Proliferative vitreoretinopathy is the main cause of failure after retinal detachment surgery. “There is going to be some proliferation in all cases of retinal detachment. It’s a matter of whether it’s so excessive that it causes enough harm to frustrate the success of the surgery,” says William Smiddy, MD, in practice at Bascom Palmer Eye Institute.
When PVR does occur, it has traditionally been treated surgically. According to Jennifer Lim, MD, in practice at the University of Illinois at Chicago.
“It requires a very meticulous and thoughtful approach in order to combat the amount of scar tissue and shrinkage that’s present in the retina and fix the PVR detachment,” Dr. Lim says. “Basically, you must know when a scleral buckle is needed in addition to pars plana vitrectomy and when you need to ‘cut the retina’ and perform a relaxing retinectomy, in order to relieve the traction, because a scleral buckle and just peeling the PVR scar tissue will be not enough. You also must know when you need to access the subretinal space and cut or sometimes remove PVR scar tissue underneath the retina, because you don’t always have to do it. Sometimes, you can just leave the subretinal PVR in place as long as the subretinal tissues/bands are not tenting up the retina. Other times, you can just segment the band, and that will relieve the tented up retina and allow it to attach to the RPE. In these cases, the retina will relax without us actually having to remove it in the subretinal space. Obviously, it depends on exactly where the subretinal band is located. For instance, if it’s right underneath the foveal region and causing elevation there, even though the retina will lie flat, you may want to remove it or move it out of the way via a retinotomy outside the foveal/macular area,” explains Dr. Lim.
She adds that there’s a high recurrence rate for PVR and retinal detachment even after surgery. “Because of that, people have tried to inject adjuvants, such as methotrexate, into the eye during the immediate postoperative period to try to decrease the proliferation of scar tissue in PVR,” she explains. “I was part of the GUARD (Gain Understanding Against Retinal Disease) study, sponsored by the company Aldeyra, which investigated the use of a formulation of methotrexate administered intravitreally, in a specific protocol for eyes with PVR undergoing retinectomy. Initially, these eyes were randomized to use of methotrexate after relaxing retinectomy for the most severe PVR versus no methotrexate.”
 |
| Figure 1. Preoperative view shows temporal retinal detachment with marked peripheral chorioretinal scarring, proliferative vitreoretinopathy, subretinal bands in the macula and a star fold with adjacent retinal break (left). Corresponding optical coherence tomography shows disorganized retinal laminations with tractional elevation. Postoperatively (right), the scleral buckle appears to support the area of inferior traction. Previous areas of macular proliferative vitreoretinopathy and subretinal bands have been released with no significant traction on the retina. Optical coherence tomography shows relief of macular traction with resolution of subretinal bands and fluid. Photo: Efrem Mandelcorn, MD. |
ADX-2191
In 2022, Aldeyra Therapeutics was investigating ADX-2191 (methotrexate injection, USP), which is a sterile, non-compounded intravitreal formulation of methotrexate, for the potential prevention or treatment of PVR and several other specific rare retinal diseases, including primary vitreoretinal lymphoma and retinitis pigmentosa. ADX-2191 received FDA Orphan Drug Designation for the prevention of PVR.1
The drug looked promising, achieving the primary endpoint in Part 1 of the Phase III GUARD Trial. ADX-2191 was statistically superior to historical control for the prevention of retinal detachment due to PVR over six months.
Part 1 of the GUARD Trial was designed to assess the preliminary activity of ADX-2191 versus historical control and routine surgical care without therapy in patients with PVR. In this study, 68 patients received ADX-2191, and 38 patients received routine surgical care. Compared to historical control, patients who received serial intravitreal injection of ADX-2191 experienced a statistically significant reduction in retinal detachment over six months. Additionally, the results of the GUARD Trial demonstrated numerical superiority of ADX-2191 over routine surgical care in reducing the dichotomous endpoints of retinal detachment rate over six months, hypotony, complete retinal attachment by six months, macular attachment by six months, and epiretinal membrane formation. Visual acuity was similar between ADX-2191 treatment and routine surgical care groups. Central macular thickness was numerically lower in ADX-2191-treated patients.
No safety signals were observed in the trial, and ADX-2191 was well-tolerated with no observed treatment-emergent serious adverse events. The most common adverse event associated with ADX-2191 treatment was punctate keratitis, which is a well-known side effect of intravitreal methotrexate. The cases of punctate keratitis were mostly mild in severity. Across all other treatment-emergent adverse events occurring in at least 10 percent of patients in either treatment group, ADX-2191-treated patients had numerically fewer side effects, including pain, cystoid macular edema, corneal edema, macular fibrosis, corneal epithelial defects, anterior uveitis, ocular hypertension and postoperative inflammation, compared to patients who received routine surgical care. One patient in the ADX-2191 group dropped out of the study due to scheduling difficulties.
According to Dr. Lim, one of the problems with the GUARD study is that it used historical controls. “This caused people to question its results. Results were positive compared to historical controls, but there is always doubt in studies that don’t have active controls,” she adds.
Dr. Lim believes that methotrexate use quiets the eyes and decreases the recurrence of the PVR. “However, I don’t know if you need to do it in everybody,” she says. “If you remove all of the scar tissue and you’re very meticulous, I think you can get really great outcomes without the use of it. However, there are certain situations, such as eyes with concomitant choroidal detachments, vitreous hemorrhage or traumatic PVR retinal detachments, in which it may be useful. I rarely use methotrexate; there is no FDA-approved formulation at the present time.”
She adds that the investigators in the GUARD study weren’t masked. “These were silicone oil-filled eyes, and we injected methotrexate into the oil bubble. These eyes were remarkably quiet, so I believe the drug led to decreased inflammation. Some people use it frequently for PVR retinal detachments,” she says.
Other studies have also shown promise in using methotrexate in patients with PVR. For example, a retrospective review was performed on a cohort of five consecutive eyes with severe PVR and recurrent retinal detachment that were treated with relaxing retinectomy, extended perfluorocarbon liquid tamponade (four to five weeks), and a series of intravitreal methotrexate injections (100 to 200 µg/0.05 mL for 10 weeks).2
All five patients remained reattached with 11 to 27 months of follow-up. Additionally, four eyes recovered ambulatory vision (>20/200) with normal intraocular pressure and non-fibrotic laser scars along with the relaxing retinectomy. The initial patient remained reattached but only had hand motion vision. Mild superficial punctate keratopathy occurred in one patient and was the only adverse effect noted. The investigators concluded that methotrexate injections may be beneficial for treating complex retinal detachment caused by PVR, but that further study is indicated.
A larger study found that the rate of redetachment associated with PVR was lower after intrasilicone injection of methotrexate at the end of vitrectomy for rhegmatogenous retinal detachment with severe PVR compared to the control group.3 However, the difference was not statistically significant.
In this prospective comparative study, pars plana vitrectomy and retinal reattachment were performed for eyes with rhegmatogenous retinal detachment with grade C PVR. In the methotrexate group, 250 µg of methotrexate was injected into the silicone oil at the end of surgery. The researchers then assessed the rate of retinal redetachment associated with PVR.
The study included 44 eyes of 44 patients (22 in the methotrexate group and 22 controls). Baseline characteristics were similar between the two groups. Retinal redetachment occurred in one eye in the methotrexate group and in five eyes in the control group. The change in visual acuity was similar between the two groups at the final visit.
While methotrexate shows promise, it does have some downsides, according to Dr. Lim. “Patients can develop severe dry eye and corneal problems after methotrexate use” she explains. “You must be very meticulous with corneal lubrication. Otherwise, you can get punctate keratitis, which is a known side effect of methotrexate. Approximately one in 15 or 20 patients will experience significant dry eyes with this drug.”
Other Pharmaceutical Approaches
According to Dr. Smiddy, some of the pharmaceutical approaches that were investigated in the 1980s include antimetabolites, antifolate agents, daunorubicin and other agents. “There’s been a resurgence of investigation in the past four or five years,” he says. “Antiproliferative agents were being evaluated in animal models in particular. The final answer from then was that those smart and prominent researchers couldn’t find anything useful. More recent studies have re-examined the question and present what I would consider encouraging, but preliminary results.”
He notes that researchers resumed their investigation of pharmaceutical agents after intravitreal injections became commonplace for other conditions. “Intravitreal injections play a major role in what we do,” Dr. Smiddy says. “The whole concept of trying to block proliferation is still a good one. It’s a matter of blocking the bad guys and allowing the good guys to proliferate, and doing it in a way that’s not just overly burdensome from a medical management perspective.”
Another reason for investigating pharmaceutical agents is the avoidance of surgery. Additionally, surgical repair of PVR isn’t always successful. “Anything that avoids the operating room is better than surgical repair,” Dr. Smiddy says. “Frankly, surgery reimbursements are being devalued, gradually. Doctors, as well as patients, don’t really want to go back to the OR. So, anything that can avoid surgery is preferable. Also, surgery is not 100 percent successful. Only 70 percent of cases with significant PVR are successfully treated with surgery. There are still plenty of failures. Another option would be very welcomed, but the right option hasn’t presented itself in a way to gain widespread acceptance and use.”
Dr. Lim agrees, noting that many other drugs have been tried, such as steroids and 5-FU. “But, chemotherapeutic and anti-proliferative agents injected intravitreally haven’t worked,” she says. “All of these things potentially can have toxicity. You must ensure that whatever you’re putting inside the eye isn’t going to destroy the retina or cause long-term harm.
“I’m a minimalist,” she adds. “I just try to do the best surgery and get rid of all of the scar tissue. I take a look at the retina, decide if it looks good and if I’m happy with the flexibility of the retina. I use a relaxing retinectomy if I feel the retina is too stiff or too foreshortened despite extensive membrane peeling. I make sure that the retinectomy ends fall neatly onto the retinal pigment epithelium without any traction, and I don’t hesitate to enlarge the retinectomy as needed. Then, I put in silicone oil as needed, sometimes gas, and then watch the eye closely for recurrent PVR in the postop period.”
Dr. Lim was a principal investigator in the Aldeyra Study. Grants went to the University of Illinois-Chicago. Dr. Smiddy has no financial interest to disclose.
1. Company communication. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-achieves-primary-endpoint-part-1-phase-3. Accessed February 19, 2025.
2. Benner JD, Dao D, Butler JW, Hamill KI. Intravitreal methotrexate for the treatment of proliferative vitreoretinopathy. BMJ Open Ophthalmol 2019;4:1:e000293.
3. Falavarjani KG, Hadavandkhani A, Mehdi M. Intra-silicone oil injection of methotrexate in retinal reattachment surgery for proliferative vitreoretinopathy. Ocul Immunol Inflamm 2020;28:3:513-516.
