Purpose IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect nearly any organ. No detailed clinical and laboratory assessments have been reported in large numbers of patients with IgG4-RD diagnoses established by strict clinicopathological correlation. Methods We reviewed the baseline features of 125 patients with biopsy-proven disease. The diagnosis was confirmed by pathology review according to consensus diagnostic criteria. Disease activity and damage were assessed by the IgG4-RD Responder Index (RI). Flow cytometry was used to assess levels of circulating plasmablasts. Results Of the 125 patients, 103 had active disease and 86 were on no treatment. Only 51% of the patients with active disease had elevated serum IgG4 concentrations. However, patients with active disease and elevated serum IgG4 concentrations were older, had a higher RI, a greater number of organs involved, lower complement levels, higher absolute eosinophil counts, and higher IgE levels compared to those with active disease but normal serum IgG4 (P<0.01 for all comparisons). The correlation between IgG4+ plasmablast level and RI (R=0.45, P=0.003) was stronger than that of total plasmablasts and RI. Seventy-six (61%) of the patients were male, but no significant differences according to gender were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Glucocorticoids failed to produce sustained remission in the majority of patients. Conclusion Nearly 50% of this patient cohort with biopsy-proven, clinically-active IgG4-RD had normal serum IgG4 concentrations. Serum IgG4 elevation identify a subset with more inflammatory features. IgG4+ plasmablasts correlate well with disease activity.

Objectives We examined the utility of circulating total and IgG4+ plasmablasts as biomarkers of diagnosis and disease activity in IgG4-related disease (IgG4-RD). Materials & Methods We evaluated patients with active, untreated, biopsy-proven IgG4-RD affecting an array of organs. Flow cytometry was used to measure total plasmablast and IgG4+ plasmablast counts by gating peripheral blood for CD19lowCD38+CD20−CD27+cells and CD19lowCD38+CD20−CD27+IgG4+cells. Serum IgG4 concentrations were measured by nephelometry. We compared 37 IgG4-RD patients to 35 controls, including healthy individuals (n=14) and patients with other inflammatory diseases prior to treatment (n=21). Results TheIgG4-RD patients’ mean age was 59, and 68% were male. Fourteen patients (38%) had three or more organs involved. The IgG4-RD patients had substantially elevated total plasmablast counts (median: 4,698/mL; range: 610–79,524/mL) compared to both untreated disease controls (median: 592/mL; range: 19–4,294/mL;P<0.001) and healthy controls (median: 94/mL; range: 1–653/mL; P<0.001). Thirteen IgG4-RD patients (36%) had normal serum IgG4 concentrations (mean: 60 mg/dL; range: 5–123 mg/dL; normal: <135 mg/dL). However, the median plasmablast count was not significantly lower in that subset with normal serum IgG4 concentrations compared to those with elevated serum IgG4: 3,784/mL versus 5,155/mL, respectively (P=0.242). Among the 12 rituximab (RTX)-treated patients, the median plasmablast level during disease flare was 6,356/mL (range: 1,123–41,589/mL), declining to 1,419/ml (range: 386/mL–4,150/mL) during remission (P<0.01). Conclusions Circulating plasmablasts are elevated in active IgG4-RD, even in patients with normal serum IgG4 concentrations. Plasmablast counts are a potentially useful biomarker for diagnosis, assessing response to treatment, and determining the time to re-treat patients.

Sialic acid–binding Ig-like lectins, or Siglecs, vary in their specificity for sialic acid–containing ligands and are mainly expressed by cells of the immune system. Many Siglecs are inhibitory receptors expressed in innate immune cells that regulate inflammation mediated by damage-associated and pathogen-associated molecular patterns (DAMPs and PAMPs). This family also includes molecules involved in adhesion and phagocytosis and receptors that can associate with the ITAM-containing DAP12 adaptor. Siglecs contribute to the inhibition of immune cells both by binding to cis ligands (expressed in the same cells) and by responding to pathogen-derived sialoglycoconjugates. They can help maintain tolerance in B lymphocytes, modulate the activation of conventional and plasmacytoid dendritic cells, and contribute to the regulation of T cell function both directly and indirectly. Siglecs modulate immune responses, influencing almost every cell in the immune system, and are of relevance both in health and disease.