Vitiligo: a guide to diagnosis and management for GPs

Vitiligo is an acquired depigmenting cutaneous disorder in which pigment cells (melanocytes) are destroyed by autoreactive T cells in the immune system. This results in characteristic white patches that can involve skin (leukoderma), hair (leukotrichia), mucosa and even the retina. The contrast between depigmented skin and normal skin can be disfiguring and have a profound impact on quality of life in both adults and children. Low self-esteem, isolation and stigmatisation are some of the many psychological manifestations reported by patients with vitiligo.¹

Most patients in Australia initially present to their primary healthcare provider for diagnosis and management advice. GPs are in a position to diagnose obvious cases of vitiligo, order appropriate screening investigations, commence simple topical therapy and refer the patient to a dermatologist early in the disease to enhance disease outcomes. GPs should also broach and address any accompanying psychological consequences of this devastating condition and recommend ongoing psychosocial support.

Epidemiology

Vitiligo is one of the most common cutaneous disorders of depigmentation with an estimated worldwide prevalence of up to 2%.² Vitiligo affects all races and does not have a sex predilection. Vitiligo can appear at any age but 50% of those affected experience pigment loss before the age of 20 years and about 80% note depigmentation before the age of 30 years.³ The disease course can be unpredictable with variable severity.

Many patients are understandably anxious about the profound discolouration, especially when exposed areas of skin are affected or when the disease becomes more generalised. Early and prompt recognition of vitiligo, commencing first-line therapy and initiating early referral lead to improved rates of repigmentation and patient outcomes.^4,5

Aetiology

The pathogenesis of vitiligo incorporates intrinsic defects within melanocytes that can activate cellular stress responses and autoimmune mechanisms. The aetiology involves an interplay between genetic and environmental risks that initiates the autoimmune destruction of melanocytes in skin.⁶ Intrinsic melanocyte defects, in addition to autoimmune destruction of melanocytes in skin, result in cutaneous depigmentation.⁶

Patients with vitiligo have increased numbers of autoreactive melanocyte-specific CD8+ T cells in their skin and blood; these T cells are directly responsible for melanocyte destruction and their levels correlate with disease severity.⁷ CD8+ T cells are major producers of the cytokine interferon-gamma (IFNγ).⁷ Studies investigating gene expression profiling have shown increased expression of IFNγ and IFNγ-induced genes in the lesional skin of patients with vitiligo.⁸ Importantly, levels of C-X-C motif chemokine ligand 10 (CXCL10), an IFNγ-induced chemokine, have also been found to be elevated in the serum of patients with vitiligo.⁹ The IFNγ–CXCL10 pathway induces vitiligo, with cytotoxic autoreactive CD8+ T cells and CD4+ regulatory T cells playing an important role in this disease.^8,9

Genetics

Studies indicate a non-Mendelian, polygenic inheritance pattern of vitiligo affecting individuals from multiple lines of the same family, with up to 50% of affected individuals having affected relatives.¹⁰ The risk of a patient’s sibling developing the disease is 6% and for an identical twin it is 23%.¹¹ Patients with vitiligo and their relatives also have an increased risk of developing other autoimmune diseases.¹¹

Autoimmunity

The frequency of comorbid autoimmune diseases, such as Addison’s disease, thyroid disease, alopecia areata, psoriasis, type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus is significantly elevated in patients with vitiligo and their first-degree relatives.¹¹ An increased frequency of organ-specific autoantibodies has been reported in patients with vitiligo.^12,13 Additionally, the presence of antibodies to surface and cytoplasmic melanocyte antigens, which are capable of inducing destruction of melanocytes grown in culture, further supports an autoimmune pathogenesis of the disease.¹⁴

Oxidative stress

Oxidative stress may also contribute to melanocyte destruction in susceptible individuals via activation of the innate immune response.¹⁵ Reactive oxygen species are capable of activating receptors to initiate inflammation.¹⁶ Depletion of antioxidants has been demonstrated in patients with vitiligo.¹⁶

The GP consultation

Diagnosing vitiligo relies on a combination of meticulous history taking (Box) and clinical examination (Table 1). The type and severity of vitiligo should be established, as well as time spent assessing the psychological impact of the condition. Laboratory investigations may assist in identifying any possible underlying autoimmune comorbidity. Histopathological tissue analysis is seldom required; however, it can be helpful if the clinical features are uncertain. Histopathology results may also be equivocal, requiring consultation with a dermatologist.

History

Past and current medication history can be helpful. Past history of treatment with tyrosine kinase inhibitors such as gefitinib (typically used to treat non-small cell lung cancers and solid tumours of the head and neck such as squamous cell carcinoma of the parotid) or imatinib (typically used to treat leukaemia) has been reported to result in depigmentation.¹⁷ Similarly, vitiligo has been reported in patients after using imiquimod 5% cream for the treatment of condylomata acuminata.¹⁸

Biologic drugs such as BRAF inhibitors, IFN-α2b and anti-MEK-MAP kinase drugs have also been implicated in the development of vitiligo.¹⁹ The presence of vitiligo in patients with melanoma is thought to be a marker of an immune response against the tumour and may be an indicator of a favourable prognosis in advanced disease.²⁰ Vitiligo lesions in untreated patients and patients treated with biologic therapy or IFN-α2b were found to be associated with improved survival rates in patients with metastatic melanoma.²¹

Taking a medication history is also helpful in identifying what treatments, if any, the patient has tried in the past and how successful they were. This can help direct and individualise future vitiligo treatment.

Vitiligo is often a diagnosis that weighs heavily on the psyche of the patient, especially when affected areas cannot be effectively camouflaged. The disfiguring depigmentation can have a major impact on the patient’s self-esteem with the emotional burden exerting a tremendous psychological effect, especially in people with skin of colour. It is therefore crucial for the clinician to assess the impact of vitiligo on the patient’s quality of life and provide psychosocial support and counselling when needed.

Clinical examination

In patients with light skin, depigmentation may be difficult to appreciate and changes may only be first noticed during warmer months when the rest of the skin becomes tanned. A Wood’s lamp (365 nm ultraviolet [UV] A light) can be helpful in revealing depigmentation, which is accentuated with fluorescence.

Physical examination

Vitiligo is characterised by acquired, symmetrical, discrete, well-demarcated, asymptomatic, irregularly shaped depigmented macules that may affect skin, mucosa and hair (Figures 1a to c).

Given the potential subtle nature of vitiligo lesions, especially in sun-protected areas, a full body skin examination should be performed to assess the extent of disease. Clinical examination can be assisted with a Wood’s light (Figure 2), especially in individuals with lighter skin types. A Wood’s light examination can accentuate well-demarcated depigmented skin where a bright blue-white fluorescence is emitted. Meticulous examination should be devoted to areas such as the ocular orifice, mouth, umbilicus, nipples and anogenital regions, as well as regions of skin folds such as the fingers, axillae, inguinal areas, elbows and knees. A systematic approach to a full body skin examination, starting at the scalp and hair, is recommended to avoid missing discrete lesions.

Patients may have vitiligo lesions in areas of cutaneous trauma including friction, pressure, cuts and abrasions. This is termed the Koebner phenomenon (Figures 3a and b). Halo naevi have been identified in a small portion of children with nonsegmental vitiligo and may be an indicator of the development of generalised vitiligo.²² Although most patients with vitiligo are affected in different areas of their body, a minority develop the segmental variant of vitiligo in which a patch of depigmentation is noted in a pattern that correlates with other mosaic skin disorders.

Scale, textural change and anaesthetic areas of skin are all clues to diagnoses other than vitiligo (see the differential diagnoses section below).

Examination for signs of systemic autoimmune or inflammatory diseases, including thyroid and connective tissue diseases, are important in the overall clinical assessment of a patient with vitiligo.

Investigations

Serology

The strong association of vitiligo with autoimmune thyroid disorders warrants screening of thyroid function (Flowchart). In a cross-sectional comparative study, thyroid dysfunction, serum thyroid-stimulating hormone (TSH) abnormalities and anti-thyroid peroxidase (TPO) antibody positivity were more common in the group with vitiligo compared with the control group.²³ Furthermore, a recent systematic review found that thyroid disease, autoimmune thyroid disease and the presence of thyroid-specific autoantibodies showed a mean prevalence of 15.1%, 14.3% and 20.8%, respectively, in people with vitiligo.²⁴

A family history or clinical examination findings suggestive of other autoimmune disorders may warrant assay testing of additional relevant antibodies.

Histopathology

Skin biopsies are not routinely required in patients with vitiligo because it is usually a clinical diagnosis. In hypopigmented skin of uncertain aetiology, a skin biopsy may be helpful. The skin biopsy (preferably a punch biopsy) should encompass the border of the depigmented patch and surrounding unaffected skin. It is necessary to include normal skin and lesional skin in the one biopsy because it provides a ‘normal skin’ comparison for the pathologist. It also provides the crucial ‘edge of the lesion’ where the inflammatory cell infiltrate can be seen.

Histopathology of the skin from a patient with vitiligo typically reveals a loss of melanin pigment in the epidermis and an absence of melanocytes.²² Occasional lymphocytes that can be highlighted as CD8+ T cells can also be observed at the advancing border of depigmented skin, along with vacuolar degeneration of basal keratinocytes, spongiosis and a lymphohistiocytic infiltrate at the dermo-epidermal junction.²⁵

Differential diagnoses

Most of the differential diagnoses of vitiligo present with hypopigmentation rather than depigmentation. These are listed in Table 2.

Management

Management options for patients with vitiligo have changed over the past few decades and recent research has provided insight into new possible treatment options.

Informing the patient that vitiligo is an autoimmune condition that can potentially be psychologically devastating and that treatment is available is the first step in validating the patient’s concerns and improving patient outcomes. Treatment goals for vitiligo should be guided by the patient, their age, their skin type, the location of the affected skin and hair, the extent of disease and the impact on the patient’s quality of life. Communication between the GP, psychologist, counsellor and dermatologist is crucial in order to facilitate an individualised treatment plan and to set realistic expectations.

The goal of treatment is to halt disease progression, assist with repigmentation and then maintain that repigmentation over time, while simultaneously providing psychological support.

Photoprotection

General photoprotective advice can help in minimising the profound colour difference between normal skin that pigments and vitiliginous skin that does not. Photoprotection involves:

• avoiding peak UV light periods from 11 am to 3 pm
• applying sunscreen 15 to 30 minutes before sun exposure
• reapplying sunscreen every two hours and after towel drying activities.

The risk of skin cancer in patients with vitiligo however, appears to be lower than in matched controls.²⁶

Cosmetic camouflage

Cosmetic camouflage can be beneficial for patients with vitiligo that affects exposed areas. Products include foundation-based cosmetics and topical tanning products containing dihydroxyacetone (DHA), which can have a longer lasting stay-on effect. Colour matching can be challenging and costly but worth trialling for cosmetically sensitive areas of skin. Tattooing should be avoided given the risk for koebnerisation and oxidation of tattoo pigment causing further dyschromia.

As part of education and management, GPs could direct patients to camouflaging services that may assist in disguising the disfiguring depigmentation. Camouflaging services and techniques should not be underestimated given the tremendous psychosocial impact that vitiligo can have on the lives of those affected.

With the unpredictable disease course and possible cutaneous side effects of vitiligo, treatment initiation and regular monitoring should be undertaken in a multidisciplinary team setting. This should involve the GP, psychologist, psychiatrist and dermatologist, in addition to other relevant physicians such as endocrinologists.

Topical treatments

Repigmentation has been demonstrated with the use of potent topical corticosteroids.²⁷ There is currently no evidence demonstrating the optimal duration of treatment with topical corticosteroids. Side effects of topical corticosteroids include skin atrophy, telangiectasia, acneiform eruptions and hypertrichosis; however, the risk of side effects is minimal when these drugs are used according to recommended guidelines.²⁸ Potent topical corticosteroids can induce hypopigmentation at the site of application. For these reasons, the use of topical corticosteroids on vitiliginous skin on the head and neck is not ideal.

For limited vitiligo affecting body sites, potent topical corticosteroids (i.e. mometasone furoate and betamethasone dipropionate) can be used as first-line treatment, applied daily in a cyclical fashion with ‘steroid-free’ weeks.

Topical calcineurin inhibitors, such as tacrolimus (off-label use), are first-line treatments for patients with vitiligo that affects the head and neck.²⁹ These preparations are available at compounding pharmacies in Australia, at a concentration of either 0.03% or 0.1%, which is mixed with an aqueous cream or ointment base. The topical preparation is applied once or twice daily and may result in gradual repigmentation. However, if the vitiligo lesions are widespread then it is best to refer the patient to a dermatologist to consider a combination of phototherapy and topical therapy, with ongoing monitoring for cutaneous side effects and efficacy.

Narrow-band UVB phototherapy

There is evidence to show that narrow-band UVB phototherapy may be able to stabilise active vitiligo. It is considered first-line treatment for patients with generalised vitiligo.²⁹ However, targeted phototherapy may also be delivered depending on the accessibility and location of the vitiligious skin. Patients should receive phototherapy two to three times per week. No studies have been performed to determine how long phototherapy should be used but patient tolerability and response are two factors taken into consideration when assessing whether further treatment should be prescribed. Ideally, patients should be assessed every 12 weeks when undergoing phototherapy to evaluate response and occurrence of potential cutaneous side effects.

Oral corticosteroids

Some studies suggest that rapidly progressive and aggressive vitiligo may be stabilised with systemic immunosuppression with pulsed low-dose oral corticosteroids. Although prospective, randomised trials are lacking, mini-pulse therapy with oral dexamethasone 2.5 mg on two consecutive days weekly for an average of three months may be helpful for a select group of patients with vitiligo.³⁰

It is important, however, to deliver this therapy for no more than 12 weeks and only to patients with no contraindications. It is also crucial to evaluate the patient for short- and long-term side effects of oral corticosteroid use.

Psychosocial support

The extent of vitiligo disease may not always correlate with psychological morbidity experienced by patients.³¹ Facial involvement of vitiligo, even if small, can have a remarkable effect on patient’s self-esteem. All clinicians should spend time listening and empathising with affected patients.

In some darker-skinned populations, the patient may feel a loss of ethnic identity and may even be stigmatised because of a misunderstanding that vitiligo is infectious. Affected patients may have fears about acceptance and feel socially and culturally isolated.³² Cumulatively, this can contribute to the overall burden the patient may already be experiencing. It is also important to note that such feelings may arise with recurrence and progression of vitiligo.³²

As well as initiating diagnosis and treatment, GPs play a pivotal role in assessing and addressing the psychosocial ramifications of vitiligo. Coping styles differ between individuals and it is important for patients to find and develop coping mechanisms that suit their personality, culture and psychosocial experience. Although medical consultations may be limited, dedicating meaningful time to listen and hear patient concerns can direct management in offering the most appropriate treatment, therapeutic alternatives and referral to patient support groups and local counselling services. Some helpful patient resources include the Global Vitiligo Foundation (www.vitiligoworkinggroup.com) and the Vitiligo Association of Australia (http://vitiligo.org.au).

Surgical therapies

Surgical therapies such as punch and blister grafting and noncultured epidermal cell grafting can be used to repigment recalcitrant yet stable vitiligo in patients who are able to tolerate the procedure, local anaesthetic and laser surgery.

Depigmenting creams

Monobenzyl ether of hydroquinone (MBEH) has been trialled for use as a depigmenting agent for patients with extensive vitiligo. MBEH can cause permanent destruction of melanocytes and induces depigmentation not only at the application site but also in other remote body areas.³³ Its use is therefore only recommended when complete depigmentation is desired in a patient with vitiligo involving more than 70% body surface area.³³

Potential side effects of MBEH include irritant contact dermatitis, pruritus, severe xerosis and even alopecia. Prior counselling about the permanent nature of the depigmenting treatment and change in appearance, and the patient’s expectations is required before embarking on therapy.

Laser therapy

Excimer laser utilises xenon-chlorine gas that produces a monochromatic laser light (308 nm wavelength) to cause repigmentation. Research has shown swifter repigmentation with this device compared with phototherapy.³⁴ Also, it is easier to use on small areas of involvement without having to expose the entire body to the light source but results are variable.³⁴ Furthermore, laser may not be suitable for all patients, and the financial burden of a lengthy treatment phase (treatment may need to be continued for many months or even up to one year) should be considered.

Vitamin D analogues

Evidence supporting sunlight exposure and the use of vitamin D analogues in patients with vitiligo remains inconclusive. The basis for the use of vitamin D analogues such as calcipotriol stems from evidence showing that receptors known as 1-alpha-hydroxyvitamin D3 can stimulate melanogenesis.³⁵ Vitamin D analogues have been used in combination with UV light and topical corticosteroids with variable results.^36,37

Complementary therapies

There is limited evidence from high-quality studies to support the use of antioxidants and vitamins for the treatment of patients with vitiligo.

Future directions

With the recent advances in our understanding of the pathogenesis of vitiligo, scientific investigations of new treatment options under specialist guidance are underway.

Janus kinase (JAK) enzymes are important signals that can direct immune cells. Antibody neutralisation of IFN or CXCL10 has been shown to reverse depigmentation.⁸ It has been proposed that because IFNγ signal transduction occurs through the JAK 1/2 pathway, the use of JAK inhibitors such as tofacitinib (JAK 1/3 inhibitor) or ruxolitinib (JAK 1/2 inhibitor) can lead to a blockade of IFNγ signalling and downstream CXCL10 expression.^8,38 With this, it is plausible to reason that repigmentation in patients with vitiligo is possible and this has been demonstrated in case reports.^39,40 Further clinical trials of biologics are now underway and will undoubtedly unveil new and promising treatments.

Conclusion

Vitiligo is a treatable, autoimmune condition best managed by a multidisciplinary team. Good communication is vital to address patient concerns, dispel myths and guide meaningful management. GPs play a crucial role in promptly diagnosing the condition, investigating the coexistence of other autoimmune conditions, addressing the psychosocial impact of the condition and promptly commencing first-line topical therapies. MT

COMPETING INTERESTS: None.

References

1. Parsad D, Dogra S, Kanwar AJ. Quality of life in patients with vitiligo. Health Qual Life Outcomes 2003; 1: 58.
2. Kruger C, Schallreuter KU. A review of the worldwide prevalence of vitiligo in children/adolescents and adults. Int J Dermatol 2012; 51: 1206-1212.
3. Yaghoobi R, Omidian M, Bagherani N. Vitiligo: a review of the published work. J Dermatol 2011; 38: 419-431.
4. Hallaji Z, Ghiasi M, Eisazadeh A, Damavandi MR. Evaluation of the effect of disease duration in generalized vitiligo on its clinical response to narrowband ultraviolet B phototherapy. Photodermatol Photoimmunol Photomed 2012; 28: 115-119.
5. Brazzelli V, Antoninetti M, Palazzini S, Barbagallo T, De Silvestri A, Borroni G. Critical evaluation of the variants influencing the clinical response of vitiligo: study of 60 cases treated with ultraviolet B narrow-band phototherapy. J Eur Acad Dermatol Venereol 2007; 21: 1369-1374.
6. Harris JE. IFN-γ in vitiligo, is it the fuel or the fire? Acta Derm Venereol 2015; 95: 643-644.
7. Ogg GS, Rod Dunbar P, Romero P, Chen JL, Cerundolo V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med 1998; 188: 1203-1208.
8. Harris JE, Harris TH, Weninger W, Wherry EJ, Hunter CA, Turka LA. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-γ for autoreactive CD8+ T-cell accumulation in the skin. J Invest Dermatol 2012; 132: 1869-1876.
9. Rashighi M, Harris JE. Vitiligo pathogenesis and emerging treatments. Dermatol Clin 2017; 35: 257-265.
10. Bhatia PS, Mohan L, Pandey ON, Singh KK, Arora SK, Mukhija RD. Genetic nature of vitiligo. J Dermatol Sci 1992; 4: 180-184.
11. Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res 2003; 16: 208-214.
12. Betterle C, Caretto A, De Zio A, et al. Incidence and significance of organ-specific autoimmune disorders (clinical, latent or only autoantibodies) in patients with vitiligo. Dermatologica 1985; 171: 419-423.
13. Grimes PE, Halder RM, Jones C, et al. Autoantibodies and their clinical significance in a black vitiligo population. Arch Dermatol 1983; 119: 300-303.
14. Naughton GK, Eisinger M, Bystryn JC. Detection of antibodies to melanocytes in vitiligo by specific immunoprecipitation. J Invest Dermatol 1983; 81: 540-542.
15. Ezzedine K, Eleftheriadou V, Whitton M, van Geel N. Vitiligo. Lancet 2015; 386: 74-84.
16. Richmond JM, Frisoli ML, Harris JE. Innate immune mechanisms in vitiligo: danger from within. Curr Opin Immunol 2013; 25: 676-682.
17. Jalalat SZ, Cohen PR. Gefitinib-associated vitiligo: report in a man with parotid squamous cell carcinoma and review of drug-induced hypopigmentation. Dermatol Online J 2013; 19: 20020.
18. Li W, Xin H, Ge L, Song H, Cao W. Induction of vitiligo after imiquimod treatment of condylomata acuminata. BMC Infect Dis 2014; 14: 329.
19. Nordlund JJ, Kirkwood JM, Forget BM, Milton G, Albert DM, Lerner AB. Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol 1983; 9: 689-696.
20. Ruiz-Villaverde R, Sánchez-Cano D. Can vemurafenib induce vitiligo in metastatic melanoma patients? Balkan Med J 2016; 33: 115-116.
21. Quaglino P, Marenco F, Osella-Abate S, et al. Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study. Ann Oncol 2010; 21: 409-414.
22. Ezzedine K, Diallo A, Léauté-Labrèze C, et al. Multivarate analysis of factors associated with early-onset segmental vitiligo: a prospective observational study of 213 patients. Br J Dermatol 2011; 165: 44-49.
23. Jishna P, Binitha MP, Abdul Latheef EN, Anilakumari VP. Prevalence of thyroid dysfunction and anti-thyroid peroxidase antibodies in vitiligo patients. Int J Res Dermatol 2017; 3: 140-144.
24. Vrijman C, Kroon MW, Limpens J, et al. The prevalence of thyroid disease in patients with vitiligo: a systematic review. Br J Dermatol 2012; 167: 1224-1235.
25. Grimes PE. Disorders of pigmentation. In: Dale DC, Federman DD, eds. ACP medicine. New York: WebMD Scientific American Medicine; 2012. p. 526.
26. Rodrigues M. Skin cancer risk (nonmelanoma skin cancers/melanoma) in vitiligo patients. Dermatol Clin 2017; 35: 129-134.
27. Khalid M, Mujtaba G, Haroon TS. Comparison of 0.05% clobetasol propionate cream and topical Puvasol in childhood vitiligo. Int J Dermatol 1995; 34: 203-205.
28. Mooney E, Rademaker M, Dailey R, et al. Adverse effects of topical corticosteroids in paediatric eczema: Australasian consensus statement. Australas J Dermatol 2015; 56: 241-251.
29. Taieb A, Alomar A, Böhm M, et al. Guidelines for the management of vitiligo: the European Dermatology Forum consensus. Br J Dermatol 2013; 168: 5-19.
30. Kim SM, Lee HS, Hann SK. The efficacy of low-dose oral corticosteroids in the treatment of vitiligo patients. Int J Dermatol 1999; 38: 546-550.
31. Bewley A. The psychological impact of vitiligo. London: Haymarket Media Group; 2008. Available online at: http://www.mims.co.uk/article/822225/psychological-impact-vitiligo (accessed June 2017).
32. Garg S, Sarkar R. Impact of vitiligo in afflicted patients. Pigment Int 2014; 1: 81-89.
33. Gupta D, Kumari R, Thappa DM. Depigmentation therapies in vitiligo. Indian J Dermatol Venereol Leprol 2012; 78: 49-58.
34. Kawalek AZ, Spencer JM, Phelps RG. Combined excimer laser and topical tacrolimus for the treatment of vitiligo: a pilot study. Dermatol Surg 2004; 30: 130-135.
35. Majid I, Masood Q, Hasan I, Khan D, Chisti M. Childhood vitiligo: response to methylprednisolone oral minipulse therapy and topical fluticasone combination. Indian J Dermatol 2009; 54: 124-127.
36. Parsad D, Saini R, Nagpal R. Calcipotriol in vitiligo: a preliminary study. Paediatric Dermatol 1999; 16: 317-320.
37. Baysal V, Yildirim M, Erel A, Kesici D. Is the combination of calcipotriol and PUVA effective in vitiligo? J Eur Acad Dermatol Venereol 2003; 17: 299-302.
38. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013; 368: 161-170.
39. Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy. JAMA Dermatol 2015; 151: 1110-1112.
40. Harris JE, Rashighi M, Nguyen N, et al. Rapid skin repigmentation on oral ruxolitinib in a patient with co-existent vitiligo and alopecia areata (AA). J Am Acad Dermatol 2016; 74: 370-371.