Falsely low IgG4 in routine analysis - How not to miss IgG4 disease

Background IgG4 disease can have apparently “normal” levels of IgG4 due to antigen excess conditions. IgG4 measurement therefore appears falsely low. UK NEQAS data and other reports have suggested this problem occurred despite pre-existing antigen excess detection steps. Methods We examined the prevalence and characteristics of prozoning in our laboratory and patient cohorts, to determine the clinical relevance of the problem. Results We establish that the prevalence of raised IgG4 in routine IgG4 analysis is low (<1%) using one of the 2 routine methods in use in the UK. We show that subsequent assay modification appears to have reduced the likelihood of misleading readings. However, the original version of the assay prozoned to low levels (below 0.64g/L) in 41% of high IgG4 samples in our patients. This may explain the previous reports of low sensitivity of raised IgG4 for IgG4RD, and predictive values should be re-evaluated in this disease using modified prozone-resistant protocols. Conclusions All laboratories providing IgG4 measurements should verify that their assays are fit for the clinical quality requirement of detection raised IgG4 levels and must verify the upper limit of their reference ranges and freedom from prozoning.