Vitiligo is a common polygenic autoimmune disease characterized by formation of the foci of skin depigmentation, resulting from the death or decreased function of   melanocytes, on various parts of the body. Segmental and nonsegmental vitiligo are distinguished. Segmental vitiligo is characterized by unilateral lesions located within one or more body segments. Nonsegmental vitiligo results in a few or multiple foci of depigmentation that are often symmetrically arranged [1]. In foreign literature, there is evidence of the higher incidence of autoimmune endocrine diseases (AEDs) in patients with vitiligo compared to the general population [1–3]. Autoimmune thyropathies are the most common in vitiligo patients (0.3–40% cases) [4–12]: autoimmune thyroiditis (AIT) is diagnosed in 0.3–31% of cases [9, 13, 14], and Graves' disease (GD) is found in 0.3–17.1% of cases [9, 14–16]; thyroid autoantibody positivity is identified in 41.8% of cases [11]. Type 1 diabetes mellitus (T1D) is found in vitiligo patients in 0.1–25% of cases [4, 5, 8–11, 17], autoimmune adrenal insufficiency (AAI) is diagnosed in 0.2–3.2% of cases [4, 5], and anti-adrenal antibodies are detected in 2.5% of cases [18, 19].

Vitiligo can not only be coupled with isolated AEDs, but also be a component of autoimmune polyglandular syndrome (APS), the primary autoimmune disorder  that affects two or more peripheral endocrine glands and usually results in the endocrine gland dysfunction. APS type 1 (APS-1) and type 2 (APS-2) are distinguished. Candidiasis involving the skin and mucous membranes, hypoparathyroidism, and AAI are the main components of APS-1. Patients with APS-2 develop such main AEDs, as AAI, T1D, autoimmune thyropathies (GD or AIT), in combination with other autoimmune diseases [2]. Vitiligo often becomes the first component of APS (in 12.6% of cases [2]). APS can occur in 27.4% of vitiligo patients [1].

At the same time, high incidence of vitiligo development in patients with autoimmune endocrine diseases have been reported: it is found in 2.6–2.8% of patients with AIT [20, 21], 1.4–2.6% of patients with GD [20, 22], 23.3% of patients with T1D [23], 37% of patients with APS-1 [24], and 20% of patients with APS-2 [2].

Published research shows that autoimmune endocrine diseases occur mostly in  patients with nonsegmental vitiligo [1, 6, 7]. No other factors contributing to the risk of AEDs in vitiligo patients have been identified. According to some reports, [1, 7, 8], the patients' gender and race, as well as vitiligo duration and activity, do not define the rate of AEDs manifestations. Meanwhile, other studies revealed more frequent association of vitiligo with AEDs in females [1, 4, 8, 9] and patients with larger skin lesions [4, 8]. Furthermore, higher prevalence of autoimmune thyropathies associated with the prolonged course of vitiligo and predominant involvement of the skin of the trunk was reported [8]. These data were not confirmed by papers reporting higher incidence of autoimmune thyroid disorders (AITDs) in patients with vitiligo patches located mostly on their limbs and joints [4], as well as predominance of APS in patients with acrofacial vitiligo [1]. The results of some studies suggest that the increased risk of AITD manifestation is associated with the late-onset vitiligo [10, 25]. However, association of vitiligo with GD is most common in young patients [14].

No full-fledged studies aimed at assessing the prevalence of AEDs in adult vitiligo patients and the prevalence of vitiligo in patients with AEDs in the Russian cohort have been conducted. Single studies on the issue were focused on assessing the incidence of vitiligo in patients with diabetes mellitus [26] or the AITD and pancreatic islet autoimmunity marker antibodies carrier state in vitiligo patients [27].

The study was aimed to assess the prevalence of AEDs in the cohort of Russian vitiligo patients.

METHODS

Patients included in the study

The first part of the study involved patients with vitiligo monitored in 2019–2021 in the Endocrinology Research Centre. The second part of the study involved patients with vitiligo monitored in 2019–2021 in the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology.

The patients were recruited and allocated to certain groups based on their compliance with the inclusion criteria and noncompliance with the exclusion criteria.

Inclusion criteria: age 18 or older; vitiligo; availability of the patient's informed consent.

Exclusion criteria: pregnancy, lactation; acute infections; exacerbation of chronic diseases; severe life-threatening conditions; congenital or acquired immunodeficiency disorders; taking medications affecting the immune system function (glucocorticoids not for vital indications, interleukins, interferons, immunoglobulins, immunosuppressants, cytostatics), and/or vaccination/revaccination within a month prior to enrollment.

Study design: cross-sectional observational descriptive study; the first part involved 39, and the second part involved 26 subjects. Continuous sampling was used during the study.

Clinical assessment

Medical researchers examined all the subjects in order to clarify their compliance with the inclusion criteria or possible non-compliance with the exclusion criteria. Initial examination included patient complaint management and history taking, as well as measuring anthropometric parameters, blood pressure and pulse rate. Family history, acute and chronic diseases, taking medications and dietary supplements, harmful habits, and gynecologic history (in women) were specified.

Dermatovenerologist performed thorough visual examination of the patient that involved assessment of the skin and skin appendages, and photodocumentation of lesions under visible light or Wood's lamp using digital camera.

Laboratory tests

Screening laboratory tests for all the major AEDs were performed in all patients. Biochemical, immunological and hormonal tests were carried out in the clinical diagnostic laboratory at the Endocrinology Research Centre. Blood was collected from the cubital vein in the vacuum tubes containing inert gel and ethylenediaminetetraacetic acid in the morning (between 08:00 am and 10:00 am) in the fasting state (fasting for 8–14 hrs prior to venipuncture). The samples were centrifuged within 15 minutes after blood collection and processed. Complete blood count, biochemical, hormonal, and immunological (thyroid peroxidase (TPO) antibodies, thyroglobulin (TG) antibodies) tests were carried out on the day of blood sampling. Serum samples for further assessment of the levels of 21-hydroxylase antibodies and markers of pancreatic islet autoimmunity had to be temporarily frozen in microtubes at a temperature of –80 °С.

Statistical analysis of the results

Statistical processing of the results was performed by standard methods using the STATISTICA 13 software package (StatSoft; USA). Chi-squared test (χ²) was used to compare qualitative traits. The differences were considered significant at р < 0.05.

RESULTS

Characteristics of study participants are provided in tab. 1.

The prevalence of autoimmune endocrine diseases in the cohort of adult patients with vitiligo initially monitored in the Endocrinology Research Centre

In the surveyed cohort, symptomatic AEDs were diagnosed in 85% of cases (n = 33). Single AED was diagnosed in 38.5% of cases (n = 15), and in 46.1% of cases (n = 18) multiple autoimmune endocrine disorders were observed. Another 6 patients (15.4%) with no symptomatic AEDs appeared to be carriers of AITD marker antibodies showing no target organ dysfunction and/or carriers of pancreatic islet autoimmunity marker antibodies showing no carbohydrate metabolism disorders.

AITDs were found in 69% of cases (n = 27): 19 patients (70%) were diagnosed with primary hypothyroidism in the outcome of AIT, 8 patients (30%) were diagnosed with GD. AAI was found in 28% of cases (n = 11), T1D/LADA (latent autoimmune diabetes in adults) in 21% (n = 8), hypoparathyroidism in 13% (n = 5), hypergonadotropic hypogonadism (HH) in 10% (n = 4), endocrine ophthalmopathy (EOP) in 10% of cases (n = 4).  

Multiple autoimmune endocrine disorders were represented by APS-2 in 61% of cases (n = 11), APS-1 in 22% of cases (n = 4); a combination of GD and EOP was found in 17% of cases (n = 3). The onset of AEDs was preceded by vitiligo in 30% of patients (n = 10), 12% of patients developed vitiligo and AEDs simultaneously (n = 4). 

The AITDs marker antibodies carrier state with no target organ dysfunction was found in 15% of cases (n = 6), while the pancreatic islet autoimmunity marker antibodies positivity with no carbohydrate metabolism disorder was diagnosed in 23% of cases (n = 9) (figure). No carriers of 21-hydroxylase antibodies having no disorders of the adrenal cortex were found.

The patients were diagnosed with nonsegmental vitiligo in 100% of cases. However, one patient with APS-2 (AAI, primary hypothyroidism in the outcome of AIT, autoimmune gastritis) was diagnosed with universal vitiligo.

Comparison of the prevalence of AEDs in female and male patients is provided in tab. 2.

The prevalence of autoimmune endocrine diseases in the cohort of adult patients with vitiligo initially monitored in the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology

AEDs were diagnosed in four patients (15%). All the diagnosed AEDs were classified as AITDs. Among them primary hypothyroidism in the outcome of AIT was found in three patients, and Graves' disease was found in one patient.

AITDs marker antibodies positivity with no thyroid dysfunction was diagnosed in 15% of cases (n = 4).

Nonsegmental vitiligo was diagnosed in 25 patients (96%). One patient with no symptomatic AEDs or antibody positivity was diagnosed with segmental vitiligo.

Comparison of the prevalence of AEDs in female and male patients is provided in tab. 3.

DISCUSSION

Our data on the prevalence of AEDs in patients with vitiligo are consistent with the results of other studies [4, 10, 28]. However, there is a report about one patient with AED (GD) among 204 vitiligo patients [16]. Most probably such low prevalence of AEDs reported by this paper is due to research methods based on the medical history analysis, while we performed active laboratory screening for AEDs.

According to the results of both first and second parts of the study, vitiligo is most often associated with AITDs, which is comparable with the data obtained by other researchers [4, 5, 10, 11]. At the same time, the study that included 50 vitiligo patients [12] revealed no cases of symptomatic AITDs, however, the authors reported high prevalence of TPO antibodies positivity (50% of cases; our study showed that the prevalence of TPO and TG antibodies positivity with no thyroid dysfunction was much lower, 15%).

Unlike other authors [1, 4, 8–10, 26], we found no signficant predominance of women among patients with AEDs associated with vitiligo, including multiple AEDs (except AAI). At the same time, we found that association of vitiligo with T1D was more frequent in the cohort on men compared to women. However, it is necessary to take into account similar gender differences in the general population (higher prevalence of T1D in men [29] and AAI in women [30]).

Furthermore, our findings confirm some data [5] that vitiligo often precedes AEDs manifestation. The results obtained justify the need for regular screening of vitiligo patients for AEDs.

Nonsegmental vitiligo was found in all patients monitored in the Endocrinology Research Centre and 96% of patients monitored in the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology. However, it must be noted that nonsegmental vitiligo was diagnosed in both patients with symptomatic AEDs or carriers of antibodies against target organs and patients with no symptomatic AEDs or target organ antibodies positivity. Since our findings do not allow an unambiguous conclusion about the risk of AEDs in patients with various types of vitiligo (due to small number of patients with segmental vitiligo), further accumulation of data is required.

CONCLUSIONS

According to our data, the prevalence of AEDs in patients with vitiligo may vary between 15–85%. Vitiligo is most often associated with AITDs. Vitiligo precedes AEDs manifestation in 30% of cases. Among patients with vitiligo and symptomatic endocrine disorders, AAI is most common in women, while T1D is most often found in men. Vitiligo patients should undergo annual screening aimed at detecting autoimmune endocrine disorders, especially of thyroid disease. In is necessary to inform physicians (primarily dermatologists, endocrinologists, and general practitioners) about the possible association of vitiligo with autoimmune endocrine disorders. Patients should be made aware of the need for annual screening and referral to endocrinologist in case of emergence of the AEDs clinical manifestations.