1. 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, Croatia
3Croatian Vitiligo Association

2. 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

3. Guideline Algorithm Adalimumab Ustekinumab
Chronic plaque-type psoriasis
Calcineurin inhibitors
Coaltar
basic
therapy
Cortico- steroids
mild
BSA < 10%
PASI < 10 P
Topical
therapy
Dithranol
Laser
Tazarotene
Combined:
Climate
balneotherapy
Vitamin D3
moderate
BSA > 10%
PASI > 10 P
Calcineurin inhibitors
Cyclosporine
Fumaric
Acid Esters
Efalizumab
Evidence-based (S3)
Guidelines for the
Treatment of Psoriasis
Vulgaris
Nast et al., J Dtsch Dermatol
Ges 5 (Suppl. 3), 2007
Nast et al., Arch Dermatol Res
, 2007 (short version)
Systemic
therapy
severe
Methotrexate
Etanercept
Infliximab
Retinoids
Adalimumab
Ustekinumab UV

4. RESULT OF: Poor criteria (diagnosis and effectiveness) sharing
Poor outcomes sharing
Variable therapy duration
Home-made non-uniform trial designs

5. 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

6. 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

7. 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

9. 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)

10. GUIDELINES FOR VITILIGO – FIRST STEPS
Tbl 1 – prvi th izbor na temelju 14 upitnika
Tbl 2 – repigmentacija temeljem 1.th.opcije na temelju 14 upitnika

11. GUIDELINES FOR VITILIGO – FIRST STEPS

12. 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)

13. Nordlund JJ 2008

14. Nordlund JJ 2008
Nordlund JJ

15. 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:
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:
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.

16. 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:
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.

17. Diagnosis of vitiligo:
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: )
Diagnosis of vitiligo:
- Classical presentation: primary care
Atypical presentations: dermatologist
Adults: thyroid blood tests
NO TREATMENT OPTION:
ADULTS AND CHILDREN WITH SKIN TYPES I and II - NO ACTIVE TREATMENT OTHER THAN CAMOUFLAGE AND SUNSCREENS

18. 2. ADULTS: TOPICAL PIMECROLIMUS (better safety profile)
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: )
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)

19. c) PHOTOTHERAPY, SYSTEMIC THERAPY AND SURGICAL TREATMENTS:
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: )
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

20. RAPIDLY PROGRESSIVE VITILIGO → SYSTEMIC STEROIDS
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:
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

21. 2nd line therapy: vitiligo recalcitrant to first line therapy
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:
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

22. Felsten LM, Alikhan A, Petronic-Rosic V
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:
3rd line therapy: vitiligo unsuccessfully treated with total body phototherapy
308 nm LASER + TOPICAL STEROIDS
ALTERNATIVE:
ADJUNCT 308 nm LASER + TOPICAL CALCINEURIN INHIBITORS

23. Felsten LM, Alikhan A, Petronic-Rosic V
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:
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

24. Avoidance of triggering factors
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
INITIAL RECOMMENDATION
NB-UVB (3 months) + - /systemic/topical therapies (LOCAL CS/TIM )
Camouflage
STABILIZATION AND REPIGMENTATION:
NB-UVB (9 months)
STABILIZATION
STABILIZATION AND REPIGMENTATION CESSATION:
SURGICAL TREATMENT

25. CS MINIPULSE (3-4 months) OTHER IMMUNOSUPPRESSANTS
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
CS MINIPULSE (3-4 months)
OTHER IMMUNOSUPPRESSANTS
STABILIZATION AND REPIGMENTATION AFTER PERIOD OF PROGRESSION: NB-UVB (9 months)
PROGRESSION
NO REPIGMENTATION, KOEBNER PHENOMENON +: DEPIGMENTATION
STABILIZATION WITH OR WITHOUT REPIGMENTATION, KOEBNER PHENOMENON -: SURGICAL TREATMENT

26. Avoidance of triggering factors
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.)
b) Algorithm for SV
Diagnosis of SV:
Avoidance of triggering factors
INITIAL RECOMMENDATION: LOCAL CS/TIM
STABILIZATION AND REPIGMENTATION: NO THERAPY
STABILIZATION
STABILIZATION WITH OR WITHOUT REPIGMENTATION: SURGICAL TREATMENT

27. NO REPIGMENTATION, KOEBNER PHENOMENON +: CAMOUFLAGE
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.)
b) Algorithm for SV
NB-UVB
MEL
STABILIZATION AND REPIGMENTATION AFTER PERIOD OF PROGRESSION: NO THERAPY
PROGRESSION
NO REPIGMENTATION, KOEBNER PHENOMENON +: CAMOUFLAGE
STABILIZATION WITH OR WITHOUT REPIGMENTATION, KOEBNER PHENOMENON -: SURGICAL TREATMENT

28. Diagnosis of vitiligo: Camouflage should be available for all patients
Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40: )
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

29. 1st therapeutic option:
Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40: )
1st therapeutic option:
NB-UVB/PUVA +/- TOPICAL CORTICOSTEROIDS/ TOPICAL VITAMIN D3 ANALOGUES
STABLE (5 years or more after occurence)
2nd therapeutic option:
TOPICAL VITAMIN D3 ANALOGUES + SUN EXPOSURE
3rd therapeutic option:
308-nm EXCIMER LASER/LIGHT
4th therapeutic option:
SKIN GRAFTING

30. 1st therapeutic option: TOPICAL VITAMIN D3 ANALOGUES
Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40: )
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

31. 1st therapeutic option: TOPICAL CORTICOSTEROIDS PROGRESSIVE
Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40: )
1st therapeutic option:
TOPICAL CORTICOSTEROIDS
PROGRESSIVE
(5 ≤ years or after occurence, or variable in size) on patient 15 ≤ years old with lesions on trunk and extremities
2nd therapeutic option:
TOPICAL TACROLIMUS
3rd therapeutic option:
TOPICAL VITAMIN D3 ANALOGUES + SUN EXPOSURE
4th therapeutic option:
SKIN GRAFTING

32. 1st therapeutic option:
Proposed algorithm for the management of vitiligo in Japan. (Modified from Oiso N et al. Source: J Dermatol. 2013;40: )
1st therapeutic option:
NB-UVB/PUVA +/- TOPICAL CORTICOSTEROIDS/ TOPICAL VITAMIN D3 ANALOGUES
PROGRESSIVE
(5 ≤ years after occurence, or variable in size) on patient 16 ≥ years old
2nd therapeutic option:
308-nm EXCIMER LASER/LIGHT OR
TOPICAL VITAMIN D3 ANALOGUES + SUN EXPOSURE
3rd therapeutic option:
ORAL CORTICOSTEROIDS /
IMMUNOSUPPRESSIVE AGENTS
4th therapeutic option:
SKIN GRAFTING

33. DEATH BY POWERPOINT! Dear God when will this presentation end!?

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

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

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

38. 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

39. Percentage of repigmentation in patients treated with 311-nm NBUVB microphototherapy(BIOSKIN® ) alone or in combination, or with active topical treatment alone
Treatment (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%
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%

40. Vitiligo Therapy 2014/15 General Short Remarks

41. 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

42. 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)

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. OTHER IMMUNUNOSUPPRESSANTS/ BIOLOGICS
Cyclophosphamide, 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

50. AFAMELATONIDE
 Simplified form of alpha-melanocyte stimulating hormone (α-MSH) - stimulates melanocytes to grow and produce melanin pigment
Afamelatonide + NBUVB = faster repigmentation?

51. OTHER SYSTEMIC INTERVENTIONS: ANTIOXYDANTS
Vitamin E
Vitamin C
Ubiquinone
Lipoic acid
Polypodium Leucotomos
Ginko biloba etc.
Antioxidant supplementation could be useful during UV therapy and reactivation phases
Combination therapy with UVB and topical therapy is recommended

52. 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

53. POTENT TOPICAL CORTICOSTEROIDS
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 OR
1st therapeutic recommendation
TOPICAL CALCINEURIN INHIBITORS (genital area and armpits in adults and children) OR
TOPICAL CORTICOSTEROIDS + TOPICAL VITAMIN D ANALOGUES OR
MINI ORAL PULSED CORTICOSTEROID TREATMENT (progressive, fast spreading vitiligo)

54. NB-UVB 311nm PHOTOTHERAPY
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 OR
2nd therapeutic recommendation
NB-UVB 311nm PHOTOTHERAPY +
POTENT TOPICAL CORTICOSTEROIDS OR
NB-UVB 311nm PHOTOTHERAPY + TOPICAL CALCINEURIN INHIBITORS OR
NB-UVB 311nm PHOTOTHERAPY + PERORAL THERAPY: CORTICOSTEROIDS, ANTIOXYDANTS, Polypodium Leucotomos EXTRACT

55. PUVA PHOTOTHERAPY (only in specialist 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.
PUVA PHOTOTHERAPY (only in specialist units)
3rd therapeutic recommendation

56. (for inactive vitiligo on prominent sites - i.e. face, hands):
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.
SURGICAL TREATMENT
(for inactive vitiligo on prominent sites - i.e. face, hands):
BLISTER GRAFT
PUNCH GRAFT
SPLIT THICKNESS SKIN GRAFT
AUTOLOGOUS MELANOCYTE SUSPENSION TRANSPLANT
4th therapeutic recommendation
Camouflage and cognitive behavioral therapy should be available for all patients.

57. 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):  

58. croatia.vitiligo.org@gmail.com http://vrfoundation.org/