Pathological Evolution of Fibrosis in IgG4-Related Ophthalmic Disease: A Retrospective Study of 100 Cases.

IgG4-related ophthalmic disease (IgG4-ROD) is a common manifestation of IgG4-related disease, but its clinicopathologic features and the mechanisms underlying fibrosis remain incompletely understood. We retrospectively analyzed 100 cases of IgG4-ROD and investigated fibrosis using immunohistochemistry for IgG4, FOXP3, CD68, and CD163, together with RNA in situ hybridization for TGFB1. IgG4-ROD was histologically categorized into four patterns (Patterns 1-4) reflecting progressive fibrosis, demonstrating a spectrum from lymphoplasmacytic inflammation to marked fibrosis. Fibrosis was absent or minimal in 51% of cases, indicating that fibrosis is not essential for diagnosis, whereas obliterative phlebitis was rare. Compared with non-fibrotic cases, fibrotic cases showed significantly increased numbers of CD68-positive and CD163-positive macrophages (p < 0.001), predominantly localized at the interface between lymphoid and fibrotic areas. In contrast, fibrosis was not associated with IgG4-positive plasma cells, FOXP3-positive regulatory T cells, or EBV status. TGFB1 expression was significantly higher in lymphocyte-rich than fibrotic areas (p < 0.001), suggesting a closer association with lymphocyte-rich inflammation than established fibrosis. These findings demonstrate progressive histologic changes from Pattern 1 to Pattern 4 and suggest that accumulation of CD163-positive macrophages is associated with fibrosis in IgG4-ROD.