The multifactorial complexities of autoimmune development in Pemphigus vulgaris: Critical evaluation of the role of environmental and lifestyle "exposome" factors.

Pemphigus vulgaris (PV) is a potentially life-threatening blistering disorder characterized by autoantibodies directed against cell-cell adhesion molecules that serves as an excellent model to study human autoimmune development. Numerous studies have identified specific Human Leukocyte Antigen (HLA) genes, in particular DRB1*0402 and DQB1*0503, that confer disease risk. Although HLA is required, it is not sufficient for the initiation of disease. As with all autoimmune diseases, the etio-pathogenesis of PV is complex, meaning it is multifactorial. Susceptibility is polygenic, and the search for non-HLA disease-linked genes continues. Moreover, twin studies across autoimmune conditions indicate that non-genetic environmental and lifestyle factors, which can be collectively grouped under the term "exposome", are also major contributors to disease development. The literature presents evidence for the potential role of multiple triggers such as medications, infections, stress, diet, immunizations, and sleep to influence the etiology, pathophysiology, and prognosis of PV. However, a clear understanding of the degree to which specific factors impact PV is lacking. In this investigation, we comprehensively review the environmental elements listed above and consider the strength of evidence for these factors. The overall goals of this work are to provide greater insights into the factors that influence disease susceptibility, disease development and disease course and ultimately help to better guide clinicians and inform patients in the management of PV.

Risk of infections in patients with pemphigus treated with rituximab vs. azathioprine or mycophenolate mofetil: a large-scale global cohort study.

BACKGROUND: The risk of infectious complications among patients with pemphigus managed by rituximab is yet to be precisely elucidated. OBJECTIVES: To evaluate the risk of infections in patients with pemphigus managed by rituximab vs. first-line corticosteroid-sparing agents [azathioprine and mycophenolate mofetil (MMF)]. METHODS: A global population-based cohort study compared patients with pemphigus initiating rituximab (n = 963) vs. azathioprine or MMF (n = 963) regarding the risk of 26 different infections. Propensity score matching was conducted to optimize comparability. RESULTS: During the initial 12 months following treatment, patients under rituximab experienced elevated risk of COVID-19 [hazard ratio (HR) 1.82, 95% confidence interval (CI) 1.06-3.14; P = 0.028], parasitic diseases (HR 3.22, 95% CI 1.04-9.97; P = 0.032) and cytomegalovirus (CMV) infection (HR 1.63, 95% CI 1.04-2.58; P = 0.033). When evaluating infections developing ≥ 12 months after drug initiation, rituximab was associated with greater risk of pneumonia (HR 1.45, 95% CI 1.00-2.10; P = 0.047), COVID-19 (HR 1.87, 95% CI 1.49-2.33; P < 0.001), osteomyelitis (HR 2.42, 95% CI 1.11-5.31; P = 0.023), herpes simplex virus (HR 2.06, 95% CI 1.03-4.11; P = 0.037) and CMV (HR 1.63, 95% CI 1.07-2.49; P = 0.023) infections. CONCLUSIONS: Within the first 12 months after treatment, patients under rituximab experience an elevated risk of COVID-19, parasitic and CMV infections. Rituximab is associated with pneumonia, osteomyelitis and viral diseases even beyond the first year after therapy. Pneumococcal vaccine and suppressive antiviral therapy should be considered even 1 year following therapy. There is no signal for elevated risk of tuberculosis, hepatitis B virus reactivation, Pneumocystis jiroveci pneumonia and progressive multifocal leukoencephalopathy.

COVID-19 and autoimmune bullous diseases: Lessons learned.

Both COVID-19 and autoimmune bullous diseases represent potentially life-threatening conditions. Autoimmunity has been a special focus during the COVID-19 pandemic considering the possible detrimental mutual influence between COVID-19 and autoimmune disorders as well as their supposed induction or triggering by SARS-CoV-2 vaccines. There is a growing need to assess the impact of the current pandemic particularly in patients with autoimmune bullous diseases requiring potent and long-term immunosuppressive treatments. This review provides the relevant state-of-the-art knowledge, including our own research, about immunobullous diseases in relation to COVID-19 and summarizes expert perspectives on their management throughout the pandemic.

COVID-19 in Three Patients with Pemphigus.

COVID-19 is an infectious disease caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). It has various clinical presentations, ranging from mild and moderate to severe manifestations. This infection has caused disruptions worldwide, particularly for healthcare professionals, regarding the prescribing of immunosuppressive drugs for chronic autoinflammatory and autoimmune pathologies, such as pemphigus. We report three pemphigus patients who being treated with immunosuppressive therapy developed the SARS-CoV-2 infection. (SKINmed. 2022;20:428-429).

Rituximab successful in COVID-19 vaccine-induced refractory pemphigus vulgaris (preprint)

Coronavirus disease 2019 (COVID-19) is the most prevalent disease in society today, and vaccination is a powerful weapon against COVID-19. However, there have been many recent reports of vaccine-induced skin side effects. Autoimmune bullous reactions caused by the COVID-19 vaccine are rare. We identified a case of refractory PV associated with COVID-19 vaccination that improved after 2 RTX injections.

Effect of FcRn antagonism on protective antibodies and to vaccines in IgG-mediated autoimmune diseases pemphigus and generalised myasthenia gravis.

Antagonism of the neonatal Fc receptor (FcRn) by efgartigimod has been studied in several autoimmune diseases mediated by immunoglobulin G (IgG) as a therapeutic approach to remove pathogenic IgGs. Whereas reduction of pathogenic titres has demonstrated efficacy in multiple autoimmune diseases, reducing total IgG could potentially increase infection risk in patients receiving FcRn antagonists. The objective of this study was to analyse the effect of FcRn antagonism with efgartigimod on existing protective antibody titres and the ability to mount an immune response after vaccine challenge. Serum levels of total IgG and protective antibodies against tetanus toxoid (TT), varicella zoster virus (VZV), and pneumococcal capsular polysaccharide (PCP) were measured in all patients enrolled in an open-label trial of efgartigimod for the treatment of pemphigus. Vaccine specific-responses were assessed by measuring changes in IgG titres in patients with generalised myasthenia gravis (gMG) who were treated with efgartigimod and who received influenza, pneumococcal, or coronavirus disease 2019 (COVID-19) vaccines during participation in the double-blind trial ADAPT or open-label extension, ADAPT+ (n = 17). FcRn antagonism reduced levels of protective anti-TT, anti-VZV, and anti-PCP antibodies and total IgG to a similar extent; anti-TT and anti-VZV titres remained above minimally protective thresholds for the majority of patients, (10/12) 83% and (14/15) 93% respectively. Protective antibodies returned to baseline values upon treatment cessation. Antigen-specific IgG responses to influenza, pneumococcal, and COVID-19 immunisation were detected in patients with gMG who received these vaccines while undergoing therapy with efgartigimod. In conclusion, FcRn antagonism with efgartigimod did not hamper generation of IgG responses but did transiently reduce IgG titres of all specificities.

Cutaneous manifestations following COVID-19 vaccination: A report of 25 cases.

Various adverse effects particularly cutaneous manifestations associated with different COVID-19 vaccines have been observed in practice. The aim of our study was to evaluate all patients who presented to our tertiary center with skin manifestations following COVID-19 vaccines injection from September to December 2021. All patients with skin manifestation within 30 days or less following COVID-19 vaccination were enrolled in our case-series. All cases included in our study were diagnosed based on clinical and/or histopathological evaluation and all other possible differential diagnoses were ruled out. Twenty-five individuals including 16 (64%) males and 9 (36%) females with the mean age of 47 ± 17.62 years (range 18-91) were enrolled in our study. Twenty-two (88%) patients developed lesions after Sinopharm vaccine injection and 3 (12%) cases manifested lesions after the AstraZeneca vaccine. Six (24%) patients developed new-onset lichen planus (LP) and 1 (4%) patient manifested LP flare-up. Two (8%) individuals developed psoriasis and 1 (4%) case showed psoriasis exacerbation. One (4%) patient developed new-onset pemphigus vulgaris (PV) and 1 (4%) case experienced a flare of PV lesions. One (4%) patient manifested pityriasis lichenoides et varioliformis acuta (PLEVA) flare-up. Other new-onset cases were as follows: toxic epidermal necrolysis (TEN) (n = 1, 4%), bullous pemphigoid (BP) (n = 2, 8%), alopecia areata (AA) (n = 2, 8%), pytriasis rosea (n = 1, 4%), herpes zoster (n = 1, 4%), cutaneous small vessel vasculitis (n = 1, 4%), erythema multiform (EM) and urticaria (n = 3, 12%), and morphea (n = 1, 4%). Physicians should be aware of the possible side effects especially cutaneous manifestations associated with COVID-19 vaccines.

Development of severe pemphigus vulgaris following ChAdOx1 nCoV-19 vaccination and review of literature.

Vaccines are indeed a boon for tackling the present COVID-19 pandemic. In India, ChAdOx1 nCoV-19 (Covishield) is the most commonly used vaccine in the government vaccination program for adults more than 18 years of age. It is a recombinant vaccine developed by Oxford-Astra Zeneca and manufactured in India by Serum Institute of India (SSI). Here, we report a case of severe pemphigus vulgaris following the second dose of ChAdOx1 nCoV-19 vaccination in an adult male. The patient developed septicemia during the course of hospital stay, and he was managed with systemic steroids, parenteral antibiotics, and intravenous immunoglobulins (IVIg) along with proper wound care. Patient started improving within 1 month of therapy. This case is being reported in view of the rarity of pemphigus vulgaris following ChAdOx1 nCoV-19 vaccine.

COVID-19 severity and SARS-Cov-2 vaccine safety in pemphigus patients.

There are safety concerns in the treatment of pemphigus patients with immunosuppressants, particularly rituximab (RTX), in times of the COVID-19 pandemic. In the beginning, the reports were more pessimistic. However, few reports have recently pointed to manageable courses in this patient group. Therefore, we investigated the disease characteristics and demographic features of pemphigus patients in the period of the COVID-19 pandemic. We aimed to investigate the impact of immunosuppressants on the course of COVID-19 in pemphigus patients. Also, we tried to find out the rate of flares due to COVID-19 and SARS-Cov-2 vaccines. This multicenter study included 247 patients with pemphigus from three tertiary dermatology clinics with the specialized outpatient clinic for autoimmune blistering diseases. Patients were asked standardized questions in person or via telephone calls. Also, demographic data were collected from patients' files. Two hundred forty-four of 247 patients took the survey between August and September 2021. The data of three patients were obtained from the National Health System. We collected the data of all pemphigus patients who visited the clinics at least once in the past 3 years. Among 51 patients having COVID-19, 40 had a non-serious disease, whereas 11 required hospitalization. One patient died because of COVID-19 infection. The number of patients is limited, and data depends mainly on patients' statements. RTX treatment does not require additional safety cautions than other immunosuppressives.