key: cord-1037503-x8zx741r
authors: Ungar, Benjamin; Glickman, Jacob W.; Golant, Alexandra; Dubin, Celina; Marushchak, Olga; Gontzes, Alyssa; Mikhaylov, Daniela; Singer, Giselle K.; Baum, Danielle; Wei, Nancy; Sanin, Antonio; Gruenstein, Diana; Lebwohl, Mark G.; Pavel, Ana B.; Guttman-Yassky, Emma
title: COVID-19 symptoms are attenuated in moderate-to-severe atopic dermatitis patients treated with dupilumab
date: 2021-11-01
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2021.10.050
sha: 5da827de2cfd18509ede4913f19cb7e11366ceee
doc_id: 1037503
cord_uid: x8zx741r

Background In the SARS-CoV-2/COVID-19 pandemic, we need to understand the impact of immunomodulatory medications on COVID-19 symptom severity in patients with inflammatory diseases, including the Type 2/Th2 polarized skin disease, atopic dermatitis/AD. Objective Since it is believed that Type 1/Th1immunity controls viral infections, and that there is a Th1/Th2 counter-regulation, we hypothesized that Th2 targeting with the IL-4Rα-antagonist, dupilumab, in patients with moderate-to-severe AD rebalances Th1/Th2 axis, potentially leading to attenuated COVID-19 symptoms. Methods 1,237 moderate-to-severe AD patients in the Icahn School of Medicine at Mount Sinai Department of Dermatology were enrolled in a registry. Patients were screened for COVID-19-related symptoms and assigned a severity score (asymptomatic[0]-fatal[5]). Scores were compared among 3 treatment groups: dupilumab (n=632), other systemic treatments (n=107), and limited/no treatment (n=498). Demographic and comorbid covariates were adjusted by multivariate generalized logistic regression models. Results The dupilumab-treated group showed reduced incidence and severity of COVID-19 symptoms versus other treatment groups. Dupilumab-treated patients were less likely to experience moderate-to-severe symptoms versus patients on other systemics (p=0.01) and on limited/no treatment (p=0.04), and less likely to experience any symptoms versus patients on other systemics (p=0.01). This effect was seen in our entire cohort and in the subgroup of patients with verified COVID-19 or high-risk exposure. Conclusions Patients on dupilumab experienced less severe COVID-19 manifestations and lesser symptoms compared to patients on other systemics and on limited/no treatment. These results suggest that Th2 modulation with dupilumab may have a protective effect on anti-viral immune response in AD patients.

issued Emergency Use Authorizations (EUA) for three vaccines (4-6). Despite the advent of 125 these vaccines, effective treatments are still a target for research and development efforts, with 126 several therapies having been granted EUA (7). Furthermore, the risk of patients with 127 inflammatory skin diseases to develop more symptomatic COVID-19 infection is unknown, 128 particularly in context of immunomodulatory medications. 129

Previous research has shown that abnormally elevated Th2 cytokines may inhibit 130 appropriate Th1 immune responses in the setting of viral exposure, impeding the reliance on Th1 131 signaling in initial responses to viral infections (8) (9) (10) (11) . This is especially relevant for atopic 132 dermatitis (AD), a disease characterized primarily by Th2 skewing (12), with an increased 133 susceptibility to viral infections (10). Moreover, elevated expression of Th2 cytokines in serum 134 (e.g., IL-4, IL-10, and IL-13) was reported in patients with COVID-19, especially during the 135 cytokine storm (2, (13) (14) (15) . 136

Despite the greater risk for viral infections and the baseline Th2 polarization in AD, the 137 risk for COVID-19 incidence and symptom severity in this common disease (~7% of the adult 138 US population) (16), is still unknown. Determining COVID-19 risk profiles is particularly 139 important in patients with moderate-to-severe AD on immunomodulatory medications. While Dupilumab, which inhibits the key Th2 cytokines IL-4 and IL-13, is the first FDA-148 approved treatment for moderate-to-severe AD, and is also approved for asthma and chronic 149 rhinosinusitis with nasal polyps (22) (23) (24) . While dupilumab has been shown to robustly modulate 150 the Th2 pathway, it does not affect Th1 signaling (23, 25). Preliminary reports have not shown 151 increased SARS-CoV-2 infection rates among patients treated with dupilumab (26) (27) (28) (29) (30) (31) . 152

However, these limited studies did not compare dupilumab-treated patients with those on other 153 treatments or not receiving systemic treatments. To date, no study has evaluated the effects of 154 SARS-CoV-2 exposure and infection in AD patients on dupilumab compared to other 155

The present study is the first large-scale, prospective evaluation of 1,237 patients with 157 moderate-to-severe AD treated with dupilumab, broad immunosuppressants, or those not 158 receiving systemic treatments. This registry study aims to investigate whether targeting type 2 159 inflammation with dupilumab may protect against symptomatic SARS-CoV-2 infections in 160 patients with AD. Our data show that patients on dupilumab were less likely to develop 161 symptomatic COVID-19 infection compared to patients on other systemic treatments for AD. 162

We performed a cross-sectional analysis of reported demographics, medical history, and 166 medications from 1,237 moderate-to-severe AD patients enrolled from April 2 nd 2020 through 167 January 31 st , 2021 in a prospective registry related to Patients were asked about past medical history, medications, demographics (i.e., age, 177 gender, and self-reported race), as well as the presence and duration of individual COVID-19-178 related symptoms, including objective or subjective fever, sore throat, cough, congestion, 179 headache, fatigue, anosmia, dysgeusia, dyspnea, nausea, vomiting, diarrhea, anorexia, and skin 180 changes. Based on the symptoms described, each patient was given a COVID-19 symptom severity 181 score from 0-5: 0: "asymptomatic"; 1: "mild disease" (no fever, no dyspnea, resolving in <7 days, 182 resembling a common cold); 2: "moderate disease" (some fever and/or cough, or other lower 183 respiratory symptoms, resolving at home in 7-14 days); 3: "severe disease" (pneumonia, required 184 hospitalization, but resolved without intubation); 4: "very severe disease" (required One thousand two-hundred and thirty-seven patients were included in the final analysis, 

We powered our study based on the range of estimates for the incidence of SARS-CoV-2 196 infected patients at Mount Sinai Hospital. We assumed a positivity rate of 21% among 600 Mount 197

Sinai Dermatology patients, with approximately n=100 SARS-CoV-2-infected patients on 198 dupilumab and n=20 infected patients in the control group. Assuming an effect size of 25% (e.g. 199 30% patients with symptoms in the control group and 5% in the dupilumab group), a sample size 200 of at least n=100 patients on dupilumab and n=20 controls is enough to detect statistically 201 significant differences between groups with 85% power using a two-sided Fisher exact test with a 202

Type I error α=0.05. Assuming a sample size five times larger, such as n=500 infected patients on 203 dupilumab and n=100 infected patients in the control group, would allow us to detect an effect size 204 of 10% (e.g. 15% patients with symptoms in the control group and 5% in the dupilumab group) 205 with 90% power using a two-sided Fisher exact test with a Type I error α=0.05.

with the secondary outcome being the incidence of any symptoms. Because of the potential for 210 multiple confounders, we associated the presence of COVID-19-related symptoms with dupilumab 211 treatment compared to other systemic treatments and with dupilumab treatment compared to 212 limited/no treatments using multivariate logistic regression models. We adjusted for known or 213 suspected COVID-19-related comorbidities (age, gender, race, hypertension, diabetes, body mass 214 index [BMI], asthma, ACE-inhibitor usage). Using a similar approach, we also associated the 215 presence of COVID-19-related symptoms with AD treatments by stratifying our cohort into a set 

Twelve-hundred, thirty-seven patients with moderate-to-severe AD were included in the 223 analysis (age range 9-95 years). Patients were initially grouped based on their AD treatment: 632 224 Table 1A . No 229 significant differences were found between groups in terms of age and race. 230

We calculated the distribution of COVID-19 symptom severity across groups in six 233 categories: 0/"asymptomatic," 1/"mild," 2/"moderate," 3/"severe," 4/"very severe," and 5/"fatal" 234 (Table 1B) . Our initial analysis focused on the entire cohort of patients, agnostic to laboratory 235 evidence of COVID-19 infection. Treatment groups were compared to determine the proportions 236 of patients in each symptom category ( Figure 1 ). Given the potential for multiple confounders 237 and risk factors for symptomatic infection (Table 1A ) (32), we adjusted for known risk factors 238 for increased COVID-19 morbidity (e.g., obesity, hypertension, etc.) using logistic regression 239 models. We found that patients on dupilumab were less likely to experience moderate-to-severe 240 symptoms compared to patients on other systemic treatments (OR=3.89; p=0.008, Table 2A) . 241 Furthermore, they were less likely to experience moderate-to-severe symptoms compared to 242 those on limited/no treatments (OR=1.96; p=0.04; Table 2B ). Additionally, BMI was 243 J o u r n a l P r e -p r o o f significantly associated with moderate-to-severe symptoms across COVID-19 related patients 244 treated with biologic and systemic therapies (p<0.001, Table 2A) . 245

When evaluating the effects of various clinical variables on the presence of COVID-19-246 related symptoms, we found that non-biologic systemic treatment was significantly associated 247 with symptomatology relative to treatment with dupilumab (OR=1.87; p=0.01, Table 2C ). 248

However, there were no differences in predicting symptomatology among patients on dupilumab 249 relative to the limited/no treatment group (Table 2D) . Table 3 ; Figure 2 ). Similar to the previous logistic regression model results, non-258 dupilumab systemic treatment was significantly associated with moderate-to-severe symptoms 259 relative to treatment with dupilumab (OR=13.79; p=0.002; Table 4A ). Additionally, being on 260 limited/no treatment was also significantly associated with moderate-to-severe symptoms 261 relative to dupilumab (OR=2.44; p=0.05; Table 4B ). BMI was a significant covariate of 262 moderate-to-severe symptoms across all systemic treatment groups in this known infection/high-263 risk exposure group (p=0.005; Table 4A ). 264

In patients with known COVID-19 infection or high-risk exposure, being on non-265 dupilumab, systemic therapies was significantly associated with symptomatology relative to 266 being on dupilumab (OR=2.97; p=0.03, Table 4C ). Similar to the entire cohort, there were also 267 no differences in predicting symptoms among high-risk exposure patients on dupilumab relative 268 to the limited/no treatment group (Table 4D) . to-severe AD in the context of immunomodulatory treatment is crucial, due to the long-term health 276 consequences of SARS-CoV-2 infection, which are more substantial with moderate-to-severe 277 symptomatology (33), as well as the massive economic burden on the United States hospital 278 system from treating COVID-19 patients (34). Patients with moderate-to-severe AD are also 279 particularly important to study in this context due to their increased susceptibility to viral infections 280 and their robust Type 2/Th2 activation (10, 35). Since Type 1/Th1immunity is considered to 281 control viral responses, and there is a Th1/Th2 counter-regulation, we hypothesized that specific 282

Th2 antagonism in patients with moderate-to-severe AD with the anti-IL-4R, dupilumab, may 283 rebalance the Th1/Th2 axis, potentially leading to attenuated COVID-19 symptomatology. 284

Our study found that dupilumab reduces both the incidence and severity of COVID-19 285 symptoms among AD patients, compared to both other systemic treatments and to no systemic 286 treatments. We found that patients treated with dupilumab were less likely to experience 287 moderate-to-severe symptoms compared to patients on other systemics (p=0.01) as well as to 288 patients on limited/no treatment (p=0.04). Patients treated with dupilumab were also less likely 289 to experience any symptoms at all compared to patients on other systemics (p=0.01). This 290 relationship holds true for patients with suspected COVID-19, as well as for patients with a 291 serologically confirmed COVID-19 diagnosis or a confirmed high-risk exposure. Those treated 292 with dupilumab were less likely to experience moderate-to-severe symptoms compared to those experience symptoms at all compared to patients on other systemics (p=0.03). 295

The robust effect of dupilumab on COVID-19 symptomatology may be due to primary 296 modulation of Th2 pathway, without downregulation of Th1 immunity. This relationship 297 between Th2 modulation and Th1/innate immune responses has been demonstrated in other 298 atopic disease states, such as asthma (36). In one study, asthma patients treated with the Th2 299 modulator omalizumab (anti-IgE) had a lower incidence of respiratory virus-induced asthma 300 exacerbations and a more robust IFN response in vitro to rhinovirus stimulation (36). Similarly, 301

our study found that COVID-19 symptoms and severity were reduced in dupilumab even when 302 compared to limited/no treatment, suggesting that Th2 suppression may normalize the Th1/Th2 303 imbalance. Unlike dupilumab, broad acting immunosuppressants downregulate Th1 and other 304

immune axes in addition to the pathogenic Th2 axis (23, 37-39), which may account for the 305 significant differences in clinical outcomes as compared to dupilumab, which reduces incidence 306 and severity of symptoms in COVID-19. These results hold even when adjusting for a number of 307 clinical and demographic variables that may affect COVID-19 severity, including race, age, and 308 BMI (32). Older age and higher BMI were significantly associated with more frequent and more 309 severe symptoms, consistent with prior knowledge (32). 310

The main analysis in our study included all patients with a likely COVID-19 diagnosis, 311 regardless of a laboratory-confirmed COVID-19 diagnosis. Thus, we acknowledge that some 312 patients who reported probable COVID-19 symptoms may have had other infections (e.g. 313 respiratory or gastrointestinal). However, we believe that this approach is crucial for several 314 reasons: primarily, because there are likely many COVID-19 cases undiagnosed by formal 315 testing in our cohort; testing was unreliable early on, and even now laboratory screening for 316 asymptomatic cases is not routinely performed. Further, including all subjects may contribute to 317 eliminating biases in testing behavior, since symptomatic patients are more likely to get tested. 318

Additionally, although the impetus for this study was to evaluate the impact of 319 immunomodulatory drugs specifically on COVID-19 symptomatology, these data showing that 320

Th2 modulation potentially ameliorates COVID-19 symptoms extends beyond the current era. 321

Our findings may thus have implications for other common viral infections, such as influenza, 322 and for possible future pandemics. 323

In the setting of the current COVID-19 pandemic, despite the advent of vaccination and 324 increasing efforts to widely distribute vaccines to the population, it remains crucial to understand 325 the impact of immunomodulatory medications in patients with chronic inflammatory diseases; 326 many people may be unable or unwilling to get vaccines, the long-term protection offered by 327 vaccines is still unknown, and the efficacy and duration of immune response to vaccination in the 328 setting of immunomodulatory medications remains unknown. Because of this, we also performed 329 an analysis focused on outcomes in patients with confirmed laboratory evidence of COVID-19 330 infection or with significant known COVID-19 exposures, and the results in this subset were 331 even more significant than those found in the entire cohort. 332

We acknowledge some limitations in this study. Primarily, there are inherent limitations to a 333 registry-based study, including sampling bias, recall bias, and patients being enrolled at a single 334 timepoint. Our study was also limited by the fact that we could not obtain laboratory 335 confirmation (via serology testing) of COVID-19 infection in many patients. Additional testing 336 will provide even more evidence for the relevance of these findings to confirmed COVID-19 337

Future studies are needed to understand the implications of our findings for other specific 339 viral conditions. Furthermore, biomarker-based studies may provide added support for the 340 proposed mechanism by which Th2 blockade might produce the results seen in this study. 341

Additionally, understanding the immune response to COVID-19 vaccination in patients on 342 immunomodulatory medications will be crucial as vaccination becomes increasingly widespread. 343

Lastly, further studies in other inflammatory conditions commonly treated with 344 immunomodulatory medications will be needed as well. The present study is the first to 345 demonstrate the significant protection potentially offered by Th2-targeting with dupilumab in 346 reducing symptom incidence and severity compared to other treatments for AD in the context of 347 COVID-19 infection. These findings have important implications, not only for the millions of 348 moderate-to-severe AD patients in this country exposed to COVID-19 and other viral infections, COVID-19 symptom severity defined as a 5-level score: 0 "asymptomatic"; 1: "mild disease" 463 (no fever, no dyspnea, resolving in <7 days, resembling a common cold); 2: "moderate disease" 464 (some fever and/or cough, or other lower respiratory symptoms, resolving at home in 7-14 days); 465 3: "severe disease" (pneumonia, required hospitalization, but resolved without intubation); 4-5: 466 "very severe disease" (required hospitalization, intubation, and other supportive measures) or 467 "fatal." symptom severity by scores of A. 0-1 (asymptomatic or mild symptoms) and 2-5 (moderately 538 symptomatic to fatal), and B. scores of 0 (asymptomatic) or 1-5 (symptomatic). *P<0.05. 539

Circulating Levels of IL-2

Longitudinal analyses 387 reveal immunological misfiring in severe COVID-19

Dermatitis in America Study: a cross-sectional study examining the prevalence and disease 390 burden of atopic dermatitis in the US adult population

COVID-19 Clinical Guidance for Adult Patients with Rheumatic