2530: Broad Screening of Inflammation-Associated Proteins Identifies Serum CCL19 and CCL2 as Versatile Biomarkers of Disease Activity in IgG4-Related Disease

Background/Purpose: IgG4-related disease (IgG4-RD) is a chronic immune-mediated disease characterized by mass-forming lesions and organ dysfunction. The smoldering tempo and often asymptomatic nature of IgG4-RD pose challenges in the monitoring of disease activity. At least fourteen protein biomarkers have been reported, including serum IgG4. However, all reported biomarkers have been studied in relative isolation without direct comparison, and none have been demonstrated to correlate with relapsing disease. The goal of this study was to comprehensively screen inflammation associated proteins to identify novel biomarkers of disease activity in IgG4-RD that correlate with relapsing disease.

Methods: Ninety-two inflammation related proteins were measured across 59 patients with IgG4-RD, 49 healthy donors (HD), and 21 patients with sarcoidosis. Six IgG4-RD patients had pre- and post-prednisone samples available that were also studied. Statistical analyses were adjusted for age, sex, and multiple comparisons. Biomarkers that distinguished IgG4-RD were studied by receiver operating characteristic curves, hierarchical clustering, and linear regression. Flow cytometry was performed in a subset of patients to quantify activated CD4⁺ T cells, activated B cell subsets, and plasmablasts.

Results: A cassette of 20 inflammation-associated proteins was identified that distinguished IgG4-RD from healthy donors (Figures 1A-B). Among these, CCL19, CCL2, CCL13, and CXCL11 were the most accurate and non-redundant in defining IgG4-RD showing a composite area under the curve of 0.811(Figure 1C). CCL19, CCL2 and CCL13 increased distinguished IgG4-RD from sarcoidosis whereas CXCL11 did not (Figure 1D). These four biomarkers correlated with disease severity based on number of organs involved and clinical laboratory parameters of disease activity, including serum IgG4, IgE, absolute eosinophil count, and complement proteins C3 and C4 (Figure 2). Furthermore, these four biomarkers showed the capacity to predict underlying states of CD4⁺ T cell and B cell activation based on correlations with flow cytometry data. CCL19, CCL2, and CCL13 showed trends of decline following treatment with prednisone suggesting dynamic changes in response to immunosuppressive therapy and values declining in conjunction with remission. CCL19 and CCL2 were able to distinguish IgG4-RD patients with relapsing disease, single organ involvement, and normal baseline serum IgG4 levels from healthy donors (Figure 3), suggesting promise in the clinical utility of these biomarkers.

Conclusion: CCL19, CCL2, CCL13, and CXCL11 are markedly upregulated in IgG4-RD. CCL19 and CCL2 may be particularly impactful in the longitudinal monitoring of disease activity while CCL19, CCL2, and CCL13 may also distinguish IgG4-RD from the mimicking condition sarcoidosis. Additional studies comparing other IgG4-RD mimickers and paired longitudinal samples are needed.