IMMUNOPATHOGENESIS OF OCULAR MANIFESTATIONS OF GRANULOMATOSIS WITH POLYANGIITIS AND POTENTIAL TARGETS FOR NOVEL BIOLOGICAL THERAPIES
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.6091Keywords:
Granulomatosis With Polyangiitis, Ocular Involvement, ANCA-Associated Vasculitis, Immunopathogenesis, Biological TherapyAbstract
Granulomatosis with polyangiitis (GPA) is a phenotypically heterogeneous form of ANCA-associated vasculitis characterized by two partially overlapping processes: extravascular granulomatous inflammation and necrotizing vasculitis of small- and medium-sized vessels. This dual pathobiology is particularly relevant in ocular disease, where some manifestations primarily reflect active vasculopathy and endothelial injury, whereas others result from locally destructive granulomatous inflammation extending from the sinonasal tract, orbit, sclera, and ocular adnexa. Ocular involvement is reported in approximately one quarter to one third of patients in contemporary pooled analyses, with higher rates in ophthalmology-based cohorts and in head-and-neck–limited disease. The most common manifestations include scleritis, episcleritis, orbital inflammatory mass or pseudotumor, peripheral ulcerative keratitis, and lacrimal system involvement; optic neuropathy, retinochoroidal inflammation, and visual loss are less frequent but potentially sight-threatening.
The immunopathogenesis of ophthalmic GPA involves dysregulated B- and T-cell responses, ANCA-mediated neutrophil activation, neutrophil extracellular trap formation, complement amplification, and local tissue-destructive programs mediated by macrophages, plasma cells, fibroblasts, and matrix metalloproteinases. Rituximab remains the best-established biologic therapy, particularly for vasculitic ocular manifestations and peripheral ulcerative keratitis, although granulomatous orbital lesions may be relatively treatment-resistant. Future therapeutic strategies should target BAFF/APRIL/BCMA/TACI signaling, CD38-positive plasma cells, IL-6/IL-6R, IL-21/Tfh/ICOS pathways, Th17/IL-23 signaling, C5a/C5aR-mediated complement activation, NETosis, and monocyte-driven tissue invasion. A layered therapeutic approach combining control of ANCA-dependent inflammation with suppression of local granulomatous tissue destruction may be especially promising, although ocular-specific randomized trials remain lacking.
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