New clues to the nature of immunoglobulin G4-related disease: a retrospective Japanese multicenter study of baseline clinical features of 334 cases
Yamada et al. Arthritis Research & Therapy
New clues to the nature of immunoglobulin G4-related disease: a retrospective Japanese multicenter study of baseline clinical features of 334 cases
Kazunori Yamada 0 1 3
Motohisa Yamamoto 0 2
Takako Saeki 7
Ichiro Mizushima 1
Shoko Matsui 6
Yuhei Fujisawa 1
Satoshi Hara 1
Hiroki Takahashi 2
Hideki Nomura 5 6
Shigeyuki Kawa 4
Mitsuhiro Kawano 1
0 Equal contributors
1 Division of Rheumatology, Kanazawa University Hospital , 13-1, Takara-machi, Kanazawa, Ishikawa 920-8640 , Japan
2 Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine , Sapporo , Japan
3 Department of Advanced Research in Community Medicine, Kanazawa University Graduate School of Medical Sciences , Kanazawa , Japan
4 Department of Internal Medicine, Matsumoto Dental University , Shiojiri , Japan
5 Division of General Medicine, Kanazawa University Hospital , Kanazawa , Japan
6 Health Administration Center, University of Toyama, Toyama , Japan
7 Department of Internal Medicine, Nagaoka Red Cross Hospital , Nagaoka , Japan
Background: The aim was to further characterize immunoglobulin G4-related disease (IgG4-RD) by a large-scale multicenter study of its clinical and laboratory features conducted by multidisciplinary physicians of IgG4-RD in Japan. Methods: Various specialists retrospectively evaluated IgG4-RD patients diagnosed between 1996 and 2015 in five hospitals by analyzing their baseline clinical features, laboratory, imaging, and pathological test findings, and treatment. Results: Of the 334 patients listed, 205 were male and median age at diagnosis was 65 years. The mean number of organs involved was 3.2 at diagnosis. The most frequently affected organs were the salivary glands, followed by the lacrimal glands, lymph nodes, pancreas, retroperitoneum/periaorta, kidneys, and lungs. The mean serum level of IgG4 was 755 mg/dl, and more than 95% of patients had elevated serum IgG4 levels. The median serum level of C-reactive protein (CRP) was 0.1 mg/dl and the level was less than 1 mg/dl in 90% of patients. A total of 34.7% of patients had low serum levels of C3. Serum levels of C3 and non-IgG4 IgG, calculated as the total IgG minus IgG4, showed an inverse correlation in patients with kidney lesions, while serum IgG4 levels were not correlated with serum C3 levels. Corticosteroid was administered in 78.0% of patients, and was effective in all. Conclusions: The serum CRP level is generally low and the serum IgG4 level is elevated in most Japanese IgG4-RD patients, in contrast to western patients. These original findings suggest that these two parameters in IgG4-RD differ in some interesting ways from those hitherto reported in western populations. Additional studies, especially international comparative ones, are needed to elucidate the extent and significance of these differences between populations. Attention will also have to be paid to whether the existence of such differences requires consideration when devising international classification criteria.
IgG4-related disease; Clinical features; Hypocomplementemia
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD), a
widely recognized systemic inflammatory disorder [
affects a broad range of organs with main features of
elevated serum IgG4 levels, copious infiltration of
IgG4positive cells into the affected organs, and a
characteristic fibrosis called storiform fibrosis [
affects a broad range of organs such as the pancreas,
lacrimal glands, salivary glands, kidneys, lungs,
retroperitoneum and/or periaorta, skin, and lymph nodes [
Owing to its extremely diverse clinical picture, individual
clinicians encounter a clinically distinct patient
population depending on his/her specialty and geographic
location, making it difficult to avoid institutional bias in a
single-center experience. Recently, several larger cohort
studies have sought to characterize the clinical
characteristics of IgG4-RD of over 100 patients [
Although these reports documented the baseline clinical
features of IgG4-RD, differences were seen in the
frequency of the affected organs and some laboratory
data possibly due to different inclusion criteria, authors’
specialty, study design, and racial biases. This prompted us
to conduct a large-scale multicenter study with
well-experienced physicians of IgG4-RD including rheumatologists,
gastroenterologists, pulmonologists, and nephrologists to
clarify the baseline clinical and laboratory features of
IgG4-RD in a large-scale cohort of 334 IgG4-RD patients.
Summary of cohort
We retrospectively evaluated 334 patients with IgG4-RD
who were diagnosed between 1996 and 2015 in
Kanazawa University Hospital, Sapporo Medical University
Hospital, Nagaoka Red Cross Hospital, University of
Toyama Hospital, Shinshu University Hospital, and
affiliated hospitals. Data related to patients’ baseline clinical
features, laboratory findings, imaging tests, pathological tests,
and treatments were derived from their medical records.
To minimize bias regarding the organs affected by
IgG4RD, the diagnosis of IgG4-RD was made by specialists of
IgG4-RD in each institution, supported by the
comprehensive diagnostic criteria (CDC) [
] and/or criteria of
each organ including type 1 autoimmune pancreatitis,
IgG4-related kidney disease, IgG4-related Mikulicz’s
disease (IgG4-related sialadenitis and dacryoadenitis),
and IgG4-related sclerosing cholangitis [
CDC consist of three parts including clinical features
showing characteristic diffuse/localized swelling or masses
in single or multiple organs, elevation of serum IgG4
concentrations (≥135 mg/dl), and histopathological findings
including marked lymphoplasmacytic infiltration, fibrosis,
and infiltration of IgG4-positive cells (IgG4+/IgG+ > 40%
and > 10 IgG4+ plasma cells/HPF). Since the cutoff
number of IgG4-positive plasma cells of the CDC is lower than
those of the Consensus statement on the pathology of
IgG4-RD , we made the diagnosis of IgG4-RD
referring to the Consensus statement on the pathology by
specialists who have treated many IgG4-RD patients and
paid particular attention to any clinicopathologic
correlations. The histopathological importance of tissue
infiltrating IgG4-positive plasma cells (IgG4+ PC) in the diagnosis
of AIP was reported in 2002, and was also confirmed in
the diagnosis of Mikulicz disease (MD) in 2005, which is
currently known as IgG4-related dacryoadenitis and
sialadenitis. Therefore, after 2005, almost all patients in our
study were diagnosed as having IgG4-RD with reference
to the immunohistochemical findings of IgG4 staining,
clinical and imaging features, and/or serum IgG4 levels. In
contrast, 30 patients who were diagnosed as having AIP
or MD before 2005 were also included in our study. Of
these, four patients were diagnosed with AIP before 2002.
Reevaluation of histopathological samples was performed
in all four of these patients, and the diagnosis of IgG4-RD
was confirmed. Similarly, 26 patients were diagnosed with
IgG4-related dacryoadenitis and sialadenitis before 2005.
Fifteen of these 26 patients were reevaluated
histopathologically and the final diagnosis was confirmed. In the
remaining 11 patients, eight had bilateral lachrymal and
submandibular gland swelling with elevated serum IgG4
levels, with this combination highly specific for the
diagnosis of IgG4-RD. The other three patients had only one
set of bilateral lacrimal or bilateral submandibular gland
swelling, and all of them had an elevated serum IgG4
level. These three patients were diagnosed with IgG4-RD
with reference to the clinical and imaging features and
elevation of serum IgG4 levels.
The numbers of patients with definite, probable, and
possible IgG4-RD according to CDC and/or
organspecific criteria were 280 (83.8%), 49 (14.7%), and 4
(1.2%), respectively. One patient was diagnosed clinically
with IgG4-RD (Table 1).
We retrospectively analyzed the medical records of all
patients included in this study. We noted the serum
levels of IgG, IgG4, IgE, C3, C4, CH50, and C-reactive
protein (CRP), the affected organs, the diagnostic
imaging tests including computed tomography (CT),
magnetic resonance imaging (MRI), gallium (Ga)
scintigraphy, and positron emission tomography (PET), and
the prevalence of biopsy of the affected organs. Serum
IgG4 levels were measured using the nephelometric
assay in all patients in this study. In addition, as a new
serological marker, we defined non-IgG4 IgG as total
IgG minus IgG4. Non-IgG4 IgG substitutes for the sum
of IgG1, IgG2, and IgG3, and an increase of non-IgG4
IgG seems to mean that the serum level of IgGs which
can activate the complement pathway is increased. We
also evaluated the prevalence of corticosteroid therapy,
average initial and maintenance dose of corticosteroid,
effectiveness of corticosteroid therapy, and recurrence rate.
The improvement of the affected organs was decided as the
changes in symptomatic, radiologic, serologic, or histologic
features. In IgG4-related kidney disease (IgG4-RKD),
improvement of renal function was also considered. The
definition of recurrence was the reappearance or worsening of
symptomatic, radiologic, serologic, or histologic features of
IgG4-RD. In IgG4-RKD, a rapid increase in the serum level
of creatinine, after careful exclusion of other renal diseases,
was also considered as recurrence. Reelevation of the serum
levels of IgG or IgG4 alone was not regarded as recurrence.
Furthermore, we determined the prevalence of diabetes
mellitus (DM) at diagnosis of IgG4-RD and malignancy
both before and after diagnosis of IgG4-RD.
Differences between groups were assessed by chi-square
test for categorical variables, and by Mann–Whitney U test
for linear variables. The analysis of the organs associated
with hypocomplementemia was performed using logistic
regression analysis, adjusted for age, sex, and presence/
absence of DM. Correlation analysis was performed to
confirm the relationship between hypocomplementemia
and serum levels of IgG4 or non-IgG4 IgG. Explanatory
factor analysis followed by Varimax rotation was used to
examine the structure of organ coinvolvement. All
statistical tests were performed using SPSS software (version
22). Significant differences were defined as p < 0.05.
Two hundred and five patients were male, and 129 were
female (male 61.4%). The mean and median ages at
diagnosis were 63.8 ± 11.5 and 65 years (range 25–91). All
patients were Japanese. The average follow-up period was
4.2 years. The prevalence of diabetes mellitus (DM) was
34.4% and was significantly higher in those with rather
than without AIP (46.2% vs 30.0%, p = 0.005) (Table 1).
Sixty-seven malignancies appeared in 57 of 334 patients
(17.1%) with IgG4-RD (Table 2). Two and six patients had
three and two malignancies, respectively. The types of
malignancy are presented in Additional file 1: Table S1. Lung
cancer was the most frequent malignancy in patients with
IgG4-RD, followed by gastric cancer, colon cancer, and
prostate cancer. Lung, colon, prostate, and renal cancers
were frequently seen both before and after the diagnosis of
IgG4-RD, whereas gastric cancer and malignant lymphoma
tended to appear after the diagnosis of IgG4-RD (Table 2).
The mean number of organs involved was 3.2 (range 1–
11). The most frequently affected organs were the
salivary glands (SG) (72.7%) followed by the lacrimal glands
(LG) (57.1%), lymph nodes (56.5%), pancreas (25.5%),
retroperitoneum (RP)/periaorta (24.9%), kidney (23.7%),
and lung (23.4%). Single organ involvement was seen in
38 of 334 patients (11.4%) (Table 1). After excluding
lymph nodes, the ratio of single organ involvement was
18.9%. The other affected organs with a prevalence of
more than 1% were the prostate (9.6%), bile duct (5.4%),
and skin (1.5%). The RP/periaorta, lung, and kidney were
more frequently affected in males than in females, and
the reverse for the LG (see Additional file 1: Table S1).
The factor analysis identified three factors, explaining
21.7% of the total variance: factor 1 explained 8.1%,
affecting LG, SG, and lymph node involvement; factor 2
explained 7.0%, affecting RP/periaorta involvement; and
factor 3 explained 6.6%, and affected kidney and lung
involvement. These results indicated that organ
involvement occurs rather randomly, although there might be
some tendency of coinvolvement in the three different
organ categories (see Additional file 2: Table S2).
Mean serum levels of IgG and IgG4 were 2403 ± 1204
and 755 ± 642 mg/dl, respectively. Elevation of serum
levels of IgG4 defined as IgG4 ≥ 135 mg/dl were seen in
318 of 333 patients (95.5%). Mean serum level of IgE
was 611 ± 1198 IU/ml, and elevated serum levels defined
as IgE ≥ 250 IU/ml were seen in 158 of 309 patients
(51.1%). Elevation of serum levels of CRP defined as
CRP ≥ 0.3 mg/dl was seen in 90 of 328 patients (27.4%).
Mean and median serum levels of CRP were 0.42 and
0.10 mg/dl, respectively. In 79.9% and 90.2% of the
patients, the serum level of CRP was less than 0.5 and
1.0 mg/dl, respectively (Table 3).
Patients with low C3 and C4 defined as C3 < 86 mg/dl
and C4 < 17 mg/dl were seen in 34.7% and 33.7%,
respectively. The frequency of low C3 in patients with
kidney lesion was significantly higher than in those
without (55.4% vs 27.8%, p < 0.000) (Table 4). The frequency
of low C3 in patients with pancreas or lung involvement
was also significantly higher than in those without
(pancreas 46.8% vs 30.3%, p = 0.009; lung 47.2% vs 30.7%, p
= 0.015) (Table 4). We performed logistic regression
analysis to explore the impact of organ involvement on
hypocomplementemia, as well as that on severe
hypocomplementemia. Kidney, lung, or pancreas involvement
was independently related to hypocomplementemia,
with odds ratios of 2.60 (95% CI 1.47–4.59, p = 0.001),
1.84 (95% CI 1.04–3.26), and 1.83 (95% CI 1.04–3.21),
respectively (Table 5). Patients with severe
hypocomplementemia defined as C3 < 50 mg/dl were seen in 30 of
Data presented as number/total (%)
Frequency of hypocomplementemia
Present Absent p
297 patients (10.1%). In a logistic regression analysis,
kidney or lung involvement, as well as DM, but not
pancreas involvement, were strongly related to severely
low C3, with odds ratios of 6.09 (95% CI 2.61–14.2),
2.47 (95% CI 1.05–5.50), and 2.38 (95% CI 1.01–5.50),
respectively (Table 5). Next, we analyzed whether serum
levels of IgG4 or non-IgG4 IgG, which is calculated as total
IgG minus IgG4, were correlated with
hypocomplementemia. In an analysis of all patients, the serum level of C3 was
significantly inversely correlated with both serum levels of
IgG4 and non-IgG4 IgG (Pearson’s product-moment
correlation coefficient –0.298, p < 0.001 and –0.352, p < 0.001,
respectively) (Fig. 1a, b), which indicated that low serum
C3 level tended to occur in patients with high serum levels
of both IgG4 and non-IgG4 IgG. On the other hand,
in patients with kidney lesion, the serum C3 level was
significantly inversely correlated with only serum levels of
non-IgG4 IgG, which indicated that IgG4 may not affect
the deposition of C3 in kidney tissue (Fig. 1c, d).
CT was performed in 99.4% of patients and
contrastenhanced CT in 93.1%. MRI, PET, and Ga scintigraphy
were also performed in 30.2%, 45.5%, and 35.1% of
patients, respectively, to determine the extent of systemic
involvement. According to the histopathological
evaluations, the most frequently biopsied organ were the SG
(49.0%), followed by the kidney (37.5%), LG (35.1%),
lung (33.8%), pancreas (12.8%), and RP/periaorta (1.2%)
(Fig. 2). These data indicated that the major SG were the
most easily accessible organ in patients with IgG4-RD.
In contrast, only a single patient underwent RP/periaorta
biopsy because these deeper structures are much more
difficult to access.
Corticosteroid therapy was administered to 245 of 314
patients (78.0%). The mean initial and maintenance dose
of prednisolone was 30.5 and 4.1 mg/day, respectively.
Corticosteroid was effective in all patients. Recurrence
was noted in 67 of 314 patients (21.3%), in whom 23 of
67 (34.3%) were not receiving corticosteroid at the time
of recurrence. The average dose of corticosteroid at first
recurrence was 7.1 mg/dl.
To the best of our knowledge, this is the largest cohort
study thus far to collect IgG4-RD patients and analyze
their clinical features. The salient findings of our cohort
study can be summarized as follows. First, elevated
serum levels of IgG4 were seen in more than 95% of
patients with IgG4-RD. Second, the median serum CRP
level was 0.1 mg/dl, and the serum CRP level was less
than 1 mg/dl in 90.2% of the patients, meaning that
serum levels of CRP are within the normal range in most
IgG4-RD patients in Japan. Third, low C3 was seen in
34.7% of patients, and its frequency differed depending
on the organs affected. The affected organs associated
with low serum levels of C3 were the kidney, lung, and
pancreas. Serum levels of C3 and non-IgG4 IgG
calculated as total IgG minus IgG4 showed inverse
correlations in patients with kidney lesion, while serum
IgG4 levels did not correlate with serum C3 levels.
Fourth, the most frequently affected organs were the
salivary glands, lacrimal glands, pancreas,
retroperitoneum/periaorta, kidneys, and lungs.
Major differences have been noted in the prevalence of
affected organs in previously published studies [
Wallace et al. [
] analyzed IgG4-RD patients all of whom
were subjected to pathological analysis. In their study,
the prevalence of organs that were difficult to access,
such as the pancreas, was relatively low and 19.2% of
patients had type I AIP. Inoue at al. [
] used a
radiology database to detect IgG4-RD patients who were
pathologically diagnosed with IgG4-RD and/or fulfilled
the diagnostic criteria of AIP. This method picked up
AIP patients without pathological analysis and showed
that 61% of patients had pancreas lesions. However, the
prevalence of retroperitoneal and/or periaortal lesions
was very low (both 4%) in both analyses, and the issue of
how to best diagnose involvement of organs which are
difficult to access remained unresolved. In our study,
patients with retroperitoneal and/or periaortal lesions were
diagnosed as having IgG4-RD without biopsy through
clinicoimaging correlations obtainable in daily medical
practice. We found six organs to be the most frequently
affected: salivary glands, lacrimal glands, pancreas,
retroperitoneum/periaorta, kidney, and lung, with the last
four organs having almost the same prevalence (around
25%). The major affected organs could be classified into
the following three subgroups using Varimax rotation:
group 1, lacrimal glands, salivary glands, and lymph
node; group 2, retroperitoneum/periaorta; and group 3,
kidney and lung (see Additional file 2). Inoue et al. [
reported that male and female patients showed a
different distribution of organ manifestations. They noted that
dacryoadenitis and sialadenitis developed more
commonly in females (female-to-male ratio 41:18 and 57:29
respectively), while periaortitis was significantly more
common in males than females (female-to-male ratio
2:25). Thus, our results of factor analysis are consistent
with their results. Although we are not yet able to clarify
the factors particular to each subgroup, recognition of
these subgroups provides a good opportunity to
speculate on the different pathogenetic mechanisms at work
in each of them.
In this study, the serum IgG4 level was elevated in
95% of patients. Inoue et al. [
] analyzed 235 patients
and found elevated serum IgG4 levels in 88% of them.
Similarly, a large Chinese cohort study [
] showed that
97.5% of patients had serum IgG4 elevation. The results
of these studies suggest that most patients with
IgG4RD in Asian countries have increased serum IgG4 levels
(Table 6). In contrast, Wallace et al. [
] analyzed 125
patients with IgG4-RD and showed that only 51% of
them had elevated serum IgG4 concentrations. In this
study, 76% were Caucasian and only 8.8% were Asian.
Therefore, the difference in the proportion of patients
with elevated serum IgG4 in these studies may be due at
least in part to racial differences. Another important
factor possibly influencing the frequency of patients with
high serum IgG4 is the proportion of patients with
single organ involvement in each study. In the study by
Wallace et al. [
] 38% of patients had single organ
involvement, in contrast to 11% in our study. Similarly,
only 4.2% had one organ involved in Lin et al.’s study
] (Table 6). Since patients with single organ
involvement tend to have low serum IgG4 levels, the percentage
of such patients is thought to influence the frequency of
high serum IgG4 patients.
In our study, elevation of the serum level of CRP was
seen only in 27.4% of patients. The median serum level
of CRP was 0.1 mg/dl, and values less than 0.5 and
1.0 mg/dl were present in about 80% and 90% of
Number of patients
Mean serum IgG level (mg/dl)
Mean serum IgG4 level (mg/dl)
Elevation of IgG4 (%)
Median serum CRP level (mg/dl) 0.10
Mean serum CRP level (mg/dl)
CRP < 0.5 mg/dl (%)
CRP < 1.0 mg/dl (%)
Elevation of CRP (%)
Single organ involvement (%)
RD patients, respectively. These data indicate that serum
levels of CRP in most patients with IgG4-RD are normal
or low. Elevated serum IgG4 and pathological features
mimicking those of IgG4-RD have been noted in other
diseases such as multicentric Castleman disease (MCD)
] and anti-neutrophil cytoplasmic antibody
(ANCA)associated vasculitis, and in particular granulomatosis
with polyangiitis (GPA) [
] and eosinophilic
granulomatosis with polyangiitis (EGPA) [
]. Important for
the differential diagnosis is the fact that serum CRP
levels are generally elevated in these diseases ,
making the serum CRP level an important serological
marker in differentiating IgG4-RD in Japanese
patients. However, the fact that 44–67% of patients had
elevated CRP levels in cohort studies from western
] indicates that interpretation of
the serum CRP level may have to take into account
racial and possibly other differences in the subjects
and populations studied (Table 6).
Hypocomplementemia is an important serological
feature of IgG4-RD, in particular IgG4-RKD [
6, 25, 26
More than 50% of IgG4-RKD patients have
hypocomplementemia, while the prevalence of hypocomplementemia
is about 30% in all IgG4-RD. This has led to speculation
about the reasons underlying the strong association noted
between hypocomplementemia and IgG4-related
tubulointerstitial nephritis (TIN). In the present study, we
noted low C3 and C4 levels in 35% and 34%, respectively,
of IgG4-RD patients. Furthermore, hypocomplementemia
in patients with kidney lesion was significantly more
frequent than in those without, supporting previous reports.
Interestingly, serum complement levels rapidly normalize
after successful corticosteroid therapy in parallel with the
reduction of the size of mass or enlarged lesions [
Moreover, a renewed decrease in serum complement levels
has been observed during the clinical course of relapse in
patients with IgG4-related TIN [
hypocomplementemia as a convenient biomarker of disease activity.
However, in general, IgG4 has been thought not to bind to
C1q, which is related to its inability to activate the classical
complement pathway. On the other hand, one report
showed that IgG4 molecules derived from patients with
IgG4-RD and hypocomplementemia can activate
complement through C1q-binding [
], although additional studies
to confirm this are necessary. Previous histopathological
immunofluorescent analyses showed that not only IgG4
but also IgG1 is deposited in the tubular basement
membrane of the kidney. This suggests that IgG1 also has a
pathogenetic role in IgG4-RKD. Using a mouse model of
AIP, Shiokawa et al. [
] showed that more destructive
injury in the pancreas was induced by injecting the patient
with IgG1 rather than IgG4. In the present study, we found
that serum levels of non-IgG4 IgG were significantly
inversely correlated with serum C3 levels in patients with
kidney lesion, while IgG4 itself has only a weak correlation
with serum C3 levels. Our finding seems to be compatible
with Shiokawa et al.’s result. To the best of our knowledge,
the present study is the first report to show that non-IgG4
IgG subclasses exert a more significant influence on
hypocomplementemia, probably through activation of
complement in patients with kidney lesions, than IgG4 subclass.
Thus, IgG subclasses other than IgG4 should also be
focused on as pathogenetic immunoglobulins.
The rate of malignancies in this study (17.1%) was
higher than those in other Japanese cohort studies (6.4%
], 10.4% [
], 13.9% [
], 12.3% [
]) but lower than
that of the study reported by Asano et al. (21.5% [
Of these five studies, three confirmed an increased risk
of malignancy in IgG4-RD using the standardized
incidence ratio (SIR), while the other two did not. Since
we did not calculate the SIR because of the limitation of
our study design, we could not easily compare the
frequency of malignancy with that in other Japanese studies.
The discordant results found in Japanese studies are likely
attributable to methodological issues related to the study
design of individual studies. Hirano et al. [
patients in whom malignancy was diagnosed ≤ 6 months
before or after the onset of IgG4-RD to avoid selection
bias, whereas other studies did not. Thus, careful
evaluation is needed to conclude that the rate of malignancies
in IgG4-RD is significantly higher than that of controls.
The recurrence rate of our study was lower than those
of western countries. Reports from Spain [
] and Italy
] described the recurrence rate to be 38.5% and 46%,
respectively. On the other hand, Inoue et al. [
the recurrence rate in Japanese patients to be 24%,
almost the same as in our study. A recent meta-analysis
] also showed that the recurrence rates in Americans
and Europeans were higher than those in Asians. The
difference in the recurrence rates between Japanese and
Caucasians may be attributable to differences in the
therapeutic strategy, especially the use or nonuse of
corticosteroid maintenance therapy, race, and various
other patient background features. However, we did not
analyze the relationship between the treatment strategy
for IgG4-RD such as the duration and tapering pace of
corticosteroid and immunosuppressant administration
and the recurrence rate. This important issue will
require further studies for clarification.
Our study has several limitations. First, biopsies of the
affected organs were not performed for 18.9% of the
patients because the affected organs were not easily
accessible. Second, methodological differences in the
measurement of laboratory parameters such as serum
complement levels among different periods and different
institutions is a weak, but unavoidable, aspect of our
retrospective cohort study. However, the effect of the
difference of the method employed among different
periods and different institutions on complement levels is
limited and the influence would seem to be quite small.
On the other hand, the serum IgG4 level was measured
using nephelometry in all institutions. Therefore, we
think no methodological difference existed. Third, we
used the serum levels of non-IgG4 IgG instead of those of
IgG1, IgG2, or IgG3, because we do not measure serum
levels of IgG1, IgG2, and IgG3 in daily clinical practice.
It remains difficult to clarify the frequency of individual
organs affected by IgG4-RD due to various biases related
to the criteria employed for diagnosis and differences in
the distribution of the specialties of clinicians making the
diagnosis of IgG4-RD. In this study, we believe that we
were better able to elucidate the baseline clinical features
of IgG4-RD by having specialists of IgG4-RD from a
variety of fields participate in the evaluations.
Another issue highlighted by this study is the finding of
differences in various clinical parameters between our
population and western ones. This raises the important
question of whether the hitherto proposed international
consensus criteria are equally applicable to all populations,
and whether the more or less universally recognized
clinical spectrum of IgG4-RD is the same in all of them.
Further exploration of the reasons underlying any differences
may also provide intriguing clues to the underlying nature
of IgG4-RD and be of use in devising more accurate
diagnostic criteria. To best characterize IgG4-RD and assess
the universality of various criteria for diagnosis, future
studies, including international comparative ones, will be
needed with larger numbers of IgG4-RD patients
diagnosed according to various criteria.
In Japanese individuals, various clinical parameters in
IgG4-RD including serum IgG4 and CRP levels appear
to differ in some interesting ways from those hitherto
reported in western populations. Additional studies,
especially international comparative ones, will be needed to
elucidate the extent and significance of these differences
between populations. Attention will also have to be paid
to whether such differences require consideration when
devising diagnostic criteria that are meant to be applied
Additional file 1: Table S1. Gender differences in affected organs.
(DOC 64.5 kb)
Additional file 2: Table S2. Factor analysis of the affected organs.
(DOC 33 kb)
CDC: Comprehensive diagnostic criteria; CT: Computed tomography;
DM: Diabetes mellitus; EGPA: Eosinophilic granulomatosis with polyangiitis;
Ga: Gallium; IgG4: Immunoglobulin G4; IgG4-RD: Immunoglobulin G4-related
disease; IgG4-RKD: Immunoglobulin G4-related kidney disease; LG: Lacrimal
glands; MCD: Multicentric Castleman disease; MRI: Magnetic resonance
imaging; PET: Positron emission tomography; RP: Retroperitoneum;
SG: Salivary glands; TIN: Tubulointerstitial nephritis
The authors thank Mr John Gelblum and Mr Eric Tusken for their critical
reading of the manuscript.
This work was supported partially by the Research Program of Intractable
Diseases of the Ministry of Health, Labor, and Welfare of Japan, JSPS KAKENHI
Grant Number 26461487 and 17 K09999, and a grant-in-aid from Kato Memorial
Availability of data and materials
KY designed the study, acquired data, contributed to analysis and interpretation
of data, and drafted the manuscript. MY acquired data and provided intellectual
content of critical importance to the work described. TS acquired data,
contributed to analysis and interpretation of data, and provided intellectual
content of critical importance to the work described. IM acquired data and
provided intellectual content of critical importance to the work described. SM
acquired data and provided intellectual content of critical importance to the
work described. YF acquired data, contributed to analysis and interpretation of
data, and provided intellectual content of critical importance to the work
described. SH acquired data and provided intellectual content of critical
importance to the work described. HT acquired data and provided intellectual
content of critical importance to the work described. HN acquired data and
provided intellectual content of critical importance to the work described. SK
acquired data and provided intellectual content of critical importance to the
work described. MK designed the study, contributed to analysis and
interpretation of data, provided intellectual content of critical importance to the
work described, and revised the manuscript. All authors read and approved the
Ethics approval and consent to participate
This study was approved by the ethics committees of Kanazawa University
Hospital, Sapporo Medical University Hospital, Nagaoka Red Cross Hospital,
University of Toyama Hospital, and Shinshu University Hospital. All data and
samples from patients were collected with their informed consent, and the
study was conducted in compliance with the Declaration of Helsinki
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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