Акценти от 3-ти ден
ROSACEA TREATMENT
According to the oral communication of Prof. Bernard CRIBIER (Dermatologist, France)
NEW DEVELOPMENTS IN ROSACEA TREATMENT
Report by Dr. Adrian ALEGRE SÁNCHEZ (Dermatologist, Spain)
The most recent European and American consensus articles agree on the fact that for rosacea, there is no classification with differentiated subtypes. Instead, the disease is considered to have a continuum on which different phenotypes manifest (e.g. presence of erythema, telangiectasias, papules, pustules, peeling, hyperplasia of tissues, etc.). Furthermore, it is known that each of these symptoms correspond to activation of a pathogenic mechanism. This allows doctors to select from available treatments according to the symptoms present at any given time to block those mechanisms. For this reason, Prof. CRIBIER focused his presentation on reviewing treatments for the following pathogenic mechanisms:
1. Vascular changes (erythema, telangiectasias, etc.): either with topical vasoconstrictors like alpha-adrenergic agonists (brimonidine and oxymetazoline) or with lasers and pulsed light. In regards to laser treatments, Prof. CRIBIER talked about a study in which it was shown that treatment with a greater number of sessions results in greater efficacy in the long term. In the case of flushing, there is also the possibility of using anti-hypertensive treatments, with beta blockers like carvedilol seeming to produce better results. A new development in recent years for the vascular treatment of rosacea is the use of botulinum toxin. There are different studies on this and it appears that intradermal injections of 0.05 ml of a 10 U/ml solution of the toxin, spaced 0.5 cm apart, produce good results.
2. Inflammation: in this case, oral antibiotherapy with tetracyclines, especially doxycycline, appears to be one of the best options. Also, topical ivermectin 1% has been demonstrated to have anti-inflammatory and anti-parasitic effects. Other effective options are metronidazole and azelaic acid. In the case of Morbihan disease, there are reports that omalizumab could possibly be useful for blocking the release of mastocytes.
3. Neurovascular component: this is often an important aspect in certain types of rosacea. In this case, laser treatment is particularly effective, as is, potentially, the use of analgesics for neuropathic pain and anti-depressants.
4. Demodex folliculorum and microbiota: there is known to be a correlation between the severity of rosacea and the density of Demodex. However, the fact that medications that do not reduce Demodex are still effective in treating inflammatory rosacea indicates to us that the rosacea-Demodex correlation is indirect. Researchers are increasingly studying if the effect of Demodex could be more related to changes that it produces in the cutaneous microbiome, rather than whether or not it is present.
5. Sebaceous gland inflammation: this can be controlled with isotretinoin at low doses (0.1 to 0.15 mg/kg/day), taking into account that this use is not one of the indications for the drug. In addition, this treatment is particularly useful for preventing rhinophyma.
6. Controlling external factors: in this regard, it is important to mention that rosacea appears to improve in patients who smoke or consume caffeine, whereas alcohol is an important risk factor. Another key risk factor is exposure to ultraviolet radiation. According to a recent study, UV radiation is an agent that activates rosacea through the innate immune system.
Finally, Dr Cribier noted that while there are various treatments with demonstrated efficacy, there are still many potential therapeutic targets. In fact, there are over 150 studies in progress that you can review on ClinicalTrials.gov.
ROSACEA: FROM THE NEW SPECTRUM TO THE NEW THERAPIES
Report by Dr. Dong Hun LEE (Dermatologist, South Korea)
Prof. CRIBIER elegantly summarized eight targets pertinent to rosacea pathogenesis and treatment, including vascular changes, innate immunity, neurovascular components, Demodex, microbiota, skin barrier, sebaceous glands, and alcohol, UV, and smoking. Vascular changes (flushing, erythema) can be treated with various lasers, photodynamic therapy (PDT), beta-adrenergic blockers such as carvedilol, and recently botulinum toxin. Innate immunity of rosacea can be targeted by doxycyclines, ivermectin, and topical serine protease inhibitors (SEI003). Neurovascular components target interactions among nerve endings, vessels, and epidermis. Some laser treatment also led to improvement in stinging test, and for neurogenic rosacea, gabapentin, pregabalin, duloxetine, amitriptyline, and antidepressants can be used. Demodex can be targeted by topical ivermectin and permethrin, and recent data suggest that microbiota inside Demodex may play a role. In terms of microbiome, while the overall composition of facial microbiome did not change in rosacea, its severity was associated with microbiome change in rosacea. Rosacea skin shows altered skin barrier. Interestingly, skin barrier function was improved after minocycline treatment, suggesting the skin barrier abnormality is related to inflammation. Regarding sebaceous gland, low-dose isotretinoin (off-label) is effective (0.1-0.15 mg/kg/d), and isotretinoin treatment is recommended in rhinophyma and hypertrophic rosacea. Finally, while smoking and alcohol decreased the risk of rosacea, ultraviolet irradiation and alcohol increased its risk. Although doxycycline metronidazole, azelaic acid, ivermectin, brimonidine, oxymetazoline, and isotretinoin have been well evaluated, carvedilol, botulinum toxin, lasers, IPL, and PDT need more trials to validate their efficacy and safety.
VASCULAR MALFORMATIONS AND TUMOURS
INFANTILE HAEMANGIOMA SEQUELAE
INFANTILE HAEMANGIOMAS IN THE ERA OF PROPANOLOL – PREDICTION AND MANAGEMENT OF SEQUELAE
Report by Dr. Adrian ALEGRE SÁNCHEZ (Dermatologist, Spain)
According to the oral communication of MD Eulalia BASELGABASELGA (Dermatologist, Spain)
Propanolol has revolutionised the treatment of infantile haemangiomas (IHs). Still, sequelae are a very common problem that requires appropriate management. IHs will involute, but they do not necessarily disappear entirely, leaving sequelae in up to 70% of cases.
Current indications for treatment with propanolol are risk to life, risk to function, persistent haemangioma, or risk of disfiguration, the latter being the most common cause for treatment with propanolol, according to Dr Baselga. The problem is that it is not easy to predict or know in advance the risk of aesthetically unappealing sequelae in many cases that appear to be mild or that are not in visible places. It has been established that IHs in the centre of the face, especially on the forehead, nose, and lips, should be treated because these are high-risk areas. Another risk area is the areola of the nipple. As such, we must properly evaluate the size, location, and characteristics of the IH. A study conducted by Dr Baselga and colleagues, published in JAMA Dermatology (JAMA Dermatol 2016; 152:239-243), looked at IHs that were not treated and left to involute on their own. The researchers found the following characteristics as being more closely associated with sequelae: mixed portion (superficial and deep) in front of only deep; pedunculated haemangiomas; exophytic and ulcerated haemangiomas. In IHs, the margin of the superficial portion and its thickness also determine if there is a risk factor in that haemangiomas that have a thick superficial portion with a jagged margin have a greater likelihood of leaving marks.
It is known that propanolol resolves 60% of cases within six months of treatment and 75% within 12 months. However, the key question is, can we avoid the risk of sequelae with propanolol or can we also succeed in reducing the risk of sequelae? In a retrospective study of patients treated with propanolol, it was determined that only 27% of IHs had significant sequelae, versus 73% with minimal or no sequelae. The risk of sequelae is more than double for untreated IHs compared to treated IHs. This is even true for cases in which the IH had already grown and had a significant superficial portion. Still, what we must bear in mind is that a key factor in preventing the appearance of sequelae is to start treatment early. For this reason, much emphasis is placed on close monitoring, for example, with photos taken by parents or paediatricians, in order to determine if the IH is growing fast so that it can be treated as soon as possible.
When sequelae have already appeared, often the treatment should be surgical in cases of fibroadipose sequelae, very large pediculated haemangiomas, or very thick vascularisation. Vascular lasers are a very good alternative for cases of residual fine telangiectasias. In addition, there are increasing numbers of articles and amounts of evidence on the positive results with fractionated resurfacing in the case of fibrous tissue or excess skin.
TOPICAL AND SYSTEMIC THERAPIES OF SKIN DISEASES
CALCINEURIN INHIBITORS: FEARS, FACTS AND POSSIBILITIES
Report by Dr. Laura BOUCHARD (Dermatologist, Finland)
According to the oral communication of Dr. Uffe NYGAARD (Dermatologist, Denmark)
Dr. NYGAARD from Denmark went through the difference in mechanism of action, side effects and indications for topical calcineurin inhibitors (TCI) covering utilization during pregnancy and malignancy risk.
Burning sensation and pruritus of the skin is the most common side effect. The rate is much lower in children and the degree correlates with disease severity. Using moderate to high potency topical corticosteroid (TCS) for 3-5 days prior to starting topical calcineurin inhibitors increases compliance to treatment.
The rationale for using 0.03% concentration in children is not more side-effects but because it was studied that the higher concentration did not offer any benefit as compared to the weaker one in children.
The incidence of skin infections in topical calcineurin inhibitors-treated patients is generally low (< 5%). Patients with a history of herpes simplex infection have an increased herpes infection risk. General infection rate is however the same in topical calcineurin inhibitors and vehicle treated patients. No skin atrophy has been reported with topical calcineurin inhibitors.
There are no studies of topical calcineurin inhibitors during pregnancy, but studies on oral use show no increased risk of malformation during pregnancy. Also skin absorption is very low. A recent paper by the European Task Force on Atopic Dermatitis recommends topical calcineurin inhibitors for management of AD in pregnancy (JEADV 2019; 33: 1644-1659).
Suspicion of malignancy associated with use of topical calcineurin inhibitors has caused a lot of stir. The lecturer went through the literature that has failed to show any increased risk of lymphoma, NMSC or other malignancy as compared to general population.
ATOPIC DERMATITIS
TOPICAL TREATMENT
According to the oral communication of Prof. Mette Sondergaard DELEURAN (Dermatologist, Denmark)
Report by Prof. Anna ZALEWSKA JANOWSKA (Dermatologist, Poland)
Prof. Mette Sondergaard DELEURAN talk on topical treatment update conclusions are as follows: intensive treatment with emollients should be used every day due to its substantial reduction in need for active treatment, treatment of atopic dermatits flare should be followed by proactive one with TCS or TCI in chronic atopic dermatits cases and we should aim for remission and always remember that “the tissue is the tissue” and skin is our main interest organ.
NEW ORAL SMALL MOLECULES
According to the oral communication of Prof. Andrea SZEGEDI (Dermatologist, Hungary)
Report by Prof. Anna ZALEWSKA JANOWSKA (Dermatologist, Poland)
Prof. Andrea SZEGEDI presented in-depth overview on new oral small molecules. Oral JAK inhibitors are promising option for atopic dermatits treatment and show rapid reduction in inflammation and most of them reduce itch, due to targeting several key atopic dermatits cytokines. Of note dosing of JAK inhibitors is crucial due to narrow therapeutic window. PDE4 inhibition seems to be promising only in topical form. NK-1 and H4 receptor antagonists have not enough data.
ANTIBODY-BASED THERAPIES IN ATOPIC DERMATITS
According to the oral communication of Prof. Carsten FLOHR (Dermatologist, United Kingdom)
Report by Prof. Anna ZALEWSKA JANOWSKA (Dermatologist, Poland)
Prof. Carsten FLOHR presented past 12-month update on antibody-based therapies in atopic dermatits. He focused his talk on current 27 RTC (12 conventional, 15 novel) and real world conditions. Of note, head to head trials only exist for conventional therapies. RTCs analysis as for short-term efficacy – 16 weeks treatment – demonstrated about 35 EASI mean % change from baseline for placebo, above 70% for dupilumab, almost 60% for MTX and 46% for nemolizumab. As for long term efficacy, placebo showed final EASI change from baseline 45%, dupilumab 80% and nemolizumab 79%. In real world, duplilumab is doing even better arriving to 90% of change in EASI from baseline. DLQI was reported in 15 trials, whereas EQ5D, preferred by HTA agencies due to cost effectiveness analyses, only in 2 trials. It was concluded that QoL impact of different treatments is similar to efficacy data for systemic agents. The speaker presented results of SOLO1 and SOLO2 studies published this year by Cork et al in J Dermatol Treat, demonstrating similar improvement for DLQI, HADS, POEM and EQ5D for all doses of dupilumab administered, reaching minimal clinically important differences (MCID). Of note no routine laboratory monitoring is required on dupilumab treatment. Speaker presented IEC expert consensus statement on conjunctivitis management in dupilumab treated atopic dermatits patients. He stated that face dermatitis on dupi therapy could result from Malasezzia skin colonization.
The speaker pointed out that new therapeutics for children below 12 years of age are urgently needed as well as head-to-head trials on conventional vs conventional regimens, conventional vs novel therapies and novel therapies against each other. He also underlined that uniform methodology in patient data collection is extremely important and will enhance comparability of the studies. The speaker underlined that we really need “real world” data on drugs. RCTs do not represent patients in daily practice and provide only short-term perspective. He also pointed out at lack of standardization of adverse effect reporting.
NO INCREASED RISK OF CANCER IN CHILDREN USING TOPICAL TACROLIMUS FOR ATOPIC DERMATITIS: A 10-YEAR PROSPECTIVE COHORT STUDY
According to the oral communication of Prof. Regina FÖLSTER-HOLST (Dermatologist, Germany)
Report by Dr. Laura BOUCHARD (Dermatologist, Finland)
The subject of malignancy and TCI was addressed in the Late Breaking News session as well.
Dr Fölster-Holst presented a non-published prospective study about long-term safety of topical tacrolimus in children under 16 y (9 countries; 314 sites; started in May 2005 and the last enrolled patient was in August 2012). 27% of enrolled patients completed a follow-up of 10 y. Patients had to use topical tacrolimus for at least 6 wks and the first exposure before the age of 16 (no restrictions on other treatments during study). The mean age was 6.0 y with moderate to severe atopic dermatitis.
The total incidence of cancer was 6 in 6 different patients. One spitzoid melanoma was observed, there were no lymphomas and no difference in incidence of all cancers as compared to general population.
They resulted in a SIR (SIR = observed events/expected number of events) of 1.01.
In conclusion, no lymphomas and one case of skin cancer were observed in what consisted of over 44 000 patient-years of follow-up. There was no evidence of increased cancer risk following exposure to topical tacrolimus in children with atopic dermatitis.
BERMEKIMAB IS A RAPID AND EFFECTIVE TREATMENT FOR ATOPIC DERMATITIS, INCLUDING MARKED REDUCTION IN PRURITUS
BERMEKIMAB, A MONOCLONAL ANTIBODY AGAINST IL1-ALPHA, RESULTS IN IMPROVEMENT OF ATOPIC DERMATITIS IN A PROOF OF CONCEPT STUDY
According to the oral communication of Prof. Alice B. GOTTLIEB (Dermatologist, United States)
Report by Dr. Nicolas KLUGER (Dermatologist, Finland)
There is a potential role of interleukin-1 alpha and Th1 pathway in atopic dermatitis (AD) . IL-1 alpha drives leukocytes recruitement and matrix proteinases, potentiates nociception (itch) and activate the vascular endothelium.
In the late breaking news session on the third day of the congress, Prof. Alice B. GOTTLIEB presented the results of a phase II open label proof-of-concept study with dosage escalation in a small cohort of patients with moderate to severe atopic dermatitis.
Bermekimab was first evaluated in 10 patients at the dosage of 200 mg every week for 4 weeks and safety was assessed. After, 28 patients were treated by 400 mg every week for 4 weeks with an evaluation at week 4 and 8.
Briefly, the treatment was well tolerated with no serious adverses events. Of note, 3% of the patients reported injection site reactions.
In terms of efficacy, the 400 mg regimen allowed that 40% the patients reached the EASI-75 at week 4 and 75% at week 8. The SCORAD was improved by 70% at week 8. Anxiety and depression improved at weeks 4 and 8 (HADS score), so did icth and pain scores at week 8, – 70% and -90% respectively.
A phase II trial should now be initiated for this drug. The IL-1 pathway blockade may be a new pathway of interest in the management of atopic dermatitis.
EFFICACY OF BARICITINIB, AN ORAL JAK INHIBITOR, IN MODERATE TO SEVERE ATOPIC DERMATITIS
EFFICACY AND SAFETY OF BARICITINIB IN COMBINATION WITH TOPICAL CORTICOSTEROIDS IN MODERATE TO SEVERE ATOPIC DERMATITIS: RESULTS OF A PHASE III RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 16-WEEK TRIAL (BREEZE-AD7)
According to the oral communication of Prof. Kristian REICH (Dermatologist, Germany)
Report by Dr. Nicolas KLUGER (Dermatologist, Finland)
Prof. Kristian REICH showed the results of a phase III study involving baricitinib, an oral selective Janus Kinase (JAK) 1 and JAK 2 inhibitor, in moderate or severe atopic dermatitis.
The study included n=329 patients with moderate to severe atopic dermatitis.
The study included 3 groups in a 1:1:1 randomization:
1) a placebo (PBO) with topical CS (TCS),
2) Baricitinib 2 mg once a day + topical CS and
3) Baricitinib 4 mg once a day + topical CS. The primary endpoint of the study was the IGA score 0 or 1.
At week 16, the proportion of patients reaching the IGA 0 and 1 score were 30.6%, 23.9% and 14.7% for baricitinib 4 mg dose, baricitinib 2 mg dose and PBO respectively.
At week 16, the proportion of patients that reached the EASI-75 score were 47.7%, 43.1%, and 22.9% for baricitinib 4 mg dose, baricitinib 2 mg dose and PBO respectively.
There were notable improvement in the patients-reported outcome of itch, pain and sleep disturbance in the treated group.
The proportion of free days with TCS use during the treatment period was increased in the 4 mg group by 32.9% versus 17.4% for PBO.
The safety profile of baricitinib was consistent with prior findings from baricitinib clinical development in atopic dermatitis. Of note, oral herpes were more frequent in the 4 mg treatment group. Acne flares were also observed with baricitinib 4 mg. A case of lung embolia occured also in the 4 mg group.
Baricitinib may represent a potential novel oral treatment option for patients with moderate to severe atopic dermatitis.
MANAGEMENT OF ADVERSE DRUG REACTIONS
EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS
According to the oral communication of Prof. Danijela DOBROSAVLJEVIC (Dermatologist, Serbia)
Report by Dr. Byeol HAN (Dermatologist, South Korea)
Overexpression of epidermal growth factor receptor (EGFR) or its ligands and activating mutations may lead to epithelial cancer of different tissues. Epidermal growth factor receptor inhibitors have been used in many kinds of solid cancer.
epidermal growth factor receptor is expressed in many different cell types (epithelial tissue, skin, hair follicles and the gastrointestinal tract) inducing cutaneous adverse events (AEs) in 65-90% patients. The most common adverse events are dermatologic toxicities and diarrhea. Major epidermal growth factor receptor-TKI related skin reactions are acneiform rash, xeroderma, pruritus, paronychia, stomatitis and mucositis, and hair changes. Rapid onset of moderate or severe rash is the best biomarker currently available to predict the effectiveness of epidermal growth factor receptor inhibitor treatment. Patients experiencing multiple cutaneous toxicity had better therapeutic outcome compared to single adverse effect.
The effective management of gastrointestinal tract related adverse events and cutaneous adverse events are as follows:
1) treatment delays,
2) dose reductions,
3) supportive medications and prophylactic measures.
Before the epidermal growth factor receptor inhibitor therapy starts, provide patient education about prevention and management of skin adverse events. Explain that rash is not acne. Prevention methods are to moisturize regularly, protect against excessive exposure to sunlight, use SPF 30UVA and UVP protective sunscreen appropriately, and use emollients or soap substitutes. Management of cutaneous AE are applied according to the grade of adverse events.
In grade 1 skin rash, administer topical steroids or topical calcineurin inhibitors or alternative topical antibiotics. In grade 2 skin rash, administer an oral antibiotics (tetracycline) for 4-6 weeks. In grade 3 or 4 skin rash, interrupt epidermal growth factor receptor inhibitors and administer oral or intravenous antibiotics according to the severity. In grade 4 skin rash, consider switching from oral antibiotic to broad spectrum/Gram-negative cover. Skin swab for bacterial culture should be considered.
In grade 3 xeroderma, interrupt epidermal growth factor receptor inhibitor treatment. And apply moisturizing cream or ointment or Vaseline or urea cream (10%). Start applying topical steroids to eczematous areas. Appropriate use of emollients is very important. Guidance for amounts of emollients that patients taking epidermal growth factor receptor inhibitors should use per 2 weeks are as following: face and neck (15-30g), both arms (30-60g), both legs (100g), trunk (100g)
In grade 3 pruritus, interrupt epidermal growth factor receptor inhibitor treatment. Apply topical antipruritics and oral antihistamines, gamma-aminobutyric acid agonists (gabapentin or pregabalin), aprepitant or doxepin. May consider administering sedative antihistamines if insomnia is occurring.
In grade 3 paronychia, interrupt epidermal growth factor receptor inhibitor treatment. Swab any pus from culture and prescribe oral antibiotics. Continue to apply topical antibiotics and/or antiseptics.
In 2016 study with erlotinib, oral minocycline prevented severe toxicity, but not a mild rash. However, prophylactic antibiotics arm had double survival duration. In 2010 study with pantumumab, prophylactic antibiotics reduced grade 2 or 3 skin adverse events from 62% to 29%. Therefore, prophylactic antibiotic use can be recommended.
VACCINE-INDUCED DRUG REACTIONS
According to the oral communication of MD Virginia VELASCO-TAMARIZ (Dermatologist, Spain)
Vaccines contain potential allergens such as adjuvants, antibiotics, stabilizers, and preservatives. Vaccine-induced adverse events are classified as local reactions, allergic reactions, and related diseases.
As local reactions after vaccine administration, pain, swelling, erythema can appear. It can be mild, severe, or local eczematous appearance. Usually local reaction disappears within 24 hours.
As allergic reactions, delayed-type hypersensitivity to vaccine aluminum adjuvant can occur. Subcutaneous nodules, sterile abscesses, and contact dermatitis are type IV hypersensitivity reactions that can occur after vaccine administration. It has been reported more commonly in young children. IgE-mediated allergic reaction can occur. If the patient has history of reactions after vaccine administration or immediate allergy to gelatin, latex, yeast or egg, skin testing with vaccine should be done before vaccine administration. Acute generalized erythematous pustulosis, DRESS, erythema multiforme, and SJS/TEN can also occur as delayed type hypersensitivity.
As related disease with vaccine administration, vasculitis, psoriasis (especially guttate psoriasis), lichen planus and lichenoid drug eruption, neutrophilic dermatosis, pityriasis rosea and pityriasis rosea-like eruptions, and infantile bullous pemphigoid have been reported.
There are numerous reports about cutaneous reactions after vaccine administration. However, there has been lack of causality. Clinicians always should consider vaccine history before administration and pay special attention in delayed reactions.
REACTIONS TO BIOLOGICS
According to the oral communication of Prof. Rolland GYULAI (Dermatologist, Hungary)
20-25% of patients on biologicals will develop a cutaneous reaction. Most common cutaneous adverse events are infections (12.5%), paradoxical reactions (10%), neoplasms (<1%), xerosis, injection site reactions, vasculitis, alopecia, etc. Risk factors for cutaneous infections and biological therapy are infliximab therapy, additional immunosuppressive therapy, malnutrition, younger age, and comorbidities. Bacterial infection comprises 60% of infections, and 25% are fungal infections. Paradoxical reactions which means development of inflammatory immune-mediated tissue manifestations in patients treated with targeted biologic agents can occur and its prevalence is 1-10% in TNF-α inhibitors. Paradoxical reactions can be classified by lichenoid, eczematous, psoriatic, hidradenitis suppurativa, neutrophilic, and granulomatous/fibrogenic. This can occur as de novo or exacerbation of existing disease. Temporal association has been reported. Withdrawal or retreatment leads to improvement or relapse respectively. These are therapeutic recommendations for paradoxical reactions. As initial strategy or mild to moderate (BSA 0-10% skin involvement) reactions, maintain current biological agent and apply topical therapies (topical corticosteroid, keratolytic agents, immunomodulators, vitamin D). In moderate to severe skin involvement (>10% BSA), keep strategies same as mild to moderate and add phototherapy and traditional systemic agents (methotrexate, acitretin, cyclosporine). When extensive skin involvement, unstable disease occurs, discontinue current biological therapy and switch to new class agent.
Another possible cutaneous reaction associated with biologics are injection site reactions. This is usually mild and disappear after 3-5 days. Cooling, topical steroids, and analgesics are usually enough to manage.
Drug-induced autoimmune diseases like lupus and vasculitis can occur rarely.
BASIC SCIENTIFIC COSMETOLOGY
RATIONALE ON ANTI-AGEING COSMETIC INGREDIENTS
According to the oral communication of Prof. Enzo BERARDESCA (Dermatologist, Italy)
Report by Dr. Dong Hun LEE (Dermatologist, South Korea)
Prof. BERARDESCA began his talk by introducing intrinsic and extrinsic aging. Skin aging is a multifactorial condition that requires cell turnover stimulation, stimulation of fibroblast proliferation, improvement of redox and antioxidant activity, inhibition of advanced glycation end-products (AGEs) formation, prevention of autophagy, modulation of matrix metalloproteinases (MMPs) activity, and protection of the skin from UV and pollution. Topical antiaging cosmeceuticals include vitamins, antioxidants, plant and marine extracts, hydroxyl acids, peptides, and biologicals. (McCook J, Clin Plast Surg 2016) Topical retinoids, particularly tretinoin, improve coarse wrinkling, smoothness, roughness, and discoloration/dyschromia via their well-established molecular mechanisms and associated histological/ultrastructural changes. (Darlenski R et al., BJD 2012) Tretinoin has a proven efficacy at the histological level to improve cutaneous signs of aging but is associated with local side effects such as irritation, photosensitivity, and retinoid dermatitis. Regarding retinol and derivatives, they are metabolized to retinoic acid, need high concentration to be effective. Topical retinaldehyde has biological activity and well-tolerated. Alpha-hydroxy acid (AHAs) stimulates collagen and hyaluronic acid synthesis in the dermis. Topical vitamin C can improve photoaging, and vitamin E is used mainly with other ingredients for photoprotection and antiaging via antioxidant activity. Topical treatment with Coenzyme Q10-containing formulas improved skin’s Q10 levels and provided antioxidant effects. Autophagic activity is decreased with age and liposomes loaded with trehalose, a naturally occurring non-reducing disaccharide and an autophagy inducer, protected against UVB-induced damage in vitro. (Emanuele et al., Biomed Rep 2014) Botanical extracts, such as resveratrol, Polypodium leucotomos, epigallocatechin gallate (EGCG), Jasmonic acid, ginseng extracts, and Punica granatum (pomegranate) have been investigated in vitro. Besides, various cytokines, growth factors, and peptides such as GHK, GEKG, KTTKS are actively being investigated, but future studies are needed. Prof. BERARDESCA concluded that retinoids, tretinoin, and derivatives have the most documented evidence, and combination treatment using multi-active formula can have synergistic effects for improved efficacy and different mechanism of actions.
DO CLEANSERS AND MOISTURERS AFFECT THE MICROBIOME?
According to the oral communication of Dr. Ester SERRA-BALDRICH (Dermatologist, Spain)
Dr. SERRA-BALDRICH introduced the concept of microbiome and pointed out that skin microbiome is less stable than gut microbiome due external factors such as cleansing. Skin in atopic dermatitis (AD) patients showed dysbiosis characterized by low bacterial diversity and high non-Malassezia fungal diversity in AD flare. Correction of dysbiosis to symbiotic state is important. Skin pH is important in several processes, including antimicrobial activity, and determined by endogenous (anatomical site, pigmentation,…) and exogenous factors. To be specific, acidic pH inhibits colonization of pathogenic bacteria. Syndet and cleansing solutions are better cleansers, and she reviewed recent advances in mild and moisturizing cleansers. (Anathapadmanabhan et al., JDD 2019) A recent study indicated that the benefit of dilute bleach bath was not attributed to direct antibacterial effects. Moisturizer can increase microbial diversity, and Dr. SERRA-BALDRICH explained the ideal properties of AD care products, such as active strengthening of natural epidermal barrier, compatibility of physiological pH, and growth support for the beneficial skin microbiota. Application of certain emollients can increase microbiome diversity, but olive oil may exacerbate xerosis and atopic dermatitis. The effective treatment strategy may include a combination of topical and oral probiotic therapy. Finally, she addressed the importance of personalization to provide different options according to individual’s location, environment, and skin conditions.
BIOLOGY OF NANOPARTICLES
According to the oral communication of Prof. Klaus Ejner ANDERSEN (Dermatologist, Denmark)
Prof. ANDERSON introduced the definition of nanomaterials, which is a natural, incidental, or manufactured material containing particles in size range of 1 nm-100 nm (EU Commission 2011), and nanosystem in dermatology. Properties of nanoparticles are different in terms of increased rate of dissolution, enhanced saturation solubility, decreased diffusional distance, higher concentration gradients, and improved adhesiveness. Nanosystems in dermatology are used to enhance drug permeability through the skin. Nanoproducts are increasing, particularly in personal care products, clothing, sporting goods, and cosmetics. There is a conceptual decision support tool for risk evaluation of nanomaterials called Nanoriskcat (http://nanodb.dk/en/nanoriskcat/), and most cases the exposure and hazard potential is either high or unknown. Nanomaterials in medicine include those used in wound healing, anticancer nanomedicines, and topical drugs. Cosmetic products such as sunscreens, moisturizers, whitening products, and antiaging products may employ nanotechnologies, including liposomes (nanosomes), nanoemulsions, solid nanoparticles, polymer systems (nanocapsule), and metal oxide nanoparticles. He introduced a case of contact allergy which showed higher reactivity with retinylpalmitate and polycaprolactone nanoparticles than retinylpalmitate alone. ‘Nanoproject’ examined the effect of nanosystems on contact allergy using mouse local lymph node assay (LLNA) and pre-sensitized human volunteers, and found that lipophilic contact allergen encapsulated in ethosomes may show enhanced allergenicity. Dr. ANDERSON emphasized that industries and dermatologists should consider the effect of encapsulation on allergenicity and the possibility of false-negative results without encapsulation, respectively.
SKIN AGEING IN THE 21ST CENTURY: ACCELERATORS AND INHIBITORS
According to the oral communication of Prof. Leonardo MARINI (Dermatologist, Italy)
Aging in the skin is associated with various contributors, such as DNA damage, mitochondrial dysfunction, nutrient signaling dysfunction, chronic inflammation, stem cell exhaustion, prostatic dysfunction, telomere erosion, and epigenetic factors. Dr. Marini comprehensively reviewed the accelerators (UV-infrared-visible light exposure, smoking, drinking, hypercaloric unbalanced diet, pollutants, unbalanced hormonal equilibrium, and a lack of exercise) and inhibitors (antioxidants, sunscreens, humectants & hyaluronans, calorie restriction balanced diet, estrogen – testosterone, regular exercise, hermetic cellular stress, photobiomodulations, and balanced microbiome). He focused on the role of estrogen on skin elasticity, water-holding capacity, pigmentation, vascularity, and skin aging and introduced that topical estrogen may prevent skin aging as demonstrated by previous studies. Interestingly, he introduced several anti-aging medicines such as metformin, pegvisomant, rapamycin, resveratrol, gut microbiota modulation (prebiotics, probiotics), and vitamin D. Topical antioxidants as well as systemic ones are important inhibitors and can be combined with sunscreens. A combination of various antiaging strategies (inhibitors) is synergistic, and it is important to keep aging accelerators under control for significant antiaging outcomes.
SYPHILIS
COMEBACK OF THE GREAT IMITATOR
According to the oral communication of Prof. Stephan LAUTENSCHLAGER (Dermatologist, Switzerland)
Report by Dr. Dong Hun LEE (Dermatologist, South Korea)
Syphilis is a big global problem because its seroprevalence rate remains high and its prevalence is increasing particularly in female sex workers and men who have sex with men (MSM). There is a high rate of HIV coinfection, and incidence of HIV significantly increased after syphilis, suggesting there are bidirectional interaction and epidemiological synergy between HIV and syphilis. The burden of syphilis is underestimated. Dermatologists should be aware of the many faces of syphilis. For example, in addition to typical lesions of stage 1, atypical forms such as nodular, herpetiform, balanitis, and extragenital forms are possible. Besides, stage 2 syphilis may show various clinical manifestations such as uveitis, optic neuritis, otosyphilis (sudden hearing loss), erythema multiforme, roseola syphilitica, granuloma annulare-like, psoriasis-like, scrotal eczema-like, annular ulcerating lesions of mouth, and alopecia areolaris. Recent reports showed that more than half were asymptomatic, and previous syphilis infection alters the course of subsequent episodes. Management includes control strategy and primary prevention, and widespread testing, improved education, timely treatment, and continued research are necessary.
SKIN AGEING
CLINICAL AND HISTOLOGICAL MANIFESTATIONS OF PHOTOAGEING
According to the oral communication of Prof. Henry W. LIM (Dermatologist, United States)
Report by Dr. Dong Hun LEE (Dermatologist, South Korea)
Prof. LIM first introduced clinical features of photoaging, such as solar lentigines, actinic keratosis, Favre-Racouchut, cutis rhomboidalis nuchae, solar purpura, and poikiloderma of Civatte. Visible light and UV-A spectra are more transmissible through window glass. The known mechanisms underlying photoaging include AP-1 transcription factor activation, upregulation of matrix metalloproteinases (MMPs), degradation of dermal matrix followed by imperfect repair leading to ‘solar scar’, mtDNA (mitochondrial) mutation characterized by common deletion (4977-bp del of mtDNA), upregulation of progerin, oxidative stress, telomere shortening, and cellular senescence. He next addressed the recent updates regarding this topic. Sirtuin-1 decreased following UVB irradiation in vitro and can inhibit MMPs. Visible light increased cyclin D1, COX2, MMP1, MMP9 in skin phototype IV-VI subjects.(Kohli et., BJD 2018) Infrared irradiation increased collagenase production. Managements (prevention and treatment) include shade, clothing, hat, sunglass, sunscreens, and non-topical agents. Traditional sunscreens do not protect against visible light and infrared irradiation.
PATHOPHYSIOLOGY OF PHOTOAGEING
According to the oral communication of Dr. Amaya VIROS (Dermatologist, United Kingdom)
Dr. VIROS first introduced various aging theories such as immunological deterioration, oxidative stress, decreased hormone, genetic alteration, and neurological deterioration. The relationship between mutational burden and aging has been described previously. For DNA damage in aged skin, the mutation is accumulated in UV-irradiated skin, and the signature mutations are found even in sun-protected skin. Healthy skin showed accumulated mutation of NOTCH1, NOTCH2, NOTCH3, FAT1, and TP53 (Martincorena et al., Science 2015; Saini et al., PLoS Genetics 2016). She focused on MC1R gene, which is associated with photosensitivity, blue eyes, red hair, and fair skin according to its variants. Liu et al. demonstrated the relationship between MC1R gene and youthful looks (Current Biology 2016). Dr. VIROS and colleagues revealed new insight how MC1R gene explains skin aging. MC1R variant fibroblasts have a higher mutation load, and MC1R loss of function increases mutation loads in dermal fibroblasts. Besides, matrix metalloproteinase 1 (MMP1) is upregulated in fibroblasts with high levels of UV damage, MC1R variants show increased MMP1 levels, and SNV load, MMP1, and wrinkles are correlated, indicating that MC1R variants are associated with less DNA repair and more MMP1 expression. She summarized that those with fair skin have MC1R variants, show less DNA repair, more MMP1, and consequently more collagen degradation.
SKIN BARRIER IN AGEING
According to the oral communication of Dr. Leonie JACOBS (Dermatologist, Netherlands)
Dr. JACOBS comprehensively reviewed the overview of skin barrier and markers of skin barrier, such as TEWL, pH, and sebum level. In aged skin, calcium gradients is collapsing with age (Rinnerthal et al., Curr Probl Dermatol 2018) Low calcium is associated with less effective corneocyte cell envelope, downregulation of cross-linking of involucrin (IVL), envoplakin, periplakin, and decreased expression of loricrin (LOR) and filaggrin (FLG), and increased expression of small protein-rich protein (SPRR). Higher skin surface pH of the elderly is attributed to downregulation of Na/H transporters, decreased UCA, decreased melanosomes (acidic) due to decreased melanocytes, and tyrosinase function. The elderly also show less effective lipid layer due to decreased secretion of lamellar bodies and ceramides. She next summarized consequences from these changes, dry skin (Mekic et al. JAAD 2018), altered drug permeability, increased risk of infection, and decreased resistance to injuries (Rinnerthal et al., Exp Dermatol 2013). Dry skin is caused by less FLG, lower lipid content and higher desquamation index. She summarized solutions targeting each barrier abnormality in the elderly, such as emollients, and less water contact for dry skin.
COLOUR-RELATED SKIN AGEING
According to the oral communication of Dr. Yolanda GILABERTE CALZADA (Dermatologist, Spain)
Dr. CALZADA first reviewed ethnic differences in skin properties and skin aging. African Americans showed more numbers of cell layers, lipid content, and sebum production. Whereas aging features of African Americans showed sagging of malar fat pad, hypertrophy of malar fat pad, accentuated nasolabial folds, and laxity of eyelids, their photoaging features include fine wrinkles, mottled pigmentation, dermatosis papulosis nigra, and accentuated nasolabial folds. A recent study suggested that Caucasian men have more intense photoaging features. (Rossi et al., Dermatol Surg 2017) More recently, Langton et al. showed that disruption to elastic fiber organization is detrimental to skin biomechanical function, and subjects with darker skin showed no solar elastosis. (JID 2019) While sun-exposed skin lightens over time in black skin people, it darkens over time in white skin. (Chien et al., JAAD 2016) There are several new skin aging scales for African Americans.(Chien et al., J Natl Med Assoc 2018) As Dr. Viros mentioned in her previous talk, some variants in MC1R gene are associated with higher perceived age (Liu et al., Curr Biol 2016). Skin color does not seem to be relevant in the aging exposome. Dr. CALZADA concluded that skin color is important for skin aging, and the amount of melanin in Caucasian skin is relevant for photoaging as well.
SKIN AND BRAIN: UNRAVELED CONNECTIONS
EADV President’s Symposium
THE SKIN-BRAIN AXIS IN INFLAMMATORY SKIN DISEASE
According to the oral communication of Prof. Christopher GRIFFITHS (Dermatologist, United Kingdom)
Report by Prof. Anna ZALEWSKA JANOWSKA (Dermatologist, Poland)
Skin and brain close connections are now more and more recognized and appreciated by “serious science” and now are among so called hot topics.
Professor Chris GRIFFITHS presented an overview on skin-brain axis in inflammatory skin diseases with focus on psoriasis. Epidemiology shows that approximately one third of psoriatic patients develop depression and anxiety and about 20% report being stigmatized or rejected because of their skin condition i.e. not admitted to the public swimming pool. Professor GRIFFITHS demonstrated brain imaging results which pointed that avoidance coping and autonomic vigilance reflect psychological disability associated with psoriasis. Emotional, insula cortex, response to expressions or pictures of disgust is processed differently in psoriasis patients being for them a coping mechanism. Of note, when single psoriatic lesions appear in psoriastic patients who were totally free of symptoms when on biologic treatment, patients’ anxiety unexpectedly highly rises. This should be taken into account in patient management. It now seems beyond discussion that broad “stress” induces and/or exacerbates psoriasis. Of importance acute stress stimulates Langerhan’s cells migration, which is associated with neuropeptides modulation. Imaging studies demonstrated that etanercept reduces brain inflammation in psoriasis. This drug also improves symptoms of depression and fatigue in psoriatic patients who report to feel better when put on the drug before any skin lesions has time to disappear. The speaker presented results of mega-analysis demonstrating that immunomodulatory drugs may have efficacy in depressive symptom management and novel immunotherapies can exert antidepressant effects in depressed patients with inflammatory disorders that are not fully explained by treatment-related changes in physical health (Wittenberg et al, Mol Psychiatry 2019 Aug 19).
PHARMACOLOGICAL RELIEF OF ITCH: WHAT IS RELEVANT IN 2019?
According to the oral communication of Prof. Sonja STÄNDER (Dermatologist, Germany)
Report by Dr. Dong Hun LEE (Dermatologist, South Korea)
Recent exciting findings regarding neuronal sensitization is associated with pharmaceutical development. Chronicity is induced by neuronal sensitization involving functional and structural components. Prof. STÄNDER introduced serlopitant (NK-1R antagonist) for the treatment of chronic pruritus (CP) (positive outcome in phase 2), chronic prurigo nodularis, psoriasis, and epidermolysis bullosa. Kappa-opioid receptor agonists such as oral nalbuphine and IV difelikefalin are under investigation for the treatment of hemodialysis-related pruritus and chronic nodular prurigo. (Pereira et al., Curr Opin Pharmacol 2019) Recently, Oetjen et al. demonstrated that peripheral neuronal sensitization in chronic pruritus, and IL-4Rα and JAK1 activation leads to chronic pruritus (Cell 2017). More recently, functional and structural changes among CP of inflammatory origin (atopic dermatitis), neuropathic origin (brachioradial pruritus), and chronic prurigo of nodular type were investigated, and there was a decrease in intraepidermal nerve density, reduced descending inhibitory system, and upregulation of NGF (Pogatzki-Zahn et al., J Invest Dermatol. 2019). Chronic prurigo is a distinct disease defined by the presence of chronic pruritus for ≥ six weeks, history, and/or signs of repeated scratching and multiple localized/generalized pruriginous skin lesions, and its treatment remains very challenging (Pereira et al. JEADV 2018). Recently, phase 2 trial of nemolizumab for prurigo nodularis showed an impressive improvement of 53.4% of peak pruritus at week 4, and 38.2% of patients achieved IGA 0/1 (EADV 2019 Late-breaking session). Novel topical medications such as TRP channel modulators and NGF receptor modulators are being developed. Recent phase 2 study of TRPV1 antagonist (PAC-14028) for the treatment of atopic dermatitis (AD) was successful and showed a significant improvement in AD signs and symptoms including itch. Topical TrkA (NGF receptor) kinase antagonist CT327 has been tested for psoriatic itch. There are NK1R antagonists (phase 3), opioid receptor modulator (phase 3), IL-4, IL-31 antagonists, ileal bile acid transporter inhibitor (for cholestatic pruritus) being investigated for pruritus. IL-13 antagonists, H4R antagonists, JAK inhibitors, and TRPV1 antagonists have high potential, and potential targets include astrocytes, GRPR, TrkA, and Sema3A. Increasing understanding of CP pathophysiology, novel target identification, and pharmaceutical development are necessary. Finally Dr. Ständer invited audience to read a recent commentary regarding this topic by Ingram and Ahluwalia (BJD 2019).