Paediatric-onset vitiligo may be associated with a higher prevalence of allergic diseases and a lower prevalence of thyroid diseases [3]. In adults, Schallreuter et al. found a high prevalence of thyroid diseases and presence of thyroid autoantibodies and a higher prevalence of congenital nevi (6.2 % compared with 2.8 % in a normal healthy population) among 321 individuals with vitiligo [4].

In another large 15-year retrospective population-based study, non-stratified analysis showed a significant association between vitiligo and psoriasis, atopic dermatitis and several autoimmune diseases such as alopecia areata, Hashimoto thyroiditis, myasthenia gravis, Graves’ disease, Sjögren’s syndrome and systemic lupus erythematosus (SLE ) [5]. However, when adjusted for age and gender, increased risks of SLE, Sjögren’s syndrome, myasthenia gravis and rheumatoid arthritis were observed only in certain age groups. In a similar study from the United States, 23 % of the vitiligo patients had one of the following autoimmune disorders: thyroid-related diseases (11.7 %), psoriasis (7.6 %), rheumatoid arthritis (2.9 %), alopecia areata (2.4 %), inflammatory bowel disease (IBD) (2.4 %), SLE(2.4 %) and type I diabetes mellitus (0.8 %). In addition, 41 % had elevated antinuclear antibody levels [6].

In a large retrospective study of 1416 vitiligo patients by Kanwar et al. from India, vitiligo was associated with other cutaneous and systemic diseases in 116 (8.2 %) patients [7]. These were classified as autoimmune and non-autoimmune diseases and both these groups were further subdivided into systemic and primary dermatologic diseases. Autoimmune diseases were present in 3.2 % of the patients and included primary dermatologic diseases (0.2 %) and systemic diseases (3 %) like hypothyroidism, hyperthyroidism and diabetes mellitus. Non-autoimmune diseases were present in 5 % of the patient population and included unrelated primary dermatologic diseases (2.6 %) such as melasma, acanthosis nigricans, cutaneous amyloidosis, lichen sclerosus et atrophicus and systemic diseases (2.4 %) like hypertension and polycystic ovary disease. However, they did not find any significant association of vitiligo with any of these disorders.

In another study from South India, Shankar et al. found among vitiligo patients a high incidence of autoantibodies (22.5 %), vitamin B12 deficiency (30 %), hypothyroidism (11.3 %), elevated absolute eosinophil count (16.3 %), hypoacusis (10 %) and retinal changes (8.8 %) [8].

Vitiligo is considered an autoimmune disease due to the presence of autoantibodies against melanocytes in patients’ sera [9], the detection of organ-specific antibodies in the patients’ sera and frequently in first-degree relatives and the association of the disease with HLA-DR4 and HLA-DR1. There is a production of autoantibodies directed against melanocyte antigens, and their titres may correlate with the activity and extent of the disease [10]. Moreover, altered cellular immunity is present, in addition to and in combination with a humoral response [11]. Equally important is the observation regarding the associations of vitiligo with other autoimmune conditions.

In a study assessing the association between vitiligo and autoimmune diseases in Caucasian probands and their families [12], the frequencies of six autoimmune disorders were significantly elevated in vitiligo probands and their first-degree relatives: vitiligo, autoimmune thyroid disease, pernicious anaemia, Addison’s disease, SLE and probably IBD. Such association can best be explained by an overall genetic susceptibility to autoimmunity.

The link of vitiligo with autoimmune thyroid disorders is the best established. They may be present in as many as one-fourth of vitiligo patients with disease onset during childhood [13–15], although the onset of the two diseases may be separated by more than a decade [16]. One study identified thyroid disease in 18.5 % of 15,126 vitiligo patients [17]. Conversely, vitiligo is more common in those with autoimmune thyroid disorders [18].

Patients with non-segmental vitiligo are more likely to have autoimmune disorders than those with segmental vitiligo [19]. In a study from Japan by Tanioka et al., one-fourth of the patients with non-segmental vitiligo had associated comorbidities [20]. Among the associations, autoimmune diseases were the most common in 43 % of patients, with autoimmune thyroid disease noted in 7.4 %. Other autoimmune associations included myasthenia gravis, Sjögren’s syndrome and autoimmune nephritis. Another study from Japan found autoimmune diseases in 20.3 % of patients with generalized vitiligo [21]. In a study comparing paediatric-onset and later-onset vitiligo, longer duration of disease and a positive family history of thyroid disease were associated with the presence of thyroid disease only in the childhood-onset group [3].

A higher incidence of thyroid microsomal antibody is found in vitiligo patients and their family members. In a multicentre study from Italy [22], at least one circulating autoantibody was detected in 61 (41.8 %) of 146 subjects. Other autoantibodies observed in this study included anti-thyroperoxidase (25.6 %), anti-thyroglobulin (23.4 %), antinuclear antibodies (16.8 %) and anti-gastric parietal cell antibodies (7.8 %). Another controlled study of 226 vitiligo patients found an increased incidence of antinuclear (12.4 %), antimicrosomal (7.1 %) and anti-smooth muscle antibodies (25.7 %) [23].

Vitiligo may be associated with several autoimmune syndromes. In a small case series assessing the association between vitiligo and multiple autoimmune syndrome, type III multiple autoimmune disease was diagnosed in all the 11 patients observed [24]. Vitiligo and thyroid disorders were noticed in seven and ten patients, respectively. Autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED)/autoimmune polyendocrine syndrome type 1 (APS1)/ polyglandular autoimmune syndrome type 1 (PGA1) presents with a combination of Addison’s disease, hypoparathyroidism, ectodermal dysplasia and/or chronic mucocutaneous candidiasis. Other manifestations may include alopecia areata, vitiligo, gastrointestinal symptoms, gonadal failure and ocular and dental anomalies [25]. A study of 68 patients with APECED found that 13 had vitiligo [25].

Schmidt syndrome/APS2 is an autosomal dominant disorder with variable expressivity [26]. Like APECED, it presents with polyglandular failure (Addison’s disease, hypothyroidism and type I diabetes mellitus) and occasionally vitiligo and/or hypogonadism [27]. Vogt-Koyanagi-Harada disease is a systemic T-cell-mediated disorder characterized by uveitis, aseptic meningitis, dysacusis, alopecia, poliosis, tinnitus and vitiligo (8–100 %) [28–30]. Alezzandrini syndrome presents with unilateral facial vitiligo, poliosis, deafness and tapetoretinal degeneration [31, 32]. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder that presents with central nervous system abnormalities, neurosensory hearing loss, diabetes mellitus and cardiomyopathy. Vitiligo may be seen in 11 % (3/28) of MELAS patients [33].

Patients with vitiligo, especially those with early-onset disease, have a significantly higher risk for atopic dermatitis. The probable pathophysiologic factors linking these two dermatoses could be common genetic factors, melanocyte destruction due to the inflammation seen in atopic dermatitis or koebnerization due to scratching. Silverberg and Silverberg found a higher prevalence of atopic disorders in patients with vitiligo compared to the general adult population [34]. They suggested that a history of atopic disease may be helpful to predict the progression of vitiligo to widespread disease. Kuriyama et al. conducted a prospective observational study to investigate the leukoderma-related clinical manifestations and bioparameters in atopic dermatitis and found that 8/52 (15.4 %) of patients had leukoderma. There is a female preponderance, a more severe eczema, a lower frequency of allergic rhinitis and a higher frequency of prurigo lesions in patients who have concurrent atopic dermatitis and vitiligo [35].

In a recent systematic review and meta-analysis, 16 studies of vitiligo were included [36]. In the pooled analysis of the studies, patients with vitiligo had significantly higher odds of atopic dermatitis than control patients without these disorders. Subgroup analysis found higher odds of atopic dermatitis in patients with early-onset vitiligo (<12 years) compared to those with late-onset vitiligo (OR, 3.54; 95 % CI, 2.24–5.63, p < .001).

Concurrent occurrence of vitiligo and psoriasis has been frequently noted. Yazdanpanah et al. reported that among the 219 and 154 patients suffering from psoriasis and vitiligo, respectively, 12 patients (0.19 %) had psoriasis and vitiligo simultaneously [37]. The simultaneous occurrence in the psoriasis group was 5.48 % and in the vitiligo group was 7.79 %. Of the 717 vitiligo patients seen at the Mayo Clinic over a 5-year period, 29 (4.04 %) had concurrent psoriasis [38]. Dermoscopic findings include dilated capillaries and red globules of psoriasis against a background of depigmentation, aptly called as “the red in white sea” sign [39].

Arunachalam et al., investigated the implications of disease association between vitiligo and psoriasis [40]. The presence of vitiligo and even mild psoriasis is significantly correlated with a family history of cardiovascular disease. Multivariate analysis demonstrated that inflammation or pruritus in vitiligo macules (OR 2.56, p = 0.047) and a family history of cardiovascular disease (OR 4.07, p = 0.02) were the most significant predictors of patients having both psoriasis and vitiligo, while the presence of organ-specific autoantibodies (OR 0.24, p = 0.007) was significantly associated with patients having only vitiligo.

Since vitiligo carries a significant social stigma in many parts of the world, it is not surprising that patients with this disease have a higher psychological morbidity. Psychological disturbances are common in patients with vitiligo and were found in 31 % of adult Sudanese patients [41]. These disturbances were mild in 17.2 % and severe in 13.8 %.

Psychological morbidity in vitiligo has frequently been compared with other chronic skin conditions, most notably psoriasis. In a study from India, 30 adult patients with psoriasis and vitiligo were studied [42]. The prevalences of psychiatric morbidity as assessed by the standardized Hindi version of the General Health Questionnaire (GHQ-H) were found to be significantly higher in vitiligo patients (53.3 % versus 16.22 %). The prevalence of depression was also much higher in the vitiligo cohort (23.3 % versus 10 %), while anxiety was observed in 3.3 % in both groups. In another study from India, Mattoo et al. found similar rates of psychiatric morbidity among patients with psoriasis (33.6 %) and vitiligo (24.7 %) [43].

Alexithymia is a personality trait characterized by difficulties in differentiating and describing feelings. Recently, alexithymia has been associated with numerous dermatologic conditions including vitiligo. In a case-control study, Picardi et al. suggested that vulnerability to vitiligo is not increased by stressful events except for unpredictable and uncontrollable aversive events which occurred three times more frequently in cases than controls [44]. Based on the Toronto Alexithymia Scale (TAS-20), and the Multidimensional Scale of Perceived Social Support, alexithymia, insecure attachment and poor social support appear to increase susceptibility to vitiligo, possibly through deficits in emotion regulation or reduced ability to cope effectively with stress.

The development of nonmelanoma skin cancer (NMSC) in patients with vitiligo is still debated. Due to the loss of melanocytes and of melanin, it has been postulated that patients with vitiligo have an increased risk of developing melanoma. Evidence supporting the concept that vitiligo has a higher incidence of melanoma and vice versa is limited [45]. In addition, a slightly higher incidence of NMSC has been reported in those with vitiligo [46, 47]. In contrast, the development of vitiligo in patients with metastatic melanoma may be associated with a favourable prognosis [48]. The immunologic mechanisms that lead to melanocyte destruction in vitiligo may also destroy malignant pigment cells.

Several mechanisms have been proposed to explain the negative association between vitiligo and skin cancer. This includes stricter sun protection likely to be undertaken by patients with vitiligo, a protective immunologic response as described above, lack of melanocytes within vitiligo lesions, overexpression of the p53 tumour suppressor gene which may protect against NMSC and overproduction of pro-inflammatory cytokines, such as interleukin-1 and tumour necrosis factor alpha (TNF-α) which stimulate the production of superoxide dismutase and glutathione peroxidase thus reducing the risk of skin cancer [49]. Teulings et al. reported a decreased risk of melanoma and NMSC in patients with vitiligo. They observed that adjusted for confounders, patients with vitiligo had a threefold lower probability of developing melanoma (adjusted OR 0.32; 95 % CI 0.12–0.88) and NMSC (adjusted OR 0.28; 95 % CI 0.16–0.50) [50]. In another study, the same authors suggested that although vitiligo occurs only in a low percentage of patients with melanoma treated with immunotherapy, induction of vitiligo lesions suggests a clear survival benefit and is important as an indicator of effective anti-melanoma immunity and improved survival [51].

Less commonly, vitiligo has been associated with cutaneous T-cell lymphoma (CTCL). Herrmann et al. analysed case records of 25 patients with CTCL and concomitant vitiligo [52]. They observed a younger age, stage IIB–IV disease and presence of a CD8 + CD4- mycosis fungoides phenotype to be associated with the development of vitiligo. Increased risk of vitiligo was associated with the use of methotrexate and CD4 antibody therapies, which may indirectly indicate advanced disease.