BACKGROUND:Data on individualized dosing regimens for dupilumab in pediatric atopic dermatitis (AD) are lacking. This study evaluated dose reduction of dupilumab in a pediatric population in daily practice. RESEARCH DESIGN AND METHODS:Pediatric patients (aged ≤16 years) treated with dupilumab were included. Patients with controlled AD were considered eligible for dose reduction. Outcomes included the percentage of (successful) dose reduction and mean Eczema Area and Severity Index (EASI) and Numeric Rating Scale (NRS) pruritus scores over time after initiating dose reduction. RESULTS:Of 278 pediatric patients, 126 with controlled disease were eligible for dose reduction (mean age 11.3 years), of whom 65 patients (51.6%) reduced their dupilumab dosage. Reasons for dose reduction included controlled disease only (72.2%), adverse events (AEs) and controlled disease (13.0%), and administration problems and controlled disease (14.8%). At 3 years of treatment, only 13/27 (48.2%) of patients considered eligible for dose reduction remained on their label dosage. Dose reduction was successful in 58 of 65 (89.2%) pediatric patients, with low and stable EASI and NRS pruritus scores. CONCLUSIONS:Dupilumab dose reduction was successful in the majority of pediatric patients with controlled AD, suggesting that individualized dosing regimens are feasible and may help address practical challenges.

Clinical trials have demonstrated the effectiveness of baricitinib, an oral selective Janus kinase 1/2 inhibitor, for patients with moderate-severe atopic dermatitis, but data from real-world practice are limited. This non-interventional cohort study evaluated clinician- and patient-reported disease severity over 16 weeks using 3 national atopic dermatitis registries: BioDay (Netherlands), SCRATCH (Denmark) and TREATgermany (Germany). Absolute scores for Eczema Area and Severity Index (EASI) and itch Numerical Rating Scale (Itch-NRS) were assessed at baseline and follow-up (Week 13/16) for each registry and for the overall pooled cohort. Descriptive analyses, generalized linear mixed modelling and meta-analysis approaches were applied to complete-case and multiply-imputed datasets. In total, 264 patients (89 BioDay, 117 SCRATCH, 58 TREATgermany) were included. Results showed improvements in EASI, with 58%, 68% and 62% achieving EASI≤7 at Week 13/16 in BioDay, SCRATCH and TREATgermany, respectively. In the pooled cohort, the proportion was 62% (95% CI: 50–73%). The pooled mean EASI change was -7.8 [14.4,–1.1]. Effectiveness was generally observed in both biologic-naïve and -experienced patients. Notable heterogeneity was observed, particularly for Itch-NRS, with the proportion achieving NRS≤4 ranging from 20% (BioDay) to 71% (TREATgermany). These real-world findings support the effectiveness of baricitinib while also highlighting variability in patient outcomes.

BACKGROUND:Limited data exist on the comparative risk of infections during biologic and Janus kinase inhibitor (JAKi) treatment for atopic dermatitis (AD) in daily practice. OBJECTIVES:To assess the differential infection risk of biologic and JAKi treatment in patients with moderate-to-severe AD in a real-world setting. METHODS:This prospective, multicentre study evaluated treatment-emergent infections in patients (age ≥ 12 years) using biologics or JAKi from the BioDay registry from October 2017 to July 2024. Crude incidence rates were calculated per 100 patient-years (PY) per treatment. Cox regression for recurrent events, adjusted for potential confounders, was used to estimate hazard ratios (HR) for the rate of infections, with subgroup and sensitivity analyses in bio-/JAKi-naïve patients. RESULTS:In total 1793 patients were included (4044.1 PY; 1886 biologic treatment episodes (TEs); 480 JAKi), with 794 infections. JAKi showed higher infection rates (58.4-65.5/100 PY) compared to biologics (13.6-22.0), especially for herpes infections (n = 195, 24.6%; JAKi 13.6-19.8 vs. biologicals 3.0-3.6). Cox regression indicated increased rates with JAKi (abrocitinib HR 4.1, 95% CI: 3.1-5.5; baricitinib HR 4.2, 95% CI: 2.9-6.2; upadacitinib HR 4.0, 95% CI: 3.2-5.0; all p < 0.0001) and a slight increase with tralokinumab (HR 1.4, 95% CI: 1.0-2.0, p = 0.039) compared to dupilumab. Sensitivity analyses confirmed these results, except for tralokinumab. Rates of severe infections were higher with JAKi compared to dupilumab, although absolute numbers were low and associations were not consistently significant. History of infection, predominantly viral or fungal skin infections (HR 1.9, 95% CI: 1.4-2.6, p < 0.0001; 2.4, 1.3-4.4, p = 0.003, resp.), was identified as an independent factor associated with infection. CONCLUSIONS:This cohort study demonstrated an increased risk of infection during JAKi treatment compared to dupilumab for moderate-to-severe AD. These findings enhance understanding of the differential infection risk with targeted therapies in AD, aiding tailored treatment choices that consider patient-specific risks such as prior skin infections.

PURPOSE:Upadacitinib is approved for treating moderate-to-severe atopic dermatitis (AD) aged ≥12 years. We evaluated upadacitinib's effectiveness and safety in AD adolescents in daily practice. MATERIALS AND METHODS:Fifteen adolescent AD patients from the BioDay registry, treated with upadacitinib 15 mg once daily were evaluated at baseline and after 4, 8, 16, and 28 weeks. Effectiveness was assessed using Eczema Area and Severity Index (EASI) score and Investigator Global Assessment (IGA) score. Patient-reported outcomes included Numeric Rating Scale (NRS) for pruritus and presence of sleep disturbance. Adverse events (AEs) were evaluated at each visit. RESULTS:Mean EASI score significantly decreased from 13.4 (95% CI 8.5-18.3) to 7.8 (95% CI 2.4-13.3) after 28 weeks (p = .002). Mean NRS pruritus significantly decreased from 6.5 (95% CI 4.9-8.2) to 4.8 (95% CI 3.0-6.6) after 28 weeks (p = .003). At week 16, 75.0% (95% CI 46.8-91.1) achieved EASI ≤7, and 50.0% (95% CI 25.4-74.6) achieved NRS pruritus ≤4. Overall, 31 AEs were reported in 10 patients (66.7%). Five patients (33.3%) discontinued treatment: two due to ineffectiveness, two due to AEs, and one due to laboratory monitoring problems. CONCLUSIONS:Our findings indicate that upadacitinib is effective and relatively safe for adolescents with moderate-to-severe AD; however, 33.3% discontinued treatment.

Limited daily practice data on the effect of abrocitinib in patients with atopic dermatitis are available. The aim of this multicentre prospective study is to evaluate the effectiveness and safety of abrocitinib in patients with atopic dermatitis treated in daily practice. In a subgroup, the effectiveness of abrocitinib on hand eczema was evaluated. A total of 103 patients from the BioDay registry were included in the study: week 4 (n = 95), week 16 (n = 61) and week 28 (n = 39). At week 28, the Eczema Area and Severity Index (EASI)-50/75/90 was achieved by 81.8%, 57.6%, and 18.2%, respectively, and the weekly average pruritus numerical rating scale ≤ 4 by 62.9%. The effectiveness of abrocitinib was not significantly different between dupilumab non-responders and dupilumab-naïve patients/responders, and between upadacitinib non-responders and upadacitinib-naïve patients/responders. Mean ± standard deviation Hand Eczema Severity Index decreased from 27.4 ± 27.7 at baseline to 7.7 ± 12.1 at week 28 (n = 31). Thirty-two patients (31.1%) discontinued treatment due to ineffectiveness (n = 17), adverse events (n = 9) or both (n = 3). The most frequently reported adverse event was nausea (n = 28). In conclusion, abrocitinib is an effective treatment for atopic dermatitis and can be effective for patients with previous inadequate response to dupilumab or upadacitinib. Furthermore, hand eczema can improve in patients treated with abrocitinib for atopic dermatitis.

Background: Dupilumab has proven to be an effective and safe treatment for atopic dermatitis (AD) in pediatric patients in clinical trials. However, few daily practice outcomes are available. Objectives: To evaluate the effect of 16 weeks dupilumab treatment on effectiveness, safety, and serum biomarkers in pediatric patients with moderate-to-severe AD in daily practice. Method: Patients visited the outpatient clinic at baseline, and after 4 and 16 weeks of treatment. Endpoints were proportions of patients achieving ≥50%, ≥75% or ≥90% improvement in Eczema Area and Severity Index (EASI), (almost) clear on Investigator Global Assessment (IGA) and ≥4 points reduction in Patient-Oriented Eczema Measure (POEM), Numeric Rating Scale (NRS)-pruritus, and -pain score at 16 weeks. Patients achieving absolute cutoff scores indicating controlled disease (EASI ≤7, POEM ≤7, NRS-pruritus ≤4) were analyzed. Nineteen severity-associated serum biomarkers were measured using Luminex-based multiplex immunoassays, and predicted-EASI (p-EASI) was calculated. Results: Forty-seven patients were included. Respectively 76.6%, 40.4%, and 19.1% reached EASI-50, EASI-75 and EASI-90, and 25.5% achieved an IGA-score (almost) clear. Improvement of ≥4 points on POEM, NRS-pruritus, and NRS-pain score was reached by 65.2%, 50.0%, and 79.2%, respectively. After 16 weeks, 83.0% achieved ≥1 cutoff score indicating controlled disease. Most frequently reported side effects were conjunctivitis (n=3 (6.4%)), hair loss (n=3) and headache (n=3). Biomarkers TARC, PARC, periostin, sIL-2Ra, and eotaxin-3 significantly decreased during treatment. The p-EASI showed a significantly high correlation with disease severity. Conclusion: Dupilumab treatment significantly improved disease severity and decreased severity-associated serum biomarkers in pediatric AD patients in daily practice.

Importance:Dupilumab, methotrexate (MTX), and cyclosporine A (CsA) are valuable treatment options for pediatric patients with refractory moderate to severe atopic dermatitis (AD). Yet, comparative data on these treatments in pediatric patients are scarce. Objective:To evaluate drug survival of dupilumab, MTX, and CsA, and identify associated predictors in a multicenter daily practice cohort study of pediatric patients with AD. Design, Setting, and Participants:This multicenter daily practice cohort study included patients with AD aged 2 to 17 years treated with dupilumab, MTX, and/or CsA in 5 tertiary centers in the Netherlands between 2013 and 2023. Data were extracted from the prospective BioDay and TREAT Netherlands registries and electronic medical records. Exposures:Dupilumab, MTX, CsA. Main Outcomes and Measures:Drug survival was analyzed using Cox proportional hazard regression models. Univariable and multivariable Cox regression analyses were conducted to identify variables associated with drug discontinuation. Results:A total of 502 treatment episodes in 362 unique patients were included, comprising 192 dupilumab episodes, 94 MTX episodes, and 216 CsA episodes. Overall, the mean (SD) age at treatment initiation was 12.9 (3.8) years, and 272 treatment episodes (54.2%) in female patients. The 1-year, 2-year, and 3-year overall drug survival rates, respectively, were 84.1%, 72.3%, and 62.0% for dupilumab; 60.7%, 39.3%, and 25.3% for MTX; and 43.9%, 21.5%, and 10.4% for CsA. Ineffectiveness was the most frequent reason for drug discontinuation, accounting for 178 episodes (35.5%), mostly in patients treated with CsA, followed by adverse effects in 94 patients (18.7%). Treatment with MTX and treatment with CsA were independently associated with a higher risk for drug discontinuation due to ineffectiveness (hazard ratio [HR], 4.45 [95% CI, 2.38-8.34] and HR, 10.88 [95% CI, 6.23-19.02], respectively) and adverse effects (HR, 4.39 [95% CI, 2.05-9.39] and HR, 3.83 [95% CI, 1.85-7.92], respectively) compared to treatment with dupilumab. Patients aged 12 to 17 years starting systemic treatment were independently associated with a higher risk for drug discontinuation due to ineffectiveness (HR, 1.55 [95% CI, 1.10-2.20]) and adverse effects (HR, 2.39 [95% CI, 1.33-4.30]). Conclusions and Relevance:This multicenter daily practice cohort study demonstrated a superior 1-year, 2-year, and 3-year overall drug survival for dupilumab, followed by MTX, with the lowest rates observed for CsA in pediatric patients with AD. This study also identified characteristics associated with discontinuation. These results provide insight into drug survival resulting from the effectiveness, safety, and tolerability of these systemic treatments in pediatric patients with AD and contribute to the optimization of patient outcomes.

Importance:Limited data are available on the long-term effectiveness and safety of dupilumab for atopic dermatitis (AD) in daily practice. Objective:To evaluate clinical effectiveness and reasons for discontinuation of dupilumab treatment in children, adults, and older adults with AD with up to 5 years of treatment in daily practice. Design, Setting, and Participants:This prospective multicenter cohort study was conducted using the BioDay registry (4 academic and 10 nonacademic hospitals in the Netherlands) to identify patients with AD of all ages who were treated with dupilumab between October 2017 and December 2022. Main Outcomes and Measures:Clinical effectiveness was evaluated by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), and numeric rating scale (NRS) for pruritus, stratified by children (<18 years), adults (18-64 years), and older adults (≥65 years). In addition, time to response, treatment responders, EASI subscores, second treatment episodes, and thymus- and activation-related chemokine and eosinophil levels were assessed. For patients who discontinued dupilumab, the reason for discontinuation was evaluated. Results:In total, 1286 patients with AD (median [IQR] age, 38 [26-54] years; 726 [56.6%] male) were treated with dupilumab, including 130 children, 1025 adults, and 131 older adults. The median (IQR) follow-up time was 87.5 (32.0-157.0) weeks. Most patients maintained controlled AD, with EASI of 7 or lower and NRS for pruritus of 4 or lower varying between 78.6% and 92.3% and 72.2% and 88.2% for up to 5 years of treatment, respectively, while up to 70.5% of all patients prolonged the dosing interval to mostly 300 mg every 3 or 4 weeks. Mean EASI and NRS for pruritus were 2.7 (95% CI, 1.2-4.2) and 3.5 (95% CI, 2.7-4.3), respectively, after 5 years of treatment. Statistically significant differences between age groups were found over time for EASI and IGA; however, differences were rather small (week 52: EASI, 0.3-1.6; IGA, 0.12-0.26). No statistically significant differences between age groups were found for NRS for pruritus. Median thymus- and activation-related chemokine levels considerably decreased from 1751 pg/mL (95% CI, 1614-1900 pg/mL) to 390 pg/mL (95% CI, 368-413 pg/mL) after 6 months of treatment and remained low. Median eosinophil levels temporarily increased up to week 16, with a subsequently statistically significant decrease over time. In total, 306 patients (23.8%) discontinued dupilumab after a median (IQR) of 54.0 (29.0-110.00) weeks, with adverse events among 98 patients (7.6%) and ineffectiveness among 85 patients (6.6%) as the most frequently reported reasons. Forty-one patients (3.2%) restarted dupilumab, and most of these patients recaptured response. Conclusions and Relevance:In this cohort study with up to 5 years of follow-up, dupilumab maintained its clinical effectiveness, while two-thirds of patients tapered to a dosing interval of every 3 or 4 weeks. Treatment was discontinued in 23.8% of patients mainly due to adverse events and/or ineffectiveness.

INTRODUCTION AND OBJECTIVES:Tralokinumab-a biological that specifically targets interleukin-13-is one of the newer advanced systemic treatments for patients with moderate-to-severe atopic dermatitis (AD). Although safety and efficacy have been shown in phase-III clinical trials, daily practice data are needed. Therefore, the aim of this study was to evaluate 28-week safety and effectiveness, serum proteins and total IgE levels in adult AD patients treated with tralokinumab in daily practice. MATERIALS AND METHODS:Data of all adult AD patients who started treatment with tralokinumab and participated in the BioDay registry were collected at baseline, and after 4,16 and 28 weeks of treatment. Clinical efficacy was evaluated by clinical outcome measures, such as the Eczema Area and Severity Index (EASI) as well as patient-reported outcome measures, such as the numerical rating scale (NRS) for pruritus. Adverse events were evaluated. In a subgroup of patients, 18 proteins as well as total IgE levels were measured in serum. RESULTS:A total of 84 patients were included, of whom 39 were dupilumab-naïve (D-naïve) and 45 were dupilumab non-naïve (D-non-naïve) patients. All primary outcomes significantly improved during 28 weeks of tralokinumab treatment and the probability of achieving EASI ≤ 7 and NRS-pruritis ≤ 4 was 75.8% (56.9-88.2) and 51.4% (28.0-74.2), respectively. The disease severity-associated proteins TARC/CCL17 and PARC/CCL18 decreased during treatment, and total IgE levels significantly decreased in the D-naïve patients. The most reported adverse events were eye disorders (n = 24, 28.6%). A total of 23 patients (27.4%) discontinued treatment due to adverse events and/or ineffectiveness, with hair loss being the most common adverse event leading to treatment discontinuation (n = 6). CONCLUSION:Tralokinumab is an effective treatment for moderate-to-severe AD in adult patients, in both dupilumab-naïve patients and patients who previously failed on dupilumab treatment. The clinical effect is supported by the biological data.

BackgroundLong-term daily practice data on patient-reported benefits of dupilumab for atopic dermatitis (AD) remains limited.ObjectiveTo evaluate patient-reported outcome measures (PROMs) and the safety of dupilumab in patients with moderate-to-severe AD over a follow-up period of up to 5 years.MethodsData were extracted from the prospective, multicenter BioDay registry (October 2017 - 2022) of patients with moderate-to-severe AD treated with dupilumab in daily practice.ResultsIn total 1223 patients, 1108 adults and 115 pediatric patients, were included. After ≥1 year of treatment, mean Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Numeric rating scale (NRS)-pruritus ranged between 7.8-8.7, 3.5-4.2, and 2.9-3.1 in adults, respectively, whilst these PROMs ranged between 8.9-10.9, 4.4-6.4, and 3.0-3.7 in pediatric patients, respectively. At follow-up, overall work impairment decreased from 40.1% to 13.3-16.3% in adults. Furthermore, class I obesity and itch-dominant patients generally had less favorable treatment response. Of all patients, 66.8% reported ≥1 adverse event, with conjunctivitis being the most common(33.7%).LimitationsThe overall percentage of missing values for selected PROMs was 26% in adults and 46% in pediatric patients.ConclusionIn addition to favorable safety, dupilumab has demonstrated sustained effectiveness across various PROMs, underscoring the treatment benefits from patients’ perspectives.

Background Limited data are available regarding patient-centred dosing of dupilumab for atopic dermatitis (AD) in daily practice. Objectives To evaluate our patient-centred dupilumab dosing regimen in daily practice, to assess prognostic factors for successful tapering and to estimate medication-related cost savings. Methods This prospective multicentre study included adult patients with AD, participating in the BioDay registry, treated with dupilumab for >= 1.3 years. Interval prolongation was considered in the case of dupilumab standard dose for >= 1 year and persistent controlled AD [Eczema Area and Severity Index (EASI) <= 7; >= 6 months]. Primary endpoints were the mean EASI and Numeric Rating Scale (NRS)-pruritus after the start of tapering. Prognostic factors for successful tapering were analysed with logistic regression and a cost-savings analysis was performed. Results A total of 595 patients were included, of whom 401 patients [mean EASI 2.5 (SD 2.3); NRS-pruritus of 2.4 ( SD 1.9) at the start of tapering] prolonged their dupilumab interval. In 83.3% of these patients tapering was successful; most patients used dupilumab every 3 or 4 weeks (Q3W/Q4W). A significant small increase was observed for EASI (highest mean 3.5) and NRS-pruritus (highest mean 3.2) (P < 0.001); however, scores remained low. Predicting successful tapering showed nonsignificant odds ratios for all incorporated variables. The estimated cost savings was (sic)3 977 033.98 for 401 patients between January 2019 and June 2022. Conclusions This study showed successful tapering of dupilumab in 83.3% of patients with AD who attempted tapering, while maintaining controlled disease and with the majority using Q3W/Q4W. Interval prolongation can be beneficial both for the patient and from a socioeconomic perspective.

BACKGROUND/OBJECTIVES Itch is one of the hallmarks of atopic dermatitis (AD), which has a significant impact on the quality of life of pediatric patients with AD and their caregivers. We aimed to conduct a systematic review and meta-analysis to evaluate the antipruritic effects of systemic AD treatments in pediatric patients with AD. METHODS PubMed, EMBASE, Cochrane, and Web of Science databases were searched, including studies providing original data on the effects of systemic treatment on pruritus in pediatric patients (<18 years) with AD. Placebo-controlled trials reporting a Peak Pruritus Numerical Rating Scale 4 (PP-NRS4) response were included in a meta-analysis. RESULTS A total of 30 studies were included, with most evidence available for dupilumab. Overall, marked improvements of pruritus (50% or greater reduction in pruritus outcome measurements) were found for treatment with cyclosporin A (2-16 years), dupilumab (6 months-17 years), abrocitinib, and upadacitinib (both 12 and 17 years). Nemolizumab (12-17 years) may be promising in reducing pruritus in pediatric patients; however, data are limited. Only five randomized controlled trials could be included in our meta-analysis, in which dupilumab, abrocitinib, and upadacitinib showed a significantly higher probability of achieving a PP-NRS4 response compared with placebo. Our study was limited by a lack of homogeneity of included studies. CONCLUSIONS Cyclosporin A, dupilumab, abrocitinib, and upadacitinib are all effective in decreasing pruritus and, therefore, in improving the quality of life in children with AD. As more systemic treatments for AD become available, it will be imperative to incorporate patient-oriented treatment goals such as reduction of pruritus into therapeutic decision-making.

Clinical trials showed that upadacitinib, a selective Janus kinase-1 inhibitor, is effective for treatment of moderate-to-severe atopic dermatitis. However, daily practice studies are limited. This multicentre prospective study evaluated the effectiveness of 16 weeks of upadacitinib treatment for moderate-to-severe atopic dermatitis in adult patients, including those with previous inadequate response to dupilumab and/or baricitinib, in daily practice. A total of 47 patients from the Dutch BioDay registry treated with upadacitinib were included. Patients were evaluated at baseline, and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed by clinician- and patient-reported outcome measurements. Safety was assessed by adverse events and laboratory assessments. Overall, the probabilities (95% confidence intervals) of achieving Eczema Area and Severity Index ≤ 7 and Numerical Rating Scale – pruritus ≤ 4 were 73.0% (53.7–86.3) and 69.4% (48.7–84.4), respectively. The effectiveness of upadacitinib was comparable in patients with inadequate response to dupilumab and/or baricitinib and in patients who were naïve for these treatments or who had stopped such treatments due to adverse events. Fourteen (29.8%) patients discontinued upadacitinib due to ineffectiveness, adverse events or both (8.5%, 14.9% and 6.4%, respectively). Most frequently reported adverse events were acneiform eruptions (n = 10, 21.3%), herpes simplex (n = 6, 12.8%), nausea and airway infections (both n = 4, 8.5%). In conclusion, upadacitinib is an effective treatment for patients with moderate-to-severe atopic dermatitis, including those with previous inadequate response to dupilumab and/or baricitinib treatment.

IL-4 and IL-13 are Type-2 (T2) inflammatory cytokines and key drivers in T2 immune response, which is considered to play a central role in the pathogenesis of several atopic diseases such as atopic dermatitis (AD) and asthma. Dupilumab, a fully human monoclonal antibody, binds to the α-subunit of the interleukin (IL)-4 receptor and blocks the signaling pathway of IL-4 and IL-13.1 It is the first antibody-based treatment that became available for the treatment of AD and is also registered for severe T2 asthma.2 Several studies reported improved clinical outcomes and sustained reduction of T2 inflammatory biomarkers for AD as well as asthma by using dupilumab.3, 4 Since the majority of AD patients have comorbid asthma,5 the aim of this study was to investigate the effect of dupilumab on asthma in patients treated for AD with dupilumab in daily practice. This study consecutively included adult AD patients with comorbid asthma and at least one measurement of the Asthma Control Questionnaire (ACQ)-5 (scale 0–6), and/or FEV1, who started dupilumab treatment for AD and participated in the BioDay registry from October 2017 to June 2022. The ACQ-5 was used as patient-reported outcome, consisting five questions on symptom control of asthma. Following The Global Initiative for Asthma (GINA)-guidelines controlled asthma in a real-life setting is defined as ACQ-5 < 0.5.6 In a subset of patients using inhaled steroids regularly, Forced Expiratory Volume in 1 s (FEV1) was assessed, partially combined with Fractional exhaled Nitric Oxide (FeNO). Levels of NO are increased in the exhaled breath of patients with T2 asthma and provide an objective biomarker of airway inflammation, with the following cut-off points: <25 parts per billion (ppb) (low), 25–50 ppb (intermediate), ≥50 ppb (high).7 Primary effectiveness endpoints were the mean change from baseline in ACQ-5 and FEV1 at weeks 16 and 52. Secondary effectiveness endpoints were: ACQ-5 < 0.5, FEV1 ≥ 80% predicted, and FeNO at weeks 16 and 52. For the analysis of continuous outcomes, a mixed model with a random intercept was used and results were used to estimate means with 95% confidence intervals (CI). Continuous variable FeNO, with a highly skewed distribution, was log-transformed. These estimated mean log-transformed were transformed back to median FeNO values (with 95% CIs). Descriptive analysis was used for the categorical endpoints. The role of T2-indicator blood eosinophilia (>0.4 × 10*9/L) at the start of dupilumab treatment on the primary endpoint FEV1 is shown in the Appendix Table 3. A total of 304 AD patients treated with dupilumab and comorbid asthma with an ACQ-5 and/or FEV1 measurement were included (see Appendix Table 1 for the baseline characteristics per cohort). All primary effectiveness endpoints significantly improved after 16- and 52 weeks of dupilumab treatment compared to baseline (see Figure 1 and Appendix Table 2). Mean ACQ-5 was 1.32 (95% CI 1.20–1.45; n = 236) at baseline, and significantly improved over time (p < 0.00), with −0.24 (95% CI −0.38 to −0.10; n = 173) at week 16 and −0.26 (95% CI −0.43 to −0.09; n = 110) at week 52. Mean FEV1 at start of treatment was 2.96 L (95% CI 2.79–3.13; n = 104) and significantly improved over time (p < 0.00) with 0.10 L (95% CI 0.03–0.16) and 0.12 L (95% CI 0.05–0.19) at week 16 (n = 81) and 52 (n = 64), respectively. No significant change for ACQ-5 and FEV1 was found between week 16 and 52. Secondary effectiveness endpoints are presented in Figure 1 and Appendix Table 2. At start of dupilumab treatment median FeNO (n = 22) was 23.43 ppb (95% CI 16.37–33.53) and significantly decreased over time (p < 0.00), to 13.13 ppb (95% CI 10.49–16.45; n = 17) at 16-weeks and to 15.24 ppb (95% CI 12.38–18.76; n = 21) at 52-weeks of treatment (Figure 1). At start of treatment, 20.8% and 58.7% of the patients had an ACQ-5 <0.5 and FEV1 ≥ 80% and increased to 28.2% and 68.8% after 1 year of treatment, respectively (Appendix Table 2). Effectiveness outcomes for asthma status during 1 year of dupilumab treatment in AD patients with comorbid asthma. (A) Absolute change in ACQ. Bars represent mean and 95% CI, (B) Percentage controlled ACQ-5 based on cut-off points; (C) Absolute change in FEV1 in L. Bars represent mean and 95% CI, (D) Percentage controlled FEV1% from predicted; (E) Absolute change in FeNO per ppb. Bars represent median and 95% CI, (F) Percentage controlled FeNO based on cut-off points. ACQ-5, Asthma Control Questionnaire; CI, Confidence Interval; FEV1, Forced Expiratory Volume in 1 s; FeNO, Fractional exhaled Nitric Oxide; Ppb, parts per billion. p-values based on overall likelihood ratio tests for time. *p < 0.05. In contrast to dupilumab studies, primarily focused on severe uncontrolled asthma, the majority of the patients in our study had relatively mild asthma with a mean ACQ-5 of 1.32 and FEV1 of 2.96 L at start of treatment. Nevertheless, ACQ-5, FEV1 and FeNO significantly improved already after 16 weeks. Previous randomized controlled trials (RCTs) investigating the efficacy and safety of dupilumab in patients with uncontrolled asthma showed a more impressive effect on the primary endpoints.3 However, similar substantial improvements are difficult to achieve in our AD patients with relatively mild asthma. As shown in the Appendix, no profound effect of T2-indicator, blood eosinophilia, at the start of treatment was found regarding the effectiveness of dupilumab on FEV1. On the contrary, in the asthma studies,3 the most robust results were observed in patients with elevated T2-indicators, including eosinophil counts. Possibly the effect of dupilumab is less dependent on T2-indicator blood eosinophilia in patients with mild asthma. A limitation of the study is the missing data due to the daily practice setting and COVID-pandemic. Additionally, spirometry measurements were only conducted in patients using inhaled corticosteroids thereby excluding patients with mild asthma. In conclusion, 1 year of dupilumab treatment primarily indicated for AD resulted in a significant improvement of comorbid asthma with the largest effect in the first 16 weeks. Dupilumab treatment in AD patients provides an additional advantage for patients with comorbid asthma. All authors have made substantial contributions to conception and design of this study and have been involved in drafting or revising the manuscript. All authors have given final approval of the version to be published an agreed to be accountable for all aspects of the work. Lotte S. Spekhorst had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Patients included in this manuscript participated in the BioDay registry sponsored by Sanofi-Regeneron, Abbvie, Eli Lilly and Company, Leo Pharma, and Pfizer. Lotte S. Spekhorst is a speaker for Abbvie. Marlies de Graaf is an advisor, consultant, speaker or investigator for Sanofi-Genzyme, Regeneron Pharmaceuticals, LEO Pharma and Eli Lilly. Lisa P. van der Rijst has nothing to disclose. Nicolaas P. A. Zuithoff has nothing to disclose. René C. Schweizer has nothing to disclose. Marijke Kamsteeg has nothing to disclose. Inge Haeck is an advisor, consultant, speaker or investigator for Sanofi-Genzyme, LEO pharma, AbbVie and Eli Lilly. Anneke M. T. van Lynden-van Nes has nothing to disclose. Paula van Lumig has nothing to disclose. Geertruida L. E. Romeijn has nothing to disclose. Marie-Louise Schuttelaar is an advisor, consultant, speaker and/or investigator for AbbVie, Pfizer, LEO Pharma, Regeneron, Sanofi Genzyme, Eli Lilly and Galderma. She has received grants from Regeneron, Sanofi Genzyme, Novartis and Pfizer. Marjolein S. de Bruin-Weller has been a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Arena, Aslan, Eli Lilly, Galderma, Janssen, Leo Pharma, Pfizer, Regeneron, and Sanofi-Genzyme. Regeneron Pharmaceuticals; AbbVie; Sanofi; LEO Pharma; Eli Lilly and Company; Pfizer. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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Importance:Long-term data on dupilumab drug survival in patients with atopic dermatitis (AD) are scarce. Furthermore, little is known about the factors associated with drug survival of dupilumab in AD.Objective:To describe the drug survival of dupilumab in patients with AD and to identify associated predictors.Design, Setting, and Participants:This cohort study was based on data from the multicenter prospective daily practice BioDay registry, in which 4 university and 10 nonuniversity hospitals in the Netherlands participated. Analysis included patients (age ≥18 years) participating in the BioDay registry with a follow-up of at least 4 weeks. The first patient treated with dupilumab was recorded in the BioDay registry in October 2017; data lock took place in December 2020, and data analysis was performed from October 2017 to December 2020.Main Outcomes and Measures:Drug survival was analyzed by Kaplan-Meier survival curves and associated characteristics by using univariate and multivariate Cox regression analysis.Results:A total of 715 adult patients with AD (mean [SD] age, 41.8 [16.0] years; 418 [58.5%] were male) were included with a 1-year, 2-year, and 3-year overall dupilumab drug survival of 90.3%, 85.9%, and 78.6%, respectively. Characteristics associated with shorter drug survival owing to ineffectiveness were the use of immunosuppressant drugs at baseline (hazard ratio [HR], 2.64; 95% CI, 1.10-6.37) and being a nonresponder at 4 weeks (HR, 8.68; 95% CI, 2.97-25.35). Characteristics associated with shorter drug survival owing to adverse effects were the use of immunosuppressant drugs at baseline (HR, 2.69; 95% CI, 1.32-5.48), age 65 years or older (HR, 2.94; 95% CI, 1.10-7.87), and Investigator Global Assessment score of very severe AD (HR, 3.51; 95% CI, 1.20-10.28).Conclusions and Relevance:This cohort study demonstrated a good overall 1-year, 2-year, and 3-year dupilumab drug survival. Patients using immunosuppressive therapy at baseline and those with an absence of treatment effect at week 4 tended to discontinue treatment owing to ineffectiveness more frequently. Using immunosuppressant drugs at baseline, older age, and Investigator Global Assessment score of very severe AD were characteristics associated with an increased risk for discontinuation owing to adverse effects. These data provide more insight and new perspectives regarding dupilumab treatment in AD and can contribute to the optimization of patient outcomes.

This study identified risk factors for the development of dupilumab-associated ocular surface disease in patients with moderate-to-severe atopic dermatitis in a large prospective daily practice cohort. Data from the Dutch BioDay Registry were used to assess the risk of developing dupilumab-associated ocular surface disease, by performing univariate and multivariate logistic regression analyses. A total of 469 patients were included, of which 152/469 (32.4%) developed dupilumab-associated ocular surface disease. Multivariate analysis showed a statistically significant association of the development of dupilumab-associated ocular surface disease with a history of any eye disease (history of self-reported episodic acute allergic conjunctivitis excluded) combined with the use of ophthalmic medication at the start of dupilumab (odds ratio 5.16, 95% confidence interval 2.30–11.56, p < 0.001). In conclusion, a history of any eye disease (history of self-reported episodic acute allergic conjunctivitis excluded) combined with the use of ophthalmic medication at baseline was associated with the development of dupilumab-associated ocular surface disease in patients with atopic dermatitis.

Clinical trials have shown that baricitinib, an oral selective Janus kinase 1/2 inhibitor, is effective for the treatment of moderate-to-severe atopic dermatitis. However, daily practice data are limited. Therefore, this multicentre prospective study evaluated the effectiveness and safety of 16-weeks’ treatment with baricitinib in adult patients with moderate-to-severe atopic dermatitis in daily practice. A total of 51 patients from the BioDay registry treated with baricitinib were included and evaluated at baseline and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed using clinician- and patient-reported outcome measurements. Adverse events and laboratory assessments were evaluated at every visit. At week 16, the probability (95% confidence interval) of achieving Eczema Area and Severity Index ≤ 7 and numerical rating scale pruritus ≤ 4 was 29.4% (13.1–53.5) and 20.5% (8.8–40.9), respectively. No significant difference in effectiveness was found between dupilumab non-responders and responders. Twenty-two (43.2%) patients discontinued baricitinib treatment due to ineffectiveness, adverse events or both (31.4%, 9.8% and 2.0%, respectively). Most frequently reported adverse events were nausea (n = 6, 11.8%), urinary tract infection (n = 5, 9.8%) and herpes simplex infection (n = 4, 7.8%). In conclusion, baricitinib can be an effective treatment option for moderate-to-severe atopic dermatitis, including patients with non-responsiveness on dupilumab. However, effectiveness of baricitinib is heterogeneous, which is reflected by the high discontinuation rate in this difficult-to-treat cohort.

BACKGROUND:Dupilumab has proven to be an effective and safe treatment for atopic dermatitis (AD) in pediatric patients in clinical trials. However, few daily practice studies are available. The aim of this study is to evaluate the effect of 28 weeks dupilumab treatment on effectiveness, safety, and serum biomarkers in pediatric patients with moderate-to-severe AD in daily practice. METHODS:Patients visited the outpatient clinic at baseline, 4, 16, and 28 weeks of treatment. Disease severity was assessed by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Numeric Rating Scale (NRS)-pruritus and -pain, and the Patient-Oriented Eczema Measure (POEM). Side effects were evaluated. Nineteen severity-associated serum biomarkers were measured. Predicted-EASI (p-EASI) was calculated. RESULTS:Sixty-one patients were included. Respectively 75.4%, 49.2%, and 24.6% reached EASI-50, EASI-75, and EASI-90 and 36.1% achieved an IGA-score (almost) clear. Improvement of ≥4 points on POEM, NRS-pruritus, and NRS-pain was reached by 84.7%, 45.3%, and 77.4%, respectively. Most reported side effects were conjunctivitis (n = 10) and headache (n = 4). Biomarkers TARC, PARC, periostin, sIL-2Ra, and eotaxin-3 significantly decreased during treatment. The p-EASI showed a significant correlation with disease severity. CONCLUSION:Dupilumab treatment significantly improved disease severity and disease-associated symptoms and decreased severity-associated serum biomarkers in pediatric AD patients in daily practice.