Corneal fibrosis is a common complication resulting from chemical and mechanical injuries, infections, complex surgeries, and scarring diseases. This stromal scarring condition significantly reduces corneal transparency and is a leading cause of legal blindness worldwide, imposing substantial social and economic burdens.⁽¹⁾ Currently, no effective medical treatments exist for established corneal scarring, with surgical options such as excimer laser phototherapeutic keratectomy (PTK) and corneal transplantation being the primary interventions.

The scarring process is driven by myofibroblast activation and fibrosis and is regulated by a complex network of cytokines and growth factors. Notably, transforming growth factor-beta (TGF-β) plays a crucial role in promoting the differentiation of local keratocytes and bone marrow-derived fibroblasts into myofibroblasts, thereby contributing to corneal scarring.^(2-5) Several studies have demonstrated that inhibiting TGF-β can diminish fibrotic responses following corneal surgeries.^(6-8)

Losartan, an oral angiotensin II receptor blocker (ARB) primarily used for hypertension, has gained attention as a potential modulator of TGF-β signalling. Research over the past two decades suggests that losartan inhibits TGF-β activity and related fibrotic processes by interrupting the Smad and ERK signalling pathways. Reports indicate that topical losartan can reduce TGF-β signalling by as much as 50%.^(3,9-15) Its application has also been potentially promising in decreasing corneal fibrosis, lowering stromal collagen IV production, and possibly minimizing neovascularization in animal models.⁽¹⁶⁾ These findings support the investigation of topical losartan for treating corneal scarring.

Notably, a case report by Pereira-Souza et al. documented effective treatment of corneal scarring following complex laser in situ keratomileusis (LASIK), with topical losartan at a concentration of 0.8 mg/mL, administered six times daily for 6 months.⁽¹⁷⁾ Additionally, Rodgers et al. reported significant improvement in corneal opacity when combining topical losartan with collagen cross-linking, even after unsuccessful steroid therapy.⁽¹⁸⁾ These cases represent the only clinical evidence available for topical losartan's role in corneal scarring, signalling a need for further inquiry into its efficacy and safety across diverse clinical scenarios.

In this case series, we present the clinical outcomes of six patients with corneal scarring due to herpetic keratitis or complex photorefractive keratectomy (PRK), all treated with topical losartan at 0.8 mg/mL prepared from losartan potassium powder in a 0.9% sodium chloride solution. Comprehensive ophthalmological examinations and corneal imaging – using anterior segment optical coherence tomography (OCT) and Pentacam Cornea OCT – document the treatment effects.

The objective of this study was to investigate the efficacy of topical losartan in treating corneal scars in patients with varying clinical backgrounds.

This retrospective review of patient data was conducted in accordance with national guidelines and, therefore, did not necessitate Investigational Review Board approval in Brazil.

Six patients diagnosed with corneal opacity were included in this case series: three were attributed to recurrent herpetic keratitis, two occurred in the context of PRK, and one was associated with either PRK or a systemic viral infection with SARS-CoV-2. Visual improvement was observed in five patients, while one patient with corneal opacity secondary to herpetic keratitis did not show any change in visual acuity following treatment, despite a reduction in opacity density on slit-lamp biomicroscopy. Patients’ description, changes in visual acuity and treatment are detailed in table 1.

Corneal fibrosis remains a significant clinical challenge, especially in refractive surgeries and following corneal injuries. This case series illustrates the potential of topical losartan, an ARB, to effectively modulate corneal scarring by inhibiting the TGF-β signalling pathway at the ERK level. This represents a valuable therapeutic option where traditional treatments have been limited. Our findings confirm and expand upon the preliminary successes reported by Pereira-Souza et al.⁽¹⁷⁾ and Rodgers et al.,⁽¹⁸⁾ highlighting the promise of losartan for patients dealing with corneal opacity caused by surgical or traumatic injuries. Notably, topical losartan at a concentration of 0.8 mg/mL, administered six times daily, has also proven beneficial in treating corneal fibrosis associated with radial keratotomy, with significant improvement in corneal transparency observed within 2 weeks.

Corneal haze is a fibrotic response characterized by the accumulation of extracellular matrix proteins and the differentiation of keratocytes and fibrocytes into myofibroblasts, primarily regulated by TGF-β. TGF-β exists in multiple isoforms (TGF-β1, β2, and β3), all of which play critical roles in the fibrotic response in the cornea and other tissues. Various injuries stimulate the release and activation of TGF-β from epithelial cells, corneal endothelial cells, and aqueous humour, promoting myofibroblast differentiation and excessive collagen production. Our findings align with the existing literature identifying TGF-β as a major driver of corneal fibrosis, including studies documenting a direct relationship between elevated TGF-β levels and corneal opacity following refractive surgery.^(7,19) Additionally, disturbances to the epithelial basement membrane (EBM) due to surgical procedures can disrupt the normal balance of this signalling pathway, increasing the risk of fibrotic outcomes.

Corneal scars that are caused by fibrosis are maintained indefinitely by viable myofibroblasts that are dependent on TGFb for survival.^(2,14,16) This TGFb is derived from the tears and epithelium and/or aqueous humour, depending on the injury, due to defective regeneration of the EBM and/or Descemet's membrane.² Even years or decades after the initial injury, topical losartan via its effects blocking ERK activation in response to TGFb binding to its receptors on these myofibroblasts can trigger their apoptosis and finally allow corneal fibroblasts to move into the fibrotic tissue, help the epithelium regenerate normal EBM to control further TGFb entry into the stroma, and remove the disordered collagens and other matrix components deposited by the myofibroblasts. So, even longstanding corneal scars may respond to topical losartan. To date, to our knowledge, the longest post-injury case was successfully treated with topical losartan was three years after Varicella zoster virus keratitis.

Established treatments for corneal haze usually involve surgical interventions like PTK or corneal transplantation. While topical corticosteroids may help mitigate inflammation and TGF-β-driven fibrosis, they often come with significant side effects, including increased intraocular pressure, cataracts, and susceptibility to infections.⁽²⁰⁾ Other pharmacological options have demonstrated only modest efficacy in previous studies.^(21,22) Although agents like MMC provide some benefits in controlled settings, corneal fibrosis continues to pose challenges, underscoring the need for innovative therapies that can be integrated into existing treatment frameworks.

In our series, six patients showed varying degrees of improvement in corneal transparency after topical losartan treatment. Significant reductions in corneal opacity were observed during slit-lamp examinations and with advanced imaging techniques, including anterior OCT and corneal tomography. Visual improvement was noted in five patients treated with losartan for periods ranging from 10 weeks to 14 months, while one patient experienced reduced opacity after 7 months without improvement in visual acuity. These results differ from those observed by Burgos-Blasco et al., in which there was no significant improvement in visual function or corneal densitometry.⁽²³⁾ The efficacy of topical losartan in preventing and treating corneal fibrosis likely hinges on achieving effective drug levels in the corneal stroma over time. While some of our patients benefited from a four-times-daily regimen, it is possible that more frequent (six-times-daily) administration could lead to higher success rates. Prolonging treatment duration might also enhance fibrotic reduction. It is probable that the stromal concentration must achieve a critical level for an extended period for the myofibroblasts to undergo apoptosis while the corneal fibroblasts are coming into the fibrotic tissue, repairing the EBM and leading to the removal/reorganization of the disordered fibrotic stroma, and six times a day is more likely to achieve that needed stromal level than four times a day regimen. We recommend continuing topical losartan for at least 3 months after optimal resolution of corneal scarring to support complete epithelial regeneration and prevent recurrence of fibrosis. It is important to note that oral losartan has shown no efficacy for corneal opacity.⁽¹³⁾

For topical losartan to effectively improve vision, the corneas overall morphology must be preserved despite injury. In cases of corneal damage from infection or trauma, although topical losartan can reduce fibrotic opacity, surgical interventions may still be necessary to restore corneal structure and enhance vision.

Losartan's efficacy is supported by its antagonistic effects on TGF-β signalling.^(8,11,23) While primarily known as an ARB, its modulation of TGF-β activity by inhibiting ERK activation plays a vital role in its ability to treat corneal fibrosis. Losartan reduces TGF-β-driven myofibroblast activation and minimizes collagen type IV production, providing a strong rationale for its use in corneal scarring.^(13,16)

The potential of losartan as a topical treatment represents a shift in the management of corneal scars. Given its excellent safety profile and existing use for other medical conditions, repurposing losartan could greatly benefit patients while minimizing risks associated with new therapies. The cases presented here enhance our understanding of how existing pharmacological agents can foster new avenues for promoting corneal healing post-surgery or overcoming chronic conditions such as scarring from herpetic keratitis.

Importantly, our findings support the idea of losartan serving both as a therapeutic and preventative measure, particularly for patients at high risk of developing corneal fibrosis after refractive surgeries.^(3,13) Its potential applications could also extend to other corneal fibrotic disorders. As noted in previous literature, the pharmacological modulation of losartan may inhibit myofibroblast survival after surgical procedures, potentially improving long-term visual outcomes and enhancing patient quality of life.⁽¹⁴⁾

While this case series offers promising evidence for the efficacy of topical losartan, each patient must be considered individually regarding their unique clinical setting. Further extensive and controlled studies are necessary to validate these results. Future clinical trials should focus on determining optimal treatment regimens, long-term effectiveness, and safety across diverse patient populations and corneal conditions.^(2,16)

This case series presents strong evidence for the use of topical losartan as a novel treatment for corneal fibrosis arising from various challenges, including surgical complications and infections. By inhibiting the TGF-β signalling pathway, losartan addresses limitations of current therapies and provides a multifaceted strategy for managing corneal scarring. Ongoing research is essential to quantify losartan's effects and clarify its mechanisms of action on corneal fibroblasts and myofibroblasts. As our understanding of corneal wound healing advances, losartan and similar agents may play a crucial role in improving treatment for corneal scarring, ultimately enhancing standards of care in ophthalmology.