VITILIGO TREATMENT GUIDELINES Professor Andrija Stanimirović, MD, PhD 1 Department of Clinical Medicine, University of Applied Health Sciences, Mlinarska

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

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

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)

RESULT OF: Poor criteria (diagnosis and effectiveness) sharing Poor outcomes sharing

Variable therapy durationHome-made non-uniform trial designs

• 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

• 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

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

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)




• 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)

Nordlund JJ 2008

Nordlund JJNordlund JJ 2008

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.

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.

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


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)


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

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


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


3rd line therapy: vitiligo unsuccessfully treated with total body phototherapy

308 nm LASER + TOPICAL STEROIDS

ALTERNATIVE:•ADJUNCT 308 nm LASER + TOPICAL CALCINEURIN INHIBITORS


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

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


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

b) Algorithm for SV


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

b) Algorithm for SV


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

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


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


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


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



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


Dear God when will this presentation end!?

DEATH BY POWERPOINT!

Falabella R, Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res. 2009;22:42-65.



• 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

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%

Vitiligo Therapy 2014/15 General Short Remarks

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

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)

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

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

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

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

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

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

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

AFAMELATONIDE

• Simplified form of alpha-melanocyte stimulating hormone (α-MSH) - stimulates melanocytes to grow and produce melanin pigment

• Afamelatonide + NBUVB = faster repigmentation?

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

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

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


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


PUVA PHOTOTHERAPY (only in specialist units)

3rd therapeutic recommendation

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.


4th therapeutic recommendation

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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Documents

VITILIGO TREATMENT GUIDELINES Professor Andrija Stanimirović, MD, PhD 1 Department of Clinical Medicine, University of Applied Health Sciences, Mlinarska