Акценти от 3-ти ден
13 June 2019
Newly described skin disorders, New Oral Small Molecules, Pemphigoid diseases, Basic Cosmetic Dermatology, Acne
Dr. Nicole JOUAN
Newly described skin disorders
New infectious diseases in Brazil
Dr. Omar LUPI DA ROSA SANTOS (Dermatologist, Brazil)
First Brazilian case of gnathostomiasis
An emerging disease associated with the consumption of raw fish. The case describes a patient returning from Peru, where the disease is endemic - along with Mexico and Southeast Asia. Skin lesions are pruritic, oedematous, with a subcutaneous larva migrans appearance. The biopsy does not always make it possible to find the larva. Clear hypereosinophilia. Albendazole is the best treatment. The severity of the disease is due to potential neurological complications linked to the larva’s migration: radiculomyelitis, encephalomyelitis, encephalitis and eosinophilic meningitis, which sometimes cause irreversible after-effects. The diagnosis is based on a number of epidemiological (stay in endemic areas, dietary exposure), clinical, biological (hypereosinophilia), serological, histological (eosinophilic panniculitis) and, where relevant, parasitological arguments. It should not be overlooked.
Are you familiar with Linuche unguiculata?
It is a small jellyfish whose larva, which is approximately 0.5 mm long, gets stuck under the swimsuit or neoprene suit of seabathers. In the shower, Lunguiculata releases numerous toxic substances and causes an itchy rash localised on the skin under the swimsuit or suit, referred to as “seabather ’s eruption”. It can be accompanied by systemic symptoms (fever, abdominal pain). These rashes, which are increasingly observed all year round on the coasts of Brazil, were initially described in Florida and the Caribbean. Treatment is symptomatic: antihistamines, topical corticosteroids, sometimes general corticosteroid therapy.
Chikungunya in Brazil
This disease is increasingly frequent in Brazil. It is most often benign and its incubation takes less than a week. The rash, which is initially maculopapular, becomes more severe, vesiculobullous. It is a way of distinguishing the rash from a ZIKA infection, which is never bullous.
- Description of a case of mother-to-child transmission of the Chikungunya infection: a 7-day old baby hospitalised for profuse vesiculobullous febrile exanthem [en imposant] for erythema multiforme, Lyell syndrome or staphylococcal necrolysis. He was diagnosed because his mother herself developed the disease 3 days after giving birth. He recovered without sequelae. The baby developed “chik-sign”, i.e. centrofacial hyperpigmentation fairly typical of the Chikungunya infection.
- The possibility of genital or perineal ulcers which resemble herpes lesions and are linked to the Chikungunya virus should not be dismissed.
New insights into bullous pemphigoid in Japan
Dr. Hideyuki UJIIE (Dermatologist, Japan)
Bullous pemphigoid (BP) is an autoimmune bullous disease caused by the presence of anti-BP180 (=COL 17) and BP230 autoantibodies which bind to the NC16a domain of the BP180 protein.
A significant link has been established between BP and neurological diseases (including Alzheimer and strokes). It is explained by the production of these antibodies in pathological circumstances.
With the type 2 diabetes “epidemic” leading to the increased use of gliptins worldwide, induced BPs are increasingly described and investigated. Gliptins are dipeptyl dipeptidase 4 (DPP-4i) inhibitors. In European cases, there seems to be no clinical or immunological difference between BP induced by gliptins and non-induced BP. This seems to be different in Japan. The latency period between the start of the treatment and the onset of skin lesions is 3 to 76 months, with a sex ratio of 7 women to 23 men in the Japanese cohort presented (1/1 SR in Europe). It also appears that these lesions have specific characteristics: less erythema around the blisters, meaning that the disease essentially takes the form of multiple erosions. In 40% to 70% of cases, no anti-BP180 ABs are found. Most Japanese patients have a specific DQB1 HLA profile, which is known to be involved in mucous membrane pemphigoid. In terms of therapy, the medication must be discontinued: 55% recovery rate when the treatment continues vs 85% when discontinued.
Cancer susceptibility: hereditary syndromes
Dr. Alexandros STRATIGOS (Dermatologist, Greece)
Many syndromes accompanied by high cancer susceptibility exhibit dermatological signs, which are often discrete but can help with the diagnosis and improve the screening and early treatment of cancer in the patient and their family.
Cutaneous signs precede malignancy, often by several years. They are not specific.
Mutations have been described for these syndromes: they are most often inherited in an autosomal dominant manner.
Focus on familial melanoma
Dr. Alexandros STRATIGOS (Dermatologist, Greece)
5% to 10% of melanoma cases are familial. The CDK2NA mutation is often associated with the atypical naevus syndrome and a risk of pancreatic cancer. The mutation of BAP1, a tumour suppressor gene, increases susceptibility to UV-induced cancer, mesothelioma, uveal and cutaneous melanoma, renal and basal cell carcinoma.
Within this spectrum, the BAP1 syndrome is singled out, characterised by atypical intradermal spitzoid tumours known as BAPomes, which histologically resemble Spitz naevus or melanoma, and whose malignancy potential is poorly documented.
Rare skin diseases described by Chinese authors
Dr. Jianzhong ZHANG (Dermatologist, China)
- Plack syndrome: Peeling skin, leukonychia, punctate acral keratoderma, cheilitis, knuckle pads, due to loss-of-function in CAST (calpastatin)
- Variable familial erythrokeratodermia with pustular lesions
- Acral hemosideric lymphatic malformation
- Chronic forms of atopic dermatitis-like GVHD
- Blashko-linear lupus, etc.
And this list is by no means exhaustive!
Dr. Rémi MAGHIA
New Oral Small Molecules
Focus on small molecule inhibitors
Dr. Marza CAPRONI (Dermatologist, Italy)
Dr. Lars IVERSEN (Dermatologist, Denmark)
Based on addresses by Marza Caproni, Italy, and Lars Iversen, Denmark.
This very topical subject deserves to be given some thought, and definitions were clarified by these two speakers.
Small molecule inhibitors are organic compounds with a molecular weight ranging from 500 to 900 Da (700 Da on average).
They can easily diffuse through cell membranes to reach intracellular sites. Once the inhibitor has penetrated the cell, it affects other molecules such as proteins.
These molecules can be categorised as natural (example of secondary metabolites) or artificial (example of antiviral drugs).
Advantages over larger molecules: easy diffusion through cell membranes, oral administration, easily combined with other treatments.
In short, when comparing small molecules with biological molecules.
In terms of chemical composition, small molecules are organic molecules, for oral or topical administration, with a molecular weight <900 Da, a generally short half-life, an intracellular target, which usually act through enzymatic inhibition, and with low or variable specificity.
Biological molecules are proteins for parenteral administration, with a molecular weight > 1kDa, a generally long half-life, an extracellular target, which usually act through blocking or depletion, with high specificity.
Small molecule inhibitors in non-melanoma skin cancer
Dr. Aleksandar SEKULIC (Dermatologist, United States)
Dr. Aleksandar SEKULIC, from the Mayo Clinic in Arizona, gave a very clear update on the subject.
Darier-Ferrand dermatofibrosarcoma (DFS)
Most types of DFS are COL1A1-PDGF beta.
A recent meta-analysis (Navarete-Dechent, JAMA Dermatology 2019) analysed the therapeutic results obtained with imatinib. Complete response 5.2%, partial response 55.2%, stable disease 27.2%, progressive disease 9.2%.
Merkel cell carcinoma
We have limited, nearly anecdotal data on the usefulness of molecules such as: survivin inhibitors, PI3K-MTOR inhibitors, imatinib, pazopanib. Future developments of small molecules are expected for patients who do not respond to the immunotherapy.
Squamous cell carcinoma
Given the high expression of EGFR, pre-clinical data suggests that the treatments targeting SCC are effective.
Cetuximab is not a small molecule (IV delivery of antibodies), but a study on 60 patients, ESMO 2018, showed the following after 6 weeks: complete response 2%, partial response 42%, stable disease 29%, progressive disease 27%.
Erlotinib (EGFR inhibitor): 10% ORR (objective response rate), all patients treated showed a partial response.
Gefitinib (EGFR inhibitor): 16% ORR, all showed a partial response.
Basal cell carcinoma (BCC)
The Hedgehog signalling pathway plays a crucial role, with sporadic PTCH1 mutations in 70% to 90% of cases, and SMO mutations in 10% to 20% of cases. The spectrum of CBC ranges from operable BCC to inoperable BCC.
Studies on vismodegib and sonidegib have shown positive results for locally advanced BCC, respectively in 43% and 44% of cases. For metastatic BCC, only vismodegib has received FDA approval and achieves responses in 30% of cases. The most common side effects of vismodegib are: muscle spasms, dysgeusia, alopecia. Side effects are the same for sonidegib, as well as creatine kinase elevation.
In practice: who to treat?
Metastatic cases (vismodegib only); locally advanced cases (with both), who experienced recurrence after surgery, or who are not eligible for surgery or radiotherapy.
Unusual cases: Multiple tumours? Gorlin syndrome? Neoadjuvant therapy?
Basal cell naevomatosis or Gorlin syndrome
Topical therapy: patidegib is currently under review (phase 2) in Gorlin syndrome.
Neoadjuvant? VISMONEO study (phase 2): final results are pending, but it appears that vismodegib as neoadjuvant treatment helps reduce the need for surgical procedure for BCC.
How to manage toxicities: for muscle cramps: hydration, Ca, Mg, K supplementation, muscle relaxants (cyclobenzaprine), intermittent treatment (“drug holiday”). The concept of intermittent therapy is based on the fact that, under the effect of the intermittent treatment, the tumour mass decreases in the form of a downward sinusoidal curve, while the “normal” mass spikes up and down but with a plateau effect (horizontal sinusoid).
For weight loss: ensure appropriate caloric intake.
What to do if a hedgehog pathway inhibitor fails?
Itraconazole, but highly interactive with other medications.
Posaconazole: promising pre-clinical data.
Immunotherapy? BCC is the form of cancer with the highest mutation rate. Responses were achieved with ipilimumab and cemiplimab. Anti-PD1s are under review.
Prof. Christian MUTEBA BASEKE
Dermatologist, Democratic Republic of the Congo
My my third day at WCD2019 was dedicated to « Pemphigoid diseases ».
Epidemiology and associations of Pemphigoid
Dr. Li LI (Dermatologist, China)
- Bullus pemphigoid (BP) acquired autoimmune sub epidermal blistering diseases, most common in the elderly, no gender difference, BPAG2/BP180 and BPAG1/BP230
- BP associated factor are neurogical deseases, drugs and malignancies
- Anti BP180 autibodies in stroke : younger, duration of follow up after first stroke attack for the BP180 positive, strong immune response in the early stage after stroke, down regulation of the autoimmune response in the late or recovery stage of stroke
- Possible mechanisme : CNS → Damage of blood brain barrier → Expose the neuronal isoform of BPAG → Anti neural isoform of BPAG autobodies → Anti epithelial isoform of BPAG autoantibodies → BP
- Immune check point inhibitor : PD-1/PD-L1 inhibitor, GLIPTINS-DPP4 INHIBITOR, influence on BP
- Mechanism of drug induced BP : semi antibodies interfering suppressive T cells, promoting eosinophil activation in skin, disturbing fibrinolytic sytem
- Solution: detailed medication history, within 6-9 month, immediately stop drug, use drug unrelated with BP
- Possible mechanisms malignancies and BP: Tumor secretion damage the epithelial BMZ, Laminin-332, cross reacting antibodies, genetic predisposition, external factor.
Clinical spectrum and presentations of the pemphigoid group of diseases
Dr. Janet FAIRLEY (Dermatologist, United States)
- Non bullus pemphigoid : pruritus, +/- eruption, or atypical eruption, histology non specific, no blisters, direct IF positive, positive indirect IF on salt-split skin
- Non NC16A BP : blistering diseases of skin, histology-subepidermal blister, direct IF linear IgG C3 at BMZ, Indirect IF-roof of NaCl-split skin, BP180 Elisa negative, Reactivity with other areas of the extracellular domain of BP180
- Non-NC16A : 609% of database, age slightly younger than over population of BP, less frequent BP230 pisitivity, milderdiseases, hugher incidence if being on a suspect medication
- P200 Pemphigoid : rare blistering, DIF, IIF positive, elisa negative fort the BP180 and BP230, reactivity with the y1 chain of laminin1,1,1, mild diseases courses
- Lichen planus pemphigoid : rare blistering diseases, distinct from bullus LP, timing-blistering before,during or after the development of LP like lesions, drug indeced?
- Pemphigoid gestationis: 1:10,000 pregnancy, junction of 2-3 timester, 50% begin around the umbilicus, papules,urticarial plaques and vesicles, antibodies against BP180
- Risk: small for gestational age, passive transfer of antibodies tot he neonate.
Pathogenesis of pemphigoid diseases
Dr. Wataru NISHIE (Dermatologist, Japan)
- BP180 is the major autoantigen for BP autoantibodies: pathogenecity of IgG directing the NC16A domain of BP180, complement activation is essential
- Pathogenesis of BP : breaking immune tolerance to BP180BP230, binding of IgG1 and complement activation, recruitment of neutrophil and proteolytic enzyme production, cleavage of BP and blister formation
- Additional information in the pathigenesis of BP: complement independent pathomechanism, finfings from patients of dipeptidyl pepdidase IV inhibotor associated BP (dpp4i.bp)
- New information learned from DPP-4i BP in Japan: DPP-4(CD26) is also expressed in activated T-Cells, tend to have less eythema, tends to have less anti-BP180 NC16AIgG, non inflammatory DPP4i-BP
- Pathogenesis of DPP4i BP (hypothesis) : HLA-DQB1*03:01+DPP4i+ ? → BP.
Diagnostic algorithm for the pemphigoid group of diseases: practical approach
Dr. Detlef ZILLIKENS (Dermatologist, Germany)
- Diagnostic steps in pemphigoid diseases : clinical criteria, histopathology of lesional skin, direct immunofluorescence microscopy of perilesional skin, indirect immunofluorescence microscopy, elisa, immunoblot
- Autoantigens of pemphigoid diseases within the dermal epidermal junction : bullus pemphigoid, pemphigoid gestationis, linear IgA diseases, mucus membrane pemphigoid, anti p200 pemphigoid, epidermolysis bullosa acquisita
- By direct IF microscopy, skin biopsie from anti p200 pemphigoid patient, like those from BP and anti laminin 332 pemphigoid patient, show an n-serrated pattern
- Indirect IF microscopy on human NaCl separated skin : epidermal binding (antibodies BP180, BP230), dermal binding(laminin 332,p200,type VII collagen)
- Characterization of specificity of serum autoantibodies in pemphigoide diseases by immunoblotting : keratinocyte extract and epidermal extract (BP180,BP230), dermal extract(p200, type VII collagen), extracellular matrix of cultured human keratinocytes(laminin 332), supernatant of cultured keratinocytes(sluble BP180 ectodomain LAD-1, recombinant proteins(fragment of type VII collagen,BP180,BP230 and laminin 332
- Diagnostic work-up in luberck if BP is suspected: perilesional skin biopsy by direct IF, serology, if direct or indirect IF are positive, but BP180 elisa negative
- Direct IF may be false negative in MMP: if direct If is negative but clinical suspicion for MMP continues, additional biopsie should be obtained for direct IF
- Anti-laminin 332 pemphigoid, a possible paraneoplasic diseases (5% of MMP patient suffer from a tumor).
Prof. Adama TRAORE
Dermatologist, Burkina Faso
Basic Cosmetic Dermatology
This was an important session that included a dozen speakers from over 7 countries.
The following items have caught my attention:
Why dermatologists should take care of cosmetic patients?
Dr. Marina LANDAU (Dermatologist, Israel)
While this skill was not previously valued in dermatology schools, having good cosmetology skills appears to be increasingly necessary for dermatology practice, currently and in the future, for the following reasons:
- The demand will increase,
- The treatment of various dermatological diseases includes cosmetic aspects,
- Some skin conditions that lead patients to see a dermatologist are straddling between medical and beauty care,
- Some cosmetic treatments help treat skin disorders,
- Taking quality of life into account is important in all medical practices,
- Dermatologists have more legitimacy to deliver quality cosmetic care because they know more about skin,
- Dermatologists certainly have economic benefits but the enthusiasm of the public is what matters most.
In order to take this interest into account, it seems important:
- To include cosmetology into dermatologist training curriculum (which is currently missing),
- To create theoretical and practical training opportunities in postgraduate courses,
- For the dermatologist to always remain aware and concerned about possible side effects and to be aware of what makes a good doctor.
The art and science of cosmetic consultation
Dr. Nancy GARCIA TAN (Dermatologist, Philippines)
- Do not assume that you know what the problem is,
- Ward off the fears and concerns of patients,
- Thorough understanding of the patient’s history is important, including all past treatments,
- Evaluate general health and medical history,
- Pay attention to contraindications,
- Discuss the treatment options that are suitable for the patient
* Possible incidents and accidents
* Presence of pain, discomfort
* Number of treatment sessions
* The cost of the session(s)
- Discuss the procedures and expectations
- Assessing patients is essential because: what you want may not be what the patients want and what the patients want may not be what they need.
Anatomical basis for safe injections in cosmetology
Dr. Tatjana PAVICIC (Dermatologist, Germany)
Understanding the complex anatomy of the face will limit the adverse effects of certain cosmetic practices.
What dermatologist should know before starting to treat a skin of color?
Dr. Pearl GRIMES (Dermatologist, United States)
The important elements to take into account are:
- Significant morphological and physiological differences,
- Differences in the modes of ageing,
- Cultural differences and beauty standards,
- The trials and tribulations of pigment disorders,
- Knowing the best tools that are usable and useful in these skin types,
- Respecting the effectiveness and safety limits.
This table presents the advantages and disadvantages of “coloured skin” in the context of beauty care and procedures
Cosmetic procedures and skincare for “coloured skin”
Dr. Arturo GALVANI
PRP: Does it really work?
In order to understand if it works, we must first understand how it will be used, that is in trichology or for treating ulcers.
PRP is a widely growing market expected to exceed $4.5 million and there are three principal factors behind its growth:
1) Persuasive advertising
2) Patient hopes
3) Critical need for new treatments.
Legislation concerning it varies across countries. There is sporadic evidence demonstrating that it works in androgenetic alopecia treatments of three separate monthly sessions followed by a maintenance phase.
Nevertheless, if the studies are adequately evaluated, the dissimilarities, even in the case of subjective patient benefits, may not be statistically significant.
There is a serious qualitative problem in the literature. In a general review of the literature, all studies demonstrated good results. However, a certain amount of bias in the English-language studies to demonstrate positive results should be considered. Furthermore, most studies are poorly designed.
In conclusion, it is likely that a large part of the push behind these studies is purely economic as, for the moment, PRP has not been adequately shown to work.
Acne scarring is associated with poor first impressions and patients with acne scars are often at a social disadvantage.
Scarring occurs at any phase of the condition and not in its advanced stages as is often believed.
Scarring seems to be due to the destruction of the dermis caused by the discharge of matrix metalloproteinases (MMPs). The condition is usually genetically determined as patients' parents will also often have scarring. There are specific genetic profiles that influence MMP discharge.
If inflammation lasts more than three weeks, an inflammatory mechanism is activated that could lead to the destruction of the dermis and scar formation.
At-risk areas are likely those lacking in underlying subcutaneous fat, which therefore cannot properly provide stem cells to reconstruct the skin.
There is little agreement among experts on how to classify scarring. We are looking for new classification systems based not on appearance, but rather on lesion size (2mm is an important threshold), as it is a less subjective parameter. Furthermore, it is useful to employ punch excision in order to measure the scars in the most accurate manner.
Prevention is key because total scar disappearance is difficult to achieve.
Three basic prevention points via a medical approach include:
1) Avoiding inflammation
2) Adjusting epithelial differentiation with retinoids
3) Regeneration: scrubs and microdermabrasion
Any skin damage will result in regeneration, regardless of the source used. When laser or peeling treatments are used, message are sent to the bone marrow, which cause the marrow to send stem cells to the skin. Skin stem cells found in the bulge are also activated.
Specific Techniques for Scar Type:
Scar contraction with a low-power electrocautery device to reduce the surface area of large scars. The subcision of rolling scars, especially if coupled with fillers, which is better when performed vertically. For ice pick scars, use filler in the whole area. Keloid cryotherapy is also an interesting technique.
Even a simple injection of saline solution and lidocaine will induce inflammation, which can help improve the condition.
Acne is the leading cause of dermatological counselling and nearly 50% of patients will have scars.
Acne is most likely a genetic disease with a specific pre-disposition in some body areas. Prevention is key and it is crucial to combine techniques.
The Microbiota in Acne
Microbiota is the sum total of the microorganisms present in a given environment.
There are different species depending on the various areas of the human body. In the sebaceous areas we mainly have Actinobacteria, of which Propionibacterium acnes is a part. It is an important commensal bacterium for our skin since it prevents other infections. P. acnes is the predominant bacterium in the pilosebaceous units of healthy people. Nevertheless, some strains are associated with acne.
Some strains of P. acnes have unique genetic elements that contribute to their virulence, whereby inducing them to produce more porphyrins. Some phylotypes also cause different immune responses.
Additionally, it is likely that Malassezia, the most common fungus in the human body, is related to acne.
Bacteriophages also potentially play a role in acne regulation.
Acne tends to be comedogenic in pre-adolescents, while in most adults it becomes inflammatory; this is a partly attributable to a change in the bacterial population.
Tetracaine reduces the amount of P. acnes and Staphylococcus.
Isotretinoin has no direct antimicrobial effects, but reducing the production of sebum causes a reduction. However, the reduction is temporary following the end of the treatment. Nevertheless, systemic treatments modify the microbiota, whereby reducing the relative number of P. acnes. There is greater bacterial diversity at the end of the treatments. There are also long-term effects (see photos).
Isotretinoin causes a reduction in P. acnes and an increase in
There are also differences in the intestinal microbiota in patients with acne.
In conclusion, different strains have a different role and systemic treatments profoundly alter the microbiota.
In the future, the elimination of virulent strains will be of crucial importance, as will the possibility of replacing the virulent strains with different and less aggressive ones.