Approach Considerations
Various types of medications, phototherapy, laser therapy, and surgical therapy exist. However, it is important to note that in patients with lighter skin, no intervention may be needed. Instead, diligent sun protection may be the best strategy in order to avoid the surrounding normal skin from becoming more tan and making the lesions more obvious. When therapy is necessary, topical steroids, topical calcineurin inhibitors, and narrow-band ultraviolet (UV)–B phototherapy are widely used and are now considered the mainstays of treatment. However, treatment must be individualized and patients should be made aware of the risks associated with therapy. No single therapy for vitiligo produces predictably good results in all patients, and the response to therapy is highly variable. [32, 33, 34, 35, 36]
Some types of vitiligo or lesions in certain locations may be more or less responsive to treatment. Segmental vitiligo and age of onset younger than 14 years have been associated with more refractory disease. [37] Segmental vitiligo is more responsive to surgical therapy.
During therapy, pigment cells arise and proliferate from the pilosebaceous unit, spare epidermal melanocytes, [38] and the border of lesions, and migrate up to 2-4 mm from the edge.
Medical Care
Phototherapy
Phototherapy induces satisfactory repigmentation in a majority of patients with early or localized disease. [4] Prolonged phototherapy courses should be encouraged, as a treatment period of at least 6 months may be necessary to accurately assess the responsiveness to the phototherapy. [39] It should be noted that phototherapy causes the normal skin surrounding the lesions to tan, thereby making the lesion more noticeable. This may be cosmetically unacceptable in some patients; therefore, careful counseling surrounding patient expectations and results is necessary before beginning treatment.
Narrowband UV-B (NB-UVB) is widely used and has become the first choice of phototherapy for adults and children with generalized vitiligo. Wavelengths of 311-312 nm typically are used. Treatment frequency is 2-3 times weekly. This treatment can be safely used in children, pregnant women, and lactating women. However, phototherapy may be difficult in pediatric patients who may be unable to cooperate. Short-term adverse effects of NB-UVB include burning, pruritus, and xerosis.
Psoralen photochemotherapy involves the use of psoralens combined with UV-A radiation and is also known as PUVA. Psoralens can be applied either topically or taken orally, followed by exposure to artificial UV-A radiation or natural sunlight. Adverse effects include phototoxic effects, nausea, and risk of skin cancer.
PUVA has largely been replaced by NB-UVB, which is highly effective and has fewer adverse effects. Literature reviews from 2017 have shown that NB-UVB therapy has an overall better response than therapy with PUVA. [39] Additional advantages of NB-UVB over PUVA include shorter treatment times, no drug costs, no nausea, and no need for subsequent photoprotection.
Laser therapy
The excimer laser produces monochromatic rays at 308 nm to treat limited, stable patches of vitiligo. This new treatment is an efficacious, safe, and well-tolerated treatment for vitiligo. However, therapy is expensive. Localized lesions of vitiligo are treated twice weekly for an average of 24-48 sessions.
Excimer laser has been combined with both topical tacrolimus and short-term systemic corticosteroids in the setting of segmental vitiligo, which is a type known to be more resistant to repigmentation in some patients. [40] Studies suggest that segmental vitiligo has a better repigmentation response with excimer laser treatment used at earlier stages of the disease. [41]
Additionally, the use of khellin 4% ointment in combination with monochromatic excimer light (MEL) at 308 nm has been investigated and may be a valid therapeutic option worthy of consideration in the treatment of vitiligo. [42]
Topical therapies
Steroids
A topical corticosteroid preparation is often chosen as a first-line treatment for localized vitiligo because it is easy and convenient for patients.. The results of therapy have been reported as moderately successful, particularly in patients with localized vitiligo and/or an inflammatory component to their vitiligo. Depending on the area being treated, a moderately potent topical steroid can be applied daily for a period of months and then tapered depending on response. Patients should be monitored closely for the possibility of steroid atrophy.
Topical Janus kinase (JAK) inhibitors
Topical JAK inhibitor therapy are an emerging option. [55] Ruxolitinib topical cream gained approval from the FDA in July 2022 for treatment of adults and adolescents aged 12 years and older with nonsegmental vitiligo. Approval was based on data from two Phase 3 trials (TRuE-V1 and TRuE-V2), that evaluated the safety and efficacy of ruxolitinib cream compared with vehicle in more than 600 people.
Topical ruxolitinib resulted in significant improvements in vitiligo area scoring index (VASI), which represent improvements in facial and total body repigmentation at Week 24 (primary analysis) compared with vehicle and in an open-label extension at Week 52. Results at Week 24, which were consistent across both studies, showed approximately 30% of patients treated with topical ruxolitinib achieved at least 75% improvement from baseline in the facial (VASI75), the primary endpoint, compared with approximately 8% and 13% of patients treated with vehicle in TRuE-V1 and TRuE-V2, respectively. At Week 52, approximately 50% of ruxolitinib-treated patients achieved F-VASI75. [56]
Additionally, at Week 24, more than 15% of patients treated with topical ruxolitinib achieved at least 90% improvement from baseline in F-VASI (F-VASI90), compared with approximately 2% of patients treated with vehicle. At Week 52, the percentage of ruxolitinib-treated patients who achieved F-VASI90 doubled to approximately 30%. [56]
Calcineurin inhibitors
Topical tacrolimus ointment (0.03% or 0.1%) and pimecrolimus cream are effective therapies for vitiligo, particularly when the disease involves the head and neck. These may be used in combination with topical steroids. Studies have suggested that augmenting topical calcineurin inhibitors with laser therapy or NB-UVB may yield better treatment results. [43, 44]
Vitamin D analogs
Vitamin D analogs, particularly calcipotriol and tacalcitol, have been used as topical therapeutic agents in vitiligo. They target the local immune response and act on specific T-cell activation. They do this by inhibition of the transition of T cells (early to late G1 phase) and inhibition of the expression of various proinflammatory cytokines that encode tumor necrosis factor-alpha and interferon-gamma. These vitamin D3 compounds influence melanocyte maturation and differentiation, in addition to up-regulating melanogenesis through pathways that are activated by specific ligand receptors (eg, endothelin receptor and c-kit). [45] More research is needed to examine the effectiveness of calcipotriol as a treatment for vitiligo, as it remains controversial. [46, 47, 48] Some studies have found that the addition of calcipotriol to combination treatments involving NB-UVB, PUVA, or topical steroids improved repigmentation, [46, 47] while others have found no significant differences. [47, 48] While the role of calcipotriol in vitiligo therapy is still not completely clear, it is more likely that it could act as a supplemental therapy rather than a monotherapy.
Systemic Therapies
Afamelanotide
Afamelanotide is an emerging treatment for vitiligo that is a long-lasting synthetic analog of alpha-melanocyte–stimulating hormone (α-MSH). [49, 50] Afamelanotide binds to the melanocortin-1 receptor and stimulates melanocyte proliferation and melanogenesis. The premise of the treatment the knowledge that patients with vitiligo exhibit defects in the melanocortin system, which manifest as decreased levels of α-MSH in both systemic circulation and skin lesions. [51] Afamelanotide is delivered as a subcutaneous implant. A 55-patient phase I/II study showed that when used in conjunction with NB-UVB, a 7- to 10-day release implant of 16 mg afamelantotide produced faster repigmentation of facial and upper extremity lesions than NB-UVB alone. Adverse reactions included hyperpigmentation of normal skin, nausea, and abdominal pain. [50, 52]
Janus kinase (JAK) inhibitor therapy
Oral tofacitinib and other JAK inhibitors have revolutionized the treatment of vitiligo. They are often combined with the other treatment modalities mentioned. Other forms of targeted immunotherapy are also emerging as treatment options. [53, 54]
Systemic corticosteroid therapy
Systemic steroids (prednisone) have been used, although this treatment method is not recommended owing to its toxicity. Systemic corticosteroids can also be used as twice-weekly pulse therapy.
Depigmentation therapy
If vitiligo is widespread and attempts at repigmentation do not produce satisfactory results, depigmentation may be attempted in very carefully selected patients.
The long-term social and emotional consequences of depigmentation must be considered. Depigmentation should not be attempted unless the patient fully understands that the treatment results in permanent depigmentation. Some authorities have recommended consultation with a mental health professional to discuss potential social consequences of depigmentation. [60]
A 20% cream of monobenzylether of hydroquinone is applied twice daily for 3-12 months. Burning or itching may occur. Allergic contact dermatitis may be seen. [61] The toxicity of monobenzylether of hydroquinone has been deemed mild; however, no research has been performed on the safety of using the drug over large surface areas of skin to induce widespread pigmentation. [62] Accordingly, it is suggested that depigmentation therapy be limited to the lesions that are most bothersome to the patient, such as ones on the face and hands.
Surgical Care
Surgical alternatives exist for the treatment of vitiligo; however, because of the time-consuming nature of surgical therapies, these treatment regimens are limited to segmental vitiligo or localized vitiligo that is limited to a small region.
Characteristics of vitiligo patients that may be a surgical candidate include the following:
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Segmental vitiligo
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Vitiligo localized to a small area
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Vitiligo in areas that tend not to repigment well (eg, dorsal fingers, ankles, forehead, hairline)
Additionally, to be considered for surgery a lesion must be stable, which is to say that the vitiligo is not actively progressing. The most important factors indicating stability are as follows:
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No progression or growth of lesions for at least 2 years
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Spontaneous repigmentation (suggests that melanocytes are not being actively destroyed and indicates relative inactivity)
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A positive minigrafting test disclosing repigmentation at 4-5 minigrafts, which, to date, is the most accurate evidence of vitiligo stability
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Absence of new koebnerization, including the donor site for the minigrafting test
The surgical treatment of vitiligo can be classified according to the type of graft as tissue grafting and cellular grafting technique [63] . The tissue grafting technique includes suction blister grafting, mini-punch grafting and split-thickness graft. The cellular grafting techniques involve non-culture epidermal suspension (NCES), non-cultured outer root sheath follicular suspension and cultured melanocyte grafting.
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Noncultured epidermal suspensions: After the achromic epidermis is removed, an epidermal suspension with melanocytes and keratinocytes previously prepared by trypsinization of normally pigmented donor skin is spread onto the denuded area and immediately covered with nonadherent dressings. Using noncultured epidermal cellular grafts, 71% of patients in one study achieved more than 75% repigmentation, especially in segmental vitiligo, piebaldism, and halo nevi. [64] Color mismatches may be problematic, and generalized vitiligo did not repigment as well. [65]
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Thin dermoepidermal grafts: The depigmented epidermis is removed by superficial dermabrasion, including the papillary dermis, and very thin dermoepidermal sheets harvested with a dermatome are grafted onto the denuded skin.
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Suction blister grafting: Epidermal grafts can be obtained by vacuum suction, usually with 150 mm Hg. The recipient site can be prepared by dermabrasion of the sites before grafting. The epidermal donor graft is placed on the vitiliginous areas. This technique is best suited for lip vitiligo [66]
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Punch minigrafting: Small donor grafts are inserted into the incision of recipient sites and held in place by a pressure dressing. The size of punch used is 1 mm for the face and 1.5 mm for the rest of the body. The graft heals readily and begins to show repigmentation within 4-6 weeks. Some pebbling persists but is minimal, and the cosmetic result is excellent. [67]
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Cultured epidermis with melanocytes or cultured melanocyte suspensions: Depigmented skin is removed using liquid nitrogen, superficial dermabrasion, thermosurgery, or carbon dioxide lasers; very thin sheets of cultured epidermis are grafted or suspensions are spread onto the denuded surface. [68]
Micropigmentation [69] is another option. Tattooing can be used to repigment depigmented skin in dark-skinned individuals. Color matching is difficult, the color tends to fade, and the treatment can possibly provoke the appearance of new lesions. Alternatively, skin can be dyed with dihydroxyacetone preparations, although the color match is often poor.
Consultations
In cases where the patient’s vitiligo may be tied to an autoimmune disease or another underlying condition, referral to the respective specialist may be necessary. Consultation with an ophthalmologist may be warranted in cases with suspected ocular involvement or ocular symptoms. Additionally, psychological needs must be addressed on a continual basis with appropriate referrals to mental health specialists. [70]
Psychological and Social Impact
Because vitiligo affects a person’s physical appearance, there are various associated psychological and social impacts. Higher levels of depression and social anxiety have been reported in patients with vitiligo. [71] Patients may also experience low self-esteem, social stigmatization, shame, avoidance of intimacy, adjustment disorder, fear, suicidal ideation, and other psychiatric morbidities. [72] Lower measures of quality of life have been reported. [73, 74, 75] Specifically, visible vitiligo lesions have been associated with more emotional distress and stigmatization than nonvisible lesions. [76, 77] With regard to the pediatric population, adolescents are more likely to report lower quality-of-life measures and greater psychological and emotional distress than young children. [72, 78]
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Trichrome vitiligo.
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Marginal inflammatory vitiligo.
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Segmental vitiligo.
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Nonsegmental vitiligo.
