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What are topical steroids? Often prescribed for chronic skin conditions, I’ll bet you’ve probably used them at some point during your treatment.
Sure, they work quickly, but are they without side effects? To answer that question, we need to talk about glucocorticoids, which are hormones naturally produced by the adrenal glands as part of the stress response.
Topical steroids fall under the glucocorticoids category, and due to those who’ve experienced something called topical steroid withdrawal, some people are described by physicians as “steroid phobic.”
While there are serious downsides, glucocorticoids can have some incredible anti-inflammatory effects on various health conditions. That’s why it’s crucial for us to have a nuanced conversation about this!
Dr. Luis Franco joins me to discuss everything you’ve wanted to know about topical steroids, types of glucocorticoids, and concerns about side effects from using topical steroids.
Dr. Luis Franco is a Tenure-Track Investigator at the National Institute of Musculoskeletal and Skin Diseases (NIAMS). He was born in Colombia and grew up between Colombia, Brazil, Mexico, and the United States. He attended medical school in Colombia before returning to the United States, initially as a postdoctoral fellow at Duke University. Dr. Franco attended Baylor College of Medicine for specialty training in internal medicine and medical genetics. In 2014, he moved to the National Institute of Health (NIH).
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In This Episode:
- What are topical steroids versus glucocorticoids?
- Are topical steroids + glucocorticoids bad?
- Cortisone vs cortisol (and glucocorticoids examples by name)
- Side effects of glucocorticoids
- What is topical steroid withdrawal?
- How glucocorticoids modulate your immune system
Quotes
“Glucocorticoids exist naturally. They are hormones that are produced by our bodies. And they're produced by this very particular gland that's above our kidneys, that's called the adrenal gland or the suprarenal gland. And so our adrenal glands produce these chemicals called glucocorticoids. And those chemicals have many, many roles in biology and the one that is sort of best understood is that they are part of the stress response.”
“I think the side effects that are important to know for topical glucocorticoids are one, something called skin atrophy, which is kind of a thinning of the skin that people notice when they've been applying glucocorticoids for a long time. Some people also notice little, kind of red, blood vessels that come up. These are called telangiectasias. These are like reddish blood vessels that become very visible on the skin of people who have used topical glucocorticoids.”
Links
Find Dr. Franco online
Topical Steroids Potency Chart
Immune regulation by glucocorticoids can be linked to cell type–dependent transcriptional responses
Glucocorticoid-induced eosinopenia results from CXCR4-dependent bone marrow migration
366: What Are Topical Steroids (aka. Glucocorticoids) + How They Actually Work In Your Body w/ Dr. Luis Franco {FULL TRANSCRIPT}
Jennifer Fugo (00:13)
Dr. Franco, I am so honored to have you here on the show. Thank you for joining us.
Luis M Franco (00:19)
It's a pleasure to be here.
Jennifer Fugo (00:21)
So for those who don't know, we got connected through Dr. Ian Myles. So for those of you who have loved watching Dr. Myles' episodes, now you know. There's a good connection here that was made to help us talk today about, well, most of you who are listeners, your experience has been with something called topical steroids and what are topical steroids. But the truth is, this is a much bigger conversation about a class of medications known as glucocorticoids.
So, Dr. Franco, can you kind of kick us off with explaining what exactly glucocorticoids are and if topical steroids are maybe a part of that? I don't know how it all fits in, so if you could explain that, that would be awesome.
Luis M Franco (01:08)
Sure. So in summary, when people talk about topical steroids, they are speaking almost always about glucocorticoids. So glucocorticoids, we can sort of understand glucocorticoids in two ways, at two levels. Glucocorticoids exist naturally. They are hormones that are produced by our bodies. And they're produced by this very particular gland that's above our kidneys, that's called the adrenal gland or the suprarenal gland. And so our adrenal glands produce these chemicals called glucocorticoids. And those chemicals have many, many roles in biology and the one that is sort of best understood is that they are part of the stress response. So whenever there's a stress response, there's a very acute increase in the function of many systems, the nervous system, the immune system, and there needs to be something to quell down, to ease that overactive immune system that happens during stress, and these hormones, these glucocorticoids naturally play a role in that.
Again, glucocorticoids are a type of hormone that is naturally occurring in our bodies. Now, it turns out that many years ago, this was in the late 1940s, as these hormones of the adrenal gland were being discovered by biochemists, there was a rheumatologist at the Mayo Clinic, Dr. Philip Hench, who was trying different stress hormones on people with autoimmune or inflammatory diseases, in particular people with rheumatoid arthritis, which is a type of autoimmune disease. And after trying multiple things, he realized that when he injected people with these glucocorticoids, what was then known as compound E, later known as cortisone, they dramatically got better.
So this was sort of a miracle drug that helped people with rheumatoid arthritis who at the time really had no good options for treatment and they were many times unable to get out of bed. Suddenly these people were quite literally dancing in the hallway of the hospital because they felt so good, and so it was seen as sort of a miracle drug. Then two of the biochemists who were purifying these chemicals from the adrenal gland and Dr. Hench shared the Nobel Prize in 1950 for this discovery that this glucocorticoid, cortisone, made people with autoimmune diseases better.
So where does the steroid part come in? So steroids are a type of chemical that has a very particular chemical structure, what people call the steroid ring. And there are many, steroids in biology, plants make steroids, mammals make steroids. In humans there are two main types of steroids. The steroids that we refer to as sex steroids, these are things like estrogen for example, which people might be familiar with. These are things like testosterone. Those are the sex steroids. Some of the hormones of reproduction like progesterone are also steroids, and those are the sex steroids. And then there are the so-called adrenal steroids which are made by the adrenal gland, and those include glucocorticoids.
So glucocorticoids are steroids. All glucocorticoids are steroids, but not all steroids are glucocorticoids. However, because glucocorticoids, these steroids, have been used to treat inflammatory diseases, including skin diseases, people often have referred to them as just steroids. But again, steroids are a broader class of molecules. And that's what steroids are, and that's what glucocorticoids are. When people talk about, I'm using topical steroids, they generally mean I'm using topical glucocorticoids, not topical testosterone or estrogen or things like that, although there are also formulations of that.
Jennifer Fugo (05:47)
So it sounds like what you're saying, then, is that while what we're using maybe from a topical exposure perspective, and obviously there's other ways to interact with medications that are in this class, like you can have them in an inhaler, you can have injections, pills, inherently glucocorticoids and glucocorticoids examples aren't bad. And it sounds like we need them in order to survive within our little body, our delicate body that we have that is very wonderful and robust and does its best to help us survive. But inherently, because I think that's an important thing where, and obviously, you know there are some in this community who are really, they're really afraid of this class and so they fear it in every single spot. Which I understand, but it's part of that misinformation that we want to help clear up today that inherently, these are important for your body in order to feel well and have a good state of well-being.
Luis M Franco (06:59)
Yes, that is absolutely true. Glucocorticoids are not inherently bad. They are hormones that are in our bodies like any other hormones, and they have a very important role to play in our bodies just in the way that our bodies work normally. Now, what happened was that hype in the early 50s of this sort of miracle drug that was making people with autoimmune diseases so much better was quickly quenched by the realization that when we give these drugs, especially when we give them by mouth or injected into people's veins directly, they can have very serious side effects.
And so two things that became evident a few years after people started using glucocorticoids were that one, they can have serious side effects. And two, that they're not really a cure for any of these inflammatory or immune conditions. They help control the symptoms, but they don't solve the underlying problem. And so the people with rheumatoid arthritis who got so much better after they started taking these glucocorticoids, if they stopped the glucocorticoid, their disease would come back. And so those two things became evident.
Now, with the side effects of the glucocorticoids, what happened was there was a lot of media attention to these drugs, and there were two particular media events that were important. In 1955 there was a big article in the New Yorker magazine called “Ten Feet Tall,” and this was about a person who had a type of autoimmune disease, a type of blood vessel inflammation, and started taking glucocorticoids and had very serious side effects including very serious psychiatric side effects, which are actually quite rare, they're actually not common and they're not nearly as severe as what was described there. But it became part of popular culture that these drugs are very good and very important to treat these conditions, but at the same time, they can be toxic. And then there was a movie a year later called Bigger Than Life, and this was a 1956 movie that had kind of a similar story, but it was even more extreme. So this was, I think, a school teacher who started taking this drug, this cortisone, this glucocorticoid or steroid, and really, really lost control of his impulses and his life. And so that, I think, led to a fear among many people of these drugs. People became fearful of cortisone, which was the main glucocorticoid in use at the time, and of its side effects.
So again, yes there are side effects. There are side effects of glucocorticoids when we apply them to the skin. There are side effects of glucocorticoids when we take them by mouth or when they're injected. But the media hype around the side effects of glucocorticoids really led a lot of people, like you said, to treat them as if they are the enemy. When in fact they're just another class of drugs that help some people.
Jennifer Fugo (10:29)
And I wanted to ask you too, because you mentioned cortisone as one glucocorticoids examples, is cortisol, is it similar to the cortisol that the adrenal glands produce?
Luis M Franco (10:39)
Yeah, it's a great question. In summary, yes, cortisol is exactly the hormone that the adrenal glands produce. And cortisone is an inactive form of cortisol that can be given by mouth, but our livers convert cortisone to cortisol. And so if somebody takes a cortisone pill, which is really rarely used anymore, but was the norm back in the 50s, that's when people were taking, cortisone. In fact, some people still, when they talk about glucocorticoids, they refer to them as cortisone. Some people say, you know, I'm taking cortisone, like topical cortisone, that's rarely the case. But cortisone is related to cortisone. It's a very similar molecule, but it's an inactive form of the molecule that our livers have to convert into cortisone, which is an active form.
Jennifer Fugo (11:29)
So I guess this begs the question, if you take the medication by mouth, you said it gets processed by the liver. But what happens if you apply a glucocorticoid to the skin in this conversation about what are topical steroids? Do you believe from your research that, is the impact just on the skin or is it possible for the active glucocorticoid to penetrate more deeply into the more systemic system and then be processed through the liver as well?
Luis M Franco (12:00)
Yeah, it's an important question. So it all depends on how much of the glucocorticoid is actually absorbed. So in principle, when you apply a glucocorticoid to the skin, most of it is not really absorbed. And certainly the concentrations that you get in the blood, for example, are very, very, very low compared to the concentrations that you get if you take it by mouth or if you inject it into someone's veins.
Now, there are many factors to this which is an important thing that I think is key for everybody to understand, that how much of a glucocorticoid is absorbed depends on many factors. So for example, if you take a baby who has a skin condition where the skin is not intact and you apply glucocorticoid all over that baby's body, you're going to have a much higher concentration in the blood than if you have an adult who has skin that is mostly intact and applies a small amount of glucocorticoid over that area. So there are many things that affect the potency of a glucocorticoid, how strong it is.
For your listeners, probably the topical glucocorticoids, the stuff that you apply on your skin, are the most relevant ones. Let's talk about those. Topical glucocorticoids are varying potencies. They have different strengths, so to speak. But the actual strength of a given drug, and also to your question, the amount that actually gets absorbed into the body, depends on many, many factors. For example, what type of molecule exactly? Which glucocorticoid? Because even though we started with cortisol, which is the same hormone that our bodies make, the pharmaceutical industry spent a lot of money and resources tweaking that molecule over the years to come up with molecules that are sometimes more potent, sometimes easier to absorb, sometimes harder to absorb so that they don't get absorbed as much.
And so from the original cortisol there are a whole lot of different glucocorticoids nowadays. So your listeners may have a prescription for, say, betamethasone, which is a type of glucocorticoid that's quite potent, or they can have a prescription for hydrocortisone, which is a type of glucocorticoid that is a lot less potent. Those two, even though they're both glucocorticoids, are used very differently by dermatologists because one is a lot more potent than the other, and one of them, betamethasone, can be combined with other molecules to make it be absorbed more or be absorbed less. So which glucocorticoid you take, what's the state of the skin, do you just apply it or do you put a bandage over it? At what temperature? There are a lot of factors that play into what happens after we put on a glucocorticoid. In principle though, when you apply a glucocorticoid compared to when you take a glucocorticoid by mouth, the absorption on the skin for the most part is considered really, really, really low compared to say, again, by mouth or injected.
Jennifer Fugo (15:29)
And would that be the same possibly for, like, an inhaler, say somebody has asthma? I mean obviously, I guess you're breathing that into your lungs, is there as high or a higher absorption rate there?
Luis M Franco (15:42)
Yeah, absolutely. So when you take an inhaled glucocorticoid, those are also, those have been, again, the molecule has been tweaked to reduce the absorption to the best of our ability, but it's clear that some of it does get absorbed into the bloodstream as well. And so these things, like most things in medicine, are never black or white. There's always some gradation. And so to say that when we apply glucocorticoid to the skin, it does not get absorbed, I think is not true, because it might be absorbed.
But again, how much of it gets absorbed? It depends on many things. And the same exact thing applies to the inhaled glucocorticoids. To say that they do not get absorbed into the bloodstream, I think is not true. But at the same time, if you compare the amount of glucocorticoid that ends up in your blood if you use an inhaler, compared to if you're injected with a glucocorticoid, it's completely different. So I think that's the important part for people to realize. It's not black or white.
Jennifer Fugo (16:44)
And so speaking of this, because obviously, you already mentioned that they learned a long time ago that there can be side effects, and there can be side effects to everything. I've even talked about here on the show how herbs and nutrients, and, I mean you can have side effects from consuming too much of certain types of foods. It's just, this is the way of life, right? I always think of it as the Goldilocks principle. You really need to find the right amount.
Luis M Franco (16:54)
Yeah, absolutely.
Jennifer Fugo (17:14)
So what are some side effects of glucocorticoids in general, but maybe also you can speak a little bit to the topical glucocorticoids that are, maybe some are known, but maybe some are less known even to physicians. Because I mean, I'll be honest with you, my dad, as I shared, was a doctor and we didn't have anybody coming in to try and educate him on steroids. He was being educated on the latest and greatest, you know, eye drop medication for treating X, Y, and Z. So I don't really know how much education there is at this point ongoing, especially given this class of medications is prescribed so frequently.
Luis M Franco (17:57)
Yeah. So I think there are, again, a broad range of side effects of glucocorticoids. For your listeners, if we're talking about topical glucocorticoids, there's a very specific set of side effects for topical glucocorticoids. The other side effects, let's say for example, if somebody has an autoimmune disease and they have to take glucocorticoids by mouth for years, there are certain risks of things like osteoporosis, for example, when they take glucocorticoids. The likelihood of that for somebody who takes topical glucocorticoids is extremely low. And so it's not something that we even consider, typically, is related to topical glucocorticoid use. That's an important thing to realize also, right? This depends on how much the glucocorticoid is getting to the rest of your body.
So I would say that some side effects of glucocorticoids like osteoporosis or muscle damage or neurological or psychiatric conditions, really don't apply to the vast majority of people who use topical glucocorticoids. On the other hand, there are some side effects of topical glucocorticoids that are very important for people to know about, because they may occur, not because they occur to everybody. To what extent any of these happens to any given person is very person-dependent. Each person can respond very differently. You can have two people who take the same exact glucocorticoid in the same amount by the same route for three months, and one of them has nothing and the other one has all of the side effects that we're about to describe. So this also is very, very person-dependent, which makes it very important for people to one, pay close attention to their response more than to whatever the internet is telling them is going to happen, but to their response, and two, to communicate with their physicians and other healthcare providers about what's happening.
So I think the side effects that are important to know for topical glucocorticoids are one, something called skin atrophy, which is kind of a thinning of the skin that people notice when they've been applying glucocorticoids for a long time. Some people also notice little, kind of red, blood vessels that come up. These are called telangiectasias. These are like reddish blood vessels that become very visible on the skin of people who have used topical glucocorticoids.
When they're applied in larger areas of the body, some people develop stretch marks, striae, that also has been described with glucocorticoids. And again, when people apply them to bigger areas of skin, some people describe easy bruising, or kind of a weaker skin that doesn't heal as well. Some people get acne when they apply their glucocorticoid, or these sort of reddish areas called rosacea that also can happen. And although glucocorticoids are typically not applied for wounds, when people happen to have an open wound, the healing of that wound tends to be delayed with glucocorticoid.
Jennifer Fugo (21:08)
Why would that be?
Luis M Franco (21:22)
Well, there are several reasons, but the main one is that glucocorticoids impair the function of some of the cells that bring tissues together after there is a cut, for example. And so when there's a wound, when there's an open wound, let's say a cut, for example, we try to avoid using glucocorticoids. This is not the same as, say, somebody who has an area of exposed skin because of an inflammatory condition. That's a different story. But if you have a cut, for example, and you apply glucocorticoid, it's probably not going to heal as quickly as if you don't apply a glucocorticoid. And so there can be issues with wound healing.
And some people report pigment changes. Color can become a little darker or a little lighter on the skin when they apply glucocorticoids. And occasionally, some people report, especially in some parts of the body, they report changes in the hair. They have more hair here, less hair there, the hair thins and so forth when they get a glucocorticoid. I think those are the main side effects to know about for people who use topical glucocorticoids. Again, noting that these can vary. Some people can get nothing of this and some people can get all of the things that we just described, it really depends on the person.
Jennifer Fugo (22:25)
Yeah, and I know too, we've actually had another ophthalmic surgeon, who knew of my dad, he was on the show a couple of years ago. And he also talked about how we have to be careful when, sometimes you have say, eczema, and the rash spreads and starts in other areas and you think, I was given the steroid, the topical glucocorticoid for this reason, so I'll start applying it in the other areas. And you really have to be careful, especially applying it around the eyes because that can cause potentially an increase in intraocular pressure and can also contribute to cataract formation, which the only solution at this point right now is to have cataracts removed in surgery.
Luis M Franco (23:10)
Absolutely, that's a very, very good point. And I think it's another reason why people using glucocorticoids really should be discussing them carefully with their healthcare providers, because that's another factor, right? If we think about what makes a glucocorticoid more potent or less potent, and therefore more or less likely to give you any of these side effects. And so this notion of potency, how strong the medication is, is important because if you have a mild skin condition, you may not need the most potent glucocorticoid out there. Whereas if you have a very serious skin condition, your dermatologist might be inclined to prescribe a very potent glucocorticoid. But the more potent glucocorticoid has a higher likelihood of giving you these serious side effects if you apply it for a long time.
And so let's think about what makes a glucocorticoid more potent. People often are focused on which drug, which molecule, is being given to them. Like we said, betamethasone or clobetasol, these are potent glucocorticoids, very highly potent glucocorticoids. Whereas, say hydrocortisone, you even find it over the counter, is a much less potent glucocorticoid. And so people usually focus on that, on which glucocorticoid did my doctor prescribe. That's one part of the issue here. That is one part of the story.
The other parts of the story are equally important. And so as you said, what part of the body are you applying the glucocorticoid to? If your doctor prescribed a potent glucocorticoid for you to apply on the sole of your feet, when you had very dry skin, very inflamed dry skin on the sole of your feet, and then you go and apply that same very potent glucocorticoid in your eyelid, the response is going to be entirely different in the two places, because the thickness of the skin could be hundreds of times different between the sole of our feet and say our eyelids. So, yes, it makes a huge difference where you apply it. And that's something that dermatologists are very, very aware of. And they will be able to say, okay, use this glucocorticoid for this time in this area of your body, but don't use it elsewhere. And so where in the body it's applied is very important.
What kind of condition you have, what's the integrity of the skin, is your skin intact or do you have a big open area of skin, that also matters in terms of how the glucocorticoid acts. Do you put a bandage over it or do you just apply it? What kind of preparation is it? Do you have an ointment, or is it a cream, or is it a foam, what type of vehicle is the glucocorticoid being delivered in? All these things lead to either more side effects or less side effects, more potent glucocorticoid effect or less potent glucocorticoid effect. So it's not just what the molecule is called, there are a lot of other things that have to be considered. And I think people, it's really important for people to discuss these things with their healthcare providers and to say, okay, I'm going to use this glucocorticoid for this long, applied in this amount, for this part of my body. And that's the correct way of using it. You can't just, you know, use them as if they're controlling inflammation anywhere. It's not quite like that.
Jennifer Fugo (26:18)
Yeah, and I think another good question, and I'd be curious to your response on this, about whether you can develop some sort of dependency or addiction to these types of, especially the more topical glucocorticoids, and may then experience topical steroid withdrawal. You know, there's a lot of talk about, I mean, I cannot dismiss, and clearly neither can Dr. Myles, that there's something strange happening that is not the skin conditions that these individuals originally had. Something is very deeply wrong. I've seen it even, just on like blood labs and looking at someone's experience from a clinical nutrition standpoint, something seems amiss here to varying great degrees. So in your research, do you think that it's possible for patients who may be using super high potency steroids, I mean, again, we don't know how this even happens, but is it possible to develop some sort of dependency, so to speak, to them?
Luis M Franco (27:39)
That's an important question because there's a lot of lack of clarity, I think, about this issue. And so if we think about addiction or dependence in the same way as we think of, say, substance abuse for people who are addicted to opioids or other drugs, no. The answer is no. There is no evidence that people can become addicted to a glucocorticoid in that way, like a sort of a physical dependence on applying or using the drug. No, there is no evidence of that whatsoever. It's important to sort of dismiss that.
Now, do people, after they stop using the glucocorticoid, can their disease come back? Yes, because these are not drugs that cure a disease. They have always been used to kind of quell down the immune response. And so can someone who is using a glucocorticoid and seeing an effect, right, their skin looks better, if they stop using it, can their disease come back? Yes, that can certainly happen because again, these are not curing the underlying disease, they're just helping to control the symptoms, the manifestations of the disease. Then comes the more complicated question, which is, are there changes in the skin that go beyond the disease, that are induced by the glucocorticoid?
We already talked about what these different side effects are. And so if say, somebody was applying a glucocorticoid to this part of the skin, and now the skin looks thinner and what we refer to as atrophic skin, could that have been caused by the glucocorticoid? Yes. Could that be permanent? Yes. That can also be lasting or permanent. Same thing with, say, stretch marks. And so are there changes in the skin that the glucocorticoids can induce that are apart from disease, separate from the disease? Yes, there can be. Now, the part that has been controversial and is a matter of study, Dr. Myles, whom you mentioned, is sort of actively trying to understand this phenomenon, is this notion of withdrawal, where people stop using a glucocorticoid and then suddenly they have all these things that they didn't have before that are really difficult to tease apart from the disease. And so is that a flare-up of the disease or does that have a different nature? That's an area that, in my view, it's important to study. And again, Dr. Myles has been studying this quite actively.
I think it's important to acknowledge the concerns of the people who have brought this up. The people who say, look, this came back, but it's not my disease. It's something else. I don't think it's reasonable for us as doctors to dismiss them and say, no, you're crazy. This is just your disease. However, teasing apart what is a flare-up of an inflammatory disease and what is something new takes very careful study and very careful research, and it takes a lot of interaction between the people who are experiencing those symptoms and people who will take them seriously and try to understand what's going on. And so, to me, that is the correct way to approach this type of thing is to say, well, let's study it carefully, and let's see if we can determine what's a flare-up of the disease, which certainly can happen. There's no question that a flare-up can happen after you stop taking glucocorticoids. And what is something different that happens after the glucocorticoid? Again, noting that in the strict sense of the term, addiction or dependence, as in substance abuse, is not something that we consider when we use glucocorticoids.
Jennifer Fugo (31:36)
Well, it's interesting too because you've talked a lot about the immune system and how these glucocorticoids quell the inflammation. And you shared with me a couple of papers which were, and I'm gonna be entirely honest with listeners, was well above my nerdiness level. That's okay. I pieced out some things that I thought were interesting and that I felt would be helpful for listeners to hear about. I'll share those papers in the show notes, so if your science nerdiness is above my level, you might absolutely eat these up and they might even give you some questions to ask beyond this. I would be curious to know.
But how do they impact the immune system, especially given now we have biologic drugs, we have JAK inhibitors that target, well, the biologic drugs tend to target very specific, like tumor necrosis factor alpha, or IL-4, IL-13, IL-17, whereas I don't think that glucocorticoids do that, but you would know better than I.
Luis M Franco (32:45)
Yep. So the issue with glucocorticoids is that part of the reason why they're so effective at, like you said, quelling an overactive immune system is that they act at many levels. Now, they act at many levels, meaning that there are many changes in a given cell that occur when that cell is exposed to a glucocorticoid. And so an analogy that has been used, not everybody likes this and I'll preface it by saying this, but I think it's actually accurate, is that the use of glucocorticoids is like firebombing an entire city to try to eliminate a few enemy battalions.
Jennifer Fugo (33:35)
Wow. Yeah.
Luis M Franco (33:36)
Right? And I think, again, you know, not everybody likes that. I had a friend whose family is from northern Germany and their city was firebombed during World War II and he really didn't like this analogy when I used it in a meeting. I think it's, with that caveat, with that caution, I think it's actually an accurate description of what we're doing when we're using glucocorticoids. Are we eliminating the enemy battalions? Yes, we are. Very effectively. But are we also doing a lot of other things that we don't want to do? Yes, we are. And that's why people like myself like to study glucocorticoids, so that we can better understand what it is that they do.
But they do many, many things. And so you mentioned biologics, right? And so they will target, like you said, one molecule, tumor necrosis factor alpha, or they will target interleukin 1. Those are very targeted interventions towards molecules that we know are important to activate the immune system. Even those have side effects, right, that sometimes are limited to the immune system, sometimes go beyond the immune system. A glucocorticoid is like using many of those biologics all at once, and in addition to that, adding some other changes that we don't quite understand very well. Again, that's part of the motivation for people like myself to really study these drugs because they're extremely effective and they have played a very important role in controlling these immune conditions. And if you give me a choice between having people whose disease makes them so impaired that they can't function and having people who are at risk for some side effects of the drug, generally I'll take the latter.
But we should acknowledge that these drugs have many effects that go beyond what we're trying to target, what we're trying to do. Sometimes we know what we're trying to target, sometimes we don't know. So glucocorticoids, for example, to give the examples that we just gave, right, tumor necrosis factor alpha or interleukin 1 or interleukin 6, these are all important molecules for developing an inflammatory response. There are biologics that will target each of those. Glucocorticoids target all of those. Each of those are targeted at the same time by glucocorticoids. And then there are many other things that have been studied over the years.
What's sort of new in this, what's unique about what my lab is doing, is that we, nowadays, it's nothing that is unique to my lab, it's just that we now have the technologies that we didn't have 10 years ago or 15 years ago. But what's new and interesting is that we now can look at these things at the level of the entire system. And so instead of say, if we think about a gene that is changing, its expression goes high, it goes low, before we could look at one or a handful of genes at a time. And so people would say, okay, let's look at tumor necrosis factor and see if that gene goes up or down after we give a glucocorticoid. Iit goes down. Well, nowadays we can look at that and every other gene in the human genome all at once. And so we have these high throughput technologies, which, like you said, make these papers extremely nerdy and difficult to follow sometimes. But it's because we have so much data that we collect and we have to use computational resources, Excel doesn't do it, we need to use other types of computer resources to tease apart what's going on. And so that's one thing that's new, is that we can now look at these things at the level of the entire system, what's changing across the board. And that has revealed a lot of interesting things about how glucocorticoids work.
I can point out maybe a few things that I think are interesting and sort of novel in terms of how glucocorticoids act. The first one is that we used to think that glucocorticoids just change the function of all cells kind of in the same way. And now we know that glucocorticoids actually affect each cell type very, very differently. The response of any given cell type, if you compare a cell from the skin to a cell of the immune system, like a neutrophil or a lymphocyte, each of those responds really, really differently to glucocorticoids. Glucocorticoids don't affect all cell types the same way. And what that means for us is that if we're really going to understand this well, we have to look at different cell types differently in terms of the response to glucocorticoids. It also means that we have to do these kinds of things directly in humans. Ideally in humans with the diseases that are treated with glucocorticoids, right? And so that interaction of patients, volunteering for clinical studies and so forth is extremely important because we're not going to figure this out with mice, and we're not going to figure this out with cell lines that have grown in the laboratory for the past 50 years that came from one person with cancer. So cancer cell lines are what has been used to try to understand glucocorticoids for a long time. Well, now we know that those respond really differently to glucocorticoids than say the cells of your skin or your lymphocytes. So we have to study these things at the level of individual cells to understand how glucocorticoids work.
The second thing that we have learned that I think is very important is that for any given effect of glucocorticoids, even though we're changing a lot of things inside the cell, the thing that's really leading to the change that we're interested in is generally one or two things. And we can, if we study this carefully enough with a lot of work, we can actually dissect this down to specific molecules. And so my lab, for example, we were curious about something that happens after you give glucocorticoids, which is that a type of cell called the eosinophil, which is a cell that's sort of around our bodies and sometimes goes into tissues, eosinophils vanish from the blood after you give people a glucocorticoid by mouth or injected. And even though we've known this for 70 years, we had no idea, until recently, why. Like, where do they go and why do they go where they go? And after a lot of study, what we found was that glucocorticoids induce the expression of a very specific gene that leads to higher levels of a protein in eosinophils, not in all cell types, but in eosinophils. And that is what leads these cells to go to the bone marrow. And so if we block that, just one single thing, if we block that, the eosinophils no longer vanish. They stay in the blood.
And so it's quite interesting because again, we are using these things that, that, you know, it's like firebombing the entire city but we can, with a lot of study, we can figure out, okay, for this effect, what is it about glucocorticoids, and we can pin it down. That's another thing that I think is quite new and interesting.
Jennifer Fugo (40:44)
I did think that was fascinating when I read that, that you have this significant drop in eosinophil levels, and that also you noted that neutrophil levels tend to increase. So if someone is actively using, or I don't want to say using isn't the right word, but is currently employing glucocorticoid, and they go for blood work. So they should be aware, and the doctor should be aware that if they're on these medications, and I don't know too, if you can say is there a difference between the topical versus the oral and whatnot, but that that could actually impact the complete blood cell count differential of these white blood cells.
Luis M Franco (41:29)
Absolutely, for oral glucocorticoids or intravenous glucocorticoids, it's very, very clear. For topical glucocorticoids, not so much. And that's one of these indications that in general, again, there are exceptions and we talked about the little baby with thin skin getting glucocorticoids all over their body, they're going to get higher absorption. But in general, if you're an adult applying a small amount of glucocorticoid on your hand because you have certain lesions, no, the blood, the CBC, the complete blood count, the differential for that doesn't typically change. On the other hand, if you're taking glucocorticoids by mouth, it changes in very predictable ways. Neutrophils go up, eosinophils disappear, lymphocytes and monocytes and other cells also go down, but not as dramatically as eosinophils. So there are all these changes to the complete blood count and doctors, we take that into account. If we are seeing a patient and there is some suspicion that they may have an infection, where the neutrophil count would go up, doctors generally ask themselves, is this person taking glucocorticoids? Because that could be one thing that could make the neutrophil count go up. So yeah, those are all changes that are induced by glucocorticoids, but mostly we're talking about taking them by mouth or injecting them.
Jennifer Fugo (42:43)
And if you stopped using, like we talked about, some individuals have gone kind of cold turkey, totally stopping their topical glucocorticoids. Do you think, and I just ask because a lot of people say, I noticed across the board that individuals who have this experience have really high eosinophils. And do you think that that could happen, where like you stop it and there's this huge rebound, or probably not? If you don't know, it's okay, but I thought I would ask you.
Luis M Franco (43:13)
Yeah. It's a good question. It brings us back to this issue of how difficult it is to tease apart. What is a recurrence of the disease, and what is something new, something different? It's very, very difficult to answer that question. It's worth it, it's worth studying, for sure. But it's really hard to tease it apart.
Jennifer Fugo (43:19)
Yeah.
Luis M Franco (43:35)
There are conditions, allergic conditions for example, that are characterized by high eosinophil counts, and those are treated with glucocorticoids. Generally when those are treated, if the disease is well controlled, you see the eosinophil count coming down. So you stop the glucocorticoid, the eosinophils go back up. Does that by itself, just by itself, tell us that there is something about the glucocorticoids themselves that is driving the eosinophil count up? Or is this a flare-up of the disease? Very difficult to know, and especially very difficult to know as a general thing, is it something that we can generalize to the population? Let's say you have a patient, an individual. That's why studying the individual and talking about the individual is so important, because we all respond differently.
And so if you have someone who had really high eosinophil counts just by their disease, before they took the glucocorticoid, they take their glucocorticoid, they stop it, and then their eosinophil count goes up, that's telling us that probably it's the disease that's coming back. If you have someone whose eosinophils were never high, they were never high, they took a glucocorticoid for some time and then they stopped the glucocorticoid, and all of a sudden the eosinophils are extremely high, that tells us that there may be something different. And so that brings us back to this notion of how hard it is to tease apart disease recurrence after you stop the glucocorticoid from something entirely new. Both are possible, both are worth studying, but we need to learn more.
Jennifer Fugo (45:12)
I love that you and Dr. Myles, and I'm sure you have many other colleagues as well, who are just curious. You're curious about this, and you're looking and actively seeking answers, and I know that listeners really will appreciate that. And so anyway, I just want to thank you so much for being with me today and sharing all of this. I am going to continue to read the papers that you are working on and I'm open to learning more on this. And I hope that we can have you come back sometime.
Luis M Franco (45:43)
Absolutely, it would be my pleasure.
