EADV President, Branka Marinović, and Treasurer, Menno de Rie, discuss the latest in dermatology Interviews: Non-Scarring Alopecia in Females: A Comprehensive Review Editor's Pick:
Foreword
Congress Review
10 Review of the European Academy of Dermatology and Venereology (EADV) Congress 2024, 25th–28th September 2024
Congress Features
23 New and Emerging Drugs in Dermatology
Victoria Antoniou
27 Inflammatory Diseases in Paediatric Dermatology
Helena Bradbury
Symposium Reviews
30 Reverse the Age Clock: Reverse Clinical Signs of Ageing with Epigenetic Skin Science
38 Vitiligo, Beyond White Patches
Poster Review
50 Mechanistic Understanding of Clinical Response to Bimekizumab in Psoriatic Disease
Abstract Reviews
58 A 13-Year Retrospective Review of Metal Series Patch Testing for Orthopaedic Devices
Maniam et al.
60 Barriers to Effective Cellulitis Management in a Primary Care Setting: An Audit Report
Chow and Siripanich
61 Chronic Cutaneous Lupus Erythematosus in a Patient with a History of Kikuchi–Fujimoto Disease
Owczarczyk-Saczonek and Jóźwicka
63 Inflammatory Filler Complications Revisited: Controversies, Literature Review, and Case Presentations
Ghanem and Darwish
65 Complete Remission of Paraneoplastic Generalised Eruptive Keratoacanthoma of Grzybowski After Treatment of the Primary Tumour
Rodríguez-Cuadrado et al.
67 Lack of Synonymity Between 'Cubital Gust of Wind' and Rheumatoid Arthritis
Elinkichari et al.
69 Abstract Highlights
Congress Interviews
76 Branka Marinović
79 Menno de Rie
Interviews
83 Skin Microbiome and Acne: Microbial Imbalances and Impact – Interview with Three Key Opinion Leaders
95 Current Landscape and Emerging Therapies in Hair Loss Treatment for Androgenetic Alopecia
103 Tralokinumab in the Era of Disruption in Atopic Dermatitis
112 Chesahna Kindred
Feature
117 The Advances in Treatment Options for Conditions Causing Hair Loss
Kaufman and Dulmage
Articles
122 Non-Scarring Alopecia in Females: A Comprehensive Review
Aristizabal et al.
134 Update on Low-Molecular Weight Hyaluronic Acid in Dermatology: A Scoping Review
Waggett et al.
147 Pathogenic Variants in the ABCA12 Gene Associated to Autosomal Recessive Congenital Ichthyosis: Report of an Attenuated Phenotype
Beltrán et al.
154 Pigmented Variants of Basal Cell Carcinoma: A Case Series
Sajjad et al.
Editorial Board
Editor-in-Chief
Prof. Simone Ribero
University of Turin, Italy
Simone Ribero trained at the University of Turin completing a PhD on the prognostic role of histological regression in cutaneous melanoma. His training included research fellowships at prestigious institutions, including Imperial College London and King's College London, UK and his research field of interest is dermato-oncology with particular focus on moles and skin tumours.
Dr. Jaishree Sharad
Skinfinitii Aesthetic Skin and Laser Clinic, India
Dr. Jennifer Cather
Modern Research Associates, USA
Dr. Michael Gold
Gold Skin Care Center, USA
Prof. Vishalakshi Viswanath
Rajiv Gandhi Medical College, India
Prof. Des Tobin
University College Dublin, Ireland
Dr. Hassan Galadari
United Arab Emirates University, United Arab Emirates
Prof. Richard Warren
University of Manchester, UK
Prof. Francesca Fametani
Univeristy of Modena and Reggio Emilia, Italy
Prof. Alin Laurentiu Tatu
"Dunărea de Jos" University of Galați, Romania
Aims and Scope
EMJ Dermatology is an open-access, peer-reviewed eJournal committed to helping elevate the quality of healthcare for skin, hair, and nail diseases. EMJ Dermatology endeavours to increase knowledge, stimulate discussion, and contribute to a better understanding of these conditions.
The journal is published annually, six weeks after the European Academy of Dermatology and Venerology (EADV) Congress, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. The journal also covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team.
EMJ Dermatology also publishes peer-reviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. The journal is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication.
EMJ Dermatology focuses on topics that are relevant to healthcare professionals in the field. We do not publish veterinary science papers or laboratory studies that are not linked to patient outcomes. We have a particular interest in topical studies that advance knowledge and inform of coming trends affecting clinical practice in the field.
Further details on coverage can be found here: www.emjreviews.com
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EMJ is supported by various levels of expertise:
• Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines.
• Invited contributors who are recognised authorities in their respective fields.
• Peer review, which is conducted by expert reviewers who are invited by the Editorial team and appointed based on their knowledge of a specific topic.
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On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review.
Editorial staff, following consultation with either a member of the Editorial Board or the author(s) if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area.
All peer review is double blind. Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected.
Editorial staff have final discretion over any proposed amendments.
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Congress Notice
Staff members attend medical congresses as reporters when required.
This Publication Launch Date: 2024 Frequency: Yearly Online ISSN: 2054-6211
All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (EADV Congress 2024) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Amsterdam, the Netherlands, the location of the EADV Congress 2024.
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Welcome
Dear Readers,
It is with great excitement that we bring you the 2024 issue of EMJ Dermatology. In this issue you will get a taste of recent breakthroughs happening in dermatology, and particularly in chronic inflammatory skin disorders, for which the drug pipeline is promising.
Dermatology has seen a flurry of successful clinical trials and approved drugs, from those targeting IL-17 to treat hidradenitis suppurativa, to potential new agents for psoriasis that might enable the move from injectable to oral drugs. Of course, JAK inhibitors are now a key player in the field for conditions ranging from alopecia areata to psoriasis, and results continue to look promising.
It’s also extremely positive to see that personalised medicine approaches in dermatology might soon be a reality for many patients, ensuring each patient is receiving appropriate care tailored to their particular needs. This would not only ensure more positive outcomes, but also provide an improvement in patient quality of life.
I would like to thank our peer reviewers, contributors, and Editorial board, for helping us to bring you this great content. Until the next issue, please do read through all the great dermatology content, and make sure you look at our interactive feature on JAK inhibitors, published earlier this year.
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Science at the core
With a single product, we invented an industry— and our pursuit of new possibilities in medical aesthetics will never stop.
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Foreword
I am delighted to welcome you to our latest issue of EMJ Dermatology, which contains a wide variety of content, including peer-reviewed articles, a feature on conditions causing hair loss, and interviews with key opinion leaders. Also included is our review of the European Academy of Dermatology and Venereology (EADV) Congress 2024, hosted in Amsterdam, the Netherlands, from 25th–28th September. The review offers a detailed overview of the most significant highlights and content presented throughout the Congress, including the latest atopic dermatitis treatment options.
EMJ had the pleasure of meeting with experts in dermatology, including EADV President Branka Marinović and Treasurer Menno de Rie, who provided a fantastic insight into the aims of the EADV and how the Congress provides a platform for nurturing the next generation of specialists through their leader development programmes. Additionally, Chesahna Kindred discussed the disparities in the representation of different skin colours in dermatology, the psychological burdens of dermatologic conditions, and her experience as a member of the Women’s Dermatological Society.
The articles included in this issue cover a broad range of topics, including the description of pathogenic variants in the ABCA12 gene associated with autosomal recessive congenital ichthyosis from
Beltrán et al.
In a review of non-scarring alopecia in females, Aristizabal et al. have explored the most common causes of the condition and the treatment options available to reverse or cease its progression. Additionally, a case series from Shaheen et al. aims to create awareness to improve the early recognition and treatment of pigmented variants of basal cell carcinoma.
As the Editor-in-Chief, I would like to thank all the authors, reviewers, and Editorial Board members for their contributions to this fantastic issue of EMJ Dermatology. I hope you enjoy reading this journal.
EMJ had the pleasure of meeting with experts in dermatology, including EADV President Branka Marinović and Treasurer Menno de Rie, who provided a fantastic insight into the aims of the EADV
Professor Simone Ribero University of Turin, Italy
EADV 2024
The purpose of the EADV is to foster knowledge exchange, improve the quality of dermatology care, and inspire advancements in dermatology research
Congress Review
Review of the European Academy of Dermatology and Venereology (EADV) Congress 2024
THIS YEAR saw the 33rd European Academy of Dermatology and Venereology (EADV) Congress that, for the third time in its history, was hosted in Amsterdam, the Netherlands. With over 160 symposia, 20 subspeciality sessions, and the ever-popular 'Late breaking news' sessions, EADV President Martin Röcken described this as the biggest year so far, with more than 17,000 participants involved in the event. Being a hybrid event, EADV committed to live-streaming all sessions, making content available on-demand to improve the reach of the Congress and maximise the inclusivity of the event.
Concluding his introduction, Röcken touched on how the focus for the EADV Congress 2024 centred around building a “bridge to the future”, a nod to the 1,200 bridges that make an elaborate web throughout the city of Amsterdam.
Dirk Jan Hijnen, Erasmus University MC, Rotterdam, the Netherlands, warmly welcomed all those at the opening ceremony to the city, jovially remarking that those attending in person should beware when out on the street, scanning for the 1.33 bikes there are per person in Amsterdam. Turning to the new programme additions, Hijnen highlighted the Residents’ Track, which was designed to engage young dermatologists at the early stages of their careers. He remarked that the purpose of the EADV is to foster knowledge exchange, improve the quality of dermatology care, and inspire advancements in dermatology research across Europe, by offering an excellent
opportunity for attendees to start new collaborations, exchange ideas, and build meaningful connections within the dermatology community.
The rest of the opening ceremony focussed on looking to the future as the keynote lecture, presented by explorer and psychiatrist Bertrand Piccard, Lausanne, Switzerland, discussed renewable energy and clean technologies which, as Piccard described, are the new medications for our world. Piccard described how the 20th century brought significant progress in life expectancy, public health, and quality of life, yet, as we venture further into the 21st century, we face daunting challenges that seem to unravel these achievements. Unsustainability, pollution, depletion of natural resources, and the extinction of biodiversity signal a dangerous regression. He stated: “Our mission must be to heal the planet,” not just individual patients, and fortunately, we have the “medication” for this
cure: renewable energy, energy efficiency, and sustainable practices. He noted that implementing these solutions requires radical change, and achieving compliance with this regime on a global scale is far more difficult than gaining compliance from a single patient. However, Piccard assured the audience the belief that these changes are impossible exists only in the mindset of those who assume the future will simply be an extrapolation of the past, and the truth is that the future is open to change and subject to disruption. The keynote lecture ended with the inspiring note that history is filled with paradigm shifts, from the moon landing to the ascent of Everest, and these feats were achieved by people who broke the rules and redefined limits. The audience members were encouraged to embrace the notion that innovation happens not when a new idea emerges, but when an old belief is cast aside.
Our mission must be to heal the planet
Key topics from the event included the cardiovascular effects of JAK inhibitors in atopic dermatitis, personalised biomarker approaches to treatment, CAR-T therapy for refractory systemic lupus erythematosus, and the treatment of vitiligo and moderateto-severe atopic hand eczema.
EMJ had the pleasure of attending the EADV Congress 2024, and is excited to share highlights from the late-breaking news sessions. Continue reading for an in-depth look at the latest research updates from this year’s Congress as we look forward to being part of the EADV community at next year’s meeting in Paris, France.
JAK Inhibitors Show No Cardiac Risk in Atopic Dermatitis Treatment
JAK INHIBITORS have become essential treatments for moderate-to-severe atopic dermatitis (AD), a condition affecting up to 20% of adolescents and 10% of adults worldwide. Despite their proven effectiveness, some dermatologists remain cautious when prescribing these medications due to concerns about their potential association with major adverse cardiac events (MACE).
This retrospective cohort study, presented at the EADV Congress 2024, aimed to assess the incidence of MACE and other cardiovascular conditions in patients with AD treated with upadacitinib or abrocitinib. Although JAK inhibitors have been linked to cardiovascular issues in treating other inflammatory skin conditions, there is limited data on their safety, specifically in patients with AD. Understanding these risks is critical for dermatologists when considering treatment options for patients who have not responded to conventional therapies.
The study utilised data from the TriNetX Research Network, identifying patients diagnosed with AD, and selecting a cohort consisting of 1,802 patients treated with upadacitinib or abrocitinib. The control cohort included over 1.2 million patients with AD who had never been treated with these medications. However, to ensure a balanced comparison, both cohorts were propensityscore matched based on factors such as age, biological sex, and cardiovascular comorbidities, resulting in 1,802 patients in each group. The incidence of cardiovascular events was then analysed in both groups.
Moderate-to-severe atopic dermatitis is a condition affecting up to: of adolescents 20 % of adults 10 %
The results showed no increased risk of MACE or other cardiovascular complications in patients with AD
The results showed no increased risk of MACE or other cardiovascular complications in patients with AD who were treated with upadacitinib or abrocitinib. These findings suggest that it is most likely safe to consider the use of these JAK inhibitors for moderate-to-severe AD, even in patients with existing cardiovascular conditions. This study provides valuable information that may help alleviate concerns about cardiovascular risks and improve the overall management of AD.
Longer Ruxolitinib Cream Use Improves Vitiligo Treatment Durability
THE RESULTS of a recent analysis of the TRuE-V long-term extension study presented at the EADV Congress 2024 suggest that longer application of ruxolitinib (RUX) cream, a JAK inhibitor, lead to more durable repigmentation in patients with vitiligo after treatment withdrawal.
The study assessed the effect of treatment duration on maintaining facial repigmentation in patients with nonsegmental vitiligo.
In the trial, 674 patients with vitiligo covering less than 10% of their total body surface area were either treated with RUX cream or a vehicle for 24 weeks. Those who achieved significant facial repigmentation, defined as at least a 90% improvement (F-VASI90), were randomised to continue with RUX or switch to a vehicle to evaluate the durability of their repigmentation after stopping the treatment.
The results revealed that patients who used RUX cream for a longer period, up to 52 weeks, maintained their repigmentation for a median of 365 days, compared to just 91 days for those who switched to a vehicle after the initial 24 weeks of treatment. Furthermore, more than 60% of patients who used RUX cream for the full 52 weeks maintained their facial repigmentation for at least 6 months, compared to only 18% of those who stopped after 24 weeks.
Treatment-related side effects were minimal, with the most common being application site reactions, such as acne and skin irritation. None of which led to treatment discontinuation.
The study concluded that continued use of RUX cream beyond achieving facial repigmentation may offer patients with vitiligo longer-lasting results. This suggests that extending the duration of treatment could be beneficial for maintaining the positive effects of the cream, particularly in those who achieve early repigmentation.
60 % more than
of patients who used RUX cream for the full 52 weeks maintained their facial repigmentation for at least 6 months
Patients who used RUX cream for a longer period, up to 52 weeks, maintained their repigmentation for a median of 365 days
Proteomic Biomarkers of Early, Late, and Nonresponses to Dupilumab in Atopic Dermatitis
RESEARCHERS have identified that there are distinct systemic biomarker profiles linked to the timing and maintenance of dupilumab response in patients with moderate-to-severe atopic dermatitis (AD).
Whilst dupilumab is an effective treatment for moderate-to-severe AD, prior research has demonstrated that fewer than 50% of patients achieve complete or near-complete clearance within 16 weeks of dupilumab use. Therefore, researchers aimed to identify biomarkers associated with early response, late response, nonresponse, and sustained response to dupilumab, to explore the timing and maintenance of dupilumab responses in patients.
The study, presented at the EADV Congress 2024, included 67 patients with moderate-to-severe AD treated with dupilumab, of whom, 39 were classed as early responders, 11 as late responders, and 17 as non-responders. Patients were evaluated at two follow-up visits (FU1 and FU2), with an average follow-up period of 8.9 months. Clinical scores and serum samples were collected at each visit, and proteomic analysis was performed using OLINK technology. Early responders achieved an investigator global assessment (IGA) of 0/1 or a ≥2-point reduction from baseline at both follow-ups, whereas late responders met the criteria at FU2 only, and non-responders did not meet the response criteria and/or experienced treatment dissatisfaction or adverse events. Differentially expressed proteins were defined by a fold-change >1.3 and p<0.05.
Late responders showed a 45% improvement in proteomic dysregulation from FU1 to FU2
Fewer than 50% of patients achieve complete or near-complete clearance within 16 weeks of dupilumab use
The results revealed that at baseline, there were no significant differences between the groups in terms of patient characteristics or clinical severity. Additionally, early responders displayed a similar proteomic profile to healthy controls at both follow-up visits, whilst late responders showed a 45% improvement in proteomic dysregulation from FU1 to FU2, with upregulation of many Th1, Th2, Th17/22, and T cell activation/ migration/dendritic cell pathways in FU1, and subsequent downregulation/normalisation at FU2. Whereas, in non-responders, there was a worsening of their blood proteome, with key Th1-related biomarkers, including CXCL9 and CXCL10, remaining significantly elevated at both follow-ups. Spearman analysis revealed positive correlations between clinical improvements and changes in blood biomarkers, particularly those involved in T cells, dendritic cells, natural killer cells, and Th2 pathways (R≥0.35; p<0.05).
The results of the study demonstrate that there are distinct biomarker profiles linked to the timing and maintenance of dupilumab responses in patients with AD. Specifically, whilst early responders show early and stable proteomic normalisation, late responders show gradual changes in Th1, Th2, and Th17/22 pathways, and non-responders demonstrate persistent dysregulation. This highlights potential biomarkers that could guide more personalised treatment strategies in clinical practice. Future research should explore targeted interventions for non-responders to improve outcomes.
Familial Hidradenitis Suppurativa Linked to Metabolic Syndrome Risk
HIDRADENITIS suppurativa (HS), also known as acne inversa, is characterised by the formation of painful nodules and fistulas, which can lead to scarring, and is driven by key cytokines such as TNF-α, IL-17, and IL-1, similar to other inflammatory skin conditions, such as psoriasis.
In these diseases, there is often a higher risk of metabolic syndrome, which includes conditions like hyperlipidaemia, cardiovascular disease, and Type 2 diabetes. However, the link between familial HS and the development of these metabolic conditions remains largely underexplored.
A meta-analysis, presented at the EADV Congress 2024, gathered data from two studies, EpiCAi and Batman, to generate a cohort of 236 participants, of whom 166 were female and 70 were male.
Approximately 25.8% of the participants reported a family history of HS, while the remaining 74.2% had sporadic cases. Notably, the age of onset was earlier in those with a familial predisposition (20.4 years on average) compared to sporadic cases (23.6 years); however, diagnosis was delayed by about 4 years in familial cases, possibly due to self-management.
While the severity of the disease was similar between familial and sporadic cases, patients with a family history of HS had a significantly higher risk of metabolic complications. The odds ratios for hyperlipidaemia, cardiovascular disease, and diabetes were 2.36, 2.99, and 1.76, respectively, for familial cases compared
to sporadic cases. This increased risk was independent of other factors such as smoking or BMI, which were similar across both groups.
The study found that patients with HS and a positive family history face a significantly higher risk of developing metabolic syndrome. The earlier onset of the disease and delayed diagnosis in familial cases highlight the need for careful cardiovascular monitoring and early intervention in these patients. This emphasises the importance of targeted care for those with a familial predisposition to HS.
The study found that patients with HS and a positive family history face a significantly higher risk of developing metabolic syndrome
Approximately 25.8% of the participants reported a family history of HS
Efficacy and Safety of the IRAK4 Inhibitor Zabedosertib in Moderate-to-Severe Atopic Dermatitis
THE PHASE IIa DAMASK study assessed the efficacy and safety of zabedosertib, an oral IRAK4 inhibitor, in adult patients with moderate-to-severe atopic dermatitis (AD). Efficacy and safety data from this study were presented at the EADV Congress 2024.
The double-blind, placebo-controlled trial included 77 participants from seven countries who had an insufficient response to topical corticosteroids. Patients received either zabedosertib or placebo for 12 weeks alongside daily use of emollients. The primary endpoint was the Eczema Area and Severity Index (EASI)-75 response at Week 12, with secondary endpoints including changes in body surface area affected, pruritus scores, and validated investigator assessments.
The results showed no significant difference between zabedosertib and placebo in the primary or secondary efficacy measures. EASI-75 responses were 32.3% for zabedosertib and 37.4% for placebo. Similar non-significant results were observed for investigator assessments, pruritus scores, and body surface area changes. Additionally, biomarker analysis did not show a therapeutic effect of zabedosertib.
In terms of safety, 44.2% of patients in the zabedosertib group experienced treatmentemergent adverse events, compared to 28% in the placebo group, with nasopharyngitis being the most common. No serious adverse events or safety concerns were reported.
In conclusion, while zabedosertib was well tolerated, it did not demonstrate efficacy in treating moderate-to-severe AD. The findings suggest that targeting IRAK4 may not be a viable strategy for AD, though it may still hold potential for other immune-mediated conditions.
44.2% of patients in the zabedosertib group experienced treatmentemergent adverse events, compared to 28% in the placebo group
EASI-75 responses were:
32.3 % for placebo
37.4 %
for zabedosertib
New CAR-T Therapy Shows Promise for Patients with Refractory Lupus
A NEW allogeneic CAR-T therapy targeting CD19+ B cells presented at the EADV Congress 2024 has demonstrated promising results for patients with refractory systemic lupus erythematosus (SLE), offering hope for those who have not responded to traditional treatments.
The study evaluated the safety and efficacy of BRL-303, a CD19-targeted CAR-T therapy developed from healthy donor cells, in treating six patients with severe, treatment-resistant lupus.
SLE is a chronic autoimmune disease that affects multiple organs and is often treated with immunosuppressive drugs. However, many patients do not achieve remission and face significant side effects from prolonged immunosuppression. BRL-303 represents a new approach by deeply depleting CD19+ B cells, potentially resetting the immune system in patients with autoimmune diseases.
In this investigator-initiated trial, patients received BRL-303 after lymphodepletion chemotherapy, which prepares the immune system for CAR-T cell infusion. Results from the trial showed that the CAR-T cells expanded rapidly in all patients within 7 days, peaking between Days 14 and 21. Over the next 1–3 months, the therapy led to deep, sustained depletion of B cells in the bloodstream.
After a median follow-up of 6 months, all six patients showed significant clinical improvements, including reductions in disease activity scores and remission of symptoms. Proteinuria, a marker of lupus nephritis, also significantly decreased in those affected. Importantly, the safety profile of BRL-303 was favourable, with only mild side effects such as low-grade cytokine release syndrome reported, and no cases of severe infection or neurotoxicity.
These early findings suggest that BRL-303 could represent a breakthrough for patients with SLE who have not responded to current therapies. The trial is ongoing, with further research planned to explore the therapy's effects in lupus and other autoimmune diseases.
After a median follow-up of 6 months, all six patients showed significant clinical improvements
Delgocitinib Cream versus Dupilumab: Comparing Eczema Treatments
A TOPICAL, investigational pan-JAK inhibitor, delgocitinib cream, has shown notable efficacy in treating various subtypes of chronic hand eczema (CHE), including atopic hand eczema (AHE), according to research presented at the EADV Congress 2024.
The cream is well tolerated, with a favourable safety profile, making it a promising option for patients. In contrast, dupilumab, a biologic that inhibits IL-4 and IL-13 signalling pathways, is approved for moderate-to-severe atopic dermatitis (AD) treatment, including AD that affects the hands. However, no direct studies have compared the efficacy of delgocitinib and dupilumab, specifically for AHE.
To address this gap, a matching-adjusted indirect comparison (MAIC) was performed using data from the DELTA 1 and DELTA 2 trials and the LIBERTY-AD-HAFT trial. The DELTA 1 and 2 trials were Phase III studies that assessed delgocitinib cream in adults with moderate-to-severe CHE. Participants were randomised in a 2:1 ratio to receive either delgocitinib, as a dosage of 20 mg/g, or a cream vehicle twice daily for 16 weeks. The LIBERTY-AD-HAFT trial included adults and adolescents (aged 12 to under 18 years) with moderate-to-severe AD involving the hands or feet, who were treated with subcutaneous dupilumab or placebo every 2 weeks for 16 weeks.
Since no direct comparisons were available, the MAIC was conducted using individual patient data from DELTA 1 and 2, and published aggregate data from LIBERTYAD-HAFT. The LIBERTY-AD-HAFT trial included 133 participants, while DELTA 1 and 2 included 959 patients, 345 of whom had been diagnosed with AHE.
Patients with AHE as the primary subtype in the DELTA trials were weighted to match baseline characteristics, such as age, race, sex, and baseline Hand Eczema Severity Index (HECSI) scores of participants in the LIBERTY-AD-HAFT trial. Efficacy endpoints included achieving HECSI 75 and HECSI 90 and the percentage improvement from
baseline at Week 16. Investigator’s Global Assessment scores (IGA), IGA-CHE for DELTA trials and HF-IGA for LIBERTY-ADHAFT, were also compared, although these scales differed in response definitions.
DELTA 1 and 2 included 959 patients, 345 of whom had been diagnosed with AHE.
The study found that topical delgocitinib demonstrated comparable efficacy to systemic dupilumab after 16 weeks in patients with AHE. However, while statistical significance was not achieved, delgocitinib may be an effective alternative for AHE treatment, warranting further investigation.
Efficacy and Safety of the TYK2 Inhibitor HS-10374 in Moderate-to-Severe Plaque Psoriasis
DATA from a Phase II trial that evaluated the efficacy and safety of HS-10374, an oral selective Tyrosine kinase 2 (TYK2) inhibitor, in treating moderate-to-severe plaque psoriasis, were presented at the EADV Congress 2024.
TYK2 is crucial for IL-12 and IL-23 signalling, which are key cytokines in psoriasis. In this randomised, double-blind, placebo-controlled study, 125 patients were assigned to three groups: HS-10374 6 mg, HS-10374 12 mg, or placebo. The treatment period lasted 12 weeks, with a 4-week follow-up.
125 patients were assigned to three groups: HS-10374 6 mg, HS-10374 12 mg, or placebo
The primary endpoint was met at Week 12. The Psoriasis Area and Severity Index (PASI) 75 response rate was 28.6% for the 6 mg group and 72.1% for the 12 mg group, compared to 7.5% for the placebo group. Additional endpoints, such as static Physician’s Global Assessment 0/1, PASI 50, and PASI 90, were also significantly higher in the HS-10374 groups.
Safety outcomes were similar across all groups, with slightly higher adverse event (AE) rates in the HS-10374 groups.
Treatment-related AEs and serious AEs were comparable, with one unrelated serious AE (limb trauma) in the 6 mg group and one gastrointestinal-related serious AE in the placebo group. Infections were the most commonly reported AEs, but there was no significant increase in skin-related AEs compared to placebo.
In conclusion, HS-10374 demonstrated significant efficacy in treating plaque psoriasis with a safety profile consistent with other TYK2 inhibitors. Further trials with larger populations and longer treatment durations are needed.
The Psoriasis Area and Severity Index 75 response rate was:
28.6 % for the 12 mg group
for the 6 mg group
72.1 % for the placebo group
7.5 %
JAK Inhibitor Delgocitinib Reduces Hair Loss and Inflammation in Frontal Fibrosing Alopecia
THE TOPICAL JAK inhibitor, delgocitinib, has shown to be effective for stabilising hair shedding and promoting hair regrowth in patients with frontal fibrosing alopecia (FFA), whilst reducing Th1/IFN-γ-driven inflammation in the scalp.
There are currently no approved or efficacious treatments for FFA, a scarring alopecia characterised by progressive frontotemporal recession which leads to permanent hair loss. This condition has an increasing prevalence, particularly in women, with prior research linking its pathogenesis to Th1/IFN-γ activation. Therefore, researchers sought to investigate the effect of the topical pan-JAK inhibitor, delgocitinib, on Th1/INF-γ-driven inflammation and clinical disease severity in FFA.
The researchers conducted a double-blind, randomised, vehicle-controlled trial with 30 patients with FFA. Participants were assigned to either receive delgocitinib cream (20 mg/g) or a matching vehicle cream twice daily for 12 weeks, followed by a 12-week open-label extension with delgocitinib for all participants. Lesional and non-lesional scalp skin biopsies were taken at baseline and after 12 weeks to assess transcriptomic changes. In addition, clinical severity scores and trichoscopic images of hair counts were monitored throughout the study.
The analysis, presented at the EADV Congress 2024, revealed a reduction in the expression of Th1/IFN-γ-related genes, including CXCL9 (–3.10; p<0.05), CXCL10 (–2.60; p<0.1), and IFN-γ (–1.49; p=0.22) in lesions that were treated with delgocitinib after 12 weeks. Furthermore, there was a 4% improvement in transcriptomic normalisation towards non-lesional profiles in delgocitinibtreated patients (p<0.001), compared to a 33% worsening in the vehicle group. Clinical severity scores, including the Lichen Planopilaris Activity Index (LPPAI) and Frontal Fibrosing Alopecia Severity Scores (FFASS), significantly improved in the delgocitinib group by Week 12 (p=0.023). Further improvements were seen during the openlabel extension, where all subjects treated
Trichoscopy analysis revealed an increase in hair density and follicular units in the delgocitinib group
with delgocitinib obtained some degree of hair regrowth. Trichoscopy analysis revealed an increase in hair density and follicular units in the delgocitinib group, whereas reductions were seen in the vehicle group. Furthermore, delgocitinib was well-tolerated, with no significant safety concerns.
In conclusion, delgocitinib demonstrated promise as a treatment for FFA, by reducing inflammation and showing signs of hair regrowth. Further studies are needed to confirm the long-term efficacy of delgocitinib, and to better define its role in clinical practice for FFA management.
Ruxolitinib Cream Shows Long-Term Safety in Paediatric Dermatitis
THE TRuE-AD3 study, presented at the EADV Congress 2024, evaluated the long-term safety and efficacy of ruxolitinib (RUX) cream in children aged 2–11 years with atopic dermatitis (AD).
In this Phase III study, children with mildto-moderate AD applied either 0.75% or 1.5% RUX cream or a vehicle cream twice daily for an initial 8-week period. Following this, patients who initially used RUX cream continued as-needed treatment for 44 weeks. Those initially assigned to the vehicle cream were rerandomised to one of the two RUX cream concentrations.
The study demonstrated that RUX cream at both strengths was safe and effective over 52 weeks
Safety was a primary focus, with no new adverse events reported during the longterm period. The study demonstrated that both concentrations of RUX cream were well tolerated, with a low rate of treatmentemergent adverse events (TEAEs). The most common TEAEs were upper respiratory tract infections and nasopharyngitis, although these were generally mild. Application site reactions were also minimal, affecting only 5.3% of participants, and no TEAEs indicated systemic absorption of the drug, consistent with low plasma levels of RUX.
The results showed the efficacy of the RUX cream, with substantial improvement in disease control in these patients who showed significantly better outcomes than those using the vehicle cream at the 8-week mark. Half of the patients using the RUX cream at a strength of 0.75% and 72.4% of those using 1.5% RUX cream achieved clear or almost clear skin, compared to only 24.5% in the vehicle group. These improvements were sustained or even enhanced by Week 52, with around 72–79% of patients achieving clear or almost clear skin regardless of the RUX cream strength. Additionally, the affected body surface area was notably reduced for patients on RUX cream, with a reduction maintained throughout the study.
The study demonstrated that RUX cream, at both strengths, was safe and effective over 52 weeks, significantly reducing AD symptoms and maintaining a low affected body surface area. This provides encouraging evidence for the long-term use of RUX cream as an effective treatment for managing AD in young children.
72.4 %
of those using 1.5% RUX cream achieved clear or almost clear skin
Thomas Bieber, University of Bonn, Germany, wasted no time in welcoming his colleagues from around the world to the fascinating session entitled ‘New and Emerging Drugs’, one of many insightful lectures at this year’s European Academy of Dermatology and Venereology (EADV) Congress 2024, taking place in Amsterdam, the Netherlands, from 25th–28th September. The session covered the latest drug developments in classical chronic inflammatory skin disorders, from psoriasis to vitiligo, with some of the world’s leading experts in their respective areas taking to the stage to discuss current and future treatments.
HIDRADENITIS SUPPURATIVA
“We’re at a great time in hidradenitis, where drugs that are being tested are really helping us to understand this incredibly complex disease,” began James Krueger, Rockefeller University, New York, USA, as he opened his talk on hidradenitis suppurativa (HS). HS is an immunological problem that spans innate and adaptive immune mechanisms with contributions from skin-based cytokines and which also likely involves bacterial dysbiosis. Compared to the other inflammatory diseases discussed in the same session, which generally have just one immune axis, HS is a much more complex disease, argued Krueger.
Explaining the background of this difficultto-treat disorder, Krueger pointed out that HS is a disease spectrum. Researchers in the field believe that it begins with bacterial growth in hair follicles, follicular plugging, and eventually swelling and inflammation of hair follicles with the potential to rupture. There is additionally inflammation of the interfollicular epidermis, involving both T cells and other immune cells, as well as the activation of specific cytokine pathways. As the disease progresses, nodules and ostia develop, along with
scarring. The clinical scoring of this aspect of HS is the inflammatory nodule count and/or the abscess count from the basis of the Hidradenitis Suppurativa Clinical Response (HiSCR) tool (50% reduction in nodule + abscess count). The approval of adalimumab, secukinumab, and bimekizumab has been based on HiSCR, implicating TNF and IL-17 isoforms in abscess development. Beyond HiSCR, tunnel inflammation is captured in draining tunnel count and International Hidradenitis Suppurativa Severity Score System (ISH4) score, though the latter is not accepted by the FDA, as the speaker clarified.
Krueger went on to discuss the many drugs in development that focus on IL-17 targeting. This is a vital part of psoriasis treatment, and using this approach with HS has revealed that IL-17A and IL-17F are major cytokines involved in HS disease activity. As a result of these findings, several drugs have been developed and approved: secukinumab (anti-IL-17) received FDA approval in 2023; positive Phase III studies of bimekizumab in HS have been reported, leading to EU approval; a positive Phase II study of sonelokimab has been presented; and positive results of isokibep were also announced at EADV 2024. Going into further detail, Krueger described
how a significantly higher proportion of participants receiving sonelokimab achieved HiSCR 50 versus those receiving a placebo at Week 12.1 Additionally, in this trial, 14.9% of patients receiving sonelokimab attained 100% improvement in inflammatory nodules.
Other research has tested the efficacy of dual IL-1α/β monoclonal antibody in treating HS, and further early studies thus far appear to support the role of B cells in active inflammation, as treatment with spleen tyrosine kinase and Bruton’s tyrosine kinase inhibitors (remibrutinib) have shown disease improvement.2
The numerous trials currently underway, along with the recent drug approvals, demonstrate that, though HS is a complex disease, the future looks bright when it comes to the treatment of people with HS.
ATOPIC DERMATITIS
Current treatment methods for atopic dermatitis (AD) are standardised and very simple across European practices; topical on the one hand, including steroids and topical calcineurin inhibitors (TCI), and systemic on the other, divided into small molecules such as baricitinib, and
biologics, such as dupilumab. Bieber, Chair of this session and expert in AD treatment, took his colleagues through the various treatment methods currently available, discussing the drugs available in Europe as well as the ones he fears will not be permitted in the EU any time soon.
Moving on to the future of the disease, Bieber briefly described the highly complex pathogenesis of AD, relating to both skin barrier dysfunction and immune response.3 This complexity has led to the current development of a very large number of drugs; there are at least 33 different kinds of biologics alone under development, highlighted Bieber. This is being done using the classical drug development approach from recent years, or what Bieber labelled the ‘downstream approach’, involving targeting T2 cytokines. Dupilumab, tralokinumab, and the ‘new kid on the block’, the recently approved lebrikizumab, are all developed in this way.
14.9 %
of patients receiving sonelokimab attained 100% improvement in inflammatory nodules.
According to Bieber, despite the continued innovation happening in the field, the majority of the most innovative drugs developed for the topical treatment of AD, which are often available in the USA, for example, ruxolitinib or PDE4 inhibitors, will likely never be available in the EU for treatment of AD. This is a result of several factors, including the restrictions of Health Technology Assessment Agencies (HTA) and market access issues. This is not, however, a reason to lose faith in the future of AD treatment. The always-evolving understanding of the pathophysiology of the disease has led to a recent revolution in drug development, not only for AD but for a whole host of inflammatory conditions. Moreover, many of these drugs are being developed with a focus on disease modification, aiming for long-term control for patients, which marks a shift from the previous focus on treating flares and controlling the condition by staying on therapy.
Many of these drugs are being developed with a focus on disease modification, aiming for long-term control for patients
Though there will never, at least in Bieber’s opinion, be a one-size-fits-all solution for the treatment of AD, the shift in drug development strategy as well as the change in mindset amongst researchers and those involved in this development means that, in the years to come, the lives of patients with inflammatory diseases have the potential to improve significantly.
ALOPECIA AREATA AND VITILIGO
Though on the surface, a disease characterised by hair loss and another by complete skin depigmentation may not appear to have many similarities, they are not as unconnected as they may appear. Julien Seneschal, University of Bordeaux, France, took to the stage as the third of four speakers to discuss the two diseases. He explained that several studies have reported
associations between the conditions,4-8 and that they both share several underlying genes, mainly associated with the immune system. Additionally, when analysing the cells, researchers have found that the area around the hair follicle of a patient with alopecia areata (AA) contains several T cells, which are also found in the melanated areas of the skin in patients with vitiligo. In both diseases, these T cells are interacting with epithelial cells, meaning that the two disorders share many similarities.
Addressing the new treatments on the horizon for each disease, Seneschal first brought to light a Phase IIa study conducted in 2022, in which 40 patients with AA were prescribed dupilumab while 20 were given a placebo for 24 weeks.9 The team involved in this research found that dupilumab worked best in patients with AA with high IgE levels. Today, several more Phase II studies are underway, each targeting a different protein, including further research into the potential of dupilumab for treating AA.
There are also several more studies currently taking place to treat vitiligo, focusing on halting depigmentation, inducing repigmentation, and ideally preventing relapses. One such study being carried out by Seneschal himself involved assessing the use of UV light in combination with baricitinib for the treatment of active vitiligo. Patients received baricitinib or a placebo alongside UV light for 12 weeks, and the yet-to-be-published data showed that though the placebo group showed a small change in their Total Body Vitiligo Area Scoring Index (T-VASI) score (–9.2), there was a significant reduction in T-VASI score amongst the baricitinib group (–44.8) at Week 36. These are promising results, pointed out Seneschal, and offer hope for the future of vitiligo treatment. The same can be said for several of the trials currently underway; however, it is also the change in approach and attitude, as with AD, that proves the most impactful in furthering the development of drugs for these diseases, focusing on earlier intervention and preventing relapses.
PSORIASIS
The final presentation, delivered by Co-chair Antonio Costanzo, Humanitas University of Milan, Italy, closed the session by addressing the new drugs being developed to treat psoriasis, a disease caused by the sequential activation of different components of the immune system. Though many therapeutic options are presently available for psoriasis, unlike some of the other afflictions discussed in the same session, there is always space for more, pointed out Costanzo, highlighting that pharmacological research continues to focus on the disease. Like his colleagues before him, Costanzo took the crown through the mechanism of the disorder and explained the specific ways in which these new drugs hope to target it.
Current trials include looking into new mechanisms of action for the inhibition of key cytokine pathways, and Costanzo expressed hope that the field may soon
References
1. Kirby B et al. The Phase 2 MIRA trial of the IL-17A- and IL-17F-inhibiting Nanobody® sonelokimab in patients with active, moderate-to-severe hidradenitis suppurativa (HS): Week 12 results. Abstract 260. ISDS Summit, November 15-18, 2023.
2. Prens E et al. Efficacy and safety of the oral Bruton’s tyrosine kinase inhibitor, remibrutinib, in patients with moderate to severe hidradenitis suppurativa in a randomized, phase 2, double-blind, placebo-controlled platform study. Poster P0022. EADV Congress, September 25-28, 2024.
be able to move away from injectable to oral drugs in the not-too-distant future, given the efficacy of some of the new oral drugs being developed. Further away is the personalisation of psoriasis treatment; as with so many inflammatory diseases, every patient benefits from different treatment approaches, and though it is not yet possible to treat each one differently, he emphasised that it is becoming a priority amongst clinicians.
The presentations delivered during this symposium demonstrated that the future of treatment for these various dermatological conditions is indeed a hopeful one. Though the road to developing these treatments is not a smooth one, and researchers may yet find themselves blocked by country-specific regulations and restrictions that limit their ability to roll out a new drug or challenges when it comes to treating the individual patient. On the whole, the many trials taking place today offer a range of new possibilities for clinicians and patients alike.
3. Clark JD et al. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014;57(12):5023-38.
4. Alkhateeb A et al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16(3):208-14.
5. Liu JB et al. Clinical profiles of vitiligo in China: an analysis of 3742 patients. Clin Exp Dermatol. 2005;30(4):327-31.
6. Sheth VM et al. Comorbidities associated with vitiligo: a ten-year retrospective study. Dermatology. 2013;227(4):311-5.
7. Chen YT. Comorbidity profiles in association with vitiligo: a nationwide population-based study in Taiwan. J Eur Acad Dermatol Venereol. 2015;29(7):1362-9.
8. Gill L et al. Comorbid autoimmune diseases in patients with vitiligo: a cross-sectional study. J Am Acad Dermatol. Comorbid autoimmune diseases in patients with vitiligo: a cross-sectional study. 2016;74(2):295-302.
9. Guttman-Yassky E et al. Phase 2a randomized clinical trial of dupilumab (anti-IL-4Rα) for alopecia areata patients. Allergy. 2022;77(3):897-906.
IN AN INSIGHTFUL session from the European Association of Dermatology and Venereology (EADV) Congress 2024, experts in the field gathered to explore key dermatological conditions affecting children, focusing on psoriasis, atopic dermatitis, and acne.
PSORIASIS IN CHILDREN
In this year’s EADV Congress, Marieke Seyger, Radboud University Medical Centre, Nijmegen, the Netherlands, opened a fascinating session on paediatric dermatology, drawing on several insightful topics including diagnosis, topical treatments, patients’ and caregivers’ preferences, biologics, and treatment algorithms. Seyger presented an interesting case study of a 6-year-old boy who exhibited 7 months of therapy-resistant psoriasis and had a family history of the condition; however, the exact type of psoriasis remained unclear, with differential diagnosis between annular pustular psoriasis and dermatomycosis.
After conducting a culture, Trichophyton soedanense, an anthropophilic fungus, was identified as the causative agent. The patient was treated with itraconazole, leading to significant improvement within 4 weeks. Seyger emphasised the important lesson that tinea incognita, a fungal skin infection, can mimic psoriasis, resulting in misdiagnosis. Notably, a psoriasis-like pattern occurs in approximately 7% of tinea incognita cases.1 She also presented images illustrating the similarities between discoid eczema and psoriasis to further highlight the complexities of differential diagnosis.
Notably, a psoriasis-like pattern occurs in approximately 7% of tinea incognita cases
Citing a 2022 study,2 Seyger outlined seven key diagnostic criteria for paediatric psoriasis, which include scaling and erythema at the hairline on the scalp, scaly erythema within the external auditory meatus, a persistent welldemarcated erythematous rash anywhere on the body, erythema in the umbilicus, scaly erythematous plaques on extensor surfaces (elbows and knees), a welldefined erythematous rash in the diaper area, and a family history of psoriasis.
When discussing treatment options for paediatric psoriasis, Seyger summarised commonly used therapies, including topical corticosteroids, vitamin D analogues (such as calcipotriol and calcitriol), and a combination of calcipotriol and betamethasone dipropionate. She also mentioned calcineurin inhibitors, particularly for facial and flexural psoriasis, and dithranol/anthralin.
Looking ahead, she highlighted promising new topical agents, including roflumilast (0.3% cream), a PDE-4 inhibitor that demonstrated a PASI75 response of 40% compared to 6% in the placebo group.3 Additionally, tapinarof, an AhR modulator, has been approved, showing a Physician's Global Assessment (PGA) response of 40% versus 6% for placebo.3
Seyger underscored that adherence to treatment is critical, especially in children,
700
ChildCAPTURE Registry currently encompasses over 700 children aged over 18 years
in order to achieve optimal results. A Dutch study4 identified the main treatment goals among 222 patients with paediatric psoriasis, revealing that 37.4% sought complete clearance, while 22.1% aimed for a reduction in visible lesions. Other concerns included itch relief and the desire to lead a normal life.
In response to these needs, the ChildCAPTURE Registry (Continuous Assessment Psoriasis Treatment Use Registry) was established to monitor major symptoms and concerns among patients, currently encompassing over 700 children aged over 18 years.
Seyger concluded her talk by listing several approved biologics for paediatric plaque psoriasis, including etanercept, adalimumab, ustekinumab, ixekizumab, and secukinumab. She also touched on ongoing Phase 3 clinical trials for paediatric plaque psoriasis featuring certolizumab, guselkumab, and risankizumab, among others.
ATOPIC DERMATITIS IN CHILDREN
Amy Paller, Northwestern University Feinberg School of Medicine, Chicago, USA, discussed the incidence of atopic dermatitis in children. She noted that topical calcineurin inhibitors have been available for over 20 years. Roflumilast, a 0.15% cream, was also recently approved by the FDA for paediatric atopic dermatitis in children over 6 years of age, showing promise for patient care. A formulation of roflumilast at 0.05% is also in development for children aged 2–5 years.
Paller highlighted other emerging treatments, including tapinarof, a 1% cream (aryl hydrocarbon receptor agonist) approved for ages 2–17 years, currently undergoing Phase 3 trials (ADORING 1 and 2).5 Dupilumab, a monoclonal antibody that blocks IL-4 and IL-13, was a focal point of her presentation. It is FDA-approved for children aged 6 months and older with moderate-to-severe atopic dermatitis. Citing a 2022 Phase 3 trial,6 Paller explained that she noted a significant improvement in patients receiving dupilumab compared to placebo at Week 16.
Paller raised awareness of new and emerging biologics for atopic dermatitis, including IL-13 inhibitors tralokinumab and lebrikizumab, as well as IL-31R inhibitor nemolizumab, which is available in Japan for paediatric patients aged 6 years and older, and recently received FDA approval for prurigo nodularis. She also mentioned amiltelimab, an OX40L inhibitor currently in trials for adolescents.
ACNE AND RELATED DISORDERS IN PRE-PUBERTAL CHILDREN
Finally, Peter Hoeger, Academic Teaching Hospital, Universities of Hamburg and Lübeck, Germany, addressed the topic of acne and related disorders in pre-pubertal children. He noted that the density of sebaceous glands is highest in neonates and infants, due to the relatively smaller skin surface area. Hoeger explained that sebaceous gland activity peaks during the neonatal period, a phenomenon often referred to as "mini puberty", driven by maternal androgens. From ages 1–8 years, gland activity typically diminishes.7
The density of sebaceous glands is highest in neonates and infants, due to the relatively smaller skin surface area
References
1. Ghaderi A et al. Updates on Tinea Incognita: literature review. Curr Med Mycol. 2023;9(2):52-63.
2. Burden-Teh E et al. Identifying the best predictive diagnostic criteria for psoriasis criteria (>18 years): a UK multicentre case-control diagnostic accuracy study (DIPSOC study). Br J Dermatol. 2022;186(2):341-51.
3. Lie et al. Topical management of
Hoeger examined the wide age range in which acne can manifest, starting with neonatal acne, which commonly appears between 2–6 weeks of age and is typically localised to the face, neck, and upper trunk. This condition is stimulated by maternal androgens. He then described infantile acne, which usually occurs between 1–12 months and is characterised by papules, pustules, and comedones, often found on the cheeks and chin. Hoeger emphasised the importance of avoiding creams, ointments, and oils for these early-stage manifestations, recommending topical acne therapies only in severe cases. Throughout his talk, he also touched on several other acneiform disorders, such as idiopathic facial aseptic granuloma.
CONCLUSION
In summary, the session provided valuable insights into the diagnosis and management of common dermatological conditions in children, emphasising the importance of accurate diagnosis and tailored treatment strategies. The discussions highlighted the need for ongoing research and awareness to address the unique challenges faced by children with psoriasis, atopic dermatitis,and acne, among other conditions.
pediatric psoriasis: a review of new developments and existing therapies. Pediatric Drugs. 2024;26:9-18.
4. Schaap M et al. Treatment goals and preferences of pediatric psoriasis patients, young adults, and parents. J Dermatolog Treat. 2022;33(5):2527-33.
5. Silverberg et al. Tapinarog cream 1% once daily: significant efficacy in the treatment of moderate to severe atopic dermatitis in adults and children down to 2 years of age in pivotal phase 3
ADORING trials. J Am Acad Dermatol. 2024;91(3):457-65.
6. Paller et al. Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebocontrolled, phase 3 trial. The Lancet. 2022;400(10356):908-19.
7. Kirivanta P et al. Transient postnatal gonadal activation and growth velocity in infancy. Pediatrics. 2016;138(1):e20153561.
Reverse the Age Clock: Reverse Clinical Signs of Ageing with Epigenetic Skin Science
This satellite symposium took place on 25th September 2024 as part of the European Academy of Dermatology and Venereology (EADV) Congress, held in Amsterdam, the Netherlands.
Chairperson: Firas Al-Niaimi1
Speakers: Firas Al-Niaimi,1 Frank Lyko,2 Elke Grönniger,3 Julia Gallinger,3 Hassan Galadari4
1. St John’s Institute of Dermatology, London, UK
2. Heidelberg University, Germany
3. Beiersdorf AG, Hamburg, Germany
4. College of Medicine and Health Sciences, United Arab Emirates University, UAE
Disclosure: Al-Niaimi, Lyko, and Galadari have received consultation fees from Beiersdorf. All other speakers have nothing to disclose.
Acknowledgements: Writing assistance was provided by Helen Boreham, HB Medical (UK) Ltd, Leeds, UK
Support: The publication of this article was funded by Beiersdorf AG.
Meeting Summary
INDUSTRY PARTNERSHIP
During this symposium, an expert panel comprising both practising dermatologists and leading figures in epigenetics research discussed the development of an innovative new approach to treating facial skin ageing based on the underlying science of epigenetics. Frank Lyko, Professor of Epigenetics at the University of Heidelberg, Germany, explored the epigenetic processes that drive skin ageing and highlighted how the reversibility of the DNA methylation changes may provide novel opportunities for intervention. Elke Grönniger and Julia Gallinger from Beiersdorf AG, Germany introduced the skin-specific age clock as an AI-based algorithm to determine the biological age of skin and to search for new ingredients which can reverse the skin age. They outlined how this led to the discovery of the key active ingredient (Epicelline®, Beiersdorf, Hamburg, Germany) in the new HyaluronFiller Epigenetic Serum (Eucerin®), a breakthrough epigenetic innovation that is able to visibly reverse ten clinical signs of skin ageing. Firas Al-Niaimi, Professor in laser dermatology at St John’s Institute of Dermatology, London, UK, discussed the potential for Epicelline to be combined with other anti-ageing aesthetic procedures, such as fractionated laser, due to synergistic effects on the expression of youthful genes. Finally, Hassan Galadari, Associate Professor of Dermatology at the United Arab Emirates University, provided case study examples showing the successful use of Epicelline in combination treatment with chemical peel, microneedling, and injectables in real-world clinical practice.
Skin Ageing
Firas Al-Niaimi
Historic depictions of the fountain of youth highlight the ongoing search for solutions to the problem of facial ageing. Al-Niaimi outlined the characteristic signs of facial ageing, which include fine lines, wrinkles, loss of elasticity, loss of skin turgor (firmness), loss of radiance (dullness), pigment alteration (telangiectasia), and skin laxity (sagginess). He explained that, slowly over time, these changes to the skin become more visible.
Research into factors influencing the ageing process has revealed that gene function plays a key role.1 Ageing involves a progressive decline in the expression of certain genes, which are involved in multiple biological processes relevant to the ageing phenotype.1 This was evidenced in a study of Caucasian females carried across 6 decades in which younger-looking subjects showed similar gene expression patterns to those observed in chronologically younger individuals.2 Although external factors such as sun exposure may influence specific genes, this is different from chronological ageing, Al-Niaimi pointed out. Key pathways linked to the ageing process include those involved in energy metabolism, oxidative stress, cellular senescence, and inflammation.2
Overall, ageing is a complex process that involves a decline in the expression of multiple genes involved in underlying biological pathways that ultimately define how we age and how fast.3 “Now that we understand we age because of our genes, how can we turn back the clock and reactivate those genes?” Al-Niaimi asked. He suggested that the answer may lie with Epicelline.
How Epigenetic Changes Drive Skin Ageing
Frank Lyko
Lyko provided an introduction to the concept of epigenetics, a young and highly dynamic field of research, and detailed the scientific findings that led to the discovery of Epicelline.
Using the analogy of a computer hard drive and an operating system, Lyko described the genome as the sum of all the genetic information at the body’s disposal and epigenetics as the mechanism that tells cells which part of this information to access and use under specific conditions. He explained that the human body contains over 100 cell types, all of which can be traced back to a single pool of stem cells. All these cells share one common genome but can have vastly different cellular phenotypes. The process of cellular differentiation is mediated by epigenetic mechanisms that specify cell fates, the most important being DNA methylation, histone modifications, and regulatory RNAs.
Lyko focused on DNA methylation, which he described as the best understood of the epigenetic regulatory mechanisms. This key epigenetic modification involves a simple covalent modification of the cytosine base in DNA, which then carries a methylation mark at the carbon 5 position.4 Although the human genome contains approximately 30 million of these methylation marks, this equates to only 4% of all cytosine residues overall. So, it is the distribution of these markers that matters, Lyko emphasised. In essence, DNA methylation writes an ‘epigenetic barcode’, which then regulates context-dependent gene expression.
Epigenetic clocks, which Lyko described as a ‘transformative innovation in the field’, are composite biomarkers based on extrinsic and intrinsic changes in DNA methylation patterns.5 Using 353 DNA methylation markers, an ageing clock was developed that is able to predict the donor age of a sample with an accuracy of +/- 3.6 years.6 Disease and inflammation increase the ticking rate of epigenetic clocks, Lyko explained, while healthy lifestyles are associated with age deceleration. This illustrates the power of age clocks to dissect ageing mechanisms and attempt to develop intervention strategies, he added.
As the outermost organ of the human body, the skin is the most environmentally exposed and therefore shows a prominent environmental ageing phenotype.7 Epigenetics provides an interface between
the environment and the genome, so environmental factors can directly affect DNA methylation, Lyko observed. He outlined three examples of collaborative research with Beiersdorf over the past 15 years that has sought to understand how DNA methylation patterns change during skin ageing. The first study analysed methylation patterns from young and old dermis samples and found a noticeable increase in age-related hypermethylation.8 This shows that the ageing skin accumulates methylation markers in positions where they are not supposed to be, Lyko remarked. These findings were confirmed in a follow-up study that used transcriptome and whole-genome bisulfite sequencing data to generate high-resolution maps of the human skin epidermis.9 Methylation was found to be consistently higher for several skin-related genes in the old versus young epidermis, which was associated with a decrease in gene expression.9 This is the textbook picture of how methylation affects gene expression, Lyko elaborated. Another large follow-up study analysed dozens of human skin samples and again showed clear differentiation between the young and old epidermis, with the latter characterised by increases in methylation.10 The DNA methylation patterns in the ageing human epidermis also appear less well-defined than in younger samples, a phenomenon known as epigenetic erosion.11
Summing up, Lyko reiterated that skin ageing is associated with moderate but significant changes in DNA methylation. These age-related methylation changes are directly linked with changes in age-related gene expression. This is important because methylation is not just a marker for ageing, it also has functional consequences, he emphasised. Overall, skin ageing is underpinned by increased DNA methylation and less well-defined methylation patterns. The sum of this research therefore provides a compelling rationale for developing intervention strategies based on the reversibility of these methylation markers, Lyko concluded.
Revolutionary Discovery of Epicelline to Reverse Clinical Signs of Skin Ageing
Elke Grönniger and Julia Gallinger
Both lifestyle and the environment can affect body and skin function by regulating gene expression, Gallinger explained. She highlighted monozygotic twins as a tangible example of this, sharing exactly the same DNA but often following very different skin ageing journeys. These differences in ageing are due to unique epigenetic markers which form on the DNA over the course of a lifetime and work as a molecular switch, turning on and off the expression of certain genes.12
We now know that epigenetic changes, especially DNA methylation, are one of the main drivers for ageing, Grönniger explained. As pioneers in this field, Beiersdorf was the first to identify genomewide epigenetic changes associated with skin ageing in 2010.8 This research showed that hypermethylation occurs in the DNA of aged skin and that these epigenetic changes are associated with reduced expression of the corresponding genes.8,9 The genes that are silenced as a result of DNA methylation contribute to several important and diverse functions in the skin, including extracellular matrix organisation and regulation of lipids and metabolism, which explains the resulting loss of tissue functionality.13 Put simply, the youth genes are switched off, Gallinger emphasised, and “this is the main driver of skin ageing”.
Over the past 15 years of research, Beiersdorf has published key scientific findings on epigenetics and skin ageing in 15 peer-reviewed publications. The main milestone and highlight of this epigenetic journey was the development of the first skin-specific age clock. Grönniger described age clocks as AI-based algorithms that use epigenetic patterns to determine a person’s biological age, which can be different to their chronological age. To create this first skin-specific age clock, data were collected on more than 1,000 skin samples and a total of 850,000 data points per sample were analysed.10 The resulting clock is able to
accurately measure the biological age of the skin, including the youthfulness of skin cells and the potential to build up younger skin tissue.10 Now, for the first time, there is a tool to objectively detect and predict biological skin age, Grönniger explained. This marks a revolution in ageing science because “you can’t optimise what you can’t measure,” she added. In a recently published study, the skin-specific age clock was used to successfully predict biological skin age in subjects with the same chronological age, with results matching expert panel assessment of perceived visual age.14
This patented skin-specific age clock technology is clinically relevant because it provides a new way to search for active ingredients with the ability to reverse epigenetic changes of skin ageing and reactivate deactivated youth genes, Grönniger explained. Up to now, Beiersdorf has screened more than 50,000 ingredients and identified Epicelline, which she described as the first cosmetic ingredient able to turn back the age clock and rejuvenate the skin’s cells to support younger-looking skin.
Grönniger went on to share recently published data on Epicelline, known by the chemical name dihydromyricetin (DHM), which is extracted from vine tea. In vitro studies in keratinocytes treated with 20 μM Epicelline for 3 days demonstrated its ability to restore the youthful epigenetic pattern and significantly reduce the biological age of skin cells (Figure 1A).13 This was followed by a clinical study providing the first in vivo evidence of the rejuvenating effect of Epicelline on the epigenetic pattern.13 In this study, Epicelline or vehicle was topically applied to the skin and an ageing stimulus (UV light) was applied. Treatment with Epicelline induced a DNA methylation pattern representative of the young epidermis for more than 95% of the agerelated DNA methylation probes analysed (Figure 1B).13 The epigenetic changes induced by Epicelline therefore shift in the direction of a young-like skin profile, Grönniger explained.
As Grönniger explained, the next step was to determine whether restoration of the epigenetic profile with Epicelline had a beneficial effect on the gene expression profile in vivo. The ensuing clinical study
Figure 1: (A) Epicelline reverses the skin age clock; and (B) Epicelline establishes a young epigenetic pattern.
employed a set of marker genes that are hypermethylated and downregulated in aged skin.13 Topical application of Epicelline induced the reactivation of these silenced youth genes in the treated skin.13 Of note, key genes that were switched back on by Epicelline treatment included those significantly correlated with in vivo wrinkle grade.13
Overall, this evidence supports the ability of Epicelline to visibility reverse signs of ageing in the skin by reactivating silenced youth genes, reversing epigenetic changes, and rejuvenating skin cells, Grönniger summarised (Figure 2).
Epicelline is available as an epigenetic serum combined with other key ingredients in a holistic formula. As Gallinger outlined, this multifaceted product contains hyaluronic acid (HA) in both long and short chain molecular sizes (2,000 kDa and 52 kDa), which acts to hydrate the skin and biostimulate epidermal HA production. Other active agents in the epigenetic serum include enoxolone, which reduces HA degradation in the skin associated
with ageing and promotes DNA repair, and glycine saponin, which biostimulates dermal HA production as well as collagen and elastin, she added.
The efficacy of this Hyaluron-Filler Epigenetic Serum has been proven in clinical studies with twice daily application, with treatment producing a reversal in ten signs of skin ageing. Results after 4 weeks of twice daily use showed positive effects on skin firmness, wrinkle volume reduction, hydration, lifting effect, smoothness, evenness, radiance, fine line reduction, contours, and rejuvenation. Focusing on two of these parameters, Gallinger explained how cutometry measurements revealed a significant increase in skin firmness with treatment in 88% of participants, which was reflected in an increase in epidermal thickness in the 3D skin model in vitro. Epicelline restores epidermal thickness, indicating that cells are active again and working as they do on younger skin, she added. When the length, area, and depth of different wrinkles in the face were measured in a clinical study of 43 subjects with wrinkle analysis based on
Figure 2: Epicelline is the first active ingredient proven to reverse the skin age clock.
3D data, up to 78% reduction in wrinkle volume was achieved after 4 weeks of treatment with the Epigenetic Serum (Figure 3).15
Patient feedback on the Hyaluron-Filler Epigenetic Serum has been favourable. Gallinger highlighted results from a patient survey in which 98% of women confirmed it visibly reverses signs of ageing, and patients agreed that it makes the skin look up to 5 years younger. Using a quality of life questionnaire, 63% of 160 volunteers said their skin appearance gave the impression of being attractive after using the serum for 4 weeks, illustrating the potential improvements in patients’ quality of life, which can be obtained with treatment.16 As to how to use the Epigenetic Serum, Gallinger advised that it be applied twice daily, in the morning and evening, as the base/starting point of a skincare routine. The Epigenetic Serum can be combined with other products from the Hyaluron-Filler range and Eucerin(R) Photoaging Control SPF 50+ and, importantly, can also be used as integrated skin care after aesthetic treatments, she noted.
Combining Epicelline with Aesthetic Procedures
Firas Al-Niaimi
Al-Niaimi explored in more detail how Epicelline can be used in combination with other aesthetic procedures in order to maximise the beneficial impact on facial ageing and rejuvenation. He described facial rejuvenation as a broad term encompassing any procedure which can make the skin look or feel younger, including botulinum toxin injections, dermal fillers, skin boosters, and energy-based procedures. Patients’ desire to look “younger and fresher” has increased demand for facial rejuvenation, he added, in turn fuelling increased utilisation of combination treatment approaches.
As Al-Niaimi reiterated, the process of ageing is largely dependent on gene expression. People who look younger for their chronologic age have the genes of youth turned on, while those who look older have these youthful genes switched off, he clarified.2 Evidence indicates that laser and energy-based procedures, such as broadband light treatment, can ‘turn on’ youthful genes.17 In one pilot study, multiple treatments with broadband light were shown
Clinical study with 43 subjects, application 2x daily for 4 weeks, instrumental measurement. A) Before application; B) After application.
Figure 3: Reduction in wrinkle volume with the Hyaluron-Filler Epigenetic Serum.15
to activate several key genes associated with youthful skin.17 Notably, these were genes involved in cell function/replication and mitochondrial activity, Al-Niaimi added, and mitochondria are known to play a pivotal role in cell senescence and how we age.
Fractional laser is a specific aesthetic procedure in which a fraction of the skin area is treated with an array of relatively small beams of light columns. Al-Naimi described how, when treated with fractional laser in the clinic, patients start to show histological improvements in wrinkles and skin quality approximately 3–6 months after the procedure. He explained that this rejuvenating effect of fractional laser technology is due to neocollagenesis, which is now known to be underpinned by changes in gene expression. Research has shown that fractional CO2 laser is able to induce gene expression in matrix metalloproteinase (MMP) production, as well as a number of other key genes including CYR61, Wnt5a, MMP-1, and HSP90 18,19 These genes play a role in favourable collagen remodelling and wound healing, in turn leading to improvements in the youthful appearance of the skin.19
Al-Niaimi stressed that it is important to do multiple fractional laser treatments in order to ‘turn on’ more youthful genes and achieve the best aesthetic results. Genes associated with ageing that can be ‘corrected’ with fractional laser fall into various pathways, including inflammation, extracellular matrix organisation, lipid metabolism, keratinocyte differentiation, and MMP production.20,21 Notably, multiple laser treatments also lead to continuous upregulation of genes such as PLIN2. 20 PLIN2 is associated with mitochondrial impairment, which is associated with cell senescence, and is upregulated by both fractional laser and Epicelline treatment.22 In addition to PLIN2, five other age-related marker genes reactivated by topical Epicelline have also been described in the context of fractional laser treatment.13 This overlap of genes and pathways affected by Epicelline and fractional laser is important because, when you combine the two together, the synergy suggests giving better results, Al-Niaimi emphasised.
In addition to their areas of overlap, Epicelline and fractional laser are also able to target different genes implicated in ageing. Al-Niami described how Epicelline upregulates key genes that are negatively correlated with wrinkle grade, while fractional laser treatment upregulates genes associated with extracellular matrix formation. Epicelline and fractional laser treatment also act on different skin layers but may support each other via cellular cross-talk, he noted. The effects of Epicelline are more superficial, while fractional laser goes deeper, allowing youthful gene expression to be targeted at both levels of the skin, Al-Niaimi elaborated.
Based on our increased understanding of the gene expression patterns associated with ageing and how these can be turned on and off, it makes sense for every patient undergoing facial rejuvenation therapy to also receive topical Epicelline, Al-Niaimi concluded, because the synergism in gene expression ultimately yields better results.
A Case Study of Epigenetics in Clinical Practice
Hassan Galadari
Galadari presented selected clinical cases of Epicelline used alone or in combination with other treatments in real-world clinical practice. In these case studies, Epicelline was supplied as a non-labelled serum for twice-daily use, in conjunction with SPF application in the mornings, and participants stopped all other skin care routines for 8 weeks. In total, 20 patients (five in each group) underwent 4 weeks of treatment with Epicelline alone or in combination with chemical peel (containing 20% salicylic acid), radiofrequency microneedling, or injectables.
Galadari explained that the rationale for combining Epicelline with beta hydroxy acid peels is that salicylic acid is known to increase the penetration of other skincare actives.23 In a similar way, microneedling creates small channels that may increase the penetration of topically applied agents
such as Epicelline.24 At the same time, it also activates nascent growth factors in the skin and stimulates the formation of collagen.24 Finally, Epicelline was utilised in combination with injectables, mainly fillers but also the perennially popular botulinum toxin. Galadari clarified that fillers ‘don’t just fill’ but also create a foreign body response in the skin that reactivates macrophages and stimulates the formation of new collagen via effects on fibroblasts. Although studies have shown that botulinum toxin does not stimulate fibroblasts in the same way as fillers, Galadari explained that it is
References
1. Robinson M et al. Genomic-driven insights into changes in aging skin. J Drugs Dermatol. 2009; 8(Suppl 7):s8-11.
2. Kimball A et al. Age-induced and photoinduced changes in gene expression profiles in facial skin of Caucasian females across 6 decades of age. J Am Acad Dermatol. 2018;78(1):29-39.
3. Rodriguez-Rodero A et al. Aging genetics and aging. Aging Dis. 2011; 2(3):186–95.
4. Phillips T. The role of methylation in gene expression. Nature Education. 2008;1(1):116.
5. He X et al. The use of DNA methylation clock in aging research. Exp Biol Med (Maywood). 2021; 246(4):436–46.
6. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:3156.
7. Krutmann J et al. Environmentallyinduced (extrinsic) skin aging: exposomal factors and underlying mechanisms. J Invest Dermatol. 2021;141(Suppl 4):1096-103.
8. Grönniger E et al. Aging and chronic sun exposure cause distinct epigenetic changes in human skin. PLoS Genet. 2010;6(5):e1000971.
9. Raddatz G, et al. Aging is associated with highly defined epigenetic changes in the human epidermis. Epigenetics Chromatin. 2013;6(1):36.
10. Bormann F et al. Reduced DNA methylation patterning and transcriptional connectivity define
able to decrease wrinkles and ‘organise’ the collagen in the skin to allow for better penetration of topicals.25,26
Overall, Galadari reported favourable experiences with the use of Epicelline alone and in combination with chemical peel, microneedling, and injectables in clinical practice. The visible antiageing benefits observed with combination treatment included a decrease in the effects of dyspigmentation and increased skin radiance.
human skin aging. Aging Cell. 2016;15(3):563-71.
11. Kosan C et al. Epigenetic erosion in adult stem cells: drivers and passengers of aging. Cells. 2018;7(12):237.
12. Christensen K et al. Perceived age as clinically useful biomarker of ageing: cohort study. BMJ. 2009;339:b5262.
13. Falckenhayn C et al. Identification of dihydromyricetin as a natural DNA methylation inhibitor with rejuvenating activity in human skin. Front Aging. 2024;4:1258184.
14. Bienkowska A et al. Development of an epigenetic clock to predict visual age progression of human skin. Front Aging. 2024;4:1258183.
15. Arrivabene F et al. WRINKLE.AI - novel AI wrinkle analysis based on 3D data. Poster P1857. EADV Congress, 25-28 September, 2024.
16. Warnke et al. Validating quality of life with a universally applicable 3-questions approach. Poster P3433. EADV Congress, 25-28 September, 2024.
17. Chang A et al. Rejuvenation of gene expression pattern of aged human skin by broadband light treatment: a pilot study. J Invest Dermatol. 2013;133(2):394-402.
18. Reilly M et al. Molecular effects of fractional carbon dioxide laser resurfacing on photodamaged human skin. Arch Facial Plast Surg. 2010;12(5):321-5.
19. Kim JE et al. Gene profiling analysis of the early effects of ablative fractional
carbon dioxide laser treatment on human skin. Dermatologic Surgery. 2013;39(7):1033-43.
20. Sherrill J et al. Transcriptomic analysis of human skin wound healing and rejuvenation following ablative fractional laser treatment. PLoS One. 2021;16(11):e0260095.
21. Garza L et al. Association of early clinical response to laser rejuvenation of photoaged skin with increased lipid metabolism and restoration of skin barrier function. J Invest Dermatol. 2023;143(3):374-85.e7.
22. Chariello A et al. Downregulation of PLIN2 in human dermal fibroblasts impairs mitochondrial function in an age-dependent fashion and induces cell senescence via GDF15. Aging Cell. 2024;23(5):e14111.
23. Zhao Q et al. Synergistic efficacy of salicylic acid with a penetration enhancer on human skin monitored by OCT and diffuse reflectance spectroscopy. Sci Rep. 2016;6:34954.
24. Singh A, Yadav S. Microneedling: advances and widening horizons. Indian Dermatol Online J. 2016;7(4): 244–54.
25. Oh S-H et al. The potential effect of botulinum toxin type A on human dermal fibroblasts: an in vitro study. Dermatol Surg. 2012;38(10):1689-94.
26. El-Domyati M et al. The use of Botulinum toxin-a injection for facial wrinkles: a histological and immunohistochemical evaluation. J Cosmet Dermatol. 2015;14(2):140-4.
Vitiligo, Beyond White Patches
This review is based on an industry-sponsored satellite symposium that took place at the European Academy of Dermatology and Venereology (EADV) Congress 2024, held between 25th–28th September 2024 in Amsterdam, the Netherlands, and is intended for healthcare professionals only.
Chairperson: Khaled Ezzedine1,2
Speakers: Albert Wolkerstorfer,3 Curdin Conrad,4 Markus Böhm5
1. Department of Dermatology, Hôpital Henri-Mondor, Assistance Publique – Hôpitaux de Paris (AP-HP), France
2. University Paris-Est Créteil Val-de-Marne (UPEC), France
3. Department of Dermatology, Netherlands Institute for Pigment Disorders, University of Amsterdam (UMC), the Netherlands
4. Polyclinic and Centre for Psoriasis, Lausanne University Hospital (CHUV), Switzerland
5. Department of Dermatology, University Hospital Münster, Germany
Disclosure: Ezzedine has been a speaker/consultant and/or investigator for AbbVie, Incyte Biosciences, Pfizer, Almirall, Pierre Fabre, Lilly France, Bristol Myers Squibb (BMS), and MSD. Wolkerstorfer has been a clinical investigator for AbbVie, Incyte Biosciences, and MSD; received grant funding from AVITA Medical, Lumenis, and Novartis; has received research equipment from PerfAction Technologies and Humeca; has been a speaker for AbbVie, Almirall, AVITA Medical, Incyte Biosciences, Janssen, Lumenis, and Novartis; and has served on the advisory board for Incyte Biosciences. Conrad has served on the advisory board and/or been a clinical investigator for AbbVie, Actelion, Almirall, Amgen, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Incyte Biosciences, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Samsung, Sanofi, Takeda Pharmaceuticals, and UCB. Böhm has received speaker honoraria for AbbVie, Almirall, derCampus, Incyte Biosciences, Isispharma, Janssen-Cilag, Omnicuris, and Pfizer; has served on the advisory board for AbbVie, Incyte Biosciences, Janssen-Cilag, MSD, and Pfizer; and has been a clinical investigator for AbbVie, Incyte Biosciences, MSD, and Pfizer.
Acknowledgements: Medical writing assistance was provided by Hannah Moir, EMJ, London, UK.
Disclaimer This symposium was intended for healthcare professionals only. The views and opinions expressed herein are those of the speakers. Not all medicines and/or indications presented in this report may be approved for use in all countries.
Support: The symposium and publication of this article were sponsored by Incyte Biosciences International Sàrl.
Meeting Summary
This article reviews an industry-sponsored satellite symposium that took place at the European Academy of Dermatology and Venereology (EADV) Congress 2024 held in Amsterdam, the Netherlands, on 27th September 2024.
The session, chaired by Khaled Ezzedine, Professor of Dermatology at Hôpital Henri-Mondor, France, addressed understanding the disease burden of vitiligo and the challenges of accessing optimal care. The session established vitiligo as an autoimmune disease requiring both early and long-term management, as well as utilising shared decision-making in treatment options.
Albert Wolkerstorfer, Professor of Dermatology at Amsterdam University Medical Centres, the Netherlands, discussed the underestimated burden of vitiligo disease, including psychological comorbidities, and the impact on quality of life (QoL) compared to other chronic diseases such as psoriasis. He also identified the challenges such as delayed diagnosis and lack of knowledge, and how this impacts access to optimal care.
Curtin Conrad, Professor of Dermatology and Head of the Polyclinic and Centre for Psoriasis Lausanne University Hospital, Switzerland, then considered the pathogenesis of non-segmental vitiligo, focusing on the role of the JAK-signal STAT pathway and how it drives the disease mechanisms and maintenance, emphasising the important need for early intervention and long-term considerations for the management of vitiligo.
Finally, Markus Böhm, Professor of Dermatology at the University Hospital Münster, Germany, identified the importance of utilising shared decision-making in vitiligo treatment strategies, especially for long-term commitment, and how ruxolitinib cream fits into this shared decision-making and overall treatment strategy, considering the efficacy and safety data.
INTRODUCTION
Vitiligo is a chronic autoimmune disease caused by a deregulation of the immune response that results in epidermal melanocyte destruction.1 With a variable and unpredictable disease course consisting of stable periods, spontaneous re-pigmentation, and new patches or flares, it should no longer be considered a cosmetic disease.
The characteristic depigmented lesions are often associated with psychological distress for patients, resulting in negative effects on mental health and QoL, with vitiligo being associated with social isolation, stigma, depression, and anxiety.2
How the Underestimated Vitiligo Burden Impacts Optimal Care
Albert Wolkerstorfer
Wolkerstorfer opened the session by considering the burden of vitiligo and what it is to live with vitiligo, including its impact on appearance, unpredictable flare-ups, itching, and association with autoimmune disorders. He said that patients are “desperate because of their vitiligo,” explaining that even those patients who look self-confident, self-assured, beautiful, and strong, “all had difficult times in life,” stating that “appearance does matter.”3 Wolkerstorfer supported this view by sharing data from a study that demonstrated that in those patients with facial abnormalities, such as
scars, strangers scored photos of those with abnormalities as being judged more often as dishonest, unsuitable for employment, unintelligent, or unattractive compared to edited images without abnormalities.4
Living with the Burden of Vitiligo, Including Psychological Comorbidities
It is not only appearance that matters, but also unpredictable flare-ups and itching, the latter of which Wolkerstorfer stated occurred in one out of five patients. Those with flare-ups have a poorer QoL5 and are impacted by vitiligo disease progression, particularly in those that were stable and then rapidly depigment.6
A study from Belgium reported that 84.1% of patients were highly motivated to follow treatment if the stability of vitiligo could be attained.7 As such, this can be an important treatment goal, especially when the extent of vitiligo is not so large, i.e., when the affected body surface area (BSA) was less than 10%, and when the disease duration was less than 2 years, patients were more highly motivated to follow a treatment.7
The session also noted that healthcare professionals (HCP) do not fully understand the physical comorbidities of vitiligo, which include the association with thyroid disease and other autoimmune disorders, including alopecia areata, pernicious anaemia, and diabetes.7-9 Wolkerstorfer reported that, in his experience, it is not even known by dermatologists, for example, that sensorineural hearing loss is six times more likely in those with vitiligo compared to controls, as reported in a meta-analysis (odds ratio: 6.02; 95% CI: 3.41–10.62).10
Wolkerstorfer emphasised the impact of psychosocial comorbidities, which he referred to as “the dark side of white patches,” including depression, anxiety and anxiety-related disorders, stigmatisation, adjustment disorders, sleep disturbance, low self-esteem, and relationship difficulties.11
A large systematic review of 168 observational studies found 11 studies that reported depression was more likely to occur in patients with vitiligo compared
to controls, 10 studies that showed an association to anxiety, and six for emotional and behavioural impairment.11 Considering depression, a systematic review and metaanalysis of observational studies reported that patients with vitiligo are approximately five times more likely to have depression compared to controls (pooled odds ratio: 5.05; 95% CI: 2.21–11.51).12
The session also highlighted the need for HCPs to look for signs of depression in their patients with vitiligo. A meta-analysis of 20 eligible cohorts (N=1,965 patients) identified a pooled prevalence of depression of 29% (95% CI: 20–39) in those with vitiligo compared with controls (across 17 unique populations [n=1,711]).13 Patients with vitiligo were 4.96 times (95% CI: 1.80–13.68) more likely to display depression, and sub-group analysis showed the prevalence was higher in female patients compared with males (standardised mean difference: 0.87; 95% CI: 0.52–1.22) and those of Asian ethnicity (pooled prevalence: 35% compared to 24% of Caucasians).13
Highlighting the global VALIANT study, an international cross-sectional online population-based survey of mental health conditions and psychosocial QoL burden among patients with vitiligo (n=3,541).14,15 The findings identified that diagnosed mental health conditions were common in 58.7% of patients with vitiligo, including anxiety (28.8%) and depression (24.5%).15 Moderateto-severe symptoms of depression were common (55.0% globally), with the highest rates seen in India (89.4%).15,16
The study also indicated that the extent of vitiligo matters. The more extensive the affected BSA (more than 5%), the higher the rate of moderate-to-severe depressive symptoms (72.0%); the same was also seen for patients with darker skin types (68.3%; as per Fitzpatrick skin phototypes), and the presence of facial or hand lesions (64.4%).15
Parallels Between Vitiligo and Other Skin Disorders
Wolkerstorfer drew parallels to other chronic skin disorders like psoriasis and eczema, emphasising similarities such as chronic course,14 unpredictable flare-ups,5
physical comorbidities,8-10 psychosocial comorbidities,11 disease burden,11,15 and the need for long-term treatment.14
In comparison with other dermatologic conditions such as acne, alopecia areata, atopic dermatitis, psoriasis, urticaria, and eczema, vitiligo has similar, if not higher percentages of psychosocial comorbidities such as depression and anxiety.11
The session also noted differences in the evolution of skin disorder care. Until recently, the treatment response has been limited, and the primary endpoint of treatment has been at least vitiligo area scoring index 50 (VASI50) i.e., 50% re-pigmentation.17,18 Whereas in psoriasis the primary endpoint is typically psoriasis area and severity index 90 (PASI90) i.e., 90%.17,18 Also, treatment response is delayed, taking 6–24 months of treatment to achieve significant re-pigmentation.18 This,Wolkerstorfer said, “makes it quite frustrating, both for physicians and for patients.”
Another important difference, compared to nearly all other skin disorders, is that the skin has a loss of melanocytes,19 meaning that vitiligo can be particularly difficult to repigment in certain regions.
Access to Optimal Care and Hurdles in Vitiligo Care
Wolkerstorfer stated that “the patient journey starts long before the diagnosis,” and there are many issues along the patient journey which decrease access to optimal vitiligo care (Figure 1).20
Access to specialist care and therefore treatment is poor for many patients across many countries. The VALIANT study, which surveyed skin disorders in Europe, the USA, and Japan (N=35,694 participants), estimated a 1.3% prevalence of vitiligo, with many patients undiagnosed (0.4%; including 0.3% vitiligo signs).6 Wolkerstorfer believes that the delay in diagnosis, which on average takes 2.4 years following the appearance of the first lesions,14 was due to a lack of HCP knowledge and awareness about the disease. Misdiagnosis is also very common, with 44.9% of patients reporting an earlier misdiagnosis.14
When there is a diagnosis of vitiligo, patients often hear that it cannot be treated. Of patients, 56.7% are told that vitiligo is untreatable, with higher rates among those with darker skin types (66%), those with extensive vitiligo affecting more than 5% BSA (65.2%), and those treated by
Issues along the patient journey.20
Public knowledge and understanding of the condition in general.20
Symptom recognition / pre-diagnosis
Many receive no treatment.6
Insufficient information about treatment options, and a lack of shared decisionmaking.14
Disease management 1: Treatment initiation
Disease management 2: Follow-up and support Diagnosis
Delay in diagnosis, misdiagnosis, HCPs downplaying the disease as a cosmetic issue, that ‘vitiligo is untreatable.’14. No adequate information.21
Figure 1: Issues along the patient journey.20
Figure 1:
a non-dermatologist (68.8%).14 This lack of knowledge of management options further adds to the burden of the disease, noted Wolkerstorfer.
A survey study conducted in the Netherlands (325 patients with vitiligo), considered the patients’ perspective regarding current treatments and the demand for novel treatments.21 The results indicated that half of the patients were dissatisfied with their current treatment, with 49% reporting that current treatments were not effective. Additionally, 94% of patients expressed the need for new and improved treatments.21
A statement from a patient who got frustrated with their healthcare experience said: “I went from dermatologist to dermatologist. Each told me there was no cure and no really effective treatment… seemed disinterested when I spoke of the dramatic change I saw in the mirror.”22
Changing the Trajectory of Vitiligo in Europe
The European white paper is a recent initiative aimed at identifying the gaps in the diagnosis, management, and care of vitiligo.23 A Delphi consensus, which gathered recommendations from patient organisations and experts, aims to improve health outcomes and access to optimal care.23 It included officially classifying vitiligo as a chronic autoimmune disease and calls on policymakers and European authorities to drive initiatives and facilitate best practices for sharing information, as a matter of urgency.23 A link for more information, which is available in the reference list, was provided.24
Wolkerstorfer concluded that the burden of vitiligo is significant, and though there are many parallels to other chronic skin disorders, some specific items make vitiligo very resistant and difficult to treat, and access to optimal care is sometimes very difficult, and there are some hurdles still to tackle.
As an Autoimmune Disease, Vitiligo Warrants Both Early and Long-Term Considerations
Curdin Conrad
Considering the treatment of chronic inflammatory diseases, Conrad highlighted the importance of finding treatment options that balance improving skin lesions while minimising side effects. He said this involved considering factors such as efficacy, benefits, risks, side effects, and inconveniences.25
The session emphasised the need to understand the pathogenesis of the deregulation of the immune system in order to understand the disease and then identify treatment opportunities. Nonsegmental vitiligo is a chronic T helper (Th)-1 autoimmune disease.26 Conrad drew comparison to other immune diseases such as psoriasis, which is a Th-17 driven disease, and lupus which is driven by Type I-interferon; alopecia areata and vitiligo are driven by Th-1 via interferon-γ, which was demonstrated by the overexpression seen in gene expression profiles.
The Role of JAK-STAT Pathway Inhibition in Vitiligo
The pathogenesis of vitiligo is driven by auto-reactive CD8+ cytotoxic T cells that produce interferon-γ, which in turn signals the JAK pathway promote the production of IL-15 which is critical in the activation and maintenance of skin keratinocytes and relapses.26-28 Within these cells form tissue-resident memory T cells (TRM) in the lesions, which are recruited by the IL-15 signalling.26,28
Conrad expressed the challenges in eliminating TRM cells and the potential for preventing their entry into the skin through early intervention. Therefore, he suggested the role of IL-15 and interferon-γ as central in the pathogenesis of nonsegmental vitiligo and identified the need to target these with treatment. However, he stated there is currently nothing to target Th-1 diseases.
As such, the session identified targeting the Th-1 cytokine receptors, IL-15 and interferon-γ, which are both important in the pathogenesis of alopecia areata and vitiligo, through the associated signalling JAK-STAT pathways.27,29
Interferon-γ receptor signalling in keratinocytes activates the JAK-STAT pathway via JAK1 and JAK2, resulting in transcription and production of CXCL9 and CXCL10, which induces CD-8 positive T cell recruitment which are capable of melanocyte destruction.30,31 By inhibiting JAK1, this would impact the response of TRM cells and interferon-γ.27,29
Conrad stated that by targeting these inflammatory processes we may diminish autoimmune attacks on melanocytes and lead to re-pigmentation over time, as damaged melanocytes are replaced by new melanocytes.2,31,32
Disease Course and the Memory of Vitiligo and Long-term Options
The challenge with current treatment options is that after successful therapy, such as phototherapy, many patients relapse within 12 months with recurrent depigmentation that typically occurs in the same lesions. This Conrad highlighted, indicated the “development of a disease memory within the skin.” He proposed that a longer disease duration may be a risk factor for (earlier) relapse. Therefore, with “early intervention, we have a higher chance to tackle that problem,” and have a higher chance of the patient going into remission and avoiding a relapse. Conrad said that this could potentially “reverse disease memory or prevent its establishment.”
The Role of Tissue Resident Memory T Cells in the Skin
The session also discussed the concept of disease memory, where TRM cells remain in the skin even when clinically healed or repigmented, or as seen in conditions such as psoriasis where you have clinically normal skin.33-36 Conrad provided an example of vitiligo, where initial T cell activation leads to melanocyte elimination and subsequent
depigmentation. Although treatment may result in clinical normalcy and re-pigmentation, he stated that the TRM cells remain. Following treatment cessation, subsequent local reactivation of these TRM cells by a disease trigger can recruit further T cells, resulting in a clinical relapse.33-36 It was suggested that for disease modification and prevention of relapse, it would be necessary to eliminate these TRM cells. A mouse model demonstrated that targeting IL-15 signalling with an antibody blockade could potentially reverse chronic vitiligo.34 However, Conrad cautioned that eliminating all TRM cells may not only remove diseasespecific cells but also those providing protection against pathogens.
In previously unaffected, non-lesional psoriasis skin, TRM cells accumulate over the course of the disease.37 Conrad identified that an alternative is to prevent TRM cells from populating the skin through early intervention. However, there is limited data on this.
Furthermore, the session noted the challenges with disease memory, not just T cell memory but also inflammatory memory through epigenetic changes.38-40 Conrad discussed the concept of epigenetic memory and its role in disease persistence and the need for long-term treatment options. For example, during infection, inflammatory cells such as monocytes undergo epigenetic modifications, such as through histone methylations or DNA methylations, which ‘train’ or ‘tolerise’ the cell.41 However, Conrad highlighted that you cannot reverse the damage from epigenetic changes.
As such, TRM cells are critical in mediating disease, therefore highlighting the importance of early interventions for the opportunity to bring about disease modification in certain patients. However, as identified by Wolkerstorfer, vitiligo is a chronic disease with patients having delayed diagnosis or late intervention, and therefore there is a need for long-term treatment. Given the safety concerns for JAK inhibitors and the need to evaluate the long-term risks and benefits in vitiligo,42 Conrad identified the need for alternative long-term treatment options.
Objectives for Long-term Vitiligo Treatment
The need to halt depigmentation, slow the disease progression, prevent relapses, and have time to induce re-pigmentation can take 6 months up to 2 years or more. Conrad concluded that the aim for early intervention, to enable disease modification by preventing or reversing the skin population of TRM and preventing or reversing epigenetic changes is still yet to be seen.
However, there is a need to tackle the burden of disease through early intervention and as early as possible so that we have treatment options available, and that there is a need for long-term management.
Considering the pathogenesis of vitiligo, the session identified potential treatment targets to block early depigmentation by targeting interferon-γ and to prevent relapses by blocking IL-15 to prevent TRM cell activation or maintenance, which can be achieved through JAK1 inhibition (Figure 2).2,30,43-50 Conrad summarised that it makes sense to
inhibit Th-1 through JAK1 inhibition as an option to achieve vitiligo remission and longterm control.
How Ruxolitinib Cream Fits in Shared Decision-Making Strategies for Effective Vitiligo Management
Markus Böhm
In the final presentation, Böhm highlighted the importance of shared decisionmaking strategies in treating patients with nonsegmental vitiligo.
Shared decision-making is an important tool in long-term management of chronic conditions such as vitiligo.51 Put simply, Böhm said shared decision-making is the “provision of information to the patient, and also to listen to the patient.” This includes considering patient expectations, providing clinically relevant information, considering the nature of the disease, diagnosis and
induce repigmentation
Figure adapted from Qi F et al.47 CC-BY-4.0
Sources of repigmenting melanoblasts
CD: cluster of differentiation; CXCL: C-X-C motif chemokine ligand; CXCR: C-X-C motif chemokine receptor; IFN: interferon; IL: interleukin; IL-R: interleukin receptor; ILC1: group 1 innate lymphoid cell; JAK: Janus kinase; MMP: matrix metalloproteinase; NK: natural killer cell; ROS: reactive oxygen species; STAT: signal transducer and activator of transcription; TRM: resident memory T cell.
Figure 2: The vitiligo pathogenesis and objectives in vitiligo treatment.2,30,43-50
CD8+
consequences, and treatment options, including what areas are difficult to treat, expectations of available therapies, and that some areas may not respond well.51
The session highlighted that the role of shared decision-making is important as it enables patients to better adhere to a given treatment, avoiding treatment failure and improving QoL.51 Böhm also noted the tools to support this, whether they are paperbased resources or mobile applications, the importance is to provide the information.
This was also highlighted by the recent treatment algorithm by the International Vitiligo Task Force (Figure 3), where under the established diagnosis there are defined treatment goals, expectations, and prognosis, shared decisions based on treatment pros and cons, disease impact, disease activity, and lesion location.52 These points, Böhm noted, are what should be explained to the patient, together with the patient, as well as discussion of the therapy options.52
The session also emphasised the importance of HCPs knowing the clinical data of treatments to answer patient questions. Böhm stressed the significance of using a shared decision-making process to communicate to the patient.
Targeted Therapy for Vitiligo
To support HCPs’ understanding of treatment options, Böhm presented data from the first vitiligo-specific immunomodulatory therapy, a selective JAK1 and JAK2 inhibitor, ruxolitinib topical cream.
The two Phase III randomised controlled trials (TRuE-V1 and TRuE-V2) and long-term extension study (TRuE-V LTE) demonstrated the role of ruxolitinib, highlighting its effectiveness in achieving meaningful facial re-pigmentation (demonstrated by improved facial-VASI [F-VASI]) in long-standing vitiligo disease.53,54
These double-blind, randomised, vehiclecontrolled studies recruited 674 patients (n=330 in TRuE-V1 and n=344 in TRuE-V2)
aged 12 years and above with nonsegmental vitiligo and a 10% or less BSA, from 101 centres in North America and Europe.53 The primary endpoint was an improvement in F-VASI75 (i.e., 75% re-pigmentation) after Week 24. Böhm noted this endpoint was selected, as previously identified by Wolkerstorfer, that facial depigmentation matters and is associated with the sites where patients are affected and stigmatised and is most important for the patient.
Those patients who were responders with F-VASI90 (i.e., 90% re-pigmentation) were invited to the extension and 2-year followup as part of the TRuE-V LTE.54,55 This cohort was randomised into two arms, one where ruxolitinib cream was applied throughout the trial, and the other was a withdrawal arm where patients stopped applying the treatment to evaluate relapse rate.54,55
Ruxolitinib Cream Patient Expectations as Part of Shared Decision-Making
The efficacy of ruxolitinib cream on the face after 6 months of continuous application achieved a meaningful endpoint of F-VASI75 by Week 52 in approximately half of the patients (50.3%), with one-third (30.3%) achieving F-VASI90.56
Böhm pointed out that this illustrated almost complete re-pigmentation of the face and non-facial areas such as the knee, highlighting the need to be consistent with treatment, manage patient expectations, and set individual patient goals.
Another point identified by Böhm is that when explaining clinical data to patients, to explain that it takes time. He said that unlike psoriasis or atopic dermatitis, with endpoints within 16 weeks or 24 weeks, it takes from 24 up to 52 weeks for vitiligo. Böhm indicated that if patients are not responding immediately, they should be persistent with the treatment.
The patient-reported outcomes included the vitiligo noticeability score, and factors such as skin colour matching and pattern of re-pigmentation to indicate treatment
Figure 3: International statement of diagnosis and care of nonsegmental vitiligo.52
Vitiligo (nonsegmental)
Define treatment goal, expectations, and prognosis (shared decision) based on treatment pros and cons, disease impact, disease activity, and lesion location*,†
Treatment goal
Stabilisation Re-pigmentation
Active in previous 6 months
Based on:
1. Pictures (or by history)‡
2. Visible disease activity signs§
Topical treatment (corticosteroids or immunomodulators) (Targeted) phototherapy (NB-UVB)**
Optional: systemic treatment††
General remarks:
Stable in previous 6 months
Based on:
1. Pictures (or by history)‡
2. Absence of disease activity signs§
Clinical follow up Consider maintenance treatment (topical corticosteroids / immunomodulators): e.g. 2x/week
Active/stable in previous 6 months
Based on:
1. Pictures (or by history)‡
2. Visible disease activity signs§
Topical treatment (corticosteroids or immunomodulators) (Targeted) phototherapy (NB-UVB)
Optional: systemic treatment††
Stable in previous 12 months and resistant to topical treatment and/or phototherapy/ limited extent
Optional: Surgical techniques
• Use algorithm in combination with information/recommendations provided in the text.
Active/stable in previous 6 months
Therapy-resistant extensive vitiligoon visible/sensitive areas
Monobenzone Pigment laser Cryotherapy
• Provide information: avoidance Koebner’s phenomenon, cosmetic skin camouflage, use of sunscreens (consider information leaflet).
• Consider and discuss the risk-benefit ratio in particular for systemic treatments, combination therapies (e.g. topical immunomodulators / systemic treatment + UV) and prolonged treatment.
*Other aspects for shared decision: e.g., skin type, disease duration, presence of comorbidities, extent on visible/sensitive areas, geographical region.
†Explain relation between body location and expected results (‘best’ to ‘worse’: face > other body areas > hands/feet); explain the treatment expectations and limitations.
‡Active: new lesions or increase in existing lesions; stable: no new lesions or no increase in existing lesions.
§Clear presence of confetti-like depigmentations, hypochromic borders/areas or Koebner’s phenomenon (for assessment consider e.g., Br J Dermatol. 2020;183(5):883–890; www.vitiligo-calculator.com).
**NB-UVB and combination therapy preferred (e.g., phototherapy + topical corticosteroids).
††Oral steroid mini pulse (most investigated) and alternatives reported: methotrexate, cyclosporine, azathioprine, minocycline, and Janus kinase inhibitors (currently investigated).
van Geel N et al. J Eur Acad Dermatol Venereol. 2023.37:2173-84.
success. The response through 52 weeks indicated 36.3% of patients perceived their vitiligo as completely gone or almost completely gone.56
For those who achieved satisfactory repigmentation that continued into the extension trial (TRuE-V LTE), 69.1% of patients who continued application twice daily maintained an F-VASI75 response at Week 104.54 Among those patients who stopped treatment, an F-VASI75 response was maintained in 39.3%.54 Following treatment discontinuation, half of the patient’s relapse events occurred within 4 months.54
This emphasised, therefore, that continued application in the second year was associated with a reduced risk of losing an almost complete re-pigmentation of F-VASI90 response (hazard ratio: 0.32; 95% CI: 017–0.610).54 After stopping the treatment, the median time to maintain an F-VASI90 response was approximately 6.5 months.54 Böhm indicated, therefore, that if patients decide to continue treatment without stopping, efficacy is maintained.
In those patients who stopped the treatment application, perhaps those who wanted a treatment break after achieving satisfactory re-pigmentation, and then restarted (n=16), 75% were able to regain F-VASI75 within a median time of 12 weeks after restating, and approximately 70% regained a F-VASI90 after 15 weeks.54 In those patients who did not achieve satisfactory facial re-pigmentation in the second year (Weeks 52–104) of treatment, F-VASI90 still increased over time.55
Böhm highlighted that, based on shared decision-making, patients who may only achieve an F-VASI75 may decide to recontinue to achieve a re-pigmentation of 90%. Those who did not respond at Week 24 also showed improvement, with an increased F-VASI75 response, from 13.3% at Week 52 to 54.9% at Week 104.56
The proportion of patients who achieved a total VASI50 for all body regions (excluding the face), in all cohorts, increased from Weeks 52 to 104 with continued treatment application.57
Böhm stated that this indicated that for those patients who are not satisfied with their re-pigmentation should continue treatment. The data demonstrates that you can use continuous treatment to lead to better re-pigmentation, even for those with a poorer re-pigmentation rate.56
Safety Profile of Ruxolitinib Cream
When considering the treatment, patients may also want to understand the safety profile. Considering treatment-related treatment-emergent adverse events, the most common adverse event was application site acne, which was low, occurring in less than 6% of patients over 2 years.54,55,58 This, Böhm stated, indicated the treatment has a favourable efficacy and safety with a low incidence of adverse events.
Real-World Data Shared DecisionMaking in Non-Segmental Vitiligo
Böhm also shared the first real-world data from Germany, showing the use of ruxolitinib cream in various patient cases, and discussed the importance of shared decision-making. In one case of nonsegmental vitiligo, the patient considered the use of newer therapies to try and stop the disease progression and, with shared decision-making, considered the use on difficult-to-treat areas and the requirement of long-term treatment. In another case of long-standing vitiligo and slowly progressive disease, shared decision-making was used for considering alternative therapy options and the continuation of treatment on all sites to prevent relapse and promote further re-pigmentation in difficult-to-treat areas. A third patient case with progressive disease with particular concern for their legs used shared decision-making to continue treatment but stopped use on non-responding areas.
Böhm concluded that shared decision-making is an important tool for the successful therapeutic management of patients with vitiligo, particularly when considering newly approved therapies. Long-term treatment is usually needed in vitiligo, making shared decision-making an
even more important tool considering the burden of using treatment against the need to get improved responses when treated for longer.
CONCLUSION
The burden of vitiligo and the challenges of accessing optimal care highlight the importance of both early and long-term management. Vitiligo is an autoimmune disease, and therefore, a better understanding of the pathogenesis focusing
References
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23. Misery L et al. White paper on psychodermatology in Europe: a position paper from the EADV psychodermatology task force and the European society for dermatology and psychiatry (ESDaP). J Eur Acad Dermatol Venereol. 2023;37(12):241927.
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38. Naik S et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature. 2017;550(7677):475-80.
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41. Italiani P, Boraschi D. Induction of innate immune memory by engineered nanoparticles: a hypothesis that
may become true. Front Immunol. 2017;8:734.
42. Samuel C et al. A review on the safety of using JAK inhibitors in dermatology: clinical and laboratory monitoring. Dermatol Ther (Heidelb). 2023;13(3):729-49.
43. Richmond JM et al. Innate immune mechanisms in vitiligo: danger from within. Curr Opin Immunol. 2013;25(6):676-82.
44. Howell MD et al. Targeting the Janus kinase family in autoimmune skin diseases. Front Immunol. 2019;10:2342.
45. Rashighi M, Harris JE. Vitiligo pathogenesis and emerging treatments. Dermatol Clin. 2017;35(2):257-65.
46. Rosmarin D et al. Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial. Lancet. 2020;396(10244):110-20.
47. Qi F et al. Janus kinase inhibitors in the treatment of vitiligo: a review. Front Immunol. 2021;12:790125.
48. Tulic MK et al. Innate lymphocyteinduced CXCR3B-mediated melanocyte apoptosis is a potential initiator of T-cell autoreactivity in vitiligo. Nat Commun. 2019;10(1):2178.
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statement from the international vitiligo task force part 1: towards a new management algorithm. J Eur Acad Dermatol Venereol. 2023;37(11):2173-84.
53. Rosmarin D et al. TRuE-V study group. Two phase 3, randomized, controlled trials of ruxolitinib cream for vitiligo. N Engl J Med. 2022;387(16):1445-55.
54. Harris JE et al. Relapse and maintenance of clinical response in the randomized withdrawal arm of the TRuE-V long-term extension phase 3 study of ruxolitinib cream in vitiligo. Abstract 46159. American Academy of Dermatology Association (AAD) 2023 Annual Meeting, 17-21 March, 2023.
55. Rosmarin D et al. Facial and total vitiligo area scoring index response shift during 104 weeks of ruxolitinib cream treatment for vitiligo: results from the open-label arm of the TRuE-V long-term extension phase 3 study. Abstract 46163. AAD 2023 Annual Meeting, 17-21 March, 2023.
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57. Passeron T et al. Effect of ruxolitinib cream on VASI50 achievement by body region through week 104 in patients with vitiligo: analysis of the TRUE-V long-term extension phase 3 study. Poster P2228. EADV Congress 2023, 11-14 October, 2023.
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Mechanistic Understanding of Clinical Response to Bimekizumab in Psoriatic Disease
One oral presentation and two posters were presented at the 33rd European Academy of Dermatology and Venereology (EADV) Congress, held in Amsterdam, the Netherlands, 25th−28th September 2024.
Presenters: Ioana Cutcutache,1 Johann E. Gudjonsson2
1. UCB Pharma, Slough, UK
2. Department of Dermatology and Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, USA
Disclosure:
Cutcutache is an employee and shareholder of UCB. Gudjonsson served as an advisor to AbbVie, Almirall, Janssen, Boehringer Ingelheim, Eli Lilly and Company, Novartis, Bristol Myers Squibb, Sanofi, and Galderma; and received grant support from Almirall, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Novartis, and Galderma.
Acknowledgements: Medical writing assistance was provided by Eleanor Roberts, Beeline Science Communications, Ltd, UK.
Disclaimer The article content and views expressed herein are those of the presenters and UCB.
Support: The publication of this article was fully sponsored by UCB.
Meeting Summary
Use of bimekizumab, a monoclonal immunoglobulin G1 (IgG1) antibody that selectively inhibits the cytokine interleukin-17F (IL-17F), in addition to IL-17A, has been shown to result in a rapid response and prolonged, high-level disease control in patients with moderate-to-severe plaque psoriasis. At the 2024 European Academy of Dermatology and Venereology (EADV) Congress, an oral presentation and a poster were presented related to furthering the understanding of the mechanisms that lead to the clinical response observed with bimekizumab. The oral presentation examined the effects of bimekizumab on subcomponents of the Psoriasis Area and Severity Index (PASI). Analyses showed ≥95% mean improvement in erythema, thickness, and scaling with bimekizumab by Week 12 of treatment, which was maintained to Week 48. Bulk transcriptomic analysis showed complete normalisation of gene signatures associated with these subcomponents by Week 8, preceding clinically apparent skin clearance. A poster presented at the 2023 5th Inflammatory Skin Diseases (ISDS) focused on the effect of bimekizumab on tissue-resident memory
PHARMA
PARTNERSHIP
T (TRM) cells, which have been associated with disease perpetuation during treatment and with psoriasis recurrence at the same location following treatment withdrawal. Bulk transcriptomic analyses showed normalisation of a TRM gene signature at Week 8 after only two doses of bimekizumab, as well as normalised expression of pro-survival factors that may be prolonging survival of pathogenic TRM cells and pathogenic IL-17A/Fsecreting cells. These results may have implications for disease modification and help explain the long-term durability of response observed with bimekizumab. The results shown in the oral presentation and poster support the rationale for initiation of the BE UNIQUE study, the protocol for which was reported at EADV 2024. This ongoing, multicentre, Phase IIIb study is recruiting patients with moderate-to-severe plaque psoriasis, with or without concomitant active psoriatic arthritis, with a primary objective to assess change in composite gene expression score at Week 48. This study aims to further elucidate the molecular mechanisms underlying the rapid, high-level, and durable clinical responses observed with bimekizumab.
Introduction
The pro-inflammatory cytokines IL-17A and IL-17F are overexpressed in the thick, scaly, erythematous plaques that are the signature of skin manifestations in psoriasis.1-4 While IL-17A is the more potent of the two cytokines,5 IL-17F is more abundant in inflamed psoriatic tissue6 and chronic stimulation of IL-17-secreting cells, especially T helper 17 cells, preferentially leads to IL-17F production.7
Bimekizumab is a humanised monoclonal IgG1 antibody with unique dual specificity for IL-17A and IL-17F.8 Use of bimekizumab is associated with immune response suppression and can lead to rapid and prolonged, high-level control of moderateto-severe plaque psoriasis. This was demonstrated in the Phase III clinical studies BE SURE (NCT03412747),9 BE VIVID (NCT03370133),10 and BE READY (NCT03410992),11 and their open-label extension study BE BRIGHT (NCT03598790).12 Among 989 patients randomised to receive subcutaneous bimekizumab in these studies, 62.7% achieved complete skin clearance at Week 16, measured as 100% improvement from baseline PASI score (PASI 100), and 87.5% achieved ≥90% improvement from baseline PASI score (PASI 90).12 Responses were durable, with 72.6% of bimekizumabrandomised patients who entered BE BRIGHT achieving PASI 100 after 4 years and 88.0% achieving PASI 90.13
Bimekizumab use has shown superior efficacy compared with placebo10,11 and with other biologics such as adalimumab,9 ustekinumab,10 and secukinumab.14 For example, in the BE RADIANT Phase IIIb trial, bimekizumab showed superiority to secukinumab at the primary endpoint, with 61.7% of the bimekizumab group (n=373) achieving PASI 100 at Week 16 compared with 48.9% of the secukinumab group (n=370; p<0.001).14 Here, findings from an oral presentation and two posters are highlighted to show the latest molecular understandings underpinning the observed clinical response with bimekizumab.
Rapid Normalisation of
Molecular Signatures Associated with Psoriasis Area and Severity Index Subcomponents Following Bimekizumab Administration
PASI is the most widely used severity scoring system to assess psoriasis drug efficacy in the clinical setting. It consists of a composite score of three lesionassociated subcomponents (erythema, thickness, and scaling), weighted by plaque area and body region. The subcomponents are infrequently reported, but separate analysis should enable understanding of the contribution of each to the composite score and whether any subcomponent is obscured in the overall weighted composite score.15
In the findings presented in this oral presentation,16 PASI subcomponent data from the BE RADIANT trial was analysed. In this trial, participants were randomised to receive 320 mg bimekizumab every 4 weeks (Q4W) from Week 0 to Week 16, then either Q4W or Q8W until Week 48 (n=373), or 300 mg secukinumab weekly to Week 4 then Q4W (n=370).14
As can be seen from Figure 1, by Week 8 there was a mean reduction from baseline in lesion-associated erythema of 89.0%, in thickness of 92.1%, and in scaling of 93.3%. By Week 12, all three subcomponents showed ≥95% mean improvement, which was maintained to Year 1. As results were similar between the subcomponents, this suggests that analysis of any subcomponent alone is potentially reliable for evaluating clinical response to bimekizumab.16
To help understand the observed clinical response to bimekizumab, it is vital to elucidate the drug’s molecular effects. PASI subcomponent-linked gene sets were curated using two public gene ontologies: DisGeNET for erythema17 and the Human Phenotype Ontology for thickness (‘acanthosis’ in the ontology) and scaling.18 Gene sets of interest were then refined to include only the genes known to be dysregulated in psoriatic lesional versus non-lesional skin. These had been shown in the analysis of data from a Phase IIa clinical trial (NCT03025542)19 where 49 participants received two injections of 320 mg bimekizumab, 4 weeks apart, which led to rapid and profound normalisation of the psoriasis transcriptome by Week 8.19
Bulk RNA-sequencing data from this aforementioned Phase IIa trial19 was used to assess dysregulation of the psoriasisspecific PASI subcomponent-linked gene sets at baseline and following bimekizumab treatment.16 These data were generated from lesional and non-lesional skin biopsies previously collected at baseline and Week 8 and on tissue from healthy controls.19 Gene set level expression changes were assessed using gene set variation analysis and limma statistical methods.16
As shown in Figure 1, at baseline, signatures of all the PASI subcomponents were significantly upregulated compared with healthy and non-lesional tissue. At Week 8, following two doses of bimekizumab, complete normalisation of the subcomponent gene sets to nonlesional levels and beyond was observed: 95.7% median percentage improvement for erythema, 105.3% for thickness, and 104.5% for scaling.16
As bimekizumab selectively inhibits IL-17A and IL-17F,8 analysis was carried out to understand the relationship between the expression levels of these cytokines with the PASI subcomponent gene signatures (reported using Spearman correlation coefficients: R). Positive correlations were shown between baseline changes in IL17A and IL17F expression levels and mean gene expression changes of each curated gene set (R: 0.36−0.53; false discovery rate <0.05).15 This is consistent with the known direct effect of IL-17 on keratinocytes and indicates that both IL-17A and IL-17F are important in psoriatic disease.20
To further understand the molecular effects of bimekizumab on the PASI subcomponents, analysis was carried out on lesional psoriatic tissue with regard to selected markers associated with erythema (CXCL8),21 thickness (KRT16),22 and scaling (LORICRIN).23 Observation prior to treatment (utilising RNAscopeTM in situ hybridisation imaging) showed high expression of CXCL8 in epidermal layers associated with the presence of IL17F-expressing cells in lesional tissue, but only marginal expression in non-lesional tissue. Similar findings comparing lesional to non-lesional tissue were shown with regard to KRT16 in epidermal keratinocytes.16 Conversely, high levels of expression of LORICRIN, a barrier function gene,23 was shown in the granular layer of the epidermis in non-lesional tissue but was only present at low levels, if at all, in lesional tissue due to barrier loss associated with skin scaling.16
These observations were confirmed by analysis of these selected genes in the bulk RNA sequencing data from lesional and non-lesional baseline tissue reported here.
Figure 1: PASI mean percentage reduction from baseline across three subcomponents in the Phase IIIb BE RADIANT trial, and expression of subcomponent gene signatures in treated lesional tissue at Week 8 versus baseline nonlesional and lesional tissue, and healthy tissue in a Phase IIa trial.16
PASI subcomponent data are presented using observed cases for bimekizumab-randomised patients only (N=373) from the BE RADIANT Phase IIIb trial. Patients with a weighted score of 0 for a given PASI subcomponent at baseline were excluded from the analysis for that subcomponent. Molecular data is from a Phase IIa trial. For PASI subcomponent signature analysis, thickness was defined by the acanthosis gene set. Violin plots show expression of PASI subcomponent signatures, using GSVA to estimate gene set expression levels in healthy tissue (patients without psoriasis: blue), baseline non-lesional (clear skin in patients with psoriasis: grey), baseline lesional (patients with psoriasis: black), and treated lesional tissue at Week 8 (BKZ Week 8: orange). Wider sections of the violin plot indicate higher density of data at the respective y-axis value. White box plots show median and interquartile range normalised expression. Red horizontal lines correspond to median baseline expression in non-lesional tissue. LogFC and FDRadjusted p-values were calculated using the limma moderated t-test. ***FDR<0.001.
BZK: bimekizumab; GSVA: Gene Set Variation Analysis; FC: fold change; PASI: Psoriasis Area and Severity Index.
Following bimekizumab treatment, by Week 8, similar analysis showed normalisation of these markers in the lesional tissue, with percentage improvements of 118.9% for CXCL8, 102.4% for KRT16, and 104.3% for LORICRIN. 16
Overall, it was concluded that this first analysis of the effects of bimekizumab on PASI subcomponents revealed changes following administration at both clinical and molecular levels on all three subcomponents. These findings, the authors concluded, indicate clinical predictivity for sustainable skin clearance as early as 12 weeks, which is preceded by molecular resolution of disease.16
TRM cells in lesional skin are implicated in psoriasis perpetuation during treatment and in location-specific lesion recurrence following treatment withdrawal.4 It is thus of interest to understand molecular mechanisms associated with TRM cells following treatment with bimekizumab, which is known to result in durable and continuous skin clearance.12
Firstly, in this poster presented at ISDS 2023, three independent single-cell RNA sequencing datasets6,24,25 (previously obtained from psoriatic lesion biopsies)
were reprocessed in a uniform manner. Results were then used to assess gene expression in specific cell types, including TRM cells and those that express IL17A and IL17F 26
Analysis of each single-cell dataset showed that approximately 5% of TRM cells in lesional psoriatic tissue expressed IL17A/F, with additional analysis suggesting that a considerable proportion of all IL17A/F expression may come from TRM cells. Analysis of these single-cell datasets also showed highly similar transcriptomes in T cells that express IL17A and IL17F, with Pearson correlation coefficients of 0.94−0.98 and p<0.0001.26
The IL-7 pathway is associated with cell survival through upregulation of antiapoptotic genes such as BCL2 and BCLXL 27 Analysis of baseline lesional tissue singlecell datasets showed that the receptor for IL-7 (IL7R) was highly expressed on both IL-17A- and, particularly, IL-17F-producing T cells in two out of the three datasets. This observation led to the postulation that the upregulation of IL7R may increase the survival of pathogenic IL-17A/Fsecreting cells.26 As a follow-up analysis, expression of IL7R was confirmed in TRM cells specifically, as was that of another T-cell pro-survival factor, the cytokine IL32, 26 which has previously been shown to be increased in cells from psoriatic skin lesions.28
To further elucidate the role of TRM cells, the effect of bimekizumab on genes and gene signatures of interest was also evaluated using pre- and post-treatment bulk RNA sequencing data from the Phase IIa trial of patients with psoriasis discussed above (NCT03025542).19 Prior to treatment, gene set variation analysis of a TRM gene signature showed this to be significantly higher in lesional tissue when compared with tissue from healthy controls and with non-lesional tissue from patients with psoriasis. Normalisation of TRM gene signature was shown following two doses of bimekizumab (Figure 2A), with a median percentage improvement of 78.1% at Week 8.26 Seventeen participants in this study also received a third dose of
bimekizumab at Week 16.19 In this group, median percentage improvement in TRM gene signature increased to 87.7% at Week 28 (Figure 2A).26
Prior to treatment, and compared with healthy and non-lesional tissue, upregulation of IL7R and IL32 expression was also shown in lesional tissue through bulk RNA sequencing. This was reversed following bimekizumab administration by Week 8, and furthermore by Week 28 (Figure 2B). Additionally observed was a baseline increase in an anti-apoptotic gene signature compared with healthy and non-lesional tissue, with bimekizumab administration leading to normalisation of this signature at Weeks 8 and 28 (median percentage improvement at Week 8 of 104.5%; Figure 2C).26
The authors concluded that ‘these mechanistic data from patient samples highlight the importance of IL-17F and IL-17A dual neutralisation in normalising both TRM cell biology and pro-survival factors’. Their findings may have implications for disease modification and for the maintenance of complete skin clearance during the treatment of psoriasis with bimekizumab.26
The BE UNIQUE Study
As discussed above, TRM cells are implicated in psoriasis4 and are found in the blood and joints of patients with psoriatic arthritis,29 a condition that occurs in around 15−20% of people with psoriasis.30,31 Findings showing rapid normalisation of the psoriatic skin transcriptome and TRM cell signatures following two injections of 320 mg bimekizumab every 4 weeks19,26 led to the development of the ongoing (as of October 2024) Phase IIIb, multicentre BE UNIQUE study (NCT06506916) presented at EADV 2024.32 This will enrol 80 adults with moderate-to-severe plaque psoriasis, defined as PASI ≥12, body surface area ≥10%, and Investigator’s Global Assessment ≥3. Of these 80, 40 participants will have concomitant, active, psoriatic arthritis, defined as disease meeting the
2: Expression of key genes and gene sets in baseline healthy, non-lesional and lesional tissue versus treated lesional tissue at Weeks 8/28 from a Phase IIa trial.26
Gene Set Variation Analysis was used to estimate gene set level of expression. Red horizontal lines correspond to the median baseline expression in non-lesional tissue. LogFC and false discover rate-adjusted p-values were calculated using the limma moderated t-test. ***false discovery rate<0.001; **false discovery rate<0.01. TRM signature: CD103, CD69, CD44; Anti-apoptotic gene signature: BCL2, BCL2L1, MCL1, BIRC5, CFLAR, BCL2A1, BIRC3, PEA 15.
BKZ: bimekizumab; GSVA: Gene Set Variation Analysis; IL: interleukin; TRM: tissue-resident memory T cells.
Classification Criteria for Psoriatic Arthritis (≥1/68 tender joint count and ≥1/66 swollen joint count). Ten matching healthy controls will also be recruited.32
As can be seen from Figure 3, in Part 1 participants initially receive 320 mg bimekizumab Q4W to Week 16, then Q8W until Week 48. In Part 2 (Weeks 48–96), participants with PASI=0 (plus low disease activity for participants with psoriatic arthritis) will be randomised 1:1 to receive bimekizumab either Q8W or Q12W, and participants with PASI >0 and/or without low psoriatic arthritis disease activity will continue on a Q8W dosing schedule.32
Lesional skin biopsies and blood samples for bulk and single-cell transcriptomics will be taken at baseline and at Week 1
(following the first bimekizumab injection), Week 48, and Week 96. Non-lesional skin biopsies will be taken at baseline and Week 48. For the cohort with psoriatic arthritis, biopsy of synovial tissue at baseline and Week 48 will be optional. Baseline skin biopsies and blood samples will be taken from a matching cohort of 10 healthy individuals.32
BE UNIQUE’s primary objective is assessment of change in composite gene expression score in the lesional skin biopsies using reverse transcriptionpolymerase chain reaction. This will utilise preselected genes based on known bimekizumab mechanisms of action and psoriatic disease pathways. The secondary objective is evaluation of the safety and tolerability of bimekizumab in these cohorts.
A
B
C A B C
Figure
Exploratory objectives include investigation of the effect of bimekizumab on skin and blood bulk, single cell, and spatial transcriptomics. Also assessed will be the clinical response to bimekizumab and systemic effects of bimekizumab on gene and protein expression in blood and serum, respectively.32
It is hoped, concluded the authors, ‘that BE UNIQUE will enable exploration of mechanisms underlying the rapid, high, durable clinical responses observed with bimekizumab treatment’, and will assess ‘whether durable clinical responses correlate with molecular, cellular, and
transcriptomic changes in skin, blood, and joints of patients with psoriatic disease’.32
Conclusion
Together, these studies highlight how the utility of bimekizumab in the treatment of psoriasis may lie with the ability of this drug to impact underlying mechanisms associated with the development of this disease. Further investigation, in the BE UNIQUE study, will add to the understanding of the molecular and cellular changes brought about by treatment with bimekizumab.
PASI=0 (Cohort A)a PASI=0 and low PsA activity (Cohort B)a
Cohort A (N=40)
Cohort B (N=40)
BKZ 320 mg Q4W BKZ 320 mg Q8W
PASI >0 (Cohort A)
PASI >0 and/or without low PsA activity (Cohort B)
Week 1
Baseline
Lesional skin biopsy
Non-lesional skin biopsy
Cohort B optional synovial tissue biopsy
Blood samples for:
Serum proteomics
DNA analysis
Bulk and single-cell transcriptomicsd
Control cohort (N=10) skin biopsy and blood samples
Week 16
BKZ 320 mg Q12W
PASI >3b
BKZ 320 mg Q8W
BKZ 320 mg Q8W (Escape Arm)
BKZ 320 mg Q8W 1:1
Week 48
Week 96c
*In addition to PASI=0, Cohort B patients must have low PsA disease activity at Week 48 (SJC ≤1 and no increase in concomitant medications for the treatment of PsA symptoms compared with baseline) to enter the Randomised Treatment Extension Period.
†Patients in Cohort A and Cohort B who have a PASI score >3 during the Randomised Treatment Extension Period will enter an Escape Treatment Period and receive bimekizumab Q8W to study end, undergoing additional assessments; a lesional skin biopsy will be taken at the visit the patient has a PASI score >3, instead of at Week 96.
‡ The safety follow-up visit will occur at least 12 weeks after the final dose and not before 4 weeks after the last skin biopsy.
§ Blood samples for single-cell transcriptomics will be collected from the subset of Cohort A and B patients from whom 6 mm skin biopsies are collected (3 mm or 6 mm skin biopsies will be possible) and from all Control Cohort participants. Blood samples for bulk transcriptomics will be collected from all study participants except the subset of Cohort A and B patients who undergo blood sampling for single-cell transcriptomics.
BKZ: bimekizumab; PASI: Psoriasis Area and Severity Index; PsA: psoriatic arthritis; Q4W: every 4 weeks; Q8W: every 8 weeks; Q12W: every 12 weeks; SJC: swollen joint count.
Figure 3: Study design for BE UNIQUE.32
References
1. Fitch E et al. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007;9(6):461-7.
2. Johansen C et al. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol. 2009;160(2):319-24.
3. Sánchez-Rodríguez G, Puig L. Pathogenic role of IL-17 and therapeutic targeting of IL17F in psoriatic arthritis and spondyloarthropathies. Int J Mol Sci. 2023;24(12):10305.
4. Puig L et al. The biological basis of disease recurrence in psoriasis: a historical perspective and current models. Br J Dermatol. 2022;186(5):773-81.
5. Kolbinger F et al. β-defensin 2 is a responsive biomarker of IL-17Adriven skin pathology in patients with psoriasis. J Allergy Clin Immunol. 2017;139(3):923-32.e8.
6. Skelton A et al. 038 Single-cell sequencing of freshly isolated cells from lesional and peri-lesional skin to explore cellular origins of IL-17 isoforms in psoriasis. J Invest Derm. 2022;142(8):S7.
7. Cole S et al. Differential regulation of IL-17A and IL-17F via STAT5 contributes to psoriatic disease. J Allergy Clin Immunol. 2023;152(3):783-98.
8. Adams R et al. Bimekizumab, a novel humanized IgG1 antibody that neutralizes both IL-17A and IL-17F. Front Immunol. 2020;11:1894.
9. Warren RB et al. Bimekizumab versus adalimumab in plaque psoriasis. N Engl J Med. 2021;385(2):130-41.
10. Reich K et al. Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, doubleblind, active comparator and placebo controlled phase 3 trial. Lancet. 2021;397(10273):487-98.
11. Gordon KB et al. Bimekizumab efficacy and safety in moderate to severe plaque psoriasis (BE READY): a multicentre, double-blind, placebo-controlled, randomised withdrawal phase 3 trial. Lancet. 2021;397(10273):475-86.
12. Strober B et al. Bimekizumab maintenance of response through 3 years in patients with moderate-to-
severe plaque psoriasis: results from the BE BRIGHT open-label extension trial. Br J Dermatol. 2023;188(6):74959.
13. Strober B et al. Bimekizumab efficacy from treatment initiation through 4 years in patients with plaque psoriasis: a comprehensive, long-term, pooled analysis from BE BRIGHT. Late breaking abstract. American Academy of Dermatology Annual Meeting, 8-12 March, 2024.
14. Reich K et al. Bimekizumab versus secukinumab in plaque psoriasis. N Engl J Med. 2021;385(2):142-52.
15. Choi CW et al. Both educational lectures and reference photographs are necessary to improve the accuracy and reliability of psoriasis area and severity index (PASI) assessment: results from Korean nation-wide PASI educational workshop. Ann Dermatol. 2018;30(3):284-9.
16. Cutcutache I et al. Bimekizumab treatment in plaque psoriasis resulted in a rapid and deep normalisation of molecular signatures associated with PASI subcomponents, that preceded clinical skin clearance. Abstract 5545. 33rd EADV Congress, 25-28 September, 2024.
17. Piñero J et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 2020;48(D1):D845-55.
18. Köhler S et al. The human phenotype ontology in 2017. Nucleic Acids Res. 2017;45(D1):D865-76.
19. Oliver R et al. Bimekizumab for the treatment of moderate-to-severe plaque psoriasis: efficacy, safety, pharmacokinetics, pharmacodynamics and transcriptomics from a phase IIa, randomized, double-blind multicentre study. Br J Dermatol. 2022;186(4):652-63.
20. Nograles KE et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008;159(5):1092-102.
21. Martin D et al. CXCL8/IL8 stimulates vascular endothelial growth factor (VEGF) expression and the autocrine activation of VEGFR2 in endothelial cells by activating NFkappaB through the CBM (Carma3/Bcl10/ Malt1) complex. J Biol Chem. 2009;284(10):6038-42.
22. Leigh IM et al. Keratins (K16 and K17) as markers of keratinocyte hyperproliferation in psoriasis in
vivo and in vitro. Br J Dermatol. 1995;133(4):501-11.
23. Schmuth M et al. Structural and functional consequences of loricrin mutations in human loricrin keratoderma (Vohwinkel syndrome with ichthyosis). J Invest Dermatol. 2004;122(4):909-22.
24. Kim J et al. Single-cell transcriptomics applied to emigrating cells from psoriasis elucidate pathogenic versus regulatory immune cell subsets. J Allergy Clin Immunol. 2021;148(5):1281-92.
25. Reynolds G et al. Developmental cell programs are co-opted in inflammatory skin disease. Science. 2021;371(6527):eaba6500.
26. Cutcutache I et al. Bimekizumab treatment in psoriasis patients: a mechanistic understanding of the durable clinical response. Poster 187. 5th ISDS, 15-18 November, 2023.
27. Chetoui N et al. Interleukin-7 promotes the survival of human CD4+ effector/ memory T cells by up-regulating Bcl-2 proteins and activating the JAK/ STAT signalling pathway. Immunology. 2010;130(3):418-26.
28. Frost B et al. Single-cell transcriptomics reveals prominent expression of IL-14, IL-18, and IL-32 in psoriasis. Eur J Immunol. 2023;53(11):e2250354.
29. Steel KJA et al. Polyfunctional, proinflammatory, tissue-resident memory phenotype and function of synovial interleukin-17A+CD8+ T cells in psoriatic arthritis. Arthritis Rheumatol. 2020;72(3):435-47.
30. Villani AP et al. Prevalence of undiagnosed psoriatic arthritis among psoriasis patients: systematic review and meta-analysis. J Am Acad Dermatol. 2015;73(2):242-8.
31. Bang CH et al. Prevalence and incidence of psoriatic arthritis among patients with psoriasis and risk factors for psoriatic arthritis in Republic of Korea: a nationwide database cohort study. Acta Derm Venereol. 2024;104:adv40110.
32. Gudjonsson JE et al. Bimekizumab: exploring the fast onset, high level, and durability of clinical and molecular responses in patients with psoriatic disease – design and rationale behind the exploratory, multicentre, openlabel phase 3b BE UNIQUE study. Poster P3282. 33rd EADV Congress, 25-28 September, 2024.
Abstract Reviews
Drawing on insights from the European Academy of Dermatology and Venereology (EADV) Congress 2024, these abstract reviews spotlight notable new advancements and key focuses in the field of dermatology.
A 13-Year Retrospective Review of Metal
Series
Patch Testing for Orthopaedic Devices
Authors: *Ganesh B. Maniam,1 Phillip J. Link,2 Jenny L. Link1
1. Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA
2. Division of Allergic Diseases, Mayo Clinic, Rochester, Minnesota, USA
*Correspondence to maniam.ganesh@mayo.edu
Disclosure: The authors declare no conflicts of interest.
There is increasing utilisation of prosthetic orthopedic implantations. These implantations include joint replacements for the knees, hips, and shoulders.1 Post-operative pain or rashes may raise concerns for an underlying allergic process, especially if these complications are associated with prosthetic joint failure.1,2 There is evidence that allergic contact dermatitis (ACD) is a possible complication for implanted devices, but there is conflicting data regarding the efficacy of patch testing for detecting an allergic reaction below the skin surface. Prior studies seem to suggest that pre-operative patch testing can be helpful in guiding device choice in patients with a history of metal allergy, but the role of patch testing in the post-implantation setting is unclear.2,3
This study investigated metal patch testing surrounding orthopaedic device implantation, and whether pre- or postoperative testing results impacted orthopaedic device management.
METHODS
An Institutional Review Board (IRB)-exempt retrospective review was conducted from 2009–2022 of adult patients at a large academic centre who underwent metal patch testing and had procedural codes for knee replacement, hip replacement, and shoulder replacement. The review identified 36 patients who met inclusion criteria (Table 1).
RESULTS
Preoperative patch testing was performed for 23 patients who underwent knee replacement (15 patients), hip replacement (seven patients), and shoulder replacement (one patient). Of these patients, 20 had a history of ACD; of the three without a history of ACD, one patient noted a history of oral lichen planus possibly related to his dental implants. In patients who underwent patch testing preoperatively, 15 had clinically relevant positives that impacted selection of joint implant in 13 of those cases; all of these patients had prior history of ACD. Relevant pre-operative patch test positives include nickel sulfate hexahydrate (eight patients), potassium dicyanoaurate (five patients), cobalt chloride hexahydrate (four patients),
Postoperative patch testing was performed for 13 patients who underwent knee replacement (10 patients) and hip replacement (three patients). Of these patients, five had a history of ACD. For these postoperative patch testing patients, nine had negative testing while four patients had positive patch testing results of questionable clinical relevance. Implant removal was not recommended in any of these patients.
CONCLUSION
These results suggest that preoperative patch testing can guide orthopedic prosthetic device selection in patients with a history of metal contact allergies, while postoperative patch testing is more limited in utility.
References
1. Reed KB et al. Retrospective evaluation of patch testing before or after metal device implantation. Arch Dermatol. 2008;144(8):999-1007.
2. Misinkovska NA et al. The effect of patch testing on surgical practices and outcomes in orthopedic patients with metal implants. Arch Dermatol. 2012;148(6):687-93.
3. Fonacier L et al. Contact dermatitis: a practice parameter-update 2015. J Allergy Clin Immunol Pract. 2015;3(S):1-39.
Table 1: Patch testing for joint replacement: demographics, results, and impact (2009–2022).
ACD: allergic contact dermatitis; SD: standard deviation.
Barriers to Effective Cellulitis Management in a Primary Care Setting: An Audit Report
1. University of Central Lancashire, School of Medicine and Dentistry, Preston, UK
2. National Centre for Remote and Rural Medicine, Moor Row, UK *Correspondence to chowyanching0225@gmail.com
Disclosure: Chow and Siripanich have received direct reimbursement for round-trip air tickets and hotel accommodations from Dr Colin Michie and the School of Medicine and Dentistry, University of Central Lancashire for the travel to the EADV Congress.
Cellulitis is a bacterial infection of the skin and underlying tissues,¹ often leading to diagnostic challenges due to its nonspecific presentation. Globally, cellulitis imposes a significant burden on healthcare systems. In the UK, the National Institute for Health and Care Excellence (NICE) NG141 guidelines provide recommendations for managing cellulitis, including proper diagnosis, antimicrobial prescribing, and the provision of safety netting advice.2 These guidelines aim to improve patient outcomes, prevent complications, and address the rising concern of antimicrobial resistance.
This audit was conducted at a general practice (GP) in remote and rural England to assess compliance with the NG141 guidelines in cellulitis management. The primary objectives were to evaluate the accuracy of diagnosing cellulitis, assess the provision of safety netting advice, and determine the appropriateness of antimicrobial prescribing. By auditing these practices, the aim was to identify areas for improvement and ensure that the GP being audited maintains high standards in cellulitis care.
MATERIALS AND METHODS
A retrospective audit was conducted, reviewing the records of 40 patients diagnosed with cellulitis at the GP between 13 December 2022–12 December 2023.
Eligible patients were those aged 18 years and over, newly diagnosed with cellulitis during the study period. Exclusions included patients diagnosed in secondary care and those with recurrent cellulitis episodes.
The NICE NG141 guidelines were used to derive three key audit criteria: the exclusion of other causes of skin redness, the provision of safety netting advice, and the prescription of appropriate antimicrobials. Target compliance rates were set at 90% for the first two criteria and 95% for the third. Data were extracted from the Egton Medical Information Systems (EMIS) and analysed using a structured spreadsheet. Each patient’s record was evaluated for adherence to these criteria, and results were compared against the target standards.
RESULTS
The audit revealed varied compliance levels with the NICE NG141 guidelines. For the first criterion, only 45% of patient consultations documented the exclusion of other potential causes of skin redness, falling well below the 90% target. Discussions with clinicians suggested that while differential diagnoses were often considered during consultations, time constraints and inconsistent documentation practices contributed to this low compliance rate.3
For the second criterion, 72% of patients received safety netting advice, which also fell short of the 90% target. The lower rate of safety netting provision was attributed to high clinician workloads and time limitations, which impacted their ability to consistently offer and document this advice during consultations.4
The third criterion, correct antimicrobial prescribing, showed a higher compliance rate of 92%, just below the 95% target. Most patients were prescribed the appropriate antimicrobials according to the NICE guidelines, though a few cases of cellulitis near the eyes and nose involved inappropriate antibiotic selection, highlighting the need for additional training in the management of more complex presentations.
CONCLUSION
This audit identified significant gaps in adherence to the NICE NG141 guidelines at the GP, particularly in documenting the exclusion of differential diagnoses and providing safety netting advice. Whilst antimicrobial prescribing practices were generally strong, the findings highlight the need for further improvement in clinician training and documentation practices.
To address these gaps, it is recommended that the GP implements regular training sessions to update clinicians on the latest NICE guidelines, with a focus on diagnosis
and patient communication. Additionally, introducing standardised documentation templates within the EMIS system could improve the systematic exclusion of differential diagnoses and ensure consistent safety netting advice. A re-audit after 12 months is recommended to evaluate the effectiveness of these interventions and ensure improved compliance. These measures are essential for enhancing the quality of cellulitis care and ensuring continued adherence to national guidelines at the GP.
References
1. Raff AB, Kroshinsky D. Cellulitis. JAMA. 2016 Jul 19;316(3):325.
2. National Institute for Health and Care Excellence (NICE). Cellulitis and erysipelas: antimicrobial prescribing. 2019. Available at: https://www.nice.org. uk/guidance/ng141. Last accessed: 2 February 2024.
3. Peat G et al. Barriers and facilitators of successful deprescribing as described by older patients living with frailty, their informal carers and clinicians: a qualitative interview study. BMJ Open. 2022;12(3):e054279.
4. Tompson A et al. Quality improvements of safetynetting guidelines for cancer in UK primary care: insights from a qualitative interview study of GPs. Br J Gen Pract. 2019;69(689):e819-26.
Chronic Cutaneous Lupus Erythematosus in a Patient with a History of Kikuchi–Fujimoto Disease
Authors: *Agnieszka Owczarczyk-Saczonek,1
Katarzyna Jóźwicka1
1. Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, Collegium Medicum, The University of Warmia and Mazury, Olsztyn, Poland
*Correspondence to agnieszka.owczarczyk@uwm.edu.pl
Disclosure: Owczarczyk-Saczonek has received payment or honoraria for lectures, presentations, speakers’ bureaus or educational events from Abbvie, Allergan, Almirall, Astra Zeneca, Boehringer Ingelheim, GSK, Jansen, Leo, Lilly, Medac, Novartis, Optopol, Sandoz, and Sunph; has received support for attending meetings and/or travel from Abbvie, Allergan, Almirall, Jansen, Leo, Lilly, Novartis, Sandoz, and USB; and has participated in the data safety monitoring board or advisory board at Abbvie, Allergan, Almirall, Boehringer Ingelheim, Novartis, Optopol, Sandoz, and USB. Jóźwicka declares no conflict of interest.
Kikuchi–Fujimoto disease (KFD), histiocytic necrotising lymphadenitis, is a benign and self-limiting disease characterised by lymphadenopathy, fever, fatigue, and leukopenia. KFD typically affects young Asian females. The symptoms of KFD can also mimic more sinister conditions such as non-Hodgkin lymphoma, tuberculous lymphadenitis, or reactive lymphadenopathy.1,2,3 The pathogenesis
of KFD is unknown, but there are viral or autoimmune aetiologies. Several reports have emphasised the importance of KFD and systemic lupus erythematosus (SLE) associations.1,4
CASE REPORT
A 26-year-old Caucasian male was admitted to the outpatient clinic with erythematous and infiltrative lesions on the right cheek and forehead, as well as in the left retro auricular area, with an irregular shape, peeling on the periphery, without subjective symptoms for 6 months.
Nine years ago the patient was treated with lymecycline and isotretinoin due to cystic acne with improvement, which initially improved. However, the condition worsened again 6 years ago, and the patient was treated with isotretinoin (0.5 mg/kg body weight).
Eight years earlier, he was diagnosed with lymphadenopathy of the cervical and submandibular nodes (up to 2 cm) with leukopenia 2.21 G/l, elevated transaminases (alanine transaminase exceeded the upper limit of normal by 6.6 times,
aspartate aminotransferase by 4.3 times), moderately elevated lactate dehydrogenase values, and antibodies against EpsteinBarr virus in the IgG class. Based on histopathological examination of the lymph node, trepanobiopsy, and additional tests excluding the lymphoproliferative process, KFD disease was diagnosed as histiocytic, necrotising lymphadenitis, and the liver damage was considered to be the result of Epstein-Barr virus infection. The symptoms of KFD lasted for about 1.5 years and resolved spontaneously.
Laboratory tests showed no significant deviations from the antinuclear antibody (1:160 normal), and the immunoblot was negative. The histopathological examination of the lesion on the forehead revealed features occurring during lupus erythematosus but the patient did not report any other symptoms typical of SLE. A diagnosis of cutaneous chronic lupus erythematosus was made, and the patient received 200 mg hydroxychloroquine once a day and methylprednisolone acetate topically, and showed good tolerance and improvement within a month. The patient was advised to avoid UV exposure and to undergo regular check-ups every 6 months (Figure 1).
Figure 1: Chronic cutaneous lupus erythematosus in a patient with a history of Kikuchi–Fujimoto disease.
DISCUSSION
KFD can occur in patients with preexisting SLE, or it can coexist with SLE, or evolve into SLE. In some cases, histologic and immunohistochemical features of SLE lymphadenopathy are indistinguishable from KFD. Therefore, antinuclear antibody screening is recommended at diagnosis and close follow-up, especially in patients with cutaneous lesions, for the early detection of an autoimmune disease.1-4
The authors’ patient had skin lesions typical of chronic lupus, without general symptoms, and the patient didn’t fulfil SLE diagnosis criteria according to both the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) classification. However, early initiation of hydroxychloroquine may prevent the development of SLE in the future. Unfortunately, there is no current literature advising how best to monitor patients with KFD for long-term complications and disease associations, such as SLE.
CONCLUSION
The authors present this case to highlight the rare clinical entity of KFD in the Caucasian population, the need for a long-term follow-up, and the high risk of associated autoimmune diseases, such as SLE. The authors’ patient only developed symptoms of chronic lupus approximately 7 years after the symptoms of KFD disappeared. Therefore, long-term follow-up of patients with this syndrome seems necessary.
References
1. Baenas DF et al. Kikuchi–Fujimoto disease and systemic lupus erythematosus. Int Med Case Rep J. 2016;9:163-7.
2. Găman M et al. A challenging case of KikuchiFujimoto disease associated with systemic lupus erythematosus and review of the literature. Case Rep Hematol. 2018;2018:1791627.
3. Salamat S et al. Kikuchi-Fujimoto disease and prognostic implications. Head Neck Pathol. 2020;14(1):272-5.
4. Sopena B et al. Clinical association between Kikuchi’s disease and systemic lupus erythematosus: a systematic literature review. Semin Arthritis Rheum. 2017;47(1):46-52.
Inflammatory Filler Complications Revisited: Controversies, Literature Review, and Case Presentations
Authors: *Hussein Ghanem,1,2 Heba Darwish1
1. Faculty of Medicine, Cairo University, Egypt
2. DermaHealth Clinics, Cairo, Egypt
*Correspondence to hmghanem@kasralainy.edu.eg
Disclosure: Ghanem and Darwish have received support for attending meetings and/or travel from Allergan and Vivacy.
Keywords: Case studies, complications, dermal fillers, diagnosis, inflammatory complications, literature review, management, photo illustrations, prevention.
Although vascular complications are considered the most serious adverse
events associated with dermal filler injections, inflammatory complications, such as infections, granulomas, and hypersensitivity reactions, also present significant challenges and can lead to serious consequences if not promptly managed.1 A thorough understanding of the causes of these complications is essential for improving prevention strategies, diagnostic accuracy, and treatment protocols, all of which are crucial for optimising patient outcomes.
This study aims to investigate the aetiology and presentation of inflammatory complications associated with dermal fillers. By providing an updated literature review and presenting a series of cases from the author’s clinical practice, the study offers practical insights into the real-world management of these adverse events.
MATERIALS AND METHODS
A comprehensive literature review was conducted using search terms such as “dermal filler complications”, “injectable filler adverse effects”, and “hyaluronic acid filler complications”. Databases such as PubMed and Google Scholar were utilised to gather peer-reviewed studies, focusing on complications related to various filler materials, including hyaluronic acid, calcium hydroxyapatite, and poly-L-lactic acid. In addition to the literature review, the authors analysed 12 clinical cases of inflammatory complications following dermal filler injections, either originating from or presenting to their practice over a 24-year period. Each case was documented with photographic evidence and detailed management strategies. Key variables, such as the type of filler, time to complication onset, diagnostic methods, and therapeutic approaches, were carefully examined to assess patterns in complication development and resolution.
RESULTS
The authors’ findings confirm that while dermal fillers are generally considered safe, inflammatory complications can arise from various factors. These were mainly infection and biofilm formation, which were implicated in several cases. Hypersensitivity reactions were possibly due to filler impurities or residues from manufacturing equipment and syringes, bolus or large volume injections, low-viscosity fillers, or the patient’s immune status.2,3
The main controversies in the literature are related to the aetiology, whether mainly infective or mainly hypersensitivity, and whether steroids should be used in the treatment if hypersensitivity is suspected. Key prevention strategies involve strict adherence to aseptic techniques, removing all makeup residues, and using high-quality fillers. Diagnosis was based on clinical signs and symptoms of inflammation, ultrasound and culture and sensitivity, and occasionally biopsy if purulence was present.
Figure 1: Sterile pus from a permanent filler injected 15 years ago.
A B
A) Aspirated pus. B) Facial abscess pre-aspiration. C) One week post-aspiration.
In the author’s series, tailored treatment approaches were successful though prolonged follow-up was needed for those with permanent fillers:
• Ten patients, where infection was suspected, received antibiotics. These were primarily a fluoroquinolonemacrolide combination, administered for 3–6 weeks.
• Systemic corticosteroids, such as prednisone (40 mg/day for 7–21 days) or intramuscular betamethasone, were used in six cases. Two of which had clear hypersensitivity reactions and four of whom did not respond to antibiotics.
• Intralesional therapies included hyaluronidase in five cases and triamcinolone acetonide in four cases. Although strongly suggested in the literature for permanent fillers, 5-fluorouracil was not used in the author’s cases.
• In three cases of permanent fillers, widebore needle extraction of collections was necessary (Figure 1), and surgical removal was attempted in two cases.
CONCLUSION
This study highlights that inflammatory complications from dermal fillers, though rare, can arise from various factors, including inadequate hygiene, filler type, and manufacturing impurities. Strict adherence to aseptic techniques and the use of high-quality fillers are critical preventive measures. Establishing standardised guidelines and encouraging further research will improve long-term outcomes. In the author’s case series, tailored management strategies led to a successful resolution.
References
1. Corduff N et al. Current practices in hyaluronic acid dermal filler treatment in asia pacific and practical approaches to achieving safe and naturallooking results. Clin Cosmet Investig Dermatol. 2022;15:1213-23.
2. Artzi O et al. Delayed inflammatory reactions to hyaluronic acid fillers: a literature review and proposed treatment algorithm. Clin Cosmet Investig Dermatol. 2020;13:371-8.
3. Lee W et al. Etiology of delayed inflammatory reaction induced by hyaluronic acid filler. Arch Plast Surg. 2024;51(1):20-6.
Complete Remission of Paraneoplastic Generalised Eruptive Keratoacanthoma of Grzybowski
After Treatment of the Primary Tumour
Authors: *Francisco José Rodríguez-Cuadrado,1
Lourdes Gutiérrez-Sanz,1 Lucía Turrión-Merino,1
Dolores Suárez-Massa,1 Gaston Roustan-Gullón,1
Rita Cabeza-Martínez1
1. Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain
*Correspondence to franciscojose.rodriguezcuadrado@gmail.com
Disclosure: The authors have declared no conflicts of interest.
Generalised eruptive keratoacanthoma of Grzybowski (GEKA) is a rare disease characterised by the sudden appearance of multiple millimetric keratoacanthomas with diffuse distribution, mainly affecting photoexposed areas, face, and intertriginous areas.1-5
The aetiology is unknown, although it has been proposed that it may be related to ultraviolet radiation, chronic inflammatory skin diseases, trauma, drugs, or malignant tumours.1-5
Figure 1: Multiple millimetric erythematous papules with a keratotic centre, on dorsum of the hand, buttocks, and knees.
MATERIALS AND METHODS
The authors present the case of a patient with GEKA refractory to multiple treatments, which finally resolved completely after surgical and chemotherapy treatment of gallbladder cancer.
RESULTS
A 55-year-old woman, with no relevant personal history, consulted for pruritic skin lesions that appeared abruptly 1 year previously on the arms and legs (Figure 1). Two biopsies were performed, both with result of keratoacanthoma. Neoplasms were ruled out in relation to possible Muir-Torre syndrome by gastroscopy, colonoscopy, ultrasound of the urinary tract, and urine cytology. Finally, it was diagnosed as GEKA according to the criteria of Nofal A et al.4
During 3 years of follow-up, different treatments were performed, all of them without success, including both local (imiquimod, tretinoin, photodynamic therapy) and systemic (isotretinoin, acitretin, methotrexate, erlotinib).
Only 1 month after discontinuation of erlotinib, the patient was admitted to the hospital for acute cholecystitis. A cholecystectomy was performed, and the
anatomopathological analysis revealed the presence of a gallbladder adenocarcinoma. The CT extension study showed peritoneal carcinomatosis, which is defined as Stage IVB. Adjuvant chemotherapy with cisplatin plus gemcitabine was started.
Three months after surgery, the patient reported that skin lesions had stopped appearing and that the pruritus had disappeared. In subsequent follow-up visits, a gradual regression of the keratoacanthomas was observed, parallel to the radiological response of the adenocarcinoma.
Due to the later progression of the metastatic disease, the patient received different lines of chemotherapy. In any case, throughout the follow-up during the 4 years after the cancer surgery, a complete response of the keratoacanthomas was maintained at a cutaneous level.
CONCLUSION
To the authors’ knowledge, this is the first described case of GEKA associated with gallbladder cancer, as well as the first case of GEKA associated with a malignant tumour with complete remission after treatment of the primary neoplasm.
References
1. Anzalone CL, Cohen PR. Generalized eruptive keratoacanthomas of Grzybowski. Int J Dermatol. 2014;53(2):131-6.
2. Schwartz RA et al. Generalized eruptive keratoacanthoma of Grzybowski: follow-up of the original description and 50-year retrospect. Dermatology. 2002;205:348-52.
1. Dermatology Department, Faculty of Medicine of Tunis, La Rabta Hospital, University of Tunis El Manar, Tunisia *Correspondence to dr.dorsafelinkichari@gmail.com
Disclosure: The authors declare no conflicts of interest. The patient has given informed consent to the publication of their case details.
Jaccoud's hand is a rare deforming arthropathy, first described in 1869 by Sigismond Jaccoud.1 Joint deformities are usually reversible, chronic, and non-erosive. Several aetiologies have been suggested.
The authors report a case of Jaccoud's hand in a patient with systemic lupus erythematosus (SLE).
OBSERVATION
A 34-year-old female patient with 20 years' follow-up for SLE with cutaneous, articular, haematological, and renal involvement, was referred to the authors’ department for trophic disorders of hands
and feet. Physical examination revealed telangiectasic malar erythema (Figure 1A), erosive cheilitis, ulcero-necrotic lesions on hands and feet, and ‘cubital gust of wind’ appearance of both hands (Figure 1B).
Rheumatological examination revealed swan-neck deformities affecting the second, third, and fourth fingers of both hands; Z-shaped deformities of the thumbs; and ulnar deviation of the fifth fingers, which returned to a normal position with a passive manoeuvre. These reducible deformities were compatible with Jaccoud's arthropathy.
The history revealed no Raynaud's phenomenon or pain in the metacarpophalangeal and interphalangeal joints. These changes developed progressively, despite treatment with systemic corticosteroids and synthetic antimalarials.
CONCLUSION
The prevalence of Jaccoud's hand in SLE is around 5%.2 Its non-erosive character distinguishes it from rheumatoid arthritis. Joint deformities result mainly from soft-tissue abnormalities such as ligament laxity, capsule fibrosis, and muscle weakness. Management relies mainly on muscle-strengthening physiotherapy and the use of orthotics.
Orthopaedic soft-tissue surgery is also an alternative in cases of significant daily impact.
Figure 1: A) Malar erythema and telangiectasia. B) Reductible Z-shaped deformities of the thumbs and ulnar deviation of the fifth fingers.
References
1. Jaccoud FS, “Sur une forme de rhumatisme chronique,” Leçons de clinique médicale faites à l’Hôpital de la Charité (1869), Paris: Adrien Delahaye, pp.598-605.
2. Santiago MB. Jaccoud-type lupus arthropathy. Lupus. 2022;31(4):398-406.
The following highlights showcase late-breaking research presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Topics covered ranged from the role of AI in detecting skin conditions such as psoriasis, multimorbidity, and the effect of eczema on both patients’ mental health and quality of life. Additionally, emphasis was placed on the current status of treatments and diagnostic tools for atopic dermatitis.
AI Enhances Early Detection of Generalised Pustular Psoriasis
GENERALISED pustular psoriasis (GPP) is a rare but severe skin condition that is often underdiagnosed, leading to delayed treatment for many patients. However, timely and accurate diagnosis is crucial given that, when left untreated, GPP flares can become lifethreatening.
AI has shown promise by analysing data from patient records to recognise complex patterns within large datasets, which can aid in the early identification of GPP.
This study, presented at the EADV Congress 2024, explored the use of AI to identify early indicators of GPP by analysing patient data from two large sources, the DataDerm clinical data registry and the OM1 RealWorld Data Cloud. Patients with an eventual GPP diagnosis, particularly those with prior psoriasis diagnoses, were identified, and their health histories were examined. An AI tool was employed to analyse these records, focusing on treatment patterns as potential signals for early GPP identification.
The study examined a cohort of 10,988 patients with GPP, and the AI tool, when using all available patient data, achieved an area under the curve of 0.79 in identifying patients with GPP. Even when the AI tool was limited to evaluating coded medication histories alone, it maintained acceptable accuracy, with an area under the curve of 0.70. The AI’s ability to distinguish potential GPP cases from other psoriasis types
was linked to distinct patterns in specific psoriasis treatments that often preceded a GPP diagnosis.
These findings demonstrate the potential of AI to aid in the early identification of GPP by examining patient treatment histories. The AI tool’s ability to detect unique treatment patterns highlights that patients who develop GPP are often managed differently from those with other forms of psoriasis, even before their GPP diagnosis, an insight that could improve early diagnosis and timely intervention for this patient group. With new treatment options now available, earlier diagnosis facilitated by AI could help alleviate patient suffering by ensuring they receive appropriate and effective treatment sooner.
These findings demonstrate the potential of AI to aid in the early identification of GPP by examining patient treatment histories
Over the 2-year follow-up, dupilumab showed significant improvements in patient outcomes
Long-Term Benefits of Dupilumab for Patients with Atopic Dermatitis
ONE of Europe’s largest atopic dermatitis (AD) registries, the TREATgermany registry, has released promising new findings on the long-term efficacy of dupilumab in treating moderate-to-severe AD, presented at the EADV Congress 2024.
The registry, established in 2016, enrolled 1,849 patients across 65 recruitment sites by July 2023
The registry, established in 2016, enrolled 1,849 patients across 65 recruitment sites by July 2023. Of these, 294 patients who began dupilumab treatment during or after joining the registry were followed for 2 years, offering valuable insights into the therapy’s sustained impact in real-world settings.
Patients in the study (mean age: 40.9 years; 42.2% female) had high disease activity at the start of treatment, with an average Eczema Area Severity Index (EASI) of 21.0 and significant impacts on quality of life, reflected by a Dermatology Life Quality Index (DLQI) score of 13.3. The majority had previously received systemic therapy for AD, including glucocorticoids (61.2%) and cyclosporine (36.1%).
Over the 2-year follow-up, dupilumab showed significant improvements in patient outcomes. By Month 24, the average EASI score dropped to 3.1, while DLQI decreased to 3.5, indicating a substantial improvement in patients' quality of life.
Additionally, the mean Patient-Oriented Eczema Measure (POEM) score, which tracks symptom frequency and severity, fell to 6.2. The study reported that 78.8% of patients achieved EASI 75 (a 75% improvement in EASI score), and 51.2% reached EASI 90, demonstrating high efficacy.
A sensitivity analysis that accounted for patients discontinuing dupilumab, treating them as non-responders, still showed strong results, with EASI 75 and EASI 90 rates of 65.6% and 42.7%, respectively. In terms of safety, 36.4% of patients reported ocular issues, with 29.9% experiencing conjunctivitis. While most cases were mild-to-moderate, 13 patients discontinued dupilumab due to these side effects.
Overall, these findings underscored dupilumab’s long-term effectiveness in reducing disease severity and improving quality of life for patients with AD in routine care settings.
Hand Eczema Effects on Mental Health and Quality of Life
THE RESULTS of a systematic review and meta-analysis presented at the EADV Congress 2024 have revealed severe psychological and quality of life impacts experienced by patients with hand eczema (HE).
The study was conducted by researchers from Copenhagen University Hospital, Denmark, and analysed data from 81 studies, encompassing 17,835 patients with HE and 31,541 controls, to assess the extent of anxiety, depression, and quality of life impairments associated with the condition.
The results revealed that hand eczema has a moderate-to-severe effect on patients' quality of life, with a weighted mean Dermatology Life Quality Index (DLQI) score of 10.66, indicating a significant impact.
The results revealed that hand eczema has a moderate-to-severe effect on patients' quality of life
A strong correlation was observed between the severity of HE (measured by the Hand Eczema Severity Index, or HECSI) and the deterioration in quality of life, with a Spearman’s rank correlation of 0.76. Patients with HE also scored significantly lower on the EQ-5D-VAS, compared to controls (68.03 versus 80.63; p<0.00001).
The study also found that patients with HE had higher levels of anxiety, with a mean score of 7.4 on the Hospital Anxiety and Depression Scale (HADS), compared to 5.8 for controls (p=0.0008). Depression scores were not significantly different between the two groups. However, the study revealed that patients with HE have an increased risk of anxiety (odds ratio: 2.60) and depression (odds ratio: 4.00). Additionally, these patients faced a higher prevalence of suicidal ideation compared to healthy controls (14.2% versus 8.3%).
The researchers concluded that HE significantly affects quality of life and is associated with higher risks of anxiety, depression, and suicidal thoughts. They called for more extensive studies to better understand these associations and to develop targeted interventions for patients with HE.
Atopic Dermatitis Linked to Increased Multimorbidity
NEW RESEARCH presented at the EADV Congress 2024 has shown that participants with atopic dermatitis (AD), especially moderate-to-severe disease, are at higher risk for having multimorbidity (MM).
The study aimed to assess the prevalence of MM and its association with AD in the Dutch adult general population, as well as the impact of MM on health-related quality of life in those with AD. Conducted within the Lifelines cohort, this cross-sectional study included 37,193 participants, of whom 3,242 (8.7%) reported having AD.
Data were collected from questionnaires, medication records, and clinical assessments, focusing on the lifetime prevalence of 52 diseases grouped into 15 domains. AD was self-reported and physician-diagnosed, with severity measured using the Patient Oriented Eczema Measure (POEM). MM was defined as the presence of two or more diseases, excluding AD.
The prevalence of MM was found to be 64.9% in those with AD, compared to 52.4% in those without AD, with the rate increasing based on AD severity: 62.4% in mild cases and 68.4% in moderate-to-severe cases. The most common comorbidities in the AD group were atopic diseases (48.4%), haematologic diseases (25.5%), and respiratory diseases (21.2%).
Individuals with AD had 1.95 times higher odds (95% CI: 1.81–2.11) of having MM than those without AD, with higher odds in moderateto-severe cases (odds ratio: 2.49) compared to mild cases (odds ratio: 1.73). The odds increased with the number of comorbidities, reaching 4.08 for individuals with five or more additional conditions.
Health-related quality of life measures also showed significant differences in those with AD and MM, especially with regard to mental health. Multimorbid individuals with AD had a lower mental component score and lower selfreported health scores.
These findings suggest that individuals with AD, particularly those with severe disease, are at a higher risk of MM and poorer mental health outcomes, warranting further investigation into the role of systemic inflammation in AD.
The most common comorbidities in the AD group were...
Atopic diseases
Haematologic diseases
Respiratory diseases
48.4% 25.5% 21.2%
The Predictive Factors for Cardiovascular Disease in Dermatomyositis
RESEARCH presented at the EADV Congress 2024 has shown that Raynaud’s phenomenon, longer disease duration, anti-Ro 52 antibodies, elevated erythrocyte sedimentation rate (ESR), and elevated lactate dehydrogenase (LDH) are significant predictors of dilated cardiomyopathy (DCM) and congestive heart failure (CHF) in patients with dermatomyositis.
Dermatomyositis is a rare autoimmune inflammatory myopathy that has been linked to an increased risk of cardiovascular diseases, although prior studies have not exclusively focused on patients with dermatomyositis. Therefore, researchers sought to investigate the predictive factors contributing to the development of cardiovascular disease in this patient population.
This retrospective study reviewed medical records of patients with adult-onset dermatomyositis from two tertiary care centres in Ontario, Canada, between January 2010–September 2023. The analysis included a total of 114 patients, with a median age of 58 years (range: 21–99), who were predominantly female (80%). Among the cohort, 16 patients (14%) developed DCM and/or CHF. Statistical analysis revealed that Raynaud’s phenomenon, longer disease duration, antiRo 52 antibodies, and elevations in ESR and LDH were significantly associated with the development of DCM/CHF. Elevated ESR, a marker of systemic inflammation, and elevated LDH, indicative of tissue damage, emerged as key predictive biomarkers.
The results of the study highlight the need for clinicians to closely monitor patients with dermatomyositis for early signs of cardiovascular complications, especially those with the identified risk factors. Future studies should aim to elucidate the underlying mechanisms that link dermatomyositis to cardiovascular outcomes, and refine risk assessment models, ultimately improving patient care and outcomes in this patient population.
The analysis included a total of 114 patients, with a median age of 58 years (range: 21–99), who were predominantly female (80%)
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Congress Interviews
EMJ was delighted to interview both the President, Branka Marinović, and Treasurer, Menno de Rie, of the European Academy of Dermatology and Venereology (EADV) Congress 2024, as they discuss cutting-edge research in dermatology and the future of EADV.
Branka Marinović
President, European Academy of Dermatology and Venereology (EADV); Professor of Dermatology and Venereology, University of Zagreb School of Medicine, Croatia
What led you to focus on dermatology and venereology after completing your medical degree?
It's quite difficult to say because, at the time when I started my residency, dermatology was not as attractive of a residency as it is today. I had different opportunities, and I tried a few other positions, and then in the end I was lucky enough to get into dermatology. Although, I have to say, it was not my first wish; I was more interested in internal medicine and other specialities. However, after a few years, I was very happy because I discovered that dermatology has a lot of opportunities, from surgery to oncology and immunology. It has many, many subspecialty fields, so there are lots of opportunities.
in the field of novel therapies. For many years, autoimmune blistering diseases were treated exclusively with systemic corticosteroids, which our patients are usually scared of because they are aware of a lot of side effects. But before the introduction of steroids in therapy, about 95% of patients were dying within 5 years.
Today, we have some new biologic drugs that can be used in treatment, and there are a lot of other drugs in pipelines, especially for treating bullous pemphigoid. It's a really exciting field and an exciting time for this group of diseases. There are a lot of trials and research currently going on.
Q3 Are there any ongoing projects at the University of Zagreb, Croatia, that you are particularly excited about?
We have some new biologic drugs that can be used in treatment, and there are a lot of other drugs in pipelines
Q2 Could you tell us a bit more about autoimmune blistering diseases, what the main developments are, and your motivation to work in this area?
This is one field of dermatology that, in the last 20 years, developed very rapidly in the field of diagnostic methods, but also
I’ve been the Head of the Department of Dermatology at Zagreb for more than 10 years, and I have a group of very enthusiastic younger colleagues who are working in different fields, from sexually transmitted diseases, dermato-oncology, to autoimmune blistering diseases.
For me, I'm always coming back to autoimmune blistering diseases, because in that field, I feel most at home and comfortable.
We are a referral centre for the whole of Croatia in the field of autoimmune blistering diseases, but we are also part of the European Reference Network (ERN) for rare diseases of the skin, currently headed by Christine Bodemer in Paris. We are the group that can help patients throughout Europe, so patients from other countries are also coming to us.
Q4
The EADV plays a crucial role in addressing both clinical and public health challenges in dermatology and venereology. What initiatives or strategies allow EADV to tackle emerging global issues, such as skin cancer prevention, inflammatory skin diseases, or the rise of sexually transmitted infections?
This year, EADV reached almost 11,500 members, so we are an organisation with power. A lot of our members are key opinion leaders in their countries. Beside
other actions, we started to be very active in advocacy a couple of years ago. This means going to the EU to present the main problems faced by patients, as well as health care professionals in our specialty; cancer prevention actions; and also speaking about inflammatory diseases and the burden of those diseases, including the availability of drugs in different countries.
As a model, we have the American Academy of Dermatology (AAD), and they have a very strong advocacy group. However, it's much easier to do advocacy in the USA because they are one country, whereas Europe is made up of many countries, each dependent on their government. This makes it a little bit more challenging.
This year, EADV reached almost 11,500 members, so we are an organisation with power
Q5
As one of the chairs of the ‘Hot topics in dermatology’ session at the EADV Congress 2024, what areas of dermatology do you believe warrant further research?
This is called the President Symposium, so it's usually organised by three presidents: the immediate past president, the current president, and the incoming president. Each of us chose one of the topics, so I chose to invite Jan Gutermuth, Head of the Dermatology Department, University Hospital Brussels, Belgium; and PresidentElect, Royal Belgian Society for Dermatology & Venereology, Belgium, who has a big interest in atopic dermatitis and some inflammatory skin diseases. He has also a big interest in following the signs of torture and different aspects of this neglect. This included older people who are being neglected by family members or nursing home staff, and now also refugees.
Q6
What sessions have you particularly enjoyed this year at the EADV Congress?
I just arrived from the session where I was speaking about lupus erythematosus, which is also one of my fields of interest. It was a very successful session where we had four speakers who spoke about pathophysiological processes, classical and available therapeutics, but also about future therapies because this field of immunology is developing quickly.
What is new in the programme in 2024 is the EADV Games. It is a completely new format, with games and representatives of residents from 18 countries competing against each other for a prize. As a completely new session, I cannot tell you too much about it, but it is an exciting development.
Q7
As EADV’s President, what are your main objectives looking into the future?
I became President 2 hours ago, so my term as president just started. I think that my main goal is to keep quality. We have really excellent congresses, spring symposia, and a lot of courses that we are offering to young physicians. We can see from new members that there's interest in the EADV from younger generations, which makes us very happy. I would like to increase the number of courses for residents because they really like it, and such events are excellent platforms for learning as well as for networking. I would also like to strengthen our scientific committee and help to bring some new formats, because if these EADV Games are successful, maybe there is a need for some other new formats. Maintaining the high quality we strive for is not an easy thing to do.
Treasurer of the European Academy of Dermatology and Venereology (EADV); Professor of Dermatology, University of Amsterdam, the Netherlands
Before specialising in dermatology, you earned a PhD in immunology, could you describe the path that first led you to immunology and then what influenced you to make the switch?
Immunology came into my path when I was studying medicine. I worked at the Immunology Lab of the Red Cross Blood Bank in Amsterdam for 6 months and enjoyed it very much. I must say, however, I was also a little bit disappointed by the internships that I did. I was thinking: “Oh, my god, is this really what I want to do for the rest of my life?”
After these 6 months in the immunology lab, I was offered a PhD position and I decided to go for it and see where it took me. This was back in the 80s when immunology was becoming more important. It was really booming with the start of monoclonal antibodies, and breakthroughs in understanding blood diseases and other conditions. I thought there were a lot of things going on, so I decided to stay for about 6 years, finished my thesis, and then I met Rudi Cormane, a Professor of Dermatology and one of the founders of the European Society for Dermatological Research (ESDR).
He was an internal doctor but later became a dermatologist. His knowledge of skin and immunology was broad. He said to me: “If you're really interested in immunology, you have to dive into dermatology.” He offered me a position to become a dermatologist in his department so that I could start doing research there as well. This was an offer that I couldn’t refuse. Unfortunately, he passed away just a couple of weeks later.
Fortunately, his successor Joannes Bos was also really into immunology. Together, we started working on psoriasis and the immunology of psoriasis, publishing many articles on it. That’s how I became a dermatologist.
Q2
Given your research often explores the connection between immunology and dermatology, how have recent advances in immunodermatology influenced treatment options for chronic skin diseases like psoriasis?
‘The development of monoclonal antibodies’, which I worked on in the immunology lab, later developed into ‘the use of monoclonal antibodies for treatment of diseases’, which made a huge difference.
When I did my training as a dermatologist, we had 24 beds for treatments in the academic hospital. Now we don't have any beds anymore, because most of these patients are treated with monoclonals or biologicals, as we call them nowadays, which are monoclonal antibodies. So, with biologicals, we have so many more options for the treatment of chronic inflammatory diseases and a much better understanding of them. It's really taking off now. It all began with TNFs, but if you look at where we are today, especially with the latest advancements such as JAK inhibitors, it feels like the sky's the limit.
It's not just about injections or parenteral use anymore; creams with JAK inhibitors are also being developed. This could potentially allow us to move away from using corticosteroids for various
Menno de Rie
If you have moderateto-severe psoriasis, it's affecting your quality of life equal to or more than having a heart attack
skin diseases. So, we might be able to forget about the old treatments and start using JAK inhibitors instead.
The discovery that TNFs can be used to treat a wide range of skin diseases, including psoriasis, made a huge impact. A lot of industries started getting interested in investing in dermatology research, whereas before, no one in pharma really cared much about it, especially when it came to creams and ointments. It wasn’t seen as a big market, and there weren’t any major developments happening. But now, with the growing understanding of the pathogenesis of diseases, people have realised that there are many points where we can effectively target treatments and start addressing diseases at their root cause.
That made a huge difference. For me, as a dermatologist still involved in research and working closely with the pharmaceutical industry, things took an interesting turn in around 2007. Novartis approached me and said: "With your background in dermatology and your interest in immunology, would you be interested in leading our Translational Medicine Department for dermatology to develop new drugs?" I thought: "Why not?" So, we sold our house and moved to Switzerland. It was quite a change! I worked there for a few years with great enthusiasm and played a part in developing several drugs.
Q3 When did the shift happen with JAK inhibitors and TNF inhibitors?
There’s a lot going on between the development of TNF inhibitors and the more recent JAK inhibitors, which started around 5 years ago. Now, we’re also seeing topicals being introduced, which is really the latest advancement. But in
between the TNF- and the JAK inhibitors, we have the IL-17 inhibitors and IL-23 inhibitors. So, there are a lot of other biologicals that have been developed and are very successful as well.
I did most of my research together with the pharmaceutical industry and gave numerous lectures to dermatologists in the Netherlands and abroad about these new drugs coming to the market, making sure dermatologists understood how they worked.
Q4
A recent paper you coauthored, ‘Review of literature and clinical practice experience for the therapeutic management of Morgellons disease’, explores the current understanding of Morgellons disease. Could you outline the key takeaways from this review?
That comes from a PhD student I mentor, Patrick Kemperman, who's the first author of the article. He's doing his research on psychodermatology, specifically on Morgellons disease, which is a psychosis, meaning patients are under the impression that there are skin infestations, which is not true. But since they think that there are infestations, they want to get treated for it. The patients start scratching and trying to convince dermatologists that there are microbes in their skin that must be treated, but the problem is in their mind, so you have to treat them with antipsychotics.
The takeaway message is that you have to do a very thorough investigation of these patients to ensure there isn’t a genuine skin infestation. Often, the issue lies ‘between the ears’, so to speak. The first step is to recognise this. Additionally, it's crucial for dermatologists to collaborate with a team, particularly psychiatrists,
To look at the efficacy of a new drug, we always incorporate a scale to assess its effects on quality of life
to help educate patients that their condition requires a different approach, that the focus should be on their mental health.
Q5
How would you say the awareness is around psychodermatology? Is that a relatively new aspect of being a dermatologist that you have to be aware of?
While it's not a new concept, there’s an increasing focus on it. People are beginning to recognise the importance of psychodermatology. As dermatologists, we understand how much a skin disease can impact someone's life and contribute to their suffering, perhaps even more so than in other specialities. Having a skin condition is visible to others, which amplifies the impact. For example, if you have moderate-to-severe psoriasis, it's affecting your quality of life equal to or more than having a heart attack.
This growing understanding of the significance of psychodermatology and its impact on quality of life has resulted in increased attention in the field. For instance, to look at the efficacy of a new drug, we always incorporate a scale to assess its effects on quality of life because we recognise that treatment of the skin is not equal to treatment of the quality of life of patients; these are distinct aspects that require separate consideration.
Q6
In your role as Treasurer, you have a unique perspective on EADV's priorities. How does the organisation balance its commitments to research, education, and public awareness within dermatology and venereology?
EADV is an organisation based in Lugano, Switzerland, where 37 people are working to make all this possible. The congress is
our main activity and also the financial driver of our organisation. We try to serve our dermatologists in many ways, but everything we do is focused on the improvement of care for our patients. We do not only organise an annual congress and symposium, but we also produce two journals, make podcasts, organise summer schools and leadership trainings for young dermatologists, run an advocacy initiative etc., and have a wide range of other activities ultimately helping dermatologists to improve the care for our patients. In addition, we decided to support the development of European guidelines so that patients are more or less treated in the optimal way.
Q7
How does the EADV support young dermatologists and researchers entering the field, and what initiatives have been most successful in nurturing the next generation of specialists?
We have leader development programmes. At this congress, you'll notice that we have special sessions dedicated to young dermatologists and residents, and they organise their own programme based on what they feel is important. It’s all about prioritising what truly resonates with them.
We also make it possible for them to come to these meetings that EADV organise. We offer reduced rates and provide over 190 grants totalling around a quarter of a million Euros each year. We support individuals from underdeveloped countries, allowing them to participate at minimal cost, and we provide facilities for students as well. We’re doing everything we can to attract young people because they are the future.
Q8 What sessions are you most looking forward to at the EADV Congress 2024? What do you think will be the highlights and what new topics have you seen emerging this year compared to the last couple of years?
That’s a challenging aspect. What I find appealing is the emphasis we need to place on being mindful of our environment. This doesn’t just mean being cautious about energy use and our footprint when organising a congress, but also raising awareness among dermatologists so that when they return to their practices, they start questioning the materials they’re using. They should consider whether their methods are truly sustainable and what the consequences are for our environment.
So, that I think, is a very new aspect of our organisation and our Congress, and we put a lot of effort into it. For instance, the plenary lecture that will kick off this afternoon will be given by a renowned researcher and adventurer who has travelled the
world in a hot air balloon and more. He aims to raise awareness about the importance of being mindful of our actions and ensuring the safety of our planet. To me, this is a crucial topic that we must prioritise right now.
There are also a lot of developments in the field of treating inflammatory diseases. While it's not a completely new area, there are constantly new drugs on the market. For me, however, the environment is my top priority right now, and that’s a very personal stance.
Q9 Are there any sessions on the programme that, say you did have all the time in the world, would be the ones you would make a beeline for?
The late-breaking sessions are the ones I find very interesting because there you hear talks about things people have done, studied, etc., that have not yet been published. Latebreaking sessions are where you can get to know the latest and the hottest pieces of work in the field.
Skin Microbiome and Acne: Microbial Imbalances and Impact –Interview with Three Key Opinion Leaders
Interviewees:
Marco Rocha,1,2 Thomas Dirschka,3,4 Alison Layton5,6
1. Federal University of São Paulo, Brazil
2. Brazilian Society of Dermatology, São Paulo, Brazil
3. CentroDerm Clinic, Wuppertal, Germany
4. Faculty of Health, University of Witten-Herdecke, Germany
5. Skin Research Centre, Hull York Medical School, University of York, UK
6. Harrogate and District NHS Foundation Trust, UK
Disclosure:
Rocha has served as a consultant for Bioderma, Esthederm, Eucerin, Galderma, Kenvue, L’Oreal, Leopharma, and Theraskin. Dirschka has received research support from AbbVie, Almirall, Biofrontera, Damae, Emulation, Galderma, Intros, ISDIN, La Roche Posay, L’Óreal, Mylan, Nordberg, Olistic, Schulze & Böhm GmbH, Scibase S.A., Smartinmedia AG, Speclipse, and Vichy; conducted lectures for Aesclepion, Almirall, Beiersdorf, Biofrontera, Damae, Dr. August Wolff, Galderma, GSK, Infectopharm, Intros, Janssen–Cilag, Leo, Mylan, Neracare, Novartis, Pierre Fabre, Pfizer, Riemser, Speclipse, and UCB; and been on advisory boards for Almirall, Beiersdorf, Biofrontera, GSK, Dr. Pfleger, Galderma, Janssen–Cilag, Leo, Mylan, Neracare, Novartis, Pierre Fabre, Scibase, Smartinmedia AG, and Vichy. Layton has acted as a consultant for, been chief investigator for research grants (funded to institution), and/or received honoraria for unrestricted educational events from Alliance, Almirall, Beiersdorf, Galderma, La Roche Posay, L’Oreal, Leo, Mylan, Meda, Novartis, Sanofi, and Viatris.
Acknowledgements: Medical writing assistance was provided by Brigitte Scott, MarYas Editorial Services, Cowlinge, UK.
Disclaimer: The opinions expressed in this article belong solely to the named interviewees.
Support: The publication of this article was funded by Beiersdorf.
Interview Summary
Acne vulgaris, commonly known as acne, is a multifactorial, chronic inflammatory skin condition involving the pilosebaceous unit, and is one of the most common skin diseases globally. Acne significantly impacts the quality of life and wellbeing of patients, and can be associated with anxiety, depression, and low selfesteem. This skin condition is also associated with substantial healthcare costs and economic burden for society. The treatment of acne is complex and challenging. For this article, EMJ conducted an interview in September 2024 with key opinion leaders Marco Rocha from Federal University of São Paulo, and Brazilian Society of Dermatology, Brazil; Thomas Dirschka from CentroDerm Clinic, Wuppertal, and University of WittenHerdecke, Germany; and Alison Layton from the Skin Research Centre, Hull York Medical School, University of York, and Harrogate and District NHS Foundation Trust, UK. The key opinion leaders, who have a wealth of experience and expertise in the clinical management of acne, were asked about the current landscape for the management of acne, and the potential role of the skin microbiome in the development and treatment of this chronic inflammatory skin disease. The experts provided valuable insights into some of the many unmet needs in acne management, particularly the overuse of antibiotics and the lack of effective alternative therapies for this condition. The experts discussed the contribution of the skin microbiome and the potential role of microbial imbalances in the development of acne, and the potential of prebiotics and probiotics in restoring skin health. The concept of integrating microbiome-modulating strategies into conventional acne treatment, and whether there is a connection between the skin microbiome and psychological conditions such as depression, were also considered. A further topic covered was educating patients and parents about acne. Finally, the experts outlined what the future landscape of acne management might look like.
INTRODUCTION
Acne vulgaris, commonly known as acne, is a multifactorial,1 chronic inflammatory skin condition involving the pilosebaceous unit,2 a structure comprising the hair follicle, hair shaft, and sebaceous gland.3 Acne is one of the most common skin diseases globally,4 affecting more than 80% of adolescents and young adults,5 many of whom develop acne scars.6 This skin disease significantly impacts the quality of life and wellbeing of patients,7-11 and can be associated with anxiety, depression, and low self-esteem.11 Individuals with acne can feel embarrassed by their lesions or post-acne marks, and often feel stigmatised.12 Acne is also associated with substantial healthcare costs and economic burden for society.13
Layton explained that knowledge of the pathophysiology of acne has unfolded significantly over the last 5 years, and understanding of this condition at a molecular level has improved; however,
there remain many unanswered scientific questions in this area. There are few studies to help guide decisions for the long-term management of acne. The treatment of acne is complex and challenging.2
THE CURRENT LANDSCAPE FOR ACNE MANAGEMENT
Overuse of
Antibiotics
in Acne Management and Limited Treatments to Reduce Sebum
Layton highlighted that one very important unmet need from a clinical perspective relates to the overuse of antibiotics for the treatment of acne,14,15 and the resulting concern about antimicrobial resistance,14,16-19 in the context of a lack of effective alternative therapies for this condition. Harbouring resistant Cutibacterium acnes (C. acnes; formerly Propionibacterium acnes) in patients with acne treated with antibiotics has been shown to correlate with
poor clinical response,20 but this depends on the balance of resistance present within the individual pilosebaceous follicles. As antibiotics work through antimicrobial as well as anti-inflammatory mechanisms, the presence of antimicrobial resistance does not necessarily impact on acne response; however, the negative impact and consequences of antimicrobial resistance may be much broader than just in the skin.
Notably, there is variation between the current guidelines on the classification of acne severity, indications for initiating treatment with oral antibiotics, and maximum duration of oral antibiotic treatment; however, there is agreement that the non-antibiotic topical treatment benzoyl peroxide should be co-prescribed when administering antibiotics, and antibiotics should be used as part of a combination regimen.21
Layton confirmed that acne is a disease of sebogenesis, and that both the regulation of sebum excretion and the composition of sebum are integral to the pathogenesis of acne. Therapies that target sebum, an oily substance produced by the sebaceous gland that forms a hydrophobic protective barrier on the skin,22 are needed to regulate sebum secretion3 and alterations in sebum composition.23 There are limited systemic treatments available for acne that effectively reduce sebum, including hormonal therapies for females (such as combined oral contraceptives, and spironolactone24), and isotretinoin for males and females.25
Up until very recently there were no topical agents that reduce sebum; however, clascoterone, a novel topical anti-androgen that is approved by the FDA for the treatment of acne in both male and female patients,26,27 has been shown to reduce sebum to some degree.28
Layton emphasised: “We need alternatives to antibiotics for the treatment of acne, I don’t think there is any question about that. Also, there are no topical therapies available that significantly reduce sebum. These remain key unmet clinical needs in the management of patients with acne.”
Further Unmet Need in Acne Treatments
When necessary, female patients may benefit from systemic treatment with offlabel use of anti-androgen drugs, such as spironolactone.29 Rocha pointed out that studies are needed in adult females with acne to understand the safety and efficacy of bicalutamide, a second-generation, oral, non-steroidal anti-androgen with a similar structure to the first-generation, oral, non-steroidal, anti-androgen flutamide.30,31 Rocha suggested that: “If additional studies are conducted to show the safety and efficacy of bicalutamide, in the future we may see different options to treat adult female acne without using oral antibiotics.”
In terms of the ‘journey’ of acne, Layton stated that there is agreement and some evidence for the use of maintenance therapy,21 but there is a lack of evidence for effective preventative therapies for acne. Layton suggested that novel therapies for the early stages of acne development, to prevent progression to a more aggressive form of the skin disease, is also an area of unmet need that requires research effort.
A further unmet need highlighted by Layton is identifying and providing the sort of treatments that patients want to use. Topical therapies are not always tolerated well by patients because they can lead to adverse effects as a result of increased transepidermal water loss and impaired skin barrier integrity. Dirschka agreed that most conventional acne treatments, including topical benzoyl peroxide and vitamin A preparations, are irritative,32 which can hinder treatment, particularly in individuals with sensitive skin. Therefore, improving formulations is a further unmet need in acne treatment.
Layton described a James Lind Alliance Acne Priority Setting Partnership,33 the process of which identifies and ranks treatment uncertainties through a collaboration between many stakeholders with a vested interest in acne, including people with acne and their relatives, allied health professionals, and regulators.33 This established National Institute for Health and Care Research (NIHR) process provides a
platform to help distinguish 'what we don’t know', and 'what we might want to know', and identifies the most common treatment uncertainties; hence defining potential areas for future research. The most common uncertainties identified by participants in this study are shown in Table 1 33
Dirschka outlined that patients with acne often try home remedies,34,35 or over-thecounter treatments,35 consult pharmacists, and search the internet before visiting a general practitioner or dermatologist. Layton concurred that patients often try to resolve their acne symptoms themselves before visiting a doctor, and the treatments they use are often numerous, expensive, and ineffective.
Treatment uncertainties
‘Which physical therapies, including lasers and other light-based treatments, are safe and effective in treating acne?’
‘Are cosmetic remedies for spot-prone skin as effective as their makers claim them to be?’
‘Which complementary and alternative therapies are safe and effective in treating acne?’
‘What is the best treatment for acne scars?’
‘What is the best topical produce for treating acne?’
Unmet Need in Managing Truncal Acne
Other clinical unmet need includes ascertaining whether truncal acne36 has the same pathophysiology as facial acne, and can be managed in a similar way. This is particularly important as truncal acne has been shown to greatly impact quality of life,37,38 but is often overlooked in clinical practice.36,39-41
Unmet Need in Managing Acne Sequelae
Acne-related scarring is common, and can even occur in patients whose acne is effectively managed.42 The psychosocial impact of post-acne scarring is substantial.7 Current treatments for scarring in patients with acne often involve invasive procedures.43 According to Layton, there is some evidence to suggest a susceptibility to scarring in patients with acne, as these patients mount a different innate immune
response,43 and there is often a family history of acne-induced scarring.44,45 Further research effort is needed to define which patients with this chronic inflammatory disease are likely to scar.
A further challenge specified by Rocha is how to prevent post-inflammatory hyperpigmentation (PIH), which is a major cosmetic concern, particularly in individuals with darker skin complexions.46,47 PIH is often perceived by patients as more distressing than the acne itself,48 and individuals with PIH are stigmatised.49
Unmet Need in Specific Patient Populations with Acne
Rocha highlighted that there are unmet acne treatment needs for specific populations, such as pregnant females,50 and transgender males.51
Table 1: The most common treatment uncertainties identified by participants in the James Lind Alliance Acne Priority Setting Partnership.33
Several commonly prescribed acne therapies are contraindicated during pregnancy and lactation, and there is a paucity of guidelines to direct management of acne in females who are pregnant or breastfeeding.50
Acne is a common adverse effect among transgender males receiving testosterone.51 Rocha noted that discontinuation of isotretinoin treatment in this population is associated with high rates of flare-ups and recurrence, as well as poor outcomes.52 Furthermore, there is limited scientific literature on the issues arising from hormone therapies in this population in the short- and long-term, as well as a lack of robust clinical studies to guide treatment of these individuals.2,53 There are several barriers to acne treatments in transgender males, including cost, absence of multidisciplinary care, mistrust of the healthcare system, and a dearth of education about transgender-specific acne care.54
Disparity in Access to Acne Treatments
In Germany, more than two-thirds of acne treatments can be purchased over-the-counter, according to Dirschka. In contrast, Layton highlighted that, although benzoyl peroxide is available over-the-counter in the UK, most treatments are only available on prescription.
The experts suggested that isotretinoin may be the most effective drug currently available for acne, as it impacts on the main pathophysiological factors of acne. Dirschka described a disparity in the availability of the acne treatment, isotretinoin. Some Asian countries have easy access to this therapy, which is in contrast to the UK, where isotretinoin is only licensed for severe acne that has not responded to combinations of topical and oral agents. Furthermore, a recent regulatory review in the UK recommends that patients under 18 years require confirmation from two prescribers that the medication is warranted.55
THE POTENTIAL ROLE OF MICROBIAL IMBALANCES IN ACNE DEVELOPMENT
The skin microbiome is composed of various microorganisms and protects the body against pathogens, trains the immune system, and facilitates the breakdown of organic matter.56 Dysbiosis (an imbalance of microorganisms) in the skin microbiome has been implicated in the development of acne.56
C. acnes is important in the maintenance of healthy skin, but can also act as an opportunistic pathogen in acne.57 However, the quantity of C. acnes does not appear to trigger acne,57,58 as patients with acne do not have higher levels of C. acnes in follicles than individuals without this skin disease.57
Rocha clarified that there is a loss of bacterial diversity in the skin microbiome in acne compared with healthy skin. Specifically, a loss of balance between the different C. acnes phylotypes, and a simultaneous dysbiosis of the skin microbiome, is associated with acne.58 The loss of diversity of C. acnes phylotypes triggers activation of the innate immune system,59 which leads to cutaneous inflammation.
Other bacterial species important in the skin microbiome include Staphylococcus epidermidis (S. epidermidis) and Cutibacterium granulosum (C. granulosum; formally Propionibacterium granulosum).60 C. acnes and S. epidermidis are commensal bacteria that have been described as ‘skin microbiota sentinels’ with a key role in the skin ecosystem, preventing microbiota disequilibrium by competing with pathogens and producing beneficial bacterial metabolites.61 The interplay between C. acnes and bacteria such as S. epidermidis is integral for skin health.60 C. granulosum is found in sebum-rich areas but at much lower levels than C. acnes. 60 This commensal bacterium rarely causes infections and is generally considered non-pathogenic.62
Rocha emphasised: “The balance in the skin microbiome has two sides, like a coin –microbial balance and microbial imbalance
(dysbiosis) – and we have to understand both sides of the coin.” Rocha explained that on one side, the bacterial diversity of the skin microbiome maintains healthy skin. On the other side, the dysbiosis of the skin microbiome can activate the immune system, causing the release of cytokines and initiation of inflammatory processes. Rocha added that understanding the skin microbiome provides a potential opportunity to prevent the development of acne.
Layton concurred that the difference between the acne microbiome and a healthy skin microbiome is well known,63,64 and there is interesting ongoing research to investigate the microbiome and explore the “science behind acne”; however, there is a lot that is still unknown about the skin microbiome. Layton disclosed that it is not yet known whether manipulating the microbiome to increase bacterial diversity to more closely resemble that of healthy skin impacts the development and progression of acne. In addition, Layton noted that there is no good model of the pilosebaceous unit and such a model would be helpful.
Dirschka pointed out that it is unknown why different individual hair follicles on the face respond differently (i.e., with inflammation versus without) in a patient with acne. According to Dirschka, as most of the hair follicles adjacent to the acne lesions are unaffected, even though they presumably have the same bacterial colonisation, there must be specific differences in the regulation of individual hair follicles. Dirschka stated: “We do not know why inflammation is triggered in some individual hair follicles and not in others. Clearly, not all follicles are alike. If we knew the reason behind these differences, it could be a very good clue to understanding acne.”
Dirschka believed that there is a misconception that the first step in acne pathogenesis is keratinisation disorder at the acro-infundibulum of the hair follicle,65 and that bacteria play a role later, after sebum has accumulated in the acroinfundibulum. Dirschka emphasised that this misconception underpins most of the current treatment guidelines, and that
the guidelines need to be updated in the context of new information about the skin microbiome and the early stages of acne development.
THE POTENTIAL OF PREBIOTICS AND PROBIOTICS IN RESTORING SKIN HEALTH
Rocha specified that there are numerous dermocosmetic products for acne that include prebiotics as they are easy to incorporate; however, these products have limited effectiveness.
According to Rocha, an important consideration in the development of probiotic creams, gels, or lotions (i.e., including live bacteria) for acne is the use of preservatives and other chemical constituents in these products that might kill the ‘good bacteria’ in the skin. The challenge is to create a product that effectively modulates the immune cells and the inflammatory processes, competes with pathologic bacteria, and does not affect the ‘good bacteria’ in the skin.
Rocha noted that most of the information available about the use of probiotics to manipulate the skin microbiome and treat acne is derived from basic scientific research rather than clinical studies, and currently there are no products on the market in this category. Rocha specified that the use of probiotics in the treatment of acne is currently hypothetical.
Probiotics in the treatment of acne are an area of great research interest,66 but there are limited studies on ClinicalTrials.gov (12 studies, as of September 2024: six of which are completed [no results reported], two are completed with results, two are active, and two have unknown status), and few published studies. Some examples of the published studies are discussed as follows.
Enterococcus faecalis is a widely used probiotic that has shown benefits for acne treatment through antimicrobial activity against C. acnes. 67 CBT SL-5, an antimicrobial peptide from E. faecalis SL5,68 was shown to be a feasible and
well-tolerated option for improving acne severity and skin microbiome dysbiosis in patients with mild-to-moderate acne in a randomised, placebo-controlled, split-face comparative study.67
A prospective, randomised, open-label study comparing the safety, efficacy, and tolerability of an acne treatment regimen comprising either probiotic supplementation or minocycline or both therapies in patients with mild-to-moderate acne showed significant improvement (p<0.001) in total lesion count 4 weeks after treatment initiation in all patients, with continued improvement seen with each subsequent follow-up visit.69 The study authors reported that probiotics are a therapeutic option or adjunct for acne vulgaris as they provide a synergistic anti-inflammatory effect with systemic antibiotics.69
In another study, an extract of Lactobacillus plantarum (L. plantarum-GMNL6) applied to the faces of study volunteers was shown to reduce melanin synthesis, formation of Staphylococcus aureus biofilm, and the proliferation of C. acnes, and improve skin moisture, skin colour, spots, wrinkles, ultraviolet spots, and porphyrins.70
Probiotic-derived lotion containing Lactobacillus paracasei MSMC 39-1 was shown in a randomised controlled trial to be safe and effective for treating mild-to-moderate acne, with the outcome comparable to that with 2.5% benzoyl peroxide.71
In addition, a capsule composed of the probiotic Lacticaseibacillus rhamnosus and the cyanobacterium Arthrospira platensis was associated with improvement in acne symptoms (severity, total number of lesions, number of non-inflammatory lesions) in a 12-week randomised, double-blind, placebo-controlled, clinical study.72
Rocha considered that further clinical studies are needed using these novel treatments (including treatment combinations) in different patient populations with varying severity of acne.
INTEGRATING MICROBIOMEMODULATING STRATEGIES INTO CONVENTIONAL ACNE TREATMENT
According to Dirschka, it is not yet possible to define how emerging research on the skin microbiome aligns or integrates with current best practices and conventional approaches in acne management: “We are entering a completely new field that is not in line with our conventional concepts of acne. We have to figure out where and how to position these new treatment options that we will have in the future. This is not an ‘add-on’; this might be a new field, a new therapeutic era.” Dirschka emphasised that the exact function of the bacteria and the precise positioning of the microbiome in the pathogenesis of acne are unknown. Therefore, it is also not yet possible to anticipate the challenges that might be associated with integrating skin microbiomemodulating products into standard acne treatment protocols, and how these might be overcome.
Dirschka clarified that further research is needed into the “new pathogenic concept of acne that integrates the microbiome”, and knowledge of how acne is triggered and the inflammatory process is set into action will bring new understanding of treatment. However, skin microbiome-modulating products that are well tolerated with minimal systemic side effects might be applicable to mass markets, rather than just for individual patients. Dirschka summarised that these products could have an important role in the management of patients with any type of acne in the future, potentially being placed as fundamental acne treatments, provided dysbiosis of the follicle is confirmed as an important pathogenic factor in the development of this skin disease. Rocha highlighted: “We are still looking for a target in acne – when we have a good target, we can create effective biologics to integrate into conventional acne treatment strategies.”
Layton described modifying the skin microbiome in acne as a complex area of research that is being explored, and proposed that using transcriptomics73-76 to reveal the chronological order of acne
is an innovative approach that could aid understanding of the pathogenesis of acne at a cellular level, thereby leading to improved research and treatment strategies. Layton expressed interest in research comprising clustered regularly interspaced short palindromic repeats (CRISPR) technology,77 with a view to using this to modify the skin microbiome in skin disease.78 However, Layton noted that removing the more virulent C. acnes strains may have the potential to trigger an acute inflammatory process, which could cause a myriad of problems for patients.
Rocha commented that it is not yet known whether oral probiotics can interact with oral antibiotics and improve outcomes, or whether this will reduce efficacy in modulating inflammatory processes. Furthermore, Rocha highlighted the potential interactions between topical acne treatments with microbiome-modulating tools, such as probiotics, and explained that new treatments have to be integrated carefully into acne management. For example, the use of benzoyl peroxide with microbiomemodulating dermocosmetics would be complicated if benzoyl peroxide kills the microbiome probiotic. In this case, it may be necessary to use the treatments separately (e.g., microbiome-modulating treatment in the morning and benzoyl peroxide in the evening). Rocha noted that there are many unanswered questions surrounding topical and systemic approaches in acne management.
IS THERE A CONNECTION BETWEEN THE SKIN MICROBIOME AND PSYCHOLOGICAL CONDITIONS?
The experts remarked that there is no strong evidence to indicate that the skin microbiome influences brain cognitive function and psychological conditions; however, this is an area of research interest. For example, Wang et al.79 suggested that there was a possible relationship between the skin microbiome and brain cognitive function in a pilot study. In addition, Wingfield et al.80 reported a potential connection between the microbiome in
the oral mucosa and depression in a survey-based study. Deterioration of lesions in psoriasis, a chronic inflammatory skin disease with systemic manifestation, is associated with increased production of inflammatory mediators, which might impact neurotransmitter levels, and could lead to the development of depression81,82 and anxiety.81
However, Layton clarified that for acne specifically, it is not known whether there is a connection between the skin microbiome and brain cognitive function and psychological conditions.
Rocha discussed that there is evidence of a connection between gut dysbiosis and the development of psychological conditions, such as anxiety and depression,83,84 but this is not completely understood. In addition, gut dysbiosis has been shown to influence the skin in some, but not all, patients, and the reasons behind this disparity are unclear.85,86 Rocha described that there is limited understanding of the way in which the pathways in the gastrointestinal system, the skin, and the brain work together, and research into the gut–skin–brain axis is an open field that requires attention.
According to Rocha, it is essential to study the gastrointestinal system, the skin and the brain together, rather than individually, to help understand the connection between the different systems: “Enhancing our understanding of the gut–skin–brain axis will help us to understand more about human science, and enable us to develop our treatment approaches and clinical practices in the future.”
EDUCATING PATIENTS AND PARENTS ABOUT ACNE
Layton described the level of knowledge and understanding of acne among patients and parents as poor, and parents are particularly concerned about the use of antibiotics for the treatment of this skin disease.87
According to Dirschka, the impact of the internet is considerable in this typically young patient population, and they are
particularly susceptible to misinformation, considering their impressionable age, concern about their appearance, and easy access to social media platforms and other online resources.88 A study to assess the awareness levels amongst young people indicates that there are several misconceptions and a gross lack of knowledge about acne that need to be addressed.89
Although there are many online resources providing information on acne, there are numerous myths and considerable misinformation spread about this dermatological condition.90-92 Layton proposed that educational programmes are needed to dispel the myths and combat the misinformation surrounding acne, and to inform patients and parents about how acne develops, as well as the potential positioning of treatments that modulate the skin microbiome. Layton acknowledged that the pathogenesis of acne and the skin microbiome are complex concepts; therefore, clinicians should build a narrative to describe the development and treatment of acne using simple language and schematics that resonate with patients and parents. Importantly, Rocha noted that “acne is related to bacteria but is not an infectious disease”, and this fact could be a starting point for educating patients about acne.
The experts suggested that clear and basic descriptions of the mechanism of action and effectiveness of treatments could be used to encourage patients to adhere to treatment protocols, thereby improving compliance. Furthermore, patient education to set expectations and providing strategies to minimise irritation associated with acne treatments could help to optimise treatment outcomes.93 Succinct and straightforward information on skin microbiome-modulating treatments (once sufficient evidence of the efficacy and safety of these therapies is accrued), and their potential use in combination treatments, underpinned by the aim to use fewer antibiotics, could provide a platform for healthcare professionals to motivate patients to consider new treatment options.
Layton referred to a NIHR-funded programme, which is developing an online tool called Acne Care Online94 for use in the community to educate patients about when and how to acquire treatments, how to use the treatments, and how they work.
The experts agreed that the quality of education of patients and their families about acne needs to improve through effective communication strategies to ensure that healthcare messages reach the target audience. Layton pointed out that adolescent patients are heavily influenced by health messaging on social media, and platforms such as TikTok are a vital tool to reach younger generations. Dirschka remarked that influencers on TikTok appear to have a greater impact on some members of the acne community than doctors and dermatologists, and this is an area requiring attention.
FUTURE LANDSCAPE OF ACNE MANAGEMENT
Layton outlined the importance of widespread adoption of a patient-centred approach95 in the management of acne to optimise outcomes in the context of the varying presentation, chronicity, and impact on health-related quality of life of this common skin disease. Furthermore, Layton emphasised the need for increased support in acne research: “Unfortunately, acne is the ‘poor cousin’ compared with other inflammatory skin conditions, such as psoriasis and eczema, when it comes to funding, despite the fact it has such a profound negative impact on our adolescent population at a time when they are undergoing significant physical and emotional transition. We need to medicalise acne as a disease with dermatological, psychological, and potential systemic impact, and we need to do more to address this common problem.”
According to Dirschka, a key goal for the future is that new treatments for acne are well tolerated, effective, with a “robust pathogenic concept” behind the treatment, and perhaps available over the counter. Furthermore, Dirschka commented: “Most of
our patients are teenagers and young adults who want to see rapid improvement in their acne, but this is impossible. Acne treatment is a marathon… We have to find good ways to communicate with this young patient population in the future.”
Effective communication and patient education are indeed essential, as managing expectations and ensuring adherence to long-term treatment plans can significantly impact outcomes.
However, alongside the evolving therapeutic approaches, it is equally important to explore how emerging scientific research, particularly
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Current Landscape and Emerging Therapies in Hair Loss Treatment for Androgenetic Alopecia
1. Ramón y Cajal University Hospital and University of Alcalá, Pedro Jaén Group Clinic, Madrid, Spain
2. Kangnam-Samsung Plastic Surgery Center, United Arab Emirates (UAE)
Disclosure: Vañó-Galván reports acting as an advisor for Lilly and Pfizer. He has received honoraria for lectures with Pierre Fabre, Cantabria Labs, Lilly, Pfizer, and L’Oréal. Park acts as a consultant plastic surgeon at Yas Clinic, Khalifa City, UAE; and is a corresponding member of the American Society of Plastic Surgeons, and an active member of the Plastic Surgery Research Council.
Acknowledgements: Writing assistance was provided by Helen Boreham, HB Medical (UK) Ltd, Wetherby, UK.
Support: The publication of this article was funded by Bioneer Corporation.
Interview Summary
Androgen hormones and signalling via the androgen receptor play a key role in regulating the hair cycle and are strongly implicated in the pathogenesis of androgenetic alopecia (AGA). CosmeRNA ARI (ARI, androgen receptor inhibitor) (Bioneer Corp, Seoul, South Korea), which utilises Self-Assembled Micelle Inhibitory RNA (SAMiRNATM) technology represents a distinct approach to treating AGA that is applied topically and selectively targets androgen receptor (AR) mRNA to downregulate overexpression of the androgen receptor. In clinical studies, inhibiting androgen receptor expression using SAMiRNA micelles was shown to be an effective approach to treating AGA that significantly increased hair growth. During interviews conducted by the European Medical Journal (EMJ), two leading experts in the field of hair loss, Sergio Vañó-Galván, Director of the Hair Disorders Unit at Ramón y Cajal University Hospital and Associate Professor of Dermatology at the University of Alcalá in Madrid, Spain, and Young-jin Park from the Yas Clinic, Khalifa City in the UAE, discussed the current and future therapeutic landscape in AGA, and considered the role of SAMiRNA as a promising new treatment approach.
THE
EVOLVING
TREATMENT LANDSCAPE IN ANDROGENETIC ALOPECIA
Current Treatments for Androgenetic Alopecia
AGA represents the most common type of hair loss in men and women, and is driven by both underlying genetic factors and an excessive response to androgens.1,2
As Vañó-Galván explained: “AGA is the most frequent type of alopecia, affecting three out of four men, and one in four women. Clinical presentation consists of thinning of the hair, so patients experience a decrease in hair density. It is not just a hair problem because it can impact quality of life,” he stressed.
Summarising the current treatment landscape in AGA, Vañó-Galván highlighted two main first-line treatments.1,3 “The first one is the antiandrogen treatments that inhibit the effects of androgens, male hormones, which are one of the key causes of AGA. We can use these antiandrogens in an oral way, as topical liquids, or injected. Antiandrogen treatments are the most effective treatment in male AGA,”
Vañó-Galván noted. “The second firstline treatment is a drug called minoxidil, which is a vasodilator drug approved for hypertension that can improve hair density and thickening of the hair. It has been used topically for years, but nowadays, the most popular use is as low-dose oral minoxidil. This treatment is probably most effective in female AGA.”
Vañó-Galván continued: “What we usually do is just combine antiandrogens and minoxidil, and we individualise a therapeutic strategy in each patient because success is based on the compliance of treatment. The treatment will only produce a benefit while the patient is using it, and if the patients stop the treatment, we observe a worsening of the AGA.”
He also added that second-line treatments may be useful in certain patients with AGA, “especially those who do not want to take pills or apply topical treatments every day.” These alternative treatment options include
mesotherapy, which involves injecting active substances into the scalp, platelet-rich plasma, low-level light therapy, and microneedling.2
The two main oral antiandrogens currently used to treat AGA are finasteride and dutasteride, which act to inhibit the enzyme 5-alpha-reductase that converts testosterone to dihydrotestosterone, thus halting disease progression.4 Both have demonstrated efficacy in the treatment of AGA in clinical trials and real-world studies.2
“The main advantage of conventional treatments is that, in the cohort of patients that have good compliance and tolerate the treatment, these therapies are really effective, and the hair density is really improved. So, the majority can avoid hair transplantation,” said Vañó-Galván.
“Another advantage is that we have different modalities of treatment so we can individualise the therapeutic strategy according to the preferences of each patient.”
Looking at the limitations of current treatments, Vañó-Galván outlined three main disadvantages. “The first one is that therapy should be maintained in the long term. This is something that we have to explain to patients: this is not curative; this is a chronic treatment. The second limitation would be the side effects, especially of antiandrogen treatment. With systemic antiandrogens, mainly finasteride or dutasteride, there is a percentage of patients that can develop sexual side effects,” he acknowledged. Vañó-Galván also alluded to a potential ‘nocebo effect’ whereby patients’ worries and concerns about potential sexual adverse events can actually contribute to their occurrence. “And of course, there are other potential side effects,” he continued. “Oral minoxidil can produce hypertrichosis, which is excessive hair growth on the body; lightheadedness because of the decrease in blood pressure; tachycardia; or fluid retention…albeit not very frequently. The third limitation, in my experience, is compliance or adherence, and the frequency of the treatment. For example, finasteride should be taken daily and dutasteride three or four times a week.”
New And Emerging Technologies for Androgenetic Alopecia
Looking to the future, Vañó-Galván remarked that “we are at a good moment for new treatments for AGA because almost every year there are new developments,” as he summarised some of the emerging treatments of interest.
“Botulinum toxin we are starting to use in clinical practice, and it has an advantage, which is that it decreases sweating of the scalp, so patients sense some improvement in the aesthetics of the hair, not only in hair density,” Vañó-Galván noted. “The best dose and frequency are not known, so it is an interesting development, but we have to wait until further research is performed,” he added.
New topical antiandrogens and topical formulations of existing oral antiandrogen agents are also under development, but Vañó-Galván indicated that results of recent clinical trials have been disappointing.2 He also described drugs targeting the prostaglandin pathway, such as the PDG2 antagonist setipiprant, as “interesting” but, based on clinical experience to date, lacking demonstrable efficacy in the treatment of AGA.2
Vañó-Galván went on to introduce what he described as a “new concept of topical antiandrogenic treatment” for AGA, namely the self-assembled, micelle inhibitory RNA. “This treatment is like a next step in antiandrogens and one of the most important new treatments, particularly in men, because it is the androgens which produce the thinning of the hair,” he remarked. “So, inhibiting the action of the androgens is one of the main objectives of treatment of AGA.”
“The self-assembled inhibitory RNA does not actually inhibit the action of the androgens, the hormones, it goes a step forward,” he elaborated. “These are micelles that bind to messenger RNA and inhibit protein synthesis, so they decrease the androgen receptors in dermal papilla cells and sebaceous glands, so it is a new mechanism of action. A separate independent study has shown the effectiveness of this weekly application comparable to the application of finasteride
1 mg daily, which is the classical and effective treatment. So, I think that this is an interesting new development that we are using more and more,” he concluded.
DEEP DIVE INTO THE SAMiRNA TECHNOLOGY
Mechanism of Action
In order to identify a potent SAMiRNA for androgen receptor silencing, over 500 candidates were synthesised and screened, leading to the eventual selection of SAMiRNA-AR68, also known by its brand name CosmeRNA ARI, for clinical development.5 SAMiRNA-AR68 represents a novel type of small interfering RNA (siRNA) micelle that, in contrast to conventional siRNA formulations, does not result in innate immune stimulation.5-8 It consists of a dual-conjugated DNA/ RNA heteroduplex that spontaneously assembles to form spherical micelles.5 These SAMiRNA micelles have a size less than 100 nm and a neutral charge, which makes them ideal for delivery into cells.5 Micelles can also benefit from more efficient delivery to hair follicles than small molecules through the pumping effect of massage after application.5 In preclinical testing, SAMiRNA-AR68 was efficiently delivered to human follicle dermal papilla cells and hair follicles, and this potent treatment decreased AR mRNA and selectively suppressed the expression of the receptor protein.5 As Park pointed out, “CosmeRNA is on the cutting edge, positioned as a cosmeceutical.”
Describing how the technology behind SAMiRNA specifically targets and improves AGA, Park explained that siRNAs can play a key role in targeting and silencing androgen receptors. “SAMiRNA is a smallmolecule material based on the concept of micelles, allowing it to selectively penetrate hair follicles and travel along the follicular wall to reach dermal papilla cells. This technology offers a significant advantage in safely targeting the androgenic receptors, ultimately rendering them non-functional,” he remarked.
Regarding the efficacy and safety profile of this new technology, Park referred to two double-blind, randomised clinical studies of SAMiRNA-AR68 that have been performed to date. These trials, conducted in both male and female patients with AGA, evaluated two different doses and frequencies of SAMiRNA-AR68.5 In the low-dose study, SAMiRNA-AR68 (0.5 mg/ mL) (n=24) or placebo (n=24) was applied topically three times per week for 24 weeks. Significant increases in total hair counts with SAMiRNA-AR68 treatment were confirmed through quantitative analysis using a phototrichogram. However, although photographic assessment revealed increased hair density in the SAMiRNA-AR68 low-dose treatment group as compared with baseline, differences were not statistically significant versus placebo.5
In order to increase both efficacy and user convenience, a high-dose clinical study was also conducted whereby SAMiRNA-AR68 (5 mg/mL) was applied once per week for 24 weeks. This second clinical study enrolled 60 patients with AGA who were randomised (1:1) to either active treatment or placebo. Results demonstrated that, in the high-dose SAMiRNA-AR68 treatment group, total hair counts increased significantly at 24 weeks compared with baseline (4.421%; p<0.001), while there were no significant changes in the placebo group (Figure 1).5 Photographic assessment scores also confirmed a significant improvement in hair density versus baseline at Week 16 and Week 24 in the high-dose SAMiRNA-AR68 group (p<0.05 for both). Notably, the SAMiRNAAR68 high-dose treatment group showed approximately 240% efficacy compared with the low-dose group at 24 weeks, despite only one application per week.5
Many of the subjects treated with highdose SAMiRNA-AR68 in this clinical study also expressed satisfaction in the selfassessment questionnaire. At 24 weeks, the majority of patients (59%) said they were “satisfied with the sample used,” half (50%) described a “feeling of fuller hair in the vertex area,” and nearly three-quarters (73%) reported a decrease in hair loss.5
Based on these results, “I think it is more effective to apply a high-dose less frequently than to apply low doses often,” Park concluded. At the higher dose, SAMiRNA-AR68 demonstrated an average increase in hair growth of 1.3–1.9 hairs per cm2 per month, which is comparable to the efficacy seen with oral finasteride.2,5
SAMiRNA-AR68 also proved well tolerated in both clinical studies and no significant side effects were observed.5 “The micelle technology is biodegraded in the human body,” Park explained. “For the safety assessments, dermatologists observed and assessed subjects for the occurrence of objective irritation, such as oedema, itching, and burning, and recorded details such as start and end date of occurrence, severity, and causal relationship with test product…. There were no skin adverse reactions, no skin irritations,” he confirmed. Park also outlined how the SAMiRNA technology has been evaluated in a raft of internal evaluations for safety as a scalp treatment. These tests included assessment of cytotoxicity in dermal papilla cells, HaCaT/ innate immune stimulation (evaluating pro-inflammatory cytokines such as IL-1α, IL-1β, and IL-6), and skin penetration. A recent ex vivo experiment performed by Bioneer involved human scalp skin, in which SAMiRNA-AR68 (labelled in red) migrated along the follicular wall to specifically target cells that overexpress androgen receptors within the dermal papilla (Figure 2).
“When skin safety was assessed by Dermatest® (Dermatest, Münster, Germany), CosmeRNA also received an excellent five-star rating, so theoretically, practically, and clinically, it can be very safe,” Park concluded. “I have not experienced any complications so far.”
Comparisons with Existing Treatments
Considering how SAMiRNA-AR68, the active ingredient of CosmeRNA, compares with existing treatments in terms of clinical results and patient outcomes, Park noted that “pre-existing drugs like androgenic hormonal blockers such as finasteride
Figure 1: Percentage of total hair count increments at 16 and 24 weeks versus baseline with SAMiRNA-AR68 (5 mg/mL) and placebo.5
***p<0.001 compared with baseline Adapted from Yun S-I et al. 2022.5
Figure 2: Ex vivo study of SAMiRNA-AR68 in human scalp skin.
and dutasteride can have complications including depression, decreased sexual drive, and feminisation. A significant concern with these antiandrogen hormonal drugs is their potential to cause congenital anomalies if a pregnant woman comes into contact with them,” he added.
“Another alternative is minoxidil,” Park continued, “which works by vasodilation, thereby increasing scalp circulation. While clinical studies show some improvement in female cases, the results are generally less significant compared to antiandrogenic drugs. Additionally, minoxidil may cause contact dermatitis. However, CosmeRNA ARI does not affect hormone levels, and instead it inhibits the overexpression of androgenic receptors. As a result, it can provide more effective results than minoxidil,” he concluded.
Vañó-Galván further explained that, from the patient perspective, a key advantage of existing topical AGA treatments is that they avoid the systemic side effects of oral antiandrogens; however, the compliance of daily application often poses a problem. “I am not an expert yet in SAMiRNA technology but have good experience with it,” he commented. “And probably one of the main advantages of this treatment is that it requires only once a week, or two times per month, application. This is one of the most important advantages when thinking about topical treatments.”
Park highlighted female patients as a specific patient population who may benefit more from SAMiRNA compared to other treatments. “SAMiRNA-AR68 can be particularly beneficial for women dealing with female pattern alopecia associated with hormonal imbalances due to menopause and ageing that can lead to hair loss,” he suggested.
“Traditional treatments like dihydrotestosterone blockers are often less effective for female pattern hair loss because this type of hair loss is more closely linked to the overexpression of androgen receptors rather than elevated androgen levels. CosmeRNA ARI addresses this by targeting and normalising the
overactive androgenic receptors. As a result, it can offer significant improvements in these cases where hormonal therapies may not provide the desired result.”
REAL-WORLD EXPERIENCE WITH SAMiRNA
Based on his experience in the UAE, Park explained how SAMiRNA has been received by healthcare professionals (HCP). “Initially, CosmeRNA ARI gained traction primarily within clinics, where HCPs began incorporating it into their treatment offerings. However, as we provided more education and assurance about the effectiveness and safety, its popularity has grown significantly. Now, we are seeing increasing interest and adoption among aestheticians, in addition to HCPs, as they recognise the benefits CosmeRNA can offer their clients.”
Park drew attention to one particular patient case study where SAMiRNA technology proved particularly effective (Figure 3).9
“In this patient, the positive effects were maintained for more than 6 months, with application every 2 weeks. Remarkably, even after discontinuing CosmeRNA, the result persisted for over 12 months. This suggests that CosmeRNA’s effectiveness is closely linked to the hair growth cycle, providing long-lasting benefits even after the treatment has ended,” he remarked. siRNA activity is maintained for extended time periods due to the RNA-induced silencing complex in cells, which supports this observation that efficient delivery is more important than frequent applications.5
In terms of patient feedback, both experts agreed that weekly application confers a convenience benefit for SAMiRNA when used to treat AGA and that this feature is viewed favourably by patients. For the patients with AGA currently using this product in his clinic, Park described it as an “amazing technology” and “totally different to other modalities like hormonal antiandrogen drugs or circulation-improving solutions such as minoxidil.” He also reiterated that feedback from patients on CosmeRNA
ARI has been “overwhelmingly positive,” particularly among Arabic individuals who often prefer to avoid antiandrogenic drugs like finasteride or dutasteride.
“For many, CosmeRNA has become the go-to alternative,” Park commented.
“Patients have reported feeling safety and confidence using this product, with noticeable improvements in their hair health and regrowth. Notably, some have shared that they experienced a significant
A) Baseline;
B) After 5 months of CosmeRNA ARI treatment.
Integration Into Clinical Practice
Park acknowledged that a frequent question from HCPs is whether SAMiRNA technology can be used in conjunction with other treatments like antiandrogenic agents.
“Since CosmeRNA works by reducing androgen receptors, it is indeed effective when used alongside medications that lower androgen levels. Combining CosmeRNA with these drugs can potentially enhance treatment outcomes,” he confirmed.
reduction in AGA symptoms and even saw improvements in their female pattern hair loss.”
“Previously, there has not been a single effective way to improve female pattern hair loss except for low-dose minoxidil medication or similar,” he explained.
“These success stories therefore highlight the unique benefits that CosmeRNA offers as a non-hormonal treatment option.”
“A common misconception among HCPs is that CosmeRNA ARI is solely an alternative to antiandrogenic drugs,” Park continued.
“While CosmeRNA can be used as an alternative, it is also highly effective when used in combination with these other medications. Educating HCPs on the versatility of CosmeRNA, whether as a standalone treatment or in conjugation with other therapies, will be key to maximising the potential in clinical practice. Ongoing education and clear communication
Figure 3: SAMiRNA-AR68 clinical case study.9
about this complementary use with antiandrogenic drugs will help dispel any myths and enhance the integration into treatment protocols.”
Vañó-Galván agreed that a key advantage of SAMiRNA is its capacity to be used both as monotherapy and in combination with other treatment approaches. “A good thing is that we can combine this mechanism of action: the inhibition of protein synthesis and the decrease of the androgen receptors,” he elaborated. “We can use it for men or women, and we can combine it with oral minoxidil, and even with low-dose oral dutasteride.”
“When we see the results of the studies, we see the effects of this treatment used in monotherapy but the good thing in real clinical practice is that we can combine several treatments as this mechanism of action is very innovative,” Vañó-Galván continued. “It is yet to be elucidated, but I guess that the combination of this mechanism of action with the classical antiandrogenic treatments like low-dose oral dutasteride will be really effective,” he suggested.
Overall, Park described the process of integrating SAMiRNA into pre-existing treatment protocols for AGA as “relatively smooth,” whether the agent is used as
References
1. Ho CH et al, Androgenetic Alopecia [Internet] (2024) Treasure Island (FL): StatPearls. Available at: https://www. ncbi.nlm.nih.gov/books/NBK430924/. Last accessed: 4 September 2024.
2. Dominguez-Santas M et al. The state‐of‐the‐art in the management of androgenetic alopecia: a review of new therapies and treatment algorithms. JEADV Clin Pract. 2022; 1(3):176-85.
monotherapy or in combination with other treatments. “The feedback has been extremely positive from both HCPs and patients,” he noted. “As soon as the initial results became apparent, the popularity of SAMiRNA surged significantly. This flexibility in its application has made it a valuable addition to clinical practice, fitting seamlessly into various treatment regimens while delivering impressive outcomes.”
Discussing practical solutions to the challenges of implementing SAMiRNA, Park emphasised that support and resources have proved helpful, both in addressing clinicians’ questions and helping to facilitate use of the product in real-world practice. “Education and reassurance have been crucial in helping HCPs effectively integrate CosmeRNA into their practice. Comprehensive training and resources that cover everything from the science behind CosmeRNA to its practical application have empowered professionals to confidently recommend it to their patients,” he explained.
Ultimately, when managing AGA, “it is important for HCPs to use a holistic approach, combining nutritional support, conventional treatments, and CosmeRNA to maximise the potential for hair regrowth and overall hair health,” Park concluded.
4. Olsen EA et al. The importance of dual 5 alpha‐reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo‐controlled study of dutasteride versus finasteride. J Am Acad Dermatol. 2006;55(6):1014-23.
5. Yun S-I et al. Weekly treatment with SAMiRNA targeting the androgen receptor ameliorates androgenetic alopecia. Scientific Reports. 2022;12(1):1607. Erratum in: Sci Rep. 2022;12(1):5675.
6. Yoon PO et al. Self-assembled micelle interfering RNA for effective and safe targeting of dysregulated genes in pulmonary fibrosis. J Biol Chem. 2016;291(12):6433-46.
7. Lee K et al. The cutting-edge technologies of siRNA delivery and their application in clinical trials. Arch Pharm Res. 2018;41(9):867-74.
8. Son SS et al. In vivo silencing of amphiregulin by a novel effective self-assembled-micelle inhibitory RNA ameliorates renal fibrosis via inhibition of EGFR signals. Sci Rep. 2021;11(1):2191. Erratum in: Sci Rep. 2023;13(1):11745.
9. Park YJ. Anti-androgen drug versus SAMiRNA (micelle). Presentation at Dubai Derma, 3 July 2022.
Tralokinumab in the Era of Disruption in Atopic Dermatitis
Interviewees:
Melinda
Gooderham,1-3 Marjolein de Bruin-Weller,4 April Armstrong5
1. SkiN Centre for Dermatology, Peterborough, Canada
2. Probity Medical Research, Peterborough, Canada
3. Queen’s University, Peterborough, Canada
4. Department of Dermatology and Allergology, National Expertise Center of Atopic Dermatitis, University Medical Center Utrecht, the Netherlands
5. Division of Dermatology, University of California, Los Angeles, USA
Disclosure: Armstrong has been a consultant, advisory board member, and/or speaker for Abbvie, ASLAN, Almirall, Amgen, Arcutis, Beiersdorf, BMS, Boehringer Ingelheim, Dermavant, EPI Health, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Mindera, Nimbus, Organon & Co, Regeneron, Sanofi, Sun Pharma, Parexel, Takeda, UCB, and Ventyx Biosciences; has received grants/ research support from Abbvie, ASLAN, BMS, Dermavant Sciences, Dermira, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Meiji Seika Pharma Co, Modernizing Medicine, Nimbus Therapeautics, Novartis, Ortho Dermatologics, Pfizer, Sanofi Genzyme, UCB, and Ventyx Biosciences; and is the Board of Director Elect at the American Academy of Dermatology. Gooderham has been a consultant, advisory board member, and/or speaker for AbbVie, AMGEN, Arcutis, Aslan, Bausch, Boehringer Ingelheim, Eli Lilly, Galderma, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB; has received grants/research support from AbbVie, Akros, AMGEN, AnaptysBio, Arcutis, Aristea, Aslan, Bausch, Boehringer Ingelheim, BMS, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa, LEO Pharma, MedImmune, Meiji, Merck, MoonLake, Nimbus, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, UCB, and Ventyx; and has received honoraria from AbbVie, AMGEN, Arcutis, Bausch, Boehringer Ingelheim, BMS, Dermavant, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, UCB, and Ventyx. de Bruin-Weller has been a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Amged, Aslan, Eli Lilly, Galderma, LEO Pharma, Pfizer, Takeda, Regeneron, and Sanofi-Genzyme.
Acknowledgements: Writing assistance was provided by Nicola Humphry, Nottingham, UK.
Disclaimer: The opinions expressed in this article belong solely to the named interviewees.
Support: This article is sponsored by LEO Pharma, with no input on editorial content except for a check on factual accuracy.
Interview Summary
While for some individuals with atopic dermatitis (AD), the disease can be controlled with topical treatments, those with moderate-to-severe AD often require systemic therapy for long-term disease control. Systemic treatments for AD include conventional systemic agents, small molecule inhibitors, and biologics, each with its own risks and benefits. For example, conventional systemic agents carry significant risks with long-term use, and small molecule inhibitors require frequent dosing. Melinda Gooderham, SkiN Centre for Dermatology, Probity Medical Research, Queen’s University, Peterborough, Canada; Marjolein de Bruin-Weller, University Medical Center Utrecht, the Netherlands; and April Armstrong, University of California, Los Angeles, USA, are internationally renowned specialists in AD. Here, they discuss how the advent of biologic therapy for AD has changed clinical practice. One of the more recent biologic therapies to become available is tralokinumab. This is administered as a single injection every 2 or 4 weeks, is well-tolerated, and can be used over the long term without diminishing efficacy. Biologics such as tralokinumab are at the forefront of a change from flare-driven treatment to the management of AD on a stable, long-term basis, with associated improvements in health-related quality of life (HRQoL) for patients.
INTRODUCTION
AD is a chronic, inflammatory skin disease characterised by pruritus and eczematous lesions, which can affect multiple body areas.1,2 For many individuals with AD, the disease can be controlled with topical treatments; however, most people with moderate-to-severe AD require phototherapy and/or systemic therapy to improve disease control and HRQoL.1,3 One of the newest systemic therapies for AD is tralokinumab, a high-affinity monoclonal antibody that specifically targets the cytokine IL-13, a key cytokine involved in the pathogenesis of AD. Tralokinumab is approved in several countries, including North America and the EU, for the treatment of moderate-to-severe AD in adults and adolescents.4,5
To discuss how the advent of biologics has disrupted the clinical management of AD and how tralokinumab fits into this paradigm, EMJ sat down with three specialists in AD: April Armstrong, Marjolein de Bruin-Weller, and Melinda Gooderham.
BIOLOGICS PROVIDE DURABLE TREATMENT RESPONSES THAT ARE WELL-TOLERATED OVER THE LONG TERM
In AD, patients can have varying degrees of baseline disease activity but also experience flares.1 Even patients with mild AD may need chronic topical therapy, such as corticosteroids and calcineurin inhibitors.6 “It is especially important that we keep the level of inflammation in check, so that patients don't develop signs and symptoms of AD and don't experience flares. To achieve this, they need to have long-term disease control with (systemic) therapeutic agents,” explained Armstrong. Gooderham places the currently approved systemic treatments for AD in three categories: conventional agents, small molecule JAK inhibitors, and biologics. Each of these groups has its own risks and benefits.6,7
Conventional systemic agents include corticosteroids, cyclosporine, and methotrexate, among others, all of which carry a significant risk, with a safety profile that includes long-term adverse events.3,8 Armstrong stressed that these risks are
often not accepted by patients; however, Gooderham explained, on a global scale, they still play an important role because they are often more accessible in terms of cost compared to other treatment options.8,9
Small molecule JAK inhibitors are newer, fast-acting systemic therapies with a short half-life.10 However, Gooderham emphasised, this means that “if a patient misses a dose or goes off therapy, they are at risk of flaring”. JAK inhibitors can provide a high degree of symptomatic improvement,6 but they are also associated with an increased risk of infection11 and are accompanied by a black box warning for major adverse cardiovascular events, based on trial data in patients with rheumatoid arthritis.12
Biologics in AD, such as dupilumab, lebrikizumab, and tralokinumab, are considered to be very well tolerated and highly efficacious,7 and they have infrequent dosing intervals.4,5,13-16 These biologics produce a durable response,4,5,17 which, de Bruin-Weller explained, is quite unique. “With a lot of treatments, you see that over time patients lose their response. We didn't see that in the trials, and I don't see it in daily practice with biologics.”17-19 Armstrong added that “biologics have really changed the landscape of how AD is treated and is controlled long term”.
The Advent of Biologics in Atopic Dermatitis Has Changed Treatment Practices
“Clinical treatment for AD has really expanded over the past few years,” said Armstrong. “The advent of both biologics and oral medications has significantly changed the way we treat our patients, especially those with moderate-to-severe AD, such that our patients now have more efficacious, relatively safer choices compared to what they had before. This is an era of tremendous growth for AD, and our patients are really seeing a continued emergence of more medications that they could potentially benefit from in the future.”
De Bruin-Weller agreed, saying that “when the biologics came on the market, we had products that were well-tolerated and that
you could really use long term. It completely changed my practice. Before [biologics], we had an inpatient ward with lots of beds for patients with AD who were admitted to the hospital for treatment with topical steroids, etc., and now that ward has completely disappeared.” The safety profile of biologics means that they can be administered at home, which is convenient for patients. “They get the instructions the first time they are at the office, then they do the injections at home and the side effect profile is relatively mild,” said de Bruin-Weller.
In the past, patients used topical therapies and increased the dose during a flare,20 but, Gooderham pointed out, treatment adherence could be an issue with this approach. Biologics require less frequent dosing, with an injection every 2 or 4 weeks.4,5,13-16
Biologics in Atopic Dermatitis Are Not Immunosuppressant
The main biologics currently available for AD are monoclonal antibodies that target either IL-4 and IL-13 together (dupilumab), or IL-13 specifically (tralokinumab, lebrikizumab). Both IL-4 and IL-13 drive Type 2 inflammation that is characteristic of AD and contributes to disease symptoms.21 This means that these biologics are immunomodulating drugs, altering a specific aspect of the immune system.22 “We always have to convince other doctors that [biologics for AD] are not immunosuppressive,” said de Bruin-Weller. “This is really unique for these biologicals because we use a lot of biologics in other diseases (such as TNF alpha inhibitors) with a more immunosuppressive effect.”23 Unlike JAK inhibitors, which target a different aspect of the inflammatory pathway,6 these biologics for AD are not associated with an increased risk of infection.11 In fact, they may actually decrease the risk of cutaneous infections.24
TRALOKINUMAB IN REAL-WORLD VERSUS CLINICAL TRIALS
The safety and efficacy of tralokinumab as monotherapy and in combination with topical corticosteroids and topical calcineurin inhibitors have been
demonstrated in Phase II and III clinical trials.18,19,25 Up to 6 years of follow-up data from the parent trials and openlabel extension trial ECZTEND,26 which included patients over 12 years of age with moderate-to-severe AD, showed that longterm use of tralokinumab was associated with robust, lasting efficacy with sustained improvements in AD signs, symptoms, and HRQoL. It was well-tolerated, with no new safety signals identified.27-29
“I think these days we especially talk about long-term control of AD with biologics,” said Armstrong. “We have over 3 years of clinical trial data assessing patients receiving tralokinumab and how they do over this long period of time. What was noted is that about seven out of 10 patients had no-to-mild disease, and, importantly, there was no-to-minimal disease fluctuation over 3 years of treatment.”30 In a post hoc analysis of ECZTEND, a stable EASI ≤7 response (at ≥80% of attended visits) was observed in 70.2% of tralokinumab-treated patients over Weeks 16–152.30 These data indicate that tralokinumab provides good control of baseline disease in AD and that patients have fewer flares.29 “I think that’s something our patients who are in a tralokinumab trial are experiencing, or expect to experience, and I think that is very important for their overall QoL.”
Real-world data for tralokinumab in AD is emerging from the ongoing TRACE study. A global, real-world, non-interventional investigation of tralokinumab in adults (≥18 years of age) with AD, TRACE aims to better understand the use of tralokinumab in clinical practice. Participants were enrolled from 11 countries across Europe, North America, and the Middle East.
A total of 631 patients were included in an interim analysis of TRACE, with a respective number of patients reaching each analysis time point. Data demonstrated that the mean Eczema Area and Severity Index (EASI) score improved from 20.1 at baseline to 6.4 at 3 months (among 482 patients), 5.4 at 6 months (among 212 patients), and 3.6 at 9 months (among 88 patients) of tralokinumab treatment. The proportion
of patients with EASI ≤7 (no or mild disease) increased from 14% at baseline to 72% at 3 months (among 482 patients), 77% at 6 months (among 212 patients), and 80% at 9 months (among 88 patients). Among the patients with a baseline Investigator Global Assessment (IGA) score ≥2 (mildto-severe disease; n=566), the proportion with at least a 2-point improvement in IGA was 46% at 3 months (among 566 patients), 58% at 6 months (among 279 patients), and 70% at 9 months (among 112 patients) of treatment. Dupilumab-naïve and dupilumabexperienced patients showed similar improvement across all efficacy endpoints, despite higher baseline disease severity in dupilumab-naïve patients.31,32
Armstrong, who presented some of the interim data from TRACE at European Academy of Dermatology and Venereology (EADV) 2024, commented that, with realworld data, “we see very good efficacy with tralokinumab, not only during the first 3 months but with continued improvement over time, as well as maintenance over a 9-month period of time.”32,33 Gooderham noted though how “we do see the classic profile of a biologic; there can be a slow onset for some patients while others respond a bit more quickly, but there is gradual improvement over time, even after the primary endpoint, which is why real-world evidence is important.”32
According to de Bruin-Weller, the real-world and clinical trial data are comparable and “match very well with our own registry data [where] we don't see a lot of side effects. It was also very nice to see that the results from TRACE show good efficacy in both dupilumab-naïve and dupilumab-experienced patients.” Armstrong agreed, saying: “The efficacy of tralokinumab seems to stand, regardless of prior biologic therapy in the real world. I think that's encouraging when considering tralokinumab for both biologicnaïve and biologic-experienced patients.”
In terms of patient-reported outcomes from TRACE, the proportion of patients with a Peak Pruritus Numerical Rating Scale ≤4 (worst itch intensity: none-to-moderate) increased from 23% at baseline (among 484 patients) to 52% at 3 months (among
261 patients), 68% at 6 months (among 125 patients), and 72% at 9 months (among 65 patients) of tralokinumab treatment. In connection with this, the proportion of patients with a Dermatology Life Quality Index score ≤5 (no-to-small effect on patient HRQoL) increased from 20% at baseline (among 446 patients) to 49% at 3 months (among 246 patients) and remained stable at 64% at 6 months (among 113 patients) and 9 months (among 69 patients) of tralokinumab treatment. The proportion of patients with a Sleep Numerical Rating Scale ≥3 (0–10, where 10 is the worst possible sleeplessness) at baseline who improved by ≥2 points increased from 65% at 3 months (among 142 patients) to 68% at 6 months (among 65 patients) and 82% at 9 months (of 39 patients) of tralokinumab treatment. Across all endpoints, similar improvements were observed in dupilumab-naïve and dupilumab-experienced patients.33
“We know (from the clinical trials) that tralokinumab is an efficacious treatment for patients with increasing benefits in skin clearance, as well as improvement in QoL and other patient-reported outcomes such as itch reduction, sleep improvement, and improvement of mental health,”18,19 said Gooderham. “Similarly, from the TRACE study, we see this gradual improvement throughout the first 9 months, with IGA scores of 0/1 [no-to-mild disease], improvement in QoL, a reduction in itch, and improvement in sleep.32,33 It’s great to see the real-world evidence confirming what we saw in the randomised controlled clinical trials. When a drug is approved based on Phase III pivotal clinical trial data, then to take it out in the real world and see it work the same way, it is very reassuring for both prescribers and patients.”
How Clinical Trial Data Differs from Real-World Data
Gooderham emphasised that clinical trial data and real-world data contribute value in different ways and discussed that while clinical trials are important for registrational purposes, “real-world evidence gives us a broader range of data to help inform us in managing our patients in clinic”.
One of the major differences between a clinical trial and real-world data is the included population. As clinical trials need to be powered to generate findings that are statistically significant, they have stringent enrolment criteria.34 However, de BruinWeller pointed out that “in daily practice, we have patients with comorbidities and co-medication who cannot enter a clinical trial”. Gooderham agreed, discussing how real-world evidence includes “patients with certain comorbidities, maybe a history of malignancy, or other systemic illnesses (that shouldn’t) preclude them from treatment of their AD”.
“When tralokinumab first came onto the market, a lot of patients who failed earlier biological treatment with dupilumab were put on tralokinumab,” said de Bruin-Weller. “And that is, of course, a more difficult-to-treat population [than that included in the clinical trials].” By expanding inclusion criteria, explained Armstrong, “real-world trials often reflect the broader range of clinical manifestations of AD (that we see in the) overall population”. Another issue de BruinWeller noted was how a patient in a more heavily controlled clinical trial environment may be compliant, but “compliance is sometimes an issue in daily practice”. She also stressed that follow-up can be longer in the real world compared with clinical trials and that the dose flexibility used in the real world can provide new information.
The benefit of clinical trials, rather than analyses of registry data, Armstrong explained, is that they are randomised. “If the trial is properly powered, you're able to make a specific statement about a medication’s efficacy compared to another arm in the clinical trial and by a certain time point […] so we have confidence that the benefit that we see is attributable to the medication itself in a very rigorous and stringent fashion. However, the limitation of the clinical trial is that the patient population may be more selected.” She added: “Real-world and clinical trial data inform us differently about how a medication performs, so I think they both have tremendous value, and I think we as dermatologists want to pay attention to both of those sets of data.”
Discussing Trial Data with Patients
Armstrong stressed that she discussed trial data with her patients because she wants them to understand when to expect benefit from a treatment and what the magnitude of that benefit is likely to be. “I do believe in shared decision-making. I'm the one who needs to provide value by informing patients of what we know from the clinical trials, and our patients can inform us of their values, such as a preference for an oral or injectable therapy. I'm there to make sure that we make the best decision for the patient such that they can actually adhere to the therapy when they leave my office, because they also have to buy into that decision.”
De Bruin-Weller explained that, before there was much real-world evidence about tralokinumab available, she would use the trial data, particularly for the combination of tralokinumab with topical steroids, which shows good responses.18 She also used trial data to discuss safety, since long-term extension trials have shown that there are no new safety issues.26 However, now that there is more real-world evidence for tralokinumab in AD, de Bruin-Weller talks to patients mostly about this data, along with her own experience in clinical practice. “I also tell patients that the results that we see in our registry, in our daily practice, are comparable to the trials because sometimes you find that if you use a medicine in daily practice, [the outcomes] are different from the trials. For the biologics, it's comparable.”
In general, Gooderham doesn’t use detailed data from clinical trials when discussing treatment options with patients. “As a clinical trialist for all of the new treatments in AD, I have the opportunity to tell stories of patients and give examples of how patients have responded to these new therapies, and I think that really speaks a bit more to my patients than using clinical trial data.” However, she admitted, “there are some patients who do their own research online and may have specific questions about treatments, in which cases, I do discuss some data with those patients”. Gooderham added that it may help “if you can discuss real-world data with patients, showing that someone like them, perhaps a
patient with a remote history of malignancy or some other medical condition, received tralokinumab and did well over time”.
TRALOKINUMAB IN HEAD AND NECK ATOPIC DERMATITIS
Head and neck region involvement is reported in more than 70% of patients with moderate-to-severe AD2 and is associated with social embarrassment, stigmatisation, and a negative impact on patients’ HRQOL and mental health.35 Armstrong explained that head and neck AD can be very hard to treat and that not all therapies treat it consistently well.2,36 De Bruin-Weller agreed, saying how “head and neck AD is the most challenging area to treat […] AD on the hands is sometimes also difficult. These are the locations that the patients suffer from the most because they are the visible areas.”
A substantial proportion (80%) of participants in the TRACE study had head and neck involvement at baseline. Of these participants, only 67% still had head and neck involvement after 3 months of tralokinumab treatment, and 52% after 9 months.37 “It’s important to both prescribers and patients to see that benefit in head and neck dermatitis (with tralokinumab) from the real-world TRACE registry,” said Gooderham.
The Future of the Atopic Dermatitis Treatment Landscape
This is an era of considerable change in the AD treatment landscape. Armstrong stressed that there are now more treatment options available for patients with AD, with even more biologic therapies in the pipeline. For example, nemolizumab, an IL-31 receptor antagonist, was recently approved in the USA for prurigo nodularis;38 although, according to de Bruin-Weller, this drug is unlikely to be a “game changer” in AD. There are also antibodies in the pipeline that target OX40, a co-stimulatory T cell receptor, and the corresponding OX40 ligand.39 “I think it's good to have biologics for a different pathway available, [in case a patient] fails [Type 2 inflammatory pathway]-targeting biologics,” said de Bruin-Weller.
Gooderham discussed how one of the unmet needs in AD at present is to develop safe, effective treatments that work for all patients. One of the reasons this is challenging is that AD “is a very heterogeneous condition with complex pathophysiology”. Expectations for how well AD-targeting drugs perform are increasing, said Armstrong. de Bruin-Weller also emphasised how, although current treatments improve AD considerably,18,19 “there is some residual disease activity and itch, and patients still need to use topical steroids so we need to improve efficacy.”
With well-tolerated biologics now available, it seems likely that systemic treatment will become more common in AD as awareness of this option increases among patients. “I still think that many patients don't yet understand that this treatment option is available for them,” said Gooderham. “I think a lot of them are afraid of systemic treatment just from historical immunosuppressants that have been used.” Armstrong added that, in the near future, biologics may be considered for earlier stages of the AD disease course “such that we may even change the natural history of a patient’s disease.”
There are already some biologics approved for a broad age range of patients with AD,4,5,13,14 explained Gooderham. “So, instead of suffering for many years, patients will be able to start therapy at a young age. They'll be able to control their disease, avoiding the cumulative life course impairment that happens with chronic illnesses such as inflammatory skin diseases. By treating patients early, with stable control over time, we will be able to reduce the anxiety and stigmatisation associated with flares, and improve the overall QoL for our patients.”40
Shifting from Flare-Driven Treatment to More Stable Disease Control
“We're moving away from a flare treatment model where patients use topical therapies, and then they increase their use when
they're having a flare,” said Gooderham, who also noted that adherence can be an issue with this approach. “By treating with biologics where you have an injection every 2 or every 4 weeks, you're able to manage the disease and prevent flares, reducing the amount of topical steroids or calcineurin inhibitors that are required.” Armstrong agreed that the conversation in AD therapy has already shifted towards stable disease control rather than flare-driven treatment. “Flare-driven treatment is really only appropriate for those patients who have just one flare per year, or maybe a seasonal flare,” explained de Bruin-Weller. “But most of our patients have more chronic disease, so we need to use maintenance treatments to extend the intervals [between flares]. I think we can reach that with biologics.”
Gradually, more patients with AD should become aware that well-tolerated, systemic treatments are an option for them. “They've spent their lives in a flaredriven treatment mode, using their topical therapies at greater frequency when they're having a flare, trying to avoid [overusing] these therapies, so they end up suffering with flares that may not be managed appropriately,” explained Gooderham. “I think it will become more common to manage underlying disease with a treatment such as a biologic that can be used safely over the long term to manage those flares, so that patients can reduce the amount of topical steroids that are being used.”
CONCLUSION
The advent of biologic therapies, such as tralokinumab, that can be used over the long term without diminishing efficacy has disrupted the way that AD is treated in clinical practice. Gooderham summarised this by saying, “I look forward to that time when a patient’s disease is controlled and we're just following them along their journey, managing their disease, and seeing the benefits in their QoL.”
References
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3. Davis DMR et al. Executive summary: guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. J Am Acad Dermatol. 2024;90(2):342-5.
4. BMS ADBRY (tralokinumab). FDA prescribing information. 2021. Available at: https://www. accessdata.fda.gov/drugsatfda_docs/ label/2024/761180s006lbl.pdf. Last accessed: 3 Oct 2024.
5. BMS ADTRALZA (tralokinumab). EMA summary of product characteristics. 2021. Available at: https://www.ema. europa.eu/en/documents/productinformation/adtralza-epar-productinformation_en.pdf. Last accessed 3 Oct 2024.
6. Shergill M et al. Biologic and small molecule therapy in atopic dermatitis. Biomedicines. 202413;12(8):1841.
7. AAAAI/ACAAI JTF Atopic Dermatitis
Guideline Panel et al. Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology joint task force on practice parameters GRADE- and institute of medicinebased recommendations. Ann Allergy Asthma Immunol. 2024;132(3):274-312.
8. Orfali RL et al. Consensus on the therapeutic management of atopic dermatitis ‒ Brazilian society of dermatology: an update on phototherapy and systemic therapy using e-Delphi technique. An Bras Dermatol. 2023;98(6):814-36.
9. Eichenfield LF et al. Costs and treatment patterns among patients with atopic dermatitis using advanced therapies in the United States: analysis of a retrospective claims database. Dermatol Ther (Heidelb). 2020;10(4):791-806.
10. Traidl S et al. Janus kinase inhibitors for the therapy of atopic dermatitis. Allergol Select. 2021;5:293-304.
11. Mansilla-Polo M et al. Biologics versus JAK inhibitors. Part II: risk of infections. A Narrative Review. Dermatol Ther (Heidelb). 2024;14(8):1983-2038.
12. Tokareva K et al. JAK inhibitors and black box warnings: what is the future for JAK inhibitors? Expert Rev Clin Immunol. 2023;19(11):1385-97.
13. DUPIXENT (dupilumab) EMA summary of product characteristics. 2024. Available at: https://www.ema.europa. eu/en/documents/product-information/ dupixent-epar-product-information_ en.pdf. Last accessed: 8 Oct 2024.
14. DUPIXENT (dupilumab) FDA prescribing information. 2024. Available at: https://www.accessdata. fda.gov/drugsatfda_docs/ label/2024/761055s064lbl.pdf. Last accessed: 8 Oct 2024.
15. Eli Lilly. EBGLYSS (lebrikizumab-lbkz). FDA prescribing information. 2024. Available at: https://www.accessdata. fda.gov/drugsatfda_docs/label/2024/ 761306Orig1s000correctedlbl.pdf. Last accessed: 3 Oct 2024.
16. Eli Lilly. EBGLYSS (lebrikizumablbkz). EMA summary of product characteristics. 2024. Available at: https://www.ema.europa.eu/en/ documents/product-information/ ebglyss-epar-product-information_ en.pdf. Last accessed: 3 Oct 2024.
17. Worm M et al. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: a randomized clinical trial. JAMA Dermatology. 2020;156(2):131-43.
18. Silverberg JI et al. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the doubleblind, randomized, multicentre, placebocontrolled phase III ECZTRA 3 trial. Br J Dermatol. 2021;184(3):450-63.
19. Wollenberg A et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021;184(3):437-49.
20. Butala S, Paller AS. Optimizing topical management of atopic dermatitis. Ann Allergy Asthma Immunol. 2022;128(5):488-504.
21. Pappa G et al. The IL-4/-13 axis and its blocking in the treatment of atopic dermatitis. J Clin Med. 2022;11(19):5633.
22. Kurtzman D et al. “Immunosuppressive and Immunomodulatory Drugs,” Kang S, et al., editors, Fitzpatrick’s Dermatology [Internet] (2019) 9th ed, New York: McGraw-Hill Education. Available at: accessmedicine.mhmedical.com/ content.aspx?aid=1161344743. Last accessed: 3 Oct 2024.
23. Connor V. Anti-TNF therapies: a comprehensive analysis of adverse effects associated with immunosuppression. Rheumatol Int. 2011;31(3):327–37.
24. Fleming P et al. Risk of infection in patients with atopic dermatitis treated with dupilumab: A meta-analysis of randomized controlled trials. J Am Acad Dermatol. 2018;78(1):62-9.e1.
25. Merola JF et al. Tralokinumab does not impact vaccine-induced immune responses: Results from a 30-week, randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis. J Am Acad Dermatol. 2021;85(1):71-8.
26. Blauvelt A et al. Long-term 2-year safety and efficacy of tralokinumab in adults with moderate-to-severe atopic dermatitis: Interim analysis of the ECZTEND open-label extension trial. J Am Acad Dermatol. 2022;87(4):815-24.
27. Reich K et al. 555 - Safety of tralokinumab for the treatment of atopic dermatitis in patients with up to 4.5 years of treatment: an updated integrated analysis of eight clinical trials. Br J Dermatol. 2024;190 (Suppl 2):ii52-3.
28. Blauvelt A et al. 551 - Continuous tralokinumab treatment over 4 years in adults with moderate-to-severe atopic dermatitis provides longterm disease control. Br J Dermatol. 2024;190(Suppl 2):ii48-9.
29. Blauvelt A et al. Long-term safety and efficacy of tralokinumab in adults and adolescents with moderate-to-severe atopic dermatitis treated for up to 6 years. FCDC, 24-27 October, 2024.
30. Blauvelt A et al. 650 - Stability of long-term therapeutic responses to tralokinumab in adults with moderate-to-severe atopic dermatitis. Br J Dermatol. 2024;191(Suppl 2):ljae266.029.
31. Thaçi D et al. 418 A global, observational, cohort study of patients with atopic dermatitis to evaluate tralokinumab real-world clinical use (TRACE): baseline characteristics from the first 100 patients in Germany. Br J Dermatol. 2023;188(Suppl 3):ljad162.038.
32. Pezzolo E. Real-world effectiveness of tralokinumab in adults with atopic dermatitis: Interim data on improvements in physician-assessed disease severity after up to 9 months of follow-up in the TRACE study. Presentation P0689. EADV 2024, 25-28 September, 2024.
33. Costanzo A. Real-world effectiveness of tralokinumab in adults with atopic dermatitis: Interim data on improvements in patient-reported outcomes after up to 9 months of follow-up in the TRACE study. Presentation P0690. EADV 2024, 25-28 September, 2024.
34. Kim HS et al. Real-world evidence versus randomized controlled trial: clinical research based on electronic medical records. J Korean Med Sci. 2018;33(34):e213.
35. Lio PA et al. Impact of atopic dermatitis lesion location on quality of life in adult patients in a real-world study. J Drugs Dermatol. 2020;19(10):943-8.
36. Maarouf M et al. Head-and-neck dermatitis: diagnostic difficulties and management pearls. Pediatr Dermatol. 2018;35(6):748-53.
37. Armstrong A. Real-world effectiveness of tralokinumab in adults with atopic dermatitis: Interim data on improvements in patients with head and neck atopic dermatitis after up to 9 months of treatment in the TRACE study. Presentation D3T01.3. EADV 2024, 25-28 September 2024.
38. Galderma. NEMLUVIO (nemolizumab). FDA prescribing information. 2024. Available at: https://www. accessdata.fda.gov/drugsatfda_docs/ label/2024/761390s000lbl.pdf. Last accessed: 3 October 2024.
39. Lé AM et al. OX40-OX40L Inhibition for the Treatment of Atopic Dermatitis—Focus on Rocatinlimab and Amlitelimab. Pharmaceutics. 2022;14(12):2753.
40. Cork MJ et al. Dupilumab improves patient-reported symptoms of atopic dermatitis, symptoms of anxiety and depression, and health-related quality of life in moderate-to-severe atopic dermatitis: analysis of pooled data from the randomized trials SOLO 1 and SOLO 2. J Dermatol Treat. 2020;31(6):606-14.
Interview
EMJ was delighted to interview Chesahna Kindred, Kindred Hair & Skin Center, Marriottsville, Maryland, USA, a leading dermatologist in ethnic skin and hair loss. She discusses her journey into dermatology, the impact of combining medical expertise with business insight to create more inclusive care, and the role of AI in her dermatology clinic.
Chesahna Kindred Kindred Hair & Skin Center, Marriottsville, Maryland, USA
What led you to decide to pursue dermatology and, more specifically, focus on ethnic skin and hair loss?
With little exposure to dermatology in medical school, the answer to why we pursue dermatology is rarely straightforward. I was the type of medical student who liked every field in every rotation. I really enjoyed them… with the exception of ear, nose, and throat (ENT) because I cannot do mucus; that is my kryptonite! During my third year of medical school, I decided to pursue ophthalmology. In between 3rd and 4th year, I earned my Master of Business Administration (MBA) and was the third person in the history of the University of Cincinnati, Ohio, USA to earn an Doctor of Medicine/MBA dual degree. My advisor suggested that expose myself to a field of medicine not well covered in school. That meant dermatology and urology.
While I was getting my MBA at the College of Business, I did a couple of research projects in dermatology. When I returned to the College of Medicine, I completed my senior ophthalmology rotation and was bored to death: no offense ophtho! One of the dermatologists who co-authored one of my publications
said: “Well, why don't you look into dermatology?” So, in my senior year, I did a dermatology rotation and loved it. I felt like it combined what I loved about many other fields of medicine. I had no intentions of “focusing on ethnic skin” when I decided to pursue dermatology. I didn’t realise it was excluded from the mainstream curriculum.
I trained at Howard University, Washington D.C., USA, and they taught us on white skin, black skin, every skin; so it was not really a focus. I learned to be a dermatologist for everyone. However, I did choose to focus on hair loss. When I graduated from Howard University, what was considered standard for what we trained was a little bit ahead of what was offered in the Baltimore, Maryland area.
Then I did a project with a fellow Dermatologist, Yolanda Lenzy, Lenzy Dermatology, Chicopee, Massachusetts, USA. Her project was called ‘Project Hair’, where we did workshops for stylists. We completed two workshops together and I did one on my own. From there, stylists referred their patients to me. It snowballed to the point that I was the first dermatologist in the USA to have a full service in-
house hair salon in a dermatology practice. It’s called PeterKINdred Hair and Scalp Wellness Center and was cofounded with Susan Peterkin, a stylist who attended the workshop I did on my own.
Recently, the stylist and I created a network called ‘S.T.R.A.N.D’, which stands for Stylists, Training, Researching, And Networking with Dermatologists. This is a network where dermatologists and stylists are members. Dermatologists train stylists in an intense 2-day course. If the stylists pass the exam, they become STRANDcertified. We have presented this at beauty shows and so on. It has really turned into something much bigger than I thought the day I decided to pursue dermatology.
Q2
You touched on the fact that you did an MBA to complement your medical degree. How do you think your business background has helped shape your approach to running the Kindred Hair and Skin Center, and being a leader within the field of dermatology?
Having my MBA helped me to know what I should know. Nowhere in my training, during high school, college, medical school, my intern year, or during residency, taught me about a balance sheet, cash flow, income statement, etc., which are common things that are important for business and leadership. It did not teach me the things to ask my accountant, or how to really manage debt and how to avoid debt. The MBA did that and also helped me to see that, and I know other physicians feel it, everything is set up for doctors to just become machines; to no longer practice the art of medicine, to take the care out of healthcare, and this is the ugly truth about healthcare right now.
When we turn everything over to the business side, we lose sight that money is not the only bottom line. The second bottom line is the patient's health, and that’s helped me to resist falling prey to private equity or knowing how to work with private equity in a way that does not throw us as physicians under the bus. It has helped me to teach younger physicians how to start their practice without a loan, which I think is very key. If we start with a lot of debt, then we end up making some of the wrong decisions early on, and that really colours the legacy of our practices. I do not think physicians necessarily have to get a full MBA, but we most certainly, at the very least, should have some type of business course that helps us to be better prepared and better armed for the business side of medicine.
Q3
Your work at Howard University, an institution known for its focus on ethnic dermatology, sparked a passion for treating patients with skin of colour. In your experience, what are some of the most common misconceptions or gaps in understanding when it comes to treating skin of different ethnicities?
I want to emphasise that Howard University taught me to be a dermatologist. It did not teach me to be a dermatologist on White skin, or Black skin. It taught me to be a dermatologist so that when a patient comes in, I can recognise the skin disease. It doesn't matter if the patient is White or Black or Latina, etc., I can recognise the difference between erythema dyschromicum perstans and melasma, I can recognise vitiligo in a White patient, and I can diagnose acanthosis nigricans versus lichen simplex chronicus. I can diagnose patients, and I am
not biased because of the colour or misled because they have a different skin tone.
We now consider if they are having anxiety when their skin looks normal because they are worried about the next flare
It really taught me to be what I think it truly means to be a dermatologist. So, there wasn't a separation, and it wasn't an extracurricular activity or a passion for treating skin of colour. The passion is for every dermatologist to fill that gap that may have been created by their curriculum, and I think more institutions should look at Howard University as the model. We're trained in the USA but trained for the US; whereas the Howard University model did train us to do this. I really love that institution for that reason.
Now, there are a few misconceptions with ethnic skin. One that unfortunately still exists is that Black people do not feel pain or have a higher resistance to pain. This is the most ridiculous thing I have ever seen printed in black and white. I think they misconstrue sometimes a patient's reaction to pain and interpret that that's how painful something is, which is, as a physician, one of the worst things I think we could do. Another misconception is that redness or erythema is the only indicator of inflammation.
Another is that hyperpigmentation is cosmetic, and I wish that weren't the case. For example, if we have a patient with acne, they want their
skin to go back to normal, and not just a little bit. They want the acne gone, the redness gone, the scar gone, and the post-inflammatory hyperpigmentation gone.
Another misconception is that the patient is non-compliant. I see that in a lot of the discourse and dialogue on certain chat groups, etc. I think that probably has to come with maybe some cultural differences, and so we all, including me, have to be intentional by making sure we are connecting with our patients. Our patients are individuals, and our patients are the same, regardless of ethnicity, and I think that is one of the skills that was really ingrained in us at Howard University.
Q4There have been studies highlighting how vitiligo can have a profound impact on mental health. Have you experienced this in your practice, and do you feel that the psychological burdens of dermatological conditions can sometimes be overlooked in modern medicine?
I think it is both. We overlook the psychological burdens,
but more and more I'm seeing the psychological burdens of dermatologic conditions taken into account. Great examples of this are psoriasis and vitiligo.
At Howard University, I still remember, and it has coloured the way I treat my patients with vitiligo, but I still remember one patient in particular. She was of Indian descent and had segmental vitiligo on her abdomen and back. It was such an eye-opener to realise just how grave the diagnosis of vitiligo was; that she would not be able to get married if her future in-laws knew she had vitiligo. So, this was something we had to be mindful of, when her husband was there, versus when her future motherin-law was there, etc. Generally, as physicians, if a patient brings someone in the room, it is understood that the patient wants that relative included in the discussion. However, we all had to make sure we knew exactly who it was she brought with her that day; whether it was on her side of the family, her immediate family such as her parents and siblings, or if it was her fiancé or fiancé’s siblings. It was a really big deal and we
always paid attention when she was on a schedule because of the impact that it had.
Aside from that, for other diseases like psoriasis and atopic dermatitis, we are taking better account of whether or not it interrupts sleep, which I think we have not paid enough attention to. We are also taking better account of how the patient feels about their skin condition when they are not flaring, as we tend to focus on the flare. We now consider if they are having anxiety when their skin looks normal because they are worried about the next flare. This includes screening questions about depression and suicide. An important point is not simply excluding a patient from a clinical trial because they had suicidal ideation 20 years ago and none since. We are getting better, but we’re not there yet. The most important thing, I think, is to not call skin diseases frivolous or unimportant or cosmetic. Most things that are considered cosmetic by insurance companies are medical conditions that have psychological burdens on our patients.
We take a picture of the patient's scalp using special software, and the software uses AI to calculate the hair density
Q5
As a specialist in alopecia areata (AA), could you talk about the status of treatments, such as plateletrich fibrin matrix (PRFM)/ plateletrich plasma (PRP) and what the future of AA treatment might look like in terms of the introduction of AI in clinical practice?
Before JAK inhibitors arrived, I would indeed use PRFM or PRP for AA, but the JAK inhibitors have really been a game changer. I no longer offer PRFM or PRP because usually I can get the patient to have meaningful, significant scalp hair regrowth with the medications.
For AI, we have been using it in our practice since 2020 and it's just awesome. We use AI for hair density checks. We take a picture of the patient's scalp using special software, and the software uses AI to calculate the hair density. We can all take photos and put before and after images side-byside and confirm they are getting better a little bit, moderately, or significantly, etc. But we are still just eyeballing it. It's the equivalent to me putting my hand against your forehead and saying: “I think you have a fever”, versus me using a thermometer. So, in our office, we call these hair density checks with AI ‘AI checks’. The AI check provides a precise number to track allowing me to determine if a patient is improving or worsening earlier than comparing before and after photos. It has been an awesome tool in my practice, and I recommend anyone who specialises in hair loss to consider one of these devices.
Q6One of your clinical focuses has been on the unique challenges and presentations of skin cancer in melanin-rich skin, where signs of cancer can often be more subtle. Given our audience is primarily healthcare professionals, could you describe what are the most common differences you have seen in the presentation of skin cancer in this patient group?
Skin cancer is such an awesome topic when it comes to skin of colour. There is a misconception in the USA that sunscreen protects Black people from skin cancer. Data shows that skin cancer in Black people tends to occur in sun-protected areas instead of sun-exposed areas. In my 3 years training at Howard and over 200 skin cancer excisions, only one was a Black patient (it was basal cell carcinoma). The exception was cutaneous T cell lymphoma or mycosis fungoides. We had a few dozen cases of mycosis fungoides (mostly in Black people), but regarding melanoma, squamous cell carcinoma, and basal cell carcinoma, it was quite uncommon in skin of colour. And by skin of colour, I mean Black, Latin, Indian, Pakistani, Filipino, and Chinese, individuals, i.e. non-White individuals. On the other hand, skin cancer significantly burdened our White patients. This is when I'm going to say something controversial: Black people need to be more aware that they can get skin cancer; not broadly undergo annual skin checks. The energy should be put towards
education and awareness. For example, Black people need to be aware that skin cancer can occur; and to monitor suspicious lesions on their feet, fingernails, and toenails. Campaigns should show photos of acral lentiginous. In contrast, for my White patients, it is most commonly in a sunexposed area that could have been protected by sunscreen. National campaigns tend to focus on just this aspect of skin cancer.
So, one of the unique challenges is we do recommend sunscreen for everyone. For my White patients, it's mostly because I want to prevent them from getting a skin cancer, whereas for my Black patients, it's mostly for anti-aging purposes. Clearly, there's some nuance here. Black individuals need to be more aware of skin cancer and the way it would look on their skin, and that's where the energy needs to go, and I don't see it going that direction enough. There is no quick phrase for that, at least I haven't come up with a quick phrase for that slight, subtle difference. If we look at annual skin screenings, and I do skin checks all the time, it's not high yield for our Black patients, but we need to make sure they know what's normal, what's not normal, and when to come in. That is the most common difference that I see on a regular basis in my patients when it comes to when it comes to skin cancer.
Q7As a member of the Women’s Dermatological Society (WDS), what have you learnt from this role and how has it impacted your day-today practice?
The WDS is awesome, it is the first women's group I ever came across in my training. When I was a resident at Howard, I was awarded their mentorship grant, and I used that to spend a week in New York shadowing Andrew Alexis, Weill Cornell Medicine, New York, USA. It was awesome to see how he practiced, and I picked up some tips for ways that he approached certain things. I also remember Valerie Callender, Howard University College of Medicine, Washington D.C., USA, sponsoring us to attend the WDS luncheons. What was great was that I saw women and men at the WDS and these luncheons are just legendary; everybody knows about the WDS luncheon.
Now, as a practising physician, I have no insecurities about being a woman in business, because in my training, I would be in a room with hundreds of women at the WDS, running their practices with excellence, including cutting-edge research, discovering things, and
inventing things. So out of my training, by seeing members of the WDS just being themselves, I feel like it helped me to be a beast and not think that I shouldn't be here because I'm a woman. I've never had imposter syndrome as a dermatologist because I'm a woman.
Q8Could you talk about your current research projects and, as you look to the future, what are your key research goals?
My research goal is to increase the number of Black dermatologists who are principal investigators. When I was Chair of the dermatology section for the National Medical Association (NMA Dermatology), I had a bird's eye view of what Black physicians were discussing. Topics included the lack of representation in clinical trials.
I tried to come up with a solution and I created the Research Committee run by the current NMA Dermatology Chair, Hope Mitchell, Mitchell Dermatology, Perrysburg, Ohio, USA. Since my tenure ended, I have made it more focused. Last year, I cocreated Raven Clinical, and that
is where we mentor a smaller number of Black physicians. We have five sites who all started with investigator-initiated trials. Now all the dermatologists currently have two trials. The goal is for each of them to have two trials for 2 years so that they learn how to be a principal investigator. The difference between this and a clinical research organisation is the goal of Raven Clinical is for the dermatologists to really know how to be a principal investigator.
Everyone in the clinical research world knows it’s really difficult to get into the clinical trials if you don't have any experience. So, we really insulated these dermatologists with experience. The goal is that these five dermatologists will then mentor one or two dermatologists, so I'll recruit the next 5–10 dermatologists, and then hopefully it will snowball from there. At the end of the day, the whole point is for patients to have medications that work for them and for every American to have a medication launched that works for them because it was proven in the clinical trial.
The Advances in Treatment Options for Conditions Causing Hair Loss
Authors: Lily Kaufman,1 *Brittany
Dulmage2
1. The Ohio State University College of Medicine, Columbus, USA
2. The Ohio State University Wexner Medical Center, Columbus, USA
*Correspondence to brittany.dulmage@osumc.edu
Disclosure: The authors have declared no conflicts of interest.
Received: 20.09.24
Accepted: 18.10.24
Keywords: Alopecia areata, hair loss treatments, JAK inhibitors, low-level laser therapy, platelet-rich plasma (PRP) therapy, stem cell therapy.
Hair loss is a common problem in clinical dermatology, with many aetiologies including but not limited to androgenetic alopecia, telogen effluvium, alopecia areata, and cicatricial alopecias.1 Identifying effective hair loss treatments is important due to the prevalence of hair loss as well as its impact on quality of life.2 In recent years, new and innovative treatments have emerged to treat hair loss caused by a variety of conditions. This feature article summarises recent advances in the drugs, procedures, and devices used to treat hair loss, summarised in Table 1.
DRUGS
Oral and topical JAK inhibitors have emerged as promising treatments for autoimmunerelated hair loss, particularly alopecia areata.3 JAK inhibitors function through inhibition of enzymes in the JAK/signal transducer and activator of transcription (STAT) signalling pathway, regulating immune system activity. Currently, three JAK inhibitors have been approved by the FDA for the treatment of alopecia areata, including baricitinib,16 ritlecitinib,17 and deuroxolitinib.18 Ruxolitinib is also frequently used off-label to treat alopecia areata.3
Baricitinib is typically started at 2 mg once daily, with dose adjustments based on response and tolerability;19 ritlectinib is typically started at 50 mg once daily;20,21 and deuroxolitinib is typically started at 8 mg twice daily.22 Ruxolitinib is typically started at 5 mg twice daily, with dose adjustments based on response and tolerability.23 Regular lab monitoring is required, including baseline and periodic complete blood counts, liver function tests, and lipid panels, due to potential side effects such as cytopenias, hepatotoxicity, and dyslipidemia. Contraindications include active serious infections, severe hepatic impairment, and a history of thrombosis or malignancy. Although less widely studied than oral formations, topical JAK inhibitors have also shown promise in the treatment of immune-mediated alopecia.11
In addition to JAK inhibitors, biologics targeting IL pathways such as IL-17A, IL-4Rα, IL-13, and IL-12/IL-23p40 are being investigated for their potential roles in treating autoimmune-mediate hair loss such as alopecia areata. IL-12/IL-23p40 inhibitor ustekinumab and IL-4Rα and IL-13 inhibitor dupilumab have both demonstrated efficacy in improving alopecia areata severity in small clinical trials, while IL-17A inhibitor secukinumab did not demonstrate clinical efficacy in reducing alopecia areata
Table 1: Recent advances in the drugs, procedures, and devices used to treat hair loss.
severity in a small trial. Further prospective studies with larger cohorts are needed to determine the efficacy and optimal dosing regimens of biologics for treating alopecia areata and other alopecias.4
Although topical minoxidil has frequently been used to treat a variety of conditions causing hair loss, low-dose oral minoxidil has emerged as a treatment for a variety of alopecias in recent years. Studies have demonstrated low-dose oral minoxidil to be generally well tolerated, with the most common adverse effect being hypertrichosis. Although most commonly studied as a treatment for androgenetic alopecia, low-dose oral minoxidil has also demonstrated efficacy for treating chronic telogen effluvium, traction alopecia, alopecia areata, loose anagen syndrome, monilethrix, chemotherapy-induced alopecia, and scarring alopecias.6
Compounding of systemic medications into topical formations has also gained traction outside of JAK inhibitors, allowing for decreased systemic absorption and associated side effects. Medications such as spironolactone, which blocks the effects of androgens, and finasteride, which inhibits the conversion of testosterone to dihydrotestosterone, have been formulated into topical versions to treat androgenetic alopecia, with studies demonstrating efficacy in promoting hair regrowth while avoiding hormonal side effects. Topical combinatorial treatments that include
minoxidil have also been demonstrated to improve hair growth in the treatment of many forms of alopecia. For example, topical minoxidil combined with topical spironolactone was found to be superior to topical minoxidil alone. Further research on the most effective combinations and strengths is needed.8
Repurposing of drugs initially intended to treat other conditions has also emerged as a potential treatment for alopecia. Topical metformin, an insulin-sensitising drug typically used orally to manage diabetes, has demonstrated potential anti-fibrotic and anti-inflammatory effects beneficial for promoting hair regrowth in patients with central centrifugal cicatricial alopecia. Although this is still an emerging area of research, initial studies have suggested that topical metformin can decrease inflammation and fibrosis associated with central centrifugal cicatricial alopecia, offering a new route for treatment.9 Bicalutamide, an antiandrogen used in the treatment of prostate cancer, has demonstrated efficacy in treating female androgenetic alopecia in retrospective studies, particularly when used in combination with oral hormonal contraceptives. Prospective studies are needed to determine efficacy and optimal dosing regimens.5 Low-dose naltrexone, an opioid receptor antagonist that has demonstrated anti-inflammatory and analgesic effects, has shown efficacy in treating scalp pruritus and erythema
in primary cicatricial alopecias including lichen planopilaris and frontal fibrosing alopecia. Due to the retrospective nature of existing research, further prospective studies are required to determine efficacy and optimal treatment regimens.7
PROCEDURES
Platelet-Rich Plasma (PRP) therapy is increasingly used to treat androgenetic alopecia and other types of non-scarring hair loss.24 PRP is derived from the patient’s own blood, which is processed to concentrate platelets and injected back into the scalp with the belief that the growth factors in the PRP may stimulate hair follicles and promote hair regrowth. Common dosing regimens for PRP therapy in alopecia typically consist of injections every 4 weeks for three sessions, followed by maintenance therapy with one to three rounds every 6–12 months.25 This approach helps maintain results over time; however, studies of PRP efficacy have been limited by small sample sizes and inadequate followup times.26 Although PRP therapy has been widely used with studies supporting its effectiveness in improving hair density and thickness, the exact mechanism behind its efficacy is not fully understood and results may vary from patient to patient.
Stem cell therapy represents a cuttingedge therapy for the treatment of hair loss, particularly androgenetic alopecia and forms of non-scarring hair loss.12 This treatment involves harvesting, processing, and injecting the patient’s own adiposederived,27 mesenchymal,28 or hair folliclederived stem cells into the scalp. Stem cells are believed to modulate androgenic alopecia by regenerating hair follicles and enhancing hair growth.12 Stem cell therapy is an emerging treatment for hair loss, and research regarding its long-term efficacy and safety is ongoing.
Mesotherapy, which involves injecting a solution of medications such as minoxidil, growth factors, vitamins, stem cells, or botulinum toxin A into the scalp, is used to treat early-stage hair loss and improve overall hair health. This delivery approach
allows for product to more effectively reach hair follicles, possibly increasing the longevity and effectiveness of injected treatments as compared with topical preparations. Common dosing regimens for mesotherapy vary by treatment type, but typically consist of weekly treatments for 7–8 sessions, followed by biweekly treatments for 8–9 sessions, followed by monthly treatments for 3–12 sessions. Dutasteride mesotherapy, for example, has demonstrated the most efficacy when dosed weekly for seven sessions, then biweekly for nine sessions, followed by monthly for 12 sessions. Although studies have reported improvements in hair growth after treatment, there is no standardised treatment regimen and research is still in the early stages.13 Bicalutamide mesotherapy has recently emerged as a potential treatment for female androgenetic alopecia, but further studies are required to determine treatment efficacy.10
DEVICES
In addition to pharmacological treatments and procedures, several at-home devices have gained popularity for promoting hair growth. These devices offer patients the convenience of self-administration and may become more cost-effective than in-office treatments over time.
Low-level laser therapy (LLLT) uses lowenergy lasers with wavelengths between 600–1,100 nm to stimulate hair follicles and improve hair growth.8,29 The lasers penetrate the scalp, enhancing cellular metabolism and blood flow to the hair follicles, which is believed to increase hair density. This treatment has demonstrated efficacy for treating androgenetic alopecia and other non-scarring alopecias; however, there is a scarcity of controlled studies to support the efficacy of LLLT.14 Red light at 650 nm30 or near-infrared light at 600–950 nm29 is believed to stimulate the mitochondria of the hair follicles, enhancing energy production and stimulating hair regeneration. Research supporting the efficacy of LLLT is limited, and further studies are necessary to standardise treatment.
Vibration therapy and scalp massagers are designed to promote scalp blood flow and hair growth via mechanical stimulation and relaxation of the hair follicles.15 The underlying mechanism is believed to be caused by mechanical stimulation affecting the cells and genes involved with hair growth, leading to increased hair thickness. Further studies to determine treatment regimens and applications for specific types of hair loss are needed to further understand this emerging method for hair regrowth.
References
1. Alessandrini A et al. Common causes of hair loss - clinical manifestations, trichoscopy and therapy. J Eur Acad Dermatol Venereol. 2021;35(3):629-40.
2. Toussi A et al. Psychosocial and psychiatric comorbidities and healthrelated quality of life in alopecia areata: a systematic review. J Am Acad Dermatol. 2021;85(1):162-75.
3. Haughton RD et al. Janus kinase inhibitors for alopecia areata: a narrative review. Indian J Dermatol Venereol Leprol. 2023;89(6):799-806.
4. Zhou C et al. Alopecia areata: an update on etiopathogenesis, diagnosis, and management. Clin Rev Allergy Immunol. 2021;61(3):403-23.
5. Müller Ramos P et al. Female-pattern hair loss: therapeutic update. An Bras Dermatol. 2023;98(4):506-19.
6. Randolph M, Tosti A. Oral minoxidil treatment for hair loss: a review of efficacy and safety. J Am Acad Dermatol. 2021;84(3):737-46.
7. Perez SM et al. Oral naltrexone in the treatment of lichen planopilaris and frontal fibrosing alopecia. Arch Dermatol Res. 2024;316(8):605.
8. Kaiser M et al. Treatment of androgenetic alopecia: current guidance and unmet needs. Clin Cosmet Investig Dermatol. 2023;16:1387-406.
9. Granja BV et al. Treatment of central centrifugal cicatricial alopecia with topical metformin 10% cream: case report and literature review. Int J Dermatol. 2024;DOI:10.1111/ijd.17345.
10. Carvalho RM et al. Mesotherapy with bicalutamide for female pattern hair loss. Indian J Dermatol Venereol Leprol. 2024;DOI:10.25259/IJDVL_99_2024.
11. Samuel C et al. A review on the safety of using JAK inhibitors in dermatology: clinical and laboratory monitoring. Dermatol Ther (Heidelb). 2023;13(3):729-49.
12. Gentile P, Garcovich S. Advances
CONCLUSION
Recent advances in hair loss treatments reflect a growing array of options for managing various causes of hair loss. Medications, procedures, and medical devices have all emerged as potential therapeutic avenues, and continued research and clinical trials will be essential to validate the efficacy and refine the applications of these treatments.
in regenerative stem cell therapy in androgenic alopecia and hair loss: Wnt pathway, growth-factor, and mesenchymal stem cell signaling impact analysis on cell growth and hair follicle development. Cells. 2019;16;8(5):466.
13. Gupta AK et al. Systematic review of mesotherapy: a novel avenue for the treatment of hair loss. J Dermatolog Treat. 2023;34(1):2245084.
14. Munck A et al. Use of low-level laser therapy as monotherapy or concomitant therapy for male and female androgenetic alopecia. Int J Trichology. 2014;6(2):45-9.
15. Koyama T et al. Standardized scalp massage results in increased hair thickness by inducing stretching forces to dermal papilla cells in the subcutaneous tissue. Eplasty. 2016;16:e8.
16. U.S. FDA. BLA approval for baricitinib (olumiant). Approval letter. 2022. Available at: https://www.accessdata. fda.gov/drugsatfda_docs/ appletter/2022/207924Orig1s007ltr.pdf. Last accessed: 7 October 2024.
17. U.S. FDA. BLA Approval for ritlecitinib (LITFULO). Approval letter. 2023. https://www.accessdata. fda.gov/drugsatfda_docs/ appletter/2023/215830Orig1s000ltr.pdf. Last accessed: 7 October 2024.
18. U.S. DFA. BLA approval for deuruxolitinib. Approval letter. 2024. https://www.accessdata.fda.gov/ drugsatfda_docs/ appletter/2024/ 217900Orig1s000correctedltr.pdf. Last accessed: 7 October 2024.
19. U.S. FDA. Olumiant (baricitinib) tablets, for oral use: prescribing information. 2022. Available at: https:// www.accessdata.fda.gov/drugsatfda_ docs/label/2022/207924s007lbl.pdf. Last accessed: 15 October 2024.
20. U.S. FDA. Litfulo (ritlecitinib) capsules, for oral use: prescribing information. 2023. Available at: https:// www.accessdata.fda.gov/drugsatfda_ docs/label/2023/215830s000lbl.pdf.
Last accessed: 15 October 2024.
21. Passeron T et al. Inhibition of T-cell activity in alopecia areata: recent developments and new directions. Front Immunol. 2023;14:1243556.
22. U.S. FDA. Leqselvi (deuruxolitinib) tablets, for oral use: prescribing information. 2024. Available at: https://www. accessdata.fda.gov/drugsatfda_docs/ label/2024/217900Orig1s000correctedlbl.pdf. Last accessed: October 15, 2024.
23. Vandiver A et al. Two cases of alopecia areata treated with ruxolitinib: a discussion of ideal dosing and laboratory monitoring. Int J Dermatol. 2017 Aug;56(8):833-5.
24. Emer J. Platelet-rich plasma (PRP): current applications in dermatology. Skin Therapy Lett. 2019;24(5):1-6.
25. Gupta AK et al. Platelet-rich plasma as a treatment for androgenetic alopecia. Dermatol Surg. 2019;45(10):1262-73.
26. Giordano S et al. Platelet-rich plasma for androgenetic alopecia: does it work? Evidence from meta analysis. J Cosmet Dermatol. 2017;16(3):374-81.
27. Tak YJ et al. A randomized, doubleblind, vehicle-controlled clinical study of hair regeneration using adiposederived stem cell constituent extract in androgenetic alopecia. Stem Cells Transl Med. 2020;9(8):839-49.
28. Elmaadawi IH et al. Stem cell therapy as a novel therapeutic intervention for resistant cases of alopecia areata and androgenetic alopecia. J Dermatolog Treat. 2018;29(5):431-40.
29. Gupta AK, Foley KA. A critical assessment of the evidence for low-level laser therapy in the treatment of hair loss. Dermatol Surg. 2017;43(2):188-97.
30. Yang K et al. Hair growth promoting effects of 650 nm red light stimulation on human hair follicles and study of its mechanisms via RNA sequencing transcriptome analysis. Ann Dermatol. 2021;33(6):553-61.
Non-Scarring Alopecia in Females: A Comprehensive Review
Editor's Pick
For this year’s edition of EMJ Dermatology, my Editor’s pick is 'Non-Scarring Alopecia in Females: A Comprehensive Review' by Aristizabal et al. This review explores non-scarring alopecia, a condition that has a variety of causes, including genetic factors, immune dysfunction, and hormonal changes. Although often dismissed as a cosmetic issue, non-scaring alopecia can lead to psychological distress, and this article aims to explore the causes, mechanisms, and treatment options for non-scarring alopecia in females, emphasising the need for accurate diagnosis and comprehensive management to mitigate its impact on patients' quality of life.
Michael Gold
Gold Skin Care Centre, Nashville, Tennessee, USA
Authors: *Miguel A. Aristizabal,1 Alison J. Bruce,1 Roy S. Rogers III,2 Thais Pincelli1
1. Department of Dermatology, Mayo Clinic, Jacksonville, Florida, USA
2. Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, USA *Correspondence to aristizabal.miguel@mayo.edu
Disclosure: The authors have declared no conflicts of interest.
Alopecia is prevalent among females, categorised as either scarring or non-scarring, depending on the potential for hair follicle regeneration. Various aetiologic factors are implicated in non-scarring alopecia, including genetic predisposition, loss of immune privilege, oxidative damage, and hormonal fluctuations. Telogen effluvium, alopecia areata, and female pattern hair loss are the main causes of non-scarring alopecia in females of all ages. This review covers the aetiology, pathophysiology, and treatment of the most common nonscarring alopecias in females.
Key Points
1. Alopecia is commonly dismissed by the general public as merely a cosmetic concern. However, for many patients, it triggers feelings of low self-esteem, lack of confidence, and even depression or anxiety. This condition, categorised as either scarring or non-scarring, is especially pertinent for females, who frequently experience nonscarring alopecia. This highlights the necessity for a thorough understanding of its causes.
2. This narrative review explores the most common causes of non-scarring alopecia. It delves into detailed discussions of telogen effluvium, alopecia areata, and female pattern hair loss, covering their pathophysiological, clinical, and treatment aspects.
3. Non-scarring alopecia in females requires thorough evaluation. Telogen effluvium typically involves several precipitating factors contributing to this limited cause of hair loss. Alopecia areata is considered an autoimmune phenomenon, which can become chronic or recur in some patients. Female pattern hair loss follows a chronic course, with various topical, oral, and procedural treatment options available to reverse or halt its progression.
INTRODUCTION
Scalp hair is often regarded as a symbol of beauty and vitality across many cultures. Consequently, the loss of hair can significantly impact the emotional and psychological well-being of affected individuals. While alopecia (hair loss affecting any area) may be perceived as merely cosmetic by the public, patients frequently experience low self-esteem, lack of confidence, and common feelings of depression or anxiety.1 Therefore, clinicians should consider these psychological impacts when assessing and treating patients with signs of alopecia.
Alopecia can be further categorised into scarring and non-scarring types, with the potential for follicle regeneration serving as the defining differentiator.2 Scarring alopecia, which entails irreparable follicular damage leading to permanent loss, is less common than non-scarring alopecia. Depending on the type of inflammation, primary scarring alopecia is classified as lymphocytic, neutrophilic, or mixed. Clinical and histological diversity make diagnosis and treatment challenging.2,3
Non-scarring alopecia may present with periods of hair loss followed by regrowth; some consider it to be the result of several factors including loss of immune privilege and genetic predisposition.3 Non-scarring alopecias include telogen effluvium (TE), alopecia areata (AA), female pattern hair loss (FPHL), and others.4
Understanding non-scarring alopecia is critical for clinicians since hair loss is a frequent complaint. This paper provides insights into types of non-scarring alopecia affecting females, namely TE, AA, and FPHL.
METHODS
A comprehensive literature search was conducted to identify relevant studies on non-scarring alopecia in females. The search included electronic databases, including PubMed, Scopus, and Web of Science. Keywords used in the search included ‘alopecia’, ‘nonscarring alopecia’, ‘female hair loss’, ‘telogen effluvium’, ‘alopecia areata’, and ‘female pattern hair loss’. The search covered articles published up to 15 October 2023. Inclusion criteria involved studies providing insights into the aetiology, pathophysiology, or treatment of non-scarring alopecia in females, with exclusion criteria applied to articles lacking relevance or focusing on male populations. Methodological rigour was evaluated directly by the authors, and data synthesis was organised around identified themes, presenting a comprehensive narrative on the causes and treatments of non-scarring alopecia. Acknowledging limitations such as language restrictions and the temporal scope of the review, this methodology ensures a thorough exploration of nonscarring alopecia in females.
NON-SCARRING ALOPECIA
In non-scarring alopecia, hair follicles have the potential for recovery and often regain function once triggers such as inflammation, mechanical damage, or chemical exposure cease. Clinically, non-scarring alopecias can be classified as focal (patchy), diffuse, or ‘patterned’.5
Patchy non-scarring alopecia encompasses conditions such as AA, pressure-induced alopecia, tinea capitis, and traction alopecia, where the alopecia is noted in discrete patches. Diffuse non-scarring alopecia includes anagen effluvium, loose anagen syndrome, TE, and certain subtypes of AA, where loss occurs diffusely across the scalp.6 Finally, patterned conditions include FPHL, and trichotillomania.
Alopecia may be a component of autoimmune systemic disorders such as systemic lupus erythematosus. It is imperative to differentiate between diffuse AA and systemic lupus erythematosus.7 In addition, non-scarring alopecia may develop as a result of acute or chronic scalp inflammation in disorders such as psoriasis,8 seborrheic,9 or atopic dermatitis.10
Medications that have been associated with non-scarring hair loss include biologics (e.g., adalimumab, infliximab), chemotherapeutics, tyrosine kinase inhibitors (e.g., erlotinib, imatinib), budesonide, tacrolimus, enoxaparin, and lamotrigine.11
TELOGEN EFFLUVIUM
Follicular activity involves three main phases: anagen, catagen, and telogen. Approximately 90–95% of scalp hairs are in the growth (anagen) phase, where rapid division and differentiation of stem cells leads to follicular growth and hair shaft lengthening. This is followed by the involution (catagen) phase, characterised by apoptosis of follicular epithelium. Finally, the transition to a quiescent or resting state (telogen) involves 5–10% of follicles.12
This cycle occurs in a mosaic pattern so that follicles are not in the same phase synchronously, preventing episodes of mass shedding. On the scalp, anagen may last 2–8 years, telogen 2–3 months, and only 1% of follicles are in the 2–3-week catagen phase. Approximately 50–100 telogen hairs are shed daily.12
TE involves the early transition of anagen hairs to telogen following a stressor, leading to sudden and substantial hair shedding manifesting weeks or months later.13 Typically, an increased number of anagen hairs transition abruptly into catagen, followed by telogen, potentially resulting in a hair shedding rate of up to 35%; compared to the usual 5–10%.13
More recently, the synchronisation of telogen phase termination (teloptosis) has been considered a defining feature of TE, regardless of anagen phase duration.14
Pathophysiology
While the exact mechanism of TE is still not completely understood, theories focus on immediate anagen release, referring to the premature shift of anagen into telogen following stressors.15 This shift could be attributed to the redirection of metabolic priorities in response to circulating stress hormones or cytokines.16 The delayed anagen release theory postulates that a prolonged anagen duration delays telogen onset, and when the anagen stimulus ceases, hair shedding increases as follicles enter telogen. This may be responsible for postpartum TE.17
TE does not have inflammatory histopathologic findings; but rather, increased telogen follicles are the hallmark, and may be accompanied by additional findings if other causes of alopecia are present.18
Clinical Features
Patients with TE observe reduced scalp hair density and severe, abrupt shedding. Loss of less than 50% of hair volume may be noted but it is not a ‘shed to bald’. TE usually manifests 2–3 months following a trigger, with regrowth occurring 6–12 months after
Trigger
resolution. In some cases, individuals may experience a chronic course, with hair loss persisting beyond 6 months.19 Table 1 provides a list of potential TE triggers.
Diagnosis
Hair loss distribution is typically diffuse, commonly affecting bitemporal areas, with unremarkable hair shafts and scalp skin. A pull test is positive if, after gently pulling 50–100 terminal hairs, close to 10% of pulled hairs are extracted. This serves as a nonspecific diagnostic clue, also seen in FPHL and AA. Clinicians should be aware that TE can affect other hair-bearing areas.
Most patients experience asymptomatic hair loss; however, some individuals may develop pain or discomfort, a condition known as trichodynia. Notably, trichodynia
Physical Stressors
Emotional Stressors
Nutritional Deficiencies
Other Factors
is not unique to TE, and can be observed in FPHL.20
Trichoscopy reveals non-specific findings such as upright regrowing hairs with a tapered end, in a vertical position, and normal hair thickness.21 Notably, trichogram shows an increased telogen count, up to 25%, characterised by club-shaped, depigmented, and degraded epithelial sheaths.22
Laboratory testing is reserved for cases where inciting factors are not identified. This may include a complete blood count, metabolic panel, thyroid-stimulating hormone, ferritin, zinc, folate, vitamin B12, and vitamin D levels. TE is a diagnosis of exclusion, and testing is based on the need to exclude other disorders or to investigate possible underlying disease.23
Description
Surgery
Major illness or injury
Rapid weight loss or extreme dieting
Telogen gravidarum/childbirth
High fever
Severe infections
Chronic illness (e.g., thyroid disorders)
Medications (e.g., anticoagulants, retinoids)
Severe emotional distress
Persistent stress and anxiety
Iron deficiency
Vitamin D deficiency
Protein deficiency
Hormonal changes (e.g., menopause)
Excessive hair styling and hair treatments
Chronic telogen effluvium (variant with no identifiable trigger)
Table 1: Potential telogen effluvium triggers.
Treatment
TE is generally self-limited and requires the identification of any associated triggers. Patient counselling, education, and reassurance are essential. Management includes treatment of underlying disease or any associated scalp disorders, dietary rectification, and discontinuation of suspected medications.
Dietary supplementation in patients without nutritional deficiencies is generally discouraged, yet some experts suggest iron supplementation to achieve specific ferritin thresholds. Observational evidence suggests that iron supplementation for patients with TE and ferritin levels below 70 ng/dL reduces the proportion of telogen hairs compared to placebo.24 However, other experts suggest a threshold of 40 ng/dL.25,26
Therapy with topical minoxidil remains controversial because efficacy has not been evaluated. However, clinical observation indicates that it may be useful when shedding begins, to support hair regrowth, or in chronic TE as maintenance therapy, requiring at least 10–12 months of daily usage. Low-dose oral minoxidil has been shown to be effective in chronic TE, with doses ranging from 0.25–2.50 mg taken for at least 6 months, resulting in reductions in hair shedding. Side effects may include postural dizziness, lower extremity oedema, and hypertrichosis in undesired areas (e.g., the face).27
ALOPECIA AREATA
AA is a common non-scarring alopecia characterised by autoimmune dysregulation of the follicular microenvironment. The global incidence of AA is about 2%, with no race or sex difference. All ages may be affected, although it is more common in the third and fourth decades.28
The precise pathogenic mechanism remains elusive. It has been postulated that hair follicles are targeted by the immune system during anagen, causing premature entry into catagen and subsequent telogen, with inhibition of recycling and hence, regrowth.29, 30
Pathophysiology
Immune privilege in hair follicles involves orchestrated immunomodulatory mechanisms to prevent autoimmunity. In AA, this phenomenon is presumptively affected due to the downregulation of protective molecules such as TGF-β, α-melanocytestimulating hormone, and IL-1031. Furthermore, increased expression of natural killer group 2D receptor ligands, such as the major histocompatibility complex class I (MHC-I) polypeptide-related sequence A, can lead to local activation of natural killer cells and secretion of interferon (IFN)-γ and IL-15. This stimulates the expression of MHC-I on hair follicle cells, thus allowing for presentation of hidden local antigens.29
Although specific autoantigens implicated have yet to be identified, synthetic epitopes derived from trichohyalin (structural protein) and tyrosinase-related protein-2 may be involved.32 Additionally, activation of the JAK–signal transducer and activator of transcription (STAT) pathway by IFN-γ and IL-15 was discovered to trigger transcription of inflammatory genes and enhance cytokine production.33
Genetic factors have shown an increased risk of AA in families of affected patients, compared to the general population.34 Moreover, twin studies suggest a greater likelihood of the other twin being affected when one monozygotic twin is afflicted, compared to dizygotic twins.35
Histopathologic findings vary depending on disease activity. During active phases, a lymphocytic infiltrate of CD4+ T lymphocytes surround anagen follicles in a honeycomb pattern within and around the bulb. Conversely, in chronic stages, the inflammatory infiltrate is less pronounced, and diagnosis is supported by the presence of eosinophils, lymphocytes, and pigment incontinence, along with an increased catagen-to-anagen ratio.18
Clinical Features
AA commonly presents as well-defined, circular, smooth patches of alopecia developing over 2–4 weeks that affect the scalp and potentially other hair-
bearing areas. In some patients, patches can progress to involve the entire scalp (alopecia totalis), or the entire skin surface (alopecia universalis). Although pruritus or pain while touching hair (trichodynia) may precede AA, it is typically asymptomatic.36
Other unusual patterns include ophiasis, where the occipital scalp is affected in a band-like pattern, sisaipho, where AA affects any other scalp area aside from the periphery, and diffuse AA, characterised by sudden, significant diffuse hair loss (AA incognito).37
Exclamation hairs, short broken hairs with the proximal end narrower than the distal, are classic.38 Nail involvement has a prevalence of 10–20% and is associated with severe AA phenotypes. It can precede, coexist, or follow hair loss and manifests as pitting, trachyonichia, onychorrhexis, onycholysis, or onychomadesis.39
Diagnosis
AA commonly presents as asymptomatic hair loss with a tendency for spontaneous resolution and relapse.40 Examination of all hair-bearing areas and nails is recommended. The hair pull test may be used to assess disease activity.41 Clinicians should be mindful of the psychological burden to patients following diagnosis and make appropriate referrals when indicated.42
Trichoscopic findings include black dots resulting from broken hairs, exclamation marks, and Pohl-Pinkus constrictions in hair shafts. In chronic AA, yellow dots are found due to accumulation of sebum in longstanding telogen follicles. Regrowing hairs seem short in a pigtail form.43
Patients with AA may benefit from screening for other autoimmune conditions, mainly thyroid disease. Thyroid-stimulating hormone levels and thyroid autoantibody tests are appropriate in patients with a positive family history.43 Additional screening should be determined by associated signs or symptoms.
Treatment
Treatment considerations rely on careful counselling to incorporate patient preference, disease impact, and evaluation of therapeutic risks. Clinical responses vary, and AA may improve without intervention, especially with limited patchy AA.44
For AA with less than 50% scalp involvement, intralesional corticosteroid injection is first-line therapy. Triamcinolone acetonide injection at 2.5–10 mg/mL is used on the scalp and face in small 0.1 mL aliquots intradermally. The dose should not exceed 40 mg due to the risk of local and systemic effects.45 Treatments can be repeated every 4–6 weeks, with an expectation of regrowth within a few cycles, and should be discontinued once complete regrowth is achieved or if there is no response within 6 months. In patients who cannot tolerate injections, topical corticosteroids are an alternative.46
Systemic corticosteroids are also an option. Oral dexamethasone at 0.5 mg/kg in a 6-week course can induce remission.47 Pulsed therapy has also been explored in extensive or recalcitrant AA. Oral dexamethasone at 0.1 mg/kg/day twice weekly for 24 weeks has improved the Severity of Alopecia Tool (SALT) scores in 40 out of 45 patients in a retrospective multicentric study.48
For scalp hair loss greater than 50%, contact immunotherapy such as diphenylcyclopropenone or squaric acid dibutyl ester may be considered. These therapies exert an immunomodulatory effect, and signs of regrowth are expected after 3 months.49
A systematic review and meta-analysis evaluating diphenylcyclopropenone or squaric acid dibutyl ester for patchy AA, alopecia totalis, and/or alopecia universalis demonstrated a 32.3% (95% confidence interval: 25.3–40.2) rate of complete (90–100%) hair regrowth. Patients with patchy AA showed a higher complete response rate (43%) than those with alopecia totalis or universalis (25%). Potential side effects of topical immunotherapy
include dermatitis, urticaria, dyschromia, lymphadenopathy, and vitiligo.50
In recent years, JAK inhibitors (JAKi) have garnered significant attention. Inhibition of the JAK–STAT downstream pathway terminates the T cell-mediated response on the hair follicle by blocking the signalling of inflammatory mediators such as IFN-γ Baricitinib, ritlecitinib, and deuruxolitinib are oral JAKis that have been used with success in the treatment of AA.51,52
A recent systematic review and metaanalysis evaluating the effectiveness and safety of JAKis in AA concluded that JAKis are associated with lower SALT scores compared to placebo. Furthermore, oral JAKis demonstrated superior outcomes compared to topical agents. In this review, the effectiveness of baricitinib, ritlecitinib, and brepocitinib appeared to be comparable.51
Side effects of JAKis include upper respiratory and urinary tract infections, elevated cholesterol and liver function tests, headaches, and acne, which appear to be temporary and reversible. Despite studies confirming the efficacy and safety of JAKis in AA, additional research is still required to address concerns related to high cost, long-term safety, and potential for relapse after discontinuation.51, 52
Minoxidil is another alternative for AA treatment. Topical daily use at 1–5% has proven efficacious and safe.53 Oral minoxidil at doses of 0.25–5.00 mg 1–2 times daily induces terminal hair regrowth in refractory AA.54 Alternative options often employed as adjuvant therapies include methotrexate and cyclosporine, both of which exhibit a high relapse rate upon discontinuation. Reports on utilisation of hydroxychloroquine, antihistamines, azathioprine, prostaglandin analogues, and calcipotriol exist.55
FEMALE PATTERN HAIR LOSS
Historically, androgenetic alopecia (AGA) is a common cause of hair loss in both males and females. It is characterised by the interplay of hormonal and genetic factors; however,
the precise role of androgens in female AGA remains uncertain. Thus, a more accurate and widely accepted term is FPHL.56
FPHL is the most common cause of alopecia in females, and studies indicate that up to 19% of females in the USA exhibit some degree of the condition.57 It has been linked to social anxiety and emotional distress, which prompt females to seek treatment.58
Pathophysiology
Many factors, including genetic, environmental, and hormonal influences have been postulated to trigger follicular miniaturisation in FPHL. This process has not been completely elucidated but seems to involve an alteration in the ratio of terminal to vellus hairs in favour of the latter. Evidence suggests that anagen duration is shortened, decreasing from years to months or weeks.58
Androgens play an important role in male AGA due to the effects of dihydrotestosterone on the hair follicle, leading to hair miniaturisation. A similar mechanism may be associated with FPHL, since females with hyperandrogenismrelated disorders (e.g., polycystic ovarian syndrome, ovarian hyperthecosis, or androgen-secreting tumours) can manifest early-onset FPHL.58
Additionally, heightened sensitivity to androgens within follicles is hypothesised to be a contributing factor in hair thinning. The potential influence of oestrogen is also significant, notably in the increased postmenopausal prevalence of FPHL; however, research shows inconsistent results regarding whether oestrogens promote or hinder hair growth.59,60
Genetic factors indicate an association between family history and FPHL risk. Notably, a positive family history has been reported in 40–54% of early-onset cases with normal androgen levels.61 Recently, researchers observed perifollicular inflammation of CD4+ T cells in individuals with FPHL and male AGA; however, specific triggers remain unknown.62
Histopathology shows miniaturisation of follicles and sebaceous pseudohyperplasia. Arao–Perkins bodies, aggregates of elastic fibres in the fibrous streamers, are common in advanced stages.18
Clinical Features
FPHL may present with increased shedding progressing to thinning in a distinct pattern, primarily affecting the frontal and vertex scalp. Like male AGA, the occipital scalp is typically spared. Some patients present with a “christmas tree-like” pattern, where frontal thinning is prominent when hair is parted at the midline, while the frontal hairline is spared.
Diagnosis
Patients may complain of increased scalp visibility, sunburn, or ponytail thinning. This is observed over months to years. Although the course is progressive, some patients report distinct bouts of accelerated hair shedding prior to a visible change in hair density.63
Diagnosis is clinical and includes a thorough medical history, incorporating onset, duration, medication history, and use of nutritional or hormonal supplements. On examination, any signs of hyperandrogenism, such as virilisation, should be noted. A hair pull test is typically negative in long-standing FPHL.64
Evaluation for hyperandrogenism may be warranted because conditions such as polycystic ovarian syndrome, adrenal hyperplasia, and ovarian or adrenal tumours can present with FPHL. Additionally, there is emerging research suggesting associations with metabolic disorders, such as insulin resistance and hypertension.65
Multiple scoring systems exist to classify FPHL. Ludwig’s classification defines hair loss severity over the vertex into three grades, while Olsen’s, also a three-grade system, focuses on the frontal area.66 The Women’s Alopecia Severity Scale (WASS) is a system based on midline hair density loss; it incorporates trichoschopy, which may increase its precision.67
Trichoscopic findings include increased anisotrichosis (variation in diameter of hair shafts), miniaturisation, curved hair shafts, focal atrichia, yellow dots, peripilar brown halos, honeycomb pigmentation areas, and white dots.68 Additional diagnostic tools include phototrichograms, a method that merges epiluminescence microscopy with automated digital image analysis that allows for the estimation of hair quantity and density.69
Scalp biopsy is not mandatory for diagnosis but in selected cases helps exclude scarring alopecia, AA, or TE. Two 4 mm punch samples extending into the subcutaneous fat are recommended for vertical and horizontal processing.70
The relationship between ferritin levels and FPHL is debatable. Certain studies have shown reduced ferritin levels in patients with FPHL in comparison to controls.
Similarly, the precise role of vitamin D requires further investigation.71
Treatment
Hair loss reduction and potential regrowth are treatment goals. Clinical responses vary; some patients experience improvement with topical treatment alone, while others require combination therapies.
Ideally, treatment should be initiated before noticeable thinning occurs. This proactive approach leads to more favourable outcomes and increased patient satisfaction. Additionally, it is crucial to address treatment duration, as several months of consistent therapy are typically necessary, and some individuals may require maintenance treatment to preserve results.
Topicals are typically the initial choice, with minoxidil being a well-established first-line treatment. It has vasodilatory properties and activates smooth muscle potassium channels, inducing cell proliferation leading to anagen prolongation.72
Minoxidil is available as a 2% or 5% solution, or 5% foam, all of which are proven efficacious. In a systematic review
assessing FPHL treatments, none of the four trials comparing minoxidil 2% with 5% observed a significant difference in efficacy between the two concentrations.73 Solutions are commonly used twice daily, with foam formulations once. Patients may experience increased shedding for the first several weeks. Side effects include pruritus, erythema, hypertrichosis, and dandruff, which may be ameliorated with use of foams with lower propylene glycol concentration.74
Oral therapies may supplement topicals. Antiandrogens, such as spironolactone, are utilised in otherwise healthy patients. Spironolactone reduces testosterone production and blocks androgen receptors. It has demonstrated efficacy as either stand-alone or combination therapy. In an interventional study involving 80 patients with FPHL, 44% experienced hair regrowth, while 44% observed no change in hair density after 12 months of spironolactone 200 mg daily.75 Side effects include menstrual irregularity, postural hypotension, and electrolyte imbalance, especially in the context of renal impairment. Contraception is highly recommended in premenopausal patients.76
Additionally, in a retrospective study of 79 FPHL adults on spironolactone 100 mg daily for 6 months, either as monotherapy or in combination with topical minoxidil or lowlevel laser therapy (LLLT), all patients either improved or maintained their initial WASS score.77 Recent reports suggest that low doses of spironolactone, up to 50 mg daily, may be effective in the treatment of FPHL if used for an average of 4 months.78
Finasteride partially blocks testosterone conversion to dihydrotestosterone by enzyme inhibition and is considered the standard treatment for male AGA, although its utility in FPHL remains controversial. Evidence indicates that a 1 mg daily dose may not yield significant benefits,79 while others report higher doses as beneficial.80 In the European literature, oral cyproterone acetate is an androgen receptor inhibitor shown to be effective in FPHL with hyperandrogenism but is not available in the USA.81
Other treatment options include plateletrich plasma (PRP), LLLT, and oral minoxidil. PRP may be a promising option, as regrowth is stimulated through the release of growth factors from platelets. Injection protocols vary, with no consensus or treatment standardisation.82-84 A recent systematic review suggests that PRP injections likely reduce hair loss; however, the authors highlight limitations such as study heterogeneity, small sample size, and potential for publication bias.83
LLLT is another resource which may increase hair density. Possible therapeutic mechanisms include increased adenosine triphosphate production and cellular metabolism, as well as growth factor upregulation, but efficacy evaluation is challenging due to potential biases.85 Recent interest in oral minoxidil has emerged, utilising low doses of 0.25–2.50 mg daily. In a retrospective analysis of 12 females on oral minoxidil, there was a significant improvement in hair density after 24 weeks.86 Other reports suggest that a combination of 0.25 mg oral minoxidil and 25 mg spironolactone decreases shedding and improves hair density.87,88
Side effects of oral minoxidil such as hypertrichosis, hypotension, and tachycardia are dose-dependent and usually resolve with discontinuation. There are reports of rare side effects such as pericardial effusion, pretibial oedema, and arrhythmias.88,89
Surgical intervention may be considered when medical treatments fail. Follicular unit extraction and follicular unit transplantation may be employed, depending on FPHL severity and donor site availability.
CONCLUSION
The prevalence of non-scarring alopecia underscores the importance that clinicians be well-versed in this entity. Recognising hair loss and accurately identifying the type and aetiology of alopecia are mandatory to provide effective care. It is helpful to perform biopsies and relevant laboratory evaluations to exclude mimicking conditions.
Numerous treatment options exist, and ongoing advancements aim to decrease the impact of alopecia. It behoves clinicians to remain updated on recent developments given the disease prevalence. Notably,
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Update on Low-Molecular Weight Hyaluronic Acid in Dermatology: A Scoping Review
1. Medical University of South Carolina, College of Graduate Studies, Charleston, USA
2. Clinical Research Center of the Carolinas, Charleston, South Carolina, USA
*Correspondence to munie@musc.edu
Disclosure: Schlesinger is a consultant and/or investigator for Abbvie, Allergan (an Abbvie company), Galderma, L’Oreal, Senté, and HTL Biotechnology, outside of the submitted work. The other authors have declared no conflicts of interest.
Background: Hyaluronan, or hyaluronic acid (HA), is a naturally occurring glycosaminoglycan present in the skin, joints, and eyes that provides hydration, lubrication, protection, and other important benefits. HA in dermatology is commonly discussed in the context of its anti-ageing properties. However, both pre-clinical and clinical studies have shown numerous applications of HA, low-molecular-weight (LMW) HA, and hybrid LMW/high-molecular-weight HA in dermatology. LMW-HA exhibits antioxidant, anti-tumour, and angiogenic properties, and given its size, an ability to fully penetrate the skin.
Aims: The purpose of this review was to explore the current science and utility of LMW-HA in clinical dermatology and provide an update on its use.
Methods: A PubMed search from 2003–2023 on LMW-HA was conducted to evaluate LMW-HA’s utility in clinical dermatology.
Results: Identified applications of LMW-HA in medical dermatology included treatment of acute and chronic wounds, rosacea, scars, and seborrhoeic dermatitis. Cosmetic applications of LMW and hybrid HA included treatment of skin ageing, enlarged pores, and skin laxity, as well as enhancement of skin hydration. Topical LMW-HA administration promoted healing after cosmetic procedures, chemical peels, and ingrown toenail surgery. Studies of topical and oral LMW-HA demonstrated adequate safety, and newer techniques of administration, such as needleless jet injection, are available.
Conclusion: Exploration and understanding of the properties and benefits of LMW-HA are key to translating its usage in the clinical setting. Basic scientists and dermatologists have achieved substantial progress over the past two decades, and several applications of LMWHA in dermatology were identified. Additional advantages of LMW-HA are worth exploring.
Key Points
1. This paper provides a comprehensive review of low molecular weight hyaluronic acid (LMW-HA) and its emerging role in dermatology. While hyaluronic acid's utility is well-established across various medical fields, LMW-HA's unique properties, such as its antimicrobial effects and ability to penetrate the skin more effectively than its high molecular weight counterpart, present new avenues for clinical applications.
2. This scoping review synthesises a wide array of small but significant studies that highlight LMW-HA's potential in treating conditions such as wound healing, post-procedural care, and ageing, as well as its promise in cosmetic dermatology.
3. By providing an up-to-date exploration of LMW-HA's dermatologic uses, this paper serves as a foundation for future research and underscores the importance of continued investigation into the safety and efficacy of LMW-HA. As dermatologists seek novel treatments for common and challenging skin conditions, LMW-HA offers an exciting, well-tolerated option that may improve both medical and aesthetic outcomes in certain conditions.
INTRODUCTION
Hyaluronan, or hyaluronic acid (HA), is an extracellular matrix glycosaminoglycan distributed throughout the body, primarily found in the skin, joint synovial fluid, and eyes. It provides key benefits such as hydration and barrier protection. Several medical fields such as orthopaedics, ophthalmology, plastic surgery, periodontics, oncology, pulmonology, neurology, and dermatology have an interest in HA and its potential uses. While the anti-ageing benefits of HA are particularly well known, the applications of HA are quite broad. Countless basic science and clinical studies have explored its utility, ranging from its relevance in the tumour microenvironment to cosmetics and inflammatory conditions. Low-molecular-weight HA (LMW-HA), in particular, is one area of current scientific and clinical interest. This molecule forms from high-molecular-weight HA (HMWHA) upon hyaluronidase-catalysed depolymerisation and has a number of effects on its local environment.
The appropriate application and utility of HA in dermatology depends on its molecular size, with both HMW and LMW forms providing distinct advantages. HMWHA provides hydration and barrier function, with size limiting its penetration into the skin.1-2 LMW-HA’s size allows for adequate skin penetration,2,3 and studies have thus explored its potential utility in drug delivery and other cutaneous applications.4,5
There are several applications for crosslinked HMW/LMW-HA, particularly in cosmetic dermatology, and hybrid HA has been utilised in other contexts as well, such as in biomaterials.6
LMW-HA exhibits antioxidant, antitumour, and angiogenic properties, and has shown potential benefit in a number of dermatologic and non-dermatologic conditions.7-9 The purpose of this study was to explore the current and potential uses of LMW-HA, specifically in dermatology, as well as avenues for continued research.
METHODS
The authors conducted a PubMed search in January 2024 for articles published on LMWHA over the past two decades (i.e., 2003–2023), which yielded 864 articles. Inclusion criteria included studies that were relevant to dermatology; discussed HA, with a focus on LMW-HA or hybrid LMW/HMW-HA; and had at least one of the following: discussion of its application to clinical, medical, or surgical dermatology; molecular properties relevant to clinical practice; or safety. Exclusion criteria included articles outside of the specified date range and non-English articles. Of the 864 articles identified, further evaluation using these criteria elicited 61 relevant articles. A general literature search yielded 14 additional pertinent articles.
RESULTS
Table 1 documents the articles relevant to the current and potential applications of LMW-HA in dermatology, and other contexts of research.
DISCUSSION
HA is a non-sulfated glycosaminoglycan, consisting of N-acetylglucoasamine and glucuronic acid disaccharides.77 HA has wide medical and cosmetic applications, with effects dependent on molecular size.
The pro-inflammatory nature of LMW-HA is of primary concern, although studies have shown that HAs, even at low molecular weights, are safe to use. LMW-HA ≤20 kDa significantly increased the expression of the pro-inflammatory cytokine, TNF-α, and Farwick et al.1 thus noted that application
of LMW-HA ≤20 kDa is not recommended; however, LMW-HA at 50 kDa was safe.1 Furthermore, a study showed that all size fragments of HA studied (except at 6 kDa) were safe and able to promote wound healing, although lower size fragments had higher pro-inflammatory potential.11 While LMW-HA has demonstrated pro-inflammatory properties, Hu et al.14 also observed antiinflammatory effects of HA, including LMW-HA, in the context of UV-associated inflammation. As introduced, LMW-HA has greater penetrative ability than HMW-HA. Witting et al.67 confirmed this finding and also showed that LMW-HA modulated protein absorption through the skin.67
Studies have examined the utility of LMWHA in a number of dermatologic applications, including wound healing, seborrhoeic dermatitis, rosacea, scarring, anti-ageing, cosmetics, and post-procedural care. Selected applications are discussed below. Context, condition, or
Table 1: Studies of LMW-HA or hybrid/crosslinked HA in dermatology: uses and contexts of research. Dental applications of HMW-HA and pre-clinical studies of LMW-HA are presented as well.
Basic science
Basic science
Basic science
Basic science
Pre-clinical studies
Basic science
Basic science
Basic science
LMW-HA activates TLRs 2 and 4 which promotes production of beta-defensin 2
LMW-HA has anti-tumour properties
All size fragments of HA studied (except at 6 kDa): safe, able to promote wound healing
Oral administration of HA to UV-irradiated mice significantly increased stratumcorneum moisture content compared to UVirradiated mice who did not receive oral HA
HMW/LMW-HA and insulin-growth factor I mitigated radiation-associated damage in keratinocytes
LMW-HA has antioxidant properties
Observed anti-inflammatory effects of HA, including LMW-HA, in the context of UV-associated inflammation
Gariboldi et al. (2008)10
Alaniz et al. (2009)8
D'Agostino et al. (2017)11
Kawada et al. (2016)12
Sörgel et al. (2022)13
Ke et al. (2011)7
Hu et al. (2022)14
Table 1: Continued.
Context, condition, or utility
Study Design (sample size)
Basic science
Basic science
Basic science
Basic science
Seborrhoeic dermatitis
Rosacea
Prospective cohort (n=13)
Prospective cohort (n=14)
Split-face RCT (n=76)
Basic science
Basic science/ case series (n=10)
Basic science
Ageing
Retrospective case series (n=22)
RCT (n=23)
Basic science
In vitro and in vivo
Comment
Skin penetration greater with LMW-HA
In context of biomaterials
Nanoparticles incorporating HA and chitosan explored in the context of drug delivery of anti-inflammatories in contact dermatitis
Potential in drug delivery
LMW-HA safe, efficacious for treatment of seborrhoeic dermatitis
LMW-HA safe, efficacious for treatment of rosacea
Improved elasticity/hydration with all HAs analysed, decreased wrinkle depth with LMW-HA
Their HA complex (LMW-HA plus its acetylated derivative) increased type I collagen and decreased matrix metalloproteinase-1; it also increased laminin-332 and fibrillin-1 in the dermoepidermal junction
Ex-vivo: novel serum (incorporating LMWHA as an ingredient) guarded against oxidative damage as well as dermal protein loss secondary to radiation and chronological ageing; in-vivo: improvement in wrinkles/hydration
Product found to increase skin thickness, reduce wrinkles, and restore adipose tissue
Ad-HMN had superior improvement compared to Ad-LMN in regard to wrinkles, elasticity, and dermal density
A hybrid LMW/HMW-HA increased adipocyte differentiation and proliferation with potential to affect fat tissue renewal
In vitro: LMW-HA had greater penetrative ability compared to HMW-HA; in vivo: showed topical LMW-HA at 50 kDa decreased roughness and appearance of wrinkles
Case series (n=30) Topical serum containing both LMW-HA and HMW-HA decreased wrinkles
Reference
Ni et al. (2023)4; Essendoubi et al. (2016)2; Nashchekina and Raydan (2018)3
Mineo et al. (2013)6
Abuelella et al. (2023)15
Ferguson et al. (2011)5
Schlesinger and Powell (2012)16; Schlesinger and Powell (2014)17
HA has shown utility in several studies on wound healing. LMW-HA activates tolllike receptor (TLR) 2 and TLR4, which promote production of beta-defensin-2, a key molecule in skin microbial defense.10 N-butyrylated LMW-HA decreases TNF-ɑ, IL-1β, and IL-6 in vivo, and promotes angiogenesis, collagen expression, and wound healing.32 Hybrid LMW/HMW-HA decreased IL-6, IL-8, TNF-ɑ, and TGF-β, and promoted wound healing in vitro. 30 Additionally, ɣ-treated LMW-HA expedited wound healing in vivo. 33 D’Agostino et al.31 showed that hybrid LMW/HMW-HA was superior to HA in vitro with regards to wound healing.
Pre-clinical and clinical studies have evaluated wound dressings incorporating LMW-HA as a means for wound healing. Studies have shown that dressings containing crosslinked HMW/LMW-HA and other factors facilitate wound healing.41-44 A prospective cohort of 32 patients and a retrospective observational study of 80 patients demonstrated that application of LMW-HA/silver sulfadiazine dressings promoted wound healing.45,26 Furthermore, Tagliagambe et al.34 report a case of LMWHA contributing to full healing of a patient's difficult-to-treat venous ulcer.
Reviews by Kaul et al.28 and Litwiniuk et al.29 nicely discuss HMW- and LMW-HA in wound healing and the mechanisms/key cells at play in these processes.
Prospective studies showed that LMWHA was safe and efficacious for the treatment of seborrhoeic dermatitis (n=13) and rosacea (n=14) in these respective cohorts.16-18 LMW-HA has also shown utility in the treatment of acne and hypertrophic scars. A prospective, splitface randomised controlled trial (RCT) of 30 patients showed that combined LMW/ HMW-HA filler and traditional filler were both beneficial in acne scar treatment and demonstrated distinct advantages.62 An RCT of 82 patients showed that a technique incorporating hybrid HA was advantageous and safe in treating acne scars.63 Furthermore, a prospective cohort study of 15 patients showed that hyaluronidase injections (prompting LMWHA formation) in hypertrophic scars were safe and improved the average Vancouver Scar Scale in these patients.64
Cosmetic Dermatology
A prospective study of 42 patients showed that intradermal LMW-HA was safe and efficacious in treating enlarged pores.27
An in vitro study showed that LMWHA increased expression of filaggrin, a structural protein that contributes to skin hydration and supports the skin barrier.51
Farwick et al.1 showed that, in vitro, LMW-HA had a greater penetrative ability compared to HMW-HA and promoted expression of a greater number of genes compared to HMW-HA. An in vivo extension of their study showed that topical LMW-HA at 50 kDa decreased roughness and the appearance of wrinkles in their small cohort of patients.1
Several studies have described LMW-HA's effectiveness in skin rejuvenation. A splitface RCT (n=76) showed that LMW-HA led to improved elasticity and hydration of the skin as well as decreased wrinkle depth.19 Chen et al.20 showed that their HA complex (LMW-HA plus its acetylated derivative) increased Type I collagen, decreased matrix metalloproteinase-1, and increased laminin-332 and fibrillin-1 in the dermoepidermal junction.20 Juncan et al.21 (n=10) reported an anti-ageing cream
containing LMW-HA that has proven to be safe and well-tolerated. The study found significant reductions in wrinkle length and depth in the periorbital area after 28 days.21
Garre et al.22 analysed ex vivo skin to find that a novel serum, incorporating LMW-HA as one ingredient, guarded against oxidative damage as well as dermal protein loss secondary to radiation and chronological ageing. The study also analysed the skin in vivo, which showed improvement in wrinkles and hydration with the serum.22
A study aiming to analyse the effect of various HA gels on adipocyte-derived stem cells found that a hybrid LMW/HMW-HA increased adipocyte differentiation and proliferation with the potential to affect fat tissue renewal.25 A retrospective case series (n=22) studying a dermal filler containing hybrid HA found that clinically, the gel had high cohesivity upon injection into dermal tissue, and its lower viscosity offered “easy extrusion”.23 The product was found to increase skin thickness, reduce wrinkles, and restore adipose tissue.23 Jang et al.24 compared “adenosine encapsulated” LMWand HMW-HA “dissolving microneedle patches” (abbreviated Ad-LMN, AdHMN). This RCT (n=23) found that both formulations showed skin improvement, but Ad-HMN had superior improvement compared to Ad-LMN in regard to wrinkles, elasticity, and dermal density.24 Finally, a case series (n=30) found that a topical serum containing both LMW-HA and HMWHA decreased wrinkles, highlighting its antiageing effect.26
Regarding LMW-HA's use in fillers, a retrospective chart review (n=2,342) found that the analysed dermal filler containing HMW- and LMW-HA for facial rejuvenation was well-tolerated, and had enduring effects for 1 year or more.47 Muhn et al.48 conducted an overview of volume restoration using published literature. Of note, they concluded that a highviscosity LMW-HA is beneficial for volume restoration, and that it is highly-malleable, can be used in different facial planes, has immediate results, and little downtime.48 Another literature review stated that the synergistic effect of LMW-HA and HMWHA in HA hybrid cooperative complexes
(HCC) is ideal for bioremodelling due its ability to increase hydration, elasticity, and skin tone, while supporting the dermis like traditional fillers.49 A case series (n=6) found that a formulation consisting of high concentrations of crosslinked HA was effective and safe in the tear-trough area.50
LMW-HA has also been published in the literature specifically for its use in treating skin laxity. A case series (n=10) found that the combination of plasma exeresis and non-crosslinked HA injection (containing both HMW-HA and LMW-HA) was effective in treating neck laxity and wrinkles.52 A clinical trial (n=25) analysing the HCCs in a relatively new dermal filler found that two injections were effective for reducing neck laxity and resulted in high patient satisfaction.53 A pilot RCT (n=19) evaluated abobotulinum toxin A injection alone versus abobotulinum toxin A injection followed by gel injection of hybrid HA for lower face and neck rejuvenation.54 The study found that patients receiving the combination of botulinum toxin A followed 2 weeks later by the filler experienced superior improvement in skin thickness and hydration.54
Other Low-Molecular-Weight
Hyaluronic Acid
or Hyaluronic
Acid Applications
Post-procedural
Post-procedural advantages involving the use of LMW-HA extend to both cosmetic and surgical procedures. A prospective, split-face RCT of 24 patients showed that application of crosslinked HA was beneficial after cosmetic procedures,55 and an RCT of 70 patients showed that application of LMW-HA post-ingrown toenail surgery improved recovery time.56 An in vivo and ex vivo study of 12 patients revealed that application of LMW-HA/hibiscus postchemical peel treatment was beneficial.57
An in vitro study found that HMW/ LMW-HA and insulin-growth factor I mitigated radiation-associated damage in keratinocytes, thus providing a potential therapeutic avenue for dermatitis associated with radiation treatment.13
Gynaecology
A prospective cohort study of 50 patients showed LMW-HA was advantageous in the treatment of post-menopausal vulvovaginal atrophy.60 A prospective RCT of 45 patients demonstrated that vaginal application of LMW-HA improved atrophy post-radiotherapy.58 Similarly, an RCT of 180 patients showed that vaginal application of LMW-HA in the setting of post-radiotherapy for cervical cancer was safe and advantageous.59 Given LMW-HA's ability to activate TLRs 2 and 4, promoting antimicrobial polypeptide formation, LMWHA facilitates vaginal healing and defense.61
Dentistry
HMW-HA has shown utility in the treatment of gingivitis, oral lichen planus, and recurrent aphthous ulcers. HA 0.2% gel may have benefit in oral lichen planus treatment according to a placebocontrolled RCT (n=124), as well as wound healing post-tooth extraction per a recent RCT (n=30).35 Both a placebo-controlled RCT (n=105) and a cross-over, split-mouth RCT (n=28) showed that HA 0.2% gel may be beneficial in gingivitis treatment.36,37,40 Furthermore, a placebo-controlled RCT and an open-label prospective study showed that HA 0.2% gel may be beneficial in recurrent aphthous ulcer treatment.37,39
Oral supplementation
Basic science and clinical research have also explored the utility of oral HA in anti-ageing and facial hydration. A pre-clinical study of skin ageing showed that oral administration of HA to UV-irradiated mice significantly increased stratum-corneum moisture content compared to UV-irradiated mice who did not receive oral HA.12 A placebocontrolled RCT (n=30) showed oral intake of a supplement containing LMW-HA (and other ingredients) twice daily for a month improved individuals' facial hydration and photoageing Visual Analogue Scales.65 Furthermore, oral intake of a supplement containing LMW-HA (in addition to collagen and another glycosaminoglycan [chondroitin sulfate]) twice daily for three months offered improvement in wrinkles and dryness in an open-label pilot study (n=26).66
Novel Applications
Jet-injection
An open-label, prospective observational (n=64) study and a retrospective observational (n=11) study both showed that a relatively new injectable hybrid HMW/ LMW-HA filler was safe and effective.68,69 Jet-injection of HA is a promising technique for cosmetic applications.70
Drug delivery
Nanoparticles incorporating HA and chitosan have also been explored in the context of drug delivery of antiinflammatories in contact dermatitis.15
Safety
Numerous studies have shown that HA, including LMW-HA, is safe and effective for use in patients both topically and orally. A pilot, prospective cohort study of 20 patients showed that oral intake of LMWHA for 1 week was safe, and consumption did not alter patients' microbiome or measured labs.71 Post-market analysis (n=42,394) data revealed that the aforementioned new hybrid HA filler was safe to use.76
Importantly, a key safety risk of HA fillers must be noted, namely, vascular occlusion and necrosis associated with improper use. Zeltzer et al.72 document a patient who experienced facial necrosis from HA filler and received rescue hyaluronidase. This case highlights the risks of filler procedures and introduces the "Avoid, Recognise, and Treat" (ART) paradigm.72 Goodman et al.73 documented a case report of a patient who experienced hypersensitivity to an HMW/LMW-HA filler, presenting as injection-site swelling (ultimately clearing without treatment).73 Granuloma formation secondary to HA filler may occur due to the pro-inflammatory properties of LMW-HA and TLR2 mediation.74 There is consensus that pro-inflammatory LMW-HA fragments from HMW-HA fillers play a role in fillerassociated nodule formation.75
Study Limitations
Most studies identified in this scoping review had small sample sizes, limiting external validity. Additionally, publication bias may have skewed the authors' results in favour of LMW-HA. Furthermore, the articles included had varying methodologies with diverse patient populations, contributing to heterogeneity. This heterogeneity may additionally limit the generalisability of the authors' study findings. PubMed was the primary search engine for this study, and additional relevant, though non-PubMed-indexed, studies may have been missed. While there are several rigorous basic science studies on LMW-HA, this review focused primarily on the clinical applications of LMW-HA.
CONCLUSION
LMW-HA has received increased attention over the past two decades, and has shown utility and application in several dermatologic conditions, including wound healing, post-procedural healing (after both surgical and cosmetic procedures), ageing, hydration, enlarged pores, facial volume, scars, rosacea, and seborrhoeic dermatitis. New advances have improved drug delivery and effectiveness, and oral supplements containing LMW-HA are available. The safety profile of topical and oral administration of LMW-HA is favourable. Though not a focus of this review, basic science research shows promise for translational applications of HA in clinical practice, and the clinical community will likely see several more advances in subsequent years. Furthermore, the benefits of HA and LMW-HA in other fields, such as dentistry (e.g., HA for recurrent aphthous ulcers, gingivitis, and oral lichen planus) and gynaecology (e.g., LMW-HA for vaginal atrophy), may extend to atrophic, ulcerative, or inflammatory dermatologic conditions. Additional large-scale, welldesigned research studies are needed to fully elicit LMW-HA's potential in the field of dermatology.
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Pathogenic Variants in the ABCA12 Gene Associated to Autosomal Recessive Congenital Ichthyosis: Report of an Attenuated Phenotype
Authors: *Gabriela Mantilla Beltrán,1 Ana María Navarro Pinilla,1 Diego Andrés
Padilla Mantilla,2 Alfonso Suárez Camacho,1 Mónica Paola Novoa Candia3
1. Fundación Universitaria de Ciencias de la Salud (FUCS), Medical Genetics Service, Hospital Infantil Universitario de San José, Bogotá, Colombia
2. Universidad de los Andes, Bogotá, Colombia
3. Fundación Universitaria de Ciencias de la Salud (FUCS), Dermatology Service, Hospital Infantil Universitario de San José, Bogotá, Colombia
*Correspondence to gmantilla@fucsalud.edu.co
Disclosure: The authors have declared no conflicts of interest. The legal representative for the family (mother) signed the informed consent for publication of clinical cases and for the publication of images. The patients signed consent for the publication of clinical cases.
Congenital ichthyosis represents keratinisation disorders characterised by abnormal skin scaling across the entire body, leading to a red, denuded, and scaly appearance. A subgroup of this is the autosomal recessive congenital ichthyosis (ARCI), characterised by a severe phenotype and classified according to the molecular mechanisms that underlie the disease. This article reports on the cases of two female patients with symptoms of palmoplantar keratoderma since birth and a variant in the ABCA12 gene that encodes an amino acid glucosylceramide transporter known as ABCA12. The primary role of ABCA12 is to facilitate the transport of molecules across cell and intracellular membranes. Variants involve large deletions and nonsense variants, resulting in a truncated protein that contributes to the severity of harlequin ichthyosis. However, the patients reported in this article present an attenuated phenotype with palmoplantar keratoderma. The subdued presentation in these patients might be elucidated by their compound heterozygous status.
Key Points
1. Most cases described in relation to the ABCA12 gene are associated with harlequin ichthyosis, a lethal phenotype that appears in neonatal stages. Generally, these cases are associated with homozygous variants. In cases of compound heterozygosity, milder phenotypes occur, such as palmoplantar keratoderma, seen in this case report, highlighting the genotype-phenotype activation of a spectrum of disease.
2. This article presents a case report of two sisters with symptoms of palmoplantar keratoderma. In one of them, the exome identified a pathogenic nonsense variant and a probable pathogenic intronic variant in the ABCA12 gene, in a compound heterozygous state. A literature review was carried out, identifying that this gene has a higher phenotypic frequency of harlequin ichthyosis, and is generally due to homozygous variants. In contrast, biallelic missense variants mainly lead to lamellar ichthyosis or congenital ichthyosiform erythroderma. In these cases, the patients reported having symptoms of palmoplantar keratoderma.
3. There is allelic heterogeneity in different genes related to genodermatosis. Molecular biology studies are useful in searching for the aetiology of a possible hereditary condition. Molecular studies help determine an aetiological diagnosis and enable a better understanding of disease pathophysiology, and as a result, aid the identification of more therapeutic options for patients.
INTRODUCTION
Congenital ichthyosis represents keratinisation disorders characterised by abnormal skin scaling across the entire body, leading to a red, denuded, and scaly appearance.1 These disorders include both syndromic and non-syndromic forms, depending on the involvement of additional systems or organs.2 Non-syndromic ichthyoses were traditionally categorised into common ichthyoses (vulgar ichthyosis and non-syndromic X-linked recessive ichthyosis), keratinopathic ichthyoses (epidermolytic ichthyosis, congenital reticular ichthyosiform erythroderma, superficial epidermolytic ichthyosis, and Curth-Macklin ichthyosis), and autosomal recessive congenital ichthyosis (ARCI; lamellar ichthyosis, congenital ichthyosiform erythroderma, harlequin ichthyosis, self-resolving collodion baby, premature baby ichthyosis syndrome, and bathing suit ichthyosis).1,3
Currently, ichthyoses are classified according to the molecular mechanisms that underlie the disease, encompassing alterations in intracellular protein networks (keratins, filaggrin, and cornified envelope), disruption of lipid metabolism (ceramides, cholesterol, lamellar bodies, and dolichol), disturbances in intercellular junctions (tight junctions, desmosomes, and proteases), or impairments in multiple functions. This classification aids in guiding specific treatment options.4
The authors report a familial case involving two sisters, born to non-consanguineous parents, both demonstrating a compound heterozygous variant in the ABCA12 gene, presenting with palmoplantar keratoderma.
CASE DESCRIPTION
Patient 1
A 14-year-old female adolescent who, at birth, presented with collodion membrane and a persistent whitish scaling on palms, soles, skin folds, and joints. Currently, the patient presents with palmoplantar keratoderma accompanied by generalised xerosis and the development of rough hyperpigmented plaques in the axillae, inguinal region, elbows, and knees, along with moderate pain (Figure 1).
A skin biopsy from the left axilla revealed orthokeratotic hyperkeratosis, papillomatosis, and acanthosis, with areas of hypergranulosis and thick keratohyalin clumps, indicative of a pattern consistent with epidermolytic hyperkeratosis. A biopsy from the left palm demonstrated marked physiological hyperkeratosis settlement in the stratum corneum, accompanied by mild hypergranulosis, consistent with keratoderma. The diagnosis of diffuse isolated palmoplantar keratoderma was established, and management with 20% and 30% urea creams was initiated, maintaining clinical stability.
Patient 2
A 5-year-old female who presented with scaling on palms and soles since birth, currently presenting with palmoplantar keratoderma and generalised xerosis (Figure 2). A left palm skin biopsy revealed physiological hyperkeratosis with hypergranulosis, thick keratohyalin clumps, and mild psoriasiform acanthosis,
A B C
Figure 1: Photos of Patient 1.
A) Palmar keratoderma. B) Plantar keratoderma. C) Rough hyperpigmented plaques in the axillae.
Figure 2: Plantar keratoderma. Photo of Patient 2.
without dermal changes, consistent with keratoderma. The diagnosis of diffuse isolated palmoplantar keratoderma was established, and management was initiated with moisturising creams, 20% and 30% urea creams, along with skin barrier care, resulting in a stable clinical evolution.
Genetic assessment excluded the existence of comparable family histories involving asymptomatic non-consanguineous parents. A Mendelian pattern of incomplete penetrance or germinal mosaicism was considered. A comprehensive trio exome analysis (Patient 1–mother–father) was undertaken, encompassing the study of over 20,000 genes through nextgeneration sequencing with DNB-SEQG400 (MGI Tech, Shenzhen, China), utilising an MGIEasy Exome Capture V5 Probe Set. Genes associated with established monogenic diseases were scrutinised,
maintaining a minimum depth of 20x. A pathogenic nonsense variant in ABCA12 (NM_173076):c.6610C>T (p.Arg2204*), was identified in both the father and the patient, alongside a probably pathogenic intronic variant in ABCA12 (NM_173076):c.6962+2T>C p.?(uncertain protein structure), present in both the mother and the patient.
The molecular findings confirmed the diagnosis of ARCI due to compound heterozygosity in the ABCA12 gene. Each parent carries a pathogenic variant, resulting in a 25% probability of disease recurrence in the patient's offspring. It was determined that both patients shared the ARCI genotype, but the late onset and clinical manifestations were consistent with the phenotype predominant palmoplantar keratoderma features (Figure 3).
Figure 3: Generalised xeroderma. Photo of Patients 1 and 2.
DISCUSSION
Ichthyoses are distinguished by an aberrant keratinisation process affecting the stratum corneum and stratum granulosum. However, molecular defects associated with barrier impairment and compensatory skin responses vary among ichthyosis types, influencing the signs and symptoms observed in patients.5 The stratum corneum, comprising corneocytes (cellular compartment) surrounded by lipids (intercellular compartment) and interconnected by numerous corneodesmosomes, undergoes proteolytic degradation, a process known as desquamation.6
ARCI constitute a diverse group of congenital ichthyoses devoid of extracutaneous involvement, distinguished by a common molecular mechanism affecting the intracellular protein network, specifically ceramides.4 Collectively, these autosomal recessive disorders have an estimated incidence of 1 in 200,000 live births, resulting in barrier defects that augment transepidermal water loss and trigger compensatory hyperproliferation or hyperkeratinisation.2 The prevalent phenotype within ARCI is lamellar ichthyosis, frequently accompanied by palmoplantar keratoderma, ectropion, and anhidrosis.5 Approximately 60–70% of patients manifest severe symptoms, including a collodion membrane at birth,7 with rare instances of harlequin ichthyosis associated with higher perinatal mortality.5
The compromise of skin barrier function has been associated with pathogenic variants in genes such as ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, TGM1, LIPN, CASP14, and SLC27A4, which play a crucial role in lipid biosynthesis (acylceramides, lipid lamellae, and cornified lipid envelope), intercellular adhesion, and detachment of differentiated cells, among other functions.6
The ABCA12 gene, located on chromosome 2q34, encompasses 53 exons that encode a 2595-amino acid glucosylceramide transporter known as ABCA12. As a member of the ATP-dependent ATP-
binding cassette (ABC) transporter superfamily, its primary role is to facilitate the transport of molecules across cell and intracellular membranes.8 The expression of ABCA12 has been demonstrated through RT-PCR methods in placental, testiclular, fetal brain, and skin tissue.8,9 Murine models have revealed that ABCA12 deficiency leads to impaired lipid transfer, disrupting the distribution and transport of glucosylceramides and reducing hydroxyceramide levels. Additionally, it is associated with defects in the transport of certain proteases, such as calpain 5 and cathepsin D, due to alterations in lamellar bodies, contributing to deficient desquamation and hyperkeratosis.10
In humans, ABCA12 is implicated in ARCI,11 specifically associated with harlequin ichthyosis, which represents the most severe and lethal form.12 Frequently observed variants involve large deletions and nonsense variants, resulting in a truncated protein and contributing to the severity of harlequin ichthyosis.13 However, missense variants have also been documented without truncating the protein, leading to milder phenotypes resembling lamellar ichthyosis or congenital ichthyosiform erythroderma with medium-sized scales.5,10
In the author’s case, the identified genetic variants, classified as pathogenic and probably pathogenic following the American College of Medical Genetics and Genomics (ACMG) criteria, consist of nonsense variants featuring premature stop codons and intronic variants, respectively. The former significantly impairs protein function, while the latter results in an uncertain protein. However, when situated in the canonical splicing donor site that disrupts the donor or acceptor splice site, it typically leads to a loss of protein function.14 It likely gives rise to a degraded mRNA transcript or a non-functional protein through mRNA degradation mediated by terminator variants and loss-of-function variants in ABCA12 are known to be pathogenic.8 Because of this, the authors thought both variants were harmful. A computer tool (autoPVS1) showed that the GT-AG splice sites are found in important gene transcripts. If exon skipping or a hidden splice site changes the gene's
reading frame, the mRNA is expected to be broken down by the NMD (nonsense mediated decay) system.15
Hotz A. et al.,15 presented a cohort of 64 patients carrying biallelic variants in ABCA12 with autosomal recessive congenital ichthyosis. The splicing site variation was not reported; however, the nonsense variant (NM_173076):c.6610C>T (p.Arg2204*) was reported in a homozygous patient associated with harlequin ichthyosis. It has been described that loss-of-function variants on both alleles generally result in harlequin ichthyosis, whereas biallelic missense variants mainly lead to lamellar ichthyosis or congenital ichthyosiform erythroderma.15
Despite the protein-level compromise, both variants might suggest a harlequin ichthyosis phenotype. However, the patients in this case exhibited a milder clinical manifestation with a self-limited collodion baby syndrome in the neonatal stage and subsequent development of palmoplantar keratoderma without additional findings. The authors propose that this presentation may be attributed to the compound heterozygous genotype, although experimental studies are recommended to validate this hypothesis.
The management of ARCI is primarily symptomatic, involving the use of topical emollients like glycerol, urea, propylene glycol, sodium chloride, vitamin E acetate, and petroleum jelly, typically formulated in creams.6 In cases of pronounced hyperkeratosis, additional keratolytic agents such as hydroxy acids (lactic and glycolic acids), salicylic acid, N-acetylcysteine, urea (> 5%), and propylene glycol can be introduced. Furthermore, keratinocyte differentiation modulators, including topical retinoids
References
1. Fischer J, Bourrat E. Genetics of inherited ichthyoses and related diseases. Acta Derm Venereol. 2020;100(7):adv00096.
2. Sun Q et al. The genomic and phenotypic landscape of ichthyosis: an analysis of 1000 kindreds. JAMA Dermatol. 2022;158(1):16-25.
3. Oji V et al. Revised nomenclature and
(tretinoin, adapalene, and tazarotene), calcipotriol, and dexpanthenol, may be incorporated into the treatment regimen.10
Presently, investigations are in progress regarding the development of biologic drugs for the treatment of ARCI. Studies involving mice with ABCA12 deficiency, revealing diminished desquamation linked to calpain deficiency, propose that the topical administration of recombinant calpain (Kallikrein-10) appears to reinstate corneodesmosome proteolytic degradation, thereby partially normalising the skin phenotype.16
CONCLUSION
Congenital ichthyosis encompasses a diverse spectrum of pathologies marked by genetic heterogeneity and variable expressivity. Variants in the ABCA12 gene are implicated in autosomal recessive congenital ichthyosis, including congenital ichthyosiform erythroderma, lamellar ichthyosis, and often fatal forms such as harlequin ichthyosis. Despite identifying a genetic variant typically associated with severe clinical phenotypes, the subdued presentation in these patients might be elucidated by their compound heterozygous status.
Presently, the management of ichthyoses remains symptomatic, with the prospect of emerging therapeutics poised to enhance the quality of life for affected individuals. The manifold clinical manifestations and intricate genetic underpinnings underscore the necessity for ongoing research in ichthyosis, aiming to unravel molecular complexities and formulate targeted therapeutic interventions.
classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorze 2009. J Am Acad Dermatol. 2010;63(4):607-41.
4. Gutiérrez-Cerrajero C et al. Ichthyosis. Nat Rev Dis Primers. 2023;9(1):2.
5. Vahlquist A et al. Inherited nonsyndromic ichthyoses: an update on pathophysiology, diagnosis and treatment. Am J Clin Dermatol.
2018;19(1):51-66.
6. Vahlquist A, Törmä H. Ichthyosis: a road model for skin research. Acta Derm Venereol. 2020;100(7):adv00097.
8. Akiyama M. ABCA12 mutations and autosomal recessive congenital
ichthyosis: a review of genotype/ phenotype correlations and of pathogenetic concepts. Hum Mutat. 2010;31(10):1090-6.
9. Online Mendelian Inheritance in Man (OMIM). 607800 ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 12; ABCA12. Available at: https:// www.omim.org/entry/607800. Last accessed: 7 September 2024.
10. Rodríguez-Pazos L et al. Ictiosis congénitas autosómicas recesivas. Actas Dermo-Sifiliográficas. 2013;104(4):270-84.
11. Natsuga K al. Novel ABCA12 mutations
identified in two cases of nonbullous congenital ichthyosiform erythroderma associated with multiple skin malignant neoplasia. J Invest Dermatol. 2007;127(11):2669-73.
12. Kelsell DP et al. Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum Genet. 2005;76(5):794-803.
13. Lefèvre C et al. Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet. 2003;12(18):2369-78.
14. Baralle D, Baralle M. Splicing in action: assessing disease causing
sequence changes. J Med Genet. 2005;42(10):737-48.
15. Hotz A et al. Mutational spectrum of the ABCA12 gene and genotypephenotype correlation in a cohort of 64 patients with autosomal recessive congenital ichthyosis. Genes. 2023;14(3):717.
16. Zhang L et al. Defects in stratum corneum desquamation are the predominant effect of impaired ABCA12 function in a novel mouse model of harlequin ichthyosis. PLoS One. 2016;11(8):e0161465.
Pigmented Variants of Basal Cell Carcinoma: A Case Series
1. Department of Dermatology, Venereology, and Leprosy, Shadan Institute of Medical Sciences, Telangana, India 2. Teaching Hospital and Research Centre, Shadan Institute of Medical Sciences, Telangana, India *Correspondence to majshaheendvl@gmail.com
Disclosure: The authors have declared no conflicts of interest.
Background: Basal cell carcinoma (BCC) is a type of skin cancer. It typically develops in areas exposed to the sun, such as the face, neck, and hands. BCC usually appears as a raised, pearly bump with a central depression, or as a flat, scaly reddish patch. There are several types of BCC, and when melanin is present in the lesion it is called pigmented BCC, which are the types the authors are reporting in this case series.
Aim: The aim of this study is to create awareness regarding a long-standing lesion turning into malignancy and to also alert health professionals for identification of signs and symptoms of BCC and the need for an early diagnosis.
Method: A prospective observational study was carried out on patients presenting with pigmented variants of BCC.
Conclusion: These cases highlight the importance of thorough clinical examination and biopsies supported by histopathological analysis aiding in diagnosis.
Key Points
1. Basal cell carcinoma (BCC) is a prevalent malignant skin cancer primarily affecting sun-exposed areas, leading to significant morbidity, recurrence, and potential tissue destruction.
2. This is a prospective observational study of five cases of pigmented BCC at a dermatology outpatient clinic, focusing on clinical presentation, histopathology, recurrence, and treatment outcomes.
3. Early recognition and treatment of pigmented BCC, including tailored therapies and photoprotection, are critical in preventing recurrence and improving patient quality of life.
INTRODUCTION
Basal cell carcinoma (BCC) is a heterogeneous malignant neoplasm and can cause great morbidity as most occur in highly visible areas of the body, often relapse, and may invade and destroy local tissues.¹ Pigmented basal cell carcinoma can resemble a melanoma clinically.² Fair skin and chronic UV B exposure are the most important risk factors.³ Individual risk factors for BCC include age, male sex, race, phenotypic characteristics, and genetic predisposition.⁴ BCC can appear in both pigmented and non-pigmented forms, each showing distinct dermoscopic characteristics. Different subtypes of BCC have specific dermoscopic criteria. The primary challenge is distinguishing superficial BCC from other subtypes, as this distinction can influence the course of treatment.⁵ Upon analysing demographic groups, it was determined that, after accounting for age and race, the rate of BCC in male patients was 1.7 times higher than in female patients. In terms of age, individuals aged 65 years and older faced an elevated risk of developing BCC during the study period. White individuals had the highest risk, with adjusted incidence rates 8–70 times greater than those seen in individuals who were Asian, Black, or Hispanic. The group at the highest risk was White individuals aged 80 years and above, who saw the largest increase in BCC incidence, with an estimated average annual percentage change (APC) of 2.23%.⁶
METHOD
A prospective observational study was carried out on patients presenting to the Department of Dermatology outpatient clinic with pigmented variant of BCC. Clinical photos were taken only after oral and written consent of the patients.
CASE 1
A 60-year-old female patient, a known diabetic and hypertensive, presented with complaints of generalised pain all over the head and body for the past 2 months.
She also had two black-coloured, roughlooking lesions on her face. The patient first noticed a small, raised lesion on the medial side of the right eyelid just medial to the right eyebrow 3 years ago. For the past 1–2 years she noticed an increase in size of the lesion and slight pain and discomfort while dressing or rubbing against the lesion.
Dermatological Examination
The patient had three well-defined, annular, hyperpigmented ulcers measuring about 2x1 cm with rolled-up edges and central depression. One located at the medial canthus of the right eye, the other at the lateral side of the right eyebrow, and ther third one over the left auricle (Figure 1A).
A biopsy was done, and it revealed a stratified squamous epithelial epidermis, showing a focal downward extension of the Basal cell. The extension showed peripheral palisading with increased pigmented dermis. Focal lymphocytic inflammatory cell infiltrate was also seen. The probable diagnosis was suggestive of an atypical BCC lesion. She was started on 5% flourouracil cream at night and tacrolimus 0.1% cream in the morning for a period of 8 months. Photoprotection was also advised, for which the patient's lesions appeared to be improved.
CASE 2
A 40-year-old male patient with a known case of diabetes presented with a complaint of mild itching on his nose. He had undergone surgical excision for BCC 3 months ago. Three months after the surgery, the patient reported to us with lesion at the same site of excision associated with itching and discharge. The discharge was seropurulent.
Dermatological Examination
On examination, the patient had a welldefined hyperpigmented ulcer present at the left medial canthus of the eye with rolledup margins, measuring 4x3 cm in size. Blood and scabbing were also observed at the site of the lesion on examination (Figure 1B).
The probable diagnosis was suggestive of a BCC lesion. Further, an excisional biopsy was done and a histopathological report was suggestive of an BCC lesion. Given recurrence, post-excisional biopsy, the patient was started on a 150 mg tablet of vismodegib once a day for about 4 months and was also advised radiotherapy.
CASE 3
A 54-year-old female patient presented with complaints of a scar on the left side of her forehead. The patient first noticed blackish discolouration on her forehead 5 months previously, which progressed to a black ulcerated scar on the left side of her forehead and was increasing in size.
Dermatological Examination
The patient had a well-defined, hyperpigmented (blackish) patch measuring about 1x1 cm, with irregular borders and central ulceration (Figure 1C).
Further, an excisional biopsy was done, and the histopathological report was suggestive of an atypical BCC lesion. After excisional biopsy, the patient was put on topical tacrolimus 0.1% and photoprotection was advised.
CASE 4
A 57-year-old female patient presented with complaints of a black lesion over the left side of her back for the past 5 years that was increasing in size.
Figure 1: Cases 1, 2, and 3.
A) Case 1. B) Case 2. C) Case 3.
Dermatological Examination
On examination, the patient had a welldefined, hyper-pigmented nodule that was 4x3x3 cm in size with one ulcerated edge on the left side of the infrascapular region (Figure 2A).
An excisional biopsy was done, and histopathological examination showed multiple fragments of a tumour composed of monomorphic basaloid cells arranged in sheets, nodules, cords, and anastomosing trabeculae. Some nodules showed peripheral palisading. Intervening stroma showed hyalinisation and focal fibromyxiod change. Epidermis showed hyperkeratosis with extensive crusting and flattening of rete ridges with pigmented dermis (Figure 3). The diagnosis was suggestive of BCC and excisional biopsy was then done.
CASE 5
A 44-year-old male presented with complaints of a lesion on the left side of his face for the past 8 months that was associated with itching and a burning sensation. The patient also complained of occasional bleeding from the lesion.
Dermatological Examination
On examination, the patient had a solitary ulcer that was 3x3 cm in size and annular in shape with hyperpigmented margin and few haemorrhagic crusts present (Figure 2B). Biopsy was suggestive of pigmented BCC. After the excisional biopsy, the team advised photoprotection and chemotherapy for the patient.
RESULTS
Among the five cases of pigmented variants of BCC described in this study, the authors have found some important results.
1. Gender: The majority of pigmented variants of BCC were in females (60%), with a female to male ratio of 3:2.
2. Age: The majority of the authors’ cases were of patients in their 40s or 50s (mean age: 51 years).
3. Site: The most common site was on photo exposed area (i.e., face [80%]), among which, lesions near to the medial canthus were present in two cases (40%).
Figure 2: Cases 4 and 5. A) Case 4. B) Case 5.
4. Recurrence: Recurrence was present among two cases of the study with lesions near the medial canthus of the eye (40%). The cause of recurrence in these cases of BCC was likely due to sunlight exposure and not related to occupational factors.
5. Comorbidities: Two cases were known diabetic and one case was hypertensive.
6. Type of pigmented variety: Three patients had multiple grey-blue globule features constituting to 60%, and the other two cases had large grey-blue ovoid nests with maple leaf-like structures.
DISCUSSION
BCCs are common skin cancers that tend to appear on sun-exposed skin. They were essentially a molecular ‘black box’ until 2008, when identification of a genetic flaw in a rare subset of patients who have a great propensity to develop BCCs pointed to aberrant Hedgehog signalling as the pivotal defect leading to formation of these tumours.⁷
Nodular, superficial, morpheaform, and a combination of these subtypes of BCC may be seen. When melanin is present in the tumour it is called pigmented BCC, as seen in the authors’ cases.⁸ This case series reported on pigmented BCC, but the clinical presentation of each case differed from the ulcerative superficial type to the nodular type. Diagnosis was made based on clinical features and histopathological examination of the lesion. Pigmented BCC presents as black papules or nodules. Its morphologic appearance can mimic that of a melanoma.⁹ Skin biopsy is essential to confirm the diagnosis and evaluate the risk of recurrence.¹⁰
Histologically, nodular BCC is identified by nodular clusters of basaloid tumour cells that extend from the epidermis into the underlying dermis, frequently exhibiting peripheral palisading at the edges of the tumour nests. In pigmented BCC, pigment is found within the tumour cells, within melanophages in the surrounding dermis, or in both, which accounts for the tumour’s black coloration.² To diagnose pigmented BCC, it must lack the negative feature of a pigment network and
must present at least one of the following six positive features: large grey-blue ovoid nests, multiple grey-blue globules, maple leaf-like structures, spoke wheel areas, ulceration, or arborising 'tree-like' telangiectasia.¹¹
Treatment depends on various factors, such as tumour size, location, and histological subtype. While excisional surgery is the preferred method for most common types of BCC, various nonsurgical treatments are also available. These include photodynamic therapy,¹² as well as topical treatments like imiquimod cream, 5-fluorouracil, and ingenol.¹³ As in Case 1, the team treated the patient with 5-Fluorouracil, tacrolimus, and photoprotection post biopsy, and later advised Mohs surgery. The importance of skin cancer screening in immunosuppressed patients, particularly transplant recipients, should be emphasised, as they are at higher risk for squamous cell carcinoma (SCC). Regular screening is vital for early detection, as studies have highlighted the prevalence of skin cancers in renal transplant recipients and the need for early cancer screening in this population.¹⁴
In solid organ transplant recipients, BCCs are now more common than SCCs, with a BCC:SCC ratio of 1.7:1 compared to
References
1. Correia de Sá TR et al. Basal cell carcinoma of the skin (part 2): diagnosis, prognosis and management. Future Oncol Lond Engl. 2015;11(22):3023-38.
2. Abudu B, Cohen PR. Pigmented basal cell carcinoma masquerading as a melanoma. Cureus. 11(4):e4369.
3. Linares MA et al. Skin cancer. Prim Care. 2015;42(4):645-59.
4. Kiiski V et al. Risk factors for single and multiple basal cell carcinomas. Arch Dermatol. 2010;146(8):848-55.
5. Ungureanu L et al. Role of dermoscopy in the assessment of basal cell carcinoma. Front Med. 2021;8:718855.
6. Asgari MM et al. Trends in basal cell carcinoma incidence and identification
the previous 1:3 ratio favouring SCC. This emphasises the need for thorough screening for both BCC and SCC.¹⁵
Long-term follow-up and monitoring are essential due to the potential for recurrence and the risk of developing additional skin cancers. Patients should be educated on sun-protective measures, such as the use of sunscreen, protective clothing like widebrimmed hats, and regular self-examination of the skin.
CONCLUSION
BCC is the most common form of cancer worldwide, and the incidence of this cancer is increasing due to prolonged exposure to sun and ageing adults with cumulative sun damage. This study highlights the presentation of pigmented variant of BCC, and the authors have analysed the demographics of BCC in terms of age, gender distribution, localisation, recurrence, and treatment. An early diagnosis and adequate treatment of this not so uncommon skin cancer will prevent associated morbidity and improve the patient's quality of life.
of high-risk subgroups, 1998-2012. JAMA Dermatol. 2015;151(9):976-81.
7. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743-54.
9. Altamura D et al. Dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. J Am Acad Dermatol. 2010;62(1):67-75.
10. Tanese K. Diagnosis and management of basal cell carcinoma. Curr Treat Options Oncol. 2019;20(2):13.
11. Menzies SW et al. Surface microscopy of pigmented basal cell carcinoma. Arch Dermatol. 2000;136(8):1012-6.
12. Collier NJ, Rhodes LE. Photodynamic therapy for basal cell carcinoma: the clinical context for future research priorities. Molecules. 2020;25(22):5398.
13. Clark CM et al. Basal cell carcinoma: an evidence-based treatment update. Am J Clin Dermatol. 2014;15(3):197-216.
14. Al-Thnaibat MH et al. Cancer screening in renal transplant recipients: real-world data. World J Oncol. 2024;15(4):592-7.
15. Trave I et al. Skin cancers in solid organ transplant recipients: a retrospective study on 218 patients. Transpl Immunol. 2023;80:101896.
