Prof. Robert Schwartz Vitiligo: Critical review of medical treatments Presentation from the World Vitiligo Symposium 2011. Sponsored by the VR Foundation.

1. 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

3. Conflicts of Interest
None

4. 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).

6. 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.

7. 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.

9. 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

13. 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

15. 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

16. Vitiligo: To Treat or Not?
No treatment Treatment
 Fair-skinned patients
 Dark-skinned patients
 Patients reassured only by
explaining the nature of their  Serious impairment in
condition
 Advice on use of
their quality of life
 Camouflage products  Patients regarded as
Sun-protection

social outcasts

17. Vitiligo Therapy
Best Candidates
 Stable vitiligo
 Vitiligo in children
 Vitiligo on sun-exposed areas
 Face and neck vitiligo
 Perioral and periorbital vitiligo

18. Vitiligo Therapy
Less Desirable Candidates
 Less effective on trunk and limbs
 Least effective on acral extremities
 Segmental vitiligo

19. Vitiligo Therapy
Goals
 Stop progression of vitiligo
 Stimulate repigmentation
 Retain repigmentation

20. Vitiligo Therapy
Repigmentation patterns
 Perifollicular: spots coalesce
 Diffuse
 Marginal

21. Vitiligo Therapy
Evaluating vitiligo therapy
 Vitiligo area scoring index (VASI)
 Dermatology Life Quality Index
 Digital measurements

23. 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.

24. 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.

25. 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.

26. 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

27. 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.

28. 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

29. Topical Steroids for Vitiligo
 Ten studies
 Quality of life
 Percentage of repigmentation > 75%
 Cessation of vitiligo spread
 Adverse effects

31. Calcineurin-Inhibitor Uses
 Comparable to high-potency steroids
 Should be rotated with topical
steroids/other agents
 May be used with systemic therapies

32. 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

33. 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.

36. Oxidative Stress in Vitiligo Skin
• 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.)

37. 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.

38. 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.

39. 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.

40. 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.

41. 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

42. 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

45. What is digital morphometry?

46. 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

47. 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

48. 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.

49. 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

51. Treatments of Localized Vitiligo: Study Data
Treatment N°of Random Trials N°
trials Trials included Patients
Methoxsalen+UVA 21 0 4 176
Trioxsalen+UVA 3 0 2 33
PS+UVA 5 0 2 40
Khellin 2-3%+UVA 5 2 3 81
Khellin 5% + UVA 4 2 3 64
Class 3 steroids 13 4 6 235
Class 4 steroids 7 2 7 277
Intralesional CTC 5 1 2 77
Catalase/dismutase 4 1 4 114

52. Treatments of Localized Vitiligo: Study Data
Reasons for exclusion:
 Double publication
 Combination treatment
 Obsolete drug or scheme
 Series <5 patients
 Absence of placebo control

53. Treatments of Localized Vitiligo: Evaluation of results
Treatment Recommended RPG RPG RPG
duration 3m 6m 1year
Methoxsalen+UVA 1 year 2xweek >25% >50% >75%
Trioxsalen+UVA 1 year 2xweek >25% >50% >75%
PS+UVA 1 year 2xweek >25% >50% >75%
Khellin 2-3%+UVA 1 year 2xweek >25% >50% >75%
Khellin 5% + UVA 1 year 2xweek >25% >50% >75%
Class 3 steroid 6 month 1xday >50% >75% -
Class 4 steroid 6 month 1xday >50% >75% -
Intralesional CTC 6 month 1xday >50% >75% -
Catalase/dismutase 1 year 2dxday >25% >50% >75%

54. Treatments of Localized Vitiligo: Results
Treatment N° of Results % Duration
Patients Results treatment
Methoxsalen+UVA 176 63 36% 4-6m (5m)
Trioxsalen+UVA 33 11 33% 1-6m (5m)
PS+UVA 40 13 32% 6-7m (7m)
Khellin 2-3%+UVA 81 10 12% 3-9m (5m)
Khellin 5% + UVA 64 14 22% 6-9m (8m)
Class 3 Corticoids 235 132 56% 2-21m(8m)
Class 4 Corticoids 277 152 55% 2-12m(6m)
Intralesional CTC 77 30 39% 4-12m(8m)
Catalase/dismutase 114 73 64% 4-24m(10m

55. Treatments of Localized Vitiligo: Side-effects
Treatment N° N° % Photo- Atrop Tel Acne
Pat S-E S-E toxic CTC
Methoxsalen+UVA 176 102 58% 102-58% 0 0 0
Trioxsalen+UVA 33 13 39% 13(39%) 0 0 0
PS+UVA 40 10 25% 10(25%) 0 0 0
Khellin 2-3%+UVA 81 0 0% 0 0 0 0
Khellin 5% + UVA 64 0 0% 0 0 0 0
Class 3 Corticoids 235 23 10% 0 5/2% 0 16/7%
Class 4 Corticoids 277 73 27% 0 39/14% 8/3% 25/9%
Intralesional CTC 77 28 36% 0 26/33% 2/3% 0
Catalase/dismutase 114 0 0% 0 0 0 0

56. Broadband & Narrowband UVB
Treatment N° Studies N° Duration Results
Stud. included Patients Treating
Broad-B 2 1 14 12 m 57%
UVB
Narrow-B
UVB
9 1 51 12 m 63%

58. 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

59. Broadband & Narrowband UVB
Treatment N° of N° of
Patients side-effects
Broad-B UVB 14 0
Narrow-B UVB 51 0