Role of ripasudil as an adjunct treatment in the management of pseudoexfoliative glaucoma

Abstract

Purpose:

Ripasudil is a class of drug which alters the trabecular meshwork to increase the aqueous outflow and has been shown to be effective in pseudoexfoliative glaucoma (PXF G). This study aimed at assessing the efficacy and safety profile of ripasudil as an adjunct treatment in patients with PXF G at maximal tolerated antiglaucoma medications.

Methods:

In this prospective, interventional study, 40 patients with PXF G were enrolled between May 2021 and Jan 2022. Ripasudil 0.4% was started as an adjunctive drug to the ongoing antiglaucoma medications. On follow-up visits at 1, 3, and 6 months, the visual acuity, intraocular pressure (IOP), anterior segment, and fundus findings were evaluated. The premedication and postmedication IOP values were compared by paired t-test, and a P-value <0.05 was considered statistically significant.

Results:

Average age at recruitment was 60.02 ± 8.74 years. Baseline premedication IOP was 25.375 ± 3.276 mmHg. IOP reduction at 6 months was found to be statistically significant in all patients, with the maximal response being 24.13%. Also, 87.5% (35/40) of patients reached target IOP or even lower IOP at the end of study. There was no statistically significant association between the PXF grade and IOP. However, the grade of inferior iridocorneal angle pigmentation was found to be higher in eyes with elevated IOP (P < 0.05). Only three patients developed conjunctival hyperemia as an adverse reaction, which was mild and transient.

Conclusion:

Ripasudil showed additional IOP-lowering effect with other antiglaucoma medications and exhibited no significant side effects.

Pseudoexfoliation (PXF) syndrome was first described by Lindbergh in the year 1917, followed by Vogt, and was initially termed “glaucoma capsulare” as the classical white flaky material was initially thought to originate from the lens capsule, but immunohistology and electron microscopy studies have proven that it is a product of abnormal extracellular matrix metabolism and is deposited throughout the anterior segment of the eye.[1] PXF is the most common identifiable cause of open-angle glaucoma worldwide, which is, in most cases, refractory to medical therapy and has a prognosis worse than primary open angle glaucoma (POAG).[2] Ripasudil hydrochloride hydrate 0.4% is a Rho-associated protein kinase (ROCK) inhibitor with a novel mechanism of structural alteration of trabecular meshwork (TM) and schlemm’s canal (SC), thereby increasing the aqueous outflow. Ripasudil 0.4% in dosing decreases the intraocular pressure (IOP) by altering the shape, contraction, motility, and extracellular matrix (ECM) production in TM and SC, thereby increasing the aqueous outflow along with having anti-inflammatory effect by inhibiting immune cell infiltration and cytokine production. Because of this novel mechanism of IOP reduction, it can even reduce IOP in weak/nonresponders to other antiglaucoma drugs.[3] Most of the studies conducted have been on POAG and ocular hypertension (OHT), and there is less data available on the role of ripasudil on PXF exclusively. Due to this novel mechanism of action, it is ideal for treatment of secondary trabecular open-angle glaucoma such as PXF. The purpose of this study was to assess the IOP-lowering effect and the safety profile of ripasudil as an adjunct treatment in patients with PXF glaucoma (PXF G) at maximal tolerated antiglaucoma medications.

Methods

This prospective, interventional study included 40 patients undergoing adjunctive therapy with ripasudil 0.4% eye drops for at least 6 months, all of whom had visited our institution between May 2021 and Jan 2022. The sampling strategy was purposive with an expected population proportion of 2.2% with 5% relative precision and 95% desired confidence interval. The sample size was calculated to be 40 based on the results of Thomas et al.,[4] considering the attrition rate of 10%. The following sampling formula has been used:

Based on this study, the prevalence of PXF based on hospital reports from India varies between 1.87% and 13.5%. This study was approved by the ethics committee and was conducted in accordance with the tenets of the Declaration of Helsinki. Patients enrolled in the study had clinically apparent PXF material on the anterior lens capsule and/or pupillary margin with other signs such as loss of pupillary ruff, iris transillumination defects, pigment dispersion over the corneal endothelium (Krukenberg’s spindle), trabecular meshwork pigmentation, and Sampaolesi’s line or PXF material in angle along with an open angle on gonioscopy. All these features were associated with IOP values which were beyond their own target IOP, despite using at least one preexisting antiglaucoma medication. The medication scores for each patient before initiation of ripasudil eye drop were designated as follows: 1- monotherapy, 2- fixed combination duo therapy, 3- triple therapy, and 4- >3 or oral medication. Exclusion criteria included narrow angle on gonioscopy, media opacity that impaired visualization of the fundus, subluxated lens, past history of intraocular surgery, uveitis or ocular trauma, history of glaucoma surgery or laser within 6 months of starting ripasudil 0.4%, starting or stopping another glaucoma medication within 4 weeks of starting ripasudil and until the first posttreatment follow-up visit, and patients who did not report for follow-up. Complete ophthalmic examinations were performed in all 40 patients, which included best-corrected visual acuity, slit-lamp biomicroscopy, IOP measurement using Goldmann applanation tonometer, anterior chamber angle examination using Posner 4-mirror gonioscope, stereofundoscopy using +90 D lens, central corneal thickness measurement, and visual field assessment using Humphrey Visual Field (HVF) analyzer. HVF was done at baseline and 6 ± 1 months after initiation of ripasudil. Severity of glaucoma was defined by the values of their mean deviation (MD) as follows: mild glaucoma, MD <−6 dB, moderate glaucoma, MD between − 6 and − 12 dB, advanced glaucoma, MD between − 12 and − 20 dB, and end-stage glaucoma, MD <−20 dB.[5] The average IOP calculated from two measurements at an interval of 15 min before initiation of ripasudil medication was defined as the premedication IOP, whereas single IOP measurement per visit at 1, 3, and 6 months was defined as the postmedication IOP. Grade of PXF was assessed using the grading scale as follows: 0- no PXF material detectable, 1- PXF in one to three quadrants, 2- bull’s eye pattern, and 3- two plus flocculent PXF material seen on the lens capsule and iris.[6] Inferior angle pigmentation was graded as 0- none, 1- trace, 2- patchy, and 3- heavy confluent pigmentation.[6] Occurrence and type of adverse effects (AEs) were documented throughout the study. Bulbar conjunctival hyperemia was assessed using the grading scale as follows: 0- none (normal), +0.5- trace (trace flush, reddish pink), +1- mild (mild flush, red), +2- moderate (bright red), and + 3- severe (deep, bright diffuse redness).

The primary outcome measure was the degree of IOP reduction at 6 months of treatment, whereas the secondary outcome measures were the percentage of patients reaching the predefined target IOP and the occurrence of adverse effects. All the data was analyzed using Statistical Package for the Social Sciences (SPSS) Statistics 16 software. The premedication and postmedication IOP were compared by paired t-test, and a P-value <0.05 was considered statistically significant.

Results

A total of 40 patients (40 eyes) (M: F = 3:1) met the inclusion criteria and were enrolled in the study [Table 1]. In case of both eyes, the eye with higher baseline IOP was used for statistical analysis. The average age at recruitment was 60.02 ± 8.74 years and the range was between 46 and 80 years.

Table 1.

Demographic details

Categories	Frequency (percentage)	Mean +/- SD (in years)
Total patients(eyes)	40(100)
Sex
Male	30(75%)
Female	10(25%)
Age		60.025+/- 8.73
Male		59.36+/-9.22
Female		62+/- 6.69

The average medication score was 1.85 ± 1.05, with 72.5% patients being diagnosed with PXF within the last 5 years. Twenty eyes were on travoprost, 11 eyes were on travoprost + timolol, four eyes were on travoprost + timilol + dorzolamide, and five eyes were under systemic carbonic anhydrase inhibitor, before treatment with ripasudil.

The average IOP before instillation of ripasudil in our cohort was 25.375 ± 3.276 mmHg (range 21–36 mmHg). After administration of ripasudil 0.4%, all the 40 eyes exhibited effective IOP reduction of 10.04% at 1 month, 17.54% at 3 months, and 24.13% at 6 months, which were significant with a P value <0.05. Thirty-five out of 40 patients reached target IOP or lower at the end of 6 months [Tables 2 and 3]. There was no statistically significant association between the PXF grade and the level of IOP elevation.

Table 2.

Percentage IOP reduction at 1, 3, and 6 months

Time duration	Study eye IOP (mmHg)	Difference (mmHg)	IOP reduction (in percentage)	P
Baseline	25.375±3.276	--	--
1 month	22.825±2.518	2.55	10.04%	0.0002
3 months	20.925±2.295	4.45	17.536%	<0.0001
6 months	19.25±2.62	6.125	24.13%	<0.0001

IOP=intraocular pressure

Table 3.

Percentage IOP reduction at 6 months in different medication score groups

Medication score	No. of patients	Pre-ripasudil IOP (mmHg)	Post-ripasudil IOP at 6 months (mmHg)	% Reduction
1 (Monotherapy)	20	23.3±1.1	17.55±1.16	24.68 (P<0.0001)
2 (Combination duo therapy)	11	26.18±1.266	20.909±1.239	20.12 (P<0.0001)
3 (Combination triple therapy)	4	25.5±0.866	17.75±1.089	30.39 (P<0.0001)
4 (>3/oral medicine)	5	31.8±4.118	23.60±2.57	25.79 (P=0.0054)

Nine eyes had grade 1, 13 eyes had grade 2, and four eyes had grade 3 pigmentation of inferior iridocorneal angle, while 14 eyes showed no pigmentation at all [Table 4]. Sampaolesi’s line, however, was present in all 40 cases. Two out of nine eyes with Grade 1, seven out of 13 eyes with Grade 2, and all four eyes with Grade 3 pigmentation had the pigmentation in more than one angle, with the highest density of pigmentation being in the inferior angle [Table 5]. The grade of inferior iridocorneal angle pigmentation was found to be higher in eyes with elevated IOP (P < 0.05).

Table 4.

PXF grade and inferior angle pigmentation grade

PXF grade (n)	Average IOP	Inferior angle pigmentation grade (n)	Average IOP
0 (0)	Nil	0 (14)	23.07±1.386
1 (13)	25.153±3.57	1 (9)	24.77±1.314
2 (17)	25.411±3.15	2 (13)	25.61±1.443
3 (10)	25.2±3.24	3 (4)	32±4.24

IOP=intraocular pressure, PXF=pseudoexfoliative

Table 5.

Correlation of percentage IOP reduction with inferior angle pigmentation grading in eyes with more than one angle pigmentation

Inferior angle pigmentation grade in eyes with more than one angle pigmentation	n	Baseline IOP	IOP at 6 months	% Reduction of IOP
Grade 1	2	25±1.414	18.5±3.535	26 (P=0.1371, t=−2.684)
Grade 2	7	25.857±1.864	19±1.988	24.86 (P<0.0001, t=−6.242)
Grade 3	4	32±4.898	24.75±3.304	22.65 (P=0.0495, t=−2.454)

IOP=intraocular pressure

Fifteen eyes had mild glaucoma on HVF with a mean MD of − 3.27 ± 1.369, 20 eyes had moderate glaucoma with a mean MD of − 8.805 ± 1.484, and five eyes had advanced glaucoma with a mean MD of − 15.858 ± 1.648. There were no eyes with end-stage disease in our study.

Only three patients developed conjunctival hyperemia (two with grade 1 and one with grade 2) as an adverse drug reaction, which was mild and transient and did not warrant discontinuation of treatment.

Discussion

PXF is the ocular manifestation of a systemic disorder and is characterized by deposition of gray-white fibrillary amyloid material in the trabecular meshwork and other ocular tissues, thus leading to secondary open angle glaucoma, which is, in most cases, refractory to medical therapy and has a prognosis worse than POAG.[7]

With conventional available medical therapy, target IOP is seldom reached with medical management alone. Since elevated IOP is a modifiable risk factor in the progression of visual impairment in this silent disease, it is only prudent to effectively reduce the IOP while minimizing the adverse effects.[8]

In this study, the IOP-lowering effect of ripasudil 0.4% eyedrop was analyzed in a total of 40 eyes of patients having PXF G, who were already on preexisting antiglaucoma medications. There was unequivocal response to the addition of ripasudil, with the maximal decrease in mean IOP being 24.13% from a baseline IOP of 25.375–19.25 mmHg at the end of 6 months, which was statistically significant (P < 0.00001). Thirty-five of 40 (87.5%) patients reached the target IOP or even lower.

The amount of pigmentation of the inferior iridocorneal angle was positively correlated with the elevated level of IOP (P < 0.05) and was likely associated with the degree of trabecular dysfunction, rather than the amount of PXF material on the anterior lens capsule, which was not found to be statistically significant. The maximum reduction in IOP in eyes having more than one angle pigmentation was in Grade 1 pigmentation group, but it was not statistically significant (P = 0.1371). Grade 2 and Grade 3 showed IOP reduction of 24.86% and 22.65%, respectively; however, there was no statistically significant difference in IOP between these groups. A study by Shuba et al. (2007) showed a positive correlation between inferior angle pigmentation and IOP, but no correlation with the severity of glaucoma.[6] In our study also, the grade of inferior iridocorneal angle pigmentation was found to be higher in eyes with more elevated IOP. Cobb et al.,[9] however, demonstrated no association between angle characteristics and severity of glaucoma in eyes with PXF.

Matsumura et al.[10] demonstrated the IOP-lowering effect of ripasudil as a second-line drug in addition to prostaglandin (PG) analogs in PXF G, with a maximum reduction of 18.7% at 5–6 months. In our study, the maximum IOP reduction at 6 months was 24.13%.

A retrospective study by Sato et al.[11] in 92 patients who received ripasudil as an additive treatment, seven of whom had PXF, showed a mean decrease in IOP from 18.9 mmHg at baseline to 15.8 mmHg at 6 months.

A study by Futakuchi et al.[12] on uveitic glaucoma (UG), steroid-induced glaucoma (SG), and PXF G demonstrated that the IOP-lowering effects of ripasudil were significantly larger in UG and SG than those in PXF G. This finding was likely related to the higher baseline IOP levels of UG and SG. In a subgroup analysis of PXF G eyes according to baseline IOP, IOP reduction rates of higher baseline IOP of PXF G cases (≥22≥mmHg) were comparable to those of UG and SG eyes.

Analyzing the visual fields done at 6 ± 1 months showed that the mean decline in MD values was not statistically significant in groups having mild, moderate, and severe glaucoma, considering age-related normal decline of MD values.[13] In Matsumura’s study (2007),[10] the mean (±standard deviation [SD]) MD in the HVF test was −5.69 ± 4.80 dB (range −17.26 to −0.32 dB) at baseline.

The most common side effects were conjunctival hyperemia (74%), blepharitis (20.6%), and allergic conjunctivitis (17.2%) in a study by Dhillon. The conjunctival hyperemia was mild (97%), transient, and showed spontaneous resolution (78%).[14] In our study, only three patients developed conjunctival hyperemia (two of them grade 1 and the remaining one grade 2) as an adverse drug reaction which was mild and transient and did not warrant discontinuation of treatment. This should not cause much of a problem if the patients are counseled properly before initiation of treatment.

Therefore, it can be assumed that patients of PXF G, in whom raised IOP principally affects the trabecular meshwork, can be benefited by addition of ripasudil. Moreover, the statistically significant lowering of IOP can avoid or delay glaucoma surgery, which is particularly important in patients who are not fit candidates for surgery. Limitation of this study was its small sample size, especially in eyes with a higher medication score. The grading systems used for PXF material and pigment may not truly represent the amount of these deposits present in the outflow pathway.

Conclusion

This study suggests that ripasudil is a propitious antiglaucoma agent that can effectively lower IOP in PXF G patients who are at maximal tolerated antiglaucoma therapy, due to its novel mechanism of structural alteration of TM and SC, thereby increasing the aqueous outflow. However, the status of the trabecular meshwork may affect the IOP-lowering effect of ripasudil because irreversible damage to the trabecular meshwork would considerably affect the drug’s efficacy. Therefore, it may be better to start ripasudil treatment during an early stage of glaucoma.[15] Regarding its safety, conjunctival hyperemia is the most common adverse reaction, but is usually transient and mild. To conclude, ripasudil is a promising novel drug for PXF G with better IOP control and high safety profile, and using it as an adjunctive therapy can avoid glaucoma surgery or delay it.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.