Zanubrutinib Improved IgG4-Related Disease Outcomes

ZANUBRUTINIB produced significant imaging defined and clinical improvements in active immunoglobulin (Ig) G4-related disease (IgG4-RD), supporting Bruton’s tyrosine kinase (BTK) inhibition as a potential steroid sparing treatment strategy.

Zanubrutinib Reduced Disease Activity

IgG4-RD is commonly managed with glucocorticoids and B cell depletion therapies. However, cumulative treatment toxicity and frequent disease relapse have highlighted the need for alternative therapeutic approaches. Investigators evaluated the efficacy, safety, and immunological effects of zanubrutinib monotherapy in patients with active lacrimal and submandibular gland Immunoglobulin G4 related disease.

This phase two, open label, proof of concept trial enrolled 10 participants with active glandular Immunoglobulin G4 related disease. Patients received zanubrutinib 80 mg twice daily for up to 24 weeks without glucocorticoid induction or background immunosuppression. The primary endpoint assessed changes in lacrimal and submandibular gland volume using blinded fluorodeoxyglucose positron emission tomography and MRI, with eight participants evaluable for imaging analyses. Secondary endpoints included metabolic imaging measures, clinical disease activity, serological biomarkers, and safety. Single cell ribonucleic acid sequencing with immune repertoire profiling was also performed to investigate treatment associated immunological changes.

At week 24, mean lacrimal gland volume decreased by 46.7% (p=0.008), while mean submandibular gland volume decreased by 29.9% (p=0.008). Total lesion glycolysis declined by 91.6 g (p=0.05) and total metabolic lesion volume decreased by 20.7 cm³ (p=0.05). Clinical disease activity also improved, with the IgG4-RD Responder Index falling by 6.0 points: (p=.01). Serum IgG4 concentrations decreased by 417 mg/dL: (p=0.008), alongside reductions in circulating plasmablasts. Imaging findings and serological improvements were strongly correlated.

Immune Changes Supported BTK Inhibition

Single cell analyses demonstrated that zanubrutinib modulated B cell transcriptional programmes, reduced IgG4 skewed plasmablasts, and attenuated cytotoxic CD4⁺ T cells. These findings suggested that BTK inhibition influenced both B cell differentiation and downstream immune pathways.

Treatment was generally well tolerated. Adverse events were predominantly mild, and one serious adverse event involving Coronavirus disease 2019 occurred after treatment had ended.

The investigators concluded that zanubrutinib monotherapy produced substantial imaging defined and clinical improvements in active glandular IgG4-RD without glucocorticoid induction. The observed immunological changes supported further development of BTK inhibition as a steroid sparing, non-B cell depleting therapeutic strategy.

Reference

Baker MC et al. Zanubrutinib monotherapy for IgG4-related head and neck disease. Ann Rheum Dis. 2026:S0003-4967(26)00367-5.

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