Zanubrutinib monotherapy for IgG4-related head and neck disease

IgG4-related disease (IgG4-RD) is commonly treated withglucocorticoids and B cell depletion, but cumulative toxicity and relapse underscore the need for alternative approaches. In this phase 2 open-label proof-of-concept trial, ten participants with lacrimal and submandibular gland IgG4-RD received zanubrutinib 80 mg twice daily without glucocorticoid induction or background immunosuppression. The primary endpoint was change in lacrimal and submandibular gland volume at week 24, assessed by blinded FDG–PET/MRI (evaluable n=8). Mean percent change from baseline was −46.7% for lacrimal and −29.9% for submandibular gland volume (both P=0.008), with concordant reductions in total lesion glycolysis (−91.6 g) and serum IgG4 (−417.0 mg/dL). We also Single-cell immune profiling demonstrated reversal of disease-associated B cell transcriptional programs, selective suppression of IgG4-skewed plasmablasts, and attenuation of cytotoxic CD4⁺ T cells. Adverse events were mild; one serious event occurred (COVID-19). These findings support BTK inhibition as a steroid-sparing, non-B-cell-depleting therapeutic strategy in IgG4-RD. ClinicalTrials.gov identifier: NCT04602598.