Акценти от 2-ри ден

Frontal fibrosing alopecia, Alopecia areata, Androgynous alopecia in menopausal women, Pyoderma gangrenosum, Pemphigus management

Dr. Joséfina MARCO-BONNET

Dermatologist, France

Workshop on frontal fibrosing alopecia (FFA)

Dr. María Eugenia Cappetta (Dermatologist, Argentina)
Dr. Gabriela Alvarez Perez (Dermatologist, Argentina)
Dr. Isabella Doche (Dermatologist, Brazil)
Dr. Sandra Garcia (Dermatologist, Argentina)
Dr. Fernando Stengel (Dermatologist, Argentina)
Dr. Maria Hodinsky (Dermatologist, United States of America)
Dr. Ricardo Romiti (Dermatologist, Brazil)
Dr. Daniel Fernandes Melo (Dermatologist, Brazil)
Dr. Rubén Eduardo Spiner (Dermatologist, Argentina)

Here are some points concerning the FFA that caught my attention.

1. It is a global epidemic that has been growing for 15 years and is beginning to affect men and pre-menopausal women.

2. The dermoscopy of the FFA makes it possible to make an early diagnosis and to evaluate the development of the pathology. We must look for peripilaris scales (not always present), the absence of vellus hair (the earliest sign), the absence of follicular openings, the presence of only isolated terminal hair, pili torti, whitish areas (sign of fibrosis, late), brown and violaceous perifollicular areas (high phototypes) and perifollicular erythema.

3. It is a systemic pathology that affects the scalp as well as the eyebrows (35 to 40%), the beard (50%) and other hair (25% on the pubis, armpits and limbs). More than 60% of FFA patients have a scalp biopsy in an unaffected area with lichenoid infiltrate.

4. Eyebrows are affected before (up to several years) the first clinical signs of FFA appear. In case of alopecia of eyebrows one must place the dermoscope on the eyebrow and on the frontal hair line. Dermatoscopically we can observe dystrophic hairs growing in different directions, white patches and erythematous spots.

The treatment is done with topical tacrolimus or pimecrolimus or infiltration of corticoids diluted to 2.5mg/ml to avoid atrophy (80% response).

5. FFA is associated with

• Rosacea in 35% of cases, most often erythemato-telangiectatic or papulopustular.
• Lichen planus pigmentosus (LPP), especially in pre-menopausal women of dark phototype. It can precede the FFA by several months.
• Papules on the face (flesh-colored, erythematous-yellow). Treatment with isotretinoin at a dose of 10-20 mg/day gives very good results with papules.

6. FFA is likely to be more severe in Hispano-Latin, pre-menopausal women with facial papules. Therefore, it will be necessary to provide more aggressive treatment to these patients.

7. In terms of aetiology, there is a PPAR-gamma deficiency (a transcription factor that regulates peroxisomal lipid metabolism, which allows to maintain the integrity of the pilosebaceous unit), an alteration of the expression of substance P and calcitonin gene-related peptide (CGRP) in affected and unaffected areas (neuropeptides involved in lipid metabolism and chronic inflammatory disorders).

Genetically, it has proven susceptible in HLA-B*07:02 allele patients and studies show that girls with FFA-affected mothers develop the disease earlier. A study shows the existence of a statistically significant relationship between FFA and the use of facial cosmetics and some ingredients in sun protection (titanium dioxide, oxybenzone and avobenzone).

8. Information about treatments:

• Treatments must be combined with each other.
• Topical corticoids are not very effective.
• Topical minoxidil should always be used as it improves density and has anti-fibrosis effects.
• Isotretinoin at a 20 mg/day dose has the same efficacy as acitretin at a dose of 20 mg daily. These molecules stabilize FFA in 76% of cases and are more effective than finasteride at a dose of 5 mg/day as monotherapy.
• Hydrochloroquine at daily doses of 400 mg slows the progression of the disease. Must be avoided in case of LPP, a high phototype or the presence of rosacea.
• Finasteride (2.5 to 5 mg/day), dutasteride (0.5 mg/day), oral corticosteroids (10 to 40 mg/day), cyclins (100 mg/day), immunosuppressants, pioglitazone (PPAR 15 mg/day) and low-dose naltrexone (2 to 5 mg).

Hair implants are to be avoided in FFA, even if it is stable, due to the Koebner phenomenon that could reactivate the pathology.

Trichology: old and new concepts

Alopecia areata (AA)

Dr. Mariana Soledad Martin (Dermatologist, Argentina)
Dr. Mariana Martin spoke about alopecia areata (AA)

Dr. Martin mentioned the factors associated with poor prognosis: early onset, significant impairment, long evolution, family history, poor response to treatments, short and incomplete remissions, atopy and nail disorders. She proceeded to speak about the physiopathology of AA. It is an autoimmune pathology with disruption of NKG2D TC8, Th1 pathway (lNF g) and Th2 (IL-9 and PDE4) and Th17-23. At the hair follicle level, there is a decrease in Langherans cells, MHC class I and II, CD4/CD8 cells. NK and an increase of TGF-beta1, MSH, IGF-I and INF g. In addition, the bacterial flora of the scalp changes with an increase in propionibacterium and a decrease in staphylococcus epidermidis.

The dermoscope is an essential tool her analysis that allows her to make diagnoses and evaluate the AA activity. The signs of activity are black dots, dystrophic hair (exclamation mark hairs), fragmented hair, constrictions and cone- shaped hair, whereas signs of stabilised AA are yellow dots (abundant, homogeneous and regular), the presence of vellus hair and the absence of black dots. These signs are not specific to AA as they can also be found in trichotillomania, however will there will also be V-shaped, snake-shaped or patchy hair...

There are few studies available on the different treatments and reimbursements vary depending on the country and the practitioner. Today I will only report on the new perspectives. First of all, JAK inhibitors (tofacitinib, ruxolitinib and baricitinib) have shown better efficacy in acute forms and a faster response in localised forms compared to extended forms. The duration of the response is variable and relapse occurs when the treatment is stopped. Few studies have been made with topical forms, which would allow us to have less side effects (respiratory and urinary tract infections, digestive disorders, viral reactivation, alteration in hemogram, immunosuppression and cancer).

PRP treatment allows long-term remissions and pigmented hair regrowth. It has few side effects. However, there few high quality studies are available in literature.

Finally, simvastatin and ezetimibe, which have immunomodulatory and anti-inflammatory effects by decreasing the activity of the Th1 pathway and by activating the Th2 pathway and modulate the JAK-STAT pathway, appear to be active when used together in acute forms. This combination would be useful for preventing relapse.

Androgynous alopecia in menopausal women (AAG)

Dr. Guerrero Araya Robinson (Dermatologist, Chile)

Here is some information on Androgynous alopecia in menopausal women (AAG) provided by Dr. Guerrero Araya Robinson.

AAG is aggravated by senile alopecia, telogen effluvium secondary to certain treatments (antihypertensive, atorvastatin, anticonvulsant...) and sometimes by FFA. It is therefore necessary to treat these pathologies, eliminate deficits in zinc, iron and vitamin D. It is also necessary to eliminate signs of hyperandrogenism.

The only treatment with MA is minoxidil 2 and 5%. However, spironolactone (50-200 mg/day), finasteride (2.5 to 5 mg/day) and dutasteride (0.5 mg/day) are also used, orally or in mesotherapy. The FDA approves the use of red or infrared laser in AAG (up to 24 sessions). This laser provides good results, increasing mitochondrial activity, ATP synthesis, protein production, cell proliferation and regeneration. It normalises sebum production and has an anti-inflammatory action. Implants should be used when possible.

PRP and mesenchymal stem cell treatments are beginning to emerge.

Dr. Silvina Daniela MALDONADO

Dermatologist, Argentina

Pyoderma gangrenosum (PG)

Dr. Osvaldo Monge Masis (Dermatologist, Costa Rica)

Dr. Osvaldo Monge Masis discussed the specialised Topic of Pyoderma gangrenosum (PG).

Because studies have shown that PG is underdiagnosed by 10 to 20%, he highlighted the recent DELPHI diagnostic criteria (sensitivity and specificity of 86% and 90%, respectively) and PARACELSUS score. As is well-known, the associated conditions (50 to 78%) are IBD, hematologic diseases (paraproteinemias, monoclonal gammopathies and myelodysplastic syndromes) and inflammatory arthropathies (RA, ankylosing spondylitis). With regard to inflammatory bowel disease (IBD), PG may present before, during or even after a total colectomy, several genetic loci (IL8RA, PRDM, TRAF31P) having been identified that recruit neutrophils via IL-17, linking the aforementioned pathologies. Following a review of the standard clinical subtypes, he mentioned the postsurgical and peristomal variants and necrotising neutrophilic dermatosis. As a treatment for the acute stage, he mentioned a protocol starting with systemic corticosteroids or cyclosporine depending on the case history, combined with dapsone as an adjuvant. For maintenance, Infliximab and (as alternatives) MMF, azathioprine, cyclophosphamide or other biologicals.

What’s new in pemphigus management?

Dr. Dedee Murrell (Dermatologist, Australia)

In the Plenary Lecture, “What’s new in pemphigus management?”, Dr. Dedee Murrell mentioned the importance of a low short-term dose of systemic corticosteroids (0.5 to 1 mg/kg/d), given that 10% of pemphigus vulgaris cases present infectious complications. Combined with rituximab, this approach achieves seven times greater remission than high doses of corticosteroids associated with conventional treatments. This likewise avoids long-term depletion of B cells, and this combination has proven effective both in new patients and in those experiencing a relapse. Bruton tyrosine kinase (BTK) inhibitors have proven highly interesting; like rituximab, they are also used in cases of lymphoma. Ibrutinib (the first to be approved) suppresses B cells and other cells (monocytes, macrophages, mastocytes, basophils and neutrophils), but not T cells. BTK inhibition appears to have a broad impact on autoimmune processes without causing severe immunosuppression. The action of Rituximab produces a decline in B-cell function by inhibiting antibodies without killing the cells, and targets antigen-presenting cells. On the other hand, corticosteroids and JAK inhibitors cause inhibition of the inflammatory cells. Oral BKT inhibitors act on all of these levels, without direct action on T cells, as already mentioned.

Another molecule called PRN1008 is a powerful and selective reversible covalent BKT inhibitor. Studies of pemphigus foliaceus conducted with dogs show 95% improvement as monotherapy, and 2 of 4 dogs experienced complete
remission. Then in humans, a Phase I study with 98 healthy volunteers was administered as a liquid formulation, capsules and/or tablets, with a half-life of 4 hrs and rapid elimination without significant drug accumulation. Less than 1% is excreted unchanged in urine, and no effects were observed in ECG or laboratory values, except for one case of elevated ALT (alanine aminotransferase).

At IID Orlando 2018, preliminary data were presented for SYNT001 in 7 patients with a reduction in the PDAI score (Pemphigus Disease Area Index) and antibody levels, presenting a good safety profile, but still in development.

In conclusion, specific treatments are currently in clinical trials or in the development stage. PRN1008 is the first BTKI to be tested on autoimmune diseases with significant potential for patients with pemphigus.