The Era of ‘And’: Combination therapy arrives
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What a wild ride these last 10 years or so have been.
In my mind, there have been three distinct eras of dry eye disease (DED) care over the millennia. These three time periods have neither established names nor officially defined boundaries like the myriad generations we use to describe our population here in the U.S. (baby boomers, etc). To the surprise of exactly no one who has read my drivel, I will therefore take it upon myself to declare what I think these eras are and then let the rubble fall wherever it may.
We can think of the decades prior to the 21st century as the Age of Innocence. Eye doctors through the ages had a shallow awareness that an entity called “dry eye” existed, probably as early as the Middle Ages. Of course, I have no proof of this, but if any enterprising soul in our world who happened to major in art history is aboard, I bet there is at least one painting in the chronicles of those times where an artist captured someone rubbing their eyes or some such.
This period lasted for centuries. DED was thought of in the simplest of ways, if it was thought of at all. One’s eyes were dry because they lacked sufficient tear volume. You know, like a desert. In this manner, we as a specialty overlapped quite nicely with our dermatology brethren: If it is dry, wet it. Drops of water begat saline drops, which led to all types of “artificial tears” one could suggest our patients obtain. Indeed, there are more than a few among our colleagues who still hew to this heuristic. The Age of Innocence included no inkling of the effect of diseases involving glands other than the lacrimal gland. Meibomian glands had their own separate set of disease states, and only the great Lorenz Zimmerman and his Armed Forces Institute of Pathology fellows gave any thought to exotica such as goblet cells.
The Age of Innocence was the “Null Age” of DED treatment.
What followed was the Age of Inquiry. Beginning in the mid- to late-1990s, with a broadening of the use of anti-inflammatories such as prednisolone and the daring experimentation with topical versions of anti-rejection medications like cyclosporine A, we discovered that a significant majority of DED was associated with inflammation on the ocular surface. As time progressed, we became aware that treating the inflammation reduced the signs and symptoms of DED. Further exploration exposed the likelihood that ocular surface inflammation was accompanied by inflammation in all three components of the lacrimal functional unit: lacrimal glands, meibomian glands and goblet cells.
The Age of Inquiry was an era in which diagnosis could be described as a binary construct. We thought of DED as a problem of either tear quantity or tear quality. One could presumably cause the other, of course, and so you looked for the primary culprit and treated that. Our efforts at treatment were similarly geared toward finding a singular therapy. Initial therapy with lubrication or anti-inflammatory agent. Either steroids or an immunomodulator. Prednisolone, fluorometholone or loteprednol. Beginning in 2016, you had a choice of immunomodulators: cyclosporine or lifitegrast. In a similar fashion, obvious meibomian gland dysfunction (MGD) treatment came down to treating a presumed staph overgrowth — steroid/antibiotic combo — or primary inflammation within the meibomian glands — steroid or, wait for it, AzaSite (azithromycin ophthalmic solution, Thea).
The Age of Inquiry was one of “Either/Or.”
Why might this have been? Why did it seem that combinations of therapies, be they pharmaceutical or in-office treatments, were seen as solely the purview of the advanced DED practice? I think it stemmed partly from the days when DED was still seen as a largely untreatable “lifestyle” issue, one not even worthy of being called a disease. Also, it seemed that a significant majority of eye doctors (and patients) were reluctant to double down on medications that traditionally were felt to have “too many” risks and side effects (eg, steroids) or took too long to demonstrate an effect (eg, immunomodulators and AzaSite).
We have now entered a new era, the Age of Investment. While the Age of Inquiry could have begun with the approval of Lotemax (loteprednol etabonate, Bausch + Lomb) in the late 1990s, it was the approval of Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) in 2003 that brought about the shift. One could say that the Age of Investment was ushered into existence with the development and deployment of in-office treatments such as LipiFlow (Johnson & Johnson Vision) and its multiple thermal/expressive kin or intense pulsed light and its relatives. However, the capital outlay necessary to offer any or all of these treatments, coupled with the fact that they remain outside of the traditional third-party payment system, relegated their addition to other therapies to the world of the advanced practitioner. To transition from one era to the next, the transformation needs to be nearly universally available.
In came the pharmaceutical industry, big and small, bringing with it the transition to the next DED era, the Age of Investment. Tiny niche companies have developed therapies that address significant unmet needs in the DED world. Unlike the in-office procedures developed over the last 10 years, all these new options live within the traditional third-party payment system familiar to both patients and doctors. Practices need not plunk down wads of cash to buy a gadget or fund inventory. Larger “strategics” have begun to gobble up these smaller companies, or they have banded together to form entities large enough to bring their drugs into the market.
This is the “Era of And.”
Got a patient with DED that is primarily inflammatory who has had a nearly complete resolution of that inflammation but continues to have symptoms due to evaporation? Now you can add Miebo (perfluorohexyloctane ophthalmic solution, Bausch + Lomb) to your immunomodulator. How about that patient with evaporative DED for whom you jumped on Miebo as primary therapy who just cannot keep up with enough tear production? This is a perfect place to add Tyrvaya (varenicline solution, Viatris) to increase the volume of the patient’s own tears or use the new breakthrough punctal occlusion device Lacrifill (Nordic Pharma) to increase the contact time of the tears they do produce. And all those patients with stubborn MGD and evaporative DED you just cannot seem to stay ahead of? Well, you finally asked them to look down, discovered that their lashes are covered with collarettes, and you can now go all Rambo on Demodex blepharitis by adding Xdemvy (lotilaner ophthalmic solution 0.25%, Tarsus Pharmaceuticals).
Dry eye doctors of all sorts are now finding that they can use combinations of therapies to better treat all the different varieties of DED. Our Age of Investment has brought with it a profound change in the clinic, and this allows us a truly new opportunity that will bring a higher success rate, as well as a higher degree of symptom resolution to our patients. We now live in an era in which all these new treatments are automatically in the quiver of every DED doctor; all we need is a little knowledge and a couple of keystrokes in our electronic medical record.
We have left behind a world of “Either/Or” and have joined our patients in a new and exciting age of “And.”
- For more information:
- Darrell E. White, MD, of SkyVision Centers in Westlake, Ohio, can be reached at dwhite@healio.com.
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