Benchside Dispatches: Pruritus

In the second installment of Benchside Dispatches, Gil Yosipovitch, MD discusses pruritus. Dr. Yosipovitch, a professor of dermatology and Director of the Itch Center at the Lewis Katz School of Medicine at Temple University, is one of the foremost researchers in the field of itch.

The classic thinking in dermatology is that pruritus is a symptom and feature of many of the skin conditions seen in the clinic on a routine basis. However, stemming largely from a growing body of scientific discoveries highlighting the complex and multifactorial nature of pruritus, there is an emerging paradigm that recognizes itch as a disease rather than a symptom. Such a shift would have far reaching implications for both the clinical management of itch, as well as for the research community.

According to Gil Yosipovitch, MD, the evolution of understanding of pruritus has a lot of parallels to the changing thinking in pain management. Like itch, pain used to be viewed as an adjunctive rather than a primary concern for treatment in the clinic (and for research). Moreover, a realization of the multiple pathways that may lead to pain led to research on novel targets and the development of more directed treatment strategies. Likewise, in pruritus, research has identified multiple potential etiologies that may be appropriate therapeutic targets, and, ultimately, may lead to more effective and comprehensive treatment strategies.

William Ju, MD: What do you see as the current biggest scientific hurdles in breakthroughs for pruritus?

Gil Yosipovitch, MD: I think the emerging science on the pathophysiology of itch is both a benefit and a potential hurdle. We are learning that there are multiple mechanisms for an itch response, that it is not simply a histamine response, and that there are in fact several pathways involved. On the one hand, that means there are a variety of potential targets for drug development. However, the complex nature of pruritus means that there is likely not a magic bullet treatment that is going to be useful for all the types of pruritus.

I think another potential hurdle is that many dermatologists tend to focus on visual signs, such as lesions or skin irritation. There may be no signs of scratching or rash and still there is still significant itch. In other cases, the rash is actually secondary to the itch. And so by focusing diagnosis and treatment on what one sees, the primary cause of the pruritus may actually go unaddressed or undertreated.

Something we use in our clinic is a grading scale where we ask patients to rate their itch from zero to 10. I think that a quantitative scale like that could be important to focus the clinician on asking about itch—especially if can be incorporated into the electronic records system. But it also could help clinicians understand the severity of the manifestation. In addition, a better understanding of how to rate and validate itch grading scales could be useful for developing better drugs.

Dr. Ju: You have been a champion of thinking of chronic itch as a disease rather than merely a symptom of a disease. Why do you advocate for that shift in focus?

Dr. Yosipovitch: I think as clinicians we need to keep a focus on the reason the patient is presenting to the clinic. A lot of patients want something that treats their itchy skin. Resolving the skin lesion that caused the itch is almost a secondary concern. There has been a similar paradigm shift in pain management; many years ago, pain was viewed as symptomatic of the chief complaint, and now it is a reasonable chief complaint. The same thinking needs to be applied to itch, and we have to be mindful of the patient’s reporting problem.

Mark Lebwohl published a large study on psoriasis a few years ago showing that many clinicians did not feel that itch was a significant problem. And yet, ask any patient with psoriasis what is bothering them and they will include ‘itch’ in the troubling aspects.

Patients with dermatologic conditions with an itch component can have significant manifestations. It may be a bit of an extreme example, but patients with dystrophic epidermolysis bullosa, which can have severe blistering and wounds, rate itch as one of the most troubling parts of the disease in a number of quality of life assessments. Many might perceive that pain would be the most troubling aspect. But these are patients who are absolutely suffering due to an intractable itch.

Dr. Ju: The research in pain has revealed multiple mechanisms and multiple pathways to a pain response. Is it similar in itch?

Dr. Yosipovitch: There are similarities. Both pain and itch are transmitted via peripheral nerve fibers to the dorsal root ganglia, and they are transmitted to the dorsal spinal horn and to the brain via the lateral spinothalamic tract. On the other hand, itch is unique, because, in the majority of patients, there is an interaction between keratinocytes, nerve fibers, and immune cells in the upper layers of the skin (the epidermis and dermal epidermal junction) not the lower layers. However, this may be an advantage for treatment. It is difficult to know how much drug will penetrate a joint for pain management, but for the skin, we have a lot of experience in how to formulate topical treatments that effectively penetrate the epidermis and reach the target tissue.

Dr. Ju: How might you approach finding a cure for pruritus? It sounds like we need strategies that address the multiple mechanisms of itch as well as an increased awareness of the multiple etiologies of itch.

Dr. Yosipovitch: That is correct. There are some common denominators of targeting the neural system that may work for different types of itch. But the take-home message to dermatologists is that itch is quite complex and there are parallels with chronic pain. In the same way that patients sometimes need multiple agents to address chronic pain, patients with pruritus may need treatments that address the multiple mechanisms.

I think we are close in some skin diseases that include itch as a major component, such as atopic eczema and psoriasis. What is potentially exciting is that what we learn in those areas is likely to spill into other areas. n

This series made possible with support from