Alopecia Areata: What`s New? - Dermatologische Praxis und

Alopecia Areata: What`s New? - Dermatologische Praxis und

2nd INTERNATIONAL HAIR SURGERY MASTER COURSE, Saturday October 13
EMAA 2012, 8th EUROPEAN CONGRESS October 12 -14 2012, Paris
Alopecia Areata:
What‘s New?
Ralph M. Trüeb, M.D.
Center for Dermatology and Hair
Diseases
Bahnhofplatz 1A
8304 Wallisellen (Zurich)
Switzerland
www.derma-haarcenter.ch
Alopecia areata
Definition:
Organ specific autoimmune disease of
the hair follicle with usually
• rapid
• circumscribed
• non-scarring loss of hair
• variable extent
• unpredictable course
• tendency to recurrence or chronicity.
Variable clinical presentations and
differential diagnosis
Co-morbidities and correlations to
prognosis
Therapeutic algorithm and evolving
treatments
Variability of Clinical Presentation
Reticular
Multilocular
Total/Universal
Eyebrows
Eyelashes
From: Trüeb RM. Haare. Praxis der Trichologie. Steinkopff Darmstadt 2003
Ophiasis
Beard
Differential Diagnosis: Congenital Universal Atrichia
Rare hereditary atrichia (gene defect on 8p12: human homolog of the mouse
hairless gene) in which patients are born with hair that falls out and is not replaced
(following the first hair cycle).
Biopsy reveals very few hair follicles which are dilated and without hairs, absence
of inflammatory infiltrate, and small keratinous cysts (atrichia with horn cysts)
Clinical examination reveals almost complete absence of hair and numerous
papular lesions in the face, on ellbows, and knesse (atrichia with papular lesions)
Ahmad et al. Alopecia universalis associated with a mutation in the human hair
less gene. Science 1998;279:720-24
Marie Antoinette Syndrome
Phenomenon of turning white overnight
From: Navarini AA, Nobbe S, Trüeb RM. Marie Antoinette syndrome.
Arch Dermatol. 2009 Jun;145(6):656.
Thomas More Syndrome
Phenomenon of turning
white overnight in a
male patient
From: Trüeb RM, Navarini AA.
Thomas More syndrome.
Dermatology 2010;220:55-6.
Why Henry of Navarre‘s Hair Could Not Turn White Overnight
Henry IV of France,
born December 13,1553
St. Bartholomew‘s Night Massacre
August 23 1572
Poliosis in alopecia
areata
Navarini AA, Trüeb RM. Why Henry III of Navarre's Hair probably did not turn
white overnight. Int J Trichology 2010;2:2-4
Acute Diffuse and Total Alopecia of the Female Scalp
Described in Asian women
Predominantly females > 40 years
Favorable prognosis
2% of cases of alopecia areata
Basically identical with:
• diffuse alopecia areata proposed in
1962 by Braun-Falco and Zaun in the
German literature
• Alopecia areata incognita proposed in
1987 by Rebora
Sato-Kawamura M, Aiba S, Tagami H. Acute diffuse and total alopecia of the female scalp. A new subtype of
diffuse alopecia areata that has a favorable prognosis. Dermatology 2002;205:367-73
Dermatoscope Diagnostic Tool in Alopecia Areata Incognita
Telogen effluvium
Alopecia areata
Tosti A, Whiting D, Iorizzo M et al. The role of scalp
dermoscopy in the diagnosis of alopecia areata
incognita. J Am Acad Dermatol 2008;59:64-7
Androgenetic alopecia
Pathobiology : Organ Specific Autoimmune Disease
Histopathology:
- Peribulbar lymphohistiocytic infiltrate („bee swarm“)
Immune genetic associations:
- HLA haplotypes
- cytokine gene polymorphisms
- susceptibility genes
- severity genes
Association with circulating autoantibodies:
- Thyroid
- Parietal cell
- hair specific antigens
Association with other autoimmune diseases
Response to immunomodulatory therapies:
- Corticosteroids
- Cyclosoporin
- Methotrexate
- Topical immunotherapy with DNCB, DCP, SADBE
King et al. Alopecia areata. Curr Dir Autoimmun. 2008;10:280-312.
Co-Morbidities
Other autoimmune diseases:
- Autoimmune thyroid disease (7-27%)
- Chronic atrophic gastritis with Vit. B12 deficiency
- Vitiligo
- Autoimmune polyendocrinopathy
-Lupus erythematosus
Low serum ferritin levels: Levels of seruf ferritin
- Androgenetic alopecia
37.3 ng/ml
- Multilocular alopecia areata 24.9 ng/ml
- Alopecia areata totalis
52.3 ng/ml
- Telogen effluvium
50.1 ng/ml
- Normal controls 59.5 ng/ml
Comorbidity screen
Kantor et al. Decreased serum ferritin is associated with alopecia in women. J Invest Dermatol 2003;121:985-8
Psychopathologic disorders:
- Trichotillomana
Trüeb und Cavegn. Trichotillomania in connection with alopecia areata. Cutis 1996;58:67-70
- Adjustment disorders
Autoimmune Polyendocrinopathy Syndrome (Type I)
Currently single known monogenetic autoimmune
disease (AR, mutation of the AIRE- or autommuneregulator gene):
Major clinical symptoms:
• Addison‘s disease
• Hypoparathyroidism
• Chronic mucocutaneous candidiasis
Additional features:
• Type I diabetes
• Autoimmune thyroid disease
• Pernicious anemia
• Hypergonadotropic hypogonadism
• Alopecia (areata)
• Vitiligo
Böni R, Trüeb RM, Wüthrich B. Alopecia areata in a patient with candidiasis-endocrinopathy syndrome:
unsuccessful treatment trial with diphenylcyclopropenone. Dermatology 1995;191:68-71
Alopecia Universalis and HIV-Infection
Alopecia universalis has been described both in association with HIV infection and
in the setting of immune restoration after highly active antiretroviral therapy.
Stewart MI, Smoller BR. Alopecia universalis in an HIV-positive patient: possible insight into pathogenesis.
J Cutan Pathol. 1993;20:180-3
Sereti et al. Alopecia universalis and Graves' disease in the setting of immune restoration after highly active
antiretroviral therapy. AIDS. 2001;15:138-40
Alopecia Universalis Elicited During Treatment with Anti-TNF
Single case reports and small case series of alopecia areata elicited during
treatment with infliximab and other anti-TNF therapies
From: Pelivani et al. Alopecia areata universalis elicited during treatment with adalimumab.
Dermatology 2008;216:320-3
Treatment of Alopecia Areata: What is the Evidence?
„17 trials ... with a total of 540 participants. Each trial included
6-85 participants and assessed a range of interventions that
included: topical and oral corticosteroids, topical ciclosporin,
photodynamic therapy, topical minoxidil. None showed
significant treatment benefit in terms of hair growth when
compared with placebo.“
„Few treatments have been well evaluated in randomised
trials. We found no RCTs on the use of DCP, DNCB,
intralesional corticosteroids or dithranol, although
commonly used. Although topical steroids and minoxidil are
widely prescribed and appear to be safe, there is no convincing
evidence that they are beneficial in the long-term. Most trials
have been reported poorly and are so small that any important
clinical benefits are inconclusive.
„Considering the possibility of spontaneous remission especially for those in the early stages
of the disease, the options of not being treated therapeutically or, depending on
individual preference wearing a wig may be alternative ways of dealing with this
condition.“
Delamere et al. Interventions for alopecia areata.
Cochrane Database Syst Rev. 2008 16;(2):CD004413
Prognosis
Spontaneous remission of initial attacks:
• 1/3 within 6 months
• 1/2 within 12 months
• 2/3 within 5 years, thereafter total remission rare.
Recurrence rates:
• 80% within 5 years
• 100% within 20 years
Prognosis of Alopecia totalis/universalis with
duratin > 5 years:
• Remission in 1% of children
• Remission in 10% of adults
Negative Prognostic Factors
Onset at young age (before puberty)
Longstanding disease
Ophiasis
Alopecia totalis, Alopecia universalis
Nail changes
Association with atopic dermatitis
(frequent)
Association with autoimmune
polyendocrinopathy (rare)
Nail Changes in Alopecia Areata
Nail pitting(> 30%)
Red lunulae
20-nail dystrophy (>10%)
van der Steen et al. Prognostic factors in the treatment of alopecia areata with diphenylcyclopropenone. J Am
Acad Dermatol 1991;24:227-30
Ajith et al. Efficacy and safety of the topical sensitizer squaric acid dibutyl ester in Alopecia areata and factors
influencing the outcome. J Drugs Dermatol. 2006;5:262-6
Treatment of Alopecia Areata: What about GMP?
Any treatment of alopecia areata should fulfill
the following criteria:
• Remission rates superior to spontaneous
remission rates of alopecia areata
• Proof of efficacy in half side treatment of
alopecia totalis or universalis
• Good safety profile with minimal toxicity
Depending on patient age, surface area, and
disease duration a treatment algorithm can
be designed
Concomitant :
• Treat disease modyfing comorbidities:
- iron deficiency
- zinc deficiency
- vitamine B12 deficiency
- thyroid disease
- emotional distress
ALOPECIA AREATA
AGE
• Hypnotherapy
< 10 years
No therapy or placebo therapy:
• 1% Topical hydrocortisone
• Topical mometasone
• Anthraline
• Oral zinc gluconate
> 10 years
% Surface area
< 30%
• Hair replacement (hair piece, wig)
• Hair coaching/self help organizations
> 30%
Disease duration
No success
Intralesional triamcinolone acetonide:
• Children: 5 mg/ml
• Adults: 10 mg/ml
• Eyebrows: 2.5 – 5 mg/ml
+ Topical minoxidil
+ Oral zinc gluconate
< 6 months
> 6 months
Optional: Topical clobetasol propionate
(under occlusion)
Steroid pulse therapy
• Oral minipuls therapy
• I.V. methylprednisolone
DCP or SADBE
or
Methotrexate
+ Prednisone
No success
Corticosteroid Pulse Therapy
Methylprednisolone pulse therapy:
500 mg i.v. for 3 consecutive days, 3x with an interval of 4 weeks
Alopecia areata duration < 6 months:
< 50% surface:
> 50% surface:
Total alopecia:
88.0% success
59.4% success
21.4% success
Duration > 6 months: 15.8% success
Nakjima et al. Pulse corticosteroid therapy for
alopecia areata: study of 139 patients.
Dermatology 2007;215:320-324
Oral minipulse therapy:
5 mg betamethasone on 2 consecutive days per week for 12 - 24 weeks
Agarwal et al. Twice weekly 5 mg betamethasone oral pulse therapy in the treatment of
alopecia areata. J Eur Acad Dermatol Venereol. 2006;20:1375-6.
In comparison, i.v. methylprednisolone pulse therapy with highest efficacy
Kurosawa et al. A comparison of the efficacy, relapse rate and side effects among three
modalities of systemic corticosteroid therapy for alopecia areata.
Dermatology. 2006;214:361-5
Half Side Treatment: Topical Corticosteroids
28 patients with alopecia totalis/universalis > 1 year duration
Daily Clobetasolpropionate 0.5% ointment under occlusion on 6 consecutive days
per week during 6 months
8/28 (28.5%) regrowth of hair within 6-14 weeks
In 3/8 recurrence within 12 months
Total success rate: 17.8% (5/28)
Negativ prognostic factors:
• positive family history for alopecia areata
• Disease onset before age of 10
• Atopy
• Autoimmune thyroid disease
Side effects: folliculitis/acne in 12/28
Tosti et al. Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis.
J Am Acad Dermatol. 2003;49:96-8.
Tosti A et al. Efficacy and safety of a new clobetasol propionate 0.05% foam in alopecia areata: a randomized,
double-blind placebo-controlled trial. J Eur Acad Dermatol Venereol 2006;20:1243-7
Half Side Treatment: Topical Immunotherapy (DCP)
Remission rate:
Non
Partial
Total
AA multilocularis
12.5%
43,8%
43,8%
AA subtotalis, Ophiasis
20,8%
45,8%
33,3%
AA totalis/universalis
46,4%
32,1%
21,4%
________________________________________________
Total success rate:
30,9%
Pericin und Trüeb. Topical immunotherapy of severe alopecia areata with diphenylcyclopropenone: evaluation of 68
cases. Dermatology 1998;196:418-21
Methotrexate (and Prednisone)
22 patients with AA totalis/universalis > 1 year
MTX 15 - max. 30 mg/week
+ Prednisone 20 mg
for max. 18 months after regrowth of hair
until regrowth of hair, thereafter tapered over 6-12 months
Total remission rate 64% (16/22):
68% (11/16)
50% (3/6)
combined therapy
Mtx (> 20 mg) alone
Regrowth of hair within 3-6 months:
Combined therapy
Mtx alone
2-4 months
5-7 months
Joly P. The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment
of alopecia totalis or universalis. J Am Acad Dermatol. 2006;55:632-6
Psychotherapy
Adjustment disorders frequent:
• with depressed mood (F43.20)
• with anxiety (F43.28)
• with disturbance of conduct (F43.24)
Positive effect of concomitant antidepressive therapy:
Perini et al. Imipramine in alopecia areata. A double-blind,
placebo-controlled study Psychother Psychosom. 1994;61:195-8
Cipriani et al. Paroxetine in alopecia areata. Int J Dermatol
2001;40:600-1.
From: Willemsen et al. Hypnotherapeutic
management of alopecia areata.
J Am Acad Dermatol. 2006;55:233-7
Succesful Treatment of Alopecia Areata
F, 66-years old, diffuse alopecia areata, methylprednisolone pulse therapy,
3 x 500 mg i.v. on 3 consecutive days, 3 times on monthly basis
Ref. Nakjima et al. Pulse corticosteroid therapy for alopecia areata: study of 139 patients.
Dermatology 2007;215:320-324
F, 21-years old, mutilocular alopecia areata, 3 months combination of intralesional triamcinolone
acetonide 10 mg/ml and 5% topical minoxidil 0.2% triamcinolone acetonide twice daily
Ref. Abell und Munro. Intralesional treatment of alopecia areata with triamcinolone acetonide by jet injector.
Br J Dermatol 1973;88:55-9
M, 38-years old, 6 month clobetasol propionate under occlusion overnight 6 days/week
Ref. Tosti et al. Clobetasol propionate 0.05% under occlusion in the treatment of
alopecia totalis/universalis.J Am Acad Dermatol. 2003;49:96-8.
F, 12-years old, subtotal alopecia areata (ophiasis), 12 months DCP therapy (1.0%)
Ref. Pericin und Trüeb. Topical immunotherapy of severe alopecia areata with diphenylcyclopropenone:
evaluation of 68 cases. Dermatology 1998;196:418-21
F, 43-years old, total alopecia (areata), 18 months, initialy methotrexate 30 mg weekly and
prednisone 20 mg daily, tapered to methotrexate 15 mg weekly and prednisone 5 mg daily
Ref. Joly P. The use of methotrexate alone or in combination with low doses of oral corticosteroids in the
treatment of alopecia totalis or universalis. J Am Acad Dermatol. 2006;55:632-6
F, 47-years old, autosuggestion therapy/visualization exercises, 12 months
Ref. Willemsen et al. Hypnotherapeutic management of alopecia areata.
J Am Acad Dermatol. 2006;55:233-7
Hair Transplantation and Dermatography (Permanent Make Up)
From: Barankin et al. Successful hair transplant of eyebrow alopecia areata. J Cutan Med Surg 2005;9:162-4
Scalp:
Unger et al. Successful hair transplantation of recalcitrant alopecia areata of the scalp. Dermatol
Surg. 2008 Nov;34(11):1589-94.
Caveat:
Frankel EB. Alopecia areata in an area of hair transplantation. Arch Dermatol. 1984;120:435.
From: van der Velden et al. Dermatography as a new treatment for alopecia
areata of the eyebrows. Int J Dermatol 1998;37:617-621
Evolving Therapies for Alopecia Areata
Genetics
Epigenetics
Cell Dynamics
Molecular
Interaction
Network
Disease
New drug treatment opportunities based on the results of a genome-wide association
study, which implicate T cell and natural killer (NK)-cell activation pathways, are
leading to new approaches in future clinical trials of alopecia areata.
Special attention is being given to the UL 16-binding protein (ULBP3) gene cluster on
chromosome 6q25, as these genes make the NKG2D-activating ligand or signal that can
trigger the NKG2D receptor, initiating an autoimmune response.
Petukhova et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.
Nature. 2010 Jul 1;466(7302):113-7.
A greater expression of ULBP3 has been found in hair follicles in scalp biopsy specimens
from patients with active disease. It is now postulated that the characteristic T cell
"swarm of bees" infiltrate seen in alopecia areata is the result of T cells being
attracted to the hair follicle by NKG2D-activating ligands.
Complexity in pathogenesis may be an opportunity in terms of targeting the disease
therapeutically:
Future treatment approaches for alopecia areata include use of drugs that:
(i)
block the NKGD-activating ligand and NKG2D receptor interaction,
(ii)
halt activated T cells, or
(iii)
modify the inflammatory cytokine network.
Drugs currently being used or being evaluated for other autoimmune diseases that
work through these mechanisms might prove to be very effective in alopecia areata:
- CTLA4-Ig fusion protein (Abatacept)
- anti-IL15Rmab
- (Janus Kinase) JAK3-inhibitor (Tofacitinib)
- JAK1/2-inhibitor (Ruxolitinib)
blocks co-stimulation of T-cells
blocks activation of CD8+ T-cells
blocks signal transduction (IL-15R)
blocks signal transduction (IL-15R)
Hordinsky MK. Treatment of alopecia areata: "What is new on the horizon?".
Dermatol Ther 2011;24(3):364-8
Thank you for your attention!