Discussion
This observational study included a large population of patients (1831 adult subjects) affected by moderate-to-severe AD and treated with systemic therapies or phototherapy, and managed during the COVID-19 pandemic in Italy. The participating centers (n=35) were highly representative of the different incidence distribution of SARS-CoV-2 infection nationwide, having 15, 10, and 10 centers located in Northern, Central, and Southern Italy, respectively.8 During the observation period, a total number of 240,578 SARS-CoV2 positive cases was registered, with a cumulative number of 190,248 recovered cases and 34,767 deaths.8 In details, national incidence at timepoint 1, 2, and 3 was 0.71% (95% CI: 0.4-1.2), 0.27% (95% CI: 0.1 - 0.64), and 0.11% (95% CI: 0.0 – 0.4), in line with the infection rate observed in our AD population (timepoint 1: 0.71%; timepoint 2: 0.16%; timepoint 3: 0%). In our study population, less than 1% of patients (16/1831) resulted positive to SARS-CoV-2, with only three patients who required hospitalization, though swab testing was not massively performed throughout the study period. During this critical sanitary emergency, clinical activity in dermatology clinics was markedly limited, and teledermatology (web- and phone- counselling) was extremely useful for reducing patient access to hospital. This modality was well accepted by AD patients who continued to have access to dermatologist consultation, guaranteeing support and treatment continuation in the majority of cases. Indeed, a relatively low number of patients were lost to follow-up (7.7%). As suggested by both national and international scientific societies, most patients were recommended to continue their current treatment during COVID-19 pandemic.2 About 86% of patients continued treatment, including 8 patients who resulted positive to SARS-CoV-2 infection, albeit common recommendations suggested to withdraw therapy. Notably, 85% of patients included in this study were treated with dupilumab, mostly prescribed as monotherapy.
Considering disease severity assessment, patients undergoing dupilumab monotherapy showed lower disease activity suggesting a better control of AD compared to patients treated with systemic immunosuppressive compounds or dupilumab combined with other systemic therapies. Albeit dupilumab-treated patient cohort exhibited lower disease severity at baseline and throughout the study period compared to the other treatments, superiority of dupilumab during COVID pandemic cannot be suggested based on this data referring to a limited timeframe and heterogeneous baseline patients’ characteristics across different treatment groups. The therapeutic regimen combining dupilumab with other systemic agents occurred in a cohort of patients with significantly higher prevalence of atopic disorders who may require this combined approach as likely they represent a high-need patient population. Nevertheless, no worsening of atopic comorbid conditions was reported. Response to treatment in these patients resulted similar to patients treated with dupilumab monotherapy or systemic immunosuppressive compounds. This latter class of agents was supposed to have an unfavorable safety profile compared to biologics but no warning signal was detected in our study. Dupilumab, does not impair the immune compartments implicated in host defense against viral infections, and thus may be considered a safer therapeutic choice for AD.9-12 In dupilumab clinical trials, rates of general infections, upper respiratory tract infections, and nasopharyngitis resulted similar to placebo, and, in particular, viral infections, were not reported as meaningful adverse event.7,13 In terms of effectiveness, dupilumab therapy obtained a satisfactory control of the disease and consistently with the other systemic compounds, treatment interruption did not cause a rapid and relevant worsening of the disease, as highlighted by the decrease of both patient-assessed severity scores and EASI score in patients discontinuing therapy. This finding is in line with a recent study reporting maintenance of EASI-75 response in 30.4% of high-responding patients treated with dupilumab, after rerandomization to placebo.14 However, the reduction of disease severity in patients discontinuing therapy was not associated with a positive patient perception of AD status: a higher percentage of patients withdrawing therapy evaluated their AD status as worsened. Likely, therapy continuation, compared to an intermittent or discontinued therapeutic regimen, might positively impact on patient perception of both disease control and severity.
Dupilumab was interrupted in a small percentage of patients, conversely to cyclosporine and oral corticosteroids. In addition, phototherapy was interrupted in most cases (about 74%) due to the lack of accessibility to phototherapy services during phase I (lockdown). Dupilumab interruption was mainly based on patient decision and the main cause of interruption was represented by non-medical reasons (lack of drug supply). Fear of having an increased risk of COVID -19 disease determined treatment interruption in 25% of patients withdrawing therapy, similarly to recent findings observed in psoriasis patients.15 Another study confirmed that patients affected by either psoriasis (233 patients) or AD (68 patients) who felt unsafe about their immunomodulatory treatment, were more concerned about having SARS-CoV-2 infection and more likely discontinued therapy during pandemic (overall treatment interruption: 7.3%).16 In particular, AD patients with asthma were more concerned about being at risk of COVID-19 disease because of AD and its treatment.16
The strength of our study is the large AD population treated with systemic therapies who was observed longitudinally, during the national lockdown period (phase I) and the following phase of partial and gradual re-opening of health care services (phase II and III), that were planned in order to face COVID-19 outbreak. In particular, this study provided evidence that continuation of immunomodulant/immunosuppressive therapies during COVID-19 pandemic can be considered safe and effective in controlling AD. This finding strengthens the recommendations issued by national and international scientific societies at the beginning of the COVID-19 outbreak that are based on experts’ opinion.2-5 Notably, this study also suggested that drug interruption did not cause AD flares, as treatment response was maintained in the short-term.
However, some limitations related to the data collection, management and disease severity evaluation via web- or phone-counselling should be considered as most of the assessment tools used were patient-reported and only a minor percentage of patients could be evaluated by regular visits during phase 3. Detailed information about atopic comorbid conditions, SARS-CoV-2 serology testing were not collected. In addition, most patients were undergoing dupilumab therapy with a satisfactory control of the disease, particularly with dupilumab monotherapy (mean T1 EASI score significantly lower than other treatment groups), and this could represent a selection bias of the study population likely related to the relatively higher number of dupilumab-treated patients managed in a dedicated AD outpatient clinic.
Data collection related to AD patients treated with systemic compounds and/or photherapy during COVID-19 pandemic is continuing by the DA-COVID-19 registry, willing to delineate the infectious risk related to the use of each immunomodulant/immunosuppressant agent in AD patient population and to better characterize COVID-19 outcomes in patients with AD, as internationally promoted by the SECURE-AD registry.17