Thursday, November 21, 2024

Mpox

DERMATOLOGIST EXPLAINS WHAT THE MPOX (MONKEYPOX) RASH LOOKS LIKE

A new strain of mpox has been found in Africa, Europe, Asia – and now the United States. Because this strain spreads easily and can cause health problems, dermatologists are helping us stay informed by sharing facts about the symptoms and other key information.

Board-certified dermatologist Esther E. Freeman, MD, PhD, FAAD,1 says symptoms of this new strain include:

Fever: This is a common symptom of mpox.
Flu-like symptoms: Headache, muscle aches, back pain, low energy, swollen lymph nodes, sore throat, chills, and exhaustion can occur.
A rash that appears 2-4 days after the above symptoms begin: Often itchy or painful, the rash usually begins on the face and can spread to other parts of the body. This rash can look like chickenpox, shingles, or herpes because it causes spots, bumps, or blisters and may change over time.

"If you have a new, unexplained skin rash or lesion on any part of your body that you think could be mpox, seek medical care immediately," cautions Dr. Freeman.

Mpox can appear on the skin in different ways. The strain found in the United States in 2024 often begins on the face and can spread to other parts of the body.

What is mpox?

Mpox is a contagious disease caused by a virus. This virus has been infecting humans since 1970, primarily in Africa, where outbreaks have occurred.

Some outbreaks have spread to the United States. In 2022, an mpox outbreak occurred that affected most of the world, including the United States.

People infected with the mpox strain that caused the 2022 outbreak tend to develop a few pox-like lesions on their skin, as shown here.

During previous mpox outbreaks, people often had widespread lesions.

The mpox strain that caused the 2022 outbreak is still in the United States. However, the number of new infections is low. Ten or fewer people become infected each week.

How do you get mpox?

You develop mpox through close contact with an infected person or animal. Here's how this happens:

An infected person: If someone has mpox, you can catch it if you:

Touch the rash or scabs or have intimate contact. This is the most common way mpox spreads.
Handle an object that an infected person has used like unwashed clothing or bedding.

An infected animal: Animals infected with mpox are found in central or western Africa, where this virus is endemic (there all the time). Most of the infected animals are wild rodents like rope squirrels and dormice.

You can get mpox from an animal infected with the virus if you:

Are bit or scratched by the animal
Handle an infected animal (even a dead one)
Eat an infected animal
Use a product like a cream or powder made from an infected animal

Getting vaccinated can reduce at-risk people from getting mpox

The vaccine used to prevent smallpox is also used to prevent mpox. If you have received this vaccine:

You have less risk of getting mpox. The vaccine is about 85% effective at preventing mpox.
Mpox tends to be less serious if you develop it. This means less risk of developing severe disease or being hospitalized.

Who should receive the mpox vaccine?

The Centers for Disease Control (CDC) recommends that people in the United States who are at risk for mpox receive two doses of the JYNNEOS vaccine. At-risk people include those who have been in contact with someone who has mpox.

The U.S. Food and Drug Administration (FDA) has approved the JYNNEOS vaccine to prevent both smallpox and mpox.

If you have risk factors that make you eligible for getting vaccinated against mpox and have never had mpox, the CDC recommends that you get:

Both doses of the JYNNEOS vaccine, waiting 28 days between doses.
The second dose of JYNNEOS if you've only received one dose. It's never too late to get the second dose.

Right now, getting more than two doses (a booster) isn't recommended.

After getting vaccinated, it takes several weeks for your body to develop immunity. That's why the World Health Organization (WHO) recommends that you take measures to prevent mpox for weeks after you receive the vaccine.

People who've had mpox don't need to get vaccinated.

Most rashes that dermatologists are seeing at this time are not caused by mpox

Still, it's important for you to be aware of mpox and get medical care if you develop a new rash with an unknown cause. Just be sure to call ahead before going to a medical office since mpox is contagious.

Dermatologist examining rash on patient's face

How do dermatologists know mpox is causing a rash?

"While the mpox rash can be mistaken for chickenpox, shingles, or herpes, there are differences between these rashes," says Dr. Freeman. A board-certified dermatologist has the expertise and training to spot the differences, so you receive an accurate diagnosis and appropriate treatment.

If mpox is a likely cause, your dermatologist will swab your rash and send the swab to a lab. At the lab, a test known as a PCR (polymerase chain reaction) test will be performed. The results from the PCR test will indicate whether the swab contains the mpox virus.

How long does mpox last?

Most people have mpox for 2 to 4 weeks. That's the amount of time it takes for the disease to run its course.

Until the rash and bumps go away, a person who has mpox is contagious and can spread the virus to others.

What should I do if I have symptoms of mpox?

Dr. Freeman notes, "Not every new rash is mpox. However, if you do think you have mpox, it's important to see your doctor quickly. Patients who delay getting medical attention may be diagnosed later when fewer treatment options are available. Waiting also means that you can expose more people to the virus, so family and others may develop mpox."

How is mpox treated?

For some people, the disease can run its course. However, people at risk of developing severe disease may receive treatment. Some antiviral medications are being used to treat people when the PCR test shows that they have mpox. There is currently no specific treatment approved by the U.S. Food and Drug Administration (FDA) for mpox.

If you are diagnosed with mpox, proper skin care can help prevent the disease from spreading to other parts of your body and reduce the risk of scarring. To see the skin care that dermatologists recommend, go to Mpox rash: Dermatologists' tips for treating your skin.

1 Dr. Freeman is the Director, Global Health Dermatology, Massachusetts General Hospital, Harvard Medical School; Associate Director, Center for Global Health, Massachusetts General Hospital; and a member of the American Academy of Dermatology's Mpox Task Force.

Images

Images 1, 2: Produced with permission from ©DermNet www.dermnetnz.org 2024.
Image 3: Used with permission of the Centers for Disease Control and Prevention (CDC). This image is also available on the CDC website, and use of this image does not constitute endorsement or recommendation by the U.S. Government, Department of Health and Human Services, or Centers for Disease Control and Prevention.
Images 4,5: Getty Images

References
Centers for Disease Control and Prevention (CDC).

"Mpox in the United States and Around the World: Current Situation." Last updated November 16, 2024. Last accessed November 18, 2024.
"U.S. case trends: Data as reported to CDC as of November 1, 2024.

U.S. Food and Drug Administration (FDA):

"Illegally sold monkeypox products." Content current as of January 31, 2024. Last accessed November 4, 2024.
"JYNNEOS." Page last updated October 22, 2024. Last accessed November 4, 2024.
"Mpox." Page last updated October 1, 2024. Last accessed November 4, 2024.

World Health Organization. "Mpox." Page last updated October 16, 2024. Last accessed October 31, 2024.

Written by:
Paula Ludmann, MS

Reviewed by:
Esther Ellen Freeman, MD, PhD, FAAD
George J. Hruza, MD, MBA, FAAD
William Warren Kwan, MD, FAAD
J. Klint Peebles, MD, FAAD
Adrian O. Rodriguez, MD, FAAD
Misha Rosenbach, MD, FAAD

Last updated: 11/18/24

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574

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Thursday, October 31, 2024

Outcomes of Red and Green LED Light Therapy in Individuals With Androgenetic Alopecia Photodermatology, Photoimmunology & Photomedicine

Abstract

BACKGROUND

Androgenetic alopecia (AGA) affects both men and women, characterized by progressive hair thinning. While current treatments like minoxidil and finasteride have efficacy limitations and side effects, low-level light therapy (LLLT) using red or near-infrared light has emerged as a promising alternative. Recent animal studies suggest potential benefits from green LED light, though human data are sparse.

METHODS

This study utilized an innovative LED helmet emitting red and green LED light on respective halves of the frontal scalp, delivering an energy density of 40 J/cm2over 20 min. Clinical photography, physician evaluations on a 7-point scale, patient satisfaction, and measurements of hair density and hair diameter were employed. Data were analyzed using linear mixed-effects models, with significance set at p < 0.05.

RESULTS

Seventeen participants (47.1% male, 52.9% female, average age 46.47 years) demonstrated notable improvements after 6 months of treatment. Red and green LEDs both significantly increased hair diameter, non-vellus hair density, and satisfaction scores. Notably, the red LED therapy resulted in a statistically significant decrease in vellus hair density and achieved a greater increase in hair diameter compared to the green LED therapy. Minimal adverse effects were reported, primarily consisting of tolerable scalp heat and mild redness.

CONCLUSION

Both red and green LED therapies effectively enhanced hair growth, increasing density and thickness over 6 months. Red LED demonstrated superior improvements in specific measures. Consequently, both therapies present safe and viable alternatives for the management of AGA, expanding the repertoire of available treatment options.

Photodermatology, Photoimmunology & Photomedicine

Red and Green LED Light Therapy: A Comparative Study in Androgenetic Alopecia

Photodermatol Photoimmunol Photomed 2024 Nov 01;40(6)e13004, J Tantiyavarong, S Charoensuksira, J Meephansan, S Hanvivattanakul, Y Rayanasukha, T Boonkoom, K Tantisantisom

TAKE-HOME MESSAGE

This clinical comparative study evaluated the efficacy of red (633 nm) versus green (522 nm) LED light therapy in patients with androgenetic alopecia. After 6 months of weekly 20-minute treatments (40 J/cm2) to the frontal scalp, both red and green LED light treatments resulted in significant improvements in hair diameter, non-vellus hair density, and patient satisfaction scores. Although both wavelengths demonstrated efficacy within the first 3 months, patients receiving red LED light treatment maintained this improvement in hair density by 6 months and showed comparatively greater improvements in hair diameter from baseline. This was thought to be due to the deeper penetrating capacity of red light.
Both red and green LED light therapy seem to show promising results in patients with androgenetic alopecia, with red LED therapy generally providing more sustained positive outcomes. Consideration of red LED therapy is warranted as part of a multifaceted treatment approach for patients who can afford it.

– Nour Yacoub, MD

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574

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Thursday, October 24, 2024

HSP como inhibidores de la inflamación

Shocking news: Heat shock protein inhibition finally enters the realm of dermatologic therapy

By Warren R. Heymann, MD, FAAD
Oct. 23, 2024
Vol. 6, No. 43

Heat shock proteins (HSP) were serendipitously discovered by the brilliant Professor Ferruccio Ritossa in 1962 while studying nucleic acid synthesis in chromosomal puffs of Drosophila salivary glands. De Maio states, "Ritossa noticed something unexpected when cells were placed at the wrong temperature, and an incredible transcriptional activity was observed as new chromosomal puffs." This was called the "heat shock response" which led to the discovery of HSP and their profound effect on biology and medicine. (1)

Ben Abdallah et al. eloquently summarizes the biology of HSP. "Heat shock proteins (HSP) are a group of chaperone molecules whose major function is the maintenance of cellular homeostasis by folding and promoting the function of endogenous proteins (referred to as ''client proteins''). The heat shock protein 90 (HSP90) is the most abundant HSP (4-6% of total protein during cellular stress); it exists in two cytosolic isoforms (HSP90α and HSP90β) and two organelle-specific isoforms including glucose-regulated protein 94 (GRP94/gp96) localized in the endoplasmic reticulum and tumor necrosis factor receptor-associated protein 1 (TRAP1) localized in the mitochondria. HSP90 consists of three conserved domains: an N-terminal domain where the ATP-binding site is located (an ATPase activity is required for its chaperone function); a middle domain which is involved in binding to client proteins: and a C-terminal domain, which is responsible for HSP90 dimerization. Several co-chaperones (e.g., HSP70, CDC37, and AHA1) modulate the ATPase activity or functional range of client proteins. HSP90 is sometimes referred to as the 'signal transduction chaperone' given a large number of kinases and transcription factors being client proteins. Many of these client proteins are involved in key inflammatory pathways. Thus, HSP90 inhibition may target these client proteins involved in inflammation, providing a rationale as a treatment for multiple inflammatory skin conditions. HSP90 inhibition has been shown to mediate anti-inflammatory effects in inflammatory models such as rheumatoid arthritis and systemic lupus erythematosus…" RGRN-305 is an imidazopyridine derivative HSP90 inhibitor displaying a high affinity to the N-terminal ATP-binding site for HSP90α and HSP90β, and thereby blocks the ATPase activity and chaperone function." (2)

HSP90 is a downstream regulator of tumor necrosis factor (TNF-α) and interleukin (IL-17A) signaling and may serve as a novel target in the treatment of psoriasis. Bregnhøj et al. performed a phase Ib study evaluating the safety and efficacy of the HSP90 inhibitor (RGRN-305) for treating plaque psoriasis. The study was an open-label, single-arm, dose-selection, single-center proof-of-concept study. Patients with plaque psoriasis were treated with 250 mg or 500 mg RGRN-305 daily for 12 weeks. Efficacy was evaluated clinically using the Psoriasis Area and Severity Index (PASI), body surface area (BSA), Physician's Global Assessment (PGA) scores, and the Dermatology Life Quality Index (DLQI). Skin biopsies collected at baseline and at 4, 8, and 12 weeks after initiation of treatment were used for immunohistochemical staining and for gene expression analysis. Safety was monitored via laboratory tests, vital signs, electrocardiogram, and physical examinations. Six of the 11 patients who completed the study responded to RGRN-305 with a PASI improvement between 71% and 94%, whereas five patients were considered nonresponders with a PASI response < 50%. No severe adverse events were reported. Four of seven patients treated with 500 mg RGRN-305 daily experienced a mild-to-moderate exanthematous drug-induced eruption attributed to the drug. Two patients discontinued the study because of this exanthematous eruption. RGRN-305 treatment resulted in pronounced inhibition of the IL-23, TNF-α, and IL-17A signaling pathways and normalization of histological changes and psoriatic lesion gene expression profiles in patients who responded to treatment. The authors concluded that treatment with RGRN-305 showed acceptable safety, especially in the low-dose group, and was associated with clinically meaningful improvement in a subset of patients with plaque psoriasis, indicating that HSP90 may serve as a novel future target in psoriasis treatment. (3)

Image for DWII on heat shock protein inhibition — Image from JAAD 2009; 60(4): 539-561.

Abdallah et al. performed a parallel-design, double-blind, proof-of-concept, placebo-controlled randomized clinical trial of RGRN-305 in 15 patients (10 female; median age, 29 years) with hidradenitis suppurativa (HS). Patients were randomly assigned (2:1) to receive oral RGRN-305, 250-mg tablet, or matching placebo once daily for 16 weeks. The primary efficacy endpoint was the percentage of patients achieving Hidradenitis Suppurativa Clinical Response 50 (HiSCR-50) at week 16. The primary endpoint HiSCR-50 at week 16 was achieved by a higher percentage in the RGRN-305 group (60% [6 of 10]) than in the placebo group (20% [1 of 5]). RGRN-305 was well tolerated, with no deaths or serious adverse events, and treatment-emergent adverse events were similarly frequent between the RGRN-305 and placebo groups. The authors suggest that heat shock protein 90 inhibition by RGRN-305 offers a novel mechanism of action in treating hidradenitis suppurativa, warranting further evaluation in larger trials. (4)

HSP90 inhibition has increasingly become a research focus in autoimmune diseases, including autoimmune bullous diseases. Preclinical rodent experiments demonstrated that HSP90 blockers ameliorate autoimmune encephalomyelitis, rheumatoid arthritis, and systemic lupus erythematosus. Tukaj et al. demonstrated that HSP90 is a promising treatment target in autoimmune bullous diseases including epidermolysis bullosa acquisita, bullous pemphigoid, and possibly dermatitis herpetiformis. (5)

The role of HSP in cancer has been a long-standing area of active inquiry. Magwenyane et al. state that the overexpression of HSP90 occurs in patients with cancer, triggering unstable harmful kinase functions, which enhance carcinogenesis. They discuss various computational models used to develop HSP90 inhibitors as anticancer agents. (6) Many clinical trials utilizing HSP inhibitors have been performed over recent decades. Pimitespib (Jeselhy^®) is an oral small molecule inhibitor of the α and β isoforms of HSP90. In 2022, the drug was approved in Japan and China for treating of gastrointestinal stromal tumors. (7,8)

In the classic film Casablanca, Captain Renault (Claude Rains), a regular attendee at Rick's Café, is under order to shut down the joint — he uses the premise of gambling to do so, declaring "I'm shocked! Shocked to find that gambling is going on in here!" as the croupier responds, "Your winnings, sir." I am equally "shocked" that heat shock protein inhibitors have entered the realm of dermatologic therapy. Perhaps the heat will be turned up on researchers to deliver some positively shocking results.

Point to Remember: Heat shock protein inhibition is a novel approach that may prove valuable for dermatologists treating inflammatory, autoimmune, bullous, and oncologic diseases.

Our experts' viewpoint

Hakim Ben Abdallah, MD
Department of Dermatology and Venereology
Aarhus University Hospital

Lars Iversen MD, DMSc
Professor, Department of Dermatology and Venereology
Aarhus University Hospital

Heat shock protein 90 is a common protein that is involved in the cellular machinery that regulates the function of client proteins. Notably, multiple client proteins play essential roles in tumor cell proliferation and survival, hence HSP90 inhibition has been pursued as a therapeutic modality in cancer. (9,10) Approximately 20 different HSP90 inhibitors have entered cancer clinical trials, with the first HSP90 inhibitor (i.e., Pimitespib) receiving its approval in 2022 for gastrointestinal stromal tumors in Japan. (8) Besides the oncogenic client proteins, numerous client proteins are implicated in inflammation, though the research concerning HSP90 inhibition and inflammation is relatively sparse, especially clinical research.

Several preclinical studies have demonstrated that HSP90 inhibition alleviates inflammation in animal models within dermatology, gastroenterology, and rheumatology. These findings support the involvement of HSP90 in numerous inflammatory pathways, highlighting its potential as a drug target in inflammatory disorders.

The first clinical data of HSP90 inhibition in a skin disease was discovered by coincidence in a cancer trial with the oral HSP90 inhibitor RGRN-305. Surprisingly, during this study, a patient with cancer and concomitant severe plaque psoriasis covering > 40% of the skin surface experienced complete skin clearance following treatment with RGRN-305. Afterward, preclinical studies and the proof-of-concept clinical study confirmed the potential of HSP90 inhibition in plaque psoriasis, and the recent randomised placebo-controlled proof-of-concept study revealed the therapeutic potential of HSP90 inhibition in hidradenitis suppurativa. (3,4)

While the recent findings suggest HSP90 may be a novel drug target for inflammatory skin diseases, drug-related skin rashes have been reported, especially in psoriasis patients receiving 500 mg RGRN-305 once daily. (3) Indeed, further research is warranted to examine the optimal dosage regimen in skin diseases, which may differ between diseases, to enhance the efficacy while maintaining a favourable safety profile. Furthermore, given that HSP90 inhibitors usually are small molecules, topical delivery may also be a feasible route of administration, which remains to be evaluated in patients.

Four distinct HSP90 isoforms exist with different client proteins, but the inflammatory activity for each isoform remains unexplored. Thus, selective inactivation of these HSP90 isoforms may provide valuable insights that can be translated into potential therapeutic benefits.

Lastly, the effects of HSP90 inhibition are likely wide-ranging due to the targeting of hundreds of client proteins; thus, the therapeutic utility of HSP90 inhibition may extend beyond psoriasis and hidradenitis suppurativa to include other skin diseases, which hopefully may benefit patients.

De Maio A, Santoro MG, Tanguay RM, Hightower LE. Ferruccio Ritossa's scientific legacy 50 years after his discovery of the heat shock response: a new view of biology, a new society, and a new journal. Cell Stress Chaperones. 2012 Mar;17(2):139-43. doi: 10.1007/s12192-012-0320-z. Epub 2012 Jan 18. PMID: 22252402; PMCID: PMC3273555.
Ben Abdallah H, Seeler S, Bregnhøj A, Ghatnekar G, Kristensen LS, Iversen L, Johansen C. Heat shock protein 90 inhibitor RGRN-305 potently attenuates skin inflammation. Front Immunol. 2023 Feb 7;14:1128897. doi: 10.3389/fimmu.2023.1128897. PMID: 36825010; PMCID: PMC9941631.
Bregnhøj A, Thuesen KKH, Emmanuel T, Litman T, Grek CL, Ghatnekar GS, Johansen C, Iversen L. HSP90 inhibitor RGRN-305 for oral treatment of plaque-type psoriasis: efficacy, safety and biomarker results in an open-label proof-of-concept study. Br J Dermatol. 2022 May;186(5):861-874. doi: 10.1111/bjd.20880. Epub 2022 Mar 30. PMID: 34748646.
Ben Abdallah H, Bregnhøj A, Emmanuel T, Ghatnekar G, Johansen C, Iversen L. Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa: A Parallel-Design Double-Blind Trial. JAMA Dermatol. 2024 Jan 1;160(1):63-70. doi: 10.1001/jamadermatol.2023.4800. PMID: 38055242; PMCID: PMC10701664.
Tukaj S, Zillikens D, Kasperkiewicz M. Heat shock protein 90: a pathophysiological factor and novel treatment target in autoimmune bullous skin diseases. Exp Dermatol. 2015 Aug;24(8):567-71. doi: 10.1111/exd.12760. Epub 2015 Jun 3. PMID: 25980533.
Magwenyane AM, Ugbaja SC, Amoako DG, Somboro AM, Khan RB, Kumalo HM. Heat Shock Protein 90 (HSP90) Inhibitors as Anticancer Medicines: A Review on the Computer-Aided Drug Discovery Approaches over the Past Five Years. Comput Math Methods Med. 2022 May 31;2022:2147763. doi: 10.1155/2022/2147763. PMID: 35685897; PMCID: PMC9173959.
Xie X, Zhang N, Li X, Huang H, Peng C, Huang W, Foster LJ, He G, Han B. Small-molecule dual inhibitors targeting heat shock protein 90 for cancer targeted therapy. Bioorg Chem. 2023 Oct;139:106721. doi: 10.1016/j.bioorg.2023.106721. Epub 2023 Jul 8. PMID: 37467620.
Hoy SM. Pimitespib: First Approval. Drugs. 2022 Sep;82(13):1413-1418. doi: 10.1007/s40265-022-01764-6. PMID: 35986838.
Miyata Y, Nakamoto H, Neckers L. The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des. 2013;19(3):347-65.
Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer. 2010;10(8):537-49.

All content found on Dermatology World Insights and Inquiries, including: text, images, video, audio, or other formats, were created for informational purposes only. The content represents the opinions of the authors and should not be interpreted as the official AAD position on any topic addressed. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

Use of Oral Tranexamic Acid for the Prevention and Treatment of Post-Inflammatory Hyperpigmentation | PracticeUpdate

Use of Oral Tranexamic Acid for the Prevention and Treatment of Post-Inflammatory Hyperpigmentation

Dermatologic Surgery

TAKE-HOME MESSAGE

Tranexamic acid (TXA) inhibits the conversion of plasminogen to plasmin, thereby resulting in anti-inflammatory, anti-melanogenic, and anti-angiogenic effects. This oral medication has been widely studied as an effective treatment for pigmentary disorders, such as melasma, at low doses. This literature review assessed the use of TXA in the management of post-inflammatory hyperpigmentation (PIH). A TXA dose range from 500 to 750 mg daily for 12 weeks represents the optimal dose and duration for PIH treatment. The use of TXA 325 mg twice daily initiated 2 weeks before and continued for 2 weeks after a laser procedure has been proposed to prevent PIH. Before starting a patient on TXA, thromboembolic and cerebrovascular accident risks should be assessed.
Although there are no guidelines published for the use of TXA in the treatment of pigmentary disorders, such as PIH, this review of the literature since 2000 suggests that treatment with low doses of TXA may be effective, with minimal side effects, in appropriate patients.

– Nour Yacoub, MD

https://www.practiceupdate.com/content/use-of-oral-tranexamic-acid-for-the-prevention-and-treatment-of-post-inflammatory-hyperpigmentation/171169

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574

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Thursday, October 17, 2024

HOMING IN ON HORNERIN: BREAKING DOWN THE BARRIER TO UNDERSTAND ITS CRUCIAL ROLE IN ATOPIC DERMATITIS

By Warren R. Heymann, MD, FAAD
Oct. 16, 2024
Vol. 6, No. 42

Atopic dermatitis (AD) is characterized by skin barrier dysfunction, inflammation, and chronic pruritus. The etiology of AD, however, is complicated and incompletely understood, with genetic, environmental (soaps, surfactants, stress), and immunological factors causing skin barrier abnormalities and immune dysregulation. This commentary will focus on some new concepts related to the skin barrier.

The epidermal barrier has three primary functions: 1) limiting passive water loss, 2) restricting environmental chemical absorption, and 3) preventing microbial infection. The epidermis achieves these goals via keratinization to form corneocytes whose main components include loricrin, involucrin, and filaggrin (filament aggregating protein, FLG). Each corneocyte is enveloped by specialized intercellular lipids (ceramides, cholesterol, and free fatty acids [FFA], present in an approximately equimolar ratio) — this combination of "bricks" (corneocytes) and "mortar" (lipids) remains a good model of the skin barrier. (1,2)

According to Elias and Wakefield, "Lamellar bodies, organelles unique to the epidermis, secrete precursors of these lipids, along with lipid hydrolases that generate the three lipids required to form these lamellar membranes. Notably, a lamellar body secretory system also regulates desquamation by co-delivering kallikreins and other proteases that digest corneodesmosomes, leading eventually to corneocyte desquamation. Two antimicrobial peptides, human β-defensin 2 and the cathelicidin peptide LL-37, also known LB cargo, are delivered in parallel with the lipid and enzyme contents noted above. Thus, these two skin "barriers" — the antimicrobial and permeability — share several characteristics, including: i) blockade of pathogen invasion; ii) competition for niche occupancy with normal flora; iii) production of both peptide and peptide ingredients that block pathogen colonization; and iv)most importantly, the acidic surface of the skin, which is hostile to the growth of pathogens such as Staphylococcus (S.) aureus and other Streptococci. Indeed, these two critical defensive functions overlap to an extent that they can be considered as integrated and interrelated." (2)

Regarding immune dysregulation, two different hypotheses have been proposed, from inside to outside and from outside to inside. The former suggests that immunological aberrations are believed to be the primary event, followed by stimulation with allergens, leading to the weakening of the epidermal barrier. The latter hypothesis is that an impaired skin barrier is the initial step in AD pathogenesis and is required for immune dysregulation to occur. (3)

Image from JAAD Int. 2021 Jun 1;4:28-31.

According to Savva et al, "The dysregulated T cell-mediated immune response, including different patterns of cytokine release, has a strong and robust role in the pathogenesis of AD. The disrupted skin barrier enhances exposure to environmental allergens, which can either activate skin antigen-presenting cells, such as the inflammatory dendritic epidermal cells (IDECs), resulting in the subsequent 'allergic response,' or induce the chemokine milieu from keratinocytes, such as the thymic stromal lymphopoietin (TSLP), and interleukins (IL)-23, IL-25, and IL-33, reinforcing the T2 response and the induction of IL-4 and IL-13 [the two main T2-cytokines associated with AD pathogenesis], IL-31 cytokines though type 2 human innate lymphoid cells. This, in turn, promotes the class switch of B cells to plasmacytes toward specific IgE induction. Nevertheless, in chronic AD cases, a TH1 and TH17 dominance is noted, mediated by interferon-gamma (IFN-γ)/tumor necrosis factor-alpha (TNF-α) and IL-17, respectively, while TH22 responses driven by IL-22, are also present." (4)

Genetic alterations are primarily due to loss-of-function mutations of FLG, an epidermal protein that is broken down into natural moisturization factor. FLG mutations are present in up to 30% of AD patients and may also predispose patients to ichthyosis vulgaris, allergic rhinitis, and keratosis pilaris. (5) FLG is a member of the S100 fused-type protein family that also includes cornulin, filaggrin-2 (FLG2), hornerin (HRNR), repetin (RPTN), trichohyalin (TCHH), and trichohyalin-like 1 (TCHHL1). (6) Although FLG mutations account for most AD patients of northern European ancestry, recent studies show that AD is also associated with mutations in the genes encoding two other S-100 proteins — HRNR and FLG2. Rather than FLG, FLG2 mutations instead are associated with AD in African Americans. Although HRNR and FLG2 are components of the corneocyte envelope, their function(s) in normal epidermis remain poorly understood. (2)

In 2001 HRNR was identified in a mouse model and was believed to be similar to profilaggrin, having a role in cornification. (7) Human HRNR was subsequently found in psoriatic skin. (8) Makino et al. sought to clarify the role of HRNR in AD. "HRNR was detected in chronic AD lesions (n = 4), whereas no HRNR signals were observed in acute AD lesions (n = 3). HRNR was detected in the cytokeratin 6-expressing epidermis, and Ki67-positive keratinocytes were more abundant in the HRNR-positive epidermis. These findings suggest that HRNR may be associated with epidermal hyperproliferation in AD lesions." (9) I have often wondered how AD transitions to a chronic, lichenified dermatosis; perhaps HRNR is involved in this phenomenon.

In conclusion, although newer therapies such as monoclonal antibodies (dupilumab, tralokinumab) and JAK inhibitors (upadacitnib, abrocitinib) are in the limelight, replenishing the skin barrier should always be a cornerstone of treating AD.

Point to Remember: Maintaining the skin barrier is crucial in managing patients with atopic dermatitis. The pathomechanism(s) of barrier impairment is complex and integrally associated with immune dysregulation. Research on newly discovered proteins in the stratum corneum, such as hornerin, may lead to novel therapeutic interventions.

Our expert's viewpoint

Jack L. Arbiser, MD, PhD, FAAD
Thomas J. Lawley Professor of Dermatology, Emeritus
Emory University School of Medicine

Atopic dermatitis is an exceedingly common inflammatory dermatitis, often characterized by itch, bacterial colonization, and, in its chronic states, skin thickening. Contributing factors to the development of AD include mutations in proteins of the stratum corneum, such as filaggrin 1 and 2. Altered expression of these proteins transmits signals to the nucleus to transcribe cytokines such as IL4 and IL13, eventually leading to hyperproliferative stimuli such as IL-22, which results in lichenification and VEGF/Angiopoetin like 4 (Angptl4), resulting in erythema. Th2 inflammation is suppressed by a ceramide-IL-12 pathway, and an intact barrier is maintained by a tonic level of ceramides.

Makino describes an additional protein of the stratum corneum, called hornerin, which may play a role in the development of atopic dermatitis. Low levels of hornerin are seen in acute AD, while the protein is expressed in high levels in lichenified and chronic lesions. It may be that polymorphisms of hornerin, leading to low expression, may predispose to AD. The chronic lichenifcation state of hornerin may represent a futile effect to repair the barrier function, resulting in a thickened yet impaired epidermis. Understanding the regulation of hornerin expression may result in improved therapies for AD.

Yang G, Seok JK, Kang HC, Cho YY, Lee HS, Lee JY. Skin Barrier Abnormalities and Immune Dysfunction in Atopic Dermatitis. Int J Mol Sci. 2020 Apr 20;21(8):2867. doi: 10.3390/ijms21082867. PMID: 32326002; PMCID: PMC7215310.
Elias PM, Wakefield JS. Could cellular and signaling abnormalities converge to provoke atopic dermatitis? J Dtsch Dermatol Ges. 2020 Nov;18(11):1215-1223. doi: 10.1111/ddg.14232. Epub 2020 Oct 13. PMID: 33048449.
Sroka-Tomaszewska J, Trzeciak M. Molecular Mechanisms of Atopic Dermatitis Pathogenesis. Int J Mol Sci. 2021 Apr 16;22(8):4130. doi: 10.3390/ijms22084130. PMID: 33923629; PMCID: PMC8074061.
Savva M, Papadopoulos NG, Gregoriou S, Katsarou S, Papapostolou N, Makris M, Xepapadaki P. Recent Advancements in the Atopic Dermatitis Mechanism. Front Biosci (Landmark Ed). 2024 Feb 22;29(2):84. doi: 10.31083/j.fbl2902084. PMID: 38420827.
Kolb L, Ferrer-Bruker SJ. Atopic Dermatitis. 2023 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 28846349.
Makino T, Mizawa M, Takemoto K, Yamamoto S, Shimizu T. Altered expression of S100 fused-type proteins in an atopic dermatitis skin model. Exp Dermatol. 2023 Dec;32(12):2160-2165. doi: 10.1111/exd.14797. Epub 2023 Mar 30. PMID: 36995036.
Makino T, Takaishi M, Morohashi M, Huh NH. Hornerin, a novel profilaggrin-like protein and differentiation-specific marker isolated from mouse skin. J Biol Chem. 2001 Dec 14;276(50):47445-52. doi: 10.1074/jbc.M107512200. Epub 2001 Sep 25. PMID: 11572870.
Takaishi M, Makino T, Morohashi M, Huh NH. Identification of human hornerin and its expression in regenerating and psoriatic skin. J Biol Chem. 2005 Feb 11;280(6):4696-703. doi: 10.1074/jbc.M409026200. Epub 2004 Oct 26. PMID: 15507446.
Makino T, Mizawa M, Takemoto K, Shimizu T. Expression of hornerin in skin lesions of atopic dermatitis and skin diseases. Clin Exp Dermatol. 2024 Feb 14;49(3):255-258. doi: 10.1093/ced/llad297. PMID: 38123340.

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Explore hundreds of Dermatology World Insights and Inquiries articles by clinical area, specific condition, or medical journal source.

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574

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Wednesday, October 09, 2024

Tumoral Melanosis

SHEDDING LIGHT ON TUMORAL MELANOSIS

By Warren R. Heymann, MD, FAAD
Oct. 9, 2024
Vol. 6, No. 41

Tumoral melanosis (TM) is a worrisome and confounding lesion for dermatologists and dermatopathologists alike. TM presents as darkly pigmented macules, papules, or nodules mimicking the appearance of a melanoma. Most cases are associated with either partial or complete regression of melanoma, although TM has been reported with solar lentigo, pigmented basal cell carcinoma, pigmented Bowen's disease, and mycosis fungoides. (1) This commentary will focus on melanoma-associated TM.

TM is defined histologically as a dense aggregate of melanophages with a complete absence of melanocytes. (2) The histological differential diagnosis includes dermal melanocytoses, pigmented epithelioid melanocytoma, deep penetrating nevus, primary dermal melanoma, and metastatic melanoma. (3) TM is differentiated from these cases by positive immunohistochemical staining of CD68 and negative melanocyte stains (Melan-A, HMB-45, and SOX-10). (2)

In their series of four TM cases, Alexandris et al. detailed the dermatoscopic findings of 'peppering,' whitish or pinkish structureless areas, and blue/grey areas. The latter feature was observed in all cases, while 'peppering' was seen in 50%. These dermatoscopic features result from dermal fibrosis and presence of dense melanophages. Shiny white structures, which are suggestive of malignancy and can only be observed with polarized dermatoscopy, were found in two out of four lesions, correlating to coarsecollagen bundles in the dermis. (4)

According to Pastukhova et al., "The pathophysiology of TM is thought to involve an immunologic response that infiltrates and destroys atypical melanocytic cells. It is theorized that tumor antigens expressed on the surface of melanoma cells potentiate cytotoxic CD8+ lymphocytes and subsequent destruction of the cutaneous melanocytic component." (3)

TM is distinct from diffuse melanosis (DM), which has a poor prognosis. DM demonstrates diffuse gray pigmentation affecting the entire skin and is frequently accompanied by melanuria. (5)

There are two basic scenarios for TM — regression of advanced or metastatic melanoma or as a consequence of therapy. Jurgens et al assert, "The prognosis of tumoral melanosis is not well understood. The literature has demonstrated that focal regression within melanoma does not have a significant effect on morbidity or mortality; however, extensive regression in larger lesions may be associated with a poor prognosis. Thus, identification of tumoral melanosis in a patient with no known history of melanoma should prompt a thorough evaluation for metastatic disease. This stands in contrast to regression occurring in the setting of immunotherapy, where reports suggest that tumoral melanosis may be associated with tumor regression secondary to treatment response." (6) Modern immunotherapy (anti-CTLA-4 ipilimumab, PD1 inhibitors pembrolizumab and nivolumab, BRAF inhibitors such as dabrafenib, LAG-3 inhibitor relatlimab, and others) has revolutionized melanoma management. (7) Jurgens et al described 10 cases of patients with metastatic melanoma who received treatment with immunotherapy before the development of TM. The length of time between the initiation of therapy and the onset of TM ranged from 2 to 20 months with a mean time of 10 months. At the end of the follow-up period, 8 patients were classified as having a complete or partial response to treatment with immunotherapy. (6)

Talimogene laherparepvec (T-VEC) is a type I herpes simplex virus (HSV) genetically modified to preferentially replicate in tumor cells, enhance antigen loading of MHC class I molecules and express granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase tumor-antigen presentation by dendritic cells. (8) Park et al. report six patients with metastatic cutaneous melanoma who were treated with T-VEC. Biopsies were performed after observing clinical responses in the injected tumors — TM was observed in all cases. Importantly, the authors note that to "accurately assess response to therapy and potentially decrease unnecessary additional T-VEC treatments, serial biopsy of 'stable' lesions should be considered to assess the presence or absence of viable tumor." (9)

In conclusion, TM is an enigmatic lesion requiring further scrutiny. Clinically, it is essential to attribute TM to either melanoma or its treatment. Such a determination helps in prognostication and possibly guiding therapy.

Point to Remember: The rare phenomenon of tumoral melanosis may become more common with advances in melanoma immunotherapy. Such cases may have a better prognosis than cases of TM due to regression from advanced disease.

Our expert's viewpoint

Ata Moshiri, MD, MPH, FAAD
Assistant Professor, Ronald O. Perelman Department of Dermatology at NYU Grossman School of Medicine
Associate Director, Dermatopathology Fellowship Program
Assistant Director, Dermatopathology Laboratory Operations

As highlighted by the commentary above, tumoral melanosis (TM) in the setting of melanoma is an interesting phenomenon with controversial clinical and prognostic implications. At its core, TM signifies the host immune system's ability to recognize and destroy melanocytes, replacing them with melanophages and other immune cells that clinically resemble residual melanoma. While TM was once a rare observation, the advent of systemic immunotherapy, oncolytic viral therapy, and effective tumor vaccines have made TM increasingly common in our patients with cutaneous metastases of their melanoma, and thus a source of confusion and consternation for the patients and everyone involved in their care.

How should one approach patients with black macules, papules, and/or nodules appearing in their skin around their melanoma scars during their immunotherapy treatment? In my view, this is one place where clinicopathologic correlation is critical to accurate counseling. As a dermatologist involved in delivering oncolytic viral therapy at a major cancer center, I received many consults for such patients with presumed progressive and refractory disease. Oftentimes, treatment had been withheld or changed based on such clinical assessments. Punch biopsies demonstrating TM and no viable melanoma helped to change the narrative entirely. Rather than despair, a finding of TM provided hope that the patient's newly activated lymphocytes were effectively fighting their cancer. Similarly, in patients receiving months or sometimes years of oncolytic viral therapy for "stable" disease, biopsies demonstrating TM allowed for discontinuation of additional (very expensive) injections. (9) While such responses are not always durable, and disease can recur after therapy is discontinued, TM signifies at least a temporary victory.

As dermatologists involved in cancer surveillance or treatment, we are uniquely positioned to provide clinicopathologic correlation to our patients and colleagues. Becoming familiar with TM and stressing the importance of biopsies to ascertain the presence or absence of viable disease is often necessary for informed clinical decision making and provides valuable histologic insights into the tumor microenvironment that, if correctly studied, may lead to further advances in immunomodulatory therapy for cancer.

Petit K, Hinrichs B, Chaudhary R. Gray-black macules in a patient with melanoma. JAAD Case Rep. 2022 Aug 23;28:113-115. doi: 10.1016/j.jdcr.2022.08.021. PMID: 36159718; PMCID: PMC9489873.
Massa A, Macchi S, Manuguerra R, Brusasco M, Aouadi M, Feliciani C, Satolli F. Is tumoral melanosis still a challenge? A case of tumoral melanosis without metastasis. Int J Dermatol. 2023 Dec;62(12):e618-e620. doi: 10.1111/ijd.16830. Epub 2023 Sep 6. PMID: 37670681.
Pastukhova E, El-Sayes Y, Nakonechny Q, Roy SF, Ghazawi FM. Chasing shadows: a series of tumoral melanosis mimicking melanoma. JAAD Case Rep 2024; DOI https://doi.org/10.1016/j.jdcr.2024.01.012
Alexandris D, Bobos M, Lallas A, Lazaridou E, Apalla Z. Clinical, dermatoscopic and histopathologic characteristics of tumoural melanosis: A case-series and literature review. J Eur Acad Dermatol Venereol. 2023 Dec 7. doi: 10.1111/jdv.19657. Epub ahead of print. PMID: 38059544.
Arias NM, Peñaranda JMS, Gaspar LS, Mosquera AC, Sánchez-Aguilar D. Tumoral melanosis associated with nivolumab therapy for metastatic melanoma. J Dtsch Dermatol Ges. 2022 Aug;20(8):1130-1131. doi: 10.1111/ddg.14809. Epub 2022 Jul 6. PMID: 35792091.
Jurgens A, Guru S, Guo R, Brewer J, Bridges A, Jakub J, Comfere N. Tumoral Melanosis in the Setting of Targeted Immunotherapy for Metastatic Melanoma-A Single Institutional Experience and Literature Review. Am J Dermatopathol. 2021 Jan 1;43(1):9-14. doi: 10.1097/DAD.0000000000001612. PMID: 32149829.
Heymann WR. Lagging ahead: LAG-3 checkpoint inhibition for advance melanoma. Dermatology World Insights and Inquiries 2022; volume 4, no. 2. https://www.aad.org/dw/dw-insights-and-inquiries/archive/2022/lag-3-checkpoint-inhibition-advanced-melanoma
Heymann WR. Oncolytic virotherapy and the dermatologist. Dermatology World Insights and Inquiries. March 8, 2018. https://www.aad.org/dw/dw-insights-and-inquiries/dermatopathology/oncolytic-virotherapy-and-the-dermatologist
Park SY, Green AR, Hadi R, Doolittle-Amieva C, Gardner J, Moshiri AS. Tumoral melanosis mimicking residual melanoma in the setting of talimogene laherparepvec treatment. J Immunother Cancer. 2022 Oct;10(10):e005257. doi: 10.1136/jitc-2022-005257. PMID: 36307152; PMCID: PMC9621191.

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574

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a mobile device.

Sunday, October 06, 2024

Uso de guantes no esteriles noafecta riesgo de infección, durante Cirugia de Mohs

TAKE-HOME MESSAGE

This systematic review and meta-analysis evaluated post–Mohs micrographic surgery (MMS) local infection rates associated with the use of sterile versus non-sterile gloves during the surgery. The analysis included data from 10,644 MMS across four studies. The results showed no significant difference in postoperative surgical site infection rates between the groups using sterile and non-sterile gloves during MMS. Based on two studies, the rates of postoperative surgical site infection during the reconstruction phase were comparable between the two groups. Notably, primary closure was associated with the highest surgical-site infection rate in both groups.
This study showed that using non-sterile gloves is as effective as using sterile gloves for preventing infections in patients undergoing MMS.

– Lillian Sun, MD

Désirée Ratner MD

There has been an ongoing debate regarding the use of sterile versus non-sterile gloves during Mohs micrographic surgery (MMS) — specifically whether using non-sterile gloves leads to increased rates of postoperative surgical-site infection. This updated systematic review and meta-analysis evaluated data from studies published up to August 2023 that assessed the use of sterile versus non-sterile gloves during MMS and reported postoperative wound infection rates. The surgical-site infection rates did not significantly differ between the two groups, with similar results noted in the excision and repair group subanalyses. These results support the effectiveness of non-sterile gloves in preventing surgical-site infection in patients undergoing MMS and providing significant cost savings without compromising outcomes. In an era of increasing overhead costs, this comes as welcome news.

Abstract