The convergence theory for vitiligo: A reappraisal

Abstract

Vitiligo is characterized by progressive loss of skin pigmentation. The search for aetiologic factors has led to the biochemical, the neurologic and the autoimmune theory. The convergence theory was then proposed several years ago to incorporate existing theories of vitiligo development into a single overview of vitiligo aetiology. The viewpoint that vitiligo is not caused only by predisposing mutations, or only by melanocytes responding to chemical/radiation exposure, or only by hyperreactive T cells, but rather results from a combination of aetiologic factors that impact melanocyte viability, has certainly stood the test of time. New findings have since informed the description of progressive depigmentation. Understanding the relative importance of such aetiologic factors combined with a careful selection of the most targetable pathways will continue to drive the next phase in vitiligo research: the development of effective therapeutics. In that arena, it is likewise important to acknowledge that pathways affected in some patients may not be altered in others. Taken together, the convergence theory continues to provide a comprehensive viewpoint of vitiligo aetiology. The theory serves to intertwine aetiologic pathways and will help to define pathways amenable to disease intervention in individual patients.

1 | INTRODUCTION

Progressive skin depigmentation in vitiligo is associated with the loss of melanocytes from the basal layer of the epidermis.^[1] Other organs can be affected, and patients sometimes incur visual or auditory impairment.^[2,3] Loss of hair pigmentation can follow depigmentation of the skin and rarely precedes it.^[4]

The convergence theory was put forward twenty-five years ago to merge available theories and ongoing research into an all-encompassing overview of vitiligo aetiology.^[5] The concept took advantage of existing expertise in the field of investigative dermatology to explain the development of newly depigmenting skin. At the time, the field was dominated by three hypotheses that seemed mutually exclusive.

The biochemical hypothesis laid the blame for pigment loss within the melanocyte itself, describing depigmentation as a consequence of aberrant melanization.^[6] Melanization involves the formation of toxic quinones, sometimes insufficiently contained within the melanosomal organelle. Such intracellular damage unique to the melanocyte could explain the consequences of UV-overexposure in vitiligo patients, as such exposure will accelerate pigment synthesis and thereby leave affected melanocytes more gravely assaulted in response to the sun.^[7]

The neural hypothesis relies on observations related to limited vitiligo development in areas affected by transverse myelitis or diabetic neuropathy.^[8] Rather than focusing on pigmentation, the neuronal theory highlights the neural crest origin and the neuron-like functions of melanocytes. Importantly, the neuronal hypothesis remains a controversial theory with little compelling evidence supporting it.^[9]

The immune hypothesis was built on observations that antibodies to melanocytes were more prevalent in animals that can develop vitiligo and in patients with active disease.^[10] Cellular immune responses were gradually assigned a greater role in depigmentation, as functional and genetic data both support a role for T cells in vitiligo progression.^[11] Subtle infiltrates that accompany depigmentation were the main reason that T-cell involvement was long overlooked.^[12]

Each concept received varied attention over the past twenty-five years, as represented in Figure 1A, however, the overall trajectory of publications relating to vitiligo has increased threefold over the 25-year period of analysis, as represented in Figure 1B.

FIGURE 1.

A, Vitiligo aetiology explored between 1990 and 2015. When the convergence theory was first proposed, it united emerging concepts surrounding vitiligo etiopathology. A PubMed search was performed using the terms “vitiligo” plus either “immune,” “genetic,” “oxidative stress” or “neuronal” and the year of publication. When separated into these four mainline theories to explain vitiligo development, the number of publications addressing each between 1990 and 2015 indicates shifts in vitiligo research over time, with the attention shifting towards genetic and immune factors by the mid-nineties and more recently, renewed attention for oxidative stress. B, Increase in vitiligo publications over time. A PubMed search was performed using the year of publication, with or without the term “vitiligo.” The proportion of publications relating to vitiligo has increased 3-fold over the 25-year period of analysis

The oxidative stress hypothesis, shown as “oxidative stress,” is in an upswing as investigators focus on early vitiligo genesis. Basic melanocyte biology supports our understanding of how melanocytes respond to stress and signal emergency responses that ultimately drive progressive depigmentation. This field is and will be important to identify preventive measures.^[13] Meanwhile, the neural hypothesis shown as “neuronal” has drawn a stable, but not increasing amount of attention. To understand factors that drive repigmentation, a better understanding of melanocyte neuronal origin and differentiation will be key, regardless of the extent of neuronal involvement in pigment cell loss.

The immune hypothesis, listed as “immune” in Figure 1, has received steadily increasing attention. Successful vitiligo treatments should involve steps to halt the autoimmune response before considering steps to repigment the lesions.^[14]

Beyond these three hypotheses, a greater arsenal of aetiologic factors was proposed. Genetic variants are now clearly recognized as predisposing elements for vitiligo development, and publications to this effect have been included in Figure 1. The individual puzzle pieces are currently merging to paint a full picture of vitiligo aetiology, thus providing ample incentive to revisit the convergence theory of vitiligo and understand how the predictions set forth in 1993 hold true in 2018. A reappraisal of the convergence theory (Figure 2) is presented here.

FIGURE 2.

Publications related to vitiligo treatment. A PubMed search was performed with the year of publication combined with ‘vitiligo’ plus the terms shown in the legend, with the exception of the black line. Here, the year of publication was combined with the search terms ‘vitiligo treatment’ and the total number was divided by five, as represented in the graph. Not represented in the graph are recent developments including JAK inhibitors and Tregs.

2 | MELANOCYTE LOSS

Although the fate of melanocytes in vitiligo skin was still unclear when the “convergence theory” was published, it is now accepted that melanocytes are lost from depigmented lesions.^[15] Melanocytes were readily quantified in vitiligo epidermis once melanocyte-specific antibodies became available, and newer antibodies have since confirmed an overall paucity of melanocytes in depigmented skin.^[16,17] These findings indicate that vitiligo therapeutics should provide means to replenish the melanocyte pool. Newer techniques for characterizing melanocyte populations via isolation of RNA using a rapid immunostaining protocol will further enable investigations into melanocyte loss.^[18] Even before melanocyte loss was established, surgical methods to restore melanocyte abundance became clinically available, with mixed results.^[19] However, the loss of melanocytes from vitiligo lesions is no longer considered complete, as several studies revealed the presence of some differentiated melanocytes in depigmented skin.^[20–22] It is unclear whether these sparse melanocytes have returned to the epidermis after the original injury, or whether a small population of intralesional cells remains.^[23] In the latter case, the physiology of such resilient melanocytes might inform us of intrinsic defense mechanisms that can prevent vitiligo.

Meanwhile, the mechanisms of cell death remain under investigation. A likely role for melanocyte apoptosis^[24] has been challenged by terms including melanocytorrhagy^[25] and passive bystander death,^[26] whereas induction of necrosis may be a trigger for lesional expansion resulting in more extensive disease.^[27] A role for melanosome autophagy leading to the shedding of antigens that activate dendritic cells has also been proposed.^[28] To explain rapid disease onset or progression in some, it helps to understand causes of initial cell death that can trigger further disease. This area of investigation involves, among others, studies of patient stress and its consequences at the cellular level.

3 | ENVIRONMENT

The term “stress” covers several presentations that are not readily explained in terms of their effects on melanocyte viability.

Among forms of stress that can induce vitiligo is mechanical stress and associated koebnerization, the latter reported by approximately half of patients.^[29] Mechanical stress may cause the aforementioned melanocytorrhagy, in particular when reduced expression of E-cadherin equates to reduced cellular adherence.^[30]

Other patients will recognize overexposure to sunlight, or contact with bleaching chemicals, as instigators for their condition.^[7,31] The defense against UV-induced skin damage involves a polymorphic UV resistance-associated gene, UVRAG, with particular haplotypes associated with vitiligo.^[32] This gene may provide insight into the nature of UV involvement in disease, as UV-induced immunosuppression could hold disease at bay,^[33] whereas UV can also induce enhanced expression of melanosomal proteins^[34] that are target molecules in antimelanocyte immune responses, as described under the section “intercellular communication.”

There is new understanding for the role of chemical exposure in vitiligo development. Depigmentation by phenolic agents is best explained as the application of alternate substrates for tyrosinase that give rise to toxic quinones in cells of the melanocyte lineage.^[27,35] The response of melanocytes to chemical stressors is addressed in more detail under section “intracellular metabolism.”

Additionally, a role for psychological stress on vitiligo development and progression is clear from responses to questionnaires, and significant insight can be gained from publications supporting the occurrence of stressful life events preceding vitiligo development.^[36] Patients with vitiligo are apparently more likely to exhibit alexithymia (the inability to identify and describe experienced emotions), insecure attachment and poor social support than controls.^[37] Thus, certain disease-associated personality traits may render patients increasingly vulnerable to stress and vitiligo development. This would imply that the same stress would have a greater effect on vitiligo patients than on controls. Although it appeared that only vitiligo patients would be sensitive to bleaching treatment, there is little evidence to support this.^[38] It is more likely that damaged patient melanocytes specifically give rise to cytotoxic immune responses, resulting in progressive depigmentation.^[39]

4 | INTRACELLULAR METABOLISM

Biochemical involvement in depigmentation has been long-postulated and has become a topic of intense investigation. The term “chemical leukoderma” is used for vitiligo developing in response to topically applied chemicals, although it’s aetiology is similar to other vitiligo cases.^[31,40] The toxic intermediates (including quinones) that form after melanocyte-specific enzymatic activity can cause autotoxicity.^[41] However, melanin synthesis takes place in both healthy and patient-derived melanocytes. To explain the selective development of progressive depigmentation in vitiligo-prone individuals, the relative activity of enzymes protecting melanocytes from oxidative damage was investigated. If reduced abundance or activity of such enzymes is associated with vitiligo, it becomes more likely that patient melanocytes cannot protect themselves against oxidative stress.^[31] An unfolded protein response might ensue within affected cells.^[31] A wealth of publications attests to the differential activity of SOD,^[42] COMT,^[43] catalase,^[44] NRF2,^[35] GPX1^[45](p1) and other enzymes in patient samples.^[46] Reduced catalase activity is now supported by promoter mutations observed in diseased samples.^[47] However, not always has reduced activity of detoxifying enzymes been reported. Thus, reduced antioxidant defenses should be weighed against other initiating factors to understand why patients selectively develop vitiligo.

As melanocytes are found at the interface of the environment and internal organs, they would be first to respond to external conditions. Thus, in response to skin insults in the absence of adequate antioxidant protection, melanocytes distress can ultimately translate into progressive depigmentation. A thorough understanding of the compounds that drive a biochemical imbalance and the enzymes that can restore balance is essential.^[48] A critical finding may be that lower ATP production caused by mitochondrial dysfunction in vitiligo melanocytes can be compensated for by stabilizing mitochondrial cardiolipin.^[49]

Patients will report itch and ongoing inflammation when lesions newly develop or expand,^[50,51] even if the severity of pruritus does not match that reported in atopic dermatitis.^[52] Interestingly, patients with vitiligo are more likely to develop vitiligo and vice versa.^[53,54] Pruritus and/or a particular lesional distribution suggest a distinct pathomechanism in this subgroup. Since itch is most frequently reported for focal disease, it is possible that scratching will in turn induce trauma to accelerate depigmentation.^[39] But biochemical involvement in vitiligo may not be limited to skin exposure. Nutritional factors could also impact depigmentation,^[55] in part by supporting a microbial imbalance that can drive disease development.

5 | MICROBIAL SYMBIOSIS

Vitiligo has been associated with infection for reasons other than a causative relationship. A similarity in appearance to leprosy continues to stigmatize vitiligo patients.^[56] Similarities in aetiology also exist, as infected Schwann cells may be a target for the same aetiologic factors as melanocytes due to a largely shared differentiation pathway.^[57]

Other findings suggesting a role for infectious agents include responses to a vitiligo patient questionnaire asking for causative factors, where “infection” and “antibiotics” were surprisingly frequent answers.^[58] The increased frequency of H. pylori infections and antibacterial serum titres among vitiligo patients is significant, although no correlation to disease activity was reported.^[59] HIV and vitiligo co-occurrence were reported, wherein vitiligo can surround HIV-associated Kaposi sarcoma nodules.^[60] Moreover, case reports of patients developing depigmentation in response to herpetic infection^[61,62] align with data from the Smyth line chicken model of vitiligo.^[63] A role for microbial dysbiosis in vitiligo becomes increasingly likely.^[64] Although the pathomechanism of microbe-mediated autoimmune disease is not fully established, gut microbes might trespass a compromised gut barrier and initiate an IL-17-mediated immune response that drives immunity not only against the microbes, but also against skin components.^[65] Ultimately however, IFN-γ-driven responses are thought to play a more prominent role in vitiligo.^[66] IFN-γ responses can likewise be provoked by cutaneous commensals.^[67] Increased production of the cytokine is found among skin-resident memory T cells reactive with melanocytes that likely contribute to disease flares and form a resource of T cells mediating antimelanoma activity.^[68,69] These factors highlight the importance of immune activation in vitiligo.

6 | IMMUNE ACTIVATION

Vitiligo patients develop antibodies to melanocytes, implicating immune responses in melanocyte loss.^[70,71] Antigens recognized largely represent intracellular gene products found in melanosomes, and their aetiologic role has therefore since been questioned. An exception is found in antibodies to the melanin-concentrating hormone receptor 1 (MCHR1).^[72] The abundance of antibodies to pigment cells may or may not correlate with disease activity.^[5,73,74] It appears that type 1 cytokines prevail in vitiligo skin.^[75] And yet, a role for infiltrating T cells was initially overlooked. Early findings suggesting that skin homing T cells might contribute to disease emerged when the convergence theory was first proposed.^[5,73,74] T-cell infiltration coincides with disease activity.^[15] Both the biopsy location and disease activity were key to these findings. T-cell infiltrates were consistently observed in perilesional skin of progressing lesions spanning a narrow subepidermal area and include both CD4 and CD8 T cells. A decreased CD4:CD8 ratio (compared to healthy skin) indicated that cellular immunity could be involved in disease.^[76]

Vitiligo melanocytes secrete increased amounts of inducible heat shock protein 70 under stress,^[77] which can drive TNF-related, apoptosis-inducing ligand (TRAIL) expression by dendritic cells (DCs).^[78] Differential expression of genes associated with proteasome function further suggests that melanocytes could ultimately be more readily recognized by T cells.^[79] Besides T cells and DCs, macrophages are included in the infiltrates, yet their contribution to disease remains poorly understood.^[80] TRAIL-expressing DCs infiltrate vitiligo perilesional skin, where melanocytes express TRAIL receptors.^[78] Thus, some pigment cell may undergo apoptosis to provide a source of antigen for DCs. Other forms of cell death such as necrosis instigated by monobenzyl ether of hydroquinone (MBEH) exposure can activate the DCs. CD4 and CD8 T cells in skin draining lymph nodes will then recognize the antigens presented by matured DCs, including haptenized neoantigens that can result from MBEH exposure.^[28] This affects the nature of the immune response that follows.^[28]

Importantly, vitiligo skin offers a source of CXCL10 expression to recruit CXCR3-expressing T cells.^[81] The importance of IL-17 producing T cells is still under debate,^[82] but IFN-γ signalling and secretion drive T-cell activity and disease development.^[83] Although antigens recognized by CD4 T cells infiltrating vitiligo skin remain elusive, it is possible that MHC class II+ melanocytes found in perilesional skin contribute to their own demise by presenting antigen to such T cells.^[84] Upon isolation from perilesional skin, CD8 T cells recognized melanosomal antigens and were cytotoxic towards autologous melanocytes,^[86] providing definitive support for a local, ongoing cytotoxic T-cell response. Such cytotoxic functions align with CD49 expression among resident memory T cells in vitiligo.^[85] These findings were elegantly supported ex vivo by combining explants of non-lesional skin with autoreactive T cells, demonstrating ongoing cytotoxicity within the skin.^[86] Finally, adoptive transfer of gp100-reactive T cells to wild-type recipient mice was sufficient to recreate vitiligo upon T-cell recruitment and activation in recipients.^[66] Although MART-1 reactive T cells appear to dominate immune responses in vitiligo,^[87] gp100 reactivity is likewise involved.^[88] The melanosome thus offers an efficient source of antigen that can explain the tissue specificity of this autoimmune disease.^[89]

7 | HEREDITY

With the advent of omics biology, high-throughput screening of DNA sequence and RNA abundance differences became informative of the disease process, albeit by different means. DNA sequence analysis can help understand the complex polygenic additive mode of inheritance of vitiligo.^[90] Vitiligo can cluster within families and populations, and with 20% of patients reporting an affected first-degree relative, parents are often concerned about the odds of an unborn child inheriting vitiligo.^[91] This underscores the importance of defining sequence variants in disease development. However, concordance between monozygotic twins is less than 25% and other, environmental parameters might influence disease on a greater scale. In its current phase, this topic benefits from advances in computational systems biology to better understand how both DNA sequence changes and differences in transcript abundance of downstream gene products dictate functional differences that may help explain disease.^[91] Currently, genome analysis has revealed a multitude of sequence variations that associate with disease (either within or across populations).^[90] A large group of investigators has unearthed vitiligo-associated sequence differences supporting the involvement of at least 50 susceptibility loci.^[93] Remarkably, the outcome to date is largely informative of the autoimmune component of disease. A smaller proportion of the currently explored genetic variation appears to define melanocyte physiology and help explain disease initiation.^[93]

Transcriptome analysis, on the other hand, defines gene products and on a smaller scale, mIRs associated with disease.^[94,95] Consistent differences among cultured melanocytes reveal differences that might define disease progression.^[96] For example, abnormal regulation of microRNA-211 in vitiligo melanocytes can lead to increased reactive oxygen species.^[97]

When performed on whole skin, differences also point to involvement from other cellular compartments in disease. These approaches can be mutually supportive. For example, a transcript less abundantly expressed in vitiligo melanocytes than in control melanocytes (VIT1, renamed FBXO11)^[98,99] was later shown to drive trafficking of tyrosinase,^[100] a gene that was itself associated with vitiligo. Together with studies supporting an HLA association with vitiligo, the testable hypothesis was formulated that processing and presentation of tyrosinase may affect recognition by, or positive selection of tyrosinase reactive T cells. Although several studies point to MART-1 as the primary immunodominant antigen in both melanoma and vitiligo, the above findings suggest that tyrosinase may drive disease initiation.^[101] This aligns with tyrosinase haptenization following interaction of the enzyme with bleaching phenols,^[102,103] which could drive T cells with increased affinity for haptenized tyrosinase. MART-1 and gp100 can then be recognized after epitope spreading.^[104] Although this theory is partly supported by empiric data, further experiments are needed to address the wealth of information becoming available from genomic and transcriptomic analysis. Vitiligo clearly involves an interplay between melanocyte malfunction and T-cell hyper-reactivity, with several other cell types involved as well. Such cell interplay brings in another topic of interest, namely intercellular communication.

8 | INTERCELLULAR COMMUNICATION

Pigmented melanosomes generated within well-differentiated melanocytes are transferred to neighbouring keratinocytes. This puts each dendritic melanocyte in contact with several recipient keratinocytes. Although melanosome transfer remains poorly understood, it is clear that both cell types are required for skin pigmentation.^[105] Thus, morphologic aberrancies in keratinocytes from patient skin, which extend well beyond the lesional area, are relevant to the disease process.^[106] A better understanding of such abnormalities is needed.^[107] Aberrant expression of E-cadherin by melanocytes in vitiligo skin before depigmentation occurs suggests a perturbed relationship of melanocytes to neighbouring keratinocytes.^[30] Keratinocytes will respond to oxidative stress by adjusting the efficiency of melanosome transfer,^[105] which may induce further stress through the transfer of immature melanosomes. Necrotic keratinocytes support ICAM-1 expression by melanocytes through TLR3, with ICAM-1 expression observed in and around lesional skin.^[74]

Under UV exposure, IFN-γ signalling in keratinocytes drives T-cell infiltration.^[81,83] These T cells then mediate progressive melanocyte loss and skin depigmentation. Although suggestive of an aetiologic contribution for keratinocytes in vitiligo, most work has focused on the limited ability of lesional keratinocytes to support repigmentation. Reduced differentiation by lesional keratinocytes is a hallmark of vitiligo.^[106] Compared to non-lesional skin, blisters generated from lesional skin contain a greater number of apoptotic keratinocytes, indicating a possible history of trauma.^[108] Indeed vitiligo keratinocytes are sensitized to apoptosis in response to stress imposed by some bleaching compounds.^[109] When lifted from their natural environment, lesional keratinocytes have a limited capacity to support melanocytes in co-cultures, although this difference is overcome in epidermal reconstructs.^[105] Lesional keratinocytes further display a reduced capacity to generate factors necessary to support melanocytes including glial cell-line-derived neurotrophic factor, which attracts developing melanocytes.^[110] Less endothelin-1 is generated in response to UV.^[111] Lesional keratinocytes also generate reduced amounts of nerve growth factor, stem cell factor (SCF) and basic fibroblast growth factor (bFGF),^[16] needed for melanocytes.^[112] Both MAPK and AKT signalling pathways have been implicated in keratinocyte vulnerability in vitiligo,^[113] possibly in response to abundant IL-33.^[114] The micro-environment becomes hostile to incoming melanocytes, melanocyte precursors, and apparently to Merkel cells,^[8] due to an abundance of inflammatory cytokines and the presence of de-adhesive tenascin.^[115–117] Other cells drawn in to the aetiologic process might be fibroblasts, which can display a myofibroblasts phenotype and premature senescence in vitiligo.^[118]

9 | STEM CELL DEVELOPMENT

Vitiligo development can be impacted by the rate of melanocyte renewal, which is especially apparent after skin damage. A combination of factors impacts pigment cell renewal, including the available stem cell pool and the migration, differentiation and proliferation of precursor cells or differentiated melanocytes. Melanocyte stem cells are found in the hair bulge, which explains perifollicular repigmentation, the dominant pattern in vitiligo. Interestingly however, white hair follicles from affected skin are not necessarily devoid of melanocytes^[119] indicating that melanocytes can be inconspicuous yet present. The same holds true where glabrous skin gives rise to repigmentation.^[120] The finding that interfollicular epidermis contains melanocyte precursors that serve as a source for newly differentiating melanocytes can also explain repigmentation in glabrous skin.^[121] Another potential resource is the presence of multi-lineage-differentiating, stress enduring (muse) cells, undifferentiated fibroblast-like cells that can be induced to generate melanin.^[122] In fact, dermal mesenchymal stem cells appear to inhibit CD8 T-cell infiltration to the skin and may keep depigmentation at bay through this mechanism.^[123]

Importantly, differentiated melanocytes might renew by proliferating within the epidermis.^[124] Indeed melanocytic differentiation requires ECM-induced integrin stimulation to be completed.^[125] Other drivers of differentiation include the endothelin-3 receptor,^[126] the stem cell factor receptor cKIT^[127] and Pax7 which is upstream of Sox10,^[128] as well as candidate contributor GLI1.^[129] Although cKIT and its ligand, stem cell factor, play a role in melanocyte stem cell recruitment, mutations affecting this pathway are more readily associated with piebaldism.^[130] Other candidate pathways driving melanoblast availability include the FGF and endothelin receptors, yet mutations therein are more commonly associated with Apert and Hirschsprung syndrome, respectively.^[130] Importantly, the availability of these receptors and their ligands can also be impacted by environmental factors.^[131]

10 | DISCUSSION

Vitiligo aetiology has been a topic of intense investigation for many years. A comprehensive set of causative factors has been compiled, illustrating the combined involvement of several pathways to mediate progressive depigmentation of the skin. Whereas originally, a few major pathways competed for a prominent role in the etiopathogenesis of the skin disorder vitiligo, it has now become increasingly clear that the proposed pathways converge to fully elucidate vitiligo development.^[132]

The genetic background of patients defines their susceptibility to environmental changes.^[133] Individuals prone to vitiligo may be increasingly susceptible to stress, yet the molecular basis for such vulnerability has yet to be fully explored.^[134] The involvement of surrounding keratinocytes in the disease process, both as a basis for disease development and as cells that are affected by vitiligo, is now being defined at a molecular level.^[135] Taken together, these factors can drive initial melanocyte loss and trigger autoimmune involvement leading to progressive loss of melanocytes.

Much attention in the last twenty-five years has gone to understanding the role of T cells. There is increasing evidence that cells of the macrophage and dendritic cell lineage contribute to the inflammatory environment that attracts such T cells to the site of depigmentation. A very exciting development is the fact that melanoma biology has provided insight into the antigens targeted by infiltrating T cells.^[136] In turn, we see that vitiligo skin can be a source of understanding of immune cells that specifically target melanoma.^[137] Indeed, this interplay may be the source of exploration for promising therapeutic targets including checkpoint enhancing agents.^[138]

The actual loss of differentiated melanocytes may not define permanent depigmentation, as diverse sources of melanocyte precursors emerge. The extent of genetic predisposition and the external circumstances of the patient then drive disease development, defining the age of onset, the velocity of disease development and quite possibly the amenability of patients to treatment.

Although there are always processes worthy of further study, we can no longer claim that vitiligo is a disease of “unknown” aetiology. That said, a deep understanding of vitiligo pathogenesis is important to identify pathways that may be targeted through gene therapy, immunotherapy and the development of pharmaceutics that may be suited for cutaneous application.

A great need in the field currently lies with the development of vitiligo therapeutics. While research regarding vitiligo treatment has steadily increased over the past 25 years, the mainstays of treatment have remained the predominating topics as demonstrated in Figure 3. Currently, Janus kinase (JAK) inhibitors that interfere with IFN-γ signalling are in clinical trials.^[139] A tolerizing version of heat shock protein 70,^[140] Treg promoting treatment^[141,142] and antibodies that interfere with T-cell recruitment^[143] are some promising new approaches that might be translated to the clinic. In the arena of therapeutics, it is important to consider that pathways may be affected in some patients and not in others, and that this can and should impact treatment choices. A better understanding of individual aetiologic factors in disease development can ultimately contribute to the development of new and more effective treatments for vitiligo.