Francesco
Bellinato
(email)Ă Francesco
Bellinato
(email)
Affiliation
Department of Medicine, Section of Dermatology and Venereology, University of Verona, Italy
Affiliation
Department of Medicine, Section of Dermatology and Venereology, University of Verona, Italy
Introduction
In December 2019, in Wuhan (China), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) was described for the first time [1]. This novel type of coronavirus spread rapidly through global population in few months with raising concern among public and health authorities worldwide until the World Health Organization (WHO) declared pandemic status on 11th March 2020 [2]. SARS-CoV-2 is the etiologic agent of Coronavirus disease 2019 (COVID-19), a condition characterized by a spectrum of symptoms, from mild (e.g., headache, cough, and fever) to severe manifestations and life-threatening events, such as acute respiratory distress syndrome (ARDS) and venous thromboembolisms, with an increased risk in chronically ill and immunologically compromised patients [3,4]. After 3 years of pandemic the number of deaths related to COVID-19 is 6.88 million out of a total of more than 761 million confirmed cases [5]. From the beginning of the first outbreak, one of the most viable ways to counter this health, social and economic burden has been to develop a vaccine using the spike (S) protein of the virus as the main activator of the immune system. With huge efforts by governments and pharmaceutical industries, numerous vaccines have been developed with the aim to prevent viral infection or, in case of infection, avoid the most severe manifestations, to reduce hospitalizations, intensive care unit admissions and, consequently, the overloading of health systems worldwide. Therefore, the largest vaccination campaign in human history was launched and only 1 year after the first vaccine was approved more than 10 billion doses had already been administered in the world [6,7]. Different categories of vaccines have been designed using different technology platforms and several of them are globally in use: (1) inactivated viral vaccines, which contain pathogens altered in a way to prevent their replication, (2) protein subunit vaccines, composed of fragments of the original virus by recombinant technology, (3) viral vector (non-replicating) vaccines, employing a carrier virus such as an adenovirus, and (4) nucleic acid-based vaccines (mRNA- or DNA-based) which code for viral proteins and induce the cells themselves to synthesize the antigen [8]. To date World Health Organization (WHO) approved 11 vaccines: Covilo (Sinopharm-Bejing), Covaxin (Bharat Biotech), CoronaVac (Sinovac) (Inactivated virus-based); Nuvaxoid (Novavax), COVOVAX (Serum Institute of India) (Protein Subunit-based); Vaxzevria (Oxford/AstraZeneca), Covishield (Serum Institute of India), Convidecia (CanSino), Jcovden (Janssen) (Non-Replicating Viral Vector-based); Spikevax (Moderna), Comirnaty (Pfizer/BioNTech) (RNA-based) [9]. Most vaccines showed a significant reduction in cases of symptomatic COVID-19 and severe or critical disease compared with placebo, and little or no difference for serious adverse events [8]. The effectiveness was also demonstrated against COVID-19-related hospitalization, intensive care unit admission and death, not only in cases of full vaccination but also in those who have received partial vaccination, although to a lesser degree [10]. Data collected by Centres of Disease Control (CDC) showed that the number of Covid-19-related deaths in the U.S. was higher in the unvaccinated than in the vaccinated with similar results across vaccine types [6]. An increase in efficiency was also observed with booster dose administration compared to primary immunization [11]. As the mass vaccination campaign progressed, increasing numbers of post-vaccination adverse reactions were reported and several studies have found that this risk is greater for mRNA vaccines [12,13]. Expected adverse events related to the body's normal reactiveness were observed in conjunction with the administration of different types of vaccine, such as local reactions at injection site, like pain, redness and swelling, or signs of systemic response, like fever, headache, chills, myalgia and fatigue, which were, however, mild and transient, [8] developing within 1 to 2 days after vaccination and lasting 1 to 2 more days [14]. It is also important to consider the relevance of the ânocebo effectâ, which led to significant frequency of adverse events even in placebo recipients, probably because of the many concerns in population regarding vaccines, their rapid development, and uncertain safety [15]. In addition to reactions at the injection site, other frequent patterns of skin manifestation were described, which were, however, self-limiting and not severe, mostly urticarial and morbilliform eruptions [16,17]. Other less common manifestations were pernio/chilblain, pityriasis rosea-like reactions, zoster, cosmetic filler reactions and herpes simplex exacerbations [16,17].The most important severe adverse events described in the literature are divided into four major organ-specific groups: immune-allergic (urticaria, angioedema, anaphylactic shock, autoimmune hepatitis, vasculitis), cardiovascular (myocarditis and pericarditis, acute coronary syndrome, pulmonary thromboembolism, hypertension crisis), hematologic (vaccine-induced thrombotic thrombocytopenia, diffuse intravascular coagulation, venous thromboembolism, immune thrombocytopenia) and neurologic events (Guillain-BarrĂ© syndrome, transverse myelitis, cerebrovascular attack, cerebral venous sinus thrombosis and Bellâs palsy) [18]. Episodes of myocarditis and pericarditis, which represent some of the main safety concerns in male young adults, appear to be more frequently Covid-associated than mRNA vaccine-associated, while thromboembolic events have been described particularly in young women with a pre-existing hypercoagulability state receiving adenoviral vector vaccines [18]. The link of causality is still under investigation for several of these adverse events [19]. Despite the low incidence of severe adverse events, SARS-Cov-2 vaccines are receiving careful surveillance by national and international programs, continuing to show a good safety and efficacy profile in several studies, including during pregnancy and in children [20]. Despite these few and rare risks associated with their administration, they continue to be recommended in the general population by the scientific communities because benefits still outweigh risks and remain the most effective strategy to facilitate the gradual transition from pandemic to endemic state [6].
Safety of SARSâCoVâ2 vaccines in patients with chronic plaque psoriasis
As SARSâCoVâ2 vaccines have become widely available, dermatologists needed to face their safety and efficacy in patients with immune-mediated inflammatory diseases, particularly those with psoriasis who take immunosuppressive/immunomodulatory treatments [21]. Drugs such as methotrexate, cyclosporine and biologics targeting tumour necrosis factor (TNF), interleukin (IL)-17, IL-12/23, IL-23 are highly effective in blocking the immune pathways of psoriasis, but also can increase the risk of certain infections and potentially reduce vaccine immunogenicity. Case reports of psoriasis flares following SARSâCoVâ2 vaccination have been reported (Figure 1) leading to hesitancy and apprehension among patients and physicians [16,17,22-30]. Such flares were frequently described after the boost dose and the mean interval between vaccination and psoriasis flare was 9.3 days [16]. The pathogenetic mechanism behind psoriasis exacerbations has not fully understood. In mRNA vaccines, single-stranded RNA can activate toll-like receptors (TLR), the inflammasome and the production of type I interferons, which are known to flare autoimmune disease. Similarly, double stranded DNA in adenoviral vector vaccines induce type I interferons production via TLR9 [16]. However, a more recent self-controlled case series analysis reported that vaccination against SARSâCoVâ2 was not statistically associated with risk for psoriasis flare. The adjusted incidence rate ratio (IRR) of psoriasis flare was 0.96 (95%CI 0.80-1.14) 21 days after vaccination [31].

Figure 1. Numerous guttate plaques of psoriasis on the back (A) and right elbow (B) of a 45-year-old patient triggered 2 weeks after administration of the booster of an mRNA vaccine
Regarding the safety of SARSâCoVâ2 vaccination in psoriatic patients on biologics, current real-world data suggest that adverse effects are comparable to those observed in healthy individuals, even if prospective randomized controlled trials excluded such patients for the current available vaccines, particularly the now widely used mRNA vaccine BNT162b2 [21]. For example, a study on 436 psoriatic patients treated with biologics (78 of whom underwent SARSâCoVâ2 vaccination) reported no vaccination-related adverse effects [32]. In another study on 369 patients with psoriasis receiving anti-IL-17 and 23 agents who underwent SARSâCoVâ2 vaccination, no serious vaccination-related adverse events were reported, while about a third developed mild adverse events (such as injection site pain, fever, fatigue, and muscle pain) that resolved within 48 hours [33]. In a study involving 505 patients with IMID treated with methotrexate, glucocorticoids, biologics and 203 healthy controls, no significant difference in frequency of adverse events between patients with IMID and controls was found [34]. A survey involving 325 patients with IMID treated with disease modifying anti-rheumatic drugs and biologics, most reactions were local and transient like those reported in vaccine trials, no series allergic reactions were reported [35]. Conversely, in a cohort study involving 127 patients with IMID and 97 controls receiving ChAdOx1-S vaccine, those with psoriasis were more likely to experience vaccine-related adverse effects than controls (72 vs 57%) [36]. In conclusion, there is no evidence that patients with psoriasis receiving biologics are at greater risk of harm from SARSâCoVâ2 vaccination.
Efficacy of SARSâCoVâ2 vaccines in patients with chronic plaque psoriasis
An open question is whether patients with psoriasis receiving biologics or other immunomodulatory treatments can mount an adequate immune response to the SARSâCoVâ2 vaccine. In vaccine-induced host protection against SARS-CoV2 a complex interaction between innate, humoral, and cellular immunity occurs. In prospective cohort studies different assessment of humoral and cellular response after SARS-CoV2 vaccination has been evaluated, including total antibody titres, neutralizing activity and T-cell mediated immunogenicity as measured by interferon-gamma releasing assay (IGRA), as summarized in Table 1. Earlier studies on vaccination against pneumococcus, meningococcus, influenza, or tetanus showed that treatment with TNF-a inhibitors, ILâ12/23 inhibitors and ILâ17 inhibitors is not associated with lower antibody response [37].

Conclusions
SARS-CoV-2 vaccination management in chronic plaque psoriasis is a clinically relevant issue. According to different guideline/recommendations including EuroGuiDerm, National Psoriasis Foundation and International Psoriasis Council, patients with psoriasis are candidate to SARSâCoVâ2 vaccination whether they are on systemic drug treatment or not. Psoriasis is not a contraindication to vaccination [46,47]. In fact, the advantages of avoiding severe COVID-19 through vaccination is much greater than the theoretical risk of its adverse events. The American College of Rheumatology, recommended to withhold methotrexate 1 week after each dose of vaccine for patients with well-controlled disease [48]. This recommendation is based on data from influenza and pneumococcal vaccines showing that methotrexate, but not target therapies, impair humoral responses [49].Although several studies support the safety and efficacy of SARSâCoVâ2 vaccination, a considerable population still expresses vaccine hesitancy, including those affected by psoriasis. Age, gender, lack of trust in science, and concerns of safety and efficacy represent determinants for vaccine hesitancy. According to the global patientâreported PsoProtectMe survey, up to 8% of patients with psoriasis have vaccine hesitancy [51]. A recent systematic review recommends strategizing the campaign for booster doses by identifying and evaluating the reasons for such hesitancy and by appropriate communication [50].In conclusion, current data suggests that SARSâCoVâ2 vaccines appear safe in patients with psoriasis undergoing immunomodulatory treatment. In some individuals receiving methotrexate or TNF-a inhibitors, waning in immunogenicity of the vaccine could occur. Consequently, such patients might require testing to assess whether adequate immune responses are elicited after vaccination and whether booster vaccination is required to generate sufficient protection against SARS-CoV-2 infection. Further studies are needed to assess the long-term impact of the different classes of biologics on humoral and cellular immunogenicity [21].
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