[Automatically generated] From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical practice. Hello, and welcome to this JAMA Clinical Review Podcast. I am Mary McDermott, Deputy Editor of JAMA, and I'm here today with Dr. Daniel Butler to discuss his recently published review on chronic pruritus. Dr. Butler is Assistant Dean of Student Affairs and Associate Professor of Dermatology at the University of Arizona College of Medicine in Tucson, Arizona. Dr. Butler, thank you so much for joining me today and welcome. Thank you so much for having me. I'm excited to talk about this, and I appreciate this forum. Wonderful. So let's get started. I wonder if you could tell us how do you define chronic pruritus and how common is it? It's a great question and one that we really want to get these facts out there. So chronic pruritus is technically defined scientifically as an itch lasting greater than six weeks. And there's a whole bucket of things that fall into that category. And when we look at how common it is, it's exceedingly common. And that's because it can happen in isolation, meaning your only symptom is itching that lasts for greater than six weeks. But it can also happen secondary to another medical phenomenon that's happening or medical condition that's happening to you where the itch is secondary to something else. So, statistically, it's about 1% of all physician visits. And even at that, it's thought to be underdiagnosed. So, it's exceedingly common, and it's the most common symptom that someone presents to a dermatologist for after the age of 50. Now, your JAMA review discusses three main categories of pruritus. And they are inflammatory pruritus, neuropathic pruritus, and a combination of those two. Let's start with neuropathic pruritus. What is neuropathic pruritus? Neuropathic pruritus is perhaps not the newest in the sense that people are experiencing it in a new way, but it's the newest when we're talking about it from an itch science perspective. So, neuropathic pruritus is dysfunction or dysregulation of the nerve that leads to itching. If you think of your nerves as sort of your sensing ability when it comes to cutaneous nerves, what happens when those nerves dysregulate is they either fire too easily or their threshold is too low and they're telling you all the time that you have to be itching. So, you can think of this as a primary neurogenic or neuropathic condition where the nerve is inappropriately or aberrantly active. So, what are the most common causes of neuropathic pruritus? So, the most common causes of neuropathic pruritus are those that are thought to be associated with nerve impingements or nerve entrapments. So, the best characterized ones that also align with how common they are are things like notalgia parasthetica, which is itching of the mid-back, thought to be related to cervical spine disease or stenosis that's causing impingement of the nerves. Similarly, another common cause of neuropathic pruritus is when those same cervical nerves get impinged and you actually get itching on the dorsal forearms. This is called brachioradial pruritus. Those are the two most common ones and perhaps the most studied. But really, this is a category that we're just starting to understand. And it's not just these local nerve impingements that can cause neuropathic pruritus. What we're starting to understand is general diseases that affect the nerves can also cause neurogenic pruritus. Things like diabetes that can have an effect on the nerves can ultimately result in a neurogenic paritic presentation. So, you can think about it in these smaller subcategories, but you can also think about it more broadly in that any condition that affects nerves either locally or systematically can cause neurogenic itch. So, that's interesting. So, for someone with neuropathic pruritus who has diabetes, would you typically see that in the same distribution as you would see peripheral neuropathy in people with diabetes? So, you know, hands and feet, for example. Yeah, it's a great question and one that we're actually looking into right now. So, you can see it in those areas unquestionably, but really the neuropathic itch in diabetes is more widespread. So, you're not just seeing it in these localized locations. And it's one of the great research questions that we still have to ask on this is that why would some people with neuropathy present with pain and others with itch? And that's really what the future of this field is going to hold. And there's a lot of brilliant people looking at that. What are the most common causes of inflammatory pruritus? Yeah, inflammatory pruritus is perhaps the most well studied because it's the one that we think about with itching. And that's when the skin has some sort of inflammation on it and you can see it. So, someone has a rash. That is typical inflammatory itch. So, the most common causes of inflammatory itch are things like eczema or subcategories of eczema, things like allergic contact dermatitis or atopic dermatitis and other systemic inflammatory skin conditions like psoriasis. But there are other causes of inflammatory itch that are really common and out there that are propagated by other things. So, many causes of infectious itch are actually inflammatory in nature. So, one great example from this is the great itch bug, which is scabies. So, what scabies does is it actually ignites your immune system to cause that itch. So, it's not the scabies itself that you're itching. It's actually the immune system that's being inside it. So, inflammatory itch is a broad category, but you can really think of it from those that are just caused by the immune system, the most common of which are what I said, allergic contact dermatitis and atopic dermatitis. But there's other causes like infectious causes such as scabies or even fungal infections of the skin. And your manuscript talks about the fact that pareitis should be evaluated according to whether or not there is a rash present. So, I wondered if you could talk a little bit about what should the generalist look for in the skin in a patient who's presenting with chronic pareitis and how the findings might help lead them toward the correct diagnosis. Yeah, you know, this is a really, really big challenge for dermatologists and generalists. So, you know, while we love to sort of split it into generalists or dermatologists and how to approach this, this is my recommendation for everybody because this is really hard. And I think, you know, just as you suggested, the first step is evaluating if there's a rash or if there's not a rash. And why that seems overly simplistic is because oftentimes these patients come in and they don't have a rash and it can be dismissed at that point. And that's what we're really trying to avoid because sometimes people say, oh, are you itchy? And if there's no rash there, it seems like it's just cast away. And so my suggestion for anybody seeing these patients is have a schematic of, okay, this is someone who's coming in. There's multiple etiologies that may be at play here. The first step I have to ask myself is if there's a rash or not, because if there is a rash, that takes me more down the inflammatory pathway. So this is possibly immune related or infectious related. And then on the other side of the equation, if there isn't much of a rash or there isn't dry skin, now I'm starting to think, okay, why is this hiding? Is this some subclinical inflammatory itch, or is this possibly what we were talking about before? Is this caused by nerves? So could this be neuropathic pruritus? And that first distinction of rash, no rash, can really start you on a path of inflammatory itch or neuropathic itch. And that's really that first distinction and hopefully the creating of a schematic for generalists and dermatologists to follow when they're seeing these patients. And then what are some of the more common causes of pruritus with rash? And would those be some of the inflammatory causes that you were mentioning earlier? Absolutely. So again, you know, it's back to those eczemas, psoriasis, and infectious causes like scabies and fungal infections, cutaneous dermatophytosis infections. Those are the most common ones that we see that are causing itch for greater than six weeks. Of course, many of those can cause itch acutely as well, but when we're looking at the subcategory of patients experiencing itch for greater than six weeks who have a rash, those are the most common ones we see. And then what about patients presenting with pruritus who do not have a rash? Tell us how they should be evaluated. Yeah, this is the hardest group, and I always like to acknowledge that. When you're seeing someone without any rash, the first thought you should have is, OK, is it possible that I'm just missing a rash today, and maybe they've had rashes in the past, or is this actually itch that's not created by a rash, such as in the cases of neuropathic pruritus? So if we just scale back, and I can give a very simplistic answer to this, I think the first way to approach a patient with itch, no rash, is to think, OK, this could either be neuropathic itch or subclinical inflammatory itch. Let me talk to the patient and approach my questions thinking about those two things. So for example, for neuropathic pruritus, I'm going to ask about conditions that may affect nerves, things like diabetes or a history of cervical spine disease. And I'm also going to ask the patient on the other side if there ever was a rash, if they've had a rash, or if they have a history of a rash. Sometimes people with a history of eczema are itchy, and they have that eczematous or atopic phenotype, but they're not showing it that day in clinic. And you can sometimes elicit that through questions. So my overall suggestion is just be really systematic about how you're thinking about these patients and try not to dismiss them even if they don't have skin changes. And then your review talks about certain blood tests that you would consider doing in a patient presenting with chronic pruritus who does not have a rash if their symptoms are less than one year in duration. Absolutely. So that's a huge part of this. And really one of the things that you want to do to look for those underlying causes of either subclinical inflammatory itch or underlying neuropathic diseases. And then there's a whole category of itch caused by secondary diseases that are unrelated specifically to those categories, but can incite those basic categories of inflammatory or neuropathic itch. So the basic lab tests that we recommend ordering for people who've had no rash and have had their symptoms for less than a year are a CDC with differential, a CMP and TSH. Now there are tons more tests out there that people have used and currently use for chronic pruritus, but those are a baseline for anyone who doesn't have other comorbidities that would be suggestive of other conditions. And specifically what you're looking for in that group of lab tests or serologic tests are of course abnormalities in the CBC that may be indicative of either a lymphoma or hypersensitivity or an allergic reaction if there's eosinophilia. You're also looking for abnormalities in the kidney or the liver that can often cause itching such as in nephrogenic pruritus or cholestatic pruritus. And then thyroid disease, most commonly hyperthyroid, can also lead to itching, and that's another one that we recommend. That's just the cursory start, and then you can use that as a branch point for your subsequent visit with patients. Let's talk about treatment. Your manuscript again divides treatment according to whether the patient has inflammatory pruritus or neuropathic pruritus. So what are first line therapies for inflammatory pruritus? So first line therapies for inflammatory pruritus really have to do with if you're worried about the immune system being the cause or an infectious etiology being the cause. So most commonly, when it's not infectious, you're dealing with something that's immune related, and that's going to be a target with topical steroids. We often start with hydrocortisone, 2.5% in either cream or ointment form, or trimacinolone, 0.1% in cream or ointment form. Those are large volume topical steroids that for the most part are very safe, as long as people aren't overusing them. And that overuse is typically when people are using them straight without a one to two week break each month. And that's often a really safe place to start with patients, as long as you're following up. I often tell my residents when we're treating patients with inflammatory skin disease who are treating with topical steroids, it's completely okay to treat a chronic parietal patient with topical steroids and send them home for three months. But what you can't do is send them home and not follow up, because it's really important to see the efficacy for that patient with the topical steroid treatment. So the three months is interesting though. What if they don't have improvement by a month? Does that mean they could still get improvement after three months? That's a great question. So often we do say that you should try it for at least four to eight weeks. But it's a great point, because I always leave the caveat there that says, okay, if you're not getting better or this hasn't mitigated whatsoever within the month or two, give us a call because that often indicates that there's something else going on. And you bring up a really good point, which is with inflammatory immune-related itch, itch should abate very quickly, at least within one to two weeks after starting topical steroids. And then what if those don't work? Do you have a second line therapy for inflammatory pruritus? Yeah. So it's a great question. And I think this is often where generalists have a hard time with their next step. And I think the first thing to always do when your presumptive diagnosis and your first line treatment are not working is the first thing to do is always reconsider the diagnosis. So in inflammatory skin conditions, you want to think, okay, do I have the right inflammatory skin disease in my mind? Is it possible actually that there's an infection going on here? So I think going back to the differential drawing board is one really important point. And then the next piece to this, from a treatment standpoint, are things like phototherapy or even injected targeted biologics. So things like Dupilumab or Tralakinumab are new targeted biologics that have been FDA approved for atopic dermatitis. And they also work really well for chronic pruritus and are tested in chronic pruritus. So these are second line options that we're often using for those who either can't tolerate or have failed topical steroids or other topical immune targeted agents, such as calcineurin inhibitors. How about neuropathic pruritus? How would you approach therapy for that? So the first line treatments that we almost always use for neuropathic pruritus are topical. And the best part about neuropathic topical treatments are that they're very safe to use. So these are often anesthetizing agents, things like either lidocaine or menthol or promoxine. These are first line agents that are pretty readily available and easy to apply to the skin without much toxicity or at least systemic toxicity. And so we usually start with that. If that isn't working, then we'll often increase to more targeted and internal neuropathic options. Things like gabapentin or pregabalin are things that we often like to use in that second line therapy. But again, you're going to want to make sure that if they're failing that first line, that you're reconsidering your diagnosis on each visit that you're seeing the patient. And for those first line therapies like menthol and promoxine, are those over the counter? Exactly. That's a great question. I'm so glad you brought it up. Those are over the counter and I love that because it decreases the burden to get them. Sometimes with access issues, some of these medications can be a challenge. And promoxine and menthol are over the counter and easy to get. So someone can leave the office and get them within the next 15 to 20 minutes, depending on where your practice is. And when should a patient with pruritus be referred to dermatology? The easy answer to that is anytime you're feeling uncomfortable managing the patient. So I tell generalists, don't try to stress yourself out too much on this if it's not an area that you're comfortable. So anytime, but I think if someone takes those first steps, it's always healthy to consider sending to dermatology when you're questioning a diagnosis. So that can be if you're looking at the morphology of a skin change and you're wondering, hey, is this actually a rash or not? Because what we can do is we can go in and do a biopsy to help see if there is inflammation or infection in the skin. That's one category where I always recommend sending to dermatology. The other one that I think is important is when someone requires a really robust internal workup, meaning that you would potentially send them over to dermatology if we were going to do imaging of the spine or further serologic workups. I think that's another subcategory that's really important. And then the last one is please refer when you're thinking about using medications that you're not comfortable using. So that's typically the third line agents for either neuropathic or inflammatory or mixed etiologies. So these are usually systemic immune suppressive agents or really targeted neuropathic pruritus options like opioid receptor targets or TCA antidepressants that we use off label for chronic pruritus. That's when I would really suggest sending over to us. So it's really those third line options or sometimes even second line options if you're not comfortable with those treatments. Great. I actually wanted to go back. When you were talking about the over the counter therapies for neuropathic pruritus, how often should those therapies be applied and how quickly would one expect to see a response to those therapies? Neuropathic treatments can take a little bit longer to work. Some of them have an immediate cooling effect. So like menthol's effect is to cool or calm the nerves. And so it can work quickly, but it's really a cumulative effect that we're looking for to decrease the chronic pruritus long term. So you can expect an immediate effect if you're using it once or twice a day, but you're also going to want to apply it for at least three months so that that application can give you that more durable effect in the case that it's effective for the patient. Thanks for listening. I've been speaking today to Dr. Daniel Butler about his recently published review in JAMA on chronic pruritus. This is Mary McDermott, Deputy Editor of JAMA. For more of our podcasts, please visit us at jamanetworkaudio.com. 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