Elsevier

Autoimmunity Reviews

Volume 14, Issue 4, April 2015, Pages 332-340
Autoimmunity Reviews

Review
Why treatments do(n't) work in vitiligo: An autoinflammatory perspective

https://doi.org/10.1016/j.autrev.2014.12.003Get rights and content

Abstract

Vitiligo is a recalcitrant depigmentary skin disorder with significant effects on the quality of life and a frequent association with other autoimmune disorders. The results of the current therapeutic options remain variable and treatment resistance is often encountered. The mainstay of treatment remains topical corticosteroids, topical calcineurin inhibitors and UVB therapy. In more extensive or progressive cases, systemic corticosteroids are effective although their prolonged use is hampered due to safety concerns. A lot of topical and systemic treatments have been investigated during the last decades. Given the elevated TNF-α levels in vitiligo lesions, the failure and even paradoxal effects of TNF-α inhibitors were highly remarkable. Nonetheless, a lot of progress has been made to unravel the pathophysiology of vitiligo. In this review, we provide an overview of the currently known underlying mechanisms leading to vitiligo and link this to the success or failure of treatments that have been used in clinical trials. We believe that this overview can direct future vitiligo research and rationalise the treatment options.

Introduction

Vitiligo is an intriguing depigmentary disorder affecting approximately 1% of the world population. It has significant effects on quality of life and remains a persistent burden for the patients. Vitiligo develops due to progressive disappearance of epidermal melanocytes. Historically, the cause of vitiligo has been an extensive topic of debate. A wide range of theories have been put forward including immune-mediated mechanisms, increased oxidative stress, melanocyte growth factors, defective melanocyte adhesion and neurogenic mechanisms. Recent research has focused mainly on the autoimmune-mediated destruction of melanocytes and established this theory as the currently leading hypothesis.

The quest for an adequate treatment for vitiligo still continues. A huge amount of therapies have been tried with variable success [1]. In the current evolution of targeted medicine, vitiligo lags still behind although several efforts (including pilot trials with TNF-α inhibitors) have been undertaken. To assist further progress in vitiligo research, an overview of the known data on pathophysiology has been linked to the available therapeutic arsenal. Furthermore, some options for new treatment strategies are proposed.

Section snippets

Melanocytes

At first glance, deficiencies in the survival capacity of melanocytes seem a plausible cause of a disorder resulting in gradual disappearance of this cell type. Historically, the first reports described a decreased proliferative capacity of melanocytes. This suggested that the melanocytes would be incapable of replenishing the pool of pigment cells in the epidermis after cell death. However after prolonged culture, no clear differences in the proliferation rate between normal or vitiligo

Pathogenesis

Increased oxidative stress has been put forward as an underlying mechanism of vitiligo by inducing melanocyte destruction due to an overproduction of reactive oxygen species. In vitro experiments indicate an increased susceptibility of vitiligo melanocytes to increased oxidative stress [22]. ROS are physiologically produced during melanogenesis and controlled by antioxidant enzymes. Normally l-tyrosine is converted into l-dopaquinone. The intermediate product O-quinone can lead to development

Pathogenesis

Acute phase proteins have recently gained increased attention. NLRP1 is an essential component in the multiprotein complex that forms the NLRP1 inflammasome. This inflammasome induces caspase-1 activation promoting the release of the proinflammatory cytokines IL-1β and IL-18. IL-1β controls the immune responses by activating lymphocytes and promoting migration of immune cells towards sites of injury or infection [36]. It has pleiotropic effects on lymphocytes by upregulating IL-2 receptor

Pathogenesis

A key role of neurochemical mediators produced by cutaneous nerve endings or by immune cells (e.g. activated macrophages) has been suggested in vitiligo. Neuropeptides are released after endogeneous or exogeneous factors. Neuropeptide Y (NPY) is one of the most frequently mentioned peptides. It is presumed to induce the dendricity of melanocytes and regulate cell adhesion and cell motility. Certain polymorphisms in NPY have been linked to vitiligo [40].

Neuropeptides exhibit a complex interplay

Melanocyte specific-T cells (Fig. 2)

The infiltration of T cells in vitiligo lesions has been published very early in vitiligo research. The ratio of CD4 + to CD8 + lymphocytes is decreased in vitiligo compared to healthy skin, indicating a dominant T helper 1 cytokine pattern. CD8 + lymphocytes are often seen in close proximity to remaining melanocytes. A major breakthrough in vitiligo research has been the detection of melanocyte-specific T cells. Both in the blood and perilesional skin, CD8 T cells directed against specific

Pathogenesis

Already more than a decade ago, the presence of antibodies against melanocytes was confirmed in vitiligo. The antibodies have been found to be directed against a wide range of antigens [68], [69]. Up till now, the functional relevance has been a topic of debate. Antibodies against melanocyte-associated antigens have the capacity to induce apoptosis of in vitro cultured melanocytes [70]. The principal antigen recognised by these antibodies is tyrosinase, followed by tyrosine hydroxylase, gp100

Pathogenesis

The role of dendritic cells has not been extensively studied in vitiligo. Nonetheless, early vitiligo lesions are infiltrated by dendritic cells which are only in later stages replaced by T lymphocytes [74]. In vitiligo, CD8 T cells can be found within the proximity of the remaining melanocytes in the epidermis. In diseases with interface dermatitis, the type I interferon pathway is often involved. A type I interferon signature is also typical of diseases with acute inflammatory responses and

Conclusion

Vitiligo remains a very puzzling disorder, especially regarding successful treatment. The relatively well documented immunologic mechanisms are accompanied by aberrancies in melanocytes and their surrounding keratinocytes. An effective inhibition of the inflammatory response might not be sufficient to induce spontaneous repigmentation. In a subset of patients the melanocyte reservoir may be depleted. In other cases, the surrounding environment may not be favourable for melanocyte proliferation,

Conflict of interest

The authors have no conflict of interest.

Funding sources

This research was supported by a postdoctoral research grant to R. Speeckaert from the Ghent University Special Research Fund (BOF; grant number: 01P12914) and a research grant to N. van Geel from the Scientific Research Foundation-Flanders (FWO Senior Clinical Investigator; grant number: FWO11/FKM/001).

Take-home messages

  • Vitiligo remains a puzzling disorder although the underlying immunologic mechanisms, which are accompanied by aberrancies in melanocytes and keratinocytes, are becoming unravelled.

  • The results of current therapeutic options remain variable and treatment resistance is often encountered.

  • Effective inhibition of the inflammatory response alone might not be sufficient to induce spontaneous repigmentation in vitiligo.

  • The known effective treatments for vitiligo not only exert immunosuppressive effects,

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