Skip to main content
Download PDF

Factors related to elevated serum immunoglobulin G4 (IgG4) levels in a Japanese general population

Arthritis Research & Therapy volume 26, Article number: 156 (2024) Cite this article

Abstract

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.

Background

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 [5,6,7,8,9,10,11,12], 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 [14,15,16]. 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 [22,23,24], 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 [4,5,6,7,8,9,10,11,12].

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
Full size table
Fig. 1
figure 1

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

Full size image

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
Full size table

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
Full size table

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
Full size table
Fig. 2
figure 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)

Full size image

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 [22,23,24], 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.

Data availability

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

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

References

  1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539–51.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet. 2015;385:1460–71.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  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, 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.

    Article  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  9. Goto H, Takahira M, Azumi A. Diagnostic criteria for IgG4-related ophthalmic disease. Jpn J Ophthalmol. 2015;59:1–7.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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.

    Article  PubMed  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  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, et al. Both comprehensive and brief self-administered diet history questionnaires satisfactorily rank nutrient intakes in Japanese adults. J Epidemiol. 2012;22:151–9.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol. 1986;124:17–27.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. 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.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

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

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.

Author information

Author notes

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

Authors and Affiliations

  1. Department of Nephrology and Rheumatology, Kanazawa University Hospital, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan

    Shunsuke Tsuge, Hiroshi Fujii, Misaki Yoshida, Nobuhiro Suzuki, Yoshinori Takahashi, Akari Takeji, Shigeto Horita, Yuhei Fujisawa, Takahiro Matsunaga, Takeshi Zoshima, Ryo Nishioka, Hiromi Nuka, Satoshi Hara, Yukiko Tani, Yasunori Suzuki, Kiyoaki Ito, Kazunori Yamada, Ichiro Mizushima, Yasunori Iwata & Mitsuhiro Kawano

  2. Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Mami Tamai & Atsushi Kawakami

  3. Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan

    Hiromasa Tsujiguchi, Akinori Hara & Hiroyuki Nakamura

  4. Department of Rheumatology, Johoku Hospital, Kanazawa, Japan

    Satoshi Nakazaki

Authors
  1. Shunsuke Tsuge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mami Tamai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiromasa Tsujiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Misaki Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuhiro Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshinori Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Akari Takeji
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shigeto Horita
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuhei Fujisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takahiro Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Takeshi Zoshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ryo Nishioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hiromi Nuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Satoshi Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yukiko Tani
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yasunori Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kiyoaki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Kazunori Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Satoshi Nakazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Akinori Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Atsushi Kawakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Hiroyuki Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Ichiro Mizushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Yasunori Iwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Mitsuhiro Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Ichiro Mizushima.

Ethics 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.

Additional information

Publisher’s note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

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/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsuge, S., Fujii, H., Tamai, M. et al. Factors related to elevated serum immunoglobulin G4 (IgG4) levels in a Japanese general population. Arthritis Res Ther 26, 156 (2024). https://doi.org/10.1186/s13075-024-03391-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13075-024-03391-w

Keywords

Arthritis Research & Therapy

ISSN: 1478-6362

Contact us