Autoreactive Plasmablasts After B Cell Depletion With Rituximab and Relapses in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 75; no. 5; pp. 736 - 747
• Main Authors: Berti, Alvise, Hillion, Sophie, Konig, Maximilian F., Moura, Marta Casal, Hummel, Amber M., Carmona, Eva, Peikert, Tobias, Fervenza, Fernando C., Kallenberg, Cees G.M., Langford, Carol A., Merkel, Peter A., Monach, Paul A., Seo, Philip, Spiera, Robert F., Brunetta, Paul, St. Clair, E. William, Harris, Kristina M., Stone, John H., Grandi, Guido, Pers, Jacques‐Olivier, Specks, Ulrich, Cornec, Divi
• Format: Journal Article
• Language: English
• Published: Boston, USA Wiley Periodicals, Inc 01-05-2023; Wiley Subscription Services, Inc; Wiley
• Subjects: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Antineutrophil cytoplasmic antibodies; Blood; Depletion; Ecology, environment; Flow cytometry; Health; Humans; Leukocytes, Mononuclear; Life Sciences; Lymphocytes B; Myeloblastin; Patients; Peripheral blood mononuclear cells; Prospective Studies; Proteinase; Proteinase 3; Recurrence; Remission; Rituximab; Rituximab - therapeutic use; Vasculitis
• ISSN: 2326-5191; 2326-5205; 2326-5205; 2326-5191
• DOI: 10.1002/art.42388

Objective
Autoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA‐associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV.
Methods
Sequential flow cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 patients with proteinase 3 (PR3)–ANCA–positive AAV who were treated with RTX for remission induction and monitored after stopping therapy during long‐term follow‐up in a prospective clinical trial. PR3 was used as a ligand to target autoreactive PR3‐specific (PR3+) B cells. B cell recurrence was considered as the first blood sample with ≥10 B cells/μl after RTX treatment.
Results
At B cell recurrence, PR3+ B cell frequency among B cells was higher than baseline (P < 0.01). Within both PR3+ and total B cells, frequencies of transitional and naive subsets were higher at B cell recurrence than at baseline, while memory subsets were lower (P < 0.001 for all comparisons). At B cell recurrence, frequencies of B cells and subsets did not differ between patients who experienced relapse and patients who remained in remission. In contrast, the plasmablast frequency within the PR3+ B cell pool was higher in patients who experienced relapse and associated with a shorter time to relapse. Frequencies of PR3+ plasmablasts higher than baseline were more likely to be found in patients who experienced relapse within the following 12 months compared to those in sustained remission (P < 0.05).
Conclusion
The composition of the autoreactive B cell pool varies significantly following RTX treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses.