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

ABSTRACT 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.