ac.jp
Received 23 November 2011; Accepted 17 January 2012
Academic Editor: Yoh Zen
Copyright © 2012 Shigeyuki Kawa et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
IgG4-related disease is a new disease entity involving IgG4 in its clinical presentation and having 6 characteristic features: (1)
systemicinvolvement;(2)solitaryormultiplelesionsshowingdiffuseorlocalizedswelling,masses,nodules,and/orwallthickening
on imaging; (3) high serum IgG4 concentration >135mg/dL; (4) abundant infiltration of lymphoplasmacytes and IgG4-bearing
plasma cells; (5) a positive response to corticosteroid therapy; and (6) complications of other IgG4-related diseases. To date, most
IgG4-relateddiseaseshavebeenrecognizedasextrapancreaticlesionsofautoimmunepancreatitis.Thispaperwilldiscusstheutility
of IgG4 as a biomarker of IgG4-related diseases, including in the diagnosis of autoimmune pancreatitis and its differentiation from
pancreatic cancer, in the prediction of relapse, in the long-term follow-up of patients with autoimmune pancreatitis and normal
or elevated IgG4 concentrations, and in patients with autoimmune pancreatitis and extrapancreatic lesions, as well as the role of
IgG4 in the pathogenesis of IgG4-related disease.
1.Introduction
IgG4-related disease is a new disease entity involving IgG4
in its clinical presentation. To date, 6 characteristic features
of IgG4-related disease have been identified: (1) systemic
involvement; (2) solitary or multiple lesions showing diffuse
or localized swelling, masses, nodules, and/or wall thick-
ening on imaging; (3) high serum IgG4 concentrations
>135mg/dL; (4) abundant infiltration of lymphoplasma-
cytes and IgG4-bearing plasma cells; (5) a positive response
to corticosteroid therapy; (6) complications of other IgG4-
related diseases [1–4].
IgG4-related disease involves organs throughout the
entire body. The major manifestations of IgG4-related dis-
ease include autoimmune pancreatitis, lacrimal and salivary
gland lesions known as Mikulicz’s disease, sclerosing cholan-
gitis, retroperitoneal fibrosis, lung disease, and tubulointer-
stitial nephritis. In addition, many minor lesions have been
reported in patients with IgG4-related disease, including
hypophysitis, thyroiditis, hepatopathy, and prostatitis. At
present, it is not clear whether these lesions are caused by the
same etiology or merely show clinical and pathological find-
ings associated with IgG4. Imaging modalities have shown
diffuse or localized swelling in the pancreas and the lacrimal
and salivary glands, masses in patients with retroperitoneal
fibrosis, nodules in patients with lung pseudotumors, and
wall thickening in the bronchi and bile ducts.
Most patients with IgG4-related disease have high serum
IgG4 concentrations, over 135mg/dL, [5] a finding both
sensitive and specific for this disease, as well as useful for
its diagnosis. Characteristic pathological findings include the
infiltrationoflargenumbersoflymphoplasmacytesandIgG4
bearing plasma cells [6]. Although storiform or swirling
fibrosis and obstructive phlebitis are also characteristics of
IgG4-related disease, they are rarely observed in specific
lesions, such as those of the salivary glands. Most lesions,
except for those that are predominantly fibrotic, respond
positively to corticosteroid therapy. For example, patients
with autoimmune pancreatitis show reduced swelling, pro-
ducts with lung pseudotumors show the disappearance of
nodules, and patients with sclerosing cholangitis show the

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2International Journal of Rheumatology
disappearance of bile duct strictures after corticosteroid
treatment. At present, most IgG4-related diseases have been
recognizedasextrapancreaticlesionsofautoimmunepancre-
atitis [2, 7, 8].
This paper will discuss the utility of serum IgG4 concen-
trations as a biomarker of the major IgG4-related disease,
autoimmune pancreatitis. Topics will include IgG4 concen-
trationandthediagnosisofautoimmunepancreatitis,aswell
as its differentiation from pancreatic cancer; IgG4 and the
prediction of relapse; long-term followup of patients with
autoimmune pancreatitis and either normal or elevated IgG4
concentration; IgG4 and extrapancreatic lesions in patients
with autoimmune pancreatitis; and the role of IgG4 in the
pathogenesis of IgG4-related disease.
2.IgG4andthe Diagnosisof
Autoimmune Pancreatitis
The sera of patients with autoimmune pancreatitis have
a polyclonal band in the rapidly migrating fraction of γ-
globulins, resulting in β–γ bridging. Immunoprecipitation
assays have confirmed that this band is always due to
elevation of IgG4 concentration [5]. IgG is composed of 4
subclasses, IgG1, IgG2, IgG3, and IgG4. In normal subjects,
IgG4 constitutes only 3–7% of total serum IgG. However,
serum IgG4 concentrations are over 10-fold higher in
patients withautoimmunepancreatitis. Elevated serumIgG4
has also been observed in individuals with allergic disorders,
parasite infestations, and pemphigus. High serum IgG4
concentrations have been observed in 90% of patients with
autoimmune pancreatitis, but rarely in patients with pan-
creatic cancer, chronic pancreatitis, primary biliary cirrhosis,
primary sclerosing cholangitis, and Sj¨ ogren’s syndrome,
suggesting that IgG4 is a sensitive and specific marker
of autoimmune pancreatitis and may be diagnostic for
this disease [5]. Corticosteroid therapy significantly reduces
serum IgG4 concentration and the IgG4/IgG ratio [5]. The
utility of IgG4 for the diagnosis of autoimmune pancreatitis
has been evaluated worldwide, with a sensitivity ranging
from 50% to 92% and a specificity over 90%. Serum IgG4
concentration is therefore considered a reliable marker for
the diagnosis of autoimmune pancreatitis and has been
included in various diagnostic criteria [9–12]. Differences in
sensitivity and specificity may be partly due to the use of
different assays to measure serum IgG4 and different cut-
offs for the upper limit of normal around the world, as well
as variations in diagnostic criteria used in individual coun-
tries, which may be associated with histological differences
between lymphoplasmacytic sclerosing pancreatitis (LPSP)
[13] and idiopathic duct-centric chronic pancreatitis (IDCP)
[14].
Clinical features of autoimmune pancreatitis have been
reported to differ based on the serum concentration of IgG4.
Compared with patients having normal serum IgG4 levels,
those with elevated IgG4 are regarded as being in a highly
active state, with a higher incidence of jaundice at onset,
more frequent diffuse pancreatic enlargement on imaging,
significantly higher 18F-2-fluoro-2-deoxy-d-glucose uptake
by pancreatic lesions, more frequent extrapancreatic lesions,
and more frequent requirement for maintenance therapy
[15].
In addition, infiltration of IgG4 bearing plasma cells is a
histologicalhallmarkofautoimmunepancreatitisandisused
in pathologic diagnoses [6].
3.IgG4and the Differentiationof Autoimmune
PancreatitisfromPancreaticCancer
Lymphoplasmacytic sclerosing pancreatitis (LPSP), which
is similar pathologically to autoimmune pancreatitis, has
been observed in 2.5% of patients undergoing the Whipple
resection [16]. Therefore, it is necessary to differenti-
ate autoimmune pancreatitis from pancreatic cancer. We
reported that IgG4 had a sensitivity of 90%, a specificity of
98%,andanaccuracyof95%indifferentiatingbetweenthese
conditions, [5] indicating that IgG4 is useful both for the
diagnosis of autoimmune pancreatitis and for differentiating
it from pancreatic cancer. Other reports have also shown
the usefulness of IgG4 in differential diagnosis [17–19]. The
sensitivity and specificity of IgG4 were superior to those of
IgG, ANA, and RF, although the additional measurement of
ANA and RF further increased the sensitivity and negative
predictive value of IgG4 [8].
4.IgG4and Predictionof Relapse
Some patients with autoimmune pancreatitis experience
relapse during their clinical course. For effective manage-
ment, it is necessary to determine the frequency of relapse
and its prevention. During the period from 1992 to 2011,
a total of 93 patients with autoimmune pancreatitis were
examined and treated at Shinshu University Hospital. Of
the 84 patients followed up for more than 1 year, 28 (33%)
experienced relapse. In Japanese patients, the relapse rate has
been estimated to vary from 30 to 50%, [20–22] although
corticosteroid therapy significantly reduced relapse rates
[22]. Japanese consensus guidelines for the management of
autoimmune pancreatitis have stated that the indications for
corticosteroid therapy include symptoms such as obstructive
jaundice, abdominal pain, and back pain, and the presence
of symptomatic extrapancreatic lesions. The major lesions
at relapse included autoimmune pancreatitis (n = 26),
sclerosing cholangitis (n = 18), lachrymal and salivary gland
lesions (n = 5), and retroperitoneal fibrosis (n = 4). In
addition, the involvement of other organs and symptoms
were seen at relapse. We failed to identify any serum markers
at diagnosis that could predict relapse, although we observed
elevated concentrations of IgG and immune complex in
the relapse compared with the nonrelapse group, although
these differences were not significant. Serial changes in
IgG4 and immune complexes in a 69-year-old woman with
autoimmunepancreatitiswhoexperienced3relapsesshowed
that these markers were elevated in serum several months
before clinically evident relapse, suggesting that regular
measurements of these markers in an out-patient clinic may
predict relapse [23].

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International Journal of Rheumatology3
Table 1: IgG4 concentrations, age and complications of more than 3 extrapancreatic lesions in patients with autoimmune pancreatitis and
major extrapancreatic lesions.
n
(male/female)
Age, yr
Median (range)
IgG4, mg/dL
Median (range)
Complications of
more than 3
extrapancreatic
lesions, n (%)
Autoimmune
pancreatitis
Mikulicz’s disease
Sclerosing cholangitis
Retroperitoneal
fibrosis
Kidney lesion
92 (72/20) 66 (38–85)545 (4–2970) 11(12%)
41 (31/10)
71 (53/18)
65 (43–82)
67 (38–84)
697 (18–2970)
500 (4–2970)
13 (32%)
13 (18%)
27 (23/4) 66 (50–80)1110 (247–2970)12 (44%)
18 (14/4) 67 (56–82)1313 (156–2970) 9 (50%)
5.Long-Term Followup of Patients with
Autoimmune Pancreatitisand Normal or
ElevatedIgG4
We followed 2 patients with autoimmune pancreatitis for
10 years each, a 55-year-old man with a serum IgG4
concentration of 1135mg/dL and a 65-year-old woman
with a serum IgG4 concentration of 42mg/dL [24]. The
first patient experienced several recurrences, developing a
pancreatic stone and pancreatic duct stenosis, whereas the
latter patient showed no duct changes over time. These
findings suggest that autoimmune pancreatitis accompanied
by normal IgG4 concentrations may represent lower activity
and a nonprogressive state [24].
6.IgG4andExtrapancreaticLesionsin
Autoimmune Pancreatitis
Extrapancreatic lesions in patients with autoimmune pan-
creatitis may involve organs throughout the entire body
[7, 8]. Serum IgG4 concentrations were well correlated with
the number of extrapancreatic organs involved, indicating
a correlation between increased serum IgG4 and extrapan-
creatic involvement. Among the 5 types of extrapancreatic
involvement, lachrymal and salivary gland lesions and hilar
lymph adenopathy have been significantly associated with
high serum IgG4 concentrations, suggesting that patients
with high serum IgG4 should be assessed for the occurrence
of these lesions [7]. However, a recent study of large
numbers of patients with autoimmune pancreatitis and
extrapancreatic lesions showed different results, as shown in
Table 1. Patients with IgG4-related retroperitoneal fibrosis
and kidney lesions had higher IgG4 concentrations than
other patients, probably because these lesions were compli-
cations of many other IgG4-related diseases (Table 1).
7.Role of IgG4
IgG4 in these patients may be (1) pathogenic, (2) anti-
inflammatory, or (3) as a rheumatoid factor. For example,
anti-desmoglein3 IgG4 autoantibody has been reported
pathogenic for pemphigus vulgaris [25]. Transfer of an anti-
desmoglein3 IgG4 autoantibody from a pemphigus vulgaris
patient to BALB/C mice resulted in a pemphigus vulgaris like
lesion, suggesting the involvement of an IgG4 autoantibody
directed against an unknown target antigen. Similarly, IgG4
deposits have been detected in tissues of patients with
autoimmune pancreatitis [26]. In contrast, IgG4 was found
to have anti-inflammatory effects against allergic reactions.
IgG4 antibodies can bind to soluble antigens, blocking the
interaction between these antigens and IgE on mast cells and
inhibiting allergic reactions. A dynamic Fab arm exchange
of IgG4 can occur, resulting in bispecific activity, loss of
monospecific cross-linking activity, and loss of the ability
to form immune complexes, resulting in anti-inflammatory
effects [27].
IgG4 may act as an autoantibody against IgG or have
rheumatoid factor activity. Western blotting has shown that
IgG4 from the sera of patients with autoimmune pancreatitis
can bind to IgG1, IgG2, IgG3, and IgG Fc [28]. Furthermore,
IgG4 Fc, but not IgG4 Fab, was found to bind to IgG Fc
[28], indicating that IgG4 binding to IgG Fc is via an Fc-
Fc interaction, not via rheumatoid activity. ELISA showed
that IgG4 from the serum of each patient with autoimmune
pancreatitis could bind to IgG1 coated onto microplates, a
bindingwellcorrelatedwithserumIgG4,butnotrheumatoid
factor, concentration [28]. The role of IgG4 Fc-IgG Fc is
unclear, but it may have physiological and/or pathological
effects, suggesting the need for further studies.
8.Conclusion
The utility of serum IgG4 concentration as a biomarker of
the major IgG4-related disease, autoimmune pancreatitis,
includes its ability to diagnose autoimmune pancreatitis as
well as to differentiate this disease from pancreatic cancer.
Moreover, serum IgG4 concentration may be a marker for
predicting relapse and for the evaluation of extrapancreatic
lesions. It remains unclear, however, whether IgG4 and
its rheumatoid factor-like activity may be beneficial or
pathogenic in these patients.
Acknowledgments
This work was supported in part by the Research Program
of Intractable Disease provided by the Ministry of Health,

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4International Journal of Rheumatology
Labor, and Welfare of Japan, and in part by Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports, and Culture of Japan (23591012).
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