Two cases with new onset of pemphigus foliaceus after SARS‐CoV‐2 vaccination

Dear Editor,

Pemphigus Foliaceus (PF) is a rare autoimmune disorder of the skin. ¹ In PF, the production of autoantibodies (Abs) against desmoglein (Dsg) 1 leads to a clinical phenotype characterized by fragile blisters that involve the skin and spare the mucous membranes. ¹ Several factors including genetic susceptibility, environment, malignant disorders, drugs intake and vaccines can provoke pemphigus. ¹ Pemphigus has been reported to be triggered or exacerbated by influenza hepatitis B rabies, tetanus and more recently, SARS‐COV2 vaccines. ¹ Herein, we present two patients developing PF, without prior history of the diseases, following SARS‐CoV‐2 vaccination.

Case 1: A 70‐year‐old patient, with a history of hypertension and hyperlipidemia, presented to our dermatology department with a 2 week‐history of a blistering eruption, which appeared 7 days after his first dose of the BNT162b2 vaccine (Pfizer/BioNtech). The patient's history revealed that he had received two doses of CoronaVac vaccine (Sinovac Biotech) 6 months prior to consultation without any incident. Physical examination revealed flaccid blisters and crusted areas on the trunk (Figure 1A), proximal thighs, axillary and inguinal folds with scalp involvement (Figure 1B). Nikolsky's sign was present. Mucous membranes were spared. A skin biopsy showed intraepidermal acantholytic blister formation (Figure 1C). Direct immunofluorescence (DIF) was positive with IgG and C3 deposit on the surface of keratinocytes throughout superficial layers of the epidermis (Figure 1D) and high titres of anti‐Dsg1 Abs (200 U/ml; normal <14 U/ml) were detected in the patient's serum by ELISA (Euroimmun®). Anti‐Dsg 3 Abs were not present. The patient was diagnosed with PF and treated with oral prednisone at 80 mg/day (1 mg/kg/day) and clobetasol 0.05% ointment. Clinical remission was obtained after 3 weeks of treatment. At the 3‐ month follow‐up, the patient's blistering had ceased, and he was tolerating an ongoing steroid taper. At the 6‐month follow‐up, the patient had successfully tapered off prednisone as we detected a significant decrease in the anti‐Dsg 1 titre (12.05 UI/ml).

FIGURE 1.

Scattered blisters, eroded and crusted lesions (A) on the back and (B) scalp. (C) Intraepidermal acantholytic blister formation (original magnification × 100, hematoxylin and eosin [H & E]). (D) Direct immunofluorescence of perilesional skin showing intercellular staining with IgG and C3 throughout the epidermis

Case 2: A 48‐year‐old patient, with no previous medical history, developed a bullous eruption 5 days after receiving the first dose of AstraZeneca‐ChAdOx1 nCoV‐19 (AZD1222) vaccine. The rash started initially on the scalp and spread after the second dose, 5 weeks later, to the face and trunk. The patient was not on concomitant medications. Physical examination revealed several erosions with scaling surrounded by erythematous borders scattered over the face (Figure 2A), chest (Figure 2B) and back without mucosal involvement. The Nikolsky sign was positive. The histopathologic (Figure 2C) and DIF examination (Figure 2D) were suggestive of PF. We detected and serological findings confirmed a diagnosis of PF. ELISA (Euroimmun®) showed positive anti‐Dsg‐1 Abs (177 UI/ml) and negative anti‐Dsg‐3 Abs (<7 U/ml). Treatment with Oral prednisone (1 mg/kg/day) and clobetasol 0.05% ointment led to a good clinical response within 2 weeks of treatment. The patient reported no further lesions at 6 months follow‐up.

FIGURE 2.

Erosions (A) on the face. (B) Erosions surrounded by erythematous borders on the chest. (C) Superficiel cleft within the epidermis with acantholysis (original magnification × 100, H&E). (D) Direct immunofluorescence shows intercellular deposition of IgG and C3 within the epidermis

SARS‐CoV‐2 vaccination has been associated with diverse autoimmune conditions. ² In a recent review, a total of 35 autoimmune bullous disorders cases triggered by the SARS‐CoV‐2 vaccination were diagnosed as Bullous Pemphigoid, Linear IgA Bullous Dermatosis, Pemphigus Vulgaris in 6 cases and PF in one case. ³ In most cases, the disease developed after BNT162b1 vaccine administration. The disease was associated with AstraZeneca vaccine in 3 cases. This figure may possibly be explained by the high utilization of the BNT162b1 vaccine compared to the others. In addition, it has been shown that, unlike CoronaVac vaccine, messenger RNA vaccination induces strong T helper‐1 responses via the activation of Toll‐like receptors. ⁴ In patients vaccinated with BNT162b1, specific antibodies appear 14–21 days later. It is very likely that in our first case the vaccination with BNT162b2, but not with CoronaVac vaccine, boosted his T/B cell response that resulted in the onset of pemphigus. In the same review, there was a predominance of males over females and clinical response was good after treatment in all cases. ³ In a study with immune‐mediated disease flares or new‐onset disease in 27 Subjects following messenger RNA/DNA SARS‐CoV‐2 Vaccination no patient had severe resistant or progressive disease with all cases showing good therapy responses. ⁴ All of these findings were compatible with both our cases. The mechanisms associated with vaccination and the development of such events are still unknown. Molecular mimicry has emerged as the most likely explanation of the onset of autoimmune diseases after vaccination. ⁵ In addition, bystander activation and epitope spreading may also contribute to autoimmunity in susceptible individuals with pre‐existing latent autoimmunity. ² , ⁵ In fact, the prevalence of PF in our country is high, especially the endemic Tunisian form in the south of the country. Anti‐Dsg1 Abs were found to be present in the serum of healthy subjects. ⁶ Authors suggested that production of non‐pathogenic anti‐Dsg1 Abs in people living in endemic areas could be related to environmental factors. Indeed, a significant association was observed between living in rural conditions with farming as main occupation and the presence of anti‐Dsg1 Abs and/or the development of endemic PF in Brazil and Tunisia, suggesting that this activity may expose individuals living in the endemic areas to particular environmental factors present in these regions. ⁶ Then, gene's susceptibility alleles would be required for epitope spreading and subclass switching from IgG1 to IgG4 in the Brazilian population and from IgG2 to IgG4 subclass in the Tunisian population leading to the progression from the preclinical to the clinical phase of the of PF. ⁵ In our cases, given the early development of PF following vaccination, it is likely that vaccines primed autoreactive T and B cells in susceptible individuals, accelerating the onset of PF. Genetic susceptibility may promote such a side effect. Our cases are possibly supportive of such hypothesis. In conclusion, even if we cannot identify a direct pathological link between vaccines and the onset of PF, there is a clear temporal relation between these two events and it is noteworthy that SARS‐CoV‐2 vaccination could induce pemphigus in susceptible people.

AUTHOR CONTRIBUTIONS

Jacem Rouatbi: Wrote the draft of the paper with support from Amina Aounallah and Maha Lahouel. Colandane Belajouza: Primary physician of the patient, and revised the paper; Mohamed Denguezli: supervised the project; Badreddine Sriha: Contributed to diagnosis by pathological examination.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.