Dupilumab in Hyper-IgE Syndrome: A Case Series of Pediatric Patients

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Hyper-IgE syndrome (HIES) encompasses a group of genetic disorders characterized by elevated serum immunoglobulin E (IgE) levels, severe atopic dermatitis, and recurrent infections. The condition can be classified into autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES), with distinct genotypes influencing clinical presentation and inheritance patterns.¹ Key genetic mutations involved include STAT3 and IL6ST for AD-HIES, and PGM3, DOCK8, TKY2, and ZNF341 for AR-HIES. Common dermatologic manifestations typically emerge in infancy, presenting as severe atopic dermatitis, predominantly affecting the face and scalp.

Recent advances in the treatment of atopic dermatitis include dupilumab, a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling. Approved for children aged 6 months and older, dupilumab has shown promise in managing atopic dermatitis; however, its role in the context of HIES has been less explored.² A recent case series presented3 pediatric patients with various genetic forms of HIES, highlighting the successful use of dupilumab in managing their dermatologic and associated non-cutaneous symptoms.³

Patient 1: 8-Year-Old Boy With AD-HIES

The first case presented was that of an 8-year-old male with AD-HIES due to a STAT3 mutation presented with extensive eczema covering over 50% of his body surface area (BSA). He reported a history of recurrent bacterial skin infections and respiratory issues, including asthma. Following the initiation of dupilumab, he received a loading dose of 400 mg, followed by 200 mg biweekly. After 2months, researchers said his dermatitis improved significantly, with BSA involvement reducing to 30% and an investigator's global assessment (IGA) score of 2. Over 3 years, the case series statedhe achieved a stable, durable response with minimal skin involvement (<2% BSA) and no respiratory exacerbations or cutaneous infections.

Patient 2: 8-Year-Old Girl With AD-HIES

Next, researchers presented the case of an 8-year-old female with AD-HIES, also due to a STAT3 mutation, who presented with severe eczematous plaques affecting over 50% of her BSA. Diagnosed with HIES at 1 year of age, her medical history included chronic otitis externa but no significant respiratory infections. After starting dupilumab with the same dosing regimen as patient 1, researchers stated she experienced rapid improvement, with BSA involvement decreasing to <2% and an IGA score of 1 within nine months. Notably, her recurrent ear infections diminished significantly, highlighting the systemic benefits of dupilumab in managing HIES-related complications.

Patient 3: 2-Year-Old Girl with AR-HIES

The third case presented was that of a 2-year-old female with AR-HIES due to biallelic ZNF341 mutations presented with severe atopic dermatitis, extensive skin involvement (>70% BSA), and a history of recurrent cutaneous infections. Her treatment commenced with dupilumab at a dose of 300 mg every 4 weeks. After 3 months, clinicians adjusted her dosing to 200 mg biweekly due to the severity of her condition. Within 6 months, researchers reported her skin condition improving dramatically, with a reduction in BSA involvement to <10% and complete resolution of pruritus. Although she experienced a temporary flare during travel, resuming dupilumab therapy allowed her to regain stability, with minimal skin involvement and no additional infections.

Discussion

The successful application of dupilumab in these 3 pediatric patients with HIES illustrated to researchers its potential to improve both cutaneous and systemic manifestations of the syndrome. HIES, characterized by a deficiency in Th17 lymphocytes and a skewed immune response towards Th2 inflammation, results in chronic skin infections and atopic dermatitis. Dupilumab targets IL-4 and IL-13 pathways, effectively down regulating the Th2 response and potentially promoting Th1 and Th17 differentiation. Researchers stated this mechanism may explain the reduction in both skin and respiratory infections, as well as the observed improvements in atopic dermatitis severity.

While existing literature has documented dupilumab's efficacy in atopic dermatitis, this case series contributes insights into its long-term use in children with HIES. Researchers stated the presented cases demonstrate not only sustained clearance of skin symptoms but also a significant reduction in associated complications, such as cutaneous and pulmonary infections. Importantly, this is the first report of a patient with AR-HIES caused by ZNF341 mutations treated with dupilumab, expanding the therapeutic horizons for this challenging condition.

Conclusion

The case series stated that dupilumab offers a promising therapeutic option for pediatric patients with HIES, effectively managing severe atopic dermatitis and reducing associated infections. Given the potential for sustained improvement in both dermatologic and systemic manifestations, researchers suggested that further clinical trials are warranted to evaluate long-term outcomes and establish guidelines for dupilumab use across the spectrum of HIES variants.

References

1. Olbrich H, Sadik CD, Ludwig RJ, et al. Dupilumab in inflammatory skin diseases: A systematic review. Biomolecules. 2023;13(4):634. Published 2023 Mar 31. doi:10.3390/biom13040634
2. Harb H, Chatila TA. Mechanisms of dupilumab. Clin Exp Allergy. 2020;50(1):5-14. doi:10.1111/cea.13491
3. Dick JK, Boull C, Pozos TC, et al. Improvement in atopic dermatitis and recurrent infection with dupilumab in children with distinct genetic types of hyper-IgEsyndrome: A case series and literature review. Pediatr Dermatol. 2024. doi: 10.1111/pde.15780