PRACTICAL THERAPEUTICS
Drugs 43 (4): 490-498. 1992 0012-666 7/92/0004-0490/$04.50/0 © Adis International Limited. All rights reserved. DRUl127
Guidelines for the Treatment of Vitiligo Christina Antoniou and Andreas Katsambas University of Athens, School of Medicine, Department of Dermatology, 'A. Sygros' Hospital, Athens, Greece
Contents 490
491 491 491 492 493 493 493 494 494 494 494 494 495 495 495 495 495 495
496 496
Summary
Summary I. Nonsurgical Therapies 1.1 Psoralen Photochemotherapy 1.1.1 Topical Photochemotherapy 1.1.2 Oral Photochemotherapy 1.2 Topical Corticosteroids 2. Surgical Therapies 2.1 Autologous Epidermal Grafts 2.2 Epidermal Grafts Obtained by Suction or Freezing Blisters 2.3 Autologous Melanocyte Transplants 2.4 Micropigmentation (Tattooing) 3. Other Forms of Experimental Treatment of Vitiligo 3.1 Topical Fluorouracil Therapy 3.2 Khellin and UV A 3.3 Phenylalanine and UV A 4. Adjunctive Therapies 4.1 Broad Spectrum Sunscreens 4.2 Cosmetic Camouflage 5. Depigmentation with Monobenzylether of Hydroquinone (MBEHQ) 6. Other Therapy - 'Melagenina' 7. Conclusions At present, there is no universally effective drug for vitiligo therapy; there are, however, various therapeutic modalities that may be beneficial. Therapeutic regimens used to treat vitiligo include psoralens and ultraviolet A light (PUV A), topical corticosteroids, fluorouracil locally applied with skin abrasion, a variety of surgical techniques to transplant autologous melanocytes from pigmented skin to nonpigmenting areas, a new photochemotherapeutic regimen using oral khellin with UV A phototherapy, and a recently proposed treatment with oral phenylalanine in combination with UV A exposure. PUV A and topical corticosteroids are the 2 most frequently used modalities. The use of effective sunscreens with a high sun protection factor (SPF) is of help in preventing the vitiliginous areas from burning and normal skin from becoming tanned. Cosmetic camouflage is also useful to disguise the white areas of skin. Finally, depigmentation should be considered in patients with >50% cutaneous involvement who fail to respond or are unwilling to undergo treatment. The selection of patients for therapy should take into consideration the patient's motivation, the psychological impact of the disease and the clinical presentation of vitiligo, and should weigh the risks and benefits of prolonged therapy.
Treatment of Vitiligo
491
Vitiligo is a common acquired idiopathic disorder characterised by patches of depigmented skin. The disease affects about I % of the population. The white amelanotic macules are hardly noticeable in many fair-skinned Caucasians with vitiligo. However, in darker-complexioned individuals it is a serious cosmetic problem (fig. I) which often leads to psychological despair. Furthermore, in certain cultures, patients with vitiligo are considered social outcasts. At present, there is no universally effective agent for vitiligo therapy. There are, however, various therapeutic modalities that can be effective. Many factors must be considered before the final decision is taken on treatment for a vitiligo patient (Kenney & Grimes 1983). First, the intensity of the patient's desire for treatment must be assessed. Many patients are satisfied with the reassurance that vitiligo is not a serious disease, and are looking only for advice on photoprotection and camouflage for the exposed white areas offace, neck and hands. Secondly, if the patient seems willing to undergo treatment, he or she must know that successful therapy may require 12 to 18 months of continuous treatment. Thirdly, the physician must consider whether to use topical or systemic therapy. If the area to be treated is small (less than 20% of the body surface), topical treatment is indicated; if the area is larger than this, a systemic therapy should be used. Finally, the age of the patient is a very important factor.
1. Nonsurgical Therapies 1.1 Psoralen Photochemotherapy Oral and topical psoralen photochemotherapy is currently the most efficacious treatment. Fig. 1. Effect of vitiligo in a dark-complexioned patient.
1.1.1 Topical Photochemotherapy Topical psoralen photochemotherapy is often considered for patients with limited involvement (less than 20% of the body surface). It can be used to treat both children over 2 years old and adults (Grimes et al. 1982). Dilutions of 1% 8-methoxypsoralen are made with alcohol, petrolatum or aquaphor for final concentrations of 0.0 I to 0.1 %
in order to minimise adverse phototoxic reactions. The preparation is applied to the vitiliginous areas 30 minutes before exposure to ultraviolet A light (UVA). The initial UVA dose is 0.12 to 0.25 J /cm 2 and is increased by increments of 0.12 or 0.25 J / cm 2 weekly according to the patient's skin type. After moderate asymptomatic erythema is achieved,
Drugs 43 (4) 1992
492
Table I. Topical PUVA therapy side effects
Pruritus Oedema/blistering Hyperpigmentation of the surrounding skin Hyperkeratosis of treated lesions
the UVA and psoralen dosage should be maintained at a constant level to retain the minimal degree of erythema. Treated areas should be washed with soap and covered with a broad spectrum sunscreen before the patient leaves the physician's office. Treatments are given once or twice per week. The psoralen should be applied by medical personnel, not by the patient. The major side effects of topical photochemotherapy are a severe phototoxic reaction and blistering (table I), and patients should be warned of this before the treatment begins. Such reactions respond readily to treatment with cool water or 'Domeboro' compresses, topical steroids and/or lowdose systemic steroids. If erythema and blistering develop, treatments are stopped until the reaction subsides. On reinstitution oftherapy, the UV A exposure is usually decreased to half the previous dosage. For 6 to 8 hours after the treatment, unnecessary exposure to sunlight must be avoided because of the high potential of developing severe phototoxic reactions (Fulton et al. 1969). Topical psoralen and natural sunlight should be avoided because of the increased risk of severe blistering reactions. Hyperpigmentation may develop in perilesional normal skin during treatment; this is a temporary phenomenon that resolves after the treatment stops. 1.1.2 Oral Photochemotherapy Oral photochemotherapy is used for patients with more than 20% of the skin surface involved and for individuals who are recalcitrant to topical photochemotherapy (Kenney 1988). Oral psoralens are not usually recommended for children under 12 years of age (Esterly 1986) [table II]. Contraindications for oral photochemotherapy include abnormal liver function and ocular defects including cataracts. In addition, the presence of photo-
sensitivity disorders contraindicates the use of both oral and topical PUV A. Before therapy is begun a blood count, sedimentation rate determination, test for antinuclear antibodies, liver function tests and a baseline ophthalmological examination are required. All these examinations should be repeated yearly (Kenney 1988). The maximum recommended 8-methoxypsoralen dose is 0.6 mg/kg. It should be taken orally 2 hours before UVA exposure. Patients may occasionally experience some gastrointestinal irritation (nausea, vomiting, abdominal pains) with psoralen, so the drug should be taken after food. An initial dose of 1 to 2 J/cm 2 is generally given, with subsequent increments of 1 J/cm 2 every other visit until moderate asymptomatic erythema is observed. The dose of UVA must be adjusted, depending on the sensitivity of the individual patient. Treatments are given twice weekly but never on 2 consecutive days (Kenney 1988; Lassus et al. 1984; Parrish et al. 1976) [fig. 2].
The genital region usually does not repigment in response to PUVA. Generally, it is not recommended that patients with vitiligo of the genitalia treat this area with PUVA because of the potential risk of cancer and the relatively poor response. If the patient strongly wants repigmentation of the genital region, it is recommended that the area be exposed to only every third treatment. The dose of UVA must be adjusted to prevent burning. Protective UVA glasses should be worn for 24 hours after oral psoralen intake (Freeman & Troll 1969; Stem et al. 1985). As a UVA source, PUV A cabinets are usually used (320 to 400nm-emitting fluorescent tubes). If the patient is unable to come to a physician's office for treatment, trioxysalen (4,5,8-trimethylpsoralen) and sunlight is suggested, in a dose of 0.6 mg/kg (Dawber 1970; Fitzpatrick et al. 1974). An Table II. Criteria for oral PUVA therapy of vitiligo
Over age 12 years Not pregnant or lactating No history of photosensitivity Able to commit to 100 to 300 treatment sessions
493
Treatment of Vitiligo
maintenance treatment. Psoralen photochemotherapy induces maximal repigmentation of the face and neck, intermediate responses on the trunk, arms and legs, and minimal responses on the hands and feet. Treatment should be continued for at least 6 months to a year before the patient is classified as recalcitrant. Often as many as 200 to 300 treatments are required to produce a uniform repigmentation of the vitiliginous areas. 1.2 Topical Corticosteroids
Fig. 2. A 45-year-old patient with vitiligo before (upper panel)
and after (lower panel) 25 treatment sessions with a psoralen plus ultraviolet A light (PUV A). Note the marked differences in the extent of the vitiliginous patches.
Topical steroids are sometimes effective repigmenting agents (Kumari 1984). Low, medium and high potency preparations have been used (see table IV). Some physicians recommend medium to higher potency preparations for the first month, tapering to the lower potency preparations. Optimal success requires treatment with topical steroids for 4 to 6 months. A lower potency preparation must be used for the face, eyelids or intertriginous areas. Patients should be followed up for side effects of topical steroid use particularly atrophy. Topical steroids should be considered in young children under 2 years of age who are not candidates for topical PUV A treatment. For children, low to medium potency steroids applied to limited areas are preferable to high strength steroids.
2. Surgical Therapies 2.1 Autologous Epidermal Grafts
initial sun exposure of 5 minutes is recommended. Subsequent exposures are increased in increments of 5 minutes with each treatment until a mild erythema is attained, after which the exposure times are held constant until an increase is necessary to maintain the erythema. Treatments are given 3 times weekly but not on 2 consecutive days. Trioxysalen, is less phototoxic than 8-methoxypsoralen and less effective as a repigmenting agent. Patients should apply broad spectrum sunscreens to the treated areas immediately after treatment, and limit further UV A exposure. The side effects of oral photochemotherapy are listed in table III (Gupta & Anderson 1987). PUV A-induced repigmentation is permanent in the majority of patients, but some may require
Autologous mini-grafting should be considered for patients with localised, non progressive vitiligo that has been present for many years and has not Table III. PUVA therapy side effects
Short term Nausea/vomiting Pruritus Erythema/oedema Hypertrichosis Hyperpigmentation Xerosis Long term Premature aging Cataracts Skin cancer Immunological aberrations
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Drugs 43 (4) 1992
Table IV. Potency guide for topical steroids Low potency Desonide 0.05% Dexamethasone 0.1 % Hydrocortisone 0.25%, 0.5%, 1%, 2.5% Methylprednisolone 1% Prednisolone 0.5% Medium potency Betamethasone valerate 0.1 % Diflorasone diacetate 0.05% Fluocinolone acetonide 0.1%, 0.2% Triamcinolone acetonide 0.01%, 0.25%, 0.1% High potency Betamethasone dipropionate 0.05% Clobetasol propionate 0.05% Fluocinonide 0.05% Halcinonide 0.1%
responded to topical corticosteroids and topical or systemic PUV A therapy. Mini-grafts are prepared by removing the standard 3 or 4mm punches from pigment donor sites and slicing them into small pieces which are inserted into small incisions (Falabella 1988). Proper training is recommended for physicians using this technique. Repigmentation done by grafting has several disadvantages, including lack of repigmentation or koebnerisation of the vitiligo into the donor sites, and scarring; koebnerisation is derived from 'Koebner's phenomenon' which usually consists of the appearance of lesions at sites of mechanical trauma (e.g. psoriasis, lichen planus, vitiligo). The repigmented skin may have a cobblestoned surface and sometimes develops a spotty pigmentation. After transplantation, patients may start PUV A therapy to enhance pigment dispersion. 2.2 Epidermal Grafts Obtained by Suction or Freezing Blisters Blisters can be produced by vacuum suction or by freezing of the epidermis. Blisters on both the donor and the recipient sites are induced simultaneously, and the blister roof of the recipient site is discarded. The blister roof of the donor site is removed and transplanted on to the surface of the
recipient site, and held in place for 7 days. Such autologous epidermal grafts will repigment leucoderma recalcitrant to PUV A therapy. The risks of blister grafts include scarring, lack of repigmentation or koebnerisation (Suvanprakorn et al. 1985). 2.3 Autologous Melanocyte Transplants Recent advances in culturing pigment cells from humans have made it possible to begin the transplantation of autologous melanocytes into areas of skin that are hypopigmented. The technique involves harvesting melanocytes from a shave biopsy of the normally pigmented skin of the patient and expansion of the melanocytes by cell culture. The cultured cells are transplanted into vitiliginous skin (Lerner et al. 1987). A different approach to the use of cells from culture has been reported by Brysk et al. (1988). In these studies, autologous melanocytes and keratinocytes were grown together from epidermal explants, and epidermal sheets containing both cell types were then placed on the denuded dermis of white patches. All these techniques require an experienced staff in cell cultures. 2.4 Micropigmentation (Tattooing) Micropigmentation involves the microsurgical placement of iron oxide pigment into the dermis of leucoderma to replace the colour in the vitiliginous area. It works best for the lip area, especially for patients with dark skin. However, the pigment tends to fade and turn grey in many patients (Halder et al. 1989).
3. Other Forms 0/ Experimental Treatments 0/ Vitiligo 3.1 Topical Fluorouracil Therapy Topical 5% fluorouracil cream can also be an effective pigment-inducing agent in some patients with vitiligo. The epidermal abrasion of vitiliginous lesions is performed with an electrically powered rotary grinder under local anaesthesia, or with sandpaper without anaesthesia (Tsuji & Hamada
Treatment of Vitiligo
1983). The cream is applied daily to the abraded area for 7 to 10 days under occlusion. The area is then allowed to re-epithelialise. Topical antibiotics are used during the healing stage to avoid secondary infection. Complications include poor wound healing, wound infection, and scarring or koebnerisation of the vitiligo. Repigmentation may be darker than the surrounding skin.
495
disease, pregnancy, breast-feeding, history of arsenic exposure and prior radiotherapy. There is no phototoxicity. The advantages of the therapy are the absence of side effects, which permits its use in children (Schul pis et al. 1989), and that the vitiliginous skin becomes less sensitive to sunlight.
4. Adjunctive Therapies 4.1 Broad Spectrum Sunscreens
3.2 Khellin and UV A Khellin (furanochromone) combined With UVA is reported to be as effective as PUVA therapy in the treatment of vitiligo, without the phototoxicity associated with the psoralens (Abdel-Fattah et al. 1982). An oral dose of khellin 50 to 100mg is given 2.5 hours before UVA exposure; the UVA dosage depends on the patient's skin type and ranges from 5 to 15 J/cm 2. The short term side effects include mild nausea, hypotension and loss of appetite. A more serious effect is the asymptomatic elevation of hepatic transaminases (Ortel et al. 1988). At present there is no information regarding long term side effects of this treatment. Khellin photochemotherapy is recommended by Ortel et al. (1988) as an alternative to conventional PUVA for the treatment of vitiligo in patients who do not develop elevated liver transaminases. It can be performed easily with sunlight or as home treatment with commercially available UV A sources. However, khellin is not approved by the FDA for use in the United States. 3.3 Phenylalanine and UV A The use of orally administered phenylalanine in combination with UV A radiation has been reported to promote repigmentation of vitiliginous patches in patients undergoing this treatment (Antoniou et al. 1989; Cormane et al. 1985). Phenylalanine 50 to 100 mg/kg is given orally 30 minutes to I hour before UV A exposure. The dosage of UVA radiation varies from 2.0 to 12.0 J/cm 2 , depending on the patient's skin type. Contraindications for this therapy include phenylketonuria, impaired liver and kidney function, malignant skin
Broad spectrum sunscreens with a high sun protection factor (SPF) should be applied to all exposed skin, both pigmented and depigmented, to decrease the short and long term effects of ultraviolet B (UVB) and UV A radiation, and to reduce contrast between the normal skin and vitiliginous areas. 4.2 Cosmetic Camouflage Cosmetic coverup is quite acceptable to some patients with vitiligo. However, many object to the fact that those products which are removed by water, or perspiration, must be frequently reapplied and may stain clothing. Camouflage may be achieved with various cosmetics and dyes including 'Lydia O'Leary', 'Clinique (Continuous Coverage)', 'Dermablend', 'Vitadye' and 'Dy-o-derm'.
5. Depigmentation with Monobenzylether
0/ Hydroquinone (MBEHQ)
Depigmentation should be considered when vitiligo patients have >50% cutaneous involvement and are recalcitrant to repigmentation. The process is permanent and irreversible, and the patient will be permanently photosensitive. For these reasons this form of therapy should be considered only for Table V. Criteria for depigmentation with monobenzylether of hydroquinone
> 50% vitiligo Over age 40 years PUVA failure or unwilling to start PUVA Acceptance of irreversible, permanent depigmentation
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Drugs 43 (4) 1992
Table VI. Suggested treatment outlines for various states of vitiligo Clinical picture
Age
Few small patches of short duration (recent)
Children adults
Segmental vitiligo Few small long-lasting chronic patches Vitiligo of the lip
!
Many disseminated patches of various size
Conventional treatment
> 2 years
Adults
5% Fluorouracil
{ Tattooing Topical steroids
Children Adults. children
Topical steroids-Topical PUVA Topical PUVA-Topical steroids Autologous epidermal grafts Topical steroids
Adults
Experimental treatment
> 12 years
Sunscreens
Phenylalanine and UVA
Oral PUVA
Khellin and UVA Phenylalanine and UVA Khellin and UVA Phenylalanine and UVA
Patches covering 50-70% of the body surface
Adults
Oral PUVA Depigmentation with monobenzylether of hydroquinone
Patches covering more than 70% of the body surface
Adults
Depigmentation with monobenzylether of hydroquinone
patients over 40 years old who have had an adequate trial of PUVA and have failed or are unwilling to undergo repigmentation therapy. The dermatologist must feel confident that complete depigmentation will be not only cosmetically satisfactory but also psychologically acceptable, especially in Black patients (table V). Monobenzylether of hydroquinone (MBEHQ) is used as a depigmenting agent. It destroys melanocytes. The treatment starts with a 10% concentration of MBEHQ by diluting the full strength preparation with any water-soluble vehicle. The preparation is then applied to pigmented areas twice daily. The concentration is increased by 5% every 1 or 2 months until the patient is using 20% MBEHQ. Patients should be advised that effective treatment may require several months to several years of therapy. The major side effect of MBEHQ therapy is dermatitis which usually responds rapidly to topical applications of steroids. Other common side effects include contact dermatitis, prur-
itus, xerosis, conjunctival melanosis, corneal pigment deposition and greying ofthe hair (Mosher et al. 1977). Once depigmented, the patient must permanently avoid exposure to the sun and must use high SPF sunscreens to prevent sunburn reactions.
6. Other Therapy - 'Melagenina' Several reports from Cuba suggest that a lipoprotein extract with a molecular weight of 1500 to 4000 Da, extracted from the human placenta, is helpful in the treatment of vitiligo. The drug, called 'Melagenina', is used topically in combination with ultraviolet light, infrared radiation or sunlight (Cao et al. 1989). Repigmentation has been claimed to have occurred in 84% of 200 cases after 4 to 11 months of treatment. However, clinical studies have been reported in Venezuela, Mexico and India which do not confirm the results of the Cuban investigators (Nordlund & Halder 1990). The medication clearly needs further and intensive study and
Treatment of Vitiligo
until more data and results are published, 'Melagenina' is not recommended for the treatment of patients with vitiligo.
7. Conclusions At the present time, no entirely safe or effective treatment is available for vitiligo; suggested treatment schemes are outlined in table VI. Many patients will require no more than reassurance about the condition, and advice on the use of sunscreens and cosmetic camouflage. Active treatment is indicated in patients who have a marked cosmetic disability, particularly those who are racially pigmented. With regard to the efficacy of treatment, different results are obtained at different sites of involvement. Vitiliginous patches on the hands and feet respond quite poorly to any method of treatment, while lesions on the face and body respond much better. In summary, treatment for vitiligo should be chosen after consideration ofthe age of the patient and the extent of the disease. The 2 most efficient treatment methods are photochemotherapy and topical corticosteroids. Therefore, patients with a few small patches of vitiligo should be treated with topical steroids and/or local photochemotherapy, while those with many extended patches should be treated with oral photochemotherapy. It must also be clearly explained to patients that repigmentation therapy often takes several years and requires a tremendous expenditure of time on the part of the patients themselves.
References Abdel-Fattah A, Aboul-Enein MN, Wassel GM, EI-Menshawi BS. an approach to the treatment of vitiligo by khellin. Dermatologica 165: 1360-140, 1982 Antoniou C, Schulpis H, Michas T, Katsambas A, Frajis BS, et al. Vitiligo therapy with oral and topical phenylalanine with UVA exposure. International Journal of Dermatology 28: 545547, 1989 Brysk MM, Newton RC, Rajaramman S, Plott T, Barlow E, et al. Autologous cultured cells as a treatment for vitiligo. Abstract. Journal of Investigative Dermatology 90: 549, 1988 Cao CM, Taboeas M, Garcia J, Gonzalez E. Estudio experimental y clinico IJel efecto pigmentante epidermico del extracto pla-
497
centario humano. In Melagenina: selecci6n de trabajos de investicagi6n publicados y presentados en Eventos Cientificos, 1976-1989, Palacio de las Convencionnes de Cuba, Havana, pp. 21-30, 1989 Cormane RH, Siddiqui AH, WesterhofW, Shutgens RBH. Phenylalanine and UVA light for the treatment of vitiligo. Archives of Dermatological Research 277: 126-130, 1985 Dawber RPR. Oral trisoralen therapy in vitiligo. British Journal of Dermatology 83: 386-390, 1970 Esterly NB (Ed.) Management of vitiligo in children (a symposium). Pediatric Dermatology 3: 498-510, 1986 Falabella-Jt. Treatment of localized vitiligo by autologous minigrafting. Archives of Dermatology 124: 1649-1655, 1988 Ftizpatick TB, Parrish JA, Pathak MA. Phototherapy of vitiligo (idiopathic leucoderma). In Fitzpatrick TB et al. (Eds) Sunlight and man, pp. 783-791, University of Tokyo Press, Tokyo, 1974 Freeman RG, Troll D. Photosensitization of the eye by 8-methoxypsoralen. Journal of Investigative Dermatology 53: 449-453, 1969 Fulton JE, Leyden JE, Papa C. Treatment of vitiligo with topical methoxsalen and black light. Archives of Dermatology 100: 224-229, 1969 Grimes PE, Minus HR, Chakrabarti SG, Enterline J, Halder R, et al. Determination of optimal topical photochemotherapy for vitiligo. Journal of the American Academy of Dermatology 7: 771-778, 1982 Gupta AK, Anderson F. Psoralen photochemotherapy. Journal of the American Academy of Dermatology 17: 703-704, 1987 Halder RM, Pham HN, Breadon JY, Johnson B. Micro-pigmentation for the treatment of vitiligo. Journal of Dermatologic Surgery and Oncology 15: 1092-1098, 1989 Kenney Jr JA. Vitiligo. In McDonald CJ and Scott DA (Eds) Dermatology in black patients: dermatologic clinics, Vol. 6, pp. 425-434, WB Saunders Co, London, 1988 Kenney Jr JA, Grimes PE. How we treat vitiligo. Cutis 32: 347387, 1983 Kumari J. Vitiligo treated with topical c1obetasol propionate. Archives of Dermatology 120: 631-635, 1984 Lassus A, Halme K, Eskelinen A, Ranki A, Puska P, et al. Treatment of vitiligo with oral methoxasalen and UVA. Photodermatology I: 170-173, 1984 Lerner AB, Halaban R, Klaus S, Moellmann G. Transplantation of human melanocytes. Journal of Investigative Dermatology 89: 219-224, 1987 Mosher DB, Parrish JA, Fitzpatrick TB. Monobenzylether ofhydroquinone: a retrospective study of 18 vitiligo patients and a review of the literature. British Journal of Dermatology 97: 669-679, 1977 Nordlund JJ, Halder R. Melagenina: an analysis of published and other availabie data. Dermatologica 181: 1-4, 1990 Ortel B, Tanew A, H6nigsmann H. Treatment of vitiligo with khellin and ultraviolet A. Journal of the American Academy of Dermatology 18: 693-70 I, 1988 Parrish JA, Fitzpatrick TB, Shea C, Pathak MA. Photochemotherapy of-vitiligo. Archives of Dermatology 112: 1531-1534, 1976 Schulpis CH, Antoniou C, Michas T, Stratigos S. Phenylalanine plus ultraviolet light: preliminary report of a promising treatment for childhood vitiligo. Pediatric Dermatology 6: 332-335, 1989 Stem RS, Parrish JA, Fitzpatrick TB. Ocular findings in patients
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treated witn PUVA. Journal of Investigative Dermatology 85: 269-273, 1985 Suvanprakorn P, Dee-Ananlap S, Pongsomboom C, Klaus SN. melanocyte autologous grafting for treatment of leucoderma. Journal of the American Academy of Dermatology 13: 968974, 1985
Tsuji T, Hamada T. Topically administered fluorouracil in vitiligo. Archives of Dermatology 119: 722-727. 1983 Correspondence and reprints: Dr Christina Antoniou. 'Andreas Sygros' Hospital, 5, Dragoumi Street, 161 21 Kesariani, Athens, Greece.
Seminar on
Pharmaceutical Emulsions Date: 15-16 June 1992 Venue: Basel, Switzerland For further information, please contact: Pharmaceutical Division Technomic Publishing AG Missionstrasse 44 CH-4055 Basel SWITZERLAND
Drugs 43 (4): 490-498. 1992 0012-666 7/92/0004-0490/$04.50/0 © Adis International Limited. All rights reserved. DRUl127
Guidelines for the Treatment of Vitiligo Christina Antoniou and Andreas Katsambas University of Athens, School of Medicine, Department of Dermatology, 'A. Sygros' Hospital, Athens, Greece
Contents 490
491 491 491 492 493 493 493 494 494 494 494 494 495 495 495 495 495 495
496 496
Summary
Summary I. Nonsurgical Therapies 1.1 Psoralen Photochemotherapy 1.1.1 Topical Photochemotherapy 1.1.2 Oral Photochemotherapy 1.2 Topical Corticosteroids 2. Surgical Therapies 2.1 Autologous Epidermal Grafts 2.2 Epidermal Grafts Obtained by Suction or Freezing Blisters 2.3 Autologous Melanocyte Transplants 2.4 Micropigmentation (Tattooing) 3. Other Forms of Experimental Treatment of Vitiligo 3.1 Topical Fluorouracil Therapy 3.2 Khellin and UV A 3.3 Phenylalanine and UV A 4. Adjunctive Therapies 4.1 Broad Spectrum Sunscreens 4.2 Cosmetic Camouflage 5. Depigmentation with Monobenzylether of Hydroquinone (MBEHQ) 6. Other Therapy - 'Melagenina' 7. Conclusions At present, there is no universally effective drug for vitiligo therapy; there are, however, various therapeutic modalities that may be beneficial. Therapeutic regimens used to treat vitiligo include psoralens and ultraviolet A light (PUV A), topical corticosteroids, fluorouracil locally applied with skin abrasion, a variety of surgical techniques to transplant autologous melanocytes from pigmented skin to nonpigmenting areas, a new photochemotherapeutic regimen using oral khellin with UV A phototherapy, and a recently proposed treatment with oral phenylalanine in combination with UV A exposure. PUV A and topical corticosteroids are the 2 most frequently used modalities. The use of effective sunscreens with a high sun protection factor (SPF) is of help in preventing the vitiliginous areas from burning and normal skin from becoming tanned. Cosmetic camouflage is also useful to disguise the white areas of skin. Finally, depigmentation should be considered in patients with >50% cutaneous involvement who fail to respond or are unwilling to undergo treatment. The selection of patients for therapy should take into consideration the patient's motivation, the psychological impact of the disease and the clinical presentation of vitiligo, and should weigh the risks and benefits of prolonged therapy.
Treatment of Vitiligo
491
Vitiligo is a common acquired idiopathic disorder characterised by patches of depigmented skin. The disease affects about I % of the population. The white amelanotic macules are hardly noticeable in many fair-skinned Caucasians with vitiligo. However, in darker-complexioned individuals it is a serious cosmetic problem (fig. I) which often leads to psychological despair. Furthermore, in certain cultures, patients with vitiligo are considered social outcasts. At present, there is no universally effective agent for vitiligo therapy. There are, however, various therapeutic modalities that can be effective. Many factors must be considered before the final decision is taken on treatment for a vitiligo patient (Kenney & Grimes 1983). First, the intensity of the patient's desire for treatment must be assessed. Many patients are satisfied with the reassurance that vitiligo is not a serious disease, and are looking only for advice on photoprotection and camouflage for the exposed white areas offace, neck and hands. Secondly, if the patient seems willing to undergo treatment, he or she must know that successful therapy may require 12 to 18 months of continuous treatment. Thirdly, the physician must consider whether to use topical or systemic therapy. If the area to be treated is small (less than 20% of the body surface), topical treatment is indicated; if the area is larger than this, a systemic therapy should be used. Finally, the age of the patient is a very important factor.
1. Nonsurgical Therapies 1.1 Psoralen Photochemotherapy Oral and topical psoralen photochemotherapy is currently the most efficacious treatment. Fig. 1. Effect of vitiligo in a dark-complexioned patient.
1.1.1 Topical Photochemotherapy Topical psoralen photochemotherapy is often considered for patients with limited involvement (less than 20% of the body surface). It can be used to treat both children over 2 years old and adults (Grimes et al. 1982). Dilutions of 1% 8-methoxypsoralen are made with alcohol, petrolatum or aquaphor for final concentrations of 0.0 I to 0.1 %
in order to minimise adverse phototoxic reactions. The preparation is applied to the vitiliginous areas 30 minutes before exposure to ultraviolet A light (UVA). The initial UVA dose is 0.12 to 0.25 J /cm 2 and is increased by increments of 0.12 or 0.25 J / cm 2 weekly according to the patient's skin type. After moderate asymptomatic erythema is achieved,
Drugs 43 (4) 1992
492
Table I. Topical PUVA therapy side effects
Pruritus Oedema/blistering Hyperpigmentation of the surrounding skin Hyperkeratosis of treated lesions
the UVA and psoralen dosage should be maintained at a constant level to retain the minimal degree of erythema. Treated areas should be washed with soap and covered with a broad spectrum sunscreen before the patient leaves the physician's office. Treatments are given once or twice per week. The psoralen should be applied by medical personnel, not by the patient. The major side effects of topical photochemotherapy are a severe phototoxic reaction and blistering (table I), and patients should be warned of this before the treatment begins. Such reactions respond readily to treatment with cool water or 'Domeboro' compresses, topical steroids and/or lowdose systemic steroids. If erythema and blistering develop, treatments are stopped until the reaction subsides. On reinstitution oftherapy, the UV A exposure is usually decreased to half the previous dosage. For 6 to 8 hours after the treatment, unnecessary exposure to sunlight must be avoided because of the high potential of developing severe phototoxic reactions (Fulton et al. 1969). Topical psoralen and natural sunlight should be avoided because of the increased risk of severe blistering reactions. Hyperpigmentation may develop in perilesional normal skin during treatment; this is a temporary phenomenon that resolves after the treatment stops. 1.1.2 Oral Photochemotherapy Oral photochemotherapy is used for patients with more than 20% of the skin surface involved and for individuals who are recalcitrant to topical photochemotherapy (Kenney 1988). Oral psoralens are not usually recommended for children under 12 years of age (Esterly 1986) [table II]. Contraindications for oral photochemotherapy include abnormal liver function and ocular defects including cataracts. In addition, the presence of photo-
sensitivity disorders contraindicates the use of both oral and topical PUV A. Before therapy is begun a blood count, sedimentation rate determination, test for antinuclear antibodies, liver function tests and a baseline ophthalmological examination are required. All these examinations should be repeated yearly (Kenney 1988). The maximum recommended 8-methoxypsoralen dose is 0.6 mg/kg. It should be taken orally 2 hours before UVA exposure. Patients may occasionally experience some gastrointestinal irritation (nausea, vomiting, abdominal pains) with psoralen, so the drug should be taken after food. An initial dose of 1 to 2 J/cm 2 is generally given, with subsequent increments of 1 J/cm 2 every other visit until moderate asymptomatic erythema is observed. The dose of UVA must be adjusted, depending on the sensitivity of the individual patient. Treatments are given twice weekly but never on 2 consecutive days (Kenney 1988; Lassus et al. 1984; Parrish et al. 1976) [fig. 2].
The genital region usually does not repigment in response to PUVA. Generally, it is not recommended that patients with vitiligo of the genitalia treat this area with PUVA because of the potential risk of cancer and the relatively poor response. If the patient strongly wants repigmentation of the genital region, it is recommended that the area be exposed to only every third treatment. The dose of UVA must be adjusted to prevent burning. Protective UVA glasses should be worn for 24 hours after oral psoralen intake (Freeman & Troll 1969; Stem et al. 1985). As a UVA source, PUV A cabinets are usually used (320 to 400nm-emitting fluorescent tubes). If the patient is unable to come to a physician's office for treatment, trioxysalen (4,5,8-trimethylpsoralen) and sunlight is suggested, in a dose of 0.6 mg/kg (Dawber 1970; Fitzpatrick et al. 1974). An Table II. Criteria for oral PUVA therapy of vitiligo
Over age 12 years Not pregnant or lactating No history of photosensitivity Able to commit to 100 to 300 treatment sessions
493
Treatment of Vitiligo
maintenance treatment. Psoralen photochemotherapy induces maximal repigmentation of the face and neck, intermediate responses on the trunk, arms and legs, and minimal responses on the hands and feet. Treatment should be continued for at least 6 months to a year before the patient is classified as recalcitrant. Often as many as 200 to 300 treatments are required to produce a uniform repigmentation of the vitiliginous areas. 1.2 Topical Corticosteroids
Fig. 2. A 45-year-old patient with vitiligo before (upper panel)
and after (lower panel) 25 treatment sessions with a psoralen plus ultraviolet A light (PUV A). Note the marked differences in the extent of the vitiliginous patches.
Topical steroids are sometimes effective repigmenting agents (Kumari 1984). Low, medium and high potency preparations have been used (see table IV). Some physicians recommend medium to higher potency preparations for the first month, tapering to the lower potency preparations. Optimal success requires treatment with topical steroids for 4 to 6 months. A lower potency preparation must be used for the face, eyelids or intertriginous areas. Patients should be followed up for side effects of topical steroid use particularly atrophy. Topical steroids should be considered in young children under 2 years of age who are not candidates for topical PUV A treatment. For children, low to medium potency steroids applied to limited areas are preferable to high strength steroids.
2. Surgical Therapies 2.1 Autologous Epidermal Grafts
initial sun exposure of 5 minutes is recommended. Subsequent exposures are increased in increments of 5 minutes with each treatment until a mild erythema is attained, after which the exposure times are held constant until an increase is necessary to maintain the erythema. Treatments are given 3 times weekly but not on 2 consecutive days. Trioxysalen, is less phototoxic than 8-methoxypsoralen and less effective as a repigmenting agent. Patients should apply broad spectrum sunscreens to the treated areas immediately after treatment, and limit further UV A exposure. The side effects of oral photochemotherapy are listed in table III (Gupta & Anderson 1987). PUV A-induced repigmentation is permanent in the majority of patients, but some may require
Autologous mini-grafting should be considered for patients with localised, non progressive vitiligo that has been present for many years and has not Table III. PUVA therapy side effects
Short term Nausea/vomiting Pruritus Erythema/oedema Hypertrichosis Hyperpigmentation Xerosis Long term Premature aging Cataracts Skin cancer Immunological aberrations
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Drugs 43 (4) 1992
Table IV. Potency guide for topical steroids Low potency Desonide 0.05% Dexamethasone 0.1 % Hydrocortisone 0.25%, 0.5%, 1%, 2.5% Methylprednisolone 1% Prednisolone 0.5% Medium potency Betamethasone valerate 0.1 % Diflorasone diacetate 0.05% Fluocinolone acetonide 0.1%, 0.2% Triamcinolone acetonide 0.01%, 0.25%, 0.1% High potency Betamethasone dipropionate 0.05% Clobetasol propionate 0.05% Fluocinonide 0.05% Halcinonide 0.1%
responded to topical corticosteroids and topical or systemic PUV A therapy. Mini-grafts are prepared by removing the standard 3 or 4mm punches from pigment donor sites and slicing them into small pieces which are inserted into small incisions (Falabella 1988). Proper training is recommended for physicians using this technique. Repigmentation done by grafting has several disadvantages, including lack of repigmentation or koebnerisation of the vitiligo into the donor sites, and scarring; koebnerisation is derived from 'Koebner's phenomenon' which usually consists of the appearance of lesions at sites of mechanical trauma (e.g. psoriasis, lichen planus, vitiligo). The repigmented skin may have a cobblestoned surface and sometimes develops a spotty pigmentation. After transplantation, patients may start PUV A therapy to enhance pigment dispersion. 2.2 Epidermal Grafts Obtained by Suction or Freezing Blisters Blisters can be produced by vacuum suction or by freezing of the epidermis. Blisters on both the donor and the recipient sites are induced simultaneously, and the blister roof of the recipient site is discarded. The blister roof of the donor site is removed and transplanted on to the surface of the
recipient site, and held in place for 7 days. Such autologous epidermal grafts will repigment leucoderma recalcitrant to PUV A therapy. The risks of blister grafts include scarring, lack of repigmentation or koebnerisation (Suvanprakorn et al. 1985). 2.3 Autologous Melanocyte Transplants Recent advances in culturing pigment cells from humans have made it possible to begin the transplantation of autologous melanocytes into areas of skin that are hypopigmented. The technique involves harvesting melanocytes from a shave biopsy of the normally pigmented skin of the patient and expansion of the melanocytes by cell culture. The cultured cells are transplanted into vitiliginous skin (Lerner et al. 1987). A different approach to the use of cells from culture has been reported by Brysk et al. (1988). In these studies, autologous melanocytes and keratinocytes were grown together from epidermal explants, and epidermal sheets containing both cell types were then placed on the denuded dermis of white patches. All these techniques require an experienced staff in cell cultures. 2.4 Micropigmentation (Tattooing) Micropigmentation involves the microsurgical placement of iron oxide pigment into the dermis of leucoderma to replace the colour in the vitiliginous area. It works best for the lip area, especially for patients with dark skin. However, the pigment tends to fade and turn grey in many patients (Halder et al. 1989).
3. Other Forms 0/ Experimental Treatments 0/ Vitiligo 3.1 Topical Fluorouracil Therapy Topical 5% fluorouracil cream can also be an effective pigment-inducing agent in some patients with vitiligo. The epidermal abrasion of vitiliginous lesions is performed with an electrically powered rotary grinder under local anaesthesia, or with sandpaper without anaesthesia (Tsuji & Hamada
Treatment of Vitiligo
1983). The cream is applied daily to the abraded area for 7 to 10 days under occlusion. The area is then allowed to re-epithelialise. Topical antibiotics are used during the healing stage to avoid secondary infection. Complications include poor wound healing, wound infection, and scarring or koebnerisation of the vitiligo. Repigmentation may be darker than the surrounding skin.
495
disease, pregnancy, breast-feeding, history of arsenic exposure and prior radiotherapy. There is no phototoxicity. The advantages of the therapy are the absence of side effects, which permits its use in children (Schul pis et al. 1989), and that the vitiliginous skin becomes less sensitive to sunlight.
4. Adjunctive Therapies 4.1 Broad Spectrum Sunscreens
3.2 Khellin and UV A Khellin (furanochromone) combined With UVA is reported to be as effective as PUVA therapy in the treatment of vitiligo, without the phototoxicity associated with the psoralens (Abdel-Fattah et al. 1982). An oral dose of khellin 50 to 100mg is given 2.5 hours before UVA exposure; the UVA dosage depends on the patient's skin type and ranges from 5 to 15 J/cm 2. The short term side effects include mild nausea, hypotension and loss of appetite. A more serious effect is the asymptomatic elevation of hepatic transaminases (Ortel et al. 1988). At present there is no information regarding long term side effects of this treatment. Khellin photochemotherapy is recommended by Ortel et al. (1988) as an alternative to conventional PUVA for the treatment of vitiligo in patients who do not develop elevated liver transaminases. It can be performed easily with sunlight or as home treatment with commercially available UV A sources. However, khellin is not approved by the FDA for use in the United States. 3.3 Phenylalanine and UV A The use of orally administered phenylalanine in combination with UV A radiation has been reported to promote repigmentation of vitiliginous patches in patients undergoing this treatment (Antoniou et al. 1989; Cormane et al. 1985). Phenylalanine 50 to 100 mg/kg is given orally 30 minutes to I hour before UV A exposure. The dosage of UVA radiation varies from 2.0 to 12.0 J/cm 2 , depending on the patient's skin type. Contraindications for this therapy include phenylketonuria, impaired liver and kidney function, malignant skin
Broad spectrum sunscreens with a high sun protection factor (SPF) should be applied to all exposed skin, both pigmented and depigmented, to decrease the short and long term effects of ultraviolet B (UVB) and UV A radiation, and to reduce contrast between the normal skin and vitiliginous areas. 4.2 Cosmetic Camouflage Cosmetic coverup is quite acceptable to some patients with vitiligo. However, many object to the fact that those products which are removed by water, or perspiration, must be frequently reapplied and may stain clothing. Camouflage may be achieved with various cosmetics and dyes including 'Lydia O'Leary', 'Clinique (Continuous Coverage)', 'Dermablend', 'Vitadye' and 'Dy-o-derm'.
5. Depigmentation with Monobenzylether
0/ Hydroquinone (MBEHQ)
Depigmentation should be considered when vitiligo patients have >50% cutaneous involvement and are recalcitrant to repigmentation. The process is permanent and irreversible, and the patient will be permanently photosensitive. For these reasons this form of therapy should be considered only for Table V. Criteria for depigmentation with monobenzylether of hydroquinone
> 50% vitiligo Over age 40 years PUVA failure or unwilling to start PUVA Acceptance of irreversible, permanent depigmentation
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Drugs 43 (4) 1992
Table VI. Suggested treatment outlines for various states of vitiligo Clinical picture
Age
Few small patches of short duration (recent)
Children adults
Segmental vitiligo Few small long-lasting chronic patches Vitiligo of the lip
!
Many disseminated patches of various size
Conventional treatment
> 2 years
Adults
5% Fluorouracil
{ Tattooing Topical steroids
Children Adults. children
Topical steroids-Topical PUVA Topical PUVA-Topical steroids Autologous epidermal grafts Topical steroids
Adults
Experimental treatment
> 12 years
Sunscreens
Phenylalanine and UVA
Oral PUVA
Khellin and UVA Phenylalanine and UVA Khellin and UVA Phenylalanine and UVA
Patches covering 50-70% of the body surface
Adults
Oral PUVA Depigmentation with monobenzylether of hydroquinone
Patches covering more than 70% of the body surface
Adults
Depigmentation with monobenzylether of hydroquinone
patients over 40 years old who have had an adequate trial of PUVA and have failed or are unwilling to undergo repigmentation therapy. The dermatologist must feel confident that complete depigmentation will be not only cosmetically satisfactory but also psychologically acceptable, especially in Black patients (table V). Monobenzylether of hydroquinone (MBEHQ) is used as a depigmenting agent. It destroys melanocytes. The treatment starts with a 10% concentration of MBEHQ by diluting the full strength preparation with any water-soluble vehicle. The preparation is then applied to pigmented areas twice daily. The concentration is increased by 5% every 1 or 2 months until the patient is using 20% MBEHQ. Patients should be advised that effective treatment may require several months to several years of therapy. The major side effect of MBEHQ therapy is dermatitis which usually responds rapidly to topical applications of steroids. Other common side effects include contact dermatitis, prur-
itus, xerosis, conjunctival melanosis, corneal pigment deposition and greying ofthe hair (Mosher et al. 1977). Once depigmented, the patient must permanently avoid exposure to the sun and must use high SPF sunscreens to prevent sunburn reactions.
6. Other Therapy - 'Melagenina' Several reports from Cuba suggest that a lipoprotein extract with a molecular weight of 1500 to 4000 Da, extracted from the human placenta, is helpful in the treatment of vitiligo. The drug, called 'Melagenina', is used topically in combination with ultraviolet light, infrared radiation or sunlight (Cao et al. 1989). Repigmentation has been claimed to have occurred in 84% of 200 cases after 4 to 11 months of treatment. However, clinical studies have been reported in Venezuela, Mexico and India which do not confirm the results of the Cuban investigators (Nordlund & Halder 1990). The medication clearly needs further and intensive study and
Treatment of Vitiligo
until more data and results are published, 'Melagenina' is not recommended for the treatment of patients with vitiligo.
7. Conclusions At the present time, no entirely safe or effective treatment is available for vitiligo; suggested treatment schemes are outlined in table VI. Many patients will require no more than reassurance about the condition, and advice on the use of sunscreens and cosmetic camouflage. Active treatment is indicated in patients who have a marked cosmetic disability, particularly those who are racially pigmented. With regard to the efficacy of treatment, different results are obtained at different sites of involvement. Vitiliginous patches on the hands and feet respond quite poorly to any method of treatment, while lesions on the face and body respond much better. In summary, treatment for vitiligo should be chosen after consideration ofthe age of the patient and the extent of the disease. The 2 most efficient treatment methods are photochemotherapy and topical corticosteroids. Therefore, patients with a few small patches of vitiligo should be treated with topical steroids and/or local photochemotherapy, while those with many extended patches should be treated with oral photochemotherapy. It must also be clearly explained to patients that repigmentation therapy often takes several years and requires a tremendous expenditure of time on the part of the patients themselves.
References Abdel-Fattah A, Aboul-Enein MN, Wassel GM, EI-Menshawi BS. an approach to the treatment of vitiligo by khellin. Dermatologica 165: 1360-140, 1982 Antoniou C, Schulpis H, Michas T, Katsambas A, Frajis BS, et al. Vitiligo therapy with oral and topical phenylalanine with UVA exposure. International Journal of Dermatology 28: 545547, 1989 Brysk MM, Newton RC, Rajaramman S, Plott T, Barlow E, et al. Autologous cultured cells as a treatment for vitiligo. Abstract. Journal of Investigative Dermatology 90: 549, 1988 Cao CM, Taboeas M, Garcia J, Gonzalez E. Estudio experimental y clinico IJel efecto pigmentante epidermico del extracto pla-
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centario humano. In Melagenina: selecci6n de trabajos de investicagi6n publicados y presentados en Eventos Cientificos, 1976-1989, Palacio de las Convencionnes de Cuba, Havana, pp. 21-30, 1989 Cormane RH, Siddiqui AH, WesterhofW, Shutgens RBH. Phenylalanine and UVA light for the treatment of vitiligo. Archives of Dermatological Research 277: 126-130, 1985 Dawber RPR. Oral trisoralen therapy in vitiligo. British Journal of Dermatology 83: 386-390, 1970 Esterly NB (Ed.) Management of vitiligo in children (a symposium). Pediatric Dermatology 3: 498-510, 1986 Falabella-Jt. Treatment of localized vitiligo by autologous minigrafting. Archives of Dermatology 124: 1649-1655, 1988 Ftizpatick TB, Parrish JA, Pathak MA. Phototherapy of vitiligo (idiopathic leucoderma). In Fitzpatrick TB et al. (Eds) Sunlight and man, pp. 783-791, University of Tokyo Press, Tokyo, 1974 Freeman RG, Troll D. Photosensitization of the eye by 8-methoxypsoralen. Journal of Investigative Dermatology 53: 449-453, 1969 Fulton JE, Leyden JE, Papa C. Treatment of vitiligo with topical methoxsalen and black light. Archives of Dermatology 100: 224-229, 1969 Grimes PE, Minus HR, Chakrabarti SG, Enterline J, Halder R, et al. Determination of optimal topical photochemotherapy for vitiligo. Journal of the American Academy of Dermatology 7: 771-778, 1982 Gupta AK, Anderson F. Psoralen photochemotherapy. Journal of the American Academy of Dermatology 17: 703-704, 1987 Halder RM, Pham HN, Breadon JY, Johnson B. Micro-pigmentation for the treatment of vitiligo. Journal of Dermatologic Surgery and Oncology 15: 1092-1098, 1989 Kenney Jr JA. Vitiligo. In McDonald CJ and Scott DA (Eds) Dermatology in black patients: dermatologic clinics, Vol. 6, pp. 425-434, WB Saunders Co, London, 1988 Kenney Jr JA, Grimes PE. How we treat vitiligo. Cutis 32: 347387, 1983 Kumari J. Vitiligo treated with topical c1obetasol propionate. Archives of Dermatology 120: 631-635, 1984 Lassus A, Halme K, Eskelinen A, Ranki A, Puska P, et al. Treatment of vitiligo with oral methoxasalen and UVA. Photodermatology I: 170-173, 1984 Lerner AB, Halaban R, Klaus S, Moellmann G. Transplantation of human melanocytes. Journal of Investigative Dermatology 89: 219-224, 1987 Mosher DB, Parrish JA, Fitzpatrick TB. Monobenzylether ofhydroquinone: a retrospective study of 18 vitiligo patients and a review of the literature. British Journal of Dermatology 97: 669-679, 1977 Nordlund JJ, Halder R. Melagenina: an analysis of published and other availabie data. Dermatologica 181: 1-4, 1990 Ortel B, Tanew A, H6nigsmann H. Treatment of vitiligo with khellin and ultraviolet A. Journal of the American Academy of Dermatology 18: 693-70 I, 1988 Parrish JA, Fitzpatrick TB, Shea C, Pathak MA. Photochemotherapy of-vitiligo. Archives of Dermatology 112: 1531-1534, 1976 Schulpis CH, Antoniou C, Michas T, Stratigos S. Phenylalanine plus ultraviolet light: preliminary report of a promising treatment for childhood vitiligo. Pediatric Dermatology 6: 332-335, 1989 Stem RS, Parrish JA, Fitzpatrick TB. Ocular findings in patients
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treated witn PUVA. Journal of Investigative Dermatology 85: 269-273, 1985 Suvanprakorn P, Dee-Ananlap S, Pongsomboom C, Klaus SN. melanocyte autologous grafting for treatment of leucoderma. Journal of the American Academy of Dermatology 13: 968974, 1985
Tsuji T, Hamada T. Topically administered fluorouracil in vitiligo. Archives of Dermatology 119: 722-727. 1983 Correspondence and reprints: Dr Christina Antoniou. 'Andreas Sygros' Hospital, 5, Dragoumi Street, 161 21 Kesariani, Athens, Greece.
Seminar on
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