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VITILIGO TREATMENT GUIDELINES
Professor Andrija Stanimirović, MD, PhD
1Department of Clinical Medicine, University of Applied Health Sciences, Mlinarska 38, Zagreb, Croatia 2Private Dermatovenerology Office, Huga Badalića 26, Zagreb, Croatia3Croatian Vitiligo Association
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Why guidelines in medicine?
• Systematically developed statements that assist the clinician in choosing the most appropriate therapy for a specific condition
• Tools to reduce inappropriate care• Tools which control geographic variations in
practice patterns• Tools which make the use of health care
resources more effective• Recommendations linked directly to
scientific evidence of effectiveness
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GuidelineAlgorithm
Chronic plaque-type psoriasis
basictherapy
mildBSA < 10%PASI < 10 P
moderateBSA > 10%PASI > 10 P
severe
Topicaltherapy
Systemictherapy
Calcineurininhibitors
Cortico-steroids
Dithranol
Laser
Tazarotene
Vitamin D3Combined:Climatebalneotherapy
Calcineurininhibitors
Coaltar
Cyclosporine
FumaricAcid Esters
Methotrexate
Retinoids
UV
Efalizumab
AdalimumabUstekinumab
Etanercept
Infliximab
Evidence-based (S3)Guidelines for theTreatment of PsoriasisVulgarisNast et al., J Dtsch DermatolGes 5 (Suppl. 3), 2007Nast et al., Arch Dermatol Res299.111-138, 2007 (short version)
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RESULT OF: Poor criteria (diagnosis and effectiveness) sharing Poor outcomes sharing
Variable therapy durationHome-made non-uniform trial designs
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• Total of 96 studies with 4512 participants state: 24/02/15
• 21/39 (54%) of the new studies assessed new treatments, most of which involved the use of light
• NB-UVB light - used in 35/96 (36% of all included studies), alone/in combination with other therapies - the best results
• The majority of studies (53/96, 55%), most of which were of combination treatments with light, assessed > 75% repigmentation
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• 9/96 (9%)- the quality of life of participants• The majority of all studies (65/96, 68%) reported
adverse effects, mainly for topical treatments• Neither mometasone furoate nor hydrocortisone
produced adverse effects• The majority of the studies reporting successful
repigmentation = combinations of various interventions with light
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Where do we stand in vitiligo?
• Lack of definitive and completely effective therapies
• The most effective treatments: phototherapy and combined therapy
• THERAPEUTIC GOALS:– Stopping the progression of the
disease – Satisfactory repigmentation– Maintenance of the pigment
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GUIDELINES FOR VITILIGO – FIRST STEPS
• TEAM (Njoo et al):– 1 main investigator – 2 staff members of the Department of
Dermatology– Clinical epidemiologist– Clinical librarian– External expert on pigmentary disorders
• EVALUATION: questionnaire + structured interview = 14 questionnaires/23 sent
• Meta-analysis of the literature (63 studies - localized vitiligo,117 studies - generalized vitiligo)
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GUIDELINES FOR VITILIGO – FIRST STEPS
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GUIDELINES FOR VITILIGO – FIRST STEPS
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GUIDELINES FOR VITILIGO – FIRST STEPS
• The guidelines were followed for most adults
• Children with vitiligo - 52% followed the guidelines (no further distinction was made in the several clinical types or the disease activity)
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Nordlund JJ 2008
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Nordlund JJNordlund JJ 2008
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PRESENT THERAPEUTIC ALGORITHMS FOR VITILIGO
TREATMENT• Gawkrodger DJ, Ormerod AD, Shaw L, et al.
Algorithm for the management of vitiligo in adults and children by non-specialists in UK. Postgrad Med J. 2010;86:466-71.
• Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol. 2011;65:493-514.
• Taieb A, Alomar A, Böhm M, et al. VITILIGO EUROPEAN TASK FORCE. Guidelines for the management of vitiligo: the European Dermatology Forum Consensus. Br J Dermatol. 2013;168:5-19.
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PRESENT THERAPEUTIC ALGORITHMS FOR VITILIGO
TREATMENT-ctd.• Oiso N, Suzuki T, Wataya-Kaneda M, et al. Proposed
algorithm for the management of vitiligo in Japan. J Dermatol. 2013;40:344-54.
• Stanimirović A, Šitum M, Kostović K, et al. Proposal for Guidelines for the Treatment of Vitiligo in Croatia. Global Journal of Dermatology and Venereology 2014;2(1):19-26.
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Algorithm for the management of vitiligo in adults and children by non-specialists in UK. (Modified from: Gawkrodger DJ et al. Source: Postgrad Med J. 2010;86:466-71.)
Diagnosis of vitiligo:- Classical presentation: primary care- Atypical presentations: dermatologist- Adults: thyroid blood tests
a) NO TREATMENT OPTION:• ADULTS AND CHILDREN WITH SKIN TYPES I and II - NO ACTIVE TREATMENT OTHER THAN CAMOUFLAGE AND SUNSCREENS
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Algorithm for the management of vitiligo in adults and children by non-specialists in UK. (Modified from: Gawkrodger DJ et al. Source: Postgrad Med J. 2010;86:466-71.)
b) TOPICAL TREATMENT:
1. ADULTS WITH RECENT ONSET OF VITILIGO AND CHILDREN: POTENT/VERY POTENT TOPICAL STEROIDS - no more than 2 months (skin atrophy - common side effect)
2. ADULTS: TOPICAL PIMECROLIMUS (better safety profile)
3. CHILDREN: TOPICAL PIMECROLIMUS/TACROLIMUS (better safety profile)
4. ADULTS SEVERELY AFFECTED BY VITILIGO: DEPIGMENTATION (only by a specialist dermatology unit)
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Algorithm for the management of vitiligo in adults and children by non-specialists in UK. (Modified from: Gawkrodger DJ et al. Source: Postgrad Med J. 2010;86:466-71.)
c) PHOTOTHERAPY, SYSTEMIC THERAPY AND SURGICAL TREATMENTS:•Only in specialist units•SURGICAL TREATMENTS- NOT RECOMMENDED IN CHILDREN
d)PSYCHOLOGICAL TREATMENT:•Assessment of the psychological and QoL effects of vitiligo on adults and children•Psychological interventions •Parents of children with vitiligo - psychological counseling
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Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol. 2011;65:493-514.
1st line therapy: treatment of naive vitiligo
•TOPICAL STEROIDS OR•TOPICAL STEROIDS + TOPICAL VITAMIN D3 ANALOGS
ALTERNATIVE:
•TOPICAL CALCINEURIN INHIBITORS•SYSTEMIC STEROIDS •TOPICAL L-PHENYLALANINE•TOPICAL ANTIOXYDANTS AND MITOCHONDRIAL STIMULATING CREAM •NATURAL SUNLIGHT WITH PO KHELLIN
RAPIDLY PROGRESSIVE VITILIGO → SYSTEMIC
STEROIDS
RECALCITRANT LESIONS ON EXTREMITIES→
TACROLIMUS NIGHTLY UNDER OCCLUSION
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Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol. 2011;65:493-514.
2nd line therapy: vitiligo recalcitrant to first line therapy
•NBUVB + TOPICAL CALCINEURIN INHIBITORS
ALTERNATIVE:
•ADJUNCT NBUVB THERAPY WITH PO ANTIOXYDANTS •SYSTEMIC STEROIDS /POLYPODIUM LEUCOTOMOS EXTRACT•PUVA •SYSTEMIC STEROIDS •TOPICAL VITAMIN D3 ANALOGS •PO KHELLIN •PO L-PHENYLALANINE/TOPICAL L-PHENYLALANINE
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Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol. 2011;65:493-514.
3rd line therapy: vitiligo unsuccessfully treated with total body phototherapy
308 nm LASER + TOPICAL STEROIDS
ALTERNATIVE:•ADJUNCT 308 nm LASER + TOPICAL CALCINEURIN INHIBITORS
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Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol. 2011;65:493-514.
4th line therapy: vitiligo recalcitrant to 1st, 2nd and 3rd line therapy
•BLISTER GRAFT •SPLIT THICKNESS SKIN GRAFT •PUNCH GRAFT •AUTOLOGOUS MELANOCYTE TRANSPLANT
SEGMENTAL VITILIGO:TREATMENT AS ABOVE, HE-NE LASER AS 3rd line
therapy
GENERALIZED VITILIGO:TREATMENT AS ABOVE,
DEPIGMENTATION AGENTS FOR
RECALCITRANT DISEASE
CAMOUFLAGE AND
PSYCHOTHERAPY SHOULD BE
OFFERED TO PATIENTS AT ALL
STAGES OF TREATMENT
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Guidelines for the management of vitiligo: the European Dermatology Forum Consensus. (Modified from Taieb A et al. Source: Br J Dermatol. 2013;168:5-19.)
a)Simplified algorithm for NSV
Diagnosis of NSV: Avoidance of triggering factors
STABILIZATION
STABILIZATION AND REPIGMENTATION:NB-UVB (9 months)
STABILIZATION AND REPIGMENTATION CESSATION:SURGICAL TREATMENT
INITIAL RECOMMENDATION NB-UVB (3 months) + - /systemic/topical therapies (LOCAL
CS/TIM ) Camouflage
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Guidelines for the management of vitiligo: the European Dermatology Forum Consensus. (Modified from Taieb A et al. Source: Br J Dermatol. 2013;168:5-19.)
a)Simplified algorithm for NSV
PROGRESSION
• CS MINIPULSE (3-4 months)• OTHER IMMUNOSUPPRESSANTS
STABILIZATION AND REPIGMENTATION AFTER PERIOD OF PROGRESSION: NB-UVB (9 months)
NO REPIGMENTATION, KOEBNER PHENOMENON +: DEPIGMENTATION
STABILIZATION WITH OR WITHOUT REPIGMENTATION, KOEBNER PHENOMENON -: SURGICAL TREATMENT
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b) Algorithm for SV
Guidelines for the management of vitiligo: the European Dermatology Forum Consensus. (Modified from Taieb A et al. Source: Br J Dermatol. 2013;168:5-19.)
Diagnosis of SV: Avoidance of triggering factors
STABILIZATION
STABILIZATION AND REPIGMENTATION: NO THERAPY
STABILIZATION WITH OR WITHOUT REPIGMENTATION: SURGICAL TREATMENT
INITIAL RECOMMENDATION: LOCAL CS/TIM
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b) Algorithm for SV
Guidelines for the management of vitiligo: the European Dermatology Forum Consensus. (Modified from Taieb A et al. Source: Br J Dermatol. 2013;168:5-19.)
PROGRESSION
NB-UVB MEL
STABILIZATION AND REPIGMENTATION AFTER PERIOD OF PROGRESSION: NO THERAPY
NO REPIGMENTATION, KOEBNER PHENOMENON +: CAMOUFLAGE
STABILIZATION WITH OR WITHOUT REPIGMENTATION, KOEBNER PHENOMENON -: SURGICAL TREATMENT
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Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40:344-54.)
Diagnosis of vitiligo:• VASI score• Age • Affected duration
a) Complication (+) refer patient to specialist: Treatment of
vitiligo as shown in complication (-)
b) Complication (-)
Camouflage should be available for all patients
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Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40:344-54.)
STABLE (5 years or more after occurence)
1st therapeutic option: NB-UVB/PUVA +/- TOPICAL CORTICOSTEROIDS/ TOPICAL VITAMIN D3 ANALOGUES
2nd therapeutic option:TOPICAL VITAMIN D3 ANALOGUES + SUN EXPOSURE
3rd therapeutic option:308-nm EXCIMER LASER/LIGHT
4th therapeutic option:SKIN GRAFTING
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Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40:344-54.)
PROGRESSIVE (5 ≤ years after occurence, or variable in size) on patient 15 ≤ years old with lesions on face
1st therapeutic option: TOPICAL VITAMIN D3 ANALOGUES
2nd therapeutic option:TOPICAL CORTICOSTEROIDS
3rd therapeutic option:SKIN GRAFTING
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Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40:344-54.)
PROGRESSIVE (5 ≤ years or after occurence, or variable in size) on patient 15 ≤ years old with lesions on trunk and extremities
1st therapeutic option: TOPICAL CORTICOSTEROIDS
2nd therapeutic option:TOPICAL TACROLIMUS
3rd therapeutic option:TOPICAL VITAMIN D3 ANALOGUES + SUN EXPOSURE
4th therapeutic option:SKIN GRAFTING
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Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40:344-54.)
PROGRESSIVE (5 ≤ years after occurence, or variable in size) on patient 16 ≥ years old
1st therapeutic option: NB-UVB/PUVA +/- TOPICAL CORTICOSTEROIDS/ TOPICAL VITAMIN D3 ANALOGUES
2nd therapeutic option:308-nm EXCIMER LASER/LIGHTORTOPICAL VITAMIN D3 ANALOGUES + SUN EXPOSURE
3rd therapeutic option:ORAL CORTICOSTEROIDS /IMMUNOSUPPRESSIVE AGENTS
4th therapeutic option:SKIN GRAFTING
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Dear God when will this presentation end!?
DEATH BY POWERPOINT!
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Falabella R, Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res. 2009;22:42-65.
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Falabella R, Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res. 2009;22:42-65.
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Falabella R, Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res. 2009;22:42-65.
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• 470 vitiligo patients, less than 10% affected skin• Tacrolimus 0.1% ointment• Pimecrolimus 1% cream• Betamethasone dipropionate 0.05% cream• Calcipotriol ointment 50mcg/g• 10% L-phenylalanine cream• ALONE/IN COMBINATION WITH 311-nm NB-UVB
MICROPHOTOTHERAPY
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Percentage of repigmentation in patients treated with 311-nm NBUVB microphototherapy(BIOSKIN® ) alone or in combination, or with active topical treatment aloneTreatment (n° of patients) Excellent
(>75%)Marked (50-75%)
Moderate (25-50%)
Minimal (<25%)
Group 1: BIOSKIN® alone (100) 72% 19.8% 4.6% 3.6%
Group 2: 0.1% Tacrolimus + BIOSKIN® (59) 76.5% 18.2% 3.3% 2%
Group 3: 1% Pimecrolimus + BIOSKIN® (63) 76.1% 20.1% 2.7% 1.1%
Group 4: Betamethasone dipropionate 0.05% + BIOSKIN® (28)
90.2% 6.7% 2.2% 0.9%
Group 5: Calcipotriol ointment 50 mcg/g + BIOSKIN® (60)
75.6% 14.1% 7.4% 2.9%
Group 6: 10% L-Phenylalanine + BIOSKIN® (60)
74.8% 11.3% 10.1% 3.8%
Group 7: 0.1% Tacrolimus alone (22) 61% 16.1% 18.4% 4.5%
Group 8: 1% Pimecrolimus alone (19) 54.6% 18.4% 21.7% 5.3%
Group 9: Betamethasone dipropionate 0.05% alone (23)
71.2% 25% 2.1% 1.7%
Group 10: Calcipotriol ointment 50 mcg/g (18)
59.1% 10.6% 27.1% 3.2%
Group 11: 10% L-Phenylalanine alone (18) 29.3% 8.1% 55% 7.6%
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Vitiligo Therapy 2014/15 General Short Remarks
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TOPICAL CORTICOSTEROIDS
• Limited, non-facial involvement: potent TCS, once daily for 4 months or 15 days/month for 6 months
• First and safest choice: potent TCS rather than super potent
• Suspicious systemic absorption: consider mometasone furoate or methylprednisolone aceponate
• Facial involvement: consider topical calcineurin inhibitors (TCI) rather than TCS
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TOPICAL CALCINEURIN INHIBITORS
• New and fast, actively spreading lesions and involvement of face/neck areas
• Twice daily, initially for 6 months, both adults and children
• Safety profile is better concerning the risk of skin atrophy
• During the treatment: moderate but daily sun exposure, without previous cream application
• If effective, consider prolonged treatment (↑12 months)
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NBUVB AND TARGETED PHOTOTHERAPIES
• Total body NB UVB for NSV- arrest and repigment vitiligo
• Targeted phototherapies: localized vitiligo, recent onset vitiligo & childhood vitiligo
• Maximum cycle duration- 1 year for adults and 6 months for children. One year interruption between cycles!
• Halting of treatment: if no results in 3 months or if ↓ 25% repigmentation in 6 months
• Maintenance treatment-not recommended• Regular follow- ups necessary
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PUVA AND PHOTOCHEMOTHERAPY
• Oral PUVA-second or third line therapy in adults
• 12 to 24 months therapy
• Topical PUVA-very low dosage psoralens creams• However, actually relatively opsolent
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COMBINATION TREATMENTS
• Topical steroids and phototherapy• In addition peroral antioxidants• For difficult to treat areas such as bony prominences,
hands and feet• Highly potent topical steroids once a day (3 weeks out
of 4) for the 3 first months of phototherapy• Whole time peroral antioxidants
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COMBINATION TREATMENTS-ctd
• Topical calcineurin inhibitors and phototherapy• Effective and provides better results that the two
treatments separately alone• Should be used with precautions due to
carcinogenicity ?• Use of adequate photoprotection due to the lack of
data on long term safety (or not) of combination of TCI and UV
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COMBINATION TREATMENTS-ctd
Vitamin D analogues and phototherapy:• Not recommended, data of efficacy lacking
Phototherapy and peroral therapy:• Phototherapy+oral antioxidants possibly beneficial
Phototherapy after surgery:• NB-UVB or PUVA should be used for 4 weeks after
melanocyte transplatation
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ORAL STEROIDS/OTHER IMMUNUNOSUPPRESSANTS
ORAL CORTICOSTEROIDS MINI PULSE:• For stabilization of vitiligo - not useful as
repigmentating therapy
• For fast spreading vitiligo- weekend OMP (2.5 mg/day) of dexamethasone before phototherapy-useful as disease halting therapy
• Optimal duration of OMP to stop vitiligo progression is 3-6 months
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OTHER IMMUNUNOSUPPRESSANTS/
BIOLOGICSCyclophosphamide, Cyclosporine, MTX, Tetracyclines, & Anti-TNF-α:• Currently not yet recommended due to lack of data
and because of the possible side effects
Statins - promising
Low dose cytokines-promising
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AFAMELATONIDE
• Simplified form of alpha-melanocyte stimulating hormone (α-MSH) - stimulates melanocytes to grow and produce melanin pigment
• Afamelatonide + NBUVB = faster repigmentation?
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OTHER SYSTEMIC INTERVENTIONS: ANTIOXYDANTS
• Vitamin E• Vitamin C• Ubiquinone• Lipoic acid• Polypodium Leucotomos• Ginko biloba etc.
o Antioxidant supplementation could be useful during UV therapy and reactivation phases
o Combination therapy with UVB and topical therapy is recommended
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SURGERY
• For NSV- patients with stable disease and negative Koebner phenomenon
• Risk of relapse?
• For SV and other localized vitiligo forms-after failure of medical interventions
• Only in specialized units
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Stanimirović A, Šitum M, Kostović K, Bulat V, Kovačević M, Kaštelan M, Puizina-Ivić N, Pustišek N, Čulav-Košćak I. Proposal for Guidelines for the Treatment of Vitiligo in Croatia. Global Journal of Dermatology and Venereology 2014;2(1):19-26.
POTENT TOPICAL CORTICOSTEROIDS
TOPICAL CALCINEURIN INHIBITORS (genital area and armpits in adults and children)
TOPICAL CORTICOSTEROIDS + TOPICAL VITAMIN D ANALOGUES
MINI ORAL PULSED CORTICOSTEROID TREATMENT (progressive, fast spreading vitiligo)
1st therapeutic recommendation
OR
OR
OR
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Stanimirović A, Šitum M, Kostović K, Bulat V, Kovačević M, Kaštelan M, Puizina-Ivić N, Pustišek N, Čulav-Košćak I. Proposal for Guidelines for the Treatment of Vitiligo in Croatia. Global Journal of Dermatology and Venereology 2014;2(1):19-26.
NB-UVB 311nm PHOTOTHERAPY
NB-UVB 311nm PHOTOTHERAPY +POTENT TOPICAL CORTICOSTEROIDS
NB-UVB 311nm PHOTOTHERAPY + TOPICAL CALCINEURIN INHIBITORS
NB-UVB 311nm PHOTOTHERAPY + PERORAL THERAPY: CORTICOSTEROIDS, ANTIOXYDANTS, Polypodium Leucotomos EXTRACT
OR
OR
OR2nd therapeutic recommendation
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Stanimirović A, Šitum M, Kostović K, Bulat V, Kovačević M, Kaštelan M, Puizina-Ivić N, Pustišek N, Čulav-Košćak I. Proposal for Guidelines for the Treatment of Vitiligo in Croatia. Global Journal of Dermatology and Venereology 2014;2(1):19-26.
PUVA PHOTOTHERAPY (only in specialist units)
3rd therapeutic recommendation
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SURGICAL TREATMENT (for inactive vitiligo on prominent sites - i.e. face, hands):• BLISTER GRAFT• PUNCH GRAFT• SPLIT THICKNESS SKIN GRAFT • AUTOLOGOUS MELANOCYTE
SUSPENSION TRANSPLANT
Camouflage and cognitive behavioral therapy should be available for all patients.
Stanimirović A, Šitum M, Kostović K, Bulat V, Kovačević M, Kaštelan M, Puizina-Ivić N, Pustišek N, Čulav-Košćak I. Proposal for Guidelines for the Treatment of Vitiligo in Croatia. Global Journal of Dermatology and Venereology 2014;2(1):19-26.
4th therapeutic recommendation
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Lotti T, Merkel A, Korobko I, Šitum M, Keqiang Li, Stanimirović A, Putin V, Valle J, Obama B, Hercogova J, Castro F. World Consensus Guidelines for the Treatment of Vitiligo. Space Intergallactic Journal of Dermatology and Venereology 2016;4(1):27-31.
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[email protected] http://vrfoundation.org/