FormalPara Key Summary Points

Why carry out this study?

Vitiligo is associated with an increased incidence of comorbid conditions relative to the general population

This retrospective study aimed to evaluate the comorbidity burden among patients diagnosed with vitiligo from the US

What was learned from the study?

This large retrospective analysis demonstrated that patients were much more likely to be diagnosed with autoimmune or psychiatric comorbidities following a vitiligo diagnosis

These results provide further evidence that vitiligo is a complex autoimmune disorder that likely contributes to increased economic burden and lower quality of life

Introduction

Vitiligo is a chronic autoimmune disorder, characterized by skin depigmentation caused by the loss of melanocytes [1, 2]. The global prevalence of vitiligo, which varies among different geographic regions and ethnic groups, ranges from 0.5 to 2.0%, with no difference by sex, age, or race [1, 3]. Vitiligo is classified into two major forms based on the distribution of lesions as either non-segmental or segmental [4]. The etiology of vitiligo is primarily autoimmune, although it may involve multiple mechanisms, including genetic predisposition, environmental triggers, and oxidative stress [1]. Depigmentation in vitiligo is primarily mediated by an immune-mediated attack on melanocytes following the recruitment of autoreactive cytotoxic T cells by pro-inflammatory cytokines [5, 6]. This in turn induces autologous apoptosis and loss of melanocytes [7]. Skin diseases, and vitiligo in particular, have profound effects on the quality of life of the patient [8, 9]. Unfortunately, there currently is no cure for vitiligo, although guidelines for repigmentation include courses of topical and systemic corticosteroids, topical calcineurin inhibitors, phototherapies, autologous transplantation, oral steroids, and other immunosuppressants [10].

Vitiligo is associated with an increased incidence of comorbid conditions relative to the general population, with the most common including thyroid disease, especially Hashimoto’s thyroiditis; psoriasis; adult-onset diabetes mellitus type 1; and alopecia areata [11,12,13]. Vitiligo is also associated with several psychiatric comorbidities, including depression and anxiety [1, 11]. Reported prevalence rates for comorbid autoimmune diseases are variable depending on the population. A low prevalence of comorbid autoimmune diseases, including morphea and alopecia areata, have been reported in India (3%) [14]. Higher rates have been reported in Taiwan (14%) [15], the US (23%) [16], Italy (42%) [17], and Turkey (55%) [18], with the most common comorbidities including atopic dermatitis, thyroid disease, autoimmune thyropathy, and Hashimoto’s thyroiditis, respectively [15,16,17,18]. Comorbid conditions associated with vitiligo may increase the economic burden on patients and lower their health-related quality of life [1, 19]. A recent meta-analysis demonstrated that patients with vitiligo were at a significantly higher risk of depressive symptoms (approximately one-third of patients) and clinical depression (approximately one-quarter of patients) compared with those without vitiligo [20, 21]. To date, no large-scale study has been published using claims databases to evaluate the burden of comorbidity among patients with vitiligo.

This retrospective study aims to evaluate the comorbidity burden among patients diagnosed with vitiligo using data from the Merative MarketScan Commercial Database [22].

Methods

Study Design and Data Source

This retrospective cohort analysis used the Merative MarketScan Commercial Database [22] as the data source. This database is one of the longest running and largest collections of proprietary de-identified claims data for privately and publicly insured people in the US. The database captures inpatient medical, outpatient medical, and outpatient prescription drug data for 145.5 million employees and their dependents covered by a variety of fee-for-service and managed care health plans. This retrospective cohort analysis using the Merative MarketScan Commercial Database did not require approval from an institutional review board or ethics committee nor was written informed consent required.

Study Population

The vitiligo cohort consisted of patients diagnosed with vitiligo as confirmed through one inpatient or two outpatient claims based on International Classification of Diseases, Revisions 9 and 10, Clinical Modification codes between January 1, 2008, and December 31, 2020. The control cohort consisted of those with no diagnosis of vitiligo between January 1, 2007, and December 31, 2021. The first date of diagnosis was used as the index date for patients with vitiligo. The index dates for the control cohort were randomly assigned between January 1, 2008, and December 31, 2020, based on the index date distribution among patients with vitiligo (Fig. 1).

Fig. 1
figure 1

Study design

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Patients with vitiligo aged ≥ 12 years with ≥ 12 months of continuous enrollment before and ≥ 12 months following the index date were eligible for the study. Key exclusion criteria for patients with vitiligo included evidence of vitiligo-related treatment during a flexible pre-index period (≥ 12 months to start of baseline continuous enrollment) and diagnosis of bullous disorders, dermatitis, eczema, papulosquamous disorders, disorders of skin and appendages, and other disorders of pigmentation during the pre-index period. Patients who met eligibility criteria were matched 1:4 (vitiligo:control) to control participants based on age, sex, and geographic location. Matched control subjects must have had no diagnosis of vitiligo and no evidence of vitiligo-related treatment during the entire study period. For patients with vitiligo and control subjects, those with a history of or current psychiatric comorbidities, autoimmune comorbidities, and non-autoimmune comorbidities during the flexible baseline period before the index date were excluded.

Outcomes

The study outcomes were incidence of comorbidities after matching, adjusted hazard ratios (HRs) of comorbidity incidence among patients with vitiligo relative to matched controls, and time to comorbidity diagnosis/incidence.

Statistical Analysis

The HR associated with risk of developing each comorbid condition after the initial diagnosis of vitiligo in patients compared with match controls was estimated using a multivariate Cox proportional hazards model. Controlled variables in the Cox proportional hazards model included the age at index date, region of the US, baseline obesity, and baseline Charlson Comorbidity Index. The time to diagnosis of each comorbidity was also assessed and reported descriptively.

Results

A total of 13,953 eligible patients with vitiligo and 1,308,073 control subjects without vitiligo were identified from the Merative MarketScan Commercial Database (Table 1). Baseline demographics were well balanced between matched cohorts (vitiligo, n = 13,687; control, n = 54,748; Table 2). Across both cohorts, the median age at index date was 39 years (range 12–64 years), and most patients were female (72.2%). Obesity rates were 2.5% and 2.2% for patients and matched control subjects, respectively. The mean Charlson Comorbidity Index was 0.1 for both cohorts. Patients were most commonly from the southern region of the US (39.9%), and a fee-for-service plan was the most common healthcare plan for both the vitiligo and control cohorts (82.4% and 83.5%, respectively).

Table 1 Attrition table identifying those included in the final study population
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Table 2 Baseline demographics after matching for age, sex, and geographic location
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Among patients, the incidence rates of any psychiatric disease and any autoimmune disease were higher among patients with vitiligo compared with the matched control subjects (28.4% [n = 3892] vs 22.8% [n = 12,457] and 13.4% [n = 1830] vs 5.1% [n = 2811], respectively; Table 3). In addition, the incidence rates of non-autoimmune comorbidities were higher among patients with vitiligo (10.0% [n = 1363]) compared with the control subjects (7.0% [n = 3854]). The most common psychiatric comorbidities among patients with vitiligo and the control cohort were anxiety (14.3% vs 11.0%, respectively), sleep disturbance (9.1% vs 7.0%), and depression (8.0% vs 6.3%). The most common autoimmune comorbidities were atopic dermatitis (3.1% vs 1.1%), psoriasis (2.7% vs 0.6%), and linear morphea (1.5% vs 0.1%), and the most common non-autoimmune comorbidities were glaucoma (3.7% vs 2.8%), sensorineural hearing loss (2.7% vs 1.7%), and folate deficiency (2.7% vs 1.6%).

Table 3 Incidence of comorbidities in patients with vitiligo
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The risk of developing any psychiatric (HR 1.31; P < 0.01) or any autoimmune (HR 2.77; P < 0.01) comorbidity was significantly higher in patients with vitiligo compared with the control cohort (Fig. 2). The greatest psychiatric comorbidity risks in patients with vitiligo included schizophrenia (HR 1.88 [95% CI 1.10–3.19]; P = 0.02), social phobia (1.71 [1.10–2.67]; P = 0.02), and adjustment disorder (1.44 [1.30–1.59]; P < 0.01). Patients with vitiligo had the greatest risk of being diagnosed with autoimmune comorbidities, such as linear morphea (HR 20.13 [95% CI 14.45–28.06]; P < 0.01), alopecia areata (5.55 [4.37–7.04]; P < 0.01), and psoriasis (4.42 [3.81–5.12]; P < 0.01) compared with the matched control subjects. A diagnosis of vitiligo versus no diagnosis was also associated with a significantly greater risk of being diagnosed with non-autoimmune conditions (HR 1.45; P < 0.01), including folate deficiency (HR 1.71 [95% CI 1.51–1.93]; P < 0.01), sensorineural hearing loss (1.59 [1.41–1.79]; P < 0.01), and glaucoma (1.34 [1.21–1.48]; P < 0.01).

Fig. 2
figure 2

Risk of developing a psychiatric, b autoimmune, and c non-autoimmune comorbidities among patients diagnosed with vitiligo compared with matched controls. HR, hazard ratio. aAdjusted HRs were estimated by Cox regressions controlling for age, obesity, Charlson Comorbidity Index, and region. bOnly statistically significant data are presented in this figure

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Among matched patients with incident events, the mean (SD) time between the first diagnosis of vitiligo and development of comorbidities was 2.1 (2.1) years for psychiatric comorbidities, 1.8 (2.1) years for autoimmune comorbidities, and 2.7 (2.4) years for non-autoimmune comorbidities (Table 4). Mean (SD) times to diagnosis of high-risk autoimmune comorbidities of linear morphea and alopecia areata were 0.8 (1.3) and 1.5 (2.0) years after a vitiligo diagnosis, respectively; psychiatric comorbidities of schizophrenia and social phobia were diagnosed at 4.1 (3.6) and 3.2 (2.3) years after a vitiligo diagnosis; non-autoimmune folate deficiency and sensorineural hearing loss were diagnosed 3.0 (2.6) and 3.0 (2.5) years after a vitiligo diagnosis. Although most comorbidities were diagnosed within 1–3 years of a vitiligo diagnosis, mean (SD) time to diagnosis of celiac disease was 3.9 (2.6) years and to diagnosis of myasthenia gravis was 3.5 (2.3) years after a vitiligo diagnosis.

Table 4 Time to diagnosis/development of comorbidities among matched patients with vitiligo with incident events
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Discussion

To the best of our knowledge, this is the largest retrospective study to describe the comorbidity burden among patients diagnosed with vitiligo versus matched controls. Using data from the Merative MarketScan Commercial Database for 13,687 patients diagnosed with vitiligo from January 1, 2008, to December 31, 2020, and 54,748 matched control subjects without vitiligo, this analysis showed higher incidence rates of psychiatric, autoimmune, and non-autoimmune diseases among patients with vitiligo compared with the control cohort. For example, the incidence rates of anxiety, sleep disturbance, depression, atopic dermatitis, psoriasis, and linear morphea were higher among patients with vitiligo. Other high-incidence comorbidities included glaucoma, sensorineural hearing loss, and folate deficiency. The risk of developing psychiatric comorbidities, such as schizophrenia and social phobia, was significantly greater among patients with vitiligo compared with matched controls, as was the risk of developing autoimmune comorbidities, such as linear morphea and alopecia areata. Among matched patients with incident events, the time to diagnosis of most vitiligo comorbidities was within 1–3 years of the vitiligo diagnosis; however, linear morphea was diagnosed less than 1 year from the vitiligo diagnosis.

Vitiligo has often been classified as a cosmetic disease [19], but these results provide further evidence that vitiligo is a complex autoimmune disorder that can have multiple associated autoimmune and psychiatric comorbid conditions. A combination of genetic susceptibility, inflammation, and autoimmune response is believed to contribute to the etiology of vitiligo [23]. Several genes and genetic abnormalities of specific loci have been identified that appear to mediate vitiligo susceptibility and are shared with several other autoimmune diseases, which supports a shared pathogenesis of autoimmune comorbidities associated with vitiligo [24].

The results from this study are consistent with previous studies identifying a high prevalence of autoimmune diseases among patients diagnosed with vitiligo. A chart review of 1873 patients with vitiligo in the US identified comorbid psoriasis in 2.2% of patients with vitiligo and linear morphea in 0.2% and found that patients with at least one comorbid autoimmune disease tended to have more extensive vitiligo disease by body surface area compared with those without comorbid autoimmune disease [12]. In addition, a retrospective population-based study of 14,883 patients with vitiligo in Taiwan identified high rates of atopic dermatitis (8.0%) and psoriasis (2.8%) and found that patients with vitiligo had a fourfold higher risk of having three or more associated autoimmune or atopic diseases compared with controls [15]. A study of 2624 patients with vitiligo in North America and the UK reported a twofold higher incidence of inflammatory bowel disease and an eightfold higher incidence of any autoimmune thyroid disease in patients with vitiligo compared with the general population [25]. Our results are consistent with a previous population-based study observing higher rates of Graves’ disease in patients with vitiligo (0.3%) compared with the general population (0.1%) [15]. That study also noted marked increased rates of another autoimmune thyroid disease (Hashimoto’s thyroiditis) in patients with vitiligo (1.26%) compared with the general population (0.24%) [15].

Recent reviews have identified anxiety and depression to be highly prevalent in patients with vitiligo and have identified an unmet need to quantify and manage psychological symptoms and disorders in these patients [20, 21, 26]. Our analysis is congruent with these findings and provides further evidence of the associations between vitiligo and psychiatric diseases.

Melanocytes in the cochlea have been shown to play a key role in hearing [27], and it has been speculated that patients with vitiligo may be at an increased risk of developing sensorineural hearing loss due to melanocyte depletion in the cochlea. This hypothesis is supported by our observations as well as a population-based cohort study examining the association between sensorineural hearing loss and vitiligo from Taiwan, which showed a 2.2-fold increased risk of developing sensorineural hearing loss in patients with vitiligo compared with the general population [28].

A strength of this analysis includes the consideration of patients who were diagnosed with vitiligo before any other autoimmune disease. However, the retrospective nature of this study is a limitation that does not allow causation to be firmly established; prospective long-term clinical studies and registries are needed in the future to confirm these results. In addition, although the study matched patients and controls on several important characteristics, there might be unmeasured confounding and selection biases that cannot be eliminated. Consequently, these results may not be generalizable to populations outside the US.

Conclusion

Patients with vitiligo were much more likely to be diagnosed with autoimmune or psychiatric comorbidities compared with matched controls. In addition, comorbid conditions likely contributed to the increased economic burden and the lower quality of life experienced by patients with vitiligo.