244: How Do Biologic Drugs For Chronic Skin Conditions Work? w/ Heather Zwickey, PhD

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Are you trying to weigh the pros and cons of possibly using a biologic like Dupixent for your skin condition? Your immune system has such a complex relationship with one another, so it's important to have complete informed consent when starting one. Look into all the side effects- they could be actually helpful, but they could also lead to cancer!

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My guest today, Heather Zwickey, earned a Ph.D. in Immunology and Microbiology from the University of Colorado and completed a postdoctoral fellowship and taught at Yale University School of Medicine.

Dr. Zwickey is recognized internationally as an expert and educator in the fields of integrative medicine, natural therapies and the immune system and has been leading natural medicine research for 20 years. Heather speaks at conferences world-wide, sharing her enthusiasm for naturopathic medicine and science. She currently serves as the Director of Communication and Innovation at Thaena Inc., a microbiome-based company.

Join us as we talk about how biologic drugs for chronic skin conditions work.

Did you know about the relationship between your immune system and your skin? Let me know in the comments!

In this episode:

• Biologic drugs – what are they, how are they prescribed, and what do they do?
• Real side effects of biologics – the bad and even the good
• Breaking down what cytokines are (in layman's terms)
• Cytokines and the JAK/STAT pathway
• Discussion of JAK inhibitors (the newest version of biologic drugs for skin issues)

Quotes

“Back when we used things like methotrexate for skin disorders, we would see that the entire immune system was blocked and as a result, there would be side effects of things like cancer. When we're only blocking one protein, we have much less severe side effects.” [2:59]

“If your skin is not in balance with its microbes, it will affect your gut. We really got to address that. That is the root cause, and usually the way that we're going to address that is with eating more plant-based foods and getting some of the toxins out of our system, and letting those microbes grow the way that they were supposed to grow in normal ecosystems.” [17:47] 

Links

Find Dr. Zwickey online here

Healthy Skin Show ep. 180:  How Hormones Impact Your Immune System + Skin Health w/ Heather Zwickey, PhD

Healthy Skin Show ep.157: How Your Immune System Can Trigger Skin Rashes w/ Heather Zwickey, PhD

Follow Dr. Zwickey on Instagram

244: How Do Biologic Drugs For Chronic Skin Conditions Work? w/ Heather Zwickey, Ph.D. FULL TRANSCRIPT

Jennifer: Dr. Zwickey, it is such a pleasure to have you back on the show. Thank you so much for being here again.

Dr. Zwickey: Hi, Jen. I'm really happy to be here.

Jennifer: Every time you come on the show, I feel like I learned so much. Some of my favorite episodes are of you breaking down some complex scientific topics, and I felt like the conversation today about biologic drugs, what they are, how do they work, how we maybe should or shouldn't think about them, I felt like you were the right person to have this conversation with, so I really appreciate it. I think the most important questions that I have for you to kick off this whole conversation are what exactly are biologic drugs and how do they work?

Dr. Zwickey: That's a great question, and in order to address that question, we first have to talk about what is a cytokine. Cytokines are these proteins that your immune system makes to communicate with the rest of the body, and you can think of them as a hormone of the immune system. You have cytokines that are inflammatory that tell the rest of your body, “Hey, this person has an infection and we need to start an immune response,” and you have cytokines that are anti-inflammatory that tell the rest of your body, “Hey, everything's good right now, we need to calm down.”

Dr. Zwickey: What happens in a lot of inflammatory diseases, and skin diseases in particular, is that the inflammatory cytokines are dysregulated, and often the reason they're dysregulated has to do with the microbes in our gut and on our skin and that they're out of balance, so the immune system is saying, “Hey, there's an infection,” when really the infection is our normal microbes overgrowing or undergrowing, but it's leading our immune system astray and telling our immune system to send out an inflammatory signal.

Dr. Zwickey: What biologics do, which is very different than some of the previous drugs that we had for skin diseases, is they target individual cytokines, so we can say, “Hey, this particular cytokine is out of balance, and we are going to pinpoint that cytokine and we're going to block it.” The early classes of biologics were blocking individual cytokines, like TNF alpha, or more recently IL17. We also have biologics that block. Interleukin-1. The cool thing about that is that because you're only targeting an individual cytokine, it has less of the broad-based side effects that the earlier medications had. Back when we used things like methotrexate for skin disorders, we would see that the entire immune system was blocked and as a result, there would be side effects of things like cancer. When we're only blocking one protein, we have much less severe side effects. Does that make sense?

Jennifer: Yeah, this is basically a more selective way, a more Jedi way, of sneaky modulating the immune system, essentially.

Dr. Zwickey: Yeah. Instead of sending in an atomic bomb, you're sending in a sniper. You're still going to do some damage because you're wiping out a protein that your body needs, but you're not going to do nearly the amount of damage that we were doing with the early immunoinhibitory proteins.

Jennifer: Okay. With cytokines, we have cytokines, which you just mentioned, that people and drug companies have been targeting, we'll say, but now there's JAK inhibitors and you'll see the term the JAK/STAT pathway. Are the cytokines the same thing as the JAK/STAT pathway, are they a part of that pathway? What is the difference between those two camps, I guess we'll say?

Dr. Zwickey: Sure. The cytokines are on the outside of the cell, so they're extra cellular, and where a cytokine works is that the cell will have a receptor, which kind of looks like a baseball mitt, and then the cytokine can bind to that receptor, so it's like a baseball hitting the mitt.

Dr. Zwickey: The JAK/STAT pathways are inside the cell, so if you imagine catching a baseball and your arm jabs backwards, that is going to send a signal, you're jabbing the cell, sending a signal into the cell to turn it on to do different things. The JAK/STAT pathways are signaling proteins, and they're similar in that they're in the same pathways as the cytokine receptors, but they tend to be more general. They can be associated with several different cytokines, whereas the cytokines are more sniper-ish, more individual. Does that make sense? The JAK/STAT pathways… They're inside.

Jennifer: The JAK inhibitors are now being considered the newest thing, though, so it's like they're looking to almost go broader in trying to block the inflammation.

Dr. Zwickey: They are. The idea with using JAK/STAT pathway is not that it is going to have less side effects because they still have side effects. It's that they're worried about blocking individual cytokines because of some of the side effects that show up. If you look at the side effects that happen with the IL-23 inhibitors, you'll see that usually, the reason IL-23 is made is when we are exposed to mold or we have fungal infections. Then, your immune system turns on the IL-23/IL-17 pathway to fight mold.

Dr. Zwickey: If you now block that pathway, that means that anytime you're exposed to black mold in your house or mold in the air, you can get these fungal infections. Likewise, you're more likely to get Candida in your genitals and that sort of thing. Anything that is a mold or fungus is going to be allowed to grow when you block that pathway. In contrast, if you use a JAK/STAT inhibitor, it's a broader effect, so you're not seeing the same fungal infections, but what you do see is nausea and headaches and some infections that come out like herpes infections that are usually suppressed by your immune system. It's a more general suppressor of the immune system. It's not as general as methotrexate, but it's more general than the targeted biologics of the IL-17/IL-23 or the TNF alpha inhibitors, or the IL-4/IL-13 for atopic dermatitis.

Jennifer: It sounds like the issues that we're so concerned about in using biologic drugs, specifically cytokines and whatnot, they're not necessarily bad things. You just literally shared that some of these are meant to protect us, they're actually helpful for the body and yet, there's consequences-

Dr. Zwickey: All of them are.

Jennifer: Right, so there's a consequence to turning them off. Would those be considered the side effects that are listed within the pamphlet or the brochure for whatever specific medication you're taking?

Dr. Zwickey: Absolutely. When you're reading the side effects, it'll tell you what that cytokine usually does. For example, the TNF alpha inhibitors, one of the big side effects is tuberculosis, that if you're in a place where tuberculosis is endemic and you take a TNF alpha inhibitor, you're going to get tuberculosis and you're not going to be able to fight it off. All of these cytokines have very specific biological activities and things that they're good for.

Dr. Zwickey: What's interesting for the atopic dermatitis is that the cytokines that are blocked, they're IL-4 and IL-13, those cytokines historically are what we used to fight worm infections. We grew up with worms in our guts, that's normal microbiota in most of the world, but in the Western industrialized world, we have figured out how to kill those worms, so we don't have worms in our guts anymore. But we grew up having worms in our guts, evolutionarily, so we made these cytokines in order to keep the worms in our gut under control.

Dr. Zwickey: If you block them, if you're in a location where worms are endemic, you're going to have out of control worm infections. In the United States, the only worms that really circulate around here are pinworms, and usually you see them in daycare centers, but we don't really have worms anymore. When we block IL-4 and IL-13, we don't see worm infections happening, but that's why we made those cytokines was-

Dr. Zwickey: Go ahead.

Jennifer: I was going to say with Dupixent, they have a specific warning about checking to make sure if you have a helminth infection, and I could never understand quite-

Dr. Zwickey: That's a worm infection.

Jennifer: Yeah, but the funny thing is it's hard for one to know if they have a helminth infection if nobody ever checks, right?

Dr. Zwickey: Yes, that is very true, although there are very few helminths that are circulating in the U.S. other than pinworm, so the likelihood that you have a helminth or a worm infection is very low here, likewise in Europe. Where we see worms still endemic is Sub-Saharan Africa, much of South America, so those places, using a drug like Dupixent is going to be a much higher risk.

Jennifer: I see. That makes a lot more sense.

Dr. Zwickey: Do you want to hear something really cool?

Jennifer: Yes, please.

Dr. Zwickey: I geek out on this stuff, of course. Interleukin-13 is one of the cytokines that is blocked for atopic dermatitis, and the role of Interleukin-13 is mucus production. When you produce Interleukin-13 in your body, you're making mucus so that the worms can't hold on in your gut and you expel them. Because we don't have worms, we make IL-13 to innocuous antigens. It's made when we have allergies, so when we sneeze and we expel all of that mucus, that's IL-13. When your nose is running because you have allergies, that's IL-13, so if you're taking an IL-13 inhibitor for your atopic dermatitis, the side effect is going to be that your allergies go away. Kind of a good side effect for that one.

Jennifer: I know also with Dupixent, it's been cleared for use with asthma, I believe, and one of my clients, I had said asked her, “Do you want to talk to your doctor about possibly stepping down off of this?” and she's like, “Well, it was so helpful with my asthma, I don't think I'm ready to try that yet.” I was like, “Okay, no problem.”

Dr. Zwickey: Yes, that's right. The same cytokines that are involved in allergies are also involved in asthma, so when you block those particular cytokines, and in the case of Dupixent it's two, it's IL-4 and IL-13, then not only are you blocking the atopic dermatitis, you're also blocking rhinitis, your runny nose, and you're blocking asthma. In some countries, Dupixent is used for asthma as well as for atopic dermatitis and allergies. It has multiple effects because you're blocking these two cytokines, and unless you have worms, that's not a bad thing. It used to be thought that some people had genetic polymorphisms, or genetic reasons, for expressing more of these cytokines, however, now we know that the reason that they probably are expressing more of these cytokines has to do with the microbes that, again, are on their skin, in their gut, in their lungs. Those microbes are out of balance, so this is your immune system trying to get those microbes back into balance.

Dr. Zwickey: The interesting thing is that atopic eczema, asthma, and allergies all share the same cytokines. They all use IL-4 and IL-13, so when they created Dupixent, which blocks IL-4 and IL-13, it's simultaneously affecting atopic dermatitis, asthma, and allergies. Some people don't want to come off Dupixent because their allergies get better, whereas other people don't want to come off it because their asthma gets better, but all of those things get better.

Dr. Zwickey: Still, we used to think that people who had chronic allergies, chronic asthma, atopic dermatitis had some sort of genetic mutation that was causing them to overproduce IL-4 and IL-13. What we know now is that there's no genetic mutation there for most people. What it is is that the microbes on their skin, in their lungs, in their gut are out of balance, and their immune systems are trying to get those microbes back into balance so the immune system is producing the IL-4 and the IL-13 and a third cytokine called IL-5 to try to bring everything back into balance. If you can bring those microbes back into balance with diet and exercise and cleaning some of the environmental toxins out of your living area, then you can actually have the same effect of lowering those cytokines without actually using a drug to do it.

Jennifer: This underscores why these are not bad. They're not actually bad. They can be extremely helpful to support good health and life and protect your body as it is exposed to various different things. One thing I was reading that I thought you might find fascinating, there was a study, and I've seen this actually several times, where they're saying that H. Pylori, for example, can help increase IL-17 quite significantly. Do you think this is a good conversation for people who've thought, “Well, if I just do a biologic drug, I don't need to do anything else. I'm…” I don't even know if they think that they're cured or healed or what somebody may think, because it depends a lot of times on what education they're exposed to around these medications, but perhaps it's an opportunity to start digging deeper. If a specific medication works for these specific cytokines, for example, then maybe that's the opportunity to begin digging around what's driving that particular cytokine higher.

Dr. Zwickey: I absolutely think that's the case. I like to use the analogy of putting a piece of duct tape over your gas indicator. You have the gas indicator that tells you whether or not you're running out of gas, and we can easily take care of that symptom by putting a piece of duct tape over it. Now, you never have to worry anymore about looking at your gas indicator and seeing that you're running out of gas, but it doesn't mean that you're not going to still run out of gas. That's a lot of what these medications do, they shut down a single pathway so that your symptom goes away. Your skin clears up, or your rhinitis clears up and your nose doesn't run anymore, but you haven't treated really the underlying cause, which is the dysbiosis either on your skin or in your gut.

Dr. Zwickey: We know that there's a gut-skin axis, so even if your gut is what is not functioning properly or what has dysbiosis, it'll affect your skin and vice versa. If your skin is not in balance with its microbes, it will affect your gut. We really got to address that. That is the root cause, and usually the way that we're going to address that is with eating more plant-based foods and getting some of the toxins out of our system, and letting those microbes grow the way that they were supposed to grow in normal ecosystems.

Jennifer: In terms of these types of medications, like the JAK inhibitors… I keep wanting to say JAK/STAT pathway. Jack inhibitor medications, they have a black box warning. Why is that? Why do you have to be careful with using those types of medications and messing with that pathway?

Dr. Zwickey: Specifically for the JAK/STATs, they are proteins that regulate the cell cycle, and when you are messing with cell cycle, you can lead to cancer ultimately, because we know that oncogenes and tumor suppressor genes are working together to keep our cells growing at a normal rate and not overgrowing or under growing. JAKs are what are called kinases, and as kinases, it means that they put a phosphate onto a protein and make it active or inactive. When we do that, we're causing the cell to go into an activation state or a growth cycle, and those growth cycles could get out of control. When you put a black box warning on a medication, you're recognizing that there are still things that may be long term consequences that have not been studied yet.

Jennifer: We just don't know what the real likelihood may be with long term use, for example, of something like developing cancer.

Dr. Zwickey: Yeah. Sorry, I didn't mean to interrupt, but yes, it takes like 20 years to develop cancer. We haven't done a 20 year clinical study on a JAK/STAT inhibitor, which means that it could still cause cancer. We just don't know yet, and we won't know until people have been taking them for more than 20 years, so we put a warning on it just in case because of course, the other big thing is that none of these companies want to be sued.

Jennifer: No, and I understand, too, that the intention is not to necessarily harm anyone, but I think sometimes we go in… I saw this in my dad's medical practice, that sometimes people don't want to even know what the potential side effects are because they're so afraid of them. They're like, “I'd just rather not know,” and that may or may not work for someone long-term, but I personally am of the opinion you really should weigh the pros and the cons and not assume that the 2%… It doesn't impact that many people.

Jennifer: You could be the 2%, so you should weigh the pros and cons of whether you're willing to possibly face that type of future ahead of you. It might not happen, but I think you should at least be aware and go in with your eyes open for these types of drugs, because for some people they're on them for a really long time. Is there any safety studies that we know of that if you're on these drugs for 20, 30, 40 years, are they safe to be on them that long?

Dr. Zwickey: We don't know. The average clinical trial for any of these medications is 12 to 36 weeks, which means that's as long as we've looked.

Jennifer: That's not even a year.

Dr. Zwickey: People are on these things for years. I know, and people are on these things for years and that's why there's a black box warning there. We don't know what's going to happen when people are on these things for years.

Jennifer: Wow, that is quite sobering. My point in having this conversation with you is not to scare anyone, I don't think that's fair. I think that there's a time and a place for medications. I've worked with clients who are really, really suffering, and if they choose a medication along their journey to help them get a better quality of life, to be able to get out and exercise because their joints are no longer hurting them or their skin isn't open wounds and they're not in debilitating pain and up all night itching themselves, it can be a huge quality of life change for some people. But there is that concern that long term, there's some problems that could be ahead if you're not keeping your eyes open and also not going to get regularly checked and making sure that nutrient levels are appropriate and whatnot.

Jennifer: With your background in immunology, do you have any words of wisdom or advice for somebody who might be considering or who's on some sort of biologic about what they could do to be proactive for themselves or to consider if they haven't quite made that decision yet to give it a shot?

Dr. Zwickey: Yeah, absolutely. The first thing is to remember that your immune system changes over time as your body is changing over time. Pay attention to key times in your life pathways. If you are on a biologic and you're going through menopause, you're going to see shift in the biologic activity as you go through different stages of hormone cycles, and pay attention because you may be at higher risk for different side effects as you're going through different phases of your life cycle. That's the first thing.

Dr. Zwickey: The second thing is, as much as it is tempting to say, “I'm on a biologic, my medication completely controls my disease or my diagnosis,” it's still really important to take care of the microbes that we live with because it is entirely possible that one of these biologics will be recalled when they see long-term side effects from them, and it would be really nice if you could come off the biologic and be healthy. Again, pay attention to taking care of these other aspects of your life as well. Just because the biologic is controlling the symptom doesn't mean that you don't still need to give your body those nutrients to make it healthy.

Jennifer: I think that's a really important reminder, and I also think, I'm just personally an advocate, that before you go on a biologic that you should really take a look at your nutrient levels and some other factors first, because I have worked with some clients who were offered a biologic and they were like, “Let me just see if anything else is going on,” and it turned out they had deficiencies in all different nutrient categories that no one had ever bothered to look at, it just wasn't on their radar. If they had gone on the biologic, some of those red flags that were showing up in their skin and their system would've disappeared, making them believe that they were completely healthy now as a result of that medication, even though in reality, their body needed crucial nutrients in order to thrive. I think there's some work that can be done ahead of time before you make the choice, but again, it depends on one's access to things and what your goals are in terms of your health. I really appreciate you having this-

Jennifer: Go ahead.

Dr. Zwickey: Oh, sorry. I would also say that remember that the side effects of the biologics are real, and we get to the point in our family that when the commercials come on TV, we laugh because they're listing so many different side effects, but the reason they're listing those side effects is people were experiencing those things. If you go on an IL-17 biologic, as an example, pay attention to the fact that you may be susceptible to Candida infection in your mouth, in your vagina, et cetera, and when those other symptoms start to appear, you're going to want to make sure you get them treated early because you don't want to go into recurrent Candida infections and those sorts of things. When you go on a biologic, it's not an excuse to not pay attention anymore. You almost have to pay attention more.

Jennifer: Just to underscore that, what you're saying is that, because I think this is important, even though you're on the medication for your skin, the infection, like a fungal infection in this instance, as you just mentioned, could be someplace else, not just on your skin.

Dr. Zwickey: Absolutely. In fact, the side effects specifically for anti-IL-17 in the phase III clinical trials, it was oral mucosa and vaginal mucosa, and mild to moderate cases of Candida anywhere between 12 and 60 weeks of treatment, so anytime during a year of treatment, they were seeing these Candida infections show up.

Jennifer: Wow. Again, underscoring the importance of the microbiome and making sure not just to shut things off, but to consider how do we better balance them and taking a lot of these other steps in order to get there. Thank you so much, Dr. Zwickey. I really appreciate you, as always, for coming back and breaking down some of these very complicated topics and enlightening all of us, and I'll make sure to put some of the ways that people can obviously connect with you in the show notes. Thank you so much for being here, I really, really appreciate it.

Dr. Zwickey: Thanks for having me, and I hope our conversation helps people take good care of their bodies and nurture their microbiomes.