key: cord-0723099-los27jwc
authors: Kridin, Khalaf; Schonmann, Yochai; Weinstein, Orly; Schmidt, Enno; Ludwig, Ralf J.; Cohen, Arnon D.
title: The risk of Coronavirus disease 2019 (COVID-19) in patients with bullous pemphigoid and pemphigus: A population-based cohort study
date: 2021-03-17
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2021.02.087
sha: 02a905c49cb35d58b034d07cc3b285104db34b9c
doc_id: 723099
cord_uid: los27jwc

Background The burden of Coronavirus disease 2019 (COVID-19) in patients with bullous pemphigoid (BP) and pemphigus is yet to be evaluated. Objective To assess the risk of COVID-19, and COVID-19-associated hospitalization and mortality in patients with BP and pemphigus, and to delineate determinants of severe COVID-19 illness among these patients. Methods A population-based cohort study was performed to compare patients with BP (n=1,845) and pemphigus (n=1,236) with their age-, sex- and ethnicity-matched control subjects regarding COVID-19 and its complications. Results The risk of COVID-19 (HR, 1.12; 95%CI, 0.72-1.73; P=0.691) and COVID-19-associated hospitalization (HR, 1.58; 95%CI, 0.84-2.98; P=0.160) was comparable between patients with BP and controls, whereas the risk of COVID-19-associated mortality was higher among patients with BP (HR, 2.82; 95%CI, 1.15-6.92; P=0.023). The risk of COVID-19 (HR, 0.81; 95%CI, 0.44-1.49; P=0.496), COVID-19-associated hospitalization (HR, 1.41; 95%CI, 0.53-3.76; P=0.499), and COVID-19-associated mortality (HR, 1.33; 95%CI, 0.15-11.92; P=0.789) was similar in patients with pemphigus and their controls. Systemic corticosteroids and immunosuppressants did not predispose COVID-19-positive BP and pemphigus patients to a more severe illness. Limitations Retrospective data collection. Conclusions BP patients experience increased COVID-19-associated mortality and should be monitored closely. Maintaining systemic corticosteroids and immunosuppressive adjuvant agents during the pandemic.is not associated with worse outcomes.

Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a pandemic that started in China in late 2019 and has subsequently spread across the globe. Since severe COVID-19 is associated with a hyperinflammatory state 1,2 , it is highly intriguing to investigate whether the presence of preexisting autoimmune diseases or the previous use of immunosuppressive agents affect the phenotype of COVID- 19 . While certain studies demonstrated an increased risk and more aggressive course of SARS-CoV-2 infection in patients with autoimmune diseases [3] [4] [5] , most others refuted this finding [6] [7] [8] [9] [10] .

Bullous pemphigoid (BP) and pemphigus are the most frequent autoimmune bullous diseases (AIBD) worldwide [11] [12] [13] . Both diseases are associated with a life-threatening potential and impose an increased burden of mortality [13] [14] [15] . The management of AIBD is challenging and oftentimes necessitates the administration of high dose systemic corticosteroids and immunosuppressive agents 16, 17 . Treatment of these diseases embodies even a greater challenge in light of the COVID-19 pandemic given the concern about the vulnerability of pharmacologically immunosuppressed patients 18 .

The burden of COVID-19 and its complication among patients with AIBD is yet to be delineated, thus leaving the literature underpowered to formulate a treatment strategy for these patients during the pandemic. To optimize the treatment of AIBD, clinicians are in desperate need to identify predictors of worse outcomes in COVID-19-positive AIBD patients and to define whether AIBD-related medications influence the prognosis of patients.

The aim of the current study is to evaluate the risk of acquiring COVID-19 infection and developing its complications among patients with BP and pemphigus. We additionally aimed to identify determinants predicting severe course of COVID-19 amongst these patients.

J o u r n a l P r e -p r o o f

The current study was designed as a historical retrospective cohort study that followed patients with BP and pemphigus to estimate the incidence of COVID-19, COVID-associated hospitalization and mortality. The current study was approved by the institutional review board (IRB) in accordance with the declaration of Helsinki (approval code: 0212-17-COM).

The computerized dataset of Clalit Health Services (CHS) was the origin of the current study.

CHS is the main health maintenance organization in Israel, which provides a wide array of private and public healthcare services for 4,540,768 enrollees as of October 2018. CHS is renowned for its inclusiveness since it retrieves data from a multitude of sources covering general community clinics, both primary care and referral center settings, and both ambulatory and hospitalized care settings. The loss to follow-up is negligible, and access to CHS services is free, rendering this dataset highly compatible with the performance of reliable epidemiological studies 19 .

The computerized dataset of CHS was systematically checked for incident cases with a diagnostic code of BP and pemphigus between the years 2002 and 2019. Eligibility was determined if (i) a documented diagnosis of BP or pemphigus was registered by a community-based board-certified dermatologist, or (ii) a diagnosis of BP or pemphigus was documented in discharge letters of patients admitted to dermatological wards.

A control group encompassing five individuals per each case of BP and pemphigus was originally recruited, with controls being matched based on sex, age, and ethnicity. The index date of matching was defined at the diagnosis of BP and pemphigus. The current analysis, however, included only participants who were alive at the beginning of the pandemic (supplementary figure 1) . Study participants` date of J o u r n a l P r e -p r o o f death was ascertained by linking the study cohort with the National Registry of Deaths Database. All study participants were followed up from the onset of the pandemic in Israel (defined as the date of the first confirmed case on 27 February 2020) until 11 September 2020, or death.

The diagnosis of COVID-19 relied on confirmation of cases by a US Food and Drug Administration (FDA)-approved molecular tests. COVID-19-associated hospitalization was defined in COVID-19-confirmed patients admitted to intensive care units, internal medicine, or pulmonology inpatient wards. All hospitalized patients with COVID-19 were assigned one of the following severity degrees; mild (mild symptoms like cough, fever, fatigue, loss of smell, etc.); moderate (clinical or radiologic diagnosis of COVID-19 pneumonia); severe (respiratory rate>30, oxygen saturation<93% on room air, and PaO2/FiO2<300); and critical (severe systemic impairment including septicemia, cardiac, hepatic, or renal insufficiency). The severity degree of non-hospitalized COVID-19-confirmed patients who were not managed in any healthcare facility was defined as subclinical.

Outcome measures were adjusted for underlying comorbidities as assessed by the Charlson comorbidity index (CCI), a validated epidemiological method of quantifying comorbidities. This index has been found to be reliable in predicting mortality and is widely utilized in large-scale epidemiological studies 20 . Among others, CCI encompasses diabetes mellitus, respiratory and cardiovascular diseases, all of which were evidenced to impose worse prognostic outcomes in COVID-19 21 . COVID-19-associated hospitalization and mortality were additionally adjusted for smoking owing to the association of the latter with worse outcomes of COVID-19 21, 22 . Moreover, COVID-19-associated hospitalization and mortality were adjusted for systemic corticosteroids and immunosuppressive adjuvant drugs (azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab) given the accumulation of evidence suggesting the vulnerability of pharmacologically immunosuppressed COVID-19 patients 23 .

J o u r n a l P r e -p r o o f Baseline characteristics were described by means and standard deviations (SD)s for continuous variables, whilst categorical values were indicated by percentages. The comparison of different variables was performed using the chi-square test and t-test for categorical and continuous variables, respectively.

Incidence rates of outcomes were calculated and expressed as the number of events per 1,000 person-years. Hazard ratios (HR)s for the risk of incident outcomes were obtained by the use of the Cox regression model. The cumulative survival of patients with COVID-19 was compared between the BP and pemphigus groups and their corresponding controls using a stratified log-rank test in the Kaplan-Meier method.

The study population included 1,845 patients with BP and 1,236 patients with pemphigus. In all, 11,117 and 6,574 control subjects were matched for the eligible patients with BP and pemphigus, respectively. While the sex and ethnic composition was comparable between cases and controls, patients with BP and pemphigus were older than their matched controls at the onset of the pandemic 

Overall, 24 (1.3%) patients with BP were tested positive for COVID-19. Of whom, 12 (50.0%) had a subclinical disease, whereas 4 (16.7%), 2 (8.3%), and 6 (25.0%) patients experienced a mild, moderate, and severe disease, respectively. While 12 (50.0%) patients were hospitalized due to COVID- 

The incidence rate of COVID-19 among patients with BP was estimated at 24.4 (95% CI, 16.0-35.7) per 1,000 person-years. The incidence rates of hospitalization and mortality due to COVID-19 complications were 12.2 (95% CI, 6.6-20.7) and 7.1 (95% CI, 3.1-14.0) per 1,000 person-years, respectively. Figure 2a) . The increased mortality was more prominent among individuals older than 80.8 years of age (HR, 3.21; 95% CI, 1.21-8.56; P=0.020) and persisted following the adjustment for age, sex, ethnicity, comorbidities, exposure to systemic corticosteroids and immunosuppressants, and smoking (adjusted HR, 2.81; 95% CI, 1.14-6.94; P=0.025).

The incidence rates of COVID-19 infection, COVID-19-associated hospitalization, and mortality among patients with pemphigus were 18 Figure 2b) . The comparable risk of the three outcomes persisted in age-and sex-stratified analyses as well as in multivariable analysis adjusting for putative confounders ( Table 2 ). 

The current population-based study revealed that although the risk of COVID-19 is comparable in patients with BP and pemphigus relative to their controls, COVID-19-associated mortality was significantly elevated among patients with BP. The duration of BP and pemphigus at the onset of the pandemic and exposure to systemic corticosteroids and immunosuppressive agents were not found to predict severe COVID-19 illness.

BP and pemphigus are among the life-threatening dermatoses posing a real therapeutic challenge and conferring a high inpatient burden 24, 25 . Patients with both conditions were found to experience an increased hazard of respiratory, cutaneous, multi-organ, and systemic infections, which were associated with considerable inpatient mortality and costs 26 . The susceptibility to bacterial and viral infectious conditions in AIBD accords with other autoimmune diseases 27 and may be attributed to immune dysregulation, higher prevalence of predisposing comorbidities (like diabetes mellitus and cardiovascular conditions), as well as to the chronic exposure to immunomodulatory medications 6, 28 . Therefore, estimating the risk of COVID-19 among patients with AIBD was an urgent unmet need.

We did not find evidence for change in the overall risk of COVID-19 among patients with BP and pemphigus, compared to their controls, in congruence with other autoimmune and rheumatic diseases [6] [7] [8] [9] [10] .

This increasing body of evidence denotes that the risk of catching the infection relies mainly on whether patients get exposed to the pathogen, adhere to social distancing, and follow safety instructions. The more interesting question, however, is whether patients with AIBD follow a more severe course of and are more predisposed to the infection`s complications. We found that patients with BP displayed an elevated COVID-19-associated mortality. While the severity of COVID-19 is yet to be elucidated in AIBD, some studies following patients with other autoimmune diseases disclosed a more aggressive course of COIVD-19 in patients with preexisting connective tissue diseases 3 , and higher frequency of mechanical ventilation among those with rheumatic diseases 5 . Notwithstanding, other studies found a J o u r n a l P r e -p r o o f similar course and comparable frequency of complications among those with various systemic autoimmune diseases 6 and inflammatory bowel disease (IBD) 10 . In the current study, smoking was proved less frequent among patients with pemphigus. Since smoking is associated with worse outcomes of COVID-19 22 , its lower prevalence in patients with pemphigus may account, at least in part, for the comparable risk of COVID-19 complications in pemphigus.

Exposure to systemic corticosteroids and immunosuppressive agents was not significantly associated with the severity of COVID-19 in the current study. This finding may provide evidence-based advice on the importance of maintaining therapies during the pandemic. Discordant findings emerged from a global registry of patients with rheumatic diseases reporting that systemic corticosteroids, but not other therapies, predicted an increased probability of COVID-19-associated hospitalization 4 . Of note, exposure to tumor necrosis factor-α (TNFα) antagonist was associated with a decreased risk of hospitalization in this study 4 . Systemic corticosteroids, but not biologic agents, were found to increase the risk of severe COVID-19 among patients with IBD 10, 29 . Solid organ transplant recipients, often placed on various immunosuppressive regimens, were found to be more susceptible to develop severe COVID-19 30,31 .

These inconsistent findings may reflect the differential role exerted by immunosuppressive agents throughout different stages of the triphasic course of COVID-19 23 . While immunosuppressive drugs can be detrimental in the initial phase of the disease, when the host immune response is essential to constrain viral replication, these drugs may confer a protective role in the advanced severe phase of the diseases. In the latter, an overshoot of the host immune response (the "cytokine storm"), also referred to as secondary hemophagocytic lymphohistiocytosis, can result in acute respiratory distress syndrome (ARDS), multiorgan failure, and mortality 23 . Further research utilizing larger sample sizes is necessary to better delineate the precise role of immunosuppressive drugs in the course of COVID-19.

The observations of the current study, once verified by other research groups, indicate that percussions should be practiced by the healthcare system for elderly patients with BP. Patients should be notified in advance that they are at increased risk for mortality, therefore BP patients should avoid contagion, even more than other people. The healthcare system should organize an outreach program to ensure BP patients wellbeing. During hospitalization, close monitoring is highly recommended. At discharge, the hospital should notify community healthcare personal about the excess risk for mortality in BP patients.

The current study throws light on an important and unexplored topic. The large sample size and the allocation of control groups enable to assess the relative risk of COVID-19 in patients with BP and pemphigus. Given that the CHS dataset facilitates comprehensive access to the whole array of healthcare services, it is highly compatible with detecting COVID-19 cases, even those occurring years following the initial diagnosis of BP and pemphigus. The latter cannot be fulfilled in hospital-based cohorts, where AIBD patients tend to lose follow-up as the time from the diagnosis goes by. The study was performed in a country typified by a high incidence rate of COVID-19, thus allowing to detect and characterize positive cases.

The study has several limitations to acknowledge. Since it was based on a computerized dataset, the current study did not follow the acceptable immunopathological criteria to define BP and pemphigus.

However, eligibility was grounded on the diagnosis distributed by board-certified dermatologists or after admission to a dermatological ward. In both settings, immunopathological diagnostics are widely utilized 32 , thus arguing in favor of the validity of the diagnosis. Since the index date dictating age matching was defined at the diagnosis of BP and pemphigus, the case and control groups displayed slightly different ages at the onset of the pandemic. However, multivariable analysis adjusting for age did not alter any of the outcome measures. An additional drawback stems from the small sample size of the subgroups compared to define predictors of COVID-19 severity among patients with BP and pemphigus.

To overcome some of these shortcomings a registry for all AIBD patients that had suffered from J o u r n a l P r e -p r o o f confirmed COVID-19 has been initiated by the AIBD task force of the European Academy of Dermatology and Venereology (https://recovab.umcg.nl).

In conclusion, the current population-based study provides a seminal report about the risk of COVID-19 in AIBD and defines the determinants of severe illness. While the risk of acquiring COVID-19 infection was comparable in BP and pemphigus patients relative to their control subjects, patients with BP demonstrated an increased COVID-19-associated mortality. The administration of systemic corticosteroids and adjuvant immunosuppressive agents and the duration of BP and pemphigus did not seem to affect the infection severity and complications. In line with current expert recommendations 18, 33 and using an evidence-based approach, the current study argues in favor of maintaining AIBD-related therapies during the pandemic. Given their greater vulnerability, patients with BP developing COVID-19

should be monitored closely.

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anytime during the course of the diseases a , n (%)