Assistant Professor Stanford Univ. Sch. of Med. Stanford, California, United States
Introduction/Rationale: IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder marked by tissue infiltration of IgG4+ plasmablasts (PB) and elevated serum IgG4 levels. Bruton’s Tyrosine Kinase inhibition (BTKi) blocks key signaling pathways in B cells and showed promising efficacy in other autoimmune diseases. This is the first trial testing BTKi in IgG4-RD, and its effects were analyzed on a single-cell level.
Methods: 10 patients with IgG4-RD affecting the submandibular and/or lacrimal glands were enrolled in this single-site, open-label, investigator-initiated trial (NCT04602598). Patients received zanubrutinib orally (80mg BID) for up to 24 weeks. The primary endpoint was the change in glandular volume at week 24 compared to baseline. Single-cell transcriptomes and immune repertoires of PBMCs were analyzed at baseline, week 12, and week 24 and compared with matched healthy controls.
Results: Two patients terminated at week 4 due to adverse events. For the 8 remaining patients, treatment with zanubrutinib 80 mg PO BID resulted in significant reductions in lacrimal (–45.4% change) and submandibular gland volumes (–30.0% change, both p < 0.001) at week 24. Serum IgG4 levels decreased by a mean of 413 mg/dL and the IgG4‑RD Responder Index decreased by a mean of 4.6 points (p = 0.02). Single-cell sequencing analyses revealed diminished numbers of IgG4+ PB and atypical B cells (ABCs). Strikingly, BTKi most strongly affected IgG4+ and IgG2+ PB, restoring the composition of Ig subclasses to those seen in healthy donors. In ABCs, BTKi significantly downregulated genes associated with B cell receptor (BCR) signaling and antigen presentation. Numbers and activation levels of proliferating CD4+ T cells correlated with IgG4+ PB and ABCs, supporting the hypothesis that an extensive B cell / T cell cross-talk drives IgG4-RD pathology.
Conclusion: Zanubrutinib inhibits pathogenic B and T cell subsets in IgG4-RD in a targeted fashion and is a promising therapeutic for IgG4-RD.
