
==== Front
Arch Dermatol Res
Arch Dermatol Res
Archives of Dermatological Research
0340-3696
1432-069X
Springer Berlin Heidelberg Berlin/Heidelberg

38850409
2965
10.1007/s00403-024-02965-7
Original Paper
A bidirectional autoimmune cluster between vitiligo and rheumatoid arthritis: a large-scale population-based study
Cohen Naama Tova 1
Schonmann Yochai 23
Kridin Khalaf dr_kridin@hotmail.com

1345
1 https://ror.org/03kgsv495 grid.22098.31 0000 0004 1937 0503 Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
2 grid.7489.2 0000 0004 1937 0511 Medical School for International Health, Ben Gurion University, Negev Be’er Sheva, Israel
3 https://ror.org/04zjvnp94 grid.414553.2 0000 0004 0575 3597 Clalit Health Services, Tel-Aviv, Israel
4 https://ror.org/000ke5995 grid.415839.2 Unit of Dermatology and Skin Research Laboratory, Galilee Medical Center, Nahariya, Israel
5 https://ror.org/00t3r8h32 grid.4562.5 0000 0001 0057 2672 Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
8 6 2024
8 6 2024
2024
316 7 36618 11 2023
21 4 2024
26 4 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
A knowledge gap exists regarding the association between vitiligo and rheumatoid arthritis (RA) due to the absence of large-scale cohort studies designed to investigate this association. To investigate the bidirectional epidemiological association between vitiligo and RA. A population-based study was conducted using Clalit Health Services (CHS) database (2002–2019) using both a cohort study and a case-control study design. Adjusted hazard ratio (HR) and odds ratio (OR) were calculated by multivariate Cox and logistic regressions, respectively. Overall, 20,851 vitiligo patients and 102,475 controls were included. The incidence of new-onset RA was 4.1 (95% CI 3.0–5.4) and 2.9 (95% CI 2.4–3.3) cases per 10,000 person-years among patients with vitiligo and controls, respectively. Patients with vitiligo had a significantly increased risk of developing new-onset RA (adjusted HR, 1.44; 95% confidence interval [CI], 1.02–2.02, P = 0.036). The likelihood of having vitiligo was significantly elevated after a preexisting diagnosis of RA (adjusted OR, 1.67; 95% CI, 1.38–2.03; P < 0.001). Relative to the remaining patients with vitiligo, those with vitiligo and comorbid RA demonstrated an elevated risk of all-cause mortality (adjusted HR, 1.61; 95% CI, 1.03–2.51; P = 0.037). Our study confirms the bidirectional association between vitiligo and RA. Physicians treating patients with vitiligo should be aware of the association in clinical practice.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00403-024-02965-7.

Keywords

Vitiligo
Rheumatoid arthritis
Cohort study
Case-control study
Bar-Ilan UniversityOpen access funding provided by Bar-Ilan University.

issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
==== Body
pmcIntroduction

Vitiligo is a chronic autoimmune skin disorder characterized by the destruction of melanocytes, resulting in depigmentation of skin regions [1]. The etiology of vitiligo is multifactorial involving genetic factors, environmental triggers, activation of inflammatory mediators, and an autoimmune response [2]. Recent advancements have led to the recognition of vitiligo as an immunological disorder, and vitiligo has been associated with various autoimmune-related disorders, including Hashimoto’s thyroiditis, Graves’ disease, type 1 insulin-dependent diabetes mellitus, and Addison’s disease, supporting the autoimmune theory [3]. This association may arise from shared autoimmune and genetic susceptibilities. Studies have shown that individuals with vitiligo have an increased incidence of other autoimmune conditions [4].

A recent genome wide association study (GWAS) has significantly advanced the understanding of the genetic basis of vitiligo. Various genetic loci and susceptibility genes have been identified, providing insights into the pathways involved in the pathogenesis of vitiligo [5].

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive joint damage and multi-system complications. RA is characterized by persistent inflammation which may result in long-lasting disability and increased mortality rate as compared to the general population [6]. There are various factors associated with the development of RA, including genetics, female sex, and environmental influences. The incidence of RA is higher in women, with females being two to three times more prone to the condition than males [7].

Both vitiligo and RA involve dysregulated immune responses, yet the pathogenesis involves distinct mechanisms. Dysregulation of cytokine activity is implicated in both conditions [8, 9]. Recently research examined the role of interleukin 27 (IL-27) that triggers Tr1 cells, which suppress the responses of Th2 and Th17 cells, which reduce the intensity of autoimmune diseases. Altered concentration in IL-27 have been observed in both RA and vitiligo emphasizing potential association [10–12]. Despite these common pathogenic themes, the epidemiological association of vitiligo with RA is yet to be firmly established.

In the current study, we sought to investigate the bidirectional associations between vitiligo and RA using a large-scale population-based study. We aimed to study the risk of new-onset RA among individuals with vitiligo and to calculate the odds of vitiligo occurring in patients who already have RA. Additionally, aimed to study determinants of RA among patients with RA.

Methods

Study design and data set

The current study aimed to investigate the bidirectional association between vitiligo and RA, a large-scale population-based study included two study designs. First, a retrospective cohort study design was used to longitudinally follow patients with vitiligo and estimate the incidence of new-onset RA. Second, a case-control study design was applied to estimate the prevalence of preceding RA (exposure) in patients with subsequent vitiligo (outcome). Considering the rare disease assumption, the latter design is likely to delineate the odds of vitiligo after RA.

We utilize the computerized data set of Clalit Health Services (CHS) as the data source. According to regulations of the National Health Insurance Law, residents in Israel are obligated to enroll in one of the four healthcare maintenance organizations. CHS is the largest healthcare provider organization in Israel, with 4,554,343 members as of 2018. CHS provides a comprehensive array of medical coverage, including both outpatient and inpatient settings. Each interaction within the healthcare system is recorded in the patient’s medical file, and the CHS database is continuously updated; the database offers an extensive overview of CHS enrollees over time, establishing its reliability as a source for epidemiological data.

Study population and definition of covariates

The CHS database was screened for incident cases with a diagnostic code of vitiligo between the years 2002 and 2019. Patients were considered eligible for inclusion if one of the following criteria was fulfilled: (i) a documented diagnosis of vitiligo as registered by a board-certified dermatologist, or (ii) a diagnosis of vitiligo in discharge letters from dermatological wards. The diagnosis of RA was based on documentation by certified rheumatologists.

We enrolled a control group including up to five individuals without vitiligo per each case. Controls were matched based on age, sex, and ethnicity and were recruited on the day in which the corresponding case was diagnosed. Outcome measures were adjusted for demographic variables and putative confounding comorbidities, including smoking, diabetes mellitus, hypertension, hyperlipidemia, and body mass index (BMI).

Statistical analysis

The comparison of variables between different comparator groups was performed using the chi-square test and t-test for categorical and continuous variables, respectively. In the cohort study design, incidence rates of RA were calculated for both vitiligo patients and controls and expressed as the number of events per 10,000 person-years. Hazard ratios (HR)s and 95% confidence intervals (CI)s for the risk of incident RA were found using the Cox regression model. Differences in the all-cause mortality of vitiligo patients with and without RA were estimated using a stratified log-rank test.

In the case-control study design, conditional logistic regression analysis was utilized to calculate odds ratios (ORs) and 95% CIs to compare cases and controls with reference to the presence of preexisting RA. Based on the temporal relationship between exposure and outcome in case-control studies, only individuals who developed vitiligo after the diagnosis of RA were included. Two-tailed P-values less than 0.05 were considered statistically significant. All statistical analyses were performed using SPSS software, version 25 (SPSS, Armonk, NY: IBM Corp).

Results

Characteristics of the study population

The study population included 20,851 patients with vitiligo and 102,475 age-, sex-, and ethnicity-matched controls. The mean (SD) age of patients with vitiligo was 34.7 (22.4) years; 10,570 (50.7%) patients were females, and 15,311 (73.4%) were of Jewish ancestry. The baseline characteristics of the study population are outlined in Table 1.

Table 1 Descriptive characteristics of the study population

Characteristic	Patients with vitiligo (N = 20,851)	Controls (N = 102,475)	p-value	
Age, years	
Mean (SD)	34.7 (22.4)	34.6 (22.4)	0.608	
Median (range)	32.4 (0.1–95.4)	32.4 (0.1–96.2)	
Sex, n (%)	
Male	10,281 (49.3%)	50,523 (49.3%)	0.991	
Female	10,570 (50.7%)	51,952 (50.7%)		
Ethnicity, n (%)	
Jews	15,311 (73.4%)	75,249 (73.4%)	0.903	
Arabs	5,540 (26.6%)	27,226 (26.6%)	
BMI, mg/kg 2	
Mean (SD)	25.2 (31.5)	24.8 (31.5)	0.241	
Smoking, n (%)	5,207 (25.0%)	29,728 (29.0%)	< 0.001	
Charlson comorbidity score, mean (SD)	0.4 (0.9)	0.4 (1.0)	0.876	
Abbreviations N, Number; SD, standard deviation; BMI, body mass index

The risk of developing RA among patients with vitiligo

In the retrospective cohort study design, patients with vitiligo were cumulatively followed for 115,210 person-years whereas controls were followed for 564,438 person-years. During the follow-up duration, 47 and 161 cases of new-onset RA occurred among patients with vitiligo and control individuals, respectively. Taken together, the incidence rates of RA were 4.1 (95% CI, 3.0–5.4) and 2.9 (95% CI, 2.4–3.3) cases per 10,000 person-years in patients with vitiligo and control individuals, respectively (Table 2).

Table 2 Incidence rates and hazard ratio of new-onset rheumatoid arthritis among patients with vitiligo (cohort study design)

	Vitiligo	Controls	
Follow-up time, PY	115,210.2	564,438.1	
Median follow-up time, years (range)	5.5 (0.1–14.5)	5.5 (0.1–14.5)	
Number of events	47	161	
Incidence rate per 10,000 PY (95% CI)	4.1 (3.0-5.4)	2.9 (2.4–3.3)	
Unadjusted HR (95% CI) [p-value]	1.43 (1.03–1.98) [0.031]	Reference	
Sex- and age-stratified analysis	
Male-specific HR (95% CI) [p-value]	1.90 (1.07–3.39) [0.029]	Reference	
Female-specific HR (95% CI) [p-value]	1.27 (0.86–1.89) [0.233]	Reference	
≥ 32.4 year-specific HR (95% CI) [p-value]	1.29 (0.90–1.86) [0.165]	Reference	
< 32.4 year-specific HR (95% CI) [p-value]	2.25 (1.06–4.74) [0.034]	Reference	
Multivariate adjusted analysis	
Age- and sex-adjusted HR (95% CI) [p-value]	1.41 (1.02–1.95) [0.040]	Reference	
Fully adjusted HR (95% CI) [p-value] a	1.44 (1.02–2.02) [0.036]	Reference	
Bold: significant value

Abbreviations HR, hazard ratio; CI, confidence interval; PY, person-year; NA, not applicable

a adjusted for age, sex, ethnicity, BMI, smoking, ischemic heart disease, hypertension, hyperlipidemia, and diabetes mellitus

The risk of RA was significantly elevated among patients with vitiligo as compared to controls (HR, 1.43; 95% CI, 1.03–1.98; P = 0.031). In sex- and age-stratified analyses, the risk of RA was prominently increased in males (HR, 1.90; 95% CI, 1.07–3.39; P = 0.029) and younger individuals (age < 32.4; HR, 2.25; 95% CI, 1.06–4.74; P = 0.034). The heightened risk of RA among patients with vitiligo retained its statistical significance after adjustment for demographics and comorbidities (fully-adjusted HR, 1.44; 95% CI, 1.02–2.02; P = 0.036; Table 2).

The likelihood of vitiligo in patients with a preexisting diagnosis of RA

To investigate the likelihood of vitiligo subsequent to a history of RA, a case-control study design was conducted (Table 3). The development of subsequent vitiligo was significantly associated with a history of RA (OR, 1.66; 95% CI, 1.38–2.00; P < 0.001). In an age-stratified analysis, RA was found to predict vitiligo in all age categories as well as in females (OR, 1.76; 95% CI, 1.43–2.18; P < 0.001; Table 3).

Table 3 The odds of vitiligo in patients with a preexisting diagnosis of rheumatoid arthritis (case-control study design)

N (%) of preexisting rheumatoid arthritis in patients with vitiligo	148 (0.7%)	
N (%) of preexisting rheumatoid arthritis in controls	440 (0.4%)	
Unadjusted OR (95%CI) [p-value]	1.66 (1.38-2.00) [< 0.001]	
Sex- and age-stratified unadjusted analysis	
Male-specific OR (95%CI) [p-value]	1.37 (0.93–2.03) [0.115]	
Female-specific OR (95%CI) [p-value]	1.76 (1.43–2.18) [< 0.001]	
≥ 32.4-year-old-specific OR (95%CI) [p-value]	1.62 (1.33–1.98) [< 0.001]	
< 32.4-year-old-specific OR (95%CI) [p-value]	2.05 (1.12–3.75) [0.017]	
Multivariate adjusted analysis	
Age- and sex-adjusted OR (95%CI) [p-value]	1.66 (1.38–2.01) [< 0.001]	
Fully adjusted OR (95%CI) [p-value] a	1.67 (1.38–2.03) [< 0.001]	
Bold: significant value

Abbreviations N, number; OR, odds ratio; n, Number; CI, confidence interval; NA, not applicable

a adjusted for age, sex, ethnicity, BMI, smoking, ischemic heart disease, hypertension, hyperlipidemia, and diabetes mellitus

In a multivariate analysis adjusting for putative confounders, a history of RA independently predicted a subsequent diagnosis of vitiligo (fully-adjusted OR, 1.67; 95% CI, 1.38–2.03; P < 0.001).

Clinical characteristics of patients with vitiligo and comorbid RA

Table 4 describes the clinical features of patients with vitiligo and comorbid RA (n = 195) as compared to patients with vitiligo without RA (n = 20,656). The former group was typified by older mean (SD) age (56.4 [18.9] vs. 34.5 [22.3] years), female (OR, 3.01; 95% CI, 2.17–4.17, P < 0.001), and Jewish ethnicity (OR, 1.45; 95% CI, 1.02–2.07, P = 0.037) preponderance.

Table 4 Determinants of rheumatoid arthritis among patients with vitiligo

	Vitiligo with rheumatoid arthritis (n = 195)	Vitiligo without rheumatoid arthritis (n = 20,656)	OR (95% CI)	p-value	
Age at the onset of vitiligo, years; mean (SD)a	56.4 (18.9)	34.5 (22.3)	1.57 (1.46–1.68) a	< 0.001	
Female sex, n (%)	147 (75.4%)	10,423 (50.5%)	3.01 (2.17–4.17)	< 0.001	
Jewish ethnicity, n (%)	156 (80.0%)	15,155 (73.4%)	1.45 (1.02–2.07)	0.037	
Obesity, n (%)	65 (33.3%)	4,090 (19.8%)	2.03 (1.50–2.73)	< 0.001	
Smoking, n (%)	65 (33.3%)	5,142 (24.9%)	1.51 (1.12–2.04)	0.007	
Ischemic heart disease, n (%)	32 (16.4%)	1,166 (5.6%)	3.28 (2.24–4.82)	< 0.001	
Hyperlipidemia, n (%)	162 (64.6%)	6,162 (29.8%)	4.30 (3.20–5.77)	< 0.001	
Hypertension	90 (64.2%)	3,268 (15.8%)	4.56 (3.43–6.06)	< 0.001	
Diabetes mellitus, n (%)	59 (30.3%)	2,272 (11.0%)	3.51 (2.58–4.78)	< 0.001	
Bold: significant values

Abbreviations n, number; SD, standard deviation

a OR per 10-year increase in age

Patients with vitiligo and comorbid RA had higher frequency of comorbidities; smoking (OR, 1.51; 95% CI, 1.12–2.04; p-value 0.007), obesity (OR, 2.03; 95% CI, 1.50–2.73; P < 0.001), ischemic heart disease (OR, 3.28; 95% CI, 2.24–4.82; P < 0.001), hyperlipidemia (OR, 4.30; 95% CI, 3.20–5.77; P < 0.001), hypertension (OR, 4.56; 95% CI, 3.43–6.06, P < 0.001), and diabetes mellitus (OR, 3.51; 95% CI, 2.58–4.78, P < 0.001).

We then carried out a survival analysis to evaluate the risk of all-cause mortality of vitiligo patients with comorbid RA relative to the remaining patients with vitiligo. Comorbid RA was associated with increased all-cause mortality in univariate (HR, 4.48; 95%CI, 2.89–6.94; P < 0.001; Fig. 1) and multivariate (fully-adjusted HR, 1.61; 95% CI, 1.03–2.51; P = 0.037) analyses.

Fig. 1 Kaplan-Meier curves demonstrating all-cause mortality of vitiligo patients with rheumatoid arthritis as compared to vitiligo patients without rheumatoid arthritis

Discussion

The current population-based study sheds light on the existence of a bidirectional association between vitiligo and RA. Patients with vitiligo are at a 1.4-fold elevated risk of developing RA, and a preexisting diagnosis of RA predisposes individuals to have vitiligo by 1.7-fold. Patients with vitiligo and comorbid RA are characterized by a high burden of comorbidities and increased all-cause mortality.

Several epidemiological studies explored the relationship between vitiligo and RA (Supplementary Table 1). In their retrospective chart review following 2,441 patients with vitiligo, Sheth et al. found that 2.9% of vitiligo patients had RA, mostly in the African American/Black population [4]. Zhang et al. reported that RA was detected in 2.2% of their 5,601 patients with vitiligo, thus representing a 6.5-times increased frequency relative to the general population [13]. A 10-year retrospective cross-sectional study in the United States found that patients with vitiligo had a statistically significant increased prevalence of RA, affecting 1.6% of the study population [14]. While these studies threw an important spotlight on the association of vitiligo with RA, they were hampered by their cross-sectional design which interferes with the ability to draw conclusions regarding temporality and causality. Furthermore, most of these studies were characterized by small study populations. The coexistence of vitiligo and RA was additionally reported in individual patients by scattered case reports throughout the years [15–18].

The mechanism underlying the co-existence of vitiligo and RA has not been definitively established. However, vitiligo and RA share inflammatory pathways. Lee et al. [19] revealed an association between TNF-α polymorphisms and susceptibility to both RA and vitiligo. Specifically, their findings indicated that TNF-α polymorphism significantly elevates the risk of vitiligo among Middle Eastern populations.

JAK signaling pathway further supports the association between vitiligo and RA. Inflammatory cytokines play a crucial role in autoimmune responses, operating through the JAK-STAT pathway. The demonstrated effectiveness of JAK inhibitor therapy in treating RA implies their potential for addressing a broader range of immune-mediated conditions [20]. Vitiligo’s pathogenesis is characterized by IFN-γ, a key component of the immune response that leads to the destruction of melanocytes. JAK inhibitors can effectively target IFN-γ. Evidence from case series and studies suggests that JAK inhibitors offer promising vitiligo treatment [21]. Recently the FDA has approved Opzelura (ruxolitinib) a topical JAK inhibitor for treatment of nonsegmental vitiligo, and ongoing clinical trials further continuing [22].

Recent advancements in RA therapy include the use of TNF inhibitors, JAK inhibitors, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) inhibitors. Recently, JAK inhibitors have emerged as a treatment for vitiligo. Utilizing these new drugs, originally developed for one disease, for the other disease, may simplify drug development and expand the therapeutic options for both diseases.

The current study provides valuable insights into the association between vitiligo and RA, utilizing a population-based study. Using the population-based CHS database, we ensure the accuracy of our estimates and minimize the risk of selection bias. The large CHS dataset used in our study includes 19,985 patients with vitiligo, which is one of the largest cohorts of vitiligo patients reported so far. This research bridges an existing gap in the field, as the absence of an extensive cohort study designed to practically investigate the association of vitiligo and rheumatoid arthritis. Our matching algorithm between case and control patients enables identical characteristics, further decreasing the risk of bias. The limitations of our study include the clinical, rather than histological, diagnosis of vitiligo. In some cases, the presentation of vitiligo may be atypical or less apparent, leading to potential inaccuracies in vitiligo diagnosis.

In conclusion, the current study confirms a significant bidirectional association between vitiligo and RA. Patients with vitiligo and comorbid RA experience a high burden of cardiometabolic comorbidities and are at a significantly elevated hazard of death. Our findings might raise awareness about the shared immunological mechanisms and potential therapeutic avenues involving JAK inhibitors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Author contributions

KK and NTC. wrote the main manuscript text and YS prepared Tables 1, 2, 3 and 4. All authors reviewed the manuscript.

Funding

Open access funding provided by Bar-Ilan University.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

None of the authors have any conflicts of interest to declare.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Joge RR, Kathane PU, Joshi SH (2022) Vitiligo: a narrative review article. Cureus Published Online September 19. 10.7759/cureus.29307
2. Chang WL, Lee WR, Kuo YC, Huang YH (2021) Vitiligo: an autoimmune skin Disease and its Immunomodulatory therapeutic intervention. Front Cell Dev Biol 9. 10.3389/fcell.2021.797026
3. Elbuluk N Ezzedine K Quality of Life, Burden of Disease, co-morbidities, and systemic effects in Vitiligo patients Dermatol Clin 2017 35 2 117 128 10.1016/j.det.2016.11.002 28317521
Elbuluk N, Ezzedine K (2017) Quality of Life, Burden of Disease, co-morbidities, and systemic effects in Vitiligo patients. Dermatol Clin 35(2):117–128. 10.1016/j.det.2016.11.00228317521 10.1016/j.det.2016.11.002
4. Sheth VM Guo Y Qureshi AA Comorbidities associated with vitiligo: a ten-year retrospective study Dermatology 2014 227 4 311 315 10.1159/000354607
Sheth VM, Guo Y, Qureshi AA (2014) Comorbidities associated with vitiligo: a ten-year retrospective study. Dermatology 227(4):311–315. 10.1159/00035460710.1159/000354607
5. Shen C, Gao J, Sheng Y et al (2016) Genetic susceptibility to vitiligo: GWAS approaches for identifying vitiligo susceptibility genes and loci. Front Genet 7(FEB). 10.3389/fgene.2016.00003
6. Finckh A Gilbert B Hodkinson B Global epidemiology of rheumatoid arthritis Nat Rev Rheumatol 2022 18 10 591 602 10.1038/s41584-022-00827-y 36068354
Finckh A, Gilbert B, Hodkinson B et al (2022) Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol 18(10):591–602. 10.1038/s41584-022-00827-y36068354 10.1038/s41584-022-00827-y
7. Smolen JS, Aletaha D, Barton A et al (2018) Rheumatoid arthritis. Nat Rev Dis Primers 4. 10.1038/nrdp.2018.1
8. Feng Y, Lu Y (2022) Advances in vitiligo: update on therapeutic targets. Front Immunol 13. 10.3389/fimmu.2022.986918
9. Noack M Miossec P Selected cytokine pathways in rheumatoid arthritis Semin Immunopathol 2017 39 4 365 383 10.1007/s00281-017-0619-z 28213794
Noack M, Miossec P (2017) Selected cytokine pathways in rheumatoid arthritis. Semin Immunopathol 39(4):365–383. 10.1007/s00281-017-0619-z28213794 10.1007/s00281-017-0619-z
10. Han L, Chen Z, Yu K et al (2022) Interleukin 27 signaling in rheumatoid arthritis patients: good or evil? Front Immunol 12. 10.3389/fimmu.2021.787252
11. Lai X, Wang H, Cao J et al (2016) Circulating IL-27 is elevated in rheumatoid arthritis patients. Molecules 21(11). 10.3390/molecules21111565
12. Hosseini SM Gholijani N Chenari N Kalantar K Decreased levels of interleukin 27 in the serum of vitiligo patients Bras Dermatol 2020 95 5 570 574 10.1016/j.abd.2020.02.005
Hosseini SM, Gholijani N, Chenari N, Kalantar K (2020) Decreased levels of interleukin 27 in the serum of vitiligo patients. Bras Dermatol 95(5):570–574. 10.1016/j.abd.2020.02.00510.1016/j.abd.2020.02.005
13. Zhang Z Xu SX Zhang FY The analysis of genetics and associated autoimmune diseases in Chinese vitiligo patients Arch Dermatol Res 2009 301 2 167 173 10.1007/s00403-008-0900-z 18839195
Zhang Z, Xu SX, Zhang FY et al (2009) The analysis of genetics and associated autoimmune diseases in Chinese vitiligo patients. Arch Dermatol Res 301(2):167–173. 10.1007/s00403-008-0900-z18839195 10.1007/s00403-008-0900-z
14. Hadi A Wang JF Uppal P Penn LA Elbuluk N Comorbid diseases of vitiligo: a 10-year cross-sectional retrospective study of an urban US population J Am Acad Dermatol 2020 82 3 628 633 10.1016/j.jaad.2019.07.036 31325552
Hadi A, Wang JF, Uppal P, Penn LA, Elbuluk N (2020) Comorbid diseases of vitiligo: a 10-year cross-sectional retrospective study of an urban US population. J Am Acad Dermatol 82(3):628–633. 10.1016/j.jaad.2019.07.03631325552 10.1016/j.jaad.2019.07.036
15. Alkan Melikoğlu M, Melikoğlu M, Karatay S, Uğur M, Şenel K A coincidence of rheumatoid arthritis, autoimmune thyroid Disease and Vitiligo in a single patient: a possible pathogenetic linkage Bir Olguda Romatoid Artrit, Otoimmün Tiroid Hastalığı ve Vitiligo Birlikteliği: Olası Bir Patogenetik Bağlantı?
16. de Carvalho JF Rheumatoid arthritis Associated with Vitiligo J Clin Rheumatol 2016 22 1 39 10.1097/RHU.0000000000000343 26693625
de Carvalho JF (2016) Rheumatoid arthritis Associated with Vitiligo. J Clin Rheumatol 22(1):39. 10.1097/RHU.000000000000034326693625 10.1097/RHU.0000000000000343
17. Abraham Z Rozenbaum M Glück Z Feuerman EJ Lahat N Kinarty A Vitiligo, rheumatoid arthritis and pernicious anemia J Dermatol 1993 20 7 418 423 10.1111/j.1346-8138.1993.tb01310.x 8408923
Abraham Z, Rozenbaum M, Glück Z, Feuerman EJ, Lahat N, Kinarty A (1993) Vitiligo, rheumatoid arthritis and pernicious anemia. J Dermatol 20(7):418–423. 10.1111/j.1346-8138.1993.tb01310.x8408923 10.1111/j.1346-8138.1993.tb01310.x
18. Sundaram M Adikrishnan S Murugan S Co-existence of rheumatoid arthritis, Vitiligo, and Bullous Pemphigoid as multiple autoimmune syndrome Indian J Dermatol 2014 59 3 306 307 10.4103/0019-5154.131427 24891673
Sundaram M, Adikrishnan S, Murugan S (2014) Co-existence of rheumatoid arthritis, Vitiligo, and Bullous Pemphigoid as multiple autoimmune syndrome. Indian J Dermatol 59(3):306–307. 10.4103/0019-5154.13142724891673 10.4103/0019-5154.131427
19. Lee YH Bae SC Associations between TNF-α polymorphisms and susceptibility to rheumatoid arthritis and vitiligo: a meta-analysis Genet Mol Res 2015 14 2 5548 5559 10.4238/2015.May.25.6 26125752
Lee YH, Bae SC (2015) Associations between TNF-α polymorphisms and susceptibility to rheumatoid arthritis and vitiligo: a meta-analysis. Genet Mol Res 14(2):5548–5559. 10.4238/2015.May.25.626125752 10.4238/2015.May.25.6
20. Shalabi MMK Garcia B Coleman K Siller A Miller AC Tyring SK Janus Kinase and tyrosine kinase inhibitors in Dermatology: a review of their utilization, Safety Profile and Future Applications Skin Therapy Lett 2022 27 1 4 9 35081305
Shalabi MMK, Garcia B, Coleman K, Siller A, Miller AC, Tyring SK (2022) Janus Kinase and tyrosine kinase inhibitors in Dermatology: a review of their utilization, Safety Profile and Future Applications. Skin Therapy Lett 27(1):4–935081305
21. Solimani F, Meier K, Ghoreschi K (2019) Emerging topical and systemic JAK inhibitors in Dermatology. Front Immunol 10. 10.3389/fimmu.2019.02847
22. Sheikh A, Rafique W, Owais R, Malik F, Ali E (2022) FDA approves Ruxolitinib (Opzelura) for Vitiligo Therapy: a breakthrough in the field of dermatology. Annals Med Surg 81. 10.1016/j.amsu.2022.104499
