Key points

Introduction

Vitiligo is a disease characterized by disappearance of melanocytes from the skin. It can negatively influence the physical appearance of affected individuals, and may profoundly affect a person’s psychosocial function and quality of life. Therefore, vitiligo should not be considered as merely a condition that affects a patient’s appearance, but needs to be actively treated in patients who seek medical help. Phototherapy has been used as the main treatment modality for patients with vitiligo. Different forms of phototherapy for vitiligo include broadband UVB (BB-UVB), narrowband UVB (NB-UVB), excimer light and excimer laser, and psoralen plus UVA (PUVA).

Introduction

Vitiligo is a disease characterized by disappearance of melanocytes from the skin. It can negatively influence the physical appearance of affected individuals, and may profoundly affect a person’s psychosocial function and quality of life. Therefore, vitiligo should not be considered as merely a condition that affects a patient’s appearance, but needs to be actively treated in patients who seek medical help. Phototherapy has been used as the main treatment modality for patients with vitiligo. Different forms of phototherapy for vitiligo include broadband UVB (BB-UVB), narrowband UVB (NB-UVB), excimer light and excimer laser, and psoralen plus UVA (PUVA).

Phototherapy of vitiligo from early ages to modern medicine

Historically, phototherapy was first used to treat vitiligo more than 3500 years ago in ancient Egypt and India, when ancient healers used ingestion or topical application of plant extracts ( Ammi majus Linnaeus in Egypt and Psoralea corylifolia Linnaeus in India) in combination with sunlight for the treatment of “leucoderma.”

Since the middle of the last century, PUVA or photochemotherapy had been the most popular form of phototherapy for patients with vitiligo. However, in recent years, it has been gradually superseded by NB-UVB, which has been shown by various studies to have greater efficacy and fewer adverse effects than PUVA.

Narrow band ultraviolet B: the winning horse

NB-UVB phototherapy is characterized by polychromatic light with a peak emission wavelength of 311 to 313 nm. In 1997, Westerhof and Nieuweboer-Krobotova first reported the efficacy of NB-UVB phototherapy compared with topical PUVA for the treatment of vitiligo. They found that after 4 months of treatment, 67% of patients receiving NB-UVB phototherapy twice a week developed significant repigmentation, whereas only 46% of patients undergoing topical PUVA twice a week developed repigmentation. Since then, several other studies also have shown that NB-UVB is effective for the treatment of vitiligo both in adults and children.

Various studies also have demonstrated that NB-UVB has superior efficacy compared with oral PUVA in the treatment of vitiligo. In a double-blind randomized study, 25 patients with generalized vitiligo received twice-weekly NB-UVB phototherapy and 25 patients were treated with twice-weekly oral PUVA. It was found that 64% of patients in the NB-UVB group achieved more than 50% overall repigmentation, compared with 36% of patients in the oral PUVA group. The efficacy of NB-UVB phototherapy in the treatment of vitiligo is summarized in ( Table 1 ).

Because most studies have demonstrated that NB-UVB has superior efficacy compared with other forms of phototherapy, NB-UVB is now considered as the first-line treatment modality for generalized vitiligo. Apart from its efficacy, NB-UVB has a better safety profile compared with PUVA, mainly due to absence of adverse effects related to psoralen.

How does it work?

The underlying mechanism for the repigmentation effects of NB-UVB phototherapy in vitiligo has not been completely defined, although several different mechanisms have been proposed. Vitiligo is characterized by 2 stages: the active stage in which there is ongoing destruction of melanocytes by immune cells, and the stable stage in which the depigmented skin lesions remain constant over time.

In the active stage of vitiligo, the main mechanism of NB-UVB phototherapy may be explained by its immunomodulatory actions. NB-UVB may stimulate epidermal expression of interleukin-10, which induces differentiation of T-regulatory lymphocytes that can inhibit the activity of autoreactive T lymphocytes. NB-UVB irradiation also has been shown to induce apoptosis of T cells in psoriatic skin lesions, and a similar mechanism may occur in vitiligo.

In the stable stage of vitiligo, the major repigmentation effect of NB-UVB may be due to stimulation of functional melanocytes in the perilesional skin or immature melanocytes in hair follicles. This effect has been described as “biostimulation.” In vitiligo lesional skin, there is a selective loss of active melanocytes in the epidermis, while the inactive/immature melanocytes in hair follicles are spared. UV radiation promotes the proliferation and migration of melanocytes located in the perilesional skin, and enhances activation and functional development of immature melanocytes in the outer root sheath of hair follicles. The upward migration of melanocytes from the outer root sheath to the epidermis leads to the commonly observed formation of perifollicular pigmentation islands. Previously, we and others have shown that NB-UVB irradiation increased the expression of endothelin-1 and basic fibroblast growth factor by keratinocytes, which in turn may promote melanocyte proliferation. Moreover, we demonstrated that NB-UVB irradiation may induce phosphorylated focal adhesion kinase (FAK) expression and matrix metalloproteinase (MMP)-2 activity in melanocytes, leading to increased melanocyte migration. Therefore, NB-UVB phototherapy may promote vitiligo repigmentation directly by increasing melanocyte mobility and indirectly by inducing melanocyte-related growth factors from keratinocytes ( Fig. 1 ). Furthermore, it is known that vitiligo lesions are characterized by increased oxidative stress, and treatment with NB-UVB had been found to reduce oxidative stress in patients with vitiligo. Due to the differences in the mechanisms of action between active-stage and stable-stage vitiligo, we propose that higher fluence of NB-UVB may be required for stabilization of active disease and lower doses for repigmentation (biostimulation).

Schematic diagram showing the proposed mechanisms of different forms of phototherapy (PUVA, excimer laser/excimer light, NB-UVB) in inducing vitiligo repigmentation. The main proposed mechanisms include the induction of T-cell apoptosis, release of melanocyte growth factors (such as endothelin-1 [ET-1] and basic fibroblast growth factor [bFGF]) from keratinocytes and fibroblasts, and increased MMP-2 secretion by melanocytes. This may lead to the proliferation and migration of functional melanocytes in the perilesional skin and immature melanocytes in hair follicles.

Adverse effects

Patients treated with NB-UVB phototherapy may experience various acute side effects, including skin pruritus, erythema, burn injury, and xerosis. The adverse effects of UV radiation on the eyes should be considered in patients receiving treatment in periocular areas. Some phototherapy centers require patients to wear eye protection, whereas others allow patients to close their eyes during phototherapy, because theoretically NB-UVB does not penetrate the eyelids. The Vitiligo Working Group (VWG) consensus was to let patients with eyelid lesions close their eyes during the entire session and the possible the use of adhesive tape to keep the eye closed. Long-term adverse effects include darkening of normal skin and possible photoaging.

There is a possible long-term risk of skin cancer in patients undergoing UV light phototherapy. NB-UVB irradiation may induce DNA damage and cause carcinogenic changes. However, a previous study found no increased risk of skin cancer in patients receiving BB-UVB or NB-UVB phototherapy for psoriasis. Another study involving 3867 patients showed no significant increase in squamous cell carcinoma or melanoma in patients undergoing NB-UVB phototherapy for various diseases. The carcinogenic risk of patients with vitiligo receiving NB-UVB treatment remains incompletely defined. Interestingly, despite the absence of melanin, the development of skin cancers in vitiligo lesions is rare. Currently, NB-UVB is regarded to be less carcinogenic than PUVA. Measuring 8-oxoguanine, a key parameter in the carcinogenic effect of ultraviolet radiation (UVR), it was found that cumulative doses of NB-UVB are safer than those of PUVA, with higher safety profile in higher skin phototypes.

Other phototherapeutic modalities

Monochromatic excimer light/excimer lamp

The monochromatic excimer light (excimer lamp) also emits light with 308-nm wavelength. It has also been shown to be effective in inducing repigmentation of vitiligo lesions. The excimer lamp has a larger treatment field compared with excimer laser, which may enable irradiation of larger areas and shorter treatment times. Moreover, the cost of excimer lamp is cheaper compared with laser devices.

The mechanism of action of monochromatic excimer light in the treatment of vitiligo is not well defined. Similar to NB-UVB, excimer light may have immunomodulatory effects, by promoting T-lymphocyte apoptosis. Moreover, excimer light may stimulate the release of endothelin-1 from keratinocytes, and thereby promote melanocyte proliferation. We also have found that when administered at the same fluence, excimer light is more effective in stimulating basic fibroblast growth factor secretion from human keratinocytes compared with NB-UVB irradiation (Cheng-Che Lan, MD, PhD, unpublished data, 2016).

Regarding the differences in the mechanisms of action of excimer light and NB-UVB, it needs to be considered that excimer light is characterized by a higher irradiance compared with NB-UVB. Previously, we have shown that irradiance (the power delivered per unit area) has a more important role than fluence (amount of energy delivered per unit area) in UVB-induced melanoblast differentiation. When administered at similar fluence, excimer light is effective in inducing melanoblast differentiation, whereas NB-UVB had no significant effect. Decreasing the irradiance of excimer light abolished its effects on melanoblasts, even though the same fluence was administered. This may provide an explanation for the superior efficacy of excimer light compared with NB-UVB for the treatment of localized vitiligo.

Excimer laser and excimer light versus narrowband ultraviolet B for treatment of vitiligo

Various studies have compared the therapeutic efficacy of excimer laser, excimer light, and NB-UVB in vitiligo. Hong and colleagues found that excimer laser had greater efficacy compared with NB-UVB in the treatment of vitiligo, and induced more rapid and greater degree of repigmentation. In Cairo University Hospital, a right-left comparison study between targeted NB-UVB and excimer light for 24 weeks showed similar repigmentation scores in both, but the onset was 2 weeks earlier on the excimer light side (unpublished data). In addition, several recent meta-analyses also have shown similar efficacy between excimer light, excimer laser, and NB-UVB for the treatment of vitiligo.

Excimer laser and excimer light for treatment of segmental vitiligo

Previously, several studies have shown that patients with segmental vitiligo respond poorly to NB-UVB phototherapy compared with patients with nonsegmental vitiligo. Anbar and colleagues found that only 1 (7.7%) of 13 patients with segmental vitiligo achieved greater than 25% repigmentation following NB-UVB phototherapy for 6 months. The efficacy of excimer laser and excimer light in treating segmental vitiligo has not been clearly defined. In a study performed in Korea involving 80 patients with segmental vitiligo treated with excimer laser, Do and colleagues found that 23.8% of patients achieved grade 4 (75%–99%) and 20% of patients achieved grade 3 (50%–74%) repigmentation. In addition, we have performed a retrospective review in our institution for patients with segmental vitiligo treated with excimer light for 3 months, and found that 9 (41%) of 22 patients achieved greater than 50% repigmentation, and 15 (68%) of 22 patients achieved greater than 25% repigmentation (unpublished data). These results indicate that excimer laser and excimer light may be effective forms of phototherapy for patients affected with segmental vitiligo.

Broadband ultraviolet B

BB-UVB is characterized by emission wavelengths ranging from 290 to 320 nm. Although it is widely used for the treatment of psoriasis and other skin diseases, there are few reports regarding its efficacy in vitiligo. A previous study involving 14 patients receiving BB-UVB showed that 8 patients (57.1%) obtained greater than 75% repigmentation after 12 months. However, these results have not been confirmed by other studies. Therefore, BB-UVB is now rarely used for the treatment of vitiligo.

Oral psoralen plus ultraviolet A

PUVA, otherwise known as photochemotherapy, has been the main form of treatment for generalized vitiligo since the 1950s until its replacement by NB-UVB. In this form of phototherapy, the patient first ingests a photosensitizer, and then is exposed to UVA (320–400 nm) irradiation. The most frequently used photosensitizer is 8-methoxypsoralen (methoxsalen, 8-MOP), which is ingested 2 hours before phototherapy, usually at a dose of 0.6 mg/kg. Other photosensitizers, including 5-methoxypsoralen (5-MOP) and trimethyl-psoralen (TMP), also have been used but have not been shown to be superior to 8-MOP.

Oral PUVA is usually administered only to patients with generalized vitiligo. Treatment is usually given twice weekly with an interval of at least 24 to 48 hours between treatment sessions. The starting irradiation dose depends on the skin phototype and can range between 0.5 and 1.0 J/cm ² . The irradiation dose is gradually increased until mild erythema develops in the vitiligo lesions.

The underlying mechanism for the photosensitizing effect of methoxsalen has not been clearly defined. Following activation by light, methoxsalen forms covalent bonds with DNA, resulting in the generation of single-stranded and double-stranded DNA adducts. PUVA phototherapy has also been found to stimulate the release of melanocyte growth factors by keratinocytes, induce proliferation of melanocytes, enhance melanocyte migration (by inducing MMP-2 secretion), stimulate melanogenesis, and decrease the expression of vitiligo-associated antigens on melanocyte cell membranes. In addition, treatment with PUVA may induce lymphocyte apoptosis, and induces differentiation of T-regulatory lymphocytes with suppressor activity.

Previously, we have investigated the effects of PUVA on melanocyte proliferation and migration. Our findings showed that PUVA irradiation did not induce the secretion of melanocyte growth factors from keratinocytes, nor did it promote melanocyte migration on single treatment. On the other hand, we demonstrated that following oral PUVA treatment for vitiligo, patients who showed signs of repigmentation were characterized by higher serum levels of melanocyte growth factors (including basic fibroblast growth factor, stem cell factor, and hepatocyte growth factor). The difference in the in vitro and clinical findings may be possibly due to the longer duration of treatment in patients receiving oral PUVA compared with NB-UVB, or the presence of other cell types in vivo, such as fibroblasts that may contribute to the secretion of these melanocyte growth factors. Therefore, the repigmentation effect of oral PUVA may be partially explained by alterations in serum levels of melanocyte growth factors after long-term treatment.

Possible adverse effects of oral PUVA include erythema, skin and ocular phototoxicity, xerosis, and nausea and headache following psoralen intake. In addition, long-term treatment with oral PUVA is associated with photoaging and an increased skin cancer risk (including squamous cell carcinoma, basal cell carcinoma, and melanoma). In general, oral PUVA is considered to be more carcinogenic compared with BB-UVB and NB-UVB. Oral PUVA should not be administered to children or pregnant women. Due to the possibility of dangerous adverse effects, PUVA has been gradually replaced by NB-UVB in the treatment of vitiligo.

Topical psoralen plus ultraviolet A

Topical PUVA may be a suitable treatment option for patients with localized vitiligo. It is safer than oral PUVA due to lower cumulative UVA dose and lack of systemic absorption of psoralen. It is also considered to be safe in children older than 2 years. Topical PUVA treatment is performed using methoxsalen in solution or cream form, which is applied topically to the vitiligo lesions 20 to 30 minutes before UVA exposure. Treatments are usually administered 1 to 3 times a week. The starting UVA dose is usually approximately 0.25 to 0.5 J/cm ² , which is gradually increased until mild erythema is observed in the vitiligo lesions. Following phototherapy, the topical psoralen needs to be washed off with soap and water to avoid skin phototoxicity. In many patients with vitiligo receiving topical PUVA phototherapy, perilesional tanning develops and may be cosmetically unacceptable. This may prevent the continuation of topical PUVA treatment.

Broadband ultraviolet A

UVA alone (wavelength 320–400 nm), without the administration of photosensitizer before phototherapy, is usually ineffective for repigmenting vitiligo lesions. Although this form of treatment has shown efficacy in a previous randomized trial involving 20 patients, with 50% of patients achieving greater than 60% repigmentation after 16 weeks, this result has not been confirmed by other studies. Therefore, broadband UVA alone is now rarely used to treat vitiligo.

Visible light

Previously, we also have shown that visible light, in the form of low energy helium-neon laser (wavelength 632.8 nm), is effective for segmental vitiligo, particularly in children with periorbital and perioral lesions. The therapeutic effects of helium-neon laser may be mediated via stimulation of melanocyte proliferation and migration, enhancement of primitive melanoblast differentiation, and improvement of lesional microcirculation.

The clinical effects of different forms of phototherapy are summarized in Table 1 , and the mechanisms involved in vitiligo repigmentation are presented in Fig. 1 .

Optimizing narrowband ultraviolet B results

Among the numerous aforementioned phototherapeutic modalities, NB-UVB and excimer light/laser remain the most popular choice for dermatologists worldwide. Although a good response is not always observed in all lesions, every patient with vitiligo deserves a fair trial of this backbone treatment with an individualized protocol to reach optimum results.

Factors to be considered in tailoring the phototherapy protocol

Protocol for phototherapy

Although NB-UVB has been in practice for more than 2 decades, no universally accepted protocol has been set. Reviewing the literature, many recommendations were lacking evidence as regards phototherapy protocols. The phototherapy committee of VWG has put together a consensus to answer those inquiries through the collaboration of 6 institutions from different parts of the world ; the data are outlined as follows, and summarized in Box 1 .

Box 1

• 
  

  Frequency of administration

  
  
• •
  

  Optimal: 3 times per week

  
  
• •
  

  Acceptable: 2 times per week

• 
  

  Dosing protocol

  
  
• •
  

  Initiate dose at 200 mJ/cm ² irrespective of skin type

  
  
• •
  

  Increase by 10% to 20% per treatment

  
  
• •
  

  Fixed dosing based on skin type is another acceptable dosing strategy that takes inherent differences in the minimal erythema dose (MED) of various skin types into account

• 
  

  Maximum acceptable dose

  
  
• •
  

  Face: 1500 mJ/cm ²

  
  
• •
  

  Body: 3000 mJ/cm ²

• 
  

  Maximum number of exposures

  
  
• •
  

  SKIN PHOTOTYPE IV–VI: No limit

  
  
• •
  

  SKIN PHOTOTYPE I–III: More data on the risk of cutaneous malignancy is needed before a recommendation can be made

• 
  

  Course of narrowband ultraviolet B (NB-UVB)

  
  
• •
  

  Assess treatment response after 18 to 36 exposures

  
  
• •
  

  Minimum number of doses needed to determine lack of response: 48 exposures

  
  
• •
  

  Due to the existence of slow responders, up to 72 exposures may be needed to determine lack of response to phototherapy

• 
  

  Dose adjustment based on degree of erythema (see Fig. 2 )

  
  
• •
  

  No erythema: Increase next dose by 10% to 20%

  
  
• •
  

  Pink asymptomatic erythema: Hold at current dose until erythema disappears then increase by 10% to 20%

  
  
• •
  

  Bright red asymptomatic erythema: Stop phototherapy until affected areas become light pink, then resume at last tolerated dose

  
  
• •
  

  Symptomatic erythema (includes pain and blistering): Stop phototherapy until the skin heals and erythema fades to a light pink, then resume at last tolerated dose

• 
  

  Dose adjustment following missed doses

  
  
• •
  

  4 to 7 days between treatments: Hold dose constant

  
  
• •
  

  8 to 14 days between treatments: Decrease dose by 25%

  
  
• •
  

  15 to 21 days between treatments: Decrease dose by 50%

  
  
• •
  

  More than 3 weeks between treatments: Re-start at initial dose

• 
  

  Device calibration or bulb replacement

  
  
• •
  

  Decrease dose by 10% to 20%

• 
  

  Outcome measures to evaluate response

  
  
• •
  

  Serial photography to establish baseline severity, disease stability, and response to treatment

  
  
• •
  

  Validated scoring systems, such as the Vitiligo Area Scoring Index or Vitiligo European Task Force, to quantify degree of response

• 
  

  Posttreatment recommendations

  
  
• •
  

  Application of sunscreen

  
  
• •
  

  Avoidance of sunlight

• 
  

  Topical products before phototherapy

  
  
• •
  

  Avoid all topical products for 4 hours EXCEPT mineral oil

  
  
• •
  

  Mineral oil can be used to enhance light penetration in areas of dry, thickened skin, such as the elbows and knees

• 
  

  Tapering NB-UVB after complete repigmentation achieved

  
  
• •
  

  First month: Phototherapy twice weekly

  
  
• •
  

  Second month: Phototherapy once weekly

  
  
• •
  

  Third and fourth months: Phototherapy every other week

  
  
• •
  

  After 4 months, discontinue phototherapy

• 
  

  Follow-up

  
  
• •
  

  SKIN PHOTOTYPE I–III: Yearly follow-up for total body skin examination to monitor for adverse effects of phototherapy, including cutaneous malignancy

  
  
• •
  

  SKIN PHOTOTYPE IV–VI: No need to return for safety monitoring, as no reports of malignancy exist with this group

  
  
• •
  

  All patients: Return on relapse for treatment

• 
  

  Minimum age for NB-UVB in children

  
  
• •
  

  Minimum age is when children are able to reliably stand in the booth with either their eyes closed or wearing goggles

  
  
• •
  

  Typically approximately 7 to 10 years of age depending on the child

• 
  

  Treatment of eyelid lesions

  
  
• •
  

  Keep eyes closed during treatment, using adhesive tape if necessary

• 
  

  Special sites

  
  
• •
  

  Cover face during phototherapy if uninvolved

  
  
• •
  

  Shield male genitalia

  
  
• •
  

  Protect female areola with sunscreen before treatment, especially in SKIN PHOTOTYPE I–III

• 
  

  Combination treatment for stabilization

  
  
• •
  

  Oral antioxidants

  
  
• •
  

  Topical treatments

  
  
• •
  

  Oral-pulse corticosteroids

• 
  

  Treatment of NB-UVB induced skin changes

  
  
• •
  

  Xerosis: Emollient or mineral oil

  
  
• •
  

  Skin thickening: Topical corticosteroids or keratolytics

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