key: cord-0711856-ynadltcu
authors: Chiricozzi, Andrea; Talamonti, Marina; De Simone, Clara; Galluzzo, Marco; Gori, Niccolò; Fabbrocini, Gabriella; Marzano, Angelo Valerio; Girolomoni, Giampiero; Offidani, Annamaria; Rossi, Maria Teresa; Bianchi, Luca; Cristaudo, Antonio; Fierro, Maria Teresa; Stingeni, Luca; Pellacani, Giovanni; Argenziano, Giuseppe; Patrizi, Annalisa; Pigatto, Paolo; Romanelli, Marco; Savoia, Paola; Rubegni, Pietro; Foti, Caterina; Milanesi, Nicola; Belloni Fortina, Anna; Bongiorno, Maria Rita; Grieco, Teresa; Di Nuzzo, Sergio; Fargnoli, Maria Concetta; Carugno, Andrea; Motolese, Alberico; Rongioletti, Franco; Amerio, Paolo; Balestri, Riccardo; Potenza, Concetta; Micali, Giuseppe; Patruno, Cataldo; Zalaudek, Iris; Lombardo, Maurizio; Feliciani, Claudio; Di Nardo, Lucia; Guarneri, Fabrizio; Peris, Ketty
title: Management of patients with atopic dermatitis undergoing systemic therapy during COVID‐19 pandemic in Italy: Data from the DA‐COVID‐19 registry
date: 2021-03-09
journal: Allergy
DOI: 10.1111/all.14767
sha: 4cb57bea965133e08e6f5e5ecd69a32880c6a7b9
doc_id: 711856
cord_uid: ynadltcu

BACKGROUND: Few and small studies have described the management of immunomodulant/immunosuppressive therapies or phototherapy in atopic dermatitis (AD) patients during coronavirus disease 2019 (COVID‐19) pandemic. METHODS: A national registry, named DA‐COVID‐19 and involving 35 Italian dermatology units, was established in order to evaluate the impact of COVID‐19 pandemic on the management of adult AD patients treated with systemic immunomodulant/immunosuppressive medications or phototherapy. Demographic and clinical data were obtained at different timepoints by teledermatology during COVID‐19 pandemic, when regular visits were not allowed due to sanitary restrictions. Disease severity was assessed by both physician‐ and patient‐reported assessment scores evaluating itch intensity, sleep disturbances, and AD severity. RESULTS: A total of 1831 patients were included, with 1580/1831 (86.3%) continuing therapy during pandemic. Most patients were treated with dupilumab (86.1%, 1576/1831) that was interrupted in only 9.9% (156/1576) of cases, while systemic immunosuppressive compounds were more frequently withdrawn. Treatment interruption was due to decision of the patient, general practitioner, or dermatologist in 39.9% (114/286), 5.6% (16/286), and 30.1% (86/286) of cases, respectively. Fear of increased susceptibility to SARS‐CoV‐2 infection (24.8%, 71/286) was one of the main causes of interruption. Sixteen patients (0.9%) resulted positive to SARS‐CoV‐2 infection; 3 of them (0.2%) were hospitalized but no cases of COVID‐related death occurred. CONCLUSIONS: Most AD patients continued systemic treatments during COVID pandemic and lockdown period, without high impact on disease control, particularly dupilumab‐treated patients.

COVID-19, caused by SARS-CoV-2 infection, has spread rapidly worldwide becoming pandemic, as defined by the World Health Organization on 18th March 2020. 1 Most patients exhibit mild-to-moderate symptoms and recover without sequelae, though hospitalization, generally due to pneumonia, and more severe respiratory involvement such as acute respiratory distress syndrome, septic shock, and/or multiple organ failure, associated with high mortality, may occur. 1 Italy has faced the first wave of SARS-CoV-2 infection out of China before the rapid worldwide pandemic spreading. To face the virus spreading, a nationwide lockdown period (phase I) limiting all kind of activities including healthcare services was decided on March 10th and lasted until May 4th, when a phase II was planned with a gradual re-opening of hospital dermatology services. During these two initial phases, medical visits were restricted to urgent cases, and the use of teledermatology was implemented in many dermatological services. On 15th June 2020, a phase III was established recovering almost all activities with sanitary restrictions, and healthcare services were restored based on the decision of local sanitary authorities.

Thereby, COVID-19 pandemic led to the sudden need of increasing the use of web and phone consulting, and defining practical guidelines for the management of immune-mediated dermatologic conditions, such as AD that in moderate-to-severe cases are commonly treated with systemic immunomodulant/immunosuppressive compounds or phototherapy. The effect of immunomodulant/immunosuppressive compounds on the clinical course of COVID-19 is currently unclear, and there is concern of an increased risk of infection in AD patients treated with systemic compounds, though the continuation of therapy during pandemic was recommended by national and international scientific societies. [2] [3] [4] [5] [6] [7] Nevertheless, immunomodulant/immunosuppressive agents, such as methotrexate, mycophenolate, azathioprine, and cyclosporine, were suggested to be tapered to the lowest effective dose, likely avoiding disease flare, and to consider drug discontinuation in patients when viral symptoms are present. 2, 5 Similarly, caution was recommended in prescribing systemic corticosteroids given their broad immunosuppressive effects. 2, 5 Furthermore, some authors recommended halting office-based phototherapy to minimize potential exposure to SARS-CoV-2 virus and instead encourage exposure of affected areas to natural sunlight, bleach baths, and wet wraps. 5 However, current recommendations are based on limited knowledge regarding the risk of systemic immunomodulant/immunosuppressive compound use, and few data related to AD patients treated during COVID-19 pandemic.

We designed a national registry, the DA-COVID-19 registry, aimed to evaluate the impact of the pandemic on the therapeutic management and clinical course of AD in patients treated with any systemic immunomodulant/immunosuppressive compound or phototherapy. This observational study analyzed clinical and demographic characteristics of moderate-to-severe AD patients, who were managed with telemedicine and eventually by regular ambulatory visits during the COVID-19 pandemic.

This cross-sectional, multicentric, observational study was conducted in 35 Italian centers. This registry, which was aimed to collect data on moderate-severe AD patients treated with systemic agents and/or phototherapy during COVID-19 outbreak, has G R A P H I C A L A B S T R A C T Among 1831 studied AD patients, 86.1% were treated with dupilumab. Patients continuing therapy experienced a marked reduction of disease severity during pandemic. The causes of treatment interruption included: fear of increased susceptibility to SARS-CoV-2 infection (24.8%), occurrence of comorbidities (5.9%), age above 60 years (5.2%), SARS-CoV-2 infection (2.8%), close contact with SARS-CoV-2positive subject (2.4%), other reasons, for example, inability to maintain drug supply, non-medical/unspecified causes (58.7%).

been promoted by the Italian Society of Dermatology (SIDeMaST) and approved by the national ethical committee for COVID-19related studies (Istituto Nazionale per le MalattieInfettive Lazzaro Spallanzani I.R.C.C.S.). The study period included the three phases of first-wave COVID-19 pandemic in Italy ( Figure S1 ).

Adult patients (aged ≥18 years) affected by moderate-to-severe AD, treated with systemic immunosuppressive/immunomodulant compounds or phototherapy, were included in the DA-COVID-19 registry if face-to-face evaluation or remote visit (via telephone or web consulting) were performed between 10th March and 30th

April 2020. By April 30th, data have been collected monthly, thereafter, on an ad hoc database. Data were collected at 3 different timepoints: April 30th (Timepoint 1), May 30th (Timepoint 2), and June 30th (Timepoint 3) ( Figure S1 ). Subjects who signed the informed consent were included in this study. Baseline data included age, gender, occupation, atopic comorbidities, smoking habits (smoker, former smoker, or non-smoker), and disease severity. Data on SARS-CoV-2 swab testing, hospitalization, clinical outcomes of COVID-19 disease, and quarantine due to close contact to COVID-9 patients were also collected.

Patients were analyzed according to their ongoing therapy to identify possible differences in any of the demographic or clinical variables collected. Frequency and percentages were the descriptive analyses performed on the categorical variables. Continuous variables were summarized as means ±standard deviation. For categorical variables, differences between groups were evaluated using chi-squared test or Fisher's exact test (if more than 20% of the cells in a contingency table have expected counts less than 5). For quantitative variables, the Shapiro-Wilk test was performed in order to test the normality of data. If the p-value was less than or equal to 0.05 (non-normality), the comparison between groups was performed by means of the non-parametric Wilcoxon rank-sum test. Otherwise, the comparison was performed using the t-test. Moreover, comparison between timepoint 1 value and the other timepoints was performed using the paired t-test (or the Wilcoxon signed-rank test in the case of non-normal data). Finally, an ANOVA test (or Kruskal-Wallis test in the case of non-normal data) was performed to compare the means in case of more than 2 groups. Differences were considered statistically different if P values resulted <0.05. Analyses were performed using software SAS 9.4 version (SAS, NC, USA).

The DA-COVID registry included 1831 patients with moderate-tosevere AD presenting demographic and clinical characteristics as illustrated in Table 1 . Overall, 142/1831 (7.7%) patients were lost to follow-up throughout the observation period. Table 2 ). AD severity was in line with the overall patient population (data not shown).

Comparing AD patients positive to SARS-CoV-2 nasal-throat swab testing with those who resulted negative, no significant difference in mean baseline EASI score was found (7.744 ± 2.062 for SARS-CoV-2-positive patients vs 5.830 ± 0.9865 for SARS-CoV-2-negative patients, P = 0.3577). Fifteen of 16 (93.8%) patients were undergoing dupilumab therapy when SARS-CoV-2 occurred (Table 2) . Dupilumab was mostly used in monotherapy (80%, 13/15) while in 20.0% (3/15) of patients was combined with systemic corticosteroids and/or methotrexate. Half of SARS-CoV-2-positive patients discontinued treatment. SARS-CoV-2-positive patients who continued treatment were all undergoing dupilumab therapy and exhibited a significant reduction of mean EASI score from timepoint 1 to timepoint 3 (7.7 ± 2.1 at timepoint 1 vs 2.3 ± 1.3 at timepoint 3, P = 0.0468). Similarly, EASI score significantly decreased in patients discontinuing therapy overtime (timepoint 1: 9.9 ± 9.5 vs time- Figure S2 ).

Immunosuppressive systemic compounds were used as either monotherapy or combination therapy as showed in Table 3 

At timepoint 1 (lockdown phase), disease severity assessment of the whole patient population showed: mean EASI score of 6.8 ± 7.7, itch NRS of 2.6 ± 2.2, sleep NRS of 1.7 ± 2.1, and self-assessment of AD severity, AD-NRS of 2.5 ± 2.1 (Table 4 ). During the study period, patients experienced a significant reduction of mean itch NRS, mean sleep NRS, and mean AD-NRS scores, achieving lower mean scores at timepoint 3, compared to timepoint 1 (Tables S2 and S3 ).

This improvement reflected the significant decrease of mean EASI score at timepoint 3 (3.4 ± 4.4) compared to timepoint 1 (6.8 ± 7.7, P < 0.0001). Reduction of mean EASI score was observed in both patients continuing treatment and patients interrupting systemic therapy, though at different extent (Table 4 ). Indeed, mean EASI score changed in the cohort of patients continuing treatment over time (6.6 ± 7.8 #P < 0.001, Wilcoxon rank-sum test was used to compare the 2 patient subcohorts at timepoint 1. §P < 0.001, chi-squared test was used for statistical analysis.

çMean EASI score was calculated on 1831 and 746 patients at timepoint 1 and 3, respectively.

*P < 0.0001, paired s test was used to compare T1 vs T3 in the total population. a 10-fold higher reduction compared to the cohort of patients withdrawing treatment (8.2 ± 7.5 at timepoint 1 vs 7.3 ± 7.7 at timepoint 3).

Self-assessment of itch, sleep, and disease severity did not reveal any marked difference between the two patient subcohorts in terms of score reduction (Table 4) .

At timepoint 1, AD improvement was experienced by a higher percentage of patients continuing therapy compared to patients discontinuing treatment (28.8% vs 15.5%, P < 0.001). Stable AD was reported by 60.9% of patients continuing therapy compared to 48.6% of patients interrupting therapy. On the contrary, an increased number of patients discontinuing therapy described worsening of disease compared to patients continuing therapy (35.9% vs 10.3%). Similarly, AD status perceived by patients continuing or interrupting therapy was significantly different at the following timepoints (P < 0.001; Table 4 ). Comparing patients treated with dupilumab monotherapy, dupilumab combined with other systemic therapies, and immunosuppressive systemic compounds, a reduction of disease severity (EASI score, and NRS scores) was detected at timepoint 3 vs timepoint 1, as well as a significantly different AD status across the three patient cohorts at each time point (P < 0.0001, Table S2 ). Patients treated with dupilumab monotherapy showed lower disease activity at timepoint 1, with a mean EASI score significantly lower compared to the other patients (P < 0.001), and this improvement was sustained thereafter (Table S2 ).

This observational study included a large population of patients 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-counseling) 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% 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 healthcare 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] [3] [4] [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 counseling 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 phototherapy 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

Peris conceptualize this study, analyzed data, and wrote the manuscript

Guarneri performed and verified statistical analyses

Feliciani contributed to both data collection and the interpretation of the results. The collaborators included in the DA-COVID-19 group contributed in managing patients during the study period. All authors revised the manuscript and approved the submitted version

Chiricozzi served as advisory board member and consultant and has received fees and speaker's honoraria or has participated in clinical trials for AbbVie

Fabbrocini acted as speaker and consultant for AbbVie and Leo Pharma. G. Girolomoni has been principal investigator in clinical trials sponsored by and/or and has received personal fees from

Rossi has received personal fee for advisory board meeting from Sanofi, Abbvie, Novartis, and Cantabria. L. Bianchi reports personal fees from speaker and as consultant for AbbVie

Patrizi has served as a speaker and received honoraria from Sanofi-Genzyme for lectures, research grants and as an advisory board member

Fargnoli has served on advisory boards, received honoraria for lectures and research grants from Almirall

Micali has been a scientific consultant/clinical study investigator for Abbvie, Eli-Lilly, Janssen-Cilag, LEO Pharma, and Novartis. C. Patruno has been a consultant and held sponsored conferences for AbbVie, Novartis, Pfizer, and Sanofi. I

Peris reports grants and personal fees for advisory board meeting from Almirall

Luca Stingeni

Data on SARS-CoV-2 pandemic worldwide provided by the World Health Organization

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Considerations on biologicals for patients with allergic disease in times of the COVID-19 pandemic: an EAACI Statement

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Effect of immunosuppressive drugs in immune-mediated inflammatory disease during the coronavirus pandemic

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Safety of dupilumab in atopic patients during COVID-19 outbreak

Safety of dupilumab in severe atopic dermatitis and infection of Covid-19: two case reports

SARS-CoV-2 asymptomatic infection in a patient under treatment with dupilumab

No evidence of increased risk for COVID-19 infection in patients treated with Dupilumab for atopic dermatitis in a high-epidemic area

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Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: a randomized clinical trial

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Global reporting of cases of COVID-19 in psoriasis and atopic dermatitis: an opportunity to inform care during a pandemic

Dermatology Unit, Department of Health Sciences

Dermatology Unit, Department of Health Sciences