Early Increase of Circulating Transitional B Cells and Autoantibodies to Joint-Related Proteins in Patients With Metastatic Melanoma Developing Checkpoint Inhibitor–Induced Inflammatory Arthritis

Abstract

Objective: To investigate potential associations between B cell–related immunologic changes and development of inflammatory arthritis (IA) after treatment with immune checkpoint inhibitors (ICIs). Methods: Patients who developed ICI-induced IA (ICI-IA) and patients who did not develop immune-related adverse events (non-IRAE) after receiving ICIs to treat metastatic melanoma were consecutively recruited. Blood samples were collected at the time of ICI-IA occurrence and at different time points during treatment. Peripheral blood B cell subsets during ICI treatment were analyzed by flow cytometry. Rheumatoid factor, anti–citrullinated protein antibodies, and antibodies against joint-related proteins were measured. Results: Proportions of CD19+ B cells were higher in patients with ICI-IA (n = 7) compared to patients with non-IRAE (n = 15) (median 11.7% [interquartile range (IQR) 9.7–16.2%] versus 8.1% [IQR 5.7–11.0%]; P = 0.03). The proportion and absolute numbers of transitional CD19+CD10+CD24highCD38high B cells were increased in patients with ICI-IA compared to non-IRAE patients (median 8.1% [IQR 4.9–12.1%] versus 3.6% [IQR 1.9–4.9%]; median 10.7 cells/μl [IQR 8.9–19.6] versus 4.4 cells/μl [IQR 2.3–6.6]; P < 0.01 for both). In addition, higher levels of transitional B cells were associated with development of ICI-IA (odds ratio 2.25 [95% confidence interval 1.03–4.9], P = 0.04). Transitional B cells increased before the onset of overt ICI-IA and decreased between the active and quiescent stages of ICI-IA (P = 0.02). Autoantibodies to type II collagen epitopes were detected in up to 43% of ICI-IA patients compared to none of the non-IRAE patients (P = 0.02). Conclusion: Development of ICI-IA is accompanied by an increase in transitional B cells and by production of autoantibodies to joint-related proteins. Monitoring of B cell–driven abnormalities upon ICI treatment may help earlier recognition of ICI-IA. (Figure presented.).