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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 39  |  Issue : 4  |  Page : 169-174

Taiwan dermatological association recommendations for coronavirus disease of 2019 vaccination in patients treated with immunotherapeutics


1 Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung; Department of Dermatology, Chang Gung University College of Medicine, Taoyuan, Taiwan
2 Department of Dermatology, Chang Gung University College of Medicine, Taoyuan; Department of Dermatology, Taipei Chang Gung Memorial Hospital, Taipei, Taiwan
3 Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

Date of Submission13-Aug-2021
Date of Decision18-Oct-2021
Date of Acceptance10-Nov-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Dr. Chia-Yu Chu
Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan South Road, Taipei 10002
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ds.ds_50_21

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  Abstract 


This article aims to present current COVID-19 vaccination considerations for patients on immunotherapeutics for the management of immune-mediated dermatological diseases and summarize the recommendations relevant to clinical practice in Taiwan. These Taiwan Dermatological Association (TDA) recommendations are intended to be dynamic in nature and serve as an interim guide to optimize patient care at this current juncture. It is expected that our clinical practice would continually evolve and be informed by new evidence that emerges in this pandemic.

Keywords: COVID-19 vaccination, immunotherapeutics, Taiwan dermatological association recommendations


How to cite this article:
Lee CH, Huang YH, Chu CY. Taiwan dermatological association recommendations for coronavirus disease of 2019 vaccination in patients treated with immunotherapeutics. Dermatol Sin 2021;39:169-74

How to cite this URL:
Lee CH, Huang YH, Chu CY. Taiwan dermatological association recommendations for coronavirus disease of 2019 vaccination in patients treated with immunotherapeutics. Dermatol Sin [serial online] 2021 [cited 2022 Jun 30];39:169-74. Available from: https://www.dermsinica.org/text.asp?2021/39/4/169/334167




  Introduction Top


The pandemic caused by the coronavirus disease of 2019 (COVID-19) is an unprecedented global public health crisis that has already claimed more than 4 million lives to date.[1],[2] Waves of COVID-19 outbreaks are still ongoing in different regions worldwide, with new variants emerging constantly.[1] The recent approval of novel mRNA and adenovirus vector vaccines has brought a glimpse of hope to managing this raging global pandemic.[3],[4] However, the effects of COVID-19 and associated vaccinations remain as unchartered territory, with numerous clinical trials still underway. The number of questions that arise parallels that of new discoveries being made on COVID-19 infection, interventions, and preventive measures.

Discussions regarding vaccine efficacy have largely centered around the mounting of adequate cellular and humoral immune responses, an issue of particular relevance to dermatologists and dermatoimmunologists managing patients already on immunotherapeutics for various autoimmune and inflammatory skin disorders.[4],[5],[6] Immunotherapeutics such as systemic immunosuppressants, biologics, small molecule inhibitors, and immune checkpoint inhibitors (ICI) are often prescribed for dermatological disorders including atopic dermatitis, psoriasis, psoriatic arthritis, urticaria, melanoma, and pemphigus.[7],[8] Since original vaccine trials excluded immunocompromised patients, the effects of COVID-19 vaccinations on patients with preexisting immunologic conditions have yet to be elucidated. Clinical decision-making up to this point is informed by evidence mostly extrapolated from previously existing vaccines or vaccine platforms.[9] Logically, questions arise regarding immunologic considerations in this vulnerable patient population in the setting of receiving timely and adequate COVID-19 vaccine coverage. What is the impact of immunosuppressive therapy on the efficacy and immunogenicity of vaccinations? Are there drug interactions and/or safety issues to be considered? Should vaccination timing be individualized for patients on immunotherapeutics to optimize vaccine coverage while adequately managing the underlying autoimmune or inflammatory disorder? These questions, if remained unanswered, can result in hesitancy in both physicians and patients to receive necessary and timely preventive vaccination measures against COVID-19.

Considering the critical impact, we reviewed the latest leading international guidelines and position statements published in 2021 to address this unique clinical challenge.[6],[9],[10],[11],[12],[13] This article aims to present current COVID-19 vaccination considerations for patients on immunotherapeutics for the management of immune-mediated dermatological diseases and summarize the recommendations relevant to clinical practice in Taiwan. These Taiwan Dermatological Association (TDA) recommendations are intended to be dynamic in nature and serve as an interim guide to optimize patient care at this current juncture. It is expected that our clinical practice would continually evolve and be informed by new evidence that emerges in this pandemic.


  Recommendations Top


General considerations

While direct evidence on the safety and efficacy of COVID-19 vaccines in patients receiving immunotherapeutics remain limited, there is overwhelming international consensus that the estimated risk of adverse events is considered low based on current published literature.[4],[6],[9],[12],[13],[14] [Table 1] summarizes the general principles and recommendations guiding the administration of COVID-19 vaccination in dermatology patients. Aside from known anaphylaxis or severe hypersensitivity to vaccine excipients, there are no additional contraindications in this patient group.[4],[9],[12] There is, however, a theoretical risk for disease flare that cannot be completely ruled out. Transient eczema exacerbation has been observed as a general immune response to other vaccinations, and cutaneous manifestations of the COVID-19 infection have been reported.[15],[16] Therefore, vaccines should optimally be given at a time when the underlying condition is well-controlled. Overall, the risk-benefit ratio of COVID-19 vaccination is exceedingly favorable in patients receiving immunotherapeutics, with vaccination highly encouraged if immunosuppression is low and there is a significant risk of COVID-19 disease development and morbidity.[4],[12] Patients with immune-mediated dermatologic disorders, in general, are not expected to have altered immunogenicity and, therefore, are not precluded from the benefits of COVID-19 vaccination. [Table 2] highlights the few selected agents that may pose an elevated risk of impaired antibody production and vaccine response attenuation, necessitating either dose modification or dosing interval adjustments.[4],[6],[9] In these cases, postvaccination antibody titers should be monitored to detect the need for additional vaccine boosters. Specific recommendations for commonly used systemic immunosuppressants, biologics, small molecule inhibitors, and ICIs in dermatology patients are also summarized in [Table 2].
Table 1: General recommendations for coronavirus disease 2019 vaccination in dermatology patients

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Table 2: Taiwan dermatological association recommendations for coronavirus disease 2019 vaccination in patients with immune-mediated dermatologic disorders

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Systemic therapy

Systemic corticosteroids are widely used to treat autoimmune and inflammatory skin disorders. However, patients receiving systemic corticosteroids may withstand the risk of reduced antibody production after COVID-19 vaccination.[4] Concerns have been raised regarding a possible attenuation of vaccine response in high-dose regimens.[4],[9] A prednisone-equivalent regimen of ≥20 mg/day has been associated with reduced seroconversion rates and/or impaired immune response in patients receiving non–COVID-19 vaccines.[4] Hence, to optimize vaccine response, a dose adjustment to a prednisone-equivalent of <20 mg/day is advisable, assuming disease stability is achieved.[9],[12]

Regarding other systemic immunosuppressive agents, methotrexate (MTX) is associated with having a negative effect on the immunogenicity of nonviral vaccines. Up to 62% of individuals with immune-mediated inflammatory diseases receiving MTX were found to have inadequate immunogenicity as measured by immunoglobulin G antibody levels after receiving the BNT162b2 mRNA vaccine compared to healthy controls.[20] Moreover, MTX was predicted to have a risk of reduced antibody production following COVID-19 vaccination.[4] Accordingly, the American College of Rheumatology (ACR) Guidance recommends that in patients with well-controlled disease, MTX should be withheld for 1 week after each vaccination in dual-dose regimens, or for 2 weeks in single-dose regimens (i.e., Johnson and Johnson's JNJ-78436735).[9] Reduced immunogenicity was also noted with mycophenolate mofetil (MMF), particularly in doses >2 g/day, in patients receiving non–COVID-19 vaccines.[4],[9] Thus, assuming that the disease is stable, MMF should be held for 1 week following each vaccination.[9]

Considering the concern for reduced antibody production is similar across systemic immunosuppressants, even though current guidelines do not explicitly address the duration of corticosteroid dose modification and the optimal time to resume prevaccination dosage, in our expert opinion, it is reasonable to infer, based on guidelines for MTX and MMF, that re-initiation of dosages ≥20 mg/day should be deferred until 2 weeks after the final vaccination. Lastly, although azathioprine and cyclosporin may reduce vaccination response in certain instances, current guidelines unanimously agree that temporary withdrawal or modifications are not necessary.[4],[9],[12]

Biologics

Biologic medications are approved by the Taiwan Food and Drug Administration for several autoimmune and inflammatory skin disorders, such as atopic dermatitis, pemphigus vulgaris, psoriasis, psoriatic arthritis, and chronic spontaneous urticaria. Among various biologics, tumor necrosis factor-α inhibitors, rituximab, and ustekinumab appear to be related to a decrease in postvaccination antibody titers. In contrast, brodalumab, ixekizumab, and secukinumab appear to have little effect on antibody levels.[4] Albeit the differences in postvaccination antibody titers with different biologics, based on current evidence and expert opinions, no modification is required for patients receiving these biologics except for rituximab, which should be withheld at the time of vaccination.[4],[9] If disease activity allows, COVID-19 vaccines should optimally be administered 4 weeks before the next scheduled rituximab cycle, and a 2–4-week interval is recommended between the final vaccination dose and re-initiation of rituximab infusions.[9] There is no increased risk of allergic reactions to COVID-19 vaccination for patients with atopic dermatitis or chronic spontaneous urticaria irrespective of active treatment; however, it should be noted that vaccine-related skin reactions, such as transient eczema or urticaria exacerbation, may occur following vaccination.[15] It is also worth noting that current guidelines do not preclude patients on omalizumab from receiving COVID-19 vaccination at any time.[4],[15] However, considering that omalizumab carries a slight risk of anaphylactic skin reactions,[21] which may, in turn, mask vaccine-associated allergic reactions, it is advisable - based on our expert opinion - to avoid administering both on the same day.

Small molecule inhibitors

Janus kinase (JAK) inhibitors have recently emerged as a class of small molecule inhibitors that effectively block JAK signaling pathway, thereby reducing the associated inflammatory and immune response.[8] JAK inhibitors have been approved for the management of various dermatological conditions such as atopic dermatitis and psoriatic arthritis.[22] Despite being considered as safe therapies during the COVID-19 pandemic, JAK inhibitors may carry a potential risk of impaired antibody production after COVID-19 vaccination.[4] The effect of JAK inhibitors on interferon signaling may subsequently lead to an attenuation of the vaccine response.[9],[23],[24] In one study, patients initiating treatment with tofacitinib, especially when taken concomitantly with MTX, demonstrated a diminished response to the 23-valent pneumococcal polysaccharide vaccine 23, though not to the influenza vaccine.[24] Nevertheless, preserved immunogenicity has been observed in patients receiving non-COVID-19 vaccines 2–3 weeks before starting tofacitinib.[4] A recent study reported that about two-thirds of patients on long-term baricitinib achieved satisfactory humoral and functional responses to the 13-serotype pneumococcal conjugate vaccine 13.[23] Based on these findings and the limited evidence available to date, it is recommended that JAK inhibitors should be held for 1 week after each vaccine dose regardless of underlying disease activity.[9]

Immune checkpoint inhibitors

ICIs are used in dermatology to treat various types of skin cancer, such as Merkel cell carcinoma, squamous cell carcinoma, and melanoma. Since ICIs exert their antitumor action by blocking inhibitory synapses, they have the potential to bolster the immune response instead of reducing it.[17],[25] Currently, the interplay between COVID-19 vaccination and ICI therapy has yet to be elucidated. A study conducted on 134 Israeli patients who received the BNT162b2 mRNA vaccine while on ICIs and ICI-chemotherapy combination demonstrated favorable safety data, with no vaccine-or ICI-related severe adverse events observed.[19] Therefore, based on our knowledge of the ICI mechanism of action, coupled with current clinical data and historic evidence of seroconversion after influenza vaccines in ICI-treated patients, COVID-19 vaccination is expected to be safe and effective during concomitant use of ICIs and should be pursued without delay.[17],[18],[26],[27] In patients receiving ICIs alone or in combination with anti-angiogenics or intratumoral oncolytic virus, COVID-19 vaccination should follow routine practice without adjustment. In patients receiving ICIs in combination with chemotherapy, or B-cell-directed immunotherapies, it is recommended to have the first COVID-19 vaccine dose 3 weeks before the initiation of treatment.[17] Another caveat for consideration surrounds patients receiving investigational ICI therapy, in which post-vaccination side effects (i.e., fever) can potentially be misattributed as treatment-related adverse events. As such, some authors suggest avoiding vaccination 1–2 days prior to scheduled ICI treatment.[27]


  Conclusion Top


Continuity of treatment is of utmost importance in this patient population. The consequences of treatment interruption or cessation can be paramount. Immunotherapeutics are expected to be safe, and most should be continued without disruption through the COVID-19 vaccination period, with a few exceptions which warrant judicious modification to dosage and/or administration timing as clinically feasible and appropriate. MTX, MMF, and JAK inhibitors are recommended to be withheld 1–2 weeks postvaccination, while rituximab infusions should be adjusted such that vaccination occurs 4 weeks before the next cycle and withheld until 2–4 weeks after the final vaccine dose [Figure 1]. Dermatologists and patients are encouraged to actively engage in shared decision-making, taking into consideration personal and societal factors such as disease activity and vaccine availability. This TDA guide for managing patients with immune-mediated disorders in the COVID-19 vaccination era is a living document. It is anticipated to evolve with emerging evidence and will be updated continually to bridge the clinical gaps.
Figure 1: Graphic summary of recommended time intervals for dose modification or withdrawal of immunotherapeutics in dermatology patients undergoing COVID-19 vaccination. IgE: Immunoglobulin E, IL: Interleukin; JAK: Janus kinase, MMF: mycophenolate mofetil; MTX: Methotrexate; TNF: Tumor necrosis factor.

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Financial support and sponsorship

Nil.

Conflicts of interest

This work was partially funded by Sanofi Taiwan Co., Ltd. and Novartis Taiwan Co., Ltd. However, both companies were not involved in any aspect of the writing or editing of this manuscript before or after its publication. The comments, views, and conclusions set out in the manuscript represent those of the authors, independent of any input or influence from both companies.

Prof. Chih-Hung Lee and Chia-Yu Chu, editorial board members at Dermatologica Sinica, had no roles in the peer review process of or decision to publish this article. Dr. Yu-Huei Huang declared no conflicts of interest in writing this paper.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]


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