Risk of COVID-19 and its complications in patients with atopic dermatitis undergoing dupilumab treatment-a population-based cohort study.

The risk of coronavirus disease (COVID-19) infection and its complications among patients with atopic dermatitis (AD) treated by dupilumab is yet to be determined. We aimed to assess the risk of SARS-CoV-2 infection, COVID-19-associated hospitalization, and mortality among patients with AD treated by dupilumab. A population-based cohort study was conducted to compare AD patients treated by dupilumab (n = 238) with those treated by prolonged systemic corticosteroids (≥ 3 months; n = 1,023), phototherapy (n = 461), and azathioprine or mycophenolate mofetil (MMF; n = 194) regarding the incidence of COVID-19 and its complications. The incidence rate of COVID-19, COVID-19-associated hospitalization, and mortality among patients treated by dupilumab was 70.1 (95% CI, 40.5-116.4), 5.0 (95% CI, 0.3-24.7), and 0.0 per 1,000 person-year, respectively. The use of dupilumab was not associated with an increased risk of SARS-CoV-2 infection [adjusted HR for dupilumab vs. prolonged systemic corticosteroids: 1.13 (95% CI, 0.61-2.09); dupilumab vs. phototherapy: 0.80 (95% CI, 0.42-1.53); dupilumab vs. azathioprine/MMF: 1.10 (95% CI, 0.45-2.65)]. Dupilumab was associated with a comparable risk of COVID-19-associated hospitalization [adjusted HR for dupilumab vs. prolonged systemic corticosteroids: 0.35 (95% CI, 0.05-2.71); dupilumab vs. phototherapy: 0.43 (95% CI, 0.05-3.98); dupilumab vs. azathioprine/MMF: 0.25 (95% CI, 0.02-2.74)]. When applicable, the risk of mortality was not elevated in patients with AD treated by dupilumab [HR for dupilumab vs. prolonged systemic corticosteroids: 0.04 (95% CI, 0.00-225.20)]. To conclude, dupilumab does not impose an increased risk of SARS-CoV-2 infection or COVID-19 complications in patients with AD. Dupilumab should be continued and considered as a safe drug for moderate-to-severe AD during the pandemic.

Increased all-cause mortality in concomitant atopic dermatitis and asthma: A nationwide registry-based study.

BACKGROUND: Excess mortality has been reported for adults with atopic dermatitis (AD) and asthma. OBJECTIVE: To assess the mortality rate in adults with concomitant AD and asthma. METHODS: Adults with hospital-diagnosed AD were matched (1:4) with non-AD individuals from the background population. RESULTS: The study cohort comprised 8,095 adults with AD (of which 1,201 (14.8%) had concomitant asthma) and 32,380 reference individuals without AD from the background population (of which 878 (2.7%) had asthma). A total of 1,057, 330, 55 and 99 deaths were observed among subjects with neither AD nor asthma, AD only, asthma only, and subjects with concomitant AD and asthma, respectively. The mortality rate per 1,000 person-years was 4.75 (95% CI 4.47-5.05) for subjects with neither AD nor asthma, 7.17 (95% CI 5.92-10.05) for asthma only, 7.09 (95% CI 6.37-7.90) for AD only and 10.87 (95% CI 8.92-13.23) for concomitant AD and asthma. Risk for all-cause mortality was increased in subjects with concomitant AD and asthma compared to asthma only (HR 1.52, 95% CI 1.07-2.15) and neither AD nor asthma (HR 2.27, 95% CI 1.83-2.81) but not compared to subjects with AD only (HR 1.10, 95% CI 0.87-1.39). However, compared to AD only subjects with AD and asthma had increased risk of death due to pulmonary disease (HR 1.81, 95% CI 1.04-3.15). CONCLUSION: Adults with AD, asthma or both conditions have increased risk of death, and further concomitant AD and asthma have increased risk of death compared with asthma alone.

Atopic eczema in adulthood and mortality: UK population-based cohort study, 1998-2016.

BACKGROUND: Atopic eczema affects up to 10% of adults and is becoming more common globally. Few studies have assessed whether atopic eczema increases the risk of death. OBJECTIVE: We aimed to determine whether adults with atopic eczema were at increased risk of death overall and by specific causes and to assess whether the risk varied by atopic eczema severity and activity. METHODS: The study was a population-based matched cohort study using UK primary care electronic health care records from the Clinical Practice Research Datalink with linked hospitalization data from Hospital Episode Statistics and mortality data from the Office for National Statistics from 1998 to 2016. RESULTS: A total of 526,736 patients with atopic eczema were matched to 2,567,872 individuals without atopic eczema. The median age at entry was 41.8 years, and the median follow-up time was 4.5 years. There was limited evidence of increased hazard for all-cause mortality in those with atopic eczema (hazard ratio = 1.04; 99% CI = 1.03-1.06), but there were somewhat stronger associations (8%-14% increased hazard) for deaths due to infectious, digestive, and genitourinary causes. Differences on the absolute scale were modest owing to low overall mortality rates. Mortality risk increased markedly with eczema severity and activity. For example, patients with severe atopic eczema had a 62% increased hazard (hazard ratio = 1.62; 99% CI = 1.54-1.71) for mortality compared with those without eczema, with the strongest associations for infectious, respiratory, and genitourinary causes. CONCLUSION: The increased hazards for all-cause and cause-specific mortality were largely restricted to those with the most severe or predominantly active atopic eczema. Understanding the reasons for these increased hazards for mortality is an urgent priority.

Allergic disorders and susceptibility to and severity of COVID-19: A nationwide cohort study.

BACKGROUND: There is inconclusive and controversial evidence of the association between allergic diseases and the risk of adverse clinical outcomes of coronavirus disease 2019 (COVID-19). OBJECTIVE: We sought to determine the association of allergic disorders with the likelihood of a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result and with clinical outcomes of COVID-19 (admission to intensive care unit, administration of invasive ventilation, and death). METHODS: A propensity-score-matched nationwide cohort study was performed in South Korea. Data obtained from the Health Insurance Review & Assessment Service of Korea from all adult patients (age, >20 years) who were tested for SARS-CoV-2 in South Korea between January 1, 2020, and May 15, 2020, were analyzed. The association of SARS-CoV-2 test positivity and allergic diseases in the entire cohort (n = 219,959) and the difference in clinical outcomes of COVID-19 were evaluated in patients with allergic diseases and SARS-CoV-2 positivity (n = 7,340). RESULTS: In the entire cohort, patients who underwent SARS-CoV-2 testing were evaluated to ascertain whether asthma and allergic rhinitis were associated with an increased likelihood of SARS-CoV-2 test positivity. After propensity score matching, we found that asthma and allergic rhinitis were associated with worse clinical outcomes of COVID-19 in patients with SARS-CoV-2 test positivity. Patients with nonallergic asthma had a greater risk of SARS-CoV-2 test positivity and worse clinical outcomes of COVID-19 than patients with allergic asthma. CONCLUSIONS: In a Korean nationwide cohort, allergic rhinitis and asthma, especially nonallergic asthma, confers a greater risk of susceptibility to SARS-CoV-2 infection and severe clinical outcomes of COVID-19.

Cause-specific mortality in adults with atopic dermatitis.

BACKGROUND: Adult atopic dermatitis (AD) has been associated with several comorbidities, but cause-specific mortality risk is unknown. OBJECTIVE: To examine cause-specific death rates and risk in adults with AD. METHODS: We performed cross-linkage of nationwide health care and cause of death registers. Adult patients with AD were matched with 10 controls per study subject. We calculated incidence rates per 1000 person-years and hazard ratios (HRs) of cause-specific death with 95% confidence intervals (95% CIs) using Cox proportional hazards models. RESULTS: A total of 8686 patients and 86,860 matched controls were studied. The risk for death due to any cause was significantly increased in patients with AD (HR 1.27, 95%CI 1.11-1.45). Significant causes included cardiovascular (HR 1.45; 95% CI 1.07-1.96), infectious (HR 3.71; 95% CI 1.43-9.60), and urogenital diseases (HR 5.51; 95% CI 1.54-19.80). No increased risk for death due to cancer, endocrine, neurologic, psychiatric, respiratory, or gastroenterologic disease was observed. LIMITATIONS: The results might not be generalizable to patients seen exclusively by primary care physicians. CONCLUSION: Adults with atopic dermatitis had slightly increased risk for death during follow-up. While the risk for death from cardiovascular, urogenital, and infectious diseases was slightly elevated among patients with AD, the absolute risk was very low.

Ten-year mortality is increased after hospitalization for atopic dermatitis compared with the general population, but reduced compared with psoriasis.

BACKGROUND: Psoriasis and atopic dermatitis (AD) are chronic inflammatory skin disorders. Mortality is increased in psoriasis, yet no studies on mortality in AD are currently available. OBJECTIVE: We investigated 10-year mortality after hospitalization for AD compared with psoriasis and the general population. METHODS: Between 1996 and 2002 all Danes aged 18 years or older with a first-time hospitalization as a result of AD or psoriasis and AD-matched healthy control subjects were examined in nationwide registers. Multivariable (adjusted for age, sex, socioeconomic status, Charlson Comorbidity Index score, smoking, and medication) hazard ratios were estimated by Cox regression. RESULTS: The study comprised 576 and 951 hospitalized patients with AD and psoriasis, respectively, with a maximum follow-up time of 10 years. During the study period, there were 65 and 286 deaths among patients with AD and psoriasis. Risk of death was decreased in patients with AD versus psoriasis (hazard ratio 0.75; 95% confidence interval 0.57-1.00), but higher than in general population control subjects (n = 5760) (hazard ratio 1.71; 95% confidence interval 1.20-2.44). Patients hospitalized with AD died on average 8.3 years younger than control subjects. LIMITATIONS: Lifestyle may have affected the risk. CONCLUSIONS: The 10-year mortality was significantly lower after hospitalization for AD compared with psoriasis, but increased when compared with the general population.

Association between varicella zoster virus infection and atopic dermatitis in early and late childhood: a case-control study.

BACKGROUND: Wild-type varicella zoster virus infection (WTVZV) early in childhood has been shown to protect against the development of asthma and atopy. OBJECTIVE: To determine whether WTVZV in childhood protects against atopic dermatitis (AD). METHODS: This retrospective, practice-based, case-control study randomly sampled 256 children and adolescents (age 1-18 years) with AD and 422 age-matched healthy controls from 2005 to 2007. Observations were made before the a priori hypothesis. RESULTS: (1) A single episode of WTVZV in childhood is associated with decreased odds ratio (OR) of developing AD (conditional logistic regression; OR, 0.55; 95% CI, 0.34-0.89; P = .01). (2) When using intervals for age corresponding to bimodal distribution of age of WTVZV infection, the effects of WTVZV infection are significant when occurring at age 0 to 8 years (OR, 0.56; 95% CI, 0.35-0.90; P = .02), but not at 8 to 18 years (OR, 0.50; 95% CI, 0.19-1.31; P = .16). Considering 5-year intervals has similar findings. (3) WTVZV is associated with decreased odds of moderate AD (multinomial logistic regression; OR, 0.08, 95% CI, 0.04-0.15; P < .0001) or severe AD (OR, 0.04; 95% CI, 0.01-0.13; P < .0001). (4) WTVZV in children is associated with prolonged AD-free survival (Kaplan-Meier; median, 15.3 years; 95% CI, 10.9-18.0) compared with controls (median, 7.5 years; 95% CI, 4.8-11.9; log-rank test, P < .0001). (5) Children with WTVZV, compared with vaccine, who eventually develop AD require fewer pediatrician sick visits for management of AD (logistic regression; OR, 0.17; 95% CI, 0.06-0.51; P = .001). CONCLUSION: WTVZV in childhood protects up to 10 years of age against AD, delays onset of AD symptoms, and decreases AD severity and office visits.

Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin.

BACKGROUND: The Notch pathway is essential for proper epidermal differentiation during embryonic skin development. Moreover, skin specific loss of Notch signaling in the embryo results in skin barrier defects accompanied by a B-lymphoproliferative disease. However, much less is known about the consequences of loss of Notch signaling after birth. METHODOLOGY AND PRINCIPAL FINDINGS: To study the function of Notch signaling in the skin of adult mice, we made use of a series of conditional gene targeted mice that allow inactivation of several components of the Notch signaling pathway specifically in the skin. We demonstrate that skin-specific inactivation of Notch1 and Notch2 simultaneously, or RBP-J, induces the development of a severe form of atopic dermatitis (AD), characterized by acanthosis, spongiosis and hyperkeratosis, as well as a massive dermal infiltration of eosinophils and mast cells. Likewise, patients suffering from AD, but not psoriasis or lichen planus, have a marked reduction of Notch receptor expression in the skin. Loss of Notch in keratinocytes induces the production of thymic stromal lymphopoietin (TSLP), a cytokine deeply implicated in the pathogenesis of AD. The AD-like associated inflammation is accompanied by a myeloproliferative disorder (MPD) characterized by an increase in immature myeloid populations in the bone marrow and spleen. Transplantation studies revealed that the MPD is cell non-autonomous and caused by dramatic microenvironmental alterations. Genetic studies demontrated that G-CSF mediates the MPD as well as changes in the bone marrow microenvironment leading to osteopenia. SIGNIFICANCE: Our data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.