First US Consensus Published on Uniform Nomenclature and Diagnosis for Neuropathic Pruritus

“This really is the start of a true academic and industry partnership where we are working together to help patients. There are tons of opportunities; there are tons of prevalence of this disease, it’s just understudied. So by shining a light on it, we’re hoping that will ignite research, ignite new therapeutics, get the pipeline going, and ultimately be able to help our patients who are suffering so much,” said Shawn Kwatra, MD, in an interview with Dermatology Times.

Kwatra, an associate professor of dermatology at Johns Hopkins University School of Medicine and director of the Johns Hopkins Itch Center in Baltimore, Maryland, and his colleagues recently published the first United States expert panel consensus on uniform nomenclature and diagnosis for neuropathic pruritus. Kwatra et al’s publication and conclusions are monumental, as there are no clear therapeutic options for patients with neuropathic pruritus.

Neuropathic pruritus is defined as “itch primarily caused by a lesion of or disease affecting the somatosensory nervous system,” according to Kwatra et al.

Ten pruritus experts came together, including Kwatra, Sarina Elmariah, MD, PhD, MPH; Sarah Chisolm, MD; Nicholas Mollanazar, MD; Marlys Fassett, MD, PhD; Emily Cole, MD; Suephy Chen, MD; Ethan Lerner, MD, PhD; Timothy Berger, MD; and Gil Yosipovitch, MD, in November 2021 to discuss the definition of neuropathic pruritus, mechanisms of diagnosis and risk stratification, and treatment strategies.

The expert panel defined subtypes of neuropathic pruritus as brachioradial pruritus, notalgia paresthetica, multilevel symmetric pruritus, scalp pruritus, postherpetic neuralgia, and small fiber neuropathy. Topical agents for treatment consideration include anesthetics, capsaicin cream, coolants, tricyclic antidepressants, and multiclass compounded medications such as amitriptyline-ketamine-lidocaine. Systemic agents include gabapentinoids, antidepressants, kappa/mu opioid axis modulators, and cannabinoids. Procedural therapies include physical therapy, intralesional botulinum neurotoxin, CT-guided nerve root injections, transcutaneous electrical nerve stimulation, acupuncture, and dorsal root ganglion stimulation.

“We hope with greater exposure, harmonized nomenclature, and being able to all start from the same page, we’re going to be able to foster innovation with new therapeutics,” concluded Kwatra.

Transcript

Shawn Kwatra: Hello, everyone, I'm Shawn Kwatra, I'm a dermatologist in Baltimore, Maryland.

Dermatology Times: Can you please explain the background of your publication as the first US consensus on neuropathic pruritus?

Kwatra: In the last few years, there's been a revolution in our understanding of chronic itch. And there have been several immune bias therapies that have been proceeding through development that are either approved or soon to be approved. However, there's a large proportion of patients that actually have very limited options, no FDA-approved therapies, and these patients have neuropathic pruritus or neuropathic itch. And these patients are very much so suffering. We have just limited case reports, uncontrolled studies, and then very limited therapeutic options, oftentimes with agents that have very significant side effects. So, this is a very big need in itch.

Dermatology Times: What is the significance of this neuropathic pruritus consensus in the US?

Kwatra: So, what we did is created the first ever United States expert consensus panel, where we brought experts together. And we said, for there to be development of new therapies, we have to as a field, all the leaders in the field have to come together, and we have to harmonize and be in agreement on nomenclature and disease definitions Because that's the basis for the development of agents through clinical trials is we have to have unified nomenclature, and then scales and other aspects. So that was the point of this discussion is to make a definition and our definition for neuropathic pruritis is primarily initiated or caused by lesion or disease in the somatosensory nervous system. So many times these patients have normal skin, or secondary skin changes, or signs of excoriation. And these forms of neuropathic pruritus can be in certain areas of the body such as the back, notalgia paresthetica, the scalp, scalp pruritis, or dysesthesia, brachioradial pruritus on the arms.

You can also have many other forms of itch, and sometimes you could have generalized neuropathic itch. And so one of the things that we did is we talked about the diagnostic workup for these patients, what are things that you might consider. We talked about therapies, we also talked about how peripheral blood biomarkers might be helpful in being able to stratify these patients at the bedside. So those are all important things that we touched upon in this article.

Dermatology Times: What challenges are present with the lack of understanding of the pathophysiology of neuropathic pruritus?

Kwatra: There's a big lack of understanding of the biology of neuropathic pruritus, because there is not an appropriate animal model. And so these studies have to occur in humans. And there are very few studies to date really investigating these patient populations. One of the big reasons for that is there isn't harmonized nomenclature for these patients. And so we're right at the surface of better understanding the pathophysiology of this condition. What our hope is, is first for clinicians at the bedside to standardize the diagnosis for neuropathic pruritus so we can label patients appropriately. In the past and also currently there isn't a specific ICD, or a diagnostic code for neuropathic pruritus patients. So they're lumped into other forms of pruritus. This has hampered development because we haven't been able to get appropriate prevalence estimates being able to phenotype these patients doing large database studies with these patients.

So first, when we made the nomenclature, the next thing that we're very focused on is for the clinician who's evaluating these patients in clinic because I believe treating these patients is arguably the most difficult thing in dermatology right now. From all of dermatology, this is probably the most difficult patient to treat. We tried to harmonize what are some of the avenues for workup? What are some of the avenues for treatment? What are some of the drugs you might consider. So class of drugs: gabapentinoids, antidepressants, the opioid axis, cannabinoids, also roles for other things like CT-guided nerve root injections, topical therapies like pramoxine or capsaicin. We wanted to give more of a guide and a roadmap. As we continue to develop and the process of learning more about this disease, it's going to focus on human patients, better classification of these patient cohorts.

Dermatology Times: In your opinion, what needs to happen next in terms of more research?

Kwatra: We're really at the point where we need more human studies on core subsets of patients that have neuropathic pruritus, we have to better define these diseases in humans now that we also have harmonized nomenclature that will provide more of a framework for potential clinical trials in the future. But we have to focus on better understanding the pathophysiology, and also being able to design trials that accurately reflect this patient population, because before this time, you couldn't really design a neuropathic pruritus study appropriately, because you didn't have an expert consensus panel that was able to say this is what the disease is, this is what exclusion criteria and inclusion criteria should be for trials. So this is very important for there even to be valid clinical trials in this field. So we're very excited about that, that we're able to harmonize that concept.

I think many scientists who are studying itch, but they are limited by the mouse models that may be available to that many of those investigators. So most of the translational and basic scientists are studying the atopic dermatitis mouse models like MC 903, or other mouse models, that well we now have many agents available for atopic dermatitis, so the science and actually the clinical front has moved away from atopic dermatitis, and move towards neuropathic pruritus. And that's where our field is moving right now. That's where the greatest need is for our patients. So we hope with greater exposure, harmonized nomenclature, and being able to all start from the same page, we're going to be able to foster innovation with new therapeutics and actually our group will be reporting soon other studies that we have been investigating and you can expect more clinical trials and clinical studies in the future for these patient populations as well.

Dermatology Times: What main findings are important for fellow colleagues to know?

Kwatra: The main findings for this expert consensus panel is first the definition of neuropathic pruritus, which is pruritus primarily initiated or caused by a lesion or disease to the somatosensory nervous system. The core symptoms are normal skin or skin with only secondary skin changes or signs of excoriation. The itch prototypically favors a localized distribution, sometimes with dermatomal involvement that may also affect multiple body sites, and be generalized sometimes due to neuronal sensitization. They're also associated dysesthesias: pain, stinging, burning, tingling, paroxysmal or perhaps persistent in nature. There are also sub optimal responses to therapy. Our group a few years ago published on chronic pruritus of unknown origin, which is actually now undergoing some clinical trials that I helped design as well and our group reported on previously. What we found is that the percentage of blood eosinophils are actually IgE, are biomarkers for type 2 inflammation. And so sometimes patients come in and they're itching all over. And although they're classified as having chronic pruritus of unknown origin, they don't respond to immune modifying therapies. They have neural sensitization. So we harmonize that here, we mentioned that these are biomarkers, they're not perfect, but they're helpful for to guide us. So anybody who has an itch clinic are seeing each patient to now be utilizing this a little bit more to help in the being able to diagnose these patients appropriately.

Then we talked about the subtypes of neuropathic pruritus: brachioradial pruritus which can affect the arms; notalgia paresthetica on the back, multilevel symmetric pruritus, scalp pruritus, post herpetic neuralgia, small fiber neuropathy and secondary syndromes affecting central nerves, as well as peripheral nerve damage. We also talked more about the diagnostic workup, things that you should think about, maybe not perhaps not doing all patients but things like a low B 12. Also imaging, MRI or imaging if patients may need that, and I think it will be helpful that we did mention some of the drugs and some of the topical agents. There are anesthetics like pramoxine and lidocaine that are able to interfere with neuronal sensitization. There's also capsaicin, coolants, menthol, and camphor, for many of these nerves are also signaling temperature. Tricyclic antidepressants, gabapentinoids, antidepressants, and even cannabinoids. Then we also talked about other things like intralesional botulinum toxin, CT-guided nerve root injections, nerve stimulation, really going through the gamut of all of the different types of things these patients are treated with.

So in my view, this is arguably the number one problem in all dermatology that we see among our patients, we have no good options for these patients, many terrible side effects. There are a number of patients suffering. So, I really think every author who contributed this donated their time to being able to come up with this first expert consensus definition. And without all of these experts giving their time, we're not able to move the field forward. I've been very frustrated also treating these patients there are no good therapeutics. And, you know, we came together with others such as Gil Yospovitch who is a true pioneer in this field. And we came together, all the experts who have been treating these patients, we're passionate about it, and it's our mission to alleviate their suffering. And we said, what can we do to help these patients and the thing that we could do was normalizing and harmonizing the nomenclature so that we could stimulate the definitions. And then once we have disease definitions, we knew we could pave the way for trials. And so we anticipate working collaboratively with academics and industry collaborations. We want to be able to look and see what type of drugs are there that are available that maybe initially went in for another indication that can be tried for neuropathic pruritus. We want to have those conversations. We listed the different conditions. We think there can be adaptive clinical trials studying multiple neuropathic pruritus indications at the same time. So we briefly alluded to that, but there are many different diseases, brachioradial pruritus, notalgia paresthetica, and scalp pruritus.

We do imagine that in the future, there may be the possibility for trials to look at multiple of these indications together because these patients are suffering so much. So this is really the start of a true academic and also industry partnership where we are working together to help patients. There are tons of opportunities, there are tons of prevalence of this disease, it's just understudied. So by shining a light on it, we're hoping that will ignite research, ignite new therapeutics, get the pipeline going, and ultimately be able to help our patients who are suffering so much.

[Transcript lightly edited for space and clarity]

Reference

Kwatra S, Elmariah S, Chisolm S, et al. United States expert panel consensus on uniform nomenclature and diagnosis for neuropathic pruritus. Itch 9(1):e0073, January-March 2024. | DOI: 10.1097/itx.0000000000000073