Dupilumab reduces inflammation and restores the skin barrier in patients with atopic dermatitis

To the Editor, The pathogenesis of atopic dermatitis (AD), a common chronic inflammatory skin disease, is based on a genetic predisposition that determines both skin barrier function and type 2 immune reaction.1,2,S1–S4 Type 2 cytokines may further impair the epidermal barrier and trigger AD inflammation.1 Therapy with dupilumab that inhibits the action of interleukin (IL)-4 and IL-13 by blocking the shared receptor results in a rapid improvement of symptoms, clinical signs, and quality of life in AD patients.3,S5–S11 Transcriptome analyses of skin samples suggest that it affects mRNA expression of genes related to type 2 inflammation, T helper (Th)17/Th22 pathways, dendritic cells, epidermal barrier, and lipid metabolism.4,5,S12–S13 This study aimed at assessing the efficacy and safety of dupilumab therapy in patients with AD referred to a tertiary center and at investigating the effect of dupilumab on both inflammation and epidermal barrier by applying immunofluorescence techniques. It has been approved by the Ethics Committee of the Canton Bern. In this retrospective study, data of 34 patients with AD under dupilumab therapy (10 females, mean age: 40.1 ± 12.4 years) were included (Table S1). All patients had severe AD with a mean SCORAD of 64.2 ± 18.5 at baseline. Patients were treated with a loading dose of 600 mg dupilumab followed by 300 mg every 2 weeks. In our patient cohort, dupilumab therapy resulted in a significant improvement of clinical signs and symptoms (Table S2). The percentage of patients achieving physician global assessment (PGA) 0–1 was 47% after 4 months and remained unchanged over time. Remarkably, our results are comparable with those of clinical and real-life studies, although exclusively patients with severe AD were eligible to get dupilumab therapy.S5–S11,S14,S15 Already one month after initiating dupilumab therapy, 60% reported that AD did not or minimally affected their quality of life (Figure 1). All ten patients with initial overlapping immunosuppressives plus dupilumab therapy were able to stop immunosuppressives during the first 3–4 months (Table S3). When PGA 0–1 was achieved and maintained for 2–3 months, we attempted to increase the intervals between injections. As a result, 12 patients were able to apply dupilumab every 3–4 weeks without loss of efficacy. Overall, dupilumab therapy was well-tolerated. The frequency of dupilumab-associated conjunctivitis was 32%. One AD patient with concomitant keratoconus discontinued therapy after developing severe keratoconjunctivitis. A longitudinal analysis revealed that worsening of SCORAD or DLQI was associated with AD onset in adulthood, presence of specific comorbidities, severe AD, and sleep loss (Table S4). From eight patients responding to dupilumab without concomitant immunosuppressive therapy, specimens of AD skin taken before and 6–8 weeks after initiating dupilumab therapy were available. Upon dupilumab therapy, a significant decrease in numbers of inflammatory cells and, concomitantly, reduced numbers of cytokines involved in the pathogenesis of AD (IL-5, IL-9, IL-13, IL-15, IL-17, IL-22, IFN-γ) were observed (Figure 2). We noted a reduction toward or even below levels found in non-lesional skin. Type 2 cytokines are known to block the production of proteins required for skin barrier formation.6,S16–S17 In parallel with the decreased inflammation, a significant increased expression of filaggrin, the protease inhibitor lymphoepithelial Kazal type–related inhibitor (LEKTI), and the antimicrobial peptides human beta-defensin (HBD)-3 and cathelicidin LL-37 were found. The improved