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Vitiligo
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Vitiligo is a common autoimmune disease of the skin resulting from the destruction of epidermal melanocytes by cytotoxic CD8+ T cells. It presents with multiple white macules and patches, which can significantly affect patients’ self-esteem and quality of life.
Vitiligo is estimated to affect about 1–2% of the population, regardless of gender and ethnicity (more than 3 million individuals in the United States). Existing treatments are non-targeted, time-consuming, and offer moderate efficacy. With the exception of monobenzone cream (monobenzyl ether of hydroquinone), which is used to permanently depigment unaffected skin in patients with widespread vitiligo, there are currently no Food and Drug Administration (FDA)–approved medical treatments, and so management of vitiligo is primarily through the use of off-label therapies.
Management Strategy
The mainstay of treatment in vitiligo is topical immunosuppressives and phototherapy . Multiple factors, including disease extent, activity, distribution, and the presence of normally pigmented hair in the lesions should be considered when developing a management strategy in each patient. In particular, lesions located in glabrous skin or that contain a large proportion of poliosis do not typically respond well to treatment, and patients’ expectations should be set for this likely outcome. Treatments may be less effective in patients with the segmental variant of vitiligo because this variant typically involves the hair at a very early stage, causing poliosis. Segmental vitiligo is characterized by rapid progression of depigmentation in a unilateral distribution, which then stabilizes and remains confined to this focal area.
Vitiligo is not a life-threatening condition; patients may therefore decline treatment. However, early and aggressive treatment is associated with better outcomes, which should be addressed with each patient. Regardless, education about the disease and psychological support should be offered to all patients. For treatment purposes, vitiligo patients are generally classified into two groups: patients with limited body surface area (BSA) involvement and patients with more widespread disease.
Segmental Vitiligo and Limited Vitiligo
First-line treatment in patients with limited body involvement, including segmental vitiligo, is treatment with potent topical steroids (clobetasol propionate 0.05%) and/or calcineurin inhibitors (tacrolimus 0.03–0.1% or pimecrolimus 1%). Weaker steroids have not demonstrated efficacy in clinical trials, and thus potent steroids are preferred. Steroids are slightly more effective than calcineurin inhibitors in head-to-head studies; however, the potential side effects limit prolonged use, especially in areas such as the face, genitals, axillae, and breasts. One common strategy is to use both steroids and topical calcineurin inhibitors in an alternating schedule. This can be achieved by application of steroids twice daily for 1 week, followed by calcineurin inhibitors twice daily for the next week, and continued in this way through an alternating weekly schedule. For sensitive areas like the face, genitals, axillae, and breasts, use of calcineurin inhibitors without steroids is preferred.
Targeted phototherapy devices (excimer laser or monochromatic lamp), which deliver light in the UVB range (peak at 308 nm), can be considered a second-line option in patients who do not respond to topical treatments. Sessions are typically administered two or three times per week and continued for at least 3 months before deciding whether the patient is responsive to the treatment or not.
Surgical procedures can be considered in a minority of carefully selected patients with highly stable disease (at least 1 year, and preferably 2 years, without worsening of the existing lesions or development of new lesions) and have the best outcome in patients with the segmental variant. The main concept of this treatment is to transfer healthy melanocytes from non-lesional skin to the affected area within the same patient (autologous transplant). There are multiple different techniques to achieve this, including punch grafting, epidermal blister grafting, and cellular grafts, each with advantages and disadvantages. Epidermal cellular suspension transplant, however, is usually considered to provide the best outcome. Regardless of the technique being used, surgical procedures are contraindicated in patients with active disease, which is marked by the presence of confetti lesions, trichrome lesions, inflammatory lesions, or evidence of the Koebner phenomenon.
Widespread Disease (>3% BSA)
Phototherapy with narrowband ultraviolet B (NB-UVB) is considered the first-line treatment in patients with widespread disease and has largely replaced older phototherapy protocols. NB-UVB has been shown to be at least as effective as psoralen and ultraviolet A (PUVA) therapy with better color match, less risk of burning, and lower risk of skin cancer. Treatment should be delivered two or three sessions per week for at least 3 months and then continued for several additional months in patients who respond.
The decision to deliver two or three phototherapy sessions per week is usually based on patient compliance and personal preference. A three-session-per-week schedule induces a more rapid response; however, there is probably no significant difference between the two schedules in terms of the extent of repigmentation achieved after a prolonged period. NB-UVB therapy can be combined with topical steroids or calcineurin inhibitors to improve the treatment efficacy, especially in limited areas that might be cosmetically more important to patients.
Systemic corticosteroids may be indicated to arrest disease activity in patients with highly progressive disease before other therapies have time to demonstrate efficacy. This is usually delivered as pulse therapy (e.g., 4 mg oral dexamethasone on Saturday and Sunday or alternate-day doses of 20 mg prednisone) to reduce the risk of side effects.
Surgical procedures may be considered to treat selected areas with high cosmetic impact that do not respond to medical treatment. However, this should be reserved for stable lesions, particularly in those with segmental vitiligo, and only in patients with no physical signs of disease activity as mentioned above.
Maintenance Therapy
Relapse of disease is common after discontinuation of treatment. Tacrolimus 0.1% ointment applied twice weekly may prevent relapse in patients and thus be a reasonable approach to maintenance therapy.
Emerging Treatments
Janus kinase (JAK) inhibitors comprise a new class of drugs that selectively inhibit enzymes involved in signal transduction of several cytokines, including IFN-γ. Recent studies have suggested promising results for oral and topical JAK inhibitors, tofacitinib and ruxolitinib. In addition, new investigational JAK inhibitors are currently being studied in early phase clinical trials. Combining NB-UVB phototherapy with JAK inhibitor treatment appears to improve efficacy.
Afamelanotide is a potent synthetic analog of α-melanocyte stimulating hormone (α-MSH), a naturally occurring neuropeptide that stimulates melanogenesis. Recently, a trial reported that afamelanotide boosts the effect of NB-UVB therapy.
Pseudocatalase is a cream that works as a topical oxygen radical scavenger. Consistent with a proposed role for elevated levels of melanocyte stress in vitiligo pathogenesis, studies have shown that there is an increased level of hydrogen peroxide (H 2 O 2 ) in lesional skin of vitiligo patients. A small number of studies have reported that pseudocatalase may enhance repigmentation when combined with NB-UVB phototherapy; however, others have been unable to reproduce these results, and larger independent studies are needed to confirm these observations.
Vitiligo is a clinical diagnosis, and a skin biopsy is rarely necessary. Patients with vitiligo generally have a higher incidence of other autoimmune diseases, including thyroiditis, type 1 diabetes, lupus, alopecia areata, Addison disease, and pernicious anemia. However, the majority of patients do not have any accompanying autoimmune disease, and directed medical history and physical examination are sufficient to identify high-risk individuals who require further evaluation.
Increased risk of comorbid rheumatic disorders in vitiligo patients: a nationwide population‐based study
Choi CW, Eun SH, Choi KH, Bae JM. J Dermatol 2017; 44: 909–13.
This cross-sectional study included 86,210 Korean patients with vitiligo and 172,420 age- and sex-matched healthy controls. Vitiligo was found to be associated with increased risk of systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and Sjögren syndrome, while there was no elevated risk of dermatomyositis/polymyositis, Behçet disease, or ankylosing spondylitis.
Low yield of routine screening for thyroid dysfunction in asymptomatic patients with vitiligo
Kroon MW, Joore IC, Wind BS, et al. Br J Dermatol 2012; 166: 532–8.
Thyroid function tests and anti-TPO antibody titers were assessed in 434 patients with non-segmental vitiligo. The overall prevalence of thyroid dysfunction was higher than reported in the general population. However, most patients had symptoms indicative of thyroid dysfunction and had been already diagnosed by their general practitioners. Moreover, in the majority of these patients, thyroid involvement preceded the onset of vitiligo. Thyroid disease was found mostly among older women and in subjects with a positive family history of thyroid disease. Thus, a thorough review of systems for signs of thyroid disease is sufficient, and routine screening is not necessary.
The efficacy and safety of tacrolimus as mono- and adjunctive therapy for vitiligo: a systematic review of randomized clinical trials
Arora CJ, Rafiq M, Shumack S, et al. Australas J Dermatol 2020; 61: e1–9.
Meta-analysis of 19 studies including 814 patients reported that combination therapy with tacrolimus ointment and NB-UVB was better to achieve >75% repigmentation compared with NB-UVB alone. Tacrolimus and steroids had comparable efficacy in inducing >75% repigmentation. However, for the same result, the combination of fractional laser and tacrolimus was not superior to tacrolimus alone.
Treatment outcomes of topical calcineurin inhibitor therapy for patients with vitiligo: a systematic review and meta-analysis
Lee JH, Kwon HS, Jung HM, et al. JAMA Dermatol 2019; 155: 929–38.
In the 46 studies (1499 patients) selected, 2–7 months’ application of topical calcineurin inhibitor alone (tacrolimus or pimecrolimus) caused at least mild (≥25%), moderate (≥50%), and marked (≥75%) repigmentation in 55.0%, 38.5%, and 18.1% of patients, respectively. When used in combination with phototherapy, 47.5% of patients achieved a marked response.
Phototherapy for vitiligo: a systematic review and meta-analysis
Bae JM, Jung HM, Hong BY, et al. JAMA Dermatol 2017; 153: 666–74.
Findings from 35 prospective studies (1428 unique patients) were analyzed. The percentage of patients who achieved marked (≥75%) repigmentation response to NB-UVB increased over time (from 13.0% at 3 months to 19.2% at 6 months and 35.7% at 12 months). The subgroup analysis revealed that the highest rate of marked response was achieved on the face and neck. In contrast, none of the patients experienced marked repigmentation on the hands and feet after 6 months of NB-UVB.
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