Use of systemic immunosuppression remains somewhat controversial after ocular surface transplantation due to perceived risks. However, according to OSN Cornea/External Disease Board Member Edward J. Holland, MD, those perceptions may be rooted in experience in the systematic literature, which may not be applicable to eye surgery.

Moreover, systemic immunosuppression improves the odds of successful transplantation, meaning a greater chance of surgical success. Increasing the chance for successful surgery to preserve or improve vision should be part of the risk-benefit calculus, Dr. Holland said in a presentation at the World Cornea Congress.

Humoral immune involvement

If the ocular surface were devoid of vascularization, it would be more amenable to transplantation. Blood vessels act as an intermediary between the host immune system and the donor tissue. In the absence of humoral immune responses, topical immunosuppression would be sufficient to counteract local, cell-mediated immune reactions.

“But with ocular surface transplants, these are very vascularized tissues and the inflammation is a key problem, and so we learned many years ago that without systemic immunosuppression, the success rate is very poor,” Dr. Holland said in an interview with Ocular Surgery News.

But the idea of systemic immunosuppression after corneal transplantation has not gained wide-scale acceptance, owing partly to the risks of side effects associated with systemic agents, including renal and liver toxicity and bone marrow suppression, he said.

“We certainly have been cautious and discuss the side effects with these patients, but they’re willing to accept some of these risks because the alternative is blindness. Patients feel like these risks are certainly worth taking to eliminate blindness,” he said.

Review of cases

In reviewing cases in his own practice, Dr. Holland has noticed a lower rate of side effects and complications than has been noted in the literature on organ transplants.

In a retrospective review of 225 eyes of 136 patients who received immunosuppression after undergoing ocular surface transplantation at the Cincinnati Eye Institute/University of Cincinnati, 23 patients had 26 adverse outcomes; however, only three severe adverse events in two patients occurred. There were two myocardial infarctions and one pulmonary embolism recorded during follow-up, which was a mean 4.5 years. The majority of adverse events were minor and non-life-threatening (23 minor events in 11 patients).

At the time the review was performed, 37 patients (35.2%) had successfully been tapered off of immunosuppressive therapy and 105 patients (77.2%) had a stable ocular surface at their last visit. Most patients still on immunosuppressive therapy were being followed with monotherapy.

Of note, 76 of the patients reviewed in the study presented to the eye clinic with no systemic comorbidities, which may explain, in part, the low rate of adverse events. Often, patients who undergo organ transplantation have multiple concomitant systemic illnesses or have elevated safety risks due to chronic comorbidities such as hypertension, diabetes or cardiovascular disease. This is not the case for patients undergoing ocular surface transplantation.

“The majority of our patients with ocular surface disease are younger and have no systemic comorbidities, and therefore the side effects we are seeing, such as renal or liver toxicity or bone marrow suppression, are not the same,” Dr. Holland said. “We have been pleasantly surprised that in our group of patients, these medications have been very well-tolerated and we’ve had … no mortalities and very, very few significant complications.”

Advances for transplants

Ocular surface transplant specialists may benefit from recent advances in systemic organ transplantation. According to Dr. Holland, newer agents such as Rapamune (sirolimus, Wyeth) and Simulect (basiliximab, Novartis Pharmaceuticals) were developed with organ transplantation in mind but may also find utility for ocular surface transplantation.

Along with these new therapeutics, new patient dosing and monitoring protocols, as well as new ideas about which drugs should or should not be given — namely, the idea of prednisone-sparing regimens — advance the knowledge base that corneal specialists can tap.

Prominent among the recent advances in organ transplantation is the concept of individualized immunosuppression. A number of host factors — including previous or current medical history, presenting diagnosis, level of conjunctival involvement, and previous blood transfusion or transplant history, both of which may increase circulating antibodies — can potentially influence whether ocular surface transplantation is successful.

Dr. Holland has developed a protocol he now employs for all cases of ocular surface transplants. However, based on individual patient needs, the exact treatment protocol can be modified.

“We titrate the level of immunosuppression based not only on the preoperative diagnosis and the degree of inflammation, but also the pre-existing immune makeup of the patient,” Dr. Holland said.

The finesse required to achieve the appropriate level of systemic immunosuppression may depend on the involvement of specialists in organ transplantation. Dr. Holland has adopted a team approach at his practice, the Cincinnati Eye Institute, where a transplant immunologist regularly consults on ocular surface transplantations.

“Because we are operating on the ocular surface, we have the added advantage of augmenting our systemic immunosuppression with topical immunosuppression. All patients receive topical steroids and cyclosporin A,” he said. This topical therapy is an adjunct to systemic treatment and is continued indefinitely.

“I think we have made great strides in our approach to severe ocular surface disease,” Dr. Holland said. “This is a group of patients who a decade ago had a relatively poor prognosis. But with the approach of a team of cornea, glaucoma and retina specialists, as well as transplant immunologists as part of the team now, we certainly have a much, much better chance of increasing our success rate and improving the visual outcome.”

• Edward J. Holland, MD, can be reached at the Cincinnati Eye Institute, 580 South Loop Road, Edgewood, KY 41017; 859-331-9000; e-mail: eholland@fuse.net.

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