TAPE STARTS – [00:00]


Male Speaker: And our first speaker is Tracey Vlahovic, which, hey, I did pretty good on your name this time, Trace. I usually butcher that name. Tracey is a specialist in dermatology. She actually is one of the few people who have had a fellowship in dermatology. She authored a book, Lower Extremity Skin Diseases. She is an excellent speaker. She is an assistant professor at the Temple University School of Podiatric Medicine. And Tracey is going to share thoughts with us this morning on the pathophysiology of onychomycosis and treatment update.

Tracey Vlahovic: Good morning, everyone. So, there are two things that will probably – that you're thinking about right now, is number one, do I have to sit through an onychomycosis lecture? I actually call this not your mama's onychomycosis lecture. So, this is something hopefully that at the end of the half hour you'll find – you'll have gained something. And also that you'll get probably two robocalls during this lecture. So, at least I know my phone will be blowing up with people I don't know and trying to sell me something.

Just so you know, my conflicts of interest, I wrote a book on nail fungus. You don't have to buy it, but it was a labor of love. And my license plate shows my love for fungus. So, if you ever see me on 95, just wave or honk, it's me. Okay.

All right, so we're going to talk today about onychomycosis, both how it happens, the research and why some therapies work and some do not. But the first thing I want to impart to you is that nails are not inert pieces of tissue. We don't really think of them as being anything beyond things that we have to debride or things that get in the way and create onycho – you know, sort of an onychocryptosis.

[02:01]

They're actually really fascinating pieces of membrane. They are membranes. They're barriers. And they're water-based. So, just keep that in mind. They are water-based membranes. They have very little to no lipid content. So, they're basically proteins and water. And they do experience what we do to them from an environmental standpoint.

Okay, so, a healthy nail plate is about 80 to 90 layers of keratin, which is the protein that these cells produce. And it is about 100 times thicker than the stratum corneum, obviously. It's a lot thicker. And it's again, water, minerals, lipids, very, very small amount of lipids. But there's no animal model that comes close to what the human nail plate is. So that's why the research that we do with nails is so expensive and so long in duration, because there's really nothing else that we can use to mimic them. So, all the nail research I've done obviously is human, even the in vitro work that I've done with nails has all been cadaver work. So, everything is human nails.

All right, so, let's talk about onychomycosis. 50% of the nail disease you see in your office, the nail disease I see in my practice, is onycho. That means 50% is something else, whether it is psoriasis, related to biomechanics, related to trauma, related to lichen planus, things like that. Of the nails that truly are – have onychomycosis, they're still mostly caused by dermatophytes no matter what lab testing you might get back. Trichophyton rubrum still causes 91.3% of onycho out there. A lot of the stuff that you get is contaminants. Some may have a role in pathogenesis, but mostly it is a dermatophyte because they have the enzyme to break down the nail bed.

[04:04]

The disease is of the nail bed, not the nail plate. It begins in the nail bed. And what happens is the keratinase that the dermatophytes have break down the tissue in the nail bed. That's what they're using as food source, is that keratin. Keratinase breaks it down and you get this reaction from it.

So, basically, that subungual debris you're seeing is a response to the infection that is happening. So, what happens is you first have that subungual debris and then the hyphae that is being produced because it has food source then goes into the lamina of the nail plate and invades the nail plate. So, keep that in mind. It is a disease of the nail bed, not – the nail plate is secondary. And also, we can have some mixed infections, but again, dermatophytes are the most cause.

We also can have patients – and I treat a lot of psoriasis in my practice. We can have onychomycosis and nail psoriasis happening at the same time. So, if you have a patient who presents with psoriatic arthritis or psoriatic skin disease, do keep in mind their nails may look fungal and they might be, but they also probably have a component of psoriatic nail. So, we treat both. I always treat the fungus first because it's a lot easier to treat fungus than it is sometimes nail psoriasis.

So, again, just how does fungus cause distal subungual onychomycosis which is the most common type? Again, exposure to the dermatophyte and that might be in the form of tinea pedis that is in between the toes or on the bottom of the foot. Trauma to the hyponychium, you know, how many times I'm sure if you had a dollar for every time a patient said to you, "Can I get a pedicure," you'd be a millionaire because it drives me absolutely insane. And, you know, I'm like there's a reason why I don't want them to pick underneath your nail plate or your cuticle because those are the barriers to the rest of your body.

[06:04]

When you compromise that, you are allowing not only fungus, but bacteria and viruses in. So, when we have trauma to that hyponychium or that barrier between the nail plate and the nail bed distally, we're allowing fungus to walk right in and start that process.

So, again, the dermatophyte invades the nail bed, has the keratinase, breaks down that protein keratin, starts that subungual debris, that mild inflammation, the pH changes because what T. rubrum is so intelligent about is that it changes the pH of your skin so the infection can take hold and your immune system can't really handle it.

Then, you have onycholysis because you're having separation of the nail plate from the nail bed because you have that subungual debris. And then, again, as I mentioned before, the hyphae or the branches of that dermatophyte, because it has so much food source in the nail bed, is going out and invading the nail plate which has some keratin but not as much wonderful keratin as the nail bed.

So, the thing is the dermatophyte starts the infection. Molds and yeast can come in because they're like, "Hey, there's some food source and there's some breakdown products. So, we can go in there and kind of create a fungus, mold, yeast party."

So, what about this whole biofilm concept that you might be hearing about? Now, we always talk about biofilms in terms of wounds, but there's a new emerging feeling about nail fungus and just fungus in general in biofilms. If bacteria can create a quorum and a protection, a slime layer of biofilm, why can't fungus? Well, they do.

The reality is, is that the long – why is it that some patients respond so well to medications and some don't? Well, the longer you've had onychomycosis, i.e. more than five years, you have an anergenic response. Meaning, you don't really mount any kind of immune response.

[08:00]

So, the sooner we treat it, the better and that's been shown in literature just in general. But, from an immunological standpoint, the sooner we treat it, the better because once this sort of slime layer comes in, everything is protecting and the cells communicate with each other. In fact, we sometimes talk about T. rubrum not really responding to Lamisil and things like that, but the reality is, is that that may not be genetically induced. That actually might be cell-to-cell signaling that's going on, telling each other kind of avoid terbinafine. So, drug resistance doesn't seem to be transferred genetically. It seems to be transferred, again, from cell-to-cell in that biofilm.

And if we start looking at how we can sort of destroy the biofilm which at this point we're not really sure how we destroy the fungal biofilm, then that's going to lead to new treatment options because perhaps if we can work on the biofilm, which T. rubrum does cause on nails, then, certainly we can hopefully conquer the infection and the irritation that it's causing. So, this is all – it's conceptual in this point, but it's like we know it exists but we're not exactly sure how we can take it from there.

All right, there we go. So, this is my algorithm when I look at my patients. I see an abnormal nail. Yesterday, I had a patient come in. She had one dystrophic nail and she admitted she's a bartender. She was on her third margarita and dropped something. She's like, "And you know I make margaritas well," and I'm like, "I'm sure you do." And the reality is I looked at her nail and I said, "You know what? This probably isn't fungus to me. This looks like trauma. This looks like true dystrophy." So, then, I have to go through my differential diagnosis and treat it properly.

However, if it's onychomycosis, certainly, I'm going to determine what level it's involved with. Is it mild, moderate, or severe, and then what do I do from there.

[10:00]

So, if it's mild, obviously topicals would probably be useful. If it's moderate, I can go either way. If it's severe, oftentimes, what I'll do is, again, I'll do both in conjunction oral and topical antifungals, depending on the situation, depending on the patient's insurance, depending on what their ability is if they can bend down, paint something on their nails, if they're willing to do something like that. So, it really just depends on what the situation is.

But, ultimately, I like to have laboratory confirmation because as I mentioned before, 50% of the nail disease we see is onycho, 50% isn't. But I like to know what organism I'm dealing with so that I can tailor the drug for the bug. And ultimately, you can choose a lot of different things. So, I'm coming from an academic research clinical background. So, I do a lot of KOH and culture and I'm not saying that that is the best in the world, but it's just what the FDA approves. So, I'm just used to doing it. I try to push myself to do more PASs and PCRs, but the reality is, is that I'm just kind of in that sort of zone.

The KOH, as we know, is not always the greatest test, but it just tells me, you know, do you see hyphae? Culture is something that obviously is annoying because it takes so long to come back but I like to know what species I'm dealing with. PAS is telling me am I dealing with a dermatophyte or sometimes it will tell me there might be trauma or might be psoriasis. And then, real-time PCR is the – it can tell you what is a viable organism that's there.

So, if you have the ability with some of your patients with insurance and you can order real-time PCR, then you can find out again what viable organisms are there. Otherwise, PCR just tells you what organisms are there, but real-time PCR tells you what's viable, meaning, what is actually growing at that time.

So, one of the things that no one really ever taught me when I was at Temple, when I was in medical school, was how do you properly take a nail specimen.

[12:00]

And I didn't know until I started doing clinical trials. And I've done multiple clinical research trials, Phase 3 and some Phase 4 for onychomycosis over the last 16 years. So, the reality is, is that when you send nail plate, you are sending dry, desiccated hyphae that will give you a false negative. When I was doing my clinical trials and still when I do clinical trials, I am only allowed to send subungual debris. That's it. If I try to send any kind of nail plate, I will get a really nasty phone call from the mycology lab that we're using.

So, basically what I was trained to do was to take up an alcohol swab, wipe the nail that you're in question or nails that you're going to look at and question, debride those nails and discard that nail plate. Get rid of it. Take a small thin metal nail curette and curette as far proximal as you can. If you can't go that far back without causing the patient pain, I just scrape underneath the nail or the nail bed.

And if I have the patient put their feet at the – bend their knees and put their feet at the edge of the treatment chair, usually, I can get a pretty decent amount. And I put it in a cup with no formalin, so an empty urine specimen cup or whatever lab you use if you need an envelope, a plastic baggy, whatever. I use urine specimen cups that are empty.

But once I started doing that, obviously, my clinical trials I found a lot more fungus. And in regular non-research practice, I certainly had my results come back much better. Now, for PAS, you could send nail plate, but if you're going to do culture or you're going to do KOH, I highly, highly recommend you send subungual debris because it really, really will change your results.

So, this is just a picture of it. So, again, you take the nail plate. You discard it. Now, they're using a 15 blade here but, again, I prefer a thin metal nail curette and I get all that ooey-gooey good stuff, all that nice, cheesy subungual debris, all right?

[14:08]

That's what I want to send.

Now, I also like to use my dermatoscope and I always say my dermatoscope is my best friend in the world, my only friend in the world. It stays in my coat pocket. It never leaves me. But the reality is, is that it also helps me really diagnose a lot of things that I wouldn't be able to do otherwise with my naked eye. And no one ever tells you that once you hit 40, you definitely really need something like this because all of a sudden, things all look blurry.

But the reality is I take my dermatoscope and I look at the nails and I can see the patterns with that – for onychomycosis with dermatoscope. So, there are certain things that I'm going to look at. I'm going to look at the top of the nail plate and I'm going to look at the tip of the nail. So, I look at those two places. I also not only look at the nail itself, I look at the capillaries because capillaries in psoriasis look very different to capillaries that are around the nail unit in onychomycosis. So, all these things give me better information so that I can treat that patient while they're sitting in front of me.

So, something called the ruin appearance. I'm from Pennsylvania. We go to Crystal Cave for field trips as kids. So, we think about stalagmites and stalactites. So, it looks like a cave or a ruin. That's really hallmark when you look at the nail from this perspective with a dermatoscope.

Homogeneous leukonychia just means that you see this whitish discoloration. Leukonychia is truly often a sign of onycholysis which is hallmark with onychomycosis. Punctate leukonychia, just those little white dots you see, and black discoloration which is often the staining from the fungus itself. So, let's look at this visually because it will make more sense to you. This is that ruin appearance.

So, here's the nail. When I look at it from the tip, you see this ruin appearance.

[16:02]

It looks like you're walking into a cave, even closer. Here's that punctuate leukonychia, so those white pieces of leukonychia, same thing here. These white streaks, all hallmark of onychomycosis. And then, this black discoloration which can be either dried blood or pigmentation from the fungus because Trichophyton rubrum is called Trichophyton rubrum for a reason. It creates pigment. And it's either going to be red to brown to black. So, that's all normal. So, these are all things that I'm looking at when I use my dermatoscope for onychomycosis.

So, you’ve got your lab results back. Maybe you did a culture or maybe you did PAS, maybe you did PCR. Well, what do you have? What’s next? So, the reality is, is that most of these are specifically looked at for T. rubrum and T. mentagrophytes because from an FDA clinical trial standpoint, they’re only going to focus on the most common dermatophytes. They’re not going to look at every single thing out there, or all the molds.

Whereas, terbinafine, itraconazole, it’s a broad dermatophytes, okay? So, again, you see nothing that says specifically mold or yeast because no one will study that. It costs a lot of money to do these trials and no one is going to specifically look at yeasts or molds. So, we can recommend what we can use for those organisms based on their MIC values in the lab, but the reality is that there’s no clinical trials out there. And laser therapy doesn’t even say anything about killing dermatophytes because all the research shows that we really don’t know what it does. It just increases the amount of clear nail temporarily, okay?

So, again, with non-dermatophyte molds from the literature, this is what I do. This is what I recommend. If you have scapular abscess, you can either do itraconazole which is really tough for me to get covered in Pennsylvania or daily terbinafine. You can do your 90 days of terbinafine.

[18:00]

Aspergillosis which I'm sure like me you get a lot that comes back like that, I usually do terbinafine instead of itraconazole because again, a lot of my patients can’t even go itraconazole because of the drug reactions.

Acremonium, again, terbinafine or topical ciclopirox, believe it or not. And fusarium which has that enzyme like the dermatophytes to break down the keratin in the nail bed, unfortunately, itraconazole, so in some of those cases because again itraconazole just isn’t achievable by most of my patients, I end up using fluconazole once weekly.

So where do topical agents come into play? Well, they are FDA-approved specifically for mild to moderate disease which depending on the drug might be labeled as 50% or 60%. It can be alternative therapy for patients who can’t go on an oral medication or won’t go on an oral medication. And I also use it off label as adjunctive therapy with the oral medications that I have outside-in and inside-out therapy. So I'm having hopefully the best result possible with these patients.

And again, there’s no research on this truly because it’s too expensive and too difficult to do, but I use it as prevention. So once we’ve achieved what I’ve wanted with those patients, the patients are happy, then, I have them use the topical medication once or twice a week just as prophylaxis. But again, we don’t have hard evidence for that.

Now, as I mentioned before, tricophyton rubrum changes the pH of your tissue so it can take hold. Did you ever consider though that your nails have a pH? We all know the skin has a pH because if you’ve been around as long as most of us have, you remember a product called acid mantle, right? Acid mantle is referring to the pH of the skin which is acidic.

The nails are a little bit more basic than the skin. Actually, the toenails are 5.4, even a little bit more basic than the fingernails which is about 5.1.

[20:01]

The skin is around 4.7.

Well, T. rubrum loves an acidic pH and what it does is it takes that acidic pH, changes things around and makes the tissue more basic. When it makes the tissue more basic, your immune system doesn’t respond. So, that’s one of the ways that T. rubrum even though we always think about fungus as not being the smartest microorganisms in the book, that’s how smart it is. So, the reality is, is when it infects, it shifts that pH to more basic and changes our skin’s defense reaction.

Nails also have pores which if you again – and looking at some of the stuff that’s come out in the last couple of years, you remember there was a drill that people were putting in the nails, trying to brute force, make force. The reality is you don’t have to do that. Your nails have pores. You just have to manipulate them. They, as I mentioned at the very beginning, nails are a water-based membrane.

So if you create physical pores like that machine was doing, you’re actually making the nail lose more water. You’re kind of not honoring the physiology of the nail. So just knowing that the nails are water-based membrane, if you swell it with something that’s water-based like a urea, you’ll swell those pores to a certain extent. It doesn’t make everything go through. It’ll help it a little bit though, okay? So that – those pores help transport the topical medications we’re trying to put into the nail. So pores are very important.

Transonychial water loss and I know you’re like, “What the heck is she talking about?” Well, your nails passively lose water. Your nails don’t have sweat glands. So, just sitting in this room, these conference rooms are typically dry, our nails are losing water to the environment. If it tends -– I think it’s going to rain today, at least that’s what they said the other day. I never trust any of those folks.

[22:00]

But if it rains today, it’s going to be very humid out. So our nails are going to swell when we go outside. So our nails are just passively handling what’s going on in the environment if it’s dry or if it’s wet. But the reality is, is that water loss in our skin means that the skin is compromised. When we lose a lot of water in our nails, it actually compromises our nails as well.

So, onychomycotic nails are dry nails. They have – they’re a little bit more porous, but they’re also compromised just like the skin is when they are dry. So we also have to think about making the nail healthier ultimately even when we’re treating our nails for nail fungus.

So, what do you need for these drugs to pass through the nail? We talked about pH. We talked a little bit about nail pores. Well, you need something that is going to fit through those pores. So that means it has to be a certain molecular weight size, okay, but it also has to be the right sort of branch. It has to have the right vehicle, something that drives it in.

So as I’ve mentioned before, the nail is a water-based membrane. So what about all those oils that you put on patient’s nails? What does oil and water do? Think about that. It lays on the surface of the nail, makes the nails look pretty, but the oil does not go through a water-based membrane. In fact, some of the drugs that are over-the-counter are over-the-counter for a reason. They don’t go through the nail plate.

Kobayashi looked at 5-fluorouracil which we would not use to treat onychomycosis but it is a water loving molecule, and compared it tolnaftate which is the product that is in most of the stuff that we sell. Tolnaftate is fat loving and a huge molecule. The reality is, is that when he did the study, 5-fluorouracil jammed right through the nail plate. Pores didn’t make it a problem, pH vehicle, et cetera.

[24:00]

But tolnaftate, they stopped the study because it is such a big clunky, heavy molecule that it didn’t get through the nail plate. So, I just want you to think about that for a second. Oils and something like Tolnaftate don’t get through the nail plate. You need a water loving product and that small enough molecular weight wise to get through the nail plate.

Again, the nails are hydrogel. Solubility is really important. We have to have something that’s water loving. The creams that we put on our skin are lipid-based because our skin is different than our nail. Our skin is lipid loving. Our nails are water loving. Putting a cream on a nail will not do anything for you. If the creams are lipid-based, it’s not going to pass through the nail plate. The nail is very specific barrier.

What about ketoconazole, miconazole, itraconazole? People have tried to use ketoconazole cream. Again, ketoconazole cream is insoluble in water and that specific azole is too large to pass through the nail plate. It won’t do it. Again, you might make the nail look a little bit prettier, but it’s not going to change much. You can add urea to try to swell those pores a little bit like we talked about, but it won’t let those azoles pass through because you can’t expand those pores that much. You can only expand them a little bit and temporarily.

Now, what about efinaconazole topical solution? This is an alcohol-based solution. So, already, we’re better than doing with the oils. It has the molecular weight that’s just at the threshold to get through those pores at the nail. So it’s one of those things that it has the right molecular weight, it has the right vehicle, it’s the right shape to get through the nail plate, to get to the nail bed where the disease is.

When they did their beginning clinical trials, nail thickness did not influence, did not change how it went through the nail so, it didn’t matter how thick it was.

[26:06]

Even though in the clinical trials and I was a phase three investigator for this trail, we could only do about 4 millimeters or 2 millimeters to get through but it didn’t matter in the very, very beginning.

What about tavaborole solution which is another alcohol-based solution. This is the smallest molecule the FDA has ever approved. So no problem getting through those pores. It’s an alcohol-based vehicle. No problem through that water base membrane.

And I actually tried to figure what vehicle would be best for tavaborole and they looked at maybe putting in the lacquer or putting it in that alcohol-based solution. They found the alcohol-based solution was a better choice.

What about ciclopirox lacquer? The lacquer we all love to hate. Well, the reality is that, yeah, it may have not the greatest results but the lacquer itself, that vehicle actually creates a barrier for the nail. So when you put that awful barrier that my male patients are like, "Doc, what’d you make me do? Why do I have black nails?" and like, that’s your sock fuzz. It’s called fuzzy toe nail syndrome. I’m going to fix that right up for you.

But the reality is that lacquer doesn’t allow spores to adhere so – and actually kind of a cool decent vehicle, but it’s just sort of misses the mark when it comes to everything else. And that lacquer also creates an exclusive barrier that actually may impart a little bit of moisture which we talked about dryness of nails.

So, topical treatment for onychomycosis is it better than the clinical data exist? Well, the reality is that clinical trial data versus real life data are totally different things. I know because I do both and the reality is that in clinical practice we seem to have better results. These are like an Elysian field that is just really difficult to get, but the reality is that things are actually are better in real life than in trials.

What about long term follow-up? Well, this is a rare thing because these are so expensive to do. They took efinaconazole, took patients 18 to 80 with up to 75% nail involvement, once a day for 48 weeks and stopped it, but then followed them up for 72 weeks.

[28:07]

And found that at 48 weeks, when they stopped using the drug, yeah, they had mycological cure which is negative KOH and culture, but week 72, we start seeing fungus creeping again.

So it’s one of those things where this is, to me, a statement saying maybe we should think about, you know, prevention therapy. We should think about socks and shoes, and the environment of patients and not just focused on pharmacological therapy.

Now as far as tavaborole with nail polish, I was involved with this study. This was cadaver nails. We just basically, you know, took those nails, put T. rubrum on them and saw did – we put tavaborole through with nail polish. Did it kill fungus? And it actually did.

So this is tavaborole through unpolished nails killed the fungus. This is through two coats of nail polish, it killed the fungus. And this is through, again, another two coats. This is four coats. So, we actually did pretty well. Tavaborole is a tiny molecule and was able to penetrate and still kill T. rubrum to up to four coats of nail polish.

Now, what about laser. Well, laser – the problem is that the data is all over the place and when you take a laser plus a topical, and this is what the study looked at, a laser plus a topical or just laser, what they found was that laser plus a topical is better. Which isn’t that what most of us were trying to sort of get away from, right?

I’ll do laser and you don’t have to do anything else. Well, the reality is that you do laser and the person puts their foot in the dirty shoe that they came into your office with and they re-infect themselves because they’re going to re-infect themselves with their shoes and their socks. So you have to do something beyond just laser.

Now, what about oral antifungal safety? This drives me insane with not only just primary care physicians, but with pharmacists who tell my patients not to go on and then like, you have no right to that but they do.

The pooled risk of treatment discontinuation from adverse events for terbinafine was 3.4, for each econazole which is always the worst animals, 4.21.

[30:04]

This is over 20,000 patients that they looked at. And the risk of liver injury requiring termination of treatment was less than 2% for all regimens. So the bottom line is it’s well tolerated and safe for the right patient. It’s not for everybody but for an immunocompetent population, not a bad a thing.

So how do you pulse oral terbinafine? Well, the way that I was taught to do it was to do one week on, three weeks off but you do two pills a day. So two pills of terbinafine a day for a week and then three weeks off.

There was really no difference between the groups. So do I use this a lot? I do, actually for patients who want to drink, for pediatric patients, people with various medication issues. So, you know, I use it there. I use it as a booster dose occasionally too.

So the reality is when these medications don’t work, go back to your diagnosis. Is it truly onychomycosis? Because the cost of getting things wrong is going to be a lot more expensive than the cost of getting it right. And ultimately, not that it happens a lot, but if you had to go on to a liver transplant, that’s a pretty expensive thing. Make sure you know what you’re dealing with before you prescribe these medications. Does that patient have inflammatory base skin condition? Think of it that way because a lot of times, psoriasis looks just like onychomycosis. You can’t tell the difference. Have the patient stand or walk, think about the biomechanics. If they have hammer toes, their nails are going to be dystrophic and may or may not be co-infected, but the reality is that you have to think about biomechanics.

This patient failed two round of terbinafine. This is not onychomycosis. This person did not do confirmatory testing before putting it on. This is like in planus.

So translating this on to clinical practice, again, 50% is not onychomycosis so make sure you get a lab diagnosis. I use dermoscopy to help me further refine my diagnosis. I use topicals but I use topicals in conjunction with orals and I use it as adjunctive and prophylactic therapy.

[32:03]

There’s no consensus on the efficacy of laser for toe nails. We really don’t know the benefit or the long term use of it. And we really need standardization to define cure in this clinical trials. These clinical trials are not real life. They’re meant to get drugs passed by the FDA but they’re not really what we deal on a daily basis.

Now, I grew up with the Phillie Phanatic and at first I was horrified by Gritty, but now I love Gritty because Gritty looks like a fungal toe nail. And once he looked like, to me, looked like a fungal toe nail, he is my boo. I love him.

All right. Thank you so much. Have a great conference.

TAPE ENDS - [32:46]