Immunoglobulin G4 (IgG4)-related disease (IgG4-RD), a widely recognized systemic inflammatory disorder [1–3], affects a broad range of organs with main features of elevated serum IgG4 levels, copious infiltration of IgG4-positive cells into the affected organs, and a characteristic fibrosis called storiform fibrosis [2, 4]. IgG4-RD affects a broad range of organs such as the pancreas, lacrimal glands, salivary glands, kidneys, lungs, retroperitoneum and/or periaorta, skin, and lymph nodes [3, 5–8]. Owing to its extremely diverse clinical picture, individual clinicians encounter a clinically distinct patient population depending on his/her specialty and geographic location, making it difficult to avoid institutional bias in a single-center experience. Recently, several larger cohort studies have sought to characterize the clinical characteristics of IgG4-RD of over 100 patients [9–11]. Although these reports documented the baseline clinical features of IgG4-RD, differences were seen in the frequency of the affected organs and some laboratory data possibly due to different inclusion criteria, authors’ specialty, study design, and racial biases. This prompted us to conduct a large-scale multicenter study with well-experienced physicians of IgG4-RD including rheumatologists, gastroenterologists, pulmonologists, and nephrologists to clarify the baseline clinical and laboratory features of IgG4-RD in a large-scale cohort of 334 IgG4-RD patients.

To the best of our knowledge, this is the largest cohort study thus far to collect IgG4-RD patients and analyze their clinical features. The salient findings of our cohort study can be summarized as follows. First, elevated serum levels of IgG4 were seen in more than 95% of patients with IgG4-RD. Second, the median serum CRP level was 0.1 mg/dl, and the serum CRP level was less than 1 mg/dl in 90.2% of the patients, meaning that serum levels of CRP are within the normal range in most IgG4-RD patients in Japan. Third, low C3 was seen in 34.7% of patients, and its frequency differed depending on the organs affected. The affected organs associated with low serum levels of C3 were the kidney, lung, and pancreas. Serum levels of C3 and non-IgG4 IgG calculated as total IgG minus IgG4 showed inverse correlations in patients with kidney lesion, while serum IgG4 levels did not correlate with serum C3 levels. Fourth, the most frequently affected organs were the salivary glands, lacrimal glands, pancreas, retroperitoneum/periaorta, kidneys, and lungs.

Major differences have been noted in the prevalence of affected organs in previously published studies [9–11]. Wallace et al. [9] analyzed IgG4-RD patients all of whom were subjected to pathological analysis. In their study, the prevalence of organs that were difficult to access, such as the pancreas, was relatively low and 19.2% of patients had type I AIP. Inoue at al. [10] used a radiology database to detect IgG4-RD patients who were pathologically diagnosed with IgG4-RD and/or fulfilled the diagnostic criteria of AIP. This method picked up AIP patients without pathological analysis and showed that 61% of patients had pancreas lesions. However, the prevalence of retroperitoneal and/or periaortal lesions was very low (both 4%) in both analyses, and the issue of how to best diagnose involvement of organs which are difficult to access remained unresolved. In our study, patients with retroperitoneal and/or periaortal lesions were diagnosed as having IgG4-RD without biopsy through clinicoimaging correlations obtainable in daily medical practice. We found six organs to be the most frequently affected: salivary glands, lacrimal glands, pancreas, retroperitoneum/periaorta, kidney, and lung, with the last four organs having almost the same prevalence (around 25%). The major affected organs could be classified into the following three subgroups using Varimax rotation: group 1, lacrimal glands, salivary glands, and lymph node; group 2, retroperitoneum/periaorta; and group 3, kidney and lung (see Additional file 2). Inoue et al. [10] reported that male and female patients showed a different distribution of organ manifestations. They noted that dacryoadenitis and sialadenitis developed more commonly in females (female-to-male ratio 41:18 and 57:29 respectively), while periaortitis was significantly more common in males than females (female-to-male ratio 2:25). Thus, our results of factor analysis are consistent with their results. Although we are not yet able to clarify the factors particular to each subgroup, recognition of these subgroups provides a good opportunity to speculate on the different pathogenetic mechanisms at work in each of them.

In our study, elevation of the serum level of CRP was seen only in 27.4% of patients. The median serum level of CRP was 0.1 mg/dl, and values less than 0.5 and 1.0 mg/dl were present in about 80% and 90% of IgG4-RD patients, respectively. These data indicate that serum levels of CRP in most patients with IgG4-RD are normal or low. Elevated serum IgG4 and pathological features mimicking those of IgG4-RD have been noted in other diseases such as multicentric Castleman disease (MCD) [17] and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and in particular granulomatosis with polyangiitis (GPA) [18] and eosinophilic granulomatosis with polyangiitis (EGPA) [19, 20]. Important for the differential diagnosis is the fact that serum CRP levels are generally elevated in these diseases [21], making the serum CRP level an important serological marker in differentiating IgG4-RD in Japanese patients. However, the fact that 44–67% of patients had elevated CRP levels in cohort studies from western countries [9, 22–24] indicates that interpretation of the serum CRP level may have to take into account racial and possibly other differences in the subjects and populations studied (Table 6).

Hypocomplementemia is an important serological feature of IgG4-RD, in particular IgG4-RKD [6, 25, 26]. More than 50% of IgG4-RKD patients have hypocomplementemia, while the prevalence of hypocomplementemia is about 30% in all IgG4-RD. This has led to speculation about the reasons underlying the strong association noted between hypocomplementemia and IgG4-related tubulointerstitial nephritis (TIN). In the present study, we noted low C3 and C4 levels in 35% and 34%, respectively, of IgG4-RD patients. Furthermore, hypocomplementemia in patients with kidney lesion was significantly more frequent than in those without, supporting previous reports.

Interestingly, serum complement levels rapidly normalize after successful corticosteroid therapy in parallel with the reduction of the size of mass or enlarged lesions [26]. Moreover, a renewed decrease in serum complement levels has been observed during the clinical course of relapse in patients with IgG4-related TIN [27], highlighting hypocomplementemia as a convenient biomarker of disease activity. However, in general, IgG4 has been thought not to bind to C1q, which is related to its inability to activate the classical complement pathway. On the other hand, one report showed that IgG4 molecules derived from patients with IgG4-RD and hypocomplementemia can activate complement through C1q-binding [28], although additional studies to confirm this are necessary. Previous histopathological immunofluorescent analyses showed that not only IgG4 but also IgG1 is deposited in the tubular basement membrane of the kidney. This suggests that IgG1 also has a pathogenetic role in IgG4-RKD. Using a mouse model of AIP, Shiokawa et al. [29] showed that more destructive injury in the pancreas was induced by injecting the patient with IgG1 rather than IgG4. In the present study, we found that serum levels of non-IgG4 IgG were significantly inversely correlated with serum C3 levels in patients with kidney lesion, while IgG4 itself has only a weak correlation with serum C3 levels. Our finding seems to be compatible with Shiokawa et al.’s result. To the best of our knowledge, the present study is the first report to show that non-IgG4 IgG subclasses exert a more significant influence on hypocomplementemia, probably through activation of complement in patients with kidney lesions, than IgG4 subclass. Thus, IgG subclasses other than IgG4 should also be focused on as pathogenetic immunoglobulins.

The rate of malignancies in this study (17.1%) was higher than those in other Japanese cohort studies (6.4% [10], 10.4% [30], 13.9% [31], 12.3% [32]) but lower than that of the study reported by Asano et al. (21.5% [33]). Of these five studies, three confirmed an increased risk of malignancy in IgG4-RD using the standardized incidence ratio (SIR), while the other two did not. Since we did not calculate the SIR because of the limitation of our study design, we could not easily compare the frequency of malignancy with that in other Japanese studies. The discordant results found in Japanese studies are likely attributable to methodological issues related to the study design of individual studies. Hirano et al. [32] excluded patients in whom malignancy was diagnosed ≤ 6 months before or after the onset of IgG4-RD to avoid selection bias, whereas other studies did not. Thus, careful evaluation is needed to conclude that the rate of malignancies in IgG4-RD is significantly higher than that of controls.

The recurrence rate of our study was lower than those of western countries. Reports from Spain [24] and Italy [22] described the recurrence rate to be 38.5% and 46%, respectively. On the other hand, Inoue et al. [10] noted the recurrence rate in Japanese patients to be 24%, almost the same as in our study. A recent meta-analysis [34] also showed that the recurrence rates in Americans and Europeans were higher than those in Asians. The difference in the recurrence rates between Japanese and Caucasians may be attributable to differences in the therapeutic strategy, especially the use or nonuse of corticosteroid maintenance therapy, race, and various other patient background features. However, we did not analyze the relationship between the treatment strategy for IgG4-RD such as the duration and tapering pace of corticosteroid and immunosuppressant administration and the recurrence rate. This important issue will require further studies for clarification.

Our study has several limitations. First, biopsies of the affected organs were not performed for 18.9% of the patients because the affected organs were not easily accessible. Second, methodological differences in the measurement of laboratory parameters such as serum complement levels among different periods and different institutions is a weak, but unavoidable, aspect of our retrospective cohort study. However, the effect of the difference of the method employed among different periods and different institutions on complement levels is limited and the influence would seem to be quite small. On the other hand, the serum IgG4 level was measured using nephelometry in all institutions. Therefore, we think no methodological difference existed. Third, we used the serum levels of non-IgG4 IgG instead of those of IgG1, IgG2, or IgG3, because we do not measure serum levels of IgG1, IgG2, and IgG3 in daily clinical practice.

It remains difficult to clarify the frequency of individual organs affected by IgG4-RD due to various biases related to the criteria employed for diagnosis and differences in the distribution of the specialties of clinicians making the diagnosis of IgG4-RD. In this study, we believe that we were better able to elucidate the baseline clinical features of IgG4-RD by having specialists of IgG4-RD from a variety of fields participate in the evaluations.

Another issue highlighted by this study is the finding of differences in various clinical parameters between our population and western ones. This raises the important question of whether the hitherto proposed international consensus criteria are equally applicable to all populations, and whether the more or less universally recognized clinical spectrum of IgG4-RD is the same in all of them. Further exploration of the reasons underlying any differences may also provide intriguing clues to the underlying nature of IgG4-RD and be of use in devising more accurate diagnostic criteria. To best characterize IgG4-RD and assess the universality of various criteria for diagnosis, future studies, including international comparative ones, will be needed with larger numbers of IgG4-RD patients diagnosed according to various criteria.

In Japanese individuals, various clinical parameters in IgG4-RD including serum IgG4 and CRP levels appear to differ in some interesting ways from those hitherto reported in western populations. Additional studies, especially international comparative ones, will be needed to elucidate the extent and significance of these differences between populations. Attention will also have to be paid to whether such differences require consideration when devising diagnostic criteria that are meant to be applied internationally.