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Arthritis Res Ther
Arthritis Res Ther
Arthritis Research & Therapy
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BioMed Central London

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10.1186/s13075-024-03391-w
Research
Factors related to elevated serum immunoglobulin G4 (IgG4) levels in a Japanese general population
Tsuge Shunsuke 1
Fujii Hiroshi 1
Tamai Mami 2
Tsujiguchi Hiromasa 3
Yoshida Misaki 1
Suzuki Nobuhiro 1
Takahashi Yoshinori 1
Takeji Akari 1
Horita Shigeto 1
Fujisawa Yuhei 1
Matsunaga Takahiro 1
Zoshima Takeshi 1
Nishioka Ryo 1
Nuka Hiromi 1
Hara Satoshi 1
Tani Yukiko 1
Suzuki Yasunori 1
Ito Kiyoaki 1
Yamada Kazunori 1
Nakazaki Satoshi 4
Hara Akinori 3
Kawakami Atsushi 2
Nakamura Hiroyuki 3
Mizushima Ichiro ichiro7753@yahoo.co.jp

1
Iwata Yasunori 1
Kawano Mitsuhiro 1
1 https://ror.org/00xsdn005 grid.412002.5 0000 0004 0615 9100 Department of Nephrology and Rheumatology, Kanazawa University Hospital, 13-1, Takara-machi, Kanazawa, Ishikawa 920-8640 Japan
2 https://ror.org/03ppx1p25 grid.444715.7 0000 0000 8673 4005 Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
3 https://ror.org/02hwp6a56 grid.9707.9 0000 0001 2308 3329 Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
4 Department of Rheumatology, Johoku Hospital, Kanazawa, Japan
6 9 2024
6 9 2024
2024
26 1561 7 2024
1 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Elevated serum immunoglobulin G4 (IgG4) concentrations are one of the characteristic findings in IgG4-related disease (IgG4-RD). This study investigated the frequency of elevated serum IgG4 levels and associated factors in a general Japanese population.

Methods

Serum IgG4 concentrations were measured in 1,201 residents of Ishikawa prefecture who underwent general medical examinations. Factors associated with elevated serum IgG4 concentrations were assessed by logistic regression analysis. Participants with elevated serum IgG4 were subjected to secondary examinations.

Results

The mean serum IgG4 concentration was 44 mg/dL, with 42 (3.5%) participants having elevated serum IgG4 levels. Age- and sex-adjusted logistic regression analyses showed that male sex, older age, and lower intake of lipids and polyunsaturated fatty acids and higher intake of carbohydrates in daily diet were associated with elevated serum IgG4 concentration. Subgroup analyses in men showed that older age, lower estimated glomerular filtration rates based on serum cystatin C (eGFR-cysC) levels, and higher hemoglobin A1c (HbA1c) levels were associated with elevated serum IgG4 concentration. Analyses in women showed that lower intake of lipids and fatty acids and higher intake of carbohydrates were significantly associated with elevated serum IgG4 concentration. One of the 15 participants who underwent secondary examinations was diagnosed with possible IgG4-related retroperitoneal fibrosis.

Conclusions

Elevated serum IgG4 levels in a Japanese general population were significantly associated with older age, male gender, and dietary intake of nutrients, with some of these factors identical to the epidemiological features of IgG4-RD.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13075-024-03391-w.

Keywords

IgG4-related disease
Resident examinations
Serum IgG4 levels
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is characterized primarily by elevated serum IgG4 levels, relatively latent onset and progression with few symptoms, and swelling of organs and/or nodular lesions, as detected clinically and/or radiologically [1, 2]. Pathologic features common to affected organs include dense lymphoplasmacytic infiltration by abundant numbers IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis [1, 2]. None of these clinical, serological, radiological, or pathological features alone, however, is sufficient for a definitive diagnosis of IgG4-RD, with combinations of all four categories required for diagnostic confirmation [3].

Serum IgG4 levels contribute to the diagnosis of IgG4-RD, although their sensitivity and specificity remain unestablished. The Japanese comprehensive diagnostic criteria for IgG4-RD [4], organ-specific diagnostic criteria [5–12], and the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for IgG4-RD [13] regard serum IgG4 levels as an important criterion, with studies in Japan, China, the United States, and Europe reporting elevated serum IgG4 levels in 55–97% of patients with IgG4-RD [14–16]. Elevated serum IgG4 levels, however, have been observed in patients with other diseases, such as eosinophilic granulomatosis with polyangiitis (EGPA) and multicentric Castleman’s disease. Serum IgG4 levels alone were reported to have a diagnostic specificity for IgG4-RD of 60–93% [17, 18]. One study reported serum IgG4 concentrations > 130 mg/dL in 80 (6.4%) of 1,258 patients, with nine (14.7%) of the 61 patients who underwent further examination diagnosed with for IgG4-RD [19]. Another study found that serum IgG4 levels > 140 mg/dL were present in 390 (6.5%) of 6,014 patients, with 39 (10%) patients having elevated IgG4 being diagnosed with IgG4-RD [20]. These results suggested that 10–15% of patients with elevated serum IgG4 levels had IgG4-RD.

Few studies to date have assessed the prevalence of elevated serum IgG4 levels and/or IgG4-RD in asymptomatic adults. A Spanish study in 413 adults found that five (1.2%) had serum IgG4 levels > 135 mg/dL, but none was diagnosed with IgG4-RD based on the tracking on the database [21]. That study, however, did not report whether those participants had undergone close examination for IgG4-RD, making the true absence of IgG4-RD unclear. Because a considerable proportion of patients with IgG4-RD are asymptomatic, there is a need to assess the prevalence of IgG4-RD in general populations, such as people undergoing general health examinations, not only in patients visiting a medical institution [19, 20]. Analyses of general populations may provide information on the epidemiology of elevated serum IgG4 levels and IgG4-RD.

Although the epidemiology of IgG4-RD remains unclear, several environmental factors and comorbidities have been implicated in its pathogenesis. Patients with IgG4-RD have been reported to be at high risk of malignancy [22–24], suggesting that IgG4-RD has aspects of paraneoplastic syndrome, similar to dermatomyositis [25]. Allergic predispositions, including elevated serum IgE, eosinophilia, and complications of bronchial asthma and/or allergic rhinitis, are frequently observed in IgG4-RD [15, 26, 27]. In addition, serum IgG4 molecules from patients with IgG4-RD have been found to react with various antigens in, for example, rice, wheat, milk, peanuts, cats, and bananas [28], suggesting associations between IgG4-RD and allergic reactions. Moreover, a recent case-control study demonstrating a significant association between smoking and IgG4-RD [29] indicated that lifestyle habits could affect the pathogenesis of IgG4-RD. These environmental factors and comorbidities may also be associated with the enhanced production of IgG4 and/or the onset of IgG4-RD in participants undergoing general health examinations. The present study assessed the frequency of elevated serum IgG4 levels and the prevalence of latent IgG4-RD in Japanese adults undergoing general health examinations by measuring serum IgG4 concentrations and by secondary examination for IgG4-RD in those with elevated IgG4.

Methods

Patients and materials

The present study included adults who underwent annual general health examinations in Noto district, Ishikawa Prefecture, Japan, between January 1, 2013, and March 31, 2019. Of 1336 consecutive participants, blood samples were collected from 1,201 (90%) for measurement of their serum IgG4 concentrations, which were measured with the nephelometry immunoassay (NIA)-based IgG subclass BS-NIA IgG4 kit (Binding Site, Birmingham, United Kingdom). Participants were asked about their daily diet and history of cancer, allergies, atherosclerotic diseases, alcohol consumption, and smoking. Subject age at the time of examination and sex were recorded; height and body weight were measured; and body mass index (BMI) was calculated. Systolic and diastolic blood pressure (BP) were measured, as were serum concentrations of IgG, IgE, CH50, C-reactive protein (CRP), creatinine, cystatin-C, uric acid, liver enzymes, total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Also measured were hemoglobin A1c (HbA1c) levels, peripheral blood counts, and the presence or absence of anti-nuclear antibody (ANA) and rheumatoid factor (RF). Participants with serum IgG4 concentrations ≥ 135 mg/dL were more closely examined for IgG4-RD, with IgG4-RD diagnosed by experts based on Japanese and 2019 ACR/EULAR criteria. Specifically, detailed medical history taking, evaluation of physical findings, and whole-body dynamic CT were performed in all participants with serum IgG4 concentrations ≥ 135 mg/dL who underwent secondary examination.

Allergic diseases included bronchial asthma, allergic rhinitis, atopic dermatitis, and food allergies, and atherosclerotic disease included cerebrovascular and ischemic heart diseases. Estimated glomerular filtration rate (eGFR) based on serum creatinine level (eGFR-creatinine) was calculated using a three-variable Japanese equation [30], whereas eGFR based on serum cystatin-C level (eGFR-cystatin-C) was calculated using a Japanese equation formulate by the Japanese Society of Nephrology [31].

Nutritional status, including the intake of proteins, lipids, carbohydrates, polyunsaturated fatty acids, and saturated fatty acids, was assessed using the brief-type self-administered diet history questionnaire (BDHQ) [32]. The relative amount of each nutrient consumed daily as a percentage of daily energy intake was calculated using the density method [33].

The upper limit of normal (ULN) of serum IgG4 levels in the present study was set at 135 mg/dL because this threshold has been found suitable for the diagnosis of IgG4-RD in Japanese [4–12].

Statistical analysis

Continuous variables are reported as mean ± standard deviation (SD) and compared using Mann-Whitney U tests. Categorical variables are reported as number (percentage) and compared using the χ2 test or Fisher’s exact probability test, as appropriate. Factors associated with elevated serum IgG4 levels and factors associated with the diagnosis of IgG4-RD were each assessed by unadjusted and age- and sex-adjusted logistic regression analysis. Based on the principle of one variable for every 10 outcomes [34], a multivariate model for elevated serum IgG4 levels could be built within four variables because the 1,201 participants included 42 with elevated serum IgG4 levels. Sub-analyses included identical logistic regression analyses in men and in women. In these logistic regression analyses, the units for increments of continuous variables to calculate odds ratios were set at 1 year for age; 1 kg/m2 for BMI; 1 mmHg for BP; 1% for fraction of peripheral blood eosinophils, HbA1c levels, and intake of proteins, lipids, carbohydrates, polyunsaturated fatty acids, and saturated fatty acids; 100 IU/mL for serum IgE levels; 1 U/mL for serum CH50 levels; 1 mg/dL for serum CRP, cholesterol, TG, and uric acid levels; and 1 mL/min/1.73m2 for eGFR. In the logistic regression analysis of each variable, patients with defective data were excluded. All statistical analyses were performed using SPSS V.25 (IBM Corp., Armonk, NY, USA), with P < 0.05 defined as statistically significant.

Results

Participant profiles

The profiles of the 1,201 participants are listed in Table 1. Their mean age was 62 ± 11 years, 46.5% were male, and their mean BMI was 23.3 ± 3.3 kg/m2. These participants had a mean systolic BP of 138 ± 19 mmHg, a mean diastolic BP of 80 ± 12 mmHg, a mean total-C concentration of 214 ± 36 mg/dL, a mean LDL-C of 130 ± 35 mg/dL, a mean HDL-C of 65 ± 17 mg/dL, a mean TG of 117 ± 81 mg/dL, a mean HbA1c of 5.9 ± 0.6%, and a mean uric acid concentration of 5.1 ± 1.4 mg/dL. Evaluation of renal function showed a mean serum creatinine level of 0.79 ± 0.46 mg/dL, a mean eGFR-creatinine of 71.2 ± 14.2 mL/min/1.73m2, a mean serum cystatin-C level of 0.91 ± 0.41 mg/dL, and a mean eGFR-cystatin-C of 83.1 ± 19.4 mL/min/1.73m2. Their mean serum IgG4 level was 44 ± 36 mg/dL, with 42 (3.5%) of the 1,201 participants having serum IgG4 levels > 135 mg/dL (Fig. 1). Their mean serum IgG, IgE, and CH50 levels were 1,319 ± 273 mg/dL, 225 ± 593 IU/mL, and 38 ± 9 U/mL, respectively, with 7.4% and 8.6% being positive for ANA and RF, respectively. Mean intake of proteins, lipids, carbohydrates, polyunsaturated fatty acids, and saturated fatty acids was 15.2 ± 3.2%, 24.7 ± 6.1%, 54.0 ± 8.7%, 6.1 ± 1.5%, and 6.5 ± 2.0%, respectively.

Table 1 Baseline clinical characteristics of 1,201 participants with/without elevated serum IgG4 level

	All (n = 1,201)	IgG4 elevation (+) (n = 42)	IgG4 elevation (-) (n = 1,159)	P-values	
Age (years)	62 ± 11	66 ± 11 b	62 ± 11	0.026	
Gender (male, %)	46	69 b	46	0.004	
BMI (kg/m2)	23.3 ± 3.3	23.4 ± 3.4	23.3 ± 3.3	0.771	
Systolic BP (mmHg)	138 ± 19	135 ± 20	138 ± 19	0.569	
Diastolic BP (mmHg)	80 ± 12	78 ± 11	80 ± 12	0.187	
Smoking history (+, %)	46	60	46	0.085	
Allergic disease (+, %)	13	18	13	0.248	
History of Malignancy (+, %)	7	6	7	0.999	
Fraction of Eosinophil (%)	2.7 ± 2.1	3.0 ± 2.4	2.7 ± 2.0	0.539	
Serum IgE level (IU/mL)	225 ± 593 (n = 1,001)	366 ± 439 b (n = 39)	219 ± 598 (n = 962)	< 0.001	
Serum IgG level (mg/dL)	1,319 ± 273 (n = 1,136)	1,564 ± 349 b (n = 40)	1,310 ± 266 (n = 1,096)	< 0.001	
Serum IgG4 level (mg/dL)	44 ± 36	172 ± 39 b	40 ± 26	< 0.001	
Serum CH50 level (U/mL)	38 ± 9 (n = 1,126)	38 ± 8 (n = 40)	38 ± 9 (n = 1,086)	0.984	
Serum CRP level (mg/dL)	0.12 ± 0.45	0.16 ± 0.32	0.12 ± 0.45	0.248	
ANA positivity (+, %)	7.4 (n = 975)	15.2 (n = 33)	7.1 (n = 942)	0.089	
RF positivity (+, %)	8.6 (n = 975)	15.2 (n = 33)	8.4 (n = 942)	0.196	
Serum creatinine level (mg/dL)a	0.79 ± 0.46	0.82 ± 0.27	0.79 ± 0.47	0.849	
eGFR-creatinine (mL/min/1.73m2)	71 ± 14	71 ± 16	71 ± 14	0.924	
Serum cystatin-C level (mg/dL)	0.91 ± 0.41 (n = 1,057)	0.99 ± 0.24 b (n = 35)	0.91 ± 0.41 (n = 1,022)	0.015	
eGFR-cystatin-C (mL/min/1.73m2)	83 ± 19 (n = 1,057)	76 ± 20 b (n = 35)	83 ± 19 (n = 1,022)	0.045	
Serum LDL-cholesterol level (mg/dL)	130 ± 35	132 ± 32	130 ± 36	0.736	
Serum HDL-cholesterol level (mg/dL)	65 ± 17	59 ± 13 b	66 ± 17	0.018	
Serum triglyceride level (mg/dL)	117 ± 81	140 ± 189	116 ± 74	0.348	
Serum uric acid level (mg/dL)	5.1 ± 1.4	5.4 ± 1.5	5.1 ± 1.4	0.135	
HbA1c level (%)	5.9 ± 0.6	6.2 ± 1.0	5.9 ± 0.6	0.176	
Protein intake (%)	15.2 ± 3.2 (n = 938)	14.2 ± 3.1 (n = 36)	15.2 ± 3.2 (n = 902)	0.116	
Lipid intake (%)	24.7 ± 6.1 (n = 938)	21.8 ± 5.9 b (n = 36)	24.9 ± 6.1 (n = 902)	0.007	
Carbohydrate intake (%)	54.0 ± 8.7 (n = 938)	57.1 ± 9.1 (n = 36)	53.9 ± 8.7 (n = 902)	0.085	
Polyunsaturated fatty acids intake (%)	6.1 ± 1.5 (n = 938)	5.4 ± 1.4b (n = 36)	6.2 ± 1.5 (n = 902)	0.011	
Saturated fatty acids intake (%)	6.5 ± 2.0 (n = 938)	5.8 ± 2.0b (n = 36)	6.6 ± 2.0 (n = 902)	0.044	
Notes a Conversion factor for creatinine: mg/dL to µmol/L, ×88.4; b P < 0.05, IgG4 elevation (+) vs. (-). ANA positivity is defined as ANA titer ≥ ×80. RF positivity is defined as RF titer ≥ 15 IU/mL

Abbreviations ANA: anti-nuclear antibody; BMI: body mass index; BP: blood pressure; CRP: C-reactive protein; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; HDL: high-density lipoprotein; IgG: immunoglobulin G; IgG4: immunoglobulin G4; IgE: immunoglobulin E; LDL: low-density lipoprotein; RF: rheumatoid factor

Fig. 1 Histogram of serum IgG4 levels in health examination participants. Elevated serum IgG4 levels were observed in 42 patients (3.5%)

Characteristics of the participants with elevated serum IgG4 levels

Compared with the participants having normal serum IgG4 levels, those with elevated serum IgG4 levels were significantly older (65.8 ± 10.5 vs. 61.9 ± 11.2 years, P = 0.026), had a greater male predominance (69% vs. 46%, P = 0.004), and had significantly lower serum HDL-C levels (58.7 ± 12.7 vs. 65.6 ± 17.3 mg/dL, P = 0.018), and significantly higher serum IgG (1,564 ± 349 vs. 1,310 ± 266 mg/dL, P < 0.001), IgE (366 ± 439 vs. 219 ± 598 IU/mL, P < 0.001), and cystatin-C (0.99 ± 0.24 vs. 0.91 ± 0.41 mg/dL, P = 0.015) concentrations. Participants with elevated IgG4 also had significantly lower eGFR-cystatin-C levels (75.6 ± 20.1 vs. 83.3 ± 19.3 mL/min/1.73m2, P = 0.045) and lower intake of lipids (21.8 ± 5.9% vs. 24.9 ± 6.1%, P = 0.007), polyunsaturated fatty acids (5.4 ± 1.4% vs. 6.2 ± 1.5%, P = 0.011), and saturated fatty acids (5.8 ± 2.0% vs. 6.6 ± 2.0%, P = 0.044). The prevalence of smoking history, which has been associated with IgG4-RD [29], tended to be higher in participants with elevated than with normal serum IgG4 levels (60% vs. 46%, P = 0.085). Other variables, including BMI, BP, HbA1c levels, fraction of peripheral blood eosinophils, and prevalence of cancer, allergic diseases, and atherosclerotic diseases, did not differ in participants with and without elevated serum IgG4 levels (Table 1).

Demographic, laboratory, and nutritional factors significantly associated with elevated serum IgG4 levels

Unadjusted logistic regression analyses showed that male sex [odds ratio (OR) 2.666, 95% confidence interval (CI) 1.372–5.180], older age (OR 1.032, 95% CI 1.003–1.062), lower eGFR-cystatin-C (OR 0.980, 95% CI 0.964–0.997), lower serum HDL-C levels (OR 0.973, 95% CI 0.953–0.994), and higher HbA1c levels (OR 1.513, 95% CI 1.107–2.068) were associated with elevated serum IgG4. Assessment of nutritional factors showed that greater carbohydrate intake (OR 1.044, 95% CI 1.003–1.086) and lower intake of proteins (OR 0.893, 95% CI 0.798-1.000), lipids (OR 0.919, 95% CI 0.869–0.972), polyunsaturated fatty acids (OR 0.713, 95% CI 0.564–0.901), and saturated fatty acids (OR 0.818, 95% CI 0.683–0.981) was associated with elevated serum IgG4. Following age- and sex-adjusted analyses, male sex (OR 2.683, 95% CI 1.379–5.220), older age (OR 1.033, 95% CI 1.004–1.063), greater intake of carbohydrates (OR 1.043, 95% CI 1.002–1.085), and lower intake of lipids (OR 0.937, 95% CI 0.884–0.994) and polyunsaturated fatty acids (OR 0.769, 95% CI 0.606–0.978) remained significant, whereas the other five factors did not (Table 2).

Table 2 Odds ratios for elevated serum IgG4 levels in the 1,201 participants

Variable	Unadjusted	Age- and sex-adjusted	
OR
(95% CI)	P-value	OR
(95% CI)	P-value	
Age (years)	1.032

(1.003 to 1.062)

	0.028	1.033

(1.004 to 1.063)

	0.027	
Male gender	2.666

(1.372 to 5.180)

	0.004	2.683

(1.379 to 5.220)

	0.004	
BMI (kg/m2)	1.011

(0.921 to 1.110)

	0.814			
Systolic BP (mmHg)	0.993

(0.976 to 1.010)

	0.399			
Diastolic BP (mmHg)	0.983

(0.956 to 1.010)

	0.223			
Smoking history	1.742

(0.931 to 3.261)

	0.083			
Allergic disease	1.483

(0.601 to 3.661)

	0.393			
History of Malignancy	0.777

(0.182 to 3.316)

	0.734			
Fraction of Eosinophil (%)	1.067

(0.943 to 1.207)

	0.304			
Serum IgE level

(per100 IU/mL)

	1.021

(0.991 to 1.051)

	0.171			
Serum CH50 level (U/mL)	0.999

(0.965 to 1.033)

	0.940			
Serum CRP level (mg/dL)	1.149

(0.732 to 1.803)

	0.546			
ANA	2.332

(0.872 to 6.235)

	0.092			
RF	1.951

(0.733 to 5.193)

	0.181			
eGFR-creatinine (mL/min/1.73m2)	0.999

(0.977 to 1.021)

	0.902			
eGFR-cystatin-C (mL/min/1.73m2)	0.980

(0.964 to 0.997)

	0.019	0.986

(0.965 to 1.007)

	0.191	
LDL-cholesterol (mg/dL)	1.002

(0.988 to 1.016)

	0.802			
HDL-cholesterol (mg/dL)	0.973

(0.953 to 0.994)

	0.012	0.982

(0.961 to 1.003)

	0.100	
Triglyceride (mg/dL)	1.002

(1.000 to 1.005)

	0.079			
Uric acid (mg/dL)	1.189

(0.961 to 1.471)

	0.111			
HbA1c (%)	1.513

(1.107 to 2.068)

	0.009	1.370

(0.980 to 1.916)

	0.065	
Protein intake (%)	0.893

(0.798 to 1.000)

	0.049	0.898

(0.801 to 1.007)

	0.066	
Lipid intake (%)	0.919

(0.869 to 0.972)

	0.003	0.937

(0.884 to 0.994)

	0.030	
Carbohydrate intake (%)	1.044

(1.003 to 1.086)

	0.033	1.043

(1.002 to 1.085)

	0.040	
Polyunsaturated fatty acids intake (%)	0.713

(0.564 to 0.901)

	0.005	0.769

(0.606 to 0.978)

	0.032	
Saturated fatty acids intake (%)	0.818

(0.683 to 0.981)

	0.030	0.875

(0.724 to 1.057)

	0.166	
Abbreviations ANA: anti-nuclear antibody; BMI: body mass index; BP: blood pressure; CRP: C-reactive protein; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; HDL: high-density lipoprotein; IgG: immunoglobulin G; IgG4: immunoglobulin G4; IgE: immunoglobulin E; LDL: low-density lipoprotein; RF: rheumatoid factor

Subgroup analyses in men showed that older age (OR 1.046, 95% CI 1.009–1.084), lower eGFR-cystatin-C levels (OR 0.981, 95% CI 0.963-1.000), and higher HbA1c levels (OR 1.519, 95% CI 1.077–2.143) were significantly associated with elevated serum IgG4. In contrast, analyses in women found that only nutritional factors, including greater carbohydrate intake (OR 1.116, 95% CI 1.040–1.197) and lower intake of lipids (OR 0.876, 95% CI 0.794–0.966), polyunsaturated fatty acids (OR 0.639, 95% CI 0.419–0.973), and saturated fatty acids (OR 0.718, 95% CI 0.521–0.989), were significantly associated with elevated IgG4 (Table 3).

Table 3 Odds ratios for elevated serum IgG4 levels in the male and female participants

Variable	Male (n = 557)	Female (n = 644)	
OR
(95% CI)	P-value	OR
(95% CI)	P-value	
Age (years)	1.046

(1.009 to 1.084)

	0.014	1.008

(0.960 to 1.058)

	0.745	
BMI (kg/m2)	0.974

(0.861 to 1.103)

	0.683	0.986

(0.830 to 1.172)

	0.875	
Systolic BP (mmHg)	0.989

(0.968 to 1.011)

	0.322	0.983

(0.952 to 1.016)

	0.313	
Diastolic BP (mmHg)	0.969

(0.939 to 1.001)

	0.060	0.987

(0.936 to 1.042)

	0.641	
Smoking history	0.830

(0.329 to 2.095)

	0.694	1.001

(0.218 to 4.586)

	0.999	
Allergic disease	2.174

(0.770 to 6.134)

	0.142	0.624

(0.079 to 4.957)

	0.656	
History of Malignancy	0.514

(0.067 to 3.933)

	0.521	1.348

(0.167 to 10.857)

	0.779	
Fraction of Eosinophil (%)	1.030

(0.888 to 1.195)

	0.698	1.073

(0.813 to 1.418)

	0.617	
Serum IgE level

(per100 IU/mL)

	1.016

(0.985 to 1.049)

	0.318	1.016

(0.893 to 1.156)

	0.810	
Serum CH50 level (U/mL)	1.028

(0.988 to 1.073)

	0.205	0.953

(0.899 to 1.010)

	0.107	
Serum CRP level (mg/dL)	0.960

(0.457 to 2.018)

	0.914	1.674

(0.789 to 3.553)

	0.180	
ANA	4.894

(1.507 to 15.895)

	0.008	0.882

(0.111 to 6.983)

	0.905	
RF	2.339

(0.651 to 8.404)

	0.193	1.812

(0.386 to 8.503)

	0.451	
eGFR-creatinine (mL/min/1.73m2)	0.998

(0.973 to 1.024)

	0.882	1.010

(0.971 to 1.050)

	0.618	
eGFR-cystatin-C (mL/min/1.73m2)	0.981

(0.963 to 1.000)

	0.048	0.985

(0.952 to 1.018)

	0.365	
LDL-cholesterol (mg/dL)	1.012

(0.992 to 1.032)

	0.239	0.992

(0.957 to 1.027)

	0.642	
HDL-cholesterol (mg/dL)	0.979

(0.952 to 1.006)

	0.127	0.981

(0.947 to 1.015)

	0.269	
Triglyceride (mg/dL)	1.002

(1.000 to 1.004)

	0.101	0.991

(0.978 to 1.005)

	0.219	
Uric acid (mg/dL)	1.032

(0.781 to 1.364)

	0.823	0.912

(0.526 to 1.580)

	0.742	
HbA1c (%)	1.519

(1.077 to 2.143)

	0.017	1.008

(0.367 to 2.771)

	0.987	
Protein intake (%)	0.954

(0.828 to 1.099)

	0.515	0.856

(0.702 to 1.044)

	0.124	
Lipid intake (%)	0.963

(0.897 to 1.035)

	0.306	0.876

(0.794 to 0.966)

	0.008	
Carbohydrate intake (%)	1.018

(0.972 to 1.067)

	0.451	1.116

(1.040 to 1.197)

	0.002	
Polyunsaturated fatty acids intake (%)	0.816

(0.609 to 1.092)

	0.171	0.639

(0.419 to 0.973)

	0.037	
Saturated fatty acids intake (%)	0.955

(0.756 to 1.205)

	0.695	0.718

(0.521 to 0.989)

	0.043	
Abbreviations ANA: anti-nuclear antibody; BMI: body mass index; BP: blood pressure; CRP: C-reactive protein; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; HDL: high-density lipoprotein; IgG: immunoglobulin G; IgG4: immunoglobulin G4; IgE: immunoglobulin E; LDL: low-density lipoprotein; RF: rheumatoid factor

In addition, we conducted a sub-analysis excluding one case of IgG4-RD. Unadjusted logistic regression analyses showed that male sex (OR 2.574, 95% CI 1.320–5.020), older age (OR 1.030, 95% CI 1.001–1.060), lower eGFR-cystatin-C (OR 0.980, 95% CI 0.964–0.997), lower serum HDL-C levels (OR 0.975, 95% CI 0.955–0.996), and higher HbA1c levels (OR 1.526, 95% CI 1.116–2.086) were associated with elevated serum IgG4. Assessment of nutritional factors showed that lower intake of lipids (OR 0.924, 95% CI 0.874–0.978), polyunsaturated fatty acids (OR 0.731, 95% CI 0.577–0.926), and saturated fatty acids (OR 0.833, 95% CI 0.693-1.000) was associated with elevated serum IgG4. Following age- and sex-adjusted analyses, male sex (OR 2.590, 95% CI 1.326–5.056), older age (OR 1.031, 95% CI 1.001–1.061), and lower intake of lipids (OR 0.942, 95% CI 0.888–0.999) remained significant, whereas the other five factors did not (Table S1). Subgroup analyses in men showed that older age (OR 1.043, 95% CI 1.006–1.081), lower eGFR-cystatin-C levels (OR 0.981, 95% CI 0.963-1.000), and higher HbA1c levels (OR 1.540, 95% CI 1.090–2.174) were significantly associated with elevated serum IgG4. Analyses in women was the same as those in Table 3 (Table S2).

Diagnosis of IgG4-RD in participants with elevated serum IgG4 levels

Fifteen participants with elevated serum IgG4 agreed to undergo secondary examinations for IgG4-RD (Table 4). Their mean age was 67.9 ± 9.0 years (range 56–93 years). One subject had chronic kidney disease with hydronephrosis and a retroperitoneal lesion (periaortitis/periarteritis) and was diagnosed with possible IgG4-RD based on the 2020 revised Japanese comprehensive diagnostic criteria. According to the 2019 ACR/EULAR classification criteria for IgG4-RD, this participant had an inclusion score of 8 points, but did not meet the threshold for inclusion due to involvement of a single organ and lack of biopsy of the affected organ. This subject was a male in his 70s with a serum IgG4 concentration of 254 mg/dL. His previous medical history included hypertension, renal insufficiency, and right hydronephrosis. Laboratory findings included serum creatinine 2.04 mg/dL; eGFR-creatinine 25.7 mL/min/1.73m2; serum IgG 2,419 mg/dL, serum IgE 464 IU/mL, serum CH50 43 U/mL, and urinary β2-microglobulin 1033 µg/L. Contrast-enhanced computed tomography (CT) showed periaortic/periarterial wall thickening of the abdominal aorta and its major branch and right hydroureteronephrosis (Fig. 2) but involvement of no other organs, such as the salivary and lacrimal glands, pancreas, bile duct, and kidneys.

. Characteristics and results of secondary examination in the 15 participants with elevated serum IgG4 levels

	Gender	IgG (mg/dL)	IgG4 (mg/dL)	IgE (IU/mL)	Hypocomple
-mentemia	Creatinine (mg/dL)	ANA	RF (IU/mL)	IGRA for TB infection	Imaging findings on CT	
1	Male	1,207	137	429	-	0.92	NA	-	NA	No significant finding	
2	Female	1,517	140	7.9	-	0.56	NA	5	-	No significant finding	
3	Male	1,150	142	674	-	0.79	NA	-	NA	No significant finding	
4	Male	1,699	142	431	-	1.13	NA	5	-	No significant finding	
5	Male	1,654	151	NA	-	0.63	NA	NA	-	Inflammatory scarring in the middle lobe and tongue area of the lung	
6	Female	1,774	154	144	-	0.71	×40	NA	NA	No significant finding	
7	Female	1,520	156	70	-	0.91	NA	NA	-	No significant finding	
8	Male	1,531	197	1,460	-	0.92	NA	4	+	No significant finding	
9	Female	1,612	205	95	-	0.60	NA	4	NA	No significant finding	
10	Male	2,292	206	1,410	-	0.80	NA	37	-	No significant finding	
11	Male	1,270	211	29	+	0.89	NA	NA	NA	No significant finding	
12	Male	892	217	NA	-	0.79	NA	5	NA	No significant finding	
13	Female	1,631	231	19	-	0.69	NA	NA	NA	No significant finding	
14	Male	1,464	236	412	-	0.53	NA	NA	NA	No significant finding	
15	Male	2,419	254	465	-	2.04	×40	14	NA	Hydronephrosis and retroperitoneal lesion (periaortitis/periarteritis)	
Note Hypocomplementemia is defined as serum CH50 levels less than reference range (32–47 U/mL)

Abbreviations ANA: anti-nuclear antibody; IgG: immunoglobulin G; IgG4: immunoglobulin G4; IgE: immunoglobulin E; IGRA: interferon-gamma release assays; NA: not available; RF: rheumatoid factor; TB: tuberculosis

Fig. 2 Hydronephrosis and periaortic/periarterial lesion in one participant with elevated serum IgG4 level. Contrast-enhanced computed tomography (CT) imaging showed right hydroureteronephrosis (A, arrow) and periaortic/periarterial wall thickening of the abdominal aorta and its major branch (B)

Discussion

The present study, which included a large number of participants undergoing general health examinations, analyzed the prevalence of elevated serum IgG4 levels in a Japanese general adult population. Of the 1,201 participants analyzed, 42 (3.5%) had serum IgG4 concentrations > 135 mg/dL, a higher percentage than the 1.2% reported in a study from Spain [21]. In addition, the present study found that male gender, older age, renal dysfunction, metabolic disturbance, and nutrition intake status were associated with elevated serum IgG4 levels. In men, older age, renal dysfunction, and glucose intolerance were associated with elevated serum IgG4, whereas, in women, nutrition intake status was associated with elevated serum IgG4, suggesting that factors associated with elevated serum IgG4 differed by gender. Moreover, one of the 15 symptom-free participants with elevated serum IgG4 who underwent a more comprehensive examination was found to have clinical features of IgG4-RD. These results suggested that, in addition to allergic diseases and IgG4-RD, other factors are associated with elevated serum IgG4, including age, gender, metabolism, and nutrition and may partly explain the reasons that elevated serum IgG4 is not always specific for the diagnosis of IgG4-RD. Some of the epidemiological factors frequently associated with IgG4-RD, such as older age and male gender, were observed in the study participants with elevated serum IgG4, whereas others, such as malignancies, were not. Additional studies are needed to determine whether and how these factors are related to the pathogenesis of IgG4-RD.

Our findings, that male gender and older age were significantly associated with elevated serum IgG4, were in agreement with findings in a Spanish population [21]. Interestingly, these factors are also associated with IgG4-RD, indicating that elevated serum IgG4 levels and the pathogenesis of IgG4-RD have common features. Metabolic syndrome-related factors, such as low serum HDL-C levels and higher HbA1c concentrations, also tended to be associated with elevated serum IgG4. One unique aspect of the present study was the determination of nutrition intake based on the BDHQ, with results suggesting that elevated serum IgG4 levels were associated with factors such as higher carbohydrate intake and lower intake of lipids and fatty acids. Because few participants in this study developed IgG4-RD, the association between nutrition intake and the development of IgG4-RD remains to be clarified.

Interestingly, the factors associated with elevated serum IgG4 differed by gender. In men, age, HbA1c, and renal function were associated with elevated serum IgG4, whereas nutrition intake was not. In women, however, nutrition intake was associated with elevated serum IgG4. This difference may have been due to the influence of sex hormones, but their concentrations were not evaluated in the present study. Moreover, this study included many elderly participants, in whom sex hormones were likely less influential. Further studies are needed to analyze the influence of sex hormones and other factors on the differences between genders.

Although the mechanisms linking dietary intake and elevated IgG4 levels have not been fully elucidated, a hypothesis worth considering is that the intestinal microbiota may mediate this relationship. In humans, a low intake of saturated fatty acids, independent of fiber intake, has been reported to result in increased diversity of intestinal microorganisms [35], suggesting a relationship between dietary intake and the state of intestinal microorganisms. On the other hand, Karashima et al. investigated the relationship between the intestinal flora and serum IgG4 levels in participants undergoing general health examinations and found that the bacteria associated with elevated serum IgG4 levels differed between men and women [36]. This may partially explain the results of the present study, where the impact of dietary intake on serum IgG4 levels varied by sex. Furthermore, changes in the composition of the intestinal flora (characterized by a decrease in beneficial bacteria and an increase in potentially pathogenic bacterial species) have been reported in individuals with IgG4-RD [37]. In a mouse model, autoimmune pancreatitis-like lesions developed in response to the induction of innate immune responses against the intestinal flora [38]. These findings suggest that both the intestinal flora and the intake of certain nutrients that can influence the flora may be involved in the elevation of serum IgG4 levels and potentially in the development of IgG4-RD.

Factors reported to be associated with IgG4-RD were not associated with elevated serum IgG4 levels in these participants. For example, a study from Taiwan reported that 13 (41.9%) of the 31 non-IgG4-RD participants with allergic disease had serum IgG4 concentrations > 135 mg/dL [39], and a Japanese study found that one (14.3%) of seven patients with bronchial asthma, but none of the healthy controls, had a serum IgG4 level > 144 mg/dL [40]. In the present study, however, the prevalence of elevated serum IgG4 levels did not differ in participants with and without allergic disease, and logistic regression analysis did not show a significant association between allergic disease and elevated serum IgG4. Similarly, a Spanish study found that patients with an atopic predisposition had a median serum IgG4 level of 38.4 mg/dL (IQR 21.7–56.6 mg/mL), suggesting that few had serum IgG4 concentrations > 135 mg/dL [21]. Although malignancy has been associated with IgG4-RD [22–24], the prevalence of elevated serum IgG4 did not differ in our study participants with and without a history of malignancy. These results suggest that factors related to IgG4-RD may not be responsible for enhancing IgG4 production.

This study also provided data on the rates of elevated serum IgG4 and IgG4-RD in a general population of adults undergoing regular health examinations, not in patients visiting a medical institution. Previous studies found that 10–15% of patients with elevated serum IgG4 levels had IgG4-RD. In the present study, although few participants underwent close secondary examination, more than 0.08% of all participants or more than 2.4% of those with elevated serum IgG4 levels had IgG4-RD, a higher prevalence than previously reported [2, 41]. In the Spanish study of adults undergoing health examinations [21], none of those with elevated serum IgG4 levels was diagnosed with IgG4-RD. This was likely due to the small number of participants and/or the low percentage who underwent close secondary examination. Studies that include much higher numbers of participants are needed to estimate the prevalence of IgG4-RD more accurately.

The results of the present study also suggest the likelihood of regional and racial differences in the prevalence of elevated serum IgG4 levels. Although comparisons are limited, the prevalence of elevated serum IgG4 was three times higher in one Japanese region than in one Spanish region. To determine whether there are regional differences in Japan, we are now evaluating the prevalence of elevated serum IgG4 levels in health examination participants in another Japanese region. Further evaluations in more countries and regions will be necessary to determine the prevalence rates of elevated serum IgG4 and IgG4-RD and the factors related to them in general populations.

This study had several limitations. First, although this study included more participants than did a comparable study [21], the number of participants was insufficient to analyze factors affecting the epidemiology of IgG4-RD. In addition, a very low rate (35.7%) of undergoing close secondary examination in patients with elevated serum IgG4 concentrations was an important limitation of the present study. Second, serum IgG4 concentrations were not measured in 10% of the consecutive participants, leading to a potential for selection bias in this study. Some missing values could also potentially affect the results. Third, because this study was limited to a single region in Japan, the associations of regional and racial factor with elevated serum IgG4 or the onset of IgG4-RD could not be sufficiently evaluated. Finally, because this study was a cross-sectional survey, the time courses of serum IgG4 elevation and IgG4-RD onset could not be analyzed longitudinally. These analyses would require nationwide multi-center and/or multi-national studies analyzing multi-year results of health examinations.

Conclusions

Elevated serum IgG4 levels are significantly associated with older age, male gender, and nutrition intake status. Although some of these factors are identical to the epidemiological features of IgG4-RD, they rarely lead to a diagnosis of IgG4-RD in the general Japanese population. Nevertheless, the prevalence of IgG4-RD may be higher than expected. Although larger-scale multi-national and multi-center studies are needed to confirm these results and clarify regional and racial differences, the present results can help determine the prevalence and clinical significance of elevated serum IgG4 levels in a general population.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Abbreviations

ACR American College of Rheumatology

ANA Anti-nuclear antibody

BP Blood pressure

BMI Body mass index

BDHQ Brief-type self-administered diet history questionnaire

CT Computed tomography

CI Confidence interval

CRP C-reactive protein

eGFR Estimated glomerular filtration rate

EULAR European League Against Rheumatism

HbA1c Hemoglobin A1c

HDL-C High-density lipoprotein cholesterol

IgG4 Immunoglobulin G4

IgG4-RD Immunoglobulin G4-related disease

LDL-C Low-density lipoprotein cholesterol

OR Odds ratio

RF Rheumatoid factor

SD Standard deviation

Total-C Total cholesterol

TG Triglycerides

ULN Upper limit of normal

Acknowledgements

We thank David Price for his critical reading of the manuscript.

Author contributions

ST, HF, IM, MK: conception and design, data collection and analysis, manuscript writing and final approval of the manuscript. HT, MY, NS, YT, AT, SHorita, YF, TM, TZ, RN, HNuka, SHara, YT, YS, KI, KY, SN: data collection and analysis, critical revision and final approval of the manuscript. MT, AH, AK, HNakamura, YI: conception and design, critical revision and final approval of the manuscript. All authors read and approved the final manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

This work was supported by Health and Labour Sciences Research Grants for the Study of Intractable Diseases from the Ministry of Health, Labor and Welfare, Japan.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the institutional ethics boards of the Medical Ethics Committee of Kanazawa University, Nagasaki University, and Johoku Hospital, and informed consent for the use of all data was obtained from each participant. This study was conducted in compliance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Shunsuke Tsuge and Hiroshi Fujii contributed equally to this work.
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References

1. Stone JH Zen Y Deshpande V IgG4-related disease N Engl J Med 2012 366 539 51 10.1056/NEJMra1104650 22316447
Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539–51.22316447 10.1056/NEJMra1104650
2. Umehara H Okazaki K Masaki Y Kawano M Yamamoto M Saeki T A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details Mod Rheumatol 2012 22 1 14 10.3109/s10165-011-0508-6 21881964
Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22:1–14.21881964 10.3109/s10165-011-0508-6
3. Kamisawa T Zen Y Pillai S Stone JH IgG4-related disease Lancet 2015 385 1460 71 10.1016/S0140-6736(14)60720-0 25481618
Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet. 2015;385:1460–71.25481618 10.1016/S0140-6736(14)60720-0
4. Umehara H Okazaki K Kawa S Takahashi H Goto H Matsui S The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD Mod Rheumatol 2021 31 529 33 10.1080/14397595.2020.1859710 33274670
Umehara H, Okazaki K, Kawa S, Takahashi H, Goto H, Matsui S, et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. Mod Rheumatol. 2021;31:529–33.33274670 10.1080/14397595.2020.1859710
5. Kawa S, Kamisawa T, Notohara K, Fujinaga Y, Inoue D, Koyama T et al. Japanese clinical diagnostic criteria for autoimmune pancreatitis, 2018: Revision of Japanese clinical diagnostic criteria for autoimmune pancreatitis, 2011. Pancreas. 2020; 49: e13-e14.
6. Nakazawa T Kamisawa T Okazaki K Kawa S Tazuma S Nishino T Clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2020: (revision of the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012) J Hepatobiliary Pancreat Sci 2021 28 235 42 10.1002/jhbp.913 33586343
Nakazawa T, Kamisawa T, Okazaki K, Kawa S, Tazuma S, Nishino T, et al. Clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2020: (revision of the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012). J Hepatobiliary Pancreat Sci. 2021;28:235–42.33586343 10.1002/jhbp.913
7. Saeki T Kawano M Nagasawa T Ubara Y Taniguchi Y Yanagita M Validation of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD) 2011, and proposal of a new 2020 version Clin Exp Nephrol 2021 25 99 109 10.1007/s10157-020-01993-7 33398598
Saeki T, Kawano M, Nagasawa T, Ubara Y, Taniguchi Y, Yanagita M, et al. Validation of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD) 2011, and proposal of a new 2020 version. Clin Exp Nephrol. 2021;25:99–109.33398598 10.1007/s10157-020-01993-7
8. Masaki Y Sugai S Umehara H IgG4-related diseases including Mikulicz’s disease and sclerosing pancreatitis: diagnostic insights J Rheum 2010 37 1380 5 10.3899/jrheum.091153 20436071
Masaki Y, Sugai S, Umehara H. IgG4-related diseases including Mikulicz’s disease and sclerosing pancreatitis: diagnostic insights. J Rheum. 2010;37:1380–5.20436071 10.3899/jrheum.091153
9. Goto H Takahira M Azumi A Diagnostic criteria for IgG4-related ophthalmic disease Jpn J Ophthalmol 2015 59 1 7 10.1007/s10384-014-0352-2 25392273
Goto H, Takahira M, Azumi A. Diagnostic criteria for IgG4-related ophthalmic disease. Jpn J Ophthalmol. 2015;59:1–7.25392273 10.1007/s10384-014-0352-2
10. Matsui S Yamamoto H Minamoto S Waseda Y Mishima M Kubo K Proposed diagnostic criteria for IgG4-related respiratory disease Respir Investig 2016 54 130 2 10.1016/j.resinv.2015.09.002 26879484
Matsui S, Yamamoto H, Minamoto S, Waseda Y, Mishima M, Kubo K. Proposed diagnostic criteria for IgG4-related respiratory disease. Respir Investig. 2016;54:130–2.26879484 10.1016/j.resinv.2015.09.002
11. Mizushima I Kasashima S Fujinaga Y Kawano M Ishizaka N IgG4-related periaortitis/periarteritis: an under-recognized condition that is potentially life-threatening Mod Rheumatol 2019 29 240 50 10.1080/14397595.2018.1546367 30474460
Mizushima I, Kasashima S, Fujinaga Y, Kawano M, Ishizaka N. IgG4-related periaortitis/periarteritis: an under-recognized condition that is potentially life-threatening. Mod Rheumatol. 2019;29:240–50.30474460 10.1080/14397595.2018.1546367
12. Mizushima I Kasashima S Fujinaga Y Notohara K Saeki T Zen Y Clinical and pathological characteristics of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis diagnosed based on experts’ diagnosis Ann Vasc Dis 2019 12 460 72 10.3400/avd.oa.19-00085 31942203
Mizushima I, Kasashima S, Fujinaga Y, Notohara K, Saeki T, Zen Y, et al. Clinical and pathological characteristics of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis diagnosed based on experts’ diagnosis. Ann Vasc Dis. 2019;12:460–72.31942203 10.3400/avd.oa.19-00085
13. Wallace ZS Naden RP Chari S Choi HK Della-Torre E Dicaire JF The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease Ann Rheum Dis 2020 79 77 87 10.1136/annrheumdis-2019-216561 31796497
Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020;79:77–87.31796497 10.1136/annrheumdis-2019-216561
14. Yamada K Yamamoto M Saeki T Mizushima I Matsui S Fujisawa Y New clues to the nature of immunoglobulin G4-related disease: a retrospective Japanese multicenter study of baseline clinical features of 334 cases Arthritis Res Ther 2017 19 262 10.1186/s13075-017-1467-x 29191210
Yamada K, Yamamoto M, Saeki T, Mizushima I, Matsui S, Fujisawa Y, et al. New clues to the nature of immunoglobulin G4-related disease: a retrospective Japanese multicenter study of baseline clinical features of 334 cases. Arthritis Res Ther. 2017;19:262.29191210 10.1186/s13075-017-1467-x
15. Lin W Lu S Chen H Wu Q Fei Y Li M Clinical characteristics of immunoglobulin G4-related disease: a prospective study of 118 Chinese patients Rheumatology (Oxford) 2015 54 1982 90 10.1093/rheumatology/kev203 26106212
Lin W, Lu S, Chen H, Wu Q, Fei Y, Li M, et al. Clinical characteristics of immunoglobulin G4-related disease: a prospective study of 118 Chinese patients. Rheumatology (Oxford). 2015;54:1982–90.26106212 10.1093/rheumatology/kev203
16. Wallace ZS Deshpande V Mattoo H Mahajan VS Kulikova M Pillai S IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients Arthritis Rheumatol 2015 67 2466 75 10.1002/art.39205 25988916
Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, et al. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol. 2015;67:2466–75.25988916 10.1002/art.39205
17. Carruthers MN Khosroshahi A Augustin T Deshpande V Stone JH The diagnostic utility of serum IgG4 concentrations in IgG4-related disease Ann Rheum Dis 2015 74 14 8 10.1136/annrheumdis-2013-204907 24651618
Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis. 2015;74:14–8.24651618 10.1136/annrheumdis-2013-204907
18. Xu WL Ling YC Wang ZK Deng F Diagnostic performance of serum IgG4 level for IgG4-related disease: a meta-analysis Sci Rep 2016 6 32035 10.1038/srep32035 27558881
Xu WL, Ling YC, Wang ZK, Deng F. Diagnostic performance of serum IgG4 level for IgG4-related disease: a meta-analysis. Sci Rep. 2016;6:32035.27558881 10.1038/srep32035
19. Yun J Wienholt L Adelstein S Poor positive predictive value of serum immunoglobulin G4 concentrations in the diagnosis of immunoglobulin G4-related sclerosing disease Asia Pac Allergy 2014 4 172 6 10.5415/apallergy.2014.4.3.172 25097853
Yun J, Wienholt L, Adelstein S. Poor positive predictive value of serum immunoglobulin G4 concentrations in the diagnosis of immunoglobulin G4-related sclerosing disease. Asia Pac Allergy. 2014;4:172–6.25097853 10.5415/apallergy.2014.4.3.172
20. Ngwa TN Law R Murray D Chari ST Serum immunoglobulin G4 level is a poor predictor of immunoglobulin G4-related disease Pancreas 2014 43 704 7 10.1097/MPA.0000000000000118 24632552
Ngwa TN, Law R, Murray D, Chari ST. Serum immunoglobulin G4 level is a poor predictor of immunoglobulin G4-related disease. Pancreas. 2014;43:704–7.24632552 10.1097/MPA.0000000000000118
21. Carballo I Alvela L Pérez LF Gude F Vidal C Alonso M Serum concentrations of IgG4 in the Spanish adult population: relationship with age, gender, and atopy PLoS ONE 2016 11 e0149330 10.1371/journal.pone.0149330 26910567
Carballo I, Alvela L, Pérez LF, Gude F, Vidal C, Alonso M, et al. Serum concentrations of IgG4 in the Spanish adult population: relationship with age, gender, and atopy. PLoS ONE. 2016;11:e0149330.26910567 10.1371/journal.pone.0149330
22. Yamamoto M Takahashi H Tabeya T Suzuki C Naishiro Y Ishigami K Risk of malignancies in IgG4-related disease Mod Rheumatol 2012 22 414 8 10.3109/s10165-011-0520-x 21894525
Yamamoto M, Takahashi H, Tabeya T, Suzuki C, Naishiro Y, Ishigami K, et al. Risk of malignancies in IgG4-related disease. Mod Rheumatol. 2012;22:414–8.21894525 10.3109/s10165-011-0520-x
23. Shiokawa M Kodama Y Yoshimura K Kawanami C Mimura J Yamashita Y Risk of cancer in patients with autoimmune pancreatitis Am J Gastroenterol 2013 108 610 7 10.1038/ajg.2012.465 23318486
Shiokawa M, Kodama Y, Yoshimura K, Kawanami C, Mimura J, Yamashita Y, et al. Risk of cancer in patients with autoimmune pancreatitis. Am J Gastroenterol. 2013;108:610–7.23318486 10.1038/ajg.2012.465
24. Yu T Wu Y Liu J Zhuang Y Jin X Wang L The risk of malignancy in patients with IgG4-related disease: a systematic review and meta-analysis Arthritis Res Ther 2022 24 14 10.1186/s13075-021-02652-2 34986892
Yu T, Wu Y, Liu J, Zhuang Y, Jin X, Wang L, et al. The risk of malignancy in patients with IgG4-related disease: a systematic review and meta-analysis. Arthritis Res Ther. 2022;24:14.34986892 10.1186/s13075-021-02652-2
25. Hirano K Tada M Sasahira N Isayama H Mizuno S Takagi K Incidence of malignancies in patients with IgG4-related disease Intern Med 2014 53 171 6 10.2169/internalmedicine.53.1342 24492683
Hirano K, Tada M, Sasahira N, Isayama H, Mizuno S, Takagi K, et al. Incidence of malignancies in patients with IgG4-related disease. Intern Med. 2014;53:171–6.24492683 10.2169/internalmedicine.53.1342
26. Inoue D Yoshida K Yoneda N Ozaki K Matsubara T Nagai K IgG4-related disease: dataset of 235 consecutive patients Med (Baltim) 2015 94 e680 10.1097/MD.0000000000000680
Inoue D, Yoshida K, Yoneda N, Ozaki K, Matsubara T, Nagai K, et al. IgG4-related disease: dataset of 235 consecutive patients. Med (Baltim). 2015;94:e680.10.1097/MD.0000000000000680
27. Saeki T Kobayashi D Ito T Tamura M Yoshikawa S Yamazaki H Comparison of clinical and laboratory features of patients with and without allergic conditions in IgG4-related disease: a single-center experience in Japan Mod Rheumatol 2018 28 845 8 10.1080/14397595.2017.1416891 29251026
Saeki T, Kobayashi D, Ito T, Tamura M, Yoshikawa S, Yamazaki H, et al. Comparison of clinical and laboratory features of patients with and without allergic conditions in IgG4-related disease: a single-center experience in Japan. Mod Rheumatol. 2018;28:845–8.29251026 10.1080/14397595.2017.1416891
28. Culver EL Vermeulen E Makuch M van Leeuwen A Sadler R Cargill T Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease Ann Rheum Dis 2015 74 944 7 10.1136/annrheumdis-2014-206405 25646372
Culver EL, Vermeulen E, Makuch M, van Leeuwen A, Sadler R, Cargill T, et al. Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease. Ann Rheum Dis. 2015;74:944–7.25646372 10.1136/annrheumdis-2014-206405
29. Wallwork R Perugino CA Fu X Harkness T Zhang Y Choi HK The association of smoking with immunoglobulin G4-related disease: a case-control study Rheumatology (Oxford) 2021 60 5310 7 10.1093/rheumatology/keab172 33751033
Wallwork R, Perugino CA, Fu X, Harkness T, Zhang Y, Choi HK, et al. The association of smoking with immunoglobulin G4-related disease: a case-control study. Rheumatology (Oxford). 2021;60:5310–7.33751033 10.1093/rheumatology/keab172
30. Matsuo S Imai E Horio M Yasuda Y Tomita K Nitta K Revised equations for estimated GFR from serum creatinine in Japan Am J Kidney Dis 2009 53 982 92 10.1053/j.ajkd.2008.12.034 19339088
Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.19339088 10.1053/j.ajkd.2008.12.034
31. Imai E, Iseki K, Nitta K, Fukagawa M, Yasuda Y, Yamagata K, et al. Clinical practice guidebook for diagnosis and treatment of chronic kidney disease 2012. Japanese Society of Nephrology; 2012. pp. 18–21.
32. Kobayashi S Honda S Murakami K Sasaki S Okubo H Hirota N Both comprehensive and brief self-administered diet history questionnaires satisfactorily rank nutrient intakes in Japanese adults J Epidemiol 2012 22 151 9 10.2188/jea.JE20110075 22343326
Kobayashi S, Honda S, Murakami K, Sasaki S, Okubo H, Hirota N, et al. Both comprehensive and brief self-administered diet history questionnaires satisfactorily rank nutrient intakes in Japanese adults. J Epidemiol. 2012;22:151–9.22343326 10.2188/jea.JE20110075
33. Willett W Stampfer MJ Total energy intake: implications for epidemiologic analyses Am J Epidemiol 1986 124 17 27 10.1093/oxfordjournals.aje.a114366 3521261
Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol. 1986;124:17–27.3521261 10.1093/oxfordjournals.aje.a114366
34. Peduzzi P Concato J Kemper E Holford TR Feinstein AR A simulation study of the number of events per variable in logistic regression analysis J Clin Epidemiol 1996 49 1373 9 10.1016/S0895-4356(96)00236-3 8970487
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996;49:1373–9.8970487 10.1016/S0895-4356(96)00236-3
35. Schoeler M Ellero-Simatos S Birkner T Mayneris-Perxachs J Olsson L Brolin H The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis Nat Commun 2023 14 5329 10.1038/s41467-023-41074-3 37658064
Schoeler M, Ellero-Simatos S, Birkner T, Mayneris-Perxachs J, Olsson L, Brolin H, et al. The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis. Nat Commun. 2023;14:5329.37658064 10.1038/s41467-023-41074-3
36. Koshida A Karashima S Ogura K Miyajima Y Ogai K Mizoguchi R Impact of gut microbiome on serum IgG4 levels in the general population: Shika-Machi super preventive health examination results Front Cell Infect Microbiol 2023 13 1272398 10.3389/fcimb.2023.1272398 37908763
Koshida A, Karashima S, Ogura K, Miyajima Y, Ogai K, Mizoguchi R, et al. Impact of gut microbiome on serum IgG4 levels in the general population: Shika-Machi super preventive health examination results. Front Cell Infect Microbiol. 2023;13:1272398.37908763 10.3389/fcimb.2023.1272398
37. Plichta DR Somani J Pichaud M Wallace ZS Fernandes AD Perugino CA Congruent microbiome signatures in fibrosis-prone autoimmune diseases: IgG4-related disease and systemic sclerosis Genome Med 2021 13 35 10.1186/s13073-021-00853-7 33648559
Plichta DR, Somani J, Pichaud M, Wallace ZS, Fernandes AD, Perugino CA, et al. Congruent microbiome signatures in fibrosis-prone autoimmune diseases: IgG4-related disease and systemic sclerosis. Genome Med. 2021;13:35.33648559 10.1186/s13073-021-00853-7
38. Kamata K Watanabe T Minaga K Hara A Yoshikawa T Okamoto A Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells Int Immunol 2019 31 795 809 10.1093/intimm/dxz050 31287532
Kamata K, Watanabe T, Minaga K, Hara A, Yoshikawa T, Okamoto A, et al. Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells. Int Immunol. 2019;31:795–809.31287532 10.1093/intimm/dxz050
39. Yu KH Chan TM Tsai PH Chen CH Chang PY Diagnostic performance of serum IgG4 levels in patients with IgG4-related disease Med (Baltim) 2015 94 e1707 10.1097/MD.0000000000001707
Yu KH, Chan TM, Tsai PH, Chen CH, Chang PY. Diagnostic performance of serum IgG4 levels in patients with IgG4-related disease. Med (Baltim). 2015;94:e1707.10.1097/MD.0000000000001707
40. Yamamoto M Tabeya T Naishiro Y Yajima H Ishigami K Shimizu Y Value of serum IgG4 in the diagnosis of IgG4-related disease and in differentiation from rheumatic diseases and other diseases Mod Rheumatol 2012 22 419 25 10.3109/s10165-011-0532-6 21953287
Yamamoto M, Tabeya T, Naishiro Y, Yajima H, Ishigami K, Shimizu Y, et al. Value of serum IgG4 in the diagnosis of IgG4-related disease and in differentiation from rheumatic diseases and other diseases. Mod Rheumatol. 2012;22:419–25.21953287 10.3109/s10165-011-0532-6
41. Masamune A Kikuta K Hamada S Tsuji I Takeyama Y Shimosegawa T Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2016 J Gastroenterol 2020 55 462 70 10.1007/s00535-019-01658-7 31872350
Masamune A, Kikuta K, Hamada S, Tsuji I, Takeyama Y, Shimosegawa T, et al. Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2016. J Gastroenterol. 2020;55:462–70.31872350 10.1007/s00535-019-01658-7
