Акценти от 5-ти ден
Spironolactone, Glycopyrronium tosylate for the treatment of paediatric primary axillary hyperhidrosis, New developments in dermatology, Psoriasis, Hidradenitis suppurativa, Biological agents in HS, Chronic hand eczema
Dr. Rémi Maghia
Dermatologist, Brest, France
Spironolactone: a genuine plea for the treatment of acne
Dr. William James, Dermatologist, United States
The management of moderate to severe acne is changing, due to a need to limit the use of oral antibiotics. Alternative tactics are increasingly being explored.
I saw a different speaker at this AAD Meeting present a strategy for treating acne without antibiotics. At a time when cyproterone acetate is no longer being used for acne vulgaris, public concerns about suicides related to isotretinoin are making this therapy appear suspicious, and combined oral contraceptives have become controversial, many articles are being published about the use of spironolactone for acne, including the publications by Brigitte Dreno's team. Let’s see how this American colleague presented and positioned this medication for us.
Spironolactone reduces testosterone production and acts by competitively inhibiting DHA and testosterone in the skin’s androgen receptors. It is an anti-androgen but has not been approved by the FDA.
It is underused despite recommendations to reduce the use of antibiotics (same high level of antibiotic use for acne between 2005 and 2013). Isotretinoin has remained at the same low level and the use of spironolactone has only slightly increased and is usually reserved for adult women.
There are reasons for this: non-approval by the FDA, an FDA black-box warning, a warning regarding cancer, the issue of potassium, and force of habit.
What about cancer? With studies with X 150 doses in animals, various cancers have been observed. Hence the black-box warning, which is now difficult to withdraw. Two large-scale retrospective studies (involving 2.3 million and 1.29 million women) did not find any association with breast, uterine or ovarian cancer.
Potassium monitoring: a study (JAMA Dermatol 2015) with 967 female patients concluded that K monitoring is not necessary in healthy young women. It is nonetheless important to verify whether the patient has heart or kidney disease or problems with high blood pressure. Certain medications should be verified, including: ACE inhibitors, NSAIDs, Trimethroprim-Sulfamethoxazole, and K and salt supplements.
The AAD guidelines are contradictory: on the one hand, the AAD allows the use of spironolactone in certain selected women, with no need to monitor K levels in plasma, and recognises that studies have proven that there is no association with breast cancer. But unfortunately in another chapter of the document, these guidelines say the opposite.
Efficacy for acne: the experiences of 600 female patients via three studies published in 2017 showed full clearance or marked improvement for the majority of the patients. The most common side effects are menstrual irregularities that can be managed with oral contraception, whose concomitant use improves the results and protects against pregnancy. Regarding pregnancy: theoretical risk of feminisation of a male foetus from six to 11 weeks. This was demonstrated in rats at 5 X the human dose and has never occurred in humans. Regarding breastfeeding: the American Medical Association and WHO consider the use of spirolactone to be compatible with breastfeeding.
The side effects are as follows: diuresis (29%), dizziness, menstrual irregularities (22%), breast tension; low blood pressure is uncommon (5% average decrease in blood pressure in healthy patients).
How should it be prescribed?
At what dose? From 50 to 200mg – the author starts at 100mg. Oral use with food to increase bioavailability. Evaluation after three months. Recommend contraception. If menstrual irregularities or breast tension, add oral conception; an implant is possible.
The author considers it a “superb” acne treatment for all women, not just acne-prone adult women, and an effective hormonal treatment. Here is his protocol:
When taking 100mg in the evening, few side effects – 85% of patients showed improvement and 40% full clearance. If no full clearance, can increase to 150mg if almost cleared or to 200mg if the response is moderate.
Around 81% of patients end up obtaining clearance. Combined oral contraception can be used in association with antibiotics.
For what indications?
Response to antibiotics, but lack of maintenance with topical agents
No clearance with combined oral conception
Relapse after isotretinoin
As first-line treatment for acne-prone women? Yes for the author.
For all women? Yes, according to the author, adult women are not the only ones who respond, and not only those with acne on the lower face or acne affected by menstruation.
Keep in mind that in France, this is still an off-label use. Let's hope that Brigitte Dréno's hospital clinical research programme on spironolactone for this indication will provide support for this attractive therapeutic option.
Glycopyrronium tosylate for the treatment of paediatric primary axillary hyperhidrosis
Prof. Lawrence F. Eichenfield, Dermatologist, United States
This topic was addressed during the last plenary session of “What's New in Dermatology” (paediatric dermatology section), by Pr Eichenfield from San Diego.
He evoked the publication by Hebert et al, Pediatric Dermatology 2019. I thought he supplemented the information I gave you earlier on the issue of hyperhidrosis and psychiatric disorders.
This was a post-hoc analysis involving children aged nine to 16 years who had had primary axillary hyperhidrosis for more than six months, with an ASDD sweating severity score >4, sweat production >50mg/5min for each underarm, and an HDSS hyperhidrosis severity score >3.
They were treated via daily application of the product, an anticholinergic agent, with a towelette for four weeks. Responders were defined as having a four-level decrease in the ASDD score. At four weeks, 60% of the treated patients had reached the objective, vs 13% for the vehicle, which was particularly significant.
Side effects: mostly moderate and transient, seldom leading to cessation of treatment: mydriasis 16%, blurred vision 12%, dry mouth 24%. Some cases of oropharyngeal pain.
The product has been approved for ages nine and up in the USA: it is the first anticholinergic agent indicated as a topical treatment for adults and children aged nine and over.
The 2019 AAD Meeting is now over and I would like to take this opportunity to thank Bioderma/Naos for their remarkable support for this report and say how pleasant and constructive it was to work alongside Lise, Nicole and Géraldine.
Dr. Lise Boussemart
Dermatologist, Rennes, France
New developments in dermatology
Dr. Alan Menter, Dermatologist, United States
Dr. Darrell S. Rigel, Dermatologist, United States
Dr. Kenneth J. Tomecki, Dermatologist, United States
Dr. Kimberly J. Butterwick, Dermatologist, United States
Dr. Lawrence F. Eichenfield, Dermatologist, United States
Dr. Linda F. Stein Gold, Dermatologist, United States
The AAD Meeting is now over and I'm thus sending you my last report.
Today's session was devoted to an overview of new developments in dermatology, and many of the topics had already been covered in the previous days.
There were a few things that seemed important to me including, as many of you already know, the affirmation that hydrochlorothiazide treatment with a cumulative dose > 50000mg is associated with an increased risk of squamous cell carcinomas (skin and lips) and, to a lesser extent, basal cell carcinomas (Perdersen et al., JAAD 2017; Pottegard et al., J Intern Med 2017).
A recently published English study (Pozniak et al., Cancer Research, 2019) showed that in a cohort of 703 melanoma patients, the overall survival rate of smokers was 40% lower than that of non-smokers, in the 10 years following excision of their melanoma. It is therefore important to encourage patients to stop smoking and also give standard photoprotection advice.
Lastly, the first phase-I/II therapeutic trial on skin microbiome transplantation (in particular with the Roseomonas mucosa bacterium) demonstrated efficacy in atopic dermatitis (Myles et al., JCI Insight 2018).
Interestingly, some cases of severe atopic dermatitis and/or psoriasis/pityriasis rubra pilaris (PRP) in childhood are related to dominant heterozygous mutations in the CARD14 gene. “Loss-of-function” CARD14 mutations are responsible for patterns of severe atopic dermatitis (Peled et al., J Allergy Clin Immunol 2019), whereas “gain-of-function” mutations, which overactivate the NF-κB pathway, cause psoriasis/PRP-like patterns. Psoriasiform patterns, which the authors recommend calling “CAPE” (CARD14-associated papulosquamous eruption), often begin before the age of one year, affecting the cheeks, chin and ears, and respond particularly well to ustekinumab (Craiglow et al., JAAD 2018).
That will be all for today. I was delighted to attend the AAD Meeting and share all this news with you day after day.
I sincerely thank my team from Rennes University Hospital for allowing me to take almost a week of leave, Laboratoire Bioderma for entrusting me with this mission, as well as my two kind and dynamic co-reporters Nicole and René. I hope to be in contact with you again soon!
Dr. Nicole Jouan
Dermatologist, Brest, France
- More side effects of TNF inhibitors in women than in men, and confirmation of weight gain with TNF inhibitors
- A “new” topical treatment: halobetasol 0.01% + tazarotene 0.045%: clinical scores improved by at least two points
- Apremilast effective in children aged six to 17 with the same safety profile as for adults
- Apremilast during HIV infection: a second case was described. Undetectable viral load, stable CD4 counts, no opportunistic infection
- Secukinumab for palmoplantar pustular psoriasis not responding to therapy
- JAK inhibitors: BMS-986165 (Tyk2 inhibitor) and baricitinib are being investigated in phase-2 studies
- Mirikizumab and bimekizumab (IL-17A and F inhibitors) are being tested in a phase-3 study; certolizumab pegol (a PEGylated anti-TNF drug already used for rheumatoid polyarthritis)
- A double-blind randomised study demonstrated the efficacy of ixekinumab in genital psoriasis
- More clearance for patients with brodalumab than with ustekinumab (the speaker “disproved” the warning regarding depression with brodalumab: to be continued).
In spite of everything, the residual expression of psoriasis genes with treatment (at least 75%), referred to as “biological scarring”, explains relapse with discontinuation of treatment. No treatments to date resolve 100% of molecular anomalies in psoriasis. But there are differences between the available treatments: might it soon be possible, instead of evaluating clinical scores, to consider the resolution of molecular anomalies to classify treatments?
Prof. Gregor B.E. Jemec, Dermatologist, Denmark
The skin flora is significantly modified in HS, with lots of anaerobic bacteria, streptococci (milleri) and staphylococci (aureus and lugdunensis), which form biofilms and develop resistance. Pr Jemec considers that antibiotics for HS are both anti-inflammatory and antibacterial. Strategies are rapidly changing since the bacteria in HS are highly resistant to clindamycin.
Biological agents in HS
A large set of pathophysiological arguments support their use in HS, especially with regard to comorbidity (IBD, pyoderma gangrenosum, axial rheumatism, etc.).
Studies are in progress with an IL-17 inhibitor (secukinumab), an IL-1a inhibitor, an anti-CD40 monoclonal antibody, a JAK inhibitor, and guselkumab (an IL-23 inhibitor).
Apremilast 30mg twice a day showed a good level of efficacy in a randomised placebo-controlled study involving 20 patients with moderate HS.
Chronic hand eczema
It is a fairly discouraging and polymorphic disease: Atopy? Irritation? Dyshidrosis? Contact eczema? Psoriasis? From a therapeutic standpoint: calcineurin inhibitors, crisaborole, local corticosteroid therapy, UV therapy, acitretin, methotrexate, alitretinoin (caution for women of childbearing age); a recent study showed the efficacy of excimer lasers (30 patients, two sessions per week), no controlled studies for apremilast, dupilumab works much better than TNF inhibitors and ustekinumab but there are no controlled studies for this indication, Th2 inhibitors? a new PDE4 inhibitor such as difamilast? JAK inhibitors?
Open your mouth!
Black hairy tongue: brush +++ and possibly with hydrogen peroxide 1% or 2% + quit smoking + high-fibre diet
Burning mouth syndrome: A list of tests to not miss secondary burning mouth syndrome: CBC, platelets, iron, ferritin, vitamins B1, B2, B6, B12, D3 and folates, zinc, TSH, glucose and HbA1c.
From a therapeutic standpoint: nothing new, tricyclic antidepressants in the evening at bedtime, gradually increasing (10 mg for four weeks, then 20, etc.).