Immunoglobulin G subclass 4 (IgG4) is hypothesized to play an immunoregulatory role which effectively decreases humoral immune responses. The presence of high serum IgG4 levels is considered a biomarker for IgG4 related diseases. On the other hand, low levels of IgG4 have been reported mainly in infectious diseases but also in healthy individuals. The role of abnormal serum IgG4 in inflammatory bowel disease (IBD) has not been fully characterized. We sought to define alterations in serum IgG4 in IBD patients and its association with multiyear disease severity.
We analyzed a prospective, longitudinal IBD registry of consented patients followed at a tertiary center over a 10-year time period. IBD patients with IgG4 serum levels available formed the study population. Demographics and multiyear clinical data were collected and analyzed. Disease severity was approximated with patterns of healthcare utilization metadata. We compared IBD patients with low, normal or high serum IgG4 levels.
There were 1213 IBD patients with IgG4 levels tested [females 54%, Crohn Disease (CD) 65%, Ulcerative Colitis (UC) 33%, IBD unclassified 2%, median age at diagnosis 25 years]. Low IgG4 levels were seen in 245 patients (20%) and elevated IgG4 levels occurred in 65 (5%). In univariate analysis, low IgG4 was associated with CD (P = 0.028) and lifetime IBD surgeries (P < 0.001). During the 10-year observation period, low IgG4 patients had higher rates of new IBD surgeries (P = 0.012), office visits (P = 0.007), requirement for biologic agents (P = 0.009), steroid use (P = 0.021) and higher cumulative healthcare charges (P = 0.015) compared with normal IgG4 patients. In the multivariate analysis (MVA), low IgG4 was associated with IBD surgeries (P = 0.003) and requirement for biologic therapy (P = 0.017) during the 10-year period as well as higher rates of lifetime IBD surgery (P = 0.002). High IgG4 levels were associated with younger age (P = 0.006), male gender (P < 0.001) and lower steroid use (P = 0.043) (univariate analysis) but were not associated with primary sclerosing cholangitis (P = 0.112); in MVA only male gender (P = 0.001) remained significant.
Low IgG4 is four times more common than IgG4 elevation in IBD and is associated with multiple markers of disease severity. Further investigation is required to determine whether this finding represents the loss of a potential anti-inflammatory molecular mechanism which contributes to more severe illness in IBD.