Dupilumab, a Monoclonal Antibody for Atopic Dermatitis: A Review of Current Literature

Kim Blakely, BSc, PhD; Melinda Gooderham, MD, MSc, FRCPC; Kim Papp, MD, PhD, FRCPC


Skin Therapy Letter. 2016;21(2) 

In This Article

Abstract and Introduction


Atopic dermatitis results when aberrant barrier function and immune activation occur within the skin. Standard therapies for atopic dermatitis have fallen short, prompting efforts to discover novel therapeutics for this disease. Of these, dupilumab, a fully human monoclonal antibody that inhibits the actions of both IL-4 and IL-13, has shown the greatest promise. Clinical trials of systemic dupilumab in moderate-to-severe atopic dermatitis have demonstrated marked improvement in patient symptoms, including pruritus and clinically visible disease. Importantly, dupilumab treatment has been correlated with changes in the molecular signature of diseased skin, with reduction of both inflammatory and proliferative markers. Dupilumab recently received US FDA breakthrough therapy designation for atopic dermatitis, with ongoing trials in both adult and pediatric populations. Altogether, dupilumab has shed new light on the pathomechanisms driving atopic dermatitis and is making unprecedented advances towards highly effective control of this debilitating disease.


Atopic dermatitis (AD) is the most common chronic in ammatory skin disease, resulting from defects in skin barrier function and innate and adaptive immune responses.[1,2] In its acute stages, AD presents with highly pruritic, inflamed lesions. Histologically, the epidermis of acute lesions is characterized by intracellular edema (spongiosis), and a sparse in ltrate consisting primarily of T lymphocytes. Marked perivascular in ammatory cell in ltrates with large numbers of T lymphocytes and macrophages are seen in the dermis. In its chronic stages, lesions are licheni ed and plaque-like. Histologically, chronic lesions are distinguished by epidermal hyperplasia with prominent hyperkeratosis and minimal spongiosis.[3–7]

It is estimated that up to 30% of children and 10% of adults are affected by AD, with approximately 85% of all cases beginning within the rst 5 years of life (early-onset AD).[3,4,8] Although many children experience remission of their disease by adolescence, a portion will continue to be affected into adulthood.[9] As well, a number of patients will have their rst episode of AD diagnosed in adult life (late-onset AD), a presentation that often results in a more treatment-refractory form of the disease.[4] Of those affected by AD, up to 20% have a moderate-to-severe presentation, which often manifests as a recurrent disease with remitting and relapsing phases.[10] Importantly, AD impacts all aspects of patients' lives, from their physical wellbeing to their psychological and economical quality of life by disrupting sleep, daily functioning, and requiring patients to attend frequent medical appointments.[11–14]

Genetics play a large role in the development of AD. Affected individuals often have a strong family history of atopy, including AD, asthma and allergic rhinitis: the atopic triad.[15] Genome-wide association studies have implicated a number of genetic loci in the development of AD, including the 1q21, 3p26, 3q21, 5q31–33, 16q, 17q25, and 20p regions. These genetic loci are primarily involved in skin barrier and immune function.[16–21] Importantly, interventions aimed at repairing these defects in skin barrier function and immune dysregulation hold promise for treatment, prevention and, potentially, a cure for AD.

Recent advances in our understanding of the underlying pathogenesis and risk factors for AD has resulted in two opposing theories that attempt to explain the onset and natural history of the disease: the outside-in and the inside-out hypotheses.[22,23] The outside-in hypothesis proposes that genetic variations within the population result in a subpopulation of individuals that harbor defects in skin barrier function. A disrupted barrier permits allergens and microbes to cross the epithelium, which in turn triggers an in ammatory reaction. Alternatively, the inside-out hypothesis proposes that the underlying defects occur at the level of the immune system. A polarized immune response in AD patients results in immunoglobulin E (IgE) sensitization to skin pathogens and contaminants. The resultant immune response induces local inflammation and skin barrier breakdown.[22,23] While debate around these theories remains, it is evident that a number of genetic and environmental factors contribute to skin barrier dysfunction and immune dysregulation in AD. The polyfactorial nature of AD accounts for the heterogeneity in severity and natural history of this disease. It is nonetheless apparent that optimal treatment of AD requires a comprehensive approach aimed at repairing defects in skin barrier function and addressing the characteristic immune abnormalities.

No currently available therapy provides complete remission or cure for affected patients. Management of AD includes patient education, optimal skin care practices, antihistamines (preferably rst generation - sedating antihistamines), topical corticosteroids or topical calcineurin inhibitors (TCIs), systemic corticosteroids, systemic calcineurin inhibitors, phototherapy, and other oral immune-suppressants.[7,24] These treatments work to restore skin barrier function and suppress the in ammatory response.

The availability of safe and effective treatment for moderate-to- severe AD remains a signi cant unmet need. Research focused on the pathophysiology of AD has identi ed promising targets for the treatment of this disease. One targeted therapy that has shown promise in early clinical development and is the focus of this review is dupilumab, an interleukin (IL)-4 receptor alpha (IL-4Rα) antagonist.