A Retrospective Statistical Analysis of Vitiligo Exacerbation after COVID-19 Vaccination in China

. At present, COVID-19 vaccination is an efective method to stop the spread of the epidemic and reduce disease severity and mortality. It has been reported that COVID-19 vaccine can activate several autoimmune diseases. However, whether it can afect development of vitiligo remains elusive. In this study, we aimed to evaluate the possible risk factors of vitiligo disease activity or recurrence after COVID-19 vaccination. We recruited 383 vitiligo patients, of whom 126 were not vaccinated and 257 had received the COVID-19 vaccine. Vitiligo disease activity (VIDA) score was used to analyze key risk factors of vitiligo in patients who underwent COVID-19 vaccination. Multivariate logistic regression models were used to explore the risk factors associated with VIDA. Compared with patients without history of undergoing vaccination, the VIDA score of vaccinated patients increased signifcantly (3(2, 4) vs. 3(2, 3) scores, P < 0 . 01). Logistic regression analysis identifed COVID-19 vaccination (odds ratio (OR): 3.040, 95% confdence interval (CI): 1.649–5.603) as an independent risk factor for VIDA. Te data showed that COVID-19 vaccination aggravated the development of vitiligo, which is a key risk factor for recurrence.


Introduction
COVID-19 vaccination is an efective method to stop the spread of the epidemic and reduce disease severity and mortality [1].It has been reported that COVID-19 vaccine can activate several autoimmune diseases, such as psoriasis, autoimmune thyroid diseases (AITDs), systemic lupus erythematosus (SLE), immune-mediated thrombotic thrombocytopenic purpura (iTTP), IgA vasculitis (IgAV), and autoimmune hepatitis [2][3][4][5][6][7].However, whether the vaccination can trigger the autoimmune reactivity of stable vitiligo remains unclear.Previous case reports showed that vitiligo as an immune disease may also be afected by COVID-19 vaccine.However, there are no clinical studies with large sample sizes to investigate this phenomenon and cytokine profles involved in the T1 type immune response.In this study, we aimed to evaluate the possible risk factors of vitiligo disease activity or recurrence after COVID-19 vaccination.

Methods
Tis was a single-center, retrospective, and longitudinal study, conducted from November 2020 to October 17, 2021.Te vitiligo disease activity (VIDA) score was used to analyze key risk factors of vitiligo patients after COVID-19 vaccination [8] (Figure 1).Te VIDA scores of vitiligo patients were obtained from the vitiligo epidemiological questionnaire of the Air Force Medical Center Dermatology, and vitiligo patients were followed up for at least 6 months after vaccination.Binary logistic regression models were used to explore the risk factors associated with VIDA.
Statistical analysis was performed using SPSS 26.0 software.In order to reduce the diferences among participants, propensity score matching (PSM) was used to match subjects with similar clinical characteristics.Te data were presented as numbers (%) for categorical variables and median (P25, P75) for continuous variables.
Te Mann-Whitney U test was used for nonnormally distributed continuous and ordered variables.Categorical variables were tested by the chi-square test and Fisher's exact probability method.Whether new lesions appeared within one month was used as a dependent variable (Y VIDA � 4 � 1, Y VIDA ≠ 4 � 0), and x 2 test was utilized for univariate analysis.Multivariable logistic regression was employed to evaluate the possible risk factors of vitiligo disease activity or recurrence after COVID-19 vaccination.Signifcant variables (P < 0.2) associated with vitiligo disease activity in univariate analysis or clinical relevance were selected for the multivariable logistic regression model.Odds ratios (ORs) with associated 95% confdence intervals (CIs) were estimated for efects of variables on each outcome.A P value ≤0.05 was considered as statistically signifcant.

Results
Tis study included 383 vitiligo patients, which 126 were not vaccinated and 257 had received the COVID-19 vaccine.After PSM, the unvaccinated group had 100 and the vaccinated group had 200 patients (Supplementary Table S1).Compared to the 100 patients without vaccination, the VIDA score of vaccinated patients increased signifcantly (3(2, 4) vs. 3(2, 3) scores, P < 0.01; Table 1).Te binary logistic regression model exhibited a promising calibration capability (Hosmer-Lemeshow test, P = 0.960).Logistic regression analysis identifed COVID-19 vaccination (OR: 3.040, 95% CI: 1.649-5.603)as an independent risk factor for VIDA (Table 2).Te data showed that vitiligo patients who had received the COVID-19 vaccine were 3.0 times more likely to aggravate the development of vitiligo than vitiligo patients who had not received the COVID-19 vaccine.Terefore, COVID-19 vaccination aggravated the development of vitiligo, which is a key risk factor for recurrence.

Discussion
Vitiligo is a chronic autoimmune disorder characterized by the destruction of melanocytes in the epidermis and hair follicles, with a prevalence of 0.5-2% in diferent races and geographical areas worldwide, and it is susceptible to recurrence [9,10].Vitiligo is the result of disturbances in systemic immune homeostasis [11,12].Innate and adaptive immune responses are involved in the pathogenesis of vitiligo, with T cell subsets playing a central role, cytotoxic CD8+ T cells mediating melanocyte clearance, regulatory T cells (Treg) maintaining immune homeostasis and suppressing infammation, and skin-resident memory T cells (TRM) inducing vitiligo recurrence.Keratinocytes exacerbate the disease by secreting chemokines to recruit more cytotoxic CD8+ T cells [13,14].
Vaccines protect the host by generating strong and longlasting memory T and B cells through a complex interaction between innate, humoral, and cellular immunity [15,16].Moreover, cytokines play a protective role in humans by stimulating innate immune responses, shaping adaptive immunity, and inducing immune memory [17].However, these immune cells and cytokines also have an equally crucial role in the pathogenesis of vitiligo.
Some studies noted a signifcant increase in IFN-c, CXCL10, IL-15, TNF-α, and IL-17 after COVID-19 vaccination [17][18][19].Bergamaschi et al. showed that the levels of IFN-c and CXCL10 were signifcantly higher in humans after the frst dose of vaccine, and the levels of IFN-c, IL-15, and CXCL10 were signifcantly higher after the second dose of vaccine than the frst dose, indicating that the second dose of vaccine induced a stronger immune response [17].Tis phenomenon was confrmed in the case report of a vitiligo patient who developed white patches after the frst dose of vaccine, and the vitiligo worsened after the second dose of vaccine [20].Tis study noted the synergistic efects of IL-15 and IFN-c, IL-15 and CXCL10, and IFN-c and CXCL10 2 Dermatologic Terapy during the immune response and the existence of synergistic efects of these cytokines in the pathogenesis of vitiligo [17].IFN-c plays a central role in infammation and autoimmunity, inducing the local accumulation of specifc CD8+ T cells targeting melanocytes in the skin, and induces production of CXCL9 and CXCL10 by keratinocytes to recruit more T cells, which induce apoptosis of melanocytes through a synergistic efect [9,21].TNF-α reduces melanin content through dendrite shedding, downregulation of MITF-M and TYR, and upregulation of TNFR, IL6, and ICAM 1 expression [22,23].Dermatologic Terapy IFN-c and TNF-α act together to induce keratinocytes to produce the protease MMP-9 to induce the cleavage of melanocyte E-calcineurin, leading to melanocyte shedding [24].IL-15 and IL-17 stimulate CD8+ TRM cells, causing upregulation of the expression of signaling pathway molecules such as JAK-STAT in CD8+ TRM cells, increasing interferonc, perforin, and granzyme B production, which leads to melanocyte destruction [23,25].Tese cytokines appear to increase after vaccination and correlate with each other, which illustrates that vaccination may trigger immune mechanisms that contribute to the development of vitiligo.Te limitations of this study included it being a singlecenter, small-sample, and retrospective study, and the relationship between vaccine type and vitiligo disease activity was not analyzed.Further clinical studies with large number of participants and multicenter prospect, assessing the impact of diferent vaccines on vitiligo, are needed.
Tis study showed an association between COVID-19 vaccine and vitiligo, and physicians should be aware of this adverse efect, especially while treating genetically susceptible patients.
* indicates statistically signifcant diferences between groups for this variable.

Table 2 :
Analysis of factors infuencing vitiligo activity (t-test, chi-square test, and binary logistic regression).Skin lesion symptom refers to itching and burning at the beginning of the white spot; b mental factors refer to depression, stress, prolonged late night, shock, overwork, and overexertion leading to onset; c history of trauma refers to frostbite, burns, trauma, and repeated rubbing leading to onset; d sun exposure refers to outdoor stay for 2 h at noon; e associated autoimmune disease includes hyperthyroidism, hypothyroidism diabetes mellitus, dermatomyositis, scleroderma, discoid erythema, systemic lupus erythematosus, pemphigus, psoriasis, atopic dermatitis/eczema, and rheumatoid arthritis.* indicates statistically signifcant diferences between groups for this variable. a