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We read with great interest the correspondence by Umehara et al 1 which discussed the difficulties in the diagnosis of IgG4-related disease (IgG4-RD). They mention that increased IgG4 concentration is not a specific marker for IgG4-RD. Therefore, the markers for the diagnosis and the disease activity of IgG4-RD are demanded.
Approximately a quarter of patients with active IgG4-RD have hypocomplementaemia defined by the lower normal limit of C3 or C4 levels.2 Complement pathways consist of three pathways: classical, alternative and lectin pathways.3 Here, we focus on complement factors as makers of IgG4-RD and attempt to evaluate the entire complement system in IgG4-RD.
We enrolled 28 patients with active and untreated IgG4-RD, diagnosed based on the 2011 comprehensive diagnostic criteria4 and 28 sex-matched and age-matched healthy donors. We evaluated the characteristics of patients with IgG4-RD, the number of affected organs and the IgG4-RD Responder Index (IgG4-RD RI).5 None of the healthy donors had a history of inflammatory disease.
In the sera of the patients with IgG4-RD and the healthy donors, we measured the levels of complement factors, C1q, C2, C3, C3b/iC3b, C4, C4b, C5, C5a, C9, factor D, factor I, mannose-binding lectin (MBL), factor B, factor H and properdin, using the MILLIPLEX MAP Human Complement Panel 1 and Panel 2 (Merck Millipore, Darmstadt, Germany). Written informed consent was obtained from all patients and donors.
Table 1 summarises the characteristics of patients with IgG4-RD. The patients with IgG4-RD at diagnosis had significantly higher levels of C5 and C5a (figure 1A) and significantly lower levels of C4, C4b and factor D compared with the healthy donors (online supplementary table 1). C5a had a significant correlation with C3 (figure 1B) but not with C4 (figure 1C).
Supplementary file 1
The levels of C5a in remission were significantly changed compared with the levels of C5a at diagnosis (16 305 pg/mL to 10 030 pg/mL, p=0.0043) (figure 1H). Other complement factors showed no significant change between the levels at diagnosis and the levels in remission (figure 1D–G,1I).
We divided the patients with IgG4-RD into two groups by the median of C5a: high-C5a and low-C5a groups. The high-C5a group had significantly higher IgG (figure 1J) and IgG4 (figure 1K) levels compared with the low-C5a group, but the IgG4/IgG ratio was not significantly different (figure 1L). The high-C5a group also had significantly higher levels of soluble IL-2 receptor (figure 1M). There were no significant differences in the number of affected organs or in the IgG4-RD RI (figure 1N,O).
Our finding that C5a is negatively correlated with C3 may indicate that patients with hypocomplementaemia as shown in a clinical study2 have higher C5a levels. In addition, the absence of a correlation between C4 and C5a levels suggests that it is not appropriate to bracket C3 and C4 as the same component of hypocomplementaemia.
C5a has a strong inflammatory potency through binding to C5a receptor (C5aR).6 Considering the reduced C5a levels observed in patients with IgG4-RD in remission, C5a-C5aR-targeted drugs may be effective against IgG4-RD. With the success of the C5 inhibitor eculizumab for paroxysmal nocturnal haemoglobinuria7 and the progression of a number of novel C5a-C5aR1-targeted drugs including the C5aR1 antagonist avacopan for antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis,8 complement therapeutics have shown great promise.9
Based on the high serum circulating immune complex in autoimmune pancreatitis, the classical pathway is thought to be involved in IgG4-RD.10 Our findings of decreased C4 and C4b and normal MBL levels in the patients are compatible with this supposition. However, because IgG4 is ineffective at activating complement (in contrast to IgG1 and IgG3),11 the mechanisms underlying complement activation remain a mystery. A limitation of our study is that we are unable to answer this question based on our results.
In conclusion, the serum C5a level has been high in active disease and low in remission in IgG4-RD. Our data suggest that C5a may be a therapeutic target for IgG4-RD.
Contributors All authors were involved in drafting this letter or revising it critically for important intellectual content, and all authors approved the final version for publication. SF had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; internally peer reviewed.
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