June-July 2020


Pharmaceutical Focus
Taking a look at the future of crosslinking

by Liz Hillman Editorial Co-Director

“I think that when we have alternative treatments that are FDA approved, we will decide to use different types of crosslinking for different
eyes in different patients.”
—Michael Raizman, MD

UV light and red aiming/focusing beams on the cornea during crosslinking procedure
Source: Michael Raizman, MD

Crosslinking is interesting in that it has both pharmaceutical and device components that cause a reaction to stiffen collagen fibrils and create linkages between the cornea’s structural components, but the procedure has moved in some ways beyond the initial riboflavin soak followed by UV light exposure.
Since it was first described by Theo Seiler, MD, PhD, in the 1990s, crosslinking has seen some evolution while preserving its goal of stopping progression of corneal steepening in patients with keratoconus or post-LASIK ectasia. The Dresden protocol—an epithelium-off procedure with a riboflavin soak and subsequent UV light exposure on corneas of at least 400 µm—with drug and device components by Avedro (now owned by Glaukos) remains the FDA-approved procedure in the U.S. But change could be coming. For example, the company is conducting a Phase 3 randomized clinical trial to evaluate the safety and efficacy of epithelium-on crosslinking.
EyeWorld spoke with William Dupps, MD, PhD, Joseph Ciolino, MD, and Michael Raizman, MD, about their thoughts on the current status of crosslinking in the U.S. and its future.
In short, they thought a customizable procedure is on the horizon.
“Crosslinking [in the U.S.] is currently the closest thing to a one-size-fits-all procedure that we do in anterior segment surgery,” Dr. Dupps said.
Customization with various techniques might improve outcomes for patients eligible for treatment under the current protocol and/or extend treatment to patients currently excluded.

Epi-on vs. epi-off

There is overwhelming evidence in the literature that an epi-off procedure results in greater stiffening and halting or even partial reversal of progression compared to most epi-on protocols. But Dr. Dupps pointed out that there is much variability in approaches to improve riboflavin penetration through the epithelium—addition of supplemental oxygen, chemical irritants, mechanical irritation, iontophoresis, etc.
“Epi-on is not one procedure,” he said, adding that this “makes it difficult for people to read the literature and draw conclusions between epi-on vs. epi-off.”
Dr. Raizman said with all other variables the same, epi-on crosslinking is less effective. “That’s without question.”
Dr. Ciolino said unless there is a contraindication, he’ll perform epi-off crosslinking, though he discusses the option of epi-on with his patients, most of whom, he said, elect to have epi-off. He said colleagues from Europe recommended use of an Orca blade (Orca Surgical) to remove the epithelium and a regimen of postoperative autologous serum tears with a long, low-dose steroid taper. He said about 75% of patients choose to pay out of pocket for the serum tears, and he hasn’t had any significant scarring or complications following this regimen.
Dr. Raizman said he has performed epi-on crosslinking with other parameters adjusted (supplemental oxygen, modified riboflavin drug, intensified UV light) to enhance the treatment’s effect as part of a clinical trial.
“We’re hoping that with these modifications we can achieve an equal degree of crosslinking,” he said of the currently ongoing study.
The draw of epi-on, Dr. Ciolino said, is not so much pain relief, but safety. There is a higher risk of complications taking the epithelium off.
“I talk to my patients about the pros and cons, and the thing is they’re both painful. The pain lasts longer with epithelium off, but they’re both painful,” he said.

Measuring biomechanical effect

As of right now, there’s not a ready-to-use device to measure the stiffening effect in real time. But Dr. Dupps said work is being done toward this goal, using Brillouin microscopy and OCT-based methods including a non-contact method in development called phase-decorrelation OCT. He said having this information would allow physicians to turn off the treatment system when the desired effect is reached, minimizing risks and shortening procedure time.
Dr. Dupps said there is an immediate stiffening effect with crosslinking that can be measured in the lab, but additional flattening happens after that, which can vary patient by patient.
At 1 month, Dr. Ciolino said most patients have a drop in vision, but by 2–3 months their corneas have flattened at least back to baseline or further. Flattening can occur beyond this timeframe as well.
“One thing that is universally true is that the amount of flattening is not predicable with the typical Dresden protocol,” he said. “It’s true that the vast majority of patients have increased steepening of the cornea at 1 month. It’s also true that nearly all of them are back to baseline by 2–3 months, but from there on, some patients stay right where they are, but others have progressive flattening.”

Crosslinking additions, targeting treatment

Supplemental oxygen is one of the most widely discussed factors that could improve the reactions in a crosslinking treatment to enhance efficacy. Dr. Raizman said there are compounds other than riboflavin that can be used to create a crosslinking reaction with UV light exposure, as well as chemical methods that don’t need UV light at all for crosslinking (though not currently used).
He also said outside the U.S. there are different devices that provide a customized light pattern to the cornea, putting more light energy on the cone itself, with evidence showing better efficacy with this technique. Dr. Dupps said this type of customization backs off other parts of the cornea that are more stable, allowing them to flex in a more favorable manner while the weakest part of the cornea is adequately strengthened.
“I think that when we have alternative treatments that are FDA approved, we will decide to use different types of crosslinking for different eyes in different patients,” Dr. Raizman said.

About the doctors

Joseph Ciolino, MD
Associate professor of ophthalmology
Harvard Medical School
Massachusetts Eye & Ear Infirmary
Boston, Massachusetts

William Dupps, MD, PhD
Professor of ophthalmology
Cleveland Clinic Lerner College of Medicine
Cleveland, Ohio

Michael Raizman, MD
Associate professor of ophthalmology
Tufts University School of Medicine
Boston, Massachusetts

Relevant disclosures

Ciolino: None
Dupps: Glaukos, Cleveland Clinic patents
Raizman: Glaukos


: Joseph_Ciolino@meei.harvard.edu
Dupps: bjdupps@outlook.com
Raizman: mraizman@tuftsmedicalcenter.org

Taking a look at the future of crosslinking Taking a look at the future of crosslinking
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