Modern Rheumatology

ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20

Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related disease in Chinese population Ping Li, Hua Chen, Chuiwen Deng, Ziyan Wu, Wei Lin, Xiaofeng Zeng, Wen Zhang, Fengchun Zhang & Yongzhe Li To cite this article: Ping Li, Hua Chen, Chuiwen Deng, Ziyan Wu, Wei Lin, Xiaofeng Zeng, Wen Zhang, Fengchun Zhang & Yongzhe Li (2016) Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related disease in Chinese population, Modern Rheumatology, 26:4, 583-587, DOI: 10.3109/14397595.2015.1117171 To link to this article: http://dx.doi.org/10.3109/14397595.2015.1117171

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Date: 10 July 2016, At: 05:28

http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2016; 26(4):583–587 ß 2015 Japan College of Rheumatology DOI: 10.3109/14397595.2015.1117171

ORIGINAL ARTICLE

Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related disease in Chinese population Ping Li*, Hua Chen*, Chuiwen Deng, Ziyan Wu, Wei Lin, Xiaofeng Zeng, Wen Zhang, Fengchun Zhang, and Yongzhe Li

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Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China Abstract Objective: This study was performed to better know diagnosis associated with serum IgG4 concentration, and to explore the possibility for development of a serum IgG4 for IgG4-related disease (IgG4-RD) in Chinese populations. Methods: We studied retrospectively 497 IgG4 serum subclass measurements from Peking Union Medical College Hospital during the four-year period, including 242 IgG4-RD, 130 other diseases and 125 healthy individuals. Results: Serum IgG4 concentrations were significantly higher in IgG4-RD than in other pathologies (1662.9 ± 3760.9 mg/L, p50.001) and healthy individuals (538.2 ± 458.6 mg/L, p50.001). There were no significant differences in serum IgG4 level between other pathologies group and healthy individuals (p ¼ 0.075). Among the 242 IgG4-RD patients analyzed, serum IgG4 concentrations were normal in 46 patients (19.0%). We found 32 patients (24.6%) with elevated serum IgG4 levels among the 130 patients who suffered from other pathologies. There were seven (5.6%) with serum IgG4 over 1350 mg/L in healthy individuals. The ROC curve analysis revealed that the optimal sensitivity and specificity were 80.0% and 88.2%, respectively, at the concentration of 1575 mg/L for Chinese patients. Conclusions: Our study demonstrated that serum IgG4 elevation was not specific of IgG4-RD. Further studies are needed to define the sensibility and specificity of IgG4 values for the diagnosis of IgG4-RD.

Introduction Four distinct heavy chain subgroups of human IgG were first demonstrated in the 1960s by using polyclonal antisera prepared in animals immunized with human myeloma proteins [1,2]. In contrast to IgG1, IgG2, and IgG3, IgG4 is a unique antibody in both structure and function [3]. IgG4 is the least abundant IgG subclass, which accounts for less than 5% of the total IgG in healthy persons. Thus, IgG4 does not activate the classical complement pathway effectively and has been traditionally considered protective against the biological effects of the complement-fixing antibodies [4]. IgG4-related disease (IgG4-RD) is a recently recognized fibroinflammatory condition that has tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, and this disease is typically associated with an increase of serum IgG4 level. It was recognized as a unified entity only 10 years ago [5,6]. Even though there are not always elevated serum IgG4 concentrations with IgG4-RD patients, indeed, no *These authors contributed equally to this work. Correspondence to: Yongzhe Li, Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China. Tel: +86 01 6915 9966. E-mail: [email protected]

Keywords Cut-off values, IgG4-related disease, Receiver operating characteristic, Serum immunoglobulin G4 concentrations, Standard deviation History Received 17 September 2015 Accepted 30 October 2015 Published online 22 December 2015

specific autoantibody has been associated with IgG4-RD. Serum IgG4 elevation becomes from this date a biological marker of IgG4-RD, and serum IgG4 elevation is considered as a diagnosis criteria for IgG4-RD [7–9]. In 2001, Hamano et al. [10] reported elevated serum IgG4 concentrations above the cut-off value of 1350 mg/L in 95% of patients with autoimmune pancreatitis (AIP). In one study, 22% of the patients with non-IgG4-RD diagnoses had serum IgG4 concentrations greater than two times the upper limit of normal [11]. Other studies have shown that 4–10% of both healthy and disease controls, including patients with pancreatic cancer, autoimmune disease, Castleman’s disease have high serum IgG4 concentrations [12–16]. Data on the test characteristics of serum IgG4 concentrations in patients are scarce, especially serum IgG4 measurements in Chinese patients. However, other studies suggest that further investigations are needed to understand fully the sensitivity and specificity of elevated serum IgG4 concentrations in patients. In order to better know diagnosis associated with serum IgG4 concentration, and to explore the possibility for development of a serum IgG4 test for IgG4-RD in Chinese population, we studied retrospectively all IgG4 subclass measurements achieved during a four-year period at the Peking Union Medical College Hospital (PUMCH).

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Materials and methods Patients All results for IgG4 were performed from January 2011 to December 2014 at the laboratory of the Department of Rheumatology, Peking Union Medical College Hospital. All samples were detected for the presence of serum IgG4 concentrations for the first time. The patients’ medical records were retrospectively analyzed and demographic, clinical characteristics were recorded. A total of 497 serum IgG4 analyses were recorded during the four-year period, including 242 IgG4-RD (154 males, 88 females, sex ratio 1.75:1), 130 other disease (78 males, 52 females) and 125 healthy individuals (83 males, 42 females). Patients were considered to have IgG4-RD if they fulfilled the following criteria: (i) clinical examination showing characteristic diffuse/ localized swelling or masses in single or multiple organs; (ii) haematological examination showing elevated serum IgG4 concentration (41350 mg/L); and (iii) histopathological examination showing: (a) marked lymphocyte and plasma cell infiltration and fibrosis and (b) IgG4 + plasma cell infiltration: ratio of IgG4 + to IgG + cells 440% and more than 10 IgG4 + plasma cells per high power field (HPF). A definite diagnosis is (i) + (ii) + (iii), a probable diagnosis (i) + (iii), and a possible diagnosis (i) + (ii) [9]. Two hundred and forty-two IgG4-RD patients fulfilled the criteria. Organ involvements of IgG4-RD patients at presentation are shown in Table 1. Mean age was 56.5 ± 13.2 years. In order to better know diagnosis associated with other biological situations, there are 130 other diseases, including 59 autoimmune disease [24 Sjogren syndrome (SS), 19 systemic lupus erythematosus (SLE), 7 mixed connective tissue disease (MCTD), 5 multiple myositis, 4 rheumatoid arthritis (RA)], 17 nephropathy, 15 cancer (8 pancreatic cancer, 2 malignant lymphoma, 1 mesothelioma, 1 Castleman’s disease, 1 adenocarcinoma, 1 adrenal gland neoplasms, 1 multiple myeloma), 17 pancreatitis and 22 other diseases (6 pneumonia, 5 ulcerative colitis, 2 diabetes mellitus, 2 repeated infections, 1 Crohn’s disease, 1 hepatic clonorchiasis, 1 liver cirrhosis, 1 chronic gastritis, 1 hyperthyresis, 1 pulmonary nodules and 1 Kimura’s disease), and patients ranged in age from 19 to 80 Table 1. Organ involvements of IgG4-RD patients (n ¼ 242). Organ involvement Autoimmune pancreatitis Sialadenitis Dacryoadenitis Retroperitoneal fibrosis Lymphadenopathy Sclerosing cholangitis Interstitial nephritis Interstitial pneumonitis Prostatitis Sinusitis Mediastinal fibrosis Aortic involvement Inflammatory pseudotumour

n (%) 111 (45.9) 65 (26.9) 60 (24.8) 35 (14.5) 14 (5.8) 13 (5.4) 12 (5.0) 12 (5.0) 5 (2.1) 5 (2.1) 4 (1.7) 4 (1.7) 2 (0.8)

years, mean age was 49.9 ± 14.7 years. The laboratory test results of healthy controls (HCs) were in the normal range, and there was no history of any specific allergic or immune diseases that could affect serum IgG4 value, mean age was 47.3 ± 11.0 years. Measurements of serum IgG4 concentrations Serum IgG subclass levels were measured using the immunonephelometric assay [17,18] with molecularbiology kits (Siemens, Marburg, Germany, N Latex IgG4 and N Supplementary Reagent/ Precipitation) and the automatic protein analyzer (Siemens BN prospec-I, Marburg, Germany) according to the manufacturer’s instructions.

Statistical analysis All data were presented as means ± standard deviation (SD). Mean values in different groups were compared using the Mann– Whitney–Wilcoxon test or the Student t-test. Results were considered significant for p50.05. All statistical analyses were carried out with SPSS version 13.0 (SPSS, Chicago, IL). Figures were drawn using GraphPad Prism version 5.0 (GraphPad, San Diego, CA).

Results Patients’ characteristics and serum IgG4 concentrations means and SD between IgG4-RD, other diseases and healthy individuals Among the 242 IgG4-RD patients analyzed, serum IgG4 concentrations were normal in 46 patients (19.0%). There were 32 patients (24.6%) and 7 (5.6%) with serum IgG4 over 1350 mg/L in other pathologies group and healthy individuals. Serum IgG4 level in IgG4-RD patients was 9287.4 ± 13076.6 mg/L, which was significantly higher in IgG4-RD than in other pathologies (1662.9 ± 3760.9 mg/L, p50.001) and healthy individuals (538.2 ± 458.6 mg/L, p50.001). There were no significant differences in serum IgG4 level between other pathologies group and HCs group (p ¼ 0.075). Serum IgG4/IgG ratio in IgG4-RD group was (49.2 ± 54.7)%, which was much higher compared with those in other diseases group (7.07 ± 11.4, p50.001) and HCs group (4.79 ± 4.04, p50.001). The reasons to perform serum IgG4 analysis are presented in Table 2 and Figure 1. Serum IgG4 elevation observed in IgG4-RD group was significantly more important than in the groups ‘‘autoimmune diseases’’ (p50.001), ‘‘nephropathy’’ (p50.001), ‘‘cancer’’ (p50.001), ‘‘pancreatitis’’ (p50.001), and ‘‘other diseases’’ (p50.001). Diagnosis of other pathologies group associated with serum IgG4 over 1350 mg/L We found that there were 32 patients (24.6%) with elevated serum IgG4 levels among the 130 patients who suffered from other diseases. Final diagnosis in patients who presented with elevated levels of serum IgG4 was divided into different categories presented in Table 3. In 15 patients (11.5%), final diagnosis was

Table 2. Serum IgG4 levels and IgG4/IgG ratios.

IgG4 (mg/L) IgG (mg/L) IgG4/IgG (%) IgG4 level41350 mg/L (%)

IgG4-RD (n ¼ 242)

Other diseases (n ¼ 130)

HCs (n ¼ 125)

9287.4 ± 13076.6 16,427.7 ± 9290.6 49.2 ± 54.7 81

16,62.9 ± 3760.9 16,703.8 ± 9059.2 7.07 ± 11.4 24.6

538.2 ± 458.6 11,456.5 ± 2447.2 4.79 ± 4.04 5.6

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Figure 1. (A) Serum IgG4 levels of IgG4-RD, other diseases patients and HCs; (B) IgG4/IgG ratios of IgG4-RD, other diseases patients and HCs.

Table 3. Final diagnosis in patients with elevated serum IgG4 level (41350 mg/L) in other disease group.

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n (%) Autoimmune disease Nephropathy Cancer Pancreatitis Other

15 3 5 4 5

(11.5%) (2.3%) (3.8%) (3.1%) (3.8%)

Mean IgG4 levels (mg/L) (extremes) 4352.3 (1350–16200) 3810 (1510–6410) 3444 (1740–7690) 6057.5 (2210–9620) 11,016 (1720–30600)

Figure 3. ROC curve of the final model predicting optimal cut-off values.

Figure 2. Serum IgG4 levels in different diagnostic categories of patients with serum IgG4 elevation. Each group of diseases with serum IgG441350 mg/L is represented on the x-axis.

an autoimmune disease: SLE in six patients, SS in four patients, multiple myositis in 1 patient and MCTD in four patients. Pancreatitis was the final diagnosis in four patients (3.1%). Three (2.3%) of these patients were considered as nephropathy. Cancer was found in five of these patients (3.8%). Five patients (3.8%) represented other categories. Serum IgG4 levels in different final diagnostic categories of patients with serum IgG4 elevation was presented in Figure 2. Receiver Operator Characteristic (ROC) curve analysis in IgG4-RD and other groups We used ROC curve analysis to determine a better cut-off choice for serum IgG4 measurement in Chinese populations. The ROC curve analysis revealed a high area under curve (AUC) 0.881, 95% confidence interval was 0.851–0.911, and the optimal sensitivity

and specificity were 80.0% and 88.2%, respectively, at the concentration of 1575 mg/L, as shown in Figure 3. Meanwhile, another separate assessment was done with 1575 mg/L in IgG4RD group and other diseases group, we found that the sensitivity and specificity were 78.9% and 80.0%, respectively. We also evaluated the test characteristics of a cut-off value for the upper limit of normal for the serum IgG4 assay that was two-fold higher, that is 2700 mg/L, with this higher cut-off value, the sensitivity and specificity of the serum IgG4 assays were 62.0% and 93.7%, respectively. Thus, the higher specificity derived from doubling the cut-off value for serum IgG4 concentrations came at a significant sacrifice in sensitivity.

Discussion Although the highest mean serum IgG4 concentrations occurred in subjects with definite IgG4-RD diagnoses, substantial elevations of serum IgG4 levels also occurred frequently in patients with nonIgG4-RD diagnoses, particularly in haematologic malignancies and allergic diseases. Misdiagnoses of IgG4-RD are increasingly common in serum IgG4 concentration. Elevated concentrations of IgG4 in serum are helpful on diagnosing IgG4-RD, but neither one is a specific diagnostic marker [19]. Ohara et al. [20] indicated that elevation level of serum (1350 mg/L) is not necessarily specific to IgG4-related sclerosing

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cholangitis (IgG4-SC) because it is also observed in atopic dermatitis, asthma, etc. A recent study by Yun [21] reported that serum IgG4 concentration had poor positive predictive value in the diagnosis of IgG4-related sclerosing disease. Few data exist on the serum IgG4 sensitivity and specificity of IgG4-related disease. Virtually, most of studies pertaining to the disease come from Japan and focus on AIP. In one study of type 1 AIP, the estimated prevalence of serum IgG4 elevation was 80% [13]. While, a study from Japan showed that serum IgG441350 mg/L demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-RD [22]. However, Paik et al. [23] reported that the sensitivity of serum IgG4 was 68% in type 1 AIP, while, they found that the relapse rate and diffuse swelling of the pancreas were not associated with serum IgG4 level. The Japan team has retained the serum IgG4 above 1350 mg/L as individual diagnosis criteria in IgG4-RD [9]. However, cut-off values are different for different reagents. A recent work found that the cut-off IgG4 level of 1350 mg/L is useful in discriminating IgG4-RD from other diseases, but this cut-off level displayed lower specificity in discriminating IgG4-RD [24,25]. Oseini et al. [26] evaluated the utility of serum IgG4 level in distinguishing IgG4-SC from cholangiocarcinoma (CC), they concluded that some patients with CC, particularly primary sclerosing cholangitis, had elevated serum IgG4 level and diagnosis using a twofold higher cut-off serum IgG4 level may not reliably distinguish IgG4-SC from CC, while, a cut-off level fourfold higher than the upper limit of normal had 100% specificity for IgG4-SC. Ohara et al. [27] established a cut-off for serum IgG4 to differentiate IgG4-SC from respective controls using serum IgG4 levels measured in Japanese centers, they found that a cut-off of 1820 mg/L can increase the specificity to 96.6% for distinguishing IgG4-SC from CC, and a cut-off of 2070 mg/L might be useful for completely distinguishing IgG4-SC from all CC. Carruthers et al. [11] confirmed that doubling the cut-off value for serum IgG4 to 2700 mg/L improved the specificity from 60% to 91%, but did so with an unacceptable reduction in sensitivity from 90% to 35%. Meanwhile, examing the serum IgG4/IgG ratio did not improve either the specificity or the positive predictive value for the diagnosis of IgG4-RD. Additionally, approximately 50% of the IgG4-RD patients included had Mikulicz disease, an IgG4-RD subset known to have particularly high serum IgG4 concentrations [28]. To better characterize pathologies associated with serum IgG4 above 1350 mg/L that could be discussed in the differential diagnosis of IgG4-RD, we retrospectively studied all IgG subclass measurements performed over a four-year period at our hospital. This study is the first in Chinese population to analyze the test characteristics of serum IgG4 concentrations for the diagnosis of IgG4-RD. Our data suggested that the serum IgG4 concentrations were significantly higher in IgG4-RD than those in other groups. However, our retrospective study clearly confirms that serum IgG4 elevation above 1350 mg/L is not specific for the diagnosis of IgG4-RD and can be observed in several clinical situations. There were 32 other pathologies patients (24.6%) in our study and could account for IgG4 elevation. In IgG4-RD group, there were only 81.0% of 242 patients with elevated serum IgG4 concentrations (41350 mg/L). Because of the large number of non-IgG4-RD diagnoses that were found to be associated with elevated IgG4 concentrations, we defined the optimal cut-off (1575 mg/L) by ROC curve for Chinese population, when all the IgG4-RD group and other diseases groups and healthy controls were compared. A cut-off level of 1575 mg/L can increase the specificity to 88.2% for distinguishing other diseases. When we analyzed the sensitivity and specificity at 1350 mg/L using the same population, the

Mod Rheumatol, 2016; 26(4): 583–587

sensitivity and the specificity were 81% and 85.5%, respectively. There were no enormous differences between the sensitivity and the specificity values obtained with a cut-off value of 1350 mg/L. When we re-evaluated the cut-off (1575 mg/L) in IgG4-RD group and other diseases group, the result showed that the sensitivity and specificity (78.9% and 80.0%, respectively) were similar to the result in all of samples, but further study should be done in the future because of a small number of other diseases group. Doubling the cut-off value for serum IgG4 to 2700 mg/L improved the specificity from 85.5% to 93.7%. High specificity can improve the overall test characteristics for the diagnosis of IgG4-RD, however, the higher specificity derived from the new cut-off value for serum IgG4 concentrations came at a significant sacrifice in sensitivity. Yamamoto et al. [29] re-evaluated the usual cut-off serum IgG4 value in AIP (1350 mg/L) that is used to diagnose whole IgG4-RD in the setting of a rheumatic clinic by measuring serum IgG4 levels in IgG4-RD and various disorders in Japanese people, they reported the optimal cut-off value of serum IgG4 for a diagnosis of IgG4-RD was 1440 mg/L, which is similar to our study. Further studies are needed to define the sensibility and specificity of IgG4 values for the diagnosis. Until more specific biomarkers for IgG4-RD are made available, it must be kept in mind that several pathologies should be evoked end excluded in case of IgG4 elevation, before IgG4-RD diagnosis is retained. In conclusion, IgG4-RD is a newly recognized condition with often but not always, elevated serum IgG4 concentrations. A serum IgG4 elevation above 1350 mg/L is currently retained as an important biomarker of the disease. We confirmed that the patients with defined IgG4-RD presented with the most elevated serum IgG4 levels, however, patients with elevated serum IgG4 concentrations might not be associated with the diagnosis of IgG4-RD. IgG4 elevation is not specific of IgG4-RD. Therefore, elevated serum IgG4 concentrations must be interpreted with caution for the diagnosis of IgG4-RD. A more comprehensive understanding of the IgG4 molecule of IgG4-RD may yield important insights into the immune system to be associated with IgG4.

Conflict of interest This work was supported by funding from the Research Special Fund for Public Welfare Industry of Health (201202004), and the National Natural Science Foundation of China Grants (81172857, 81373188), the Chinese National High Technology Research and Development Program, Ministry of Science and Technology Grants (2011AA02A113), and the National Science Technology Pillar Program in the 12nd Five-year Plan (2014BAI07B00).

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Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related disease in Chinese population.

This study was performed to better know diagnosis associated with serum IgG4 concentration, and to explore the possibility for development of a serum ...
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