Title : Beyond Corticosteroids: TNF-? Inhibitors as Emerging Standard of Care in Non-Infectious Uveitis – Mechanistic insight, Clinical Evidence, Disease-specific efficacy and Long-term tolerance (Comprehensive Literature)
Abstract:
Background
Non-infectious uveitis encompasses a spectrum of intraocular inflammatory diseases involving the uveal tract, retina, vitreous, and optic nerve. Complications such as cystoid macular oedema (CME), cataract, and secondary glaucoma contribute to nearly 10% of legal blindness in industrialised nations. While corticosteroids remain the mainstay for acute treatment, their chronic use is limited by systemic and ocular side effects, including glaucoma, cataract progression, and immunosuppression. Consequently, attention has shifted toward biologic therapies, notably tumour necrosis factor-alpha (TNF-α) inhibitors, as alternatives offering sustained immunomodulation and steroid-sparing potential.
Methodology
A systematic search of PubMed, Medline, Cochrane, and Elsevier databases was conducted up to May 2025, incorporating clinical trials, observational studies, and mechanistic research on TNF-α inhibitors for non-infectious uveitis. Key search terms included “TNF-alpha inhibitors,” “non-infectious uveitis,” “adalimumab,” “infliximab,” and “steroid-sparing therapy.” Relevant references were further sourced from bibliographies of key studies.
Mechanistic Insight
TNF-α is a central cytokine driving uveitis pathogenesis. Produced by activated macrophages and T-cells, it increases vascular permeability by disrupting tight junctions and upregulating matrix metalloproteinases. TNF-α also promotes leukocyte recruitment through secondary mediators such as IL-6, VCAM-1, and eicosanoids. It signals via TNFR1 and TNFR2, triggering apoptosis and chronic immune activation. Preclinical models show a significant reduction in leukocyte infiltration and protein leakage after TNF-α blockade, underscoring its role as a therapeutic target.
TNF-α Inhibitors
Adalimumab, a fully human monoclonal antibody, targets both soluble and membrane-bound TNF-α. Subcutaneous administration allows for sustained levels, and its efficacy in reducing inflammation and macular oedema is attributed to reverse signalling.
Infliximab, a chimeric monoclonal antibody delivered intravenously, acts quickly but has higher immunogenicity, often necessitating combination with immunosuppressants. It shows pronounced efficacy in refractory cases, such as Behçet’s disease and juvenile idiopathic arthritis (JIA)-associated uveitis.
Golimumab, a newer fully human TNF-α inhibitor, is administered monthly via subcutaneous injection. While not yet licensed for uveitis, it shows promise in spondyloarthropathy-related cases unresponsive to other biologics.
Clinical Evidence and Efficacy
Randomised controlled trials such as VISUAL-1 and VISUAL-2 established adalimumab’s ability to extend remission and reduce visual deterioration in both active and inactive uveitis. In JIA-associated uveitis, its combination with methotrexate halved failure rates and reduced ocular flare frequency.
Infliximab has demonstrated rapid efficacy in Behçet’s disease, reducing inflammation within weeks and enabling corticosteroid tapering. Long-term studies show improved visual acuity and decreased macular thickness even in previously treatment-resistant cases.
Golimumab, though investigational for uveitis, has shown effectiveness in patients who failed other TNF-α agents. Multicentre reports highlight its steroid-sparing impact and sustained remission, but paradoxical flares emphasize the need for further study.
Long-Term Tolerance and Safety
TNF-α inhibitors generally offer durable control, but long-term safety remains a concern. Adverse events include infusion reactions, infections, and rare complications such as demyelinating disorders and malignancies. Infliximab is more immunogenic, whereas adalimumab has a more favourable safety profile. Golimumab’s long-term effects are not yet well defined, though early data are encouraging.
