Акценти от 4-ти ден
14 June 2019
Hidradenitis suppurativa, Treatment of itching, Vitiligo and Paediatric dermatology
Dr. Nicole JOUAN
Dr. John INGRAM (Dermatologist, United Kingdom)
Dr. Gregor JEMEC (Dermatologist, Denmark)
Dr. Stanislav TOLKACHJOV (Dermatologist, United States)
Dr. Brian KIRBY (Dermatologist, Ireland)
Dr. Hessel VAN DER ZEE (Dermatologist, Netherlands)
Dr. Dunja VEKIC (Dermatologist, Austria)
Comorbidities in hidradenitis suppurativa (HS)
Based on a series of 23,352 cases of HS contained in English registers, it is once again confirmed that the association with pilonidal sinus, acne (x3 with respect to the control population), Crohn’s disease (x3 versus control population) and depression is statistically significant. Regarding the pilonidal sinus, given its frequent association with the HS, the message must be passed on to surgeons.
Is psoriasis an independent risk factor for cardiovascular disease? The same question arises with HS where type 2 diabetes is 3 times more common than in the general population, and hyperglycaemia and hypertension are very common. Do not forget to evaluate it in patients with HS.
Auto-inflammatory syndromes associated with HS: PAPA, PASH, PAPASH, PASS, PsAPASH
It should be remembered that in this context we are dealing with severe HS in young patients and that “traditional” treatments work in only a little percentage of cases (antibiotics, dapsone, etc.) requiring the use of high-dose biological treatments, which are not “magical” either: anti-TNF (infliximab) at doses higher than 5 mg/kg, with or without methotrexate, anti-IL1, such as anakinra, especially when joint symptoms are present. Anti-IL17 is probably a way forward.
Nothing particularly new: recurrence after surgery is approximately 50%, on the periphery of the operated area, especially in the perineum, and especially after an intervention under local anaesthesia. Weight loss, cessation of tobacco and alcohol are recommended without convincing statistical data on the impact of these measures.
Local anaesthetic, Liposomal bupivacaine or Exparel* allows to control the pain until 72 hours after the operation.
Do not forget to perform anatomopathological examination due to the risk of squamous cell carcinoma.
Trials have been on the rise since an improvement in secukinumab (anti-IL17) in a patient with both psoriasis and HS: guselkumab (IL23 P18), risankizumab (Il23), bermekimab (Il1), brodalumab (Il17)... Rituximab (anti-CD20 antibody used in pemphigus) may also represent a promising pathway: a case of dramatic regression in a kidney transplant patient for carpal-tarsal osteolysis with nephropathy.
HS is not an infectious disease, but bacteria activate the inflammasome and its inflammatory cascade. The microbiome changes according to the stage, consisting mainly of negative coagulase-negative staphylococcus aureus, corynebacteria (but studies are unreliable), and tends to organise into biofilms in subcutaneous sinuses. The antibiotic resistance of the corresponding germs is widespread: 64% of strains for tetracyclines, 58% for macrolides, 54% for Bactrim*, 51% for clindamycin, 75% for beta-lactam antibiotics. Randomized studies are needed to evaluate the proposed combinations of antibiotics: rifampicin + clindamycin, ofloxacin + clindamycin, moxifloxacin + metronidazole + rifampicin, etc. as well as to give antibiotics their true place in therapeutic strategy.
It is increasingly recognized that the NdYag laser improves HS (depilatory and anti-inflammatory effect). Controlled trials are needed.
Dr. Rémi MAGHIA
New developments in the treatment of itching
Prof. Thomas LUGER (Dermatologue, Germany)
Treatments are usually classified into peripheral and central according to their therapeutic target.
Peripheral therapies include: antihistamines, calcineurin inhibitors (ciclosporin A, tacrolimus, pimecrolimus), TRPV1 agonists (capsaicin), NK1R antagonists (aprepitant), small molecules (JAK inhibitors) , PDE4 inhibitors), and biological treatments (dupilumab, nemolizumab, tralokizumab).
Central therapies include: selective serotonin reuptake inhibitors (paroxetine), μ-opioid receptor antagonists (Naltrexone), κ-opioid receptor agonists (nalfurafine), anticonvulsants (gabapentin, pregabalin).
New approaches to the treatment of pruritus are essentially anti-inflammatory: biological and small molecule therapy.
Biological treatments: Dupilumab, Nemolizumab, Tralokinumab, Lebrikizumab, an anti-IL7C under review, an anti-IL33 under review.
Small molecule treatments: JAK inhibitors, PDE4 inhibitors, H4R antagonists, tapinarof (AhR agonist).
Dupilumab targets IL4 and IL13
It significantly improves pruritus and eczema in patients with moderate to severe atopic dermatitis (AD). Doses of 2 and 4 mg/kg showed similar efficacy. Side effects are usually mild (conjunctivitis and injection site reactions). Further developments are to be expected for use in children and adolescents.
Nemolizumab targets IL31
Evaluated at 64 weeks in patients with moderate to severe AD, a significant reduction in pruritus and eczema was achieved. No security alert identified after long-term use. Future developments will evaluate the usefulness of nemolizumab for patients with AD + nodular prurigo.
Tralokinumab targets IL13
Used together with topical corticosteroids, it has demonstrated significant improvements in case reports. The tolerance and safety profile is acceptable. Greater therapeutic responses were obtained by patients with increased IL13 activity, suggesting a key role for IL13 in the pathophysiology of AD.
JAK inhibitors (per os)
Baricitinib combined with topical corticosteroids showed a rapid improvement in eczema and pruritus, with a significant improvement in symptoms in the first week. The 4 mg dose showed a more pronounced early efficacy. Baricitinib has an acceptable safety profile in adults with moderate to severe AD. Phase 3 studies are underway.
Topical anti-inflammatory drugs
New developments for:
- PDE4 inhibitors: Crisaborole and two molecules currently tested.
- JAK inhibitors: tofacitinib, ruxolitinib, JTE-052.
- AhR agonists: tapinarof.
Crisaborole is the first commercially available PDE4 inhibitor with a boron structure that increases penetration and affinity of the PDE4 site. Crisaborole Ointment 2% significantly and rapidly improves the eczema and pruritus of patients with AD. The most common side effects are injection site pain and upper respiratory tract infections. No severe side effects reported.
Note on air pollution and AD: activation of the aryl hydrocarbon receptor (AhR) via air pollutants induces the expression of artemin, alloknesis, epidermal hyper-innervation and inflammation.
Tapinarof directly activates the AhR of keratinocytes, and increases the expression of the protein barrier.
The repeated administration of tapinarof cream in subjects with moderate to severe AD allows the improvement of all efficacy scores. However, conclusions regarding its efficacy are limited due to the open studies and the small number of patients treated. Additional investigations are in progress.
In addition to the anti-inflammatory approach, there is an anti-pruriceptive approach:
- Κ-agonists in combination with μ-antagonists.
- NK1R antagonists.
- Topical treatments: TRPM8 agonists, TrkA antagonists.
Dr. Christian MUTEBA BASEKE
Dermatologist, Democratic Republic of the Congo
On the fourth day of the WCD, I got interested in vitiligo.
Role of genes and epigenetics
Dr. Rehab HEGAZY (Dermatologist, Egypt)
- Oxidative stress, defective melanocytes growth abd development, autoimmunity and other hypotheses(neural, viral) → Loss of functional melanocytes in vitiligo lesions
- The role of genetics in vitiligo is now indisputable(heritability 46-72%, 15-20% of patients vitiligo have one o more affected first degree relatives, the concordance for generalized vitiligo in monozygotic twins is 23%)
- Important facts: among vitiligo probands affected relatives, the frequency of vitiligo was the same in male/female, in comparison to singleton cases, in multiple vitiligo families(showed earlier age of onset,greater skin surface involvement, greater frequency of other autoimmune diseases), together, the identified genes provides a framework for the genetic architecture and pathobiology of vitiligo, highlight relationship with other autoimmune diseases and melanoma, and offer potential targets for treatment.
- Epigentic mechanism may involve modification to DNA and surrounding structures : DNA methylation, histone modification, noncoding RNA (miRNA)
- First do no harm should be mentioned in the development of epigenetics drugs and must be important consideration
- New medication with well-defined target specificity, prolonged activity, and optimum delivery system are required in the furure
- Genome-wide epigenetic studies in autoimmune diseases are few
- Epigenome wide association studies (EWAS) is sufficiently powered with large sample sizes or twin designs with epigenome wide coverage, will have great potential of biomarkers for diseases onset, progression, or treatment response.
Genetics and epigenetics are corner stones in the pathogenesis of vitiligo,
- Deeper understanding of them holds the key to conquering this diseases.
Immunological aspects of vitiligo
Dr. Julien SENESCHAL (Dermatologist, France)
- Melanocyte metabolic defects to activation of the immune response: chemical damage, UV, genetic bacкground
- Innate immune response ; initiation of the diseases (genetic predisposition),
- Adaptative immune response in vitiligo : looking at resident memory T CELLS (Trm=resident memory T cells)
- Interaction between resident memory T Cells and epithelial cells (melanocyte specifics CD8+ Trm cell)
- Targeting Trm to treat vitiligo : antibody blockage of IL-15 signaling hast he potential to durably reverse vitiligo (presence of resident memory T cells (Trm) in vitiligo lesional skin of both humans and mice), 50% of patient will develp vitiligo on the same area, role of a maintenance therapy.
Non immunological aspects
Dr. Mauro PICARDO (Dermatologist, Italy)
- From innate to adaptive immune response in vitiligo : initiation (non lesional skin) → progression (pre-lesional skin) → depigmentation (lesional skin)
- Morphological alteration in normal pigment skin : normaly pigmented vitiligo skin shows acanthosis compared with healthy controls
- Mechanical trauma as an extrinsic pathomechanism for explaining the induction of melanocytes loss in vitiligo, 4h after friction application detached melanocyte moving toward the upper layers of the epidermis, 24h after friction application melanocytes arrows are located under the granular layer, ectopic distribution of melanosomes outside or within keratinocytes
- Vitiligo melanocytes present an alteration of the intracellular antioxidants and are more susceptible to the external oxidative stress (lower induction of catalase and detoxification enzyme expression upon exposure to oxidative stress)
- Molecular and cellular basis of depigmentation in vitiligo patient : poly morphisms in E-cadherin (CDH1 CC genotype) and discoidin domain receptor tyrosine kinase 1 (DDR1 CC genotype) genes are significantly associated with vitiligo
- Keratinocytes dysfunction in vitiligo epidermis : SCF and ET-1 Mrna are reduced in lesional and perilesional vitiligo epidermis whereas the expression of (TNF)-α Mrna , with has an inhibitory effect on pigmentation, is increased in vitiligo epidermis
- Involvement of the skin, with dermal presence of myofibroblast and premature senescent cells, capable of influencing melanocyte functionality and adhesion, favoring the detachment and disappearance
- Stressful event are capable to modify the biological behavior and the survival of the skin cells
- Therapies with a wide range of targets T cells, keratinocytes, denditric cells, fibroblast.
Chemical and Environmental factors
Dr. Tamio SUZUKI (Dermatologist, Japan)
- A number of workers who wore rubber gloves exhibited depigmentation over areas covered by gloves. Subsequent patch test using monobenzyl ether of hydroquinone (MBEH), a component in the gloves, caused a positive reaction on affected workers only (in japan 1939)
- MBEH induced an inflammatory response, which then followed by pigmentation
- Additional reports have subsequently been published demonstrating leukoderma in people working with phenolic/catecholoid derivatives
- Characteristics: these chemicals may be selectively toxics to melanocytes and thus responsible for inducing vitiligo, the most common melanotoxic agent are derivatives of phenols and catechols, vitiligo patient seem more susceptible to these agents, suggesting a genetic tendency.
- Rhododenol (RD) induced leukoderma? RD is a naturally occuring phenolic compound, and was developed as a tyrosinase inhibitor for lightening/whitening cosmetics. In 2013 depigmentation occurred on the skin of more than 2% in the consumers of RD
- RD induced leukoderma : the partial/complete depigmentation appeared on the face, the neck, and the hands at the application sites of the application sites of the products with or without inflammation
- Histopathology : absence or decrease of melanin and melanocyte (anti melan A positive cells in basal layer, indicating RD might be selectively toxic to the melanocytes
- The progress for 6 month in patient with RD- induced leukoderma after quitting the cosmetics (total of 1339), 72% were comprehensively evaluated as slightly improved or cured
- In the order to search an effective therapy to make the repigmentation faster, VitD3 ointment would promonte repigmetation
- Combination of VitD3 + UVB occurred repigmentation better than only VitD3, indicating that UVB has a synergy effect for the repigmentation.
Prof. Adama TRAORE
Dermatologist, Burkina Faso
Paediatric dermatology from A to Z
Context and specific characteristics of paediatric dermatology
It should be kept in mind that this Medical specialty focuses on:
- a state of constant change, it is not just a medical specialty for young adults,
- a variety of clinical signs,
- different ages,
- certain conditions which are not found in adults,
- birth marks to a large extent,
- common and rare diseases,
- sometimes certain warning signs of a more serious, potentially life-threatening underlying disease,
- the prospects of new therapeutic and clinical approaches.
Specific aspects relating to the needs of the patients and parents must also be taken into account.
Parents’ needs relate to:
- the management of guilt feelings,
- the acceptance of the disease, especially for chronic diseases,
- the acceptance of sometimes heavy treatments and, more importantly in some cases, of the absence of treatment,
- and the effective management of transitional responsibility.
Children’s needs relate to:
- understanding the disease,
- understanding the need to behave in a certain manner,
- understanding and dealing with social exclusion and treatment alignment problems.
It can be summarized in eight points:
- Dermatological manifestations as part of normal and physiological aspects
- Birth marks
- Inflammatory diseases
- Autoimmune diseases
- Genetic diseases
- Infiltrative and tumour diseases
- Induced and toxic diseases
Paediatric dermatology consultation must also take into account the specific needs of adolescence and puberty (tattoos, piercing, body odour, affirmation of one’s personality, etc.)
Non-genetic neonatal bullous rash
- Ensure the differential and aetiological diagnosis of non-genetic neonatal bullous rash,
- Distinguish between benign, severe and potentially lethal forms.
The main elements of the analysis include: morphology, topography and specific signs.
- Vesicular and/or bullous
- Generalised with or without mucosal disorder
* Single or multiple
* Head and/or scalp damage
* Deep damage
* Unaffected, untouched areas
Specific signs associated
- Darier’s sign
- Nikolsky’s sign
- Burrows’ sign
Focus on congenital cutaneous candidiasis and congenital syphilis
Congenital cutaneous candidiasis
- Differences between neonatal cutaneous candidiasis and congenital cutaneous candidiasis:
- Congenital cutaneous candidiasis diagnosis
* Clinical: diffuse rash
* Diagnosis by isolating Candida in the skin, mucous membranes, placenta and umbilical cord
We are witnessing a resurgence of this condition, notably in developed countries including the USA and Canada. Its incidence is estimated by the WHO at 1,575,000 cases per year due to insufficient perinatal prevention.
- Intra-uterine from the 4th month of pregnancy through the placenta
- At birth when in contact with birth canal lesions
- Asymptomatic in 60% to 90% of cases
- Symptoms appear after five weeks of life
- Cutaneous symptoms can appear earlier at one week of life, and unusual forms of early congenital syphilis include:
* Diffuse and fissural erythemato-squamous palmoplantar keratoderma (Pediatrics 2018 Article ID 1761454)
* Pemphigus syphiliticus (Pediatr. Dermatol 2018; 35: e110-e113).
The conclusion that emerges from this presentation is that there are:
- Traditional forms of epidermolysis bullosa; simple, junctional, dystrophic forms and Kindler syndrome
- Diseases involving skin fragility:
* Desquamative skin fragility,
* Erosive skin fragility,
* Skin fragility with hypertrophy and
* Skin fragility with connectivitis.
In India, the prevalence of atopic dermatitis is very high:
- Eczema around the eyes
- Forefoot eczema
- Damage to posterior thighs and buttocks
- Penoscrotal eczema
- Seborrhoeic dermatitis
- Dermatitis herpetiformis
- Miliary dermatitis
The objective is to combat dry skin, pruritus and inflammatory reactions
- Topical corticosteroids
- Topical Cyclosporine, Tacrolimus and Pimecrolimus
- PUVA therapy
Parents and patient counseling are important elements in managing atopic dermatitis.
The use of propranolol has revolutionised the treatment and prognosis of Infantile Hemangioma. Two questions arise with respect to infantile hemangioma: When to treat? and When to worry?
When to treat?
Treatment is required in four situations
- Life-threatening risk (size, growth, bleeding, etc.)
- Preserving a function
- Extensive ulceration with no tendency to healing
- Risk of disfiguring the patient, this risk depends on the size, location, characteristics of the border and surface area of the lesion.
Referral and treatment decision must be made early, ongoing monitoring by the physician and parents must assess the growth of the lesion.
When to worry?
Always worry about the risk of occurrence of PHACE syndrome
- P: Posterior fossa malformation
- H: Large segmental facial Hemangioma
- A: Abnormal Arteries in the brain
- C: Coarctation of the aorta
- E: Eye anomalies
- S: Sternal cleft
This syndrome must be sought in the presence of:
- Infantile segmental hemangioma more than 5cm in diameter,
- Segmental hemangioma on the scalp,
- Segmental hemangioma plus other revealing manifestation
- Signs suggestive of the syndrome, even without a hemangioma.
All anomalies, notably coarctation of the aorta, must be sought and treated to avoid fatal accidents.
- Steadily increasing incidence worldwide
- One third of psoriasis cases begin in childhood,
- Psoriasis accounts for approximately 4.1% of dermatosis cases in children,
- The average age of onset is 7 to 10
- More frequent earlier in female children
- In 30% of cases there is a family history of Psoriasis
Contributing factors and comorbidities include:
There are a variety of clinical aspects and treatment methods.