Vitiligo is a common, disfiguring autoimmune skin disease. It is caused by selective destruction of epidermal melanocytes, resulting in the appearance of depigmented macules and patches that frequently affect the face and other visible areas of the body 1. Vitiligo is not merely a cosmetic condition 2. In fact, it is a psychologically devastating disease of the skin with severe emotional disturbances and psychological consequences, leading to depression, anxiety, sleep disturbances, sexual dysfunction, feelings of discrimination, and even suicidal attempts 3,4. The incidence of the disease is 0.5–2% of the total population or 35–70 million people worldwide, afflicting its targets regardless of sex or race 5. The estimated direct healthcare cost burden of vitiligo in the USA is $175 million each year, a particularly high cost considering there are few effective treatment options 6.
Current treatments for vitiligo include topical and systemic immunosuppressants, phototherapy, and surgical techniques, which together serve to turn off disease progression, stabilize depigmented lesions, and enhance repigmentation 1,7. However, existing medications for the disease are time-consuming, utilize a nontargeted approach, and offer only a moderate degree of efficacy. Moreover, the vast majority are used off-label, as they are not Food and Drug Administration (FDA)-approved for use in vitiligo. Currently, the only FDA-approved treatment for the disease is monobenzone cream [monobenzyl ether of hydroquinone (MBEH) or Benoquin], which is used to permanently depigment the normal skin in patients with widespread vitiligo, rather than repigment the white patches, resulting in an even depigmented skin tone 8. In fact, it is one of a limited number of treatments used in medicine to intentionally make disease worse, and is appropriate only for patients with extensive disease. However, treatments focused on reversing vitiligo, with a more targeted approach that would result in better efficacy and lower side effects, are greatly needed.
Although the risk of developing vitiligo is ∼0.5–2% in the general population 5, this risk is increased in siblings of vitiligo sufferers to 6.1%, and further increased in an identical twin to 23% 9, implying a strong genetic component of the disease 10. In addition, the genetic risk for vitiligo is strongly suggested also by clinical observations that it clusters in families 11.
Indeed, a large number of genetic associations have been reported using genome-wide association studies, which not only confirm a genetic contribution in vitiligo but also reveal that it is inherited in a polygenic pattern (i.e. multiple alleles contribute to the genetic risk for disease). Over 30 genes have been identified as important risk factors for vitiligo 10. The majority of these genes, including the earliest to be discovered, are genes known to modulate the immune response, supporting the strong causative role of the immune system in vitiligo pathogenesis. Some of these genes are known to be major components of innate immunity (NLRP1, IFIH1, CASP7, TICAM1, and others), whereas others are key factors in mediating adaptive immunity (CTLA4, CD80, HLA, GZMB, FOXP3, and others), supporting the integrated contribution of both arms of the immune system in vitiligo pathogenesis 12. In addition, a small subset of melanocyte-specific genes (TYR, OCA2, and MC1R) have been reported, confirming the role of melanocytes in initiating disease. XBP1, a melanocyte-specific cellular stress modulating gene, has also been reported to be important in initiating the inflammation process. However, further studies through functional genomics are still required to define the exact roles of each gene in directing and operating the pathogenesis of vitiligo 13.
As mentioned above, the risk of developing vitiligo in an identical twin of a vitiligo sufferer is 23% 9. As not all identical twins are affected, nongenetic factors must also play a role, and this is thought to be in the form of environmental factors that initiate disease 10. Evidence suggests that the most established environmental risk factor for vitiligo is exposure to phenolic compounds, which is also known as chemical-induced vitiligo, occupational vitiligo, or chemical leukoderma, and constitutes an important connection between cellular stress and autoimmunity 12. Indeed, it was the first environmental exposure connected to vitiligo, when in 1939 a large number of factory workers developed depigmentation on their hands and other locations of their bodies due to wearing gloves containing MBEH. MBEH is an organic chemical compound that belongs to the phenol family, which is now used to depigment the normal skin in patients with severe vitiligo, resulting in even skin tone 7.
In 2013, another unexpected outbreak of patients with depigmentation occurred in Japan with the use of brightening/lightening cosmetics containing ‘rhododendrol’, a tyrosinase-competitive inhibitor that suppresses melanin biosynthesis, which resulted in over 16 000 cases of vitiligo. Macules and patches of depigmentation were located in areas that were both exposed and unexposed to the product 14,15. Most chemicals linked to vitiligo share a common feature – they are chemical phenols, bearing a benzene ring with an attached hydroxyl group. This chemical structure is similar to the amino acid tyrosine (a naturally occurring phenol), which is oxidized by tyrosinase (the rate-limiting enzyme in melanin biosynthesis process) to produce melanin. The mechanism of action of these chemicals is by acting as tyrosine analogs within melanocytes, interfering with tyrosinase, inducing a higher stress level in melanocytes, and resulting in the release of inflammatory factors that activate the innate immune system. This in turn activates autoreactive cytotoxic T cells and initiates autoimmune destruction of the melanocytes 16,17,18,19.
Recently, the use of permanent hair dyes has been reported to increase the risk of developing vitiligo 20. This risk was higher when the first use of hair dyes was before the age of 30, and with longer duration of use 21,22. This might be attributed to the fact that hair dyes contain multiple phenol ingredients, including phenylenediamine, which has been reported to induce depigmentation in a number of individuals 21–26.
Vitiligo pathogenesis incorporates both intrinsic defects within melanocytes that activate the cellular stress response, as well as autoimmunity that targets these cells 27,28.
Melanocyte-intrinsic pathogenesis: cellular stress
An early recognition that melanocytes in vitiligo suffer from high levels of stress led to investigation of stress pathways in this autoimmune disease 12. Multiple groups observed that melanocytes isolated from the nonlesional skin of vitiligo patients were difficult to culture in vitro with a slower replication rate compared with melanocytes from healthy individuals 29. Electron microscopy revealed that the endoplasmic reticulum in melanocytes from vitiligo patients was dilated compared with melanocytes from healthy controls, denoting an elevated level of cellular stress 30. In addition, exposing cultured human melanocytes to exogenous stressors in vitro (such as heat shock or peroxide) led to cell death in melanocytes from vitiligo patients, but not from healthy controls 31,32.
The toxic effects of these exogenous stimuli on melanocytes were produced only when they were administered at very high levels in comparison with the actual exposures in vivo12. In addition to chemical-induced stress, accumulating evidence suggests the presence of an additional source of stress endogenously within the melanocyte, which may originate directly from the steps of melanin biosynthesis. This results in the activation of the unfolded protein response and increased production of reactive oxygen species from mitochondria and from the epidermal location of the melanocytes that expose them to the ultraviolet rays 33,34. Although melanocytes in all humans are subject to cellular stress, vitiligo patients either have particularly vulnerable melanocytes with a lower sensitivity threshold to normal stress levels, or experience higher levels of stress compared with healthy individuals 12.
Despite accumulating evidence on the role of cellular stress in the pathogenesis of vitiligo, therapeutic counteraction of melanocyte stress in vivo is not yet a major part of current treatments. Taken together, melanocyte-intrinsic defects and extrinsic sources of stress (i.e. chemicals), although important, are not sufficient for causing vitiligo 35. Chemical-induced stress of the melanocyte may be a key initiating event in vitiligo pathogenesis by inducing inflammatory signals that activate the innate immune system 36.
Role of innate immunity
Multiple investigators reported activation of various types of innate immune cells in the skin of vitiligo patients, including recruitment of natural killer cells 37 and inflammatory dendritic cells 38,39. These cells are found to be infiltrating lesional skin in vitiligo, suggesting that innate immunity plays a fundamental role in the disease. Innate immune cells, particularly antigen-presenting cells, migrate out of the skin to the draining lymph nodes to present melanocyte-specific antigens to T cells and activate them. Furthermore, these autoreactive T cells secrete cytokines that recruit more autoreactive T cells, which directly kill melanocytes, representing an important crosstalk between adaptive and innate immunity in vitiligo 40.
Indeed, innate immunity may serve as a bridge between cellular stress and adaptive immunity 17, with the activation of various innate immune cells, release of cytokines and chemokines that promote recruitment of autoreactive cytotoxic T cells, and the subsequent T-cell-mediated autoimmune destruction of melanocytes 12.
Role of adaptive immunity: autoimmune pathogenesis (T-cell cytotoxicity)
Since 1968, vitiligo has been thought to be an autoimmune disease based on observations that patients with vitiligo and their close relatives appeared to have an increased risk for other autoimmune diseases, including type 1 diabetes, thyroiditis, and pernicious anemia 41. Moreover, this theory was further supported when high levels of melanocyte-specific autoantibodies were detected in vitiligo patients’ sera 42,43, which reportedly damage melanocytes both in vitro44 and in vivo45. However, antibody levels do not correlate with disease activity 46, and the distinct distribution of vitiligo patches in the body despite the systemic presence of antibodies in the serum suggests that antibodies are not the entire answer. Thus, alternative theories were sought to identify the true pathogenesis of vitiligo 12.
In 1990, T-cell infiltrates were first detected in the skin biopsies of vitiligo patches, and were found to localize to the dermal–epidermal junction, infiltrating the epidermis and in direct apposition to dying melanocytes. The majority of these cells were CD8+/perforin+/granzyme+, consistent with a cytotoxic phenotype of T cells 19. Further functional studies using human skin ex vivo confirmed the critical role of autoreactive cytotoxic CD8+ T cells in vitiligo 47. This group isolated CD8+ T cells from lesional skin and showed their ability to infiltrate the epidermis and kill melanocytes of normal skin samples from the same patient 48.
In addition to the well-recognized pathogenic role of cytotoxic, autoreactive CD8+ T cells in vitiligo, CD4+ T regulatory cells (Tregs) appear to play an important role in preventing and controlling disease. Tregs help in preventing vitiligo in humans, as patients with immune polyendocrinopathy, X-linked (IPEX) syndrome, who lack Tregs, have an increased risk of developing vitiligo 49. A recent study reported that vitiligo patients lack Treg-mediated control of autoreactive CD8+ T cells that is normally present in healthy individuals 50. However, it is currently unclear whether the Treg defect is in their number, impaired homing to the skin, or whether they are functionally altered in vitiligo patients 51–55. Further studies are required to specify the exact function of Tregs in the skin, and how this is dysregulated in vitiligo patients.
Identifying the pathways responsible for autoimmunity in each disease is an important step in understanding the pathogenesis and the subsequent development of new targeted therapies. Recent advances in understanding the key cytokines that promote psoriasis and related autoimmune diseases have resulted in treatments with excellent efficacy and safety profiles by specifically targeting tumor necrosis factor-α and interleukin (IL)-17, key inflammatory mediators in disease pathogenesis 56. Although the expression of some of these cytokines have been reported in vitiligo patients, their functional role is currently unclear 57. In fact, patients taking biologics that block tumor necrosis factor-α, IL-12/IL-23, and IL-17 for other diseases reportedly develop de-novo vitiligo or worsened disease. This strongly suggests that vitiligo is driven by a distinct set of cytokines that is not shared with psoriasis 58,59.
Gene expression profiling in both patients and a mouse model of vitiligo revealed that vitiligo lesions are enriched for the expression of interferon γ (IFN-γ) and IFN-γ-induced genes, which represent the predominant cytokine profile in lesional skin 60. In this context, vitiligo is more similar to alopecia areata (AA) than it is to psoriasis 61. IFN-γ is critical for the recruitment of skin-homing, melanocyte-specific, autoreactive CD8+ T cells (Fig. 1) 62. Furthermore, the IFN-γ-induced chemokine CXCL10, one of the most highly expressed genes in vitiligo lesions, promotes the migration of melanocyte-specific, autoreactive T cells into the skin during vitiligo progression 60. Blocking this cytokine pathway can both prevent vitiligo onset and reverse established depigmentation in a mouse model of vitiligo. Thus, targeting this pathway may provide a targeted new treatment strategy 63.
Emerging treatment modalities
These recent discoveries in the pathogenesis of vitiligo provide an excellent opportunity for the development of new treatments 63. On the basis of the current understanding of vitiligo, the best result will most likely be obtained with a treatment strategy that achieves three main goals: reducing melanocyte stress, reducing autoimmune-mediated melanocyte destruction, and enhancing melanocyte regeneration (Fig. 2).
Reducing melanocyte stress
As discussed above, increased oxidative stress within melanocytes from vitiligo patients compared with normal melanocytes, as well as the impaired tolerance of melanocytes to that stress, suggest that antioxidant treatments might be a helpful tool in treating vitiligo 12.
One study tested this approach in 71 children with vitiligo. This uncontrolled retrospective study was conducted to assess the efficacy of topical pseudocatalase, a cream developed to absorb reactive oxygen species from the skin. The majority of enrolled patients reportedly exhibited at least 75% repigmentation on their face, neck, and trunk, but not on the hands or feet 64. However, others failed to repeat these results, and thus it is currently unclear whether this theoretically promising treatment modality will become a viable treatment option for vitiligo 65. Another group concluded that administration of oral antioxidants before and during narrow-band ultraviolet B (NB-UVB) significantly improved its clinical effectiveness by reducing vitiligo-associated oxidative stress 66. Additional studies will be required to assess the efficacy of topical and systemic antioxidant supplements in the treatment of vitiligo.
On the basis of an understanding of the key signaling pathways that drive disease pathogenesis over the past decades, the use of targeted immunotherapy has revolutionized the management of many inflammatory skin diseases such as psoriasis, urticaria, and atopic dermatitis 56. Targeted immunotherapies (unlike the majority of traditional drugs and nontargeted biologics) are designed to selectively inhibit specific components of an inflammatory pathway responsible for driving disease pathogenesis, resulting in safer, more specific, and more effective treatment options. This fascinating new approach has the potential to revolutionize the management of vitiligo based on the significant advances that has been achieved in recent translational research.
As addressed above, the IFN-γ–chemokine axis is a critical signaling pathway in vitiligo (Fig. 1), beginning with binding of IFN-γ to the IFN-γ heterodimeric receptor, which activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway that leads to STAT1 activation. This is followed by STAT1 translocation to the nucleus and subsequent transcription of IFN-γ-inducible genes, including CXCL9 and CXCL10 67. This suggests that interfering with these cytokines and their receptors in this chemokine axis may be an effective strategy to develop novel, targeted immunotherapies for vitiligo 63.
Indeed, blocking CXCL10 with neutralizing antibody was able to both prevent and even reverse established depigmentation in a mouse model of vitiligo 60. Different additional monoclonal antibodies and small-molecule inhibitors have already been developed to target various aspects of this pathway, which were proven to be safe in early phase clinical trials for the treatment of other autoimmune diseases, including psoriasis 68. The failure to demonstrate efficacy in these trials is likely because IFN-γ is not a major driving cytokine in these diseases. However, the clear role of the IFN-γ–chemokine axis in vitiligo suggests that testing these drugs in vitiligo patients could demonstrate excellent efficacy 63.
Tofacitinib is a pan-JAK inhibitor that was approved by the US FDA in 2012 for the treatment of moderate-to-severe rheumatoid arthritis. Within dermatology, the success of oral tofacitinib in treating forms of AA has recently been reported 69,70. Accumulating evidence suggests that the pathogenesis of AA and vitiligo share a common IFN-γ-mediated pathway 61. As such, a medication that targets this pathway could be effective in treating both diseases. In the end of 2015, the first reported case of a vitiligo patient successfully treated with an oral JAK inhibitor, tofacitinib, revealed significant repigmentation from the treatment 70.
Ruxolitinib is another small-molecule JAK inhibitor that inhibits IFN-γ signaling through the preferential inhibition of JAK1 and JAK2. It is approved by the FDA for the treatment of intermediate-risk or high-risk myelofibrosis and polycythemia vera 71. A patient with coexistent vitiligo and AA was initiated on 20 mg twice daily of oral ruxolitinib, and 12 weeks after starting the treatment some repigmentation in addition to scalp hair regrowth was noted. At week 20, the patient exhibited substantial repigmentation on more areas. However, although hair regrowth was maintained, much of the regained pigment had regressed when the patient discontinued ruxolitinib, suggesting that continuous treatment would be required to maintain the effect. Importantly, measuring the patient’s serum CXCL10 level using enzyme-linked immunosorbent assay revealed significant reduction following treatment with ruxolitinib after over a year of a stable high level, strongly suggesting that JAK inhibition works by targeting the IFN-γ–CXCL10 axis 72. Although these advances and case reports of JAK inhibitors in vitiligo are promising for both patients and dermatologists, larger controlled trials are still required to confirm the safety and efficacy of targeted therapies for vitiligo.
The second main component of the JAK-STAT pathway, a family of transcription factors called STAT, incorporates seven members, of which only STAT1 has been implicated in IFN-γ signaling. A study reported that statins, or HMG-CoA reductase inhibitors, could block STAT1 function in vitro73, and one patient repigmented significantly after taking simvastatin for hypercholesterolemia 74. We found that simvastatin both prevented and reversed depigmentation in a mouse model of vitiligo 75. However, a clinical trial in a small number of vitiligo patients did not show efficacy with this treatment, possibly due to dose-limiting toxicity that is observed in humans, but not in mice 76.
Enhancing melanocyte regeneration
Afamelanotide is a potent synthetic analog of the naturally occurring α-melanocyte-stimulating hormone, an important member of the melanotropin family for stimulating melanogenesis 77. It is currently approved by the European Medicines Agency to prevent photosensitivity in erythropoietic protoporphyria 78. On the basis of its ability to stimulate melanocyte growth and differentiation, it was hypothesized to be beneficial in improving the efficacy of phototherapy treatment of vitiligo patients. Thus, it was investigated as an adjunct to NB-UVB in a randomized, double-blinded, multicenter study. Fifty-five patients with generalized vitiligo were treated with NB-UVB plus monthly subcutaneous implantation of 16 mg of afamelanotide versus NB-UVB alone. The authors of the study concluded that the combination treatment resulted in a significantly superior and faster repigmentation compared with NB-UVB monotherapy, especially in patients with a darker skin type. Side effects were relatively minimal, including hyperpigmentation, itch, and nausea 79. Further studies using this promising treatment are needed.
Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was found to be altered specifically in vitiligo skin. One group developed an ex-vivo skin model and reported decreased activation of the WNT pathway in vitiligo patient skin subjected to oxidative stress compared with that from healthy controls 80. Furthermore, they found that activating the WNT pathway with pharmacological agents successfully induced differentiation of resident stem cells into premelanocytes. These results highlight the role of WNT activation in the differentiation of melanocytes in depigmented vitiligo skin, encouraging further exploration of WNT agonists as promising new treatments for vitiligo 81.
Melanocyte-specific autoimmunity in vitiligo results from an interaction of various factors, including genetic predisposition, environmental triggers, and melanocyte stress. Those factors together initiate the innate and adaptive immune responses, which results in melanocyte destruction. On the basis of our current understanding of vitiligo, the best treatment strategy would accomplish three main goals: reducing melanocyte stress, reducing autoimmunity, and enhancing melanocyte regeneration (Fig. 3). Current treatment modalities such as phototherapy, immunomodulators, and surgical techniques approach these goals to some extent. However, they are time-consuming, nontargeted, and have limited efficacy. Recent advances in understanding the pathogenesis of vitiligo provide new insights into potential strategies to develop new, targeted treatment options that have better efficacy and fewer side effects. These advances are promising for the patient as well as treating physicians, and may spark a revolution for the future of treating vitiligo.
Conflicts of interest
There are no conflicts of interest.
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