Research in context
Evidence before this study
Long-term treatment options are limited for patients with moderate-to-severe atopic dermatitis refractory to topical therapy. Long-term use of systemic corticosteroids and other systemic immunosuppressants is not recommended, due to risk of serious toxicities. Dupilumab is a fully human monoclonal antibody that binds specifically to the shared α chain subunit of the interleukin-4 and interleukin-13 receptors, thereby inhibiting the signalling of interleukin 4 and interleukin 13. Dupilumab showed efficacy and acceptable safety in randomised, placebo-controlled, double-blind early-phase studies of dupilumab monotherapy for 4 weeks or 12 weeks, and with concomitant topical corticosteroids for 4 weeks, and as monotherapy for 16 weeks in phase 2b and phase 3 studies in patients with moderate-to-severe atopic dermatitis. To identify randomised, controlled, blinded clinical trials of long-term (>16 weeks) systemic treatment in atopic dermatitis, we searched PubMed using the search terms: “atopic dermatitis”, “eczema”, “systemic”, “cyclosporine”, “ciclosporin”, “methotrexate”, “azathioprine”, “mycophenolate”, “methylprednisolone”, “dexamethasone”, “prednisolone”, “prednisone”, “corticosteroids”, “glucocorticoids”, “antibody”, “clinical trial”, and “human”, published from Jan 1, 1995, to Jan 25, 2017. We identified four randomised, controlled long-term studies of ciclosporin with or without topical treatments. No other randomised, controlled studies of long-term systemic treatment were identified, and thus neither a meta-analysis nor a systemic review was done.
Added value of this study
LIBERTY AD CHRONOS is the first long-term, placebo-controlled, double-blinded study with dupilumab that allowed for the concomitant use of medium-potency or low-potency topical corticosteroids with or without topical calcineurin inhibitors as background therapy in patients with moderate-to-severe atopic dermatitis and inadequate response to topical medications. Patients were randomly assigned (3:1:3) to dupilumab 300 mg weekly, dupilumab 300 mg every 2 weeks, or placebo weekly; all patients used concomitant topical corticosteroids with or without topical calcineurin inhibitors, which could be tapered or stopped and restarted depending on need, or topical calcineurin inhibitors where inadvisable for topical corticosteroids. Our results show significant benefit of adding dupilumab to topical corticosteroids with or without topical calcineurin inhibitors over a broad range of efficacy outcomes. Both dupilumab plus topical corticosteroids dose groups, compared with placebo plus topical corticosteroids, improved multiple measures of clinical severity, reduced rates of atopic dermatitis flares, and improved pruritus and other patient-reported symptoms of atopic dermatitis, symptoms of depression and anxiety, and quality of life. Dupilumab plus topical corticosteroids had an acceptable safety profile with no clinically meaningful differences in laboratory values. No new safety signals were identified in this study, showing no additional safety concerns resulting from concomitant topical corticosteroids with or without topical calcineurin inhibitors with dupilumab.
Implications of all the available evidence
In view of the chronicity and dynamic nature of atopic dermatitis and the resulting need for long-term treatment, the 1-year safety and efficacy outcomes of this study provide critical evidence for assessment of the benefit-to-risk profile of dupilumab for long-term management of moderate-to-severe atopic dermatitis not adequately controlled with topical corticosteroids with or without topical calcineurin inhibitors alone. Dupilumab added to a background of concomitant topical medications improved multiple aspects of clinical and patient-reported outcomes considered to be crucial to positively modify the natural history of moderate-to-severe atopic dermatitis. Because these topical medications are a mainstay of treatment for moderate-to-severe atopic dermatitis per current treatment guidelines, their concomitant use (as needed) in this study closely mimics real-world treatment protocols and might provide relevant guidance on the use of a biological background therapy in adults with moderate-to-severe atopic dermatitis.