Акценти от 4-5 дни
Paediatric psoriasis,Vitiligo, Acne,Rosacea, Alopecia areata
The sun was back out in San Diego on Monday and the meeting continued at the San Diego Convention Center amidst a very Californian work ambiance. Don't be fooled by appearances: the atmosphere may be ultra-cool, but work on the West Coast is intensive!
On Monday, Dr Maghia attended a session run by Amy Palmer from Chicago dedicated to an update on systemic treatments and emerging therapies for paediatric psoriasis. On Tuesday, he chose to focus on treatments for alopecia areata. Dr Jouan attended a therapeutic hotline, devoted this time to vitiligo and new breakthroughs in acne and rosacea. For the last day, key moments in therapy from the year were reviewed.
Dr. Nicole JOUAN
Dermatologist, Brest, France
Therapeutic hotline session
What's new in vitiligo?
- A pilot study with good results with a 311nm titanium sapphire picosecond laser (Lee, JAMA dermatol 2017).
- Home UVs are as effective as narrowband UVB therapy at the dermatologist's three times a week.
- Microneedling with triamcinolone combined with narrowband UVB therapy in 60 patients with good benefits (JAAD 2017).
- Efficacy of methotrexate 12.5 to 25 mg per week in a small-scale open-label study (J Drug Dermatol 2017).
- Dimethyl fumarate (Tecfidera*): an antioxidant used for multiple sclerosis, promising for vitiligo? An in vitro study shows it reduces depigmentation induced by monobenzone (Exp Dermatol. 2017).
- Should vitamin D be measured? Should patients be supplemented? Several studies suggest it (J Dermatol. 2018), but they need to be confirmed.
- Two studies on bimatoprost solution 0.03%: eight cases of facial vitiligo (four excellent results, two moderate, two nil); another study combining it with UVB therapy (J Eur Acad Dermatol Venereol. 2018 and J Cosmet Dermatol. 2017).
- More and more cases published on the efficacy of JAK inhibitors, especially in facial vitiligo: tofacitinib, topical ruxolitinib (Jakafi®) 1.5% cream on its own (Rothstein JAAD 2017) or in combination with narrowband UVB in a study including 12 patients (JAMA Dermatol, Kim 2018).
What's new in acne and rosacea?
- The combination of topical ivermectin + brimonidine seems more effective than each product separately (90 patients, double-blind trial), both against erythrosis and inflammatory lesions.
- The relevance of biological monitoring for transaminases during isotretinoin treatment is still called into question: GGT, specific to the liver, is considered more relevant (study already shown last year, retrospective study, 246 cases). Regarding CPK: a non-fatal case of rhabdomyolysis in a young 17-year-old athlete taking 20 mg isotretinoin daily for two months sparks the question: what should be recommended in terms of sport activity? How should CPK be monitored? The speaker suggests measuring CPK in young athletes at the beginning of treatment at least four days after a workout session to have a baseline level (a marathon is likely to increase it 20-fold, rhabdomyolysis with renal risk appears for levels from 10 to 25000). She recommends limiting intensive exercise and drinking a lot of water during sport.
- Olumacostat glasaretil 7.5% gel in a controlled study including 108 patients (Bissonnette JAAD 2017): significant decrease in inflammatory and non-inflammatory lesions at 12 weeks.
Highlights from JAAD: a medley
Professor Thiers, South Carolina
- Still more molecules for psoriasis: new IL-23 inhibitors following from guselkumab (Tremfya*): risankinumab, tildrakizumab, mirikizumab. These new molecules, with very impressive efficacy in trials, risk not keeping their promises in real life, given as second- or third-line therapy to patients with particularly resistant psoriasis.
- Infectious complications of biotherapies: an alert involving bacterial meningitis, to be confirmed.
- New molecules for atopic dermatitis: After dupilumab (monoclonal antibody against IL-4/IL-13), in the spotlight of course, nemolizumab, an IL-23 inhibitor that relieves pruritus without clearing eczema, non-steroidal inhibitors of phosphodiesterase 4: crisaborole (Eucrisa*, Pfizer) continues to be studied in a phase 3 trial, and OPA-15406 has emerged for the future delight of corticophobics and their dermatologists.
- Treatment of pemphigus, bullous pemphigoid and resistant mucous membrane pemphigoid with rituximab +/- Immunoglobulins IV (and its controversies pointed out by Professor Caux, Ahmed 2016).
- A small-scale open-label study on the efficacy of adalimumab in seven patients with granuloma annulare: adalimumab could be an option for generalised granuloma annulare (Min, 2016).
- Topical timolol: after a retrospective study of 30 children with ulcerated hemangiomas (Boos), observations of the healing of hydroxyurea-induced leg ulcers by an occluded timolol 0.5% gel; an observation of the control of an African endemic Kaposi's sarcoma of the penis (posters). Timolol continues its breakthrough for healing and angiomas, but would undoubtedly benefit from controlled prospective studies.
- Recommendations regarding the treatment of hospitalised patients with shingles: strict isolation to prevent the contamination of fragile patients (Ahronwitz JAAD 2018).
- Identifying patients with a high risk of melanoma metastasis through a genetic test based on the analysis of 31 genes in the tumour (Ferris) would help enhance their surveillance and improve their survival.
And for those who want to develop further knowledge of JAK inhibitors and their uses, two impressive reviews:
- JAK inhibitors in dermatology: the promises of a new drug class (Damsky JAAD 2017;76:736-44),
- JAK inhibitors in dermatology: a systematic review (Shreberk-Hassidem JAAD 2017;76:745-53).
Dr. Rémi MAGHIA
Dermatologist, Brest, France
Update on systemic treatments and emerging therapies for paediatric psoriasis
Amy Palmer, Chicago
What are the possible systemic treatments for plaque psoriasis in children?
Phototherapy is possible but compliance is difficult.
Methotrexate, retinoids, ciclosporin, fumaric acid (not available in the USA)
Biotherapies include: etanercept and ustekinumab, which are approved by the FDA; adalimumab, which has not yet been approved.
As first-line therapy for pustular psoriasis in children, also often for plaque and palmoplantar psoriasis. Various efficacy studies have found from 33% to 44% for PASI-75 and 65% for PASI-50.
The dose ranges from 0.2 to 0.5 mg/kg/day. Reduce it to maintain at the lowest effective dosage. Non-immunosuppressive treatment. No loss of efficacy if resumed.
Good response for plaque, pustular and erythrodermic psoriasis. Dose: 3 to 5 mg/kg/day. PASI-75 achieved by 40% to 50% of children.
Risk of immunosuppression, kidney and liver toxicity, high blood pressure.
Methotrexate has been very commonly used in children for decades.
Dose: from 0.2 to 0.5 mg/kg/week. PASI-75 for 34% (J Dermatol 2016).
Update vaccinations, basic and annual tuberculin tests.
Patience is required to have the best effect. Van Geel study in 2015: 40% PASI-50 achievement at 12 weeks, 40% and 80% PASI-75 and PASI-50 achievement at 36 weeks.
Dose: 0.8 mg/kg/week. 65% PASI-75; approved in 2016 for children aged 6 and over.
Papp study, Lancet 2017 vs methotrexate. MA pending for children. Standard dose of 0.8 mg/kg/2 weeks.
Advice for using TNF inhibitors
Give higher doses for older and obese children. Efficacy can decrease over the years. TNF inhibitors do not prevent psoriatic arthritis. The most common side effects are injection site reactions. There may be more infections than with methotrexate. No lymphomas reported.
Ustekinumab: CADMUS study in 110 adolescents
Primary objective cleared (0) or minimal (1) PGA at 12 weeks. Achieved for 69% of the subjects at the standard dose, 67% of the subjects at the half-standard dose.
Secondary objective: PASI-75 80% and PASI-90 61% at the standard dose and very close at the half-standard dose.
Ustekinumab seems to be a treatment of choice for the CARD14 mutation (plaque, erythrodermic and pustular psoriasis and PRP).
Comparison of various systemic treatments
Advantage of biotherapies: adaptable doses, few laboratory tests, few side effects. Reservations: possible anti-medication antibodies, no stoppage, unknown long-term risks.
Cost: MTX < acitretin < ciclosporin <<< biotherapies.
US trial in progress for apremilast in children. Attempt to obtain an MA for adalimumab in children.
US trial on ustekinumab for children under the age of 12 years.
US trial on ixekizumab for children and adolescents.
Trials are planned for other Th17/IL-23 inhibitors.
Would IL-22 be a better target for children than for adults?
Immunological therapies for alopecia areata
Jerry Shapiro, New York, presented various breakthroughs in the treatment of alopecia areata. I was surprised to see that in his daily practice, although not as first-line therapy of course, he uses some of these molecules, which have no FDA approval for this indication and which are not without side effects. They are also very expensive. JAK inhibitors are now part of his treatment algorithm for alopecia areata.
Janus Kinase inhibitors
JAK inhibitors have been approved by the FDA for other diseases (tofacitinib for rheumatoid polyarthritis, ruxolitinib for myelofibrosis). They represent progress in the initiation and maintenance of alopecia areata treatment. However, as always with alopecia areata, the effects are purely suspensive.
Oral JAK inhibitors
In open-label studies, patients with forms resisting standard treatments, or with extensive disease, or alopecia universalis, or total alopecia areata, responded with total regrowth after ruxolitinib twice daily within three to five months.
To date, three JAK inhibitors have proven effective against alopecia areata: ruxolitinib, tofacitinib and baricitinib. Ruxolitinib and tofacitinib block multiple JAKs, indicating immunosuppression. Baricitinib, a JAK-1 and -2 inhibitor, probably has a better tolerance profile; it has not yet been approved by the FDA.
Tofacitinib has also been capable of treating nail dystrophy associated with alopecia areata.
Topical JAK inhibitors
Tofacitinib 2% ointment and ruxolitinib 0.6% cream have shown very significant regrowth effects.
Clinical trials on JAK inhibitors for alopecia areata:
• Incyte: ruxolinitib, JAK 1 / 2 inhibitor, topical
• Leo Pharma: pan-JAK inhibitor, topical
• Concert Pharma: ruxolitinib, oral
• Aclaris: topical and oral
• Pfizer: oral (covalent JAK inhibitor) and JAKA/TYK2 inhibitor
Phosphodiesterase-4 (PDE4) inhibition: Apremilast*
PDE4 is significantly increased in skin lesions associated with alopecia areata in humans, representing a therapeutic target. Apremilast is a PDE4 inhibitor that has been shown to be capable of preventing the development of alopecia areata on human scalp transplants in mice. This molecule is currently being investigated in a clinical trial in humans.
In the scalp of alopecia areata patients, IL-23 sub-units p19 and p40 are significantly up-regulated. The Th2 and Th17 immunological pathways may be involved in the development of alopecia areata. In a small series of cases, patients responded well to ustekinumab, including a patient with alopecia universalis.
Two key Th2 cytokines, IL-13 and IL-4, have been associated with alopecia areata, hence the possibility of beneficial action with dupilumab. Alopecia areata shares phenotypic similarities with atopic dermatitis, such as pruritus, increased IgE, filaggrin mutations, and molecular activation that includes Th2, IL-23, and Th1 activation.