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Introduction
The introduction of dupilumab, a monoclonal IgG4 antibody that inhibits the action of both interleukin (IL)-4 and IL-13, constituted a revolutionary milestone in the management of atopic dermatitis (AD). In adulthood, approval in Europe and the United States occurred in 2017, with its efficacy initially demonstrated in three phase III trials: LIBERTY AD SOLO1 and SOLO21,2, versus placebo, and LIBERTY AD CHRONOS3, with the addition of topical corticosteroids in both dupilumab and placebo groups. In addition, an extension of the SOLO 1 and II trials (LIBERTY AD SOLO-CONTINUE)4 revealed a maintained clinical efficacy of up to 36 weeks, but there are data already supporting the persistence of this effect up to 76 weeks5, 3 years (LIBERTY AD OLE)6, and 4 years7.
Regarding the pediatric population, there has also been consistent progress in the use of the drug. Evidence from the LIBERTY AD ADOL (12-17 years)8 and LIBERTY AD PEDS (6-11 years)9 trials allowed for extrapolation of efficacy and safety data from the adult population to this age group, culminating in FDA and EMA approval for the use of dupilumab from 12 years of age in 2019 and from 6 years of age in 2020. More recently, favorable data from the LIBERTY AD PRESCHOOL10 trial served as the basis for FDA approval in 2022 and EMA approval in March 2023 for the use of the drug from 6 months of age. In adolescents, data on the extension of dupilumab use up to 52 weeks are additionally available, with the achievement of Eczema Area and Severity Index (EASI)-75 in 81% of the recruited individuals11.
At present, we witness the emergence of so-called real-world evidence regarding the efficacy of dupilumab in patients with AD. While in the adult population, there is already significant evidence devoted to this matter12, in the pediatric population, the number of publications is still limited. A prospective multicenter Italian study including 139 adolescents with AD displayed a mean EASI reduction of 79.8% at week 1613, a result superior to that observed in clinical trials. A Chinese publication, including 15 children with AD, observed a significant reduction of the mean EASI score from 19.2 to 1.69 at up to 6 months of follow-up14. A study from the United States featuring 23 children and adolescents with AD who received dupilumab for 1 year or more revealed an achievement of EASI-75 in all patients and EASI-90 in 60.8% of them15. Finally, a Dutch publication involving 61 children and adolescents with AD, described, at 28 weeks of therapy, 75.4%, 49.2%, and 24.6% of patients reaching EASI-50, EASI-75, and EASI-90, respectively16.
Although these data already hint at a favorable performance of dupilumab in pediatric populations in a real-world setting, there is a visible need for additional evidence, namely in what pertains to longer periods of follow-up. We aim to provide real-world data on this matter in a Portuguese pediatric population.
Methods
Retrospective analysis of clinical charts of patients with AD below the age of 18 treated with dupilumab under follow-up in two Portuguese tertiary hospitals. Data regarding comorbidities, previous therapies, activity scores (EASI, NRS-pruritus, and DLQI), and adverse reactions were collected.
Statistical analysis was performed using IBM SPSS Statistics 28. Categorical variables are reported as proportions and/or percentages. Continuous variables are reported as mean (± SD) or median (range) values, depending on normal distribution. The correlation between categorical variables was obtained by performing a Chi-square test.
Results
Thirty patients were included in the analysis (19 male patients, 63%), with a median age of 14 years (IQR 8.5-16 years, min-max 2-17 years). Information on patient’s allergic comorbidities is available in table 1. The previously most used immunosuppressants were oral corticosteroids (28 patients, 93%), cyclosporine (23 patients, 77%), methotrexate, and azathioprine (both in five patients, 17%). The median follow-up after starting treatment with dupilumab was 80 weeks (IQR 52-104 weeks). Median baseline EASI score was 32.3 (IQR 25.7-40). Sixty percent of patients achieved EASI-90 and 77% EASI-75 at week 16 (n = 30); 62% EASI-90 and 79% EASI-75 at week 28 (n = 29); 79% EASI-90 and 92% EASI-75 at week 52 (n = 24); 78% EASI-90 and 78% EASI-75 at week 72 (n = 18); 64% EASI-90 and 82% EASI-75 at week 104 (n = 11); and 75% EASI-90 and 100% EASI-75 at week 132 (n = 4). In five patients (17%), there was a need for a dose increase, with treatment failure occurring in two patients (7%) – one primary and one secondary failure. In two patients (7%), there was a worsening of the EASI score during therapy with dupilumab after an initial favorable response, with a subsequent reattainment of disease control while maintaining therapy. Ninety-seven percent of patients (n = 29) achieved an EASI score below 7, 97% (n = 29) EASI-50, and 93% (n = 28) EASI-75 and EASI-90 at some point of follow-up. Complete results are shown in table 2. Ninety-three percent of patients (n = 28) achieved at some point a reduction superior to 4 points in the NRS pruritus scale and of more than 6 points in the DLQI questionnaire. Regarding the most common adverse reactions, four patients (12%) presented facial erythema, two (7%) patients asymptomatic eosinophilia above 2000/μL, and two (7%) patients mild conjunctivitis (Table 1). All events were manageable or transient and there was no need to stop treatment.
Table 1 Patients’ previous therapies, allergic comorbidities, and observed adverse reactions
| Previous therapies | |
| ≤ 1 immunosuppressant | 6 (20) |
| ≥ 2 immunosuppressants | 24 (80) |
| Oral corticosteroids | 28 (93) |
| Cyclosporine | 23 (77) |
| Methotrexate | 5 (17) |
| Azathioprine | 5 (17) |
| Mycophenolate mofetil | 4 (13) |
| Omalizumab | 1 (3) |
| Atopic comorbidities | |
| Allergic rhinitis | 15 (50) |
| Asthma | 14 (47) |
| Conjunctivitis | 1 (3) |
| Adverse reactions | |
| Facial erythema | 4 (13) |
| Eosinophilia (> 2000/µL) | 2 (7) |
| Conjunctivitis | 2 (7) |
| Herpes virus infections | 1 (3) |
| Injection-site reaction | 0 (0) |
| Skin infections | 0 (0) |
Table 2 Eczema Area and Severity Index (EASI) score at different follow-up points
| Timepoint | ||||||
|---|---|---|---|---|---|---|
| Disease activity | Week 16 (n = 30) | Week 28 (n = 29) | Week 52 (n = 24) | Week 72 (n = 18) | Week 104 (n = 11) | Week 132 (n = 4) |
| Median EASI | 3 (1-8.2) | 2 (1-6) | 1 (0-3) | 1.5 (0-3.8) | 2 (0-6.1) | 4.5 (0-8.9) |
| EASI 75 | 23 (77) | 23 (79) | 22 (92) | 14 (78) | 9 (82) | 4 (100) |
| EASI 90 | 18 (60) | 18 (62) | 19 (79) | 14 (78) | 7 (64) | 3 (75) |
Discussion
Our results suggest that treatment outcomes with dupilumab in pediatric AD in a real-world setting corroborate those observed in clinical trials, even surpassing them in some cases.
Our data reports 77% of patients achieving EASI-75 at week 16, a value higher than those observed in pediatric trials: in the LIBERTY AD ADOL (12-17 years)8 trial, achieved by 42% of patients in the every-2-week regimen and 38% in the every-4-week regimen; in the LIBERTY AD PEDS (6-11 years)9 trial, achieved by 67% of patients in the every-2-week regimen and 70% in the every-4-week regimen; and in the LIBERTY AD PRESCHOOL9 trial (6 months-5 years), achieved by 53% of patients. Comparing our data with other real-world evidence studies, the value EASI-75 at week 16 observed in 77% of our patients also surpasses the available evidence, with reported values ranging from 43 to 65%13,15,16. Regarding long-term outcomes, our results fall in line with the reported literature, with the LIBERTY AD PED-OLE11 trial in adolescents providing evidence on the extension of dupilumab use up to 52 weeks, with EASI-75 in 81% of recruited individuals, whereas a real-world study from the United States featuring 23 children and adolescents with AD who received dupilumab for 1 year or more revealed an achievement of EASI-75 in all patients15. In our case, 93% of patients achieved EASI-75 and EASI-90 at some point of follow-up, being noteworthy that our cohort displays a median follow-up of 80 weeks, with patients followed up to 132 weeks. Our cohort also provides relevant data in what concerns the significant reduction of the NRS pruritus score and DLQI in the vast majority of our patients, highlighting the impact of treatment, not only in disease activity scores but also on the quality of life reported by patients, as already stressed by other real-world publications16. An additional novel information added by our data regards the specific treatment outcomes of need for dose increase and treatment failure, with the former occurring in 17% and the latter in 7%. In addition, the fact that, in two patients, there was a worsening of the EASI score during therapy with dupilumab after an initial favorable response, with subsequent reattainment of disease control with maintained therapy, strengthens the rationale of not suspending the treatment at the first signs of clinical deterioration.
Regarding safety and adverse reactions, pediatric clinical trials revealed no serious events, with conjunctivitis and injection-site reactions as the most common occurrences8,9, whereas, in real-world pediatric studies, conjunctivitis, flushing, joint pain, and headache featured among the most reported13,14-16. In our cohort, conjunctivitis was also present, but facial erythema and asymptomatic eosinophilia were additionally noted. No serious events occurred, corroborating the previously observed safety of dupilumab.
Our study presents both strengths and limitations. On the one hand, our sample is composed of a significant number of pediatric patients, originating from two different centers, featuring detailed data on their evolution across a substantial time span. On the other hand, data were collected retrospectively, with expectable shortcomings, and two-thirds of the patients were above the age of 11, a fact that might constitute the source of certain biases, making our data particularly applicable to this age group.
Overall, treatment with dupilumab in pediatric AD in a real-world setting corroborated the data from clinical trials, highlighting its maintained efficacy and adequate safety profile in this age group.
