COVID vaccine recommendations in dermatologic patients on immunosuppressive agents: Lessons learned from pandemic

Abstract

Background

Since SARS‐CoV2 vaccines were approved without enough long‐term monitoring due to emergent situations, some issues have been raised about timing and protocol of receiving them by patients treated by different immunosuppressive agents.

Aim and Method

Here, we present different aspects of SARS‐CoV‐2 vaccination in such patients in the field of dermatology.

Result

In brief, SARS‐CoV‐2 vaccination is recommended in all dermatologic patients, regardless of their disorders and therapeutic regimens. Nevertheless, special considerations should be given to the immunosuppressive therapy and its association with vaccination timing due to the decreased immunogenicity of vaccines in this setting.

Conclusion

Novel biologic immunotherapies are advantageous over conventional systemic therapies not only in their safety and selective functions but also in this aspect that many of them do not affect vaccines immunogenicity.

1. INTRODUCTION

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has posed any field of medicine to challenges through various routes. Many of the dermatologic disorders are chronic, long‐lasting and sometimes, difficult‐to‐treat; moreover, most dermatologic disorders are immune‐mediated; therefore, immunosuppressive or immunomodulatory medications are administered for achieving favorable response. On the other hand, these patients who are iatrgenically immunosuppressed are prone to severe infections, including SARS‐CoV‐2 infection. Therefore, vaccination may be a necessity in these patients in order to prevent unfavorable consequences of the coronavirus disease 2019 (COVID‐19) and the related mortality. ¹ However, vaccine‐induced antibody response may be affected by concomitant immunosuppressive therapy, so as necessitating a temporary interruption of treatment, but this should be done on a logical basis and according to authorized guidelines since it can sometimes lead to increased risk of dermatologic disorders flare. ² Therefore, challenges and questions arise about the immunogenicity of SARS‐CoV‐2 vaccinations in these patients, that should be discussed.

As SARS‐CoV‐2 vaccines are newly introduced, most of the information about the impact of immunosuppressive agents on this vaccine type turns back to that of previously administered or routine vaccines; however, many of the experiences can be attributed to COVID‐19 vaccines and it is supposed that immunosuppressive agents can also decrease the efficacy of SARS‐CoV‐2 vaccines. ³

Here, we present a comprehensive review of immunosuppressive agents used in dermatologic patients, and provide an overview on vaccine‐induced immune response and the ideal timing of vaccination in these patients.

1.1. Immunosuppressive/immunomodulatory agents and their use in dermatology

Systemic medications utilized in dermatology are quite diverse and numerous. Depending on the pathophysiologic mechanism underlying every certain dermatosis, a specific class of medications are applied for treatment. In general, immunomodulatory agents have narrower spectrum of action and affect a specific pathway or cell type, while targets of immunosuppressive agents are broader and function on intracellular immune pathways. ⁴

Systemic conventional immunosuppressants consist of systemic corticosteroids, azathioprine, cyclophosphamide, cyclosporine, methotrexate and mycophenolatemofetil (MMF). Systemic corticosteroids, mostly prednisolone, are used in almost all dermatologic disorders that do not respond to topical therapy; examples include eczema, dermatitis and pemphigus. ⁵ Azathioprine is the common medication of use in systemic lupus erythematosus (SLE); however, it has been administered in recalcitrant cases of atopic dermatitis. ⁶ Cyclosporine and methotrexate have also been included in the therapeutic regimens of psoriasis and atopic dermatitis patients. ⁷ , ⁸ Mycophenolatemofetil (MMF) is administered in many immune‐mediated dermatologic disorders, namely SLE, lichen planus and pemphigus. ⁹ Cyclophosphamide had been conventionally used for the treatment of autoimmune blistering disorders like pemphigus. ¹⁰ And lastly, hydroxychloroquine is usually the first DMARD of choice in the treatment of SLE. ¹¹

The invention of novel immunosuppressants/immunomodulators with selective targets has opened a promising window in the management of dermatologic diseases with less side effects and drug interactions. Biologics, small molecule inhibitors, and immune checkpoint inhibitors (ICI) are among the most popular novel immune therapeutics. Biologics include IL‐4R inhibitors (dupilumab) used for atopic dermatitis; IL‐17 inhibitors (brodalumab, ixekizumab, secukinumab), IL‐12/23 inhibitor (ustekinumab), and IL‐23 inhibitors (guselkumab, risankizumab) used for psoriasis; anti‐IgE (omalizumab) used for chronic spontaneous urticaria; anti‐CD20 agents (rituximab) used for pemphigus vulgaris; and TNF inhibitors (adalimumab, certolizumab, infliximab, etanercept, golimumab) used for psoriasis. Novel small‐molecule inhibitors, including JAK inhibitors (Baricitinib, tofacitinib, and upadacitinib), are sometimes used in the treatment of atopic dermatitis and psoriasis. Immune checkpoint inhibitors (ICIs), including CTLA‐4 inhibitors (ipilimumab), PD‐1 inhibitors (nivolumab, pembrolizumab), and PD‐L1 inhibitors (avelumab), are common components of skin cancers immunotherapy. ¹² , ¹³ , ¹⁴ , ¹⁵

1.2. The necessity of vaccination in dermatologic patients

Although COVID‐19 vaccination has been associated with several cases of new‐onset or exacerbated dermatologic disorders, the estimated risk of these complications is sufficiently low to recommend vaccination in this population. ¹⁶ , ¹⁷ , ¹⁸ Moreover, as immunocompromised dermatologic patients are more vulnerable to COVID‐19‐related morbidity and mortality, preventive measures, predominantly by vaccination, is a reasonable approach in order to prevent unfavorable consequences. ¹⁹ Despite the lower humeral response to vaccination in dermatologic patients on immunosuppressive therapy, these patients should be encouraged to get vaccinated as soon as possible since the benefits of vaccination outweigh the potential risks of acquiring a life‐threatening disease. ²⁰ This recommendation is stronger for those dermatologic patients who are on at least two immunosuppressive/immunomodatory agents; those with at least one comorbidity, including diabetes mellitus, chronic kidney disease (with stage 5), ischemic heart disease and hypertension; and older age. ²¹

1.3. The impact of immunosuppressive/immunomodulatory therapy on vaccine‐induced humoral or cellular response

Conventional DMARDs and novel biologic agents have different mechanisms of action, thereby leading to various degrees of immune response impairment following vaccination. In addition, a combination of two or more immunomodulators can further reduce SARS‐CoV‐2 vaccine efficacy. ²² It seems that the degree of seroconversion alone does not represent vaccine immunogenicity, since vaccine‐induced cellular immunity seems to have even a more important role, compared with humoral immunity for achieving protection against respiratory viruses such as influenza and SARS‐CoV‐2. ²³ , ²⁴ It has been demonstrated that despite the decreased vaccine‐induced humoral immune responses in patients receiving B‐call depleting agents, T‐cell responses are still intact and the mere cellular responses following vaccination may suffice for protection against SARS‐CoV‐2. ²⁵ , ²⁶

1.4. Conventional systemic therapies

Among the conventional immunosuppressive agents, dimethyl fumarate and hydroxychloroquine do not influence vaccine‐induced humoral immune responses, while cyclosporine, cyclophosphamide and azathioprine might show poor responses to vaccination. MMF also can decrease vaccine‐induced immunogenicity particularly in doses of more than 2 g/day. ²⁷ , ²⁸ , ²⁹ Corticosteroids may also affect antibody responses to vaccination; however, the impact is correlated with the dose and length of treatment. Prednisolone at a dose of 10 mg/day might decrease vaccine‐induced humoral responses, while high dose corticosteroids equivalent to more than 20 mg/day of prednisone for longer than 2 weeks definitely interferes with antibody production. ¹⁵ The most profound impairment of the immunogenic response is demonstrated following methotrexate therapy. This unfavorable outcome is reported both in methotrexate monotherapy and combination therapy with biologics. ³⁰ , ³¹ , ³²

1.5. Novel systemic therapies

In general, antibody production is preserved during anti‐TNF monotherapy; sometimes, it may be delayed up to 4 weeks post‐vaccination but the ultimate outcome is favorable; however, the immune response may be diminished during combination therapy with methotrexate. Therefore, SARS‐CoV‐2 vaccination is supposed to be both safe and effective during anti‐TNF therapy. ³³ , ³⁴ , ³⁵ Similarly, IL‐12/IL‐23 Inhibitors appear to lead to no meaningful decrease in SARS‐CoV‐2 vaccine‐induced immune response. ³⁶ Moreover, adequate vaccine‐induced response has been demonstrated during treatment with IL‐17 and IL‐17 Receptor antagonists, even in combination with DMARDs. ³⁷ , ³⁸ Anti‐IgE agents (omalizumab) also do not seem to result in antibody titers decrease after vaccination. JAK inhibitors, including baricitinib, tofacitinib and upadacitinib, may lead to suboptimal vaccine‐induced immune responses, but consumers most often can mount adequate immunity. ³⁹ ICIs do not seem to diminish responsiveness to vaccines, including COVID vaccines. And the last, but not the least, monoclonal antibodies like rituximab exert B‐cell depleting effects, therefore they are associated with reduced seroprotection and antibody production after vaccinations, even up to 6 months.

1.6. Timing of vaccination in accordance with the use of immunosuppressive/immunomodulator agents

Almost all guidelines, including the Advisory Committee on Immunization Practices (ACIP), the British Association of Dermatology, the American Academy of Dermatology, the American College of Rheumatology, the New England Journal of Medicine (NEJM) and the Centers for Disease Control and Prevention, have consensus on how and when to vaccinate immunocompromised patients who are on immunosuppressive agents.

In dermatologic patients who are planned to be started on immunosuppressive/immunomodulator agents, it is reasonable to expedite COVID‐19 vaccination in order to mount optimum antibody response before treatment initiation. However, SARS‐CoV‐2 vaccination status should be evaluated before starting dermatologic patients who are already on immunocompromising agents. Ideally, SARS‐CoV‐2 vaccination should be completed at least 2 weeks prior to starting dermatologic patients on immunosuppressive therapies. ⁴⁰ Then, depending on the immunosuppressant type and the vaccine platform, decision should be made to define the interval between treatment and vaccination in order to optimize the vaccine efficacy. ⁴¹

In general, live attenuated vaccines are contraindicated during immunomodulatory/immunosuppressive therapy since they may be followed by virus transmission or active infection. However, in conditions that benefits of administration of live vaccines outweigh the risks, they should be given either 2–4 weeks prior to treatment initiation or after 1–3 months of therapy cessation, with the aim of achieving a favorable antibody response. Fortunately, none of the introduced SARS‐CoV‐2 vaccines have been of this type up to the present time, thus the risk of vaccine‐induced severe infections are minimal in immunosuppressed patients. Conversely, non‐live vaccines, including protein‐based, viral‐vector, inactivated and recombinant ones, have more suitable safety profile and can be given concomitantly to immunomodulatory/immunosuppressive therapies. ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ It is important to know that if the dermatologic disorder is in its active and exacerbating phase, immunosuppressive systemic therapies should not be ceased because of vaccination and can be continued along with vaccination schedule.

Most of the immunosuppressive agents can be administered concomitantly with SARS‐CoV‐2 vaccination. For example, topical medications, non‐immunosuppressive systemic agents like acitretin and apremilast, and phototherapy have no impact on the efficacy of COVID vaccines, therefore, they can be administered concomitantly with vaccination. ⁴⁶

Dermatologic patients who are on corticosteroid therapy at a prednisone‐equivalent dose of more than 20 mg/day and are stable should be advised to get vaccinated after reducing the steroid dosage to less than 10 mg prednisolone daily if possible. ⁴⁷

Although azathioprine and cyclosporine may lead to decreased post‐vaccination antibody titers, no interruption is needed in treatment while receiving SARS‐CoV‐2 vaccine doses. However, there is controversy as many authorities recommend continuation of cyclosporine and azathioprine when being vaccinated, while others advise to temporarily withhold them before and after vaccination. It is postulated that since cyclosporine is usually used as a temporary or bridging therapy, vaccination should be done before starting it. ¹⁹ , ⁴⁸ Some authorities believe that due to the short half‐life of cyclosporine, interruption of therapy for at least 3 days before vaccination and more than 2 weeks after vaccination can increase the immunogenicity of the vaccines. ⁴⁹ For patients on cyclophosphamide, vaccination can be held while being on oral therapy, but it is better to interrupt treatment for 1 week after every vaccine dose if the patient is on intravenous treatment. ⁴⁷ Inactivated vaccines can be effectively administered at any time during hydroxychloroquine therapy. ²

The issue is different for methotrexate and MMF as a minimum of 2 week interval is warranted between methotrexate and MMF use and the vaccine dose. Nevertheless, some guidelines recommend 1 week interval between the last methotrexate and MMF dose and each COVID vaccine dose in dual‐dose regimens (i.e., AstraZeneca and Pfizer), and 2 weeks interval in single‐dose regimens (i.e., Johnson and Johnson's) in well‐controlled diseases in order to improve COVID vaccine immunogenicity. ⁵⁰ However, it is emphasized that if interruption of treatment is not feasible due to the active disease, SARS‐CoV‐2 vaccines can be administered while on treatment. Lowering the immunosuppressant dose can be an alternate strategy if stopping the therapy or delaying vaccination is not feasible. ⁵¹

Biologic agents like IL‐17, IL‐23/IL‐12 blockers and anti‐TNF agents are supposed to impair vaccine‐induced humoral response; nevertheless, these agents have been proved to be noninterfering with vaccine‐induced immunity in practice and can be administered safely and effectively concomitantly with vaccination, but it is still better to space at least 7 days between vaccination and biologic/immunomodulator dosing. ⁵² , ⁵³ However, for non COVID vaccines, it had been advised to ideally delay anti‐TNF therapy until 4 weeks after vaccination. ⁵⁴ The important issue is the fact that starting/stopping of anti‐TNFs can decrease their long‐term efficacy, hence, more prolonged intervals should be avoided. ⁵⁵

Omalizumab withholding or dose reduction is not necessary while being vaccinated against SARS‐CoV‐2. JAK inhibitors like baricitinib, tofacitinib and upadacitinib, should be held for 1 week after each vaccine dose, but ICIs do not need to be temporarily interrupted at the time of SARS‐CoV‐2 vaccination, even in combination with anti‐angiogenic or intratumoral oncolytic agents. Nonetheless, if B cell‐depleting or chemotherapeutic agents are planned to be administered simultaneously with ICIs, vaccination should be done at least 3 weeks before beginning treatment. ⁴⁷ , ⁵⁶

Monoclonal antibodies are quite different from other immunosuppressants/ immunomodulators. In stable dermatologic disorders, anti CD‐20 agents, namely rituximab, should be temporarily withdrawn at the time of vaccination and the first vaccine dose should be administered at least 4 weeks before the next rituximab cycle. This agent can be resumed 2–4 weeks after the last vaccine dose. However, antibody production might be affected even up to 6 months post rituximab therapy. ⁵⁷ , ⁵⁸

On the other hand, vaccine type or platform is also important in the decision‐making to interrupt immunosuppressive therapy. For example, since the routine interval between Pfizer BioNTech and Moderna vaccines doses ranges between 3 and 4 weeks, interruption of immunosuppressants for several weeks might be required, which predisposes the patient to exacerbation of the underlying dermatologic disorder, while AZD1222 (Oxford/Astra Zeneca) vaccine with an interval of 3 months between the doses, might rarely need a prolonged interruption in treatment. ⁵⁹

Another important question is whether additional vaccine dose is needed for dermatologic patients who are on immunosuppressive therapy. Up to the present time, no recommendation has been updated for additional vaccine dosing in these individuals. Furthermore, monitoring neutralizing antibody titers after vaccination for justifying efficacy has not been recommended; however, assessment of antibody titers after vaccination and considering booster doses based on vaccine response is reasonable. ²⁹ , ⁶⁰

2. CONCLUSION

Dermatologists might also be involved in counseling about SARS‐CoV‐2 vaccination as they are the ones who can convince patients of the safety and efficacy of COVID vaccines. Every decision should be made after weighing the risk‐benefits of vaccination in this group of patients. In general, SARS‐CoV‐2 vaccination is recommended in all dermatologic patients, regardless of their disorders and therapeutic regimens. The reason is both their immune dermatologic conditions that make them susceptible to severe SARS‐CoV‐2 infection and the medications used in this context. Nevertheless, special considerations should be given to the immunosuppressive therapy and its association with vaccination timing. This is due to the decreased immunogenicity of vaccines in the settings of taking immunosuppressive agents. Novel biologic immunotherapies are advantageous over conventional systemic therapies not only in their safety and selective functions but also in this aspect that many of them do not affect vaccines immunogenicity. Nonetheless, being assured of vaccine response might sometimes be necessary in these patients. Finally, since many studies incorporated in this review are small and a lot of information presented is based on guideline recommendations or expert opinion which should be further studied, making final decision based on specific features of each patient is recommended.

AUTHOR CONTRIBUTIONS

M.Z., Z.R., P.H. and Z.M. performed the research. K.B. and Z.A. designed the research study. Z.R., Z.A. and K.B. analyzed the data. P.H. and Z.M. wrote the paper. All authors contributed to the finalization of this article.

CONFLICT OF INTERESTS

All the authors declare that there is no conflict of interest.

ETHICAL APPROVAL

None.

Aryanian Z, Balighi K, Afshar ZM, Zamanian MH, Razavi Z, Hatami P. COVID vaccine recommendations in dermatologic patients on immunosuppressive agents: Lessons learned from pandemic. J Cosmet Dermatol. 2022;21:6568‐6573. doi: 10.1111/jocd.15448

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.