New Onset and Exacerbation of Psoriasis Following COVID-19 Vaccination: A Review of the Current Knowledge

COVID-19 vaccination was the main measure to overcome the pandemic. As with other drugs and vaccines, mild to moderate adverse events have been reported following vaccination. In addition, several cutaneous reactions have been described. In particular, there are several reports investigating de novo psoriasis or the exacerbation of psoriasis following COVID-19 vaccination. However, data on the possible pathogenetic mechanisms as well as comprehensive manuscripts on the topic are scant. Thus, the aim of our manuscript was to perform a review of the current literature on post-COVID-19 vaccination exacerbations and new-onset psoriasis in order to offer a wide perspective on this area and to point out possible pathogenetic mechanisms. Research on the current literature was performed following PRISMA guidelines. In total, 49 studies involving 134 patients developing new-onset psoriasis (n = 27, 20.1%) or psoriasis exacerbation (n = 107, 79.9%) were collected. Although cases of de novo psoriasis or a worsening of psoriasis have been reported following vaccination, all of the cases have been successfully treated while overall benefit–risk profile of COVID-19 vaccination does not justify vaccine hesitancy due to the risk of psoriasis being developed or worsening. Certainly, further studies are needed to identify possible pathogenetic mechanisms in order to identify “at-risk” patients. Finally, vaccination should not be discouraged.


Introduction
Psoriasis is a chronic, inflammatory skin disorder that affects millions of individuals worldwide (with up to a 3% prevalence) [1,2].Clinically, it is characterized by the presence of thick, red, scaly patches on the skin's surface [2,3].Moreover, several comorbidities can be associated with the psoriatic disorder (hypertension, dyslipidemia, obesity, psoriatic arthritis, anxiety/depression, inflammatory bowel disease, diabetes mellitus, etc.), making this disease a burden for patients' mental and emotional well-being, leading to social isolation and a reduction in quality of life [4][5][6].Therefore, psoriasis treatment is not limited to skin lesions but also to its comorbidities and the psychosocial aspects of the disease [7][8][9].Currently, several treatment options for psoriasis are available.These include topical treatments (creams and ointments) which may be used for the mild form of the disease, phototherapy (exposure to ultraviolet light), conventional systemic medications (cyclosporin, methotrexate, acitretin, and fumarates), small molecules, and biologic therapies which are used for moderate-to-severe forms [10][11][12][13].In particular, the introduction of biologic drugs specifically targeting interleukins (IL) 23 and 17 and tumor necrosis factor-alpha (TNFα), involved in psoriasis pathogenesis, revolutionized the management of the disease, showing promising results in terms of effectiveness and safety [14][15][16].
Globally, treatment plans are tailored to everyone's specific needs, taking into account the severity of the disease, its impact on a patient's quality of life, and the comorbidities [17,18].
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has had a profound impact on global health, economies, and societies worldwide [19,20].Due to the high transmissibility of the virus, preventive measures such as wearing masks, practicing physical distancing, and frequent hand hygiene played a crucial role in mitigating transmission [21,22].As regards dermatological clinical practice, teledermatology emerged as a valuable tool in providing remote dermatological care during the pandemic.Indeed, it has played a vital role in maintaining access to dermatological care, reducing viral transmission, improving access to care, and ensuring the continuity of treatment [23,24].Globally, the introduction of COVID-19 vaccination was the main measure to overcome the pandemic.Indeed, COVID-19 vaccination played a vital role in controlling the spread of the virus and reducing the severity of the disease [25][26][27].Multiple vaccines have been developed and authorized for emergency use around the world, working by stimulating the immune system to recognize and respond to the SARS-CoV-2 virus, preventing infection or reducing the severity of illness if infection occurs [25][26][27].In particular, four vaccines have been approved by the European Medicines Agency (EMA), based on two different mechanisms of action: mRNA-based vaccines (Pfizer/BioNTech;BNT162b2 and Moderna; mRNA-1273) and viral vector-based vaccines (AstraZeneca; AZD1222 and Johnson & Johnson; Ad26.COV2.S) [25][26][27].
As with other drugs and vaccines, mild to moderate adverse events (AEs) have been reported following vaccination, including fatigue, diarrhea, headache, fever, muscle aches, pain or redness at the injection site, chills, etc. [28,29].Fortunately, most of these reactions have been mild and self-limited.In addition, several cutaneous reactions have been described following COVID-19 vaccination [28,29].In particular, there are several reports investigating de novo psoriasis or an exacerbation of psoriasis following COVID-19 vaccination [30,31].However, data on the possible pathogenetic mechanisms as well as comprehensive manuscripts on the topic are scant.Thus, the aim of our manuscript was to perform a review of the current literature on post-COVID-19 vaccination exacerbations and new-onset psoriasis in order to offer a wide perspective on COVID-19 vaccination and psoriasis and to point out possible pathogenetic mechanisms.

Materials and Methods
Research on the current literature was performed using the following databases: PubMed, Cochrane Skin, Embase, EBSCO, MEDLINE, and Google Scholar (up to 1 June 2023).Studies were identified, screened and extracted for relevant data following PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines [32], using the following keywords: "COVID-19", "vaccine", "cutaneous", "vaccination", "side effects", "adverse events", "safety", "efficacy", "skin manifestations", "mRNA", "viral vector", "Pfizer/BioNTech", "BNT162b2", "Moderna", "mRNA-1273", "AstraZeneca", "Johnson & Johnson", "Ad26.COV2.S", "AZD1222", and "psoriasis".The manuscripts analyzed included reviews, meta-analyses, letters to the editor, real-world studies, and case series.Manuscripts that fit the aim of our review were considered.Studies reporting at least one patient who developed new-onset psoriasis or experienced a worsening of psoriasis following at least one dose of COVID-19 vaccine were included.Only the BNT162b2, mRNA-1273, AZD1222 and Ad26.COV2.S vaccines were considered in our review.Studies reporting de novo psoriasis or an exacerbation of psoriasis following other types of vaccines were excluded and studies investigating psoriatic arthritis were not considered.All the clinical phenotypes of psoriasis were included (plaque, guttate, pustular, erythrodermic, inverse, palmoplantar, etc.).The search was then refined by reviewing the texts and abstracts of the collected articles.The bibliography was also revised to include articles that may have been missed.Only English-language manuscripts were considered.
This article is based on previously conducted studies and does not contain studies with human or animal participants conducted by any of the authors.
This article is based on previously conducted studies and does not contain studies with human or animal participants conducted by any of the authors.

Discussion
Psoriasis is a complex autoimmune disorder characterized by an abnormal immune response that leads to chronic inflammation and the accelerated growth of skin cells [77].Cytokines play a crucial role in the pathogenesis of psoriasis, serving as key mediators in the inflammatory process [78,79].In particular, TNFα, IL23, IL17, IL22 and IL6 have been reported to play a central role in the initiation and maintenance of psoriatic inflammation, promoting the recruitment and activation of immune cells, and the production of other cytokines [78,79].Targeting these cytokines has been a successful approach in the treatment of psoriasis [80][81][82].Indeed, biologic drugs, such as anti-TNFα, IL17, and IL23, have been developed to specifically block the actions of these cytokines and reduce inflammation in psoriatic skin, revolutionizing the psoriasis treatment scenario [80][81][82].
The COVID-19 pandemic impacted daily clinical practice [83,84].In particular, several strategies have been adopted to contain the spreading of the infection [85,86].Among these, vaccination was the main one.However, although the preliminary safety concerns and doubts raised at the beginning of the vaccination campaign related to vaccines' safety were overcome, several cutaneous adverse events were reported, most of these not being shown in clinical trials [87][88][89].Fortunately, the majority of these were mild and self-limiting, and did not require medical attention [90,91].In addition, the vaccination campaign was also limited by several personal burdens (a fear of vaccination and its side effects, stress from needing a vaccination to travel or work, etc.) [84,92,93].
As regards psoriasis, several cases of exacerbation or a new onset of the disease were reported.However, comprehensive manuscripts collecting all these data in order to offer a wide perspective are scant.In this context, we performed a review with the purpose of showing a wide analysis of COVID-19 vaccination and psoriasis development/exacerbation and pointing out possible pathogenetic mechanisms.It is important to note that the information provided is based on the current understanding of these topics and may evolve as further research becomes available.Globally, in total, 49 studies involving 134 patients developing new-onset psoriasis (n = 27, 20.1%) or experiencing a psoriasis exacerbation (n = 107, 79.9%) were collected.In both cases, mRNABNT162b2 was the commonest vaccine associated and plaque psoriasis was the commonest clinical phenotype, while a significant gender predominance was not reported and cutaneous reactions were reported following each dose of a vaccine.In our opinion, mRNABNT162b2 was the commonest vaccine related to cutaneous reactions since it was the most commonly used during the vaccination campaign, and plaque psoriasis is the commonest clinical phenotype according to psoriasis phenotype epidemiology.Moreover, all of the cases have been successfully treated with topical or systemic medications, including biologics.In particular, a difference between patients starting or switching to biologic treatment for psoriasis has been found between new-onset and flare-up groups (11.1% vs. 36.4%).In our opinion, the increased awareness of psoriatic disease in patients already suffering from the disease has reduced the number of consultations for mild exacerbations.Indeed, patients affected by psoriasis are more used to self-medication with topical drugs, reducing the need for medical advice in the case of mild forms of the disease.This may explain the difference between the predominance of moderate-to-severe forms of disease in patients who developed a psoriasis flare-up and those with mild forms in de novo cases where the use of topical treatments for the management was predominant (33.3% vs. 21.5%).Unfortunately, ongoing treatment prior to COVID-19 vaccination was often not reported, which prevented the results from being analyzed to reveal whether or not some psoriatic treatments may increase the risk of disease exacerbation.
Of interest is that 19 (17.8%) patients who developed psoriasis exacerbation were under biologic treatment for psoriasis at the moment of the flare-up.Reviewing the current literature, being on biologic drugs at the moment of vaccination seems to reduce the risk of psoriasis worsening [30,31,94,95], but clinical studies comparing patients undergoing biologics and patients receiving other medications and/or a placebo at the moment of vaccination are absent, not allowing a confirmation of these data.Certainly, biologic drugs were also shown to be safe and effective during the pandemic period.
In addition, the number of days between new-onset psoriasis or the exacerbation of psoriasis and vaccination is not reported in most of the studies.Moreover, the onset or exacerbation of nail psoriasis should also be discussed.Indeed, there are few cases reporting the onset or worsening of this form of disease and the time between vaccination and reporting is too short to limit this condition to the COVID-19 vaccine.
Thus, while there have been anecdotal reports of new-onset psoriasis or psoriasis exacerbation following COVID-19 vaccination, it is essential to evaluate these cases in the context of existing scientific knowledge.Firstly, there is currently no direct evidence linking COVID-19 vaccination to the development of psoriasis.Vaccines, including COVID-19 vaccines, work by stimulating the immune system to produce a protective response against the virus [96][97][98].The mechanisms involved in vaccine-induced immune responses are different from those implicated in psoriasis pathogenesis [96][97][98].It is unlikely that COVID-19 vaccination would directly trigger the development of psoriasis in individuals without a pre-existing predisposition [96][97][98].However, it is important to consider the potential of immune system activation or modulation following vaccination [96][97][98].In some cases, vaccines can induce immune responses that may lead to transient inflammation or immune system activation [96][97][98].This immune activation may theoretically contribute to the exacerbation of pre-existing psoriasis in individuals already diagnosed with the condition [96][97][98].In addition, the induction of neutralizing antibodies and T-cell responses via vaccination may lead to an increasement and production of TNFα and Interferon (IFN) γ [96][97][98].Similarly, vaccination can activate plasmacytoid and dermal myeloid dendritic cells which may be a trigger for the psoriasis cascade [96][97][98].Finally, vaccinations might induce the production of IL6, which may be a trigger for Th17 cells to produce IL22, which itself stimulates keratinocyte proliferation [96][97][98].
Notably, cases of de novo psoriasis or an exacerbation of psoriasis have been reported following both mRNA and viral vector-based vaccines, suggesting that the onset or the worsening of the disease is not related to the mechanism of action of the vaccines but to the vaccination itself.
Furthermore, it is crucial to differentiate between coincidence and causation when assessing the relationship between COVID-19 vaccination and new-onset psoriasis.Psoriasis is a relatively common skin condition, and it is possible for new cases to emerge coincidentally after vaccination, without a direct causal relationship.Robust epidemiological studies and careful evaluation of individual cases are needed to determine any potential association between COVID-19 vaccination and the development of psoriasis.Moreover, it is mandatory to emphasize the overall benefit-risk profile of COVID-19 vaccination.Indeed, COVID-19 is a severe and potentially life-threatening illness, and the benefits of vaccination in preventing infection, reducing severe disease, and limiting the spread of the virus far outweigh the potential risks.

Strengths and Limitations
The number of investigated studies and the literature review using the PRISMA methods are the main strengths of our manuscript.The absence of clinical studies and consistent data such as data from registries are the main limitations.Moreover, we hypothesize that cases of psoriasis exacerbations or de novo disease developed following vaccination were underestimated, since not all patients seek medical advice due to the limited severity of the disease, tending to self-medicate (particularly in patients affected by psoriasis who are more accustomed to self-medication with topical drugs, reducing the need for medical advice in the case of mild forms of the disease), and many reactions have not been reported.Finally, psoriatic arthritis was not considered in our manuscript.

Conclusions
To sum up, the COVID-19 vaccination campaign was a success.Although cases of de novo psoriasis or disease worsening have been reported following vaccination, all of the cases have been successfully treated (mainly with topicals in de novo cases and systemic treatments in psoriasis flare-ups), while the overall benefit-risk profile of COVID-19 vaccination do not justify the vaccine hesitancy due to the risk of psoriasis being developed or worsening.Globally, plaque psoriasis was the most common clinical phenotype both in terms of de novo psoriasis and the exacerbation of psoriasis.Moreover, more severe forms of the disease have been reported in patients with a history of psoriasis compared to the new onset cases where mild forms were predominant.This difference may be explained by psoriatic patients' ability to self-medicate with topical drugs for mild forms of the disease, reducing the need for medical advice for moderate-to-severe conditions.Certainly, further studies are needed to identify possible pathogenetic mechanisms in order to identify "at-risk" patients.Finally, vaccination should not be discouraged.
Author Contributions: L.P.: data curation, formal analysis, investigation, visualization, writing-original draft preparation, writing-review and editing.T.B.: data curation, formal analysis, investigation, visualization, writing-original draft preparation, writing-review and editing.S.C.: data curation, formal analysis, investigation, visualization, writing-original draft preparation, writing-review and editing.A.R.: data curation, formal analysis, investigation, visualization, writing-original draft preparation, writing-review and editing.F.M.: data curation, formal analysis, investigation, visualization, writing-original draft preparation, writing-review and editing.L.F.: data curation, formal analysis, investigation, visualization, writing-original draft preparation, writing-review and editing.E.C.: data curation, formal analysis, investigation, visualization, writing-original draft preparation, writing-review and editing.M.M.: data curation, formal analysis, investigation, visualization, writing-original draft preparation, writing-review and editing.All authors have read and agreed to the published version of the manuscript.