Author Interviews, Dermatology / 05.04.2021
Mechanism of Horrible Itching of Liver Disease Identified in Superficial Skin Cells
MedicalResearch.com Interview with:
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Dr. Liedtke[/caption]
Wolfgang Liedtke, M.D., Ph.D.
Professor (tenured) of Neurology, Anesthesiology and Neurobiology
Attending Physician, Duke Neurology Clinics for Headache, Head-Pain and Trigeminal Sensory Disorders
Attending Physician, Duke Clinics for Innovative Pain Therapy at Brier Creek (Dept of Anesthesiology)
Duke University School of Medicine, Center for Translational Neuroscience
Durham NC 27710 Since April 2021 Chair of Neurology Global Development Scientific Council Regeneron Pharmaceuticals Tarrytown NY 10591 MedicalResearch.com: What is the background for this study? Response: There are systemic diseases that are characterized by intense itching, yet without inflammation of the skin and not associated with allergic inflammation. For example and importantly, liver disease with non-functional secretion of bile (cholestatic liver disease, most common primary biliary cholangitis, an autoimmune disease), but also chronic end-stage renal disease (also certain lymphomas and pruritic psoriasis where the itch is whole-body, not only restricted to diseased skin). We thought that these diseases might be great starting points to better understand itch because there is no inflamed skin and no allergies. Thus, there must be some systemic factor that causes itch, and we were intent on discovering such factors, and with them, molecular mechanisms how they cause itch. For cholestatic liver disease, one of the best candidates to fit this profile has been lysophosphatidic acid (LPA), since the pioneering discoveries of Andreas Kremer, one of our co-authors. My research laboratory at Duke has been rooted in my discovery of TRPV4 ion channels 20 years ago, out of the Friedman Lab at The Rockefeller University in NYC. Over the years, with my colleague Yong Chen out of my lab, now leading his own independent research operation, we focused on the role of TRPV4 ion channels in skin. 5 years ago Yong and I published a paper that provided some evidence for TRPV4 in skin perhaps playing a role in itch. Working with phospholipids, we made the serendipitous discovery that lysophosphatidyl choline (LPC) is a more potent itch-inducing lipid molecule than LPA. Of note, LPC is the metabolic precursor of LPA. We then found that LPA does not depend on TRPV4 to elicit itch. The more robust itch evoked by LPC was significantly reduced when we knocked down TRPV4 in skin keratinocytes. Itch was NOT affected when TRPV4 was deleted from sensory nerve cells that innervate the skin. In terms of background, my long-term goal has been to elucidate how innervating peripheral nerve cell and innervated organ, such as skin, talk to one another so that the sensation that is felt is regulated or modulated, e.g how can skin influence itch or pain, how can joint cells influence pain. That became the exciting bedrock of our study, and we took it from there, 5 years of hard work with collaborations spanning the globe, and a final stretch of exhausting work during the pandemic.
Dr. Liedtke[/caption]
Wolfgang Liedtke, M.D., Ph.D.
Professor (tenured) of Neurology, Anesthesiology and NeurobiologyAttending Physician, Duke Neurology Clinics for Headache, Head-Pain and Trigeminal Sensory Disorders
Attending Physician, Duke Clinics for Innovative Pain Therapy at Brier Creek (Dept of Anesthesiology)
Duke University School of Medicine, Center for Translational Neuroscience
Durham NC 27710 Since April 2021 Chair of Neurology Global Development Scientific Council Regeneron Pharmaceuticals Tarrytown NY 10591 MedicalResearch.com: What is the background for this study? Response: There are systemic diseases that are characterized by intense itching, yet without inflammation of the skin and not associated with allergic inflammation. For example and importantly, liver disease with non-functional secretion of bile (cholestatic liver disease, most common primary biliary cholangitis, an autoimmune disease), but also chronic end-stage renal disease (also certain lymphomas and pruritic psoriasis where the itch is whole-body, not only restricted to diseased skin). We thought that these diseases might be great starting points to better understand itch because there is no inflamed skin and no allergies. Thus, there must be some systemic factor that causes itch, and we were intent on discovering such factors, and with them, molecular mechanisms how they cause itch. For cholestatic liver disease, one of the best candidates to fit this profile has been lysophosphatidic acid (LPA), since the pioneering discoveries of Andreas Kremer, one of our co-authors. My research laboratory at Duke has been rooted in my discovery of TRPV4 ion channels 20 years ago, out of the Friedman Lab at The Rockefeller University in NYC. Over the years, with my colleague Yong Chen out of my lab, now leading his own independent research operation, we focused on the role of TRPV4 ion channels in skin. 5 years ago Yong and I published a paper that provided some evidence for TRPV4 in skin perhaps playing a role in itch. Working with phospholipids, we made the serendipitous discovery that lysophosphatidyl choline (LPC) is a more potent itch-inducing lipid molecule than LPA. Of note, LPC is the metabolic precursor of LPA. We then found that LPA does not depend on TRPV4 to elicit itch. The more robust itch evoked by LPC was significantly reduced when we knocked down TRPV4 in skin keratinocytes. Itch was NOT affected when TRPV4 was deleted from sensory nerve cells that innervate the skin. In terms of background, my long-term goal has been to elucidate how innervating peripheral nerve cell and innervated organ, such as skin, talk to one another so that the sensation that is felt is regulated or modulated, e.g how can skin influence itch or pain, how can joint cells influence pain. That became the exciting bedrock of our study, and we took it from there, 5 years of hard work with collaborations spanning the globe, and a final stretch of exhausting work during the pandemic.
Matt Spick[/caption]
Matt Spick, Post-Graduate Researcher
University of Surrey
Faculty of Engineering and Physical Sciences
Guildford, UK
MedicalResearch.com: What is the background for this study? Are you measuring lipids or the virus?
Response: In this study, we aimed to detect what the virus does to us, rather than the virus itself. The gold standard for detecting COVID-19 is the RT-PCR test, but by their nature, PCR tests only provide diagnostic information, and at times during the pandemic the availability of PCR tests has been a bottleneck for the identification of the disease. Our goal was to investigate a novel method for the diagnosis of COVID-19, at the same time as learning more about what the disease does to us through lipidomics.
Anne Cust[/caption]
Anne Cust | PhD, Professor of Cancer Epidemiology
The University of Sydney
Faculty of Medicine and Health
Sydney School of Public Health
MedicalResearch.com: What is the background for this study? Are the screeners specially trained, use full body photographs, dermoscopy etc?
Response: The Melanoma High-risk Clinic Study was developed to optimise the early detection of new melanomas in people at high risk of developing melanoma. A previous single-centre study observed fewer excisions and healthcare costs, thinner melanomas and better quality of life when surveillance of high risk patients was conducted in a melanoma dermatology clinic with a structured surveillance protocol involving 6-monthly full body examinations aided by total body photography (TBP) and sequential digital dermoscopy imaging (SDDI). The initial pilot study was performed in a single tertiary referral specialist centre using trained dermatologists who routinely used the diagnostic interventions.
Our objective was to examine longer-term sustainability and expansion of the program to multiple practices including a primary care skin cancer clinic setting. The hypothesis was that the outcomes would be similar if using the same protocol and diagnostic tools. The participating doctors were trained to follow the protocol, which included instruction on how to respond and interpret changing lesions, but not in use of dermoscopy or skin examinations, which were routinely and consistently used in all clinics prior to the study commencing. There were 593 participants assessed as very high risk of melanoma who participated in the Melanoma High-risk Clinic Study from 2012-2018. Nearly all of the participants had had a previous melanoma and had additional melanoma risk factors. 57% were male and the median age at study entry was 58 years.
Dr. Swerlick[/caption]
Robert A. Swerlick, MD
Professor and Alicia Leizman Stonecipher Chair of Dermatology
Emory University School of Medicine
Atlanta, GA 30322
MedicalResearch.com: What is the background for this study?
Response: Financial incentives have the potential to drive provider behavior, even unintentionally. The aim of this study was to evaluate differences in clinic “productivity” measures that occur in outpatient dermatology encounters. Specifically, we used data from 2016-2020 at one academic dermatology practice to evaluate differences in work relative value units (wRVUs, a measure of clinical productivity) and financial reimbursement by patient race, sex, and age. 66,463 encounters were included in this study, among which 70.1% of encounters were for white patients, 59.6% were for females, and the mean age was 55.9 years old.
Dr. Kim[/caption]
Brian Kim, MD
Associate Professor of Dermatology
Co-Director, Center for the Study of Itch & Sensory Disorders
John T. Milliken Department of Internal Medicine
Washington University in St. Louis
MedicalResearch.com: What is the background for this study?
Response: Patients with eczema suffer from chronic itch due to the rashes they have on their body. However, as a physician, I have always noticed that patients with eczema will have sudden flares of their itching all over there body that is often triggered by what appear to be allergens – being around a cat, pollen, mold in a house, etc. Eczema is in the family of allergic diseases such as food allergy, asthma, and hay fever. All of these conditions are noted for patients being reactive to allergens by way of an antibody called IgE that coats a cell called the mast cell. Upon IgE binding an allergen, mast cells produce tons of histamine which can cause symptoms like itching. So we speculated that perhaps because patients with eczema have such misbehaving IgE, that exposure to allergen is what triggers this kind of severe itch flare that we see in patients.
Dr. Jonathan Silverberg[/caption]
Jonathan Silverberg, MD, PHD, MPH
Associate Professor
Director of Clinical Research
Director of Patch Testing
George Washington University School of Medicine and Health Sciences
Washington, DC
MedicalResearch.com: What is the background for this study
Response: Chronic hand eczema was previously shown to be associated with higher rates of allergic contact dermatitis. Yet, little is known about recent trends in North America with respect to the clinical presentation and allergen profile in chronic hand eczema. This study sought to determine the clinical characteristics and etiologies of hand eczema in a large North American cohort of adults referred for patch testing. The patients in the study were patch tested using the North American Contact Dermatitis Group’s allergen screening series.
Dr. Gernand[/caption]
Jeremy M. Gernand
![MedicalResearch.com Interview with: Selin Tokez, PhD Student Department of Dermatology Erasmus MC, Rotterdam MedicalResearch.com: What is the background for this study? Response: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer worldwide with still increasing incidence rates. Given these high incidence rates together with the associated health costs and possibility of fatal progression, it is extremely important to have accurate and complete data on the epidemiology of this disease. Nevertheless, national cancer registries in many countries do not routinely record cSCC cases and therefore currently known numbers are mainly based on incomplete data sources. Additionally, if cSCC cases are registered, this usually only concerns the first cSCC per patient while we know that, contrary to many other malignant neoplasms, patients may develop numerous cSCCs over time. MedicalResearch.com: What are the main findings? Response: In the present study, we analyzed Dutch nationwide data comprising about 145,000 patients with a first invasive cSCC diagnosis between the years 1989 and 2017. We found that the incidence rates of a first cSCC per patient almost tripled in male patients and increased about fivefold in female patients in this 30-year time period. Also, we had data on all cSCCs per patient for the year 2017 and could therefore compare this with the data on only the first cSCC per patient: incidence rates increased by 58% for men and 35% for women when multiple cSCCs were considered. In absolute numbers, this resulted in an increase of 45% in cSCC diagnoses in 2017. Lastly, we extended our analyses by predicting future cSCC incidence rates up to 2027. Given that no substantially effective measures are undertaken in the near future, current cSCC incidence rates will increase with 23% in males and 29% in females in the next decade. MedicalResearch.com: What should readers take away from your report? Response: We could summarize our main message in two points: while people generally know that cSCC is a very common disease with increasing incidence rates, it is not taken into account that these numbers are often based on incomplete data registries and that the real numbers are even higher. In this paper, we provided these numbers for a period of 30 years based on highly accurate data from the Netherlands Cancer Registry. On top of that, as a second main finding, we showed that the real burden caused by cSCC is approximately 50% higher (taken males and females together) when all cSCC diagnoses in 1 year are registered instead of only the first tumor per patient. Together with our prediction analyses that showed an on average 26% further increase for the coming decade, this will have enormous implications for the dermato-oncological health care planning and cost management. Our results urgently call for revision of skin cancer health policies to be able to cope with this rising burden of cSCC management. Ultimately, primary prevention will remain the key strategy to halt the increasing trend in cSCC incidence and the occurrence of multiple cSCCs per patient, which we hope to further stimulate with our paper as well. MedicalResearch.com: What recommendations do you have for future research as a result of this work? Response: As we had data on multiple cSCCs for only one year, we would suggest to perform trend analyses for multiple cSCCs per patient as well when a longer follow-up duration has been reached. Furthermore, it would be very relevant to identify high-risk cSCCs or patients at risk for multiple cSCCs in order to be able to establish efficient follow-up regimens and take these high risk groups into account when revising skin cancer health policies. MedicalResearch.com: Is there anything else you would like to add? Response: The authors of this study have no conflicts of interest that are relevant to this article. Citation: Tokez S, Hollestein L, Louwman M, Nijsten T, Wakkee M. Incidence of Multiple vs First Cutaneous Squamous Cell Carcinoma on a Nationwide Scale and Estimation of Future Incidences of Cutaneous Squamous Cell Carcinoma. JAMA Dermatol. Published online October 28, 2020. doi:10.1001/jamadermatol.2020.3677 [subscribe] Last Modified: [last-modified] The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.](https://medicalresearch.com/wp-content/uploads/2020/10/squamous-cell-cancer-dermnetnz-image.jpg)
Dr. Falchi[/caption]
Dr Mario Falchi
Head of Bioinformatics for the School of Life Course Sciences
Department of Twin Research & Genetic Epidemiology
King’s College London
MedicalResearch.com: What is the background for this study?
Response: The relationship between sun exposure and health is a double-edged sword, on one side there is the beneficial effect of vitamin D production and on the other the increased risk of skin cancer, depending on length and frequency of exposure, and on the individual skin type.
Despite public health campaigns, changing sun-seeking behaviour seems to be challenging for some people, even for those with a familial or personal history of skin cancer. Previous investigations have suggested that exposure to UV could be addictive. 
Alyssa M. Thompson[/caption]
Alyssa M. Thompson is currently a 2nd year medical student at the UA-COM Tucson. She graduated from the University of Arizona, Summa Cum Laude in 2018 as the athletic department's Valedictorian with a degree in Physiology and an Entrepreneurship certificate. Her passion for research and dermatology stems from her innovative and integrative mindset with specific interest in inflammatory skin disease.
MedicalResearch.com: What is the background for this study?
Response: Eczema is very common in children. Prescription medications are important for managing eczema flares, but a lot of the work in treating eczema is preventative, done by consistently moisturizing the skin at home with drug store products. Allergic contact dermatitis occurs more commonly in people with eczema. A previous study was done in characterizing the allergenic potential of drug-store moisturizers and found that 88% of moisturizers contain at least one common allergen. Many moisturizers are marketed specifically to eczema, but the allergen content of these products are unknown.
Dr. Schoch[/caption]
Jennifer Schoch, MD
Dr. Schoch is a pediatric dermatologist and
Associate Professor of Dermatology at the University of Florida.
Her research focuses on the infantile skin microbiome and its role in pediatric skin disease.
She is a member of the Society for Pediatric Dermatology.
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Dr. Harper[/caption]
Julie C. Harper, MD
Clinical Associate Professor of Dermatology
University of Alabama-Birmingham
MedicalResearch.com: What is the background for this study?
How common is rosacea?
What are the clinical manifestations of facial rosacea or psoriasis?
![MedicalResearch.com Interview with: Dr Herman Anne Service de Dermatologie Cliniques Universitaires Saint-Luc Avenue Hippocrate, 10 1200 Bruxelle MedicalResearch.com: What is the background for this study? Response: In the context of the COVID-19 pandemic, several cases of acro-located lesions (on foot or hands) suggestive of chilblains have been reported and were possibly related to COVID-19. We wanted to determine if chilblains, observed in many patients recently referred to our department, are indicative of COVID-19. MedicalResearch.com: Would you briefly explain what is meant by chilblains? Response: Chilblains are frequent cold induced inflammatory lesions. Chilblains are typically seen in winter and occur after repeated exposure to cold temperatures. Clinical presentation includes erythema and swelling on toes and/or digits followed by red-purple macules or patches. However, given the large number of patients affected, and the exceptionally high outdoor temperatures for the spring season over the past month and at the time of case-observation, cold-exposure seemed unlikely. These lesions were, therefore, suspected to be associated with COVID-19. However, to date, no study has proven a pathological link between these lesions and COVID-19. MedicalResearch.com: What are the main findings? Response: In our series of 31 patients who recently developed chilblains, negative nasopharyngeal swabs and the absence of anti-SARS-CoV-2 blood immunoglobulin (Ig)M and IgG antibodies in all patients included in your study suggested that these patients had not been infected with COVID-19. These lesions appeared not to be directly related to COVID-19. MedicalResearch.com: What should readers take away from your report? Response: One hypothesis points to an indirect consequence of the COVID-19 pandemic due to imposed community containment and lockdown measures. Indeed, all patients in this study had either been working from home or were home-schooled since the beginning of containment measures in Belgium (March 11, 2020) or were temporarily unemployed. As a result of containment measures, the majority (64.5%) of patients reported a decrease in their physical activity and significantly more time spent in sedentary positions in front of screens. Most of the patients declared that they remained barefoot or in socks most of the day. All these lifestyle changes can be considered as risk factors for developing chilblains. Therefore, it seems plausible that containment, through its collateral effects, may induce chilblains. Interestingly also, the mean BMI of the patients included was relatively low, suggesting that thin people may be more at risk of developing chilblains. MedicalResearch.com: What recommendations do you have for future research as a result of this work? Response: During the current pandemic, several reports have suggested a possible link between cutaneous manifestations including aural lesions such as chilblains, and COVID-19, however, only few patients were tested for SARS-CoV-2 by RT-PCR and no serologic tests were performed. Therefore, reliable testings (RT-PCR and serologic testing) are essential to confirm a potential association with COVID-19. Citation: Herman A, Peeters C, Verroken A, et al. Evaluation of Chilblains as a Manifestation of the COVID-19 Pandemic. JAMA Dermatol. Published online June 25, 2020. doi:10.1001/jamadermatol.2020.2368 https://jamanetwork.com/journals/jamadermatology/fullarticle/2767774 [subscribe] Last Modified: [last-modified] The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.](https://medicalresearch.com/wp-content/uploads/2020/06/chilblain-example-dermnet-nz.jpg)
Dr. Shumel[/caption]
Brad Shumel, MD
Senior Director of Medical Affairs, Immunology
Regeneron
MedicalResearch.com: What is the background for this study?
Response: Atopic dermatitis is a chronic inflammatory disease and one of the most common skin disorders in children. Severe atopic dermatitis is characterized by skin lesions that often cover a large body surface area and can include intense, persistent itch. Uncontrolled moderate-to-severe atopic dermatitis can have a physical, emotional and psychosocial impact on children, resulting in sleep deprivation, activity restriction, poor school performance, depression and anxiety that can have a greater impact on quality-of-life.
The standard of care for this pediatric population has been topical corticosteroids. Children with severe atopic dermatitis who remain uncontrolled with topical therapies have limited treatment options.
This Phase 3 trial was conducted to evaluate the safety and efficacy of dupilumab plus topical corticosteroids (TCS) compared with TCS alone in children with uncontrolled severe atopic dermatitis across two treatment arms – every four weeks and every two weeks (Q4W and Q2W).
Dr. Yosipovitch[/caption]
Gil Yosipovitch, MD, Professor
Miami Itch Center
Lennar Medical Foundation
South Miami Clinic in Coral Gables
University of Miami Health System
MedicalResearch.com: What is the background for this study?
Response: Chronic Pruritus is a common and burdensome condition in patients with end stage chronic kidney disease (CKD). It is Present at all stages of CKD, not only in patients undergoing hemodialysis (including stage 3-5 CKD). There are no approved treatments for this condition in US and Europe. CKD pruritus has significant impact on quality of life of patients with higher mortality rates due to its effect on sleep.
Studies in the last 2 decades have shown that in patients with CKD pruritus there is an imbalance between endogenous mu opioids that are over expressed to Kappa Opioids that are down regulated.
Difelikefalin (DFK) is a novel peripherally selective kappa opioid receptor (KOR) agonist. Study of IV DFK administration in hemodialysis patients has recently been published and showed significant anti Pruritic effect ( NEJM Fishbane et al. 382: 289-290, 2020).
