COVID-19 vaccine is a risk factor accelerating time to bullous pemphigoid onset

Bullous pemphigoid (BP) is the most common autoimmune bullous disease characterized by autoantibodies against hemidesmosomal components: BP180 and BP230. Although a causal association between vaccine and BP has never been proved, since mass vaccination against COVID-19 started, more than 90 vaccine-associated BP were reported. Of note, a recent study comparing very large cohorts of vaccinated and not-vaccinated individuals found no increased incidence of BP in vaccinated people, concluding that COVID-19 vaccine does not directly cause BP. To bring to an agreement among real-life clinical observations on patients with new-onset BP after COVID-19 vaccine and recent epidemiologic data, a cohort study was performed. Fifty-nine BP patients visiting our institute in 2021 were clinically and immunologically characterized. Fourteen patients (23.7%), experiencing BP onset 1-34 days after the first or second dose, were considered vaccine-associated. Vaccine-associated and non-associated patients had the same M/F ratio (1.3) and similar disease severity (mean BPDAI: 41.1 vs 38.6) and mean age (76.7 vs 79.5 years). Interestingly, BP230 reactivity was higher in vaccine-associated patients (87.5% vs 41.4%, p=0.042), while no other significant differences in autoantibodies profiles and titers were found. Noteworthy, the comparison of the monthly distribution of BP onset throughout the year before and during mass vaccination showed significant differences: in 2021, BP onsets on April-May and June-July increased (p=0.009) and declined (p=0.064) compared to 2018-2020, respectively. In conclusion, our findings suggest that COVID-19 vaccine may be considered an accelerating factor rather than an inducing one: vaccination, in genetically predisposed individuals with sub-clinical autoreactivity against BP antigens, of which high BP230 reactivity at diagnosis could represent an indicator, could slightly anticipate BP onset without increasing its incidence.Copyright © 2023

Epidemiology of Pemphigus.

Pemphigus is an epidemiologically heterogeneous group of autoimmune bullous diseases comprising pemphigus vulgaris (PV), pemphigus foliaceus, paraneoplastic pemphigus, IgA pemphigus, and pemphigus herpetiformis. Recently, our knowledge about the frequency of pemphigus, which is highly variable between different populations, has considerably expanded, and the first non-HLA genes associated with PV have been identified. In addition, a variety of comorbidities, including other autoimmune diseases, hematological malignancies, and psoriasis, have been described in this variant. Here, initial data about the impact of COVID-19 on this fragile patient population are discussed and perspectives for future epidemiological studies are outlined.

Clinical and immunological impact of booster immunization with recombinant mRNA vaccines for SARS-CoV-2 in patients with pemphigus and bullous pemphigoid

Vaccines based on recombinant mRNA technology helped to control the pandemic caused by the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). Clinical trials for showed that these vaccines are safe and effective and promote a strong type 1 driven T cell response. Yet, several reports claimed that SARS-CoV-2 mRNA vaccination might favor the onset, worsening or the reactivation of autoimmune disorders like pemphigus and bullous pemphigoid. However, no study demonstrated a direct immunological link between mRNA vaccination and disease appearance/worsening. We aimed to analyze the immunological and clinical effects exerted by mRNA booster vaccinations for SARS-CoV-2 in a cohort of patients with pemphigus (n=9), bullous pemphigoid (n=4) and in healthy individuals (n=5). Patients and healthy individuals were monitored at baseline, and after two and four weeks of mRNA vaccination. We assessed the clinical disease status, antibodies against the SARS-CoV-2 spike protein, antibody levels for BP180/230, DSG1/3 and tetanustoxoid. We also determined the distribution of peripheral T helper / T follicular cell subsets, intracellular cytokine production of T cells and cytokine serum levels. Our results show that booster vaccination increased anti spike protein IgG, while tetanustoxoid igC and skin-specific autoantibody titers were not or minimally affected. We observed an increase in Th1/Th17.1 cells, together with an increase in the intracellular production of IFN-gamma, IL-4 and IL-21 in peripheral T cells of pemphigus patients. Importantly, clinical activity in both remittent patients and in patients with active disease remained stable. In summary, vaccination with mRNA vaccines induced a specific activation of the humoral system with production of protective antibodies against the Sars-CoV-2 spike protein without affecting autoimmune disease activity in patients with pemphigus and bullous pemphigoid.Copyright © 2023

Histopathological Spectrum of Cutaneous Reactions following COVID-19 Vaccine - An Observational Study.

Background: Owing to the myriad clinical presentations of COVID-19 vaccine-induced adverse events, clinicopathological correlation is the key to understanding the underlying pathophysiology of these reactions. However, there is still a dearth of such systematic studies across a wide spectrum of vaccine reactions. Aim and Objectives: This study provides a clinical and histopathological correlation of COVID-19 vaccine-induced mucocutaneous reactions. Materials and Methods: The study population included all the individuals developing any form of self-reported mucocutaneous adverse events within 4 weeks of receiving the COVID-19 vaccine. The clinical and histopathological features were recorded. Results: A total of 126 cases were identified. Seven histopathological patterns were recognized. The most common histopathological feature was spongiotic dermatitis, seen in all the patients with "vaccine-related eruption of papules and plaques" (VREPP). Other patterns included lichenoid or interface dermatitis, dermal hypersensitivity reaction, leukocytoclastic vasculitis, subepidermal blistering, psoriasiform hyperplasia, and dermal granulomatous reaction. Conclusion: Owing to such myriad clinical presentations, utilizing a histopathological classification could ease categorizing the vaccine-induced mucocutaneous eruptions.

Rapidly progressing generalized bullous fixed drug eruption after the first dose of COVID-19 messenger RNA vaccination.

Generalized bullous fixed drug eruption (GBFDE) is a rare type of life-threatening severe cutaneous adverse reaction that is considered a medical emergency because of its potential lethality. Currently, only a few cases of bullous adverse reactions have been reported after coronavirus disease 2019 (COVID-19) vaccination. We describe a patient with distinct clinical, histopathological, and immunological findings that are consistent with severe GBFDE, after Pfizer messenger RNA COVID-19 vaccination. An 83-year-old man presented with a fever and well-demarcated multiple erythematous patches that occurred only 4 h after receiving the first dose of COVID-19 Pfizer vaccination. Over the next few days, the patches became generalized and turned into blisters covering approximately 30% of the body surface. The patient was started on intravenous methylprednisolone and oral cyclosporine. There were no additional blistering lesions after 10 days of treatment, prompting a gradual dose reduction. Our case suggests that a stepwise vaccination adhering to the standard dosing schedule should be warranted with close monitoring for possible significant side effects.

Inpatient teledermatology service: baseline review - it works!

Setting up an inpatient teledermatology service over 1 year at our National Health Service-based district general hospital made absolute sense on two grounds: The COVID pandemic and the ever-increasing role of teledermatology enabling dermatology departments, often with limited resources, to 'work smart'. Over a 43-week period, 124 referrals were dealt with on our teledermatology platform (around 12 referrals per month). Average response time to referral was 0.65 days: 56% same-day response, 32% next-day response;and 92% a response within 3 days. Following this, 32% of patients were seen face to face on the wards and 40% were dealt with via remote advice and guidance. Around 10% of referrals were deemed not to be appropriate for dermatology review/advice. Around 12% of referrals were given dermatology face-to-face outpatient appointments rather than review on the wards, and 7% were declined an appointment (pending further information being received) as insufficient information was given for triage/advice and guidance. Initially, just 10% of referrals were sent (first time) with clinical images, but this increased to 54% after 4 months, and although there has been some monthly variation, up to 64% has been achieved (noting that clinical images are not always required for the question being asked). Around 50 different diagnoses were made, illustrating the diversity and complexity of dermatological practice, and the scale of the diagnostic problems facing ward-based teams. Previously published data revealed that around one-third of inpatient dermatology referrals were for 'red legs', which was replicated in the current results, with diagnoses of venous or atopic eczema (14%), drug reactions (12%), skin neoplasia (6%), cellulitis/erysipelas (5%), intertrigo (4%), erythroderma (4%), Gianotti-Crosti syndrome (2.5%), bullous pemphigoid (2.5%), pyoderma gangrenosum (2.5%) and vasculitis (2%). Having an inpatient teledermatology service benefits dermatology departments, enabling efficient working, appropriate triage, training opportunities and ease of second opinions from colleagues. Benefits for referrers are acute ward-based teams including rapid responses to referrals, enabling skin concerns to be dealt with quickly and avoiding delays in investigation, treatment and discharge. Some hospitals where dermatology does not have a permanent base may be able to access dermatology advice and guidance via teledermatology. Overall, patients benefit from teledermatology and it is COVID secure.

Severe epidermolysis bullosa acquisita in a patient with graft-versus-host disease: causal or coincidental?

Graft-versus-host disease (GvHD) is common after haematopoietic cell transplantation (HCT). Mucocutaneous manifestations are variable and may simulate autoimmune bullous dermatoses. However, the association of GvHD with autoimmune disorders, including bullous dermatoses, is also well recognized. We describe a patient with GvHD in whom severe and relapsing epidermolysis bullosa acquisita (EBA) was diagnosed 3 years after transplant and propose a causal association with GvHD. A 66-year-old woman developed GvHD following allogeneic HCT for acute myeloid leukaemia in 2016. This affected her gastrointestinal tract and skin but improved with oral corticosteroids and ciclosporin. In 2019 she presented with a widespread rash consisting of large, tense, haemorrhagic blisters. Histological features were in keeping with EBA. Direct immunofluorescence was also consistent with EBA, demonstrating linear positivity for IgG and C3 confined to the blister base, as was detection of collagen VII antibodies on indirect immunofluorescence. She was admitted and treated with high-dose oral steroids, ciclosporin and intravenous immunoglobulin (IVIg) with eventual resolution of blistering. Although further IVIg administration was planned as an outpatient, this coincided with the start of the COVID-19 pandemic and she elected not to attend and also stopped all medication. Despite this, her EBA remained quiescent until September 2021 when she was readmitted with a severe deterioration in blistering and significant dysphagia due to an oesophageal stricture, with a weight of 31.7 kg. Once again, she responded rapidly to oral prednisolone and IVIg. Dapsone was considered but precluded by G6PD deficiency and there were clinical and adherence concerns about using mycophenolate mofetil. Upon discharge she was again nonadherent to medication and failed to attend for planned IVIg. She flared and was admitted for a third time in December 2021, requiring gastrostomy for nutritional support;her weight at this time was 26.4 kg. Her EBA is currently well controlled on prednisolone and IVIg. EBA is a rare, acquired blistering disorder secondary to autoantibodies targeting type VII collagen. Previous studies have found circulating basement membrane zone (BMZ) antibodies in 24% of chronic GvHD patients, possibly generated in response to chronic BMZ damage (Hofmann SC, Kopp G, Gall C et al. Basement membrane antibodies in sera of haematopoietic cell recipients are associated with graft-versushost disease. J Eur Acad Dermatol Venereol 2010;24: 587-94). Corresponding clinical manifestations are rare, with bullous pemphigoid the most frequently reported. EBA is much less common with four previously reported cases [Brassat S, Fleury J, Camus M, et al. (Epidermolysa bullosa acquisita and graftversus- host disease). Ann Dermatol Venereol 2014;141: 369-73 (in French)]. As a fifth case of EBA, our patient provides further evidence of a likely pathophysiological relationship between GvHD and autoimmune subepidermal bullous dermatoses, and highlights the significant challenges of managing these vulnerable patient groups during the COVID-19 pandemic.

COVID 19 and Bullous Pemphigoid: a hypothesis for a causal link

Although onset/exacerbation of bullous Pemphigoid (BP) has been reported to occur frequently following exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the link, if any, between BP dermatoses and the viral infection remains obscure. Therefore, searching for possible molecular mechanisms, we hypothesise that molecular mimicry between BP antigens and the SARS-CoV-2 proteins might lead to autoimmune responses cross-reacting with the BP proteins, thus triggering the dermatosis pathologies. Using this research paradigm, we analyzed the Bullous Pemphigoid antigen 1 (BP230) and the SARS-CoV-2 proteome to share minimal immune determinants, i.e., pentapeptides. Results indicate a high level of molecular mimicry between BP230 and SARS-CoV-2, thus supporting the hypothesis of cross-reactivity as a possible major mechanism in the SARS-CoV-2-associated BP etiopathogenesis.Copyright © by BIOLIFE, s.a.s.

New-onset pemphigus foliaceus following COVID-19 vaccine

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are a rare group of immunobullous disorders that can lead to high morbidity and mortality. The produced antibodies, via the aberrant B cells, are considered to be the culprits responsible for the disease development. We present a patient with PF whose disease developed after administration of the first dose of ChAdOx1 nCoV-19 (AstraZeneca) vaccination and exacerbated following the second dose of this vaccine. A 62-year-old female, with no previous history of skin diseases, received the first dose of AstraZeneca COVID-19 vaccine on 26 February 2021. She developed a generalized erythematous itchy rash in early March 2021, a few days after her vaccination. She received the second dose of the AstraZeneca COVID-19 vaccine on 14 May 2021, which resulted in significant worsening of her skin in just a couple of days, with extensive scaling and erythema. Physical examination demonstrated large erosive annular erythematous plaques on her face, trunk and limbs. No mucosal involvement was present. Histology demonstrated subcorneal pustules containing few acantholytic keratinocytes and a large number of neutrophils. Direct immunofluorescence revealed fishnet-like positivity for IgG and C3 at the intercellular epidermal spaces. Based on the characteristic clinical and histological findings, the diagnosis was confirmed as new-onset PF following COVID-19 AstraZeneca vaccination. Two patients with PV flare-up following COVID-19 Moderna and Pfizer vaccine administration (Damiani G, Pacifico A, Pelloni F, Iorizzo M. The first dose of COVID-19 vaccine may trigger pemphigus and bullous pemphigoid flares: is the second dose therefore contraindicated? J Eur Acad Dermatol Venereol 2021;35: e645-7), and a single patient with new-onset PV occurring after vaccination with COVID-19 Pfizer vaccine (Solimani F, Mansour Y, Didona D et al. Development of severe pemphigus vulgaris following SARS-CoV-2 vaccination with BNT162b2. J Eur Acad Dermatol Venereol 2021;35: e649- 51) have been reported. The main proposed mechanisms for AstraZeneca vaccine-induced pemphigus could be a hyperimmune reaction in genetically predisposed individuals, with eventual formation of anti-desmoglein antibodies. An alternative hypothesis is that vaccine components could act as foreign antigens resulting in a cross-reaction with pemphigus antigens. The close association of COVID-19 vaccination with the acute onset of pemphigus in our patient, as well as exacerbations after subsequent vaccine administration, is more than coincidental. Considering the recent pandemic with COVID-19 and the widespread administration of the COVID-19 vaccine, continued observation and documentation of true adverse events is essential.

Pemphigus Vulgaris Possibly Associated with COVID-19 Infection.

Pemphigus vulgaris (PV) represents damage to epidermal keratinocytes, resulting in acantholysis due to the production of autoantibodies against desmoglein-1 and desmoglein-3. Autoimmune blistering disorders such as pemphigus vulgaris or bullous pemphigoid that develop following coronavirus disease 2019 (COVID-19) have been reported in several studies. Herein, we report a case of PV onset following COVID-19 infection in a 17-year-old female, demonstrating --the potential pathogenic capacity of SARS-CoV-2 to develop PV.

Autoimmune bullous diseases during COVID-19 pandemic: 2022 update on rituximab and vaccine.

Autoimmune bullous diseases (AIBDs) are a heterogeneous group of life-threatening disorders associated with subepidermal or intraepidermal blistering. Skin barrier alterations and prolonged immunosuppressive treatments increase the risk of infections in patients with AIBDs, who are considered fragile. COVID-19 pandemic had a heavy impact on these patients. Although advances have been made in terms of prevention and treatment of COVID-19, this topic remains significant as the pandemic and its waves could last several years and, so far, a relevant proportion of the population worldwide is not vaccinated. This review is a 2022 update that summarizes and discusses the pandemic's burden on AIBD patients mainly considering relevant studies in terms of: (i) sample dimension; (ii) quality of control populations; (iii) possible standardization by age, gender and country. The findings show that: (i) the risk of COVID-19 infection and its severe course were comparable in AIBD patients and in the general population, except for rituximab-treated patients that presented a higher risk of infection and severe disease; (ii) the mortality rate in COVID-19-infected bullous pemphigoid patients was higher than in the general population, (iii) 121 cases of AIBD onset and 185 cases of relapse or exacerbation occurred after COVID-19 vaccination and a causal relationship has not been demonstrated so far. Altogether, acquired knowledge on COVID-19 pandemic could also be important in possible, albeit undesirable, future pandemic scenarios.

Vesiculobullous and Other Cutaneous Manifestations of COVID-19 Vaccines: a Scoping and Narrative Review.

As coronavirus disease (COVID-19) vaccines continue to be administered, dermatologists play a critical role in recognizing and treating the cutaneous manifestations (CM) associated with the vaccines. Adverse cutaneous reactions of COVID-19 vaccines reported in the literature range from common urticarial to rare vesiculobullous reactions. In this study, we performed a (1) scoping review to assess the occurrences of vesicular, papulovesicular, and bullous CMs of COVID-19 vaccines and their respective treatments, and (2) a narrative review discussing other common and uncommon CMs of COVID-19 vaccines. Thirty-six articles were included in the scoping review, and 66 articles in the narrative review. We found that vesicular, papulovesicular, and bullous lesions are infrequent, reported mostly after the first dose of Moderna or Pfizer vaccines. Eleven of the 36 studies reported vesicular reactions consistent with activation or reactivation of the herpes zoster virus. Most vesicular and bullous lesions were self-limited or treated with topical corticosteroids. Other CMs included injection-site, urticarial or morbilliform reactions, vasculitis, toxic epidermal necrolysis, and flaring of or new-onset skin diseases such as psoriasis. Treatments for CMs included topical or oral corticosteroids, antihistamines, or no treatment in self-limited cases. Although most CMs are benign and treatable, the data on the effect of systemic corticosteroids and immunosuppressive therapies on the immunogenicity of COVID-19 vaccines is limited. Some studies report reduced immunogenicity of the vaccines after high-dose corticosteroids use. Physicians may consult local guidelines where available when recommending COVID-19 vaccines to immunosuppressed patients, and when using corticosteroids to manage the CMs of COVID-19 vaccines.

Eosinophil-rich linear IgA bullous dermatosis induced by mRNA COVID-19 booster vaccine.

We present a case of eosinophil-rich linear IgA bullous disease (LABD) following the administration of a messenger RNA COVID-19 booster vaccine. A 66-year-old man presented to the emergency department with a 3-week history of a pruritic blistering rash characterized by fluid-filled bullae and multiple annular and polycyclic plaques. He was initially diagnosed with bullous pemphigoid based on a biopsy showing a subepidermal blister with numerous eosinophils. However, direct immunofluorescence studies showed linear IgA and IgM deposition along the basement membrane zone with no immunoreactivity for C3 or IgG. Additionally, indirect immunofluorescence was positive for IgA basement membrane zone antibody. The patient was subsequently diagnosed with LABD and initiated on dapsone therapy with resolution of his lesions at 3-month follow-up. This case illustrates the growing number of autoimmune blistering adverse cutaneous reactions from vaccination. Dermatopathologists should be aware that features of autoimmune blistering diseases can overlap and may not be distinguishable based on these histopathological findings alone. Confirmation with direct immunofluorescence and/or serological studies may be necessary for accurate diagnosis.

Concomitant Severe Psoriasis and Bullous Pemphigoid Induced by COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first isolated in Wuhan, China, is currently a pandemic. At the beginning of the pandemic, pulmonary issues were the most discussed and studied. However, now 3 years later, the role of the dermatologist has become increasingly central. Often the diversity in the presentation of these manifestations has made it difficult for the dermatologist to recognize them. In addition to the common symptoms involving fever, cough, dyspnea, and hypogeusia/hyposmia that have been widely discussed in the literature, much attention has been paid to dermatologic manifestations in the past year. The vaccination campaign has been the most important strategy to combat the COVID-19 pandemic. Specifically, two viral vector-based vaccines [Vaxzervria® (AstraZeneca; AZD1222) and COVID-19 Janssen® vaccine (Johnson & Johnson; Ad26.COV2. S)] and two mRNA-based vaccines [Comirnaty® (Pfizer/BioNTech; BNT162b2) and Spikevax® (Moderna; mRNA-1273)]. However, several cutaneous adverse reactions have been reported following vaccination, making the dermatologist's role critical. It is possible to group these adverse reactions according to a classification with six main clinical pictures: urticarial rash, erythematous/maculopapular/morbid rash, papulovesicular rash, chilblain-like acral pattern, livedo reticularis/racemose-like, and purpuric "vasculitic" pattern. Beyond this classification, there are several reports of other dermatologic manifestations associated with the infection, such as pityriasis rosea, herpes zoster, or, particularly, the worsening of pre-existing chronic inflammatory dermatologic diseases. Here we report the case of a 61-year-old patient who presented at our clinic with a diffuse psoriasiform eruption mixed with a concomitant blistering rash induced by COVID-19. The uniqueness of our case has two features: the first is the concomitance of the two events after infection that seems to be unprecedented; the second is the management of the patient that could help dermatology colleagues in the management of these conditions during infection.

Peptide sharing between SARS-CoV-2 and Bullous pemphigoid 180

Bullous pemphigoid (BP) has been repeatedly reported to occur following exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study analyzes the molecular mimicry between the 180 kDa bullous pemphigoid antigen 2 (BP180) and the SARS-CoV-2 proteome to further our understanding of the molecular link between the BP and the SARS-CoV-2 infection. Results indicate a high degree of molecular mimicry between BP180, SARS-CoV-2, hCoV-229E and hCoV-NL63. Copyright © by BIOLIFE, s.a.s.

SARS-CoV-2 vaccine-triggered conversion from systemic lupus erythematosus (SLE) to bullous SLE and dipeptidyl peptidase 4 inhibitors-associated bullous pemphigoid.

Bullous systemic lupus erythematosus (BSLE) is a rare blistering disease in patients with SLE. BSLE is a heterogenous disease caused by autoantibodies to the basement membrane, mainly type VII collagen. The pathogenesis of the development of autoantibodies in BSLE remains unknown. We report a case of SLE taking dipeptidyl peptidase 4 inhibitors (DPP4i) who developed tense blister lesions after administration of SARS-CoV-2 vaccine. Initial erythematous lesion before administration of SARS-CoV-2 vaccine had not shown IgG deposition at basement membrane both direct and indirect immunofluorescence (IIF). However, the result of those examinations became positive after the administration of SARS-CoV-2 vaccine. Furthermore, IIF test results using NaCl split skin had shown positive against epidermal side. These observations suggest that SARS-CoV-2 vaccination triggered production of autoantibodies that cause bullous SLE. The present case fulfills the diagnostic criteria for both BSLE and DPP4i-associated bullous pemphigoid. Skin lesions were cleared after withdrawal of DPP4i. Therefore, physicians should ask patients who develop blisters after the vaccination whether they are taking DPP4i.