Bullous pemphigoid (BP), predominantly found among older populations, is the most common autoimmune blistering disorder [1]. This ailment exhibits a remarkably low incidence rate, with a prevalence ranging from 2 to 40 cases per million individuals [1,2]. This pathological condition arises from reduced resilience in cutaneous structural proteins and is characterized by the generation of autoantibodies that specifically target adhesive proteins in the epidermal and subepidermal membranes [2]. The impairment of cellular adhesion within this cell layer leads to reduced epithelial pliancy, inducing the formation of intraepithelial or subepithelial blisters and subsequent mucosal erosion of the skin [2]. This phenomenon predominantly occurs because of autoantibodies being generated against collagen XVII (BP180 or BPAg2) and dystonin-e (BP230 or BPAg1), which are key components of hemidesmosomes [1,2]. BP primarily manifests as blisters on urticarial plaques, typically observed on the trunk and extremities, concomitant with intense pruritus [1].

The diagnosis of BP involves a comprehensive examination encompassing a clinical examination, including patients’ medical history and immunopathological findings. Immunopathological findings include histopathologic examination, direct and indirect immunofluorescence (IF), and Enzyme-Linked Immunosorbent Assay (ELISA) [1,2].

As the population ageing continues to grow, along with an increase in drug-induced cases and advancements in diagnostic technologies, there is a tendency for BP cases to rise progressively [1]. Drug-induced bullous pemphigoid (DIBP) exhibits comparable clinical, histological, and immunological features to the classic BP [3], possibly due to the systemic administration or topical usage of specific medications [3,4].

Considering the recent global outbreak of the coronavirus disease 2019 (COVID-19) pandemic, various types of vaccines have been widely administered [5]. Consequently, numerous reports documenting diverse discomforts experienced by vaccinated individuals have emerged [6-12]. Some patients have reported experiencing oral lesions or exacerbations of pre-existing oral lesions following vaccination [6,7]. In this study, we aim to present and discuss patients who developed BP after receiving the Severe Acute Respiratory Syndrome (SARS)-COVID-19 vaccine.

This study was approved by the Institutional Review Board of Chosun University Dental Hospital (CUDH 1RB-2203-004), and the need for collecting written informed consent was waived by the committee.

1. Case 1

A 47-year-old woman visited Chosun University Dental Hospital with a chief complaint of recurring blister formation, rupture, and subsequent reappearance in both intraoral and extraoral regions, including the soft palate, gingiva, and oral commissures, following the administration of the second dose of the COVID-19 vaccine. Clinical examination revealed bullae, ulceration, and erosive changes in the palate, lower vestibule, and oral commissure area (Fig. 1). Initially, the patient received antibiotics at a private dental clinic, which temporarily improved her condition. However, symptoms recurred upon discontinuing the medication, leading to a clinical diagnosis of oral lichen planus. The patient underwent systemic steroid administration and low-level laser treatment (LLLT), and significant improvement was observed during the treatment period. However, the symptoms recurred upon discontinuing drug treatment.

After the third COVID-19 vaccination, the patient developed a progressive blistering disease on various areas of her skin. A biopsy of the affected region confirmed the diagnosis of BP at the Department of Dermatology. Subsequently, the patient commenced drug therapy, comprising medications such as Mechiron Tab (methylprednisolone), Dicamax (calcium carbonate/cholecalciferol), and Myrept Tab (mycophenolate mofetil, MMF). Significant symptomatic improvement was observed, leading to the discontinuation of dental drug treatment.

2. Case 2

Following the administration of the COVID-19 vaccine in April 2021, a 53-year-old woman started experiencing symptoms, including skin reactions (such as pruritus and tiny vesicles), a high fever, and burst capillaries. The symptoms exacerbated after receiving the second and third vaccinations. In March 2022, she was diagnosed with COVID-19. Subsequently, she developed oral lesions, leading to her referral to the hospital for further evaluation and management. Until her initial visit to our clinic, the patient had been experiencing recurrent episodes of skin pruritus and the periodic formation of blister-like lesions on her body. During the initial clinical examination, the patient presented with blisters on both the buccal mucosa and upper and lower gingiva, as well as hyperkeratotic changes on the dorsal surface of the tongue (Fig. 2). The patient reported severe pain and difficulty eating. Consequently, we initiated the general administration of steroids alongside topical analgesics to alleviate the symptoms. A laboratory examination was conducted to rule out other infections and inflammations, and no significant irregularities were detected. Owing to the recurring appearance of skin blisters, the patient was referred to the Department of Dermatology for a biopsy. The biopsy results confirmed the presence of BP. In the dermatology department, drugs such as MMF and topical corticosteroid ointment were administered for BP treatment. At our clinic, topical applications of oral steroids and LLLT were performed in the intraoral area. Recurrent blister formation and subsequent disappearance were observed.

COVID-19, caused by a novel coronavirus strain (SARS-CoV-2), is a highly contagious respiratory illness that emerged in the late 2019, leading to a global pandemic [5]. To effectively address the pandemic, mandatory vaccination policies have been implemented in most countries [5]. While adverse reactions were rare in most cases, the number of patients reporting oral discomfort following specific vaccinations has increased considerably [5,7]. Oral ulcers and blister-like lesions resembling viral infections have been reported, along with cases of oral pain without discernible specific lesions [6,7]. In this study, the lesions were extensive and persistent, present both within the oral cavity and on the skin, indicating a multifocal manifestation of the condition. All patients involved in this study received a confirmed diagnosis of BP based on the findings from skin biopsies. BP is generally more prevalent among older individuals compared to the younger population. However, both cases in our study involved women in their 40s to 50s, which is not the typical age range for BP onset. Furthermore, these cases can be categorized as DIBP, as the symptoms manifested following COVID-19 vaccination. The COVID-19 vaccines administered were AZD1222 (AstraZeneca; ChAdOx1 nCov-10) and BNT162b2 (Pfizer). In the first case, AZD1222 was administered for the first dose, followed by BNT162b2 for the second and third doses. In the second case, AZD1222 was administered for the first and second doses, followed by BNT162b2 for the third dose. In the first case, oral lesions emerged after the second vaccination and worsened following the third vaccination, with no lesions observed on other body parts except for the oral commissures area. In contrast, in the second case, mild skin lesions emerged after the first vaccination, and as subsequent vaccines were administered, the symptoms intensified. Finally, after the third vaccination, oral symptoms manifested.

BP is an autoimmune disorder characterized by an unregulated immune response of T cells [13]. This leads to the production of autoantibodies against hemidesmosome proteins, specifically BP180 and BP230 [13]. BP230, an intracellular component of hemidesmosomes, belongs to the plakin protein family [13]. Immunoglobulin G (IgG) autoantibodies target the C-terminal domain of BP230 [13]. In contrast, BP180 is a transmembrane glycoprotein with an extracellular domain known as NC16A, a major antigenic epitope in BP [13]. In addition to NC16A, patients with BP produce IgG autoantibodies against other epitopes, including those in the C-terminal and intracellular regions, which are associated with mucosal involvement in the early stages of the disease [13]. The binding of anti-NC16A autoantibodies to BP180 triggers various pathways, such as complement activation and deposition, release of proteases and elastases from neutrophils, and destruction of the basement membrane zone, leading to blister formation [13]. IgA and IgE antibodies also contribute to the inflammatory response, complement activation, recruitment of inflammatory cells, and formation of subepithelial blisters [13]. DIBP shares similarities with classic BP but also exhibits some differences [3,4]. For example, classic BP rarely affects mucosal surfaces and does not preferentially target keratinized mucosa, whereas DIBP primarily manifests in mucosal regions [3,4]. In both the cases presented in our study, we observed periodic blister formation and disappearance, accompanied by severe oral pain. Changes in tongue keratinization were also evident. There are many studies about cases of skin reactions following COVID-19 vaccination [6-12,14,15]. According to the COVID-19 Dermatology Registry of the American Academy of Dermatology/International League of Dermatological Societies, there have been 733 recorded cases of skin reactions after COVID-19 vaccination [14], and they have also reported their first 12 cases of subepidermal blistering eruptions without a history of BP or autoimmunity [14].

While BP predominantly affects the older population, drug-induced cases have been reported across various age groups [16]. DIBP is known to be associated with various medications, although not all of its etiologies and mechanisms have been fully understood [16]. Certain drugs are considered to inadvertently disrupt immune regulation or induce immunoreconstitution, resulting in the dysregulation of endogenous regulatory processes controlling the disease phenotype [17]. Many drugs have been associated with BP, and this number is expected to increase as new treatments emerge [3,17]. Among the various drugs, several studies have suggested a connection between vaccines and DIBP [3], although the precise mechanisms by which vaccines contribute to BP induction remain unclear [3]. However, considering the lack of structural similarities between vaccines and basement membrane proteins, a direct antibody response to the vaccine is unlikely to be responsible [3]. Moreover, vaccine-induced BP is not a common symptom observed in most vaccinated individuals and may be due to genetic susceptibility in certain individuals [3,18].

As with BP diagnosis, DIBP diagnosis must be thoroughly conducted, from clinical to histopathologic examinations. Clinical findings indicate that a BP diagnosis can be made when lesions are observed as tense bullae with an erythematous or urticarial base on the skin, particularly in patients older than 70 years, and immunopathological findings (including histopathologic examinations, direct IF, indirect IF, and ELISA) are positive [19]. However, in cases where the diagnosis occurs at a younger age with a positive Nikolsky sign and necrotic keratinocytes, DIBP should be considered [19]. In such cases, a thorough investigation of the patient’s recent medication history is crucial.

In treating DIBP, discontinuing the causative agent is crucial and should be done promptly [3]. Subsequently, similar to classic BP, drug treatment is administered to manage symptoms while minimizing side effects [3]. The primary therapy involves applying oral and topical corticosteroids, often in combination with adjuvant medications [20,21]. In our study, treatment for the first case comprised systemic corticosteroids and MMF as immunosuppressants, whereas in the second case, systemic MMF and topical corticosteroids were administered.

In this study, both cases were ultimately diagnosed with BP within the Department of Dermatology, and conclusive laboratory results for the final diagnoses were not obtained. The treatment progress for the first case could not be documented as the patient discontinued treatment after the final diagnosis. Collaborative treatment was pursued for the second case in conjunction with the Department of Dermatology. During the initial visit, capturing intraoral photographs, excluding those of the tongue, was challenging because of the patient’s severe discomfort (Fig. 2). Thus, the intraoral images were captured 3 months later (Fig. 2).

As new diseases are discovered and novel drugs are developed for their treatment, the likelihood of developing DIBP is expected to increase [22]. Therefore, further research on the diagnosis and appropriate treatment of DIBP is necessary.

No potential conflict of interest relevant to this article was reported.

The datasets used in this study are available from the corresponding author upon reasonable request.

This study was supported by a research fund from Chosun University Dental Hospital in 2021.

Conceptualization: HJP. Data curation: JHK. Funding acquisition: HJP. Methodology: JMA, JWR. Project administration: JWR. Visualization: JHK. Writing original draft: HJP. Writing review & editing: HJP.