IgG4-related disease (IgG4-RD) is an immune-mediated disorder characterized by organ enlargement and dysfunction. The formation of tertiary lymphoid tissues (TLTs) in affected organs is crucial for understanding IgG4-RD, as T follicular helper (Tfh) 2 cells within TLTs drive IgG4+B cell differentiation, contributing to mass formation. Key cytokines IL-4 and IL-10, produced by Tfh2 cells, are essential for this process. Additionally, cytotoxic T cells and M2 macrophages significantly contribute to inflammation and fibrosis in the lesions. These insights into IgG4-RD have led to the development of innovative targeted therapies. While glucocorticoids are effective in many cases, they often cause disease flares during tapering and rarely result in long-term, treatment-free remissions. Long-term glucocorticoid use poses significant challenges owing to potential side effects, particularly in older patients who may already have complications such as diabetes and atherosclerotic diseases. In contrast, targeted therapies offer a promising alternative, potentially providing more effective disease control with fewer side effects. Current research is exploring several exciting approaches, including B-cell depletion, targeted immunomodulation of B cells, Bruton’s tyrosine kinase inhibition, disruption of co-stimulation pathways, targeting the SLAMF7 cytokine or its receptor blockade (BAFF, IL-4, or IL-6), and JAK-STAT signaling pathway inhibition. These emerging strategies hold the promise of improving patient outcomes and advancing the management of IgG4-RD.
© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.