New clues to the nature of immunoglobulin G4-related disease: a retrospective Japanese multicenter study of baseline clinical features of 334 cases

We retrospectively evaluated 334 patients with IgG4-RD who were diagnosed between 1996 and 2015 in Kanazawa University Hospital, Sapporo Medical University Hospital, Nagaoka Red Cross Hospital, University of Toyama Hospital, Shinshu University Hospital, and affiliated hospitals. Data related to patients’ baseline clinical features, laboratory findings, imaging tests, pathological tests, and treatments were derived from their medical records.

To minimize bias regarding the organs affected by IgG4-RD, the diagnosis of IgG4-RD was made by specialists of IgG4-RD in each institution, supported by the comprehensive diagnostic criteria (CDC) [12] and/or criteria of each organ including type 1 autoimmune pancreatitis, IgG4-related kidney disease, IgG4-related Mikulicz’s disease (IgG4-related sialadenitis and dacryoadenitis), and IgG4-related sclerosing cholangitis [6, 13‐15]. The CDC consist of three parts including clinical features showing characteristic diffuse/localized swelling or masses in single or multiple organs, elevation of serum IgG4 concentrations (≥135 mg/dl), and histopathological findings including marked lymphoplasmacytic infiltration, fibrosis, and infiltration of IgG4-positive cells (IgG4⁺/IgG⁺ > 40% and > 10 IgG4⁺ plasma cells/HPF). Since the cutoff number of IgG4-positive plasma cells of the CDC is lower than those of the Consensus statement on the pathology of IgG4-RD [16], we made the diagnosis of IgG4-RD referring to the Consensus statement on the pathology by specialists who have treated many IgG4-RD patients and paid particular attention to any clinicopathologic correlations. The histopathological importance of tissue infiltrating IgG4-positive plasma cells (IgG4⁺ PC) in the diagnosis of AIP was reported in 2002, and was also confirmed in the diagnosis of Mikulicz disease (MD) in 2005, which is currently known as IgG4-related dacryoadenitis and sialadenitis. Therefore, after 2005, almost all patients in our study were diagnosed as having IgG4-RD with reference to the immunohistochemical findings of IgG4 staining, clinical and imaging features, and/or serum IgG4 levels. In contrast, 30 patients who were diagnosed as having AIP or MD before 2005 were also included in our study. Of these, four patients were diagnosed with AIP before 2002. Reevaluation of histopathological samples was performed in all four of these patients, and the diagnosis of IgG4-RD was confirmed. Similarly, 26 patients were diagnosed with IgG4-related dacryoadenitis and sialadenitis before 2005. Fifteen of these 26 patients were reevaluated histopathologically and the final diagnosis was confirmed. In the remaining 11 patients, eight had bilateral lachrymal and submandibular gland swelling with elevated serum IgG4 levels, with this combination highly specific for the diagnosis of IgG4-RD. The other three patients had only one set of bilateral lacrimal or bilateral submandibular gland swelling, and all of them had an elevated serum IgG4 level. These three patients were diagnosed with IgG4-RD with reference to the clinical and imaging features and elevation of serum IgG4 levels.

The numbers of patients with definite, probable, and possible IgG4-RD according to CDC and/or organ-specific criteria were 280 (83.8%), 49 (14.7%), and 4 (1.2%), respectively. One patient was diagnosed clinically with IgG4-RD (Table 1).

We retrospectively analyzed the medical records of all patients included in this study. We noted the serum levels of IgG, IgG4, IgE, C3, C4, CH50, and C-reactive protein (CRP), the affected organs, the diagnostic imaging tests including computed tomography (CT), magnetic resonance imaging (MRI), gallium (Ga) scintigraphy, and positron emission tomography (PET), and the prevalence of biopsy of the affected organs. Serum IgG4 levels were measured using the nephelometric assay in all patients in this study. In addition, as a new serological marker, we defined non-IgG4 IgG as total IgG minus IgG4. Non-IgG4 IgG substitutes for the sum of IgG1, IgG2, and IgG3, and an increase of non-IgG4 IgG seems to mean that the serum level of IgGs which can activate the complement pathway is increased. We also evaluated the prevalence of corticosteroid therapy, average initial and maintenance dose of corticosteroid, effectiveness of corticosteroid therapy, and recurrence rate. The improvement of the affected organs was decided as the changes in symptomatic, radiologic, serologic, or histologic features. In IgG4-related kidney disease (IgG4-RKD), improvement of renal function was also considered. The definition of recurrence was the reappearance or worsening of symptomatic, radiologic, serologic, or histologic features of IgG4-RD. In IgG4-RKD, a rapid increase in the serum level of creatinine, after careful exclusion of other renal diseases, was also considered as recurrence. Reelevation of the serum levels of IgG or IgG4 alone was not regarded as recurrence. Furthermore, we determined the prevalence of diabetes mellitus (DM) at diagnosis of IgG4-RD and malignancy both before and after diagnosis of IgG4-RD.

Differences between groups were assessed by chi-square test for categorical variables, and by Mann–Whitney U test for linear variables. The analysis of the organs associated with hypocomplementemia was performed using logistic regression analysis, adjusted for age, sex, and presence/absence of DM. Correlation analysis was performed to confirm the relationship between hypocomplementemia and serum levels of IgG4 or non-IgG4 IgG. Explanatory factor analysis followed by Varimax rotation was used to examine the structure of organ coinvolvement. All statistical tests were performed using SPSS software (version 22). Significant differences were defined as p < 0.05.

Two hundred and five patients were male, and 129 were female (male 61.4%). The mean and median ages at diagnosis were 63.8 ± 11.5 and 65 years (range 25–91). All patients were Japanese. The average follow-up period was 4.2 years. The prevalence of diabetes mellitus (DM) was 34.4% and was significantly higher in those with rather than without AIP (46.2% vs 30.0%, p = 0.005) (Table 1). Sixty-seven malignancies appeared in 57 of 334 patients (17.1%) with IgG4-RD (Table 2). Two and six patients had three and two malignancies, respectively. The types of malignancy are presented in Additional file 1: Table S1. Lung cancer was the most frequent malignancy in patients with IgG4-RD, followed by gastric cancer, colon cancer, and prostate cancer. Lung, colon, prostate, and renal cancers were frequently seen both before and after the diagnosis of IgG4-RD, whereas gastric cancer and malignant lymphoma tended to appear after the diagnosis of IgG4-RD (Table 2).

The mean number of organs involved was 3.2 (range 1–11). The most frequently affected organs were the salivary glands (SG) (72.7%) followed by the lacrimal glands (LG) (57.1%), lymph nodes (56.5%), pancreas (25.5%), retroperitoneum (RP)/periaorta (24.9%), kidney (23.7%), and lung (23.4%). Single organ involvement was seen in 38 of 334 patients (11.4%) (Table 1). After excluding lymph nodes, the ratio of single organ involvement was 18.9%. The other affected organs with a prevalence of more than 1% were the prostate (9.6%), bile duct (5.4%), and skin (1.5%). The RP/periaorta, lung, and kidney were more frequently affected in males than in females, and the reverse for the LG (see Additional file 1: Table S1). The factor analysis identified three factors, explaining 21.7% of the total variance: factor 1 explained 8.1%, affecting LG, SG, and lymph node involvement; factor 2 explained 7.0%, affecting RP/periaorta involvement; and factor 3 explained 6.6%, and affected kidney and lung involvement. These results indicated that organ involvement occurs rather randomly, although there might be some tendency of coinvolvement in the three different organ categories (see Additional file 2: Table S2).

Mean serum levels of IgG and IgG4 were 2403 ± 1204 and 755 ± 642 mg/dl, respectively. Elevation of serum levels of IgG4 defined as IgG4 ≥ 135 mg/dl were seen in 318 of 333 patients (95.5%). Mean serum level of IgE was 611 ± 1198 IU/ml, and elevated serum levels defined as IgE ≥ 250 IU/ml were seen in 158 of 309 patients (51.1%). Elevation of serum levels of CRP defined as CRP ≥ 0.3 mg/dl was seen in 90 of 328 patients (27.4%). Mean and median serum levels of CRP were 0.42 and 0.10 mg/dl, respectively. In 79.9% and 90.2% of the patients, the serum level of CRP was less than 0.5 and 1.0 mg/dl, respectively (Table 3).

Patients with low C3 and C4 defined as C3 < 86 mg/dl and C4 < 17 mg/dl were seen in 34.7% and 33.7%, respectively. The frequency of low C3 in patients with kidney lesion was significantly higher than in those without (55.4% vs 27.8%, p < 0.000) (Table 4). The frequency of low C3 in patients with pancreas or lung involvement was also significantly higher than in those without (pancreas 46.8% vs 30.3%, p = 0.009; lung 47.2% vs 30.7%, p = 0.015) (Table 4). We performed logistic regression analysis to explore the impact of organ involvement on hypocomplementemia, as well as that on severe hypocomplementemia. Kidney, lung, or pancreas involvement was independently related to hypocomplementemia, with odds ratios of 2.60 (95% CI 1.47–4.59, p = 0.001), 1.84 (95% CI 1.04–3.26), and 1.83 (95% CI 1.04–3.21), respectively (Table 5). Patients with severe hypocomplementemia defined as C3 < 50 mg/dl were seen in 30 of 297 patients (10.1%). In a logistic regression analysis, kidney or lung involvement, as well as DM, but not pancreas involvement, were strongly related to severely low C3, with odds ratios of 6.09 (95% CI 2.61–14.2), 2.47 (95% CI 1.05–5.50), and 2.38 (95% CI 1.01–5.50), respectively (Table 5). Next, we analyzed whether serum levels of IgG4 or non-IgG4 IgG, which is calculated as total IgG minus IgG4, were correlated with hypocomplementemia. In an analysis of all patients, the serum level of C3 was significantly inversely correlated with both serum levels of IgG4 and non-IgG4 IgG (Pearson’s product-moment correlation coefficient –0.298, p < 0.001 and –0.352, p < 0.001, respectively) (Fig. 1a, b), which indicated that low serum C3 level tended to occur in patients with high serum levels of both IgG4 and non-IgG4 IgG. On the other hand, in patients with kidney lesion, the serum C3 level was significantly inversely correlated with only serum levels of non-IgG4 IgG, which indicated that IgG4 may not affect the deposition of C3 in kidney tissue (Fig. 1c, d).

CT was performed in 99.4% of patients and contrast-enhanced CT in 93.1%. MRI, PET, and Ga scintigraphy were also performed in 30.2%, 45.5%, and 35.1% of patients, respectively, to determine the extent of systemic involvement. According to the histopathological evaluations, the most frequently biopsied organ were the SG (49.0%), followed by the kidney (37.5%), LG (35.1%), lung (33.8%), pancreas (12.8%), and RP/periaorta (1.2%) (Fig. 2). These data indicated that the major SG were the most easily accessible organ in patients with IgG4-RD. In contrast, only a single patient underwent RP/periaorta biopsy because these deeper structures are much more difficult to access.

Corticosteroid therapy was administered to 245 of 314 patients (78.0%). The mean initial and maintenance dose of prednisolone was 30.5 and 4.1 mg/day, respectively. Corticosteroid was effective in all patients. Recurrence was noted in 67 of 314 patients (21.3%), in whom 23 of 67 (34.3%) were not receiving corticosteroid at the time of recurrence. The average dose of corticosteroid at first recurrence was 7.1 mg/dl.