Proliferative vitreoretinopathy (PVR) is one of the most frustrating impediments to successful retinal detachment repair that vitreoretinal surgeons face. It is characterized by the growth of abnormal membranes in the preretinal or subretinal space, along with intrinsic foreshortening and stiffening of the retina.^1-4 These processes can contract the retina, which then leads to traction, stretch holes, and recurrent retinal detachment.⁵ It can be difficult to predict which patients may develop PVR, although certain risk factors make the development of PVR membranes more likely, such as the presence of intraocular hemorrhage, uveitis, preoperative or postoperative choroidal detachment, size of retinal tears, multiple retinal tears, chronic retinal detachments, and multiple previous surgeries.^1,6,7 Additionally, smoking has been reported to be a risk factor for PVR formation.⁸ It has been challenging to pinpoint an exact chemical target to treat or prevent PVR, as multiple cytokines and growth factors have been implicated in the development of PVR membranes.³ However, dispersion of retinal pigment epithelial cells in the vitreous cavity and/or breakdown of the blood–ocular barrier is known to accelerate PVR formation.^1,3

The presence of PVR can lead to failure of primary retinal detachment repair along with a cascading cycle of recurrent retinal detachments, hypotony, phthisis, and loss of the eye. The incidence of PVR is estimated to be anywhere between 5% and 10% of all retinal detachment repairs and generally occurs within 1 month to 2 months of surgery.^1,5,9

SURGICAL REPAIR

To date, the best management of PVR remains surgical repair.¹⁰ The goal of surgical repair is to relieve traction and reattach the retina. This can be accomplished in a variety of ways, including scleral buckle, vitrectomy, membrane peeling, subretinal band removal, internal limiting membrane peeling, retinectomy, laser, perfluorocarbon use, and often silicone oil tamponade.¹⁰ Depending on the lens status, the lens can be removed by lensectomy, cataract surgery with IOL implantation, or even IOL removal, all of which can allow better access behind the lens for fine membrane dissection and hyaloid removal.¹⁰ Surgeons will often leave patients with complex detachments aphakic, to remove a potential scaffold for anterior PVR formation. Surgeons often place silicone oil at the time of surgery to allow PVR to “mature” and thereby allow the life cycle of cellular proliferation to “burn out.” Visual prognosis with PVR remains unpredictable and can range from excellent vision to blindness.^11,12

METHOTREXATE

An ongoing clinical trial is exploring the use of intravitreal methotrexate for the treatment and prevention of proliferative vitreoretinopathy, titled the Gain Understanding Against Retinal Disease (GUARD) trial.¹³ Methotrexate is proposed to suppress inflammation and cellular proliferation, thereby decreasing PVR formation. Initial investigator-sponsored trials by Elliot and Stryjewski utilizing intravitreal methotrexate in the setting of PVR showed favorable results.¹⁴ Because the PVR life cycle can last for several weeks, the GUARD trial involves serial injections of intravitreal methotrexate over many weeks.

This phase 3 clinical trial is sponsored by Aldeyra Therapeutics and is investigating ADX-2191 (intravitreal methotrexate 0.8%) compared to standard surgical care in regards to PVR.¹³ ADX-2191 has received orphan drug status and fast track designations from the US Food and Drug Administration, helping to fast track the development and review of intravitreal methotrexate in this setting, accelerating patient access to a therapy that could prevent vision loss.

GUARD TRIAL

The GUARD trial is a phase 3, unmasked, multicenter, randomized trial in the United States. There are 2 parts to the trial. Part 1 has completed enrollment with 110 total patients.¹⁵ The results of part 1 will power part 2 of the study, which will enroll a larger number of patients. Eligible patients are 18 years or older and have PVR with star folds in at least 3 cumulative clock hours documented on retinal imaging. Patients with retinal detachment associated with open-globe injury are also included. All patients must be undergoing vitrectomy surgery. Patients excluded include no light perception vision, pre-pthisis, severe nonproliferative diabetic retinopathy or proliferative diabetic retinopathy, history of intraocular inflammation, or hypersensitivity to methotrexate. Additionally, patients with other planned eye surgery or a history of more than 6 retinal detachment repairs in the study eye are excluded.^13,16

In the GUARD trial, all patients have standard surgical care, which includes extensive epiretinal, subretinal, and ciliary membrane removal followed by retinal reattachment using standard surgical technique. The use of perfluorocarbon, ancillary membrane staining dyes, and retinectomy are allowed as per standard surgical care. Any breaks are lasered using moderate to intense laser burns and then all eyes receive either 1,000-centistoke or 5,000-centistoke silicone oil. The use of additional periocular or intraocular steroids is prohibited. Lensectomy, IOL removal, or standard cataract surgery with IOL implantation is allowed as per the discretion of the investigator, although secondary IOL implantation is not allowed in aphakic eyes. Only eyes that achieve successful retinal reattachment are then randomized into the GUARD trial, with a ratio of 1:1 intraoperatively between ADX-2191 or control, which is standard surgical technique.¹⁶

Patients in the treatment group receive ADX-2191 at the conclusion of surgery or on postoperative day 1, followed by weekly injections for 8 weeks, then every other week from week 8 to 16, for a total of 13 injections. The primary outcome studied is the rate of retinal redetachment due to PVR requiring reoperation within the 24 weeks of the study period.¹⁶

Intravitreal methotrexate is known to cause epithelial toxicity, and so all patients receiving ADX-2191 are prescribed frequent artificial tears for corneal lubrication.¹⁶ Top-line results from part 1 of the GUARD trial are expected in the second half of 2022.¹⁵

CLINICAL EXPERIENCE WITH METHOTREXATE

While we are awaiting the results of the GUARD trial, some vitreoretinal surgeons are currently attempting off-label use of intravitreal methotrexate as an option to treat patients with severe recurrent PVR detachments. Several methods have been reported, including replicating the GUARD trial protocol, treat-and-extend methotrexate, and as-needed therapy.^17,18 It is important to recognize that these methods represent off-label use of medication, and that efficacy of intravitreal methotrexate has not been established to date. That being said, anecdotal reports have shown favorable results in preventing progression of PVR.^17,18

CASE REPORT

A surgical patient received intravitreal methotrexate for the treatment and prevention of PVR. This is a 63-year-old female who initially presented with a superior rhegmatogenous macula-on retinal detachment treated with standard vitrectomy, laser, and gas fill. Subsequently, she developed PVR with recurrent inferior retinal detachment, requiring scleral buckle surgery with vitrectomy, laser, and gas fill. She experienced multiple additional retinal detachments which required surgical correction with a combination of multiple retinectomies, oil fill, lensectomy, and extensive membrane peeling. In total, she had 5 prior retinal detachment repairs over the course of 14 months, and presented to our clinic at this time. Her most recent surgery had been 2 months prior. Upon presentation she had hand motion vision and was aphakic, with 1,000-centistoke silicone oil filling the vitreous cavity and a visible recurrent PVR retinal detachment (Figure 1). Visible on examination was a retinal detachment with traction emanating from the prior retinectomies, suspicious for recurrent intrinsic PVR causing recurrent retinal detachment.

Given her history of multiple surgeries and scarcity of “real-estate” to cut more retinal tissue, the decision was made to attempt off-label use of intravitreal methotrexate. The patient received standard surgical care with vitrectomy, membrane peeling, and localized retinectomy formation followed by moderate laser burns around the retinectomy and any open retinal breaks. She received 1,000-centistoke silicone oil, and at the conclusion of the case, the retina was flat and attached. Intravitreal methotrexate 400 μg/0.1 mL was injected on postoperative day 1.

The patient returned for subsequent intravitreal methotrexate injections weekly, although by week 6 she had developed significant corneal toxicity with significant dry eye. Therefore, the patient had 3 more injections of intravitreal methotrexate every other week before stopping the therapy, for a total of 9 intravitreal methotrexate injections.

At 1 year follow-up, the patient remained flat and attached under 1,000-centistoke silicone oil (Figure 2). Still visible were some areas of inactive PVR, although there had been no progression or recurrent detachment over the course of the year. The goal for the patient is potential oil removal in the future should she continue to show stability.

FINAL THOUGHTS

The verdict is still out on whether intravitreal methotrexate will be a therapeutic modality for treatment and/or primary prevention of PVR. We look forward to the results of the GUARD trial to further clarify the efficacy of methotrexate in patients with complicated retinal detachment. RP

REFERENCES

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