Taking Timely Action in DME with a Multimodal Approach

by Joanna Lee

Currently, the prevalence of diabetes in the United States is 30 million and that number is expected to increase dramatically over the next 10 to 20 years. Further, about 25 percent of these patients will develop diabetic retinopathy (DR) and 10 percent will develop diabetic macular edema (DME). At the recently held Virtual American Society of Retina Specialists 38th Annual Meeting (ASRS 2020), a multimodal approach to manage DME was discussed by Dr. Nancy Holekamp, director of retina service at Pepose Vision Institute in St. Louis, Missouri, USA, and Dr. Arshad Khanani, director of clinical research at Sierra Eye Associates in Reno, Nevada, USA. Both shared their views and clinical experience using Ozurdex (dexamethasone intravitreal implant) to treat patients with DME. Symposium Moderator Dr. Peter Kaiser from Cleveland Clinic in Ohio, USA, said DME patients are often of working-age and thus, can find it challenging to keep up with monthly or bimonthly clinical treatments. The speakers began by detailing the usual way of treating DME patients (with persistent fluid during the first six months of diagnosis. Dr. Holekamp said it’s important for patients to get injections for the first six months. “We don’t want to undertreat because we don’t know if the treatment is really working or not,” she said. Apart from measuring visual acuity, she also believes in OCT as a primary biomarker for making decisions. Good foveal depression and a dry macula are factors that enhance patients’ chances of

I n D M E t r e a t m e n t , t i m i n g i s e v e r y t h i n g .

better vision, she said. After the third or fourth month of injections, and if OCT results do not show any improvement, she would then discuss steroid treatment.

Experience with the first line of defense

Patients’ progress seems to hinge on their initial response to treatment. The DRCR.net Protocol T study has shown that if a patient responds positively after the first three antiVEGF injections, this course of treatment would most likely be continued.

Dr. Khanani shared that he treats conservatively at first, moving from one anti-VEGF to another, only counseling patients to switch to other modes of treatment after six months.

“I think Protocol T is very helpful

in guiding treatment. If a patient has good vision, they probably have early disease, so it’s going to be a VEGF response. Protocol T tells us that patients do well with all the agents,” said Dr. Holekamp.

“But if someone has a really thick retina and extremely poor vision, you might as well start with aflibercept, as data suggests these eyes do better with it,” she continued.

The percentage of DME patients gaining three lines or more of bestcorrected visual acuity (BCVA) with monthly treatments after at least one year seems small. In Dr. Khanani’s experience, it is less than 50 percent. The challenge is in the heavy treatment burden in real world situations: DME patients, he said, are significantly undertreated with a high rate of appointment no-shows.

Furthermore, Dr. Kaiser cited studies like RISE and RIDE, and VIVID and VISTA, which showed less than 50 percent of patients gained three lines gains of BCVA.

The pandemic’s influence in patient management patterns

“Especially in the COVID-19 era, patients don’t want to come in. So, really, we need options that are more durable and more potent to control the disease,” Dr. Khanani said, echoing real world studies which show how it is difficult to get patients to come in consistently for 12 months.

The pandemic has also caused a change in how doctors see patients over the past few months. Most DME patients are diabetic and are elderly, thus, more likely to contract the disease. Due to this situation, Dr. Khanani said he’s now using more intravitreal steroids.

COVID-19 has also altered doctors’ ways for imaging DME. “I’m trying to streamline visits and socially distance patients while they’re in the office, so I really can’t have a bottleneck at the Heidelberg, where I’m trying to do the OCT and fluorescein. I have cut back on fluorescein and in DME patients, I’m primarily using just the OCT,” shared Dr. Holekamp.

Along with this, she also stated patients’ DR scores can be lowered, noting how intravitreal corticosteroids could also have this effect. “I feel that if they’re being categorically treated, I can pull back on the invasive testing,” she said.

A new factor to consider

Diabetes is also now being recognized as systemic inflammation, affecting the entire body, rather than simply localized inflammation.

“We’re also starting to realize these inflammatory factors lead to both vascular dysfunction in the form of leakage and neuronal dysfunction,” Dr. Kaiser mentioned.

There have been recent papers 1 looking at this idea — that inflammation within the retina leads to neurodegeneration. The fact of the matter is . . . diabetes is a neurodegenerative disease.

It was thought that inflammation only played a role in the initial part of the disease, which was VEGF-dependent — but now, they’ve discovered that it plays a role throughout the disease process. Higher inflammatory cytokine levels can be observed in DME patients. Dr. Kaiser said attacking inflammation earlier may prevent some of the neurodegeneration affecting patients.

Thus, incorporating steroids in the treatment plan for DME patients could address these inflammatory issues.

Dealing with biomarkers

Some inflammatory biomarkers include hyperreflective spots, DRIL, subretinal fluid, lipid exudates, peripheral ischemia, vessel leakage and staining. Dr. Khanani said he would look at DRIL, but would still want to see patients’ response to anti-VEGF, to which Dr. Kaiser concurred that DRIL and hyperreflective foci would be consistent with poor outcome and inflammation.

For Dr. Holekamp, she said she’s changed her thinking 180-degrees over fluid in DME treatment. “In DME, the fluid is more damaging. It tends to be intraretinal as opposed to subretinal. I think it is destructive and can limit future visual acuity gain because of this functional loss of neurons. I now have zero tolerance on fluid in DME,” she said.

For comparison, Dr. Kaiser said that in the Cleveland, Ohio, trials, it had been shown that dexamethasone, a very powerful type of steroid, seems to work a little better than triamcinolone.

Combinations of treatment, frequency

For Dr. Khanani, he would treat with anti-VEGF for one month and then add a steroid the next month and observe. Dr. Holekamp thinks differently, though. She rarely mixes her drugs and would prefer to “switch” instead. They both met in the middle by agreeing that a combination of switching treatments from anti-VEGF to steroids does show durability and efficacy.

However, Dr. Holekamp cautioned that switching sooner is better than later, as there is not much randomized clinical data on combo-therapies. “The one thing I learned from Protocol-U, is that we’ve got to switch or add sooner because those eyes that ended up having combination therapy really have lost the ability to recover vision,” she said.

In answer to a question by a member of the audience on the frequency of Ozurdex injections, Dr. Holekamp said she usually gives the corticosteroid injection and then sees them after 6 to 8 weeks followed by another injection and would see them after 6 to 8 weeks again.

“You have to actually follow them through the first or two or three injections to get a feel for what their eye is telling you it needs,” she said, adding that in the beginning, it’s like a treat-and-extend interval, “right before they fall off the cliff.”

Based on the MEAD 2 study, Ozurdex has been approved to treat DME, retinal vein occlusion and

Like with these clothes, DME treatment isn’t one size fits all . . .

posterior segment uveitis, with contraindications if there has been a presence of active infection at baseline, as well as with glaucoma patients with a disc at risk (greater than 0.8), or in patients with torn or ruptured posterior lens capsule or hypersensitivity.

For Dr. Kaiser, he said the MEAD study’s OCT findings seemed better than the visual acuity results. Dr. Holekamp agreed. “The one thing I learned from the MEAD study is that Ozurdex is really good at drying the retina, and we see the results after one (injection of) Ozurdex,” she said, adding this influenced her decision to employ a “switch” approach as opposed to adding on.

Navigating side effects

What about side effects? Intraocular pressure increases (IOP), as well as cataracts (in 6-8 percent of patients), are known side effects of Ozurdex. Dr. Kaiser said that although 28 percent in the patient group experienced an increase in IOP, it is episodic and could be addressed with topical medication.

Thus, both Drs. Holekamp and Khanani expressed their confidence in using Ozurdex despite IOP and cataract risks. Dr. Khanani said most of his patients are elderly and have cataracts anyhow, while younger patients would be counseled pertaining to the risks of developing cataract one or two years after the treatment (depending on their age, whether they are phakic or pseudophakic and other factors).

On IOP spikes, Dr. Khanani said: “I tell my patients that a third of patients on steroids would get them, but I don’t call it glaucoma because we can control the high pressure and not use the steroids again.”

Another factor that helped, according to Dr. Khanani is the predictability of IOP spikes during the week 6 and onward with Ozurdex. “So we can catch it and treat it without any severe damage,” he said.

“Bazooka in your eyes”

For an acute and urgent response to control and dry the eyes, Dr. Khanani said he would prescribe the more potent steroids instead of delaying the long-term delivery system.

Dr. Khanani uses a simple analogy with his patients: Although antiVEGFs are powerful, you sometimes need something even more powerful than that.

“They’re like bazookas in your eyes,” he said, adding that steroids cover more inflammatory markers, whereas anti-VEGF agents don’t.

In conclusion, Dr. Kaiser said DME is still increasing and with newer understanding of its behavior, it is becoming clearer that inflammation plays a large role, especially in the idea of neurodegeneration, not only in the eye but the whole body. Ozurdex’s anti-inflammatory effects in DME (as well as in diabetic retinopathy) are very profound, with changes seen in OCT and BCVA.

References:

1

2 Romero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A, et al. Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory. J Diabetes Res. 2016; 2016: 2156273. Boyer DS, Young HY, Belfort R Jr, et al. (Ozurdex MEAD Study Group) Threeyear, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914.

Editor’s Note:

This satellite symposium took place at ASRS 2020 on 30 th July 2020. Reporting for this story also took place during the session.

INDUSTRY UPDATE

APAO COVID-19 Guidelines

The Asia-Pacific Academy of Ophthalmology (APAO) recently published the APAO COVID-19 Prevention Guidelines for Ophthalmic Practices.* T he World Health Organization declared the Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 a “Pandemic” on March 11, 2020. As of August 28, 2020, Severe Acute Respiratory Syndrome Coronavirus 2 has infected >24.4 million people and caused >832,000 deaths, including many health care personnel. It is highly infectious and ophthalmologists are at a higher risk of the infection due to a number of reasons including the proximity between doctors and patients during ocular examinations, microaerosols generated by the noncontact tonometer, tears as a potential source of infection, and some COVID-19 cases present with conjunctivitis. This article describes the ocular manifestations of COVID-19 and the APAO guidelines in mitigating the risks of contracting and/or spreading COVID-19 in ophthalmic practices.

For the continued safety of physicians, staff and patients, we encourage you to read the full article, with additional tips, data and in-depth explanations. Free access here.

*Wong, R, Ting, D Lai K, et al. COVID-19: Ocular Manifestations and the APAO Prevention Guidelines for Ophthalmic Practices. Asia-Pacific Journal of Ophthalmology: July-August 2020;(9)4:281-284.

INTRODUCING NEW VITREORETINAL ACCESSORIES DISTINCTIVE FEATURES FOR ENHANCED SURGERY

CHANDELIER

SUPER GRIP FORCEPS

• SILICONE RING THAT FITS INTO THE TROCAR CANNULA FOR PERFECT SEALING AND DEPTH ADJUSTMENT • TROCAR CANULA MOUNTED ON ULTRA SHARP KNIFE FEATURING A SAFETY MAGNET

JOIN OUR OPHTHALMIC COMMUNITY!

• MICRO SERRATIONS FOR FIBROUS MEMBRANES PEELING • 360° HANDLE ACTUATION • INNOVATIVE «3D» ANTI-SHREDDING TIPS WITH EXTRA GRASPING POWER • LONGER SHAFT FOR MYOPIC EYES