Reply to 'The first dose of COVID-19 vaccine may trigger pemphigus and bullous pemphigoid flares: is the second dose therefore contraindicated?' by Damiani G etal.

Abstract

We read with interest the article by Damiani et al.,1 who reported three bullous pemphigoid (BP) and two pemphigus vulgaris (PV) patients in complete remission who experienced a disease flare-up after the first dose of COVID-19 vaccination. One of them showed an additional BP worsening following the second dose of BNT162b2 vaccine. The authors raise the question whether the second dose should be contraindicated. We describe the case of a patient who recently came to our attention because of a PV relapse after BNT162b2 vaccine. In September 2021, an otherwise healthy 46-year-old man with a one-year history of PV presented with mild blistering lesions developed on the trunk and arms five days after the first dose of BNT162b2 vaccine. Small erosive lesions on the oral mucosa were observed as well. Detection of anti-desmoglein antibodies 1 and 3 titre (170 and 78 U/mL, respectively) was performed. Histological examination and direct immunofluorescence confirmed our hypothesis of PV relapse (Fig. 1a,b). The patient had been in remission for 10 months after oral prednisone and azathioprine and was on maintenance therapy with 5 mg/day of prednisone when he came to our attention for the relapse. Based on updated recommendations,2, 3 the low-dose oral steroid was maintained. Therefore, the patient received the second dose of vaccine 21 days after the initial one: five days later he was admitted to our department because of a sudden worsening of his pre-existing skin lesions. The physical examination revealed several confluent erosions and crusts on the upper part of the body accompanied by few flaccid, thin-walled blisters (Fig. 2a,b). Worsening of the oral lesions was not observed. Blood tests were performed and showed a further elevation of anti-desmoglein antibodies 1 and 3 (221 and 160 U/ml, respectively). Eventually, rituximab (two infusions of 1000 mg each 15 days apart) was given in combination with oral prednisone (50 mg/day), which is still ongoing. Although a direct pathological link between the vaccine and PV onset cannot be established, the temporal association between the two events should not be overlooked either. Thus, our work adds on to the already suspected association between mRNA vaccines and relapses in autoimmune bullous disease patients, as shown in other works.4, 5 The particularity of our case lies in the PV flares observed after both the first and second dose, with a progressive worsening of severity. To date, no clear explanation of this phenomenon has been provided. However, immunological mechanisms of mRNA vaccines could be partially held accountable for it. The vaccine elicits a profound T cell-mediated response, which leads to the development of memory T cells and B cells, resulting in the production of specific antibodies. In addition, the vaccine triggers an inflammatory response with the production of type I interferons, which are known to flare autoimmune disease, even if modifications in the vaccine production have been made to reduce this risk.3, 4, 6 Moreover, genetic susceptibility could promote such a side effect, shedding light on the different manifestations of the disease observed after vaccination. This letter does not intend to generate doubts concerning the safety of mRNA vaccines, rather to attract scientific attention on this phenomenon in a period of large-scale vaccination programmes. On the basis of the above, attention should be paid to patients with a history of PV, since we suspect a PV relapse after the third dose of vaccine could occur. However, further studies on wider samples are needed to clarify these aspects and to determine predictive factors for risk categories. The patients in this manuscript have given written informed consent to publication of their case details. The authors have no conflict of interest to declare. None declared. All authors have contributed significantly to this publication. All available information is contained within the manuscript.