Publications by authors named "Gil Yosipovitch"

305 Publications

Atopic dermatitis and hidradenitis suppurativa: An under-recognized pair.

J Am Acad Dermatol 2021 Jun 29. Epub 2021 Jun 29.

Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arizona. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.03.126DOI Listing
June 2021

Rapid Improvement of Itch Associated With Atopic Dermatitis With Abrocitinib Is Partially Independent of Overall Disease Improvement: Results From Pooled Phase 2b and 3 Monotherapy Studies.

Dermatitis 2021 Jul 7. Epub 2021 Jul 7.

From the Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St Louis, MO The George Washington University School of Medicine and Health Sciences, Washington, DC Münster University Hospital, Münster, Germany Miami Itch Center, Miller School of Medicine, University of Miami, Miami, FL Oregon Health and Science University, Portland, OR Pfizer, Inc, New York, NY Pfizer Pharma GmbH, Berlin, Germany Pfizer R&D UK, Inc, Surrey, United Kingdom.

Background: Itch, the most bothersome symptom in atopic dermatitis, is largely mediated by pruritogenic cytokines via Janus kinase 1 signaling in cutaneous sensory neurons.

Objectives: The aims of the study were to assess the magnitude and rapidity of itch relief with the Janus kinase 1 selective inhibitor abrocitinib and to evaluate the extent to which the effect of abrocitinib on itch relief is independent of overall disease improvement.

Methods: Pooled data from 1 phase 2b (NCT02780167) and 2 phase 3 (NCT03349060, NCT03575871) double-blind, randomized, placebo-controlled monotherapy trials in moderate to severe atopic dermatitis (N = 942) were analyzed.

Results: Abrocitinib produced significant and clinically meaningful itch relief versus placebo from week 2 through week 12 (end of treatment) that was associated with marked sleep and quality-of-life improvements. Mean percentage reductions in itch scores 24 hours after the first dose were greater for both abrocitinib doses (200 and 100 mg) versus placebo. Itch improvement occurred regardless of baseline itch severity, sex, race, body mass index, or Investigator Global Assessment response, suggesting that abrocitinib-associated itch relief is at least partially independent of overall disease improvement.

Conclusions: Abrocitinib showed a rapid and profound antipruritic effect, partially independent of improvement in overall disease.
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http://dx.doi.org/10.1097/DER.0000000000000770DOI Listing
July 2021

Association of Neuropathic Itch With Patients' Quality of Life.

JAMA Dermatol 2021 Jun 16. Epub 2021 Jun 16.

Miami Itch Center,Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida.

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http://dx.doi.org/10.1001/jamadermatol.2021.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209571PMC
June 2021

Chronic itch in African Americans: an unmet need.

Arch Dermatol Res 2021 Jun 15. Epub 2021 Jun 15.

Dr. Phillip Frost Department of Dermatology and Miami Itch Center, University of Miami, Miami, FL, USA.

Chronic pruritus carries a significant burden of disease and is associated with a negative impact on quality of life. African Americans are disproportionately burdened by chronic pruritic disorders, including but not limited to atopic dermatitis, prurigo nodularis, inflammatory scalp dermatoses, pathologic scarring, and HIV-related dermatoses. Racial differences in skin structure and function may contribute to the pathogenesis of itch in African Americans. Itch perception and response to treatment in African Americans remain understudied and not well understood. As such, there is a large unmet need with regard to the knowledge and management of pruritus in African Americans. This review highlights notable differences in the epidemiology, pathophysiology, genetic predisposition, clinical presentation, and response to treatment for select pruritic skin conditions. By addressing itch as an unmet need in African Americans, we hope to improve patient outcomes and lessen disparities in dermatologic care.
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http://dx.doi.org/10.1007/s00403-021-02255-6DOI Listing
June 2021

Approach to the Patient with Chronic Pruritus.

Med Clin North Am 2021 Jul;105(4):699-721

Dr Phillip Frost Department of Dermatology and Miami Itch Center, University of Miami, University of Miami Hospital, 1600 Northwest 10th Avenue RMSB Building, 10th Street, 2067B Miami, FL, USA. Electronic address:

Chronic pruritus (itch lasting ≥6 weeks) is a bothersome chief complaint that may present in a broad variety of diseases. Most itch-causing diagnoses fit into 1 of 5 categories (inflammatory, secondary to systemic disease, neuropathic, chronic pruritus of undetermined origin, and psychogenic itch) and this broad differential can be narrowed using key findings in the history and physical. In this article, we discuss which key findings are most pertinent for narrowing this differential and guiding further workup and treatment, as well as how to treat many itchy conditions.
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http://dx.doi.org/10.1016/j.mcna.2021.04.007DOI Listing
July 2021

The pruritogenic role of the type 2 immune response in diseases associated with chronic itch.

Exp Dermatol 2021 May 25. Epub 2021 May 25.

Dr Phillip Frost Department of Dermatology and Miami Itch Center, University of Miami, Miami, FL, USA.

While there is a vast array of aetiologies that may lead to chronic pruritus, recent data suggests that many of these conditions share similar interactions between keratinocytes, nerves, and the immune system. Specifically, the type 2 immune response, including Th2 T Cells and their related cytokines, has been noted to play a major role in the development of pruritus in a variety of itchy conditions. To date, atopic dermatitis is the most striking example of this pathogenesis. However, the body of literature supporting its role in many other itchy conditions, including other inflammatory, bullous, as well as systemic diseases, continues to grow. In addition, new treatments targeting this type 2 immune system continue to be developed and investigated. In the current review, we present the current body of literature supporting the role of the type 2 immune response in itchy conditions beyond atopic dermatitis as well as potential therapeutic options that target this pathway for chronic itch.
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http://dx.doi.org/10.1111/exd.14401DOI Listing
May 2021

Periostin, an Emerging Player in Itch Sensation.

J Invest Dermatol 2021 May 19. Epub 2021 May 19.

Miami Itch center, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA. Electronic address:

Periostin, an extracellular matrix and matricellular protein, binds to several types of integrins that transduce its signals. Its function in allergic inflammation is the establishment of sustained chronic inflammation through an amplification of T helper type 2‒immune responses. In addition, recent studies have shown a significant role of periostin in itch sensation through direct integrin-mediated stimulation of nerve fibers and interaction with immune and nonimmune cells (e.g., macrophages, eosinophils, basophils, and keratinocytes). The objective of this review is to describe the role of periostin in itch induction in human and animal models and its expression in human pruritic conditions.
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http://dx.doi.org/10.1016/j.jid.2021.03.009DOI Listing
May 2021

Itch and pain intensity in skin cancer: Why should dermatologic surgeons assess it?

Clin Dermatol 2021 Jan-Feb;39(1):119-122. Epub 2020 May 8.

Miami Itch Center Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine University of Miami, Miami, Florida, USA. Electronic address:

Nonmelanoma skin cancer is the most common type of cancer in the United States. Due to its rising incidence, better screening modalities assessing patient symptomatology are imperative. We reviewed the literature regarding pain and pruritus as presenting clinical manifestations of cutaneous malignancies and elucidate the clinical presentations among skin cancer subtypes. Multiple studies have indicated a higher prevalence of reported pain for squamous cell carcinoma than basal cell carcinoma, but no statistically significant difference was found between these subtypes for itch. Transplant patients, a subset of patients commonly affected with aggressive nonmelanoma skin cancers, ranked the severity of their pain higher in comparison to nontransplant patients. The following cutaneous tumors: keratoacanthomas, infiltration sclerosing BCCs, morpheaform BCCs types and those with perineural invasion, were reported as eliciting the most pain. With the increasing incidence of skin cancer, it is important to recognize the associated presenting clinical manifestations of pruritus and pain, which are shown to be useful in the identification of undiagnosed cutaneous malignancies. Implementation of a numerical rating scale should be considered when evaluating patients with a history of skin cancer or those at high risk, such as transplant recipients.
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http://dx.doi.org/10.1016/j.clindermatol.2020.05.001DOI Listing
May 2020

Impact of Oral Abrocitinib Monotherapy on Patient-Reported Symptoms and Quality of Life in Adolescents and Adults with Moderate-to-Severe Atopic Dermatitis: A Pooled Analysis of Patient-Reported Outcomes.

Am J Clin Dermatol 2021 Jul 5;22(4):541-554. Epub 2021 May 5.

Pfizer Inc., New York, NY, USA.

Background: Atopic dermatitis imparts a substantial patient burden, including itch, sleep disturbance, and decreased health-related quality of life.

Objective: This analysis evaluated changes in patient-reported outcomes of disease-specific signs/symptoms and health-related quality of life in adult and adolescent patients with moderate-to-severe atopic dermatitis treated with once-daily oral abrocitinib 200-mg or 100-mg monotherapy.

Methods: Pooled data from one phase IIb (NCT02780167) and two phase III (NCT03349060, JADE MONO-1; NCT03575871, JADE MONO-2) monotherapy trials in adult and adolescent patients with moderate-to-severe atopic dermatitis were analyzed. Patient-reported outcome assessments included: global severity, itch, and multi-item measures that assess other signs and symptoms of atopic dermatitis. Additional patient-reported outcome assessments measured depression, anxiety, fatigue, disease-specific and general health-related quality of life, and work and general productivity among employed patients.

Results: Overall, 942 patients were included in this analysis. Improvements were observed from the first post-baseline assessment to week 12 across all patient-reported outcomes, including Patient Global Assessment (PtGA) score of 0/1 (35.5%, 19.8%, and 5.9% for 200 mg, 100 mg, and placebo, respectively), ≥ 4-point improvement in Night Time Itch Scale (NTIS; 57.0%, 42.7%, and 12.7%), change from baseline in Patient-Oriented Eczema Measure (POEM) score (- 11.4, - 8.2, and - 3.4), 1-point improvement in Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD; 75.2%, 65.1%, and 33.5%), Hospital Anxiety and Depression Scales (HADS) anxiety (- 2.0, - 1.7, and - 1.0) and depression (- 1.7, - 1.3, and - 0.1).

Conclusions: Abrocitinib monotherapy improved disease-specific signs/symptoms and health-related quality of life across multiple domains as reported by adult and adolescent patients with moderate-to-severe atopic dermatitis, complementing clinician-reported efficacy and safety outcomes.

Clinical Trial Registration: NCT02780167 (registered 23 May, 2016), NCT03349060 (registered 21 November, 2017), NCT03575871 (registered 3 July, 2018).
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http://dx.doi.org/10.1007/s40257-021-00604-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200343PMC
July 2021

New Frontiers in Psoriatic Disease Research, Part II: Comorbidities and Targeted Therapies.

J Invest Dermatol 2021 Apr 19. Epub 2021 Apr 19.

Department of Dermatology, University of California San Francisco, San Francisco, California. Electronic address:

Although psoriasis and psoriatic arthritis (PsA) have been classically considered to be diseases of the skin and joints, respectively, emerging evidence suggests that a combination of innate and environmental factors creates widespread immune dysfunction, affecting multiple organ systems. A greater understanding of the pathogenesis of psoriasis and the systemic effects of psoriatic inflammation has allowed for the development of new, more effective treatments. The second portion of this two-part review series examines the comorbidities associated with psoriasis and PsA as well as the most recent advances in targeted systemic therapies for these conditions.
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http://dx.doi.org/10.1016/j.jid.2021.02.743DOI Listing
April 2021

Pruritus as a Distinctive Feature of Type 2 Inflammation.

Vaccines (Basel) 2021 Mar 23;9(3). Epub 2021 Mar 23.

Section of Dermatology and Venereology, Department of Medicine, University of Verona, 37126 Verona, Italy.

Pruritus is a common symptom of several skin diseases, both inflammatory and neoplastic. Pruritus might have a tremendous impact on patients' quality of life and strongly interfere with sleep, social, and work activities. We review the role of type-2 inflammation and immunity in the pathogenesis of chronic pruritic conditions of the skin. Type 2 cytokines, including IL-4, IL-13, thymic stromal lymphopoietin, periostin, IL-31, IL-25, and IL-33 are released by mast cells, innate lymphoid cells 2, keratinocytes, and type 2 T lymphocytes, and are master regulators of chronic itch. These cytokines might act as direct pruritogen on primary sensory neurons (pruriceptors) or alter the sensitivity to other itch mediators Type 2 inflammation- and immunity-dominated skin diseases, including atopic dermatitis, prurigo nodularis, bullous pemphigoid, scabies, parasitic diseases, urticaria, and Sézary syndrome are indeed conditions associated with most severe pruritus. In contrast, in other skin diseases, such as scleroderma, lupus erythematosus, hidradenitis suppurativa, and acne, type 2 inflammation is less represented, and pruritus is milder or variable. Th2 inflammation and immunity evolved to protect against parasites, and thus, the scratching response evoked by pruritus might have developed to alert about the presence and to remove parasites from the skin surface.
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http://dx.doi.org/10.3390/vaccines9030303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005108PMC
March 2021

Relationship Among Treatment, Pruritus, Investigator's Static Global Assessment, and Quality of Life in Patients with Atopic Dermatitis.

Dermatol Ther (Heidelb) 2021 Apr 9;11(2):587-598. Epub 2021 Mar 9.

Pfizer Inc., Collegeville, PA, USA.

Introduction: The Investigator's Static Global Assessment (ISGA) is a 5-point rating scale that is recommended by the US Food and Drug Administration for assessing the severity of atopic dermatitis (AD), and ISGA success is a widely used endpoint in AD clinical studies. In this study, we seek to interpret the relationship of ISGA with treatment, pruritus, and quality of life (QoL) by conducting post hoc analyses of pooled data from two phase 3 crisaborole studies.

Methods: Patients aged ≥ 2 years with baseline ISGA of 2 (mild) or 3 (moderate) were randomly assigned 2:1 to receive crisaborole or vehicle for 28 days. Disease severity, pruritus severity, and QoL were assessed with the ISGA, Severity of Pruritus Scale (SPS), and Dermatology Life Quality Index (DLQI; patients aged ≥ 16 years), or Children's Dermatology Life Quality Index (CDLQI; patients aged 2-15 years), respectively. The effect of treatment on ISGA and the relationship between ISGA and QoL were analyzed using a longitudinal repeated-measures model. The interrelationship between treatment, disease severity, pruritus, and QoL was analyzed with a mediation model.

Results: Overall, 1522 patients (crisaborole, n = 1016; vehicle, n = 506) were included. Estimated longitudinal profiles indicated changes in ISGA by day 8 were large for crisaborole (effect size [ES]: - 0.68) and small for vehicle (ES: - 0.34). There was a direct relationship between ISGA and DLQI and CDLQI severity bands in the longitudinal repeated-measures model. For both QoL mediation models, treatment effects on QoL were mediated indirectly by reduction in pruritus (DLQI, 42.4%; CDLQI, 58.1%) and disease severity (DLQI, 12.2%; CDLQI, 33.1%).

Conclusions: These post hoc analyses suggest that ISGA success is a clinically meaningful endpoint associated with reduction in the severity of pruritus and improvement in QoL.
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http://dx.doi.org/10.1007/s13555-021-00506-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018915PMC
April 2021

Impact of Itch on Sleep Disturbance in Patients with Prurigo Nodularis.

Acta Derm Venereol 2021 Mar 31;101(3):adv00424. Epub 2021 Mar 31.

Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 33136 Miami, FL, USA.

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http://dx.doi.org/10.2340/00015555-3778DOI Listing
March 2021

Cutaneous Presentation of T-Cell Prolymphocytic Leukemia Mimicking Dermatomyositis.

Am J Dermatopathol 2021 Jul;43(7):521-524

Dr Phillip Frost Department of Dermatology and Miami Itch Center, University of Miami, Miami, FL.

Abstract: T-cell prolymphocytic leukemia (TPLL) is a rare form of leukemia by T lymphocytes at a post-thymic intermediate stage of development with an α/β immunophenotype. Facial involvement is common in TPLL and displays significant heterogeneity of the lesions' description and location. TPLL also contains a wide array of histology findings, cell cytology, and molecular studies. Here, we describe a TPLL patient who presented with an ill-defined erythematous patch involving the right axilla progressing to the left axilla, upper back, and face that resembled dermatomyositis. The diagnosis of TPLL was established using flow cytometry of bone marrow and peripheral blood, and histopathology of the involved skin. Dermatologists should be aware of these unique features.
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http://dx.doi.org/10.1097/DAD.0000000000001874DOI Listing
July 2021

Itch intensity in prurigo nodularis is closely related to dermal interleukin-31, oncostatin M, IL-31 receptor alpha and oncostatin M receptor beta.

Exp Dermatol 2021 Jun 1;30(6):804-810. Epub 2021 Feb 1.

Miami Itch Center, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA.

Prurigo nodularis (PN) is a chronic skin dermatosis with hyperkeratotic and intensely pruritic nodules. Managing PN-associated itch is difficult because its aetiology is still unknown. This study aimed to investigate the correlation between itch intensity in PN and the expression of a pruritogenic cytokine interleukin (IL)-31, its receptor complex components IL-31 receptor α (IL-31RA) and oncostatin M receptor β (OSMRβ), and oncostatin M (OSM), which is a ligand of OSMR β, through immunofluorescence staining examination. Itch intensity in PN was closely correlated with the number of dermal IL-31(+) cells (Spearman's r = 0.551, p < 0.05), dermal IL-31RA(+) cells (r = 0.475, p < 0.05) and dermal OSM(+) cells (r = 0.505, p < 0.05). In addition, the number of dermal OSMRβ (+) cells was increased in PN (t test, p < 0.05), despite not being correlated with itch intensity (Spearman's r = 0.375, p > 0.05). Major cellular sources of dermal IL-31 were T cells (27.0% of total IL-31-expressing cells) and macrophages (35.0%), while those of OSM were mainly T cells (49.8%) and mast cells (26.8%). IL-31RA-expressing dermal cells were mostly mast cells (49.3%) and macrophages (36.6%), and OSMRβ was mainly expressed by macrophages (51.8%) in the dermis. These findings indicate that IL-31 (mainly from macrophages and T cells) and OSM (principally from T cells and mast cells) stimulate dermal cells expressing IL-31RA and OSMRβ (e.g. macrophages), which may further promote itch and inflammation in PN. This complex dermal milieu of cell/cytokine/receptor network can be a therapeutic target for PN-associated itch.
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http://dx.doi.org/10.1111/exd.14279DOI Listing
June 2021

Hydrolysed formula, delayed food introduction and fatty acids for atopic dermatitis prevention in infancy.

Acta Paediatr 2021 06 14;110(6):1784-1787. Epub 2021 Jan 14.

Department of Dermatology and Cutaneous Surgery, and Itch Center University of Miami Miller School of Medicine, Miami, FL, USA.

Aim: The role of nutrition in preventing atopic diseases including atopic dermatitis has recently gained interest in the medical community. Caregivers of infants and children at an increased risk for developing atopic dermatitis often employ exclusion diets or other measures in hopes of preventing the development of this burdensome disease. This paper reviews the current literature in regard to the role of preventative dietary measures in the context of atopic dermatitis, with a special focus on the topics of hydrolysed formula, early vs. delayed introduction of certain foods and fatty acid supplementation.

Methods: Literature pertaining to preventative dietary measures for infants at risk for atopic dermatitis was reviewed.

Results: Analysis of the literature suggests that hydrolysed formula should not be routinely offered to infants for prevention of atopic dermatitis. Formulas utilised should contain concentrations of polyunsaturated fatty acids similar to that in breast milk. Finally, infant caregivers should not delay or restrict introduction of food, which can be more harmful than helpful to the patient.

Conclusion: Recommendations to caretakers providing for infants at risk for atopic dermatitis should include infant consumption of breast milk and avoid delayed introduction of foods.
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http://dx.doi.org/10.1111/apa.15742DOI Listing
June 2021

Cutaneous Gene Expression in Primates with Itch.

J Invest Dermatol 2021 Jun 17;141(6):1586-1588. Epub 2020 Dec 17.

Miami Itch Center, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miami, Florida, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.11.017DOI Listing
June 2021

The experience of itch in children with psoriasis: A qualitative exploration of the Itch Numeric Rating Scale.

Pediatr Dermatol 2021 Mar 18;38(2):405-412. Epub 2020 Dec 18.

Evidera Inc, Bethesda, MD, USA.

Background/objectives: Psoriasis is a chronic, immune-mediated dermatologic disorder with a prevalence among children estimated at 0.1%-0.45%, and a median age of onset at approximately 7-10 years. Pediatric psoriasis is known to have negative impacts on health-related quality of life. Among the most bothersome symptoms, itch has been measured using the Itch Numeric Rating Scale (NRS). This study explored the symptom and impacts of itch with pediatric psoriasis patients and evaluated the content validity of the Itch NRS in children.

Methods: Semi-structured qualitative interviews were conducted among a sample of pediatric patients diagnosed with plaque psoriasis.

Results: Concept elicitation interviews were completed with 22 children (ages 7-17 years). When asked about most frequent symptoms, 61% reported itching (n = 14) and 65% reported flaking (n = 15). The majority reported itching as bothersome; about half described impacts on their regular activities. Cognitive interviews were completed with 25 children (ages 8-17 years). Most reported that independently completing the Itch NRS would be easy, and all described the meaning of the response options similar to the intended value. Overall, the Itch NRS was received favorably, with comments that the scale was easy or relevant to their experience with psoriasis.

Conclusions: This qualitative study supports the content validity of the Itch NRS for use in a pediatric psoriasis population aged 8-17. Given the established importance of itch to pediatric psoriasis patients, future research exploring the impact of itch on the lives of pediatric psoriasis patients may provide a valuable contribution to the field.
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http://dx.doi.org/10.1111/pde.14403DOI Listing
March 2021

THE SKIN MICROBIOTA AND ITCH: Is There a Link?

J Clin Aesthet Dermatol 2020 Jun 1;13(6 Suppl):39-46. Epub 2020 Jun 1.

Dr. Kim is with the Department of Dermatology and Cutaneous Surgery at Miami Itch Center, Miller School of Medicine at University of Miami in Miami, Florida, the Department of Dermatology at Incheon St. Mary's Hospital, The Catholic University of Korea in Seoul, Korea, and the Department of Biomedicine and Health Sciences, at The Catholic University of Korea in Seoul, Korea.

Itch is an unpleasant sensation that emanates primarily from the skin. The chemical mediators that drive neuronal activity originate from a complex interaction between keratinocytes, inflammatory cells, nerve endings, and the skin microbiota, relaying itch signals to the brain. Stress also exacerbates itch via the skin-brain axis. Recently, the microbiota has surfaced as a major player to regulate this axis, notably during stress settings aroused by actual or perceived homeostatic challenge. The routes of communication between the microbiota and brain are slowly being unraveled and involve neurochemicals (i.e., acetylcholine, histamine, catecholamines, and corticotropin) that originate from the microbiota itself. By focusing on itch biology and by referring to the more established field of pain research, this review examines the possible means by which the skin microbiota contributes to itch.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710288PMC
June 2020

The Amygdala Network for Processing Itch in Human Brains.

Acta Derm Venereol 2020 Dec 9;100(19):adv00345. Epub 2020 Dec 9.

Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 33136 Miami, FL, USA. E-mail:

Itch is an unpleasant and aversive somatosensory experience. These negative emotions significantly affect mental health in patients with chronic itch; it is therefore important to understand the brain mechanism of negative emotions due to itch. The amygdala is a key hub of networks regulating negative emotions due to itch. However, the exact network involved in this process is unknown. This study used functional magnetic resonance imaging to investigate the amygdala network processing itch in 25 healthy subjects. Brain activity was measured during electrical itch stimuli using functional magnetic resonance imaging. During itch stimuli the amygdala exhibited increased functional connectivity with key brain regions of the serotonergic system responsible for negative emotions (the medial habenula and the median raphe nucleus) and with the memory system, which is responsible for consolidating emotional experiences (the parahippocampus and perirhinal cortex). The serotonergic and memory systems may become therapeutic targets to prevent or reduce diminished mental health commonly seen in chronic itch patients.
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http://dx.doi.org/10.2340/00015555-3703DOI Listing
December 2020

Dermal Periostin: A New Player in Itch of Prurigo Nodularis.

Acta Derm Venereol 2021 Jan 20;101(1):adv00375. Epub 2021 Jan 20.

Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, 33136 Miami, USA.

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http://dx.doi.org/10.2340/00015555-3702DOI Listing
January 2021

An evaluation of difelikefalin as a treatment option for moderate-to-severe pruritus in end stage renal disease.

Expert Opin Pharmacother 2021 Apr 14;22(5):549-555. Epub 2020 Dec 14.

Dr Phillip Frost Department of Dermatology and Miami Itch Center, University of Miami, Miami, FL, USA.

: Chronic kidney disease-associated pruritus (CKD-aP), or uremic pruritus, is a severely distressing condition that occurs in greater than 60% of patients undergoing dialysis. However, there are currently no FDA approved treatments for CKD-aP in the United States or Europe. Difelikefalin (DFK) is a kappa opioid receptor agonist with limited central nervous system (CNS) penetration that aims to fill this void by effectively and safely reducing itch in these patients.: Through a review of the current literature (using PubMed and Google Scholar keyword searches of difelikefalin, CR845, pruritus, itch, opioids, hemodialysis, chronic kidney disease, uremic pruritus), the authors review DFK's mechanism of action and use published clinical trial data to evaluate its effectiveness in treating CKD-aP both individually and comparatively to other treatment alternatives.: DFK's IV formulation seems to provide safe, rapid-acting and effective itch reduction in hemodialysis patients without many of the negative mu opioid receptor (MOR)- or CNS- related side effects or drug-drug interactions of other currently available opioids. Its administration through IV bolus immediately after dialysis sessions at dialysis centers also increases availability to and ease of drug scheduling for this target population.
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http://dx.doi.org/10.1080/14656566.2020.1849142DOI Listing
April 2021

Dupilumab Significantly Modulates Pain and Discomfort in Patients With Atopic Dermatitis: A Post Hoc Analysis of 5 Randomized Clinical Trials.

Dermatitis 2020 Nov 5. Epub 2020 Nov 5.

Regeneron Pharmaceuticals, Tarrytown, NY.

Background: Pain is a frequent symptom of atopic dermatitis (AD).

Objectives: The aims of the study were to evaluate the effects of dupilumab on pain/discomfort in AD and to determine whether pain correlates with other outcomes.

Methods: This was a post hoc analysis of 5 randomized, placebo-controlled clinical trials in which adults with chronic AD received placebo or dupilumab 300 mg every 2 weeks or once weekly with and without topical corticosteroids. Proportions of patients with no pain/discomfort on this dimension of the 5-dimension EuroQoL (EQ-5D) at week 16 (all trials) and week 52 (CHRONOS) were compared between placebo and dupilumab. Correlations were evaluated between pain/discomfort and signs and symptoms of AD.

Results: Among 2632 evaluated patients, 72.9% to 83.1% reported at least moderate pain/discomfort at baseline. Higher proportions treated with dupilumab reported no pain/discomfort at week 16 relative to placebo; risk differences ranged from 22.3% (95% confidence interval = 11.5%-33.1%) to 42.2% (95% confidence interval = 26.6%-57.8%, all P ≤ 0.0001), with similar effects observed at week 52. Correlations at baseline of pain/discomfort with signs and symptoms of AD were low to moderate.

Conclusions: Pain/discomfort, present in a substantial proportion of patients with moderate-to-severe AD, was significantly reduced by dupilumab treatment. Given the low-to-moderate correlations with other AD symptoms at baseline, pain likely represents a distinct AD symptom.

Trial Registration: ClinicalTrials.gov identifiers NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.
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http://dx.doi.org/10.1097/DER.0000000000000698DOI Listing
November 2020

IL-23 modulates histamine-evoked itch and responses of pruriceptors in mice.

Exp Dermatol 2020 12 19;29(12):1209-1215. Epub 2020 Oct 19.

Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miami Itch Center, University of Miami Miller School of Medicine, Miami, FL, USA.

Accumulating evidence has highlighted the essential roles of cytokines in itch processing. Although IL-23 and Th17 cytokines are elevated in inflammatory skin disorders, their role in itch is unknown. Here, we investigated the role of IL-23 and IL-17A in itch response using an in vitro calcium imaging of mouse dorsal root ganglion (DRG) neurons and an in vivo behaviour test. Calcium imaging studies revealed that a few DRG neurons (~5%) responded to either IL-23 or IL-17A. Pretreatment cells with IL-23 significantly reduced calcium responses to histamine and capsaicin but not chloroquine. Behaviour experiments showed neither IL-23 nor IL-17A evoked scratching. IL-23 significantly decreased histamine-evoked scratching without affecting chloroquine-evoked scratching. There was no difference in scratching between IL-17A- and vehicle-treated groups. These results indicate that IL-23 might play a role in regulating histaminergic itch via modulation of TRPV1 activity.
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http://dx.doi.org/10.1111/exd.14206DOI Listing
December 2020

Improvement in disease severity and pruritus outcomes with crisaborole ointment, 2%, by baseline atopic dermatitis severity in children and adolescents with mild-to-moderate atopic dermatitis.

Pediatr Dermatol 2020 Nov 27;37(6):1030-1037. Epub 2020 Sep 27.

Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background/objectives: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). This pooled post hoc analysis of two phase 3 trials (NCT02118766, NCT02118792) assessed improvement and time to improvement in Investigator's Static Global Assessment (ISGA) and Severity of Pruritus Scale (SPS) outcomes in pediatric patients with mild-to-moderate AD.

Methods: Patients aged ≥2 years were randomly assigned 2:1 to receive twice-daily crisaborole or vehicle for 28 days. Patients aged 2-17 years were pooled for this analysis. Proportions of patients and time to achieving ISGA success (clear [0] or almost clear [1] with ≥2-grade improvement from baseline), ISGA clear/almost clear, ≥1-grade improvement in ISGA, SPS success (SPS score ≤1 with ≥1-grade improvement), or ≥1-grade improvement in SPS score were analyzed and stratified by baseline ISGA.

Results: At first postbaseline assessment (day 8), significantly higher proportions of crisaborole- than vehicle-treated patients achieved ISGA success, ISGA clear/almost clear, ≥1-grade ISGA improvement, SPS success, or ≥1-grade improvement in SPS regardless of baseline ISGA. Differences were significantly greater over time for all outcomes for patients with moderate baseline ISGA and numerically greater for those with mild baseline ISGA. Median times to ISGA and SPS outcomes were shorter for crisaborole versus vehicle.

Conclusion: Improvement in ISGA and SPS outcomes were observed with crisaborole in pediatric patients with mild-to-moderate baseline AD.
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http://dx.doi.org/10.1111/pde.14328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756882PMC
November 2020

The Role of the Microbiome and Microbiome-Derived Metabolites in Atopic Dermatitis and Non-Histaminergic Itch.

Am J Clin Dermatol 2020 Sep;21(Suppl 1):44-50

Miami Itch Center, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.

Recent advances in our understanding of the pathophysiology of atopic dermatitis (AD) have revealed that skin microbiome dysbiosis plays an important role in the disease. In this review, we describe how changes in the structure and function of the microbiome are involved in the pathogenesis of AD. We highlight recent data showing that differential changes in microbial diversity, both within and across communities from different body habitats (including the skin, gut, and oral mucosa), are associated with the development and severity of AD. We also describe recent evidence demonstrating that the metabolic activity of the skin microbiome can act as a regulator of inflammation, with alterations in the level of a skin microbiome-derived tryptophan metabolite, indole-3-aldehyde (IAId), being shown to play a role in AD. The various mechanisms by which interactions between the microbiome and components of the non-histaminergic pathway result in itch in AD are also discussed.
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http://dx.doi.org/10.1007/s40257-020-00538-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584541PMC
September 2020

Foreword.

Am J Clin Dermatol 2020 09;21(Suppl 1):2-3

Miami Itch Center, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.

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http://dx.doi.org/10.1007/s40257-020-00550-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584521PMC
September 2020

Dupilumab use in atopic dermatitis and beyond in skin diseases.

Immunotherapy 2020 12 7;12(17):1221-1235. Epub 2020 Sep 7.

Dr Phillip Frost Department of Dermatology & Cutaneous Surgery & Miami Itch Center, University of Miami Miller School of Medicine, 1600 NW 10 Ave, RMSB 2023, Miami, FL 33136, USA.

Atopic dermatitis (AD) is a chronic inflammatory condition that affects 5-10% of adults and 9-18% of children and its pathology is rooted in the Th-2-mediated immune response. Dupilumab is a fully human IgG4 monoclonal antibody that targets the IL-4 receptor alpha subunit that is endogenously bound by the Th-2 cytokines IL-4 and IL-13. Successful clinical trials of dupilumab showing marked improvements in clinical signs of AD, patient reported symptoms and quality of life measures led to its approval for clinical use for moderate-to-severe AD in 2017. This review details the current body of evidence on the drug's mechanism of action, pharmacology, clinical efficacy and safety as well as post market and real world use.
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http://dx.doi.org/10.2217/imt-2020-0175DOI Listing
December 2020

Substance use disorders and chronic itch.

J Am Acad Dermatol 2021 Jan 3;84(1):148-155. Epub 2020 Sep 3.

Dr Phillip Frost Department of Dermatology and Miami Itch Center, University of Miami, Miami, Florida. Electronic address:

Chronic pruritus is one dermatologic manifestation of an underlying substance use disorder. Recent literature has uncovered similarities between the general neurologic mechanisms of addiction and chronic itch, largely involving activation of the dopaminergic reward circuits within the brain and imbalances between mu and kappa opioid receptor activation. It is likely that the use of specific drugs, like central nervous system stimulants and opioids, results in further activation and imbalances within these pathways, perpetuating both addiction and pruritus simultaneously. Opioid users often present to dermatology clinics with a generalized pruritus, whereas individuals using central nervous system stimulants like cocaine and methylenedioxymethamphetamine (MDMA), as well as legally prescribed drugs like treatments for attention deficit hyperactivity disorder, frequently complain of crawling, delusional infestation-like sensations underneath the skin. Because of these overlapping mechanisms and similar clinical presentations to many other chronically itchy conditions, it is necessary for dermatologists to consider and investigate an underlying substance use disorder to effectively treat these patients.
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http://dx.doi.org/10.1016/j.jaad.2020.08.117DOI Listing
January 2021

The Pleasurability of Scratching an Itch Amongst Different Pruritic Conditions.

Acta Derm Venereol 2020 Aug 25;100(15):adv00254. Epub 2020 Aug 25.

Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 33136 Miami, FL, USA.

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http://dx.doi.org/10.2340/00015555-3605DOI Listing
August 2020
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