Description
Vitiligo is an idiopathic skin disorder that causes depigmentation of sections of skin, most commonly on the extremities. Topical corticosteroids, alone or in combination with topical vitamin D3 analogues, are common first-line treatments for vitiligo. Alternative first-line therapies include topical calcineurin inhibitors, systemic steroids, and topical antioxidants. Treatment options for vitiligo recalcitrant to first-line therapy include, among others, ultraviolet B light box therapy and psoralen plus ultraviolet A (PUVA). Targeted phototherapy is also being evaluated.

For individuals who have vitiligo who receive targeted phototherapy, the evidence includes randomized controlled trials (RCTs). Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. The studies tend to have small sample sizes, and few were designed to isolate the effect of laser therapy. There is a lack of clinical trial evidence that compares this technique with more conservative treatments or no treatment/placebo. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have vitiligo who receive PUVA, the evidence includes RCTs. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. There is some evidence from randomized studies, mainly those published before 1985, that PUVA is more effective than placebo for treating vitiligo. PUVA for vitiligo is recommended in British guidelines for adults who do not respond to more conservative treatments. Based on the available evidence and clinical guidelines, PUVA may be considered in patients with vitiligo who have not responded adequately to conservative therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.  

Background  
VITILIGO
Vitiligo is an idiopathic skin disorder that causes depigmentation of sections of skin, most commonly on the extremities. Depigmentation occurs because melanocytes are no longer able to function properly. The cause of vitiligo is unknown; it is sometimes considered an autoimmune disease. The most common form of the disorder is nonsegmental vitiligo in which depigmentation is generalized, bilateral, symmetrical, and increases in size over time. In contrast, segmental vitiligo, also called asymmetric or focal vitiligo, covers a limited area of skin. The typical natural history of vitiligo involves stepwise progression with long periods in which the disease is static and relatively inactive, and relatively shorter periods in which areas of pigment loss increase.

Treatment
There are numerous medical and surgical treatments aimed at decreasing disease progression and/or attaining repigmentation. Topical corticosteroids, alone or in combination with topical vitamin D3 analogues, are common first-line treatments for vitiligo. Alternative first-line therapies include topical calcineurin inhibitors, systemic steroids, and topical antioxidants. Treatment options for vitiligo recalcitrant to first-line therapy include, among others, light box therapy with narrow-band ultraviolet B (NB-UVB) and psoralen plus ultraviolet A (PUVA).

Targeted phototherapy with handheld lamps or lasers is also being evaluated. Potential advantages of targeted phototherapy include the ability to use higher treatment doses and to limit exposure to surrounding tissue. Original UVB devices consisted of a Phillips TL-01 fluorescent bulb with a maximum wavelength (lambda max) of 311 nm. Subsequently, xenon chloride lasers and lamps were developed as targeted UVB treatment devices; they generate monochromatic or very narrowband radiation with a lambda max of 308 nm. Targeted phototherapy devices are directed at specific lesions or affected areas, thus limiting exposure to the surrounding normal tissues. They may, therefore, allow higher dosages compared with a light box, which could result in fewer treatments. 

PUVA uses a psoralen derivative in conjunction with long wavelength ultraviolet A (UVA) light (sunlight or artificial) for photochemotherapy of skin conditions. Psoralens are tricyclic furocoumarins that occur in certain plants and can also be synthesized. They are available in oral and topical forms. Oral PUVA is generally given 1.5 hours before exposure to UVA radiation. Topical PUVA therapy refers to the direct application of psoralen to the skin with subsequent exposure to UVA light. With topical PUVA, UVA exposure is generally administered within 30 minutes of psoralen application.

Regulatory Status
In 2001, an XeCl excimer laser (XTRAC™ by PhotoMedex) received 510(k) clearance from the U.S. Food and Drug Administration (FDA) for the treatment of skin conditions such as vitiligo. The 510(k) clearance has subsequently been obtained for a number of targeted UVB lamps and lasers, including newer versions of the XTRAC system including the XTRAC Ultra™, the VTRAC™ lamp (PhotoMedex), the BClear™ lamp (Lumenis), the 308 excimer lamp phototherapy system (Quantel Medical) and the Excilite™ and Excilite μ™ XeCl lamps. The intended use of all of these devices includes vitiligo among other dermatologic indications. Some light-emitting devices are handheld. FDA product code: GEX.

The oral psoralen products Oxsoralen-Ultra® (methoxsalen soft gelatin capsules) and 8-MOP^® (methoxsalen hard gelatin capsules) have been approved by FDA; both are made by Valeant Pharmaceuticals. Topical psoralen products have also received FDA approval, e.g., Oxsoralen^® (Valeant Pharmaceuticals).

Related Policies
20144 Dermatologic Applications of Photodynamic Therapy
20147 Light Therapy for Psoriasis

Policy
PUVA for the treatment of vitiligo which is not responsive to other forms of conservative therapy (e.g., topical corticosteroids, coal/tar preparations, and ultraviolet light) may be considered MEDICALLY NECESSARY.

Targeted phototherapy (e.g. Excimer Laser) is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for the treatment of vitiligo.

Policy Guidelines
During psoralen plus ultraviolet A therapy, the patient needs to be assessed on a regular basis to determine the effectiveness of the therapy and the development of side effects. These evaluations are essential to ensure that the exposure dose of radiation is kept to the minimum compatible with adequate control of the disease. Therefore, psoralen plus ultraviolet A is generally not recommended for home therapy.

Coding
Please see the Codes table for details.

Benefit Application
BlueCard/National Account Issues
Coverage eligibility of PUVA, particularly as a treatment of vitiligo or alopecia areata, may be subject to contractual exclusions regarding cosmetic services.

Rationale  
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Targeted Phototherapy
Clinical Context and Therapy Purpose
The purpose of targeted phototherapy in patients who have vitiligo is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of targeted phototherapy improve the net health outcome in those with vitiligo?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with vitiligo.

Interventions
The therapy being considered is targeted phototherapy. Targeted phototherapy with handheld lamps or lasers is also being evaluated. Potential advantages of targeted phototherapy include the ability to use higher treatment doses and to limit exposure to surrounding tissue.

Comparators
The following therapies are currently being used to treat vitiligo: topical medications and narrowband ultraviolet B (NB-UVB) light box therapy. The most appropriate comparison for targeted phototherapy is NB-UVB, which is considered a standard treatment for active and/or widespread vitiligo based on efficacy and safety.

Outcomes
The general outcomes of interest are a change in disease status, QOL, and treatment-related morbidity. Progression of vitiligo can lead to extreme sensitivity to sunlight, skin cancer, iritis, and hearing loss. Quality of life is another relevant outcome (e.g., emotional distress as skin discoloration progresses).

The application of targeted phototherapy can require multiple weekly treatments over several weeks. In time, treatment results can fade or disappear.

Study Selection Criteria
Methodologically credible studies were selected for each indication within this review using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs. 
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, prefer larger sample size studies and longer duration studies.

Review of Evidence
Systematic Reviews
A systematic review by Lopes et al. (2016) identified 3 studies that compared targeted phototherapy using a 308-nm excimer lamp with NB-UVB (315 patients, 352 lesions) and 3 studies that compared the excimer lamp with the excimer laser (96 patients, 412 lesions).¹ No differences between the excimer lamp and NB-UVB were identified for the outcome of 50% or more repigmentation (relative risk [RR], 1.14; 95% confidence interval [CI], 0.88 to 1.48). For repigmentation of 75% or more, only 2 small studies were identified, and they showed a lack of precision in the estimate (RR, 1.81; 95% CI, 0.11 to 29.52). For the 3 studies that compared the excimer lamp with the excimer laser, there were no significant differences at the 50% or more repigmentation level (RR, 0.97; 95% CI, 0.84 to 1.11) or the 75% or more repigmentation level (RR, 0.96; 95% CI, 0.71 to 1.30). All treatments were most effective in lesions located on the face, with the worst response being lesions on the extremities. There was some evidence of an increase in adverse events such as blistering with targeted phototherapy.

Whitton et al. (2015) updated a Cochrane review of RCTs on treatments for vitiligo.² The literature search, conducted through October 2013, identified 12 trials on laser light devices: 6 trials evaluated the combination of laser light devices and a topical therapy; 2 evaluated the combination of laser devices and surgical therapy; 3 compared regimens of laser monotherapy; and 1 compared a helium-neon laser with a 290- to 320-nm broadband UVB fluorescent lamp. Due to heterogeneity across studies, reviewers did not pool study findings. In most trials, all groups received laser light treatment, alone or as part of combination therapy, and thus the effect of targeted phototherapy could not be isolated. Adverse event reports across the studies included burning, stinging, moderate-to-severe erythema, itching, blistering, and edema.

Sun et al. (2015) published a systematic review of RCTs that focused on the treatment of vitiligo with the 308-nm excimer laser.³ In a literature search conducted through April 2014, reviewers identified 7 RCTs (N = 390) for inclusion. None of the studies were conducted in the U.S.; 5 were from Asia and 3 of those 5 are available only in Chinese. Three trials compared the excimer laser with an excimer lamp, and 4 compared the excimer laser with NB-UVB. One trial had a sample size of only 14 patients and another, published by Yang et al. (2010),⁴ did not report repigmentation rates, providing instead, the proportion of patients with various types of repigmentation (perifollicular, marginal, diffuse, or combined). Repigmentation rates at 75% and 100% levels did not differ significantly between groups treated with the excimer laser versus NB-UVB. Reviewers conducted a meta-analysis of the 2 studies not published in English, though results cannot be verified. Results showed that the likelihood of 50% or more repigmentation was significantly higher with the excimer laser than with NB-UVB (RR, 1.39; 95% CI, 1.05 to 1.85). Two of the 4 studies discussed adverse events, with itching and burning reported by both treatment and control groups and erythema and blistering reported only by the patient in the laser group.

Randomized Controlled Trials
Two RCTs comparing targeted phototherapy to alternate treatment options are summarized in Tables 1 through 4 below.^5,6 Poolsuwan et al. (2020) compared the treatment of 36 paired vitiligo lesions with either targeted phototherapy (308-nm excimer light) or NB-UVB in a single-blind study of 36 patients.⁵ Treatment of lesions with targeted phototherapy led to significant reductions in the Vitiligo Area Scoring Index (VASI) score and significantly improved repigmentation grade compared to treatment with NB-UVB; however, the differences between groups in these outcomes were marginal and may not be clinically significant. An older, open-label study by Nistico et al. (2012) compared 3 different treatment arms in 53 patients with localized or generalized vitiligo: (1) excimer laser plus vitamin E (n = 20); (2) excimer laser plus topical tacrolimus ointment 0.1% and oral vitamin E (n = 20); and (3) oral vitamin E only (n = 13).⁶ The investigators found that patients treated with targeted phototherapy were significantly more likely to achieve a "good" or "excellent" repigmentation response (55% in group 1 and 70% in group 2) than those who received oral vitamin E alone (0%). The rate of good or excellent responses did not differ significantly between groups that received targeted phototherapy with and without topical treatment (p = .36). This study was limited by its open-label design and the fact that the comparator group, oral vitamin E, does not reflect the optimal standard of care treatment for vitiligo.

Table 1. Summary of Key RCT Characteristics

IU: international units; NB-UVB: narrowband ultraviolet B; NR: not reported; RCT: randomized controlled trial.
a Both interventions given for 3 non-consecutive days per week x 48 treatment sessions.
b Frequency of interventions were as follows: Targeted 308-nm excimer laser, twice weekly; oral vitamin E, twice daily; tacrolimus ointment, once daily. All interventions given for 12 weeks. 

Table 2. Summary of Key RCT Results

NA: not applicable; NB-UVB: narrowband ultraviolet B; RCT: randomized controlled trial; VASI: Vitiligo Area Scoring Index
a Repigmentation was reported as a graded score from 1 to 4 with 1 being "poor" and 4 being "excellent."
b Good repigmentation defined as 51% to 75% repigmentation; excellent repigmentation defined as 76% to 100% repigmentation.
c Repigmentation reported as number of patients out of the total number of patients in subgroup (%) for each category. 
d P value reported for good to excellent repigmentation response in each intervention group versus control (oral vitamin E alone). 

Table 3. Study Relevance Limitations

VASI: Vitiligo Area Scoring Index
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context for treatment is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. 5. Study population is subpopulation of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Not CONSORT reporting of harms; 4. Not established and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefits; 2. Not sufficient duration for harms.

Table 4. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Follow-up key: 1. High loss to follow up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f.Statistical key: 1. Test is not appropriate for outcome type: a) continuous; b) binary; c) time to event; 2. Test is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p-values not reported; 4. Comparative treatment effects not calculated.

Retrospective Studies
Fa et al. (2017) retrospectively analyzed 979 Chinese patients (3478 lesions) treated with the 308-nm targeted laser for vitiligo.⁷ Patients had Fitzpatrick skin phototype III or IV and were followed for 2 years after the last treatment. Repigmentation was assessed by 2 dermatologists. A total of 1374 (39%) lesions reached at least 51% repigmentation, with 1167 of the lesions reaching over 75% repigmentation. Complete repigmentation was seen in 219 lesions. Among the cured lesions, the recurrence rate was 44%. Patients with longer disease duration and older age experienced significantly lower efficacy rates. Application of 16 to 20 treatments resulted in higher repigmentation rates than fewer treatments, and increasing the number of treatments beyond 21 did not appear to improve repigmentation rates. There was no discussion of adverse events.

In another retrospective analysis, Dong et al. (2017) evaluated the use of a medium-band (304 to 312 nm) targeted laser for treating pediatric patients (age ≤ 16 years) with vitiligo.⁸ Twenty-seven patients (95 lesions) were evaluated by 2 dermatologists following a mean of 20 treatments (range, 10 to 50 treatments). After 10 treatment sessions, 37% of the lesions reached 50% or more repigmentation. After 20 treatment sessions, 54% of the lesions achieved 50% or more repigmentation. Six children experienced adverse events such as asymptomatic erythema, pruritus, and xerosis, all resolving in a few days.

Section Summary: Targeted Phototherapy
For individuals who have vitiligo who receive targeted phototherapy, the evidence includes systematic reviews of RCTs, 2 individual RCTs, and 2 retrospective studies. Individual studies tend to have small sample sizes, and few were designed to isolate the effect of laser therapy. Two meta-analyses were attempted; however, results from a meta-analysis could not be verified because the selected studies were not available in English, and 1 estimate was imprecise due to the small number of studies and participants. Randomized controlled trials have shown targeted phototherapy to be associated with statistically significant improvements in VASI scores and/or repigmentation compared to alternate treatment options. However, 1 of the RCTs only showed marginal differences between groups in these outcomes, limiting clinical significance ; the second compared phototherapy to oral vitamin E, which is not an optimal comparator. Overall, there is a lack of clinical trial evidence that compares targeted phototherapy with more conservative treatments or no treatment/placebo.

Psoralens With Ultraviolet A
Clinical Context and Therapy Purpose
The purpose of psoralen plus ultraviolet A (PUVA) in patients who have vitiligo is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of PUVA improve the net health outcome in those with vitiligo who have not responded to conservative therapy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with vitiligo who have not responded to conservative therapy.

Interventions
The therapy being considered is PUVA.

Comparators
The following therapies are currently being used to treat vitiligo: topical medications and NB-UVB light box therapy. The most appropriate comparison for PUVA is NB-UVB, which is considered a standard of care treatment for active and/or widespread vitiligo based on efficacy and safety.

Outcomes
The general outcomes of interest are a change in disease status, QOL, and treatment-related morbidity. Progression of vitiligo can lead to extreme sensitivity to sunlight, skin cancer, iritis, and hearing loss. Quality of life is also a relevant outcome (e.g., emotional distress as skin discoloration progresses).

The application of PUVA can require multiple weekly treatments for up to 6 to 12 months.

Study Selection Criteria
Methodologically credible studies were selected for each indication within this review using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, prefer larger sample size studies and longer duration studies.

Review of Evidence
Systematic Reviews
Bae et al. (2017) published a systematic review and meta-analysis on the use of phototherapy for the treatment of vitiligo.⁹ The literature search, conducted through January 2016, identified 35 unique studies for inclusion with 1201 patients receiving NB-UVB and 227 patients receiving PUVA. The category of evidence and strength of recommendation were based on the study design of the selected studies. The outcome of interest was the repigmentation rate. Meta-analytic results are summarized in Table 5. Adverse events were not discussed.

Table 5. Response Rates to NB-UVB Therapy and PUVA in the Treatment of Vitiligo by Treatment Duration

Adapted from Bae et al. (2017).⁹
CI: confidence interval; NB-UVB: narrowband ultraviolet B; PUVA: psoralen plus ultraviolet A.
The Cochrane review by Whitton et al. (2015), which assessed trials on treatments for vitiligo (discussed in the previous section), identified 12 RCTs evaluating PUVA.2, Four trials assessed oral PUVA alone and 8 assessed PUVA in combination with other treatments (e.g., calcipotriol, azathioprine, Polypodium leucotomos, khellin, or surgical treatment). Seven of the 8 studies used 9-methoxypsoralen. A meta-analysis of 3 studies that compared PUVA with NB-UVB found that a larger proportion of patients receiving NB-UVB achieved greater than 75% repigmentation compared with patients receiving PUVA; however, the difference was not statistically significant (RR, 1.60; 95% CI, 0.74 to 3.45). Patients treated with NB-UVB experienced significantly less nausea (RR, 0.13; 95% CI, 0.02 to 0.69) and erythema (RR, 0.73; 95% CI, 0.55 to 0.98) compared with patients receiving PUVA.

A meta-analysis of nonsurgical treatments for vitiligo was published by Njoo et al. (1998).¹⁰ Pooled analysis of 2 RCTs evaluating oral unsubstituted psoralen plus sunlight for generalized vitiligo (N = 97) found a statistically significant treatment benefit for active treatment compared with placebo (pooled odds ratio [OR], 19.9; 95% CI, 2.4 to 166.3). Pooled analysis of 3 RCTs, 2 of oral methoxsalen plus sunlight and 1 of oral trioxsalen plus sunlight (181 patients), also found a significant benefit for active treatment versus placebo for generalized vitiligo (OR, 3.8; 95% CI, 1.3 to 11.3). Adverse events included nausea, headache, dizziness, and cutaneous pruritus. All studies were published before 1985, had relatively small sample sizes (CIs were wide), and used sun exposure rather than artificial ultraviolet A.

Randomized Controlled Trial
Yones et al. (2007) published an RCT that used a psoralen formulation available in the U.S.¹¹ This trial was included in both the Bae et al. (2017) and Whitton et al. (2015) systematic reviews. The trial enrolled 56 patients in the United Kingdom who had nonsegmental vitiligo. Outcome assessment was blinded. Patients were randomized to twice-weekly treatments with methoxsalen hard gelatin capsules PUVA (n = 28) or NB-UVB therapy (n = 28). The NB-UVB treatments were administered in a Waldmann UV500 cabinet containing 24 Phillips 100 NB-UVB fluorescent tubes. In the PUVA group, the starting dose of irradiation was 0.5 J/cm2, followed by 0.25 J/cm2-incremental increases if tolerated. Patients were evaluated after every 16 sessions and followed for up to 1 year. All patients were included in the analysis. The median number of treatments received was 49 in the PUVA group and 97 in the NB-UVB group. At the end of treatment, 16 (64%) of 25 patients in the NB-UVB group had 50% or more improvement in body surface area affected compared with 9 (36%) of 25 patients in the PUVA group. Also, 8 (32%) of 25 in the NB-UVB group and 5 (20%) of 25 patients in the PUVA group had 75% or more improvement in the body surface area affected. Although the authors did not provide p values in their outcomes table, they stated the difference in improvement did not differ significantly between groups for the patient population as a whole. Among patients who received at least 48 treatments, the improvement was significantly greater in the NB-UVB group (p = .007). A total of 24 (96%) patients in the PUVA group and 17 (68%) in the NB-UVB group developed erythema at some point during treatment; this difference was statistically significant (p = .02).

Section Summary: Psoralens with Ultraviolet A
For individuals who have vitiligo who have not responded to conservative therapy who receive PUVA (photochemotherapy), the evidence includes systematic reviews and RCTs. There is some evidence from randomized studies, mainly those published before 1985, that PUVA is more effective than a placebo for treating vitiligo. When compared with NB-UVB in meta-analyses, results have shown that patients receiving NB-UVB experienced higher rates of repigmentation than patients receiving PUVA, though the differences were not statistically significant. Based on the available evidence and clinical guidelines, PUVA may be considered in patients with vitiligo who have not responded adequately to conservative therapy.

Summary of Evidence
For individuals who have vitiligo who receive targeted phototherapy, the evidence includes systematic reviews of RCTs, 2 individual RCTs, and 2 retrospective studies. Relevant outcomes are a change in disease status, QOL, and treatment-related morbidity. Individual studies tend to have small sample sizes, and few were designed to isolate the effect of laser therapy. Two meta-analyses were attempted; however, results from a meta-analysis could not be verified because the selected studies were not available in English, and 1 estimate was imprecise due to the small number of studies and participants. Randomized controlled trials have shown targeted phototherapy to be associated with statistically significant improvements in VASI scores and/or repigmentation compared to alternate treatment options. However, 1 of the RCTs only showed marginal differences between groups in these outcomes, limiting clinical significance ; the second compared phototherapy to oral vitamin E, which is not an optimal comparator. Overall, there is a lack of clinical trial evidence that compares targeted phototherapy with more conservative treatments or no treatment/placebo. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have vitiligo who have not responded to conservative therapy who receive PUVA (photochemotherapy), the evidence includes systematic reviews and RCTs. Relevant outcomes are a change in disease status, QOL, and treatment-related morbidity. There is some evidence from randomized studies, mainly those published before 1985, that PUVA is more effective than a placebo for treating vitiligo. When compared with NB-UVB in meta-analyses, results have shown that patients receiving NB-UVB experienced higher rates of repigmentation than patients receiving PUVA, though the differences were not statistically significant. Based on the available evidence and clinical guidelines, PUVA may be considered in patients with vitiligo who have not responded adequately to conservative therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in "Supplemental Information" if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Vitiligo Working Group
The Vitiligo Working Group is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health. In 2017, the group published guidelines on current and emerging treatments for vitiligo.¹² The Working Group indicated that psoralen plus ultraviolet A (PUVA) has largely been replaced by NB-UVB, but that “PUVA may be considered in patients with darker Fitzpatrick skin phototypes or those with treatment-resistant vitiligo (level I evidence).” The Working Group also stated that “Targeted phototherapy (excimer lasers and excimer lamps) can be considered when < 10% of body surface area is affected (level II evidence).”

U.S. Preventive Services Task Force Recommendation
Not applicable

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in October 2021 did not identify any ongoing or unpublished trials that may influence this review.

References 

1. Lopes C, Trevisani VF, Melnik T. Efficacy and Safety of 308-nm Monochromatic Excimer Lamp Versus Other Phototherapy Devices for Vitiligo: A Systematic Review with Meta-Analysis. Am J Clin Dermatol. Feb 2016; 17(1): 23-32. PMID 26520641
2. Whitton ME, Pinart M, Batchelor J, et al. Interventions for vitiligo. Cochrane Database Syst Rev. Feb 24 2015; (2): CD003263. PMID 25710794
3. Sun Y, Wu Y, Xiao B, et al. Treatment of 308-nm excimer laser on vitiligo: A systemic review of randomized controlled trials. J Dermatolog Treat. 2015; 26(4): 347-53. PMID 25428573
4. Yang YS, Cho HR, Ryou JH, et al. Clinical study of repigmentation patterns with either narrow-band ultraviolet B (NBUVB) or 308 nm excimer laser treatment in Korean vitiligo patients. Int J Dermatol. Mar 2010; 49(3): 317-23. PMID 20465673
5. Poolsuwan P, Churee C, Pattamadilok B. Comparative efficacy between localized 308-nm excimer light and targeted 311-nm narrowband ultraviolet B phototherapy in vitiligo: A randomized, single-blind comparison study. Photodermatol Photoimmunol Photomed. Mar 2021; 37(2): 123-130. PMID 33047405
6. Nistico S, Chiricozzi A, Saraceno R, et al. Vitiligo treatment with monochromatic excimer light and tacrolimus: results of an open randomized controlled study. Photomed Laser Surg. Jan 2012; 30(1): 26-30. PMID 22054204
7. Fa Y, Lin Y, Chi XJ, et al. Treatment of vitiligo with 308-nm excimer laser: our experience from a 2-year follow-up of 979 Chinese patients. J Eur Acad Dermatol Venereol. Feb 2017; 31(2): 337-340. PMID 27538097
8. Dong DK, Pan ZY, Zhang J, et al. Efficacy and Safety of Targeted High-Intensity Medium-Band (304-312 nm) Ultraviolet B Light in Pediatric Vitiligo. Pediatr Dermatol. May 2017; 34(3): 266-270. PMID 28318054
9. Bae JM, Jung HM, Hong BY, et al. Phototherapy for Vitiligo: A Systematic Review and Meta-analysis. JAMA Dermatol. Jul 01 2017; 153(7): 666-674. PMID 28355423
10. Njoo MD, Spuls PI, Bos JD, et al. Nonsurgical repigmentation therapies in vitiligo. Meta-analysis of the literature. Arch Dermatol. Dec 1998; 134(12): 1532-40. PMID 9875190
11. Yones SS, Palmer RA, Garibaldinos TM, et al. Randomized double-blind trial of treatment of vitiligo: efficacy of psoralen-UV-A therapy vs Narrowband-UV-B therapy. Arch Dermatol. May 2007; 143(5): 578-84. PMID 17519217
12. Rodrigues M, Ezzedine K, Hamzavi I, et al. Current and emerging treatments for vitiligo. J Am Acad Dermatol. Jul 2017; 77(1): 17-29. PMID 28619557

Coding Section   

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

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