Anterior Subcapsular Cataract Formation With Long-term Topical Netarsudil Treatment for Glaucoma

Purpose: The purpose of this study was to describe anterior subcapsular cataract development in patients on long-term topical netarsudil use. Patients and Methods: This clinical observational study summarizes a similar cataract pattern demonstrated in a series of patients from a single physician practice and a university-based outpatient clinic during their routine clinical follow-up visits from October 2020 to August 2021. All patients have been using topical netarsudil once daily for at least 15 months. No anterior capsular changes have been observed in any patient at the time when netarsudil was initiated. Results: Five eyes from 4 patients between the ages of 41 and 61 and 1 eye from a patient aged 84 were found to develop anterior subcapsular opacities 15 to 37 months after beginning netarsudil. These cataracts were overall small, 1 to 3 mm, round, oval or ring-shaped, central or paracentral with mild density. No other risk factors for cataract development apart from age were found in these patients. Conclusion: Patients on long-term netarsudil should be monitored for potential development of anterior subcapsular cataracts.

G laucoma is a chronic optic nerve degeneration associated with elevated intraocular pressure. It is the second leading cause of blindness internationally, estimated to affect 79.6 million of the world's population in 2020. 1 Although there are currently many surgical and injectable treatment options for glaucoma, surveys suggest that a majority of patients and their ophthalmologists still prefer to manage glaucoma using topical eye drops. 2 Netarsudil is a Rho-kinase (ROCK) inhibitor approved as a treatment for open-angle glaucoma and ocular hypertension by the Food and Drug Administration (FDA) in December 2017. ROCK plays a role in regulating cell cytoskeletal dynamics and smooth muscle contraction in the trabecular meshwork. 3 ROCK inhibitors such as netarsudil increase trabecular meshwork outflow, thus lowering intraocular pressure to treat glaucoma.
Netarsudil ophthalmic solution 0.02% daily dosing has been shown to be noninferior to timolol maleate ophthalmic solution 0.5% twice-daily dosing. 4 Ocular adverse effects of netarsudil including hyperemia, verticillata, instillation site pain, conjunctival hemorrhage, eyelid erythema, reduced visual acuity, and increased lacrimation have been reported. 4,5 All these effects are reversible with the discontinuation of netarsudil. In addition, corneal endothelial guttata 6 and reticular corneal edema 7 may rarely develop. However, these phenomena do improve with the cessation of netarsudil.
Previous studies have found an increased incidence of nuclear or posterior subcapsular cataract in patients received topical ocular hypotensive eye drops. 8,9 Research suggested preservatives in eye drops, such as benzalkonium chloride, could contribute to the development of these cataracts. 9,10 However, to our knowledge, the formation of the anterior subcapsular cataract (ASC) has not been documented as an adverse effect of any specific topical glaucoma agent. We report herein 5 cases of a unique type of ASC that developed in patients who were on netarsudil for over 15 months.

PATIENTS AND METHODS
This clinical observational series reports 5 consecutive patients with incidental ASC findings in a single physician practice and a university-based outpatient clinic from October 2020 to August 2021. All patients have been followed by the reporting physicians routinely every 4 to 6 months for at least 3 years. All patients were treated with topical netarsudil for over 15 months. No anterior subcapsular lens change was observed at the initiation of netarsudil. Findings were observed and documented during a routine office visit. The institutional review board/ethics committee guideline ruled that institutional review board approval was not required for this case series.

Case 1
A 41-year-old male with pigmentary glaucoma since age 27 was found to have asymptomatic, small, nebulous, paracentral, anterior subcapsular lenticular opacities in each eye (Figs. 1A, B) on a routine glaucoma follow-up visit. His visual acuity was unaffected, measuring 20/15 right eye and 20/20 left eye. He was initially treated with topical latanoprost, with the eventual addition of timolol, dorzolamide, and brimonidine. Netarsudil was added to each eye 15 months before the visit when his cataracts were first detected. He is currently using a combination product containing netarsudil and latanoprost. He is not taking any systemic medications except daily multivitamin supplements. Ten months after the detection of cataracts, his vision remains correctable to 20/20 or better in each eye.

Case 2
A 61-year-old male with normal-tension glaucoma diagnosed at age 50 was found to have a small, central, ringshaped, asymptomatic, anterior subcapsular opacity in his left lens 26 months after beginning topical netarsudil/latanoprost combination therapy (Fig. 2). His vision was correctable to 20/ 20 in the affected left eye. His glaucoma therapy began with latanoprost. Three years later, he was switched to combined netarsudil/latanoprost in both eyes. He was otherwise healthy and not taking any systemic medications other than daily multivitamins and vitamin D 3 supplements.

Case 3
A 54-year-old male with primary open-angle glaucoma (POAG) was found to have a small, central, oval-shaped anterior subcapsular lenticular opacity in the right eye (Fig. 3). He was started on topical netarsudil in each eye 37 months before the ASC developed. He was taking dorzolamide/timolol combination and bimatoprost eye drops before netarsudil was added to both eyes. In his last office visit, his best-corrected vision remained 20/25 both eyes, with no visual complaints. The only systemic medication he was taking was terazosin for the treatment of benign prostate hypertrophy.

Case 4
A 55-year-old female patient with POAG developed a small, central, oval-shaped anterior subcapsular lenticular opacity in her right eye (Fig. 4). She started taking netarsudil in both eyes 17 months before this unilateral ASC was observed. In her last office visit, her best-corrected vision was 20/20 right eye and 20/25 left eye, with no visual symptoms. In addition to netarsudil, she was also taking topical bimatoprost in both eyes.

Case 5
An 84-year-old female with POAG and preexisting nuclear sclerotic cataracts was found to have a small, round, central, anterior subcapsular opacity in her left lens (Fig. 5). She began using netarsudil/latanoprost combination in each eye 24 months before developing the ASC. Systemically, she was taking ezetimibe, metoprolol, levothyroxine, and rivaroxaban for unrelated conditions. Her uncorrected visual acuity was 20/50-2 with her right eye and 20/60-2 with her left eye, improving with a pinhole to 20/20-2 with her right eye and to 20/40 with her left eye.

DISCUSSION
ASC has not been reported at the increased frequency with any of the modern topical agents used to treat glaucoma. This case series of patients raises the possibility that this new class of glaucoma medication, the ROCK inhibitors, may be associated with the development of ASC.
Cataracts described in this case series are central or paracentral, round, oval, or ring-shaped opacities with mild density measuring 1 to 3 mm in diameter. In cases 1 to 4, the opacities developed in younger patients with no previous history of cataract. We found no corresponding posterior subcapsular or other cortical changes in any of these patients. The ASC was found in both male and female sexes. Interestingly, although all patients received netarsudil treatment in both eyes, most ASC findings were unilateral except case 1. POAG, normal-tension glaucoma, and pigmentary glaucoma were represented in this small case series. No patient has been followed long enough to draw conclusions on whether cataracts progress over time or if they are reversible, or the fellow eye would be affected in unilateral cases.
ASC is associated with atopic dermatitis. 11 It has been proposed that higher serum lipids, lipid peroxide, and decreased superoxide dismutase in atopic dermatitis patients lead to increased free radical damage in the lens. 12,13 ASC may also occur following ocular trauma, surgery, electrical burn injuries, and herpetic keratouveitis. 14,15 Trauma and inflammation causing injury to the anterior lens epithelium may contribute to the formation of ASC through damage of the lens epithelial ion pumps. 16 None of the patients in this case series had exposure to these risk factors. A review of systemic medications and supplements did not reveal any potential association with ASC in any patient.
Lens epithelial cells in ASC were found to resemble myofibroblasts, containing actin and myosin, which are key cytoskeletal components. 17 Mouse model studies have confirmed that transforming growth factor β (TGF-β) contributes to ASC development by activating α-smooth muscle actin and type 1 collagen. 18 The ROCK pathway impacts cytoskeletal changes such as actomyosin contraction, cell migration, and cell proliferation. In lens epithelial cells, activation of Rho GTPase (which is downstream to the ROCK pathway) induced actomyosin cytoskeletal reorganization and formation of focal adhesions. 19 This suggests that the ROCK pathway plays a role in maintaining cytoskeletal integrity of lens epithelium. Korol et al 20 showed that the ROCK pathway may activate myocardinrelated transcription factor A and lead to TGF-β activation of α-smooth muscle actin in lens epithelial cells causing an increased risk of ASC formation. Conversely, ROCK inhibitors have been shown successfully in preventing ASC formation in mice exposed to UV-B. 21 The relationship between ROCK and TGF-β is complex, with regulation from various molecular signaling proteins. Therefore, further studies are needed to elucidate the effects of the ROCK pathway and TGF-β on lens epithelial cells.
Small ASCs may have been missed in clinical trials of netarsudil due to a population bias toward older age groups where preexisting cataracts may have obscured their presence. Most of the patients in this case series were younger than those recruited in previous clinical trials. 4 Furthermore, patients in the ROCKET-1 and ROCKET-2 clinical trials were followed for 3 months, but the earliest these ASCs were observed in the clinic was 15 months after netarsudil initiation. It is uncertain when ASCs may develop after starting netarsudil since the use of electronic health records with diminished capacity for drawing images of findings may have prevented earlier detection. We advise ophthalmologists to carefully monitor patients for ASC development between 3 and 15 months after netarsudil initiation.
This brief case study does not attempt to address the incidence rate of ASC in patients on chronic netarsudil. The discovery of 5 cases with minimal visual symptoms suggest that the ASCs may be underdetected. While all our cases shared a common exposure to the long-term use of netarsudil, other unrecognized risk factors that may contribute to the development of the ASC cannot be excluded. Although a causal link cannot be established from this small series, ASC formation in the setting of netarsudil topical therapy suggests the need for a closer investigation of patients on this therapy to determine if a true causal relationship exists.
In the meantime, ophthalmologists should be aware of the potential for cataract formation when using these agents. Additional molecular studies are needed to examine the role of ROCK and the effects of its inhibition on lens epithelial cell function.   Figure 5 can be viewed in color online at www.glaucomajournal.com.