Corneal irregularities can be treated and resolved without complicated surgery in some cases. 

This article was reviewed by Christopher Rapuano, MD


	
	For many ophthalmologists, epithelial basement membrane dystrophy (EBMD) or anterior BMD, Salzmann’s nodular degeneration, and band keratopathy are frequent offenders in clinical practices. Today, there are numerous techniques to identify these diseases, along with treatments that do not require complex surgeries.


	EBMD is characterized by reduplicated epithelial basement membrane that causes loose adherence of the corneal epithelium to the stroma leading to recurrent painful erosions and/or irregular astigmatism on slit-lamp examination that may or may not be apparent on corneal topography or K readings. 

However, clinicians should be alert to irregular astigmatism, according to Christopher Rapuano, MD, because it affects vision. In addition, if a 

is being considered, it can result in inaccurate K readings and incorrect intraocular lens power calculations, affect the postoperative quality of the vision, and worsen postoperatively, causing significantly decreased vision.
	
	

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When diagnosed postoperatively, these issues become the surgeon’s problem, noted Dr. Rapuano, chief of the Cornea Service, Wills Eye Hospital, and professor, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia.

Picking up EBMD can be tricky in some cases, but Dr. Rapuano demonstrated that fluorescein staining will often make it readily apparent. When deciding whether or not to treat,  Rapuano shared some pearls that might solve the dilemma. 

“If there was no negative staining or irregularity on topography or K readings centrally, then the problem probably does not require treatment,” he explained. “Conversely, consider treating if the patient is symptomatic or awaiting 

and wait about six weeks before rechecking the biometry twice to ensure the stability.”

Treatment can consist of epithelial debridement alone, or debridement in conjunction with diamond burr polishing or excimer laser phototherapeutic keratectomy (PTK). The process of debridement includes removal of all loose or irregular epithelium and basement membrane with a cellulose sponge or blade. 
	
	

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Dr. Rapuano said he likes to perform diamond burr polishing, which begins with epithelial debridement. He then uses a 5-mm diameter diamond-dusted burr to polish Bowman’s layer uniformly over the entire cornea for about five to six seconds to ensure that all reduplicated basement membrane has been removed.

According to Dr. Rapuano, some patients who undergo this procedure may have transient haze postoperatively that can be alleviated with steroids.

The key when performing excimer laser PTK, after debridement, he advised, is treating the entire epithelial defect with a uniform ablation of only about 5 Î¼m. 
	
	

ETM valuable in planning, evaluation of outcomes 


	This pathology appears a creamy white mild to moderately elevated lesion often in the peripheral 

, but occasionally is seen centrally. It can be associated with EBMD and can cause dry eye symptoms and irregular astigmatism despite a peripheral location.

Dr. Rapuano advised treating in the presence of any centrally located irregular astigmatism. If the patient is awaiting a cataract or refractive surgery, he also suggested waiting about six weeks after treatment before rechecking the biometry before any surgery.
	
	

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The treatment options include lamellar keratectomy using a blade with or without diamond burr polishing. In some cases, he noted, the nodules will easily peel off of Bowman’s layer and leave a smooth surface. In cases in which the underlying stroma remains unsmooth, he performs excimer laser PTK with or without mitomycin C (MMC).

If PTK is performed, he usually uses MMC. During this procedure, he advises using a blade to remove the nodules and subepithelial fibrosis and then smooth the surface with PTK. MMC 0.02% should be applied on an 8-mm sponge for 60 seconds and then irrigated with 30 cc of saline.


	This pathology, which appears as a white calcium deposit, is often related to chronic inflammation but may be idiopathic. If located centrally, the vision can be affected. However, if elevated and in the periphery vision also can be affected. In cases when it is elevated or irregular, it can cause patient discomfort.

Dr. Rapuano advised performing a workup to determine the etiology. 
	
	

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The treatment is ethylenediaminetetraacetic acid (EDTA) chelation. The key point in this procedure is removal of the epithelium over all of the calcium using a number 15 blade or Tooke knife. The presence of any epithelium will prevent absorption of the EDTA. Diluted EDTA 3% to 4% should be applied to the calcium on a cellulose sponge or cotton-tipped applicator for 10 to 45 minutes until all of the calcium has dissolved.

“Corneal irregularities and opacities are common and they can affect comfort, clarity, and corneal curvature, making it especially important to diagnose before cataract and refractive surgeries,” Dr. Rapuano concluded. “There are numerous techniques to identify them, and there are excellent treatment options for clinically relevant pathology.”
	
	

This article is based on Dr. Rapuano’s presentation at the American Academy of Ophthalmology 2019 annual meeting. Dr. Rapuano has no financial interest in any aspect of this report.

Articles

Doing justice to corneal irregularities 

As physicians, we usually want to prescribe what’s best for our patients. Sometimes that means specifying a branded glaucoma drop rather than a generic. Perhaps a patient needs the predictability of branded latanoprost (Xalatan, 

) because the molecule is sensitive, and differences in manufacturing process, quality of bottling material, or the vehicle can affect its efficacy.

Or maybe a patient who has been using a generic drop has ocular surface irritation, and I want to prescribe a preservative-free brand-name formulation. It used to be that physicians could prescribe any medication they felt was necessary for patients and the patient would be able to get the same medication without much hassle.

Those days are unfortunately in the past. In prescribing a brand-name medication over a generic in the current insurance market, my staff and I often need to scale three or four obstacles, but I think it is still worth it to do what is best for my patients.

Here are some pearls for facing those obstacles, based on experience.

When I prescribe a branded glaucoma drop, insurance companies frequently tell us it is a non-preferred or non-formulary medication, and they do not cover it, trying to prompt a switch. With so many different plans and sub-plans, it is hard for us to know what will be covered for a specific patient in advance. When a medication is not covered, one strategy is to seek prior authorization.

My staff goes through that process, which entails an approval period and sometimes even an appeals process if prior authorization is not granted. To bridge the gap, we usually give patients a sample.

Delays in approval or appeals usually do not outlast the sample. We sometimes have to allow the patient to use a generic, prove that the patient is not tolerating it or that it is not as efficacious as the brand name, and then get prior authorization based on that evidence. It also helps to be familiar with peer-reviewed published studies we can provide to the insurance companies demonstrating better efficacy or tolerability for our preferred branded medication.

The battle puts a burden on the doctor, requires staff hours, increases the number of patient visits, and prolongs the desiredgoal of treatment – but it is our ethical duty to get patients the best individualized treatment for this chronic, progressive disease.

Pharmacies represent another complex challenge.

Some pharmacists feel, even if the prescription states “dispense as written,” that they are free to substitute a generic. Occasionally, pharmacists also speak directly to patients about accepting a cheaper generic option, implying that the medication works just as well or is equivalent when that might not be true. In a recent development, when I prescribe a medication that has no generic equivalent, the patient’s pharmacy plan recommends a switch to a different class of drug instead of the one I have chosen. This is particularly annoying because I usually choose medication classes specifically to avoid certain side effects or contraindications. Some of these barriers require the same kind of staff work and appeals as insurance approval.

Others can be solved or prevented by connecting patients with a local pharmacy that respects doctors’ preferences. I speak directly with two local, private pharmacies about which brands I prefer and why, and then I explain the same information to patients and let them know that those pharmacies help me fight for them to get the medications that are best for their specific situation.

These pharmacies in turn assist the patient and my staff to get my preferred medication approved at the lowest cost to the patient possible.

When we get approval for a branded medication, some insurance companies add the caveat that it is a “higher tier” medication, which will cost patients more out of pocket. However, most drug companies offer discount programs and rebates for patients with commercial insurance. It is important for physicians to know about these programs and to have staff educate commercial insurance patients to use these programs to minimize their costs. Patients are a lot more likely to be compliant when they can afford to buy their medications.

In every aspect of this process, my patients and I need to be on the same page. That simply means educating them about why I want them using certain medications. When I want a patient to use a brand-name medication, I explain the reasons. “If it is not covered, give me a call and we will take other steps. Please do not just tell the pharmacist, ‘Sure, give the generic.’”

For example, when I prescribe an alpha agonist, I tell my patient that I prefer the brand name brimonidine tartrate 0.1% (Alphagan P, 

) because it has a lower concentration and it is less likely to cause side effects in my experience. I explain that the medication might be covered with a higher copay than the generic – for example, $20 versus $5 – or it might not be covered at all.

If is not covered, patients should call me and keep using their sample. We have to make our patients more informed and better prepared for what they encounter at the pharmacy and help them become their own advocate.

Fighting for a brand-name glaucoma drug when appropriate is the ethical thing to do for our patients. There are logistical difficulties and a financial burden to the clinic, but do not give up and prescribe generics that you do not believe are in your patient’s best interest. When you understand the differences between each of the branded and generic medications for glaucoma based on the published science and personal clinical experience, you can determine the classes of medications and the situations in which you prefer a brand name.

And once you have your preferences, try to fight and be an advocate for your patients despite the investment of clinic staff time and resources. The entities throwing obstacles in our path want us to get frustrated and give up, but we need to continue to be advocates for our patients.


	Dr. Vosoghi is a glaucoma specialist at Dougherty Laser Vision, Los Angeles. Dr. Vosoghi is a paid speaker for Allergan and Aeri.

It is imperative for physicians to ensure that patients are receiving the correct medications that they prescribe, and not a generic brand that may not meet the objectives. 

Overcoming common hurdles when branded drugs are what physicians ordered 

This article was reviewed by Arshad M. Khanani, MD, MA, and Joshua Mali, MD


	
	Retinal specialists are ushering in the year 2020 with the availability of a new anti–vascular endothelial growth factor (VEGF) therapy, since the FDA approval of brolucizumab (Beovu, Novartis) for the treatment of patients with wet age-related macular degeneration (AMD) in the last quarter of 2019.
	
	“[Brolucizumab] is a welcome treatment for patients, and it is the first new treatment for wet AMD in about eight years,” according to Joshua Mali, MD, vitreoretinal surgeon, private practice in Sarasota, FL.

“There has been a meticulous process to create a drug that provides advantages over currently available therapies for wet AMD,” Dr. Mali added. “[Brolucizumab] maintains robust visual gains and provides superior retinal drying compared with aflibercept with the potential for 12-week dosing intervals.”
	
	As background, the FDA approval was based on the results of the phase III HAWK and HARRIER 2-year clinical trials that placed brolucizumab head-to-head with aflibercept (Eylea, Regeneron Pharmaceuticals).

The key finding was that in both study arms at 48 weeks and two years brolucizumab achieved its primary endpoint and was found to be noninferior to aflibercept regarding the best-corrected visual acuity [BCVA].

Study targets potential treatment for nAMD

“An important point to consider is that the dosing of the two drugs was quite different, with aflibercept dosed every four weeks for three loading doses with subsequent extension to every eight weeks,” according to Mali, who is also founder and chief executive officer of Mali Enterprises. “In contrast, brolucizumab was dosed every four weeks for three loading doses and then extension to every eight or potentially 12 weeks based on the assessment of the disease activity.”
	
	Other relevant findings, Dr. Mali pointed out, were that the visual gains achieved with brolucizumab were noninferior to those achieved with aflibercept at the two time points with longer treatment intervals in most patients; about 56% of patients in the HAWK trial and 51% in the HARRIER being treated with brolucizumab were maintained on three-month dosing during the first year.
	
	In addition, the central retinal thickness in patients receiving brolucizumab in both study arms decreased more compared with aflibercept at both week 16 and years one and two, he noted.
	
	

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	“Retinal fluid is a critical indicator of disease activity in patients with wet AMD and how they are responding to treatment,” he said. “The presence of fluid is also an extremely important factor in the determination of BCVA.”
	
	Safety profiles of the two drugs were similar. A difference was seen in inflammation between brolucizumab and aflibercept, 4% and 1%, respectively.

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	Brolucizumab is a single-chain antibody fragment and is a smaller molecule compared with other anti-vascular endothelial growth factor (VEGF) formulations that are currently available, according to Arshad M. Khanani, MD, MA, clinical associate professor, University of Nevada, Reno School of Medicine.
	
	“The small size of the molecule and the 6-mg injection results in a relative molar dosing of about 12 times compared with aflibercept,” Dr. Khanani said. “This is what accounted for the greater drying of the retina compared with aflibercept in the HAWK and HARRIER phase III studies.”

Anti-VEGF therapy targeted as potential nAMD treatment

For Dr. Khanani, perhaps the greatest impact brolucizumab will have for both patients and physicians is a substantially reduced treatment burden.
	
	“Patients with neovascular AMD require treatment anywhere from every four to eight weeks,” he said. “When considering the real-world outcomes, the gains in vision are minimal, about eight to 12 letters, compared with the results in the clinical trials. This speaks to the unmet need for durable agents that last longer to decrease the treatment burden.”
	
	Another factor, he noted, is many patients still have active disease despite  monthly injections. These patients have persistent fluid and a high need for anti-VEGF therapy. Two weeks after an injection the retina is dry, but by four weeks, the fluid returns.
	
	“Having a more potent drug to control the disease in a patient with a higher VEGF load is a big advantage,” he said.

Brolucizumab: Next-generation of anti-VEGF therapy? 


	
	In his clinical practice brolucizumab fulfills two needs for patients, Dr. Khanani noted. He starts treatment-naÃ¯ve patients with the more durable brolucizumab to control the disease for a longer period. For his previously treated patients who have persistent fluid on monthly injections, they can be switched to brolucizumab to dry the retina and better control the disease

Patients receive three loading doses of the drug followed by two doses at 8 or 12 weeks based on the HAWK and HARRIER trials. 

“Even if a patient had been previously treated for AMD, they can be treated according to this schedule, but they may not need the loading doses if the retina is dry after one injection,” Dr. Khanani said.

Dr. Khanani has not seen any significant adverse events in patients that he has treated so far in the brolucizumab clinical trials or in his clinic after approval. He is, however, aware of higher rates of inflammation in the brolucizumab-treated patients in the HAWK and HARRIER studies.

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“As with any new drug, we need to watch for any adverse events that can develop in patients who are receiving treatment,” he said.
	
	Patients are encouraged about the increased time between treatments, thus lessening the burden on them and their families, he noted.
	
	“We have not had a new drug for these patients since 2011 when aflibercept was approved. It is exciting for our patients and for physicians to have this new drug that is more durable than the available drugs and achieves better drying of the central retina and better control,” Dr. Khanani concluded.
	
	Beovu was granted a Permanent J code that began Jan. 1, 2020.

Dr. Khanani is a consultant andn speaker for Novartis and receives research funding from Novartis.

Dr. Mali is a consultant to and receives speaker honoraria from Novartis. He previously was a speaker for and received funding from Regernon Pharmaceuticals.

Ophthalmology Times: January 2020

Doing justice to corneal irregularities

Overcoming common hurdles when branded drugs are what physicians ordered

Brolucizumab: Less frequent dosing/maintenance of robust visual gains in wet AMD