Clinical trials offer promise of corneal cross-linking

Corneal cross-linking, the process of placing riboflavin on the ocular surface followed by exposure to ultraviolet light, may offer hope for stiffening the cornea. The process, which has been widely used in Europe and Asia since the early part of this decade and has been investigated since the early 1990s, has proven highly successful in treating a disease course that otherwise lacks a highly efficacious and predictable treatment option.

The treatment, however, is not approved for use in the United States and, to date, no application for licensure has been presented to the U.S. Food and Drug Administration. Several clinical trials that are currently enrolling patients or collecting data may soon aid efforts to make the treatment available to U.S. surgeons.

These trials, centered largely on the treatment of keratoconus and corneal ectasia but also novel applications such as treatment of infectious keratitis, may allow for the eventual widespread adoption of the procedure. In the meantime, U.S. clinicians remain optimistic and encouraged by the potential offered by corneal cross-linking.

A promising option

Francis W. Price Jr.

In addition to treating keratoconus, corneal cross-linking may offer the benefit of increasing the number of patients who can receive refractive surgery, according to Francis W. Price Jr., MD, a Cornea/External Disease Board Member of Primary Care Optometry News sister publication Ocular Surgery News.

“Anywhere from 2% to 5% of the people who come in for refractive surgery screenings have latent keratoconus or some abnormalities noticed on their cornea that point toward keratoconus, and typically those people are not treated with laser refractive surgery,” Dr. Price said.

The cross-linking procedure theoretically could stiffen the cornea in patients with structural deficiencies that contraindicate them for refractive laser correction. The procedure may also offer promise as a prophylactic step to reduce the risk of postoperative corneal ectasia.

Combined with other advances in refractive surgical technology, corneal cross-linking could make refractive surgery safer in certain patients. Specifically, Dr. Price said, newer femtosecond lasers can cut corneal flaps at obtuse angles, which may help the healing process. More rigid corneal architecture and flaps with stronger wound configurations may make refractive surgery an option for patients who currently are poor candidates.

“If we had the ability to basically lock in the cornea and stiffen it a little bit, we could not only treat their refractive errors, but in those cases, probably treat some of the changes in topography to give them more normal shape to the cornea,” Dr. Price said.

Clinical trials

Several clinical trials are currently investigating the safety and efficacy of corneal cross-linking. According to ClinicalTrials.gov, at least 15 studies are currently enrolling or collecting data on corneal cross-linking for keratoconus, ectasia or corneal infection.

To date, most treatment modalities for keratoconus have focused on mitigating the refractive error induced by the thinning and bulging of the cornea. Glasses and contact lenses, the primary treatment methods, allow patients to see beyond the corneal irregularity. However, the only currently available treatment methods that address the changes in corneal architecture are corneal implants and corneal transplantation.

R. Doyle Stulting

“So far, we have had no treatment modality that addresses the underlying problem,” R. Doyle Stulting, MD, PhD, an OSN Cornea/External Disease Board Member, said.

Dr. Stulting is the study director for three clinical trials on corneal cross-linking: a physician-sponsored protocol through Emory University with indications for keratoconus and LASIK-induced ectasia; a multicenter trial, sponsored by Peschke Meditrade, with the same indications; and a compassionate-use protocol for progressive keratoconus in patients who do not qualify for the physician-sponsored clinical trial protocol.

Corneal cross-linking may have an impact beyond treatment of the disease course, as the one-time procedure would potentially reduce long-term treatment costs and lost work time experienced by patients. According to Dr. Stulting, keratoconus is responsible for about 15% of corneal transplants in the United States each year, and there is the possibility that corneal cross-linking may eliminate that need.

There is also the chance that keratoconus is the tip of the iceberg for the procedure’s utility. For instance, because “cross-linking makes the eye resistant to enzymatic degradation of the cornea,” Dr. Stulting said, it may have utility in treating noninfectious corneal ulcers secondary to rheumatoid arthritis or other autoimmune diseases.

Infectious keratitis

Another application of corneal cross-linking currently under review is in treating infectious keratitis. In a study monitored by Erik Letko, MD, patients with any nonperforating corneal ulcer are being followed prospectively after treatment with riboflavin and the UVA light.

“There is solid clinical and research evidence that application of riboflavin and the UVA light is able to kill microorganisms,” Dr. Letko said. “In fact, the technology is used to sterilize blood products, which is the background for this study outside of eye care.”

Dr. Letko’s study picks up where the European experience with the technology leaves off. Clinicians in Europe have used riboflavin and UVA light in infectious keratitis that has failed prior therapy. A retrospective study by Iseli and colleagues in 2008 noted that it is “a promising option for treating patients with infectious keratitis who do not respond to broad-spectrum antibiotic therapy,” and the procedure may stall or eliminate the need for emergency keratoplasty in these patients.

The exact mechanism of action for how riboflavin and UVA light work in infectious keratitis remains unknown at this point, Dr. Letko said, but several theories have been postulated: The interaction between the two kills microorganisms; it may strengthen the corneal stroma through cross-linking, which may act as a barrier against penetrating organisms; or it may reduce scarring by inactivation of white blood cells.

Dr. Letko said he is looking at the procedure as a primary therapeutic option. The study will track safety and efficacy, including a need for débridement of the epithelium in an inflamed cornea and a minimum corneal thickness, both of which are considered important factors in keratoconus and ectasia patients.

Questions remain

The corneal cross-linking procedure offers tremendous potential for U.S. clinicians in treating infectious keratitis, but several questions remain regarding how the procedure should be performed and who should or should not receive it.

“We hope that we will be able to avoid corneal perforation in patients who would otherwise have that with the standard treatment,” Dr. Letko said. “The caveat is that it’s going to be difficult for the study to show this because it is hard to provide a control group, and it’s hard to say whether this or that patient, without the application of the UVA and riboflavin, would have ended up with a perforation.”

Another important question regarding corneal cross-linking is whether débridement of the epithelium is necessary to achieve penetration of the riboflavin. The FDA trials, including those being monitored by Dr. Stulting, are all “epithelium off” procedures, in which a portion of the epithelium is removed to allow the large riboflavin molecules to penetrate.

“There are no good data showing that the riboflavin penetrates if the epithelium remains on the cornea,” Dr. Stulting said.

Brian S. Boxer Wachler

However, a procedure invented by Brian S. Boxer Wachler, MD, called C3-R, has so far produced similar results while leaving the epithelium intact. He has been performing this procedure in the United States for 5 years.

By pre-treating the cornea with tetracaine, Dr. Boxer Wachler said he is able to achieve riboflavin penetration without scraping the corneal surface.

“We found that the preservative in the tetracaine helps loosen the epithelium, and that’s how we do the procedure with the epithelium in place, what we call transepithelial cross-linking,” Dr. Boxer Wachler said.

European experience

The technique of cross-linking collagen in the cornea, which was first developed and put into practice by Theo Seiler, MD, PhD, an OSN Europe Edition Editorial Board Member, has been adopted by an increasing number of European surgeons. The technology has evolved, treatment protocols have come to a better definition, and indications are slowly becoming clearer.

“The international data from a number of sources, including a randomized, controlled, prospective study in Australia, clearly shows the safety and efficacy of the procedure, and it’s unfortunate that we in this country have to test this through a painstaking, lengthy and expensive process to get FDA approval for it, which puts us and our patients at quite a disadvantage for something that is approved in many other countries,” Dr. Stulting said.

In Dresden, where now more than 400 eyes have been treated, it was demonstrated that cross-linking has an impact on corneal biomechanics, as it strengthens and stiffens the cornea. It was also shown that keratoconus progression was halted in most of the cases, maximum keratometry readings decreased, and all Pentacam-measured keratoconus indexes were reduced.

These results were confirmed by controlled prospective trials.

From 1999 to 2004, side effects were investigated by the Dresden group. It was shown that the procedure induces keratocyte depopulation about 300 µm deep within the stroma and that repopulation requires up to 6 months. Therefore, a minimum corneal thickness of 400 µm, as previously recommended, was confirmed as the safety threshold for the treatment to avoid damage to the endothelium and deeper structures such as the lens and retina.

In a recent publication, however, Prof. Seiler and colleagues showed that preoperative swelling of the cornea using hypo-osmolar riboflavin solution safely broadens the spectrum of corneal cross-linking indications to thin corneas that would otherwise not be eligible for treatment.

Another area of this group’s research is indications in relation to age.

“Following approval from the ethic committee, we have started applying the technique to 10- to 16-year-old patients, and now more than 60% of our treatments are performed in this age group,” Aldo Caporossi, MD, said.

When keratoconus develops at such a young age, it is particularly severe, evolves quickly and inevitably leads to early corneal transplantation.

It is likely that this study will confirm his previous conclusion: In all cases of progressive keratoconus, cross-linking should be performed as early as possible.

“On average, the time of maximum evolution of the disease is between 12 and 26 years, and it is at this stage that we should cross-link the cornea,” he said.

Protocol in progress

In the nearly 450 centers where cross-linking is currently performed worldwide, the procedure follows a fairly standardized protocol. However, a few variations have been proposed by individual specialists to improve safety, efficacy and patient comfort and to widen indications.

Dr. Boxer Wachler’s transepithelial technique is currently being studied by Aylin Ertan Kılıç, MD, of Kudret Eye Hospital in Ankara, Turkey. Specifically, Dr. Ertan Kılıç is studying the use of transepithelial cross-linking in conjunction with the use of Intacs.

“In advanced cases of keratoconus, cross-linking may be considered after Intacs [Additional Technology, Des Plaines, Ill.] implantation to provide slight improvement in refractive and visual results with possible stabilization effect and without significant adverse consequences,” Dr. Ertan Kılıç and colleagues said in a recent article in Cornea.

Another transepithelial approach is also being studied by Dr. Ertan Kılıç, which involves impregnating the corneal surface with a 20% alcohol solution for 25 seconds.

“Alcohol breaks the tight junctions of epithelial cells, so the epithelium is no longer a barrier to riboflavin penetration,” Dr. Ertan Kılıç said.

There are several advantages in leaving the epithelium on, she said. Healing and visual rehabilitation are faster, and the patient experiences no pain. In addition, the risk of complications is significantly lowered.

For more information:

• Francis W. Price Jr., MD, can be reached at Price Vision Group, 9002 N. Meridian St., Suite 100, Indianapolis, IN 46260; (317) 844-5530; fax: (317) 844-5590; e-mail: fprice@pricevisiongroup.net.
• R. Doyle Stulting, MD, PhD, can be reached at the Department of Ophthalmology, Emory University, Atlanta, GA 30319; (404) 778-6166; fax: (404) 778-6165; e-mail: ophtrds@emory.edu.
• Erik Letko, MD, can be reached at Price Vision Group, 9002 N. Meridian St., Suite 100, Indianapolis, IN 46260; (317) 844-5530; fax: (317) 844-5590; e-mail: erikletko@pricevisiongroup.net.
• Brian S. Boxer Wachler, MD, can be reached at Boxer Wachler Vision Institute, 465 N. Roxbury Drive, Suite 902, Beverly Hills, CA 90210; (310) 860-1900; fax: (310) 860-1902; e-mail: bbw@boxerwachler.com.
• Theo Seiler, MD, PhD, can be reached at IROC AG, Institut für Refraktive und Ophthalmo-Chirurgie, Stockerstrasse 37, CH-8002 Zürich, Switzerland; 41-43-488-38-00; fax: 41-43-488-38-09; e-mail: michele.rellstab@iroc.ch (personal secretary).
• Aldo Caporossi, MD, can be reached at Policlinico Le Scotte, V.le Bracci, 53100 Siena, Italy; 39-0577-233356; fax: 39-0577-233358; e-mail: caporossi@unisi.it.
• Aylin Ertan Kılıç, MD, can be reached at Kudret Eye Hospital, Kennedy Street 71, Kavaklidere, Ankara, Turkey; 90-312-4466464; e-mail: aylinclzy@hotmail.com.

References:

• Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, Caporossi A. Corneal cross-linking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg. 2009;35(5):893-899.
• Coskunseven E, Jankov MR 2nd, Hafezi F. Contralateral eye study of corneal collagen cross-linking with riboflavin and UVA irradiation in patients with keratoconus. J Refract Surg. 2009;25(4):371-376.
• Ertan A, Karacal H, Kamburoglu G. Refractive and topographic results of transepithelial cross-linking treatment in eyes with Intacs. Cornea. 2009;28(7):719-723.
• Hafezi F, Mrochen M, Iseli HP, Seiler T. Collagen cross-linking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg. 2009;35(4):621-624.
• Iseli HP, Thiel MA, Hafezi F, Kampmeier J, Seiler T. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea. 2008;27(5):590-594.
• Kamburoglu G, Ertan A. Intacs implantation with sequential collagen cross-linking treatment in postoperative LASIK ectasia. J Refract Surg. 2008;24(7):S726-S729.
• Kerautret J, Colin J, Touboul D, Roberts C. Biomechanical characteristics of the ectatic cornea. J Cataract Refract Surg. 2008;34(3):510-513.
• Knox Cartwright N, Tyrer J, Marshall J. Corneal biomechanical change with age and following cross-linking treatment. Paper presented at: ESCRS Winter Meeting; February 2009; Rome.
• Koller T, Iseli HP, Hafezi F, Vinciguerra P, Seiler T. Scheimpflug imaging of corneas after collagen cross-linking. Cornea. 2009;28(5):510-515.
• Mazzotta C, Traversi C, Baiocchi S, et al. Corneal healing after riboflavin ultraviolet-A collagen cross-linking determined by confocal laser scanning microscopy in vivo: early and late modifications. Am J Ophthalmol. 2008;146(4):527-533.
• Vinciguerra P, Albè E, Trazza S. Refractive, topographic, tomographic and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology. 2009;116(3):369-378.