1st meeting of the French Dermatology Societies
The SFD meeting at the world dermatology congress in Vancouver was an opportunity for friendly get-togethers and discussions between the different French-language representatives of the dermatology world. Organised jointly by SFD, ADF (French-speaking dermatologists' society) and ADQ (Quebec dermatologists association), it offered a wide overview of all the French-speaking dermatological organisations, their history, scientific scope and future perspectives.
One point that particularly struck me was the private dermatological clinical research activity in Quebec, which is behind a very large number of on-going projects. Many independent centres, like in the USA, participate in sponsored clinical trials for all phases (I to IV). For example, Quebec's CRDQ (centre of research in dermatology) alone has 7 projects under way in atopic dermatitis (AD), 10 in psoriasis, 1 in BCC, 1 in acne and 1 in Hidradenitis suppurativa (HS).
In the scientific field, we were all impressed by Marie Beylot-Barry's brilliant presentation of the main, leading French-language publications of the past 4 years (May 2011 to May 2015). J-F Sei, in the Vancouver newsletter, has already mentioned the articles concerning sirolimus in kidney transplant patients, and propranolol for hemangioma in infants. Here are a few other subjects, along with an extract from Marie Beylot-Barry's bibliographic selection.
There has been a real revolution in melanoma, thanks to mutation targeting, restoration of anti-tumour immunity (ipilimumab, slow response, minority of responders, but long-lasting response), leading to new concepts and algorithms that are constantly developing. Regarding mutation targeting, it has become necessary to overcome and anticipate resistance in order to increase the rate and duration of the therapeutic response [1-3].
More recently, we have seen the huge success of anti-PD1 treatments, whose response levels are better than with ipilimumab, as well as rapid, long-lasting responses, a lower level of toxicity but a higher level in the case of association [4-7].
For Sézary syndrome, identification of a specific marker, CD158k, used for diagnosis and monitoring. And now with a therapeutic target, via the development of an anti-CD158k .
A French study of 89 cases of foot-hand-mouth disease (HFMD) revealed clinical semiology that is often deceptive, showing affection beyond the HFM regions (87%), and in some cases, diffuse (41%) .
Skin symptoms associated with parvovirus B19: retrospective review of 29 patients. There are 4 patterns that are sometimes associated: exanthema, "glove and sock" lesions, flexural lesions, infiltrated purpura. Please note: 21% of systemic complication cases: cytolysis, aplasia, kidney failure, interstitial lung disease .
Bullous perphigoid is an increasingly frequent and serious illness. A few statistics for France: Incidence x3 over 15 years, average age 82.6 years, survival after 1 year: 62%. Mortality x6 compared with the rest of the population .
A retrospective study of 97 patients (Créteil-Reims) reported 25% recurrence after interruption of the treatment; positive IFD after interruption of treatment is predictive of relapse, better than BP180 ELISA .
Pemphigus vulgaris: rituximab as first intention treatment? It has an immediate and long-term effect. 2 French studies tested it as a first line treatment in association with generalised or local corticosteroid treatment [13,14].
Lupus: the plasma rate of hydroxychloroquine, while useful for assessing observance, has no beneficial effect on therapeutic adaptation.
Meta-analysis shows that tobacco reduces the effectiveness of anti-malarials in cutaneous lupus [15,16]
Alopecia areata: pilot study: treatment by IL-2, 5 patients: partial response 
Vitiligo: 0.1% tacrolimus ointment twice a week prevents relapse after repigmentation: 9.7% relapse compared with 40% for the placebo .
DRESS: local corticosteroids vs oral corticosteroids: retrospective study of 38 patients: fewer adverse effects and lower rate of viral reactivation .
Rosacea, in the eyes of Diane Thiboutot, USA
What are the current treatment strategies?
- Avoid trigger factors to limit outbreaks
- Reduce facial erythema: laser, alpha adrenergic agonists*, carvedilol*
- Reduce papules and pustules: cyclins, azelaic acid, metronidazole, topical ivermectin
- Reduce telangiectasias: laserReduce rhinophyma: surgery and laser
Topical ivermectin: a hot topic
Ivermectin is an avermectin, which has shown anti-inflammatory effects: inhibition of inflammatory cytokines such as TNF alpha and IL1-beta; increased IL10, an anti-inflammatory cytokine.
Ivermectin has anti-parasite properties: via the oral route on demodicosis and scabies; via the local route on lice.The FDA has approved ivermectin in cream form for the treatment of rosacea, based on 2 randomised, double-blind studies over 12 weeks, comparing the daily application of ivermectin with the vehicle only in 1,371 patients with moderate to severe rosacea. Total or almost total success for approximately 40% of ivermectin patients, compared with 12-18% of vehicle-only patients.
Two studies extended to 40 weeks showed an increase in the percentage of total-almost total results from 71 to 76%.
A European phase 3 trial (A Taieb et al. Br J Dermatol 2015) compares 1% cream ivermectin 1 x/day with 0.75% cream metronidazole 2x/day: ivermectin is significantly more effective in reducing the inflammatory lesions (83% vs 73.7%).
Isotretinoin for recalcitrant rosacea
Studies have already showed the efficacy of oral isotretinoin (ISO) in treating recalcitrant papulopustular rosacea, at doses between 0.5 and 1 mg/kg/day. Low doses (10mg/day) have also proved to be effective, with fewer adverse effects.
Another study (Gollnick, 2010) compared the effectiveness of lower doses of ISO (0.1, 0.3, or 0.5 mg/kg/day) with doxycyclin and a placebo in 573 patients. After 12 weeks, the 0.3mg/kg/day was the most effective ISO dose. This dose is more effective than doxycyclin (90% reduction in inflammatory lesions compared with 83% for doxycyclin).
Therapeutic options for ocular rosacea
Artificial tears, palpebral hygiene (hot compresses, removal of scabs with baby shampoo), antimicrobial or sub-antimicrobial dose doxycyclin , cyclosporine eye drops, azithromycin eye drops.
A small-scale German trail investigated doxycyclin at anti-inflammatory doses (40mg/day): clinical improvement was observed after an average of 2.29 months and the average period of improvement was 5.86 months.
*Reminder of elements previously published in the Vancouver newsletter
Oxymetazoline: agonist of the alpha-1 adrenergic receptor inducing vasoconstriction, currently in clinical trials in topical form.
Carvedilol: non-selective beta/alpha1 blocker, used orally.
Anagen effluvium of alopecia induced by chemotherapy
Rodney Sinclair from Sydney, Australia, gave an excellent talk on alopecia due to chemotherapy, which is a topic shrouded in questions.
This condition is due to the fact that the intense cell proliferation in the anagen phase hair bulb makes it particularly vulnerable to any anti-mitotic chemotherapy. The anagen phase is temporarily interrupted; the hair fibres grow thinner and end up breaking, resulting in the loss of dystrophic or broken hair. Constrictions of the hair shaft are observed in the subsequent hairs.
Low doses of cyclophosphamide result in thinning and fracturing of the remaining follicles in the anagen phase, while higher doses result in the catagen phase.
If the anagen phase continues, recovery is immediate. However, with the repetition of chemotherapy cycles, a growing number of follicles enter the catagen phase, which slows down the recovery process.
After a single chemotherapy cycle, hair loss starts after between a few days and 2 months and stops after 1-2 months. The repetition of chemotherapy cycles accentuates the phenomenon, and total hair loss generally occurs within 2-3 months. In most cases, recovery is complete 3-4 months after the end of the chemotherapy cycle.
The frequency and severity of hair loss differs according to the four main classes of anti-cancer drugs:
- More than 80% for antimicrotubule agents, such as paclitaxel
- 60-80% for topoisomerase inhibitors, such as doxorubicin
- More than 60% for alkylating agents, e.g. cyclophosphamide
- 10-20 % for anti-metabolites, such as 5-fluorouracil
The risk obviously increases with the association of two or more anti-mitotic agents.
The agents that are generally associated with alpoceia are: adriamycin, cyclophosphamide, daunorubicin, docetaxel, epirubicin, etoposide, irinotecan, paclitaxel, topotecan, vindesine.
Other agents known to cause alpoceia occasionally include: bleomycin, busulphan, cytarabine, 5-fluorouracil, gemcitabine, lomustine, melphalan, thiotepa, vinblastine, vincristine.
The following are rarely involved: carboplatin, capecitabine, carmustine, cisplatin, methotrexate, procarbazine, streptozoticin.
A small-scale study suggests that topical minoxidil accelerates hair regrowth after alopecia due to chemotherapy. However, no preventive effects are observed in women receiving doxorubicine for different types of solid tumours.
The most widely used preventive method is the cooling cap. Vasoconstriction reduces blood flow to the hair follicles. The lower level of biochemical activity makes the follicles less vulnerable to chemotherapy. Compact mobile cooling systems for connection to lightweight silicone caps have been developed. The temperature of the patient's scalp is lowered to 18° (using a coolant at -4°).
The cap is applied 30 min before the chemotherapy session (which can last up to 2 hours) and until 90 min after it ends.
In a review of 53 published studies, 7 of which were randomised, 6 out of the 7 randomised studies showed a significant benefit when the scalp was cooled. The most obvious results were with anthracyclines or taxanes.
Risk of metastases?
Meta-analysis of 20,380 patients with various tumours found a rate of incidence of cutaneous metastases on the scalp of 5.3%. Analysis of a cancer register in Munich shows that the incidence of cutaneous metastases of the scalp is very low, with no difference between cooled scalps (0.04%-1%) and uncooled scalps (0.03-3%) in breast cancer patients.
Breast.2013 Oct; 22(5): 1001-4
Permanent post-chemotherapy alopecia
Alopecia is not always reversible. Permanent alopecia is particularly associated with bone marrow transplant conditioning protocols involving busulfan and with breast cancer treated with taxane. The extent of the alopecia appears to be dose-dependent, but there is no clearly determined threshold above which patients treated with busulphan or taxane develop permanent alopecia.
Carcinology, Dermoscopy and Therapeutic
Prof. Patrick Moore from the Pittsburg University Cancer Institute recalled during the plenary session that 20% of human cancers are caused by viruses: 1 in 5 cancers is therefore virus-induced.
The Epstein Barr virus was discovered in 1964, oncogenic HPV in 1983, the KSHV herpes virus in 1994 and Merkel cell polyomavirus in 2006, the last two viruses having been discovered in his laboratory. The genetic revolution has enabled the discovery of 11 new polyomaviruses over the past 8 years and more than 200 papillomaviruses, some of which are oncogenic, have been described to date. The carcinogenesis process induced by the viruses involves a large number of steps: often early infection, sometimes even during infancy (as is the case of the polyomavirus) followed by a latent phase, integration of fragments of the viral genome in certain cells, then, depending on other factors (fall in immunosurveillance due to immunodeficiency, old age, ultraviolet radiation or certain toxics), triggering of a malignant proliferation. The occurrence of cutaneous squamous cell carcinoma in transplant patients underlines the role of HPV. Furthermore, in a recent series, Bertrand Richert indicates that squamous cell carcinoma of the nail bed is most often associated with HPV 16, opening new perspectives for the prevention of certain cancers by way of vaccination.
- The occurrence of Cutaneous Squamous Cell Carcinoma in kidney transplant recipients can put life at risk and therefore requires adaptation of the immunosuppressive therapy. The results of a multi-centre study coordinated by Sylvie Euvrard were published in the New England Journal of Medicine and relate to 120 kidney transplant patients who suffered from CSCC: these patients are randomised after the surgical excision and will either remain on their usual immunosuppressive treatment or switch to Sirolimus as the sole preventive graft rejection treatment.
The results favour the sirolimus group, with:
- fewer new cases of CSCC ( 22% instead of 39%)
- delayed onset of potential new cases of CSCC (15 months vs 7 months)
While the transplant is not rejected, adverse effects are more frequent in the sirolimus group, which raises the issue, for each individual case, of whether, in practice, this switch is pertinent depending on the severity of the CSCC.
According to Chrysalyne Schmults - an American Mohs surgeon - squamous cell carcinoma is becoming a more and more common tumour in the USA, reaching the incidence of basal cell carcinomas. Its gravity is greatly underestimated: it is responsible for more deaths than melanoma in the central and southern American states, i.e. close to 9,000 deaths per year. It is therefore essential to identify high-risk squamous cell carcinoma characteristics, and a clinical tumour classification is provided based on 1,393 patients treated by the Brigham and Women’s Hospital (BWH) (Jambusaria and Schmults: JAMA April 2013; Karia, Schmults et al: J Clinical Oncology December 2013) based on the acronym 3D/PNI, i.e. 4 criteria: Clinical diameter >2 cm, Depth in sub-cutaneous fatty tissue, Low differentiation and Perineural invasion
T1: no criteria, T2a: 1 criterion, T2b: 2 or 3 criteria, T3: 4 criteria or bone invasion
The T1 stage shows a good prognosis with 0.6% of relapsing and 0.1% of nodal metastasis: in these cases and in the event of full excision, the patient is considered cured.
Stage T2a shows an intermediary prognosis: the risk is low, but this group still presents a 17% chance of death by squamous cell carcinoma - the importance here resides in finding additional bad prognosis elements, such as a diameter smaller than but close to 2 cm, and immunosuppression for instance.
The T2b stage (and rare T3 cases) only represents 6% of the BWH group, but also 76% of nodal metastasises and 83% of deaths by squamous cell carcinoma. The first goal is therefore to fully excise the tumour and carefully assess the area's nodal extent - first using radiology and/or an ultrasound; if these tests are negative, a sentinel lymph node test is conducted. Chrysalyne Schmults greatly insisted on how important the early detection of node involvement is: 7% of all T2a and 29% of T2b patients show a positive sentinel lymph node (Schmidt JAMA dermatol January 2014). Yet the death rate for squamous cell carcinoma is linked - in 85% of all cases - to loco-regional involvement (which makes the search for sentinel nodes quite different to melanoma, where metastasises can exist remotely at the time the sentinel node is searched for): in the event of a positive sentinel node, a lymph node dissection could thus improve overall survival in high-risk squamous cell carcinoma patients. Furthermore, additional radiotherapy is recommended in T3 and certain T2a stages.
We could in the end be surprised to notice the absence of certain clinical criteria from this classification (relapse tumours, location in the body's extremities), as well as certain histological criteria (tumour thickness and desmoplasia), but the focus should be set on searching for the sentinel node in high-risk squamous cell carcinomas.
The surgical treatment of in situ lentigo melanoma raises the issue of size and excision margins. Recommendations in France since 2005 have been of 10 mm (instead of the 5 mm previously recommended, that remains acceptable for other types of in situ melanomas). This high margin requires fairly large resections, for lesions that are often facial, and could actually be too large. However this is not the case: the communication issued by David Zloty, a dermatologist in Vancouver University, British Colombia, confirms that an average of 7.1 mm (between 4 and 19 mm) of lateral margin is required for full excision: our standard margin of 10 mm can therefore even be insufficient at times. Micrographic surgery is used to adapt the margin according to the extent of the treated tumour, so full excision can be accomplished. With this technique, the relapse rate after 5 years is only 4.3%. Radiotherapy - only seldom used in France - is an option, whereas the use of imiquimod has not yet been sufficiently assessed in such cases.
Following the excision of a basal cell carcinoma, anatomopathological responses sometimes indicate that the excision was incomplete. Immediate recommended revision surgery is once again analysed, and the response is more often than not "changes in fibro-scarring structure with no residual tumour proliferation found". Revision surgery could thus be deemed unnecessary: Vanessa Palmer, from St John's Institute of Dermatology in London, recounts her experience in the revision of 100 Mohs surgeries for BCC in which excision was incomplete: 12% of these patients had a clinically visible residual tumour, and a tumor was found in 69% of all cases. The recommendation for immediate revision surgery is confirmed, as opposed to a "wait and see" strategy: relapse is in fact common in the event of incomplete excision, and treating a relapse tumour is always more difficult, in addition to there being a higher risk of relapse than with primary tumours - including with Mohs surgery.
Giuseppe Argenziano, during the advanced Dermoscopy session at this 23th World Congress, explains the cognitive process of a Dermatologist with dermoscopy expertise: he describes a three stage mental process: "Blink, Think, Compare"
"Blink" is the diagnosis in the blink of an eye: this instant recognition is based on experience gained over time. The grounds for the diagnosis are analysed later to support a diagnosis already made: this is the "Top to Bottom" reasoning, from the peak (the diagnosis) to the base (the grounds for the diagnosis). This is the recognition method used most frequently in everyday life, e.g. for diagnosing psoriasis or recognising an elephant…
"Think" is the second stage, required when there is no immediate diagnosis. This time, the semiology of lesions must be examined in detail to reach a diagnosis: this is "Bottom to Top", where the semiology (Bottom) leads to the diagnosis (Top).
"Compare" is the third step in the cognitive process: faced with a suspicious image which leaves some doubt as to whether it is benign or malignant, and in particular in the case of a "suspicious" (or even unusual) naevus, a comparison with the patient’s other naevi provides additional information: if the patient only has one naevus of this type, this one is the ugly duckling, described clinically primarily but also relevant in dermascopy: here an excisional biopsy is a must. On the other hand, if the "suspicious" appearance is also found on plenty of other naevi in the patient, the lesion is most certainly benign and this reassuring comparison will have prevented an excision found to be unnecessary.
He also gives some tips for distinguishing a recurrent naevus after excision (Acekerman's pseudomelanoma with its diagnostic difficulties) from a recurrent melanoma (RM): the recurrent naevus affects younger patients (on average 35 years of age versus 63 for recurrent melanoma) and recurrence happens sooner (8 months versus 25 months). The most common architecture in dermascopy features radius lines in RN and circles in RM (often Dubreuilh's melanoma). But the most relevant argument is the location of the pigmentation in the recurrence: for RN, the pigmentation remains in the scar, while it spreads outside the scar for RM.
Iris Zalaudek presented 2 new pieces of information related to pigmented facial lesions:
- Dubreuilh's melanoma (according to a recent study published in JAAD in 2015) is found in different locations according to sex: in women, it is most often an isolated pigmented macule on the cheek while in men the most common locations are the tip of the nose, the preauricular and retroauricular areas and the scalp.
- A differential diagnosis between Dubreuilh's melanoma and pigmented actinic keratosis is challenging: in dermascopy, the follicular orifices look white in actinic keratosis due to the hyperkeratotic corneal plugs whereas they have a grey edge in Dubreuilh's melanoma because of the proliferation of malignant melanocytes: these grey circles are highly indicative of melanoma.
In all cases, Iris recommends avoiding the use of lasers or liquid nitrogen to treat any pigmented lesions for which there is even the slightest doubt as these methods could modify the natural history of the lesion and possibly make a potential melanoma more aggressive: guided biopsy, preferably by the shave method (simple, quick, barely leaving any scar) makes it possible to clarify the diagnosis.
A Japanese poster, designed by Sumiko Ishizaki and coll. from the University of Tokyo, compares the average diameter of the BCCs operated in the Pre-dermoscopy Era (PE) (1998-2005) with that observed in the Dermoscopy Era (DE) (2006-2013): the difference is statistically significant with an average diameter of 13.3mm in PE versus 10.5mm in DE (p = 0.03) and a diameter of less than 15mm for 2/3 of the BCCs operated upon in PE versus 3/4 of the BCCs/DE. Of course, the dermatoscope is probably not the only factor responsible for this evolution but its early diagnosis efficacy certainly contributes to the treatment of smaller lesions.
The number of plantar wart treatments is a good indicator of the difficulties in dealing with this condition. A poster designed by Dipali Ratod and coll., from Mumbai, India, proposes a simple "needling" technique. 25 patients with at least 3 plantar warts which had evolved for more than 5 years and were resistant to the usual treatments were included in this study. Under local anaesthetic, the warts were repeatedly pricked with an 18G needle until this caused minor localised bleeding: 18 patients recovered after 3 weeks, with no notable adverse effects and no recurrence after 3 months; partial responses were observed in 5 patients and 2 were lost to follow-up. Another study conducted by Longhurst (J. Clin. Med. 2013,2,13-21) shows a recovery within 8 weeks in 69% of cases with 46 patients. This simple, rapid and inexpensive method could therefore have its place in our range of therapeutic treatments.
Pr Chris Zachary pointed out during today's plenary session that "Daylight mediated PDT (DL-PDT)" is suitable for the treatment of mild to moderate AK. A chemical sunscreen must first be applied onto the areas exposed to the sun and ALA applied after skin cleansing and light curettage of the lesions 60 minutes before exposure to light: the patient is then exposed to natural light for 2 1/2 hrs. The weather can be cloudy but not rainy. The patient must not go out in the sun for the following 48 hours. This technique is much less painful than the traditional PDT, requires no particular equipment and has proved to be as efficient as traditional PDT: in his presentation, he also presented the spectacular results achieved by picosecond laser in tattoo removal: this laser injects high levels of energy into the tissues, enabling the localised destruction of pigment granules with very limited reaction from the surrounding tissues
The use of propanolol to treat infantile hemangiomas, as discovered by Christine Labreze after a period of observation, is an example of serendipitous medical discovery. No controlled trial was conducted: a multi-centre randomised trial involving 460 patients aged 1 to 5 months suffering from infantile hemangioma was published in the New England Journal of Medicine in 2015. The children were randomly divided into 5 groups (Placebo, 1 mg/kg and 3 mg/kg for 3 months, and 1 mg/kg and 3 mg/kg for 6 months) and the results assessed in terms of tolerance and effectiveness after 6 months: a clinical improvement was observed from the 5th week in 88% of patients compared with only 5% of patients taking the placebo and the 3 mg/kg/day dose maintained over 6 months turned out to be the most efficient, with a 60% success rate, compared with 4% for the placebo. The expected adverse effects of propanolol (hypoglycaemia, bradycardia, low blood pressure and bronchospasm) are rare and very similar to those observed in the placebo group. 10% of patients experienced an evolution in their hemangioma after they stopped the treatment, particularly in the most severe forms of hemangioma.
An interesting form of communication during this Congress was the debate: for a set theme, 2 speakers spoke in favour of 2 opposite approaches, such as "Faced with a chronic rash, should the etiological investigation be extensive or minimal?" or "Is there a future for PUVA?" or "In cases of toxic epidermal necrolysis, which is the right choice: immunotherapy or symptomatic treatment?" . One such debate found Pascal Joly promoting local corticosteroid treatment for bullous pemphigoid against Branca Marinovic, Croatia, who prefers generalised corticosteroid treatment. Pascal Joly recalls that the occurrence of pemphigoid increases with age, affecting senior patients with a large number of co-morbid illnesses, particularly neurological disorders, that affect the prognosis and that mortality is between 30 and 40% with high dose corticosteroid treatment (around 1 mg/kg) . The efficacy of local corticosteroid treatment (above 90%, in both moderate and severe forms of BP, defined by the appearance of more than 10 new blisters) and its higher level of tolerance (significant reduction of mortality of between 25 and 40%) have now been proved by meta-analysis of data from more than 1,000 patients. The initial form of treatment is therefore 20-30 g per day of topical Clobetasol for moderate forms and 30-40 g for severe cases. The treatment is applied (P Joly et al , J of Invest Dermatol 2009) over the entire body (except for the face) in severe cases, including over the cutaneous BP lesions, and more locally for more moderate forms; application is daily for one month, then every other day for one month, then twice a week for the third month and once a week for the fourth month; after 4 months, either the treatment is stopped or continued until the 9th or 12th month at a frequency of once a week. What are the alternatives to local corticosteroid treatment? Generalised corticosteroid treatment at low dose (0.3 mg/kg) is not effective. It is effective at moderate dose, but only in moderately severe cases of BP. A comparative study of methotrexate and corticosteroid treatment is currently in progress; the efficacy of immunosuppressants has not been proved; tetracycline has been effective in one minor study and could be useful in recurrent forms; Rituximab has been used in recurrent forms after interruption of corticosteroid treatment but mortality is very high (40%) and the rate of effectiveness much lower than for pemphigus.
Branca Marinovic pointed out that oral corticosteroid treatment is much more practical to administer, that the cost of oral treatment is three to four times lower and easily available, and that patients prefer taking tablets rather than having to apply several tubes of cream each day. The fact is that there are two pitfalls associated with local corticosteroid treatment: firstly, incorrect compliance with the treatment schedule, associated with a high risk of relapse multiplied by 4 (assistance to apply the cream is essential, requiring intervention of a nurse, participation of the family, etc.) and secondly, stopping too soon after disappearance of the cutaneous lesions and itching that cause relapse.
At the end of this debate, and with no chauvinism whatsoever, the reduction of the mortality rate and the better proven effectiveness in more than 1,000 patients meant that local corticosteroid treatment was found to be more convincing as a first intention treatment.
Auto-inflammatory syndromes, interventional dermatology
An excellent plenary session enabled us to hear Dr Daniel Kastner - scientific director of the Division of Intramural Research at the National Human Genome Research Institute in Bethesda - speaking about auto-inflammatory syndromes. These patients suffer from systemic or localised inflammatory outbreaks with no high levels of antibodies or antigen-specific T cells due to innate immunity deregulation that may or may not be hereditary. These illnesses are characterised by inflammatory episodes with no apparent cause, relapsing regularly with manifestations involving the skin, mucous tissues, joints, bones, digestive tract, blood vessels and the central nervous system with the possible complication of evolving towards amyloidosis. Most of these illnesses are related to activation of the interleukine-1 pathway, whose inhibition constitutes one therapeutic possibility. Other syndromes are characterised by a granulomatous inflammation. The cases most recently described (CANDLE, SAVI) are interferon-dependent.
Dr Kastner and his team proposed this concept of auto-inflammatory illness in 1999, having discovered a new disease, TRAPS (TNF Receptor-Associated Periodic Syndrome). TRAPS and the other auto-inflammatory illnesses have a number of points in common: recurrent fever, migratory cutaneous eruptions, severe abdominal pain, episodes of arthritis. Because of these skin symptoms, dermatologists may find themselves among the first consulted and must therefore be able to bring up this possibility and thus enable precious time to be saved in starting treatment. Certain pathologies can be very severe, such as the most recently described DADA 2 (Deficiency of ADA 2), causing strokes from the age of 2.
The best known of these illnesses is Familial Mediterranean fever (FMF): a recessive, autosomal, hereditary illness, comprising self-limited episodes lasting 1-3 days of fever, serotitis, arthritis and eruptions due to mutation of the Familial Mediterranean fever (MEFV) gene on chromosome 16. The rash is evocative in cases of Erysipelas-like erythema, resembling an isolated insect bite, or associated with systemic manifestations. It may develop into amyloidosis AA and outbreaks are controlled by colchicine which reduces IL-1 levels. Clostridium difficile or botulinum may also be involved in this pathology.
TRAPS associated with a dominant autosomal mutation of the TNFRSF1A gene may also develop into amyloidosis AA, but unlike the case of Mediterranean fever, there is no ethnic predisposition; it involves episodes of fever, serotitis and eruptions that may last several weeks and there is no response to colchicine. Two eruption characteristics are evocative of this syndrome: periorbital oedema or erythema starting on one thigh for example, then becoming generalised by migration.
Between the two, Hyper IgD with periodic fever syndrome (HIDS), now more commonly known as MKD (Mevalonate Kinase Deficiency), involves outbreaks of abdominal pain, arthritis, encephalitis, rash, cervical adenopathy for between 3 and 7 days, which start very young (during the first year of life) and may be triggered by vaccinations or minor infections. The onset of amyloidosis AA is rarer in this case, transmission of the Mevalonate Kinase gene mutation is recessive and it mainly affects the populations of northern Europe. Outbreaks react to Anakinra, IL-1 receptor antagonist.
CAPS (Cryopyrin Associated Periodic Syndromes) is a group of dominant, autosomal transmission diseases characterised by increased release of IL-1 and including pathologies dominated by an urticarial rash. These include Muckle Wells syndrome, familial cold autoinflammatory syndrome (FCAS with cold-induced rash with arthralgia and conjunctivitis) and aseptic chronic meningitis. These pathologies have no ethnic predisposition, are related to mutation of the NLPR 3 gene and there is a possibility of amyloidosis developing. NOMID/CINCA syndrome (Neonatal-Onset Multisystem Inflammatory Disease/Chronic Infantile Neurologic Cutaneous and Arthritis) is part of the spectrum and represents the most severe phenotype. The over-production of IL-1 is chronic and in this syndrome, inflammation is continuous, with intermittent outbreaks affecting the central nervous system, internal ear and bones. Anakinra enables rapid resolution of the inflammatory manifestations.
Dr Kastner also mentioned the PAPA syndrome, caused by a mutation of the PSTPIP 1 gene, characterised by the association of septic arthritis, pyoderma gangrenosum and acne, DIRA (Deficiency of IL-1 Receptor Antagonist) with skin rash and multifocal bone locations, STING-associated Vasculopathy with onset in Infancy (SAVI) liable to result in finger amputations and counted among the interferonopathies Ref available for download: Lui Y et al, Activated STING in a vascular and pulmonary syndrome. N Engl J Med 2014; 371:507-18 and CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy with Elevated temperature syndrome) Available for download: Liu Y et al, Mutations in PSMB8 cause CANDLE Syndrome with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum 2012;64:895-907. This syndrome reported for 5 young patients starts during the first year of life and consists in recurrent fever outbreaks, purpural skin lesions, and violaceous swelling on the eyelids, arthralgias, and progressive lipodystrophy. Cutaneous biopsy typically reveals an atypical, mixed, mononuclear and neutrophilic infiltrate and enables diagnosis to be confirmed.
He emphasised the most recently described illness, DADA 2 (Deficiency of ADA 2: adenosine deaminase), characterised by fever and strokes, occurring from an early age, with a presentation of two clinical cases. The first was a child of 2 years, with a rash and catastrophic neurological damage, the second, a six year-old who had already suffered 6 strokes; both children exhibited the same genetic anomaly resulting in an ADA 2 deficiency. Clinical presence of eruptions, helix necrosis and haemorragic and ischemic strokes. Anti-TNF treatments appear to be effective.
These may be extremely rare and often paediatric syndromes, but most of them involve a more or less characteristic dermatological manifestation at some point. Knowing to mention them when faced with sometimes banal but old, recurrent skin lesions with a family history may help to launch a genetic investigation that could result in proper treatment.
Coming back to a more practical subject, interventional dermatology. Another plenary session, led by Prof. Christopher Zachary - Chair of the Department of Dermatology at the University of California - enabled a review of 5 new technologies that may impact our practices.
- Daylight PDT appears to be less used in the US than in Europe. Prof. Zachary recalls its advantages: a technique that is less painful and just as effective as conventional PDT, with a highly satisfactory cost-effectiveness ratio
- "Body Sculpting" is booming, particularly thanks to cold techniques which have proved their effectiveness with predictable results in reducing the thickness of fat by up to 25% and a relatively pain-free procedure. New arrivals to this market are devices that use heat with systems similar to infra-red (1060 nm), the results of which were presented at the congress of the American Society for Laser Medicine and Surgery in 2015. However, Prof Zachary warned against rushing into early purchase because of the large number of systems that are ineffective for this indication.
- Picosecond lasers now exist for tattoo removal, offering better results for a wider range of pigments than Q-switched nanosecond systems. The current cost of acquisition of around $300,000 is expected to fall as competition increases in the future, and is likely to settle at around $150,000.
- Ablative and non-ablative fractional lasers can now be used for the treatment of scars, particularly for victims of the wars in Afghanistan and Iraq or for serious burn victims, improving not only the scar's appearance, but also the functionality of the limbs treated. Prof Zachary also uses these lasers for sclerodermal symptoms in GVH patients, with improved mobility and sensations and less pain.
- The pulsed colour laser is not the only instrument for treatment vascular malformations. The 755nm Alexandrite is effective for deeper lesions, and the 532nm and even the 1064nm can be used with the necessary precautions to reduce the risk of scarring. Systems using the Traser (Total Reflection Amplification of Spontaneous Emission of Radiation) will soon be available on the market. These systems will be very powerful, offering the possibility of varying wavelength and duration of the pulse and a very large spot size.