Zanubrutinib monotherapy for IgG4-related head and neck disease

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is commonly treated with glucocorticoids and B-cell depletion, but cumulative toxicity and relapse underscore the need for alternative approaches. We evaluated the efficacy, safety, and immunological effects of Bruton's tyrosine kinase (BTK) inhibition with zanubrutinib in active IgG4-RD.

In this phase 2, open-label, proof-of-concept trial, 10 participants with lacrimal and submandibular gland IgG4-RD received zanubrutinib 80 mg twice daily for up to 24 weeks without glucocorticoid induction or background immunosuppression. The primary endpoint was change in lacrimal and submandibular gland volume at week 24 by blinded fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (evaluable n = 8). Secondary endpoints included metabolic imaging parameters, clinical disease activity, serologic biomarkers, and safety. Single-cell RNA sequencing with immune repertoire profiling was performed to define cellular mechanisms.

At week 24, mean gland volume decreased by 46.7% (lacrimal) and 29.9% (submandibular) (both P = .008), with concordant reductions in total lesion glycolysis (-91.6 g; P = .05) and total metabolic lesion volume (-20.7 cm³; P = .05). Clinical disease activity improved (IgG4-RD Responder Index -6.0 points; P = .01), alongside reductions in serum IgG4 (-417 mg/dL; P = .008) and circulating plasmablasts. Imaging and serologic changes were strongly correlated. Single-cell analyses demonstrated treatment-associated modulation of B-cell transcriptional programmes, reductions in IgG4-skewed plasmablasts, and attenuation of cytotoxic CD4⁺ T cells. Adverse events were predominantly mild; 1 serious event (COVID-19) occurred off treatment.

Zanubrutinib monotherapy produced substantial imaging-defined and clinical improvements in active glandular IgG4-RD without glucocorticoid induction. BTK inhibition was associated with modulation of B-cell differentiation states and downstream immune programmes, supporting its development as a steroid-sparing, non-B-cell-depleting therapeutic strategy.