Акценти от 2-ри ден
General dermatology, Oncology/Dermatology, Atopic dermatitis, Sunscreens and the environment
Dr. Lise Boussemart
Dermatologist, Rennes, France
Dr. Ruth Ann Vleugels, Dermatologist, United States
Dr. David Eric Cohen, Dermatologist, United States
Dr. Edward W. Cowen, Dermatologist, United States
Dr. Jean L. Bolognia, Dermatologist, United States
Dr. Kenneth J. Tomecki, Dermatologist, United States
This morning, I signed up for the session on “general dermatology”. It was an update of knowledge in general dermatology and was very useful to me, as I have been specialising in oncodermatology for the past few years.
Dr Ruth Ann Vleugels described a relatively recent entity: dermatomyositis with circulating anti “MDA-5” antibodies.
This is a form of dermatomyositis that, as its name does not indicate, is amyopathic.
Most importantly, from a semiological standpoint, it is unique in that it induces painful ulcers on the dorsal surface of the fingers, where Gottron papules are generally located, as well as highly evocative and sensitive erythematous papulo-macules on the hands and feet.
In the presence of these clinical signs, it is necessary to consider dermatomyositis with anti MDA-5 antibodies and treat the rapidly progressing interstitial lung disease that often accompanies it.
Still regarding dermatomyositis, Dr Vleugels noted that only 10% of dermatomyositis cases with exclusive skin involvement improve with hydroxychloroquine on its own. She thus recommends:
- directly combining it with methotrexate, or
- IVIG 1g/kg/day (every four weeks at first, then gradually reduce the frequency over several years), or
- mycophenolate mofetil, which should be favoured if there is associated interstitial lung disease (positive anti-Jo1 or MDA-5 blood tests).
A JAK inhibitor, tofacitinib 10mgx2/day, also seems promising for the treatment of resistant dermatomyositis, due to interferon-mediated autoimmunity.
Regarding subacute cutaneous lupus erythematosus, a Swedish case-control study showed it was associated with the use of certain medications, in particular terbinafine (OR 52.9, 95% CI 6.6-∞), TNFα inhibitors (OR 8.0, 95% CI 1.6-37.2), antiepileptic drugs (OR 3.4, 95% CI 1.9-5.8) and proton pump inhibitors (OR 2.9, 95% CI 2.0-4.0) within six months before lupus diagnosis (Grönhagen et al., Br J Dermatol 2012).
A third of subacute cutaneous lupus erythematosus cases could be associated with exposure to one of these medications and could improve with discontinuation of use.
The following speaker, Dr David Cohen from New York University, reported cross-allergies between formaldehyde (contained in Brazilian straightening products) and aspartame which, as I did not know, is degraded after digestion into formaldehyde.
Dr Edward Cowen then delved into the topic of auto-inflammatory diseases, with overactivation of innate immunity, as opposed to auto-immune diseases, with overactivation of T cells or presence of circulating auto-antibodies.
He described the spectrum of CAPS syndromes (cryopyrin-associated periodic syndrome, whose forms include familial cold urticaria and Muckle-Wells syndrome) caused by “gain-of-function” mutations in the NLRP3 encoding gene for cryopyrin, which all respond to anakinra including Schnitzler's syndrome.
But most importantly, he spoke of two new auto-inflammatory syndromes, caused by mutations activating the NLRP1 gene: multiple self-healing palmoplantar carcinoma and familial keratosis lichenoides chronica (Zhong et al., Cell 2016).
Dr Jean Bolognia from Yale then described the cutaneous side effects of new treatments for metastatic melanoma.
These are particularly important to know since anti-PD-1 immunotherapy is now also commonly prescribed for lung and bladder cancer and Hodgkin's lymphoma. Lastly, PD-1 inhibitors have only recently been authorised as adjuvant therapy for stage III melanoma, and a study published on 25 February 2019 even proposed them for neoadjuvant therapy (Huang et al., Nature Medicine 2019).
Rashes occurring with anti-PD-1 therapy are usually lichenoid and eczematous; they are sometimes psoriasiform and very rarely bullous.
The therapeutic recommendations published in JCO in 2018 proposed topical corticosteroids +/- antihistamines for grades I-II, oral corticosteroids (1 to 2mg/kg/day) for grade III and intravenous corticosteroids for grade IV. Dr Bolognia criticised these recommendations and suggested adding, according to clinical practice, etretinate/acitretin, apremilast or methotrexate by analogy to standard psoriasis treatments. In my experience, acitretin has been very effective against anti-PD-1-induced psoriasis. Moreover, the cutaneous side effects of targeted therapies have been minimal since BRAF inhibitors have been systematically combined with an MEK inhibitor. The main thing to keep in mind is the risk of secondary tumours, erythema nodosum and drug-induced maculopapular rash.
To close the morning session, Dr Kenneth Tomecki from Cleveland presented a review of HIV, regretting that only half of the 33 million HIV-positive people around the world are currently receiving a specific treatment. There are now more than 30 different antiretroviral drugs, and patients should take at least three at the same time as soon as their HIV-positive status is known, before their CD4 count starts to decline. He also mentioned a new recombinant shingles vaccine, Shingrix*, which will probably overshadow its competitor Zostavax* (live attenuated vaccine), considering its high level of efficacy (90% of shingles cases prevented in the three to five years following its administration compared to a placebo) and its probable safety for immunocompromised subjects (Lal et al., NEJM 2015).
Dr Abigail Baird Waldman, Dermatologue, États-Unis
Dr Matthew D. Belcher, Dermatologue, États-Unis
Dr Murad Alam, Dermatologue, États-Unis
Dr Ashley Decker, Dermatologue, États-Unis
Dr Evan A. Rieder, Dermatologue, États -Unis
Dr Jason Riis, Psychologue, États-Unis
In the afternoon, I attended a more “cancer”-oriented session. Dr Abigail Waldman started the session by discussing the various classifications for cutaneous squamous-cell carcinomas (AJCC8, BWH, etc.). According to the American National Comprehensive Cancer Network (NCCN), a >2cm (vs <2cm) diameter and a poorly differentiated nature multiply the risk of recurrence by two to three, whereas a >6mm thickness or hypodermal involvement multiplies this risk by 10 to 11. The most worrisome histological marker in primary tumours is perineural or vascular invasion (x23 risk of local recurrence, x12 for distant recurrence), which means priority should be given to a complete circumferential histological analysis of the peripheral and deep margins, and adjuvant radiotherapy should be discussed. In the event of lymph node metastasis, nodal dissection is indicated, with 30 sessions of 60 Gy adjuvant radiotherapy over a six-week period.
Cemiplimab or Libtayo* (PD-1 inhibitor) has been approved by the US FDA as the first therapy for metastatic cutaneous squamous-cell carcinoma.
The following presentation, by Dr Matthew Belcher, dealt with the 8th edition of the AJCC melanoma staging system. For information, this latest edition lowered the melanoma severity threshold to 0.8mm in Breslow depth (vs 1mm previously). The sentinel lymph node technique should now be discussed for melanoma from the T1b stage, i.e. from 0.8mm in Breslow depth or regardless of Breslow depth when there is ulceration. Since Breslow depth is now to be expressed with only one number after the period, a melanoma with Breslow depth of 0.75mm should be considered a 0.8mm and thus stage T1b melanoma. A positive sentinel lymph node (with metastasis > 1mm) enables adjuvant treatment to be proposed based on pembrolizumab or dabrafenib+trametinib for one year. Operated stages IIIb, IIIc and IV can also be treated with nivolumab as adjuvant therapy. We are thus witnessing a complete change of habits in the therapeutic care of melanomas, with the sentinel lymph node technique moving from “optional” to “decisive” – until stage II adjuvant trials have been undertaken.
Dr Murad Alam then spoke of the relevance of publishing official expert recommendations, as part of an inter-speciality collaboration if possible, for both common and rare cancers, to guarantee at least some homogeneity and safety in practices. In the United States, there are “NCCN” and “AAD” recommendations for the main forms of skin cancer, and there are equivalent guidelines in Europe.
The next speaker, Dr Ashley Decker, spoke of the advantages of using multimedia content such as explanatory videos to improve the “patient experience”. Of course, videos cannot replace patient dialogue, but a well-designed video can, without taking up more of the doctor’s time, enhance the patient's level of understanding and education and thus improve the treatment experience (randomised clinical trial by Love et al., JAAD 2016).
In aesthetic dermatology, Dr Evan Rieder then warned about dysmorphophobic patients, who are almost always dissatisfied, with an unknown risk of suicide, and whose truly “enlightened” consent is questionable. Little research has been conducted into dysmorphophobia, described in relatively few publications, contrasting with the danger these patients impose on their own bodies and on their doctors (laws uits, physical and verbal violence, etc.). Some short questionnaires can help screen for dysmorphophobia, such as the BDD Q questionnaire: Body Dysmorphic Disorder Questionnaire (BDDQ)
Among doctors specialising in aesthetic procedures, the reported proportion of dysm orphophobic patients ranges from one speciality to the next (15% for dermatologists, 5% for general practitioners). This variation gives rise to concerns about a lack of “identification”. Dr Rieder recommends refusing to perform aesthetic procedures for this “fragile” population, saying: “I wonder if you might have dysmorphophobia. I sense that you feel frustration going beyond your external appearance. Would you agree to first work on this dislike instead of undergoing multiple aesthetic procedures?” Of course, a good psychiatrist colleague or a psychodermatology specialist will be invaluable if exploring the why and how of things is not our strong point.
To conclude, Dr Jason Reis, a psychologist, sought to show us how dermatology can benefit from knowledge of behavioural sciences. Behavioural sciences are based on the observation that human beings constantly make judgement/decision errors, through automatic thoughts and emotions, which can be improved with intention and technique. This requires motivation, living in the present moment (“here and now”), facilitation (people are lazy by nature) and intentional positive feedback. I insist on the word “intentional” since studies have shown that we always think we have given more positive feedback than what has actually been perceived.
Dr. Nicole Jouan
Dermatologist, Brest, France
Co-morbidity in atopic dermatitis
Dr. Aaron Mark Drucker, Dermatologist, United States
While we are used to detecting co-morbidity in our psoriasis patients, this is slightly less true for those with atopic dermatitis. Wrongly so, it would seem. Such was the theme of the presentation by Pr Drucker. First of all, there are sleep disturbances. Nothing very recent on the topic. We should always remember to question our patients, even children (22% of children with severe AD sleep poorly more than four nights per week, and the rate of insomnia in adults is three times that for the general population). The restoration of good sleep quality has been assessed with dupilumab, of course, as well as more recently with baricitinib (Guttman‐Yassky E, JAAD). Attention problems and hyperactivity are also commonly observed.
Regarding anxiety and depression, the rates are multiplied by 2.2 compared to the general population (Rønnstad ATM JAAD 2018), and the risk of suicide is 22% higher. Note that 13% of atopic patients who commit suicide have seen a doctor for their skin condition in the previous month (Drucker BMJ 2018). What is the role of inflammation and that of the psychosocial burden and sleep disturbances in the onset of these anxio-depressive disorders? It is not clear. What is certain, however, is that the treatment of AD, with dupilumab in particular (de Bruin‐Weller Br J Dermatol. 2018), improves depression scores. We should remember to ask our patients about their mood and consult with their general practitioner to assess and monitor their condition. The speaker uses a simple two-item questionnaire, on a scale from 0 (not at all) to 3 (almost every day): how many times in the past two weeks have you felt depressed or powerless? Have you taken little interest or enjoyment in doing things?
Regarding cardiovascular co-morbidity: the risk of angina is increased by 18%, that of heart attack by 12% and that of ischemic stroke by 17% (Ascott, J Allergy Clin Immunol. 2018). The risk evolves in parallel with AD severity. In fact, the absolute risk is low, but we can advise our patients to quit smoking and exercise on a regular basis.
Auto-immune diseases: AD is observed in combination with alopecia areata, vitiligo, lupus erythematosus, chronic urticaria, Coeliac disease, IBD and auto-immune thyroid diseases. However, there is an inverse association with diabetes. This association with auto-immune diseases should not, in the current state of knowledge, be systematically screened for. However, the therapeutic implications are clear: it is important to remember the efficacy of tofacitinib and dupilumab, administered to two patients with alopecia areata combined with atopic eczema, in treating the two conditions (Morris GM. JAAD 2018, Darrigade Br J Dermatol. 2018). Note, however, that cases of alopecia areata have been observed with dupilumab.
Pathophysiology of atopic dermatitis and its therapeutic implications
Dr. Emma Guttman-Yassky, Dermatologist, United States
AD has a complex, multifactorial pathophysiology, which can be summed up via two approaches: one involves the impairment of the epidermal barrier: AD is a genetic disease of this barrier, and barrier function disorders cause keratinocyte hyperplasia and reactional immune activation. The other approach considers AD as an immunological disease: the AD phenotype is due to increased expression of Th2 cytokines (IL-4 and IL-13) which induce barrier anomalies and inhibit antimicrobial peptides, causing microbiome anomalies: homogenisation and colonisation by staphylococcus aureus during flare-ups. But is AD a single disease? Nothing could be less certain: while Th2 inflammation and Th22 overexpression are constant, Th1 and Th17 profiles are different between children and adults and African American and Asian populations: are personalised treatments on the horizon?
New therapeutic targets in AD
Despite very recent progress, the ambitions of the medical profession for the treatment of AD and its long-term maintenance are far from being satisfactory, whether for children or for adults.
- Phosphodiesterase-4 inhibitors
It is relevant to block phosphodiesterase since circulating monocytes have increased PDE4 activity in AD. Blockage reduces levels of IL-4, -12, -17 and -23. Difamilast 1% cream is under development, with rapid and lasting efficacy against pruritus. Crisaborole, already marketed in the USA for mild to moderate atopic dermatitis, belongs to the same class. Some side effects: pain, infection at the application site.
- Monoclonal antibodies:
A promising phase-2 study dealing with an anti-IL-22 antibody, fezakinumab (Guttman Yassky E, JAAD January 2018).
A topical LX (Liver X) receptor agonist: skin barrier restoration is observed, but with no improvement in clinical scores for AD.
Tralokinumab, an anti-IL-13 antibody, is promising, as is lebrikizumab, combined with local corticosteroid therapy in a trial.
Nemolizumab, an anti-IL-31 antibody, has shown to be effective against pruritus. Some case of AD aggravation and peripheral oedema during treatment require an explanation.
Tradipitant, an NK1 antagonist that blocks substance P: its anti-pruritus efficacy in AD is not impressive, the improvement in clinical scores for AD is not major, and pruritus improvement is delayed.
- JAK inhibitors:
Oral baricitinib: a convincing phase-2 study, but with the side effects of its therapeutic category: headaches, elevated CPK, rhino-pharyngitis; two phase-3 studies (BREEZE-AD1 and 2). Three doses assessed (1, 2 and 4 mg). No major side effects.
Upacitinib seemed promising in a phase-2b trial (three doses, 7.5, 15 and 30 mg/day).
Topical ruxolitinib (0.15, 0.5, 1.5% cream) is effective and well tolerated.
Note that cats and dogs with eczema can already benefit from an oral JAK inhibitor, Apoquel*, which is oclacitinib (around $1.6 per tablet).
Tapinarof, a new topical NSAID, has been tried at several concentrations and seems effective with a dose-dependent response.
Lastly, dupilumab showed to be effective in a phase-3 study on AD in adolescents aged 12 to 17 years. We are thus probably on the brink of a therapeutic revolution with AD, as was the case a few years ago with psoriasis. This can provide us and our atopic patients with a sense of hope!
Dr. Rémi Maghia
Dermatologist, Brest, France
Sunscreens and the environment
Dr. Henry W. Lim, Dermatologist, United States
Patients rightly ask us questions about the use of cosmetic products and environmental protection. I found that Henry Lim, from Detroit, provided very useful answers to these questions and concerns regarding sunscreens.
Oxybenzone and octinoxate: not just sunscreens
Oxybenzone, octocrylene and octinoxate are used in body care products such as cosmetics and fragrances and as photostabilisers for plastics. The CDC considers that 96% of the US population is exposed.
Oxybenzone has endocrine effects in rats. But no known safety issues in humans (product used in the USA since 1978).
Calculations have been performed to determine how many years of daily sunscreen application are necessary to obtain the rates observed in rats: according to the various scenarios, the number ranges from 34.6 to 277 years, which is completely unrealistic.
There remains the issue of why coral reefs are dying: oxybenzone damages DNA in the larval stage under laboratory conditions. In addition, oxybenzone has been detected in fish, although at low concentrations. Along the Great Barrier Reef in Australia, coral bleaching has occurred in remote zones, with infrequent human contact. The main cause of this bleaching is rising ocean temperatures.
Since 1960, in the central equatorial Pacific, eight severe (>30%) and two moderate (>30%) bleaching events have all coincided with extreme heat associated with El Nino. Rapidly rising ocean temperatures in the last few decades have led to the destruction of coral reefs and the decline of ice caps.
And yet measures have been taken regarding oxybenzone and octinoxate. For January 2021, prohibition expected in Hawaii and Key West, Florida. A law has been planned in 2019 to prohibit the sale of sunscreens containing these two products in two US states: California and Florida.
ZNO and TiO2
Many “reef-safe” sunscreens contain non-nano zinc oxide (ZnO).
In laboratory conditions, uncoated ZnO causes rapid coral bleaching (ZnO particles are coated in sunscreens).
Titanium dioxide (TiO2) does not cause bleaching.
In the end, the following can be said for TiO2 and ZnO nanoparticles: no relevant evidence of percutaneous penetration, no side effects in humans; no sufficient data on inflamed skin with impairment of the epidermal barrier; very few harmful effects on the environment.
An FDA document from 26 February 2019:
Recognises the importance of sunscreens as ONE aspect of photoprotection.
The use of sunscreens has changed: they are applied more frequently and in greater quantities.
The 16 UV filters listed in 1999 are divided into three categories:
- Category I: Two filters: ZnO and TiO2: classified as GRASE = Generally Recognized As Safe and Effective.
- Category II: Two filters: PABA, trolamine salicylate: not GRASE.
- Category III: 12 filters: insufficient safety data to make a positive GRASE determination.
What should we tell our patients?
The harmful effects of sun exposure are well known.
Photoprotection is essential: seek out shade and wear protective clothing, a wide-brimmed hat and sunglasses; apply broad-spectrum SPF>30 sunscreens to exposed areas.
For patients concerned about the environmental effects of oxybenzone or octinoxate: use mineral (inorganic) sunscreens, with rigorous photoprotection and vitamin D supplementation (600 to 800 IU per day).