Remediation of IgG4 Cross-Reactivity in IgG1 and IgG2 Subclass Assays

To the Editor: We congratulate van der Gugten and colleagues on their publication identifying spurious IgG subclass (IgGSc)1 results in patients with IgG4-related disorders (IgG4-RD) (1). Their observations provide the opportunity for in vitro diagnostics (IVD) manufacturers to improve the performance of routine clinical chemistry assays. Measurement of IgGSc is widely used in the investigation of pediatric patients with suspected immunodeficiencies. Since 2001, IgG4 measurement has been recommended for the assessment of IgG4-RD (2), and physicians often coincidentally order the accompanying IgGSc assays. The observations by van der Gugten et al. present a challenge to IVD manufacturers; IgG4-RD is rare, and at normal serum concentrations there is no apparent cross-reaction. Previously, Ladwig et al. (3) reported good correlations between IgGSc concentrations by nephelometry and LC-MS/MS. These contrasting reports may result from variations in IgGSc measurements by LC-MS/MS, but most likely represent the different patient populations analyzed. While cross-reaction is not evident in normal or pediatric patients, the results presented by van der Gugten offer an opportunity for assay remediation. We sought to identify IgG4 cross-reactivity in our IgG1 and IgG2 Optilite® assays in accordance with CLSI standard EP07-A2. Briefly, purified polyclonal IgG4 was supplemented at either 2 or 4 g/L with the …