Акценти от 5-ти ден

Dermatomyositis, Melanoma, Emerging Systemic Treatments for AD and Humanitarian dermatology

Prof. Nadège CORDEL

Dermatologist, France

Diagnosis and management of dermatomyositis

Dr. Alisa N. FEMIA (Dermatologist, United States)
Prof. Jeffrey CALLEN (Dermatologist, United States)
Prof. Hector CHINOY (Dermatologist, United Kingdom)
Prof. Manabu FUJIMOTO (Dermatologist, Japan)
Dr. Ruth Ann VLEUGELS (Dermatologist, United States)
Dr. Victoria WERTH (Dermatologist, United States)
Dr. Sueli CARNEIRO (Dermatologist, Brazil)

This workshop on the diagnosis and management of dermatomyositis was facilitated by leading international experts, including Prof. Jeffrey CALLEN, Manabu FUJIMOTO and Hector CHINOY.

What can we learn for our practice?

Clinical

Attention should be paid to:
- Mid facial impairment: eyelids-glabella-nasal bridge with nasolabial fold impairment (unlike acute lupus which does not affect it) which can be confused with eczema or rosacea,
- Erythematous and pruritic scalp condition, which can be confused with psoriasis or incipient SD,
- Purpuric macules of the helix and antihelix equivalent to hand lesions characteristic of dermatomyositis with MDA5 antibody (Fujimoto M et al Br J Dermatol. 2019;180:1226-27).

Therapeutic

- Dermatomyositis sine myositis: plaquenil as monotherapy is rarely sufficient to achieve complete remission and the use of an immunosuppressant is often required (Vleugels et al in press JAMA Dermatol. 2019 Jan 23. doi: 10.1001/jamadermatol.2018),
- JAK inhibitors, particularly Tofacitinib, are clearly effective in the treatment of refractory dermatomyositis for which usual immunosuppressants have failed, with a fairly good clinical-biological tolerance,
- Ulcerated lesions of dermatomyositis with immunosuppressant resistant anti-MDA5 antibodies: effectiveness of active treatments on obstructive vasculopathy: aspirin, pentoxifylline, nifedipine.

Immunology

Over the past 15 years, the identification of new antibodies in dermatomyositis has revolutionised the immunological landscape of the disease. These autoantibodies, i.e. anti-MI2, anti-SAE, anti-MDA5, anti-NXP2 and anti-TIF1 gamma, are associated with a phenotype specific to the disease in terms of skin condition, visceral complications, progression or associated cancer.
Example of dermatomyositis with anti-MDA5 antibody initially described in Japan by M. Fujimoto’s team (2012):
1) typical lesions such as purpuric, often ulcerated palmar papules, characterised histologically by an obstructive vasculopathy
2) other lesions described: mechanic’s hands, alopecia, mucosal lesions
3) prognosis directly linked to the associated pulmonary impairment, the progression of which is devastating
4) need to initiate the specific treatment as soon as possible
5) never treat with corticosteroids alone, even in the absence of pulmonary impairment at the time of the diagnosis, as this impairment can manifest itself later - always combine with an immunosuppressant from the outset (generally mycophenolate mofetil)
6) ferritinemia and the level of anti-MDA5 autoantibodies are useful in monitoring the progression of the disease under treatment.

Dermatomyositis and cancer
Prof. Jeffrey CALLEN (Dermatologist, United States)
Prof. Hector CHINOY (Dermatologist, United Kingdom)

The link between dermatomyositis and cancer has been established for 40 years by large-scale cohort studies.
The identification of phenotypes specific to dermatomyositis linked to the presence of certain autoantibodies also concerns the frequency of cancer associated with the disease. Anti-TIF 1 gamma antibodies are associated with cancer in 60% to 80% of cases, as illustrated by research involving the SFD’s theme group - study of systemic diseases in dermatology, which have been cited twice.
A high prevalence of ovarian cancer is observed in patients with TIF 1 gamma positive dermatomyositis
Note: cancer must also be sought in the event of pure cutaneous dermatomyositis or dermatomyositis sine myositis.
In 2019: in the absence of international recommendations, what is the appropriate disease staging? And when?
A PET scan is irrelevant according to data from the literature and the experience of experts.
Disease staging must include a thoracic-abdominal-pelvic scan and must be adapted to the patient’s gender (mammogram, Pap smear), age and ethnicity.
It is carried out when dermatomyositis is diagnosed, and subsequently once a year for 3 years. After 3 years, the incidence of cancer within the population of dermatomyositis patients is the same as that of the general population.

Adjuvant therapy in stage 3 melanoma (locoregional metastases) have also started to change the image of melanoma: it is now clear that one-year adjuvant therapy with anti-PD-1 immunotherapy or BRAF-MEK targeted therapy is effective in preventing relapse of stage III melanoma. The improvement in relapse-free survival, from 15% to 5 years with interferon, increased to approximately 50% with immune checkpoint inhibitory immunotherapies: ipilimumab (anti-CTLA-4), marginalised due to its poor tolerance, nivolumab and pembrolizumab (anti-PD-1), andtargeted therapies, dabrafenib (BRAF) + trametinib (MEK), when melanoma presents mutations (50% of melanomas).

These drugs are therefore prescribed in stage 3 melanoma: lymph node or transit metastases are surgically treated and, assuming there are others in subclinical phase, and adjuvant therapy is prescribed to prevent relapses.
Do all patients really benefit from these new adjuvant treatments in the long term? For ipilimumab, the answer is quite clear: survival without metastasis within 7 years is 44.5% against 36.9% with placebo, but its immunological side effects are too significant, marginalising it in favour of nivolumab and pembrolizumab.
For patients with BRAF-mutated melanoma, targeted therapy and immunotherapy are equally effective. The COMBI-AD Phase III trial of dabrafenib and trametinib showed an overall survival rate of 54% versus 37% with placebo.

How long should the treatment be used for? One year was chosen arbitrarily, it seems especially important to start the treatment early to block the tumour clones, rather than prolong the treatment and thus increase its side effects.

What about stage II melanomas? Are we moving towards adjuvant treatment at this stage? Melanomas of less than 1 mm and between 1 and 2 mm are so common that they eventually account for 50% of deaths, despite a low individual risk of fatality. The rationale is clear: if we want to reduce melanoma mortality, we must try adjuvant treatments in these patients. A Phase 3 Keynote 716 trial is underway in stage 2 melanoma (pembrolizumab vs. placebo for one year).

Recent ASCO recommendations for sentinel lymph node will significantly increase the number of candidates for adjuvant therapy: the sentinel lymph node technique can now be offered to stage IB (Breslow index > 1 mm or 0.8-1 mm with other poor prognostic factors: ulceration, mitotic index > 1/mm2) and stage II patients.
Hence the importance of knowing the side effects: severe toxidermia vitiligo, lichen planus... and in general, myocarditis, Guillain-Barre syndrome, hepatitis, thyroiditis followed by permanent hypothyroidism, panniculitis, diabetes... “Bearable” in a metastatic disease but certainly less so in adjuvant treatment at an early stage of the disease... For the moment, there is a lack of bio-markers which allow to select the patients who will respond to the treatment, those who will relapse without treatment, and those who will develop side effects with adjuvant therapy.

What about neo-adjuvant treatments, i.e. before surgery? Their goal is to facilitate the operation or to replace it. Two promising trials are currently underway, one of which combines ipilimumab and nivolumab.

Do you know about the abscopal effect? It refers to a therapeutic effect of radiotherapy away from the irradiated area that occurs during immunotherapy. This effect has been reported or at least suspected in a recent French prospective cohort study of 25 patients with advanced and rapidly progressive melanoma. Only one metastatic area was irradiated, with joint administration of an anti-PD1.

In melanomas with asymptomatic brain metastases: the ipilimumab + nivolumab combination seems effective.

Once again...: BRAF inhibitor encorafenib in combination with binemitinib (anti-MEK) is currently being tested: 39% survival without relapse after 30 months.
Not to forget bempegaldesleukin, agonist of the IL2 pathway, whose purpose is to transform cold tumours, i.e. that elude the immune system, into hot tumours. Preliminary studies are underway.

Regarding the markers: Pleckstrin homology domain-interacting protein (PHIP) is a marker of poor prognosis together with melanoma ulceration, a decrease in survival without metastasis, especially in case of NRAS-mutant melanoma or with expression of the PTEN protein. This makes it a complementary marker of LDH, increased in metastatic melanoma, and especially a potential therapeutic target.

Photoprotection
It is recognized that the application of sunscreens reduces the incidence of melanoma, especially if the practice started in childhood. It is worth noting that it is the amount of applied sunscreen that is important, rather than the SPF index; switching from SPF 30 to 50 blocks only 1.7% more UV. On the other hand, an SPF 30 applied at 0.5 mg/cm2 is actually an SPF 8.8, an SPF 50 at 0.5 mg/cm2 becomes an SPF 14: the correct dose is therefore 2 mg/cm2, which is the volume of a golf ball for the entire body of an adult and which is almost never done in real life... Behavioural studies highlight the importance of accompanying our sunscreen prescription not only with a written explanation on the benefits of photoprotection, but also a “live” demonstration of the quantity that should be applied.
The state of Hawaii has recently banned sunscreens containing chemicals known to be harmful to coral reefs. The bill, which was passed by legislators in May 2018, will come into force on January 1, 2021. At this point, the sale or distribution of non-prescription sunscreens containing oxybenzone and octinoxate will be prohibited. Note that in the United States sunscreens have the “Reef friendly” label whenever possible.
Ecological considerations complicate our message, but there is no doubt that manufacturers will find effective solutions respectful of the environment and the patients, who are more and more worried about the endocrine disruptors and the toxicity of products.
An emerging problem related to this issue: home-made sunscreens. In the best case scenario, the recipes on the Internet contain zinc oxide, but often only essential oils, shea butter, coconut or avocado oil... which only have anti-inflammatory and soothing actions.