The baseline features of the patients enrolled in this study.
Totally 459 IgG4-RD patients were selected in this study, and the demographic and clinical features were shown in Table 1. The mean age at onset was 53.4 ± 12.8 years, male patients accounted for the majority with the gender ratio (Male: Female) 1.7:1. It was noted that 201 (43.8%) patients had allergy diseases. Among them, patients with inhalation allergy (141/201, 70.1%) accounted for the majority, mostly allergic rhinitis (99/141, 70.2%) (Fig. 2A-B).
Lacrimal gland, parotid gland, submandibular gland, lung, pancreas, lymph nodes and paranasal sinus were the most frequently affected organs of the IgG4-RD patients recruited in this study. As for the IgG4-RD related serological parameters, serum IgE, IgG, and IgG4 were elevated. Through the Pearson correlation analysis we found that serum IgE was positively correlated with serum IgG4 level (r = 0.1779, P = 0.0001), eosinophil count (r = 0.3004, P < 0.0001) and serum IgG level (r = 0.2189, P < 0.0001) (Fig. 2C-G).
The differences of clinical features between normal IgE group and high IgE group.
All patients were subdivided into two groups, patients whose serum IgE level > 60KU/L were divided into high IgE group (n = 399), while the IgE level ≤ 60KU/L patients were divided into normal IgE group (n = 60). Table 2 showed the comparison of the baseline clinical features between the two groups. Compared with normal IgE level group, high IgE level group had more patients with allergy disease (P = 0.004), more organ involvements (P = 0.003), and higher IgG4-RD RI scores (P = 0.002). As for the difference of the affected organs between two groups, high IgE patients were more likely to have submandibular gland (P = 0.022) and pancreas (P = 0.048) affected (Fig. 3A). High IgE level patients also had higher serum IgG4 level (P = 0.003), higher serum IgG level (P = 0.011), eosinophil count (P = 0.014) and ESR (P = 0.023) at baseline (Fig. 3B-H).
Then, we divided the high IgE group patients into three subgroups through their serum IgE levels at baseline. Group A (n = 101) was the patients with the serum IgE level between 60–180 KU/L, Group B (n = 57) was the patients with serum IgE level between 180–300 KU/L and Group C (n = 241) was the patients with serum IgE level > 300 KU/L, the clinical features of these three subgroups were displayed in Table 3, and more patients were found to accompany with allergy disease in Group B (serum IgE 180–300 KU/L). By comparing the serological features among the three subgroups, we found that Group C (serum IgE > 300 KU/L) had the highest serum IgG4, IgG concentration, eosinophils and ESR; Group B had the lowest C3 level; and Group C had the lowest C4 level (Fig. 4A-G). Figure 3H-I displayed the comparison of the affected organs among the three subgroups, the proportion of the most affected organs were similar in the three subgroups, while Group A (IgE 60–180 KU/L) seemed to have more retroperitoneal tissue affected, and Group B seemed to have more pancreas and bile duct affected and Group C seemed to have more kidney and lymph nodes affected than the other two groups (Fig. 4H-I).
The difference in disease prognosis between two groups at the follow-up period
Then 312 patients (Table 1) who have been followed up for more than one year were selected in this study to compare the difference of disease prognosis between high IgE level patients (n = 269) and normal IgE level patients (n = 43). All these patients have been followed up for a median of 36 (24–54) months. Throughout the follow-up period, patients’ serum IgE level decreased rapidly and was paralleled to the serum IgG4 level and IgG4-RD RI scores in the first 3 months. But during the long-time follow-up period after first 3 months, patients’ serum IgE level showed a slowly growth curve and became unparalleled to the serum IgG4 level and IgG4-RD RI scores (Fig. 5A-B). We divided patients’ treatment regime into four types, including GCs monotherapy, GCs combined with IM, GCs sparing and watchful waiting. The treatment regimes between two groups had no significantly statistical difference (Fig. 5C).
Through the Chi-square test, we found that comparing with normal IgE patients, high IgE group had more relapse patients (29.0% vs. 16.2%, P = 0.039). While the normal IgE group patients had higher remission induction rate than high IgE group patients (88.4% vs. 73.6%, P = 0.035) (Fig. 5D-E). The summary of patients’ relapsed organs was shown in Fig. 5F-G. Normal IgE group patients were more likely to relapse at lacrimal gland (42.9%), while lacrimal gland (30.2%), submandibular gland (14.0%), lung (14.0%) and pancreas (10.5%) were the most commonly relapsed organs in high IgE group patients.
The relationship between serum IgE and disease relapse
Next, we want to know whether there was a relationship between serum IgE level and disease relapse. Throughout the whole study, there were totally 78 patients suffered from disease relapse. We analyzed the serum IgE levels before and during patients’ disease relapse. The results showed that the median serum IgE only had the increasing trend without statistical difference at the disease relapse (P = 0.234, Fig. 6A). In addition, at the time of disease relapse, patients’ serum IgE level was not positively correlated with relapse, some patients’ serum IgE levels would increase while others showed a decline, which indicated serum IgE level might not help predicting the disease relapse during follow-up (Fig. 6B). Through the comparison of the baseline serum IgE level between patients with or without relapse we found that relapsed patients had higher serum IgE level at baseline (P = 0.046, Fig. 6C), indicating that baseline high IgE level were associated with disease relapse during follow up.
The different risk factors of relapse between two groups
Since the two groups had different clinical features and relapse rate during the follow-up period, we wanted to know whether they had different risk factors for disease relapse. The results of the Cox regression analysis were listed in Fig. 7. Through the Cox Univariate regression analysis we found that both two-group patients had no risk factor in demographic features, while the elevation of the eosinophils was the risk factor for relapse in both the normal IgE group (HR 8.504 (1.071–42.511), P = 0.009) and high IgE group patients (HR 2.078 (1.277–3.380), P = 0.003). The biggest differences of risk factors for two groups were the affected organs, we found no risk factors in normal IgE group patients, while the involvement of lacrimal gland (HR 1.756 (1.108–2.782), P = 0.017), submandibular gland (HR 1.654 (1.037–2.639), P = 0.035), kidney (HR 3.413 (1.076–10.831), P = 0.037) were the risk factors for high IgE group patients.