Various aspects of the relationship between vitiligo and the COVID‐19 pandemic or SARS‐CoV‐2 vaccines: Clinical pearls for dermatologists

Coronavirus disease 2019 (COVID‐19) has given rise to several new onset or exacerbated dermatologic disorders including vitiligo.


| INTRODUC TI ON
Vitiligo is a pigmentary disorder that is manifested as the development of pale depigmented patches over any areas of the skin or mucous membrane. It affects 0.5%-2% of the world population. Vitiligo is classified as localized (segmental) or generalized (non-segmental) types. 1 This condition occurs as a result of progressive destruction of skin melanocytes. There are different opinions about the etiopathogenesis of vitiligo; however, no exact explanation has been found. Nevertheless, T-cell autoimmunity and prolonged cytokine release are believed to play an important role. 2 Vitiligo is more common in the black people, those with genetic predisposition and those with psychological distress. Other risk factors include sunburn, cutaneous trauma, use of some chemicals such as phenolic compounds, pregnancy, and autoimmunity. 3 On the other hand, the coronavirus disease 2019 (COVID-19) has given rise to several new-onset or exacerbated dermatologic disorders. 4 Moreover, medications used in the settings of SARS-CoV-2 infection, as well as various types of COVID vaccine, have also been followed by cutaneous adverse events. 5,6 The incidence and prevalence of vitiligo have increased considerably since the beginning of the COVID-19 pandemic. The reason could be the viral infection itself, medications used for the treatment, and vaccines introduced to prevent the disease as well as psychologic distress of pandemics. [7][8][9] There are many aspects and conflicts on this issue that we want to discuss in this article.

| The impact of the COVID pandemic on patients with vitiligo
In general, medical treatment of vitiligo is aimed to stop disease progression and achieve repigmentation. Phototherapy, topical agents, and immunosuppressive agents, such as glucocorticoids, methotrexate, mycophenolate mofetil (MMF), azathioprine, and apremilast, are the basis of therapy. 10 However, the decision to continue or cease any of the aforementioned options should be made cautiously so as preventing vitiligo from getting out of control while minimizing the risk of SARS-CoV-2 infection. 11,12 For example, topical treatment, due to lack of systemic immunosuppressive effects, had been recommended to be continued. In addition, replacing high-dose steroids by regimens with lower doses, such as oral mini-pulse therapy, had been a good option to minimize the risk of infection. 13 Methotrexate and azathioprine, which were second-line therapeutic options for cases of rapidly progressive vitiligo without response to high-dose steroids, were administered with caution during the peaks of SARS-CoV-2 infection, as they increase the risk and severity of COVID-19 disease. 14 Moreover, home phototherapy was proposed in order to avoid frequent clinic visits during the quarantine. 15

| The impact of vitiligo on the morbidity and mortality of SARS-CoV-2 infection
The impact of some comorbidities on the severity of SARS-CoV-2 infection has been a well-established issue. However, some autoimmune underlying diseases are supposed to protect against COVID-19 or modulate the course. This condition is an issue of conflict for vitiligo. Some authorities hypothesize that non-segmental vitiligo (NSV) may protect against severe SARS-CoV-2 infection through having genes involved in immune activation and regulation, similar to previously reported protective effects of NSV against melanoma and non-melanoma skin cancer. 16 Moreover, the increased serum levels of pro-inflammatory cytokines such as TNFα and IL-17 in autoimmune skin disorders such as vitiligo is a well-established fact, which can affect the clinical course and severity of SARS-CoV-2 infection. 17,18

| SARS-CoV-2 infection-associated vitiligo
Vitiligo is seldom associated with infectious pathogens unless in the settings of autoimmune reactions. Previously, vitiligo had been reported in individuals with human immunodeficiency virus (HIV),

hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus
(EBV), cytomegalovirus (CMV), smallpox, and helicobacter pylori infection. [19][20][21][22][23][24] The effect of SARS-CoV2 infection on the development of vitiligo could either be through direct invasion of melanocytes or activating the immune system and shifting it toward adaptive type 1 immunity. In fact, immune activation during COVID-19 disease might increase vitiligo disease activity through a shift toward adaptive type 1 immunity (CD8 T cells and IFNγ). 16 Not only vitiligo results in a devastating psychological distress but also it can occur as a result of stressful conditions including lockdown and the quarantine due to COVID-19 pandemic. [25][26][27][28] In fact, stress can elevate serum levels of cortisol, catecholamines, and neuropeptides, and increased oxidative stress stimulates high-mobility group box 1 (HMGB1) release, a skin component that is essential for melanogenesis. On the other hand, oxidative stress leads to a decrease in glutathione peroxidase level, which is related to the inflammatory response of vitiligo. 25,29 It has been shown that severe infection with SARS-CoV-2 can cause transient immunosuppression and dysregulation of CD8 + lymphocytes, leading to disruption of previously established tolerance to self-antigens. 30 On the other hand, dysregulation of CD8 + T cells has also been described in the pathogenesis of vitiligo. 24 Hence, this post-viral inappropriate immune reconstitution could be considered as a logical mechanism for developing vitiligo following some viral infections, especially in HIV-positive patients. 24,31 The COVID pandemic has also been related to vitiligo in another interesting way; facial frictional dermatitis under skin areas covered by face masks has led to vitiligo, called as "mask vitiligo." 32

| COVID vaccine-related vitiligo
In general, since vitiligo is a very common pigmentary disorder throughout the world, and because vaccination program is held universally with expectable adverse events, the onset of vitiligo after SARS-CoV-2 vaccination can be a mere incidence. Nonetheless, the temporal relationship between vaccination and development of vitiligo and the reports of various autoimmune phenomena following vaccination could raise the suspicion of the causal association between SARS-CoV-2 vaccination and vitiligo. 33 Besides the wide range of dermatologic manifestations and complications following SARS-CoV-2 infection, COVID-19 vaccines have also given rise to a variety of cutaneous reactions and disorders. 34,35 Many post-COVID vaccine cutaneous reactions are mild and temporary and do not cause great morbidity or mortality; nevertheless, some adverse events such as vitiligo pose significant concerns due to their disfigurement and the subsequent stigma and psychological burden.
The incidence of COVID vaccine-related cases of vitiligo has been quite higher than the one following SARS-CoV-2 infection. Several cases of hypo pigmentations have been reported after receiving COVID vaccines, resulting from cutaneous reactions such as toxic epidermal necrolysis (TEN), subacute cutaneous lupus erythematosus (SCLE), and pityriasis lichenoides. [36][37][38] However, vitiligo that is presented as skin depigmentation has also

| JAK inhibitors: a shared therapeutic option in both vitiligo and COVID-19
Janus kinases (JAKs) are a family of cytoplasmic tyrosine kinases, acting through the JAK/STAT pathway. 51 Medications inhibiting this pathway have been recently shown to have a promising effect in treating numerous Immune-based disorders including vitiligo. 52 Tofacitinib and baricitinib are the most commonly used JAK inhibitors in treating vitiligo in various ways such as topical application, systemic administration, or in combination with phototherapy. 52 On the other hand, several JAK inhibitors including baricitinib and tofacitinib have been suggested as alternative treatment in COVID-19 53 and baricitinib is even recommended as a first-line treatment in severe cases of COVID-19 by the WHO due to its proven effect in reducing mortality 54 which might be resulted from its direct antiviral effect separated from its anti-inflammatory effects. 55 Considering the therapeutic effect of JAK inhibitors in both vitiligo and COVID-19, continuing these agents for treating vitiligo in COVID era seems a wise choice. Moreover, JAK inhibitors seem to have the least adverse effect regarding COVID vaccination, compared to other immunosuppressing agents 56 which make them a favorable choice for treating intractable patients in COVID era.

| CON CLUS ION
The COVID-19 pandemic has had a great impact on every field of medicine, including dermatology. The SARS-CoV-2 infection and the associated vaccines have brought about several dermatologic adverse events, some of which are serious or disfiguring like vitiligo. On the other hand, despite these complications, the benefits of getting vaccinated against SARS-CoV-2 frequently outweigh the risks since the incidence of these side effects is quite low in the whole population. Moreover, in individuals with previously recognized vitiligo, who are at risk of developing SARS-CoV-2 infection or those who are currently infected, special dermatologic consultation is needed in order to balance the immunosuppressive agents in their therapeutic regimen to prevent COVID-related morbidity and mortality.
Although it seems that the pandemic is ending, COVID vaccination will continue in future. Hence, a rigid surveillance for development of new autoimmune disorders including vitiligo in genetically predisposed patients and early treatment of them (but not too early which interfere with immunologic body response to vaccination) should be strongly considered by clinicians all over the world. analyzed the data. Z.M and A.G wrote the paper. All authors contributed to the preparation of data and finalization of this article.

Development Center and Autoimmune Bullous Diseases Research
Center for their technical and editorial assistance.

FU N D I N G I N FO R M ATI O N
We received no funding for this project.

CO N FLI C T O F I NTE R E S T
All the authors declare that there is no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E TH I C A L A PPROVA L
The protocol of this study was approved by relevant ethics committee.