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).