Pemphigus Foliaceus after COVID-19 Vaccination: A Report of Two Cases

Autoimmune bullous diseases (AIBDs) following coronavirus disease (COVID-19) vaccination have been previously documented in medical literature, given the comparable nature of the RNA antigen in these vaccines to that of the cellular nuclear matter. However, pemphigus foliaceus has been reported less frequently than other postimmunization AIBDs worldwide. Two women were admitted to our hospital with skin erosion over their faces, trunks, and extremities after receiving COVID-19 vaccination. Upon examination and consultation with pathologists, the diagnosis of pemphigus foliaceus was confirmed for both patients. In an effort to contribute to the knowledge on this intriguing topic, we present these two aforementioned cases of pemphigus foliaceus following COVID-19 vaccination, which may initially appear as a typical occurrence but exhibit some noteworthy characteristics.


Introduction
Autoimmune bullous disease (AIBD) is characterized by vesicles, bullous lesions, and/or mucosal erosions.Autoantibodies target epidermal keratinocyte anchoring factors such as desmosomes and hemidesmosomes, resulting in the disease.AIBD can be intraepidermal or subepidermal based on clinical appearance, histology, and immunofuorescence.Pemphigus (intraepidermal bullae subtype) is less common than subepidermal bullae, with an incidence of 0.6-32/million/year [1].Vaccines are central in the fght against COVID-19, and since their introduction, their efcacy and adverse efects have been researched globally.AIBDs have been reported after COVID-19 vaccination, whereas pemphigus foliaceus is rarely documented.We present two cases of pemphigus foliaceus following COVID-19 vaccination in previously healthy patients.

Case 1.
A 53-year-old woman was hospitalized for complaints of skin erosion that developed rapidly within 1 month (Figure 1).She had no family history of autoimmune diseases.Te lesions frst appeared on her face 3 weeks after the 4 th COVID-19 vaccination, which was the frst AZD1222 (viral vector vaccine, AstraZeneca, UK) dose after three previous doses of BBIBP-CorV (inactivated vaccine, Sinopharm, China).Despite the local hospital diagnosis of pemphigus, and the treatment of 16 mg/day methylprednisolone for 2 weeks, the lesion spread throughout her trunk and extremities.She had a history of well-controlled hypertension with amlodipine 5 mg/day for approximately 2 years, without other health problems or treatment.She had multiple clear fuid-oozing erosions on her scalp, face, and back, with individual lesions measuring up to 10 cm 2 .Several erosions had thick crusts, and Nikolsky's sign was positive.Complete blood counts, serum creatinine, liver enzyme levels, and metabolic profles were normal.Histopathology revealed acantholysis above the stratum basalis and lymphocyte and neutrophil infltration in the dermis.Direct immunofuorescence (DIF) revealed IgG and C3 epidermal reticular deposition and absence of IgM, IgA, and fbrinogen.Te diagnosis of pemphigus foliaceus was made based on the aforementioned fndings.Oral methylprednisolone therapy equivalent to 1 mg/kg of prednisone was initiated daily; however, the patient did not respond well after 10 days of treatment, leading to further lesions.Rituximab was then started, and the patient was discharged a week later after she improved and the lesion partially healed.Two weeks later, the clinical response was excellent and the corticosteroid dose was reduced to 10 mg/ day.

Case 2.
A 30-year-old woman presented to the clinic with crusty erosion on her face.Her condition had fuctuated, with deteriorations and improvements, over the previous 4 months.No family history of autoimmune diseases was recorded.All symptoms started 2 months after her second dose of mRNA-1273 vaccine (Moderna, USA), with erosion and crusting on her neck and around the injection site, which spread to other places on her body (Figure 2).Te patient was self-treated, with no improvement.On visiting the local hospital, she was diagnosed with atopic dermatitis and treated with methylprednisolone at 8 mg/day (highest dose).Te lesions on her neck progressively healed; however, new blisters appeared on her face and torso.When the patient visited our hospital, she had crusting erosions on both cheeks and less erosion on her trunk with positive Nikolsky's sign.Te blood test results were at normal levels.Histopathologically, acantholysis was observed above the stratum basalis.DIF showed intraepidermal net-like deposition of IgG and C3.Tese signs, symptoms, and laboratory results led to a diagnosis of pemphigus foliaceus.Te patient responded to high-dose systemic corticosteroid equivalent to 1 mg/kg of prednisone combined with topical clobetasol propionate 0.05%.Her condition was stable for a month before the systemic corticosteroid was progressively reduced and the topical agent was changed to tacrolimus 0.1%.After 4 months, the patient responded well with the oral methylprednisolone dose equivalent to 10 mg/day prednisone and the lesions were healed.

Discussion
AIBDs are caused by autoimmunity to skin structures.Desmogleins 1 and 3, which act as desmosome adhesion molecules, are targets of IgG autoantibodies that characterize the autoimmunity of the pemphigus spectrum.T and B lymphocytes are crucial in the pathogenesis of these diseases [2].It is unclear how autoimmune diseases develop after antiviral vaccination.However, because they may be exacerbated by external factors, including infections and medications, cross-reactivity across vaccine antigens, including adjuvants, may cause postvaccination autoimmunity.Studies have suggested that COVID-19 vaccinations may induce autoimmune diseases because they contain the genetic material of the virus [3].Moreover, molecular mimicry and cascades of immunological events targeting the nuclear components of predisposed individuals can trigger the autoimmunity in autoimmune diseases.Terefore, the pathogenesis of AIBDs following COVID-19 immunization is predicted to follow the same immunological pattern.Tissue-specifc expression patterns of desmoglein isoforms and the antidesmoglein IgG profle can be used to explain the location of blister formation.Clinical, histological, and immunochemical investigations are used to diagnose and confrm AIBD [2].A recent article summarized several cases of pemphigus after COVID-19 vaccination [4].At the time of publication, pemphigus foliaceus appeared to be less prevalent than pemphigus vulgaris, with only one reported case.However, at the time of our report, at least six more cases of pemphigus foliaceus had been reported globally (Table 1) [5][6][7][8][9].Tese case reports, which came from several nations and varied in their underlying diseases and immunization schedules, involved healthy individuals with new-onset foliaceus pemphigus.Tese characteristics are similar to those of our two cases.
Most cases in the literature had similar regimens with the BNT162b2 vaccine, which made our two cases unique.Our frst patient had mixed regimens, three shots of BBIBP-CorV, and one AZD1222 dose, and the second patient was fully immunized with mRNA-1273.We did not fnd any patients with pemphigus foliaceus after mRNA-1273 and AZD 1222 vaccination.However, a report from Iran is notable as it is possibly the only documented case of pemphigus foliaceus associated with BBIBP-CorV vaccination [5].Our frst case was also related to BBIBP-CorV vaccine; however, the adverse efect manifested after the booster dose of AZD 1222.Tis made it challenging to identify whether the disease was induced by AZD 1222 or BBIBP-CorV.In addition, no case report involved both vaccines.
Another distinctive characteristic is the number of vaccine doses administered before the onset of pemphigus foliaceus.Similar to other earlier cases of the disease, our second patient began to manifest symptoms after receiving two mRNA-1273 doses.However, in our frst patient, the onset of pemphigus foliaceus followed three doses of BBIBP-CorV and one dose of AZD 1222.We also used the Najaro scale to assess the possibility of vaccines contributing to the induction of this disease, similar to the study by Lua et al. [6,10].Te vaccinations were identifed as probable causes of pemphigus foliaceus in the frst and second patients, respectively, with Najaro scores of 3 and 7.As we currently lack an efective method for identifying the role of medication when drug-induced allergic reactions occur, apart from the questionnaire-based inquiries outlined above, identifying the medicine that causes adverse efects in these case reports is challenging.
Te time to the onset of vaccine-induced pemphigus foliaceus following the fnal vaccine dose ranged from 2 days to 2 months, as observed in the case studies cited earlier [5][6][7][8][9].Tis was comparable to the latency time of our second case; however, we found no study on the latency of mRNA-1273 vaccine-induced pemphigus foliaceus.Determining the latency time in our frst case was as difcult as identifying the vaccination that caused the condition.Based on the 3-week latency period, we hypothesize that AZD 1222 caused the disease because a much longer latency time of 5 months following the last BBIBP-CorV dose appeared inappropriate.However, we cannot determine which of the 2 Case Reports in Dermatological Medicine two vaccines caused pemphigus foliaceus due to the lack of adequate evidence.
Although most patients with pemphigus foliaceus reported worldwide were aged 50-83 years, our second patient was 30 years old [5][6][7][8][9].Polydrug usage is widespread among older adults, compounding the difculty in identifying the real cause of pemphigus foliaceus.Our frst patient had taken other medications for up to 2 years, with no adverse efects.Moreover, she continued when she was admitted to the hospital without worsening disease.Terefore, we can exclude other medications as the origin of her condition.
We observed that almost all documented cases worldwide had comparable clinical features that were typical of pemphigus foliaceus [5][6][7][8][9].Our two cases were also clinically typical since there were no mucosal lesions, and erosion was more prominent than bullous.Histopathology and DIF were performed for all case reports.However, indirect immunofuorescence was not performed in our cases as noted in two other studies [5,8].Corrá et al. performed indirect immunofuorescence, with negative results [7].We considered the clinical and pathologic features of the patients to diagnose pemphigus foliaceus, which was consistent with other cases worldwide.Case Reports in Dermatological Medicine Te majority of COVID-19-vaccine-induced pemphigus foliaceus patients improved after a short therapy, typically 2-4 weeks [5][6][7][8][9].(oral and topical) were frequently used conjunction with azathioprine, mycoand rituximab.Te frst patient showed a quick response to rituximab, and the lesions healed within 3 weeks.Te second patient responded well to oral and topical corticosteroid therapy after 4 weeks.Based on our experience and the literature, COVID-19-vaccine-induced pemphigus foliaceus responds to treatment better than classical cases.However, owing to the scarcity of pemphigus foliaceus cases in general, and postvaccination in particular, studies to confrm our assumption would be challenging to conduct.
In conclusion, based on reports worldwide, AIBDs and foliaceus pemphigus following COVID-19 immunization should receive greater attention.Rare cases of pemphigus foliaceus after COVID-19 vaccination are not difcult to diagnose because of the typical clinical manifestations, histopathology, and immunofuorescence results.However, lack of previous studies and other factors make it difcult to determine which vaccine causes the disease.Te disease may appear serious; however, based on our experience and the literature, it responds well to appropriate treatment.4 Case Reports in Dermatological Medicine