We included 52 patients with IgG4-RD and 40 controls (25 with SS and 15 with sarcoidosis). Age among IgG4-RD patients and controls was similar (49.4 ± 15.3 vs. 55.3 ± 12.3 vs. 43.1 ± 16.6 years, p=0.08) and SS patients were less frequently male (53.3% vs. 4% vs. 33.3%, p<0.001).
Seven patients with IgG4-RD were excluded due to eGFR < 60 mL/min/1.73 m2 attributable to kidney and retroperitoneal involvement, age and comorbidities. Forty five patients with IgG4-RD were included in the analysis with a mean age of 49.4 ± 15.3 years, twenty four (53.3%) were male. Seven (15.5%) patients had single organ, 7 (15.5%) 2 organs and 31 (78.8%) 3 ≥ organs involved during the course of the disease. Most frequently involved organs were: submandibular glands in 26 (57.8%), pancreas in 20 (44.4%), lymph nodes in 20 (44.4%), lacrimal glands in 17 (37.8%), parotid glands in 14 (31.3%), biliary tract in 14 (31.1%), paranasal sinus in 13 (28.9%) and kidney in 11 (24.4%). Phenotyping classification and other clinical features are given in Table 1.
IgG4 serum levels were elevated in 30 out of 44 (68.2%) patients ever during the disease course. At recruitment, serum IgG1 levels were elevated in 17 (37.7%) patients and serum IgG4 levels in 16 (35.5%), 10 with active IgG4-RD. Thirty five (77.7%) patients had biopsy proven disease.
Twenty five (55.5%) patients were under immunosuppressive treatment at recruitment. Type of immunosuppressive treatment is given in Table 1.
sFLC assessment in patients with IgG4-RD.
Twenty nine (64.4%) IgG4-RD patients had high k sFLC levels with a median of 24.37 mg/L (1.61-287.96), 13 (28.9%) had high λ sFLC levels with a median of 19.19 mg/L (4.57-130.46) and 13 (28.9%) had an elevated k/λ ratio with a median of 1.33 (0.35-3.92). Only one patient with inactive IgG4-RD had diminished k and λ sFLC levels. There were not IgG4-RD patients with low k/λ ratio.
There were no differences in the proportion of IgG4-RD patients with high k sFLC (29 [64.4%] vs. 21 [84%] vs. 8 [53.3%], p = 0.08) and elevated k/λ ratio (13 [28.9%] vs. 4 [16%] vs. 2 [13.3%], p = 0.30) when compared with SS and sarcoidosis patients. Indeed, patients with SS had more frequently high levels of λ sFLC than IgG4-RD and sarcoidosis patients (13 [28.9%] vs.11 [44%] vs. 1 [6.7%], p = 0.04). Furthermore, the serum levels of k sFLC, λ sFLC and k/λ ratio were not significantly different among IgG4-RD patients and control groups (Figure 1).
sFLC in clinical phenotypes of IgG4-RD.
There were no differences in the proportion of patients with high k sFLC (4 [50%] vs. 3 [50%] vs. 9 [64.3%] vs. 12 (75%), p = 0.56), λ sFLC (1 [12.5%] vs. 3 [50%] vs. 3 [21.4%] vs. 5 (31.3%), p = 0.42) and k/λ ratio (2 [25%] vs. 2 [33.3%] vs. 4 [28.6%] vs. 5 (31.3%), p = 0.98) among pancreato-hepato-biliary, retroperitoneum and aorta, head and neck-limited and Mikulicz and systemic phenotypes of IgG4-RD. Levels of k sFLC, λ sFLC and k/λ ratio were not significantly different among the four IgG4-RD clinical phenotypes (Figure 2). The only patient with unclassifiable phenotype (pericardium limited involvement) was not included in this analysis.
There were no differences in the proportion of patients with high k sFLC (23 [63.9%] vs. 6 [66.7%] p = 0.87), λ sFLC (9 [25%] vs. 4 [44.4%], p = 0.25) and k/λ ratio (10 [27.8%] vs. 3 [33.3%], p = 0.74) between proliferative and fibrotic phenotypes of IgG4-RD. Levels of k sFLC, λ sFLC and k/λ ratio were not significantly different among these clinical phenotypes (Figure 3).
Relationship of sFLC and organ involvement in IgG4-RD.
We observed a significant positive correlation between the number of involved organs at recruitment and k sFLC (rho = 0.33, p = 0.03) and the k/λ ratio (rho = 0.34, p = 0.02), but not with λ sFLC (rho = 0.13, p = 0.40). A positive correlation with the IgG4-RD RI score was also observed with k sFLC (rho = 0.34, p = 0.02) and the k/λ ratio (rho = 0.38, p = 0.01), but not with λ sFLC (rho = 0.17, p = 0.26).
Patients with renal involvement (n=11 [24.4%]) had higher levels of k sFLC (58.9 mg/L [13.32-287.96] vs. 22.03 mg/L [1.61-170.66], p = 0.006) and λ sFLC (22.48 mg/L [12.55-130.46] vs. 16.43 mg/L [4.57-49.50], p = 0.03) compared to patients without renal involvement (Figure 4).
The AUC for k sFLC and λ sFLC, for predicting renal involvement, with a cut-off value of 33.42 mg/L and 29.55 mg/, was 0.78 and 0.72, respectively (Figure 4).
Only 2 patients with renal involvement had mild kidney dysfunction (eGFR 60-89 mL/min/1.73 m2) and the rest had normal kidney function; eight had active disease. At the linear regression analysis, eGFR did not correlate with k (β=-0.03, p=0.92) and λ sFLC levels (β=0.05, p=0.74) nor the k/λ ratio (β=-0.008, p=0.17).
Patients with lymph node involvement (n=20, 44.4%) had higher levels of k sFLC (31.94 mg/L [8.40-287.96] vs. 21.63 mg/L [1.61-170.06], p = 0.026) and a trend for higher levels λ sFLC (21.89 mg/L [7.40-130.46] vs. 16.26 mg/L [4.57-49.06], p = 0.058) compare to patients without lymph node involvement. We did not find any association with other organs.
Relationship of sFLC with activity and damage in IgG4-RD.
When analyzing the 25 patients with active IgG4-RD, we did not find differences in the proportion of IgG4-RD patients with high k sFLC (19 [76%] vs. 21 [84%] vs. 8 [53.3%], p = 0.11) compare to SS and sarcoidosis patients. High λ sFLC were more frequent in the SS group (9 [36%] vs. 11 [44%] vs. 1 [6.7%], p = 0.04). Conversely, patients with active IgG4-RD had more frequently elevated k/λ ratio compare to SS and sarcoidosis patients (12 [48%] vs. 4 [16%] vs. 2 [13.3%], p = 0.02). Notably, half of the 12 active IgG4-RD patients with a high k/λ ratio had normal serum IgG4 levels.
Patients with active IgG4-RD had more frequently high k sFLC compared to patients with inactive IgG4-RD, although without reaching a statistical significance (19 [76%] vs. 10 [50%], p = 0.07); whereas the proportion of patients with high λ sFLC was similar (9 [36%] vs. 4 [20%], p = 0.23). Patients with active IgG4-RD had more frequently an elevated k/λ ratio than patients with inactive disease (12 [48%] vs. 1 [5%], p = 0.002). The concentrations of k sFLC (28.95 mg/L [5.83-287.96] vs. 19.37 mg/L [1.61-92.45], p = 0.04) and the k/λ ratio (1.56 [0.82-3.92] vs. 1.16 [0.35-2.77], p = 0.02) were higher in active than in inactive IgG4-RD (Figure 5).
The AUC for k sFLC and k/λ ratio, for predicting active IgG4-RD, with a cut-off value of 33.42 mg/L and 1.61 mg/L, were 0.67 and 0.70, respectively (Figure 5).
IgG4-RD patients with damage at the time of recruitment did not have differences in sFLC levels compare to patients without damage (data not shown).
Relationship of sFLC and serum IgG1 and IgG4 levels.
There was a significant positive correlation between serum IgG1 levels and k sFLC (rho = 0.74, p <0.001), λ sFLC (rho = 0.74, p <0.001) and the k/λ ratio (rho = 0.44, p = 0.003). Serum IgG4 levels correlated as well with k sFLC (rho = 0.49, p <0.001), λ sFLC (rho = 0.35, p = 0.018) and the k/λ ratio (rho = 0.43, p = 0.003).
sFLC in IgG4-RD patients under immunosuppressive treatment.
There were no differences in the prevalence and levels of k sFLC, λ sFLC and the k/λ ratio between patients with and without immunosuppressive treatment (data not shown).
In a sensitive analysis including the 14 patients with active untreated IgG4-RD, an elevated k/λ ratio remained more frequent compare to SS and sarcoidosis patients (7 [50%] vs. 4 [16%] vs. 2 (13.3), p = 0.04).