Use of Dupilumab in Pediatric Atopic Dermatitis and in Inborn Errors of Immunity-Associated Atopic Skin Disease: An Italian Society of Pediatric Research (SIRP) Multicenter Real-World Study

1. Introduction

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that commonly begins in early childhood and may persist over time, with a substantial impact on symptoms, sleep, daily functioning, psychosocial well-being, and family burden. In pediatric patients, severe disease is often associated with intense pruritus, recurrent flares, impaired quality of life, and repeated need for systemic treatment, making timely recognition and effective disease control a major clinical priority [1,2,3,4,5].

From a pathobiological standpoint, severe pediatric AD is considered a polygenic inflammatory disorder resulting from the interplay between genetic susceptibility, skin barrier dysfunction, and immune dysregulation, with a predominant type 2 inflammatory signature with variable contributions of other immune pathways depending on the individual phenotype [6,7].

Nevertheless, atopic manifestations may feature several inborn errors of immunity (IEI) and although the prevalence is still uncertain, atopic dermatitis stands out as the most widely experienced. These IEI-associated atopic phenotypes encompass a heterogeneous group of disorders characterized by early-onset, severe, and often treatment-refractory atopic dermatitis coexisting with recurrent infections and/or variable signs of immune dysregulation [8]. This spectrum includes primary atopic disorders (PAD), as named in 2018, that recognize a subgroup of more than 50 causing, by diverse mechanisms, severe allergic inflammation [8,9,10,11]. The identification of distinct molecular pathologies is critical to highlight the essence of human allergy and pave the basis for targeted therapies for both patients with PAD and those with common polygenic allergic disease. Further, early distinction of IEI-associated atopic skin disease and polygenic atopy is essential for prompt and appropriate management of each atopic patient. A recent Italian consensus document and other expert reviews have emphasized the need to systematically consider IEI with atopic manifestations, including PAD in children with severe, early-onset, atypical, or treatment-resistant atopic dermatitis, particularly when accompanied by “red flags” such as recurrent severe infections, autoimmune manifestations, dysmorphic features, or extreme laboratory abnormalities [10,12,13]. Although the clinical relevance of these conditions is increasingly recognized, more knowledge would better assist an optimal diagnostic work-up and therapeutic strategies [8,11,14]. This is particularly true in tertiary pediatric settings where children with severe, early-onset, atypical, or treatment-refractory atopic skin disease are frequently evaluated and where IEI with atopic manifestations, despite being individually rare, must be systematically considered in the differential diagnosis [12].

Dupilumab, a fully human monoclonal antibody targeting the interleukin-4 receptor alpha subunit and inhibiting IL-4 and IL-13 signaling, has significantly changed the treatment landscape of moderate-to-severe AD in children and adolescents. Clinical trials and extension studies have shown that dupilumab is an effective and generally well-tolerated therapeutic option in pediatric AD, with sustained benefit on disease severity, pruritus, and quality of life [15,16,17,18,19,20,21,22,23]

Emerging evidence from small series and case-based reports - reflecting the intrinsic rarity of these conditions - also suggests that dupilumab may be a valuable therapeutic option in pediatric patients with IEI-associated atopic manifestations, with an overall favorable safety profile [24].

Despite these advances, several clinically relevant questions remain unsolved in everyday pediatric therapeutic practice, especially in patients with early-onset, severe, atypical disease. In these settings, the main uncertainties concern patient selection, effectiveness across heterogeneous phenotypes, the role of combination or sequential treatment regimens, and whether earlier treatment initiation may lead to a better clinical response. Moreover, most existing studies have focused either on polygenic AD or on selected IEI entities, and have rarely provided longitudinal comparative data in cohorts including both disease categories. For this reason, multicenter real-world data are needed to clarify the clinical phenotype, treatment patterns, safety profile, and quality-of-life impact of dupilumab in pediatric polygenic vs monogenic AD.

In this context, the present multicenter study was designed to characterize, in a real-world approach, a pediatric cohort with severe atopic skin disease treated with dupilumab in routine clinical practice, including both patients with severe polygenic AD and patients with IEI associated atopic skin disease. Given the rarity of IEI with atopic manifestations, we deliberately included these patients alongside those with polygenic AD, accepting a numerically unbalanced but clinically meaningful comparative cohort in order to capture real-world patterns of disease and treatment across the full spectrum of severe pediatric atopic dermatitis patients. In particular, we aimed to characterize phenotype in relation to clinical outcome, identify potential biomarkers of response, and assess effectiveness, safety, and quality-of-life indicators in these cohorts.

2. Materials and Methods

This multicenter observational study was conducted within the Italian Society of Pediatric Research (SIRP) Network and included children and adolescents who had initiated dupilumab before 18 years of age according to local eligibility criteria for systemic treatment of severe atopic dermatitis.

The study population consisted of patients with polygenic and monogenic IEI-associated severe atopic skin disease. Patients were recruited at participating Italian Pediatric Referral Centers involved in the project network with expertise in pediatric allergy, immunology and dermatology.

Eligibility was based on pediatric age and start of dupilumab within the approved or clinically indicated setting for severe disease, according to prescribing criteria adopted in routine practice. Patients with concomitant atopic comorbidities, autoimmune manifestations, or confirmed IEI were eligible provided that dupilumab had been prescribed for severe cutaneous disease.

Clinical and demographic data were collected from medical records and standardized follow-up assessments performed during routine care. Baseline variables included sex, age at assessment, age at disease onset, age at dupilumab initiation, family history, distribution of skin involvement and associated comorbidities. In line with the current conceptual framework of IEI-associated severe atopic skin disease, particular attention was given to features potentially suggestive of an underlying monogenic atopic disorder, including severe eczema, early-onset disease, recurrent infections, elevated IgE, eosinophilia, and other signs of immune dysregulation when available in the clinical records. Information on previous and concomitant treatments was also collected, including topical corticosteroids, topical calcineurin inhibitors, systemic corticosteroids, cyclosporine, and other adjunctive or disease-specific therapies. Dupilumab exposure was recorded according to routine prescribing practice, including monotherapy and combination treatment with topical or other therapies. Vaccinations performed during treatment and their tolerability were documented when available in the medical charts.

Disease severity and treatment response were assessed using validated clinical and patient-reported outcome measures collected during follow-up, including the Eczema Area and Severity Index (EASI), Numeric Rating Scale (NRS) for pruritus, and Children’s Dermatology Life Quality Index (CDLQI).

Safety assessment included documentation of adverse events and treatment discontinuation.

Follow-up data were analyzed longitudinally according to routine clinical visits after dupilumab initiation. Baseline characteristics, treatment patterns, and clinical outcomes were described for the overall cohort and according to the underlying disease category (severe polygenic AD versus IEI-associated severe atopic skin disease).

2.1. Sample Size and Statistical Analysis

Continuous variables were summarized as median and range (minimum–maximum), whereas categorical variables were expressed as frequencies and percentages. Baseline comparisons between patients with polygenic atopic dermatitis and those with IEI-associated atopic skin disease were performed using the Wilcoxon rank-sum test for continuous variables and Fisher's exact test for categorical variables.

Associations between baseline clinical characteristics and IEI status were explored using univariable logistic regression models. Variables considered clinically relevant were subsequently included in a multivariable logistic regression model. The variable 'severe/recurrent infections' was not included in the multivariable analysis because complete separation prevented reliable maximum likelihood estimation.

Longitudinal changes in EASI, NRS and CDLQI after Dupilumab initiation were evaluated using linear mixed-effects models including IEI status, follow-up time and their interaction as fixed effects, with patient-specific random intercepts to account for repeated measurements.

Odds ratios (ORs), regression coefficients (β), 95% confidence intervals (95% CIs) and two-sided p-values are reported. Statistical significance was defined as p<0.05. Analyses were performed using R."

3. Results

A total of 127 pediatric patients (60 males, 67 females) were enrolled in the study; 116/127 (91%) had polygenic AD and 11/127 (9%) had IEI-associated severe atopic skin disease.

Among the 11 patients with IEI-associated atopic skin disease, eight had hyper-IgE syndrome (HIES), of whom one with STAT3 loss-of-function; one had Netherton syndrome, one had combined immunodeficiency with epidermodysplasia verruciformis, and one an unclassified immunodeficiency. Demographic and clinical-laboratory characteristics at baseline are reported in Table 1.

A family history of AD and of other allergic diseases were reported in 29/127 (23%) and 43/127 (34%) patients, respectively.

The median age at AD onset was 12 months (range 1–192) in the overall cohort, with a trend toward earlier diagnosis in patients with IEI-associated severe atopic skin disease than in those with polygenic AD (6 vs 12 months, p = 0.080). Overall, 41/127 patients (32%) had disease onset within the first 6 months of life, a feature that was significantly more common in the IEI group than in the polygenic AD group (7/11, 64% vs 34/116, 29%; p = 0.037).

The median current age was 17 years (range 6–20), and the median age at dupilumab initiation was 14 years (range 2–17), with no significant differences between the two groups.

At disease onset, the limbs and the face/neck were the most frequently involved sites (102/127, 80% and 89/127, 70%, respectively), followed by the trunk (70/127, 55%), genitalia (37/127, 29%) and hands/feet (36/127, 28%). Face/neck, trunk, genital and hand/foot involvement were more often affected in the IEI group than in those with polygenic AD. Overall, involvement of at least one visible or sensitive area was reported in 89/127 patients (70%), including all 11 patients with IEI versus 78/116 patients with polygenic AD (100% vs 67%; p = 0.033). Complete involvement of all visible areas was present in 28 patients (22%) and was again more frequent in the IEI group (6/11, 55% vs 22/116, 19%; p = 0.014), while generalized involvement of the entire body was observed in 17 patients (13%), with a marked difference between IEI and polygenic AD (6/11, 55% vs 11/116, 9.5%; p < 0.001). By contrast, isolated involvement of sensitive areas was uncommon (3/127, 2.4%) and did not differ between groups.

At baseline/T0, corresponding to the start of dupilumab treatment, disease remained extensive, with involvement of the face/neck in 92 patients (72%), the arms and/or legs in 109 (86%), and the trunk in 77 (61%). Involvement of genital sites and hands/feet was less common, affecting 14 patients (11%) and 41 patients (32%), respectively. Overall, 92 patients (72%) had at least one visible or sensitive area involved, 11 (8.7%) had all visible areas affected, 1 (0.8%) had isolated sensitive-area involvement, and 6 (4.7%) had generalized involvement of the entire body. Patients with IEI more frequently showed genital involvement and generalized disease at baseline (p < 0.001).

Consistently with the extensive clinical involvement described above, at T0, disease severity was high across the cohort, with a median EASI score of 26 (range 7–72), a median NRS pruritus score of 9.0 (range 2.0–10.0), and a median CDLQI of 18 (range 2–30). Patients with IEI had a significantly higher baseline EASI than those with polygenic AD (50 vs 25; p < 0.001) (Figure 1), whereas pruritus severity and quality-of-life impairment were comparable between groups (NRS pruritus: 8.0 vs 9.5, p = 0.34; CDLQI: 18 vs 18, p = 0.88).

At baseline, 68/127 patients (54%) had at least one atopic comorbidity, with no significant difference between patients with polygenic AD and those with IEI-associated severe atopic skin disease (63/116, 54% vs 5/11, 45%; p = 0.75). Allergic conjunctivitis before treatment was reported in 25/127 patients (20%), again without significant between-group differences (21/116, 18% vs 4/11, 36%; p = 0.22), while autoimmune comorbidities were uncommon, being documented in 5/127 patients (3.9%) overall (4/116, 3.4% vs 1/11, 9.1%; p = 0.37). In contrast, severe recurrent infections were observed exclusively in the IEI group, occurring in all 11/11 patients (100%) and in none of the patients with polygenic AD (0/116; p < 0.001).

Regarding laboratory features, hyper-eosinophilia, available in a subset of patients, was observed in 23 cases and did not significantly differ between groups (18/67, 27% vs 5/11, 45%; p = 0.28), whereas total IgE levels >2000 IU/mL were significantly more frequent among patients with IEI than among those with polygenic AD (10/11, 91% vs 16/116, 14%; p < 0.001).

Before dupilumab initiation, all patients had received topical corticosteroids, while 35/127 (28%) had been treated with topical calcineurin inhibitors, 13/127 (10%) with cyclosporine, and 55/127 (43%) with systemic corticosteroids. Three patients (2 in the polygenic AD group and 1 in the IEI group) had performed off-label omalizumab therapy and one polygenic AD patient has used crisaborol creme. Seven patients (6 in the polygenic AD group and 1 in the IEI group) underwent sublingual Allergen Immunotherapy (AIT); among them, 3 patients continued the treatment throughout the course of Dupilumab therapy. Moreover, two IEI patients were receiving immunoglobulin replacement therapy, according to the underlying immunodeficiency. Vaccinations administered during dupilumab treatment were documented in 23/127 patients (18%), with identical proportions in the two groups (21/116, 18% vs 2/11, 18%; p > 0.99). Among recorded cases, no adverse reactions to vaccination and no AD exacerbations temporally associated with vaccination were reported.

At baseline, patients without prior cyclosporine exposure had a lower EASI score than those who had previously received the drug (p = 0.014), whereas no difference in baseline EASI score was observed between patients with and without prior systemic corticosteroid use (p = 0.30).

At the time of dupilumab initiation, treatment was most commonly administered in combination with topical corticosteroids (98/127, 77%), whereas 22/127 patients (17%) received dupilumab as monotherapy. Monotherapy was significantly more frequent in the IEI group (82% vs 11%, p < 0.001). Less frequently, dupilumab was combined with topical calcineurin inhibitors (4/127, 3.1%) or with both topical and systemic corticosteroids (3/127, 2.4%).

Although dupilumab monotherapy showed a strong association with IEI in univariate analysis (OR 35.7, 95% CI 8.15–252; p = 0.001), this variable was not retained in the multivariable model because of the limited number of exposed patients. Similarly, severe/recurrent infections were not entered into the multivariable logistic regression because complete separation occurred, as this variable perfectly discriminated patients with IEI from those with polygenic atopic dermatitis, preventing reliable coefficient estimation.

In the multivariable logistic regression analysis, early disease onset (≤6 months) remained independently associated with IEI (OR 29.3, 95% CI 2.40–1003, p=0.024), together with increasing baseline EASI score (OR 1.23, 95% CI 1.09–1.52, p=0.011). Baseline NRS (OR 0.48, 95% CI 0.16–1.12, p=0.13), CDLQI (OR 0.95, 95% CI 0.77–1.17, p=0.60) and total IgE >2000 IU/mL (OR 3.31, 95% CI 0.18–104, p=0.40) were not independently associated with IEI in the multivariable logistic regression analysis.

During follow-up, EASI, pruritus NRS, and CDLQI progressively improved over time, with changes already evident by month 4 and maintained through later visits (overall p < 0.001 for all three outcomes). Median EASI decreased from 26 at baseline to 5 at month 4 and remained low thereafter, while median pruritus NRS decreased from 9.0 to 2.0 and median CDLQI from 18 to 3 over the same time interval (Figure 2; Supplementary Table 1).

Improvement in quality of life was assessed as a reduction of at least 6 points from baseline in the CDLQI score. Among patients with an available CDLQI assessment at each follow-up visit, this threshold was achieved by 94/115 (81.7%) patients at month 4, 91/108 (84.3%) at month 8, 83/100 (83.0%) at month 12, 78/89 (87.6%) at month 18, 73/84 (86.9%) at month 24, and 42/49 (85.7%) at month 36 (Figure 3A). Time to first achievement of a clinically meaningful improvement in CDLQI was additionally evaluated using a time-to-event approach (Figure 3B). The cumulative probability curve showed that most patients achieved the target early during follow-up, with relatively few additional first responses occurring thereafter.

Longitudinal analyses were performed using linear mixed-effects models including time, IEI status and their interaction. Patients with IEI had significantly higher baseline EASI scores (β=16.0, 95% CI 8.9–24.0, p<0.001). A significant reduction in EASI was observed over time in the overall cohort (β=-0.55 per month, 95% CI -0.64 to -0.46, p<0.001). The significant IEI×time interaction (β=-0.41, 95% CI -0.79 to -0.02, p=0.037) indicates a faster reduction in disease severity among IEI patients. Baseline NRS values were higher in IEI patients (β=1.10, 95% CI 0.09–2.10, p=0.033), whereas the interaction between IEI and time was not statistically significant (β=0.04, 95% CI -0.02 to 0.10, p=0.20), indicating a similar rate of improvement in both groups. No significant baseline difference was observed in CDLQI (β=1.30, 95% CI -1.20 to 3.70, p=0.30). Although CDLQI significantly improved over time (β=-0.31, 95% CI -0.38 to -0.25, p<0.001), no differential longitudinal trend was detected between groups (interaction β=0.00, 95% CI -0.12 to 0.12, p>0.90).

Overall, 112 of 127 patients (88.2%) achieved EASI-50, of whom 127 (84.3% of the overall cohort) maintained this response over time. EASI-75 was achieved by 104 patients (81.9%) and maintained by 88 patients (69.3%). Finally, EASI-90 was achieved by 84 patients (66.1%) and maintained by 60 patients (47.2%). Kaplan–Meier analyses (Figure 4) showed no significant differences between patients with and without IEI in either the achievement or maintenance of EASI-50 responses. Patients without IEI appeared to achieve EASI-75 and EASI-90 responses earlier than those with IEI. In particular, the median time to EASI-90 was 8 months in patients without IEI, whereas it was not reached in the IEI subgroup during follow-up. No significant differences were observed in the maintenance of EASI-75 or EASI-90 responses between the two groups.

In the exploratory univariable analyses of factors associated with EASI response, previous cyclosporine therapy was less frequently observed among patients achieving and maintaining EASI-50 responses (p = 0.009 and p = 0.033, respectively). Previous systemic corticosteroid use was also less frequent among patients maintaining EASI-50 (p = 0.048) and among those achieving EASI-75 (p = 0.022) or EASI-90 (p = 0.023). In addition, patients with arm or trunk involvement at disease onset were less likely to achieve EASI-90 (p = 0.026 and p = 0.034, respectively). No significant associations were observed for maintenance of EASI-75 or EASI-90 responses.

Dupilumab was generally well tolerated throughout follow-up, with no significant difference between patients with polygenic AD and those with IEI-associated severe atopic skin disease. Conjunctivitis occurring during follow-up was observed in 6/127 patients (4.7%), again without significant differences between groups (6/116, 5.2% vs 0/11, 0%; p > 0.99). The exposure-adjusted incidence of conjunctivitis was 2.5 cases per 100 patient-years.

At T4 months time point, conjunctivitis was observed in 3 patients, together with 1 injection-site reaction. All three cases of conjunctivitis responded to treatment, and none required dupilumab discontinuation. At 8 months, no adverse events were recorded. At 12 months, 2 patients developed conjunctivitis, both requiring treatment discontinuation and 2 had injection-site reactions. At 18 months, one patient with IEI experienced a VZV flare, which was considered related to the underlying disease, and one patient reported arthralgia; neither event led to dupilumab interruption. At 24 months, one case of conjunctivitis and one case of myalgia were reported. No adverse events were recorded at 36 months.

Dupilumab was discontinued during follow-up in 6/127 patients (4.7%). Treatment discontinuation due to an adverse event (conjunctivitis) was uncommon, being recorded in two cases overall. In detail, 3 patients stopped dupilumab at 8 months: 1 due to clinical remission, 1 due to personal choice and 1 because of inefficacy. At 12 months, 3 additional discontinuations were recorded: 2 for conjunctivitis unresponsive to treatment and 1 because the patient refused to continue injections due to local pain. All discontinuations occurred in the non-IEI group, although this difference was not statistically significant (6/116, 5.2% vs 0/11, 0%; p > 0.99).

4. Discussion

Severe pediatric atopic dermatitis encompasses a clinically heterogeneous spectrum, ranging from polygenic disease to IEI-associated atopic skin manifestations. Although these conditions may share severe eczema, pruritus, and a high burden on quality of life, they differ substantially in their underlying pathobiology, associated immune abnormalities, risk of infectious and not-infectious comorbidities, and long-term management needs. In this context, real-world evidence is particularly relevant to assess whether targeted type 2 inhibition provides comparable clinical benefit across these heterogeneous pediatric phenotypes [14].

Our multicenter real-world study confirms that dupilumab is an effective and generally well-tolerated treatment for pediatric patients with severe atopic dermatitis, including those with an underlying IEIs. In the overall cohort, improvement was rapid, clinically significant, and sustained over time, with reductions in EASI and pruritus already apparent by month 4 and maintained through the follow-up. Quality-of-life improvement followed the same trajectory, with most patients reaching a clinically relevant CDLQI improvement early in treatment and then maintaining benefit thereafter. This pattern is highly consistent with the results reported in the pivotal pediatric trials, where dupilumab added to topical corticosteroids produced significant improvements in skin signs, itch, and quality of life already within the first weeks of therapy [15,17,21,23].

In the registrative phase III trial in children aged 6 to 11 years, dupilumab plus topical corticosteroids achieved EASI-75 responses in approximately 70% of treated patients at week 16, together with marked improvement in pruritus and patient-reported outcomes [17]. Long-term analyses from the open-label extension of the same pediatric program showed that clinically meaningful responses were observed in the vast majority of children, with improvements evident as early as week 4 and sustained through 52 weeks of treatment [18]. Likewise, in children aged 6 months to 5 years, the LIBERTY AD PRESCHOOL trial confirmed significant and sustained efficacy across signs, symptoms, and quality of life, with an acceptable safety profile up to 16 weeks and later extension data supporting durability of response [15,16,23]. In adolescents aged 12–17 years, the phase III LIBERTY AD ADOL trial also demonstrated significant efficacy, with EASI-75 achieved at week 16 by 41.5% and 38.1% of patients receiving dupilumab every 2 or 4 weeks, respectively, compared with 8.2% in the placebo group [25]. Our real-world findings align with this body of evidence and extend it to a broader tertiary-care pediatric population with longer observation and more heterogeneous disease profiles. This is important because the phase III trials largely enrolled selected patients with severe but otherwise typical atopic dermatitis, whereas our cohort reflects day-to-day specialist practice, where dupilumab is often used after previous treatment failures or in the setting of atypical phenotypes. In this respect, the strong efficacy observed in our comparative cohort suggests that dupilumab retains its therapeutic value even in more refractory and complex pediatric cases. Our findings are also supported by the multicentre real-world study by Pirov et al., including 230 pediatric and adolescent patients, which reported high treatment persistence, with an estimated 52-week drug-survival probability of 94.0% [26].

The quality-of-life findings deserve separate emphasis. In our cohort, a clinically meaningful improvement in CDLQI was defined as an improvement of at least 6 points from baseline. Most patients achieved this threshold early during follow-up, and the cumulative probability curve showed that the great majority of CDLQI responders were captured in the first months after starting dupilumab. This pattern closely mirrors the rapid and sustained improvement in patient- and caregiver-reported outcomes observed in pediatric trials. In the LIBERTY AD PEDS phase III trial in children aged 6–11 years, approximately 77–81% of patients receiving dupilumab plus topical corticosteroids achieved a ≥ 6-point improvement in CDLQI by week 16, compared with about 36–42% in the placebo group, with benefits evident from the first weeks of treatment [27]. Similarly, in the open-label extension study in infants and young children (6 months to 5 years) reported by Paller et al. in 2026, about 89% of patients achieved a ≥ 6-point improvement in CDLQI by week 104, confirming that quality-of-life gains are not only rapid but also durable over long-term treatment [23]. In a disease such as pediatric AD, where sleep disturbance, pruritus, emotional distress, and family burden are major determinants of disease severity, these findings underscore that treatment success should be measured not only by lesion extension but also by patient-centered outcomes.

Pre-dupilumab treatment pathways reflected the multidisciplinary nature of care for severe pediatric AD patients. Topical calcineurin inhibitors, systemic cyclosporine, and crisaborole were mainly prescribed within dermatology settings, whereas allergen immunotherapy was prescribed in allergy settings for selected patients with clinically relevant sensitization and atopic comorbidities. Notably, one patient with IEI had also received allergen immunotherapy. In addition, the absence of documented vaccine-related adverse events or AD flares among vaccinated patients provides limited but reassuring real-world data on vaccine tolerability during dupilumab treatment.

Patients with previous cyclosporine therapy had higher EASI scores at dupilumab initiation than those without this drug history (median 39 vs 25; p = 0.014), whereas baseline EASI did not differ according to prior systemic corticosteroid use. This finding may reflect a prescription bias based on disease severity, as cyclosporine had been preferentially prescribed to patients with more severe or difficult-to-control disease before biologic initiation.

In the overall cohort, 88%, 82%, and 66% of patients achieved EASI-50, EASI-75, and EASI-90, respectively, while the corresponding maintenance rates were 84%, 70%, and 47% during the follow-up confirming dupilumab as an effective treatment option for severe pediatric AD in routine clinical practice. Previous cyclosporine therapy was less frequent among patients achieving and maintaining EASI-50, whereas prior systemic corticosteroid use was less frequent among patients achieving EASI-75 or EASI-90 and among those maintaining EASI-50. In addition, involvement of the arms or trunk at disease onset was associated with a lower probability of achieving EASI-90. Taken together, these exploratory findings raise the possibility that, in more severe phenotypes, earlier initiation of dupilumab without prior exposure to systemic immunosuppressants such as cyclosporine or systemic corticosteroids may be associated with a higher possibility to achieve and maintain the EASI response. Although these data do not prove a causal benefit of “biologic-first” strategy, they support the hypothesis that avoiding prolonged treatment escalation in severe disease could optimize long-term control and should be further investigated in large prospective studies.

A particularly relevant finding of this study is the comparison between polygenic AD and IEI-associated atopic skin disease. IEI were associated with an approximately fourfold higher probability of AD onset within the first 6 months of life and with greater disease extension, as reflected by the association between IEI status and higher baseline EASI score (OR 1.16 per EASI-point increase). They also had a significant higher burden of recurrent infections and markedly elevated IgE levels, consistent with the red flags proposed for primary atopic disorders [12]. Beyond the higher EASI score, patients with IEI more frequently showed extensive involvement of visible and sensitive areas and generalized disease, supporting the concept that the cutaneous phenotype of IEI-associated disease is not simply more severe but also more widespread and clinically challenging. In contrast, pruritus severity and CDLQI impairment were comparable between groups, suggesting that patient-reported burden is relevant in both IEI-associated and polygenic severe AD. Therefore, patient-reported outcomes alone may not adequately distinguish IEI-associated eczema from severe polygenic AD, whereas disease distribution, EASI severity, early onset, and systemic features may be more informative in identifying patients deserving of IEI work-up. These findings are in line with the concept that IEI-associated eczema is not merely a more severe form of ordinary AD, but rather part of a broader syndrome of immune dysregulation, where skin disease represents a component of a complex systemic phenotype [10].

Treatment patterns at dupilumab initiation differed between groups. Although dupilumab was most commonly administered in combination with topical corticosteroids in the overall cohort, monotherapy was more frequent among patients with IEI (82% IEI vs 11% polygenic AD; p < 0.001). The more extensive skin involvement observed in the IEI group may have made widespread topical corticosteroid application less practical and less acceptable, thereby favouring the use of dupilumab as monotherapy. However, the observational design does not allow the reasons underlying treatment selection to be established.

Although patients with IEI had substantially higher EASI scores at baseline, they showed a significantly steeper decline over time, leading to a progressive narrowing of the difference in EASI scores between the two groups, whereas the trajectories of pruritus and quality-of-life improvement were comparable between the two groups.

Importantly, our study extends the available IEI literature by evaluating not only longitudinal changes in disease severity, but also the achievement and maintenance of EASI-50, EASI-75, and EASI-90 in comparison with a larger polygenic AD cohort. Indeed, to our knowledge, this is the first real-world pediatric study to provide this comparative time-to-event assessment of both achievement and maintenance of multiple EASI response thresholds in IEI-associated and polygenic AD.

Although no significant differences were observed between groups in the achievement or maintenance of EASI-50, patients without IEI appeared to achieve the EASI-75 and EASI-90 thresholds earlier. Previous reports have mainly described absolute EASI improvement or response rates at predetermined follow-up visits in non-comparative IEI cohorts. For example, we reported EASI-50 improvement in all the six enrolled patients by week 16 and EASI-75 improvement in four of five evaluable patients by week 24; nevertheless, the improvement in disease severity appeared slower than in immunocompetent patients from randomized clinical trials [28]. In a nationwide French study of 37 patients with IEI-associated AD-like eczema, 89.2% of patients improved by month 3 and 62.5% of those still receiving treatment at month 12 achieved a complete response, although EASI-specific time-to-response and maintenance outcomes were not assessed [29]. Alsediq et al. described sustained EASI-75 improvement in all 10-patient pediatric IEI patients, and EASI-90 in more than half of the cohort over 18 months, but without a polygenic AD comparative group or analysis of response maintenance [24].

Taken together, these results suggest that IEI-associated eczema may require a longer time to reach deep skin clearance, despite the marked overall improvement with IL-4/IL-13 blockade. However, once a response is achieved, the absence of significant differences in maintenance suggests that the durability of clinical benefit may be comparable to that observed in polygenic AD. This interpretation should remain cautious, given the limited number and heterogeneity of patients with IEI, but it may help in counselling patients/families and planning treatment expectations. In particular, a slower achievement of the EASI thresholds should not necessarily be interpreted as treatment failure in patients with IEI.

Dupilumab was generally well tolerated during follow-up, and its safety profile was consistent with that reported in pediatric clinical trials and real-world cohorts [15,17,21,23,26].

Conjunctivitis was the most frequently observed adverse event, occurring in less than 5% of our cohort, mainly responsive to conventional treatment; only two patients discontinued dupilumab because of therapy-resistant conjunctivitis. The cumulative frequency of conjunctivitis in our cohort (4.7%) was within the wide range reported in pediatric dupilumab studies (2.8%–20%) [26,30,31,32,33,34,35,36]. The exposure-adjusted incidence of conjunctivitis was 2.5 cases per 100 patient-years, which appears lower than the 9.7 patients per 100 patient-years reported in the 104-week LIBERTY AD PED-OLE study by Paller et al. in children aged 6 months to 5 years [23]. The lower cumulative frequency observed in our cohort should nevertheless be interpreted cautiously, given differences in follow-up duration, age distribution, baseline disease characteristics, and event assessment. None of the patients with IEI in our cohort developed conjunctivitis during follow-up. This differs from the 10-IEI patients cohort previously reported, in which two patients experienced conjunctivitis: one in association with a mild immediate hypersensitivity-like reaction after the first injections, and the other occurring 3 months post treatment. Both events were successfully managed with temporary treatment interruption, and dupilumab was subsequently restarted [28].

In our cohort, one patient with IEI experienced VZV reactivation at month 18. The event was considered related to the underlying immunodeficiency, did not require interruption of dupilumab, and was not followed by further infectious complications. This observation is consistent with a previous where two skin infectious events were observed during follow-up—skin abscesses and new cutaneous warts—occurred in a patient with pre-existing recurrent HPV-related disease receiving concomitant immunosuppressive treatment. Both events were successfully managed and were considered not attributable to dupilumab [28]. Similarly, in a French IEI cohort, infectious adverse events occurred in 4/37 patients (10.8%), including herpes labialis, lower respiratory tract infections, and anal condyloma, none of which related to dupilumab [29]. Taken together, these observations suggest an infectious safety pattern in IEI patients treated with Dupilumab. Nevertheless, given the small number of patients, the heterogeneity of underlying immune defects, and the intrinsic susceptibility to infection in this population, continued individualized clinical and infectious-disease monitoring remains warranted.

Dupilumab was discontinued during follow-up in 6 of 127 patients (4.7%), all belonging to the polygenic AD cohort. In addition to the two discontinuations due to conjunctivitis, treatment was stopped for clinical remission (1/6), personal choice (1/6), inefficacy (1/6), and injection-site pain (1/6). Notably, the patient who discontinued treatment due to clinical remission experienced a relapse after a few months requiring treatment restart, which led to rapid and effective clinical control. The low proportion of our patients discontinuing for clinical remission is in accordance with other cohorts with polygenic AD. In the Dutch BioDay registry, which included 1286 patients with atopic dermatitis - 130 of whom in pediatric age - followed for up to 5 years, approximately 24% interrupted dupilumab, predominantly because of adverse events or ineffectiveness, while 0.8% stopped the treatment due to controlled disease [37]. In a UK pediatric real-world series, about 11% of children were able to discontinue dupilumab due to sustained remission, supporting the feasibility of treatment interruption in selected patients, although relapse after suspension is common and may require treatment resumption [34].

Our study has several limitations. Its observational design and reliance on routine clinical data may have introduced missingness and variability across centers. The number of patients with IEI was relatively small, and the IEI subgroup was heterogeneous, limiting the possibility of drawing conclusions for individual IEI entities. Indeed, because of the limited sample size in this subgroup, multivariable regression analyses should be considered exploratory and the estimated associations interpreted with caution. Nonetheless, these limitations are intrinsic to real-world studies and are counterbalanced by the strengths of multicenter recruitment, extended follow-up, and the inclusion of a clinically relevant, despite underrepresented, IEI subgroup.

Overall, our findings confirm and extend the evidence supporting dupilumab as an effective and safe treatment for severe pediatric atopic dermatitis. The study also adds valuable data for the IEI population, in whom diagnosis is often delayed and disease burden is high. Taken together with the registrative pediatric trials and the emerging IEI literature, our results support a broader role for dupilumab in tertiary pediatric practice, including in selected patients with IEI-associated severe atopic skin disease.