REVIEWS Atopic dermatitis: an expanding therapeutic pipeline for a complex disease Thomas Bieber 1,2,3 Abstract | Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a complex pathophysiology that underlies a wide spectrum of clinical phenotypes. AD remains challenging to treat owing to the limited response to available therapies. However, recent advances in understanding of disease mechanisms have led to the discovery of novel potential therapeutic targets and drug candidates. In addition to regulatory approval for the IL-4Ra inhibitor dupilumab, the anti- IL-13 inhibitor tralokinumab and the JAK1/2 inhibitor baricitinib in Europe, there are now more than 70 new compounds in development. This Review assesses the various strategies and novel agents currently being investigated for AD and highlights the potential for a precision medicine approach to enable prevention and more effective long-term control of this complex disease. Atopic disorders Atopic dermatitis (AD) is the most common chronic inhibitors tacrolimus and pimecrolimus and more 1,2 A group of disorders having in inflammatory skin disease . About 80% of disease cases recently the phosphodiesterase 4 (PDE4) inhibitor cris- common a genetic tendency to typically start in infancy or childhood, with the remain- aborole. For the more severe forms of AD, besides the develop IgE- mediated allergic der developing during adulthood. Whereas the point use of ultraviolet light, current therapeutic guidelines reactions. These are atopic dermatitis, food allergy, allergic prevalence in children varies from 2.7% to 20.1% across suggest ciclosporin A, methotrexate, azathioprine and 3,4 rhino- conjunctivitis and countries, it ranges from 2.1% to 4.9% in adults . The mycophenolate mofetil. allergic asthma. disease displays a high heterogeneity in its natural The approvals of the anti- IL-4Rα antibody dupi- course and individual trajectories are unpredictable. lumab (2016, FDA/2017, EMA) and more recently of Rhino- conjunctivitis AD is characterized by sensitive and dry skin, localized the small- molecule Janus kinase inhibitor baricitinib An atopic disorder of the eyes and nose as the clinical or disseminated eczematous lesions usually accompa- (2020, EMA) and the anti-IL-13 antibody tralokinumab manifestation of an allergic nied by a severe itching sensation. The heterogeneous (2021, EMA) have provided first-in- class representatives reaction to environmental clinical phenotype varies by age, severity and ethnic of different therapeutic strategies for the treatment of allergens. background5. AD has a significant impact on the quality moderate to severe forms of AD. Dupilumab and traloki- 6 biologic therapies Biologic therapies of life of the patients and their relatives and represents numab are examples of targeted that Therapeutic approach using an important socio- economic burden with an average specifically address a distinct immune pathway and its antibodies or other biological yearly total (direct and indirect) cost per patient of cytokines or receptors16, whereas baricitinib exemplifies and recombinant products €15,000 (REFS7–9). a more wide-ranging approach using small molecules17 typically directed against AD belongs to the spectrum of the atopic disorders, that interact with multiple signal transduction pathways pathway- related structures. including food allergy, allergic asthma and allergic rhino- linked to several cytokine receptors and immune path- 10 1Department of Dermatology conjunctivitis, which are relevant comorbidities . ways. Despite these recent developments, the current and Allergy, University Immunoglobulin E (IgE)- related allergic reactions to therapeutic armamentarium remains very limited and Hospital, Bonn, Germany. environmental allergens represent the common aspect disease management still follows a ‘one- size- fits- all’ 2Christine Kühne- Center of atopic diseases. Recently, cardiovascular and neuro- paradigm. In particular, the high incidence of AD in for Allergy Research psychiatric disorders have also been reported to be the paediatric population, the highly fluctuating and and Education, Davos, Switzerland. relevant comorbidities to AD, although the mechanisms unpredictable course of disease and the limited arma- underlying these associations remain elusive11–13. mentarium of approved drugs with an adequate benefit– 3Davos Biosciences, Davos, Switzerland. So far, however, AD has primarily been considered as risk ratio represent major challenges in the field. To e- mail: Thomas.Bieber@ merely a skin disorder in which local anti- inflammatory address this, a better understanding of the mechanisms ukbonn.de therapy of the disease flares should be the first- line that underlie the epidermal barrier dysfunction and the 14,15 https://doi.org/10.1038/ approach . Such topical therapies include various sequence of immune responses that underlie the chronic s41573-021-00266-6 topical corticosteroids (TCSs), the topical calcineurin inflammatory reaction is needed, which would ideally NATURE REVIEWS | DRUG DISCOVERY 0123456789();: REVIEWS Exposome Itch–scratch cycle Phase 3 (tissue damage) Autoimmune variant of AD IgE sensitization Phase 2 to ‘self + / – Adaptive immune proteins’ Phase 1 responses Atopic comorbidities Epigenetic Phase 0 Innate Core T 2 + (food allergy, regulation Preclinical immune H asthma, rhinitis) response (IgE sensitization TH1, TH17, to allergens) T 22 H + / – Non-atopic comorbidities (neuropsychiatric, cardiovascular) Microbiome (Staphylococcus aureus colonization) Genetics Fig. 1 | A multidimensional model of atopic dermatitis. A high-level schematic view of the complex interactions that underlie the immunological heterogeneity of atopic dermatitis (AD). This multidimensional disease model generates an ‘immunological march’, which can schematically and tentatively be dissected in several, potentially overlapping phases: first, an asymptomatic preclinical phase (phase 0); second, activation of skin innate immunity (phase 1), rapidly followed by activation of the adaptive immune response (phase 2) starting with a core T helper 2 (TH2) response accompanied by IgE sensitization to environmental allergens, and a widening of the adaptive immunity with TH1, TH17 and TH22 responses. This widening of the immune response paves the way for the development of atopic and non-atopic comorbidities (phase 3). Each putative phase offers opportunities for preventive and targeted therapeutic intervention, including disease modification. In this scenario, the composition of the skin microbiome and the itch–scratch cycle potentially have a crucial role in directing the adaptive immunity and the development of sensitization to self proteins, atopic and non-atopic comorbidities. translate into optimized long- term, disease- modifying a potential systemic impact of the inflammatory reac- management of this chronic disorder. tion, that is, secondary involvement of other organs. In the past two decades, significant progress has been The main cellular and soluble components involved in made in our understanding of the complex phenotype the pathophysiology of AD represent the key targets of and mechanisms that underlie AD18, offering multiple current efforts in pharmacological intervention (FIg. 2). new potential targets for pharmacological intervention19. Moreover, the complexity of the immune pathways that More than 70 new compounds are in development and operate in AD offers the opportunity to explore the this Review will assess those that are being investigated potential of bispecific or trispecific antibodies. in clinical trials. The variety of targets and strategies For practical purposes, disease severity remains offers significant potential for a precision medicine the basis for the treatment algorithm in the current approach to the management of AD. guidelines31–35. The spectrum of AD has been divided into mild, moderate and severe forms, and cut-off points Therapeutic strategies and targets using the scoring tools for the assessment of severity Exposomal factors The pathophysiology of AD has been discussed in detail and efficacy as well as patient- reported outcomes (see A highly heterogeneous elsewhere18. The disease exhibits a wide spectrum in its BOx 2) have been defined36,37. Depending on the indi- group of exogenous and environmental factors that clinical phenotype, mirroring a complex and multidi- vidual patient’s natural and unpredictable course of the influence the human body mensional interaction between components that rep- disorder, its management has two main goals: the rapid and immune system. resent potential fields of preventive and therapeutic and efficacious treatment of acute flares and the far more interventions (FIg. 1; BOx 1): first, the environmental challenging control of the disease in the long term. Thus, Skin microbiome exposomal factors20,21 The sum of all bacteria and (which will not be addressed besides efficacy, the long- term safety profile is a key 22–26 colonizing the surface or in this Review); second, the skin microbiome ; third, aspect of any new compound in a clinical development deep structures of the skin. the epidermal barrier27,28; and fourth, the immune programme. and inflammatory responses18, which cause, fifth, the Immunological march itch–scratch cycle29. These interactions develop on Modulating the skin microbiome Sequence of physiological 30 or pathophysiological events a particular genetic and yet- to- be explored epige- Several distinct strategies to restore or modulate the