Alexander B. Dillon, MD; Andrew Sideris, MSc; Ali Hadi, BA; Nada Elbuluk, MD, MSc* The Ronald O. Perelman Department of Dermatology, New York University, New York, New York
Disclosure: The authors report no relevant conflicts of interest.
Vitiligo is one of the most common cutaneous disorders of depigmentation. Although its underlying causes are still being studied and no definitive cure currently exists, recent research has provided insight into pathogenic mechanisms and new treatment options. Objective: The aim of this paper is to provide a comprehensive overview of the medical and surgical therapies for vitiligo with emphasis on the most recent treatment modalities. Design: This review was conducted through a literature search using PubMed and the National Institutes of Health’s ClinicalTrials.gov databases from January 2010 to July 2015. This yielded 86 studies, 12 of which were excluded, and 74 of which were reviewed. Results: Recent studies and ongoing clinical trials indicate that there are many promising new medical and surgical treatment modalities for this chronic condition. Conclusion: A combination of traditional and newer treatments may work synergistically to provide additional improvement in patients’ disease state and quality of life. J Clin Aesthet Dermatol. 2017;10(1):15–28
Vitiligo is an acquired disease with a variable course. It is characterized clinically by well-defined depigmented macules or patches thought to occur secondary to melanocyte dysfunction and loss. It is the most common depigmentation disorder, affecting approximately 0.5 to 2.0 percent of the population and has no predilection for gender or race. Vitiligo is categorized into nonsegmental (NSV) and segmental (SV) subtypes, the latter occurring in a minority (5–16%) of patients. Onset and disease course may vary by subtype. In addition, individuals with vitiligo may experience significant psychosocial manifestations, including low self-esteem and depression.
Pathogenic causes are likely multifactorial, including genetic influences, dysfunctional biochemical pathways, autoimmune processes, melanocyte adhesion deficits, and nervous system imbalances., Traditional vitiligo treatments include topical and oral immunomodulators and phototherapy. On rare occasions, depigmentation creams may also be used when repigmentation therapies prove inadequate and greater than 50 percent of body surface area (BSA) is involved. Advancements in understanding of the pathogenesis of vitiligo have contributed to newer promising therapeutic options. This paper aims to provide a comprehensive overview of these newer treatment options. A review of PubMed and the National Institutes of Health’s ClinicalTrials.gov database from January 2010 to July 2015 using the search phrases “vitiligo,” “vitiligo pathogenesis,” “vitiligo treatments,” and “vitiligo + [drug class or treatment technique]” was performed and clinical trials, case studies, case series, and reviews were included (Figure 1). Studies on alternative or holistic vitiligo treatments were excluded.
Topical creams. First-line vitiligo treatment includes moderate-to-high strength topical corticosteroids and calcineurin inhibitors, both of which dampen the cellular immune response (Table 1, Table 1 Part 2). Several recent studies comparing the use of topical steroids to calcineurin inhibitors have found topical steroids (mometasone 0.1% or clobetasol 0.05% daily) similar in efficacy to calcineurin inhibitors (tacrolimus 0.1% or pimecrolimus 1.0% BID), both with tolerable adverse drug reaction (ADR) rates., A study by Kose et al8 showed mean repigmentation rates of 65 percent with mometasone and 42 percent with pimecrolimus after three months of daily treatment (p=0.154). The authors concluded that pimecrolimus may be preferable for localized facial vitiligo due to the potential for steroid-induced cutaneous atrophy, telangiectasia, and striae formation.
Comparing tacrolimus response among vitiligo subtypes, Udompataikul et al9 found that patients with NSV, both generalized and focal, experienced higher response rates than those with SV and acrofacial NSV (94% vs. 77% vs. 56%, respectively). Children displayed nine times higher odds of response than adults (95% CI: 1.09–1.88). Disease duration of less than five years also correlated with an improved response. A randomized Phase 4 trial, using köebnerized lesions as a model for early stage disease, aims to compare topical tacrolimus to pimecrolimus and topical mometasone (NCT01082393).
Systemic medications. Systemic corticosteroids are generally employed in rapidly progressive cases to help with disease stabilization. In a large, retrospective study, Kanwar et al11 found that low-dose oral dexamethasone mini pulse therapy (2.5mg/day on 2 consecutive days/week) halted progressive vitiligo in 91.8 percent of subjects at a mean of 13.2±3.1 weeks. Some degree of repigmentation was observed in all lesions at a mean of 16.1±5.9 weeks, and relapse occurred in 12.3 percent of patients at an average of 55.7±26.7 weeks post-treatment. Lee et al12 also reported favorable results with a combination of topical and systemic immunosuppressants, including two patients with focal NSV who experienced complete remission within 2 to 3 months of treatment with 0.03% topical tacrolimus and oral prednisone (20mg) daily.
The oral antibiotic minocycline has also shown promise in the treatment of vitiligo due to its anti-inflammatory free-radical scavenging properties that confer a protective effect on melanocytes against H2O2-induced apoptosis. A preliminary study assessing the efficacy of oral minocycline (100mg daily) in progressive, slowly spreading vitiligo showed initial arrest of disease progression in 91 percent (29/32) of patients and arrest of re-progression in 10 patients after one month. A larger randomized controlled trial (RCT) further demonstrated that six months of 100mg minocycline daily was comparable to oral mini pulse corticosteroids (2.5mg for 2 consecutive days/week x 6 months) in halting actively spreading disease.
Statins, best known for combating atherosclerosis, have also garnered interest in vitiligo treatment due to their immunomodulatory activity. Statins downregulate expression of a variety of adhesion molecules involved in the cellular immune response, as well as MHC II in antigen presenting cells (APCs), T cell chemokine receptors, and inflammatory cytokines including tumor necrosis factor (TNF)-a, interferon (IFN)-g, interleukin (IL)-6, and IL-2. They are also antioxidants, blocking nitric oxide synthase and increasing the production of regulatory markers IL-12 and TGF-?., Interest in statins as a treatment for vitiligo began with a case report of vitiligo regression in a patient taking simvastatin 80mg daily. Preclinical data suggests statins prevent and reverse depigmentation by halting the influx and proliferation of cutaneous autoreactive cytotoxic T cells and by decreasing production of IFN-g. Based on these promising findings, a Phase 2 RCT is evaluating the efficacy of simvastatin 80mg daily in adult vitiligo patients, including its effect on peripherally circulating autoreactive cytotoxic T cells (NCT01517893).
Methotrexate, known for its use in inflammatory and immune-mediated conditions, such as psoriasis and inflammatory bowel disease, has also been studied in treating vitiligo. Sandra et al reported the first case in the literature of methotrexate being used in a patient with rapidly progressive vitiligo in 1998. The depigmentation halted the vitiligo from spreading and within three months of initiating treatment at 7.5mg weekly, substantial repigmentation was seen. This led to a pilot study of six patients with stable vitiligo by Alghamdi et al, in which patients were treated with methotrexate 25mg weekly for six months. No improvement was seen in any patient. Singh et al  recently conducted a randomized, open-label trial of methotrexate (10mg weekly) compared with oral mini-pulse steroid therapy in 52 patients with unstable vitiligo, and found no difference in effectiveness between the two treatment modalities in halting the spread of depigmentation.
Biologics, used to combat other immune-mediated diseases, such as psoriasis and rheumatoid arthritis, are also gaining attention as potential treatment options for vitiligo. A recent case report describes the successful use of tofacitinib citrate, an oral janus kinase 1/3 inhibitor, to treat a woman with generalized vitiligo affecting nearly 10 percent of her total BSA. She was treated for five months and had significant repigmentation with no adverse effects. Ruxolitinib, a janus kinase 1/2 inhibitor, was also described in a case report of a patient with concurrent vitiligo and alopecia areata, who had substantial repigmentation after 20 weeks of therapy. Unfortunately, most of the repigmented areas had depigmented within 12 weeks of drug cessation. A pilot study will assess the efficacy of another biologic, abatacept, a fusion protein that prevents co-stimulatory activation of T cells by APCs, in the treatment of vitiligo (NCT02281058).
Ultraviolet light therapy. Ultraviolet (UV) light therapy represents another staple treatment of vitiligo, with both innate and cellular immunosuppressive as well as mitogenic and melanogenic properties that promote melanocyte proliferation and melanin synthesis. A 2012 study by Anbar et al showed that UVA light therapy combined with psoralen (PUVA) helps reverse melanocyte and keratinocyte degeneration in and around lesions of NSV. The sun can also be the source of UVA light in PUVA—a technique termed PUVA sol—which utilizes fewer healthcare resources. A nonrandomized comparative trial, however, suggests that it falls short of PUVA in repigmentation rates (46% vs. 26% repigmentation at 9 months, respectively, p=0.06) and quality of life improvement outcomes. El Mofty et al showed that broadband (BB)-UVA produces similar repigmentation rates to PUVA, along with lower rates of phototoxicity, making it a viable alternative in situations where psoralen cannot be used.
UVB therapy is classified as narrowband (NB-UVB, 311–313nm) or broadband (BB-UVB, 280–320nm). While randomized, controlled data suggest BB-UVB may more effectively stimulate repigmentation than does NB-UVB, use of the latter predominates due to its exclusion of more harmful wavelengths. Psoralen has also been shown to potentiate NB-UVB therapy. At five months follow-up, Bansal et al29 noted a reduction in Vitiligo Area Severity Index (VASI), scores of 29.2 vs. 21.7 percent in patients using psoralen and NB-UVB compared to NB-UVB alone (p=0.043).
UVA-1 has also been studied in the treatment of vitiligo, and randomized controlled data suggests that NB-UVB yields superior results to UVA-1 therapy with comparable ADRs.30 NB-UVB also yields comparable repigmentation rates to PUVA therapy with better color matching and significantly fewer ADRs, making it a preferred treatment option.31 Furthermore, in a recent RCT, NB-UVB therapy has been shown to outperform minocycline, reducing disease activity by 76.2 vs. 33.9 percent over three months (p<0.05) with both resulting in minimal ADRs.
Monochromatic excimer light (MEL) laser therapy. MEL laser therapy is akin to focused, high-intensity UVB light therapy using a wavelength of 308nm. Excimer lamp, with an equivalent wavelength, has been shown to yield results and ADRs comparable to MEL laser therapy with one study reporting mean repigmentation rates >50 percent in 79 percent of patches treated by laser and 87.5 percent patches treated by the excimer lamp (p>0.05).34 A retrospective review evaluating the effects of MEL therapy in segmental vitiligo observed that higher repigmentation rates correlated positively with treatment duration (r=0.315, p=0.004) and cumulative UV dosage (r=0.366, p=0.001) and correlated negatively with disease duration (r=-0.265, p=0.017). A separate small RCT (n=11) observed zero lesions with >50-percent repigmentation after three months of MEL therapy, underscoring the outcome variability of this treatment modality.
Combination UV and topical therapies. NB-UVB has been studied as a monotherapy and in combination with topical therapies including immunomodulators and steroids. One 48-subject, intra-patient comparison study found NB-UVB comparable to 0.1% topical tacrolimus, with at least partial repigmentation rates of 69 and 71 percent, respectively.37 Majid et al38 further observed that the combination of NB-UVB and tacrolimus 0.1% yielded faster and greater repigmentation compared to NB-UVB alone (71% vs. 60.5%, p<0.05). Nordal et al39 since noted a cumulative dose-dependent relationship between topical tacrolimus and repigmentation in NSV patients treated with NB-UVB and found this treatment combination superior to NB-UVB alone (median reduction in target lesions were 42.1% vs. 29% respectively at three months, p=0.005).
A 45-patient RCT comparing NB-UVB alone to NB-UVB with topical calcipotriol, and NB-UVB with topical calcipotriol and betamethasone observed significantly greater repigmentation at six months with the topical steroid combination therapy compared to NB-UVB alone (63.3±7.6% vs. 46.7±8.0%, p=0.0048), and no other significant differences between treatment arms.
The combination of MEL and calcineurin inhibitors has also been studied. An RCT comparing the combination of topical tacrolimus, MEL therapy, and vitamin E versus MEL therapy and vitamin E versus vitamin E alone in 52 vitiligo patients showed significantly greater repigmentation in the combination arms compared to the vitamin-only arm at four months (70% and 55% vs. 0% with >50% repigmentation, p<0.001). No statistical difference between the combination therapy groups was observed (p=0.36). In contrast, Hui-Lan et al compared MEL therapy and topical 0.1% pimecrolimus BID to MEL therapy alone in 48 patients and found that the combination yielded significantly greater repigmentation at 7.5 months (71 vs. 50% of subjects with >50% repigmentation, p=0.001). A recent pilot study reported comparable repigmentation success with combined MEL therapy, topical 0.1% tacrolimus, and low-dose oral prednisolone (0.3mg/kg daily) in 14 patients with recent-onset localized vitiligo at less than half the follow-up time (5 segmental, 9 focal; 71.4% with >50% repigmentation at 3 months). Initial repigmentation was observed within two weeks in most patients. Larger RCTs in the future might further explore the efficacy of triple therapy compared to MEL and topical treatments. Other studies on the horizon are assessing the efficacy of topical compounds that convert sunlight into NB-UVB (NCT01992185) and comparing the combination of NB-UVB and PUVA to NB-UVB alone (Phase 4, NCT01732965).
Afamelanotide. Vitiligo patients are known to have melanocortin system defects including reduced serum and cutaneous lesion alpha-melanocyte stimulating hormone (?-MSH)., Afamelanotide is a longer lasting synthetic analogue of ?-MSH that binds to the melanocortin-1 receptor, stimulating melanocyte proliferation and melanogenesis. A small pilot study of afamelanotide (16mg implant) implanted monthly in four patients, one month post-initiation of tri-weekly NB-UVB, resulted in significant repigmentation within a month and eventual diffuse hyperpigmentation of the GV lesions of all four patients. Subsequently, a 55-patient Phase 1/2 study comparing combination 7 to 10 day release afamelanotide 16mg bioresorbable implants with NB-UVB to NB-UVB alone found combination therapy yielded faster repigmentation of facial (41 vs. 61 days, p=0.001) and upper extremity lesions (46 vs. 69 days, p=0.003), and greater six-month repigmentation rates in NSV (48.6 vs. 33.3%).45 Though subjects’ Fitzpatrick skin types (FSTs) ranged from III to VI, the differences were significant only for FSTs IV to VI. ADRs included nausea, abdominal pain, and hyperpigmentation. Of note, afamelanotide-induced hyperpigmentation of normal skin can accentuate the differential pigmentation between normal and lesional skin. This may be more problematic in lighter skin types, and must be taken into account when considering this treatment option.
Latanoprost. Latanoprost (LT) is a prostaglandin F2alpha analogue that can induce skin pigmentation, a side effect discovered through its use in glaucoma therapy.[47–49] It upregulates tyrosinase and promotes melanocyte proliferation. A recent, 22-patient, randomized, placebo-controlled trial comparing topical LT to NB-UVB and to the combination of the two, reported that the LT and NB-UVB combination was superior to NB-UVB therapy alone (62.5 vs. 12.5% with >50% repigmentation at 6 months, p<0.05).47 LT alone yielded comparable results to NB-UVB (42.9 vs. 28.6% with >50% repigmentation at 6 months, p>0.05) and superior outcomes to placebo (42.9 vs. 0% with >50% repigmentation at 6 months, p<0.05). A Korean case series reported three patients with periorbital vitiligo who experienced 20, 50, and greater than 90-percent repigmentation after two months of topical LT therapy. Likewise, a Phase 4 clinical trial in India investigating topical bimatoprost 0.03% solution twice daily observed 50 to 100-percent repigmentation in 7 of 10 patients after four months. Results were first visible at two months, and patients with recalcitrant, focal vitiligo as well as those with disease duration less than six months tended to respond best. These promising results clearly warrant further investigation into LT’s safety and efficacy for the treatment of vitiligo.
Erbium laser-assisted dermabrasion. Various lasers and surgical procedures have also been studied in the treatment of vitiligo (Table 2)., In a randomized, 18-patient, intra-patient controlled study, Bayoumi et al compared the efficacy of erbium laser-assisted dermabrasion followed by topical steroid use for three weeks, a one-week break, and then three months of NB-UVB treatment to the same regimen without laser dermabrasion. Nearly 50 percent of lesions in the laser cohort achieved >50-percent repigmentation versus 4.2 percent of paired lesions without laser treatment (p<0.0001). Despite the greater repigmentation rates in the laser cohort, tolerance to laser therapy was approximately half that of the non-laser regimen due to adverse effects including pain, edema, delayed healing, and hypertrophic scar formation.
CO2 fractional laser. Fractional CO2 lasers, originally developed for tissue rejuvenation and scar remodeling, have also been evaluated in the treatment of vitiligo. In a 10-patient, randomized, intra-patient controlled trial, fractional CO2 laser therapy followed by NB-UVB was more efficacious in treating NSV than NB-UVB alone, based on semi-quantitative and subjective assessments at five months follow-up. Recently, Vachiramon et al have shown in a prospective, randomized trial comparing NB-UVB therapy, clobetasol, and fractional CO2 laser therapy with NB-UVB and clobetasol alone that adding fractional CO2 laser treatment to above conventional therapies improves repigmentation rate as well as patient satisfaction. A similar study comparing NB-UVB alone to NB-UVB with fractional CO2 laser therapy to CO2 laser with topical steroid is currently recruiting (NCT02290717).
Surgical transplantation. A variety of cellular transplantation techniques have been investigated in vitiligo, including needling, melanocyte keratinocyte transplantations, split-thickness grafts, autologous punch, and suction blister grafts. Surgical techniques are traditionally most effective in SV, in which lesions tend to be stable and focal.
One of the least invasive surgical options is needling. Needling involves the selective relocation of melanocytes from vitiligo lesion margins into the centrally depigmented area to serve as reservoirs for melanogenesis. Two small studies (n=4–12) assessing the efficacy of needling have reported 10- to 100-percent (mean = 61.36%) repigmentation at four months., A Phase 2/3 RCT comparing needling with and without topical corticosteroids is currently recruiting (NCT02191748).
A recent systematic review of surgical treatments for vitiligo assessed various techniques of grafting and cellular transplantation and found that split-thickness and suction blister skin grafting consistently yielded 80- to 90-percent repigmentation rates.56 Suction blister grafting involves iatrogenic separation of the epidermis from the dermis and subsequent harvest and transplantation of the viable epidermis to a similarly treated recipient site. It has been found to have high success and low complication rates. A retrospective study of 28 patients and 129 grafts reported 87-percent graft survival and repigmentation in 68 percent of patients. Subjects less than 20 years old experienced the highest graft survival (100%), while those older than 40 years experienced the lowest rates (75–78%). Recipient sites on the neck and face also tended to experience superior outcomes, while those on the hands and feet experienced the least repigmentation.
Another technique, termed non-cultured epidermal cell suspension (NCES) or melanocyte keratinocyte transplant (MKTP), involves obtaining an autologous skin graft and blood sample, suspending the cells from the dermo-epidermal junction in the patient’s plasma, and transferring the solution to a receipient site, which has been mechanically or thermally dermabraded. Other techniques have also included injecting the cell suspension into iatrogenic blisters at the recipient site.58 A clinical trial assessing the efficacy of this method showed repigmentation in all 10 patients in the study (>76% [n=4], 51–75% [n=2], 26–50% [n=2], 0–25% [n=2]).59 Randomized studies have shown that NCES is significantly more effective than suction blister grafting at inducing repigmentation and increasing patient quality of life.60 NCES also yields comparable objective results and higher patient satisfaction than non-cultured hair follicle outer root sheath cell suspensions, with comparable safety.61 Furthermore, this technique has been shown to yield good-to-excellent (50–100%) repigmentation in greater than 90 percent of patients with leucotrichia at 9 to 12 months, obviating the need for hair transplantation.
MKTP has also been shown to be more effective than dermabrasion alone, and results in an average VASI decrease of 45 percent (95% CI: 26–64%)., Quezada et al conducted a small study of 11 patients to evaluate the safety and efficacy of dermabrasion and grafting for unresponsive vitiligo. They compared simple dermbarasion to dermabrasion of the recipient site combined with the use of the “sandpaper method,” in which sandpaper was used to obtain the melanocytes and epidermal cells used for grafting. They concluded that although early repigmentation was more prominent in the sandpaper group, there was no significant difference between the two groups by three months. A prospective, randomized, placebo-controlled, multicenter trial (n=22) found that MKTP using poly (DL-lactic acid, PLA) film as a vector for transplanted cells yielded greater than 70-percent repigmentation in 45 percent of patients vs. 4.5 percent of controls (p=0.002). A related cellular transplantation method, ReCell®, which involves spraying a cell suspension derived from a superficial skin graft pre-treated with UVA onto laser-dermabraded lesions, has also shown impressive results. Future directions include comparing combinations of different dermabrasion techniques (CO2 laser vs. mechanical) and dressing methods (collagen dressing vs. Vaseline®-impregnated gauze) at the MKTP recipient site (NCT02038257).
Epidermal punch grafting, which entails transplantation of small, round plugs of normal skin and subcutaneous fat to similarly prepared recipient sites, has also resulted in successful repigmentation well beyond graft borders, particularly when accompanied by phototherapy. A retrospective, 30-patient case series, including more than 600 grafts, reported 87-percent graft survival with at least partial repigmentation at all surviving graft sites at a minimum of 10-weeks follow-up. Similar to the trends observed with suction blister grafting, patients younger than 20 years old and those with neck and trunk recipient sites experienced the highest mean repigmentation rates (61, 65, and 63%, respectively), while subjects over 60 years old and those with acral and joint involvement experienced the lowest repigmentation rates (38 and 46%, respectively).
Although surgical therapies can be effective for vitiligo, particularly segmental and focal vitiligo, certain limitations preclude this modality from being more commonly used. In addition to being costly and time consuming, special training, staff, and equipment are needed in order to perform the procedures. The size of the lesions must also be considered with grafting procedures necessitating small-to-medium sized lesions while cellular transplantation is typically limited to a size of 250cm2 or less. Additionally, patients must have stable vitiligo in order to be considered ideal surgical candidates. Criteria for stable vitiligo generally include the following: 1) no change in the size of lesion(s) for a period of at least six months, 2) no new lesions should appear during that time, 3) lack of koebnerization, and 4) no history of keloids or hypertrophic scars.
Combination Medical and Surgical Treatments
A number of promising therapeutic combinations utilizing medical and surgical modalities have been investigated in the treatment of vitiligo (Table 2). Saldanha et al demonstrated in a small study (n=11) that punch grafting and topical mometasone yielded superior repigmentation to punch grafting alone. Similarly, a study of nine patients with stable SV treated with two weeks of prednisolone 20mg by mouth daily followed by epidermal blister grafting yielded excellent results (>90% repigmentation) in all patients at 1 to 2 months follow-up, complicated only by mild donor site hyperpigmentation.
Other investigators have combined skin grafting with phototherapy. Multiple studies have found MEL therapy comparable to NB-UVB following skin grafting, with variable, and, at times, modest results, seemingly dependent on grafting technique., A study of 40 stable vitiligo patients treated with ultra-thin split-thickness grafts followed by NB-UVB, yielded >90-percent repigmentation in 83 percent of subjects, with good-to-excellent cosmetic results in 90 percent of recipient sites. A similar study of cultured melanocyte transplantation with NB-UVB compared with NB-UVB alone resulted in 90- to 100-percent repigmentation in 80.5 percent of patients in the treatment arm, compared with 43.6 percent in the control group. Perigraft depigmentation was seen in 15 percent, and five percent experienced hypertrophic scarring. A randomized study is currently comparing epidermal transplantation using the ReCell® method with or without adjuvant NB-UVB therapy (NCT00615355).
In a more involved combination therapy investigation, El Hoseny et al treated 14 patients with stable NSV of the extremities with 0.3mg/kg oral prednisolone followed by CO2 laser resurfacing of the recipient site, subsequent epidermal skin grafting, and topical 0.1% betamethasone. This combination halted progression in 87.7 percent and yielded good-to-excellent (80–100%) repigmentation in 70.4 percent of patients.
Over the last decade, significant progress has been made in understanding the complex and multifactorial pathogenesis of vitiligo. It is now theorized that intrinsic metabolic, neuronal, and/or biochemical cutaneous perturbations trigger autoimmune melanocytic destruction, to which patients may be predisposed by certain genetic mutations and polymorphisms. How different pathogenic mechanisms give rise to vitiligo subtypes remains to be further elucidated. While at present there is no cure for vitiligo, a variety of advances in medical and surgical treatments as well as combinations of the two working synergistically have shown the ability to improve patients’ disease state and quality of life. A number of clinical trials are underway, and the future is looking promising for patients afflicted with this traditionally stigmatizing and challenging condition.
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