Methotrexate as an Adjunctive Therapy for Proliferative Vitreoretinopathy: A Critical Review of Evidence with Emphasis on Intra-Silicone Oil Administration Strategies

Abstract

Background: Proliferative vitreoretinopathy remains the leading cause of surgical failure following rhegmatogenous retinal detachment repair, imposing a significant clinical burden due to recurrent detachments and poor visual outcomes. Despite surgical advances, effective adjunctive therapies are lacking. Methotrexate, a folate antagonist with established anti-proliferative, anti-inflammatory, and anti-fibrotic properties, has emerged as a promising candidate. Recent interest has focused on administering methotrexate within silicone oil tamponade, aiming for sustained delivery during the critical proliferative vitreoretinopathy development window.

Objective: To critically synthesize the current evidence regarding the efficacy, safety, and pharmacological rationale of intravitreal methotrexate for proliferative vitreoretinopathy prevention and treatment, with a specific focus on the potential and challenges of intra-silicone oil administration routes.

Methods: A narrative review was conducted using the provided research materials, including preclinical studies, case series, retrospective analyses, and clinical trials that investigated various methotrexate regimens for proliferative vitreoretinopathy. Emphasis was placed on studies evaluating or comparing intra-silicone oil methotrexate delivery.

Results: Methotrexate demonstrates a strong preclinical rationale, targeting key proliferative vitreoretinopathy pathways distinct from those of previously unsuccessful agents, such as corticosteroids or 5-fluorouracil. Intra-silicone oil administration offers theoretical advantages, including sustained release (depot effect), targeted delivery, potential safety benefits over gas or aqueous injections, and synergy with silicone oil tamponade. However, clinical evidence remains inconclusive. While numerous case series report high anatomical success rates (often >70-80%), rigorous randomized controlled trials have yielded mixed results regarding primary retinal reattachment. Notably, some randomized control trials suggest that methotrexate may modulate proliferative vitreoretinopathy severity, significantly reducing the recurrence of limited proliferative vitreoretinopathy or macula-off re-detachments, even if overall re-attachment rates are not significantly improved. The safety profile appears generally favorable, with transient corneal epitheliopathy being the most common adverse event; however, the incidence varies widely. Intra-silicone oil-specific safety data are currently limited but encouraging, despite theoretical pharmacokinetic concerns (hydrophilic drug in a hydrophobic medium). Significant limitations pervade the literature, including methodological weaknesses, heterogeneity in protocols and populations, and short follow-up durations.

Conclusion: Intravitreal methotrexate, particularly via intra-silicone oil administration, represents a potentially valuable but currently unproven adjunctive strategy for the management of proliferative vitreoretinopathy. Its pleiotropic effects and the theoretical advantages of sustained intra-silicone oil delivery warrant further investigation. However, its status remains firmly investigational pending results from large-scale, well-designed randomized control trials addressing optimal dosing, delivery route (including definitive intra-silicone oil pharmacokinetics), long-term safety, and efficacy in preventing clinically significant proliferative vitreoretinopathy recurrence.