Clinical features and relapse risks factors of immunoglobulin G4–related disease: a single-center retrospective study

Abstract

Objective: The aim of this study was to observe the demographic and clinical characteristics of immunoglobulin (Ig) G4–related disease (IgG4-RD). We aimed to compare different treatment methods and to identify the risk factors for non-response and relapse after treatment.

Methods: We performed a retrospective study of 201 IgG4-RD patients initially diagnosed and treated at the First Affiliated Hospital of China Medical University from January 2016 to December 2020. Patients’ sex, age, clinical manifestations, baseline biochemical values, the number of organs involved, and the type of organ involvement were recorded. All patients received glucocorticoid (GC) monotherapy or GC + immunosuppressant combination therapy. The serum IgG4 concentration as well as the details of clinical response, relapse, and side effects were recorded at 1, 3, 6, and 12 months after treatment.

Results: The incidence of IgG4-RD was primarily centered in the age group of 50–70 years old, and the proportion of affected male patients increased with age. The most common clinical symptom was swollen glands or eyes (42.79%). The rates of single- and double-organ involvement were 34.83% and 46.27%, respectively. The pancreas (45.77%) was the most frequently involved organ in cases of single-organ involvement, and the pancreas and biliary tract (45.12%) was the most common organ combination in cases of double-organ involvement. Correlation analysis showed that the number of organs involved was positively related to the serum IgG4 concentration (r = 0.161). The effective rate of GC monotherapy was 91.82%, the recurrence rate was 31.46%, and the incidence of adverse reactions was 36.77%. Meanwhile, the effective rate of GC + immunosuppressant combination therapy was 88.52%, the recurrence rate was 19.61%, and the adverse reaction rate was 41.00%. There were no statistically significant differences in response, recurrence, and adverse reactions. The overall response rate within 12 months was 90.64%. Age (<50 years old) and aorta involvement were significantly associated with non-response. The overall recurrence rate within 12 months was 26.90%. Age (<50 years old), low serum C4 concentration, a high number of involved organs, and lymph node involvement were significantly associated with recurrence.

Conclusion: The clinical features vary among different age groups and according to gender. The number of organs involved in IgG4-RD is related to the serum IgG4 concentration. Age (<50 years old), low serum C4 concentration, a high number of involved organs, and lymph node involvement are risk factors for recurrence.

Introduction

Immunoglobulin (Ig) G4–related disease (IgG4-RD) is an immune-mediated chronic fibro-inflammatory condition. Pancreas, bile duct, salivary glands, and lacrimal glands are common affected organs. More rarely affected organs includes lung, kidneys, gastrointestinal tract, thyroid, and retroperitoneum^[1–3]. It is clinically characterized by diffuse or focal enlargement and sclerosis of affected organs or tissues, leading to obstruction or compression symptoms and even organ dysfunction. Most patients exhibit an elevation of the serum IgG4 concentration. The pathological feature is the infiltration of a large number of lymphocytes, especially IgG4-positive plasma cells, into the involved tissues^[4]. Due to the wide variety of organs that may be involved, patients may present with different clinical manifestations, including swelling, fatigue, jaundice, and abdominal pain, and they can be easily misdiagnosed clinically as a result. Glucocorticoids (GCs) are the first-line therapy for the treatment of IgG4-RD^[5]. Hormone therapy has a rapid onset, but it is easy for the disease to relapse during the reduction or maintenance phase, and the recurrence rate can be as high as 38.5%–50% [6]. Unfortunately, long-term use of GCs can cause serious adverse reactions. Therefore, the use of immunosuppressants is recommended to help maintain the curative effect and reduce the recurrence rate^[7]. However, which of the two available treatment options are more effective still needs to be confirmed by clinical studies. In addition, since patients with IgG4-RD are prone to recurrence, and repeated disease recurrence can easily cause irreversible damage, it is necessary to explore the risk factors of recurrence, which will help health care practitioners to formulate long-term treatment plans and improve the patient prognosis^[8]. However, few risk factors for the disease have been found so far, and more research is needed to explore and confirm them.

Because IgG4-RD is relatively rare, and there are few clinical studies in China on the condition, in this study, we enrolled IgG4-RD patients living in Liaoning province to comprehensively describe the demographic and clinical characteristics of IgG4-RD. By exploring the risk factors of response and recurrence, we hope to further improve the understanding of IgG4-RD and better formulate diagnostic and management strategies.

Methods

Study subjects

This was a retrospective study of IgG4-RD patients who were diagnosed at the First Affiliated Hospital of China Medical University between January 2016 and December 2020. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the ethics committee of the First Hospital of China Medical University ([2022]20). The ethics committee of the First Hospital of China Medical University waived the requirement for informed consent because of the retrospective nature of the study. Eligible patients included those aged >18 years old who were newly diagnosed and treated. Patients with other liver diseases were excluded. Finally, 215 patients were included in this study. 

Diagnosis of IgG4-RD

The diagnostic criteria for IgG4-RD were as follows^[7]: 1) a swelling or mass in ≥1 more tissues and organs, 2) IgG4 concentration ≥ 1350 mg/L, and 3) a ratio of IgG4/IgG plasma cells in the pathologically affected tissue of >40% or a ratio of IgG4-positive plasma cells of >10 cells/per high-power field. These 3 criteria had to be med at the same time to confirm the diagnosis. However, according to the 2015 international consensus^[5], an IgG4 concentration of 3%–30% in patients is normal. So, the diagnosis of IgG4-RD depends on a large degree of IgG4 infiltration in pathological tissues. The affected organs were identified by clinical manifestations and imaging examination.  In our study, all 215 patients underwent pathological biopsy and met pathological conditions. However, only serum IgG4 concentration of 13 cases was in the normal range. So 202 cases (93.95%) met three diagnostic criteria at the same time, and only 13 cases met two diagnostic criteria. Relapse was defined when any emerging or worsening of existing organ function disorders, swelling or mass lesions was detected on physical or radiological examination, with or without the elevation of serum IgG4 concentration. Non-reponse was defined when there was no improvement or resolution of clinical symptoms, imaging findings, and serum IgG4 level.

Laboratory examination 

We recorded the basic information of patients, including their age, gender, clinical manifestations, and affected organs. Data on liver function (alanine transaminase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], gamma-glutamyl transferase [GGT], total bilirubin [TBIL], and albumin [ALB]), complement protein levels, and IgG4 concentration at initial diagnosis were collected and assessed using a model 7600 autoanalyzer (Hitachi, Tokyo, Japan). All physical blood tests included in this study are part of the routine examination and were also assessed using the model 7600 autoanalyzer (Hitachi, Tokyo, Japan).

Treatment and follow-up

All enrolled patients received GC monotherapy or GC + immunosuppressant combination therapy (composed of cyclophosphamide, triptolide, mycophenolate mofetil, leflunomide, methotrexate, tacrolimus, and azathioprine). The initial dose of oral glucocorticoid (prednisone) was 30–40 mg/d; then, after 1 month, it was reduced by 5 mg every 1–2 weeks according to clinical and serological improvements. Finally, a dose of 2.5–5.0 mg/d was used for maintenance treatment^[5]. All patients were followed up with for 1 year in the First Affiliated Hospital of China Medical University, and the IgG and IgG4 concentrations at 1, 3, 6, and 12 months after treatment were recorded. Patients who were lost to follow-up and discontinued treatment were excluded. Finally, 171 patients (85.07%) completed the 1-year follow-up and were divided into response and non-response groups as well as recurrence and non-recurrence groups according to the situation within 1 year.

Statistical analysis 

We described the characteristics of patients according to their sex and gender. SPSS version 23 (IBM Corporation, Armonk, NY, USA) was used for statistical analysis. All categorical data are expressed as n (%) and were analyzed using the chi-squared test, and all continuous variables conforming to the normal distribution (according to the Kolmogorov–Smirnov test) are expressed as mean ± standard deviation values and were analyzed using Student’s t-test. Non-normally distributed continuous variables are presented as median (interquartile range values) and were analyzed using the Mann–Whitney U test. Spearman’s correlation analysis was used to analyze the relation between the number of affected organs and the IgG4 concentration. P < 0.05 were considered to be statistically significant.

Results

Characteristics of the study subjects

The basic features of study participants are shown in Table 1. The average age of the study population was 57.55 ± 12.77 years, and there were 115 men and 86 women, respectively. The most frequent symptom at presentation was swelling of the glands or eyes (n = 86, 42.79%), followed by dry mouth and eyes (n = 45, 22.39%), jaundice (n = 36, 17.91%), and abdominal pain or fatigue (n = 30, 14.93%). Baseline biochemical indicators were recorded in all 201 patients, and the average ALT, AST, ALP, GGT, TBIL, ALB, C3, and C4 values were all abnormal. The mean IgG4 concentration was 11.28 ± 14.13 g/L. More patients were in stage < 2 ULN (37.31%). The number of patients decreased with advancement of the IgG4 stage.

In this study, we prospectively included a total of 201 IgG4-RD patients divided into 2 groups according to gender. The average age of male patients was 58.64 ± 13.15 years, and that of female patients was 56.08 ± 12.17 years. There was no statistically significant difference between the 2 sexes (P = 0.160). At disease onset, the occurrence of swelling (P = 0.008) or dryness (P = 0.049) was more frequent in the female group. The biochemical test results at baseline were not statistically significantly different between the 2 groups. We also divided patients into 4 groups according to age. Patients 50–70 years of age, regardless of gender, had a greater risk of developing IgG4-RD. However, the proportion of male patients increased with advancing age (P = 0.042). The clinical manifestations were not statistically different across age groups. We further compared the laboratory test values at baseline among the 4 age groups. TBIL (P = 0.018) and ALB (P = 0.030) were statistically different across age groups, while there was no statistically significant difference in IgG4 concentration in different age groups.

Organ involvement

In terms of the organs involved in IgG4-RD, table 1 was used to elucidate the difference across age and gender groups, showing different frequencies of organ involvement. There was no statistically significant difference in the number of organs between groups. Female patients were more likely to present with thyroid involvement (P = 0.039), while the rates of other organs being involved were comparable between male and female patients. The pancreas (P for trend = 0.043) and salivary glands (P for trend = 0.004) were significantly different among age groups, showing upward trends with advancing age. However, the proportions of other superficial organ involvements were comparable between different age groups. 

In terms of the types of organs involved, the pancreas was the most common organ, accounting for 45.77% of cases, while cases involving the salivary glands (83 cases, 41.29%), lymph nodes (80 cases, 39.80%), biliary tract (57 cases, 28.36%), and lacrimal glands (38 cases, 18.91%) followed the pancreas in order of descending frequency. The retroperitoneum, kidneys, aorta, lung, gastrointestinal area, and thyroid were involved in a few IgG4-RD patients. It is worth noting that the prostate was involved in only 1 patient.

The mean number of organs involved was 1.90 ± 0.90. Most patients had single- or double-organ involvement. Only 1 organ was involved in 70 patients (34.83%). Among them, the pancreas was most commonly involved in 31 cases (44.29%), followed by the lymph nodes (20.25%), salivary glands (17.72%), and biliary tract (5.60%). Double-organ involvement was present in 93 patients (46.27%). Most IgG4-RD patients had both pancreatic and biliary tract involvement (36.46%), while 21.88% of patients had both lymph node and salivary gland involvement and 16.67% of patients had both salivary gland and lacrimal gland involvement. Three organs were involved in 26 patients (12.94%), with the combination of the salivary glands, lacrimal glands, and lymph nodes being most common (46.43%). At least 4 organs were involved in 12 patients (5.97%), of which the biliary tract, pancreas, salivary glands, and lymph nodes together accounted for 41.67% of cases. Fig. 1 shows the correlation analysis of the number of involved organs. The results revealed that there was a positive correlation between the number of involved organs and the serum IgG4 concentration (r = 0.161, P = 0.018). However, age, IgG4 concentration, liver function (ALT, AST, ALP, GGT, TBIL, and ALB), levels of complement proteins (C3, C4), and C-reactive protein level did not significantly differ between groups (P > 0.05).

Treatment

All 171 participants were followed up with regularly for a mean period of 29.5 months. During a 12-month period, 110 of the 171 patients received GC monotherapy and 61 received GC + immunosuppressant combination therapy. 32 patients received cyclophosphamide, 20 patients received triptolide, 7 patients received mycophenolate mofetil, 1 patient received methotrexate, 1 patient received tacrolimus.

The effective rate of GC monotherapy was 91.82%, the recurrence rate was 31.46%, and the incidence rate of adverse reactions was 36.77%. Separately, the effective rate of GC + immunosuppressant combination therapy was 88.52%, the recurrence rate was 19.61%, and the incidence rate of adverse reactions was 41.00%. There were no statistically significant differences in the rates of response, recurrence, or adverse reactions (all P > 0.05).

The overall serum IgG4 concentration showed a significant decrease in the first 3 months, with 42.45% of patients showing reductions of >50% of the baseline level and 29.25% of patients achieving levels within the normal range after 1 month of treatment. Meanwhile, 54.44% of patients had normalized IgG4 concentrations after 3 months of treatment. 

During the course of treatment, patients were divided into a response group (n = 155) and a non-response group (n = 16) according to the results of treatment response. The overall response rate was 90.64%. Table 2 shows the univariate and multivariate analysis in response subgroups; there was a statistically significant difference in the C-reactive protein and ALB level by univariate analysis, but multivariate analysis were not statistically significant (P > 0.05). In addition, Fig. 2A shows the IgG4 concentration at baseline and 1, 3, 6, and 12 months of follow-up in the response and non-response groups; there was no significant difference between the groups at baseline or 1 month of follow-up, but the IgG4 concentration was higher in the non-response group at 3, 6, and 12 months after therapy (all P < 0.05). In addition to biochemical indexes, compared to patients aged >50 years, patients aged <50 years had lower treatment response rates (P = 0.016), while there was no significant difference between male and female patients (P = 0.675) (Fig. 2B). In terms of the number of affected organs, the overall trend in the non-response group was not statistically significant (P = 0.846) (Fig. 2C). Considering the type of affected organ, only patients with aortic involvement had a poorer response rate than patients without aortic involvement (P = 0.005); the remaining organs were not found to trigger a statistically significant difference in response (Fig. 2D), and no difference in the non-response rate existed between the 2 treatment methods (P = 0.120) (Fig. 2E). 

Separately, all 171 patients were divided into a non-recurrence group (n = 125) and a recurrence group (n = 46) according to the follow-up results at 12 months. The total recurrence rate at 12 months was 26.90%. The comparison of biochemical indicators (Table 2) showed that there was a statistically significant difference in the C4 level (P = 0.042), and patients with low C4 levels were relatively more likely to relapse. Fig. 3A shows the IgG4 concentration at baseline and 1, 3, 6, and 12 months of follow-up in the recurrence and non-recurrence groups. The IgG4 concentration decreased significantly in both groups in the first 3 months, then gradually increased thereafter in the recurrence group. Although there was no significant difference between the 2 groups at baseline or 1, 3, and 6 months of follow-up, the IgG4 concentration was higher in the recurrence group at 12 months after therapy (P < 0.001). The Kaplan–Meier curve shows that the cumulative relapse rates of young patients (<50) were higher than those of older patients (≥50) (P = 0.016) (Fig.3B). In terms of the affected organ, patients with larger numbers of involved organs or lymph node involvement were more likely to relapse (all P < 0.05) (Fig. 3C–D). There was no significant difference in gender or treatment method between the 2 groups (all P > 0.05) (Fig. 3B,E).

Discussion

To our knowledge, this is the retrospective study to reveal the clinical features of IgG4-RD. In this paper, we focused on documenting the demographic features, nature of organ involvement, laboratory test values, risk factors of relapse, and response rate.

IgG4-RD is more common in men aged 50–70 years, and the male-to-female ratio is 1.6–4:1^[9]. Two epidemiological studies reported that the male-to-female ratios in the United States and Japan were 2.3:1 and 4:1, respectively^[10,11]. Meanwhile, the ratio in China during 2011–2013 was 2.3:1^[12]. In our study, the male-to-female ratio was approximately 1.34:1. The demographic characteristics of the 4 age groups were different, and male patients were predominant in the elderly patient group, consistent with other reports^[12,13].

IgG4-RD can affect multiple organs. In our study, the average number of organs involved was 1.88, and double-organ involvement was most common, accounting for 45.12% of cases, while the proportion of cases with single-organ involvement was 36.28%. There are regional differences in the types of organs involved, and the results of this study are consistent with those conducted in Italy and other countries^[14]. The pancreas is the most commonly involved organ, followed by the liver, gallbladder, salivary glands, and lymph nodes^[15]. Orbital involvement is predominant in Thailand ^[16], lymph node involvement is predominant in France^[17], and submandibular gland involvement is predominant in the United States^[18]. There are also gender and age differences in the types of organs involved. Studies have shown that female patients are more likely to have superficial organs like the lacrimal glands and salivary glands involved, while visceral organs such as the pancreas and retroperitoneum are more predominantly involved in male patients^[19]. There are also some studies reporting that common organs (e.g., salivary glands) are more often involved in women^[20], while rarer organ involvement (e.g., fibroseptitis, lung, and kidneys) mainly occurs in men^[21,22]. In a 10-year study, the rate of IgG4-related ocular disease was similar between the sexes^[23]. In terms of the age distribution of IgG4-RD, Lu et al. found that superficial organs like the lacrimal glands and sinuses are less involved with increasing age, while the involvement of the mandibular glands, parotid glands, and skin did not differ across age groups. In terms of internal organs, the proportions of cases involving the pancreas, biliary tract, retroperitoneum, prostate, and lungs increased with age, indicating that these internal organs in elderly patients are more susceptible to IgG4-RD damage^[24]. In our study, thyroid involvement was more common in female patients. Rates of pancreas and salivary gland involvement varied in different age groups but showed upward trends with advancing age, while no gender or age differences were found for other organs. In addition, the involvement of different organs is linked, as shown by simultaneous or sequential involvement of the lacrimal glands, salivary glands, and lymph nodes. Kidney involvement is rare but closely related to the involvement of more commonly infected organs like the salivary glands, lymph nodes, and pancreas^[22]. Renal biopsy may be a good diagnostic tool for diagnosing renal involvement in patients with IgG4-related lymphadenopathy, IgG4-related sialadenitis, or autoimmune pancreatitis. In addition, Zhao et al. found that the orbit and salivary glands were the most severely affected tissues due to direct exposure to the external environment and lack of barrier protection^[23], which may trigger symptoms in the early stage. Meanwhile, patients with internal organ involvement may have atypical clinical manifestations. Therefore, the discovery of biomarkers is very important for the early diagnosis of patients with internal organ tissue involvement. According to some studies, serum T-cell immunoglobulin and mucin-containing molecule-3 levels are significantly elevated in IgG4-RD patients with internal organ tissue involvement. These potentially useful biomarkers are gradually being explored^[25].

The history of IgG4-RD discovery began when Hamano first described the association between elevated serum IgG4 concentrations and autoimmune pancreatitis^[26]. It is hypothesized that the pathogenesis of IgG4-RD is an increase in the activity of T-regulatory cells and overexpression of interleukin (IL)-10, which promotes the production of transforming growth factor β and the upregulation of Th2 responses, of which the main roles are IL-4, IL-5, and IL-13. The activity of these cytokines promotes the activation of B-cells and plasma cells for IgG4 production (IL-10, IL-4, and IL-5)^[27]. Therefore, the serum IgG4 concentration can reflect disease activity, and it is positively correlated with the number of organs involved and the severity of the disease. Previous studies have suggested that an abnormal increase in IgG4 may be related to the degree of inflammatory activity, and a large amount of IgG4 will also damage the tissue structure. In our process of exploring factors related to the number of organs involved in IgG4-RD, we came to the same conclusion that the higher the concentration of IgG4, the greater the number of organs involved. At present, elevated serum IgG4 concentrations are often used as a diagnostic criterion for IgG4-RD. However, in addition to IgG4-RD, other autoimmune diseases or inflammatory diseases also involve elevated serum IgG4 concentrations. Since the pathogenesis of IgG4-RD is not yet clear, there is still no international unified serum IgG4 standard reference for the condition. Therefore, the best cutoff value for diagnosing IgG4-RD still requires further investigation. There are also significant differences in the IgG4-positive rate between countries. The IgG4-positive rate reported in France was 48%^[28], while those in the United States and Japan were 51.4% and 95.5%, respectively^[29,30]. The baseline IgG4 concentration of all patients was abnormal in our study, which may be related to ethnic differences. The IgG4-positive rate in the Asian population is higher than that in the European or American population.

According to the international consensus, GC is the first-line treatment for IgG4-RD, which has obvious advantages in improving clinical symptoms and reducing blood biochemical indicators, with an effective rate of >90%^[31]. At present, there is no specific time for treatment cessation, and a long-term plan needs to be formulated according to the patient's condition. At present, the recurrence rate and side effects associated with GC therapy are also not optimistic. Reasonable control of adverse reactions and recurrence is an important direction for future research. In recent years, the use of immunosuppressants combined with GC has attracted attention. Common immunosuppressants include mycophenolate mofetil, azathioprine, cyclophosphamide, and leflunomide^[15,32]. Many studies have compared the efficacy of immunosuppressants combined with hormones and hormone monotherapy. At present, however, different studies have drawn different conclusions. Some investigators believe that hormones combined with immunosuppressants can control the disease more effectively and reduce the recurrence of the disease, but there are also studies showing that there is no difference in the recurrence rate of the 2 treatments^[33–35]. Therefore, large-scale prospective clinical studies are needed to further confirm the role of immunosuppressants in reducing relapse. In addition, whether immunosuppressive agents can replace hormones to maintain disease stability after treatment remission still needs clinical evidence.

Previous studies have shown that most patients are sensitive to hormone therapy and experience short-term improvement. However, it is easy for the disease to recur during the maintenance phase, with a recurrence rate of >30%. Therefore, it is worthwhile to study disease characteristics and risk factors for recurrence. In this study, among the 171 patients enrolled with IgG4-RD, most (90.64%) were sensitive to treatment. 26.90% of patients experienced recurrence during 12 months of follow-up. Consistent with previous findings, recurrence appeared to be more common in the pancreas, bile duct, lacrimal glands, and salivary glands. We explored risk factors for relapse by comparing clinical characteristics and baseline values in the recurrence and non-recurrence groups. Several parameters have been reported as risk factors for IgG4-RD recurrence, including male sex, young age, high baseline serum IgG4 concentration, multiorgan involvement, high baseline IgG4-RDRI score, and increased eosinophilia^[5]. Due to the diversity of treatment options and definitions of recurrence, it is reasonable to have different risk factors in different studies. We found that young age (<50 years) and multiorgan involvement were associated with disease recurrence. Additionally, we found that lymph node involvement was associated with disease recurrence, which was also suggested in another study^[36]. Interestingly, patients with low C4 concentrations appeared to be more prone to relapse in our study. In another study describing hypocomplementemic IgG4-RD, patients with hypocomplementemia had more organs involved and greater disease activity compared to the normal complement group; however, the recurrence rate was not significantly different between these groups. Therefore, we consider that the predictive value of a low C4 concentration for IgG4-RD recurrence in this study may be biased considering that patients with low complement levels are given more aggressive treatment due to greater disease activity^[37]. Few studies have explored risk factors for poor responders, which may be due to the early high response rate of IgG4-RD. More than 90% of patients can respond to GC, and the overall response rate was 90.64% in our study. We found that young age (<50 years old) and aorta involvement were significantly associated with non-response. These findings may be related to our small sample size and require further verification.

Conclusion

In conclusion, IgG4-RD is more common in middle-aged and elderly individuals, and the clinical characteristics of different genders and age groups are different. Most patients have single-organ or double-organ involvement. The number of organs involved is positively correlated with the serum IgG4 concentration. The pancreas, salivary glands, lymph nodes, and lacrimal glands are the commonly involved organs. Long-term GC monotherapy or its combination with immunosuppressive therapy can effectively control IgG4-RD, and there is no difference in the response, recurrence, or adverse reaction rate between the 2 treatment regimens. Young age (<50 years old) and aortic involvement are considered to be associated with non-response to IgG4-RD treatment. Young age (<50 years old), low serum C4 concentration, a high number of organs involved, and lymph node involvement are considered to be associated with IgG4-RD recurrence.

Declarations

Acknowledgment: No applicable.

Funding: No applicable

Conflict of interest: The authors declare that they have no conflict of interest.

Data availability statement: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Ethical statement: The study was conducted in accordance with Declaration Helsinki. The ethics committee waived the requirement for informed consent because of the retrospective nature of the study. But the protocol was approved by the Ethics Committee of the First Hospital of China Medical University ([2022]20).

Author contributions: Yiling Li designed the study; Ningning Wang, Ying Wang, Jing Tong and Bing Chang collected the data; Xinhe Zhang, Xiuli Jin, Haoyu Tian, Die Huang, Yanmeng Wang and Huipeng Cui organized data; Xinhe Zhang and Zilu Zeng wrote the original draft; Xinhe Zhang, Yiling Li and Lin Guan reviewed and edited; All authors read, revised and approved the final manuscript

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Tables

Table 1. Comparison of basic characteristics among different gender and age

Table 2 Univariate and multivariate analysis of predictive factors for response and recurrence