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New therapies for acne, Paediatric dermatology, JAK inhibitors

Dr. Lise Boussemart

Dermatologist, Rennes, France

Paediatric dermatology

Dr. Anita N. Haggstrom, Dermatologist, United States
Dr. Price Harper, Dermatologist, United States
Dr. Tollefson Megha, Dermatologist, United States
Dr. James R. Treat, Dermatologist, United States
Dr. Erin Mathes, Dermatologist, United States
Dr. Barbara Reichert, Geologist, United States

Dear all,
I am delighted that Laboratoire Bioderma has given me the opportunity to share my first AAD Meeting with you. I will be reporting highlights from each day as part of a team, along with Dr Nicole Jouan and Rémi Maghia from Brest. This meeting is being held at the enormous Washington Convention Center, where dozens of sessions are taking place in parallel. We have thus had a wide choice of topics, and today I chose to attend the session on “paediatric dermatology”.

The first speaker, Dr Haggstrom, opened the session by addressing the topic of common infantile hemangiomas. Among other things, she discussed which ones should be treated with propranolol and when. She reiterated that they do not all need to be treated, especially for reasons of cost but also because of the side effects, in particular hypoglycaemia (which is neither dose- nor age-dependent), sleep disturbances and, in the long term, neuro-cognitive consequences that are subject to debate (memory problems?) and for which we still have little hindsight. She insisted on the indications requiring treatment as early as possible, such as ulcerated forms, periocular forms, a “beard” distribution (since 60% have an associated subglottic infantile hemangioma, especially when there is a telangiectatic aspect in beard hemangiomas), syndromic forms (PHACE, LUMBAR, miliary hemangiomatosis) and forms that are potentially “disfiguring”. An irregular surface texture in hemangiomas is an important parameter to consider, since it causes more cosmetic sequelae after involution. When there is doubt, Dr Haggstrom recommends using the score she published in Archives of Dermatology in 2012.

Twenty-five percent of hemangiomas treated with propranolol resume their growth phase with cessation of treatment, especially when it is discontinued before nine to 12 months, whether it affects the head and neck or the lower face (beard segment S3 in particular), especially in girls.

Dr Harper Price then spoke of giant congenital naevi, of which 77% harbour NRAS mutations and 8% BRAF (V600E) mutations. Those with BRAF mutations appear to be more nodular and less hairy than those with NRAS mutations. The risk of carcinogenesis is low (1-2%) and requires visual examination as well as palpation of the congenital naevus, whose transformation often begins deep down (subcutaneous nodule). Note that congenital naevi of the scalp often lighten considerably with age, reducing the need for cosmetic excision.

The third speaker was Dr Megha Tollefson, who discussed morphea plaques in children, which are often linear. Facial morphea “en coup de sabre” is sometimes (13% of cases) associated with brain lesions non-proportional to skin involvement: warning signs such as epilepsy or chronic headaches may be due to MRI-visible cerebral atrophy or T2 signal loss.

For Dr Tollefson, any linear morphea (on the face or a limb) should be treated with methotrexate 0.3 to 1mg/kg/week, orally or subcutaneously, +/- 1mg/kg/day of corticosteroids.

Systemic treatment, effective in 75% of cases, should be continued for at least two years (methotrexate), obviously with suitable contraception for young girls.

For the treatment of plaque morphea, Dr Tollefson recommends topical corticosteroids (clobetasol twice a day), tacrolimus or phototherapy. In the event of non-inflammatory post-treatment residual scleroderma, imiquimod can be proposed.

Atopic dermatitis was also reviewed, with emphasis on its natural history: genetic predisposition with impaired barrier function, colonisation by staphylococcus aureus, passage of allergens, and shift from a TH1 to a TH2 response.

In a family predisposed to atopy, thoroughly moisturising a newborn's skin reduces the risk of atopic dermatitis by 50% at the age of six months. According to a “PASTURE” group study, prenatal maternal exposure to a cat or dog as well as the consumption of yoghurt before the age of 12 months reduce the risk of developing atopic dermatitis (Roduit et al., JAMA Pediatrics, 2017).

From a therapeutic standpoint, it seems common in the United States to propose daily diluted bleach baths for atopic patients (1/2 cup of pure bleach diluted in bath water, no need to add soap). The speaker affirmed that these baths, combined with successive applications of topical corticosteroids followed by vaseline, with the wearing of wet pyjamas at night, effectively improve the skin of her young patients. To improve compliance, she systematically performs a bacteriological culture and then calls the parents back 48 hours later, to inform them of the results (there is staphylococcus aureus!) and ask them about the bleach baths. But, while remaining persuaded of the benefits of these baths, the speaker recognised that their use is currently controversial.

In the event of failure, however, she uses off-label dupilumab for children, with one injection every two weeks, at a dose of 300mg for children over 60kg, 150-200mg for those with a weight of 20-60kg, and 4-6mg/kg every two weeks for those under 20kg. But clinical trials are in progress (e.g. the Regeneron AD1539 trial, for children between the ages of six months and six years with severe atopic dermatitis.

Dr James Treat spoke of new forms of contact dermatitis.

He affirmed that contact eczema should be evoked when eczema does not improve with topical corticosteroids. He warned about allergy to methylchloroisothiazolinone, which is found in slime, a stretchy play material that is all the rage among children aged three to 11.

Another important form of contact dermatitis is toilet-seat contact dermatitis, caused by the polypropylene or polyurethane contained in toilet seats or by the use of toilet disinfecting wipes. The “contact-toilet” factor should be evoked when eczema (or irritant dermatitis) is predominant on the sides of the buttocks and posterior thighs. A variant is car-seat eczema, occurring mainly in the summer, on the backs of the legs and elbows, when they are in direct contact with the seat.

He also warned about burns self-induced by the simultaneous application of salt and ice on the skin; this “salt and ice challenge” is a new craze among adolescents.

The next speaker addressed the issue of dermatitis of the scalp in African Americans.

She insisted on the therapeutic alliance, which is based on asking patients with dark phototypes the right questions. For example, it is ridiculous to ask whether hair is washed every day: a dermatologist should know that people with frizzy hair do not wash their hair every day, since this is a procedure that can take three hours, with multiple processing, washing, detangling and styling steps. If you ask the question “do you wash your hair every week or every other week?” you will immediately appear more credible.

In the event of tinea capitis, it is also necessary to wash barrettes and other hair accessories, with soap and hot water. If frizzy hair is “not growing”, it is highly likely that this is due to breakage at the distal end rather than to a problem of proximal growth, even though frizzy hair does grow more slowly than straight hair (0.259mm/day vs 0.33mg/day, respectively). To avoid breakage, we should suggest brushing hair starting at the distal end instead of the proximal end.

Dr Erin Mathes discussed viral skin diseases in children.

She started by addressing measles, which is making a comeback, in a context of declining vaccination coverage. It appears that parents who put their children in private schools, or in alternative schools (Montessori), tend to vaccinate their children less often than parents of children in public schools.

As for chickenpox, most Americans are vaccinated at the ages of 12-15 months and then 4-5 years. Following chickenpox vaccination, some children develop shingles, usually on the same side as the vaccine.

Certain highly visible granulomatous dermatoses of the face in children can be caused by the rubella vaccine (live vaccine) in immunocompromised individuals.

Lastly, coxsackievirus A6, identifiable by PCR, causes more severe hand, foot and mouth disease than the standard form, with extension of the vesicles around the mouth and widespread eczematous patches. Coxsackie outbreaks are increasing with global warming since the spread of the virus is highly sensitive to temperature and humidity increases (Coates SJ, Int Journal Dermatology 2018).

Today's last topic of interest: the role of diet in skin diseases.

Barbara Reichert recommended the use of probiotics (as varied as possible) when pregnant or breastfeeding, to reduce the risk of atopic dermatitis without posing risks to the baby. It appears that 30% of children with confirmed atopic dermatitis are also allergic to a food, usually eggs, cow's milk, soya or wheat.

There are also pro-acne foods, in particular skimmed milk, although the pathophysiology is poorly understood. One assumption is that people tend to drink more skimmed milk than with whole milk, resulting in greater activation of the mTor pathway as well as the production of sebum, IGF1 and androgens. Acne can also be reduced by eating a diet with a low glycaemic load (Kwon et al., Acta Derm Venereol, 2012, Smith et al., Am J Clin Nutr, 2007). The glycaemic load takes into account both the glycaemic index of a food and its quantity.

And that’s it for this first busy day of the AAD Meeting, dedicated to paediatric dermatology! I hope you enjoyed this information and I look forward to being in contact with you tomorrow.

Dr. Nicole Jouan

Dermatologist, Brest, France

The future gods of dermatology: JAK inhibitors

Dr. Brett Andrew King, Dermatologist, United States

Within the past few years, the therapies at our disposal as dermatologists have shifted from compounds with broad effects (prednisolone, methotrexate, azathioprine, mycophenolate mofetil, ciclosporin) to more targeted therapies (TNF, IL-12/23, IL-17, IL-23, IL-4/3 and now JAK inhibitors). This is something we will have to get used to. The JAK/STAT (Janus kinase/Signal transducer and activator of transcription) system is an intracellular signalling system. More than 50 cytokines use this pathway (IFN-γ, IFN-α, IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, IL-5, IL-6, IL-12, IL-13 and IL-23) that involves the JAK1, 2, 3 and Tyrosine kinase 2 (Tyk2) kinase-enzymes, which work in pairs, hence their name “Janus kinase”, the two-headed Greek god.

These JAKs bind to transmembrane receptors. Once a cytokine is bound to its receptor, the JAK will be activated, leading to the activation of a STAT transcription factor that will activate, in the cell nucleus, genes involved in cytokine production. JAK blockage thus results in blockage of the inflammatory cascade.

The JAK inhibitors currently used for therapeutic purposes are as follows: tofacitinib for rheumatoid polyarthritis, psoriatic arthritis and ulcerative colitis, ruxolitinib for myelofibrosis and polycythemia vera, and baricitinib for rheumatoid polyarthritis.

They have multiple side effects: infections that vary in severity, rhino-pharyngitis, pneumonia, Herpes zoster infection, opportunistic infections, tuberculosis. Nausea, headaches, dose-dependent arterial hypertension, cytopenia and elevated cholesterol and transaminase levels are also observed and require monitoring for solid tumours and lymphoma.

Indications being developed in dermatology:

Alopecia areata: activation of the JAK pathway is responsible for the induction of alopecia areata (production of interferon-γ and IL-15, activating cytotoxic CD8 T cells). The first observation of efficacy with tofacitinib in alopecia areata dates back to 2014, and involved a patient presenting with both alopecia areata and psoriasis, both of which considerably improved. Moreover, many trials are being undertaken in adults, not only with tofacitinib at the dose of 5 mg twice daily, but also with ruxolitinib 20 mg twice daily. Tofacitinib has also been tested in adolescents (aged 12 to 17), in particular by Brittany Craiglow’s team at Yale, with positive results. To minimise the side effects, topical forms are being developed: ruxolitinib 0.6% cream, applied twice a day, with very good results for eyebrows but little effect on the scalp. It seems that the liposomal form of tofacitinib achieves better results than the traditional cream, but the overall impression is unfortunately quite disappointing with discontinued trials and unpublished results.

Vitiligo: CD8+ T cells and their CXCR3 receptor, interferon-γ, and CXCL9 and 10 cytokines are highly involved in the pathogenesis of vitiligo. Therefore, the inhibition of IFN-γ or its downstream effectors such as JAKs would be worth exploring. The first study with tofacitinib was that by Liu, who in 2017 published a retrospective case series of 10 patients treated for at least three months with a dose of 5 or 10 mg once or twice daily. Repigmentation was promoted by concomitant exposure to sunlight or narrow-band UVB therapy. Rothstein published a pilot study in JAAD in 2017: 11 patients (average age of 52, 8.45 years since disease onset on average) were treated with topical ruxolitinib 1.5% cream for 20 weeks. All of the patients demonstrated a statistically significant average improvement in vitiligo. Three clinical trials are in progress. The first two, undertaken by Incyte and Aclaris, involve topical JAK inhibitors. The third, carried out by Pfizer, is a phase-2 trial currently under way with an oral compound.

Psoriasis: the challenge is greater for these new compounds since they are competing with numerous biological agents with increasing efficacy. Keep in mind that despite positive results vs etanercept, the FDA did not approve tofacitinib for psoriasis.

BMS-986165 is a Tyk2 inhibitor currently being investigated in a phase-3 trial vs apremilast 30 mg and a placebo (POETYK-PSO-1 and -2).

No trials are in progress for baricitinib.

The trial with abrocitinib was interrupted and topical tofacitinib was not more effective than the placebo at week 12.

Atopic dermatitis: the challenge with atopic dermatitis is to find new oral treatments (without dupilumab-associated conjunctivitis) or non-steroidal local treatments or treatments that do not burn after application like tacrolimus:

A phase-2 trial is currently being undertaken on topical delgocitinib in adults (Leo Pharma), while topical ruxolitinib cream rapidly reduces pruritus. A phase-2 trial with baricitinib was published in JAAD in February 2018 (E Guttman-Yassky). Almost 70% of patients achieve EASI-50 by week 16. Phase-2b trials are currently being undertaken with the JAK-1 inhibitors abrocitinib and upacitinib.

To conclude, JAK inhibitors have been successfully administered for resistant forms of lupus erythematosus, sarcoidosis and generalised granuloma annulare, which are diseases in which the JAK/STAT pathway is activated. Histological examination has shown a reduction in granulomas and improvement not only in the skin lesions but also in the visceral manifestations of sarcoidosis.

Dr. Rémi Maghia

Dermatologist, Brest, France

New therapies for acne

Dr. James Del Rosso, Dermatologist, United States
Dr. Linda Stein Gold, Dermatologist, United States

Topical clascoterone, 1% cream

The first topical androgen receptor (AR) antagonist with anti-inflammatory properties. It has been assessed in acne vulgaris from the age of nine years.

It targets ARs in sebocytes and hair follicles. It inhibits DHT, sebum lipid production and the expression of cytokines such as IL-1B, IL-6 and IL-8.

In phase-II trials, it led to a significant improvement in IGA scores and a reduction in the total number of lesions.

It was clinically superior to and better tolerated than topical tretinoin in a phase-IIa trial.

Very good safety profile comparable to that of the vehicle, no systemic effects.

Two phase-III trials in 2018 with IGA success rates of 20.4% and 22.2% vs 7.3% and 5% for the vehicle.

Topical minocycline, 4% foam

The advantages would be to offer therapeutic benefits similar to those achieved with the oral route, avoid systemic antibiotic selection pressure with the development of bacterial resistance, and reduce local and systemic side effects. Topical minocycline 4% foam, applied once a day for 52 weeks, showed significant efficacy in terms of clear to almost clear IGA scores (two studies, 37.7% and 50.3% obtained IGA 0/1 after 52 weeks) and led to a reduction in inflammatory lesions and comedones. Minocycline assays in plasma indicated negligible systemic exposure.
Minocycline, 1% biphasic gel

Phase-II study: after four weeks, >90% reduction in P acnes, 4.3% reduction in inflammatory lesions after four weeks and 58.5% reduction after 12 weeks; no significant systemic exposure to minocycline.

Topical trifarotene, 50ug/g cream once daily

Trifarotene is a topical selective RAR gamma retinoid. Two phase-III studies on moderate acne of the face and torso: after 12 weeks, highly significant efficacy (p<0.001) against inflammatory and non-inflammatory lesions, side effects mainly related to local tolerance occurring early, less common on the torso.

Topical cannabidiol

Demonstrated effects in acne: it reduces sebocyte proliferation; it has antimicrobial action and anti-inflammatory action on sebocytes.

Regarding topical agents, there is also topical nitric oxide, 0.4% gel.

Oral sarecycline, 1.5mg/kg/day, once daily

Historically, it was the first antibiotic specifically developed for acne. The prescribed dose is based on body weight.

Sarecycline has a narrow spectrum of activity and strong anti-inflammatory properties.

Two phase-III trials: after 12 weeks, significant reduction in inflammatory lesions, significant efficacy in terms of IGA scores, whether for acne of the face or torso.