TOPLINE

Patients with active immunoglobulin G4-related disease (IgG4-RD) involving the lacrimal and/or submandibular glands who received zanubrutinib experienced reductions in gland enlargement and metabolic activity, improvements in clinical disease activity, and lower IgG4 levels; the treatment was generally well tolerated.

METHODOLOGY

• Investigators conducted an open‑label phase 2 proof‑of‑concept trial to assess the effect of zanubrutinib in patients with active IgG4‑related head and neck disease.
• They included 10 adults (median age, 58 years; 70% men) with active lacrimal and/or submandibular gland IgG4-RD who had not responded adequately to, could not tolerate, or had relapsed after glucocorticoid therapy at a US center.
• Patients received zanubrutinib 80 mg twice daily for up to 24 weeks without glucocorticoid induction or background immunosuppression.
• The primary endpoint was the change in lacrimal and submandibular gland volume at week 24, measured using blinded FDG-PET/MRI. Secondary endpoints included metabolic imaging parameters, clinical disease activity, serologic biomarkers, and safety monitoring through week 32.
• Blood was collected at each visit for immunoglobulin assays and flow cytometry of plasmablasts. Researchers performed single-cell RNA sequencing with immune-repertoire profiling to map B-cell and T-cell transcriptional changes.

TAKEAWAY

• At week 24, mean lacrimal gland volume decreased by 46.7%, corresponding to an absolute reduction of 1.42 cm³ (P = .008), and mean submandibular gland volume decreased by 29.9%, corresponding to an absolute reduction of 3.37 cm³ (P = .008). This analysis was based on a per-protocol population of eight patients rather than all 10 because two discontinued as a result of adverse events within 4 weeks of treatment initiation.
• Total lesion glycolysis decreased by 91.6 g, and total metabolic lesion volume decreased by 20.7 cm³ from baseline to week 24 (P = .05 for both).
• The mean IgG4-RD Responder Index score reduced by 6.0 points at week 24 (P = .01), indicating improved disease activity. Disease activity evaluated by physician global assessment decreased by 51.0 mm, and serum IgG4 concentrations decreased by a mean of 417 mg/dL.
• Single-cell sequencing showed reductions in IgG4-skewed plasmablasts and cytotoxic CD4⁺ T cells. Adverse events were mostly mild to moderate; two patients stopped the treatment because of adverse events, and one serious COVID event occurred after treatment cessation.

IN PRACTICE

“[The] findings support BTK [Bruton tyrosine kinase] inhibition as a promising steroid-sparing therapeutic strategy for active glandular IgG4-RD,” the authors of the study wrote.

SOURCE

The study was led by Matthew C. Baker, MD, Stanford University, Stanford, California. It was published online on July 14, 2026, in Annals of the Rheumatic Diseases.

LIMITATIONS

The study lacked a control group and included only patients with lacrimal and submandibular gland involvement. Researchers did not systematically evaluate responses in other organ manifestations of IgG4-RD.

DISCLOSURES

The study received funding from BeOne Medicines, which also supplied zanubrutinib at no cost. Several authors reported receiving consulting fees from pharmaceutical and biotechnology companies. Some authors reported equity interests, such as stock ownership or stock options, in biotechnology firms. A few authors reported serving as co-founders of or consultants to biotechnology start-ups. Detailed disclosures are available in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.