Drugs in R&D https://doi.org/10.1007/s40268-021-00349-0 CURRENT OPINION Vaccinations in Patients Receiving Systemic Drugs for Skin Disorders: What Can We Learn for SARS‑Cov‑2 Vaccination Strategies? Reinhart Speeckaert1 · Jo Lambert1 · Luis Puig2 · Marijn Speeckaert3 · Hilde Lapeere1 · Sofie De Schepper1 · Nanja van Geel1 Accepted: 14 May 2021 © The Author(s) 2021 Abstract Large-scale vaccination strategies are currently being deployed against severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2). Whether systemic medication for skin diseases affects the efficacy of vaccination and whether temporary interruption or extension of the dosing interval is necessary is under debate. Most immunomodulating/immunosuppressive drugs only affect vaccine-induced immune responses to a limited or moderate extent, preserving sufficient immunity in most patients. Mycophenolate mofetil, Janus kinase inhibitors, and rituximab require a more cautious approach, and judicious tim- ing of vaccination might be appropriate in patients receiving these treatments. It should be noted that, for most drugs except methotrexate, data on the length of the interruption period to restore vaccine-induced immune responses to normal levels are either very limited or absent. In these cases, only the drug half-life can be used as a practical guideline. In most patients, systemic medication can be continued through the vaccination process, although case-by-case decisions can be considered. Key Points 1 Introduction For most patients receiving immune-based treatments In recent decades, the number of systemic medications avail- for inflammatory skin disorders, the therapy can be able for skin disorders has increased. Given the inflamma- continued without affecting protective vaccine-induced tory nature of most dermatologic disorders, the majority of immunity. treatments act by influencing different parts of the immune system. Despite initial concerns, most systemic treatments For some drugs, temporary treatment interruption or in dermatology appear to carry a limited risk for severe coro- administration of the vaccine at the optimal period navirus disease 2019 (COVID-19) infections. Some medica- according to the pharmacokinetics of the drug and the tions have even been proposed as useful in the treatment of individual level of disease control can be considered. the cytokine storm associated with COVID-19. Cyclosporine inhibits replication of different coronaviruses in vitro [1]. Data do not suggest an increased susceptibility to infection or severe disease course in patients treated with biologics [2]. Interestingly, epidermal cells express the angiotensin- converting enzyme receptor (ACE)-2, which acts as an entry receptor for SARS-CoV-2, indicating that the skin could be an entry site for SARS-CoV-2 infection in case of barrier * Reinhart Speeckaert dysfunction. As such, appropriate treatment of skin diseases Reinhart.Speeckaert@uzgent.be with impaired integrity of the skin such as eczema may be 1 Department of Dermatology, Ghent University Hospital, protective [3]. Corneel Heymanslaan 10, 9000 Ghent, Belgium While some systemic drugs in dermatology are termed 2 Department of Dermatology, Hospital de la Santa Creu i Sant immunomodulatory and others immunosuppressive, the Pau, Universitat Autònoma de Barcelona, Barcelona, Spain question remains as to whether the response to severe acute 3 Department of Nephrology, Ghent University Hospital, respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccina- Ghent, Belgium tion will be hampered by these treatments. This is a valuable Vol.:(0123456789) R. Speeckaert et al. question, as the benefits of temporary interruption of the the host cell via the S1 subunit. After a cleavage process, the treatment may outweigh the risks, given that long-lasting S2 subunit inserts into the host membrane [6]. irreversible damage is not expected for the most common Different strategies are being used to develop vaccines skin diseases such as psoriasis, eczema, or urticaria. In this against SARS-CoV-2: RNA and DNA vaccines, replicating paper, we summarize the evidence of the effects of systemic and nonreplicating viral vectors, inactivated vaccines, live immune-based interventions for skin disorders on vaccine attenuated vaccines, protein subunit vaccines, and virus-like responses and discuss the implications for SARS-CoV-2 particle vaccines. vaccination. RNA vaccines are a new approach to the vaccine arsenal (Fig. 1). Via intramuscular injection of RNA encapsulated in lipid nanoparticles to improve cell delivery, host cells 2 Types of COVID Vaccines and Assessment encode proteins that induce a B- and T-cell response. The of Efficacy BioNTech SE/Pfizer vaccine contains the messenger RNA (mRNA) for the S glycoprotein. Similarly, the Moderna vac- SARS-CoV-2 is a member of the betacoronavirus genus, a cine also contains mRNA encoding for the S protein in the family of RNA viruses that induce respiratory tract infec- stabilized prefusion form [6]. tions. It is the seventh type that can infect humans and the Self-amplifying RNA vaccines are genetically engineered third (besides severe acute respiratory syndrome and the amplicons that contain the mRNA coding for the desired Middle East respiratory syndrome) to be associated with antigen plus mRNA encoding an RNA-dependent RNA pol- severe disease. Although controversy remains about its ori- ymerase complex that amplifies synthetic transcripts in situ gin, the approximately 96% sequence homology with the [7]. One such vaccine by the Imperial College London is RaTG13 virus found in bats suggests a plausible site of ori- currently in phase I of clinical development [8]. gin in zoonotic transmission [4]. SARS-CoV-2 is composed The replicating vectors are based on attenuated viruses or of four main structural proteins: the spike (S) glycoprotein, a specialized strains of viruses developed for vaccination pur- small envelope glycoprotein, a membrane glycoprotein, and poses. These vectors harbor a gene that encodes for a viral a nucleocapsid protein, with several additional accessory protein, which is most frequently the S protein. Replicating proteins [5]. The S protein binds to the ACE2 receptor on vectors will invade host cells, which will lead to the pro- duction of the viral antigen and generation of more vectors. Fig. 1  Working mechanism of mRNA-based vaccines for SARS- blockers, IL-23i interleukin-23 inhibitors, JAKi JAK inhibitors, MMF CoV-2 and the main pathways where immunosuppressive/immu- mycophenolate mofetil, mRNA messenger RNA, MTX methotrexate, nomodulating treatments interact. CD cluster of differentiation, RITU rituximab, SARS-CoV-2 severe acute respiratory syndrome cor- CYCLO cyclosporin, IL-17i interleukin-17-inhibitors or receptor onavirus-2, Th17 Type 17 T-helper cell What Can We Learn for SARS-Cov-2 Vaccination Strategies? These will subsequently infect additional cells and amplify for prevention but crucial to attack virally infected cells. the amount of viral antigen, leading to a robust humoral and To create a C­ D8+-specific immunity, the antigen should be cellular response. Both replicating and nonreplicating viral presented via human leukocyte antigen molecules by anti- vectors are in development, and some have already been gen-presenting cells and/or infected cells. In general, vacci- approved. The AstraZeneca/University of Oxford and Rus- nation strategies induce a modest long-term T-cell response, sian Sputnik V vaccines are based on nonreplicating viral especially when compared with vaccine-induced humoral vectors. The Janssen Pharmaceuticals vaccine uses a recom- immunity. For preventive purposes, this might be acceptable binant adenovirus. For all these vaccines, the SARS-CoV-2 as ­CD8+ lymphocytes play their primary role after the host spike gene is inserted into the vector. cells are infected [10]. Inactivated vaccines are made by inoculation of (in most cases) mammalian Vero cells, followed by chemical inac- tivation. Live attenuated vaccines have previously been shown to be an effective approach for numerous infections, 3 Efficacy of Vaccinations during Systemic including measles, mumps, rubella, varicella, tuberculosis, Treatment yellow fever, and influenza. The route of administration is important, as intramuscular injections only elicit a strong 3.1 Methotrexate immunoglobulin (Ig)-G humoral immunity without leading to an increased IgA production in the respiratory tract or Methotrexate is an antimetabolite and antifolate drug that mucosal surfaces [9]. Intranasal delivery offers particular is used in many autoimmune skin disorders because of its protection of the entry point of SARS-CoV-2, the upper res- anti-inflammatory effects (including inhibition of T-cell piratory tract. Protein subunit vaccines are the most popu- proliferation). Substantial evidence shows that methotrex- lar approach in terms of developed vaccines. In contrast to ate decreases the efficacy of vaccination. Vaccine responses RNA-based vaccines, which require the host cells to produce (e.g., at least fourfold increase in antibody titer after vaccina- the antigen, protein subunit vaccines consist of synthetic tion compared with baseline) to influenza are decreased by peptides or recombinant proteins. The most obvious choice 15–20% [14, 15]. Stopping methotrexate 2 weeks before and is again the S protein, as the induction of neutralizing anti- 2 weeks after or for 4 weeks postvaccination largely reverses bodies is likely to prevent infection. Virus-like particles are this phenomenon [15]. Another study found no difference another strategy and involve the administration of nonrepli- regardless of the timing of the last dose of methotrexate if cating, noninfectious nanostructures that expose crucial viral patients stopped methotrexate for 2 weeks after vaccination. proteins. Finally, DNA vaccines use plasmids encoding for This short stop period was sufficient to restore the humoral the S protein. Although these types of vaccines are used immunity despite the slow working mechanism of this drug in animals, the theoretical possibility of the DNA plasmid in many inflammatory diseases [14]. Stopping treatment for integrating into the host genome raises some concerns [10]. longer periods (e.g., 4 weeks) induces the risk of disease The primary goal of efficient vaccination is to induce a flares [15]. neutralizing humoral response preventing the virus from invading host cells. IgG antibodies are considered the most 3.2 Cyclosporine important, especially the IgG1 and IgG3 classes, as they offer the most protection. Nonetheless, as mucosal surfaces The calcineurin inhibitor cyclosporine decreases T- and and both epithelial and endothelial cells in the respiratory B-cell proliferation by reducing interleukin (IL)-2 produc- tract are identified as cellular targets, the generation of tion. This conventional immunosuppressant diminishes sufficient IgA antibodies may also represent an important antibody titers after vaccination. Studies have mainly been protective barrier. Serum IgA dominates the early neutral- conducted in transplant patients and have revealed decreased izing antibody response to SARS-Cov-2, and dimeric IgA, immunologic responses after vaccination for influenza, teta- the primary form of antibody in the nasopharynx and other nus, and hepatitis B [16, 17]. In most studies, the adminis- mucosae, is on average 15 times more potent. Intramuscu- tration of cyclosporine seems to be not associated with a lar administration of vaccines is unlikely to elicit significant reduced immune response to influenza vaccination compared divalent IgA response in the mucosae, as opposed to intra- with other immunosuppressants [18]. Nonetheless, in lung nasal administration, which can result in both IgA and IgG transplant patients, antibody responses were borderline sig- responses such as intended for the attenuated COVI-VAC nificantly decreased in the cyclosporine versus the tacroli- vaccine (NCT04619628) [11–13]. mus group [19]. In renal transplant patients, cyclosporine To produce a robust antibody response, both B cells was associated with impaired immune responses to influenza and cluster of differentiation (CD)-4+ T-helper cells must vaccination, in contrast to azathioprine [17]. Cyclosporine be stimulated. ­CD8+ cytotoxic T cells are less essential has a relatively short half-life of 18 h. No data are available R. Speeckaert et al. on how long cyclosporine needs to be stopped for optimal 3.7 Azathioprine responses to vaccination. Azathioprine has immunosuppressive effects as it inhibits purine metabolism, resulting in decreased lymphocyte prolif- 3.3 Mycophenolate Mofetil eration. Anti-hepatitis b surface antigen (anti-Hbs) titers were decreased in patients with inflammatory bowel disease receiv- By selectively inhibiting inosine 5ʹ-monophosphate dehy- ing azathioprine (anti-HBs > 10 UI/L: 55% in the azathioprine drogenase, a crucial enzyme in purine synthesis, mycophe- group vs. 88% in controls) [30]. One study found that azathio- nolate mofetil (MMF) decreases lymphocyte proliferation. prine did not affect the response to pneumococcal vaccination MMF is one of the strongest inhibitors of postvaccination [31], whereas another detected an impaired antibody response humoral immunity. This may not be surprising, as MMF is for one of the 12 serotypes after pneumococcal polysaccharide particularly useful in blistering skin disorders as it reduces vaccine-23 (PPSV-23) compared with controls [32]. Anti-influ- pathogenic antibody formation. Significantly reduced anti- enza vaccination evoked antibody responses similar to those body titers were confirmed in patients receiving MMF after in healthy controls in kidney transplant recipients and patients pneumococcus and influenza vaccination [18, 20]. MMF has with inflammatory bowel disease on azathioprine. Most find- a half-life of 15.7–17.9 h [21]. No trials have investigated ings suggest that azathioprine has a better vaccine-induced how long MMF should be discontinued to prevent a damp- immunity profile than MMF and cyclosporine [17, 33]. ened vaccine immunity. 3.8 Janus Kinase Inhibitors 3.4 Corticosteroids Janus kinase (JAK) blockers reduce different cytokines and Data in elderly patients receiving corticosteroids confirmed signaling of growth factor receptors depending on the type sufficient serum antibody responses following influenza vac- of JAK inhibition (JAK1, JAK2, JAK3, or tyrosine kinase-2). cination [22, 23] Also, children who took prednisone for an The JAK1/3 inhibitor tofacitinib has major effects on naïve acute asthma exacerbation were able to mount a humoral B-lymphocyte development. This suggests a lost ability to response similar to that in healthy controls [24]. Likewise, raise immunologic protection against novel antigens [34]. nephrotic children on high-dose prednisone had an antibody Diminished responsiveness to PPSV-23 (tofacitinib: 45.1% response comparable to that in controls [25]. In contrast, a vs. healthy controls: 68.4%) was found, especially in patients study in asthma revealed an attenuated response to influenza concomitantly receiving methotrexate. In contrast, results for B antigen in subjects on high-dose inhaled steroids [26]. influenza were reassuring. Temporary drug interruption for Varicella zoster vaccination was also successful in patients 2 weeks (1 week before and 1 week after vaccination) did on chronic/maintenance corticosteroids [27]. not restore the vaccine’s effectiveness [34]. Nonetheless, most patients with psoriasis treated with tofacitinib mounted ade- quate immunity against pneumococcal infection (after pneu- 3.5 Dimethyl Fumarate mococcal conjugate vaccine-13) and tetanus [35]. PCV-13 vaccination was successful in 68% of patients with rheumatoid Fumaric acid esters are used for moderate to severe psoria- arthritis treated with the JAK1/2 inhibitor baricitinib, whereas sis and decrease lymphocyte counts, although its working only 43% achieved an at least fourfold increase in antiteta- mechanism has not been fully elucidated. Findings for dime- nus IgG concentrations. However, most patients in this study thyl fumarate are reassuring: most patients receiving dime- were also taking methotrexate (89%) and/or corticosteroids thyl fumarate mount responses against tetanus-diphtheria (30%) [36]. Similar results were found for the JAK1 inhibitor toxoid, pneumococcal, and meningococcal vaccine [28]. upadacitinib, with a satisfactory humoral response (at least twofold increase in antibody levels compared with baseline) 3.6 Apremilast to PCV-13 at 12 weeks in 65% and 55% of patients for 15 mg and 30 mg upadacitinib, respectively [37]. No data were found Apremilast, a selective phosphodiesterase-4 inhibitor, for the JAK1/2 inhibitor ruxolitinib. reduces the production of proinflammatory cytokines and is registered for psoriasis. No data are available on this drug 3.9 Biologics following vaccination. Given the limited immunosuppressive properties of apremilast, vaccination is likely to be effective 3.9.1 Tumor Necrosis Factor‑α Blockers and no different than in the general population. Apremilast does not affect B-/T-cell proliferation or the production of Tumor necrosis factor (TNF)-α blockers seem to modestly immunoglobulins [29]. impair the serological response to influenza vaccination What Can We Learn for SARS-Cov-2 Vaccination Strategies? in patients with spondyloarthritis (anti-TNFα: 51.6% vs. 3.9.5 Omalizumab healthy controls: 74.3%; P = 0.002) [38]. In patients with rheumatoid arthritis, one study mentioned that this effect was No data are available on the anti-IgE antibody omalizumab. more pronounced than with methotrexate [39]. In contrast, Reduced efficacy of vaccination is not expected as IgE anti- another report showed the opposite, with normal responses bodies play no role in developing protective vaccine-induced in anti-TNFα-treated patients and decreased results in meth- humoral responses. otrexate-treated patients [40]. There is an overall consen- sus that immune responses are lesser in patients receiving 3.9.6 Rituximab anti-TNFα treatment after influenza vaccination, although enough protective immunity is usually reached. The half- As rituximab specifically targets ­CD20+ B cells, it may life of anti-TNFα agents is relatively long (e.g., 14 days for inhibit protective vaccine-induced immunity. CD20 is not adalimumab, 20 days for certolizumab pegol) but shorter expressed on early precursor pro-B cells and long-lived for etanercept (4 days). Except for etanercept, which can be plasma cells. Therefore, preexisting antibody titers are interrupted without marked reduction in efficacy after restart largely unaffected. Vaccination responses and the formation and is quickly eliminated from the circulation, interruption of neutralizing antibodies are expected to be blunted until of TNFα-specific biologics for vaccination is more challeng- naïve B cells reappear [58]. Decreased levels of seroconver- ing. Longer injection intervals and start/stop strategies might sion and reduced titers to pneumococcal, tetanus, and influ- lead to increased antidrug antibodies and reduced long-term enza vaccines have been confirmed. The response partially efficacy [41]. Moreover, it is unclear which critical threshold recuperates but is still impaired 6–10 months after infusion of dosing is required to level the vaccination responses to [59]. Inactivated herpes zoster vaccine can induce a T-cell those in healthy controls. response [60]. This might be important for vaccination as 3.9.2 Interleukin (IL)‑17 Inhibitors and IL‑17 Receptor ­CD8+ T-cell responses have been confirmed to be crucial for Blocker protective immunity against SARS-CoV-2 [61, 62]. Secukinumab does not affect the humoral response to influ- enza or meningococcal vaccine [42–44]. Similar reassuring 4 Discussion data have been reported for tetanus and pneumococcal vac- cination for ixekizumab [45]. Secukinumab has a half-life Several systemic treatments for skin disorders have been of 27 days, ixekizumab 13 days, brodalumab 10.9 days, and linked to reduced vaccine-induced protective immunity. bimekizumab 17–26 days [46–49]. No reports have been Given the reversible damage caused by most inflammatory published on brodalumab and bimekizumab. skin diseases, a temporary interruption might be considered for some patients in the context of SARS-CoV-2 vaccina- 3.9.3 IL‑23 Inhibitors tion (Table 1). Especially in patients with adequate disease control, holding treatment for a limited time period causes The IL-12/-23 inhibitor ustekinumab does not impair the limited harm. The most data are available for methotrexate, immunogenicity of influenza, pneumococcus, and tetanus where clinical studies have shown that a 2-week interruption vaccination [50, 51]. No data have been published regard- after influenza vaccination is sufficient to reverse vaccine- ing guselkumab, risankizumab, or tildrakizumab, although induced immunity to normal levels. similar results are to be expected. Ustekinumab has a half- Data for other drugs such as cyclosporine and corti- life of 20–39 days, guselkumab 12–19 days, risankizumab costeroids are more limited, although their short half-life 28 days, and tildrakizumab 23 days [52–55]. suggests that a similar strategy might work. Nonetheless, most patients receiving corticosteroids or cyclosporine are able to develop sufficient responses without discontinua- 3.9.4 Dupilumab tion. MMF severely affects antibody formation, and tempo- rary treatment adaptation might be considered if possible, The IL-4/-13 inhibitor dupilumab did not affect immunity although no strong evidence for the correct timing before in patients with eczema after tetanus and meningococcal or after vaccination is available. For TNF blockers (exclud- vaccines [56]. Interestingly, transient inhibition of IL-4 and ing etanercept), the moderately reduced efficacy of vacci- IL-13 using the decoy receptor IL-13Rα2 is being explored nation might not outweigh the risk of reduced long-term as a vaccine strategy to enhance mucosal and systemic efficacy because of the small increased risk for the devel- immunity. IL-4 and IL-13 negatively modulate ­CD8+ T-cell opment of antidrug antibodies. The available data indicate avidity [57]. that vaccine-induced immunity is not decreased in patients receiving IL-17 or IL-23 inhibitors. A largely uninvestigated R. Speeckaert et al. Table 1  Efficacy and practical information for systemic medication regarding SARS-Cov-2 vaccination for skin disorders Drug Half-life 94% elimination Reduced efficacy What can we say to our patients? (4 × half-life) of vaccination Methotrexate 3–15 h 12–60 h Mild–moderate Vaccine-induced immunity is decreased but expected to be sufficient in most patients [14, 15] Stopping treatment for 2 weeks after vaccination has successfully increased the efficacy of influenza vaccination [14] Cyclosporine 18 h 72 h Mild–moderate Vaccine-induced immunity is decreased but expected to be sufficient in most patients [16–18] Cyclosporine has a short half-life. Temporary interruption (e.g., stop 3 days before vaccination and ≥2 weeks after vaccination) might increase the effi- cacy of vaccination, but RWE is lacking Mycophenolate mofetil 15–18 h 60–72 h Moderate–severe Decreased antibody titers after vaccination are likely [18, 20] Temporary interruption (e.g., stop 3 days before vaccination and ≥ 2 weeks after vaccination) might increase the efficacy of vaccination, but RWE is lacking Corticosteroids 2–4 h 8–16 h Mild Vaccination responses are adequate in most patients [22–24] Dimethyl fumarate 1h 4h No–mild Vaccination responses are adequate in most patients [28] Apremilast 6–9 h 24–36h Unknown No data are available, but normal responses are expected Azathioprine 3–5 h 12–20h Mild Vaccination responses are adequate in most patients [17, 32, 33] JAK inhibitors 3 h; 12.5 h 12h; 50h Severe Diminished responses have been reported, but most patients can still mount (tofacitinib; baricitinib) sufficient immunity [34–37] A 2-week interruption (1 week before and 1 week after vaccination) seems inef- fective for reversing the decreased vaccine responses [34]. Therefore, a mini- mum treatment-free period of ≥2 weeks after vaccination could be necessary for optimal antiviral immunity. However, this is not substantiated by RWE TNF-α blockers 4–20 d 16–80d Mild–moderate Modestly impaired immunity after vaccination [38–41] Longer intervals and starting/stopping can cause reduced long-term efficacy, except for etanercept, which also has a short half-life Administration of vaccine midcycle or 2 weeks before the next dosage might be considered IL-17 inhibitors, IL-17 11–27 d 44–108 d No Currently available vaccines (influenza, meningococcus) have excellent efficacy receptor blocker (only based on data for secukinumab and ixekizumab) [42–45] It is unclear whether the vaccine-induced protection (IgA) in the upper airways will be as effective as in healthy controls Ixekizumab and brodalumab have a moderately short half-life (13 and 11 days, respectively) No evidence is available about whether temporary interruption seems reason- able IL-23 inhibitors 12–39 d 48–156 d No Currently available vaccines (influenza, tetanus, meningococcus, pneumococ- cus) have excellent efficacy (based only on data for ustekinumab) [50, 51] It is unclear whether the vaccine-induced protection (IgA) in the upper airways will be as effective as in healthy controls Long half-life No evidence is available as to whether temporary interruption seems reasonable in real life Dupilumab NR NR No Data suggest that COVID vaccination will be as effective as in normal individu- als [56] Omalizumab NR NR Unknown No published data No signals that vaccination is affected Rituximaba NR NR Severe Protective antibody formation is severely impaired [59] Cell-specific immunity is likely largely preserved Given the partial recuperation of B cells after 6–10 months, this time period is preferable for vaccination COVID coronavirus disease 2019, d days, IgA immunoglobulin A, IL interleukin, JAK Janus kinase, NR not relevant (the drug does not decrease the efficacy of vaccination), RWE real-world evidence, TNF tumor necrosis factor a The drug half-life of rituximab does not represent the duration of its immunologic effect What Can We Learn for SARS-Cov-2 Vaccination Strategies? topic is the theoretical decrease in IgA responses. IL-17A vaccines because of differences in the types of vaccination. acts as a defense line for outside body barriers, includ- The classic influenza vaccines are inactivated, mostly split- ing the respiratory tract and mucosae, by influencing IgA virus or subunit vaccines, and some contain live attenuated antibody formation. In mice, subcutaneous priming with a influenza virus (e.g., nasal spray vaccines). Pneumococcal recombinant antigen in a Th17-inducing adjuvant followed vaccines (PCV 13 and PPSV-23) carry a mixture of capsular by airway boosting promotes high and sustained levels of polysaccharides from Streptococcus pneumoniae. Tetanus dimeric IgA in the lungs, which are dependent on Th17 cells vaccines are based on tetanus toxoid combined with alu- and deficient if IL-17A is depleted [63]. Systemic vaccina- minum or calcium salts, and meningococcal vaccines are tion is unlikely to elicit significant divalent IgA responses in conjugate or recombinant protein vaccines. This contrasts the upper respiratory tract, unlike mucosal (e.g., intranasal) with the emphasis on RNA-based and viral vector vaccines vaccination. Additionally, the influence of blocking IL-17 or most frequently used for SARS-CoV-2 vaccination. IL-23 on the protective upper inflammatory tract responses Based on these differences, (inter-)national guidelines after mucosal vaccination remains to be elucidated. struggle to give consistent recommendations [66, 67, In patients receiving rituximab, the timing of vaccination 70–72]. Although some expert statements indicate that beyond 6 months after the last infusion leads to improved the risk of reduced SARS-Cov-2-induced vaccine protec- outcomes. JAK inhibitors decrease vaccination results. Evi- tion is not proven and no measures should be taken, others dence of how long this treatment should be interrupted to recommend performing the vaccination before initiating reach the efficacy seen in healthy controls is lacking, except treatment, interrupting some treatments, or administering that it is likely to be longer than 2 weeks. Anti-IL-4, anti- the vaccine midcycle in patients receiving biologics. In IL-13, or anti-IgE are unlikely to interfere with proper vacci- our opinion, the data on rituximab are sufficient to post- nation responses. Other drugs used in dermatology for their pone the vaccination until 6 months after the last dos- immunomodulating effects, such as dapsone, hydroxychloro- age of rituximab. For immunosuppressive drugs such as quine, and antibiotics (e.g., tetracyclines), have limited data methotrexate and cyclosporine, we recommend stopping and/or are not expected to interfere with vaccination [64]. treatment for 2 weeks after vaccination for patients aged How long immunomodulating/immunosuppressive drugs > 65 years or for patients with comorbidities that place should be stopped before and after vaccination is controver- them at risk for a more severe COVID-19 infection. Spe- sial. For live vaccines, biological agents or disease-modify- cial consideration should be given to patients receiving ing drugs should not be started until after 5 half-lives after multiple immunosuppressants. However, in our opinion, administration (high-dose corticosteroids: 4 weeks; etaner- treatment should only be temporarily stopped in patients cept: 4 weeks; TNFα inhibitors: 3 months; methotrexate ≥20 with well-controlled skin disorders where the risk of dis- mg/week: 4 weeks; and rituximab: 6–12 months) [65]. None ease flare is low. We believe that biologics (excluding of the currently authorized COVID-19 vaccines contain rituximab) can be continued without additional measures, live virus particles. For nonlive vaccines, this period is less although administering the vaccine midcycle or 2 weeks clearly defined as most recommendations state that treat- before vaccination can be considered for TNFα inhibitors ment should be continued in patients with immune-mediated if practicable. The value of shared decision making seems conditions [21]. As this also applies for COVID-19 vaccines, underappreciated in most national guidelines. most national guidelines on SARS-CoV-2 vaccination agree that treatment should be continued [66, 67]. In general, after 4–5 half-lives, 94–97% of a drug will be eliminated, which is 5 Conclusion believed to lie below clinically relevant concentrations [68]. Humoral responses for primary vaccinations begin with the Although most guidelines recommend continuing the production of specific low-affinity IgM antibodies after a immunosuppressive/immunomodulating treatments for lag phase usually within the first week after vaccination. skin disorders, dermatologists should be aware of their Higher affinity and avidity IgG antibodies can be detected potential to decrease vaccine-induced immunity. This is after 10–14 days, with maximum titers taking up to 4–6 especially clinically relevant in patients aged > 65 years weeks [21]. A minimum period of 2 weeks, up to 4 weeks, or those with comorbidities that place them at risk for a is generally recommended before (re-)initiation of the immu- more severe COVID-19 infection. nosuppressive/immunomodulatory treatment [69]. For drugs given in dosage intervals of ≥4 weeks, administration of Acknowledgements The research activities of R. Speeckaert and N. van Geel are supported by the Scientific Research Foundation-Flan- vaccines midcycle or 2 weeks before the next dose seems a ders (FWO Senior Clinical Investigator: 18B2721N and 1831512N, reasonable option [21]. It should be noted that the data on respectively) influenza, pneumococcal, meningococcal, and tetanus vac- cination may not be directly generalizable to SARS-CoV-2 R. Speeckaert et al. Declarations 9. Su F, Patel GB, Hu S, Chen W. Induction of mucosal immunity through systemic immunization: phantom or reality? Hum Vaccin Immunother. 2016;12:1070–9. Funding The research activities of R. Speeckaert and N. van Geel 10. Speiser DE, Bachmann MF. COVID-19: mechanisms of vaccina- are supported by the Scientific Research Foundation-Flanders (FWO tion and immunity. Vaccines (Basel). 2020;8:404. Senior Clinical Investigator: 18B2721N and 1831512N, respectively). 11. Sterlin D, Mathian A, Miyara M, Mohr A, Anna F, Claër L, et al. IgA dominates the early neutralizing antibody response to SARS- Conflict of Interest Reinhart Speeckaert, Jo Lambert, Luis Puig, Mari- CoV-2. Sci Transl Med. 2020;13:eabd2223. jn Speeckaert, Hilde Lapeere, Sofie De Schepper, and Nanja van Geel 12. Wang Z, Lorenzi JCC, Muecksch F, Finkin S, Viant C, Gaebler have no conflicts of interest that are directly relevant to the content of C, et al. Enhanced SARS-CoV-2 neutralization by dimeric IgA. this article. Sci Transl Med. 2020;13:eabf1555. 13. King RG, Silva-Sanchez A, Peel JN, Botta D, Meza-Perez S, Allie Availability of data and material Not applicable. SR, et al. Single-dose intranasal administration of AdCOVID elic- its systemic and mucosal immunity against SARS-CoV-2 in mice. Ethics approval Not applicable. bioRxiv. Cold Spring Harbor Lab 2020;2020:331348. 14. Park JK, Choi Y, Winthrop KL, Song YW, Lee EB. Optimal time Consent Not applicable. between the last methotrexate administration and seasonal influ- enza vaccination in rheumatoid arthritis: post hoc analysis of a Author contributions RS performed the literature search and wrote the randomised clinical trial. Ann Rheum Dis. 2019;78:1283–4. draft of the article. All authors critically revised the review. All authors 15. Park JK, Lee YJ, Shin K, Ha Y-J, Lee EY, Song YW, et al. Impact read and approved the final manuscript. of temporary methotrexate discontinuation for 2 weeks on immu- nogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis. 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