Abstract
Background
Atopic dermatitis (AD) patients usually wonder if their condition will worsen after vaccination or if they should continue with the treatment they are receiving. Considering that many patients treated with dupilumab had previously experienced severe AD symptoms and flares, the concerns are more understandable.
Objective
This study aimed to investigate the safety of the coronavirus disease 2019 (COVID-19) vaccination in patients with AD treated with dupilumab.
Methods
We enrolled 133 patients (101 dupilumab-treated and 32 systemic oral agents-treated as control group) with AD from six hospitals. Patients were asked about worsening pruritus and AD (5-point Likert scale) after vaccination. AD variables (eczema area and severity index [EASI], investigator’s global assessment [IGA], itch numerical rating scale [NRS], sleep NRS, and patient-oriented eczema measure [POEM]) were compared pre- and post-vaccination. Adverse reactions to the COVID-19 vaccination were observed.
Results
The incidence of adverse reactions to COVID-19 vaccines and worsening AD symptoms in dupilumab-treated patients were not significantly different compared with that in the control group. The itch NRS score increased significantly after vaccination (p<0.001). However, there were no statistically significant differences between the pre-and post-EASI, IGA, and POEM scores. Eight patients (7.9%) had worse EASI scores and required rescue therapy; however, most were easily managed with low-dose steroids or topical agents. None of the patients discontinued dupilumab treatment.
Conclusion
No serious adverse reactions were observed in patients with AD after COVID-19 vaccination. Exacerbation of pruritus and AD symptoms was observed but was mostly mild and transient.
Keywords: Atopic dermatitis, COVID-19 vaccines, Dupilumab
INTRODUCTION
Vaccination is an important component of the current global effort to overcome the coronavirus disease 2019 (COVID-19) pandemic. Dermatologists are not free from questions related to vaccinations; patients with atopic dermatitis (AD) are aware of a predisposition to develop allergies, and wonder if their condition will worsen after vaccination, or if they should continue with the treatment they are receiving.
Dupilumab is a monoclonal antibody that targets the alpha subunit of the interleukin (IL)-13 receptor which has shown significant efficacy in patients with moderate-to-severe AD1. The current understanding and recommendations for COVID-19 show no indication that AD is a risk factor to alter the vaccination schedule, and its potential to cause AD flare-up is unclear2,3, while dupilumab is also not expected to cause vaccine attenuation4. However, considering that many patients treated with dupilumab have experienced moderate to severe AD symptoms and may have experienced flares, concerns regarding vaccination are understandable. Therefore, the aim of this study was to investigate whether the COVID-19 vaccines were safe for AD patients being treated with dupilumab, and whether vaccination caused a flare of AD symptoms in a real-world setting.
MATERIALS AND METHODS
Study design and population
This multicenter, observational study was conducted between July and October 2021 at six hospitals. Patients with AD aged ≥18 years who had been treating with dupilumab for at least 1 month and those who were vaccinated against COVID-19 within 2 weeks prior to the study were considered eligible. AD patients treated with systemic oral agents including cyclosporine or methotrexate of the same criteria were included as a control group. Patients taking concomitant topical steroids and oral antihistamines were included. Physicians evaluated the patients to determine the AD variables, and both demographic and clinical information was retrieved from the medical records. Patients who had insufficient medical records were excluded. The institutional review board of each participating site reviewed and approved the retrospective study protocol and waiver of informed consent (IRB number of the Chosun University Hospital: 2021-10-003).
Patient demographics included age, sex, underlying diseases, allergic disease history, and cutaneous allergic history. The checked records included an investigation of the type and dose of the vaccine, systemic and cutaneous adverse events, pruritus, any change in AD symptoms change (assessed on a 5-point Likert scale: much worse, worse, no change, better, much better), the type of aggravated AD symptoms (erythema, edema/papule, excoriation, dryness, lichenification), and its duration. If rescue therapy was performed due to worsening AD symptoms, treatment and progress were also collected.
The AD variables pre- and post-vaccination were compared by physicians. The eczema area and severity index (EASI), 5-point investigator’s global assessment (IGA), itch numeric rating scale (NRS), sleep NRS, and patient-oriented eczema measure (POEM) were included. The primary endpoint was the change in EASI score, and the changes in IGA, itch NRS, sleep NRS and POEM were considered as the secondary endpoint.
Statistical analysis
Pearson’s chi-square test and Fisher’s exact test were performed to determine significant differences in demographic data, adverse events, and change in pruritus and AD symptoms between dupilumab-treated and control group patients. Independent sample t-test was used for the difference in mean age between both groups. The Wilcoxon signed-rank test was performed to determine if there were statistically significant differences in AD variables, including EASI, IGA, itch NRS, sleep NRS, and POEM between pre- and post-vaccination. Statistical analysis was performed using SPSS 22.0 (IBM Corp., Armonk, NY, USA), and a p-value <0.05 was considered statistically significant.
RESULTS
Patient characteristics
A total of 133 patients (n=101 for dupilumab-treated and n=32 for control group) were included. In the dupilumab-treated group, the mean age of the patients was 31.9 years (range, 18~54 years). Males (n=67, 66.3%) outnumbered females (n=34, 33.7%), and the underlying diseases included hypertension (n=3, 3.0%), hyperlipidemia (n=3, 3.0%), psychiatric disorders (n=2, 2.0%), and cataracts (n=2, 2.0%). Other histories of cutaneous diseases included urticarial eruption (n=5, 5.0%), and one patient had a history of drug rash caused by erythromycin. None of the patients had a history of anaphylactic reaction. The most common history of allergic disease was allergic rhinitis (n=50, 49.5%), followed by allergic conjunctivitis (n=19, 18.8%), and asthma (n=12, 11.9%). The most commonly administered vaccine was Pfizer-BioNTech (BNT162b2) (n=71, 70.3%), followed by Moderna (mRNA-1273) (n=22, 21.8%) and Janssen (Ad26.COV2.S) (n=7, 6.9%). The first dose was administered to 77 patients (n=77, 76.2%) In the control group, 31 patients were treated with cyclosporine (100~200 mg/day) and 1 patient was treated with methotrexate (15 mg/week). The mean age of the patients was 29.3 years (range, 18~57 years) and there was no statistically significant difference with the dupilumab-treated group in sex, underlying disease, allergic disease history, vaccine type and dose (Table 1).
Table 1. Demographic data of the patients.
| Variable | Dupilumab-treated group (n=101) | Control group (n=32)* | p-value | |
|---|---|---|---|---|
| Age (yr) | 31.9 (18~54) | 29.3 (18~57) | 0.181† | |
| Sex | 0.559‡ | |||
| Male | 67 (66.3) | 23 (71.9) | ||
| Female | 34 (33.7) | 9 (28.1) | ||
| Underlying disease | ||||
| Hypertension | 3 (3.0) | 0 (0) | >0.999§ | |
| Diabetes mellitus | 1 (1.0) | 1 (3.1) | 0.425§ | |
| Hyperlipidemia | 3 (3.0) | 0 (0) | >0.999§ | |
| Psychiatric disorder | 2 (2.0) | 0 (0) | >0.999§ | |
| Cataract | 2 (2.0) | 0 (0) | >0.999§ | |
| Allergic disease history | ||||
| Allergic rhinitis | 50 (49.5) | 19 (59.4) | 0.418‡ | |
| Allergic conjunctivitis | 19 (18.8) | 4 (12.5) | 0.593§ | |
| Asthma | 12 (11.9) | 6 (18.8) | 0.322‡ | |
| Vaccine type | 0.292‡ | |||
| Pfizer-BioNTech (BNT162b2) | 71 (70.3) | 26 (81.3) | ||
| Moderna (mRNA-1273) | 22 (21.8) | 3 (9.4) | ||
| Janssen (Ad26.COV2.S) | 7 (6.9) | 2 (6.3) | ||
| Astrazeneca (ChadOx1 nCoV-19) | 1 (1.0) | 1 (3.1) | ||
| Dose | 0.064‡ | |||
| First dose | 77 (76.2) | 19 (59.4) | ||
| Second dose | 24 (23.8) | 13 (40.6) | ||
Values are presented as mean (range) or number (%). *Included atopic dermatitis patients treated with cyclosporine (n=31) and methotrexate (n=1). †Independent sample t-test. ‡Pearson’s chi-square test. §Fisher’s exact test.
Adverse events
In the dupilumab-treated group, the most common complaint of systemic reactions after vaccination was myalgia (n=47, 46.5%), followed by fatigue/malaise (n=18, 17.5%), and fever/chills (n=15, 14.9%). The most common cutaneous reactions were injection site swelling and urticarial eruption in six patients (n=6, 5.9%). In the control group, the most complaint of systemic reaction and cutaneous reaction after vaccination were myalgia (n=15, 46.9%) and injection site erythema (n=2, 6.3%), respectively. There was no statistically significant difference between both groups in adverse events (Table 2). None of the patients experienced an anaphylactic reaction.
Table 2. Adverse events after COVID-19 vaccination.
| Variable | Dupilumab-treated group (n=101) | Control group (n=32)* | p-value | |
|---|---|---|---|---|
| Systemic reactions | ||||
| Fever/chill | 15 (14.9) | 5 (15.6) | 0.915† | |
| Fatigue/malaise | 18 (17.8) | 6 (18.8) | 0.905† | |
| Headache | 12 (11.9) | 4 (12.5) | >0.999‡ | |
| Myalgia | 47 (46.5) | 15 (46.9) | 0.849† | |
| Arthralgia | 6 (5.9) | 0 (0) | 0.335‡ | |
| Nausea | 4 (4.0) | 3 (9.4) | 0.358‡ | |
| Cutaneous reactions | ||||
| Injection site swelling | 6 (5.9) | 1 (3.1) | >0.999‡ | |
| Urticarial eruption | 6 (5.9) | 0 (0) | 0.335‡ | |
| Eczematous eruption | 2 (2.0) | 0 (0) | >0.999‡ | |
| Injection site erythema | 1 (0.9) | 2 (6.3) | 0.144‡ | |
Values are presented as number (%). *Included atopic dermatitis patients treated with cyclosporine (n=31) and methotrexate (n=1). †Pearson’s chi-square test. ‡Fisher’s exact test.
Change of pruritus and AD symptoms reported by patients
In the dupilumab-treated group, pruritus and AD symptoms worsened after vaccination in 23.8% and 25.7% of patients, respectively. Assessment of the 26 patients who answered that AD symptoms worsened, showed that erythema accounted for 88.5%, papule/edema 69.2%, dryness and excoriation 50.0%, and lichenification 38.5% (Table 3). Regarding the course of worsening symptoms, 61.5% of patients improved without treatment and 19.2% improved after treatment, including oral low-dose steroid (4~8 mg methylprednisolone/day), antihistamines, and topical corticosteroids. The rest of them did not improve immediately, but it was well controlled over time. The mean duration of aggravated AD symptoms was 6.1 days. None of the patients discontinued dupilumab treatment. In the control group, pruritus and AD symptoms worsened in 25.0% of patients. Assessment of the 8 patients who answered that AD symptoms worsened, showed that erythema accounted for 87.5%, followed by papule/edema and excoriation 75.0%. There was no statistically significant difference between both groups in pruritus and AD symptoms change by patients (Table 3).
Table 3. Change in pruritus and AD symptoms reported by patients.
| Variable | Dupilumab-treated group (n=101) | Control group (n=32)* | p-value | |
|---|---|---|---|---|
| Change of pruritus | 0.618§ | |||
| Much better | 0 (0) | 0 (0) | ||
| Better | 0 (0) | 0 (0) | ||
| No change | 77 (76.2) | 24 (75.0) | ||
| Worse | 23 (22.8) | 7 (21.9) | ||
| Much worse | 1 (1.0) | 1 (3.1) | ||
| Change of AD symptoms | >0.999§ | |||
| Much better | 0 (0) | 0 (0) | ||
| Better | 3 (3.0) | 1 (3.1) | ||
| No change | 72 (71.3) | 23 (71.9) | ||
| Worse | 25 (24.8) | 8 (25.0) | ||
| Much worse | 1 (1.0) | 0 (0) | ||
| Aggravated AD symptoms† | ||||
| Erythema | 23 (88.5) | 7 (87.5) | 0.314‡ | |
| Papule/edema | 18 (69.2) | 5 (62.5) | 0.722‡ | |
| Dryness | 13 (50.0) | 2 (25.0) | 0.257§ | |
| Excoriation | 13 (50.0) | 6 (75.0) | 0.213‡ | |
| Lichenification | 10 (38.5) | 3 (37.5) | >0.999§ | |
Values are presented as number (%). AD: atopic dermatitis. *Included atopic dermatitis patients treated with cyclosporine (n=31) and methotrexate (n=1). †Based on the results of allowing multiple answers in patients who reported that their AD symptoms worsened (much worse or worse). ‡Pearson’s chisquare test. §Fisher’s exact test.
Change of AD variables
When comparing mean scores before and after vaccination, the primary endpoint (EASI score) improved from 6.42 to 6.07, but the difference was not statistically significant in the dupilumab-treated group. The secondary endpoint including IGA, sleep NRS and POEM changed after vaccination, but the differences were not statistically significant. The itch NRS score increased significantly after vaccination (p<0.001) (Table 4). Eleven patients had an itch NRS score of 3 points or more, of whom seven patients were female, showing a higher proportion than the entire study population. Of the patients with NRS≥3, except for one who received the Janssen vaccine, the remaining 10 patients were all vaccinated with the Pfizer vaccine. Eight patients (7.9%) had a worsened EASI score and required rescue therapy, which was considered an AD flare. In the control group, the primary endpoint (EASI score) improved from 13.8 to 13.0. The secondary endpoint including itch NRS score, and POEM score improved from 4.6 to 4.4, and 13.5 to 12.1, respectively. IGA and sleep NRS were slightly increased, from 2.31 to 2.41 and 2.81 to 3.03, respectively. However, all the differences were not statistically significant.
Table 4. Change in each AD variables in the dupilumab-treated group.
| Variable | Pre-vaccination | Post-vaccination | p-value |
|---|---|---|---|
| EASI | 6.42±6.06 | 6.07±4.95 | 0.321 |
| IGA | 1.76±0.88 | 1.71±0.86 | 0.275 |
| Itch NRS | 2.57±2.08 | 3.08±2.25 | <0.001 |
| Sleep NRS | 1.87±2.77 | 2.02±2.74 | 0.522 |
| POEM | 7.53±6.43 | 7.56±5.86 | 0.861 |
Values are presented as mean±standard deviation. AD: atopic dermatitis, EASI: eczema area and severity index, IGA: investigator’s global assessment, NRS: numeric rating scale, POEM: patient-oriented eczema measure.
DISCUSSION
The major concerns of dermatology patients receiving COVID-19 vaccines are adverse events, including cutaneous reactions, and the worsening of underlying skin diseases. Safety issues associated with COVID-19 vaccines have been extensively reported; these issues depend on the type of vaccine, and include systemic and local reactions. In a clinical trial of the Pfizer vaccine5 in patients aged 16 to 55 years of age, the systemic reaction (first/second dose) was 4%/16% for fever, 47%/59% for fatigue, 42%/52% for headache, and 21%/37% for myalgia. Meanwhile, in a clinical trial of the Moderna vaccine6, the systemic reactions were 0.5%/16% for fever, 37%/66% for fatigue, 33%/59% for headache, and 22%/58% for myalgia. Compared to the above results, the systemic reactions in this study showed similar or lower rates of fever, fatigue, headache, and myalgia (15%, 18%, 12%, and 47%, respectively) in the dupilumab-treated patients. The most common cutaneous adverse events of COVID vaccination are local injection site reactions, including erythema, swelling, tenderness, and pain7. Erythema and swelling at the injection site have been reported in up to 9% and 12% of participants, respectively, in clinical studies of Pfizer5, Moderna6, and Janssen8 vaccines. In this study, erythema and swelling were observed in 0.6% and 6% of dupilumab-treated patients, respectively. Serious adverse reactions were not observed. The above results show that patients with AD treated with dupilumab do not significantly differ from healthy individuals in terms of COVID-19 vaccine safety. Furthermore, there was no significant difference in AD patients treated with dupilumab compared to the group of patients treated with systemic oral agents in this study. A retrospective cohort analysis in 55 healthcare organizations has demonstrated that COVID-19 vaccinated AD patients, even those receiving immunomodulatory treatment, did not have significant differences in adverse events compared to controls9. Urticarial-like eruption was observed in 6 patients (5.9%) of this study. It is important to differentiate whether urticarial eruption occurs immediately within 4-hour after vaccination because it may be an immunoglobulin E-medicated (type 1) allergic reaction10. This is most likely due to the vaccine ingredient, and if it occurred in the first dose, it could be a potential contraindication of the second dose of the same vaccine11. However, none of the patients in this study experienced immediate reaction, angioedema, or anaphylaxis. Furthermore, there is a view that allergic cutaneous symptoms such as urticarial eruption may not be an allergy to the vaccine, but may instead be an immune response to nonsteroidal anti-inflammatory agents taken due to fever or pain after vaccination11. Delayed local hypersensitivity reactions with erythema, induration, and pain may occur approximately one week after vaccination12, but this was not observed in this study.
Many cases of underlying dermatologic diseases flared after COVID vaccination have been reported. In a registry-based study analyzing the 414 cutaneous manifestations of mRNA COVID-19 vaccines (Pfizer and Moderna), the flares of underlying dermatology conditions included herpes simplex virus (HSV) (4 cases), AD (2 cases), and psoriasis (2 cases)11. In a nationwide Spanish cross-sectional study, among 405 cutaneous manifestations, flare/reactivation of skin diseases were found to include cases of varicella zoster virus (41 cases), HSV (15 cases), and psoriasis (6 cases)13. There have also been reports of generalized eczematous reactions after Pfizer COVID-19 vaccination in patients with a personal or family history of atopy14,15. According to a study evaluating post-COVID-19 vaccination flares in 407 dupilumab-treated AD patients16, 11 patients (2.7%) reported exacerbation of EASI score or required rescue therapy. In all patients, the condition was controlled with topical corticosteroids or calcineurin inhibitors, and none of the patients discontinued dupilumab. In this study, the 8 patients with AD flares who had worsened EASI scores and received rescue therapy accounted for 7.9% of the patients. Similar to previous studies, all patients with AD flares were mostly controlled with low-dose steroids (4~8 mg methylprednisolone/day) or topical corticosteroids, and none of the patients discontinued vaccination or dupilumab. Additionally, in this study, the absence of a statistically significant difference in EASI and IGA before and after vaccination suggests that COVID-19 vaccination may not be discouraged in patients with AD treated with dupilumab.
Indeed, an essential feature of AD is that it is a disease with a chronic or relapsing course17. Various triggers may be involved, but whether vaccines have an effect has been debated. Although previous studies have shown that live attenuated vaccines affect AD relapse or complications, such as eczema herpeticum18,19, COVID-19 vaccines are non-live vaccines. Although it is known that egg-related allergic reactions are high in patients with AD20, COVID-19 vaccines are not egg-based and therefore do not carry this risk. In addition, the currently used COVID-19 vaccine is relatively safe and stable because it is based on a non-replicating recombinant viral vector that cannot replicate inside the host cell21,22. However, the self-replicating viral vector based COVID-19 vaccines are in clinical trials22, future vaccines may have different effects. Consequently, relapsing patterns or exacerbations of AD after vaccination are most likely coincidental rather than vaccine-related. However, in this study, the results showed that 26 patients (25.8%) reported that their AD symptoms had worsened, representing a higher proportion than those diagnosed by their physicians as AD flares. This result may reflect the patient’s concerns and sensitive psychological state that their skin disease can worsen after vaccination. From this point of view, informed discussion and reassurance of dermatologists with their AD patients may play an important role in the control of AD symptoms after vaccination. As such, it may be necessary to recognize that pruritus control may be required considering dupilumab-treated patients showed increase in itch NRS (p<0.001) after vaccination, and 24 patients (23.8%) reported that pruritus worsened.
Another major concern for AD patients who will be vaccinated against COVID-19 is the reduced efficacy of the immune response. No studies have yet demonstrated changes in the immune response to COVID-19 vaccines in patients with AD. According to the available results of studies with other vaccines, an open label study of 336 AD and non-AD patients showed similar seroprotection rates for either influenza B, H1N1, or H3N2 when inoculated by intradermal inection23. In addition, the study demonstrated that the immune response was reduced by intradermal injection rather than intramuscular injection in AD patients colonized with Staphylococcus aureus23. However, since the COVID-19 vaccines are administered by intramuscular injection, there is no such risk factor. A randomized, double-blinded study with dupilumab or placebo in AD patients showed similar positive immune responses to non-live vaccines, including tetanus and meningococcal polysaccharides4. Because dupilumab acts on the type 2 cytokines IL-4 and IL-13, it is different from the main cytokine profile of the COVID-19 vaccine immune response of CD4+ or CD8+ T cells24. As a result, neither the atopic status or dupilumab treatment appears to have a significant effect on COVID-19 vaccine-induced immunity, but further studies are needed to demonstrate this.
As for the time-lag between COVID-19 vaccination and dupilumab injection, the authors believed that the time-lag would not be important, based on the results of this study and the above literature reviews. However, if patients are concerned about it, dermatologists may recommend that the best time-lag between COVID-19 vaccination with dupilumab injection could be one week because dupilumab is administrated every two weeks, so that half time point may minimize the impact of the COVID-19 vaccine25.
This study had some limitations. Most of the patients’ data were collected after the first dose; therefore, there is a possibility that adverse events or worsening of AD symptoms may not be fully reflected in this study. In addition, the generalizability of AD patients may be limited because most subjects were patients whose AD symptoms were well controlled with dupilumab and all participating hospitals were university or general hospitals.
In conclusion, this study was significant in that AD patients treated with dupilumab did not show significant differences in adverse event or AD symptoms change after COVID-19 vaccination compared to AD patients treated with systemic oral agents or the general population in a real-world setting. Some patients experienced exacerbation of pruritus and AD symptoms, but most were mild and transient. As ongoing vaccination against different strains is likely to be recommended under the impact of the COVID-19 pandemic, the authors believe that the results of this study will help to understand and explain to patients with AD who are about to be vaccinated or who have undergone vaccination.
Footnotes
CONFLICTS OF INTEREST: The authors have nothing to disclose.
FUNDING SOURCE: This study was supported by research fund from Chosun University, 2020.
DATA SHARING STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.