vitiligo - critical review of medical treatments by prof. r. schwartz
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Prof. Robert SchwartzVitiligo: Critical review of medical treatmentsPresentation from the World Vitiligo Symposium 2011. Sponsored by the VR Foundation.TRANSCRIPT
Vitiligo: Critical Review of
Medical Treatments 4th Russian Congress of Dermatovenereology
2nd Continental Congress of Dermatology
Saint Petersburg, July 6-9, 2011
Robert A. Schwartz MD, MPH, FACP
Professor and Head, Dermatology
Professor of Preventive Medicine
Professor of Pathology
Professor of Medicine
Professor of Pediatrics
UMDNJ-New Jersey Medical School
Conflicts of Interest
None
Vitiligo
Milk white splattering of patches
1-2% of the general population worldwide
Two types: nonsegmental and segmental
Loss of melanocytes in skin and rarely retina
Huggins RH, Janniger CK, Schwartz RA: Childhood vitiligo. Cutis 79: 277-280, 2007.
Lotti TM, Berti SF, Hercogová J, Huggins RH, Schwartz RA, Janniger CK: Vitiligo: recent
insights and new therapeutic approaches. Giornale Ital Dermatol Venereol (in press).
Vitiligo
• Non-segmental (bilateral vitiligo): chronic progressive autoimmune
• Segmental unilateral: develops at earlier age, shortened course, stabilizes
Schwartz RA, Janniger CK: Vitiligo. Cutis 60: 239-244, 1997.
Huggins RH, Janniger CK, Schwartz RA: Vitiligo. Acta Dermatovenerol Alp Panonica Adriat 14: 137-145, 2005.
Vitiligo
• Koebner phenomenon
Schwartz RA, Trotter, M.G.: Generalized vitiligo after erythroderma. Dermatologica (Basel) 167: 42-46, 1983.
Schwartz RA, Janniger CK: Vitiligo. Cutis 60: 239-244, 1997.
Huggins RH, Janniger CK, Schwartz RA: Vitiligo. Acta Dermatovenerol Alp Panonica Adriat 14: 137-145, 2005.
Vitiligo: Systemic Associations
• Other autoimmune diseases and syndromes
• Erythroderma
• Ocular pathologies
• Vogt-Koyangi-Harada (uveomeningitic) syndrome
• Alezzandini’s syndrome: uveitis, poliosis, retinitis
Huggins RH, Janusz CA, Schwartz RA: Vitiligo – a sign of systemic disease.
Indian J Dermatol Venereol Leprol 72: 68-71, 2006. Janniger CK: Alezzandrini’s syndrome. eMedicine from WebMD. Updated
2011. http://emedicine.medscape.com/article/1117255-overview
Tuberous Sclerosis
Autosomal dominant; 2/3 sporadic mutations
Characterized by widespread hamartomas of brain, eyes, skin, kidney, liver, heart and lungs
Diagnostic triad: mental retardation, epilepsy, facial angiofibromas (adenoma sebaceum)
Hypopigmented macules: earliest sign, best seen with Wood’s lamp, called “Fitzpatrick patches”
Schwartz RA, Fernández G, Kotulska K, Józwiak S: Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol 57: 189-202, 2007.
Schwartz RA, Jozwiak S, Johnson CL, Pedersen R: Tuberous sclerosis. eMedicine Pediatrics [Journal serial online]. 2011. http://emedicine.com/ped/topic2796.htm
Hypomelanosis of Ito
Bizarre bilateral irregularly shaped patches
Neurologic and muscular abnormalities
3rd commonest phakomatosis: after TSC, NF 1
Janniger CK, Sotero de Menezes M: Hypomelanosis of Ito. eMedicine Pediatrics
[journal serial online]. 2011. http://emedicine.medscape.com/article/909996-overview
Vitiligo: To Treat or Not?
No treatment
Fair-skinned patients
Patients reassured only by
explaining the nature of their
condition
Advice on use of
Camouflage products
Sun-protection
Treatment
Dark-skinned patients
Serious impairment in
their quality of life
Patients regarded as
social outcasts
Vitiligo Therapy
Best Candidates
Stable vitiligo
Vitiligo in children
Vitiligo on sun-exposed areas
Face and neck vitiligo
Perioral and periorbital vitiligo
Vitiligo Therapy
Less Desirable Candidates
Less effective on trunk and limbs
Least effective on acral extremities
Segmental vitiligo
Vitiligo Therapy
Goals
Stop progression of vitiligo
Stimulate repigmentation
Retain repigmentation
Vitiligo Therapy
Repigmentation patterns
Perifollicular: spots coalesce
Diffuse
Marginal
Vitiligo Therapy
Evaluating vitiligo therapy
Vitiligo area scoring index (VASI)
Dermatology Life Quality Index
Digital measurements
Therapy for Vitiligo
57 trials, most with less than 50 participants
15 studies showed difference in > 75% repigmentation
Combinations + UV were most with significant differences
Topical steroids produced the most adverse effects
Some evidence supports existing therapies
No studies documented long-term benefit
Whitton ME et al: Interventions for vitiligo. Cochrane Review 2010, issue 7.
Therapy for Vitiligo
Low-quality RCT for many products
Moderate evidence for topical steroids
Calcineurin inhibitors promising, esp. + UV
Combinations + UV better than monotherapy
Eximer laser better with topicals than alone
No RCT on depigmentation for severe vitiligo
Whitton ME et al: Interventions for vitiligo. Cochrane Review 2010, issue 7.
Vitiligo: Current Treatments
Oral and topical PUVA
Oral phenylalanine + UVA
Oral and topical khellin + UVA
UVB narrowband or broadband
Oral, topical and intralesional steroids
Antioxidants and calcineuron inhibitors
Falabella R, Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res
2009;22:42-65.
Topical Therapy for Vitiligo
Topical steroids
Calcineurin inhibitors
Pseudocatalase, catalase/dismutase superoxide
Vitamin D analogues (calcipotriol, tacalcitol)
Melagenina (human placental extract)
5-fluorouracil, lactic acid, anti-oxidants
Topical Khellin for Vitiligo
Topical
Chemically resembles psoralen but less phototoxic
Used to treat in conjunction with sunlight or UVA
Best study is by Cestari and associates (2001)
She compared 2% khellin plus UVA v. PUVA
Burning sensation in 3 of 14 with 2% khellin
Cestari TF, Dias MCS, Fernandes EI, Albaneze R. Comparative study of two psoralens in topical
phototherapy for vitiligo [Estudo comparativo entre psoralenos na fototerapia topica do vitiligo]. Anais Brasileiros de Dermatologia 2001;76:683–692.
Topical Steroids for Vitiligo
May arrest vitiligo and encourage repigment
Class 3 and 4 preferred: clobetasole 0.05%
Ultrapotent more effective, but limit is 2-4 mo
Follow with tacrolimus or pimecrolimus
Side effects: atrophy, striae, telangiectasia
Topical Steroids for Vitiligo
Ten studies
Quality of life
Percentage of repigmentation > 75%
Cessation of vitiligo spread
Adverse effects
Calcineurin-Inhibitor Uses
Comparable to high-potency steroids
Should be rotated with topical
steroids/other agents
May be used with systemic therapies
Topical Calcineurin Inhibitors
Fresh approach inhibits calcineurin phosphate
Lowers intracellular signaling
Inhibits T-cell activation
Inhibits transcription of pro-inflammatory cytokines
No steroid side effects
Long-term safety unproven
Calcineurin-Inhibitor Uses
Skin burning is common adverse effect
Can be severe and long-lasting
Small amount of alcohol can produce
Aspirin 500 mg one hour before prevents
Can anticipate with ASA 2-3 days before
Mandelin J, Remitz A, Reitano S: Effect of oral aspirin on burning by tacrolimus. Arch Dermatol 146: 1178-1180, 2010.
• 1991: Epidermis with vitiligo: consistent reduction in levels of catalase compared to normal healthy controls (Schallreuter & Wood)
1999: High levels of hydrogen peroxide (H2O2) confirmed in epidermis of vitiligo (Schallreuter)
1999: Vacuolation was observed in vitro in melanocytes from epidermis of patients with vitiligo, and was reversible upon addition of catalase (Schallreuter et al.)
Oxidative Stress in Vitiligo Skin
Oxidative Stress in Vitiligo Skin 2000: Melanocytes proven to remain present in the
depigmented epidermis of patients with vitiligo even after stable disease of 25 years’ duration, and can recover their functionality in vivo and in vitro upon the removal of hydrogen peroxide (Tobin et al)
2002: Results support the necessity of epidermal H2O2 removal as well as the influence of solar UV-light in the successful treatment of vitiligo
Tobin DJ et al: Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol 191: 406-416, 2000.
Schallreuter KU, Salem MM. Vitiligo. What is new. Hautarzt 61: 578-585, 2010.
Anti-oxidant Therapy for Vitiligo
Curcumin and capsaicin increase ERK
phosphorylation, thus inhibiting apoptosis
Antioxidants might represent an alternative
approach to protect against vitiligo progression
Vitiligo skin from 12 pts examined
Becatti M, Prignano F, Fiorillo C, Pescitelli L, Nassi P, Lotti T, Taddei N. The involvement of
Smac/DIABLO, p53, NF-kB, and MAPK pathways in apoptosis of keratinocytes from perilesional
vitiligo skin: Protective effects of curcumin and capsaicin. Antioxid Redox Signal. 2010;13:1309-21.
Antioxidant Therapy for Vitiligo
Dietary curcumin may not be helpful in people
using topical pseudocatalase cream for vitiligo
Based on 15 Asian vitiligo patients
8 of these avoided curcumin, with 6 having
nearly complete facial repigmentation
Schallreuter KU, Rokos H. Turmeric (curcumin): a widely used curry
ingredient, can contribute to oxidative stress in Asian patients with acute
vitiligo. Ind J Dermatol Venereol Leprol. 72:57-59, 2006.
Topical Catalase/Dismutase Superoxide
Catalase/dismutase superoxide (DSO)
Topical 0.05% betamethasone vs. DSO + 15 min sun
25 patients, each with bilateral vitiligo
Skin repigmentation assessed: digital morphometry
After 10 months, 18% v 12% same statistically
Sanclemente G, Garcia JJ, Zuleta JJ, Diehl C, Correa C, Falabella R. A double-
blind, randomized trial of 0.05% betamethasone vs. topical catalase/dismutase
superoxide in vitiligo. J Eur Acad Dermatol Venereol. 2008;22:1359-64.
Topical Catalase/Dismutase Superoxide
Catalase is of vegetable origin
Catalase + dismutase superoxide in microsphere formation
Applied to one side of face/steroid to other + sun
15 min sun between 10:30 AM and 2 PM
52% on betamethasone v. 57% repigmented
Percentage of repigmentation, 18% v 12% same statistically
Objective skin assessment: digital morphometry
Topical Catalase/Dismutase Superoxide
High epidermal H2O2, low catalase levels in vivo and
in vitro
Topical pseudocatalase + UVB phototherapy: mixed
results
Catalase DMO combination is a topical antioxidant
Reduces oxidative stress
What is digital morphometry?
Oral Therapy for Vitiligo
Ginkgo biloba
Other anti-oxidants
Polypodium leucotomos (photoprotective fern)
Betamethasone and azathioprine
L-phenylalanine, vitamin B-12, folic acid
Systemic steroids
Oral Steroid Therapy for Vitiligo
Useful to retard rapid course of vitiligo
Low dose: prednisone 0.3 mg/kg may arrest
Undesirable in other circumstances
Oral Ginkgo biloba for Vitiligo
Ginko is immunomodulatory, antioxidant, etc.
Mechanism of action in vitiligo unknown
60 mg bid x 12 weeks in 12 patients
Small 2011 Canadian study favorable
Significant improved total VASI
60 mg capsules: 240 for $5.99
Szczurko O, Shear N, Taddio A, Boon H. Ginkgo biloba for the treatment of
vitiigo: an open label pilot clinical trial. BMC Complimentary Alternative Medicine 2011: 11:21.
Ginkgo biloba
Distinctive non-flowering large tree, up to 164 feet tall
A living fossil, dating back 270 million years
Single surviving species, the ginkgo tree
Common in New York City
Treatments of Localized Vitiligo: Study Data
Treatment N°of
trials
Random
Trials
Trials
included
N°
Patients
Methoxsalen+UVA
Trioxsalen+UVA
PS+UVA
Khellin 2-3%+UVA
Khellin 5% + UVA
Class 3 steroids
Class 4 steroids
Intralesional CTC
Catalase/dismutase
21
3
5
5
4
13
7
5
4
0
0
0
2
2
4
2
1
1
4
2
2
3
3
6
7
2
4
176
33
40
81
64
235
277
77
114
Treatments of Localized Vitiligo: Study Data
Reasons for exclusion:
Double publication
Combination treatment
Obsolete drug or scheme
Series <5 patients
Absence of placebo control
Treatments of Localized Vitiligo: Evaluation of results
Treatment Recommended
duration
RPG
3 m
RPG
6 m
RPG
1year
Methoxsalen+UVA
Trioxsalen+UVA
PS+UVA
Khellin 2-3%+UVA
Khellin 5% + UVA
Class 3 steroid
Class 4 steroid
Intralesional CTC
Catalase/dismutase
1 year 2xweek
1 year 2xweek
1 year 2xweek
1 year 2xweek
1 year 2xweek
6 month 1xday
6 month 1xday
6 month 1xday
1 year 2dxday
>25%
>25%
>25%
>25%
>25%
>50%
>50%
>50%
>25%
>50%
>50%
>50%
>50%
>50%
>75%
>75%
>75%
>50%
>75%
>75%
>75%
>75%
>75%
-
-
-
>75%
Treatments of Localized Vitiligo: Results
Treatment N° of
Patients
Results %
Results
Duration
treatment
Methoxsalen+UVA
Trioxsalen+UVA
PS+UVA
Khellin 2-3%+UVA
Khellin 5% + UVA
Class 3 Corticoids
Class 4 Corticoids
Intralesional CTC
Catalase/dismutase
176
33
40
81
64
235
277
77
114
63
11
13
10
14
132
152
30
73
36%
33%
32%
12%
22%
56%
55%
39%
64%
4-6m (5m)
1-6m (5m)
6-7m (7m)
3-9m (5m)
6-9m (8m)
2-21m(8m)
2-12m(6m)
4-12m(8m)
4-24m(10m
Treatments of Localized Vitiligo: Side-effects
Treatment N°
Pat
N°
S-E
%
S-E
Photo-
toxic
Atrop Tel Acne
CTC
Methoxsalen+UVA
Trioxsalen+UVA
PS+UVA
Khellin 2-3%+UVA
Khellin 5% + UVA
Class 3 Corticoids
Class 4 Corticoids
Intralesional CTC
Catalase/dismutase
176
33
40
81
64
235
277
77
114
102
13
10
0
0
23
73
28
0
58%
39%
25%
0%
0%
10%
27%
36%
0%
102-58%
13(39%)
10(25%)
0
0
0
0
0
0
0
0
0
0
0
5/2%
39/14%
26/33%
0
0
0
0
0
0
0
8/3%
2/3%
0
0
0
0
0
0
16/7%
25/9%
0
0
Broadband & Narrowband UVB
Treatment N°
Stud.
Studies
included
N°
Patients
Duration
Treating
Results
Broad-B
UVB
Narrow-B
UVB
2
9
1
1
14
51
12 m
12 m
57%
63%
Timing for repigmentation
First results visible at 3 months of treatment
Sometimes, results visible at 1st month
Best results between 6 months-1 year
Stop treatment if no result visible after –6month
treatment
Broadband & Narrowband UVB
Treatment
N° of
Patients
N° of
side-effects
Broad-B UVB
Narrow-B UVB
14
51
0
0