Patients’ profiles
Among the 602 patients with IgG4-RD, 350 were male and 252 were female (male-female ratio, 1.4:1). The mean (± standard deviation (SD)) age at the first visit was 64.11 ± 11.46 years. The mean (± SD) optical density serum IgG concentration was 2,204.14 ± 1,146.86 mg/dL, and the mean (±SD) serum IgG4 concentration was 666.00 ± 660.46 mg/dL. Of the 602 patients, 499 had dacryoadenitis and sialadenitis, 192 had autoimmune pancreatitis, 51 had sclerosing cholangitis, 107 had renal involvement, 87 had respiratory involvement, and 182 had retroperitoneal fibrosis (including duplicates). The number of patients with two or more organ lesions was 350 (58.1%) (Table 2).
In the 212 patients with the diseases that needed to be differentiated from IgG4-RD, the male-female ratio was 1:4.0 (42 men and 170 women). The mean (±SD) age at the first visit was 54.20 ± 16.09 years, which was significantly younger than that in the IgG4-RD group (p < 0.001). The details of the diseases are shown in Table 2. Of the patients with non-IgG4-RD, 114 had Sjögren’s syndrome (SS) alone, and 25 had systemic lupus erythematosus (SLE). In addition, 19 patients with multicentric Castleman’s disease (MCD) and 11 patients with eosinophilic granulomatosis with polyangiitis (EGPA), which often presents with elevated serum IgG4 levels, were included. In the MCD group, the mean (±SD) serum IgG and IgG4 concentrations were 3,828.05 ± 1,850.66 and 710.42 ± 1,156.82 mg/dL, respectively. No significant difference in serum IgG4 level was found between the MCD and IgG4-RD groups (p = 0.63). The missing data rate was less than 3%.
Prediction of IgG4-RD diagnosis in patients with rheumatic diseases requiring differentiation
We performed diagnostic prediction of IgG4-RD using 814 cases of IgG4-RD and non-IgG4-RD. When the serum IgG4 level was known, the diagnosis of IgG4-RD was predicted by a decision tree (Figure 1A). First, if the serum IgG4 level is ≥115 mg/dL, go to the right, and if the CRP is <2.08 mg/dL, go to the rightmost column, which is probable IgG4-RD. If CRP ≥2.08 mg/dL, but CH50 <51.5 U/mL, the diagnosis of IgG4-RD is more likely. If the laboratory findings meet all of the following conditions, IgG4 <115 mg/dL, C3 ≥96.5 mg/dL, sIL-2R <671.5 U/mL, and IgG <1843.5 mg/dL, the likelihood of IgG4-RD increases significantly. The ROC curve for this algorithm is shown in Figure 1B. The accuracy, sensitivity, and specificity of the algorithm were 0.932, 0.981, and 0.810, respectively, and the AUC was 0.937. The validation of this algorithm showed that its accuracy, sensitivity, and specificity were 0.915, 0.983, and 0.727, respectively, and the AUC was 0.905 (Figure 1C).
The same subjects were then analyzed using the random forest method. The Gini Impurity is shown in Figure 2A. In this algorithm, the serum IgG4 concentration is the most important variable, followed by the serum sIL-2R concentration, age at the first visit, serum IgM concentration, and serum CRP concentration. The ROC curve for this algorithm is shown in Figure 2B. The accuracy, sensitivity, and specificity of the algorithm were 0.934, 0.981, and 0.833, respectively, and the AUC was 0.993. The validation of this algorithm showed that its accuracy, sensitivity, and specificity were 0.951, 0.983, and 0.864, respectively, and the AUC was 0.970 (Figure 2C).
When the serum IgG4 level was unknown, the diagnosis of IgG4-RD was predicted by a decision tree (Figure 3A). First, if the serum IgM level is <139.5 mg/dL, go to the right, and if the IgG level is ≥1,254 mg/dL and age at the first visit ≥49.5 years, go to the rightmost column, which is probable IgG4-RD. Even if the patient is younger than 49.5 years old at the first visit, if the serum IgA concentration is <217 mg/dL, IgG4-RD is still highly likely. If the laboratory findings meet all of the following conditions, IgM <139.5 mg/dL, IgG <1,254 mg/dL, amylase <78.5 U/L, and neutrophil count <4,414/µL, there is a strong possibility of IgG4-RD. Alternatively, when the initial node, IgM concentration is ≥139.5 mg/dL, the possibility of IgG4-RD is higher when the age at the first visit is ≥63 years and the white blood cell count is < 7,655/µL, and when the age at the first visit is <63 years and the IgA concentration is < 151 mg/dL. The ROC curve for this algorithm is shown in Figure 3B. The accuracy, sensitivity, and specificity of the algorithm were 0.823, 0.933, and 0.571, respectively, and the AUC was 0.800. The validation of this algorithm showed that its accuracy, sensitivity, and specificity were 0.732, 0.900, and 0.273, respectively, and the AUC was 0.581 (Figure 3C).
The Gini Impurity is shown in Figure 4A. In this algorithm, the age at the first visit is the most important variable, followed by serum IgM concentration, serum sIL-2R concentration, serum IgE concentration, and serum amylase concentration. The ROC curve for this algorithm is shown in Figure 4B. The accuracy, sensitivity, and specificity of the algorithm were 0.912, 0.990, and 0.714, respectively, and the AUC was 0.981. The validation of this algorithm showed that its accuracy, sensitivity, and specificity were 0.890, 1.000, and 0.591, respectively, and the AUC was 0.919 (Figure 4C).