Indian Dermatology Online Journal

REVIEW ARTICLE
Year
: 2019  |  Volume : 10  |  Issue : 3  |  Page : 234--243

What is new in narrow-band ultraviolet-B therapy for vitiligo?


Urmi Khanna1, Sujay Khandpur2,  
1 Department of Dermatology, Cleveland Clinic, Cleveland, Ohio, USA
2 Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Sujay Khandpur
Department of Dermatology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India

Abstract

Vitiligo is an acquired disorder of skin pigmentation that produces significant psychological impact especially in those with skin of color. Narrow-band ultraviolet B (NB-UVB) therapy, which was first used in vitiligo in 1997 by Westerhof and Nieuweboer-Krobotova, has emerged as one of the safest and most effective therapy for this dermatosis. The light source used for NB-UVB phototherapy is the TL-01 lamp, and the most common model of the NB-UVB phototherapy device is the upright in-office booth or chamber which has 24–48 such lamps. In recent years, there have been several advances in the understanding of the mechanism of action of NB-UVB and the use of combination treatments, many of which increase the efficacy of NB-UVB. In 2017, the Vitiligo Working Group made vital recommendations on the dosage, frequency, and safety of NB-UVB in vitiligo. Furthermore, home phototherapy devices are gaining popularity as they lead to an improved patient compliance. There is still need for large multicenter randomized controlled trials to assess benefits of home phototherapy in vitiligo and studies investigating additional benefits of phototherapy following surgical therapy.



How to cite this article:
Khanna U, Khandpur S. What is new in narrow-band ultraviolet-B therapy for vitiligo?.Indian Dermatol Online J 2019;10:234-243


How to cite this URL:
Khanna U, Khandpur S. What is new in narrow-band ultraviolet-B therapy for vitiligo?. Indian Dermatol Online J [serial online] 2019 [cited 2019 Sep 17 ];10:234-243
Available from: http://www.idoj.in/text.asp?2019/10/3/234/258600


Full Text



 Introduction



Vitiligo is an acquired disorder of skin pigmentation that produces significant psychological impact especially in those with skin of color.[1] Various topical and systemic treatment modalities are available; however, phototherapy especially narrow-band ultraviolet B (NB-UVB) has emerged as one of the safest and most effective therapy for this condition.[2] Among the phototherapeutic modalities, psoralen plus ultraviolet A (PUVA) was very popular earlier. However, the side effects of psoralen such as nausea, vomiting, phototoxicity, and carcinogenic potential of PUVA therapy resulted in its decreased popularity.[3] NB-UVB was first used in vitiligo in 1997 by Westerhof and Nieuweboer-Krobotova.[4] The light source used for NB-UVB phototherapy is the TL-01 lamp, and the most common mode of delivery is through the upright in-office booth or chamber which has 24–48 such lamps. TL-01 lamp is a phosphor-coated fluorescent bulb emitting wavelengths between 310 and 315 nm. The peak emission is at 311 nm and this ensures reduction of superfluous radiation, consequently minimizing the risk of severe burning or other cutaneous side effects of UV radiation. This specific wavelength is very effective in vitiligo because it can stimulate the dormant skin melanocytes and also modulate the cutaneous immune system.[5] However, the exact mechanism of NB-UVB-induced pigmentation still remains unknown.[6]

Westerhof et al. first provided encouraging results in favor of NB-UVB in vitiligo in which 63% of their patients achieved 75% or greater repigmentation after 12 months of twice-weekly therapy when compared with 46% of patients achieving similar degree of repigmentation with topical PUVA.[4] Scherschun et al. who treated their vitiligo cases with NB-UVB monotherapy three times/week, with end points of 75% repigmentation or no further improvement, reported this result in five of their seven patients after a mean of 19 treatments, with improved clinical outcomes in patients with shorter disease duration.[2] Yones et al. in a randomized study of 25 patients each of generalized vitiligo receiving either twice-weekly NB-UVB phototherapy or twice-weekly oral PUVA showed greater than 50% overall repigmentation in 64% of patients in the NB-UVB group compared with 36% patients in the oral PUVA group. The median number of treatment sessions was 97 and 47, respectively. Excellent color match was seen in all patients treated with NB-UVB when compared with only 44% cases in the PUVA group.[7] Njoo et al., in their meta-analysis of nonsurgical therapies in generalized vitiligo, observed repigmentation in higher percentage (63%) of NB-UVB treated cases than with oral PUVA (51%).[8] Due to absence of psoralen-related side effects and better color match, NB-UVB is also preferred in childhood vitiligo.[8],[9] In an open trial consisting of 51 children with generalized vitiligo, NB-UVB was found to be effective and safe. It is also safe in pregnancy and lactation.[9] Therefore, NB-UVB has emerged as a leading treatment modality for vitiligo, and in this article, we aim to discuss the recent advances in NB-UVB-based phototherapy for this condition. [Table 1] below summarizes the evolution of NB-UVB.{Table 1}

 New Concepts in NB-UVB's Mechanism of Action in Vitiligo



NB-UVB has been found to be the most powerful stimulus for vitiligo repigmentation; however, the exact pathomechanism is still not clearly understood. A part of NB-UVB-induced repigmentation may be explained by NB-UVB-activated vitamin D3 synthesis,[18] which is explained as follows in [Figure 1].{Figure 1}

In more recent studies, authors have proposed that cumulative doses of NB-UVB could improve low vitamin D and this in turn may influence the rate of repigmentation.[19],[20] Patients with vitiligo have been noted to have lower expression of vitamin D receptor and also lower serum levels of vitamin D when compared with a control population.[20] Atas et al. in their study found that while treatment with NB-UVB improved vitiligo, it led to decrease in serum vitamin B12 level.[21] However, serum levels of folate and homocysteine showed no significant change after treatment. The authors proposed that more studies are needed to clarify the influence of NB-UVB phototherapy on vitamin B12 and homocysteine and consequently their effect on repigmentation in vitiligo patches.[21] [Table 2] further summarizes other recent studies exploring the mechanisms of NB-UVB in vitiligo.{Table 2}

 Clinical Practice Updates for NB-UVB-Based Therapy in Vitiligo



The Vitiligo Working Group's (VWG) phototherapy group addressed 19 critical questions to formulate the phototherapy recommendations for vitiligo, for better clinical management and help identify areas warranting future research in the field of phototherapy for vitiligo. These consensus guidelines on NB-UVB treatment in vitiligo are summarized in [Table 3]. The VWG guidelines highlighted that repigmentation is dependent on the total number of sessions, with earlier onset of pigmentation seen in patients who receive thrice-weekly dosing, with no published literature directly comparing the differential efficacy of twice- versus thrice-weekly regimens.[27] To avoid phototoxic adverse effects and also for the sake of convenience, it recommended that a fixed dosing protocol be initiated at 200 mJ/cm 2 regardless of skin type.[27] For darker skin types, dosing strategy tailored to skin type could also be used. The group also proposed the maximum acceptable dose for the face in a given treatment to be 1500 mJ/cm 2, while the maximum dose for the body to be 3000 mJ/cm 2. Often 18–36 exposures are necessary before assessing treatment response. A lack of response is said to occur in those who fail to respond after a minimum of 48 NB-UVB sessions.[27]{Table 3}

A meta-analysis published in 2017 assessed the treatment response to phototherapy in vitiligo by identifying prospective studies on NB-UVB and PUVA. A total of 35 studies were finally included in the analysis, of which 29 were based on NB-UVB and 9 on PUVA. The meta-analysis showed that NB-UVB resulted in better treatment response. It also concluded that longer treatment duration should be encouraged to enhance treatment response, and a minimum period of 6 months is required to assess response to phototherapy. The best response was seen on face and neck, whereas the least responsive areas to phototherapy were hands and feet.[28] Chahar et al. conducted a study to assess the impact on quality of life in patients with vitiligo treated with NB-UVB. A total of 54 patients, both adults and children, were included, and they received NB-UVB doses of 300 and 150 mJ/cm 2 twice weekly with 20% increment in doses. The Dermatology Life Quality Index (DLQI) improved significantly, especially in younger patients.[29] Mou et al. also demonstrated similar significant improvement in DLQI after NB-UVB treatment in their patients with vitiligo.[30] A recent study on 28 patients with head and neck vitiligo, evaluating low-dose NB-UVB (doses being held constant for six sessions before actually increasing them) compared with conventional NB-UVB therapy, concluded that low dose may be sufficient to induce repigmentation in cases with stable vitiligo and slow increase in fluence may actually have a noninferior efficacy to conventional UVB, while having advantages of lesser tanning and aging effects due to a lower cumulative dose.[31] All vitiligo lesions in a patient may not have a similar therapeutic response and this was clearly demonstrated by Anbar et al. in their study assessing response to NB-UVB in 25 patients with nonsegmental generalized vitiligo. The authors concluded that vitiligo lesions may not act as one unit and close follow-up using both objective and subjective measures may be necessary.[32]

A recent retrospective study that assessed treatment outcome and persistence of repigmentation from twice-weekly NB-UVB concluded that persistence of repigmentation was seen in 80% of patients even after a year of stopping therapy.[33]

 The Concept of “very Slow Responders”



In a retrospective cohort study of 579 patients, Cabrera et al. attempted to develop a predictive model for response rate of nonsegmental vitiligo to NB-UVB phototherapy.[34] Treatment was continued for many patients who were previously considered nonresponders. Response rates were classified as very rapid, rapid, average, slow, and nonresponders.[34] The authors reported a new subgroup among the nonresponders as those who failed to respond in the first 48 sessions, but showed significant repigmentation after 96 sessions of NB-UVB. They termed this subgroup as “very slow responders.” According to the observations of VWG committee members, a slower than usual response could be seen in some patients, thus a minimum of 72 NB-UVB sessions should be administered before labeling a patient as a nonresponder.[27]

 NB-UVB for Childhood Vitiligo



The VWG recommends that children 7–10 years of age who are able to stand in the cabinet with either of their eyes closed or while wearing goggles can receive phototherapy.[27] For younger children, an adult can remain with the child; however, incomplete photoprotection may often lead to unnecessary exposure of the adult, and also in some cases the body of the adult can shield the child from the therapeutic radiation.[9],[27] In a study of 28 children treated with NB-UVB, 43% showed good to excellent response, with no major side effects.[35] Dayal et al. assessed the efficacy of NB-UVB monotherapy versus phototherapy following topical tacrolimus ointment (0.03%) application in 20 children between 4 and 14 years of age and found significant advantage of using NB-UVB in combination with tacrolimus.[36]

 NB-UVB – safety Recommendations



Phototherapy is an effective treatment for eyelid vitiligo.[37] In vitro studies have shown that NB-UVB has negligible penetration through the eyelid, and thus patients are advised to keep their eyes closed firmly during the treatment session. In a study evaluating the ocular side effects of NB-UVB over a 13-month treatment period, it was noted that there was no decrease in visual acuity or ocular complications including cataract.[37]

During therapy, the face if uninvolved should be covered, male genitalia should be shielded to reduce risk of genital malignancy, and a sunscreen should be applied over the female areola to protect it from burns.[38] The cutaneous carcinogenic effect of NB-UVB has been hypothesized but not proven. In a retrospective study involving 375 patients, with vitiligo and psoriasis being the predominant diseases, in which the carcinogenic potential of NB-UVB was evaluated during a mean follow-up period of 6.9 years, 8 patients (2.1%) were diagnosed with nonmelanoma skin cancer after about 5 years of the onset of phototherapy and these were particular seen in elderly patients with psoriasis. No malignant melanoma was observed.[39] In fact, NB-UVB has been safely used in vitiligo-induced by immune check point inhibitors used to treat melanoma.[40]

 Combination Treatments – what is New?



Combination treatments have several advantages including reduced total number of phototherapy sessions, decreased side effects, and quicker repigmentation. Shin et al. studied the combined use of NB-UVB and excimer laser and found that it could enhance treatment responses and increase patient compliance.[41] They first treated their patients with NB-UVB; excimer laser was then used along with phototherapy in those with delay or plateau in response with continuous NB-UVB monotherapy. Among 80 patients, 54 (67.5%) responded after combined treatment with excimer laser, while the remaining 32.5% subjects showed no significant repigmentation. About 46% of the nonresponders had acral vitiligo, a treatment resistant site.[41] Lee et al. in their study concluded that oral methyl prednisolone mini-pulse therapy combined with NB-UVB rapidly induced repigmentation and arrested vitiligo progression with minimal side effects. All 32 patients with nonsegmental vitiligo showed arrest in disease progression within 12 weeks, and about 40% cases reported satisfactory repigmentation in more than 50% of their lesions.[42] Doghaim et al. evaluated the safety and efficacy of fractional carbon dioxide (CO 2) laser therapy followed by NB-UVB phototherapy in 32 patients with stable resistant vitiligo. The authors concluded that combination therapy shortens treatment duration and improves efficacy and patient compliance.[43] In contrast to this study, another trial combining the two modalities in nonsegmental vitiligo failed to show significant advantage over NB-UVB alone.[44] More studies evaluating this combination over longer follow-up periods are needed. Namazi et al. in their study proposed that vanillic acid ethyl ester, available as 20% cream formulation and used twice a day, could serve as a useful adjunct to NB-UVB.[45] Vanillic acid scavenges hydrogen peroxide which is present in high levels in vitiligo patches. This reduces the oxidative stress which is one of the theories implicated in the pathogenesis of vitiligo, thereby enhancing the effect of NB-UVB. An innovative topical cream (Photocil ®) blocks the nontherapeutic solar radiation and selectively delivers NB-UVB therapy.[46] It is water-in-oil emulsion and is applied only on vitiliginous patches thrice a week for 12 weeks, with average treatment time of 30 min. Diethylamino hydroxybenzoyl hexyl benzoate and alpha-glucosyl hesperidin, the glucosylated derivatives of natural plant flavonoids, are the active ingredients of the cream.[46] Stanimirovic et al. investigated a unique treatment strategy for resistant vitiligo, especially acrofacial lesions.[47] They used NB-UVB and topical latanoprost solution (0.005% solution) with or without microneedling. Repigmentation rates were low (38%) with more than 50% of repigmentation seen only in 8.8% of repigmenting lesions. Addition of microneedling did not improve treatment outcome. However, this study did provide some evidence supporting the combined used of latanoprost with NB-UVB phototherapy to induce repigmentation in difficult-to-treat vitiligo lesions.[47] A meta-analysis by Li et al. assessing utility of combination treatment of topical agents with NB-UVB, in which seven randomized controlled trials were included, found no significant difference in clinical outcomes by addition of topical calcineurin inhibitors/vitamin D3 analogs to NB-UVB. The study, however, did report that the addition of calcineurin inhibitors to NB-UVB improved repigmentation rates in vitiligo affecting face and neck.[48] Decreasing oxidative stress in vitiligo by addition of oral and topical (pseudo-catalase) antioxidants has been found to improve repigmentation rates and decrease the mean number of combination therapies needed with NB-UVB.[49] Dell'Anna et al. found that the addition of a tablet containing vitamins E and C, alpha-lipoic corrosive, polyunsaturated fats, and cysteine monohydrate led to 47% of subjects achieving greater than 75% of repigmentation compared with just 18% attaining a similar response in the NB-UVB monotherapy group.[50] Afamelanotide is a synthetic analog of naturally occurring α-MSH which has a potent and long-lasting effect. In a study combining afamelanotide with NB-UVB, it was noticed that there was quicker and deeper repigmentation due to its effect on melanoblast differentiation, proliferation, and eumelanogenesis.[51] In another recent study, patients with vitiligo with skin photo types III–VI were subjected to combination treatment (afamelanotide with NB UVB) versus NB-UVB monotherapy. The combination therapy group received four monthly subcutaneous afamelanotide implants. The authors concluded that patients with darker skin types responded more rapidly to combination treatment.[52] In another study, intradermal 5-fluorouracil appeared to enhance NB-UVB efficacy, with 48% of patients accomplishing >75% repigmentation in contrast to 7% patients treated with NB-UVB monotherapy.[53] Other recent studies evaluating the role of NB-UVB in combination with other treatment modalities in vitiligo are listed in [Table 4].{Table 4}

 Home Phototherapy – new NB-UVB Delivery Devices



Handheld NB-UVB units are portable and lightweight devices, useful for treating vitiligo affecting small areas. The advantages of using handheld devices at home include significant reduction in the number of hospital visits, which in turn leads to reduced traveling expense, sparing of uninvolved skin, and decreased threshold to start treatment in individuals with limited disease activity.[62] The Hi-Light trial registered in 2015 was a placebo-controlled randomized feasibility trial in which 29 patients with nonsegmental vitiligo received therapy with handheld NB-UVB home phototherapy devices or placebo, using placebo irradiation.[63] Various CE marked brands of hand-held NB-UVB units were used, with dummy units being identical to the active devices. Treatment lasted for 4 months, with three to four sessions per week in which 84% of subjects were compliant with their treatment regimen and most of them said they would recommend the handheld device due to its portability, convenience, and compactness. This trial was not of sufficient duration to formally assess repigmentation rates, but it paved the way for further studies, defining outcomes, minimal erythema dose testing prior to initiating phototherapy, and training patients on their use.[63] In the classic phototherapy in office chamber, it has been shown that the intensity of light is less at the upper and lower ends of the bulbs.[62] Consequently, patients with lesions on the lower legs have to stand on a small stool to ensure adequate exposure. This problem can be easily overcome by handheld devices which can target such areas in a uniform manner. Other models for home phototherapy include single-, double-, and triple-paneled units, handheld wands, and hand and foot devices.[64] Triple-paneled units are most commonly prescribed for home phototherapy when significant body surface area is involved. They usually consist of 8–12 lamps and can be used to treat the whole body with two sets of exposures. The handheld wands are useful in treating scalp and localized lesions. They consist of one to two lamps and are used over vitiliginous areas of 1 × 4.5 inches to 3.3 × 5.5 inches.[62] The hand–foot units usually have a single panel with 4–20 lamps per unit, with some available as table top units that can be used in a table top cart for simultaneous treatment of hand–foot vitiligo.[62] The prerequisites for home-based phototherapy include motivated patients who are able to comply with instructions and return regularly to the physician for reevaluation.[62] A survey study from the Netherlands compared twice-weekly office versus home phototherapy in 104 patients (57 home phototherapy and 32 in-office phototherapy).[65] The results showed that home phototherapy patients received greater number of treatments per week, with no significant difference in the cumulative dose, the degree of repigmentation, or adverse events. However, time investment was much lower in the home phototherapy group. Shan et al. treated 93 patients with localized vitiligo with NB-UVB handheld device thrice weekly and observed onset of regimentation mainly in the perifollicular areas at 1 month of initiation. Most subjects repigmented in the first 3 months and those who did not repigment during this time failed to respond to further treatments.[66]

 Home-Based Phototherapy – handle With Care!



It is important to recognize patients who are at highest risk of side effects with home phototherapy. They are the ones who independently purchase units and self-administer phototherapy without physician advice.[62] Many devices are equipped with safety features such as timers, which allow for administration of a fixed number of treatments after which a new physician-generated code is required and key-locked on/off switches, limiting the length of treatment.[62] In addition, physicians can track treatments using an electronic data logger.[67] Support-staff can help reduce adverse effects by conducting patient education sessions on shielding special sites, wearing cut out clothing at each session, recognizing side effects, and contacting their dermatologist at appropriate times.[62],[64]

 Future Goals



Since no consistent protocols still exist for NB-UVB therapy in vitiligo, further controlled studies are warranted which can help unify the therapeutic guidelines of this promising treatment. We also need multicenter trials comparing in-office versus home phototherapy and studies investigating the additional benefit of phototherapy following surgical treatment. Steps in this direction would definitely help us use this therapeutic modality to its fullest potential.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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