vitiligo - critical review of medical treatments by prof. r. schwartz

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