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ORIGINAL ARTICLE
Diagnostic performances of serum IgG4 concentration
and IgG4/IgG ratio in IgG4-related disease
Chang-sheng Xia
1
&Chun-hong Fan
1
&Ya n - y i ng L i u
2
Received: 9 March 2017 /Revised: 27 April 2017 / Accepted: 15 May 2017 / Published online: 24 May 2017
#International League of Associations for Rheumatology (ILAR) 2017
Abstract Patients with IgG4-related disease (IgG4-RD) often
have elevated serum IgG4 levels. Here, we aimed to evaluate
the diagnostic performances of elevated serum IgG4 concen-
tration and IgG4/IgG ratio for IgG4-RD. We retrospectively
analyzed 1381 patients subjected to serum IgG subclass test-
ing to differentiate IgG4-RD from other diseases at Peking
University People’s Hospital from 2012 to 2016. This sample
included 133 IgG4-RD patients and 1248 non-IgG4-RD pa-
tients. Serum IgG subclass concentrations were measured
using Siemens reagents. The median values (25th–75th per-
centile) for serum IgG4 concentration and IgG4/IgG ratio,
respectively, were 8640 (3970–17750) mg/L and 0.339
(0.229–0.517) in IgG4-RD patients and 450 (220–920) mg/
L and 0.032 (0.014–0.061) in non-IgG4-RD patients
(p< 0.001). For distinguishing IgG4-RD from non-IgG4-
RD, the optimal cut-off values of IgG4 and IgG4/IgG were
2100 mg/L and 0.114, respectively. The corresponding area
under the curve (AUC) values were 0.964 and 0.970, respec-
tively. Comparison of the receiver operating characteristic
curves revealed a significant difference between these AUC
values (p= 0.002). The sensitivity, specificity, positive
predictive value (PPV), and negative predictive value
(NPV), respectively, were 94.7, 91.6, 54.5, and 99.4% for
the IgG4 optimal cut-off value and 96.2, 92.1, 56.4, and
99.6% for the IgG4/IgG optimal cut-off value. Our results
confirmed that elevated serum IgG4 concentration and IgG4/
IgG ratio were of great value for IgG4-RD diagnosis.
Keywords Area under curve .Cut-off value .IgG4 .
IgG4-related disease
Introduction
IgG4-related disease (IgG4-RD) is a systemic chronic fibro-
inflammatory disorder that affects multiple organ sites [1,2].
Characteristic disease signs include diffuse/localized swelling
or masses in one or more organs and frequent serum IgG4
elevations. The established diagnostic criteria for IgG4-RD
[3,4] include elevated serum IgG4 concentration (>1350 mg/
L). However, reference material selection is critical for accurate
measurement of IgG subclasses. To improve diagnostic perfor-
mance, some studies utilize the serum IgG4/IgG ratio for IgG4-
RD diagnosis [5,6].
Siemens and Binding Site are two major manufactures of
reagents for IgG subclass measurement. Siemens IgG subclass
assays are calibrated against an internal standard manufactured
by Sanquin, while Binding Site IgG subclass assays are stan-
dardized using a purified IgG subclass preparation against
CRM470. Previous studies report differences between IgG sub-
class measurements using Siemens vs. Binding Site assays [7,
8]. In particular, serum IgG4 measurements are significantly
higher with the Siemens assay than with the Binding Site assay.
The reference interval of serum IgG4 concentrations measured
using the nephelometry method is 40–870 mg/L when using
the Binding Site assay and 30–2010 mg/L when using the
*Chang-sheng Xia
xiachangsheng@bjmu.edu.cn
Chun-hong Fan
chunhongfan9681@163.com
Yan-ying Liu
liuyanying2003801@msn.com
1
Department of Clinical Laboratory, Peking University People’s
Hospital, No.11 Xizhimen South Street, Beijing 100044, China
2
Department of Rheumatology and Immunology, Peking University
People’s Hospital, No.11 Xizhimen South Street, Beijing 100044,
China
Clin Rheumatol (2017) 36:2769–2774
DOI 10.1007/s10067-017-3685-7
Siemens assay. The upper limit of normal (ULN) serum IgG4
concentrations when measured with the Siemens assay is sig-
nificantly higher than the ULN when using the Binding Site
assay. Since a serum IgG4 concentration cut-off value of
1350 mg/L is used for IgG4-RD diagnosis, it may be more
appropriate to use the Binding Site assay rather than the
Siemens assay for this measurement.
In the present study, we aimed to establish cut-off values
for serum IgG4 level and IgG4/IgG ratio, as measured using
Siemens reagents for IgG4-RD diagnosis in Chinese popula-
tions. We further evaluated the diagnostic performances of our
presently established cut-off values for distinguishing IgG4-
RD from non-IgG4-RD.
Methods
Patients
We performed a review of all serum IgG subclass concentration
measurements obtained in the Department of Clinical
Laboratory, Peking University People’s Hospital from
June 2012 to June 2016. Based on test request details and a
review of the clinical notes, we identified a total of 1389 pa-
tients subjected to serum IgG subclass concentration analysis to
distinguish IgG4-RD from non-IgG4-RD inflammatory, auto-
immune, or malignant conditions. These 1389 patients includ-
ed 141 IgG4-RD patients and 1248 non-IgG4-RD patients.
Fifteen IgG4-RD patients showed normal serum IgG4 concen-
trations, of whom eight were excluded because they received
corticosteroid treatment prior to serum IgG subclass measure-
ment. Thus, 1381 subjects were analyzed in our study, includ-
ing 133 IgG4-RD patients and 1248 non-IgG4-RD patients.
Among the non-IgG4-RD patients, 153 had pancreatic dis-
ease, 60 lung disease, 216 hepatobiliary disease, 148 kidney
disease, 18 lymphoma, 12 Castleman’s disease, 12 eosinophilic
disorders, 46 vasculitis, 343 other rheumatic diseases, and 240
had other various diseases. IgG4-RD was diagnosed following
international pathology consensus guidelines that propose the
diagnostic terminology for IgG4-RD, including histology highly
suggestive of IgG4-RD, probable histological features of IgG4-
RD, and insufficient histopathological evidence of IgG4-RD
[4]. Single organ involvement was defined as the involvement
of only one organ system and multiple organ involvement as the
involvement of more than one organ system. Collected data
included sex, age at onset, clinical features at presentation, and
laboratory test results from the first evaluation.
Laboratory analysis
Serum levels of IgG subclasses 1 to 4 were measured by neph-
elometry using a Siemens BN II Nephelometer (Siemens
Healthcare Diagnostics, Malburg, Germany) and Siemens
reagents (NAS IgG1, NAS IgG2, N latex IgG3, and N Latex
IgG4). Analyses were performed in the Department of Clinical
Laboratory at Peking University People’s Hospital, which was
certified by the College of American Pathologists in 2015. The
IgG4/IgG ratio was calculated by dividing IgG4 by the sum of
the IgG subclasses. In parallel with the samples, we assayed
three internal quality controls, and the measurements were
within the range required by our laboratory. Our laboratory also
verified the performance of our method of analyzing IgG sub-
classes, including determination of precision, analytical accu-
racy, analytical sensitivity, analytical interferences, and refer-
ence intervals. The reference interval for serum IgG4 level was
30–2010 mg/L, in accordance with the manufacturer’s package
insert. For this study, a serum IgG4 concentration of >2010 mg/
L was considered elevated.
Statistical analysis
The continuous variables, age, serum IgG4 concentration,
and IgG4/IgG ratio, showed non-normal distributions and
are, thus, expressed as median (25th–75th percentile). We
used the Mann-Whitney U test to compare numerical data
regarding the partial distribution in two groups, and we
used the Kruskal-Wallis test for comparisons among mul-
tiple groups. The best cut-off values for IgG4 and IgG4/
IgG were determined by receiver operating characteristic
(ROC) analysis and of area under the curve (AUC) calcu-
lations. Categorical variables were analyzed with a χ
2
test
and are shown as percentages. A pvalue of <0.05 was
considered statistically significant. All statistical analyses
were performed using SPSS software version 16.0.
(SPSS, Inc., Chicago, IL), except for the ROC curve com-
parison, which was analyzed using MedCalc software ver-
sion 11.4.2.0 (D JINN).
Results
Demographics
Median age was 60 (53–66) years in IgG4-RD patients and 56
(44–66) years in non-IgG4-RD patients (p< 0.001). Among
the 133 patients with IgG4-RD, males were predominant:
56% men and 44% women. In contrast, females were predom-
inant within the non-IgG4-RD patient group: 59% women and
41% men (p<0.001).
Organ involvement among IgG4-RD patients
Tab le 1shows the involved organs among the 133 patients
with IgG4-RD. Commonly involved organs included the pan-
creas, submandibular gland, lacrimal gland, and parotid gland.
2770 Clin Rheumatol (2017) 36:2769–2774
Multi-organ involvement was noted in 46.6% (62/133) of pa-
tients with IgG4-RD.
Serum IgG4 level and IgG4/IgG ratio
Tab le 2shows the median values for serum IgG4 concentra-
tion and IgG4/IgG ratio in the different groups. Among IgG4-
RD patients, median serum IgG4 concentration was 8640 mg/
L, and median IgG4/IgG ratio was 0.339. In non-IgG4-RD
patients, these values were 450 mg/L and 0.032, respectively
(p< 0.001). Each of these median values for the IgG4-RD
group was significantly higher than the corresponding median
value in each non-IgG4-RD subgroup (p< 0.001). Among
the 133 IgG4-RD patients, 126 (94.7%) had elevated serum
IgG4 levels (>2010 mg/L). Among the 1248 non-IgG4-RD
patients, 109 (8.7%) had elevated serum IgG4 levels. The
percentage of elevated IgG4 level (>2010 mg/L) in the
IgG4-RD group was significantly higher than that in the total
non-IgG4-RD group or each non-IgG4-RD subgroup
(p<0.001).
Diagnostic performances of serum IgG4 concentration
and IgG4/IgG ratio
The optimal cut-off value of serum IgG4 concentration for
IgG4-RD diagnosis was 2100 mg/L. The AUC for IgG4 was
0.964, with a 95% confidence interval (CI) of 0.953–0.974
(p< 0.001). The optimal cut-off value of serum IgG4/IgG ratio
for IgG4-RD diagnosis was 0.114, and the AUC for IgG4/IgG
was 0.970 (95% CI 0.960–0.978, p< 0.001). ROC curve com-
parison revealed a significant difference between the AUC
values for IgG4 and IgG4/IgG (p= 0.002) (Fig. 1). Table 3
presents the diagnostic performances of serum IgG4 level and
IgG4/IgG ratio for distinguishing IgG4-RD from non-IgG4-RD.
Tabl e 1 Involved organs in 133
patients with IgG4-RD Involved organ Number of patients Involved organ Number of patients
Pancreas 50 Kidney 12
Submandibular gland 48 Lung 7
Lacrimal gland 41 Prostate 5
Parotid gland 39 Thyroid 2
Lymph node 15 Liver 2
Bile duct 13 Hypophysis 1
Retroperitoneum 13
Tabl e 2 Serum IgG4 level,
IgG4/IgG ratio, and the
percentage of elevated IgG4 level
(>2010 mg/L) in different patient
groups
Groups Number
of cases
IgG4 in mg/L,
Median
(25th–75th percentile)
IgG4/IgG,
Median
(25th–75th percentile)
IgG4 >2010 mg/L
number (%)
IgG4-RD 133 8640 (3970–17,750) 0.339 (0.229–0.517) 126 (94.7)
Non-IgG4-RD 1248 450 (220–920) 0.032 (0.014–0.061) 109 (8.7)
Pancreatic disease 153 444 (227–821) 0.038 (0.019–0.059) 8 (5.2)
Lung disease 60 469 (201–891) 0.032 (0.014–0.066) 6 (10.0)
Hepatobiliary disease 216 563 (255–932) 0.031 (0.016–0.057) 13 (6.0)
Kidney disease 148 409 (227–765) 0.035 (0.017–0.060) 11 (7.4)
Lymphoma 18 471 (184–1395) 0.022 (0.009–0.079) 4 (22.2)
Castleman’s disease 12 700 (116–2023) 0.037 (0.011–0.087) 3 (25.0)
Eosinophilic disorders 12 1120 (489–2188) 0.098 (0.042–0.148) 4 (33.3)
Vasculitis 46 1170 (322–2073) 0.074 (0.026–0.118) 12 (26.1)
Other rheumatic diseases 343 358 (174–901) 0.021 (0.010–0.050) 26 (7.6)
Other various diseases 240 463 (213–883) 0.035 (0.015–0.066) 22 (9.2)
The Kruskal-Wallis test was used to compare the medians of serum IgG4 concentration and IgG4/IgG ratio among
the IgG4-RD group and all non-IgG4-RD subgroups (p< 0.001). The Mann-Whitney test was used to compare
the medians of serum IgG4 concentrationand IgG4/IgG ratio between the IgG4-RD group and the total non-IgG4-
RD group or each non-IgG4-RD subgroup (p<0.001).Aχ
2
test was used to compare the percentages of elevated
IgG4 level (>2010 mg/L) between the IgG4-RD group and the total non-IgG4-RD group or each non-IgG4-RD
subgroup (p<0.001)
Clin Rheumatol (2017) 36:2769–2774 2771
Discussion
IgG4-RD is a systemic disease that can impact a single organ
or multiple organ systems and tissues. Our present population
of IgG4-RD patients commonly showed involvement of the
pancreas, submandibular gland, lacrimal gland, and parotid
gland, which is in agreement with the findings of another
recent Chinese study [9]. Of the 133 IgG4-RD patients, 62
(46.6%) exhibited multi-organ involvement. Similarly, anoth-
er study reported multi-organ involvement in 43.1% of IgG4-
RD patients [10].
Many studies about IgG4-RD have been conducted in
Japan, and Binding Site IgG subclass assays are used in al-
most all Japanese IgG4-RD studies [11–15]. Hamano et al.
first reported that high serum IgG4 was a useful marker for
distinguishing type 1 autoimmune pancreatitis (AIP) from
other diseases of the pancreas or biliary tract [11]. Umehara
et al. established the comprehensive diagnostic criteria for
IgG4-RD [3]. Japanese studies have reported that IgG4 can
be used for diagnosis of IgG4-RD or AIP with sensitivities
ranging from 82.1 to 97% and specificities ranging from 79.6
to 97% [5,11–15]. Consistent with these Japanese studies,
two Korean studies demonstrated that serum IgG4 measure-
ments obtained with Binding Site reagents can be used for AIP
diagnosis, with cut-off values of 1410 and 1270 mg/L, respec-
tively, sensitivities of 73.3 and 95.1%, and specificities of 83
and 96% [16,17]. These data indicated that serum IgG4 con-
centrations of >1350 mg/L, as measured using Binding Site
reagents, were valuable for the diagnosis of IgG4-RD or AIP
in Japanese and Korean populations.
Studies from the UK have also shown that elevated serum
IgG4 concentration (measured with Siemens reagents) is a
good marker for IgG4-RD and AIP diagnosis. Sadler et al.
reported that a serum IgG4 cut-off value of 1300 mg/L could
be used to differentiate AIP from general pancreatitis and can-
cer, with sensitivity of 90.2%, specificity of 91.5%, PPV of
65.5%, and NPV of 98.2% [18]. It was also recently reported
that an IgG4 cut-off of 1400 mg/L for IgG4-RD diagnosis had
a sensitivity of 82.8%, specificity of 84.7%, PPV of 22.4%,
and NPV of 98.9% [10]. In a study from the Netherlands and
the UK, a serum IgG4 cut-off value of 1400 mg/L could be
used to differentiate IgG4-associated cholangitis from primary
sclerosing cholangitis, yielding a sensitivity of 90%, specific-
ity of 85%, PPVof 59%, and NPVof 97% [19]. As mentioned
above, the ULN of serum IgG4 measured with Siemens re-
agents is 2010 mg/L. Thus, the use of a cut-off value of 1300
or 1400 mg/L for serum IgG4 concentration measured with
Siemens reagents would likely decrease the specificity and
PPV for IgG4-RD diagnosis.
Several studies from the USA also report that elevated se-
rum IgG4 concentration is useful for IgG4-RD diagnosis.
Oseimi et al. studied the usefulness of serum IgG4 (measured
with Siemens reagents) for distinguishing IgG4-associated
cholangitis from cholangiocarcinoma [20]. We combined the
data from their test and validation cohorts (n= 384) and found
that the use of a serum IgG4 cut-off value of 1400 mg/Lyielded
a sensitivity of 71.1%, specificity of 87.1%, and PPVof 65.1%.
Carruthers et al. also studied the use of serum IgG4 concentra-
tions (measured with Siemens or Binding Site reagents) for
IgG4-RD diagnosis and reported a sensitivity of 90%, specific-
ity of 60%, PPVof 34%, and NPVof 96% when using an IgG4
cut-off of >1350 mg/L [6]. When the IgG4 cut-off value was
doubled (>2700 mg/L), these values were 35, 91, 48, and 86%,
respectively, and when instead using the IgG4/IgG ratio (with a
cut-off value of >0.08), the sensitivity was 86%, specificity was
59%, PPV was 33%, and NPV was 95%. The authors conclud-
ed that neither doubling the cut-off for serum IgG4 nor utilizing
the serum IgG4/IgG ratio improved the overall test character-
istics. We analyzed this study design and advised that the diag-
nosis performance of IgG4 would likely be improved if study
included all patients who had IgG4 tests for distinguishing
IgG4-RD from non-IgG4-RD.
Fig. 1 Receiver operator characteristic (ROC) curve distinguishing
between IgG4-RD patients and non-IgG4-RD patients based on serum
IgG4 concentration and IgG4/IgG ratio. The area under the curve was
0.964 for IgG4 concentration and 0.970 for IgG4/IgG. Methodology of
DeLong et al. was used to compare the ROC curves (p= 0.002)
Tabl e 3 Diagnostic performances of serum IgG4 level and IgG4/IgG
ratio for distinguishing IgG4-RD from non-IgG4-RD
Diagnostic performance (%) IgG4 >2100 mg/L IgG4/IgG >0.114
Sensitivity 94.7 96.2
Specificity 91.6 92.1
PPV 54.5 56.4
NPV 99.4 99.6
PPV positive predictive value, NPV negative predictive value
2772 Clin Rheumatol (2017) 36:2769–2774
In studies performed in Mainland and Taiwan of China,
serum IgG4 concentrations are predominantly measured using
Siemens reagents. Our present results showed that 2100 mg/L
was the optimal cut-off value of serum IgG4 concentrations
for IgG4-RD diagnosis, yielding a sensitivity of 94.7%, spec-
ificity of 91.6%, PPV of 54.5%, and NPVof 99.4%. Similar to
our present results, a recent study performed in Taiwan
showed an optimal serum IgG4 cut-off value of 2480 mg/L
for IgG4-RD diagnosis, with a sensitivity of 77.6%, specific-
ity of 92.8%, PPVof 39%, and NPVof 99% [21]. Their values
reported for sensitivity and PPV were lower than the values
determined in our present study, possibly because the IgG4-
RD incidence rate in our study (9.6%, 133/1381) was higher
than that found in the study in Taiwan (5.5%, 161/2901). Li
et al. reported that the optimal IgG4 cut-off value for differen-
tial diagnosis of IgG4-RD was 1575 mg/L, at which the sen-
sitivity was 80.0% and specificity was 88.2% [9]. In our study,
we found a higher optimal cut-off value for serum IgG4, with
ahigherspecificity.
IgG4-RD patients can exhibit normal serum IgG4 concen-
trations following corticosteroid therapy. Our study excluded
eight IgG4-RD patients with normal serum IgG4 concentra-
tions who had been treated with corticosteroids before the
measurement of serum IgG subclasses. If our study had in-
cluded IgG4-RD patients who received corticosteroid treat-
ment prior to IgG subclass measurements, we probably would
have identified a lower optimal cut-off value of serum IgG4
concentration for IgG4-RD diagnosis, with a lower sensitivity.
Most previous studies have not reported details regarding cor-
ticosteroid therapy. Thus, the lower optimal cut-off value of
serum IgG4 and lower sensitivity reported in earlier studies
was likely because some of the included IgG4-RD patients
had received corticosteroid therapy prior to measurement of
serum IgG subclasses.
In an effort to improve the diagnostic performance of se-
rum IgG4 concentration, we tested the use of IgG4/IgG ratio
for IgG4-RD diagnosis. The optimal serum IgG4/IgG cut-off
value was 0.114, yielding a sensitivity of 96.2%, specificity of
92.1%, PPVof 56.4%, and NPV of 99.6%. AUC values were
0.970 for IgG4/IgG ratio and 0.964 for IgG4, which had a
significant difference from each other. Thus, IgG4/IgG ratio
was superior to IgG4 concentration in the diagnosis of IgG4-
RD.
Notably, elevated IgG4 concentration can be associated
with multiple non-IgG4-RD conditions. In our study, we
found increased serum IgG4 levels in vasculitis and eosino-
philic disorders. However, the median serum IgG4 concentra-
tions in patients with vasculitis or eosinophilic disorders were
significantly lower than those in patients with IgG4-RD.
Among patients with IgG4-RD, 94.7% (126/133) had elevat-
ed serum IgG4 levels (>2010 mg/L). In contrast, elevated
serum IgG4 levels were present in only 8.7% (109/1248) of
non-IgG4-RD patients. Thus, elevated IgG4 level showed
high sensitivity and specificity for distinguishing IgG4-RD
from non-IgG4-RD patients.
One important strength of our present study is that we
analyzed a large number of patients, including 133 IgG4-RD
patients and 1248 non-IgG4-RD patients. Additionally, the
non-IgG4-RD patients were divided into 10 subgroups for
analysis of serum IgG4 concentrations. On the other hand, a
weakness of our present investigation is that it was performed
at a single center.
In conclusion, here, we successfully established cut-off
values of serum IgG4 concentration and IgG4/IgG ratio, using
measurements with Siemens reagents, for IgG4-RD diagnosis.
Our results showed good performances of serum IgG4 con-
centration and IgG4/IgG ratio for the IgG4-RD diagnosis.
More prospective and large-scale studies are warranted to con-
firm these findings.
Acknowledgements We thank Hong Liu, Xiao He, Da-min Liu, Chun
Di, and Hui-zhang Bao for helping us to process blood specimens.
Compliance with ethical standards The study was approved by the
Institutional Review Board of Peking University People’sHospital.
Disclosures None.
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