Melanocytes are found in both the retinal pigment epithelium (RPE) and the choroid of the eye, with the RPE originating from the neural ectoderm and the latter from the neural crest (10). Melanocytes in the RPE are crucial for the metabolism of rod outer segments and retinoids and photoprotection of the retina, whereas melanocytes in the choroid contribute to eye pigmentation and UV protection (9, 11). Damage to these melanocytes and reduced melanogenesis may result in ocular abnormalities and even vision impairments.

Prabha et al. (12) found various ocular abnormalities, such as hypopigmented trabecular meshwork, pigment clumps, uveitis, and RPE atrophy, in patients with vitiligo, and periorbital depigmentation was associated with eye abnormalities. Another cross-sectional study by Genedy et al. (13) revealed a significantly higher prevalence of ocular abnormalities in patients with vitiligo but no significant differences in visual acuity, which may be because ocular melanocytes are not directly involved in detecting or transferring visual information. There have also been reports of vitiligo comorbidities that cause loss of vision. For example, Dertlioğlu et al. (14) found that among 49 patients with vitiligo, 9 patients (18.4%) had normal-tension glaucoma (NTG), whereas there were no signs of NTG in the control group. In the absence of treatment, NTG can cause permanent loss of vision because it is a chronic progressive neuropathy that damages the optic nerve. Moreover, Rogosić et al. (15) confirmed primary open-angle glaucoma in 24 of 42 patients (57%) with vitiligo suspect of glaucoma. Multivariate logistic regression revealed that advanced age and a long vitiligo duration were risk factors for primary open-angle glaucoma.

According to one study by Ma et al. (7), patients with vitiligo had significantly reduced tear production, shorter tear film break-up time, and more symptoms related to dry eyes, which may be attributed to localized autoimmunity, such as T-helper (Th) 17 cells and related cytokines, concomitant rheumatologic diseases and adhesion defect theory (16–19). Additionally, subfoveal choroidal thickness was significantly thinner in the vitiligo group, possibly reflecting melanocyte depletion within this structure. Several external irritants, such as trauma, toxic chemical agents, ultraviolet radiation, and infection, can trigger oxidative stress, resulting in excessive reactive oxygen species production, autoimmune reactions, and melanocyte death (4, 20). It is also evident from the Köebner phenomenon that friction and trauma play critical roles in the pathogenesis of vitiligo (21). These stress signals spread to melanocytes in other parts of the body, potentially increasing their comorbidity risk.

In the auditory system, melanocytes are distributed in the stria vascularis and spiral ligament of the cochlea, which are required for maintaining the endocochlear electrical potentials that play an essential role in normal hearing (22). Melanin has been demonstrated to reduce oxidative stress by scavenging free radicals, and oxidative stress is considered one of the most important factors underlying sensorineural hearing loss (23, 24).

Accordingly, numerous studies have examined the relationship between vitiligo and hearing impairment but with varying results (25–28). A recent systematic review indicated that patients with vitiligo had a 6.02-fold increased risk of developing sensorineural hearing loss compared with the control group, but the definition of hearing loss was heterogenous between included studies (29). Lien et al. (6) conducted a similar analysis, and only studies meeting the criteria that examined hearing loss by assessing the pure-tone thresholds (PTTs) were included. According to their research findings, patients with vitiligo had significantly elevated PTTs only at high frequencies, including 2,000, 4,000, and 8,000 Hz, not at low frequencies ranging from 250 to 1,000 Hz. Since most of the sound in our daily life are at low and intermediate frequencies, we are generally not sensitive to hearing damage in the high frequency region. As a result, most cases of hearing loss among patients with vitiligo are subclinical. Furthermore, Anbar et al. (30) conducted a study to compare cochlear function in patients with nonsegmental vitiligo (NSV) and segmental vitiligo (SV), and the results showed that bilateral cochlear dysfunction was common in both disease subtypes. Regarding the age of onset, one study revealed a tendency towards an increased severity of sensorineural hearing loss in the older group and patients with late-onset vitiligo (28). In contrast, another study found that late-onset vitiligo was not statistically associated with abnormalities of the auditory system (27).

Based on the findings of the above studies, we recommend regular evaluation of patients with vitiligo to detect ocular and auditory abnormalities and to treat these conditions in the early stage. Melanocyte destruction in patients with vitiligo can affect melanocytes that share a common embryological origin, ultimately affecting the function of the organs in which they reside. However, small sample sizes and heterogeneous definitions have led to conflicting results between these studies. Further large-scale studies are required to clarify the disease burden and the associated pathogenesis of ocular and auditory abnormalities in patients with vitiligo.

Vogt–Koyanagi–Harada syndrome (VKH) is an autoimmune disease that mainly affects melanocyte-containing systems, such as the eyes, ears, meninges, skin, and hair follicles (31). It is characterized by granulomatous uveitis with varying degrees of extraocular manifestations, such as headache, meningismus, hearing loss, poliosis, and vitiligo (32). According to the current theory, VKH is an exacerbated response by melanocytes and their precursor cells compared with vitiligo. The study by Egbeto et al. (33) supports the theory that T cell responses (particularly cytotoxic CD8+ T cells), type 1 cytokines, memory T cell responses, and chemokines are involved in the development of VKH and vitiligo.

Melanocytes are also located in the brain and leptomeninges, possibly with neuroendocrine and detoxification functions (9). Melanocytes are also present in the heart, where they may play a role in electrical signaling (34). However, there are few clinical studies of diseases associated with melanocyte destruction in these regions, and the correlation between these diseases and vitiligo requires further study.

Several observational studies have found an increased prevalence of pernicious anemia (PA) in the vitiligo population. A 10-year cross-sectional retrospective study of 1,487 vitiligo patients in urban USA showed that an estimated 0.4% of patients have combined PA (69). Another study in 1,098 patients in the USA suggested a similar incidence of approximately 0.5% (36). It is worth noting that the prevalence of PA was significantly increased in a study conducted in Canada, with 1.3% of 300 vitiligo patients reporting the disease (74), which was higher than the general population prevalence of 0.15%. However, in a similar population-based study that enrolled 14,883 vitiligo patients in Taiwan, no statistically significant association of PA with vitiligo was revealed (57). This lower prevalence may be responsible for the differences in comorbidity profiles between Easterners and Westerners.

PA occurs in the later stage of AAG with severe gastric intrinsic factor deficiency and consequent vitamin B12 deficiency (75). PA is linked to but different from AAG. Anti-parietal cell antibodies (APCAs) are a serum biomarker of AAG present in most patients with AAG and 85–90% of individuals with PA (76), and APCAs are more frequent among individuals with vitiligo (77). Hence, associations of vitiligo with AAG and PA indicate a common immunopathogenic pathway.

The most commonly reported comorbid connective tissue diseases (CTD) in vitiligo patients are SLE and RA. Other associated CTDs include Sjögren’s syndrome (SS), systemic sclerosis (SSc), and dermatomyositis/polymyositis (DM/PM).

Choi et al. (78) performed a large-scale cross-sectional study and indicated that 86,210 patients with vitiligo were at an increased risk of SLE, SSc, SS, and RA. Subgroup analysis showed an increased risk of DM/PM for males and ankylosing spondylitis for female vitiligo patients. Research conducted by Gill et al. (36) in a US population found a statistically significant higher prevalence of SLE (0.3%), SS (0.2%), discoid lupus (0.2%), and linear morphea (0.2%) in vitiligo patients, and SLE was observed only in Black patients. Another similar study in vitiligo patients in the United States reported a considerably higher prevalence, with 2.2% for SLE and 2.9% for RA. Stratified analyses based on race/ethnicity suggested that these two comorbidities were more common in the African-American/Black population, which is consistent with the previous study (35). In Taiwan, a case–control study also showed a significant association of vitiligo with SLE and SS. In the age- and gender-stratified analysis, only patients with onset between 60 and 79 years of age were found to display an increased risk of SLE (79). In summary, age-, sex-, or ethnicity-specific approaches for comorbid CTDs in vitiligo patients will assist in the proper management of these disorders by clinicians.

Recent studies have suggested an observational link between vitiligo and neuroimmune disorders involving the peripheral and central nervous systems. According to a cross-sectional analysis of 1,098 patients with vitiligo, three had Guillain-Barré syndrome (0.2%), two had multiple sclerosis (0.2%), and two had myasthenia gravis (0.2%) (36). Considering that both the skin and the nervous system originate from the ectoderm, the underlying pathogenesis may be related to the fact that the epitopes of the neuronal cell surface are more likely to be attacked by autoantibodies induced by exposure to antigens triggered by vitiligo.

Autoimmune encephalitis is a group of disorders characterized by antibodies reacting with the extracellular epitopes of neuronal cell membranes or synaptic proteins (80). Of the three cases reported by Ren et al. (81), two suffered from anti-leucine-rich glioma-inactivated 1 encephalitis, and one had anti-IgLON5 encephalopathy. A Mayo Clinic cohort study showed that in a series of 62 patients with anti-glutamate decarboxylase 65 antibody-positive autoimmune cerebellar ataxia (ACA), 10 patients (16%) had vitiligo (82). In addition, Han et al. (83) reported a patient with ACA with anti-delta/notch-like epidermal growth factor-related receptor antibodies who suffered from vitiligo for more than 20 years. Most published studies on the association of vitiligo with neurological disease are case series or small sample studies. Therefore, further studies are warranted to investigate the cross-links between them.

Based on the above, we speculate that vitiligo may be a clue to understanding the diagnosis or autoimmune etiology of other autoimmune disorders. Patients with vitiligo are prone to disruption of autoimmune tolerance and autoimmune attack, thereby increasing their risk of concomitant autoimmune diseases. Similarly, if vitiligo lesions are observed in patients with diseases of other tissues, autoimmunity may be responsible for the pathogenesis. A diagnosis based on this information may be more accurate. Several large cross-sectional or retrospective studies have also noted that these diseases often occur alongside one another, which implies that their pathologies are inextricably linked. As a result, vigilance should be exercised when searching for possible concomitant diseases, and patients should be referred to specialists where necessary. Nevertheless, further studies are required to determine whether therapies for vitiligo can slow the progression of concomitant autoimmune disorders.

Vitiligo and alopecia areata (AA) are common autoimmune conditions characterized by white spots on the skin (vitiligo) and bald spots on the scalp (AA) (84). A retrospective study of 1,098 patients with vitiligo showed that AA is the second most common autoimmune disease associated with vitiligo after ATD, occurring in 3.8% of patients with vitiligo (36). Notably, a relatively high AA prevalence of 5.3% was observed in a study involving 133 NSV patients in Japan (85). Conversely, a Danish nationwide register-based cohort study showed that a diagnosis of AA was significantly associated with a higher risk of vitiligo (86), and the same phenomenon has been reported in pediatric patients (87).

Oxidative stress and autoimmunity with genetic susceptibility are associated with the pathogenesis of AA and vitiligo (88). Both conditions are characterized by a prominent interferon (IFN)-γ + signature and cytotoxic CD8 + T cell attack, selectively targeting the anagen hair follicle bulbs in AA and the epidermal melanocytes of the basal layer in vitiligo (84). Additionally, Tomaszewska et al. (89) found elevated levels of the oxidative stress markers IFN-γ, IL-1β, and IL-6 in the serum of both NSV and AA patients. In clinical practice, oral Janus kinase inhibitors are a promising treatment with demonstrated effectiveness in AA and vitiligo patients (90, 91). Together, these facts indicate a similar pathogenesis of both diseases.

Psoriasis is a relatively common disease with an estimated prevalence ranging from 0.51 to 11.43% in adults (92). A recent systematic review showed that compared with controls, psoriasis patients were 2.29-fold more likely to have vitiligo, and vitiligo patients were 3.43-fold more likely to be diagnosed with psoriasis (93). However, regarding its incidence in vitiligo patients, there is a large heterogeneity across studies. In a descriptive and cross-sectional study, 7.79% of 154 vitiligo patients simultaneously had psoriasis (94). However, in a similar study in 712 vitiligo patients, only 3% of the vitiligo group had associated psoriasis (95). In another cross-sectional study, in addition to the current comorbidities, Canu et al. (96) evaluated the history of psoriasis, and the results showed that 16.9% of 463 vitiligo patients had a past and/or current personal history of psoriasis. Remarkably, a case–control study demonstrated that inflammation or pruritus in vitiligo macules and a family history of cardiovascular disease were the most significant predictors of patients having both psoriasis and vitiligo (97).

Shared cell-mediated immune pathogeneses, including Th1 and Th17 pathways activated by IFN-γ, may play a role in the similar patterns of autoimmune inflammation in both diseases (98). Moreover, genome-wide association studies have provided extensive evidence that psoriasis and vitiligo share common genetic variants with similar effect sizes, including allelic variations in genes related to immune responses, such as AIS1, PSOR7 (99), and the major histocompatibility complex (100).

Increasing evidence suggests that vitiligo is associated with atopic dermatitis (AD). A meta-analysis of 16 studies showed that patients with vitiligo had a 7.82-fold increase in AD compared with control patients without these disorders. Intriguingly, the odds of having AD were higher in those with early-onset vitiligo than in those with adult-onset vitiligo (101). Similarly, the results of a recent population-based cohort study of 173,709 patients newly diagnosed with AD showed that people with AD had a higher incidence of vitiligo compared with the general population, particularly when AD is more severe (102). In addition, Roh et al. (103) conducted a study to characterize the real-world comorbidities associated with adult AD. They also found that AD was associated with increased odds (odds ratio = 4.44) of vitiligo, and the same findings were confirmed in another identical study in a pediatric population (104). Furthermore, AD prevalence was stratified by vitiligo BSA, and the results showed that a BSA of 76% or higher was associated with an increased risk of AD (105).

There are a few possible explanations for the pathomechanism linking AD and vitiligo. Campione et al. (106) suggested that although AD is associated with a Th2-mediated immune response in its acute phase, its chronic phase is predominantly Th1-mediated with remodelling and fibrosis of the tissues. In addition, Th17 cells, which produce IL-17A and IL-17F, seem to play a role in AD by interacting with eosinophils and triggering the Th2 response, which are also involved in the development of vitiligo (107). What’s more, Silverberg et al. (105) proposed that the proinflammatory state of AD may lead to melanocyte destruction, while scratching of pruritic AD lesions may köebnerize vitiligo.

Vitiligo and other associated dermatological diseases are characterized by a complex combination of factors, including genetic predisposition and the immune response triggered by exogenous stimulation. Vitiligo can precede or co-occur with other skin comorbidities, or emerge at different stages of the development of other skin comorbidities. Despite these obvious clinical differences, skin diseases share much in common, and understanding their similarities may help us to better determine their pathogenesis and develop common therapeutic approaches to treat them in a more efficient way, such as biological agents or Janus kinase inhibitors.