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Speakers: Carsten Flohr (United Kingdom), Laurent Misery (France), Sandy Skotnicki (Canada)
Moderator: Stéphane Fauverghe (France)
Related topics
• Conventional systemic treatments remain the standard first line treatments for severe pediatric AD in most countries
• Of those, methotrexate (0.4 mg/kg/week) is now increasingly used
• Cyclosporin A at 4-5 mg/kg/day may be indicated for a faster onset of action, but data from an adequately powered RCT comparing Cyclosporin A with Methotrexate is currently lacking
• Dupilumab is now licensed for children from 6 years of age
• JAK inhibitors (Abrocitinib and Upadacitinib) are promising new therapies, even in those patients who failed treatment with Dupilumab
• Treatment registries to assess the long-term treatment effectiveness and safety are needed, as well as more head-to-head (rather than placebo-controlled)
• Network meta-analyses allow us to compare the efficacy of the different conventional and novel therapies, even if most of the evidence comes from placebo-controlled trials
Professor Carsten FLOHR holds the Chair in Dermatology and Population Health Science at St John’s Institute of Dermatology, King’s College London, where he directs the Unit for Population-Based Dermatology Research.
He studied at Cambridge and Oxford Universities and then trained in both Paediatrics and Dermatology.
Carsten FLOHR was the first UK National Institute for Health Research (NIHR) Clinician Scientist in Dermatology (2009-2014) and the only dermatologist awarded a Career Development Fellowship from the NIHR (2014-2019).
He has a particular interest in novel methods of atopic dermatitis (AD) prevention (early life risk factors) and therapeutics, especially in severe AD.
He is Chief Investigator of the UK-Irish TREatment of severe eczema in children Trial (TREAT), which compares cyclosporine with methotrexate in children with recalcitrant atopic eczema. He is also Chief Investigator of the Softened water for eczema prevention trial (SOFTER) and the UK-Irish Atopic Eczema Systemic Therapy Register (A-STAR), as well as the EU-funded BIOMAP and Trans-Foods consortia.
Prof. FLOHR is a Founding Director of the International Eczema Council and Past President of the British Society of Paediatric Dermatology, as well as an Honorary Member of the Société Française de Dermatologie.
He is also Founding Editor of the Evidence-Based Dermatology Section of the British Journal of Dermatology and the Clinical Trials Editor of the F1000 Atopic Dermatitis Section.
• Itch is the main concern for patients with atopic dermatitis (and their relatives/friends)
• Research on itching (especially in atopic dermatitis) provides numerous targets for the alleviation of itch
• Emollients are useful for both skin dryness and itch alleviation
After studies and his first professional years in Lyon and Saint Etienne, Laurent MISERY became professor of Dermatology at the University of Brest.
He is now head of the department of Dermatology at the University Hospital of Brest.
Laurent MISERY founded and is the director of the Laboratory on Interactions Neurons-Keratinocytes (LINK) and the French Expert Centre on Itch. His team is dedicated to translational research on itch, from fundamental (biological and physiological) to pathophysiological, clinical, psychological and therapeutic aspects.
He is especially interested in the relationship between skin and the nervous system, from the biological point of view (co-cultures between skin cells and neurons) to the clinical (pruritus, sensitive skin) or psychological points of view.
Prof. MISERY is chairman of the EADV task force of psychodermatology.
His research interest is : sensitive skin; skin irritation; irritant; sensitivity; skincare products.
He was distinguished with the Herman Musaph Award in 2017.
• Skincare products are useful in the protection and the reinforcement of the skin barrier for patients with atopic dermatitis
• Skincare must include both emollients and cleansing/bathing products
• Topical therapy has to be adapted to the specific needs of each single patient
• Emollients and cleansing products need to be well tolerated and pleasant to use, in order to encourage suitable compliance from the patients
Dr. Sandy SKOTNICKI is the founding director of the Bay Dermatology Centre and is Assistant Professor at the University of Toronto, Department of Medicine in the Divisions of Dermatology and Occupational and Environmental Health. Dr. SKOTNICKI started the Bay Dermatology Centre in 2006 in an effort to provide a full-service Dermatology centre that focuses on the patient, not procedures.
She is a Diplomat of the American Board of Dermatology, and a member of the Canadian Medical Association, Canadian Dermatology Association, American Dermatology Association and American Contact Dermatitis Society.
Dr. SKOTNICKI is a consultant Dermatologist at St. Michael’s Hospital in Toronto and is an expert in Allergic Skin Disease. She is also a consultant for the Workplace Safety Insurance Board.
Active in research and education, Dr. SKOTNICKI has been teaching University of Toronto Dermatology, Allergy and Family Medicine residents at her St. Michael’s Hospital clinic since 1999. She is also a member of the Centre for Research Expertise in Occupational Disease & has published numerous articles on different aspects of Allergic Skin Disease.
Widely regarded as the “go to” Dermatologist in Canada for ingredient reactions and safety, she regularly provides commentary and contriÂbutes to medical journals, media outlets and speaks on reactions to chemicals in the skinÂcare industry.
According to the communication of Carsten Flohr
Report written by RĂ©mi Maghia
Some new targeted therapies are emerging for atopic dermatitis (AD): lebrikizumab, tralokinumab, dupilumab, nemolizumab, omalizumab, and selective JAK inhibitors.
However, for part of our practice, conventional systemic treatments will continue to be used as first-line therapies for severe cases of AD in adults and children: azathioprine, cyclosporin (approved for more than 16 years), methotrexate, and mycophenolate mofetil.
The studies carried out in paediatrics have been few in number and mainly included case series and case-control studies. In the studies available, the data of paediatric patients are not frequently reported separately.
Severe AD is a complex disease. Several factors come into play that include skin infections, food allergies, asthma, hay fever, sleep disturbances, anxiety and depression. There is a vicious circle of itching-scratching-skin inflammation.
Treating severe AD often requires a multidisciplinary approach and teamwork, with the involvement of a paediatric dermatologist, paediatric allergist, clinical psychologist, paediatric pulmonologist, clinical research team, and patient education programme.
Dupilumab is approved for the treatment of moderate to severe AD in adults and adolescents aged 12 and over who are candidates for systemic therapy. It is also approved children aged six to 11 with severe AD who are candidates for systemic therapy.
Dupilumab-associated conjunctivitis
It occurs in over 30% of cases in real-life cohorts. It takes the forms of foreign body sensations, burning and itching. There is limbal hyperaemia. This side effect is not observed in trials on asthma and nasal polyps.
Its pathophysiology is not yet clear. Simultaneous blockage of the IL-4 and IL-13 signalling pathways may increase the activity of the ligands involved in atopic keratoconjunctivitis. Another hypothesis: Demodex may proliferate in an environment of reduced ocular cytokines.
This side effect is also observed in trials with lebrikizumab, but not with tralokinumab, which tends to show that it is not related to specific IL-13 blockage.
We are lacking head-to-head trials for severe paediatric AD:
Such as: conventional vs conventional treatment, conventional vs new treatment, new treatments compared with one another.
The TREAT trial, undertaken in the United Kingdom with a focus on children aged two to 16, compares methotrexate with cyclosporin A. The study is now complete and will be published in 2022.
The speaker is leading a network meta-analysis (NMA) currently being published in the BMJ (1). It provides a systematic review of systemic immunomodulatory treatments for AD. It combines the data of children and adults, since in the majority of studies, paediatric data are not reported separately. The results of this NMA have not yet been published, so without going into detail, we can say that for the difference in terms of EASI vs dupilumab, the following perform better: abrocitinib 200 mg once/day, and upadacitinib 15 and 30 mg once/day. These two medications are approved for patients aged 12 and over.
With regard to abrocitinib, the speaker participated in a study in adolescents (aged 12-17) in combination with topical treatment for moderate to severe AD. It was published in JAMA Dermatology in 2021. Two hundred and eighty-seven adolescents were randomly treated with abrocitinib 200 mg, abrocitinib 100 mg or a placebo. All received topical corticosteroids. In the two abrocitinib groups, around 70% of patients achieved an EASI 75 response, versus 40% in the placebo group. These were similar to the results in adults.
Carsten Flohr is also running the UK-Irish Atopic Eczema Systemic Therapy Register (A-STAR), whose goal is to obtain long-term real-life data concerning the efficacy and safety of new and conventional systemic AD treatments.
(1) Network meta-analysis by Drucker A, et al. Flohr C. JAMA Dermatology 2022 in press – www.eczematherapies.com
According to the communication of Laurent Misery
Report written by RĂ©mi Maghia
The human burden of chronic pruritus in inflammatory dermatoses is high. This was shown in a European study (JAAD 2018) that included 1552 patients with various pruritic dermatoses (psoriasis 32%, AD 29%). Pruritus can be experienced very frequently as stressful, horrible, terrible and refractory, making patients aggressive.
Pruritus is a challenge
It is the main symptom of AD, on and away from lesions. It is chronic and has a major impact on sleep, cognition, appearance, psychological well-being, quality of life, and sex life.
Pruritus has been poorly understood up to now and treatments are disappointing.
There are many factors that aggravate pruritus: heat, clothing (wool), insomnia, anxiety, depression, the vicious cycle of scratching, perspiration, inflammation, dry skin, and night time.
Pruriceptors
These are specific receptors of itching sensations in the skin’s nerve endings (epidermal and sub-epidermal). Numerous receptors are expressed. It should be noted that the histamine H1 receptor is one of them, even though it is not very involved in pruritus in AD. Through mediators such as cytokines, enzymes (proteases) and neuromediators, these receptors interact with many cells (macrophages, keratinocytes, mast cells, T cells).
There are several pruritogenic mediators in AD, including kallikrein, tryptase, bradykinin, serotonin, endothelin-1, IL-3, TSLP, substance P, PAF, artemin, IL-2, GRP, and CGRP.
The role of TSLP
TSLP is a cytokine produced by keratinocytes in the epidermis; through dendritic cells, it increases the production of pro-inflammatory cytokines (Th2 pathway) such as IL-4 by T cells. TSLP does not act on the Th1 and Th17 pathways.
In response to various stimuli (nettle, parasites, mast cells), proteases lead to the production of PAR2 within keratinocytes, causing Ca2+ to be released. This results in the release of TSLP which activates TSLP-R receptors in the afferent C fibre endings with membrane depolarisation. Nerve impulses reach the spinal cord and then the brain, thereby triggering pruritus.
The role of IL-31
Th2 cells produce IL-31, which alters the skin barrier with action on dermal eosinophils, macrophages, basophils and mast cells. This results in dermal inflammation, nerve elongation (increased neuronal growth and nerve ending density) and pruritus.
The role of IL-4 and IL-13
IL-4 and IL-13 directly activate sensory neurons. IL-4 increases the neuronal response to various pruritogens. JAK1 is involved.
Sensitisation for pruritus
In cases of chronic pruritus, epidermal peripheral stimulation via pruriceptors activates the central nervous system. Chronic stimulation of the peripheral and central nervous systems ends up leading to sensitisation for pruritus, with phenomena such as alloknesis (where normal sensations are perceived as itchy) and hyperknesis (exacerbated sensations of itching in an area adjacent to that scratched).
Skin barrier impairment and pruritus
Skin barrier impairment causes nerve endings to be in closer contact with the external environment.
Barrier impairment or inflammation causes skin and immune cells to release mediators that can activate pruriceptors on the nerve endings of C fibres.
There are many targets for improving pruritus
A statement on the management of pruritus and pain in AD was published in JEADV 2021
According to the communication of Sandy Skotnicki
Report written by RĂ©mi Maghia
The skin barrier
It limits transepidermal water loss (TEWL), prevents dryness and protects against harsh external factors.
It is made of a dense network of intracellular keratin filament aggregates, hydrolipidic film, intercellular lipidic cement and tight junctions.
In atopic dermatitis (AD), there is a lack of barrier proteins, a lack of lipids, an altered surface pH, cutaneous bacterial dysbiosis, and an altered immune response.
As a result, allergens can penetrate more easily, NMF decreases and TEWL increases, causing skin inflammation.
Therapeutic importance of emollients
Emollients are included in the European recommendations: they should be used in appropriate quantities, at a good frequency, and should contain higher levels of lipids in winter. In moderate to severe AD, this reduces the need for steroids, but it is first necessary to achieve remission through topical corticosteroids or calcineurin inhibitors. In the European recommendations, this is valid for adults and children. It is also part of the US recommendations, which also indicate that these emollients should be applied shortly after taking a bath.
Emollients should be used on a daily basis. The quantities should be appropriate and they are high:
According to Fleischer et al. Atopic dermatitis: skin care and topical therapies. Semin Cutan Med Surg. 36: 104-110.
Compliance is frequently lacking in AD: two out of three patients do not comply with their topical treatment, and one in two patients uses a quantity of emollients lower than the recommended quantity.
What ingredients do these emollients contain?
Some useful ingredients include ceramides, cholesterol, phytosphingosine (a natural component of ceramides), essential fatty acids, and colloidal oatmeal.
Which ones should we choose?
We should combine: efficacy, safety, absence of burning and tingling sensations, and convenience of use, to ensure long-term compliance and results.
The example of Atoderm Intensive Baume* by Bioderma*
The Lipigenium complex* contains pure phytosphingosine and biomimetic lipids that help restore the lipid barrier.
Enoxolone has anti-inflammatory and anti-pruritic action and reduces the expression of TSLP in the atopic epidermis.
Topical palmitoylethanolamide (PEA) has anti-pruritic action.
A randomised, placebo-controlled double-blind study with 130 patients between the ages of six months and 15 years with moderate AD compared treatment with topical corticosteroids or tacrolimus combined with either Atoderm Intensive Baume* or an emollient acting as a placebo for six months.
Without going into the details of the study, the differences were constantly significant in favour of Atoderm Intensive Baume* vs the placebo, both for the decrease in the SCORAD observed by the doctors and patients and in terms of improved quality of life. Seventy-six percent of the patients treated with the balm had not experienced any relapse after six months and had 20 more relapse-free days than those treated with the placebo. Ninety-four percent of the patients had less of an urge to scratch and 88% had a sustained break from pruritus.
