Background Granulomatosis with Polyangiitis (GPA) is a form of vasculitis characterized by inflammation of blood vessels in lungs, kidneys and the ear, nose and throat region. Regular monitoring and treatment adjustments are common, as the disease activity tends to fluctuate over time. Unfortunately, good markers for disease activity are lacking. This leads to both over- and undertreatment. Immunoglobulin G4 positive (IgG4+) B-cells and plasma cells are implicated in the pathogenesis of GPA, but the level of serum IgG4 does not seem to be a good disease activity marker. Recently we developed a test that indirectly measures the presence of IgG4+ B-cells/plasma cells by measuring the IgG4:IgG RNA ratio¹. We hypothesized that this test could be used as disease activity marker.

Objectives To test the IgG4:IgG RNA ratio in peripheral blood as a disease activity marker in GPA.

Methods 27 PR3+ ANCA+ positive GPA patients were included in this cross-sectional study. Mean age was 52 years, 56% were female, and 39% had active disease. For each patient the ESR, CRP, BVAS, and ANCA titre were measured and peripheral blood samples were obtained. Patients were defined as having active disease if the BVAS was ≥3. In addition we included 10 healthy controls, and 63 patients with other immune mediated inflammatory diseases (systemic lupus erythematosus (SLE) (n=24), rheumatoid arthritis (RA) (n=19), primary sclerosing cholangitis (PSC) (n=20)). A validated qPCR test was performed in all groups to measure the IgG4:IgG RNA ratio in peripheral blood samples ¹

Results The median IgG4:IgG RNA ratio was significantly higher in the GPA cohort (5.7, IQR 2.6 – 19.7) compared to all control groups: 1.2 in SLE (0.7 - 3.3; p<0.01), 2.5 in RA (0.7 - 4.1; p<0.05), 1.6 in PSC (1.0 - 2.8; p<0.001) and 1.3 in HC (0.6 - 1.8, p<0.01). In addition, the median IgG4:IgG RNA ratio was significantly higher in patients with active disease (23.8; IQR 12.1 – 29.1) compared to patients in remission (3.5; IQR 2.0 – 5.5) (p<0.0001). The height of the IgG4:IgG RNA ratio significantly correlated with height of the BVAS (r² =0.76, p<0.0001), while the ESR, CRP and ANCA titre did not. Interestingly, IgG4/IgG RNA ratios among patients with active disease were consistently above 9.3, and among patients in remission they were below this threshold.

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Conclusions The IgG4:IgG RNA ratio distinguishes active GPA from GPA in remission with excellent specificity and sensitivity. Moreover the ratio shows a significant correlation with disease severity, in contrast to ESR, CRP and ANCA titre. Retesting in another, prospective study is indicated to validate the IgG4:IgG ratio as a novel, highly sensitive and specific marker of disease activity in GPA.

References

1. Doorenspleet ME et al. Hepatology 2016; 64(2): 501–7.

References

Acknowledgements We thank D. van der Coelen for the technical assistance, the doctors of the vasculitis outpatient clinic, especially Dr. B.J.H. van der Born and Dr. A.E. Hak, for the contribution to patient inclusions, and all the patients that participated in this study.

Disclosure of Interest None declared