Beyond Eczema Control: Long-Term Outcomes of Dupilumab Therapy in Six Patients with Netherton Syndrome

Abstract

Netherton syndrome is a rare and severe genodermatosis caused by pathogenic variants in SPINK5, leading to epidermal barrier dysfunction, immune dysregulation, and prominent atopic manifestations. Therapeutic options remain limited, and long-term real-world data on biologic treatment are scarce. We report a retrospective two-center real-world case series of six patients with Netherton syndrome treated with dupilumab, with emphasis on long-term outcomes, safety, and clinical effects beyond eczema control. Five patients were managed at one dermatology referral center and one patient at a second center. Clinical data were collected retrospectively from medical records, including disease severity scores, pruritus, quality of life, genetic findings, comorbidities, treatment duration, adverse events, and additional clinically relevant observations. Dupilumab was initiated because of severe, chronic, and refractory inflammatory skin disease with intense pruritus and impaired quality of life. Follow-up ranged from 13 to 34 months. All patients achieved sustained, clinically meaningful improvement in inflammatory skin lesions, pruritus, and quality of life, although complete remission was not observed. Treatment was well tolerated, including in patients with recurrent infections, immunodeficiency-like features, severe food allergy, and a history of acute lymphoblastic leukemia. Additional observations included improvement in hair abnormalities and sweating in selected patients, reduced infectious burden, improved growth parameters, and absence of further anaphylactic episodes in one patient. These findings suggest that dupilumab may represent a valuable long-term therapeutic option for Netherton syndrome with prominent type 2 inflammatory features. Potential benefits beyond eczema control should be regarded as hypothesis-generating and require confirmation in larger multicenter studies.

Plain Language Summary

Netherton syndrome is a very rare inherited skin disease. It usually begins early in life and may cause red and scaly skin, abnormal hair, severe itching, allergies, high IgE levels, and recurrent infections. There is no approved targeted treatment specifically for this condition.

Dupilumab is a biologic medicine that blocks interleukin-4 and interleukin-13, two signals involved in type 2 inflammation. Since many patients with Netherton syndrome have strong allergic and atopic features, dupilumab may be a useful treatment option.

We describe six patients with Netherton syndrome treated with dupilumab in two dermatology centers. Follow-up ranged from 13 to 34 months. All patients had meaningful improvement in skin inflammation, itching, and quality of life, although complete disease clearance was not achieved. Treatment was well tolerated, including in patients with recurrent infections, severe allergies, immunodeficiency-like features, and a history of acute lymphoblastic leukemia.

Some additional improvements were also observed, including better hair growth, improved sweating, fewer infections, improved growth parameters, and no further anaphylactic episodes in one patient. These findings are promising but should be interpreted with caution because the study was retrospective and did not include a control group. Larger studies are needed to confirm these observations.

Introduction

Netherton syndrome (NS; OMIM #256500) is a rare and severe genodermatosis caused by pathogenic variants in the SPINK5 gene, which encodes lymphoepithelial Kazal-type-related inhibitor (LEKTI), a serine protease inhibitor essential for epidermal barrier integrity. The estimated incidence of NS is approximately 1:200,000. The classic clinical triad includes congenital ichthyosiform erythroderma, trichorrhexis invaginata (“bamboo hair”), and severe atopic diathesis. However, the clinical spectrum is broad and may also include markedly elevated serum IgE levels, eosinophilia, recurrent bacterial infections, food allergies, failure to thrive, impaired growth, enteropathy, renal complications, and neurodevelopmental abnormalities.¹

The pathogenesis of NS is complex and results from profound epidermal barrier dysfunction combined with immune dysregulation. LEKTI deficiency leads to uncontrolled activity of epidermal kallikrein-related peptidases, particularly KLK5, KLK7, and KLK14, which contribute to excessive desquamation, impaired corneodesmosome integrity, altered profilaggrin processing, and disruption of lipid-processing enzymes.² In addition to their structural effects on the epidermal barrier, kallikreins promote cutaneous inflammation through activation of protease-activated receptor 2 (PAR2) and downstream inflammatory pathways.³ These mechanisms result in increased production of epithelial and inflammatory mediators, including thymic stromal lymphopoietin (TSLP), IL-8, TNF-α, and cytokines associated with Th2, Th17, and Th22 immune responses.⁴

From a clinical perspective, the prominent atopic phenotype of NS is particularly important. Many patients present with severe eczema-like inflammation, intense pruritus, food allergy, asthma, allergic rhinitis, eosinophilia, and markedly elevated IgE levels. This inflammatory profile partially overlaps with severe atopic dermatitis and provides a rationale for targeting type 2 inflammation in selected patients. Nevertheless, NS is not simply a variant of atopic dermatitis. The underlying genetic barrier defect and protease-driven inflammation may explain why responses to anti-inflammatory treatment are often incomplete and why therapeutic outcomes remain heterogeneous.

Management of NS remains challenging. There is currently no approved targeted therapy specifically for this condition, and treatment is largely supportive, including emollients, topical anti-inflammatory agents, infection control, nutritional support, and, in selected cases, systemic immunomodulatory therapy. However, conventional systemic treatments may be limited by toxicity, infections, comorbidities, and only partial efficacy. Therefore, biologic therapies targeting key inflammatory pathways have gained increasing interest as potential therapeutic options in NS.

Dupilumab is a fully human monoclonal antibody that inhibits IL-4 and IL-13 signaling by binding to the IL-4 receptor alpha subunit (IL-4Rα), which is shared by type I and type II IL-4 receptor complexes. The drug has demonstrated high efficacy and a favorable safety profile in moderate-to-severe atopic dermatitis and other type 2 inflammatory diseases.^5,6 Given the prominent Th2-skewed immune activation observed in many patients with NS, dupilumab has emerged as a biologically plausible treatment option. Several case reports and small case series have suggested clinical benefit, particularly in reducing eczema-like inflammation, pruritus, and quality-of-life impairment.^7–23 However, the available evidence remains limited, and long-term real-world data are still scarce.

Here, we report a retrospective two-center real-world case series of six patients with Netherton syndrome treated with dupilumab, with particular emphasis on long-term clinical outcomes, pruritus, quality of life, safety, and additional observations beyond skin inflammation.

Methods

Study Design and Patients

This was a retrospective, two-center real-world case series including six patients with Netherton syndrome treated with dupilumab. Five patients were managed at one dermatology referral center, and one patient was treated at a second dermatology center. All patients had a diagnosis of Netherton syndrome established on the basis of characteristic clinical features, including congenital ichthyosiform erythroderma, atopic manifestations, and hair shaft abnormalities consistent with trichorrhexis invaginata, supported by genetic testing for pathogenic or likely pathogenic variants in the SPINK5 gene whenever available. Cases 1, 4, and 6 had biallelic pathogenic or likely pathogenic SPINK5 variants and were considered genetically confirmed. Cases 2 and 3 had a single reported heterozygous pathogenic or likely pathogenic SPINK5 variant, with the second variant not identified or not available in the original genetic report. Case 5 had no available genetic testing result and was diagnosed on the basis of characteristic clinical and trichoscopic findings.

Patients were included if they had received dupilumab for Netherton syndrome–associated severe inflammatory skin disease and had available clinical follow-up data. The decision to initiate dupilumab was made by the treating physicians because of severe, chronic, and refractory skin involvement, intense pruritus, impaired quality of life, and insufficient disease control with previous topical and/or systemic therapies. The duration of dupilumab treatment and clinical follow-up ranged from 13 to 34 months.

Data Collection

Clinical data were collected retrospectively from medical records. The following variables were extracted: sex, age at disease onset, age at diagnosis, age at dupilumab initiation, clinical phenotype, comorbidities, history of recurrent infections, allergic manifestations, previous treatments, genetic findings, dupilumab dosing regimen, duration of follow-up, treatment response, and adverse events.

Disease severity was assessed using available clinical outcome measures recorded during routine care, including the Eczema Area and Severity Index (EASI), Scoring Atopic Dermatitis (SCORAD), body surface area involvement (BSA), Investigator Global Assessment (IGA), Dermatology Life Quality Index (DLQI), Children’s Dermatology Life Quality Index (cDLQI), and peak pruritus numeric rating scale (ppNRS) or visual analogue scale (VAS), depending on patient age and local clinical practice. Laboratory parameters, including total IgE levels and eosinophil counts, were analyzed when available. Additional clinically relevant observations, such as changes in hair growth, sweating, infectious burden, allergic manifestations, growth parameters, and treatment tolerability, were also recorded.

Treatment

Dupilumab was administered according to age, body weight, regulatory approval status, and clinical judgement of the treating physicians. In pediatric patients, dosing regimens were adapted to body weight and local reimbursement/therapeutic program requirements, while adult patients received the standard adult regimen. Concomitant emollient therapy and topical anti-inflammatory treatment were continued as needed. In selected cases, previous systemic therapy was tapered during dupilumab treatment according to clinical response. Baseline demographic, genetic, phenotypic, and clinical characteristics of the patients are summarized in Table 1. Dupilumab treatment regimens, treatment duration, clinical outcomes, additional observations during therapy, treatment-related adverse events and concomitant systemic treatments during dupilumab therapy and their modifications were recorded on a patient-by-patient basis and are presented in Table 2.

Table 1.

Baseline Demographic, Genetic, Phenotypic, and Clinical Characteristics of Patients with Netherton Syndrome Treated with Dupilumab

	Sex M/F	Age of Diagnosis	Age of Dupilumab Initiation (Years)	Genetic Findings	Phenotype ILC/CIE	Major Comorbidities	Atopic/Allergic Features	Previous Treatment
1.	M	3 years	15	Compound heterozygous pathogenic SPINK5 variants: p.Arg217Ter and p.Cys510Ter	CIE	Recurrent urinary, respiratory and bacterial skin infections; two episodes of staphylococcal bacteremia; growth retardation/low weight gain; epilepsy; glucosuria with normal blood glucose	Severe atopic manifestations; multiple food and inhalant allergies; eosinophilia; elevated total IgE; elevated specific IgE to multiple food allergens	Emollients, TCS, TCI, oral antihistamines, frequent systemic antibiotics; acitretin discontinued after a single dose because of disease exacerbation
2.	M	5 months	12	Heterozygous likely pathogenic SPINK5 splice-site variant: c.1431–12G>A; second variant not identified/not available	CIE	Recurrent bacterial skin, urinary tract and respiratory infections; right-sided nephrocalcinosis; epilepsy	Allergic rhinitis; bronchial asthma; polyvalent food and inhalant allergy; eosinophilia; elevated IgE	Emollients, TCS, systemic antibiotics, hydrocortisone, intravenous immunoglobulins
3.	M	1 year	14	Heterozygous pathogenic SPINK5 variant, reported in the original genetic result as c.2468insA; second variant not identified/not available	ILC	No major non-atopic comorbidities reported	Extensive food and inhalant sensitization; severe pruritus; chronic atopic dermatitis–like erythroderma	Emollients, TCS, intermittent systemic corticosteroids, long-term acitretin
4.	F	1 year	6	Homozygous pathogenic SPINK5 nonsense variant: c.1530C>A, p.Cys510Ter	CIE	Neonatal sepsis; recurrent bacterial, viral and fungal infections; chronic otitis externa; suspected immunodeficiency requiring immunoglobulin substitution; severe failure to thrive	Marked eosinophilia; extremely elevated total IgE; multiple food and inhalant sensitizations; cow’s milk-induced anaphylaxis	Emollients, TCS, systemic anti-infective therapy, intravenous immunoglobulins, acitretin discontinued because of disease exacerbation, methotrexate as bridging therapy
5.	M	3 months	21	Genetic testing result not available	CIE	History of acute lymphoblastic leukemia in remission after intensive oncological treatment	Bronchial asthma; food allergy; latex hypersensitivity	Emollients, TCS; conventional systemic immunosuppressive therapy avoided because of previous acute lymphoblastic leukemia
6.	F	5 years	6 years and 10 months	Homozygous deletion of SPINK5 exons 1–5, likely pathogenic	CIE	Aortic valve stenosis requiring cardiac surgery; ischemic stroke in the course of PRES; clotting abnormalities; hypopituitarism with somatotropin deficiency; short stature; iatrogenic adrenal insufficiency; pancreatitis; EPEC gastrointestinal infection; recurrent sepsis	Respiratory allergy to house dust mites and birch pollen	Emollients, TCS, acitretin discontinued because of elevated liver enzymes and severe skin adverse effects

Abbreviations: M, male; F, female; SPINK5, Serine Peptidase Inhibitor, Kazal Type 5; ILC, ichthyosis linearis circumflexa; CIE, congenital ichthyosiform erythroderma; PRES, posterior reversible encephalopathy syndrome; TCS, topical corticosteroids; TCI, topical calcineurin inhibitors; EPEC – enteropathogenic Escherichia coli.

Table 2.

Dupilumab Treatment Regimens, Clinical Outcomes, Additional Observations, and Safety in Patients with Netherton Syndrome

No.	Dupilumab Treatment Duration (Months)	Dupilumab Regimen	Severity Score Before Treatment	Severity Score Last Follow-Up	Reduction in Severity Score	DLQI/cDLQI Before Treatment	DLQI/cDLQI Last Follow-Up	ppNRS Before Treatment	ppNRS Last Follow-Up	Additional Observations During Dupilumab Therapy	Concomitant Systemic Treatment During Dupilumab Therapy	Treatment-Related Adverse Events
1.	28	Loading dose 400 mg followed by 200 mg s.c. every 2 weeks	EASI 41.4	EASI 14.0	66.2%	21	6	10/10	5/10	Partial hair regrowth; improved sleep; reduced infection frequency	None	None
2.	32	Loading dose 400 mg followed by 200 mg s.c. every 2 weeks	EASI 37.2	EASI 17.6	52.7%	29	13	10/10	4/10	Partial hair regrowth with increased hair density and shaft length; reduction in bamboo hair structures; improved sweating; improved sleep; reduced infection frequency	None	None; mild skin infections during follow-up
3.	13	Loading dose 400 mg followed by 200 mg s.c. every 2 weeks	EASI 48	EASI 7.8	83.8%	15	7	10/10	5/10	No additional extracutaneous observations reported	None	None
4.	31	Loading dose 300 mg at weeks 0 and 2, followed by 300 mg s.c. every 4 weeks, after 12 months 300 mg every 2 weeks	EASI 36.4	EASI 14.4	60.4%	22	6	10/10	4/10	No further anaphylactic episodes; reduced infection burden; improved growth parameters	Methotrexate as bridging therapy; subsequently reduced during dupilumab treatment	None; herpes labialis and persistent external ear P. aeruginosa colonization during follow-up
5.	34	Loading dose 600 mg, followed by 300 mg s.c. every 2 weeks	EASI 40.8	EASI 13.7	66.4%	24	3	10/10	4/10	No additional extracutaneous observations reported	None	None
6.	24	Loading dose 400 mg followed by 200 mg s.c. every 2 weeks	SCORAD 99	SCORAD 57	42.4%	26	13	10/10	3/10	Reduced infection frequency	None	None

Notes: Additional observations were recorded retrospectively from medical charts and should be interpreted as exploratory, hypothesis-generating findings. They do not imply definite causal attribution to dupilumab. Only events considered by the treating physicians as related to dupilumab were classified as treatment-related adverse events. Infectious episodes or colonization occurring during follow-up were reported separately and were not considered definitively attributable to dupilumab. No conversion between EASI and SCORAD was performed. EASI was available in five patients and SCORAD in one patient.

Abbreviations: DLQI, Dermatology Life Quality Index; cDLQI, Children’s Dermatology Life Quality Index; ppNRS, peak pruritus Numeric Rating Scale; EASI, Eczema Area and Severity Index; SCORAD, Scoring Atopic Dermatitis.

Literature Review

To place our findings in the context of current evidence, a literature review was performed using PubMed/MEDLINE. The search terms included “Netherton syndrome”, “dupilumab”, “IL-4”, “IL-13”, “biologic therapy”, and “atopic dermatitis”. Relevant case reports, case series, and review articles describing the use of dupilumab in patients with Netherton syndrome were included. Additional references were identified by screening the reference lists of selected articles. Particular attention was paid to patient age, treatment duration, clinical response, effects on pruritus and quality of life, extracutaneous manifestations, and safety.

Ethical Considerations

The study was conducted in accordance with the principles of the Declaration of Helsinki. Because this was a retrospective descriptive study based exclusively on anonymized data obtained from routine clinical care, approval by the Bioethics Committee of the Medical University of Silesia in Katowice, Poland, was not required under institutional regulations. No additional diagnostic or therapeutic procedures were performed for the purpose of this analysis. Written informed consent for publication of clinical data and clinical images was obtained from adult patients or from parents/legal guardians of pediatric patients.

Results

The baseline demographic, genetic, phenotypic, and clinical characteristics of all six patients are summarized in Table 1. Dupilumab treatment regimens, treatment duration, clinical outcomes, additional observations during therapy, and treatment-related adverse events are presented in Table 2. Individual cases are described below.

Case Presentation

Case 1

The first patient was a male with Netherton syndrome diagnosed at the age of 3 years on the basis of congenital ichthyosiform erythroderma, trichorrhexis invaginata, severe atopic manifestations, recurrent infections, and pathogenic SPINK5 variants p.Arg217Ter and p.Cys510Ter. His early course was complicated by recurrent urinary, respiratory, and bacterial skin infections, including two episodes of staphylococcal bacteremia, as well as growth retardation, epilepsy, multiple allergies, eosinophilia, and elevated IgE levels.

Dupilumab was initiated at the age of 15 years because of severe, refractory inflammatory skin disease with generalized involvement, intense pruritus, and marked impairment of quality of life. Clinical improvement was observed within the first month. During follow-up, the patient achieved sustained partial improvement, with substantial reduction in EASI, pruritus, and cDLQI scores. Additional observations during therapy included partial hair regrowth, improved sleep, and reduced frequency of infections. Periodic exacerbations occurred, but the response remained clinically meaningful. Treatment has been continued for 28 months without adverse events.

Case 2

The second patient was a male with erythroderma, scaling, and facial and limb edema present from birth. The diagnosis of Netherton syndrome was supported by trichoscopy showing trichorrhexis invaginata and by detection of a probably pathogenic SPINK5 variant, c.1431–12G>A. His clinical course was characterized by recurrent bacterial skin, urinary tract, and respiratory infections, as well as allergic rhinitis, bronchial asthma, nephrocalcinosis, epilepsy, polyvalent allergy, eosinophilia, and elevated IgE levels.

Dupilumab was started at the age of 12 years due to severe congenital ichthyosiform erythroderma, generalized skin involvement, intense pruritus, and severely impaired quality of life. Improvement in skin inflammation and pruritus was noted within the first month and remained stable during long-term follow-up. In addition to improvement in skin disease activity, trichoscopy showed increased hair density and shaft length with a marked reduction in bamboo hair structures, and the patient reported improved sweating. Dupilumab has been continued for 32 months. No treatment-related adverse events were reported; mild disease exacerbations and occasional mild skin infections occurred during follow-up.

Case 3

The third patient was a 14-year-old male with genetically confirmed Netherton syndrome caused by a heterozygous pathogenic SPINK5 variant, reported in the original genetic result as c.2468insA. He had chronic severe atopic dermatitis–like erythroderma with ichthyosiform lesions, recurrent exacerbations, severe pruritus, and extensive food and inhalant sensitization. Trichoscopic examination showed trichorrhexis invaginata, while dermoscopy demonstrated features consistent with ichthyosis linearis circumflexa (Figure 1). Previous treatment with topical corticosteroids, intermittent systemic corticosteroids, and long-term acitretin provided insufficient disease control.

Figure 1.

Trichoscopic and dermoscopic findings in Case 3. (A) Trichoscopic examination showing trichorrhexis invaginata (“bamboo hair”), a characteristic hair shaft abnormality in Netherton syndrome. (B) Dermoscopic image showing erythematous background with superficial scaling corresponding to ichthyosis linearis circumflexa.

Dupilumab was introduced in March 2025 because of severe persistent inflammation and pruritus. The response was rapid and pronounced, with marked improvement in EASI and cDLQI after 4 months. During 13 months of follow-up, the patient maintained partial clinical improvement, although mild erythematous lesions and ichthyosis linearis circumflexa persisted. Treatment was well tolerated, with no significant adverse events.

Case 4

The fourth patient was a female with severe Netherton syndrome presenting from birth with generalized erythroderma and ichthyosiform scaling. Her early course was complicated by neonatal sepsis, recurrent bacterial, viral, and fungal infections, chronic otitis externa, marked eosinophilia, extremely elevated IgE levels, multiple food and inhalant sensitizations, recurrent anaphylactic reactions after cow’s milk exposure, suspected immunodeficiency requiring immunoglobulin substitution, and severe failure to thrive. The diagnosis was supported by trichorrhexis invaginata and pathogenic variants in SPINK5.

Because of severe refractory disease, methotrexate was introduced as bridging therapy, followed by dupilumab at the age of 6 years. Clinical improvement was observed within the first 3 months, with reduction in inflammatory skin lesions, pruritus, cDLQI, and total IgE levels. Due to partial response, the dupilumab dosing interval was shortened, allowing reduction of methotrexate. During more than 2.5 years of follow-up, no further episodes of anaphylaxis occurred, infectious burden decreased, and growth parameters improved. One severe post-influenza exacerbation occurred during the third year of therapy, but dupilumab was continued. No significant treatment-related adverse events were observed.

Case 5

The fifth patient was a male with Netherton syndrome presenting from birth with generalized erythroderma and ichthyosiform scaling, later accompanied by bronchial asthma, food allergy, and latex hypersensitivity. The diagnosis was supported by trichoscopic findings consistent with Netherton syndrome; genetic testing result was not available. At the age of 15 years, he was diagnosed with acute lymphoblastic leukemia and underwent intensive oncological treatment, after which complete remission was achieved.

After completion of oncological therapy, he was referred because of persistent severe Netherton syndrome–associated skin disease. Conventional systemic immunosuppressive therapies were considered contraindicated due to the history of malignancy, and dupilumab was initiated at the age of 21 years. During 34 months of follow-up, the patient achieved sustained improvement in skin inflammation, pruritus, and quality of life. Clinical improvement in trunk erythema and inflammatory skin involvement is shown in Figure 2. Treatment was well tolerated, with no significant adverse events, and dupilumab is being continued.

Figure 2.

Clinical course of Case 5 during dupilumab therapy. (A) Baseline clinical presentation before dupilumab initiation, showing diffuse erythema and inflammatory skin involvement of the trunk and upper limbs. (B) Clinical presentation after 34 months of dupilumab therapy, showing partial but clinically meaningful improvement in erythema and inflammatory skin lesions. The patient remained on dupilumab treatment with sustained improvement in pruritus and quality of life.

Case 6

The sixth patient was an 8-year-old girl with severe Netherton syndrome characterized by erythroderma, generalized dryness, erythematous-exfoliative lesions, absence of terminal scalp hair, and trichoscopic features of bamboo hair. Whole-exome sequencing identified a homozygous deletion involving exons 1–5 of SPINK5, which, to the best of our knowledge, has not previously been reported in the medical literature or registered in ClinVar and was considered highly likely to be pathogenic. Her medical history was complex and included aortic valve stenosis requiring surgery, ischemic stroke in the course of posterior reversible encephalopathy syndrome, clotting abnormalities, hypopituitarism with somatotropin deficiency, short stature, iatrogenic adrenal insufficiency, respiratory allergy, pancreatitis, gastrointestinal infection, and recurrent sepsis.

Previous treatment included emollients, topical corticosteroids, and acitretin, which was discontinued because of adverse effects. Dupilumab was initiated at the age of 6 years and 10 months due to severe generalized skin disease, intense pruritus, and markedly impaired quality of life. During 24 months of follow-up, skin disease stabilized, with substantial improvement in SCORAD, cDLQI, and pruritus. Clinical improvement in generalized erythema and inflammatory skin involvement is shown in Figure 3. Treatment has been well tolerated, with no adverse events, and is being continued as long-term therapy.

Figure 3.

Clinical course of Case 6 during dupilumab therapy. (A) Baseline clinical presentation before dupilumab initiation, showing generalized erythema and inflammatory skin involvement. (B) Clinical presentation after 24 months of dupilumab therapy, showing stabilization of skin disease and reduction in inflammatory activity. Treatment was associated with improvement in SCORAD, cDLQI, and pruritus and was well tolerated.

Discussion

Netherton syndrome (NS) is a rare and severe genodermatosis in which congenital epidermal barrier dysfunction is accompanied by marked immune dysregulation and a prominent atopic phenotype. Loss-of-function variants in SPINK5 result in LEKTI deficiency, excessive kallikrein activity, impaired barrier integrity, and downstream activation of inflammatory pathways, including Th2- and Th17-related responses. This complex pathophysiology provides a rationale for biologic therapies targeting dominant inflammatory axes, while also explaining why clinical responses may remain incomplete in some patients.

In this retrospective two-center real-world case series, we describe six patients with NS treated with dupilumab, with follow-up ranging from 13 to 34 months. To our knowledge, this represents one of the larger real-world series evaluating long-term dupilumab therapy in NS. The main finding of our study is that dupilumab provided sustained and clinically meaningful improvement in all patients, particularly with regard to inflammatory skin lesions, pruritus, and quality of life. Importantly, these benefits were observed in patients with severe baseline disease, extensive erythroderma, intense pruritus, multiple atopic comorbidities, recurrent infections, and complex systemic histories.

Our observations are consistent with the growing body of evidence suggesting that dupilumab may be beneficial in NS-associated inflammatory skin disease. Most published case reports and small case series describe improvement in eczema-like inflammation, pruritus, sleep disturbance, and quality of life following IL-4/IL-13 pathway inhibition.^7–23 Huang et al reported effective control of inflammation and pruritus in a pediatric patient, with marked improvement in erythroderma and quality of life.¹¹ Similarly, Martin-García et al described two sisters with NS who achieved substantial improvement in skin inflammation and atopic symptoms, with good tolerability during follow-up.²⁴ Our series expands these observations by providing longer-term real-world data in a group of patients with heterogeneous and severe clinical phenotypes.

A key observation from our cohort is that treatment responses were not complete, but they were clinically meaningful. Although none of the patients achieved full disease remission, all experienced improvement in disease severity, pruritus, and/or quality of life. This point is particularly important in NS, where the therapeutic goal may not necessarily be complete clearance, but rather durable reduction of inflammation, pruritus, infections, sleep disturbance, and functional impairment. Partial improvement may be especially relevant in children, in whom chronic inflammation, pruritus, recurrent infections, nutritional compromise, and impaired growth may have long-term developmental consequences. Therefore, even moderate reductions in clinical scores and symptom burden should be regarded as meaningful treatment outcomes in this population.

The heterogeneity of response observed in our patients is also consistent with previous reports. Although many patients with NS respond favorably to dupilumab, limited, partial, or temporary responses have also been described.^25–28 Aktaş et al reported a temporary response, with improvement in eczema but limited effect on ichthyosis linearis circumflexa lesions.²⁹ This variability likely reflects the complex biology of NS. While IL-4/IL-13 blockade may effectively reduce Th2-driven inflammation, it does not directly correct the underlying genetic barrier defect, abnormal kallikrein activity, or keratinization abnormalities. This may explain why erythema, pruritus, and eczematous inflammation may improve more substantially than ichthyosis linearis circumflexa or hair shaft abnormalities.

The possible contribution of non-Th2 pathways should also be considered. Recent reports have highlighted the role of IL-17-mediated inflammation in NS, supported by clinical improvement observed with secukinumab, an IL-17A inhibitor.^30–32 These findings suggest that NS should not be viewed exclusively as a Th2-driven disease. Rather, it likely involves a dynamic interplay between epidermal protease dysregulation, barrier disruption, microbial factors, and Th2-, Th17-, and Th22-related immune responses. This broader immunologic background may have therapeutic implications. In selected patients with insufficient response to dupilumab, targeting IL-17 or other inflammatory pathways may represent a potential alternative or future strategy, although evidence remains very limited.

An important strength of our series is the inclusion of patients with complex comorbidities and high baseline clinical risk. Several patients had recurrent bacterial, viral, or fungal infections, extensive atopic sensitization, severe food allergy, asthma, or immunodeficiency-like features. One patient had a history of acute lymphoblastic leukemia, which limited the use of conventional systemic immunosuppressive therapies. In this context, dupilumab appeared to be a particularly valuable option because of its targeted mechanism of action and favorable safety profile. Across our cohort, treatment was well tolerated, and no significant treatment-related adverse events were observed during long-term follow-up. This is consistent with previous reports, in which dupilumab was generally well tolerated in NS, with only occasional adverse events such as conjunctivitis or bacterial superinfection.^6,23–25,29

Beyond improvement in skin inflammation and pruritus, several additional clinical observations were recorded during dupilumab therapy. In selected patients, we observed improvement in hair growth and hair shaft abnormalities, better sweating, reduced infectious burden, improvement in growth parameters, and fewer severe allergic events, including absence of further anaphylactic episodes in one patient despite accidental exposure to cow’s milk proteins. Similar extracutaneous or adnexal improvements have been reported previously, including hair regrowth, reduction in bamboo hair, normalization of sweating, improved heat tolerance, and reduced nail dystrophy.²⁵ These observations are intriguing and may suggest that reducing chronic type 2 inflammation and improving epidermal barrier function can have broader clinical consequences in NS.

However, these findings should be interpreted cautiously. The retrospective and uncontrolled design of our study does not allow causal attribution of reduced infections, improved growth, improved sweating, hair regrowth, or reduced allergic events directly to dupilumab. These outcomes may have been influenced by age, supportive care, nutritional interventions, infection prevention, changes in concomitant medications, and natural disease variability. Nevertheless, such observations are clinically relevant and should be systematically captured in future studies, as conventional dermatologic scores may not fully reflect the broader burden of NS or the full range of treatment benefits.

The timing of dupilumab initiation may also be important. A recent report describing dupilumab treatment in a 9-week-old infant with NS showed rapid and sustained control of allergic inflammation, profound symptom improvement, normalization of the skin microbiome, and favorable effects on somatic and psychomotor development.⁶ These data raise the possibility that earlier control of severe inflammation and barrier dysfunction could modify the clinical trajectory of NS. Our findings support this concept, particularly in pediatric patients with severe pruritus, recurrent infections, failure to thrive, and marked impairment of quality of life. However, the optimal timing, dosing regimen, and long-term safety of early dupilumab initiation in infants and young children with NS remain to be established.

Our study has several limitations. First, the retrospective design and small sample size limit the strength of conclusions. However, given the rarity of NS, even small real-world series provide clinically valuable information. Second, the study included patients from two centers, and clinical assessment was based on data collected during routine care rather than according to a standardized prospective protocol. As a result, not all outcome measures were available for all patients, and different severity scores, including EASI, SCORAD, DLQI/cDLQI, BSA, IGA, ppNRS, and VAS, were used depending on patient age and local practice. Third, laboratory parameters such as IgE and eosinophil counts were not uniformly available at all time points. Finally, the absence of a control group prevents assessment of the relative contribution of dupilumab compared with natural disease fluctuation, supportive treatment, or concomitant therapies.

Despite these limitations, our case series adds to the current evidence by providing long-term real-world data on dupilumab therapy in six patients with NS. The results suggest that dupilumab may offer sustained and clinically meaningful benefit, especially in patients with prominent atopic inflammation and severe pruritus. The treatment appeared safe even in clinically complex patients, including those with recurrent infections, immunodeficiency-like features, and a history of hematologic malignancy. Moreover, the potential effects beyond eczema control, including improvement in hair, sweating, infectious burden, growth, and allergic manifestations, deserve further investigation in larger multicenter cohorts.

Conclusion

Dupilumab may represent a valuable therapeutic option for patients with Netherton syndrome and prominent type 2 inflammatory features. In our retrospective two-center real-world case series of six patients, long-term dupilumab therapy was associated with sustained improvement in inflammatory skin lesions, pruritus, and quality of life, with a favorable safety profile over 13 to 34 months of follow-up. Although responses were partial and complete remission was not achieved, the observed clinical benefits were meaningful in the context of a severe, chronic, and difficult-to-treat genodermatosis.

Several broader clinical observations were recorded during dupilumab therapy, including possible improvement in hair abnormalities, sweating, infection burden, growth parameters, and allergic manifestations. Given the retrospective design, small sample size, lack of a control group, and predominantly qualitative nature of these observations, they should be interpreted as exploratory and hypothesis-generating rather than as proven treatment effects. Larger, standardized, multicenter studies and prospective registries are needed to systematically assess these outcomes, define predictors of response, and determine the long-term place of dupilumab among emerging biologic treatment strategies for Netherton syndrome.

Disclosure

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.