¹Department of Dermatology, Beaumont-Farmington Hills, Detroit, MI, USA
²Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA

Conflict of interest:
Dr. Hamzavi is an investigator for Incyte Corporation, Clinuvel, Bayer, Estée Lauder, Unigen Inc., and Ferndale Laboratories. Dr. Nahhas and Dr. Braunberger are former sub-investigators for Ferndale Laboratories, Bayer, Estée Lauder, and Unigen Inc., with grants that were paid to the institution.

Abstract
Vitiligo is an acquired, autoimmune disease characterized by depigmented macules and patches on the skin, which occur secondary to melanocyte destruction. Available therapeutic options are broadly divided into medical, surgical and phototherapy, though treatment of vitiligo can be challenging. Early diagnosis and management can maximize treatment efficacy. The purpose of this discussion is to review updates in the management of vitiligo, including existing and emerging therapies.

Key Words:
medical management, phototherapy, treatment, vitiligo

Introduction

Vitiligo is an acquired, autoimmune disease characterized by depigmented macules and patches on the skin, which occur secondary to melanocyte destruction. Focal and segmental vitiligo patterns involve ≤10% body surface area (BSA) and are considered stable patterns. Generalized vitiligo typically involves ≥10% BSA, appears bilaterally in a symmetric distribution, and generally follows a relapsing and remitting disease course.

Treatment can be challenging, though available modalities of therapy include pharmacologic, surgical, and phototherapy. Appropriate characterization of vitiligo type, consideration of disease extent and duration, and efficacy of prior therapies can guide management and maximize treatment efficacy.

Medical Management

In early, stable, localized disease (≤12 months since onset), topical corticosteroids, topical immunomodulators, targeted narrowband ultraviolet B (NB-UVB) phototherapy, or a combination can be effective. In generalized, stable disease, topical corticosteroids or immunomodulators in combination with NB-UVB phototherapy are the mainstay of therapy. In patients with generalized, rapidly progressive vitiligo, a 3-month trial of pulsed oral corticosteroids may help induce stabilization.¹

Topical Therapies

Topical corticosteroids are effective agents in vitiligo due to their immunosuppressive and anti-inflammatory properties. Super-potent or potent corticosteroids are appropriate for treating the trunk and extremities, whereas mid-potency topical corticosteroids (or topical calcineurin inhibitors) are better suited for the face, neck, or intertriginous regions and in children. Cyclical application (1 week on and 1 week off for 6 months or for 5 days on and 2 days off ) can help avoid the cumulative adverse effects of topical corticosteroids, including skin atrophy, telangiectasias, and steroid-induced acne.¹ Treatment should not exceed 14 days in a month per package insert.²

Topical calcineurin inhibitors, such as tacrolimus (0.1%) or pimecrolimus (1%), are immunomodulatory, steroid-sparing agents that may be used anywhere with the exception of mucous membranes, and are nearly as effective as topical corticosteroids but more favorable with steroid-sparing properties.³ Twice daily use can promote disease stabilization and twice weekly applications may be considered for maintenance therapy.⁴ Topical calcineurin inhibitors may be used in combination with topical corticosteroids on ‘off’ days. Although tacrolimus poses a theoretical, long-term risk of carcinogenicity due to its immunosuppressive properties, no cases in humans have been reported.^1,5 In a mouse model investigating dermal photocarcinogenicity, topical 0.1% tacrolimus was associated with the development of lymphoma. An intra-individual left-right comparison study by Ostovari et al. involving 9 patients with generalized vitiligo found that repigmentation was optimized when topical calcineurin inhibitors were combined with UVB (308 nm excimer laser) exposure in all patients, whereas no repigmentation was observed on the side treated with topical 0.1% tacrolimus alone.⁶

Vitamin D analogs, such as topical calcipotriene, used in combination with phototherapy, may reduce time to repigmentation and the overall cumulative dose delivered.⁷

Oral Therapies

In progressive vitiligo, oral minipulse corticosteroid therapy (OMP) may be used to promote disease stabilization through immunosuppression. A typical regimen includes low-dose oral betamethasone or dexamethasone taken on 2 consecutive days per week for 3 to 6 months.¹ Lack of disease stabilization after 3 months of combination therapy (OMP plus NB-UVB phototherapy) warrants discontinuation of the OMP only and reevaluation at 3-month intervals.¹ Alternatively, upon failure of OMP, daily dosing with 20 mg of oral prednisone may be considered until disease progression has halted.⁸ In an early study published in 1993, 40 patients with extensive or rapidly progressive vitiligo were treated with 5 mg of betamethasone/ dexamethasone as a single oral dose on consecutive days weekly. Within 1 to 3 months, disease progression was arrested in 89% of the patients. In 2 patients, the dose was increased to 7.5 mg per day in order to halt disease progression. Within 2 to 4 months of treatment, 80% of patients noted increased spontaneous repigmentation that was maintained with continued therapy. Side effects consistent with oral corticosteroid use were observed in 42.5% of patients.⁹ In a study published in 2001, 29 patients with either progressive (n = 25) or stable (n = 4) vitiligo received 10 mg of oral dexamethasone on consecutive days weekly for 24 weeks. After an average of 18.2 ± 5.2 weeks, 88% (22 of 25) of patients with progressive vitiligo had arrest in disease activity. Side effects associated with oral corticosteroid use were observed in 69% of the patients studied.¹⁰ In a more recent study published in 2013, 444 patients with progressive vitiligo were treated with 2.5 mg of oral dexamethasone on consecutive days weekly. Using this regimen, arrest of disease progression was noted in 91.8% of these patients, with some repigmentation noted within 16.1 ± 5.9 weeks on average. Disease relapse occurred in 12.25% of patients, though the average disease-free survival until first relapse was 55.7 ± 26.7 weeks. Adverse effects consistent with oral corticosteroid use were observed in 9.2% of patients.¹¹ Side effects associated with any oral corticosteroid use (i.e., acne, weight gain, headache, nausea, and lethargy) should be reviewed with patients. There is evidence to suggest that confetti-like macules and koebnerization are good physical markers of instability.¹² These are markers the authors may use when deciding to initiate oral corticosteroid therapy.

Minocycline, through its anti-inflammatory, immunomodulatory, antioxidant, direct free radical scavenging, and anti-apoptotic properties, may be an effective therapy to arrest progression of vitiligo as well as induce repigmentation.^13-14 In a study involving patients with gradually progressive vitiligo (majority being of the generalized vitiligo type), patients were instructed to take 100 mg of oral minocycline daily. Of the 32 patients included in the study, 29 showed arrest of disease progression, with onset as early as 4 weeks after initiation of treatment in 10 of the 29 patients. Seven of 32 patients showed moderate to marked repigmentation.¹⁵ A randomized trial comparing 6-month treatment with oral dexamethasone (5 mg weekly, 2.5 mg given on 2 consecutive days per week) versus oral minocycline (100 mg daily) in 50 patients with unstable, generalized vitiligo showed there were no statistically significant differences in vitiligo disease activity scores and Vitiligo Area Scoring Index between groups.¹⁶ Another study compared 3-month treatment of oral minocycline (100 mg daily) with NB-UVB phototherapy (twice weekly) in 42 patients with unstable vitiligo and found a statistically significant improvement in repigmentation in the group treated with NB-UVB.¹⁷

Use of methotrexate, an immunomodulating systemic agent, has been shown to improve vitiligo in 1 of 3 patients with rapidly progressive, generalized vitiligo when administered in an uptitrating dose of 12.5-25 mg per week, as reported in a recently published case series. Repigmentation was noted as early as 6 weeks to 14 months in this patient, who had previously failed to respond to topical calcineurin inhibitors and phototherapy.¹⁸ A prospective, randomized trial was performed comparing 24-week treatment with oral methotrexate (10 mg weekly) versus OMP (dexamethasone, 5 mg weekly, 2.5 mg given on 2 consecutive days per week) in 50 patients with unstable vitiligo. New lesions developed in 6 of 25 patients in the methotrexate group and 7 of 25 patients in the OMP group, though the difference was not statistically significant. Both groups demonstrated similar reductions in vitiligo disease activity scores.¹⁹ Due to the limited availability of studies supporting its superior efficacy compared to other available treatments, use of methotrexate can be considered as a steroid-sparing agent in patients with vitiligo refractory to topical treatment and phototherapy.

The role of antioxidants in the treatment of vitiligo remains controversial. Based upon a systematic review of the literature performed by Speeckaert et al., the oxidative stress pathway is deregulated in patients with vitiligo, although it is not considered disease specific, but rather consistent with findings that are expected in an immune-mediated skin disorder. Furthermore, it was noted that increased oxidative stress in non-lesional skin may be specific to vitiligo.²⁰

Among the antioxidant therapies, oral Polypodium leucotomos (PL) extract has been studied in patients with generalized vitiligo due to its notable antioxidant and immunomodulatory properties. In a 26-week randomized clinical trial, patients received NB-UVB phototherapy (twice weekly) combined with either oral PL (250 mg thrice daily) (n = 25) or placebo (n = 24). Improvement in repigmentation was greatest in the group receiving oral PL and NB-UVB phototherapy and most prominent on the head and neck, which was statistically significant.²¹ A pilot, randomized, placebo-controlled clinical trial evaluated the effects of oral PL plus psoralen ultraviolet A (PUVA) versus placebo plus PUVA in 19 patients. Greater than 50% repigmentation was observed more frequently in the PL plus PUVA group compared to the placebo plus PL group.²²

Ginkgo biloba extract has been shown to have some antioxidant and anti-inflammatory properties and may help induce stabilization of vitiligo. In a placebo-controlled, double-blind study evaluating the efficacy of Ginkgo biloba extract in patients with gradually progressive vitiligo, 40 mg of oral Ginkgo biloba extract was administered to 24 patients 3 times daily for 6 months, while 18 patients received the placebo. Twenty patients in the active treatment and 8 patients in the placebo-controlled group had arrest in progression of disease, which was statistically significant. Ten patients in the active treatment group showed marked to complete repigmentation, compared to 2 patients in the placebo-controlled group.²³ A separate 12-week pilot clinical trial involving 11 patients showed that twice daily administration of 60 mg of oral Ginkgo biloba extract resulted in improved total Vitiligo Area Scoring Index measures and spreading as noted by Vitiligo European Task Force scores, with trends toward improvement of vitiligo lesion area and staging on Vitiligo European Task Force scores.²⁴ More clinical trials with larger cohorts are needed to better evaluate the efficacy of antioxidants, including Polypodium leucotomos and Ginkgo biloba extracts.

Phototherapy

NB-UVB is recommended in rapidly spreading vitiligo or extensive generalized vitiligo involving >5% to 10% of BSA.¹ Its immunosuppressive effects and ability to induce differentiation of melanocytes and production of melanin makes it an effective therapy.²⁵ A starting regimen of 200 mJ, delivered twice or thrice weekly, is appropriate in all phototypes, as it avoids risk of phototoxic reactions.²⁶ Once asymptomatic, when light pink erythema lasting less than 24 hours (the treatment endpoint) is no longer observed, the dose can be escalated in 10% to 20% increments until this endpoint is reestablished.²⁶ Patients should be warned of the risk of phototoxicity, and if this occurs, the next dose should be decreased or skipped, depending on the severity of the reaction. Alternatively, a fixed dosing schedule may be used that considers skin phototype differences in minimum erythema dose,²⁷ but this is only recommended in darker skin phototypes due to the increased risk of phototoxic reactions.²⁶

In patients with limited BSA of vitiligo (<10%) or in early, segmental disease, targeted phototherapy (excimer lasers and excimer lamps), is appropriate.^28,29 This approach avoids the generalized skin tanning effect induced by NB-UVB, although it does not address disease stabilization since clinically unaffected skin is not treated.¹

Either twice or thrice weekly phototherapy may be prescribed, as available comparison studies have not demonstrated superior efficacy in the final degree of repigmentation.^30,31 In studies using excimer laser, onset of repigmentation was observed earlier with thrice weekly dosing and repigmentation had greater dependence upon the total number of treatments, which likely can be extrapolated to NB-UVB phototherapy.^1,31

The Vitiligo Working Group recently released guidelines on the use of NB-UVB that advise the maximal acceptable delivered NB-UVB dose in a given treatment as 1500 mJ/cm² and 3000 mJ/cm² for the face and body, respectively.²⁶ In patients with skin phototypes IV-VI, the Vitiligo Working Group advises against defining an upper limit of NB-UVB dosing. In patients with skin phototypes I-III, a NB-UVB dosing upper limit is not suggested, as limited long-term studies are available to investigate the association between cumulative NB-UVB exposure and the potential for cutaneous malignancy, which remains a concern.²⁶ Skin phototype and photosensitivity may also be used to guide upper limits of NB-UVB dosing.¹

NB-UVB has become the preferred route of phototherapy as it has been demonstrated to be more efficacious, lacks a photosensitizer, requires a lower cumulative dose, and has fewer adverse effects compared to PUVA.³² NB-UVB is also safe in children and pregnant or lactating women.¹ PUVA may still be an option in darker skin phototypes and treatment refractory vitiligo.¹ Though concern exists, studies demonstrating increased risk of cutaneous malignancy with PUVA or NB-UVB are lacking. Recent literature suggests vitiligo may be protective against nonmelanoma and melanoma skin cancer.³³

Surgical Management

Surgical therapies may be considered in vitiligo that is local or generalized, stable, or untreated for over a year since onset; it is also appropriate in patients who have failed a 6-month course of topical therapy with or without phototherapy.¹ In generalized vitiligo, outcomes are less promising, which is attributable to the unstable disease course.

Disease stability is an important variable in surgical candidate selection. Published studies define stability as the lack of new or expanding depigmented patches for 6 months to 2 years. Other cutaneous markers of instability include the presence of koebnerization, confetti-like macules of depigmentation, trichrome pattern, or inflammatory borders.¹ Patient report, serial photography, and validated scoring systems such as the Vitiligo Area Severity Index, Vitiligo European Task Force assessment, and Vitiligo Disease Activity Score can be used to confirm stability.¹ In uncertain cases, a test punch graft in a stable, depigmented lesion may be performed.¹

Recipient site (RS) locations on the face and neck have the most favorable repigmentation outcomes, followed by the extremities (excluding digits), and then the trunk.³⁴ Acrofacial vitiligo (including distal fingertips and periungual and perioral areas) typically exhibits poor responses to repigmentation.³⁵ Skin overlying joints also has poor treatment responses due to susceptibility to trauma.³⁵ History of keloid formation, coagulopathy, and blood-borne infections should be considered, among other contraindications to surgery.¹ Surgical therapy can be divided into tissue- and cellular-based grafting techniques.

Tissue Grafting Techniques

Tissue grafting involves transfer of intact tissue from an area of normal, unaffected skin (donor site, DS) to an area of depigmented skin (RS). Many tissue grafting techniques are available, but suction blister epidermal grafting and minipunch grafting are the most widely utilized.

In suction blister epidermal grafting, blisters are raised, harvested, and transferred from a DS to RS. Suction blister epidermal grafting is useful for difficult to treat areas such as the eyelids.³⁶ Complications such as peripheral ‘halo’ depigmentation, milia, hypertrophy, and hyperpigmentation (especially in darker skin phototypes) may occur, including infection rarely.³⁷

Using minipunch grafting, grafts are transferred from DS into RS chambers approximately 5 to 10 mm apart from each other, with slightly larger DS punches taken to account for graft contracture. Complications such as cobblestoning, color mismatch, hypertrophic scarring, keloid formation, and graft rejection can occur at the RS, and depigmentation and scarring at the DS. Minipunch grafting is considered the easiest, fastest, and most cost-effective surgical treatment and, with the exception of the angle of the mouth, can be used anywhere.³⁸

Follicular unit transplant (FUT) capitalizes on the concept that pigmentation can be restored to affected vitiligo patches by targeting reservoirs of undifferentiated stem cells associated with hair follicles.³⁹ Epidermal removal (or ultraviolet radiation) can induce inactive melanocytes to convert to active melanocytes that can then migrate upwards to the epidermis from the outer root sheath to induce perifollicular repigmentation.⁴⁰ Donor grafts are typically harvested from the posterior-auricular or occipital scalp using the ‘strip method’ (also known as the FUT method), then dissected into follicular units and inserted with jeweler’s forceps into slits made at the RS using either a hair transplantation machine, curved cutting needle, or an 18-guage needle.⁴¹ FUT can be advantageous for hair-bearing sites, including difficult to treat areas such as the eyelashes.⁴²

Follicular unit extraction accomplishes hair follicle isolation via 1-mm punch biopsies that are subsequently transferred to RS chambers created via 1-mm punch biopsies, spaced approximately 3 to 10 mm apart.⁴¹ In contrast to FUT, follicular unit extraction is considered an easier procedure and is preferred when limited DS area is available and also favored as a spot-treatment for achromic areas that have not repigmented following FUT.⁴²

Cellular Grafting Techniques

Cellular grafting involves transferring melanocytes and keratinocytes from a DS to the RS as a suspension with or without the use of cell culture. Noncultured epidermal suspensions (also referred to as a melanocyte keratinocyte transplant procedure; NCES) has gained worldwide acceptance as a standard for vitiligo grafting, as it can be performed in a single office visit and does not require use of a laboratory.¹

The main advantage of NCES is the small DS area required to cover a large RS area, in a 1:10 ratio, respectively. An ultra-thin skin graft is harvested from the DS and following cell processing, a cellular suspension is formed and applied to a RS denuded to the dermal-epidermal junction by either dermabrasion or ablative carbon dioxide laser.

Hair follicle outer root sheath cell suspensions were somewhat recently introduced in 2009 by Vanscheidt and Hunziker.⁴³ This method involves the harvesting of hair follicles using the follicular unit extraction method, induction of cell separation using trypsin, incubation, centrifugation, and eventually application of collected cells to the RS. A notable drawback to hair follicle outer root sheath cell suspension is the low cell yield.⁴⁴

Treatment-Refractory Options

A lack of response, delineated by lack of stability or repigmentation following 3 and 6 months of combination therapy, respectively, should warrant consideration of other treatment modalities to improve dyschromia. Disease extent and impact on quality of life can guide treatment selection.

Camouflaging Agents

In vitiligo, camouflaging agents are broadly classified as temporary or permanent. Temporary treatment options include foundation and sunless-tanners, whereas permanent methods include micropigmentation (tattooing).⁴⁵ The ideal camouflaging agent is one that is waterproof, sweat resistant, opaque, and demonstrates good skin color match.⁴⁵

Camouflaging makeup foundations contain 25% more pigment compared to traditional makeup and are generally waterproof, decreasing the need for reapplication.⁴⁵ Dihydroxyacetone is a sunless tanning product that induces temporary staining of the skin by reacting with proteins in the stratum corneum to form brown chromophores termed melanoidins.⁴⁶ Dihydroxyacetone provides longer-lasting coverage (approximately 5 to 7 days),⁴⁷ though use may be limited by poor color match, allergic contact dermatitis,⁴⁸ and the potential cytotoxic effect on keratinocytes as seen in a recent in vitro study.⁴⁹

Micropigmentation (skin tattooing) is generally not recommended due to the risk of koebnerization and color variations over time, secondary to incorrect depth of pigment positioning, resulting in the need for re-application. Oxidation of tattoos containing metal oxides can also lead to a black discoloration, which can be difficult to remove.⁴⁵ Summer tanning can also lead to undesirable skin color contrasts.⁵⁰ Other reactions, including contact dermatitis, granulomatous reactions, and acquired transmission of herpes simplex virus, human immunodeficiency virus, hepatitis B and C, and secondary infections may also occur.⁴⁵

Depigmentation Therapies

In patients with extensive, treatment-refractory vitiligo involving greater than 50% of the BSA, depigmentation therapies can be considered.¹ Monobenzyl ether of hydroquinone (MBEH) is the only drug approved by the US Food and Drug Administration to induce depigmentation.¹ In areas of residual pigmentation, 20% MBEH can be applied twice daily. Lack of response after 4 months of therapy is an indication to increase to 30% MBEH, and if no response is observed by 6 months, MBEH should be discontinued.¹ Once complete depigmentation is achieved, applications can be reduced to a few times per week as maintenance. Complete depigmentation typically takes approximately 4 to 12 months, although darker skin phototypes may require longer treatment.¹ Side effects include irritant contact dermatitis⁵¹ and rarely conjunctival melanosis.⁵² Mequinol is a phenol derivative that may be used to achieve depigmentation, though onset of depigmentation is typically slower.¹

Laser-mediated depigmentation may be used to target remaining melanosomes in melanocytes through photothermolysis and photoacoustic effects.^53,54 The Q-switched ruby (694 nm), Q-switched alexandrite (755 nm), and Q-switched Nd:YAG lasers (532 nm), are most commonly used. This modality is usually reserved for treatment resistant areas on the hands and face. The potential for koebnerization associated with laser therapy can also be an asset to enhance depigmentation.⁵⁵

New Treatments in Vitiligo

Recent studies reveal the IFN-y-CXCL10 axis may be an effective target to treat vitiligo, which has given rise to a new class of targeted immunotherapies, the Janus kinase inhibitors.⁵⁶ Significant repigmentation has been reported following treatment with 2 oral Janus kinase inhibitors, tofacitinib⁵⁷ and ruxolitinib.⁵⁸ Topical ruxolitinib has also shown efficacy, especially with respect to facial repigmentation.⁵⁹ Combination with natural sunlight or NB-UVB may lead to improvements in their efficacy, as observed using oral tofacitinib.⁶⁰ Although these therapies appear promising, studies involving larger cohorts are needed to validate their efficacy. A multi-center phase II clinical trial (ClinicalTrials.gov Identifier: NCT03099304) involving the use of topical ruxolitinib in vitiligo is currently underway.

Afamelanotide, a synthetic alpha melanocyte stimulating hormone, requires the presence of melanocortin 1 receptor and supplementation with NB-UVB to stimulate melanoblast differentiation, and may be an effective new vitiligo therapy.⁶¹

Follow-Up

Frequent disease response monitoring is important to ensure appropriate management and allow for recognition of treatment failure early on, allowing for transition to alternative, potentially more effective therapies as needed. Generally, it is recommended that patients be reevaluated every 3 to 6 months until an effective, stable treatment regimen is established.¹ Due to the significant psychosocial burden experienced by patients with vitiligo, providers should be mindful of the importance of incorporating conversations addressing mental health into patient visits.

Conclusion

Vitiligo is a psychosocially debilitating disease requiring a multidisciplinary approach to treatment. Patients should be made aware of all of the options available geared at repigmentation and depigmentation prior to formulating a treatment plan. Frequent follow-up for disease monitoring and incorporation of discussions centered on quality of life impact can provide treatment guidance and allow for individualized care.

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¹Michigan State University College of Osteopathic Medicine, East Lansing, MI, USA
²Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA
³Department of Dermatology, Beaumont-Farmington Hills, Farmington Hills, MI, USA

Conflict of interest:
Dr. Hamzavi is an investigator for Incyte Corporation, Bayer, Clinuvel, Estée Lauder, Unigen Inc., and Ferndale Laboratories with grants received by the institution. Dr. Nahhas and Dr. Braunberger are sub-investigators for Bayer, Estée Lauder, Unigen Inc., and Ferndale Laboratories with grants received by the institution. Morgan McNeil has no conflicts of interest to declare. Dr. Nahhas and Dr. Braunberger were former sub-investigators for Ferndale Laboratories, Bayer, Estée Lauder, and Unigen Inc., with grants paid to the institution.
Funding: This article has no funding source.

Abstract
Afamelanotide, an α-melanocyte stimulating hormone analogue, has become an emerging therapeutic option for a variety of skin conditions previously refractory to other treatments. Its efficacy has been demonstrated in several dermatologic conditions, including erythropoietic protoporphyria (EPP), solar urticaria, polymorphic light eruption (PMLE), vitiligo, acne, and Hailey-Hailey disease. Its relatively low risk side effect profile makes it an attractive treatment option and also paves the way for innovative use in other disorders.

Key Words:
acne, afamelanotide, alpha-melanocyte stimulating hormone, erythropoietic protoporphyria, Hailey-Hailey disease, polymorphic light eruption, solar urticaria, vitiligo.

Introduction

Afamelanotide (Scenesse^®) is a subcutaneous, controlledrelease, injectable α-melanocyte stimulating hormone (α-MSH) analogue.¹ Afamelanotide is composed of a linear peptide of thirteen amino acids, two of which differ from α-MSH. These two different amino acids increase the affinity of afamelanotide to the melanocortin 1 receptor (MC1R), which in turn increase the stability, potency, and half-life of afamelanotide.¹ Afamelanotide, like α-MSH, binds to MC1R in dermal cells and in melanocytes, thereby stimulating melanocyte production of eumelanin as well as melanocyte proliferation.¹ Eumelanin exhibits numerous roles, including photoprotection against ultraviolet (UV) light and scavenging of free radicals, while also filtering out longer wavelengths of visible light.¹ Therefore, afamelanotide is photoprotective against visible light photosensitivity and, thus, it is an effective treatment option for disorders such as erythropoietic protoporphyria (EPP), solar urticaria, and polymorphic light eruption (PMLE). Melanin also has antioxidant effects that help protect the skin against free radicals. Since such oxidative stress is responsible for inducing the painful symptoms experienced by patients with EPP and certain other dermatologic disorders in which oxygen free radicals are created upon visible light exposure, melanin replacement can help alleviate the associated discomfort.¹

Pharmacokinetics studies reveal that subcutaneous delivery of afamelanotide results in full bioavailability, whereas oral and transdermal routes of administration inhibit measurable plasma concentrations or a pigmentation response, thus establishing its development as a subcutaneous injectable implant.¹ Although not recommended by the manufacturer for use as a sunscreen, afamelanotide has been shown to enhance DNA repair processes following UV damage in keratinocytes through MC1R signaling.^1,2 The side effect profile is reported to be minimal and includes nausea, headache and pigmentation, the latter of which could be seen as either a desirable endpoint in conditions such as vitiligo if inducing new pigment formation in previously depigmented macules or patches, or as an adverse event if new pigment appears hyperpigmented relative to a patient’s baseline skin hue.¹ Afamelanotide was first approved for the treatment of EPP in Europe and is currently under study in both the United States and Europe for its use in other dermatologic disorders.³ We present a discussion of the various conditions that have been treated by afamelanotide and the rationale supporting its use in each condition.

Indications

Erythropoietic Protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited disorder of metabolism characterized by painful photosensitivity leading to swelling and redness of exposed skin areas.⁴ Accumulation of protoporphyrin levels in the skin and dermal blood vessels of these patients at baseline predisposes them to form reactive oxygen species upon exposure to visible light. Formed reactive oxygen species are then capable of inducing tissue and blood vessel damage.⁵ In the setting of EPP, melanin production may provide defense against oxidative stress by neutralizing free radicals and the reactive oxygen species produced, thus helping decrease symptom severity.²

Afamelanotide has been shown to significantly reduce phototoxic reactions and the recovery time associated with visible light exposure in patients with EPP.² In both the United States and in the European Union, multicenter, randomized, double-blinded, placebo-controlled phase III trials of afamelanotide have been performed.² In both trials, there was increased tolerance to direct sunlight exposure in patients receiving afamelanotide compared to those receiving the placebo.² In patients who received afamelanotide in the European arm of the study, phototoxic reactions were less severe (P = 0.04) and recovery time was faster with a median duration of phototoxicity of 1 day for patients receiving afamelanotide versus 3 days for those receiving placebo (P = 0.04).² EPP quality of life questionnaires performed in this study also demonstrated improvements in patients treated with afamelanotide versus placebo.² In summary, it was shown that afamelanotide was safe, effective and capable of improving quality of life.²

In an observational study conducted in Italy and Switzerland, which took place over a period of 8 years, the results showed that 97% of patients considered afamelanotide to be effective in decreasing the symptoms of EPP and, furthermore, 93% of patients were able to adhere to treatment for a prolonged time period.⁶ Since afamelanotide has been proven to be effective in decreasing photosensitivity in EPP, regulatory approval has been granted for use in the European Union and Switzerland.⁵ Its use in EPP has been established for more than 8 years in Italy and Switzerland.²

In addition to the significant dermatological benefits in EPP, afamelanotide also positively impacts patient quality of life. By shortening recovery time from photosensitive reactions, affected individuals are able to be more productive and experience fewer absences from school and work.² The photoprotective nature of afamelanotide also offers patients a longer duration of time to experience activities from which they may have been precluded previously, due to the symptoms associated with their disease while exposed to visible light. Since the elevated protoporphyrin levels do not change with treatment, afamelanotide does not impact liver disease that may occur in some patients with EPP.²

Solar Urticaria

Solar urticaria is a chronic photosensitivity disorder characterized by an itch, wheal and flare reaction that occurs within minutes of sunlight exposure.⁷ Though the exact cause is unknown, it is proposed that mast cells play a major role and an immunoglobulin E-mediated response to photo-induced endogenous cutaneous antigens may also be involved.⁸ Since melanin decreases the amount of UV radiation penetration, it is thought to be photoprotective in solar urticaria.⁷ Afamelanotide’s ability to increase melanin pigment has led to decreased wheal formation across a broad spectrum of wavelengths.⁷ In an openlabel, phase II investigator-initiated study, 5 participants received a single 16 mg subcutaneous implant of afamelanotide. At 30 days, all subjects showed increases in minimum urticarial dose, defined as the lowest dose at which a visible wheal response occurs, for various wavelengths.⁷ A significant decrease in wheal area occurred between 300-600 nm at 60 days post-insertion of the afamelanotide implant, suggesting a photoprotective effect.⁷ Subjects in this study also experienced a significant increase in melanization at sites exposed to photoprovocation with a light source across wavelengths of 300-600 nm and at unexposed sites.⁷ It may also be true that the decreased urticarial response with afamelanotide use is partially due to its immunomodulatory effects; however, additional studies are needed to evaluate this further.⁷ Overall, afamelanotide has shown to be a promising treatment in solar urticaria with the added benefit of improving quality of life.

Polymorphic Light Eruption

Polymorphic light eruption (PMLE) is a photodermatologic, immune disorder characterized by the development of pruritic papules and vesicles on sun-exposed areas of skin.¹ The cause is unknown, though PMLE is considered a delayed-type hypersensitivity response to undefined, endogenous cutaneous photo-induced antigens.^8,9 UV radiation-induced alteration of skin antioxidative capacity is thought to contribute to onset of disease.^10-12 Although self-limited, many patients experience a decrease in quality of life due to efforts to avoid sun exposure in order to prevent the subsequent discomfort associated with PMLE flares.¹³ Treatment generally consists of sun avoidance and photoprotective measures (e.g., sunscreen, clothing, and a wide brim hat). During an eruption and for prevention of flares, local or systemic corticosteroids may be prescribed.¹ Phototherapy with either low-dose psoralen ultraviolet A (PUVA), broadband ultraviolet B (BB-UVB) or narrowband UVB (NB-UVB) radiation is considered a standard part of prophylactic therapy in patients who seek treatment due to its photo-hardening effect.¹³ Photohardening implies the induction of melanization, epidermal thickening, immunomodulatory, and anti-inflammatory effects, which are beneficial in protecting against PMLE.¹⁴ Thus, afamelanotide, by increasing the pigment in the skin, could be photoprotective for these patients and induce this same photoadaptation without the need for phototherapy.

In a pilot trial involving 36 subjects with PMLE who were treated with a 20 mg subcutaneous implant of slow-release afamelanotide, dermal symptoms were reduced in the treatment group compared to the placebo group.¹⁵ All subjects in this study were found to have an increase in melanin density at 120 days in sun-exposed areas, which may have contributed to the improvement of symptoms.¹⁵

Vitiligo

Vitiligo is an acquired, autoimmune disorder involving the development of depigmented macules and patches secondary to epidermal melanocyte destruction.¹ It has been postulated that an α-MSH defect could be present in vitiligo secondary to loss of melanocytes, since these are a major source of MSH.¹⁶ The melanogenic effect of afamelanotide requires MC1R to be present. This mechanism is thought to be the reason behind the efficacy of afamelanotide in vitiligo. Since melanocytes are destroyed within lesions of vitiligo, the presence of MC1R is also lacking. However, since melanoblasts in the hair bulbs are preserved, NB-UVB phototherapy can activate their differentiation, thereby upregulating MC1R and allowing afamelanotide to exert its effect on those receptors.^1,17 Therefore, it may be reasonable to consider supplementing afamelanotide treatment with NB-UVB in vitiligo, however, clinical studies are needed to further evaluate the efficacy of this approach.¹⁷

Studies have shown faster and more complete repigmentation when using afamelanotide as adjuvant treatment in vitiligo.¹ A double-blind, multicenter study involving 55 subjects with generalized vitiligo (skin phototypes III-VI) compared combinat ion therapy (afamelanot ide plus NB-UVB phototherapy) versus NB-UVB phototherapy alone. One patient from each group failed to fulfill the criteria of the intent to treat population, which included those participants who received at least 1 treatment and underwent an efficacy evaluation at day 28 of the trial, leaving the study with 53 participants that fulfilled this criterion. There was 1 drop out from each of the 2 groups. Onset of repigmentation was found to be significantly earlier when afamelanotide was combined with NB-UVB phototherapy beginning at day 56. By day 168, repigmentation was more pronounced in the combination group (48.6%) versus the NBUVB phototherapy alone group (33.26%).¹⁷ This was evidenced by a relative reduction in the vitiligo area scoring index of 48.64% at day 169 versus 33.26% in the NB-UVB monotherapy group. Median time to onset of repigmentation in the face and upper extremities was also reported to be 20 days sooner in the combination therapy group and responses were reported to be rapid in skin phototypes IV-VI.¹⁷ The most common adverse effects in the aforementioned study were erythema, hyperpigmentation, pruritus, and nausea.¹⁷

In a case series involving 4 subjects with generalized vitiligo, the results of combination therapy (NB-UVB plus afamelanotide) revealed that following a 1-month course of bi- to tri-weekly NB-UVB phototherapy, a 16 mg dose implant delivered every 4 weeks for 4 months led to faster and deeper repigmentation.¹⁶ Further studies are needed to define the optimal treatment regimen for the synergistic use of afamelanotide in combination with NB-UVB for vitiligo treatment and to determine the rate of recurrence upon treatment discontinuation.

Hailey-Hailey Disease

Hailey-Hailey disease is a benign, familial pemphigus condition characterized by the formation of blisters with predilection to the intertriginous areas.¹⁸ Increased oxidant stress occurs secondary to a reduced intracellular antioxidant response in the keratinocytes of affected areas.¹⁸ Treatment can be challenging, as traditional therapies often fail to produce long-term results in many patients.¹⁸ MSH has been shown to increase the expression of a transcription factor (nuclear factor [erythroid-derived 2]- like 2 [Nrf2]) that coordinates the expression of antioxidant enzymes in keratinocytes.¹⁹ Afamelanotide may restore the defective proliferative capability of intralesional keratinocytes and defend against the harmful effects of oxidative stress.¹⁸

During a phase II, open-label pilot study, 2 patients with longstanding lesions of Hailey-Hailey disease were treated with subcutaneous afamelanotide implants delivered at a dose of 16 mg on day 0 and on day 30.¹⁹ Lesions improved by 30 days following the first injection and both demonstrated complete clearance by day 60.¹⁸ The results showed that the impaired oxidative stress balance in Hailey-Hailey disease leads to defects associated with downregulated expression of Nrf2; in this study, subjects treated with afamelanotide showed improvement in Nrf2 expression.¹⁹ Moderate skin pigmentation was the only reported side effect and following drug discontinuation, there was no evidence of disease recurrence sooner than 8 months.¹⁹

Acne

Acne vulgaris is an inflammatory skin disorder that occurs due to a combination of events, including increased sebum production, inflammation, hyperkeratinization, and proliferation of Propionibacterium acnes within hair follicles.¹ It is proposed that afamelanotide, through its anti-inflammatory effects, can decrease the amount of acne lesions.²⁰ In a phase II, open-label pilot study, 3 subjects with mild-to-moderate facial acne were given a 16 mg implant of afamelanotide subcutaneously and the results revealed that the total number (including inflammatory lesions and non-inflammatory open and closed comedones) and number of inflammatory acne lesions (papules, pustules and nodes) decreased in all subjects 56 days following implantation.²⁰ In all subjects, quality of life improved as measured by the Dermatology Life Quality Index.²⁰ Optimal dosing of afamelanotide for acne treatment has not yet been established, though larger studies are needed to further evaluate this (Table 1).²⁰

Conclusion

Afamelanotide has a promising future as a treatment for a variety of skin diseases including EPP, solar urticaria, PMLE, acne vulgaris, vitiligo and Hailey-Hailey disease. In consideration of the limited data available on afamelanotide use in children, elderly patients, pregnant or lactating women, and those with hepatic or renal impairment, more studies are needed to evaluate safety and efficacy in these populations.⁵ The anti-inflammatory, pigmenting and free radical scavenging effects produced by the stimulation of melanin production, coupled with a mild side effect profile, make afamelanotide an attractive and versatile compound that shows therapeutic potential in a variety of dermatologic conditions.

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