CC-chemokine ligand 18 is a useful biomarker associated with disease activity in IgG4-related disease

LetterCC-chemokine ligand 18 is a useful biomarker associated with disease activity in IgG4related disease IgG4-related disease (IgG4-RD) is a systemic disorder characterised by elevated serum IgG4 levels, tissue infiltration by IgG4 + plasma cells and severe fibrosis. 1 2However, biomarkers for IgG4-RD disease activity are lacking. 3A recent report demonstrated that CC-chemokine ligand 18 (CCL18) was a substantial biomarker for fibrotic diseases. 4Here, we investigated the correlation between serum CCL18 levels and clinical features of patients with IgG4-RD.Written informed consent was obtained from all patients and healthy controls.Twenty-eight consecutive patients with active, untreated IgG4-RD diagnosed based on the 2011 comprehensive diagnostic criteria 5 and 16 healthy controls were enrolled.Diagnosis of IgG4-RD was biopsy proven in 26 patients (93%).Disease activity was assessed using the IgG4-RD responder index (IgG4-RD RI). 6Healthy controls had no autoimmune diseases, atopic diseases or active infections at enrolment.Serum CCL18 levels were measured using a human CCL18/ PARC Quantikine ELISA Kit (R&D Systems, Minneapolis, Minnesota, USA).Characteristics of patients are shown in table 1.The mean age of patients with IgG4-RD and healthy controls was 59.7 and 47.3 years, and the proportion of females were 50% (14/28) and 69% (11/16), respectively.Serum CCL18 levels in patients with IgG4-RD (median 44.5 ng/mL, range 3.6-120.9ng/mL) were significantly higher than those in healthy controls (median 13.0 ng/mL, range 0.1-63.8ng/mL; p=0.01) (figure 1A).The number of IgG4-RD patients with above normal levels of serum CCL18 (mean+1.96SD of the healthy controls: 27.79 ng/mL) was 17 (61%), which was significantly higher than that of healthy controls (n=3, 19%; p=0.01).Of note, serum CCL18 levels were positively correlated with IgG4-RD RI score (ρ=0.54,p<0.005), number of affected organs (ρ=0.56,p<0.005), serum IgG4 level (ρ=0.50, p<0.01) and soluble Interleukin (IL)-2 receptor level (ρ=0.56,p<0.005), but not serum IgE level (ρ=-0.05,p=0.79) or blood eosinophil count (ρ=0.18,p=0.38), suggesting that serum CCL18 level is associated with IgG4-RD disease status rather than allergic condition (figure 1B,C).In line with this observation, serum CCL18 levels were similar between IgG4-RD patients with and without an atopic history (mean 47.8 vs 40.0 ng/mL, p=0.51; figure 1D).There was no statistically significant correlation between specific organ involvement and higher serum CCL18 levels.Serum CCL18 levels significantly decreased after glucocorticoid treatment (44.7 ng/mL vs 12.7 ng/mL, p<0.01; figure 1E) with declining disease activity (IgG4-RD RI: 12 vs 2, p<0.01).Recent reports suggest that M2 macrophages are involved in the process of fibrosis. 7CCL18 is primarily secreted from activated M2 macrophages induced by T helper type 2-associated cytokines such as IL-4 and IL-13, 8 and plays a role in the stimulation of collagen production by fibroblasts. 9Importantly, DNA microarray analysis showed that CCL18 was upregulated in IgG4-RD-affected tissues. 10Moreover, CCL18 expression was colocalised with massive infiltration of M2 macrophages and positively correlated with the fibrosis scores at affected IgG4-RD sites. 7Thus, CCL18 secreted by M2 macrophages plays a significant role in the fibrotic process in IgG4-RD.