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Vitiligo - critical review of medical treatments by Prof. R. Schwartz


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Prof. Robert Schwartz …

Prof. Robert Schwartz

Vitiligo: Critical review of medical treatments

Presentation from the World Vitiligo Symposium 2011. Sponsored by the VR Foundation.

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  • 1. 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
  • 2. Conflicts of InterestNone
  • 3. 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).
  • 4. 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.
  • 5. 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.
  • 6. 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.
  • 7. 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.
  • 8. 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.
  • 9. 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
  • 10. Vitiligo TherapyBest Candidates Stable vitiligo Vitiligo in children Vitiligo on sun-exposed areas Face and neck vitiligo Perioral and periorbital vitiligo
  • 11. Vitiligo TherapyLess Desirable Candidates Less effective on trunk and limbs Least effective on acral extremities Segmental vitiligo
  • 12. Vitiligo TherapyGoals Stop progression of vitiligo Stimulate repigmentation Retain repigmentation
  • 13. Vitiligo TherapyRepigmentation patterns Perifollicular: spots coalesce Diffuse Marginal
  • 14. Vitiligo TherapyEvaluating vitiligo therapy Vitiligo area scoring index (VASI) Dermatology Life Quality Index Digital measurements
  • 15. 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.
  • 16. 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.
  • 17. 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.
  • 18. 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
  • 19. 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.
  • 20. 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
  • 21. Topical Steroids for Vitiligo Ten studies Quality of life Percentage of repigmentation > 75% Cessation of vitiligo spread Adverse effects
  • 22. Calcineurin-Inhibitor Uses Comparable to high-potency steroids Should be rotated with topical steroids/other agents May be used with systemic therapies
  • 23. 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
  • 24. 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.
  • 25. 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.)
  • 26. 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.
  • 27. 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.
  • 28. 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.
  • 29. 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.
  • 30. 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
  • 31. 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
  • 32. What is digital morphometry?
  • 33. 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
  • 34. 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
  • 35. 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.
  • 36. 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
  • 37. Treatments of Localized Vitiligo: Study DataTreatment N°of Random Trials N° trials Trials included PatientsMethoxsalen+UVA 21 0 4 176Trioxsalen+UVA 3 0 2 33PS+UVA 5 0 2 40Khellin 2-3%+UVA 5 2 3 81Khellin 5% + UVA 4 2 3 64Class 3 steroids 13 4 6 235Class 4 steroids 7 2 7 277Intralesional CTC 5 1 2 77Catalase/dismutase 4 1 4 114
  • 38. Treatments of Localized Vitiligo: Study DataReasons for exclusion: Double publication Combination treatment Obsolete drug or scheme Series <5 patients Absence of placebo control
  • 39. Treatments of Localized Vitiligo: Evaluation of resultsTreatment Recommended RPG RPG RPG duration 3m 6m 1yearMethoxsalen+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%
  • 40. Treatments of Localized Vitiligo: ResultsTreatment N° of Results % Duration Patients Results treatmentMethoxsalen+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
  • 41. Treatments of Localized Vitiligo: Side-effectsTreatment N° N° % Photo- Atrop Tel Acne Pat S-E S-E toxic CTCMethoxsalen+UVA 176 102 58% 102-58% 0 0 0Trioxsalen+UVA 33 13 39% 13(39%) 0 0 0PS+UVA 40 10 25% 10(25%) 0 0 0Khellin 2-3%+UVA 81 0 0% 0 0 0 0Khellin 5% + UVA 64 0 0% 0 0 0 0Class 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% 0Catalase/dismutase 114 0 0% 0 0 0 0
  • 42. 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%
  • 43. 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
  • 44. Broadband & Narrowband UVB Treatment N° of N° of Patients side-effectsBroad-B UVB 14 0Narrow-B UVB 51 0