Psoriasis and the Mad Itch

Shiva: My name is Shiva Mozaffarian and here today for a discussion about the itch often associated with psoriasis and potential treatment options is dermatologist Dr. Shawn Kwatra, Associate Professor of Dermatology at Johns Hopkins University School of Medicine where he also serves as the Director of the Johns Hopkins Itch Center. His primary clinical and research interest is around the pathogenesis and treatment of chronic pruritus which means chronic itch. He is also a member of professional organizations that include the American Academy of Dermatology, the International Forum for the Study of Itch, the Society for Investigative Dermatology, and the Skin of Color Society.

Welcome Dr. Kwatra and thank you for joining Psound Bytes™ today!  Itch is such a topic of interest since most people with psoriasis experience pruritus or itch. Let’s first start with the basics and how the body knows when to react to sensations such as an itch? What’s the science behind the itch?

Dr Kwatra: Thank you so much for having me on the podcast. I'm really excited to share some insights. So starting with the basics of itch, the message to get yourself to scratch, to feel that impulse of itch is transmitted by nerves. And so you have nerves that go all the way out basically to the farthest point of the skin, pretty much so. And then they go all the way to the spinal cord and the brain and go back and forth together. So these nerves are traveling from the skin to the spinal cord to the brain and then back. It's a bidirectional message. That's one of the reasons that even psychological factors like stress or actually mirror neurons can be activated by seeing someone else itch can make you itch as well. Maybe me even talking about itching is making some of our listeners scratch a bit. So the nerves are the most important aspect mediating the itch message. Now what we have is we have immune cells that are present and there’s been very elegant work done to show what aspects of the immune system are involved and activated in psoriasis. But there's an interaction in psoriasis between the nerves and the immune cells. The immune cells can release a lot of inflammatory mediators like cytokines that then stimulate the nerves. We know that the nerves can actually be hyper stimulated and secrete a lot of neurotransmitters. So things like neuropeptides, some of the names are substance P or nerve growth factor, things like that. And then they stimulate the immune cell. So it's very much so bidirectional. Many of the therapies that are approved now for psoriasis are modulating different aspects of the immune system and the mediators that they release, and so that's causing the nerves to get less irritated and improving itch. But there's recently been some studies, actually one in the Journal of the Investigative Dermatology, looking at even infusions with things like anesthetics or things that affect the nerves that that can reduce the itching and then also affect the appearance of psoriasis. So we're very much so learning a lot more. Now we know it's the nerves and the immune cells that are in a close relationship together that's setting off the itch of psoriasis.

Shiva: So you mentioned psoriasis and inflammatory mediators. How is current research exploring why the itch occurs with psoriasis?

Dr. Kwatra: It’s a great question of why we think itch occurs in psoriasis. We know that in psoriasis we have these raised, red, scaly plaques and a lot of the research have found there's very important cytokines like IL-23, IL 17, TNF. These are all just the names of a few of these important cytokines. And in psoriasis you also have memory or tissue resident memory cells. For example in psoriasis that's one of the reasons that you tend to have itch and you tend to have psoriasis in similar appearing areas is that you're having the cytokines that are then stimulating the nerves and also these neuropeptides that are being involved in itch transduction. So now we know that it's very much so a neuroimmune process. We know that the reason that psoriasis keeps coming back as we seem to have more of these memory cells that remember to keep secreting these substances that are causing itch. But there's actually even some studies and thoughts of new therapeutics going on to even target memory in psoriasis because now that we can get the disease under control, well, how do you eliminate it? Then one of the new frontiers, actually, there's a study going on with Risankizumab, also known as Skyrizi, where they're giving high dose early on trying to see if that can affect these memory T cells. So very interesting in terms of biology, of the inflammation, and the itch which are so intricately linked and how that's being advanced very fast.

Shiva: Wow, that’s so interesting. So what is the prevalence of itch as a symptom of psoriasis and what locations tend to be impacted by itching?

Dr. Kwatra: Well there's a number of different studies and they have a number of different percentages of patients that they'd report, but I'll say there's a recent study published in June of 2021 and they actually had a multinational, multicenter study in psoriasis and itch or pruritus was in that study present in 92.9% of patients.  Some that may be a little bit higher than other studies, but I would say most patients with psoriasis have a lot of itch and there's certain areas that tend to be very itchy and difficult to treat. The genital regions, the scalp, sometimes intertriginous or body fold regions, also in the groin or the armpit. Those can be some of the difficult areas. But as we know with psoriasis, these lesions can be so itchy, folks are scratching at it and they're bleeding, and then folks are bleeding everywhere. And then the act of scratching actually gives an element of pain that can provide that momentary itch signal to be distracted. So then you get this itch, scratch cycle. You're itching. You're scratching. You're bleeding, but you're getting that very brief relief in terms of the itch through scratching that's making you go back and do it again. That's what we don't want, but that is the basis for this itch scratch cycle.

Shiva: And we know something that comes with the itch scratch cycle you just explained is the Koebner phenomenon. Can you explain a little bit more about what the Koebner phenomenon is?

Dr. Kwatra: Absolutely. The Koebner phenomenon was actually first described a very long time ago, I think 1876 by Heinrich Koebner. And so describe this phenomena where you get the appearance of new skin lesions on previously unaffected skin secondary to trauma. So that trauma could be areas where you have a site of injury on a certain area of the body so that could be a place that you may not typically experience lesions. And so the act of scratching can actually also serve as a trigger to either worsen lesions as they are right now or to kind of have new de novo lesions. What's interesting is this gentleman, Heinrich Koebner, is a German dermatologist. So the German dermatology is very advanced and he was actually a founder of a dermatology department in Breslau. So he was the first person that actually reported these formation of lesions in psoriasis patients where they had trauma such as excoriations, but also other things like even tattoos, bites, and now we're recognizing that this can happen in other conditions as well like vitiligo, lichen planus, other conditions like that, so it's very interesting.

Shiva: So what factors determine the severity of itch? Is disease severity or type of psoriasis a factor? You already mentioned some of the locations where psoriasis occurs and tends to itch.

Dr. Kwatra: Yeah. So it's interesting because some folks with psoriasis may not have as exaggerated itch as other patients. One thing we tend to note is that folks who have greater disease severity overall, the amount of area in their body that's affected tend to have higher rates of itch. So some folks who come in that are erythrodermic, also means that most of their body, the majority has redness and itching associated with it as well. So the amount of your body that's affected is very important in terms of the amount of itch that you have. I'd say right now we're living in truly a golden age for psoriasis. Unfortunately, one of the big gaps we have right now is there's so many therapies that are approved or being approved, but we don't have as robust itch data as compared to studies for atopic dermatitis. And it's interesting because for some reason, even though the data shows that folks with psoriasis, itch just as much, if not more than patients who have eczema. Eczema’s thought more intrinsically to be linked to itch. And so I think that's a big gap that we have that it's a little bit difficult to compare a lot of different biologic therapies or small molecule inhibitor therapies in terms of their itch relief. So the main endpoint that a lot of clinical trials are focused on is the PASI score which I'm sure folks have heard of before. It's the Psoriasis Area and Severity Index and really the gold standard for a long time, was the PASI 75, so the Psoriasis Area and Severity Index having that 75% improvement. So many of these drugs went through approvals for that. So I would say we can compare many of these biologics. First, we had the TNF inhibitors and then IL-17 inhibitors. Now we have IL-23 inhibitors that are really doing an amazing job and actually have very infrequent injections as well. But in those trials, they don't have a very important place for itch reduction. So I think that can be very difficult for patients. But what I will say is that many of these drugs target immune components of disease and through improving the lesions, the itch improves as well. So luckily, we are having most of our patients be controlled and we have several new topical agents. There's many such as roflumilast which is a topical too. It modulates PDE4. With a lot of these inflammatory cytokines there's other drugs out as well like tapinarof and other drugs. They're even modulating the microbiome or the microbes on your skin because microbes can even set off a lot of these nerves. That's the very interesting thing about itching in psoriasis is that these nerves have very close apposition to your external environment. So where are you live can be important factor. Even how much sunlight you get because that can be anti-inflammatory. The pollution or smoking, things like that, areas that you're around, all of these things can set off this itch scratch cycle. Stress in particular. I personally sometimes get hives when I get very stressed, and most of my patients talk about how there's that very important relationship between stress and their itch as well.

Shiva: So that’s a nice segway to my next question. It seems like there could be a psychological component to itch. Is that correct?

Dr. Kwatra: What I would say is some folks think that, is itching in your head? I would say yes and no. Yes, stress and your thoughts can contribute and worsen and aggravate your itch. There are mirror neurons in your brain. You can watch a video of someone else scratching and you'll get itchy. You can feel that high stress level and that can make your itch worse. But it's also part of the mechanics of the disease is that these nerves in psoriasis oftentimes may have altered intervation in the skin, and then many of these pathways going to the brain. There have been studies showing that these nerves can be either less in density in the epidermis of the outer layer of the skin or increased in density as well. And then it can set off this chain reaction. So I would say a little bit of yes, and yes and no in that of course psychological factors can exacerbate it. But inherently the brain is just as much a part of disease pathogenesis as many of these other factors cause itch and many other symptoms have to go through your central nervous system. It's a very cool, emerging concept, and there's a study about using an anesthetic with lidocaine as infusion and then that reduced people's psoriasis. So I think it's very much so paradigm shifting and one of the next frontiers is understanding more how neuropeptides are involved in the transmissions of inflammatory skin diseases. There's been so much work done on immunology, but we know that itch is a neuroimmune process. How are these neurons and nerves modulated that are transmitting disease? Because many of the neural markers they're called some ion channels or TRP channels. Many of these other substances are found to be dysregulated in psoriasis lesions, also in the bloodstream of patients, they've been found to have more itch related mediators as well. 

Shiva: Wow, lots of different factors then. So one area that we haven’t spoken about is impact on overall quality of life. Can you elaborate on how itch impact’s day to day activities? I’m sure itch could impact quality of sleep for example.

Dr. Kwatra: Absolutely. So in our group, I have an itch clinic and center and we see a lot of patients. All comers that have chronic itch and that includes psoriasis patients. And so when we studied these patients, we published this recently, we found that the overall impact on quality of life among chronic itch patients is as severe or in the ballpark of folks who are going through chronic heart failure, hemodialysis, uncontrolled diabetes, stroke. This is the landscape of the effect that itch can have on quality life. And I think sometimes folks don't recognize that, that type of burden that patients are feeling and that's a big deal. And itch is inherently tied, as you mentioned, to sleep. If you're itching, you're often times gonna have dysregulated sleep. And actually many measures of new therapies are how fast does the itch improve and then the sleep should mirror that improvement and improve with it. So sleep then mediates worsening of psychological conditions like worsening anxiety, depression, your focus? You can't focus cuz you can't sleep. You're going to have impaired work related productivity.  So then things can compound and truly devastate folks. And this is not even addressing the psychosocial impact of psoriasis, because psoriasis is a little bit different from other diseases in that you have these very apparent lesions that many of my patients reported that other folks think that they may even be contagious, heaven forbid. I had a patient who was uncontrolled before and itching a lot. She had trouble retaining a partner because of that. It's very damaging and the act of itching and scratching and all of that can be very embarrassing for folks too. Not to mention the fact that they're not sleeping, that they may be depressed or anxious, and that it's a vicious cycle that compounds on itself. So I think we underestimate the impact on quality of life that the patients can be gone through a very difficult time with this. And so I'm hoping that medicine broadly, the House of Medicine, is recognizing this. I think we're at an inflection point where we're getting more interest in understanding the science that therapeutics, the effects on quality of life, interventions that you can have. I'm encouraging these different pharmaceutical companies also to look at itch as a very important endpoint in psoriasis patients. So hopefully things are turning.

Shiva: It’s such an important point. We really do need to keep quality of life at the forefront of these discussions. So you’ve mentioned some updates about current research in itch during our discussion today. Do you have any other comments you'd like to add about some exciting areas of research that perhaps we haven't heard about yet? 

Dr. Kwatra: Yeah. So what my lab is looking at is we see a lot of patients who have psoriasis and we are interestingly looking at a lot of the blood mediators of itch and psoriasis. So there's a ton of different cytokines as well that I mentioned we have new therapies for. But we're also looking at the cascade of different neuropeptides that are upregulated in psoriasis patients and the itch that they have. So that's one of the big areas of work that's going on. I'm in particular very interested in this new access of how neuromodulation injection with even anesthetics can modulate patient’s disease as well. So I think that's going to be a very interesting, illuminating new area because we know that in many ways there's neurogenic factors where there's pro inflammatory factors that may be related to neuraly secreted compounds, things that are released from the sensory neural endings, neuropeptides that communicate with these immune cells. So I think a lot of the science has gone as far as it can with mice, but actually, looking in humans, that's one of the things that we're very interested in learning more about that access, and then also looking at new and novel therapies and seeing how they can affect this neuroimmune axis as well.

Shiva: Yeah, I mean if you solve this, you'll have so many people behind you who are so appreciative of getting rid of their itch. So we've spent some time looking at the science and impact of the mad itch. Let's turn now to how the itch can be treated and you've talked about some treatments earlier. Let’s step back and talk about some basics here. There are four types of treatment, neuromodulating, immune modulating, complementary and integrative medicine, and rescue. Which of the four types would you say is the most effective at treating the itch currently associated with psoriasis pending the location?

Dr. Kwatra: I currently believe, based on the available medications that we have and data that the most effective way to treat itch in psoriasis is through attacking the inflammation. So the immune involvement that we know is dysregulated. So there's different immune axis in psoriasis, and that's been most clearly delineated actually of all diseases in dermatology is in psoriasis. So we know in particular very effective therapies targeting IL-23, IL-17, compounds like that and that's systemically. And then we have a number of new novel therapies such as topical roflumilast or tapinarof, and especially roflumilast I've looked into this a little bit more as targeting multiple cytokines on different axis through modulating PDE4 (phosphodiesterase 4). So that's been very interesting. And then in terms of, there's always room for other therapies, so complementary and integrative medicine, neuromodulating therapies. The problem is we don't have much data behind any of that. I have had patients who have done acupuncture, topical anesthetics like pramoxine or camphor, menthol that are over the counter. We've heard of neuromodulating agents like lidocaine infusions. The problem is the data is just not there. Most of the data here is for biologic therapies, topical therapies that are new agents in the area that are having some effect. But the most important realm to interrogate is immune modulating medicines in psoriasis since that avenue of research is just at that highest point.

Shiva: Yeah, that makes sense. So you mentioned over the counter products like pramoxine, camphor and menthol. What about the use of capsaicin for itch? We’ve heard it’s recommended for itch quite a bit. 

Dr. Kwatra: Yeah. So those products have been recommended quite about a bit, products that have menthol. Capsaicin is difficult because it causes you to burn. So I only put capsaicin more on normal appearing skin because capsaicin can actually cause the skin to itch a lot. I don't actually recommend patients with psoriasis use capsaicin because most of the time it can release a lot of inflammatory mediators for about a week before the nerves get desensitized. And during that time, if you already have inflammation, it can be unbearable. So I actually don't use capsaicin in folks who have actually active rashes in psoriasis patients.

Shiva: That’s great to know. So what about use of antihistamines? We know histamines are useful with acute itch but is it a viable treatment for chronic itch?

Dr. Kwatra: So it's a remnant historically, histaminergic versus nonhuman histaminergic itch. What we're finding is almost all forms of itch are nonhistaminergic now. So if you have hives then antihistamines are thought to help some. But most forms actually including psoriasis don't involve the histamine pathway directly. It's just that if you take Benadryl it will make you tired and make you sedated. But I don't recommend them. I recommend going to the source of the problem with many of these novel immune directed therapies.