1. Aetna considers the following established methods medically necessary for the treatment of vitiligo:

   1. Excimer laser (e.g., XTRAC, PhotoMedex, Radnor, PA; EX-308, Ra Medical Systems, Inc., Carlsbad, CA)
   2. Narrow-band ultraviolet B (UVB)
   3. Topical and oral psoralen photochemotherapy (PUVA)
   4. Topical and systemic corticosteroids  

2. Aetna considers continued PUVA or narrow-band UVB therapy not medically necessary unless there is significant follicular pigmentation after 6 months of therapy (8 to 10 treatments per month).

3. Aetna considers home phototherapy experimental and investigational for the treatment of vitiligo because there is a lack of evidence regarding the safety and effectiveness of home phototherapy for this condition.

4. Aetna considers treatments for vitiligo cosmetic if they do not affect the underlying condition and do not result in improved protection against skin cancer; specifically micropigmentation (tattooing) and depigmentation (with monobenzylether of hydroquinone/monobenzone) are considered cosmetic.

5. Aetna considers melanocyte transplantation for the treatment of vitiligo experimental and investigational because its effectiveness has not been established.

6. Aetna considers vitamin D analogs (e.g., calcitriol and paricalcitol) experimental and investigational for the treatment of vitiligo because their effectiveness for this indication has not been established.

7. Aetna considers tumor necrosis factor-alpha agents (e.g., adalimumab, etanercept, and infliximab) experimental and investigational for the treatment of vitiligo because their effectiveness for this indication has not been established.

8. Aetna considers α-melanocyte stimulating hormone (e.g., afamelanotide) for the treatment of vitiligo experimental and investigational because its effectiveness has not been established.

Vitiligo is an acquired pigmentary disorder of skin and mucous membranes, manifesting itself by expanding depigmented lesions.  While the cause is not well understood, the observed variation in clinical manifestations of the condition has suggested several possible etiologies, including association with other medical conditions.  The 3 prevailing theories of the pathogenesis of vitiligo include an immune hypothesis, a neural-mediated hypothesis, and a “self-destruct” hypothesis.  These 3, plus newer hypotheses suggesting that vitiligo may be due to a melanocyte growth factor deficiency or to an abnormal melatonin receptor on melanocytes, have not been definitively proven, and it is likely that the loss of epidermal and follicular melanocytes in vitiligo may be the result of several different pathogenic mechanisms.

Psoralen photochemotherapy (psoralen and ultraviolet light A or PUVA) is appropriate for properly selected patients with vitiligo.  The treatment involves taking oral psoralen or applying it topically followed by carefully timed exposure to UVA.  Repigmentation may begin after 15 to 25 treatments.  Approximately 50 % of patients will develop repigmentation after 150 to 200 PUVA treatments over 12 to 24 months.  The response is slow and repigmentation may not be complete.  Response to PUVA is unlikely to occur if follicular pigmentation has not appeared after 3 months of PUVA therapy.  Dark-skinned patients respond better than fair skin patients do; the latter are unlikely to benefit from PUVA unless there is marked disfigurement.  Most patients who respond do not develop new areas of pigment loss; furthermore, maintenance with PUVA therapy is not necessary.

Children under age 10 are generally not treated with oral phototherapy; instead, a mild topical corticosteroid cream is often prescribed.  A stronger topical corticosteroid cream can be prescribed for adults.  Patients must apply the cream (e.g., triamcinolone 0.1 %, desonide 0.05 %) once-daily to the white patches on their skin for at least 3 to 4 months before seeing any results.  Systemic corticosteroids can stop the progression of vitiligo for some patients, but may also produce unacceptable side effects.  Oral mini-pulse therapy with 5 mg betamethasone/dexamethasone may stop the progression and induce spontaneous repigmentation in some vitiligo patients.

A number of recently published studies have demonstrated that narrow-band UVB is an effective treatment for vitiligo, and compares favorably to UVA and psoralens (e.g., Westerhof, 1997; Njoo et al, 2000; Scherschun et al, 2001).  Unlike PUVA, narrow-band UVB does not involve the use of sensitizing agents.  Narrow-band UVB is typically administered 2 to 3 times per week for several months.  However, there is a lack of evidence regarding the safety and effectiveness of home narrow-band UVB phototherapy for the treatment of vitiligo.

In a randomized controlled study, Ada et al (2005) concluded that narrow-band UVB phototherapy is effective in treating vitiligo, and the addition of topical calcipotriol does not improve treatment outcome.

In a double-blind randomized study, Yones et al (2007) compared the effectiveness of oral PUVA with that of narrowband-UVB (NB-UVB) phototherapy in patients with non-segmental vitiligo.  A total of 56 patients received twice-weekly therapy with PUVA or NB-UVB.  The change in body surface area affected by vitiligo and the color match of repigmented skin compared with unaffected skin were assessed after 48 sessions of therapy, at the end of the therapy course, and 12 months after the end of therapy.  The results in the 25 patients each in the PUVA and NB-UVB groups who began therapy were analyzed.  The median number of treatments was 47 in the PUVA-treated group and 97 in the NB-UVB-treated group (p = 0.03); this difference was probably due to differences in effectiveness and adverse effects between the 2 modalities, such that patients in the NB-UVB group wanted a longer course of treatment.  At the end of therapy, 16 (64 %) of 25 patients in the NB-UVB group showed greater than 50 % improvement in body surface area affected compared with 9 (36 %) of 25 patients in the PUVA group.  The color match of the repigmented skin was excellent in all patients in the NB-UVB group but in only 11 (44 %) of those in the PUVA group (p < 0.001).  In patients who completed 48 sessions, the improvement in body surface area affected by vitiligo was greater with NB-UVB therapy than with PUVA therapy (p = 0.007).  Twelve months after the cessation of therapy, the superiority of NB-UVB tended to be maintained.  The authors concluded that in the treatment of non-segmental vitiligo, NB-UVB therapy is superior to oral PUVA therapy.

In a randomized, investigator-blinded and half-side comparison study, Casacci and colleagues (2007) compared the effectiveness of NB-UVB phototherapy and 308-nm monochromatic excimer light (MEL) in patients with vitiligo.  A total of 21 subjects with symmetrical vitiligo lesions were enrolled in this study.  Vitiligo lesions on one body side were treated twice-weekly for 6 months with 308-nm MEL, while NB-UVB phototherapy was used to treat lesions on the opposite side.  At the end of the study, 6 lesions (37.5 %) treated with 308-nm MEL and only 1 lesion (6 %) treated with NB-UVB achieved an excellent repigmentation (score 4) while 4 lesions (25 %) treated with 308-nm MEL and 5 lesions (31 %) treated with NB-UVB showed a good repigmentation (score 3).  The authors concluded that it appears that 308-nm MEL is more effective than NB-UVB in treating vitiligo lesions and it induces repigmentation more rapidly.

Several clinical studies have demonstrated that the Xenon-Chloride excimer laser is effective in repigmentation of vitiligo patches (Hadi et al, 2004; Choi et al, 2004; Esposito et al, 2004; Kawalek et al, 2004; Taneja et al, 2003; Spencer et al, 2002).  The excimer laser may be especially useful in treatment of localized vitiligo that is refractory to topical corticosteroids.  Treatments are typically administered twice weekly and up to 60 treatments may generally be medically necessary.  Recent studies have also suggested that combination treatment with excimer laser and topical methoxypsoralen resulted in better repigmentation than excimer laser alone.  However, due to the small sample sizes in these studies, their findings need to be validated by additional studies (Grimes, 2005).

Transplantation of autologous pigment cells is considered experimental and investigational for the treatment of vitiligo because of a lack of adequate clinical evidence of effectiveness from randomized controlled clinical trials.

van Geel and colleagues (2006) investigated the the effectiveness of non-cultured epidermal cell transplantation in treating stabilized vitiligo using objective and subjective evaluation methods.  Non-cultured autologous melanocytes and keratinocytes were grafted in a hyaluronic-acid-enriched suspension on superficially laser-abraded vitiligo lesions in 40 patients with refractory stable vitiligo (30 with generalized and 10 with localized vitiligo).  The repigmentation was evaluated 3 to 12 months after grafting using a digital image analysis system.  Furthermore, the treatment was evaluated from patients' point of view with the DLQI (Dermatology Life Quality Index) and a global assessment.  The mean percentage of repigmentation, evaluated at the last follow-up visit, was 72 % (median of 84 %), and a repigmentation of greater than or equal to 70 % was observed in 62 % of patients.  The best results were achieved in the neck and the pre-sternal region.  A subjective evaluation was performed in 50 % of the subjects.  The mean DLQI score at inclusion (6.95, SD = 6.68, n = 20) was significantly lowered after treatment (p = 0.013, mean 3.85, SD = 4.13, n = 20).  The patients were satisfied with the achieved result, and they found it worthwhile to undergo the treatment and would choose it again.  The authors concluded that according to both subjective and objective evaluation methods, non-cultured epidermal cell transplantation is promising in patients with stable vitiligo.

In a randomized, double-blind clinical trial, Rodríguez-Martín and colleagues (2009) assessed the safety and effectiveness of tacalcitol (a vitamin D analog) ointment plus sunlight exposure in the treatment of non-segmental vitiligo.  A total of 80 patients participated in this study.  Effectiveness was assessed by quantification of the lesional re-pigmentation area at the end of the study compared with the baseline.  Tacalcitol (n = 40) or matching placebo ointment (n = 40) was applied once-daily at night.  Daily exposure to sunlight for 30 mins was performed.  Treatment was continued for 4 months.  The response of the lesions was clinically verified every 2 weeks by a "blinded" medical investigator.  All adverse effects were recorded.  Over 16 weeks, 64 patients completed the study requirements.  There was no significant difference in the re-pigmentation response at the 16-week time point between the vehicle plus sunlight exposure and the tacalcitol plus sunlight exposure groups.  No reduction in the size of the lesions greater than 25 % was observed in the tacalcitol-treated patients.  No serious adverse effects were observed.  The authors concluded that the combination of tacalcitol with heliotherapy has no additional advantages compared with heliotherapy alone.

In a Cochrane review on interventions for vitiligo, Whitton et al (2010) stated that new interventions include MEL, polypodium leucotomos, melanocyte transplantation, oral anti-oxidants, Chinese zengse pill, and pimecrolimus.  These investigators analyzed the data from 28 studies that met their outcome criteria of improvement in quality of life and greater than 75 % repigmentation.  A total of 15 analyses from studies comparing various interventions showed a statistically significant difference between the proportions of participants achieving more than 75 % repigmentation.  The majority of analyses showing statistically significant differences were from studies that assessed combination interventions that generally included some form of light treatment.  Topical preparations, in particular corticosteroids, reported most adverse effects.  However, in the combination studies it was difficult to ascertain which treatment caused these effects.  None of the studies was able to demonstrate long-term benefits.  Very few studies were conducted on children or included segmental vitiligo.  These researchers found 1 study of psychological interventions and none evaluating micropigmentation, depigmentation, or cosmetic camouflage.  The authors concluded that this review has found some evidence from individual studies to support existing therapies for vitiligo, but the usefulness of the findings is limited by the different designs and outcome measurements and lack of quality of life measures.  There is a need for follow-up studies to assess permanence of repigmentation as well as high quality randomized trials using standardized measures and which also address quality of life.

Alghamdi and colleagues (2012) stated that although the exact pathogenesis of vitiligo is not fully understood, it appears to be an autoimmune disease.  It is hypothesized that tumor necrosis factor-alpha (TNF-alpha) plays an important role in vitiligo.  Tumor necrosis factor-alpha can destroy melanocytes through the induction of various apoptotic pathways.  In addition, TNF-alpha can inhibit melanocyte stem cell differentiation.  These researchers evaluated the safety and effectiveness of treating vitiligo patients with anti-TNF-alpha agents.  A total of 6 patients were recruited.  All patients had widespread non-segmental vitiligo.  Biologics, including infliximab, etanercept, and adalimumab, were given according to treatment regimens used for psoriasis.  Photographs were taken at the initial visit, every 2 months during the therapy and then 6 months after therapy completion.  All patients completed the treatment; 2 patients were treated with infliximab, 2 with etanercept, and 2 with adalimumab.  All of the biologics were well- tolerated throughout the treatment period, and none of the patients reported any significant adverse events.  Digital images were compared before, during and after treatment.  Repigmentation of the vitiliginous areas was not observed in any of the patients.  Vitiligo worsened in 1 patient who was treated with infliximab and developed a psoriasiform rash.  However, the remaining patients did not develop any new depigmented patches during treatment or at the 6-month follow-up; vitiligo was considered stable in these 5 patients.  The authors concluded that although the anti-TNF-alpha agents were well-tolerated in all 6 vitiligo patients, efficacy was not observed.  They stated that further evaluation with larger studies may be required.

In a pilot study, Dayel et al (2013) evaluated the safety and effectiveness of alefacept in the treatment of vitiligo.  After providing informed written consent, 4 adult patients with widespread vitiligo (covering a body surface area greater than or equal to 5 %) were treated with weekly intra-muscular injections of 15 mg alefacept for 12 weeks.  All patients were monitored clinically, by laboratory investigation, and by digital image analysis.  All patients were followed-up with for 24 weeks.  All patients tolerated alefacept well, without any adverse events.  None of the patients showed any re-pigmentation.  However, 1 patient developed new de-pigmented patches during treatment with alefacept.  The authors concluded that alefacept as a monotherapy for vitiligo treatment did not result in any patient improvement, and further evaluation in larger studies may be required.

Wong and Lin (2013) stated that topical calcineurin inhibitors (e.g., pimecrolimus and tacrolimus) are indicated for the treatment of atopic dermatitis, but they have been studied in many off-label uses.  These investigators reviewed the English language literature to define their roles in treatment of vitiligo.  Double-blind studies showed that tacrolimus 0.1 % ointment combined with excimer laser is superior to placebo, especially for UV-resistant areas, such as bony prominences of the extremities.  When used alone, tacrolimus 0.1 % ointment is almost as effective as clobetasol propionate 0.05 % ointment.  Other studies suggested it can also be effective for facial lesions.  Double-blind studies showed that pimecrolimus 1 % cream combined with narrow band UVB is superior to placebo, especially for facial lesions.  Moreover, the authors concluded that additional studies would further clarify the role of topical calcineurin inhibitors in vitiligo.

An UpToDate review on “Vitiligo” (Goldstein and Goldstein, 2013) states that “Topical calcineurin inhibitors (e.g., tacrolimus, pimecrolimus) may be an effective therapy for vitiligo; however, most of the evidence of their use comes from small case series and uncontrolled trials …. In 2005, the Unites States Food and Drug Administration (FDA) issued an alert about a possible link between topical tacrolimus and pimecrolimus and cases of lymphoma and skin cancer in children and adults, and in 2006 placed a "black box" warning on the prescribing information for these medications.  No definite causal relationship has been established; however, the FDA recommended that these agents only be used as second-line agents for atopic dermatitis.  If these agents are used for the treatment of vitiligo, it would be reasonable to follow the additional safety recommendations made by the FDA for their use in atopic dermatitis”.

Grimes et al (2013) noted that many recent studies have demonstrated defects in the melanocortin system in patients with vitiligo, including decreased circulating and lesional skin levels of α-melanocyte stimulating hormone (α-MSH).  Afamelanotide is a potent and longer-lasting synthetic analog of naturally occurring α-MSH.  These investigators described the preliminary results of 4 patients with generalized vitiligo who developed re-pigmentation using afamelanotide in combination with narrowband UV-B (NB-UV-B) phototherapy.  Patients were treated 3 times weekly with NB-UV-B and starting in the 2nd month received a series of 4 monthly implants containing 16 mg of afamelanotide.  Afamelanotide induced faster and deeper re-pigmentation in each case.  All patients experienced follicular and confluent areas of re-pigmentation within 2 days to 4 weeks after the initial implant, which progressed significantly throughout treatment.  All patients experienced diffuse hyper-pigmentation.  The authors proposed that afamelanotide represents a novel and potentially effective treatment for vitiligo.  The combined therapy of NB-UV-B and afamelanotide appears to promote melanoblast differentiation, proliferation, and eumelanogenesis.  They stated that further studies are necessary to confirm these observations.