Vitiligo is an acquired pigmentary disorder characterized by depigmented macules and patches secondary to the loss of functional melanocytes. It is a chronic disease that affects between 0.1 and 2% of the general population, affecting both sexes and all races. The appearance and the unpredictable course are psychologically and socially devastating 1.
Current therapies require many months to years of treatment and sometimes result in disappointing outcomes. Photochemotherapy with the photosensitizer psoralen plus ultraviolet A (PUVA) is an effective treatment, but carries the potential risk of limitations and complications. An alternative for PUVA therapy is narrowband ultraviolet B (NB-UVB) phototherapy using lamps that have a maximum emission at 311–312 nm and is now considered as the ‘gold standard’ for the treatment of diffuse vitiligo. The treatment with two recently introduced UVB sources that emit 308 nm wavelengths, the 308 nm xenon chloride (XeCl) excimer laser and the 308 nm XeCl excimer light, has also been reported to be effective and might be the treatment of choice for localized disease: this treatment modality has been defined as ‘targeted phototherapy’ 2, all aiming at sparing the unaffected skin undue radiation exposure.
A more recently emerging phototherapeutic modality in the treatment of vitiligo and other photoresponsive dermatoses is broadband ultraviolet A (BB-UVA), which awaits short-term and long-term safety evaluation studies, both clinical and laboratory.
The aim of the current work was to focus on the efficacy of the diverse phototherapeutic modalities used in the treatment of this common, chronic, devastating disorder in a trial to clarify the factors influencing the efficacy of each phototherapeutic modality. Furthermore, we aimed to review the comparisons between the different phototherapeutic lines and their various combination options, in an attempt to aid in the proper selection of the regimens used to treat vitiligo.
Narrowband ultraviolet B
In 1981, Parrish and Jaenicke 3 found that 311 nm wavelength of UVB radiation was the most effective and least erythemogenic along the UVB range in the treatment of psoriasis. This led to the development of the TL-01 fluorescent bulb, a narrowband UVB source. In 1997, Westerhof et al.4 first reported the use of NB-UVB phototherapy for the treatment of vitiligo.
There is no universally accepted protocol for NB-UVB therapy; hence, treatment protocols differ from one study to another 5. Other constraints included the lack of a unified quantitative scale to measure the response to the therapy used in most studies, paucity of controlled studies, and inconsistent follow-up periods 6. However, recently, researchers have begun utilizing the vitiligo area scoring index or its modification such as the vitiligo European task force in a trial to unify scores allowing an objective and comparative assessment in various studies 7,8.
Two or three times a week
The influence of the frequency of treatment (whether two times a week 9,10 or three times a week 6,11–14 on nonconsecutive days) could not be determined upon critical evaluation of the studies available in the literature on NB-UVB therapy in vitiligo. However, we favor the three times weekly regimen as it appears to be more beneficial and at the same time rational vis-à-vis phototoxic reactions that are unlikely to occur after 24 h of exposure to UVB 15.
Initially, the recommended starting dose in adults was suggested to be 0.3–0.4 J/cm2 on the basis of the fact that vitiligo skin ‘Fitzpatrick type I’ shows minimal erythema after exposure to this dose 2. In subsequent studies 4,13,14, the starting dose ranged between 0.3 and 0.7 J/cm2, with a 10 to 20% increase per session, and was maintained constant after achieving mild erythema; others maintained it constant with the first signs of repigmentation 6. On the basis of the assumption that a better response to treatment could be achieved upon using a more aggressive treatment protocol, a group of investigators carried out a continuous increase in the NB-UVB dose for as long as the patient could tolerate 10. Nevertheless, no comparative studies between the different dosing regimes adopted are available. Anbar et al.13 suggested calculation of the dose according to each patient’s daily sun exposure, differential dosimetry per body area, and individualization of increments.
Factors affecting response to treatment
The overall response of vitiligo to NB-UVB has been variable. More than 75% repigmentation generally considered as ‘cosmetically acceptable’ has been achieved by 12.5% 16 to 75% 17 of treated patients, after ∼1 year of treatment. The best results reported in the literature (71.4% 9 and 75% 17) have been reported in two studies from the same center in India, whereas lower success rates have been reported from the Netherlands (53% 18 and 63% 4). The lowest response rates have been reported in Asian patients from Thailand 19, Taiwan 16, and Turkey 20: 33, 12.5, and 15%, respectively.
Several factors – besides the treatment protocol – have been assessed to determine a possible reason for the variability in the therapeutic response of vitiligo patients to NB-UVB. Factors that have been found to influence this response include skin phototype, the location of skin lesions, type of vitiligo, the duration of disease, and compliance to therapy 4.
All patients in the studies from India 9,17 were skin phototypes IV or V, and the two studies from the Netherlands 4,18 included a high percentage of patients with skin phototypes III to V. In an 84-patient series 10, 64.2% of patients were skin phototypes III to V and a multivariate analysis showed a significantly better ability for these patients to achieve a cosmetically acceptable repigmentation on the face, compared with patients with skin phototypes I to II. However, this tendency was not observed in nonfacial skin. In contrast, other studies have 6,18,19,21 found no correlation between response to treatment and skin phototype.
In terms of the location of lesions, several studies 4,9,17,18,21 have reported better response rates for facial lesions compared with lesions on other body areas, exposed or unexposed. Resistant areas on the face include preauricular and postauricular areas, the lips, and mouth angles 11. Lesions on acral sites (hands and feet) consistently show a minimal response 4,6,9,10,12,16–19,21. The reason for this anatomic variation in the response to treatment is unclear, but it may be attributed to the regional variation in the density of hair follicles that have been shown to be reservoirs for melanocytes 22 in the face and acral parts.
At the Phototherapy Unit, Kasr El Aini Hospital, an immunohistochemical study (unpublished data) carried out on 20 patients with active vitiligo compared acral (poorly responsive) lesions with nonacral (photoresponsive) lesions. Acral lesions showed lower pilosebaceous, melanocyte, and Langerhans cell counts and lower stem cell factor (SCF) expression. Following PUVA therapy, immunohistochemical changes were observed in both acral and nonacral lesions in the form of decreased Langerhans cells, increased melanocytes, and decreased SCF accompanied by clinical pigmentation only in nonacral areas. Failure to respond to phototherapy in acral areas was attributed to lower SCF and/or melanocyte count or other unstudied factors such as melanocyte motility.
Type of vitiligo
The type of vitiligo, segmental or nonsegmental, is another influential factor. Although several studies 13,23 have reported failure of response to NB-UVB in segmental vitiligo, Lotti et al.24 reported normal pigmentation in 62.5% of their studied cases with segmental vitiligo. Recently, Lee and Choi 25 proposed a treatment guideline for segmental vitiligo where NB-UVB was among the first-line therapies along with topical therapies (topical corticosteroids, calcineurin inhibitors) and targeted phototherapy (excimer laser) for at least 3 months, and to continue for 1 year if a response is achieved.
Disease duration and time to initial response
The association between response to treatment and the duration of vitiligo is unclear: some studies 9,13,21 have established such a connection, whereas others have not 6,10,18. An earlier response to treatment has been correlated to a higher level of post-treatment repigmentation 10,16. Patients who started to respond after 1 month of treatment achieved greater repigmentation, in contrast to those who responded later. If this finding is verified, it may be possible to identify patients with a greater chance of achieving satisfactory final repigmentation early in the course of treatment 5.
Age, sex, and family history
On the basis of the results of multiple studies, there seems to be no association between response to treatment and patients’ sex 6,10,18, age 6,10,16,18, family history of vitiligo 10,18, affected body surface area 8,16, disease progression, and thyroid disease 6,10,13,19,20.
Comparison of narrowband ultraviolet B with psoralen plus ultraviolet A
A multitude of studies have been performed and their results have been published in trials to compare the efficacy of NB-UVB with a wide spectrum of single or combined modalities. The most frequent comparative therapeutic modality has been PUVA, being considered by many as the mainstay of therapy in vitiligo 9.
A right–left comparative study 12 was carried out on 15 vitiligo patients comparing NB-UVB and PUVA at Phototherapy Unit, Kasr Al Aini Hospital. On the PUVA-treated side, the skin type protocol was used and on the NB-UVB side an erythemogenic protocol was used. The study showed no significant differences between the two sides in terms of the clinical response and the side effects, symptomatic erythema in particular (66.6% for PUVA vs. 73.3% for NB-UVB occurred), possibly resulting from the aggressive protocol used by our group at the time of the study. Accordingly, it was concluded that both NB-UVB and PUVA were equally effective; however, suberythema doses were better tolerated by patients. Many other studies have been carried out to compare those two therapeutic modalities in the treatment of vitiligo (Table 1).
Narrowband UVB appears to be an efficacious and well-tolerated treatment option in vitiligo, with distinct advantages:
- The lack of psoralen-related side-effects and precautions that favor it in patients’ opinion. Oral PUVA therapy restrictions include previous administration, protection of the eye after treatment, and contraindication in pregnancy, in patients with hepatic impairment and in those receiving warfarin or phenytoin 14.
- NB-UVB therapy offers a cosmetically more acceptable color match than PUVA therapy. Several studies 11,13,29 have reported the dramatic difference in the nature of repigmentation between both modalities. The tanning that occurs in the unaffected patient’s skin achieved by both therapeutic modalities has a variable outcome. In patients treated with PUVA, this darker color tended to persist and was cosmetically unsatisfactory, whereas, in patients treated with NB-UVB (mainly skin phototypes IV and V), this hyperpigmentation resolved after a couple of months, yielding a better cosmetic result 10,30.
- A higher incidence of erythema has been reported with PUVA therapy rather than with NB-UVB, 14 leading to cessation of therapy particularly with more aggressive protocols. However, this side effect could be minimized with proper patient care and a careful increase in the ultraviolet (UV) increments in both lines of treatment.
- NB-UVB offers a much higher safety profile in the treatment of children with vitiligo 17,18,21.
- Although of no statistical significance, skin thickening was more frequent in PUVA-treated than in NB-UVB-treated patients 4,12.
Nevertheless, PUVA therapy should not be undermined, as the relative stability of NB-UVB versus PUVA-induced repigmentation, the maximum safe treatment duration, and the cumulative dose allowed 9 still need to be documented in further studies.
A retrospective analytical study 28 at Phototherapy Unit, Kasr Al Aini Hospital reviewed 309 vitiligo patients over 10 years, who were treated with oral and topical PUVA, BB-UVA, NB-UVB, BB-UVB, and psoralen NB-UVB. Among these patients, 150 were treated with oral PUVA and 96 were treated with NB-UVB. Excellent (80–100% pigmentation) or good (60–80% pigmentation) response was achieved in 76% of PUVA-treated versus 54% of NB-UVB-treated cases. In vitiligo, at early sessions, no difference in the response was observed, but given a longer time, oral PUVA showed statistically significant better results than NB-UVB.
Comparison of narrowband ultraviolet B with other modalities
Narrowband ultraviolet B versus excimer light/laser
Phototherapy is usually reserved for patients with more extensive vitiligo, as the entire body surface is exposed during treatment. In patients with localized vitiligo, this would mean that a large surface of normal healthy skin is unnecessarily irradiated with UV. From this perspective, several new devices have been developed to deliver phototherapy in a localized manner. The two most commonly used devices are a 308-nm xenon-chloride (XeCl) excimer 31–34 laser and 308-nm monochromatic excimer light (MEL) 35,36.
Further details are discussed under (targeted phototherapy), and other scientific studies reporting comparisons between NB-UVB with other therapeutic modalities in vitiligo, most importantly, the excimer laser (308 nm) are summarized in Table 2.
Narrowband ultraviolet B versus topical calcineurin inhibitors
An open randomized study 40 compared NB-UVB with topical pimecrolimus and topical tacrolimus. The patients were randomly divided into three groups: NB-UVB phototherapy three times a week, pimecrolimus 1% cream bid, and tacrolimus 0.1% ointment bid, for 24 weeks. The study concluded that all three treatments can be considered comparably good options in the treatment of vitiligo.
Narrowband ultraviolet B combination therapy
Different combinations have been attempted aiming to potentiate NB-UVB to improve therapeutic results and minimize exposure and doses.
NB-UVB+vitamin D analogs: The value of combining topical calcipotriol with NB-UVB is controversial. In a randomized study 41, the effectiveness of NB-UVB alone and in combination with topical calcipotriol in the treatment of generalized vitiligo was evaluated in 40 patients who were divided into two groups: 15 patients were treated with calcipotriol plus NB-UVB and 25 patients were treated with NB-UVB alone. Statistical analysis of the results indicated that the addition of topical calcipotriol to NB-UVB did not show any advantage over the use of NB-UVB as monotherapy.
This finding has been confirmed by several other studies 20,42, as well as a single-blind, right–left placebo-controlled clinical trial (unpublished data) performed in our phototherapy unit on 24 vitiligo patients aiming to assess the value of adding topical calcipotriol to different phototherapeutic modalities. Thirteen patients received NB-UVB and 11 patients received PUVA three times a week for 5 months. All patients applied topical calcipotriol on the right side and a placebo on the left side. The results achieved showed that this combination does not have any superior pigmentogenic effect over either type of phototherapy.
However, two other comparative studies 43,44 suggested that this combination not only provides earlier pigmentation with a lower total NB-UVB dose and less adverse effects but also reduces the duration and the cost of treatment. Moreover, a study 45 carried out on 32 patients with generalized vitiligo and symmetrical lesions showed that the application of tacalcitol ointment – a vitamin D3 analog – in combination with twice-weekly NB-UVB phototherapy is an effective alternative treatment for patients with generalized vitiligo.
NB-UVB+pseudocatalase cream: The value of adding pseudocatalase cream to NB-UVB remains questionable. It was first reported by Schallreuter et al.46, who treated 33 vitiligo patients with pseudocatalase cream and broadband UVB phototherapy, reporting a complete repigmentation of the face and hands in 90% of the treated patients over a mean 15 months. Repigmentation began in all cases within 4 months of the commencement of therapy. This was contradicted by Patel et al.47, who showed that twice-daily application of topical pseudocatalase mousse to the hands and face in patients with vitiligo, in combination with twice-weekly suberythemogenic narrowband UVB phototherapy, over 24 weeks was not effective. This protocol even slightly worsened the patients’ vitiligo. In addition, Bakis-Petsoglou et al.48 carried out a randomized, double-blind, placebo-controlled, 24-week trial to assess the efficacy of pseudocatalase cream and NB-UVB versus placebo and NB-UVB for the treatment of vitiligo. This combination did not appear to provide any incremental benefit to NB-UVB alone. The failure of different researchers to replicate the successful results obtained earlier can be attributed to the difference in the chemical composition of the pseudocatalase, influencing its efficacy and reducing its shelf-life 49.
NB-UVB+antioxidants: The value of adding antioxidants to NB-UVB has been suggested by several authors. In a randomized, double-blind, placebo-controlled multicenter trial 50 of 35 patients with nonsegmental vitiligo, 47% of patients receiving oral supplementation with an antioxidant pool containing vitamins C and E, α lipoic acid, and polyunsaturated fatty acids, 2 months before and for 6 months during NB-UVB phototherapy achieved more than 75% repigmentation versus 18% in the placebo group. Elgoweini and Nour El Din 51 reported an additional favorable therapeutic outcome by the addition of vitamin E to NB-UVB. Antioxidants are suggested to repair oxidative stress, thus preventing lipid peroxidation of melanocyte cell membranes believed to occur in vitiligo and positively influencing repigmentation.
NB-UVB±punch grafting (PG)±laser: Postsurgical exposure of 2613 PGs in 66 patients with stable, refractory vitiligo to a suberythema dose of NB-UVB led to successful repigmentation in 57 (86.36%) cases. The average time of appearance of repigmentation was 20.6 days and the maximum pigment spread reached 12 mm, with an average of 6.5 mm. Cobble-stoning was the most common complication (31.8%), but improved with time and/or interference. This combination was found to be an easy, safe, inexpensive, and effective modality in static and refractory vitiligo 52. In another study, Anbar et al.53 combined NB-UVB with a preliminary session of ER:YAG laser skin ablation, followed by the application of 5-fluorouracil, with a marked improvement in the outcome.
Recently, in a single-center prospective randomized trial 54 that included patients with nonsegmental vitiligo who had at least two symmetrical lesions located on bony prominences and/or extremities, the value of laser dermabrasion in association with topical steroids and UVB in difficult-to-treat areas was assessed. Almost 50% of lesions achieved at least 50% repigmentation in the dermabrasion side, whereas only 42% did so with topical steroids and UVB alone (P<0.001). The side effects were delayed healing, pain, and two hypertrophic scars. They concluded that laser dermabrasion significantly improves the repigmentation rate in vitiligo lesions. However, despite a high rate of repigmentation in such difficult-to-treat areas, the high rate of side effects and the poor tolerance strongly limit its use in current practice.
Other combination studies: An open-labeled, comparative clinical study 55 was carried out on 86 patients with progressive vitiligo to assess the efficacy and tolerability of oral minipulse of steroids (OMP) alone and OMP in combination with PUVA, NB-UVB, and BB-UVB. The study showed that OMP had only an adjunct value and was not very effective by itself. NB-UVB+OMP had a definitive advantage over BB-UVB+OMP and had comparable efficacy to PUVA+OMP.
In a randomized study 56 on 27 patients with long-term stable vitiligo, the addition of vitamin B12 and folic acid to NB-UVB had no significant influence on the response of the patients to the NB-UVB phototherapy. However, the combination of NB-UVB both with a pimecrolimus 1% cream 57, especially the facial lesions 58, and with oral polypodium leucotomos 59 (a 20% antioxidant product) improved the outcome of NB-UVB.
In conclusion, NB-UVB therapy is an effective treatment for vitiligo that leads to high levels of patient and physician treatment-related satisfaction. Although there are disadvantages to NB-UVB therapy, the advantages outweigh the drawbacks 60.
Photo(chemo)therapy is considered one of the most efficient therapeutic modalities in the treatment of vitiligo. Its history dates back to ancient Egypt, where vitiligo lesions were treated with extracts of the Ammi majus plant, followed by exposure to the sun. This principle is the basis of systemic photochemotherapy, whereby UV irradiations are provided 2 h after the administration of a photosensitizer 61.
Several photosensitizers have been developed and combined with the UV irradiation. The most important photosensitizing compounds used are the psoralens.
Psoralens belong to the furocoumarin groups that are found in more than 30 plants, which include lime, lemon, bergamot, parsley, celery, fig, and clove. The use of purified 8-methoxypsoralen (8-MOP) was introduced by AM El-Mofty in 1948 62 in the treatment of vitiligo using topical, oral, or combined psoralens with solar and artificial UV light 63. In the fifth and sixth decades of the past century, psoralens were used in combination with the sun’s rays (UVA and UVB), with mercury lamps (UVB), and then with low output black light lamps (UVA). Later, the high-output UVA lamps – the well-known PUVA therapy – were used 64. Lerner et al.65 found that (320–400 nm) was the best range to activate psoralen; they published several papers on the treatment of vitiligo using PUVA.
Forms and dosing
8-MOP: The photosensitizer used most often is 8-MOP (methoxsalen); it is used 2 h before irradiation, generally at a dose of 0.6 mg/kg body weight 2. It is worth noting that a special form of 8-MOP (ultramicronized) was created and tried in 1994 66. This new preparation was used in a trial on 26 vitiligo patients and was found to be effective at a dose of 0.25 mg/kg, reaching its peak concentration in only half an hour. This preparation was well tolerated by patients, causing no epigastric discomfort, nausea, or vomiting, overcoming the biggest disadvantage of oral 8-MOP. It was also well tolerated by patients known to be sensitive to oral and/or topical 8-MOP therapy.
5-Methoxypsoralen (5-MOP) and trimethylpsoralen (TMP): 5-MOP is mainly used in some European countries and is less erythemogenic and not associated with gastrointestinal intolerance in comparison with the more common 8-MOP. The synthetic 4,5,8-trimethylpsoralen (TMP) was compared with 8-MOP in the context of PUVA therapy for vitiligo. At the end of 60 settings 67, an acceptable cosmetic response was observed over the face, neck, and upper extremities in both groups, whereas the trunk and lower extremities showed a lesser response. Patients on 8-MOP showed an earlier response, requiring a lower cumulative UVA dose; that is, 75 J/cm2 as compared with TMP (i.e. 106 J/cm2). Phototoxicity was observed more often with 8-MOP. In conclusion, 8-MOP was the drug of choice in PUVA therapy of vitiligo, with adequate precautions against phototoxicity.
Psoralen can also be applied topically, leading to the development of topical PUVA. Halder 68 outlined the safe use of topical PUVA therapy for treating patients with less than 20% skin surface involvement with vitiligo. This treatment yielded a response rate of ∼50%. The most commonly used compounds are topical 8-MOP, topical 5-MOP, and 5′-trimethylazapsoralen (bergamot oil). In a study 69 quantitatively assessing the epidermal melanogenesis in mice treated with topical furocoumarins and UVA radiation, topical 8-MOP showed more increased pigmentation, followed by topical 5-MOP and finally bergamot oil.
Psoralen has been utilized with various phototherapeutic modalities in the management of vitiligo
Psoralen plus ultraviolet A (PUVA)
PUVA therapy have been shown to be efficacious in many studies 12,28,29,70–72. Different protocols have been followed, with PUVA therapy being administered twice or thrice weekly. However, no published studies comparing the effect of different frequencies of therapy on the treatment of vitiligo are available. There were protocols of four times weekly, used in the USA and sometimes in Europe. Initial doses calculated according to the minimum phototoxic dose (MPD) are preferred to those predetermined according to the skin type, as intense erythema may induce koebnerization and worsening of the vitiligo. Usually, the starting dose is 50–70% of the MPD calculated in a vitiliginous area that is normally not sun exposed (e.g. the buttocks). The dose is then increased according to the response more carefully than in other dermatoses because of increased photosensitivity. The dose is usually increased every 3–5 sessions by 10–20% of the MPD 4.
No comparative studies have been carried out to evaluate the effect of different dosing schedules. However, Kao and Yu 73 carried out an in-vitro study in which they examined the various effects of PUVA treatment on cultured human melanocytes, which showed that: (a) the higher the dose of PUVA treatment, the more significant the inhibition of cell DNA and protein synthesis; (b) the higher the dose of PUVA treatment, the more significant the depletion of epidermal growth factor receptor expression; (c) PUVA treatment at 124 mJ/cm2 depleted the vitiligo-associated melanocyte antigens immediately after irradiation, and both the vitiligo-associated melanocyte antigens and the epidermal growth factor receptor expression recovered progressively at 24 or 72 h after PUVA; and (d) PUVA treatment stimulated tyrosinase activity, but not in a dose-dependent manner. In vitiligo vulgaris, PUVA treatment may stimulate the regrowth of melanocytes from hair follicles, but deplete the epidermal Langerhans cells in depigmented lesions of patients with stable vitiligo.
Besides the protocol adopted, the variability in response achieved by vitiligo patients to PUVA therapy can be attributed to the same factors as those influencing the response to NB-UVB described previously, including the skin phototype, the site of vitiligo lesions, and the type of vitiligo.
8-methoxypsoralen plus narrowband ultraviolet B
8-MOP was also used with other UV wavelengths in the treatment of vitiligo, namely, NB-UVB and BB-UVB.
In a right–left comparative study 12 carried out in the Phototherapy Unit, Kasr Al Aini Hospital, 20 patients were exposed to NB-UVB on the left side of the body, followed by the ingestion of psoralen and exposure to NB-UVB 90 min later to the right side of the body. Patients, while exposing one side of their bodies, protected the other side with a UV-proof gown. Clinical improvement was comparable on both sides and although the cumulative dose required to achieve the same response on the 8-methoxypsoralen plus narrowband ultraviolet B (PNB-UVB) side was lower than that on the NB-UVB side, the difference was not statistically significant. Moreover, the incidence of phototoxic reactions was significantly higher on the PNB-UVB-treated side.
Psoralen plus broadband ultraviolet B
To compare the efficacy and side effects of oral 8-MOP plus UVB (broadband, 290–320 nm PUVB) and oral 8-MOP plus UVA (PUVA) in the treatment of vitiligo, El-Mofty et al.72 carried out a randomized right–left comparison study on 24 cases of bilateral symmetrical vitiligo involving more than 30% of the body surface area. The patients received three weekly treatments for a total of 30 sessions. Both modalities were found to be equally effective. However, the long-term side effects of psoralen plus UVB are unknown.
Psoralen plus ultraviolet A combination therapy
Oral PUVA has been combined with topical and systemic agents or skin grafts.
PUVA plus vitamin D analogs
In a placebo-controlled double-blind right–left comparative study 74 of 27 patients with generalized vitiligo, calcipotriol or placebo was applied to similar lesions 1 h before exposure to PUVA. Treatment with calcipotriol and PUVA resulted in significantly higher percentages of repigmentation for both initial (81%) and complete pigmentation (63%) compared with placebo and PUVA (7 and 15%, respectively). This was also reported by Cherif et al.75, who carried out a comparative study on 23 patients. Calcipotriol ointment (0.005%) was applied twice daily over one side of the body and the other side was not treated. PUVA was performed three times per week. At the 45 session, 52% showed a marked improvement on the calcipotriol side compared with 30% on the PUVA-only side, with more intense repigmentation on the calcipotriol-treated side. Treatment was well tolerated and no adverse effects were observed. This efficacy was further documented in another study, which reported that 13 of 27 patients showed more than a 30% improvement using this combined regimen 76. It was concluded that this combination was effective in the treatment of vitiligo, specially in initiating repigmentation, as in-vitro experiments have shown that tacalcitol – a topical vitamin D3 – upregulated the expression of c-Kit mRNA by melanocytes irradiated with linear polarized infrared, UVA, or short-duration solar irradiation 77.
However, in another study 78 as well as in an unpublished work carried out in our unit, the combination of topical calcipotriol and PUVA did not lead to any significant increase in the response rate of patients with vitiligo compared with PUVA alone.
PUVA plus systemic therapies
It is well known that systemic corticosteroids arrest the progress of vitiligo and lead to repigmentation, but they may produce unacceptable side effects. The use of high-dose methylprednisolone (pulse therapy) to minimize the side effects of systemic steroids has been reported, but there have been no reports on the effectiveness of this treatment combined with phototherapy. In one study 79, the efficacy and safety of combination therapy with intravenous prednisolone and PUVA was assessed. In 36 patients with vitiligo, intravenous methylprednisolone for 3 days was followed by PUVA twice weekly. After 6 months, vitiligo lesions on the face were reduced in size by 57.5%, on the upper extremities by 34.5%, on the trunk by 30.4%, and on the lower extremities by 26.3%. Overall, improvement was observed in 13 patients (36.1%), with more than 50% repigmentation. Side effects were mild and transient. They concluded that the combination treatment of high-dose prednisolone therapy and PUVA might represent a highly effective therapeutic option for generalized vitiligo. It is surprising that the results of such a combination (PUVA and systemic steroids) are poor, although PUVA alone is able to produce much better results 12,28,29,70–72
Vitamin E has been suggested to prevent oxidative stress resulting from PUVA therapy, but was not shown to affect the clinical improvement of the vitiligo lesions 80.
Sixty vitiligo patients were randomly chosen to receive either low-dose azathioprine (0.6–0.75 mg/kg) and oral PUVA or oral PUVA alone. Perifollicular repigmentation started after a mean of five sessions in the first group and eight sessions in the second group and the mean total repigmentation rate after 4 months was 58.4 and 24.8%, respectively. Therefore, it was suggested that azathioprine might potentiate the repigmentary effects of PUVA in vitiligo patients 81.
PUVA plus grafting
In 100 patients with stable refractory vitiligo, epidermal grafting with suction blisters was carried out, followed by PUVA treatment 82. The grafted sites were examined for repigmentation for up to 5 years. Excellent repigmentation was observed, especially on the face, except for the lip and the alae nasi. Poor results were observed on the neck, axillae, and overlying bony prominences. Hyperpigmentation of the recipient and the donor sites was frequently observed. Only six patients had recurrence and/or adjacent new lesions. Depigmentation developed at the donor site in only one patient with generalized vitiligo. Long-term observation (average 5 years) in these patients indicated that repigmentation achieved using this method is permanent. Although epidermal grafting in combination with PUVA is indicated only in localized cases of vitiligo, it can be considered an easy, safe, inexpensive, and effective treatment for various types of stable refractory vitiligo.
Later on, several studies followed to confirm the efficacy of such a procedure, with different techniques and combinations. One study 83 compared the efficacy of PG, followed by topical corticosteroid versus PG, followed by PUVA therapy in stable vitiligo. The study showed that the pigment spread with topical corticosteroid is comparable with that with PUVA. However, studies with long-term follow-up are required to establish this. The advantages of topical corticosteroid are that its use is easy, less cumbersome, cheaper, and more cost effective than PUVA.
Van Geel et al.84 carried out a double-blind placebo-controlled study of autologous transplanted epidermal cell suspensions for repigmenting vitiligo to examine the efficacy of epidermal noncultured cellular grafting in patients with vitiligo and the role of postinflammatory, spontaneous, or UV-induced pigmentation in achieving repigmentation. A total of 33 paired, symmetrically distributed leukodermic lesions, all resistant to therapy, were observed in 28 patients. Nineteen patients appeared to have stable vitiligo (group 1), whereas the stability of the disease in nine patients was unclear (group 2). After laser ablation, a hyaluronic acid-enriched cellular graft was applied to one lesion, whereas the paired lesion received a placebo. Three weeks later, all lesions were exposed to UV irradiation twice per week for ∼2 months. In group 1, repigmentation of at least 70% of the treated area was achieved in 55, 57, and 77% of the actively treated lesions 3, 6, and 12 months after the treatment, whereas in group 2, repigmentation of at least 70% of the treated area was not observed at any time point. The repigmentation pattern was diffuse in 94% of the responding patients.
Another study 85 compared PG and suction blister epidermal grafting (SBEG) in the treatment of stable lip vitiligo. All patients were maintained on PUVAsol (psoralen+ultraviolet A therapy of solar origin) treatment after grafting. The results were evaluated after a follow-up period of 6 months. The color match was statistically significant in PG when compared with SBEG. In the recipient site, cobblestone appearance was the predominant complication in PG, whereas hyperpigmentation and thickening of grafts were common in SBEG. In the donor site, superficial scarring and hypopigmentation were the common findings in the PG group, whereas hyperpigmentation was the main problem in the SBEG group.
Psoralen and solar exposure
PUVAsol, which is commonly used in countries where sunlight is in abundance and where the facilities for artificial sources of light are often lacking, works on the same principle, except that natural sunlight is used instead of UVA. PUVAsol can be systemic or topical: the same types of oral and topical preparations are used as for PUVA. The initial exposure is of a short duration and subsequent exposures are gradually increased until satisfactory erythema is achieved. In sunnier climates, treatments can be performed throughout the year and this kind of treatment is still quite popular. The Egyptian experience was among the primary experiences in this territory. In 1968, El-Mofty 86 carried out a study on 75 vitiligo patients receiving topical psoralen and sunlight and showed that cosmetically acceptable results could be achieved in more than 60% of the patients, reaching a complete repigmentation in 20% of the patients.
Usually, TMP, at a dose of 0.3 mg/kg, is used, being administered 2–4 h before the initial 10–15-min sun exposure, increasing 5 min per treatment until development of perceptible erythema 87. The results reported in the past have been fairly good 88. In a retrospective study 89 on a large series of patients, good results have been reported with both systemic and topical PUVAsol, but phototoxicity was frequently observed with systemic PUVAsol. It has been reported recently that the combination of PUVAsol and calcipotriol is highly effective and works faster than PUVA alone 90. In the case of natural phototherapy or sun exposure, variable factors including the compliance of the patient, the degree of exposure, and the country where the trial is conducted can limit the interpretation and applicability of results. Nevertheless, when artificial sources for PUVA and narrowband UVB are readily available, this rather empiric procedure should be discouraged because of its potentially dangerous and frequent side effects 2.
Broadband ultraviolet A (320–400 nm)
The use of BB-UVA alone without the addition of photosensitizers has been attempted in a pilot study 91 that included 20 randomly selected patients with bilateral symmetrical vitiligo involving more than 30% of the body surface area. They were equally divided into two groups and all patients received three weekly sessions of UVA, 15 J/cm2 in group I and 5 J/cm2 in group II. A total of 48 sessions over 16 weeks were provided. An overall pigmentation of 60% and above was recorded in 50 and 10% of patients in groups I and II, respectively. Thus, it can be concluded that UVA (320–400 nm) alone, without psoralens, and in appropriate doses may be of important therapeutic value in vitiligo.
Comparative studies of broadband ultraviolet A
Broadband ultraviolet A versus psoralen plus ultraviolet A
A randomized-controlled comparative clinical study (submitted paper) was carried out to compare the effect of UVA phototherapy on PUVA. Forty five patients were randomized into three groups: one group received broadband UVA at a fixed dose of 15 J/cm2 per session, the second group received broadband UVA at a fixed dose of 10 J/cm2 each session, and the third group received PUVA; the starting dose was 1.5 J/cm2/session and was increased gradually. Although patients treated with BB-UVA showed a significantly lower response than patients with PUVA at 30 sessions upon the continuation of therapy, at session 60, only patients treated with UVA 15 J/cm2/session showed a comparable response to patients treated with PUVA. It was concluded that BB-UVA therapy was valuable in the treatment of vitiligo at a dose of 15 J/cm2 and that PUVA therapy was a faster line of therapy, with more satisfactory results for patients despite a higher rate of phototoxic reactions such as erythema, burning, and itching.
Broadband ultraviolet A with fluticasone propionate
The combination of UVA with fluticasone propionate (FP) proved to add much value to the UVA phototherapy in a prospective, randomized-controlled, left–right comparative study 92 on 150 patients. These patients were divided into two groups and treated on two symmetrical lesions for 9 months. The first group was treated with FP alone on one side and a combination of FP and UVA (10 J/cm2) on the other side and the other group was treated with UVA (10 J/cm2) on one side and a combination of FP and UVA (10 J/cm2) on the other side. FP cream was applied once daily at bedtime and UVA (10 J/cm2) exposure was twice a week.
A high-energy UVA device was introduced as early as 1981; however, minimal therapeutic results were observed in the phototherapy of vitiligo 93.
UVA1 therapy in vitiligo does not appear promising. In a prospective, randomized-controlled comparative clinical trial 94, 20 patients received NB-UVB and 20 received UVA1 three times weekly for 12 weeks of medium-dose or low-dose UVA1. NB-UVB was found to be superior to UVA1, with a significant difference in the blinded dermatological assessment (P<0.001) and in the percentage change in the vitiligo area scoring index score (P<0.001). No significant difference in the side effects was observed between both groups. Response to UVA1 in vitiligo seems to be dose dependent and appears to be of limited value in the treatment of vitiligo as a monotherapy.
In a prospective study 95 using a multiwavelength-targeted intense pulse light system UVA1–UVB in association with fluticasone cream, only one patient out of 10 showed good improvement, and in the rest, the treatment failed.
Khellin with ultraviolet A
Khellin is a naturally occurring furocoumarin structurally resembling psoralen. Khellin combined with ultraviolet A (KUVA) was reported to repigment vitiliginous skin as effectively as PUVA 96. However, there have been conflicting reports on this drug, which can be used orally and topically. The oral administration of khellin, followed by exposure to UVA, was described as being fairly effective in one study, but up to 200 treatments were necessary 62.
The exact mechanism of KUVA-induced repigmentation is unknown. Its photobiological activity on yeast was found to be much lower than that of psoralens and it was found to be a poor photosensitizer. It does not photoinduce cross-links of DNA in vitro or in Chinese hamster cells in vivo. This behavior might explain the lack of a phototoxic erythemogenic response when treating vitiligo with khellin 97.
A study of the effect of KUVA on the proliferation and melanogenesis of normal human melanocytes and melanoma cells in vitro showed that KUVA stimulates melanocyte proliferation and melanogenesis. It also indicated that treatment regimens could be improved if reduced khellin doses are applied 98.
A study 99 was carried out to assess the effectiveness, short-term, and long-term safety of oral KUVA in patients with vitiligo. KUVA was administered in 17 patients mostly with extensive generalized vitiligo of more than 6 months’ duration. A good response (>70%) was observed in seven patients after a mean of 194 sessions, whereas a lower response was observed in the patients with a lower number of treatment. The most common short-term side effect was mild nausea, mainly in the first few weeks of treatment. Follow-up assessment at a mean of 40 months after the end of KUVA therapy indicated no skin cancers or actinic skin damage in any patient. These data indicate that KUVA seems to be safe as well as effective for vitiligo, provided that therapy is administered long enough; however, a marked increase in liver transaminases has been reported after KUVA therapy 100. Bech-Thomsen and Wulf 101 showed that topically applied khellin increased the carcinogenic effect of both UVA and sunlight in lightly pigmented mice.
A pilot study 102 of 33 patients compared the effectiveness of topical KUVA and oral PUVA therapy for vitiligo. Topical KUVA required a longer duration of treatment and higher UVA doses. Better results were achieved in younger individuals. No side effects were observed in patients treated with KUVA in contrast to erythema, itching, and gastrointestinal disturbances occurring in some patients treated with oral PUVA.
L-phenylalanine and ultraviolet A therapy
Since 1983, the administration of phenylalanine combined with ultraviolet A exposure (PA-UVA) has been a well-known therapy for vitiligo. L-phenylalanine can be administered either orally or topically. To compare the effectiveness of oral versus combined oral and topical regimens, 21 patients with vitiligo were treated with oral L-phenylalanine at a dose of 100 mg/kg and UVA exposure; 10 of these patients also applied a cream containing 10% L-phenylalanine to the vitiligenous areas. The best results were achieved in the second group and no side effects were found in either group 103.
In a retrospective study 104 on 25 patients who had received PA-UVA therapy for about 5 years previously, permanent repigmentation occurred in 44% of patients and depigmentation occurred either during or after PA-UVA therapy in 64% of patients. None of the patients developed long-term side effects.
Targeted phototherapy has been added to the armamentarium of therapeutics for photoresponsive disorders in a trial to minimize unnecessary exposure of clinically uninvolved skin to conventional lamps, thus reducing the risks of hyperpigmentation of the unaffected skin, premature skin aging, and possible tumorigenesis related to total-body irradiation 105.Targeted therapy may either use broadband UVB, NB-UVB (308) laser or light beams, NB-UVB (311 nm), or UVA1. The phototherapy is usually applied using a hand-held device with special adjustment according to the size and site of the anatomical area or the hand piece in case of the laser equipment.
In 1999, Lotti et al.24, in a placebo-controlled study, reported that five of eight patients treated with BB-UVB irradiation directed only to the lesions manifested normal pigmentation after 6 months in more than 75% of the treated areas. Three of these patients even had complete repigmentation. Two other patients had 50–75% repigmentation of the treated areas. In the control group, only one patient had limited repigmentation of less than 50%. In another retrospective study 106, 32 patients with localized vitiligo were analyzed to evaluate the efficacy and safety of broadband UVB-targeted phototherapy administered twice–thrice weekly, totaling 20–60 sessions. Only four patients (12.5%) showed visible repigmentation; in two patients repigmentation was more than 75% and in two other patients it was less than 25%. Only facial lesions were responsive to the treatment.
The superiority of targeted BB-UVB in the treatment of facial lesions has been shown in a subsequent study on 12 patients 107. They received 30 sessions of UVB-targeted phototherapy administered twice weekly. The assessment of repigmentation was carried out by a comparison of baseline photographs with those after 30 sessions by two independent investigators. Repigmentation with an average of 66.25% was achieved on lesions of the face, and of 31.5% on the neck, trunk, and genitalia. On the extremities, there was no repigmentation. Itching, a burning sensation, erythema, desquamation, and transitory hyperpigmentation were observed in some patients. Minimal blistering and ulceration were observed in one patient. They concluded that targeted UVB phototherapy could to be effective for the repigmentation of vitiligo in lesions located on the face, to a lesser degree on the trunk, and with no response in acral lesions.
On comparing targeted BB-UVB with targeted NB-UVB in a randomized, double-blind study 108 carried out on 10 patients with 20 identical vitiliginous lesions, both types of therapy produced similar clinical responses in the treatment of nonsegmental type of vitiligo. In this study, treatments were carried out twice weekly for 12 weeks and fluencies were started at 50% of the minimal erythema dose and were then gradually increased.
Lotti et al.105 carried out a large comparative evaluation study on 458 patients with vitiligo treated with multiple modalities, and concluded that both targeted UVB microphototherapy and potent topical corticosteroid preparations should be the first-line treatment in vitiligo vulgaris that affects less than 10% of the skin surface. The association of these two treatments yielded better results, with a very high repigmentation rate in more than 90% of the patients.
Targeted phototherapy equipment has developed vastly and several laser and light devices are being utilized, in clinical trials, or marketed for therapy. One device that has been shown to be successful is the 308-nm XeCl excimer laser 32,109. It emits a wavelength of 308 nm and has the physical properties of lasers: a monochromatic and coherent beam of light, selective treatment of the target, and the ability to deliver high fluencies 31. The use of the 308-nm excimer laser in the treatment of vitiligo was first reported by Baltás et al.109. Since then, many studies have shown the efficacy of this laser for repigmenting vitiligo lesions 31,32,34,109. The treatment of vitiliginous patches three times weekly for 5 weeks and then twice weekly led to almost complete repigmentation at the end of 6 months in a single patient in one study 109. A larger study 32 treating lesions three times a week for 12 treatments resulted in some repigmentation in 82% of the treated patches. Moreover, in another study 110, twice-weekly exposure of selected vitiligo lesions, previously nonresponsive to at least one modality of treatment, to a 308-nm excimer laser was followed by various degrees of repigmentation on different sites, most rapidly on the face after a maximum of 60 treatments. The initial doses were 100 mJ/cm2, with increments of 10–25% per session, and all patients tolerated the treatment well.
Another development was the nonlaser 308-nm MEL. This light source has already been used in the treatment of localized psoriasis lesions and has the advantage that larger areas can be treated than with an excimer laser 111. In 2003, Leone et al.35 published a pilot study of MEL in the treatment of vitiligo, with promising results. Repigmentation started earlier than what was expected with NB-UVB, limiting the cumulative dose and the possible long-term risk of carcinogenicity. Also, treatment sessions were markedly shorter, possibly improving patient satisfaction and compliance. Excimer light (308) (unpublished study) has been reported in one study to produce a moderate improvement in more than half of the studied patients and resulted in equivalent or even a better pigmentation response than NB-UVB (311) in the left–right comparison. These results were in contrast to those obtained by another prospective monocentric intrapatient randomized clinical trial 36 conducted on 11 patients. In each patient, three lesions were selected and treated with NB-UVB, MEL, and placebo during 24 sessions, respectively. Repigmentation was evaluated clinically and by an objective surface measurement. Twenty percent of the lesions treated with NB-UVB achieved repigmentation scores above 50%. None of the lesions treated with MEL achieved repigmentation higher than 50% after 24 sessions. In this study, the efficacy of localized 311-nm NB-UVB was superior to that of 308-nm MEL.
The results of a randomized comparative study 112 of the efficacy of 308-nm excimer lamp and 308-nm excimer laser on 20 patients with nonsegmental vitiligo produced comparable clinical results. For the same fluence, the 308-nm lamp induced more erythema, indicating photobiological differences between the two devices.
Several studies 37–39 have compared the use of an excimer laser with NB-UVB in the treatment of localized vitiligo (Table 2).
Targeted light combinations
The targeted 308-nm excimer laser has been combined with other therapeutic modalities aiming to increase its efficacy. A randomized-controlled trial 113 conducted on 84 patients, comparing the effectiveness of 308-nm excimer laser alone and in combination with topical hydrocortisone 17-butyrate cream in the treatment of vitiligo of the face and neck, concluded that recalcitrant vitiligo of the face and neck may benefit from the combination.
The combination of topical calcipotriol with a 308-nm XeCl excimer laser in the treatment of vitiligo did not significantly enhance the efficacy of excimer laser, in a prospective right/left comparative, single-blind trial 114 on 10 patients with bilateral symmetrical disease. However, another comparative, prospective, randomized, intraindividual study 115 carried out on 14 patients with 43 vitiligo lesions showed that the combination treatment of 0.1% tacrolimus ointment plus the 308-nm excimer laser is superior to that of 308-nm excimer laser monotherapy for the treatment of UV-resistant vitiliginous lesions. The latter study confirmed the efficacy tolerance of the 308-nm excimer laser as a monotherapy for the treatment of localized vitiligo and proposed that this treatment regimen should only be used for UV-sensitive areas. Furthermore, double-blind and open studies 58,116 of vitiligo have yielded favorable results with tacrolimus in combination with an excimer laser, especially for vitiligo lesions over bony prominences and on the extremities.
Finally, it is noteworthy that although the safety of targeted UVB phototherapy in the treatment of localized vitiligo is good, its therapeutic effectiveness is limited and depends on the locations of vitiligo lesions. Moreover, excimer laser is an expensive modality and its efficacy should be evaluated in a rigorous controlled manner before its widespread clinical practice 6.
It is clear that several phototherapeutic modalities can be used successfully in the management of vitiligo. Photochemotherapy has long been considered a conventional treatment of vitiligo. However, different UV ranges have been found to achieve comparable effects without psoralens, especially NB-UVB. It has gradually replaced PUVA because of its greater safety profile through sparing the disadvantages of psoralens. In terms of the efficacy, several studies have shown that the use of NB-UVB was equally effective as oral PUVA; yet, we believe that PUVA is slightly superior. The relative stability of NB-UVB versus PUVA-induced repigmentation, the maximum safe duration, and the cumulative dose allowed have still not been fully determined.
The idea of focusing the UV rays on the affected areas, sparing the normal skin, being available in different spot sizes and outputs, was found to be very useful for localized vitiligo. Although the high-energy targeted sources were shown to be superiority in psoriasis, only a slightly earlier response was achieved in vitiligo.
Conflicts of interest
There are no conflicts of interest.
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