Vitiligo: Critical Review of Medical Treatments 4th Russian Congress of Dermatovenereology 2nd Continental Congress of Dermatology Saint Petersburg, July 6-9, 2011Robert A. Schwartz MD, MPH, FACPProfessor and Head, DermatologyProfessor of Preventive MedicineProfessor of PathologyProfessor of MedicineProfessor of PediatricsUMDNJ-New Jersey Medical School
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: 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. eMedicinePediatrics [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 1Janniger 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 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
Vitiligo TherapyBest Candidates Stable vitiligo Vitiligo in children Vitiligo on sun-exposed areas Face and neck vitiligo Perioral and periorbital vitiligo
Vitiligo TherapyLess Desirable Candidates Less effective on trunk and limbs Least effective on acral extremities Segmental vitiligo
Vitiligo TherapyEvaluating 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 benefitWhitton 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 vitiligoWhitton 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 inhibitorsFalabella R, Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res2009;22:42-65.
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 beforeMandelin J, Remitz A, Reitano S: Effect of oral aspirin on burning by tacrolimus. Arch Dermatol 146: 1178-1180, 2010.
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.)
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 examinedBecatti M, Prignano F, Fiorillo C, Pescitelli L, Nassi P, Lotti T, Taddei N. The involvement ofSmac/DIABLO, p53, NF-kB, and MAPK pathways in apoptosis of keratinocytes from perilesionalvitiligo 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 repigmentationSchallreuter KU, Rokos H. Turmeric (curcumin): a widely used curryingredient, can contribute to oxidative stress in Asian patients with acutevitiligo. 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
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
Broadband & Narrowband UVBTreatment N° Studies N° Duration Results Stud. included Patients TreatingBroad-B 2 1 14 12 m 57%UVBNarrow-BUVB 9 1 51 12 m 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 N° of Patients side-effectsBroad-B UVB 14 0Narrow-B UVB 51 0