Акценти от 3-ти ден
Infectious disease, Skin cancer,Spironolactone, Clinical trials on AD and psoriasis
There was peak attendance on Sunday for the AAD Annual Meeting. As always, participants from North and South America made up a large share of the audience, but this event has also attracted countless visitors from other continents, confirming its success as a major international event. San Diego is a cultural melting pot, and the world of dermatology has followed suit!
Our trio of reporting doctors took time out for a selfie before sending us their reports for the day, so you can put faces to names! Dr Jouan chose to dedicate her report to an overall update on the prescription of spironolactone. Professor Caux reported on the session on the latest clinical trials in progress to treat atopic dermatitis and psoriasis. Lastly, Dr Maghia attended a session entitled "Therapeutic Hotline", with a focus on infectious diseases and skin cancer.
Dr. Nicole JOUAN
Dermatologist, Brest, France
Update on spironolactone (sp)
Julie Harper, Birmingham, Alabama, gave an overview of hormonal treatments for acne and hirsutism. In light of the article by a team from Nantes, Adult female acne treated with spironolactone: a retrospective data review of 70 cases, Eur J Dermatol 2017, which considers low-dose spironolactone as an alternative of choice for women in whom isotretinoin has failed for their acne, I selected spironolactone (sp) from the anti-androgens mentioned in this update.
Sp for acne: the efficacy of sp was closely studied in the Japanese study by Sato in 2006. 20 weeks of treatment: 8 weeks at 200mg/day, then 12 weeks at 50mg. Of the 64 women who completed the study, 53% had excellent clinical improvement and 47% had good improvement.
Sp is not approved by the FDA for acne treatment in the US (it also does not have an MA in France).
Sp for hirsutism
It can be a first line of treatment as an anti-androgen, at a dose of 50 to 200mg/day. A meta-analysis by Cochrane in 2015 showed that sp 100mg/day is effective and well tolerated in the treatment of hirsutism, although the level of evidence in the literature is low.
The side effects of sp
They are dose-dependent: diuretic effect, menstrual irregularities, breast sensitivity, fatigue, headaches and dizziness.
Sp and potassium levels: potassium monitoring is not necessary for healthy women taking sp for acne.
But potassium should be monitored if: older age, heart or kidney disease, impaired liver function, high doses of sp (200mg/day). Be careful when combining with certain medications, especially AEC inhibitors, sartans, NSAIDs.
There is an FDA black box warning regarding sp and breast cancer. And yet the Danish registry of 1.3 million sp prescriptions does not show an increase in the risk of breast cancer or gynaecological cancers.
Prescription in practice
25 to 200mg dose; preference for a maximum dose of 100mg.
The more the dose is increased, the more side effects there are.
Concomitant food intake increases bioavailability by almost 100%.
It often takes two months to start seeing an effect.
Combination with oral contraception reduces menstrual irregularities and prevents pregnancy (risk of feminisation of a male foetus).
Dr. Rémi MAGHIA
Dermatologist, Brest, France
What's new in infectious diseases? Professor Ted Rosen, Houston
- The decline in the number of Chikungunya and Zika cases in North America has been confirmed.
- Two new antibiotics approved by the FDA in 2017:
IV and oral delafloxacin (Baxdela®), a fluoroquinolone active against MRSA, MSSA, Strepto pyogenes, E. coli, Pseudomonas aeruginosa, Enterobacter, Klebsiella.
Ozenoxacin (Xepi®) 1% cream, a quinolone developed in response to growing resistance to mupirocin.
- A new shingles vaccine (Shingrix®) approved by the FDA in October 2017 (recombinant varicella zoster virus glycoprotein E with AS01 adjuvant, not live attenuated), of interest for immunocompromised patients.
- Recent flooding following the Harvey, Irma and Maria hurricanes has caused cases of leptospirosis to increase. Doxycycline 200 mg as a single dose or once a week for two to four weeks offers good protection against the disease (Int J Environ Res Public Health. 2017 Jun).
- Doxycycline again: prevention of bacterial infection (gonorrhoea, chlamydia, syphilis) with a 200 mg dose within 24 hours of unprotected sex in patients all receiving antiretroviral pre-exposure prophylaxis (a French study published in Lancet Infect Dis. 2017 Dec).
- HIV: an important message: antiretroviral treatments do not eliminate the virus from sperm as effectively as from blood (presented in 2017 at the annual meeting of the American Urological Association).
What’s new in skin cancer? Professor Rigel, NYC
- The frequency of squamous cell carcinoma is underestimated in the USA: in central and southern regions, it is thought to cause as many deaths as kidney and oropharyngeal cancer and melanoma.
- Melanoma – US 2018
• 91270 new cases of invasive melanoma, 87290 new cases of melanoma in situ. The incidence continues to rise but mortality has been decreasing over the last two years, suggesting good secondary prevention (early diagnosis), but primary prevention is lacking (sun protection messages).
• A meta-analysis showed a link between the use of Viagra and melanoma (Tang et al, JAAD, 2017)
• Ditto for hydrochlorothiazide and squamous cell carcinoma. - SPF100 sun creams provide significantly better protection against sunburn than SPF50 sun creams for all evaluated skin types (Williams et al, JAAD, 2018)
- Topical 5‐FU applied daily for two or four weeks to the face and ears significantly reduces the risk of squamous cell carcinoma but not that of basal cell carcinoma in patients with a history of keratinocyte tumours (Weinstock JAMA Dermatol, 2018, a randomised study of 932 veterans having had at least two carcinomas in the past five years)
- A pilot study on promoting early melanoma diagnosis to raise awareness of skin self-examinations in women undergoing a mammogram (Rzepeckial, International Journal of Women’s Dermatology, 2017)
- Bioimpedance spectroscopy: a new ex vivo technique already used in urology with perioperative treatment to distinguish between tumour tissue and healthy tissue, determining excision margins, especially during Mohs surgery (Svoboda, JAAD)
- An algorithm for melanoma in situ with confocal microscopy (Borsari et al, Br J Dermatol, 2018)
Professor Frédéric CAUX
Dermatologist, Bobigny, France
Clinical trials on AD and psoriasis
In the session devoted to recent news from clinical trials, a festival of information was presented regarding original molecules, for atopic dermatitis (AD) in particular. Dr Emma Guttman (New York, USA) reported on the efficacy of upadacitinib for moderate to severe AD in a phase 2B study. This selective JAK1 inhibitor administered orally once a day was tested at three doses (30, 15 and 7.5 mg/day) versus a placebo. After 16 weeks, there was 74% improvement in skin lesions and 68% improvement in pruritus. EASI-50 and EASI-90 scores were achieved in 83% and 50% of the patients respectively. Side effects such as moderate acne on the torso were observed, as was an increase in CPK in 9% of the patients for the 30 mg/day dose. A phase 3 study has been planned. Another molecule, ASN002, which has a low level of selectivity since it inhibits JAK1, JAK2, JAK3, TYK2 and SYK, was tested in the same population of patients and showed rapid efficacy, from 15 days. EASI-50 and EASI-75 scores were achieved in 100% and 63% of the patients respectively after one month of treatment at the 40 mg/day dose. Pruritus was reduced by 70% for the 80 mg/day dose. A third molecule, baricitinib, which inhibits JAK1 and JAK2, is a medication available in France for the treatment of rheumatoid polyarthritis under the name of Olumiant. It was tested for atopic dermatitis at doses of 4 mg/day and 2 mg/day versus a placebo, in combination with local corticotherapy. This treatment has advantages over local corticotherapy on its own since EASI-50 at 16 weeks was 61% for the 4 mg/day dose while for the placebo, it was 37% (efficacy in the placebo group related to authorised local corticotherapy). The other evaluation criteria (pruritus, sleep) had also improved, with no difference between the two tested doses. The side effects were moderate (headaches, increase in CPK).
In the area of biotherapies, a phase 2a study with ANB020, a biotherapy directed against interleukin-33, was presented. The rationale is that interleukin-33 which is an alarmin (molecule capable of alerting the immune system in the event of tissue or cell damage), is increased in the skin of atopic patients. It is released by keratinocytes after the skin is exposed to an allergen and is capable of inducing the production of interleukins-4, -5 and -13 and mastocyte degranulation. ANB020 was tested in 12 patients with atopic dermatitis as a single 300 mg infusion. Local corticotherapy was authorised as needed. EASI-50 was achieved in 80% of patients at one month and continued for 67% of patients at 3.7 months and for 42% of patients at 4.6 months. The side effects consisted of headaches for 25% of the patients. This was a significant effect after a single infusion of this medication. That is why a phase 2B study has been planned with a larger number of patients (200 to 300). Another biotherapy directed against interleukin-17C, MOR106, was presented. This molecule is capable of reducing cutaneous inflammation in animal models of psoriasis and atopic dermatitis. It is different from other biotherapies such as Cosentyx (secukinumab) and Taltz (ixekizumab) that target interleukin-17A. Interleukin-17C, which is synthesised by keratinocytes, is overexpressed in the skin of patients with atopic dermatitis. This cytokine is capable of amplifying the expression of other inflammatory mediators. MOR106 was administered intravenously and 25 patients received one weekly infusion for one month. The EASI-50 score was achieved in 83% of patients one month after the last infusion for the 10 mg/kg dose, and there was still improvement at four months.
These studies all show the vitality of research in the area of atopic dermatitis. This research has given rise to two new molecules available in the USA: crisaborole, which is a phosphodiesterase 4 inhibitor in topical form for moderate atopic dermatitis, and dupilumab (Dupixent), which inhibits interleukins-4 and -13. Molecules under study include pitrakinra which inhibits interleukins-4 and -13, lebrikizumab and tralokinumab which inhibit interleukin-13 only, and tezepelumab which inhibits the TSLP alarmin. As stated by Professor Alan Irvine from Dublin in his plenary conference, atopic dermatitis represents a market of billions of dollars, which explains why pharmaceutical companies are heavily investing in research. These molecules are also often tested for other allergy manifestations such as asthma and end up benefiting our dermatological patients, especially for severe forms of atopic dermatitis.
In the area of psoriasis, bimekizumab was presented; it is a biotherapy that blocks both interleukin-17A and interleukin-17F. In a phase 2B study including 250 patients with moderate to severe psoriasis, five different doses were compared to a placebo. Efficacy was very good, since for the 320 mg dose, PASI-90 and PASI-100 were achieved by 79% and 55% of the patients in week 12. The side effects were mild with a few cases of candidiasis. Regarding risankizumab which inhibits interleukin-23, two phase 3 studies were presented. The efficacy of this molecule was good, since PASI-90 and PASI-100 were achieved respectively by 75% and 40% of patients after 16 weeks. Lastly, Dr Joel Gelfand (Philadelphia, USA) presented a phase 4 study evaluating the effects of ustekinumab in vascular inflammation. It investigated whether the reduction by biotherapy of skin lesions in widespread forms of psoriasis is capable of reducing vascular inflammation associated with psoriasis. Dr Gelfand had previously undertaken a clinical trial with adalimumab but this biotherapy had not been capable of reducing vascular inflammation evaluated by PET imaging. In the presented study, dealing with 43 patients, two injections of ustekinumab led to a 6% decrease in the aortic vascular inflammation score compared to the placebo group. This preliminary result will need to be confirmed by a second trial, and a study is in progress in which patients will receive ustekinumab for one year.