Characteristics of IgG4-related Disease Complicated With Allergic Rhinitis or Chronic Rhinosinusitis: A Large Cohort Study in China

Objective Patients of IgG4-related disease (IgG4-RD) often present nasal symptoms that could be diagnosed as allergic rhinitis (AR) or chronic rhinosinusitis (CRS). In this study, demographic, clinical and laboratory characteristics of IgG4-RD patients complicated with AR/CRS were investigated. Methods We retrospectively analyzed 756 IgG4-RD patients who were recruited in ve medical centers from 2009 to 2021. We divided 756 IgG4-RD patients into 2 groups: the case group included IgG4-RD patients complicated with AR/CRS, and the control group included IgG4-RD patients without AR/CRS. Results 411 were as AR/CRS among the 756 Patients in the case group showed longer disease duration and interval between symptom onset and diagnosis. Multiple organs involvement( ≥ 3) and allergic disease were more common in the case group. The most frequently involved organs in the case group were lung, salivary gland and lacrimal gland. Patients in the case group had a higher level of serum IgG4, IgE and ESR. High IgE level and complication of allergic disease were risk factors for patients in the case group. In the case group, most patients had nasal manifestations before the diagnosis of IgG4-RD. The median time interval from nasal symptoms appearance to IgG4-RD diagnosis was -120 and -90 months for patients complicated with AR and CRS, respectively. This study revealed the clinical characteristics of IgG4-RD patients complicated with AR/CRS. Our ndings may be conducive to determine a new clinical entity of IgG4-RD and suggest underlying association of pathogenesis of IgG4-RD and AR/CRS.


Introduction
IgG4-related disease (IgG4-RD) is an immune-mediated systemic disorder that is typi ed by sclerosing lesions in multiple organs (1,2). The characteristic pathological features of IgG4-RD are lymphocyte and plasmacyte in ltration, storiform brosis, and obliterative phlebitis (1,(3)(4)(5). IgG4-RD was recognized as isolated entities incipiently and was rst described in pancreas in a cohort of Japanese patients in 2001 (6). Subsequent studies found that it was a systemic condition and could affect nearly any anatomic site (7,8).
Sinusitis was rst recognized as a complication of extra-pancreatic lesions of autoimmune pancreatitis in 2011 (9). However, studies about the nasal complications of IgG4-RD was scarce and mainly focused on chronic rhinosinusitis (CRS) (9)(10)(11)(12)(13). In clinical practice, we found that many patients diagnosed as IgG4-RD had nasal symptoms, such as nasal obstruction and rhinorrhea, that could be diagnosed as allergic rhinitis (AR) (14) or CRS (15) accordingly, and were sensitive to glucocorticoid therapy. In this study, we retrospectively analyzed the demographic, clinical and laboratory disparities in the 756 IgG4-RD patients. To our knowledge, this is the largest cohort study comparing the two phenotypes of IgG4-RD with and without CRS/AS. Con rming the characteristics of these two groups could contribute to identify risk factors and comprehend underlying differences in pathogenesis.

Patients
We retrospectively analyzed 756 IgG4-RD patients ful lled 2020 revised comprehensive diagnostic criteria for IgG4-RD (16), and 479 (63.4%), 96 (12.7%) and 181 (23.9%) cases were diagnosed as de nite, probable and possible IgG4-RD in all enrolled patients, respectively. All the patients were recruited in 5 medical centers from 2009 to 2021. AR was diagnosed according to the clinical manifestations, medical history, examinations and investigations (14). CRS was diagnosed on the basis of clinical manifestations, endoscopic ndings and radiographic imaging results (15). The clinical diagnosis of AR or CRS was made by otolaryngologists. Patients diagnosed as IgG4-RD was categorized into the case group if they met the diagnostic criteria of AR (14) and/or CRS (15). The control group included IgG4-RD without AR or CRS (Table 1).
Demographic features like age and gender, and clinical characteristics including clinical manifestation, disease duration and organ involvement were recorded. The time interval from disease onset to diagnosis was de ned as the time interval from extra-nasal symptoms (such as enlargement of salivary gland) onset to the diagnosis of IgG4-RD.
Laboratory studies, image features and histological examinations Laboratory tests were recorded comprising serum IgG4 level, serum IgG4/IgG ratio, serum IgE level, complement, eosinophilia, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and autoantibodies (including RF and ANAs).
All patients underwent radiological examinations comprising of ultrasonography, Computed Tomography (CT), or Magnetic resonance imaging (MRI); and some patients underwent 18 F-uorodeoxyglucose PET/CT. Tissue biopsy samples were xed in formalin and embedded in para n wax, then stained with haematoxylin and eosin (H&E) and immunocytochemistry (IHC). IHC was performed using antibodies against CD3, CD20, IgG, IgG4, CD138 and CD38.

Statistical analysis
All statistical analyses were performed by GraphPad Prism 8.0 using descriptive methods, with standard summary statistics including mean (S.D.), median, interquartile range (IQR), and proportions. Student's t test was used for differences for continuous, normally distributed data; Mann-Whitney test was used for differences for continuous, non-normally distributed data. Categorical variables were processed by X 2 or Fisher's exact tests. Logistic regression analysis with enter method was performed to compare the patients in the case group and control group. Factors with P<0.05 and clinical signi cance in the univariate analysis were included in the multivariate analysis. P-value < 0.05 was deemed as statistically signi cant.

Demographic characteristics
Demographic characteristics of a total of 756 patients diagnosed as IgG4-RD were listed in Table 1. A total of 408 patients (53.97%) were categorized into the case group for complication of AR or CRS. The rest of 348 patients (46.03%) without AR or CRS were categorized into the control group.
Patients in the case group had longer time interval from onset to diagnosis (24 months vs 12 months, p=0.0089), longer disease duration (24 months vs 12 months, p=0.0096) and longer follow-up period (51.5 months vs 41 months, p=0.0107) compared with patients in the control group (Table 2).

Clinical nasal manifestations of patients in the case group
The main clinical nasal manifestations of patients in Group A were sneezing (29.04%), nasal obstruction (27.47%), nasal itching (20.57%) and rhinorrhea (20.09%) as shown in Figure 1. The main clinical nasal manifestations of patients in Group B were nasal obstruction (35.32%), decreased sense of smell (24.26%), mucopurulent drainage (20.85%) and facial pain-pressure-fullness (11.49%), which were consistent with previous study (10).

Risk factors for the patients in the case group
In univariate analysis, disease duration, complication of allergic disease, number of involved organs≥3, lymph node involvement, salivary gland involvement, thyroid gland involvement, lung involvement, biliary system involvement, gallbladder involvement, salivary gland involvement, lacrimal gland involvement, parotid gland involvement, higher level of serum IgG4, higher level of serum IgE, higher level of ESR, eosinophilia and hypocomplementemia were associated with higher rate of IgG4-RD complicated with AR or CRS (Table 3).
In multivariate analysis, only IgE and complication of allergic disease were associated with complication of AR or CRS ( Figure 2).

Time interval between complication of AR/CRS and disease diagnosis in the case group
The time interval was calculated between the time of complication of AR or CRS and the time of IgG4-RD diagnosis. Positive or negative results meant the complication of AR or CRS occurred after or before IgG4-RD diagnosis, respectively. The time relationship of complication of AR or CRS and IgG4-RD diagnosis was divided into 3 groups including: complication of AR or CRS occurred before IgG4-RD diagnosis, complication of AR or CRS occurred after IgG4-RD diagnosis and complication of AR or CRS occurred simultaneously with IgG4-RD diagnosis (de ned as the time interval between complication of AR or CRS and IgG4-RD diagnosis was no more than 12 months). Figure 3, the percentage of each group in Group A was 84.83% (complication of AR or CRS occurred before IgG4-RD diagnosis), 12.32% (complication of AR or CRS occurred simultaneously with IgG4-RD diagnosis) and 2.84% (complication of AR or CRS occurred after IgG4-RD diagnosis), respectively. The percentage of each group in Group B was 78.41% (complication of AR or CRS occurred before IgG4-RD diagnosis), 17.05% (complication of AR or CRS occurred simultaneously with IgG4-RD diagnosis) and 4.55% (complication of AR or CRS occurred after IgG4-RD diagnosis), respectively. The median time interval of each group in Group A was 144 months (IQR: 96-306; complication of AR or CRS occurred before IgG4-RD diagnosis), 9 months (IQR: 2-12; complication of AR or CRS occurred simultaneously with IgG4-RD diagnosis) and 54 months (IQR: 39-69; complication of AR or CRS occurred after disease IgG4-RD diagnosis), respectively. The median time interval of each group in Group B was 120 months (IQR: 60-360; complication of AR or CRS occurred before IgG4-RD diagnosis), 12 months (IQR: 6-12; complication of AR or CRS occurred simultaneously with IgG4-RD diagnosis) and 35.5 months (IQR: 32.25-57; complication of AR or CRS occurred after IgG4-RD diagnosis), respectively.

Discussion
In the present study, we described the clinical manifestations of IgG4-RD patients complicated with AR or CRS in a large cohort. Moreover, we compared the demographic, clinical and laboratory disparities of 408 IgG4-RD patients complicated with AR or CRS and 348 IgG4-RD patients without AR or CRS. The chronological relationship of complication of AR or CRS and IgG4-RD disease diagnosis was analyzed. To our current knowledge, this is the rst and largest cohort study focusing on the complication of both AR and CRS of IgG4-RD, and exploring the differences of IgG4-RD with AR or CRS and IgG4-RD without AR or CRS phenotypes.
IgG4-RD is an immune-mediated systemic disorder that is typi ed by sclerosing lesions in multiple organs. Organs in the head and neck region are commonly involved in IgG4-RD, such as salivary gland, lacrimal gland and parotid gland (17,18). However, few studies have discussed nasal involvement in IgG4-RD, which is mainly because there is no classi cation diagnostic criterion for IgG4-related rhinitis or IgG4-related rhinosinusitis. Clinical symptoms of exocrine gland involvement are common in IgG4-RD patients (8) and secretory gland is a major part of the nasal membrane, which indicates that the nasal membrane may be theoretically involved in IgG4-RD (13). Moreover, patients with IgG4-RD do have a higher proportion of being complicated with AR or CRS based on previous study (9) and our clinical practice experiences. Therefore, this study retrospectively analyzed the demographic, clinical and laboratory characteristics of IgG4-RD patients complicated with AR or CRS, which could be conducive to determine a new clinical entity of IgG4-RD and better understanding of the pathogenesis of IgG4-RD.
The percentage of complication of AR or CRS in the present study was 54.0%, which was higher than previous studies (43.5%(11), 37.0%(10) and 32.3% (9)). The different inclusion criteria may explain for the discrepancy. IgG4-RD patients complicated with AR or CRS seemed to have longer time interval from disease onset to diagnosis. Multiple organs involvement (≥3 organs) was more common in patients complicated with AR or CRS than patients without AR or CRS, and the distribution of involved organs were also different, suggesting different underlying pathogenesis.
IgG4-RD patients complicated with AR or CRS had higher serum IgG4 level and serum IgE level. Complication of allergic disease and eosinophilia were also more common in these patients because many IgG4-RD patients with AR or CRS had an allergic constitution. IgG4-RD patients complicated with AR or CRS presented more elevated ESR level and hypocomplementemia that indicated high disease activity, which was correlated with more multiple organs involvement.
Higher serum IgE level and complication of allergic disease were risk factors for complication of AR or CRS in IgG4-RD patients. Both factors suggest the existence of allergic disease, which is a known risk factor for AR (19), and AR was a common concomitant disease of IgG4-RD patients with CRS(9). We found that most patients in the case group had nasal symptom onset years earlier before IgG4-RD diagnosis, which may be due to the ignorance of underlying relationship of IgG4-RD and AR/CRS. The relationship of AR/CRS and IgG4-RD is unclear based on previous studies and there is no uni ed de nition of IgG4-related nasal lesions. However, many patients diagnosed as IgG4-RD were complicated with AR/CRS in the present study, which was consistent with previous studies(9-13). Therefore, patients with AR/CRS should be followed-up to observe if they have complicated with IgG4-RD in the future because most patients had AR/CRS months before the diagnosis of IgG4-RD in our study.
In our opinion, IgG4-RD patients with AR/CRS may be considered as a new clinical entity, which is supported by several ndings: 1) 54.0% patients (408) in our study had AR or CRS (34.0% for AR, 15.3% for CRS and 4.7% for both), which was higher than the morbidity of general population (20,21); 2) IgG4-RD patients with AR/CRS showed different demographic, clinical and laboratory characteristics than patients without AR/CRS; 3) IgG4-RD patients with AR/CRS in our study were sensitive to glucocorticoid therapy and their nasal symptoms alleviated or disappeared after treatment, while CRS alone is insensitive to glucocorticoid therapy. Although AR alone is sensitive to glucocorticoid therapy, IgG4-RD patients complicated with AR had outstanding allergic symptoms and showed different laboratory characteristics than patients with IgG4-RD alone. Therefore, we consider AR may be related to IgG4-RD. To further explore the relationship of AR/CRS with IgG4-RD, pathological ndings of nasal lesions are necessary in future study.
There are several limitations of this study. First, although most cases underwent general examinations, its retrospective nature made some involved organs neglected. Second, due to the long time-interval of complication of AR or CRS and IgG4-RD diagnosis, the nasal manifestations of IgG4-RD patients with AR/CRS may be inaccurate because of recall bias.

Conclusion
In the present study, we compared the demographic, clinical and laboratory differences between IgG4-RD patients with AR/CRS and IgG4-RD patients without AR/CRS. IgG4-RD patients with AR/CRS had longer time interval from onset to diagnosis. Complication of allergic disease and multiple organs involvement were more common in these patients. IgG4-RD patients with AR/CRS showed higher levels of serum IgG4 and IgE, and higher percentages of ESR elevation, eosinophilia and hypocomplementemia. Physicians should pay attention to the medical history of AR/CRS because AR and CRS occurred several years earlier than IgG4-RD diagnosis in the present study. These ndings may be conducive to determine a new clinical entity of IgG4-RD and suggest underlying association of pathogenesis of IgG4-RD and AR/CRS. Consent for publication: All authors of this study have their consent for publication.
Availability of supporting data: The datasets generated during and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Competing interests: The authors have declared no con icts of interest.
Funding: No speci c funding was received from any bodies in the public, commercial or not-for-pro t sectors to carry out the work described in this manuscript.
Authors' contributions: & Yanying Liu and Qianyu Shi contributed equally to this study.