Efficacy of dupilumab for controlling severe atopic dermatitis in a patient with hyper-IgE syndrome

TO THE EDITOR

Autosomal dominant (AD) hyper-IgE syndrome (HIES) is caused by STAT3 dominant-negative mutations, whereas loss-of-function mutations of ZNF341, which governs STAT3 activity through transcriptional mechanisms, or DOCK8 cause autosomal recessive (AR) HIES^1,2. HIES patients present early-onset allergy, including features of severe atopic dermatitis, thought to result at least in part from increased Th2 cytokines. Topical corticosteroids and calcineurin inhibitors, associated with oral antihistamines are the main treatment, whereas immunosuppressive agents are not recommended given a higher risk of infection.

We report the successful treatment of severe atopic dermatitis in a 48-year-old patient with AR ZNF341 deficiency. This patient’s major complaint was chronic, severe, intractable, generalized pruritus. She had confluent papules on her shoulders, flank, abdomen and thighs, multiple excoriated, achromic and atrophic lesions, predominantly on her scalp, arms, legs and abdomen, fissures and lichenification of the inner elbows, and atrophic scars due to life-long scratching (Figure 1A–E). She applied ultra-high potency class I topical corticosteroids daily, and topical tacrolimus, which were ineffective. Standardized questionnaires revealed severe atopic dermatitis (SCORAD score of 85.5/103), with a profound effect on quality of life (DLQI score of 22/30).

Figure 1.

(A-E) Comparative photographs of the patient’s skin lesions, taken before dupilumab initiation (upper panels) and after one year of treatment (lower panels). From left to right, photographs of the patient’s head, forearms, left shoulder, left thigh and right flank. (F-G) Standardized SCORAD (Scoring Atopic Dermatitis) and DLQI (Dermatology Life Quality Index) scores at dupilumab initiation and at multiple time points on treatment. (H) Serum IgE levels before dupilumab initiation (mean of 7 separate samples) and at multiple time points on treatment. K-L) Levels of cytokines and chemokines in the patient’s serum, determined by LUMINEX methods, at dupilumab initiation and after six and 12 months on treatment. The black line represents the mean value for 10 healthy non-atopic individuals tested in parallel at a single time point. The dot lines represent the range of the values obtained for the 10 healthy individuals. The values are given in pg/ml. TARC: Thymus- and activation-regulated chemokine; MDC: Macrophage-derived chemokine.

Dupilumab, which blocks the alpha chain of the interleukin-4 receptor, was recently licensed for the treatment of severe atopic dermatitis in adults and in adolescents from the age of 12 years in most countries^3,4. Our patient received an initial dose of 600 mg dupilumab, followed by subcutaneous injections of 300 mg dupilumab at two-week intervals. At each visit, she completed the DLQI and SCORAD questionnaires, and gave a serum sample.

The patient reported rapid improvement after three injections, with strong decreases in DLQI and SCORAD scores (Figure 1F,G). She stopped applying topical treatment after three months. Continuous treatment during one year led to complete response and was well tolerated. No further scratching-induced lesions were observed. The papulonodular lesions progressively disappeared, as did skin inflammation in previously excoriated areas (Figure 1A–E). This improvement was accompanied by a progressive decrease in total serum IgE, and allergen-specific IgE (Figure 1H, and Supplemental Figure 1). Likewise, the serum concentrations of chemokines involved in leukocyte trafficking in the skin including Th2-driven chemokines like TARC and Eotaxin-3, and inflammatory cytokines normalized over time (Figure 1 I–K).

This observation suggests that Th2-mediated IL-4 and/or IL-13 signaling plays a central role in atopic dermatitis in HIES. Dupilumab should be considered for patients with AD STAT3 or AR ZNF341 deficiency, and possibly other primary immunodeficiencies in which Th2-mediated atopic disorders are suspected or have been demonstrated, such as AR DOCK8 deficiency and X-linked WAS deficiency⁵.

Supplementary Material

1629459_Sup1

Supplemental figure Serum allergen-specific IgE levels before (black bars) and 4 months (red bars) after dupilumab initiation, measured by ImmunoCAP ISAC chip. ISU-E: ISAC standardized unit for IgE.